PMC9633672_01
Clinical monitoring of treatment response in a patient with recurrent and metastatic UC. (A) Red blood cell count monitoring in urine. (B). Images of bladder UC (arrowhead) and metastatic lesions (arrowheads) before and after combined immunotherapy, exhibiting vanishing and stabilization of tumors.
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F1
He also received six consecutive cycles of docetaxel (75 mg/m2, 120 mg on day 1, every 21 days) between 9 December 2018 and 13 March 2019, during which urinalysis displayed consistently high red blood cell (RBC) counts (Figure 1A). Imaging on 14 March 2019 revealed progressive bladder UC and aggravated bilateral lung metastasis and left femur metastasis (Figure 1B). April 2019. After cycle two, a CT scan on 4 June 2019 revealed a disappeared nodule in the bladder, lung, and left proximal femur (Figure 1B). Urinalysis (Figure 1A) and CT imaging (Figure 1B) showed a sustained response to therapy.
Predictive biomarkers for assessment of therapeutic response. (A) Loss of MSH2 and MSH6 expression in UC. Bar = 100 mum. (B) MSI analysis based on a pentaplex panel. (C) CD8 and PD-1 expression in UC. Bar = 50 mum.
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F2
As shown in Figure 2A, loss of MSH2 and MSH6 expression was observed in UC, suggesting a dMMR status in UC. The results showed four (BAT-25, BAT-26, NR-21, and MONO-27) loci with instability (Figure 2B), indicating an MSI-H status. IHC staining showed abundant CD8+ (clone SP16, 1:200; ZSGB-BIO, China) T-cell infiltration either at the tumor-stroma interface or within the tumor mass (Figure 2C). PD-1 (clone OTI4F10, 1:100, ZSGB-BIO) expression was identified mainly on immune cells (ICs) in the stroma of UC, as well as in scattered single tumor cells (TCs), with a combined positive score (CPS: number of PD-1 expressing cells TCs and ICs relative to the total number of TCs) = 8 (Figure 2C).
Genetic testing and pedigree analysis. (A) Heterozygous pathogenic germline mutation in the MSH2 gene of the proband. (B) Schematic representation of deleterious C.715C>T (p.Gln239*) mutation in MSH2 exon 4, leading to premature transcription termination and non-functional MSH2 protein product. (C) Pedigree chart of the family.
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F3
In genetic assessment using direct sequencing, we detected a heterozygous pathogenic germline mutation of c.715C>T (p.Gln239*) in MSH2 exon 4 (Figure 3A), which resulted in a premature stop codon and caused a truncated or absent MSH2 protein (Figure 3B). The pedigree chart of the family is presented in Figure 3C.