Stereotactic Body Reirradiation in Gynaecological Cancer: Outcomes and Toxicities from a Single Institution Experience.

AIMS: To report toxicity profile, outcomes and quality of life (QoL) data in patients with recurrent gynaecological cancer who underwent stereotactic body radiotherapy (SBRT) retreatment. MATERIALS AND METHODS: Data from patients' folders were retrospectively extracted, focusing on the primary neoplasm, previous systemic therapies and previous radiotherapy. Concerning SBRT, the total dose (five daily fractions) was delivered with a linear accelerator using intensity-modulated radiotherapy techniques. Acute and late toxicities were assessed by the CTCAE 4.03 scale. QoL was evaluated according to the Cancer Linear Analogue Scale [CLAS1 (fatigue), CLAS2 (energy level), CLAS3 (daily activities)]. RESULTS: Between December 2005 and August 2021, 23 patients (median age 71 years, range 48-80) with 27 lesions were treated. Most patients had endometrial (34.8%), ovarian (26.1%) and cervical cancer (26.1%) as the primary tumour. The most common SBRT schedules in five fractions were 30 Gy (33.3%), 35 Gy (29.6%) and 40 Gy (29.6%). The median follow-up was 32 months (range 3-128). There were no patients reporting acute or late toxicities higher than grade 2, except for a bone fracture. One- and 2-year local control was 77.9% and 70.8%, respectively. One- and 2-year overall survival was 82.6% and 75.1%, respectively. The overall response rate was 96.0%. Regarding QoL, no statistically significant difference was identified between the baseline and follow-up values: the median CLAS1, CLAS2 and CLAS3 scores for each category were 6 (range 4-10) at baseline and 6 (range 3-10) 1 month after SBRT. CONCLUSIONS: This preliminary experience suggests that SBRT retreatment for recurrent gynaecological cancer is a highly feasible and safe treatment with limited side-effects and no short-term QoL impairment.

Volumetric Intensity-Modulated Arc Stereotactic Radiosurgery Boost in Oligometastatic Patients with Spine Metastases: a Dose-escalation Study.

AIMS: To report the final results of a dose-escalation study of volumetric intensity-modulated arc stereotactic radiosurgery (VMAT-SRS) boost after three-dimensional conformal radiation therapy in patients with spine metastases. MATERIALS AND METHODS: Oligometastatic cancer patients bearing up to five synchronous metastases (visceral or bone, including vertebral ones) and candidates for surgery or radiosurgery were considered for inclusion. 25 Gy was delivered in 10 daily fractions (2 weeks) to the metastatic lesion, affected vertebrae and adjacent ones (one cranial and one caudal vertebra). Sequentially, the dose to spinal metastases was progressively increased (8 Gy, 10 Gy, 12 Gy) in the patient cohorts. Dose-limiting toxicities were defined as any treatment-related non-hematologic acute adverse effects rated as grade ≥3 or any acute haematological toxicity rated as ≥ 4 by the Radiation Therapy Oncology Group scale. RESULTS: Fifty-two lesions accounting for 40 consecutive patients (male/female: 29/11; median age: 71 years; range 40-85) were treated from April 2011 to September 2020. Most patients had a primary prostate (65.0%) or breast cancer (22.5%). Thirty-two patients received 8 Gy VMAT-SRS boost (total BED α/ß10: 45.6 Gy), 14 patients received 10 Gy (total BED α/ß10: 51.2 Gy) and six patients received 12 Gy (total BED α/ß10: 57.6 Gy). The median follow-up time was over 70 months (range 2-240 months). No acute toxicities > grade 2 and no late toxicities > grade 1 were recorded. The overall response rate based on computed tomography/positron emission tomography-computed tomography/magnetic resonance was 78.8%. The 24-month actuarial local control, distant metastases-free survival and overall survival rates were 88.5%, 27.1% and 90.3%, respectively. CONCLUSION: A 12 Gy spine metastasis SRS boost following 25 Gy to the affected and adjacent vertebrae was feasible with an excellent local control rate and toxicity profile.

2020 update on the clinical validity of cerebrospinal fluid amyloid, tau, and phospho-tau as biomarkers for Alzheimer's disease in the context of a structured 5-phase development framework.

