Microscope integrated MHz optical coherence tomography system for neurosurgery: development and clinical in-vivo imaging.

Neurosurgical interventions on the brain are impeded by the requirement to keep damages to healthy tissue at a minimum. A new contrast channel enhancing the visual separation of malign tissue should be created. A commercially available surgical microscope was modified with adaptation optics adapting the MHz speed optical coherence tomography (OCT) imaging system developed in our group. This required the design of a scanner optics and beam delivery system overcoming constraints posed by the mechanical and optical parameters of the microscope. High quality volumetric OCT C-scans with dense sample spacing can be acquired in-vivo as part of surgical procedures within seconds and are immediately available for post-processing.

Flow-controlled air-jet for in vivo quasi steady-state and dynamic elastography with MHz optical coherence tomography.

OBJECTIVE: Optical coherence elastography (OCE) has been introduced for several medical applications to determine tissue mechanical parameters. However, in order to measure sensitive healthy tissue like brain in vivo, the excitation force needs to be carefully controlled and as low as possible (under 100 µN). Preferably, the excitation should be applied in a non-contact manner. METHODS: In this work, an air-jet excitation source for this specific purpose has been developed and characterized. The design focus was set on the exact measurement and control of the generated excitation force to better comply with in vivo medical safety requirements during surgery. RESULTS: Therefore, an excitation force control and measurement system based on the applied gas flow was developed. CONCLUSION: This system can generate short, high dynamic air-puffs lasting fewer than 5 ms, as well as quasi-static excitation forces lasting 700 ms. The force range covers 1µN to 40 mN with a force error margin between 0.1% and 16% in the relevant range. The excitation source, in conjunction with a 3.2 MHz optical coherence system, enables phase-based, dynamic, and quasi steady-state elastography, as well as robust non-contact classical indentation measurements. SIGNIFICANCE: The presented system is a preliminary prototype intended for further development into a clinical version to be used in situ during brain tumor surgery.

An attempt to identify brain tumour tissue in neurosurgery by mechanical indentation measurements.

BACKGROUND: The intraoperative differentiation between tumour tissue, healthy brain tissue, and any sensitive structure of the central nervous system is carried out in modern neurosurgery using various multimodal technologies such as neuronavigation, fluorescent dyes, intraoperative ultrasound or the use of intraoperative MRI, but also the haptic experience of the neurosurgeon. Supporting the surgeon by developing instruments with integrated haptics could provide a further objective dimension in the intraoperative recognition of healthy and diseased tissue. METHODS: In this study, we describe intraoperative mechanical indentation measurements of human brain tissue samples of different tumours taken during neurosurgical operation and measured directly in the operating theatre, in a time frame of maximum five minutes. We present an overview of the Young's modulus for the different brain tumour entities and potentially differentiation between them. RESULTS: We examined 238 samples of 75 tumour removals. Neither a clear distinction of tumour tissue against healthy brain tissue, nor differentiation of different tumour entities was possible on solely the Young's modulus. Correlation between the stiffness grading of the surgeon and our measurements could be found. CONCLUSION: The mechanical behaviour of brain tumours given by the measured Young's modulus corresponds well to the stiffness assessment of the neurosurgeon and can be a great tool for further information on mechanical characteristics of brain tumour tissue. Nevertheless, our findings imply that the information gained through indentation is limited.

Microscope-integrated optical coherence tomography for in vivo human brain tumor detection with artificial intelligence.

