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PET is increasingly used for target volume definition in the radiotherapy of glioblastoma, as endorsed by the 2023 ESTRO-EANO guidelines. In view of its growing adoption into clinical practice and upcoming PET-based multi-center trials, this paper aims to assist in overcoming common pitfalls of FET PET-based target delineation in glioblastoma., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: The PRIDE trial (NOA-28; ARO-2024-01; AG-NRO-06; NCT05871021) is designed to determine whether a dose escalation with 75.0 Gy in 30 fractions can enhance the median overall survival (OS) in patients with methylguanine methyltransferase (MGMT) promotor unmethylated glioblastoma compared to historical median OS rates, while being isotoxic to historical cohorts through the addition of concurrent bevacizumab (BEV). To ensure protocol-compliant irradiation planning with all study centers, a dummy run was planned and the plan quality was evaluated., Methods: A suitable patient case was selected and the computed tomography (CT), magnetic resonance imaging (MRI) and O-(2-[ 18 F]fluoroethyl)-L-tyrosine (FET) positron emission tomography (PET) contours were made available. Participants at the various intended study sites performed radiation planning according to the PRIDE clinical trial protocol. The treatment plans and dose grids were uploaded as Digital Imaging and Communications in Medicine (DICOM) files to a cloud-based platform. Plan quality and protocol adherence were analyzed using a standardized checklist, scorecards and indices such as Dice Score (DSC) and Hausdorff Distance (HD)., Results: Median DSC was 0.89, 0.90, 0.88 for PTV60, PTV60ex (planning target volume receiving 60.0 Gy for the standard and the experimental plan, respectively) and PTV75 (PTV receiving 75.0 Gy in the experimental plan), respectively. Median HD values were 17.0 mm, 13.9 mm and 12.1 mm, respectively. These differences were also evident in the volumes: The PTV60 had a volume range of 219.1-391.3 cc (median: 261.9 cc) for the standard plans, while the PTV75 volumes for the experimental plans ranged from 71.5-142.7 cc (median: 92.3 cc). The structures with the largest deviations in Dice score were the pituitary gland (median 0.37, range 0.00-0.69) and the right lacrimal gland (median 0.59, range 0.42-0.78)., Conclusions: The deviations revealed the necessity of systematic trainings with appropriate feedback before the start of clinical trials in radiation oncology and the constant monitoring of protocol compliance throw-out the study., Trial Registration: NCT05871021., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Background and Purpose: The PRIDE trial (NOA-28; ARO-2022-12; NCT05871021) is scheduled to start recruitment in October 2023. Its primary objective is to enhance median overall survival (OS), compared to historical median OS rates, in patients with methylguanine methlyltransferase (MGMT) promotor unmethylated glioblastoma by incorporating isotoxic dose escalation to 75 Gy in 30 fractions. To achieve isotoxicity and counteract the elevated risk of radiation necrosis (RN) associated with dose-escalated regimens, the addition of protective concurrent bevacizumab (BEV) serves as an innovative approach. The current study aims to assess the dosimetric feasibility of the proposed concept., Materials and Methods: A total of ten patients diagnosed with glioblastoma were included in this dosimetric analysis. Delineation of target volumes for the reference plans adhered to the ESTRO-EANO 2023 guideline. The experimental plans included an additional volume for the integrated boost. Additionally, the 60 Gy-volume was reduced by using a margin of 1.0 cm instead of 1.5 cm. To assess the risk of symptomatic RN, the Normal Tissue Complication Probability (NTCP) was calculated and compared between the reference and experimental plans., Results: Median NTCP of the reference plan (NTCP ref ) and of the experimental plan (NTCP ex ) were 0.24 (range 0.11-0.29) and 0.42 (range 0.18-0.54), respectively. NTCP ex was a median of 1.77 (range 1.60-1.99) times as high as the NTXP ref . In a logarithmic comparison, the risk of RN is enhanced by a factor of median 2.00 (range 1.66-2.35). The defined constraints for the organs at risk were feasible., Conclusion: When considering the potential protective effect of BEV, which we hypothesized might reduce the risk of RN by approximately two-fold, achieving isotoxicity with the proposed dose-escalated experimental plan for the PRIDE trial seems feasible., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Author(s).)

The advancement of systemic targeted treatments has led to improvements in the management of metastatic disease, particularly in terms of survival outcomes. However, brain metastases remain less responsive to systemic therapies, underscoring the significance of local interventions for comprehensive disease control. Over the past years, the threshold for treating brain metastases through stereotactic radiosurgery has risen. Yet, as the number of treated metastases increases, treatment complexity and duration also escalate. This trend has made multi-isocenter radiosurgery treatments, such as those with the Gamma Knife, challenging to plan and lengthy for patients. In contrast, single-isocenter approaches employing linear accelerators offer an efficient and expeditious treatment option. This review delves into the literature, comparing different linear-accelerator-based techniques with each other and in relation to dedicated systems, focusing on dosimetric considerations and feasibility.

