Toward image-based personalization of glioblastoma therapy: A clinical and biological validation study of a novel, deep learning-driven tumor growth model.

Background: The diffuse growth pattern of glioblastoma is one of the main challenges for accurate treatment. Computational tumor growth modeling has emerged as a promising tool to guide personalized therapy. Here, we performed clinical and biological validation of a novel growth model, aiming to close the gap between the experimental state and clinical implementation. Methods: One hundred and twenty-four patients from The Cancer Genome Archive (TCGA) and 397 patients from the UCSF Glioma Dataset were assessed for significant correlations between clinical data, genetic pathway activation maps (generated with PARADIGM; TCGA only), and infiltration (Dw) as well as proliferation (ρ) parameters stemming from a Fisher-Kolmogorov growth model. To further evaluate clinical potential, we performed the same growth modeling on preoperative magnetic resonance imaging data from 30 patients of our institution and compared model-derived tumor volume and recurrence coverage with standard radiotherapy plans. Results: The parameter ratio Dw/ρ (P < .05 in TCGA) as well as the simulated tumor volume (P < .05 in TCGA/UCSF) were significantly inversely correlated with overall survival. Interestingly, we found a significant correlation between 11 proliferation pathways and the estimated proliferation parameter. Depending on the cutoff value for tumor cell density, we observed a significant improvement in recurrence coverage without significantly increased radiation volume utilizing model-derived target volumes instead of standard radiation plans. Conclusions: Identifying a significant correlation between computed growth parameters and clinical and biological data, we highlight the potential of tumor growth modeling for individualized therapy of glioblastoma. This might improve the accuracy of radiation planning in the near future.

Multicentric Assessment of Safety and Efficacy of Combinatorial Adjuvant Brain Metastasis Treatment by Intraoperative Radiation Therapy and Immunotherapy.

PURPOSE: After surgical resection of brain metastases (BMs), intraoperative radiation therapy (IORT) provides a promising alternative to adjuvant external beam radiation therapy by enabling superior organ-at-risk preservation, reduction of in-hospital times, and timely admission to subsequent systemic treatments, which increasingly comprise novel targeted immunotherapeutic approaches. We sought to assess the safety and efficacy of IORT in combination with immune checkpoint inhibitors (ICIs) and other targeted therapies (TTs). METHODS AND MATERIALS: In a multicentric approach incorporating individual patient data from 6 international IORT centers, all patients with BMs undergoing IORT were retrospectively assessed for combinatorial treatment with ICIs/TTs and evaluated for toxicity and cumulative rates, including wound dehiscence, radiation necrosis, leptomeningeal spread, local control, distant brain progression (DBP), and estimated overall survival. RESULTS: In total, 103 lesions with a median diameter of 34 mm receiving IORT combined with immunomodulatory systemic treatment or other TTs were included. The median follow-up was 13.2 (range, 1.2-102.4) months, and the median IORT dose was 25 (range, 18-30) Gy prescribed to the applicator surface. There was 1 grade 3 adverse event related to IORT recorded (2.2%). A 4.9% cumulative radiation necrosis rate was observed. The 1-year local control rate was 98.0%, and the 1-year DBP-free survival rate was 60.0%. Median time to DBP was 5.5 (range, 1.0-18.5) months in the subgroup of patients experiencing DBP, and the cumulative leptomeningeal spread rate was 4.9%. The median estimated overall survival was 26 (range, 1.2 to not reached) months with a 1-year survival rate of 74.0%. Early initiation of immunotherapy/TTs was associated with a nonsignificant trend toward improved DBP rate and overall survival. CONCLUSIONS: The combination of ICIs/TTs with IORT for resected BMs does not seem to increase toxicity and yields encouraging local control outcomes in the difficult-to-treat subgroup of larger BMs. Time gaps between surgery and systemic treatment could be shortened or avoided. The definitive role of IORT in local control after BM resection will be defined in a prospective trial.

SBRT of Spinal Metastases Using a Simultaneous Integrated Boost Concept in Oligometastatic Cancer Patients Is Safe and Effective.

