M. Stuschke’s research while affiliated with University of Duisburg-Essen and other places

With the development of modern techniques, intensity-modulated radiotherapy (IMRT), volumetric modulated arc therapy (VMAT), and image-guided and adaptive radiotherapy (IGRT and ART), modern radiotherapy of esophageal cancer has become a well-tolerated treatment modality that can also be used for the elderly with greater precision and optimized conformity. Normal tissue, especially the heart and lungs, is carefully considered during treatment planning. In combination with chemotherapy, radiotherapy is a potentially curative treatment option for functionally inoperable patients and for surgically or endoscopically unresectable esophageal cancer. The indication for radiochemotherapy should be made by an experienced, interdisciplinary team after considering all therapeutic alternatives. The frequency of complete clinical remission after definitive radiochemotherapy ranges between 30% and 55%. Post-therapeutic supportive measures can be of decisive importance for quality of life. Further increases in the effectiveness of radiochemotherapy at a dose of 50.4 Gy with conventional fractionation are expected through sequential or simultaneous immunotherapy with immune checkpoint inhibitors and further optimization of the chemotherapy component.

BACKGROUND Olfactory impairment is a common neurologic deficit among glioblastoma patients. We have previously shown that glioblastoma patients with reduced smell sensitivity had lower overall survival rates compared to those with normal olfactory function. A notable limitation in that study was the unequal distribution of prognostic factors between the two groups, and the absence of continuous olfactory assessments during treatment to investigate if therapy-associated neurotoxicity could be a contributing factor to diminished olfactory acuity. In this trial olfactory function will be evaluated in glioblastoma patients as a prognostic marker with regard to overall survival, neurocognition and quality of life. METHODS This prospective, multicenter study is set to recruit 64 glioblastoma patients alongside 64 healthy controls. Stratification of participants is based on prognostically relevant variables such as resection status, MGMT promoter methylation status, radiographic involvement of olfactory brain areas, olfactory function, age, and Karnofsky performance status scale. We utilize Sniffin´ Sticks to evaluate olfactory function through identification and threshold tests, and this assessment is carried out longitudinally throughout the therapy starting from tumor diagnosis. Infiltration of the olfactory nerves or olfactory brain are scrutinized using a high-resolution coronal T2-weighted sequence which is added to a dedicated brain tumor protocol. MRI images are independently reviewed by two board-certified radiologists from distinct institutions, who are blinded to the patients’ olfactory function status. Furthermore, quality of life data, neuropsychological testing, and psychosomatic screening are performed at specific intervals throughout the study. Also, we examine next-generation sequencing results to investigate potential genetic associations with hyposmia in glioblastoma patients. RESULTS The first participant was enrolled in May 2023. Currently, 16 patients and three controls are already enrolled (April 2024). Plans are underway to open a second study site in 2024, with the aim to complete recruitment by December 2025. Follow-up assessments will continue until December 2027. We anticipate that the final results of the study will be available in 2028. CONCLUSIONS In the process, this study is the first prospective study which investigates the olfactory function systematically as prognostic factor in glioblastoma patients.