Backgrounds & Aims: Fluoropyrimidine c (5-fluorouracil [5FU]) increasingly represents the chemotherapeutic backbone for neoadjuvant, adjuvant, and palliative treatment of pancreatic ductal adenocarcinoma (PDAC). Even in combination with other agents, 5FU efficacy remains transient and limited. One explanation for the inadequate response is insufficient and nonspecific delivery of 5FU to the tumor., Methods: We designed, generated, and characterized 5FU-incorporated systematic evolution of ligands by exponential enrichment (SELEX)-selected epidermal growth factor receptor (EGFR)-targeted aptamers for tumor-specific delivery of 5FU to PDAC cells and tested their therapeutic efficacy in vitro and in vivo., Results: 5FU-EGFR aptamers reduced proliferation in a concentration-dependent manner in mouse and human pancreatic cancer cell lines. Time-lapsed live imaging showed EGFR-specific uptake of aptamers via clathrin-dependent endocytosis. The 5FU-aptamer treatment was equally effective in 5FU-sensitive and 5FU-refractory PDAC cell lines. Biweekly treatment with 5FU-EGFR aptamers reduced tumor burden in a syngeneic orthotopic transplantation model of PDAC, in an autochthonously growing genetically engineered PDAC model (LSL-Kras G12D/+ ;LSL-Trp53 flox/+ ;Ptf1a-Cre [KPC]), in an orthotopic cell line-derived xenograft model using human PDAC cells in athymic mice (CDX; Crl:NU-Foxn1 nu ), and in patient-derived organoids. Tumor growth was significantly attenuated during 5FU-EGFR aptamer treatment in the course of follow-up., Conclusions: Tumor-specific targeted delivery of 5FU using EGFR aptamers as the carrier achieved high target specificity; overcame 5FU resistance; and proved to be effective in a syngeneic orthotopic transplantation model, in KPC mice, in a CDX model, and in patient-derived organoids and, therefore, represents a promising backbone for pancreatic cancer chemotherapy in patients. Furthermore, our approach has the potential to target virtually any cancer entity sensitive to 5FU treatment by incorporating 5FU into cancer cell-targeting aptamers as the delivery platform., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Pancreatic ductal adenocarcinoma (PDAC) is an extremely challenging disease with a high mortality rate and a short overall survival time. The poor prognosis can be explained by aggressive tumor growth, late diagnosis, and therapy resistance. Consistent efforts have been made focusing on early tumor detection and novel drug development. Various strategies aim at increasing target specificity or local enrichment of chemotherapeutics as well as imaging agents in tumor tissue. Aptamers have the potential to provide early detection and permit anti-cancer therapy with significantly reduced side effects. These molecules are in-vitro selected single-stranded oligonucleotides that form stable three-dimensional structures. They are capable of binding to a variety of molecular targets with high affinity and specificity. Several properties such as high binding affinity, the in vitro chemical process of selection, a variety of chemical modifications of molecular platforms for diverse function, non-immunoreactivity, modification of bioavailability, and manipulation of pharmacokinetics make aptamers attractive targets compared to conventional cell-specific ligands. To explore the potential of aptamers for early diagnosis and targeted therapy of PDAC - as single agents and in combination with radiotherapy - we summarize the generation process of aptamers and their application as biosensors, biomarker detection tools, targeted imaging tracers, and drug-delivery carriers. We are furthermore discussing the current implementation aptamers in clinical trials, their limitations and possible future utilization.

Purpose: In this prospective study we evaluate the effect of combined transurethral resection of early muscle invasive bladder cancer and immunotherapy with bacillus Calmette-Guerin (BCG) in patients unfit for radical cystectomy or refusing more aggressive therapies., Materials and Methods: A total of 22 patients with a mean age 73.6 years were included in the study. Inclusion criteria were histologically proven muscle invasive transitional cell carcinoma of the bladder with a tumor-free second resection and negative staging examinations in patients unfit for radical cystectomy or refusing more aggressive therapies. All patients received 6 weekly instillations of 120 mg. BCG starting 14 to 21 days after the last transurethral resection of the tumor. Followup at 3 months included cystoscopy, urinary cytology, ultrasound of the abdomen and chest x-ray. Every 6 months computerized tomography of the abdomen and bone scans were performed., Results: The overall 5-year survival rate was 69.1%, while the disease specific 5-year survival rate was 94%. One muscle invasive recurrence was noted at 69 months, which was again treated with the same regimen but ultimately led to radical cystectomy 21 months later. One patient died of progressive recurrence in the upper urinary tract. The 5-year recurrence-free survival rate was 46.5%. The only severe complication was BCG pneumonitis., Conclusions: The data show encouraging results for transurethral resection of bladder tumor with intravesical BCG therapy in select patients with T2a bladder cancer who are not candidates for radical cystectomy.

Objectives: To demonstrate a difference between the two assisted fertilization procedures. Can either of these procedures be preferred on the basis of preoperative parameters or criteria? A protocol was created to facilitate the patient's decision, as the results of IAF are better that those of DAF., Methods: We have performed 39 in vitro fertilizations after testicular or epididymal sperm extraction since December 1995. We performed deferred assisted fertilization (DAF) in 19 patients with normal hormone assessment and normal testicular volume or after vasectomy and immediate assisted fertilization (IAF) for 20 patients with an abnormal assessment., Results: The two groups, IAF and DAF, were homogeneous and did not present any differences in terms of age, aetiology of sterility, risk factors or preoperative hormonal parameters. Direct examination of sperm samples, the site of sampling and histological examination did not demonstrate any significant difference between the two groups. ICSI (IntraCytoplasmic Sperm Injection) was performed for 16 couples by IAF and for 14 couples by DAF. We obtained 6 pregnancies (37.5%) in the IAF group and 2 pregnancies (14.3%) in the DAF group. The two groups were identical in terms of the number of oocytes taken and embryos transferred., Conclusion: No significant difference was observed between the immediate and deferred fertilization techniques in terms of predictive factors, histology and quality of the direct examination, but the pregnancy rate was higher for IAF. We therefore think that this method should be preferred as the first-line procedure.