OBJECTIVE: It has been shown that optical coherence tomography (OCT) can identify brain tumor tissue and potentially be used for intraoperative margin diagnostics. However, there is limited evidence on its use in human in vivo settings, particularly in terms of its applicability and accuracy of residual brain tumor detection (RTD). For this reason, a microscope-integrated OCT system was examined to determine in vivo feasibility of RTD after resection with automated scan analysis. METHODS: Healthy and diseased brain was 3D scanned at the resection edge in 18 brain tumor patients and investigated for its informative value in regard to intraoperative tissue classification. Biopsies were taken at these locations and labeled by a neuropathologist for further analysis as ground truth. Optical OCT properties were obtained, compared, and used for separation with machine learning. In addition, two artificial intelligence-assisted methods were utilized for scan classification, and all approaches were examined for RTD accuracy and compared to standard techniques. RESULTS: In vivo OCT tissue scanning was feasible and easily integrable into the surgical workflow. Measured backscattered light signal intensity, signal attenuation, and signal homogeneity were significantly distinctive in the comparison of scanned white matter to increasing levels of scanned tumor infiltration (p < 0.001) and achieved high values of accuracy (85%) for the detection of diseased brain in the tumor margin with support vector machine separation. A neuronal network approach achieved 82% accuracy and an autoencoder approach 85% accuracy in the detection of diseased brain in the tumor margin. Differentiating cortical gray matter from tumor tissue was not technically feasible in vivo. CONCLUSIONS: In vivo OCT scanning of the human brain has been shown to contain significant value for intraoperative RTD, supporting what has previously been discussed for ex vivo OCT brain tumor scanning, with the perspective of complementing current intraoperative methods for this purpose, especially when deciding to withdraw from further resection toward the end of the surgery.

Mechanical characteristics of glioblastoma and peritumoral tumor-free human brain tissue.

BACKGROUND: The diagnosis of brain tumor is a serious event for the affected patient. Surgical resection is a crucial part in the treatment of brain tumors. However, the distinction between tumor and brain tissue can be difficult, even for experienced neurosurgeons. This is especially true in the case of gliomas. In this project we examined whether the biomechanical parameters elasticity and stress relaxation behavior are suitable as additional differentiation criteria between tumorous (glioblastoma multiforme; glioblastoma, IDH-wildtype; GBM) and non-tumorous, peritumoral tissue. METHODS: Indentation measurements were used to examine non-tumorous human brain tissue and GBM samples for the biomechanical properties of elasticity and stress-relaxation behavior. The results of these measurements were then used in a classification algorithm (Logistic Regression) to distinguish between tumor and non-tumor. RESULTS: Differences could be found in elasticity spread and relaxation behavior between tumorous and non-tumorous tissue. Classification was successful with a sensitivity/recall of 83% (sd = 12%) and a precision of 85% (sd = 9%) for detecting tumorous tissue. CONCLUSION: The findings imply that the data on mechanical characteristics, with particular attention to stress relaxation behavior, can serve as an extra element in differentiating tumorous brain tissue from non-tumorous brain tissue.

Phase unwrapping for MHz optical coherence elastography and application to brain tumor tissue.

During neuro-oncologic surgery, phase-sensitive optical coherence elastography (OCE) can be valuable for distinguishing between healthy and diseased tissue. However, the phase unwrapping process required to retrieve the original phase signal is a challenging and critical task. To address this issue, we demonstrate a one-dimensional unwrapping algorithm that recovers the phase signal from a 3.2 MHz OCE system. With a processing time of approximately 0.11 s per frame on the GPU, multiple 2π wraps are detected and corrected. By utilizing this approach, exact and reproducible information on tissue deformation can be obtained with pixel accuracy over the entire acquisition time. Measurements of brain tumor-mimicking phantoms and human ex vivo brain tumor samples verified the algorithm's reliability. The tissue samples were subjected to a 200 ms short air pulse. A correlation with histological findings confirmed the algorithm's dependability.

Ultrasonic Aspirator for Tissue Contact Detection: An Online Classification on Time-Series.

The goal of neurosurgical tumor surgery is to remove the tumor completely without damaging healthy brain structures and thereby impairing the patient's neurological functions. This requires careful planning and execution of the operation by experienced neurosurgeons using the latest intraoperative technologies to achieve safe and rapid tumor reduction without harming the patient. To achieve this goal, a standard ultrasonic aspirator designed for tissue removal is equipped with additional intraoperative tissue detection using machine learning methods.Since decision-making in a clinical context must be fast, online contact detection is critical. Data are generated on three types of artificial tissue models in a CNC machine-controlled environment with four different ultrasonic aspirator settings. Contact classification on artificial tissue models is evaluated on four classification algorithms: change point detection (CPD), random forest (RF), recurrent neural network (RNN) and temporal convolutional network (TCN). Data preprocessing steps are applied, and their impacts are investigated. All methods are evaluated on five-fold cross-validation and provide generally good results with a performance of up to 0.977±0.007 in mean F1-score. Preprocessing the data has a positive effect on the classification processes for all methods and consistently improves the metrics. Thus, this work indicates in a first step that contact classification is feasible in an online context for an ultrasonic aspirator. Further research is necessary on different tissue types, as well as hand-held use to more closely resemble the intraoperative clinical conditions.

