External validation and reliability assessment of posterior urethral morphology on initial voiding cystourethrogram as a predictor for infants with posterior urethral valves.

INTRODUCTION: The morphology of the bladder and posterior urethra on initial voiding cystourethrogram (VCUG) in posterior urethral valve (PUV) has been proposed as a meaningful early metric for short- and long-term kidney outcomes. Here, we seek to externally validate the proposed association and assess the reliability of PUV morphology characteristics. MATERIALS AND METHODS: We reviewed our institutional database for patients managed for PUV between 2000 and 2022 and included those treated with primary ablation with at least 1 year of follow-up for kidney function. Each VCUG was evaluated by three independent raters for the height-width ratio of the bladder (HW-B), height-width ratio of the posterior urethra (HW-PU), and posterior-anterior urethral ratio (PA-UR), and trabeculation (none, fine, or coarse). We assessed the reliability in these with intra-class coefficient and Fleiss kappa for continuous and categorical data, respectively. We performed univariate analysis with nadir creatinine and five-year follow-up glomerular filtration rate (GFR). RESULTS: In total, 98 patients met inclusion criteria. The median age at diagnosis and ablation was 10 and 21 days, respectively. Patients with nadir creatinine <0.8 mg/dL had higher follow-up GFR (101 vs. 20 ml/min/1.73 m2, p = 0.04), and lower risk of CKD (odds ratio 14.7, p = 0.002). The median value for HW-B was 1.4, median HW-PU was 2.1, and median PA-U was 4.7, There was significant inter-class agreement between all three measures of 0.80, 0.51, and 0.70 (p < 0.001). The inter-rater agreement for bladder trabeculation was fair (Fleiss K = 0.40, p < 0.001). There was no statistically significant correlation between HW-B, HW-PU, PU-A with nadir creatinine (p = 0.07, 0.33, 0.91) or 5-year GFR (0.27, 0.45, 0.62), respectively. DISCUSSION: There is significant interest in determining prognostic factors and metrics in PUV. The morphological characteristics on VCUG are reliable and is available information for all boys diagnosed with PUV, resulting in an attractive metric. While we do not demonstrate correlation with kidney outcomes, VCUG features warrant further attention as prognostic factors in PUV. CONCLUSIONS: PUV morphology on initial VCUG is a reliable metric of lower urinary tract deformity but is not associated with 5-year kidney outcomes.

The Prolactin Inducible Protein Modulates Antitumor Immune Responses and Metastasis in a Mouse Model of Triple Negative Breast Cancer.

The prolactin inducible protein (PIP) is expressed to varying degrees in more than 90% of breast cancers (BCs). Although high levels of PIP expression in BC has been shown to correlate with better prognosis and patient response to chemotherapy, some studies suggest that PIP may also play a role in metastasis. Here, we investigated the role of PIP in BC using the well-established 4T1 and E0771 mouse BC cell lines. Stable expression of PIP in both cell lines did not significantly alter their proliferation, migration, and response to anticancer drugs in vitro compared to empty vector control. To assess the effect of PIP expression on breast tumorigenesis in vivo, the 4T1 syngeneic transplantable mouse model was utilized. In immunocompetent syngeneic BALB/c mice, PIP-expressing 4T1 primary tumors displayed delayed tumor onset and reduced tumor growth, and this was associated with higher percentages of natural killer cells and reduced percentages of type 2 T-helper cells in the tumor environment. The delayed tumor onset and growth were abrogated in immunodeficient mice, suggesting that PIP-mediated modulation of primary tumor growth involves an intact immune system. Paradoxically, we also observed that PIP expression was associated with a higher number of 4T1 colonies in the lungs in both the immunocompetent and immunodeficient mice. Gene expression analysis of PIP-expressing 4T1 cells (4T1-PIP) revealed that genes associated with tumor metastasis such as CCL7, MMP3 and MMP13, were significantly upregulated in 4T1-PIP cells when compared to the empty vector control (4T1-EV) cells. Collectively, these studies strongly suggest that PIP may possess a double-edge sword effect in BC, enhancing both antitumor immunity as well as metastasis.