BACKGROUND Despite their unique histological features, gliosarcomas belong to the group of glioblastomas and are treated according to the same standards. Fibroblast-activation-protein (FAP) is a component of a tumor-specific subpopulation of fibroblasts that play a critical role in tumor growth and invasion. Few case studies suggest an elevated expression of FAP in glioblastoma and a particularly strong expression in gliosarcoma, possibly for its predominant mesenchymal differentiation. However, the prognostic impact of FAP in glioblastoma and gliosarcoma is unclear. METHODS In a retrospective analysis, patients diagnosed with glioblastoma without sarcomatous differentiation and gliosarcoma were enrolled. Histological examination was performed using immunohistochemical FAP-staining and quantitative analysis with a standardized FAP score (0 to 3, with higher values indicating stronger expression). In a subset of patients, FAPI46-PET has been performed. The SUV values are planned to be correlated with FAP-expression in the tumor tissue. Data obtained from immunohistochemical analysis and SUV values are planned to be brought into perspective with clinically relevant prognostic factors, including survival estimates. RESULTS We enrolled 61 patients, including 13 diagnosed with gliosarcoma. Our analysis revealed that gliosarcomas exhibit significantly higher FAP expression (median FAP score: 3) compared to glioblastomas without sarcomatous differentiation (median FAP score: 0.5, p<0.0001), where FAP was predominantly observed in the perivascular space. In gliosarcomas, FAP was also expressed by neoplastic cells. Moreover, a significant relationship was established between the immunohistochemical FAP scores and the SUVmean and SUVpeak values on PET, suggesting that the PET tracer uptake accurately reflects the tumor’s FAP expression. However, the differential expression of FAP suggests its potential as both a diagnostic marker in 68Ga-FAPI-46 PET and a therapeutic target. This hypothesis is further supported by the application of 68Ga-FAPI-46 PET in a 66-year-old female patient with recurrent gliosarcoma, alongside immunohistochemical analysis of tumor tissue. Both methods identified elevated FAP expression and uptake, underscoring the feasibility of FAP as a target for nuclear medicine therapies in brain tumors. CONCLUSIONS Our study establishes a significant correlation between SUVmean/SUVpeak in 68Ga-FAPI-46 PET scans and FAP expression in glioblastoma. Gliosarcomas express significantly more FAP than other glioblastomas. These insights suggest FAP’s potential as a theranostic target. We plan to investigate the effectiveness of FAP-specific tracers in treating recurrent gliosarcoma, aiming to open new therapeutic avenues.

BACKGROUND This trial aimed to investigate whether re-irradiation based on (O-(2-Fluoroethyl)-L-tyrosine, FET)-positron emission tomography (PET) leads to an improvement in progression-free survival (PFS) in patients with recurrent glioblastoma (rGBM), compared to a target volume delineation based on contrast-enhanced T1-weighted MRI (T1Gd-MRI). MATERIAL AND METHODS GLIAA was a prospective, multicenter, randomized clinical trial (NOA 10/ARO 2013-1, DKTK-a., NCT01252459). Patients with rGBM of 1-6 cm were randomized 1:1 at 14 centers in Germany between a FET-PET- and a T1Gd-MRI-based target volume delineation. The RT was performed with 3 Gy/d, 5x/week, to a total dose of 39 Gy. All patients had been previously irradiated with 59.4-60Gy at least 6 months before study treatment and had a histologically confirmed rGBM with a diameter of 1 - 6 cm on both FET-PET and T1Gd-MRI. The primary end point was PFS. Secondary end points included overall survival (OS), locally controlled survival, assessment of delineated volumes, topography of progression, rate of radiation necrosis after re-irradiation, and safety of FET-application in PET imaging. RESULTS Between November 2013 and September 2021, 200 patients were randomized between FET-PET-based (n=100) and GdT1-MRI-based (n=100) target volume delineation. A total of n=98 and n=97 patients, respectively, were treated per protocol. Median PFS was 4.0 months (95% confidence interval [CI] 3.7-5.2) in the FET-PET arm and 4.9 months (95% CI 3.7-6.0) in the GdT1-MRI arm (one-sided stratified log-rank test p=0.98; adjusted HR for the experimental versus the control arm 1.14 [95% CI 0.85-1.52], p=0.39;). Median OS was 9.4 months (95% CI 7.8-11.1) in the FET-PET arm and 9.0 months (95% CI 7.6-10.5) in the GdT1-MRI arm (HR 1.01 [95% CI 0.75-1.37], p=0.92). Median LCS was 6.3 months (95% CI 5.1-7.2) in the FET-PET arm and 6.8 months (95% CI 6.2-7.3) in the GdT1-MRI arm (HR 1.20 [95% CI 0.88-1.62], p=0.25). At 12 months, the local control rate was 22% in the FET-PET arm (95% CI 14%-31%) and 20% in the GdT1-MRI arm (95% CI 12%-29%). In the PET arm, 45.0% of recurrences were in field, 28.3% out of field, and 21.7% marginal. In the MRI arm, 47.4% relapsed in field, 31.6% out of field, and 14.0% marginal. 25.5% of patients in the FET-PET arm and 21.6% in the GdT1-MRI arm had a documented radiation necrosis. There were no adverse events related to the application of the FET tracer. CONCLUSION This is the first randomized trial to investigate the relevance of FET-PET in the irradiation treatment planning of rGBM. There was no survival benefit identified for patients treated with FET-PET- versus GdT1-MRI-based re-irradiation. Both imaging modalities led to similar outcomes and can be therefore used for radiation treatment planning for rGBM. The FET-PET investigation and the re-irradiation were well-tolerated, supporting the safety of this treatment.