(1) Purpose: To assess the safety and effectivity of stereotactic body radiotherapy (SBRT) on spinal metastases utilizing a simultaneous integrated boost (SIB) concept in oligometastatic cancer patients. (2) Methods: 62 consecutive patients with 71 spinal metastases received SIB-SBRT between 01/2013 and 09/2022 at our institution. We retrospectively analyzed toxicity, local tumor control (LC), and progression-free (PFS) and overall survival (OS) following SIB-SBRT and assessed possible influencing factors (Kaplan-Meier estimator, log-rank test and Cox proportional-hazards model). (3) Results: SIB-SBRT was delivered in five fractions, mostly with 25/40 Gy (n = 43; 60.56%) and 25/35 Gy (n = 19, 26.76%). Estimated rates of freedom from VCF were 96.1/90.4% at one/two years. VCF development was significantly associated with osteoporosis (p < 0.001). No ≥ grade III acute and one grade III late toxicity (VCF) were observed. Estimated LC rates at one/two years were 98.6/96.4%, and histology was significantly associated with local treatment failure (p = 0.039). Median PFS/OS was 10 months (95% CI 6.01-13.99)/not reached. Development of metastases ≥ one year after initial diagnosis and Karnofsky Performance Score ≥ 90% were predictors for superior PFS (p = 0.038) and OS (p = 0.012), respectively. (4) Conclusion: Spinal SIB-SBRT yields low toxicity and excellent LC. It may be utilized in selected oligometastatic patients to improve prognosis. To the best of our knowledge, we provide the first clinical data on the toxicity and effectivity of SIB-SBRT in spinal metastases in a larger patient cohort.

[Tumour immunotherapy - mechanism and side effects].

INTRODUCTION: Since the development of the first immune checkpoint inhibitor, a new era in tumour immunotherapy has been initiated and response and survival rates have improved in many tumour entities. Despite this encouraging progress, the number of patients who achieve a durable response is limited by resistance mechanisms, and immune-related adverse events (irAEs) complicate treatment. The mechanism of irAE is not understood in all details. In this review, we summarise the mechanisms of action of immune checkpoint inhibitors, the different forms of irAE and their possible mechanisms of development, and describe possible prevention strategies and treatment options. strategies for prevention and treatment options.

Opportunities and Alternatives of Modern Radiation Oncology and Surgery for the Management of Resectable Brain Metastases.

Postsurgical radiotherapy (RT) has been early proven to prevent local tumor recurrence, initially performed with whole brain RT (WBRT). Subsequent to disadvantageous cognitive sequalae for the patient and the broad distribution of modern linear accelerators, focal irradiation of the tumor has omitted WBRT in most cases. In many studies, the effectiveness of local RT of the resection cavity, either as single-fraction stereotactic radiosurgery (SRS) or hypo-fractionated stereotactic RT (hFSRT), has been demonstrated to be effective and safe. However, whereas prospective high-level incidence is still lacking on which dose and fractionation scheme is the best choice for the patient, further ablative techniques have come into play. Neoadjuvant SRS (N-SRS) prior to resection combines straightforward target delineation with an accelerated post-surgical phase, allowing an earlier start of systemic treatment or rehabilitation as indicated. In addition, low-energy intraoperative RT (IORT) on the surgical bed has been introduced as another alternative to external beam RT, offering sterilization of the cavity surface with steep dose gradients towards the healthy brain. This consensus paper summarizes current local treatment strategies for resectable brain metastases regarding available data and patient-centered decision-making.

Hypofractionated stereotactic radiotherapy (HFSRT) versus single fraction stereotactic radiosurgery (SRS) to the resection cavity of brain metastases after surgical resection (SATURNUS): study protocol for a randomized phase III trial.

