First-in-Human Safety, Imaging, and Dosimetry of a Carbonic Anhydrase IX-Targeting Peptide, [68Ga]Ga-DPI-4452, in Patients with Clear Cell Renal Cell Carcinoma.

[68Ga]Ga-DPI-4452, a first-in-class carbonic anhydrase IX-binding radiolabeled peptide, is the imaging agent of a theranostic pair with [177Lu]Lu-DPI-4452, developed for selecting and treating patients with carbonic anhydrase IX-expressing tumors. Here, [68Ga]Ga-DPI-4452 imaging characteristics, dosimetry, pharmacokinetics, and safety were assessed in 3 patients with clear cell renal cell carcinoma. Methods: After [68Ga]Ga-DPI-4452 administration, patients underwent serial full-body PET/CT imaging. Blood and urine were sampled. Safety was monitored for 7 d after injection. Results: Tumor uptake was observed at all time points (15 min to 4 h). Across 36 lesions, the SUVmax at 1 h after administration ranged from 6.8 to 211.6 (mean, 64.6 [SD, 54.8]). The kidneys, liver, and bone marrow demonstrated low activity. [68Ga]Ga-DPI-4452 was rapidly eliminated from blood and urine. No clinically significant toxicity was observed. Conclusion: [68Ga]Ga-DPI-4452 showed exceptional tumor uptake in patients with clear cell renal cell carcinoma, with very high tumor-to-background ratios and no significant adverse events, suggesting potential diagnostic and patient selection applications.

Concentration-dependent effects of antimicrobials on Staphylococcus aureus toxin-mediated cytokine production from peripheral blood mononuclear cells.

BACKGROUND: Toxins contribute to the pathogenicity of Staphylococcus aureus infections by inducing a dysregulated inflammatory response. This study evaluated the impact of anti-staphylococcal antibiotic exposures over an increasing concentration range on cytokine production from peripheral blood mononuclear cells (PBMCs) after S. aureus toxin exposures. METHODS: Human PBMCs were suspended in complete Roswell Park Memorial Institute (RPMI) 1640 medium with 10% fetal bovine serum at 10(6) cells/mL with 100 ng/mL S. aureus toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxin A (SEA), α-toxin or Panton-Valentine leucocidin (PVL). Vancomycin, trimethoprim/sulfamethoxazole, tigecycline, daptomycin, linezolid, clindamycin and azithromycin were added at a concentration range of 0.5-100 mg/L. Cytokine [interleukin-1ß (IL-1ß), IL-6, IL-8, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNF-α)] concentrations were measured in duplicate by ELISA following exposure and were compared with response with toxin alone. RESULTS: At concentrations approximating serum C(max), tigecycline decreased IL-6 by 52%-57% and IFN-γ production by 43%-53% compared with toxin alone (P ≤ 0.05) and linezolid inhibited TNF-α by 12%-35% and IL-8 by 25%-42% (P ≤ 0.02). However, trimethoprim/sulfamethoxazole increased TNF-α and IL-8 production (P = 0.002). Clindamycin, daptomycin, vancomycin and azithromycin had no consistent significant effect at approximate serum C(max) concentrations. All antibiotics had a concentration-dependent effect on cytokine production, with tigecycline, clindamycin and trimethoprim/sulfamethoxazole being the most potent inhibitors of cytokine production at concentrations exceeding 25 mg/L. CONCLUSIONS: S. aureus toxins stimulate production of inflammatory cytokines in PBMCs. Antimicrobials with high tissue penetration, including tigecycline, clindamycin, trimethoprim/sulfamethoxazole and linezolid, reduced cytokine production, which, along with their antimicrobial effects, may have importance in the therapeutic outcome of severe infections.

Cost-effectiveness of UGT1A1*28 genotyping in preventing severe neutropenia following FOLFIRI therapy in colorectal cancer.

PURPOSE: Functional polymorphisms of the UGT1A1 gene, particularly the UGT1A1*28 variant, are associated with the severity of the bone marrow suppression in patients with metastatic colorectal cancer receiving irinotecan. This study assesses the cost-effectiveness of screening for UGT1A1*28 polymorphism associated with primary prophylactic Granulocytes Colony Stimulating Factor in patients homozygous for the *28 allele. The effectiveness was estimated based on the number of neutropenia avoided. METHODS: We modelled a theoretical population treated with combined 5-fluorouracil, leucovorin and irinotecan (FOLFIRI) for metastatic colorectal cancer. A decision tree simulated the health outcomes, measured by the prevalence of neutropenic events for two strategies, with or without UGT1A1 genotype screening. The model incorporated direct hospital costs and was validated with a sensitivity analysis. We calculated the cost-effectiveness ratio: CE=∆C / ∆E = "genotyping" cost - "no genotyping" cost / number of febrile neutropenia avoided. RESULTS: In the "genotyping strategy", the cost to avoid one febrile neutropenia event per 1000 patients treated was € 942.8 to € 1090.1. The sensitivity analysis showed a better CE ratio of € 733.4 to € 726.6 per febrile neutropenic event avoided. CONCLUSIONS: UGT1A1 genotype screening before irinotecan treatment is a cost-efficient strategy for the hospital. Systematic genotyping prior to chemotherapy, and administration of CSF in patients homozygotes for the *28 allele allow to avoid 91 febrile neutropenias at an acceptable cost.