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IntroductionBreast cancer is globally the leading cancer in women, and despite the high 5-year survival rate the most frequent cause of cancer related deaths. Surgery, systemic therapy and radiotherapy are the three pillars of curative breast cancer treatment. However, locoregional recurrences frequently occur after initial treatment and are often challenging to treat, amongst others due to high doses of previous radiotherapy treatments. Radiotherapy can be combined with local hyperthermia to sensitize tumor cells to radiation and thereby significantly reduce the required radiation dose. Therefore, the combination treatment of mild local hyperthermia, i.e. locally heating of the tissue to 39-43°C, and re-irradiation with a reduced total dose is a relevant treatment option for previously irradiated patients. The mechanisms of this effect in the course of the therapy are to date not well understood and will be investigated in the HISTOTHERM study.Methods and analysesPatients with local or (loco)regional recurrent breast cancer with macroscopic tumors are included in the study. Local tumor control is evaluated clinically and histologically during the course of a combination treatment of 60 minutes mild superficial hyperthermia (39 - 43°C) using water-filtered infrared A (wIRA) irradiation, immediately followed by hypofractionated re-irradiation with a total dose of 20-24 Gy, administered in weekly doses of 4 Gy. Tumor and tumor stroma biopsies as well as blood samples will be collected prior to treatment, during therapy (at a dose of 12 Gy) and in the follow-up to monitor therapy response. The treatment represents the standard operating procedure for hyperthermia plus re-irradiation. Various tissue and blood-based markers are analyzed. We aim at pinpointing key mechanisms and markers for therapy response which may help guiding treatment decisions in future. In addition, quality of life in the course of treatment will be assessed and survival data will be evaluated.RegistrationThe study is registered at the German Clinical Trials Register, Deutsches Register Klinischer Studien (DRKS00029221).

IntroductionAccurate detection and segmentation of the intraprostatic gross tumor volume (GTV) is pivotal for radiotherapy (RT) in primary prostate cancer (PCa) since it influences focal therapy target volumes and the patients’ cT stage. The study aimed to compare the performance of multiparametric resonance imaging (mpMRI) with [18F] PSMA-1007 positron emission tomography (PET) for intraprostatic GTV detection as well as delineation and to evaluate their respective influence on RT concepts.Materials and MethodsIn total, 93 patients from two German University Hospitals with [18F] PSMA-1007-PET/CT and MRI (Freiburg) or [18F] PSMA-1007-PET/MRI (Dresden) were retrospectively enrolled. Validated contouring techniques were applied for GTV-PET and -MRI segmentation. Absolute tumor volume and cT status were determined for each imaging method. The PCa distribution from histopathological reports based on biopsy cores and surgery specimen was used as reference in terms of laterality (unilateral vs. bilateral).ResultsIn the Freiburg cohort (n = 84), mpMRI and PET detected in median 2 (range: 1–5) and 3 (range: 1–8) GTVs, respectively (p < 0.01). The median GTV-MRI was significantly smaller than the GTV-PET, measuring 2.05 vs. 3.65 ml (p = 0.0005). PET had a statistically significant higher concordance in laterality with surgery specimen compared to mpMRI (p = 0.04) and biopsy (p < 0.01), respectively. PSMA PET led to more cT2c and cT3b stages, whereas cT3a stage was more pronounced in mpMRI. Based on the cT stage derived from mpMRI and PET information, 21 and 23 as well as 59 and 60 patients, respectively, were intermediate- and high-risk according to the National Comprehensive Cancer Network (NCCN) v1.2022 criteria. In the Dresden cohort (n = 9), similar results were observed.ConclusionIntraprostatic GTV segmentation based on [18F] PSMA-1007 PET results in more and larger GTVs compared to mpMRI. This influences focal RT target volumes and cT stage definition, but not the NCCN risk group.