BACKGROUND: The brain is a common site for cancer metastases. In case of large and/or symptomatic brain metastases, neurosurgical resection is performed. Adjuvant radiotherapy is a standard procedure to minimize the risk of local recurrence and is increasingly performed as local stereotactic radiotherapy to the resection cavity. Both hypofractionated stereotactic radiotherapy (HFSRT) and single fraction stereotactic radiosurgery (SRS) can be applied in this case. Although adjuvant stereotactic radiotherapy to the resection cavity is widely used in clinical routine and recommended in international guidelines, the optimal fractionation scheme still remains unclear. The SATURNUS trial prospectively compares adjuvant HFSRT with SRS and seeks to detect the superiority of HFSRT over SRS in terms of local tumor control. METHODS: In this single center two-armed randomized phase III trial, adjuvant radiotherapy to the resection cavity of brain metastases with HFSRT (6 - 7 × 5 Gy prescribed to the surrounding isodose) is compared to SRS (1 × 12-20 Gy prescribed to the surrounding isodose). Patients are randomized 1:1 into the two different treatment arms. The primary endpoint of the trial is local control at the resected site at 12 months. The trial is based on the hypothesis that HFSRT is superior to SRS in terms of local tumor control. DISCUSSION: Although adjuvant stereotactic radiotherapy after resection of brain metastases is considered standard of care treatment, there is a need for further prospective research to determine the optimal fractionation scheme. To the best of our knowledge, the SATURNUS study is the only randomized phase III study comparing different regimes of postoperative stereotactic radiotherapy to the resection cavity adequately powered to detect the superiority of HFSRT regarding local control. TRIAL REGISTRATION: The study was retrospectively registered with ClinicalTrials.gov, number NCT05160818, on December 16, 2021. The trial registry record is available on  https://clinicaltrials.gov/study/NCT05160818 . The presented protocol refers to version V1.3 from March 21, 2021.

Outcome of patients with soft tissue sarcomas of the extremities and trunk treated by (neo)adjuvant intensity modulated radiation therapy with curative intent.

BACKGROUND: Soft tissue sarcomas (STS) are a relatively rare group of malignant tumors. Currently, there is very little published clinical data, especially in the context of curative multimodal therapy with image-guided, conformal, intensity-modulated radiotherapy. METHODS: Patients who received preoperative or postoperative intensity-modulated radiotherapy for STS of the extremities or trunk with curative intent were included in this single centre retrospective analysis. A Kaplan-Meier analysis was performed to evaluate survival endpoints. Multivariable proportional hazard models were used to investigate the association between survival endpoints and tumour-, patient-, and treatment-specific characteristics. RESULTS: 86 patients were included in the analysis. The most common histological subtypes were undifferentiated pleomorphic high-grade sarcoma (UPS) (27) and liposarcoma (22). More than two third of the patients received preoperative radiation therapy (72%). During the follow-up period, 39 patients (45%) suffered from some type of relapse, mainly remote (31%). The two-years overall survival rate was 88%. The median DFS was 48 months and the median DMFS was 51 months. Female gender (HR 0.460 (0.217; 0.973)) and histology of liposarcomas compared to UPS proved to be significantly more favorable in terms of DFS (HR 0.327 (0.126; 0.852)). CONCLUSION: Conformal, intensity-modulated radiotherapy is an effective treatment modality in the preoperative or postoperative management of STS. Especially for the prevention of distant metastases, the establishment of modern systemic therapies or multimodal therapy approaches is necessary.

Influence of radiation treatment technique (IMRT vs. 3D-RT) on acute toxicity and prognostic factors for survival for anal cancer.

We compared our institutional experience with intensity-modulated radiotherapy (IMRT) and 3D-conformal radiotherapy (3D-RT) for definitive treatment of primary anal cancer. We performed a single-institution retrospective review of all patients with anal squamous cell carcinoma treated with definitive (chemo) radiotherapy with curative intent from 2004 through 2018. We assessed several prognostic factors in respect to relevant survival endpoints. In addition, acute toxicities were determined and compared between IMRT and 3D-RT patients. This study included 94 patients (58 IMRT, 36 3D-RT). Mean follow up for all patients, for IMRT and 3D-RT patients was 61 months (range 6-176), 46 months (range 6-118), and 85 months (range 6-176), respectively. 5-year overall survival (OS) was 86%, disease-free survival (DFS) was 72%, and colostomy-free survival (CFS) was 75% in the IMRT cohort. In the 3D-RT cohort, OS was 87%, DFS was 71%, and CFS was 81% (all p > 0.05). Male gender and Karnofsky Index (KI) were revealed as independent prognostic factors for 5-year OS (p = 0.017; p = 0.023). UICC stage was an independent prognostic factor for DFS and CFS (p = 0.023; p = 0.042). In addition, the pre-treatment leukocyte count was an independent prognostic factor for CFS (p = 0.042). Acute grade ≥ 3 toxicity was not significantly different between IMRT and 3D-RT patients, but the IMRT cohort had favorable outcomes. This study confirmed IMRT as the primary definitive treatment of anal cancer. With similar survival rates, IMRT had the potential to reduce acute toxicity by sparing organs at risk. Promising prognostic factors such as BMI, KI, and leucocyte and hemoglobin levels should be further investigated.

