Regulatory Measures to Improve the Safety of CAR-T-Cell Treatment.

Introduction: Regulatory activities aim to facilitate the safe use of novel therapeutics such as genetically engineered chimeric antigen receptor (CAR)-T cells. Toxicities associated with CAR-T-cell therapies have led to modified safety management guidance in clinical trials and the implementation of post-marketing requirements. The aim of this study was to estimate the effect of individual risk-minimizing measures to evaluate the appropriateness of regulatory activities. Methods: We re-examined clinical trial data prior to and after the introduction of revised treatment guidelines; we analysed spontaneous adverse drug reaction (ADR) reports submitted to the EudraVigilance database in 2019/2020 regarding their completeness; and we performed a survey of treatment centres in Germany that have been qualified for the use of commercial CAR-T cells. Results: Lower combined incidences of severe cytokine release syndrome (CRS) as well as neurotoxicity occurred following CAR-T-cell treatment after a revision of management guidelines, suggesting earlier intervention compared to before (12.6% vs. 20.5%). Numerous post-marketing ADR reports lacked information important for case assessment. Full details on treatment indication, CRS onset, outcome, and grading were available for just 38.3% of CRS cases. Survey responses support the majority of regulatory requirements for centre qualification. Time investment was highest for training of healthcare professionals, which required an average of 6.5 staff members (range 2-20) and lasted more than 2 days per person in half of the facilities. The need to harmonize the regulatory requirements for the different CAR-T-cell therapeutics was emphasized. Conclusion: Defined regulatory measures can support the safe and effective use of new therapies and are indicated for structured recording of post-marketing data, and the evaluation of such measures appears to be necessary for the continuous improvement.

Impact of pathognomonic genetic alterations on the prognosis of papillary thyroid carcinoma. ESES vienna presentation.

INTRODUCTION: BRAF mutations and RET or NTRK1 rearrangements were identified as causing events that drive the malignant transformation of the thyroid follicular cell. The impact of these alterations on the course of papillary thyroid carcinoma (PTC) is still unsettled. PATIENTS AND METHODS: Tumor tissues of 290 (98 male, 192 female) patients were intra-operatively snap frozen or harvested from archival paraffin-embedded blocks and used for extraction of DNA and RNA. Comprehensive analysis of RET/PTC and NTRK1 rearrangements was carried out by multiplex screening RT-PCR, hybrid-specific RT-PCR and sequencing of detected hybrids. A mutation-specific PCR was used for BRAF analysis. RESULTS: The BRAF V600E mutation was detected in 122/290 (42%), RET rearrangements in 20/137 (14.6%), and NTRK1 rearrangements in 15/93 (16.1%) PTCs. One hundred forty one out of 290 (48.6%) PTCs demonstrated none of the genetic alterations studied. Eight PTCs expressed two different mutations (1 RET/PTC + BRAF, 6 NTRK1 + BRAF, 1 RET/PTC + NTRK1). Tumor-specific survival analysis (mean follow-up, 5.5 years) demonstrated no significant difference, but a tendency toward worse prognosis of BRAF-positive patients compared to BRAF-negative patients or rearrangement-positive patients, respectively. CONCLUSION: Long-term follow-up data on large tumor panels are needed to disclose significant survival differences of prognostic predictors on PTC. This study provides further evidence that patients harboring BRAF-V600E-positive PTCs may experience an unfavorable course of the disease compared to patients with tumors carrying other genetic alterations.

In vivo release of non-neuronal acetylcholine from human skin by dermal microdialysis: effects of sunlight, UV-A and tactile stimulus.

Non-neuronal acetylcholine (ACh) is expressed in epithelial, endothelial and immune cells. For example, the in vivo release of ACh from the human skin pretreated with botulinum toxin has recently been demonstrated. In the present experiments the effects of light (sunlight and solar radiation by a commercial UV-A applier) and of a tactile stimulus on the release of non-neuronal ACh were investigated. Release of ACh from the proximal and distal shin, i.e. anterior tibial region, was measured by dermal microdialysis in 20 min samples over a time period of at least 140 min. Control experiments were performed in a dark room throughout. In some experiments volunteers were exposed to sunshine (80-140 min) or the shin region was illuminated (80-95 min) by a commercial UV-A lamp (400 W at a distance of 50 cm). In control experiments ACh release between 20 and 80 min (B1) amounted to 118+/-32 pmol (n=17) and gradually declined between 80 and 140 min (B2) to 112+/-34 pmol, resulting in a B2/B1 ratio of 0.95. When the skin was exposed to sunlight ACh release increased from 205+/-58 pmol (B1) to 349+/-122 pmol resulting in a B2/B1 ratio of 1.70. UV-A radiation, however, had no significant effect on the B2/B1 ratio. When very smooth tactile stimuli were applied by a cotton wool tip for 20 min to the skin close to the microdialysis membranes in a dark room, ACh release was increased from 9+/-2 pmol/20 min to 52+/-36 (n=7). In conclusion, the in vivo release of ACh from the human skin appears to be regulated by external stimuli like sunlight and tactile stimuli.