PurposeMultiparametric magnetic resonance tomography (mpMRI) and prostate specific membrane antigen positron emission tomography (PSMA-PET/CT) are used to guide focal radiotherapy (RT) dose escalation concepts. Besides improvements of treatment effectiveness, maintenance of a good quality of life is essential. Therefore, this planning study investigates whether urethral sparing in moderately hypofractionated RT with focal RT dose escalation influences tumour control probability (TCP) and normal tissue complication probability (NTCP).Patients and Methods10 patients with primary prostate cancer (PCa), who underwent 68Ga PSMA-PET/CT and mpMRI followed by radical prostatectomy were enrolled. Intraprostatic tumour volumes (gross tumor volume, GTV) based on both imaging techniques (GTV-MRI and -PET) were contoured manually using validated contouring techniques and GTV-Union was created by summing both. For each patient three IMRT plans were generated with 60 Gy to the whole prostate and a simultaneous integrated boost up to 70 Gy to GTV-Union in 20 fractions by (Plan 1) not respecting and (Plan 2) respecting dose constraints for urethra as well as (Plan 3) respecting dose constraints for planning organ at risk volume for urethra (PRV = urethra + 2mm expansion). NTCP for urethra was calculated applying a Lyman-Kutcher-Burman model. TCP-Histo was calculated based on PCa distribution in co-registered histology (GTV-Histo). Complication free tumour control probability (P+) was calculated. Furthermore, the intrafractional movement was considered.ResultsMedian overlap of GTV-Union and PRV-Urethra was 1.6% (IQR 0-7%). Median minimum distance of GTV-Histo to urethra was 3.6 mm (IQR 2 – 7 mm) and of GTV-Union to urethra was 1.8 mm (IQR 0.0 – 5.0 mm). The respective prescription doses and dose constraints were reached in all plans. Urethra-sparing in Plans 2 and 3 reached significantly lower NTCP-Urethra (p = 0.002) without significantly affecting TCP-GTV-Histo (p = p > 0.28), NTCP-Bladder (p > 0.85) or NTCP-Rectum (p = 0.85), resulting in better P+ (p = 0.006). Simulation of intrafractional movement yielded even higher P+ values for Plans 2 and 3 compared to Plan 1.ConclusionUrethral sparing may increase the therapeutic ratio and should be implemented in focal RT dose escalation concepts.

PurposeAccurate contouring of intraprostatic gross tumor volume (GTV) is pivotal for successful delivery of focal therapies and for biopsy guidance in patients with primary prostate cancer (PCa). Contouring of GTVs, using 18-Fluor labeled tracer prostate specific membrane antigen positron emission tomography ([18F]PSMA-1007/PET) has not been examined yet.Patients and MethodsTen Patients with primary PCa who underwent [18F]PSMA-1007 PET followed by radical prostatectomy were prospectively enrolled. Coregistered histopathological gross tumor volume (GTV-Histo) was used as standard of reference. PSMA-PET images were contoured on two ways: (1) manual contouring with PET scaling SUVmin-max: 0–10 was performed by three teams with different levels of experience. Team 1 repeated contouring at a different time point, resulting in n = 4 manual contours. (2) Semi-automatic contouring approaches using SUVmax thresholds of 20–50% were performed. Interobserver agreement was assessed for manual contouring by calculating the Dice Similarity Coefficient (DSC) and for all approaches sensitivity, specificity were calculated by dividing the prostate in each CT slice into four equal quadrants under consideration of histopathology as standard of reference.ResultsManual contouring yielded an excellent interobserver agreement with a median DSC of 0.90 (range 0.87–0.94). Volumes derived from scaling SUVmin-max 0–10 showed no statistically significant difference from GTV-Histo and high sensitivities (median 87%, range 84–90%) and specificities (median 96%, range 96–100%). GTVs using semi-automatic segmentation applying a threshold of 20–40% of SUVmax showed no significant difference in absolute volumes to GTV-Histo, GTV-SUV50% was significantly smaller. Best performing semi-automatic contour (GTV-SUV20%) achieved high sensitivity (median 93%) and specificity (median 96%). There was no statistically significant difference to SUVmin-max 0–10.ConclusionManual contouring with PET scaling SUVmin-max 0–10 and semi-automatic contouring applying a threshold of 20% of SUVmax achieved high sensitivities and very high specificities and are recommended for [18F]PSMA-1007 PET based focal therapy approaches. Providing high specificities, semi-automatic approaches applying thresholds of 30–40% of SUVmax are recommend for biopsy guidance.

Late diagnosis and systemic dissemination essentially contribute to the invariably poor prognosis of pancreatic ductal adenocarcinoma (PDAC). Therefore, the development of diagnostic biomarkers for PDAC are urgently needed to improve patient stratification and outcome in the clinic. By studying the transcriptomes of independent PDAC patient cohorts of tumor and non-tumor tissues, we identified 81 robustly regulated genes, through a novel, generally applicable meta-analysis. Using consensus clustering on co-expression values revealed four distinct clusters with genes originating from exocrine/endocrine pancreas, stromal and tumor cells. Three clusters were strongly associated with survival of PDAC patients based on TCGA database underlining the prognostic potential of the identified genes. With the added information of impact of survival and the robustness within the meta-analysis, we extracted a 17-gene subset for further validation. We show that it did not only discriminate PDAC from non-tumor tissue and stroma in fresh-frozen as well as formalin-fixed paraffin embedded samples, but also detected pancreatic precursor lesions and singled out pancreatitis samples. Moreover, the classifier discriminated PDAC from other cancers in the TCGA database. In addition, we experimentally validated the classifier in PDAC patients on transcript level using qPCR and exemplify the usage on protein level for three proteins (AHNAK2, LAMC2, TFF1) using immunohistochemistry and for two secreted proteins (TFF1, SERPINB5) using ELISA-based protein detection in blood-plasma. In conclusion, we present a novel robust diagnostic and prognostic gene signature for PDAC with future potential applicability in the clinic.