nTMS-derived DTI-based motor fiber tracking in radiotherapy treatment planning of high-grade gliomas for avoidance of motor structures.

BACKGROUND: Management of high-grade gliomas (HGGs) close to motor areas is challenging due to the risk of treatment-related morbidity. Thus, for resection, functional mapping of the corticospinal tract (CST) with navigated transcranial magnetic stimulation (nTMS) combined with diffusion tensor imaging (DTI)-based fiber tracking (DTI-FTTMS) is increasingly used. This study investigated the application of DTI-FTTMS in adjuvant radiation therapy (RT) planning of HGGs for CST avoidance. METHODS: The preoperative DTI-FTTMS-based CST reconstructions of 35 patients harboring HGGs were incorporated into the RT planning system and merged with planning imaging. The CST was delineated as the planning risk volume (PRV-FTTMS). Intensity-modulated RT (IMRT) plans were optimized to preserve PRV-FTTMS. Segments within the planning target volume (PTV) were not spared (overlap). RESULTS: With plan optimization, mean dose (Dmean) of PRV-FTTMS can be reduced by 17.1% on average (range 0.1-37.9%), thus from 25.5 Gy to 21.2 Gy (p < 0.001). For PRV-FTTMS segments beyond the PTV dose, reduction is possible by 26.8% (range 0.1-43.9%, Dmean 17.4 Gy vs. 12.5 Gy, p < 0.001). Considering only portions within the 50% isodose level, Dmean is decreased by 46.7% from 38.6 Gy to 20.5 Gy (range 19.1-62.8%, p < 0.001). PTV coverage was not affected: V95% and V90% were 96.4 ± 3.1% and 98.0 ± 3.9% vs. 96.1 ± 3.5% (p = 0.34) and 98.3 ± 2.9% (p = 0.58). Dose constraints for organs at risk (OARs) were all met. CONCLUSION: This study demonstrates that DTI-FTTMS can be utilized in the RT planning of HGGs for CST sparing. However, the degree of dose reduction depends on the overlap with the PTV. The functional benefit needs to be investigated in future prospective clinical trials.

Quality of life in patients treated with radiochemotherapy for primary diagnosis of anal cancer.

Anal cancer and the related treatment are generally known to affect patients' quality of life. The aim of this study was to assess self-reported quality of life (QoL) of anal cancer patients after combined radiation and chemotherapy, and to identify patient-, disease-, and therapy-related factors associated with QoL. A total of 94 patients treated with definitive chemoradiation for anal cancer at our institution in the period from 2004 to 2018 were identified from our database. QoL was assessed in the remaining 52 patients using the EORTC QLQ-C30 questionnaire (cancer-specific QoL) and the newly developed anal cancer module QLQ-ANL27 (site-specific QoL). Differences in QoL between anal cancer patients and a German age and sex adjusted reference population were examined. The median follow-up was 71 months (range, 7-176). In the cancer-specific QoL module, the anal cancer cohort presented with significantly lower scores in role (- 12.2 points), emotional (- 6.6 points), and social functioning (- 6.8 points), but higher scores in diarrhea (+ 36.3 points) and constipation (+ 13.3 points) than the German reference population. There were no significant differences in disease- or therapy-related factors, but age greater than 70 years and a follow-up time greater than 71 months had a negative impact on global QoL. As for the site-specific QoL, patients with a tumor relapse showed significantly higher symptom scores than patients with a complete clinical remission in all scales except of micturition frequency. Compared to 3D conformal radiotherapy, IMRT treatment seemed to improve non-stoma bowel function (+ 23.3 points), female sexual functioning (+ 24.2 points), and came along with less scores in the symptom scales pain (- 35.9 points), toilet proximity (- 28.6 points), and cleanliness (- 26.2 points). Most of the functional scores of anal cancer patients were lower compared to the general German population, but did not seem to affect the general QoL. Fatigue, physical, and role functioning had the strongest impact on global QoL causing psychological symptoms as important as physical.

