Abstract
Sex-specific differences have been increasingly recognized in many human diseases including brain cancer, namely glioblastoma. Primary CNS lymphoma (PCNSL) is an exceedingly rare type of brain cancer that tends to have a higher incidence and worse outcomes in male patients. Yet, relatively little is known about the reasons that contribute to these observed sex-specific differences. Using a population-representative cohort of patients with PCNSL with dense magnetic resonance (MR) imaging and digital pathology annotation (n = 74), we performed sex-specific cluster and survival analyses to explore possible associations. We found three prognostically relevant clusters for females and two for males, characterized by differences in (i) patient demographics, (ii) tumor-associated immune response, and (iii) MR imaging phenotypes. Upon a multivariable analysis, an enhanced FoxP3+ lymphocyte-driven immune response was associated with a shorter overall survival particularly in female patients (HR 1.65, p = 0.035), while an increased extent of contrast enhancement emerged as an adverse predictor of outcomes in male patients (HR 1.05, p < 0.01). In conclusion, we found divergent prognostic constellations between female and male patients with PCNSL that suggest differential roles of tumor-associated immune response and MR imaging phenotypes. Our results further underline the importance of continued sex-specific analyses in the field of brain cancer.
Highlights
Sex-specific differences play an important yet probably not fully appreciated role in the majority of human diseases
No statistically significant differences were observed among other variables such as age, MTX-based therapy, magnetic resonance (MR) imaging-based differences were observed among other variables such as age, MTX-based therapy, MR imagingtumor volumetrics, and tumor-associated immune response
We first explored sex-specific differences in a large, population-representative cohort of patients with Primary CNS lymphoma (PCNSL) using a multimodal dataset with dense clinical, MR imaging, and digital pathology annotations
Summary
Sex-specific differences play an important yet probably not fully appreciated role in the majority of human diseases. The importance of sex-specific analyses in cancer and brain cancer has recently been highlighted by a seminal study on glioblastoma, the most common malignant brain tumor in adults that tends to be more common and aggressive in males. By splitting their molecular data in male and female patients, applying specific bioinformatic methods, and introducing sex-specific stratification in functional validation experiments, the authors were able to identify previously unrecognized tumor molecular, magnetic resonance (MR) imaging, and pharmacokinetic factors that explain the observed survival differences [5]. One relevant aspect that has been recognized from that and similar analyses relates to the opposing effect sizes in females and males, which might cancel each other when using conventional joint analyses [5,6]
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