Dose-Escalated Salvage Radiotherapy for Macroscopic Local Recurrence of Prostate Cancer in the Prostate-Specific Membrane Antigen Positron Emission Tomography Era

Background: The purpose of this study was to access the oncological outcome of prostate-specific membrane antigen positron emission tomography (PSMA PET/CT)-guided salvage radiotherapy (SRT) for localized macroscopic prostate cancer recurrence. Methods: Between February 2010 and June 2021, 367 patients received SRT after radical prostatectomy. Out of the 367 screened patients, 111 patients were staged by PSMA PET/CT before SRT. A total of 59 out of these 111 (53.2%) patients were treated for PSMA PET-positive macroscopic prostatic fossa recurrence. Dose-escalated SRT was applied with a simultaneous integrated boost at a median prescribed dose of 69.3 Gy (IQR 69.3–72.6 Gy). The oncological outcome was investigated using Kaplan-Meier and Cox regression analyses. The genitourinary (GU)/gastrointestinal (GI) toxicity evaluation utilized Common Toxicity Criteria for Adverse Events (version 5.0). Results: The median follow-up was 38.2 months. The three-year biochemical progression-free survival rate was 89.1% (95% CI: 81.1–97.8%) and the three-year metastasis-free survival rate reached 96.2% (95% CI: 91.2–100.0%). The cumulative three-year late grade 3 GU toxicity rate was 3.4%. No late grade 3 GI toxicity occurred. Conclusions: Dose-escalated PSMA PET/CT-guided salvage radiotherapy for macroscopic prostatic fossa recurrence resulted in favorable survival and toxicity rates

Enumeration of circulating endothelial cell frequency as a diagnostic marker in aortic valve surgery - a flow cytometric approach

Background: The frequency of circulating endothelial cells (CEC) in patients' peripheral blood can be assessed as a direct marker of endothelial damage. However, conventional enumeration methods are extremely challenging. We developed a novel, automated approach to determine CEC frequencies and tested this method on two groups of patients undergoing conventional (CAVR) versus trans-catheter aortic valve implantation (TAVI). Methods: CEC frequencies were assessed by a flow cytometric approach, including automated pre-enrichment of CD34 positive blood cell subpopulation and isotype controls. The efficacy and reproducibility of the CEC enumeration method was validated by spiking blood samples of healthy control donors with defined numbers of endothelial cells. Results: CEC frequencies were significantly higher in the TAVI group before (9.8 +/- 4.1 vs. 5.5 +/- 2.2, p = 0.019) and 1 h after surgery (13.4 +/- 5.1 vs. 8.2 +/- 4.1, p = 0.030) corresponding to higher Euroscore, STS score in higher risk patients from the TAVI group. Five days after surgery, CEC frequencies became significantly higher in the more invasive CAVR group (39.0 +/- 13.0 vs. 14.3 +/- 4.4, p < 0.001) compared to minimally invasive TAVI approach. Conclusions: The new flow cytometric approach might be a robust and reliable method for CEC enumeration. Initial results show that CEC frequency is a valid clinical marker for the assessment of pre-operative risk, invasiveness of surgical procedure and clinical outcome. Further studies are necessary to validate the practical clinical usefulness and the potential superiority compared to conventional markers

No inflammatory effects after acute inhalation of barium sulfate particles in human volunteers

$\bf Background:$ Most threshold limit values are based on animal experiments. Often, the question remains whether these data reflect the situation in humans. As part of a series of investigations in our exposure lab, this study investigates whether the results on the inflammatory effects of particles that have been demonstrated in animal models can be confirmed in acute inhalation studies in humans. Such studies have not been conducted so far for barium sulfate particles ($BaSO_{4}$), a substance with very low solubility and without known substance-specific toxicity. Previous inhalation studies with zinc oxide (ZnO), which has a substance-specific toxicity, have shown local and systemic inflammatory respones. The design of these human ZnO inhalation studies was adopted for $BaSO_{4}$ to compare the effects of particles with known inflammatory activity and supposedly inert particles. For further comparison, in vitro investigations on inflammatory processes were carried out. $\bf Methods:$ Sixteen healthy volunteers were exposed to filtered air and $BaSO_{4}$ particles ($4.0 mg/m^{3}$) for two hours including one hour of ergometric cycling at moderate workload. Effect parameters were clinical signs, body temperature, and inflammatory markers in blood and induced sputum. In addition, particle-induced in vitro-chemotaxis of $BaSO_{4}$ was investigated with regard to mode of action and differences between in vivo and in vitro effects. $\bf Results:$ No local or systemic clinical signs were observed after acute $BaSO_{4}$ inhalation and, in contrast to our previous human exposure studies with ZnO, no elevated values of biomarkers of inflammation were measured after the challenge. The in vitro chemotaxis induced by $BaSO_{4}$ particles was minimal and 15-fold lower compared to ZnO. $\bf Conclusion:$ The results of this study indicate that $BaSO_{4}$ as a representative of granular biopersistent particles without specific toxicity does not induce inflammatory effects in humans after acute inhalation. Moreover, the in vitro data fit in with these in vivo results. Despite the careful and complex investigations, limitations must be admitted because the number of local effect parameters were limited and chronic toxicity could not be studied

Guidelines for the use of flow cytometry and cell sorting in immunological studies

International audienceThe classical model of hematopoiesis established in the mouse postulates that lymphoid cells originate from a founder population of common lymphoid progenitors. Here, using a modeling approach in humanized mice, we showed that human lymphoid development stemmed from distinct populations of CD127(-) and CD127(+) early lymphoid progenitors (ELPs). Combining molecular analyses with in vitro and in vivo functional assays, we demonstrated that CD127(-) and CD127(+) ELPs emerged independently from lympho-mono-dendritic progenitors, responded differently to Notch1 signals, underwent divergent modes of lineage restriction, and displayed both common and specific differentiation potentials. Whereas CD127(-) ELPs comprised precursors of T cells, marginal zone B cells, and natural killer (NK) and innate lymphoid cells (ILCs), CD127(+) ELPs supported production of all NK cell, ILC, and B cell populations but lacked T potential. On the basis of these results, we propose a "two-family" model of human lymphoid development that differs from the prevailing model of hematopoiesis