Serum amyloid A4 and cognitive functioning in long-term testicular germ cell tumor survivors.

606 Background: Long-term cognitive impairment has been described in survivors of testicular germ cell tumors (GCT) following curative treatment. Serum Amyloid A4 (SAA4) is a constitutively expressed apolipoprotein involved in lipid transport and metabolism. Unlike other SAA family members, SAA4 is not markedly induced during acute inflammation but has been linked to chronic inflammation, suggesting a potential role in neuroinflammatory processes and cognitive decline. Elevated SAA levels have been associated with post-stroke cognitive impairment and neurodegenerative diseases; however, SAA4 has not previously been studied in GCT survivors. This study aimed to evaluate the association between plasma SAA4 levels and self-reported cognitive functioning in long-term GCT survivors. Methods: GCT survivors (N = 177) followed at the National Cancer Institute, Slovakia, completed the Functional Assessment of Cancer Therapy – Cognitive Function (FACT-Cog) questionnaire during annual follow-up. The median follow-up time was 9 years (range 4-32). Peripheral blood was obtained during the same visit, and plasma SAA4 concentrations were quantified by ultra-high performance liquid chromatography and mass spectrometry in selected reaction monitoring mode (UHPLC-SRM/MS). Cognitive outcomes were assessed across four domains and overall cognitive function score, dichotomized into high (better) and low (worse) groups by median split. Survivors were treated with orchiectomy and active surveillance (n=23), cisplatin-based chemotherapy (n=131), radiotherapy (n=14), or both chemotherapy and radiotherapy (n=9). Results: Survivors with lower overall cognitive function scores had higher SAA4 plasma levels compared with those with higher scores (mean ± SEM: 26.42 ± 1.24 mg/L vs. 21.94 ± 1.23 mg/L; p = 0.02). Similarly, higher SAA4 was observed in survivors with worse perceived cognitive impairment (26.13 ± 1.25 mg/L vs. 22.23 ± 1.24 mg/L; p = 0.03) and poorer quality of life affected by cognitive impairment (25.75 ± 1.26 mg/L vs. 22.64 ± 1.24 mg/L; p = 0.056). No statistically significant differences in SAA4 plasma levels were found across treatment groups, which may be partly due to small subgroup sizes. Conclusions: Higher plasma SAA4 levels were associated with worse cognitive functioning in long-term GCT survivors. To our knowledge, this is the first study to evaluate SAA4 in this population. The findings suggest that chronic inflammation and altered lipid metabolism may contribute to cognitive impairment after cancer treatment. SAA4 and related apolipoproteins warrant further investigation as potential biomarkers of cancer-related cognitive impairment and other long-term treatment toxicities in GCT survivors.