Low-Energy X-Ray Intraoperative Radiation Therapy (Lex-IORT) for Resected Brain Metastases: A Single-Institution Experience.

BACKGROUND: Resection followed by local radiation therapy (RT) is the standard of care for symptomatic brain metastases. However, the optimal technique, fractionation scheme and dose are still being debated. Lately, low-energy X-ray intraoperative RT (lex-IORT) has been of increasing interest. METHOD: Eighteen consecutive patients undergoing BM resection followed by immediate lex-IORT with 16-30 Gy applied to the spherical applicator were retrospectively analyzed. Demographic, RT-specific, radiographic and clinical data were reviewed to evaluate the effectiveness and safety of IORT for BM. Descriptive statistics and Kaplan-Meyer analysis were applied. RESULTS: The mean follow-up time was 10.8 months (range, 0-39 months). The estimated local control (LC), distant brain control (DBC) and overall survival (OS) at 12 months post IORT were 92.9% (95%-CI 79.3-100%), 71.4% (95%-CI 50.2-92.6%) and 58.0% (95%-CI 34.1-81.9%), respectively. Two patients developed radiation necrosis (11.1%) and wound infection (CTCAE grade III); both had additional adjuvant treatment after IORT. For five patients (27.8%), the time to the start or continuation of systemic treatment was ≤15 days and hence shorter than wound healing and adjuvant RT would have required. CONCLUSION: In accordance with previous series, this study demonstrates the effectiveness and safety of IORT in the management of brain metastases despite the small cohort and the retrospective characteristic of this analysis.

Dose Reduction to Motor Structures in Adjuvant Fractionated Stereotactic Radiotherapy of Brain Metastases: nTMS-Derived DTI-Based Motor Fiber Tracking in Treatment Planning.

Background: Resection of brain metastases (BM) close to motor structures is challenging for treatment. Navigated transcranial magnetic stimulation (nTMS) motor mapping, combined with diffusion tensor imaging (DTI)-based fiber tracking (DTI-FTmot.TMS), is a valuable tool in neurosurgery to preserve motor function. This study aimed to assess the practicability of DTI-FTmot.TMS for local adjuvant radiotherapy (RT) planning of BM. Methods: Presurgically generated DTI-FTmot.TMS-based corticospinal tract (CST) reconstructions (FTmot.TMS) of 24 patients with 25 BM resected during later surgery were incorporated into the RT planning system. Completed fractionated stereotactic intensity-modulated RT (IMRT) plans were retrospectively analyzed and adapted to preserve FTmot.TMS. Results: In regular plans, mean dose (Dmean) of complete FTmot.TMS was 5.2 ± 2.4 Gy. Regarding planning risk volume (PRV-FTTMS) portions outside of the planning target volume (PTV) within the 17.5 Gy (50%) isodose line, the DTI-FTmot.TMS Dmean was significantly reduced by 33.0% (range, 5.9−57.6%) from 23.4 ± 3.3 Gy to 15.9 ± 4.7 Gy (p < 0.001). There was no significant decline in the effective treatment dose, with PTV Dmean 35.6 ± 0.9 Gy vs. 36.0 ± 1.2 Gy (p = 0.063) after adaption. Conclusions: The DTI-FTmot.TMS-based CST reconstructions could be implemented in adjuvant IMRT planning of BM. A significant dose reduction regarding motor structures within critical dose levels seems possible.

A new, innovative, and safe treatment in vitiligo: Results of a randomized, double-blinded, parallel-group study.