PURPOSE: In the last decade, the research community has focused on defining reliable biomarkers for the early detection of Alzheimer's disease (AD) pathology. In 2017, the Geneva AD Biomarker Roadmap Initiative adapted a framework for the systematic validation of oncological biomarkers to cerebrospinal fluid (CSF) AD biomarkers-encompassing the 42 amino-acid isoform of amyloid-ß (Aß42), phosphorylated-tau (P-tau), and Total-tau (T-tau)-with the aim to accelerate their development and clinical implementation. The aim of this work is to update the current validation status of CSF AD biomarkers based on the Biomarker Roadmap methodology. METHODS: A panel of experts in AD biomarkers convened in November 2019 at a 2-day workshop in Geneva. The level of maturity (fully achieved, partly achieved, preliminary evidence, not achieved, unsuccessful) of CSF AD biomarkers was assessed based on the Biomarker Roadmap methodology before the meeting and presented and discussed during the workshop. RESULTS: By comparison to the previous 2017 Geneva Roadmap meeting, the primary advances in CSF AD biomarkers have been in the area of a unified protocol for CSF sampling, handling and storage, the introduction of certified reference methods and materials for Aß42, and the introduction of fully automated assays. Additional advances have occurred in the form of defining thresholds for biomarker positivity and assessing the impact of covariates on their discriminatory ability. CONCLUSIONS: Though much has been achieved for phases one through three, much work remains in phases four (real world performance) and five (assessment of impact/cost). To a large degree, this will depend on the availability of disease-modifying treatments for AD, given these will make accurate and generally available diagnostic tools key to initiate therapy.

Clinical validity of increased cortical uptake of [18F]flortaucipir on PET as a biomarker for Alzheimer's disease in the context of a structured 5-phase biomarker development framework.

PURPOSE: In 2017, the Geneva Alzheimer's disease (AD) Biomarker Roadmap initiative adapted the framework of the systematic validation of oncological diagnostic biomarkers to AD biomarkers, with the aim to accelerate their development and implementation in clinical practice. With this work, we assess the maturity of [18F]flortaucipir PET and define its research priorities. METHODS: The level of maturity of [18F]flortaucipir was assessed based on the AD Biomarker Roadmap. The framework assesses analytical validity (phases 1-2), clinical validity (phases 3-4), and clinical utility (phase 5). RESULTS: The main aims of phases 1 (rationale for use) and 2 (discriminative ability) have been achieved. [18F]Flortaucipir binds with high affinity to paired helical filaments of tau and has favorable kinetic properties and excellent discriminative accuracy for AD. The majority of secondary aims of phase 2 were fully achieved. Multiple studies showed high correlations between ante-mortem [18F]flortaucipir PET and post-mortem tau (as assessed by histopathology), and also the effects of covariates on tracer binding are well studied. The aims of phase 3 (early detection ability) were only partially or preliminarily achieved, and the aims of phases 4 and 5 were not achieved. CONCLUSION: Current literature provides partial evidence for clinical utility of [18F]flortaucipir PET. The aims for phases 1 and 2 were mostly achieved. Phase 3 studies are currently ongoing. Future studies including representative MCI populations and a focus on healthcare outcomes are required to establish full maturity of phases 4 and 5.

The CST3 B haplotype is associated with frontotemporal lobar degeneration.

BACKGROUND AND PURPOSE: Frontotemporal lobar degeneration (FTLD) is a common cause of early-onset dementia. Given the role of cystatin C in brain neurodegeneration and neuroregeneration, the aim of this study was to determine whether the cystatin C gene (CST3) was genetically associated with FTLD. METHODS: Hundred and eighty-six FTLD patients and 457 controls underwent CST3 analysis by PCR and KspI enzyme digestion. RESULTS: In FTLD patients negative for the presence of PGRN mutations, we found an over-representation of the CST3 haplotype B [odds ratio (OR = 1.619, P = 0.002)] and of AB/BB genotypes (OR = 1.704, P = 0.008) in FTLD patients. CONCLUSIONS: The present study indicated the CST3 B haplotype as a putative risk factor for FTLD in PGRN mutations negative patients. The reduced level of cystatin C, previously associated with the B haplotype, might represent the molecular factor responsible for the increased risk. Long-term depletion of neurotrophic factors, such as cystatin C and progranulin proteins, seem to be a common theme in FTLD: boosting the expression of such proteins might be a promising therapeutic strategy for FTLD.