The neurosurgical benefit of contactless in vivo optical coherence tomography regarding residual tumor detection: A clinical study.

Purpose: In brain tumor surgery, it is crucial to achieve complete tumor resection while conserving adjacent noncancerous brain tissue. Several groups have demonstrated that optical coherence tomography (OCT) has the potential of identifying tumorous brain tissue. However, there is little evidence on human in vivo application of this technology, especially regarding applicability and accuracy of residual tumor detection (RTD). In this study, we execute a systematic analysis of a microscope integrated OCT-system for this purpose. Experimental design: Multiple 3-dimensional in vivo OCT-scans were taken at protocol-defined sites at the resection edge in 21 brain tumor patients. The system was evaluated for its intraoperative applicability. Tissue biopsies were obtained at these locations, labeled by a neuropathologist and used as ground truth for further analysis. OCT-scans were visually assessed with a qualitative classifier, optical OCT-properties were obtained and two artificial intelligence (AI)-assisted methods were used for automated scan classification. All approaches were investigated for accuracy of RTD and compared to common techniques. Results: Visual OCT-scan classification correlated well with histopathological findings. Classification with measured OCT image-properties achieved a balanced accuracy of 85%. A neuronal network approach for scan feature recognition achieved 82% and an auto-encoder approach 85% balanced accuracy. Overall applicability showed need for improvement. Conclusion: Contactless in vivo OCT scanning has shown to achieve high values of accuracy for RTD, supporting what has well been described for ex vivo OCT brain tumor scanning, complementing current intraoperative techniques and even exceeding them in accuracy, while not yet in applicability.

Identification of Patients With Glioblastoma Who May Benefit from Hypofractionated Radiotherapy.

BACKGROUND/AIM: Standard radiotherapy (RT) for glioblastoma lasts 6 weeks. We aimed to identify patients who would benefit from a hypofractionated approach. PATIENTS AND METHODS: In 167 patients receiving standard fractionation, 10 factors were analyzed for local control (LC) and overall survival (OS). A survival score was developed and compared to a previous instrument. RESULTS: On multivariate analysis, better LC was significantly associated with the presence of only one lesion and O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation. Better OS was associated with one lesion, better performance status, MGMT promoter methylation, and receipt of chemotherapy. Lesion diameter ≤40 mm and upfront resection were associated with improved OS on univariate analyses. Based on assigning scores to these six factors, three groups, with 32-35, 36-44 and 45-48 points, were designed with 12-month OS-rates of 0%, 56%, and 92%, respectively. Accuracy in predicting death within 12 months and survival ≥12 months was 100% and 92%, respectively, versus 67% and 83% with the previous scoring system. CONCLUSION: A new survival score with higher accuracy was developed for patients with glioblastoma. Our model can be utilized to individualize RT dose-fractionation recommendations for glioblastoma.

Pre-treatment Emotional Distress in Patients Irradiated for Malignant Glioma.

BACKGROUND/AIM: A recommendation of radiotherapy for patients with malignant gliomas may trigger emotional distress. Frequency and risk factors of this complication were investigated. PATIENTS AND METHODS: Prevalence of six emotional problems and 11 potential risk factors were evaluated in 103 patients irradiated for grade II-IV gliomas. p-Values <0.0045 were considered significant. RESULTS: Seventy-six patients (74%) had ≥1 emotional problem. Prevalence of specific emotional problems ranged between 23% and 63%. Associations were found between ≥5 physical problems and worry (p=0.0010), fear (p=0.0001), sadness (p=0.0023), depression (p=0.0006), and loss of interest (p=0.0006), and Karnofsky performance score ≤80 and depression (p=0.0002). Trends were found for physical problems and nervousness (p=0.040), age ≥60 years and depression (p=0.043) or loss of interest (p=0.045), grade IV glioma and sadness (p=0.042), and ≥2 involved sites and loss of interest (p=0.022). CONCLUSION: Three-fourths of glioma patients had pre-radiotherapy emotional distress. Psychological support should be offered very soon, particularly for high-risk patients.