Vitiligo is a chronic autoimmune disease affecting around 1% of the population worldwide. No existing treatment is giving fully satisfactory results. Further investigations are welcomed for innovative and safe treatments bringing better results. This trial aimed to compare the efficacy and tolerance of various treatment protocols on vitiligo lesions. Four randomized groups of 10 patients with vitiligo covering 8% to 14% of skin surface, except hands and feet were assigned during 8 weeks to (a) UVB microphototherapy 300 to 320 nm (Bioskin-) 1 x week; (b) VITILSI- gel 2 x day; (c) VITILSI- gel 2xday + Bioskin- 1 x week; and (d) placebo 2 x day. Efficacy of the treatment was assessed by planimetry, comparing the photographs of the patients taken at baseline and after 8-week treatment. After completion of the treatment, the increase of the pigment area was 28% in G1 (Bioskin-), 19% in G2 (VITILSI-), 41% in G3 (Bioskin- + VITILSI-) and null in G4. No subject stopped the treatment and no side effect was observed. It was demonstrated that the gel under study was able per se to induce repigmentation in vitiligo lesions and that the results were significantly better when combined with NB-UVB. The protocols used in this trial resulted safe and efficient.

Is local radiotherapy a viable option for patients with an opening of the ventricles during surgical resection of brain metastases?

BACKGROUND: Local hypofractionated stereotactic radiotherapy (HFSRT) of the resection cavity is emerging as the standard of care in the treatment of patients with a limited number of brain metastases as it warrants less neurological impairment compared to whole brain radiotherapy. In periventricular metastases surgical resection can lead to an opening of the ventricles and subsequently carries a potential risk of cerebrospinal tumour cell dissemination. The aim of this study was to assess whether local radiotherapy of the resection cavity is viable in these cases. METHODS: From our institutional database we analyzed the data of 125 consecutive patients with resected brain metastases treated in our institution with HFSRT between 2009 and 2017. The incidence of LMD, overall survival (OS), local recurrence (LC) and distant recurrence were evaluated depending on ventricular opening (VO) during surgery. RESULTS: From all 125 patients, the ventricles were opened during surgery in 14 cases (11.2%). None of the patients with VO and 7 patients without VO during surgery developed LMD (p = 0.371). OS (p = 0.817), LC (p = 0.524) and distant recurrence (p = 0.488) did not differ in relation to VO during surgical resection. However, the incidence of distant intraventricular recurrence was slightly increased in patients with VO (14.3% vs. 2.7%, p < 0.01). CONCLUSION: VO during neurosurgical resection did not affect the outcome after HFSRT of the resection cavity in patients with brain metastases. Particularly, the incidence of LMD was not increased in patients receiving local HFSRT after VO. HFSRT can therefore be offered independently of VO as a local treatment of tumor bed after resection of brain metastases.

Dosimetric comparison of organs at risk using different contouring guidelines for definition of the clinical target volume in anal cancer.

BACKGROUND: There are different contouring guidelines for definition of the clinical target volume (CTV) for intensity-modulated radiation therapy (IMRT) of anal cancer (AC). We conducted a planning comparison study to evaluate and compare the dose to relevant organs at risk (OARs) while using different CTV definitions. METHODS: Twelve patients with a primary diagnosis of anal cancer, who were treated with primary chemoradiation (CRT), were selected. We generated four guideline-specific CTVs and subsequently planned target volumes (PTVs) on the planning CT scan of each patient. An IMRT plan for volumetric arc therapy (VMAT) was set up for each PTV. Dose parameters of the planned target volume (PTV) and OARs were evaluated and compared, too. RESULTS: The mean volume of the four PTVs ranged from 2138 cc to 2433 cc. The target volumes contoured by the authors based on the recommendations of each group were similar in the pelvis, while they differed significantly in the inguinal region. There were no significant differences between the four target volumes with regard to the dose parameters of the cranially located OARs. Conversely, some dose parameters concerning the genitals and the skin varied significantly among the different guidelines. CONCLUSION: The four contouring guidelines differ significantly concerning the inguinal region. In order to avoid inguinal recurrence and to protect relevant OARs, further investigations are needed to generate uniform standards for definition of the elective clinical target volume in the inguinal region.

Spreading Depolarization during the Acute Stage of Experimental Subarachnoid Hemorrhage in Mice.