BACKGROUND Detecting pseudoprogression (PSP) in glioblastoma during first-line treatment remains challenging and has significant clinical implications for patient management. The detection of PSP has been shown feasible using FET-PET. The prognostic impact of FET-PET diagnosed PSP on overall survival is still uncertain, as retrospective studies provide limited insights due to the substantial differences in the distribution of prognostic factors between TP and PSP groups. This study aims to address these uncertainties by leveraging advanced analysis techniques. MATERIAL AND METHODS Patients with newly diagnosed glioblastoma (WHO 2021) who underwent chemoradiation and contrast-enhanced MRI suspected for TP and subsequent FET-PET scan at Essen University Hospital were retrospectively evaluated. The modified Response Assessment in Neuro-Oncology (RANO) criteria were used to diagnose PSP. FET-PET analysis included mean (TBRmean) and maximum tumor-to-brain ratios (TBRmax). The two groups (TP/PSP) were balanced using a propensity scoreanalysis including age at diagnosis, extent of resection, Karnofsky-Performance-Status Scale (KPS) and MGMT methylation status. Overall survival was predicted using Kaplan-Meier and multivariate analysis as well as conventional FET-PET parameters, PET/MRI volumetry, and FET/MRI-derived radiomics. An independent cohort was used for validation. Results: Out of the 165 patients analysed in this study, 38 were diagnosed with PSP. Following balancing analysis, our study cohort consisted of 40 patients (20 TP/20 PSP). Patients with PSP had a significantly longer mean overall survival (mOS) compared to those with TP (mOS TP 20.24 months; mOS PSP 33.25 months; p=0.0023). The multivariate Cox-Regression analysis confirmed PSP as a significant prognostic marker for overall survival (p=0.0153). Confirmation of these results on an independent validation cohort is pending and will be presented at the meeting.Conclusion: This study shows that PSP is an independent prognostic factor for overall survival in newly diagnosed glioblastoma patients.

Purpose: Glioblastomas are resistant to conventional therapies, including radiotherapy. Our previous study proved that epigenetic regulation influences the radiation response of glioma cells. This study evaluated the role of the acetyltransferase Tip60 on the radiation response. Material and methods: Tip60 expression was down-regulated by transfecting specific siRNA's in A7 and MO59K cells with high and low expression of Tip60, respectively, and its effect on survival was assessed. DNA repair was analyzed by foci scoring (γH2AX, Rad51, 53BP1, pATM). The interaction of Tip60 with ATM and DNA-PK was investigated using the specific inhibitors KU55933 and NU7441, respectively. Results: Knockdown of Tip60 significantly (p < .001) reduced survival in both cell lines, but the effect was more pronounced in A7 cells. ATMi and DNA-PKi significantly reduced the surviving fraction following irradiation. However, no further effect of siTip60 on the radiosensitivity of ATMi treated A7 cells was observed. In contrast, DNA-PKi effectively enhanced the sensitizing effect of siTip60. Mechanistically, siTip60 reduced the number of initial Rad51 and ATM foci formation after irradiation and prevented their dissolution at 24 h. siTip60 had no impact on the formation of 53BP1 and γH2AX foci and did not further affect these end-points if combined with ATMi or DNA-PKi. Conclusions: Downregulation of Tip60 enhances the radiation sensitivity of both glioma cells and markedly elevates the radiation sensitivity when combined with DNA-PKi. Therefore, treatment with DNA-PK inhibitors represents a promising approach to augment the radiation sensitivity of glioma cell lines with deficient Tip60 activity in a synergistic manner.