Pulsed thulium laser blood vessel haemostasis as an alternative to bipolar forceps during neurosurgical tumour resection.

Due to wavelength-specific water absorption, infrared lasers like the thulium laser emitting at 1940 nm wavelength proved to be suitable for coagulation in neurosurgery. Commonly bipolar forceps used for intraoperative haemostasis can cause mechanical and thermal tissue damage, whilst thulium laser can provide a tissue-gentle haemostasis through non-contact coagulation. The aim of this work is a less-damaging blood vessel coagulation by pulsed thulium laser radiation in comparison to standard bipolar forceps haemostasis. Ex vivo porcine blood vessels in brain tissue (0.34 ± 0.20 mm diameter) were irradiated in non-contact with a thulium laser in pulsed mode (1940 nm wavelength, 15 W power, 100-500 ms pulse duration), with a CO2 gas flow provided simultaneously at the distal fibre tip (5 L/min). In comparison, a bipolar forceps was used at various power levels (20-60 W). Tissue coagulation and ablation were evaluated by white light images and vessel occlusion was visualised by optical coherence tomography (OCT) B-scans at a wavelength of 1060 nm. Coagulation efficiency was calculated by means of the quotient of the difference between the coagulation and ablation radius to the coagulation radius. Pulsed laser application achieved blood vessel occlusion rate of 92% at low pulse duration of 200 ms with no occurrence of ablation (coagulation efficiency 100%). Bipolar forceps showed an occlusion rate of 100%, however resulted in tissue ablation. Tissue ablation depth with laser application is limited to 40 µm and by a factor of 10 less traumatising than with bipolar forceps. Pulsed thulium laser radiation achieved blood vessel haemostasis up to 0.3 mm in diameter without tissue ablation and has proven to be a tissue-gentle method compared to bipolar forceps.

Differentiation of different stages of brain tumor infiltration using optical coherence tomography: Comparison of two systems and histology.

The discrimination of tumor-infiltrated tissue from non-tumorous brain tissue during neurosurgical tumor excision is a major challenge in neurosurgery. It is critical to achieve full tumor removal since it directly correlates with the survival rate of the patient. Optical coherence tomography (OCT) might be an additional imaging method in the field of neurosurgery that enables the classification of different levels of tumor infiltration and non-tumorous tissue. This work investigated two OCT systems with different imaging wavelengths (930 nm/1310 nm) and different resolutions (axial (air): 4.9 µm/16 µm, lateral: 5.2 µm/22 µm) in their ability to identify different levels of tumor infiltration based on freshly excised ex vivo brain samples. A convolutional neural network was used for the classification. For both systems, the neural network could achieve classification accuracies above 91% for discriminating between healthy white matter and highly tumor infiltrated white matter (tumor infiltration >60%) .This work shows that both OCT systems with different optical properties achieve similar results regarding the identification of different stages of brain tumor infiltration.

Toward intraoperative tissue classification: exploiting signal feedback from an ultrasonic aspirator for brain tissue differentiation.

PURPOSE: During brain tumor surgery, care must be taken to accurately differentiate between tumorous and healthy tissue, as inadvertent resection of functional brain areas can cause severe consequences. Since visual assessment can be difficult during tissue resection, neurosurgeons have to rely on the mechanical perception of tissue, which in itself is inherently challenging. A commonly used instrument for tumor resection is the ultrasonic aspirator, whose system behavior is already dependent on tissue properties. Using data recorded during tissue fragmentation, machine learning-based tissue differentiation is investigated for the first time utilizing ultrasonic aspirators. METHODS: Artificial tissue model with two different mechanical properties is synthesized to represent healthy and tumorous tissue. 40,000 temporal measurement points of electrical data are recorded in a laboratory environment using a CNC machine. Three different machine learning approaches are applied: a random forest (RF), a fully connected neural network (NN) and a 1D convolutional neural network (CNN). Additionally, different preprocessing steps are investigated. RESULTS: Fivefold cross-validation is conducted over the data and evaluated with the metrics F1, accuracy, positive predictive value, true positive rate and area under the receiver operating characteristic. Results show a generally good performance with a mean F1 of up to 0.900 ± 0.096 using a NN approach. Temporal information indicates low impact on classification performance, while a low-pass filter preprocessing step leads to superior results. CONCLUSION: This work demonstrates the first steps to successfully differentiate healthy brain and tumor tissue using an ultrasonic aspirator during tissue fragmentation. Evaluation shows that both neural network-based classifiers outperform the RF. In addition, the effects of temporal dependencies are found to be reduced when adequate data preprocessing is performed. To ensure subsequent implementation in the clinic, handheld ultrasonic aspirator use needs to be investigated in the future as well as the addition of data to reflect tissue diversity during neurosurgical operations.