Spreading depolarization (SD) has been suggested as a pathomechanism for delayed cerebral ischemia after subarachnoid hemorrhage (SAH). However, the role of SD during the acute phase of SAH is still unclear. The objective of this study was to investigate (a) the occurrence of SD with intrinsic optical signal (IOS) imaging, (b) the effect of ketamine on SD, and (c) the resulting brain edema (brain water content (BWC)) during the acute stage of experimental SAH in mice. SAH was elicited by the endovascular filament perforation method. After SAH or sham operation, ketamine or saline, 30 mg/kg, was given every half hour. Changes in tissue light reflectance were recorded with IOS. BWC was measured during the acute stage. Overall, 199 SDs occurred in SAH groups and 33 SDs appeared in sham groups. These SDs displayed distinct originating and spreading patterns. Compared with saline, ketamine decreased SD spread and influenced the amplitude, duration, and speed of SD. However, the occurrence of SD was not prevented by ketamine. Moreover, ketamine did not reduce BWC after SAH. These results demonstrate that SD occurs with a high incidence during the acute stage of SAH. SDs are heterogeneous in incidence, origination, and propagation. It remains unclear whether ketamine effects on SD may be viewed as therapeutically beneficial after SAH.

Integration of PET-imaging into radiotherapy treatment planning for low-grade meningiomas improves outcome.

PURPOSE: Meningiomas have an excellent survival prognosis, and radiotherapy (RT) is a central component of interdisciplinary treatment. During treatment planning, the definition of the target volume remains challenging using MR and CT imaging alone. This is the first study to analyze the impact of additional PET-imaging on local control (LC) and overall survival (OS) after high-precision RT. METHODS: We analyzed 339 meningiomas treated between 2000 and 2018. For analyses, we divided the patients in low-grade (n = 276) and high-grade (n = 63) cases. We performed RT in an adjuvant setting due to subtotal resection or later due to recurrent tumor growth. The target volumes were delineated based on diagnostic CT and MRI and, if available, additional PET-imaging (low-grade: n = 164, 59.4%; high-grade: n = 39, 61.9%) with either 68Ga-Dotanoc/Dotatoc, 18F-fluoroethyltyrosine or 11C-methionine tracer. Patients were treated with fractionated stereotactic RT with a median total dose and dose per fraction of 54 Gy and 1.8 Gy, respectively. RESULTS: Median follow-up was 5.6 years. For low-grade meningiomas, mean OS was 15.6 years and mean LC was 16.9 years; for high-grade cases mean OS was 11.6 years, and mean LC was 11.1 years. In univariate analyses, PET-imaging had a significant impact on OS (p = 0.035) and LC (p = 0.041) for low-grade meningiomas and remained significant (p = 0.015) for LC in the multivariate analysis. For high-grade cases, PET did not influence both OS and LC. Further prognostic factors could be identified. CONCLUSIONS: For low-grade meningiomas, we showed that the addition of PET-imaging for target volume definition led to a significantly enhanced LC. Thus, PET improves the detection of tumor cells and helps distinguish between healthy tissue and meningioma tissue, especially during the treatment planning process.

Patient-Reported Outcome (PRO) as an Addition to Long-Term Results after High-Precision Stereotactic Radiotherapy in Patients with Secreting and Non-Secreting Pituitary Adenomas: A Retrospective Cohort Study up to 17-Years Follow-Up.

High-precision radiotherapy has been established as a valid and effective treatment option in patients with pituitary adenomas. We report on outcome after fractionated stereotactic radiotherapy (FSRT) in correlation with patient-reported outcomes (PROs). We analyzed 69 patients treated between 2000 and 2019. FSRT was delivered with a median total dose of 54 Gy (single fraction: 1.8 Gy). PRO questionnaires were sent to 28 patients. Median overall survival was 17.2 years; mean local control was 15.6 years (median not reached). Median follow-up was 5.8 years. Twenty (71%) patients participated in the PRO assessment. Physicians reported symptoms grade ≥3 in 6 cases (9%). Of all, 35 (51%) patients suffered from hypopituitarism at baseline, and during follow-up, new or progressive hypopituitarism was observed in 11 cases (16%). Patients reported 10 cases of severe side effects. Most of these symptoms were already graded as CTCAE (Common Terminology Criteria for Adverse Events) grade 2 by a physician in a previous follow-up exam. PROs are an essential measure and only correlate to a certain extent with the physician-reported outcomes. For high-precision radiotherapy of pituitary adenomas, they confirm excellent overall outcomes and low toxicity. In the future, the integration of PROs paired with high-end treatment will further improve outcomes.