Registration of histological brain images onto optical coherence tomography images based on shape information.

Identifying tumour infiltration zones during tumour resection in order to excise as much tumour tissue as possible without damaging healthy brain tissue is still a major challenge in neurosurgery. The detection of tumour infiltrated regions so far requires histological analysis of biopsies taken from at expected tumour boundaries. The gold standard for histological analysis is the staining of thin cut specimen and the evaluation by a neuropathologist. This work presents a way to transfer the histological evaluation of a neuropathologist onto optical coherence tomography (OCT) images. OCT is a method suitable for real timein vivoimaging during neurosurgery however the images require processing for the tumour detection. The method demonstrated here enables the creation of a dataset which will be used for supervised learning in order to provide a better visualization of tumour infiltrated areas for the neurosurgeon. The created dataset contains labelled OCT images from two different OCT-systems (wavelength of 930 nm and 1300 nm). OCT images corresponding to the stained histological images were determined by shaping the sample, a controlled cutting process and a rigid transformation process between the OCT volumes based on their topological information. The histological labels were transferred onto the corresponding OCT images through a non-rigid transformation based on shape context features retrieved from the sample outline in the histological image and the OCT image. The accuracy of the registration was determined to be 200 ± 120µm. The resulting dataset consists of 1248 labelled OCT images for each of the two OCT systems.

OCT-Guided Surgery for Gliomas: Current Concept and Future Perspectives.

Optical coherence tomography (OCT) has been recently suggested as a promising method to obtain in vivo and real-time high-resolution images of tissue structure in brain tumor surgery. This review focuses on the basics of OCT imaging, types of OCT images and currently suggested OCT scanner devices and the results of their application in neurosurgery. OCT can assist in achieving intraoperative precision identification of tumor infiltration within surrounding brain parenchyma by using qualitative or quantitative OCT image analysis of scanned tissue. OCT is able to identify tumorous tissue and blood vessels detection during stereotactic biopsy procedures. The combination of OCT with traditional imaging such as MRI, ultrasound and 5-ALA fluorescence has the potential to increase the safety and accuracy of the resection. OCT can improve the extent of resection by offering the direct visualization of tumor with cellular resolution when using microscopic OCT contact probes. The theranostic implementation of OCT as a part of intelligent optical diagnosis and automated lesion localization and ablation could achieve high precision, automation and intelligence in brain tumor surgery. We present this review for the increase of knowledge and formation of critical opinion in the field of OCT implementation in brain tumor surgery.

A New Survival Score for Patients Receiving Radiotherapy for Newly Diagnosed Glioblastoma Multiforme.

BACKGROUND/AIM: In a previous study investigating radiotherapy for newly diagnosed glioblastoma multiforme (GBM), significant or almost significant associations with survival were found for performance status, upfront resection, O6-methylguanine-DNA methyl-transferase (MGMT) promoter methylation and unifocal GBM. This study aimed to create a survival score based on these factors. PATIENTS AND METHODS: Most of the 81 patients included received resection of GBM followed by radiochemotherapy (59.4 Gy/33 or 60 Gy/30 fractions). The previously identified predictors of survival were re-evaluated. Factors significantly associated with survival were used for the score. RESULTS: All factors were significantly associated with survival. For each factor, 0 points (less favorable survival) or 1 point (more favorable survival) were assigned and added for each patient. Three groups were designed, 0-1 (n=10), 2 (n=21) and 3-4 points (n=50); 12-month survival rates were 0%, 38% and 78% (p<0.001). CONCLUSION: A new survival score was created for patients requiring radiotherapy for GBM that can improve treatment personalization.

Neurocognitive functioning and health-related quality of life in adult medulloblastoma patients: long-term outcomes of the NOA-07 study.

BACKGROUND: Combined radiochemotherapy followed by maintenance chemotherapy with cisplatin, lomustine and vincristine within the NOA-07 study resulted in considerable short-term toxicity in adult medulloblastoma patients. Here we investigated the long-term impact of this treatment, focusing on neurocognitive functioning and health-related quality of life (HRQoL). METHODS: Neurocognitive functioning and HRQoL scores over time were determined, and differences between the post-treatment and follow-up assessments were calculated up to 18 months for neurocognition and 60 months for HRQoL. RESULTS: 28/30 patients were analyzed. The three preselected HRQoL scales (role, social and cognitive functioning) showed improved scores, to a clinically relevant extent (≥ 10 points), compared to post-treatment levels up to 30 months, but decreased afterwards. Z-scores for verbal working memory were worse during follow-up compared to post-treatment scores and remained impaired during 18 months follow-up (i.e. z-score below - 1 standard deviation). Attention was impaired post-treatment, and remained impaired to a clinically relevant extent during follow-up. Coordination/processing speed and lexical verbal fluency improved compared to post-treatment scores, and remained within the normal range thereafter. Other tests of verbal fluency were stable over time, with z-scores within the normal range. CONCLUSIONS: This long-term follow-up study showed that the NOA-07 treatment regimen was not associated with a deterioration in HRQoL in the post-treatment period. Verbal working memory deteriorated, while other neurocognitive domains did not seem to be impacted negatively by the treatment.

Prospective, randomized, multicenter study with 2-year follow-up to compare the performance of decompression with and without interlaminar stabilization.

OBJECTIVE Surgical decompression is extremely effective in relieving pain and symptoms due to lumbar spinal stenosis (LSS). Decompression with interlaminar stabilization (D+ILS) is as effective as decompression with posterolateral fusion for stenosis, as shown in a major US FDA pivotal trial. This study reports a multicenter, randomized controlled trial in which D+ILS was compared with decompression alone (DA) for treatment of moderate to severe LSS. METHODS Under approved institutional ethics review, 230 patients (1:1 ratio) randomized to either DA or D+ILS (coflex, Paradigm Spine) were treated at 7 sites in Germany. Patients had moderate to severe LSS at 1 or 2 adjacent segments from L-3 to L-5. Outcomes were evaluated up to 2 years postoperatively, including Oswestry Disability Index (ODI) scores, the presence of secondary surgery or lumbar injections, neurological status, and the presence of device- or procedure-related severe adverse events. The composite clinical success (CCS) was defined as combining all 4 of these outcomes, a success definition validated in a US FDA pivotal trial. Additional secondary end points included visual analog scale (VAS) scores, Zürich Claudication Questionnaire (ZCQ) scores, narcotic usage, walking tolerance, and radiographs. RESULTS The overall follow-up rate was 91% at 2 years. There were no significant differences in patient-reported outcomes at 24 months (p > 0.05). The CCS was superior for the D+ILS arm (p = 0.017). The risk of secondary intervention was 1.75 times higher among patients in the DA group than among those in the D+ILS group (p = 0.055). The DA arm had 228% more lumbar injections (4.5% for D+ILS vs 14.8% for DA; p = 0.0065) than the D+ILS one. Patients who underwent DA had a numerically higher rate of narcotic use at every time point postsurgically (16.7% for D+ILS vs 23% for DA at 24 months). Walking Distance Test results were statistically significantly different from baseline; the D+ILS group had > 2 times the improvement of the DA. The patients who underwent D+ILS had > 5 times the improvement from baseline compared with only 2 times the improvement from baseline for the DA group. Foraminal height and disc height were largely maintained in patients who underwent D+ILS, whereas patients treated with DA showed a significant decrease at 24 months postoperatively (p < 0.001). CONCLUSIONS This study showed no significant difference in the individual patient-reported outcomes (e.g., ODI, VAS, ZCQ) between the treatments when viewed in isolation. The CCS (survivorship, ODI success, absence of neurological deterioration or device- or procedure-related severe adverse events) is statistically superior for ILS. Microsurgical D+ILS increases walking distance, decreases compensatory pain management, and maintains radiographic foraminal height, extending the durability and sustainability of a decompression procedure. Clinical trial registration no.: NCT01316211 (clinicaltrials.gov).