Neoadjuvant stereotactic radiosurgery for intracerebral metastases of solid tumors (NepoMUC): a phase I dose escalation trial.

BACKGROUND: More than 25% of patients with solid cancers develop intracerebral metastases. Aside of surgery, radiation therapy (RT) is a mainstay in the treatment of intracerebral metastases. Postoperative fractionated stereotactic RT (FSRT) to the resection cavity of intracerebral metastases is a treatment of choice to reduce the risk of local recurrence. However, FSRT has to be delayed until a sufficient wound healing is attained; hence systemic therapy might be postponed. Neoadjuvant stereotactic radiosurgery (SRS) might offer advantages over adjuvant FSRT in terms of better target delineation and an earlier start of systemic chemotherapy. Here, we conducted a study to find the maximum tolerated dose (MTD) of neoadjuvant SRS for intracerebral metastases. METHODS: This is a single-center, phase I dose escalation study on neoadjuvant SRS for intracerebral metastases that will be conducted at the Klinikum rechts der Isar Hospital, Technical University of Munich. The rule-based traditional 3 + 3 design for this trial with 3 dose levels and 4 different cohorts depending on lesion size will be applied. The primary endpoint is the MTD for which no dose-limiting toxicities (DLT) occur. The adverse events of each participant will be evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 continuously during the study until the first follow-up visit (4-6 weeks after surgery). Secondary endpoints include local control rate, survival, immunological tumor characteristics, quality of life (QoL), CTCAE grade of late clinical, neurological, and neurocognitive toxicities. In addition to the intracerebral metastasis which is treated with neoadjuvant SRS and resection up to four additional intracerebral metastases can be treated with definitive SRS. Depending on the occurrence of DLT up to 72 patients will be enrolled. The recruitment phase will last for 24 months. DISCUSSION: Neoadjuvant SRS for intracerebral metastases offers potential advantages over postoperative SRS to the resection cavity, such as better target volume definition with subsequent higher efficiency of eliminating tumor cells, and lower damage to surrounding healthy tissue, and much-needed systemic chemotherapy could be initiated more rapidly. Trial registration The local ethical review committee of Technical University of Munich (199/18S) approved this study on September 05, 2018. This trial was registered on German Clinical Trials Register (DRKS00016613; https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00016613) on January 29, 2019.

Stereotactic irradiation of the resection cavity after surgical resection of brain metastases - when is the right timing?

Purpose: This study aimed to evaluate whether an early beginning of the adjuvant stereotactic radiotherapy after macroscopic complete resection of 1-3 brain metastases is essential or whether longer intervals between surgery and radiotherapy are feasible.Material and methods: Sixty-six patients with 69 resection cavities treated with HFSRT after macroscopic complete resection of 1-3 brain metastases between 2009 and 2016 in our institution were included in this study. Overall survival, local recurrence and locoregional recurrence were evaluated depending on the time interval from surgery to the start of radiation therapy.Results: Patients that started radiotherapy within 21 days from surgery had a significantly decreased OS compared to patients treated after a longer interval from surgery (p < .01). There was no significant difference between patients treated ≥ 34 and 22-33 days from surgery (p = .210). In the univariate analysis, local control was superior for patients starting treatment 22-33 days from surgery compared to a later start (p = .049). This effect did not prevail in a multivariate model. There was no significant difference between patients treated within 21 days and patients treated more than 33 days after surgery (p = .203). Locoregional control was not influenced by RT timing (p = .508).Conclusion: A short delay in the start of radiotherapy does not seem to negatively impact the outcome in patients with resected brain metastases. We even observed an unexpected reduction in OS in patients treated within 21 days from surgery. Further studies are needed to define the optimal timing of postoperative radiotherapy to the resection cavity.