Multicenter pilot study of radiochemotherapy as first-line treatment for adults with medulloblastoma (NOA-07).

Background: Medulloblastoma in adult patients is rare, with 0.6 cases per million. Prognosis depends on clinical factors and medulloblastoma entity. No prospective data on the feasibility of radiochemotherapy exist. The German Neuro-Oncology Working Group (NOA) performed a prospective descriptive multicenter single-arm phase II trial to evaluate feasibility and toxicity of radio-polychemotherapy. Methods: The NOA-07 trial combined craniospinal irradiation with vincristine, followed by 8 cycles of cisplatin, lomustine, and vincristine. Adverse events, imaging and progression patterns, histological and genetic markers, health-related quality of life (HRQoL), and cognition were evaluated. Primary endpoint was the rate of toxicity-related treatment terminations after 4 chemotherapy cycles, and the toxicity profile. The feasibility goal was reached if at least 45% of patients received at least 4 cycles of maintenance chemotherapy. Results: Thirty patients were evaluable. Each 50% showed classic and desmoplastic/nodular histology. Sixty-seven percent were classified into the sonic hedgehog (SHH) subgroup without TP53 alterations, 13% in wingless (WNT), and 17% in non-WNT/non-SHH. Four cycles of chemotherapy were feasible in the majority (n = 21; 70.0%). Hematological side effects and polyneuropathy were prevalent toxicities. During the active treatment period, HRQoL and verbal fluency improved significantly. The 3-year event-free survival rate was 66.6% at the time of databank lock. Conclusions: Radio-polychemotherapy did lead to considerable toxicity and a high amount of dose reductions throughout the first 4 chemotherapy cycles that may affect efficacy. Thus, we propose frequent patient surveillance using this regimen. Modifications of the regimen may increase feasibility of radio-polychemotherapy of adult patients with medulloblastoma.

The prognostic value of tumor necrosis in patients undergoing stereotactic radiosurgery of brain metastases.

BACKGROUND: This retrospective study investigated the outcome of patients with brain metastases after radiosurgery with special emphasis on prognostic impact of visible intratumoral necrosis on survival and local control. METHODS: From 1998 through 2008, 149 patients with brain metastases from solid tumors were treated with stereotactic radiotherapy at Luebeck University. Median age was 58.4 years with 11%, 78%, 10% in recursive partitioning analysis (RPA) classes I, II, III, respectively. 70% had 1 metastasis, 29% 2-3 metastases, 2 patients more than 3 metastases, 71% active extracranial disease. Median volume of metastatic lesions was 4.7 cm3, median radiosurgery dose 22 Gy (single fraction). 71% of patients received additional whole-brain irradiation (WBI). All patients were analyzed regarding survival, local, distant failure and prognostic factors, side effects and changes in neurologic symptoms after radiotherapy. The type of contrast-enhancement in MR imaging was also analyzed; metastatic lesions were classified as containing necrosis if they appeared as ring-enhancing with central areas of no or minimal contrast enhancement. RESULTS: Median survival was 7.0 months with 1-year and 5-year survival rates of 33% and 0.4%, respectively. Tumor necrosis (ring-enhancement) was visible on pretreatment MRI scans in 56% of all lesions and lesions with necrosis were larger than non-necrotic lesions (6.7 cm3 vs. 3.2 cm3, p = 0.01). Patients with tumor necrosis had a median survival of 5.4 months, patients without tumor necrosis 7.2 months. Local control rate in the irradiated volume was 70%, median survival without local failure 17.8 months. Control in the brain outside the irradiated volume was 60%, median survival without distant failure 14.0 months. Significant prognostic factors for overall survival were KPS (p = 0.001), presence of tumor necrosis on pretreatment MRI (p = 0.001) with RPA-class and WBI reaching marginal significance (each p = 0.05). Prognostic impact of tumor necrosis remained significant if only smaller tumors with a volume below 3.5 cm3 (p = 0.03). Side effects were rare, only one patient suffered from serious acute side effects. CONCLUSIONS: Results of this retrospective study support that stereotactic radiotherapy is an effective treatment option for patients with metastatic brain lesions. The prognostic impact of visible tumor necrosis (ring-enhancement) on pretreatment MRI scans should be further investigated.