HYAL4-V1/Chondroitinase (Chase) Drives Gemcitabine Resistance and Predicts Chemotherapy Failure in Patients with Bladder Cancer.

PURPOSE: Gemcitabine-based chemotherapy regimens are first-line for several advanced cancers. Because of better tolerability, gemcitabine + cisplatin is a preferred neoadjuvant, adjuvant, and/or palliative chemotherapy regimen for advanced bladder cancer. Nevertheless, predicting treatment failure and overcoming resistance remain unmet clinical needs. We discovered that splice variant (V1) of HYAL-4 is a first-in-class eukaryotic chondroitinase (Chase), and CD44 is its major substrate. V1 is upregulated in bladder cancer and drives a malignant phenotype. In this study, we investigated whether V1 drives chemotherapy resistance. EXPERIMENTAL DESIGN: V1 expression was measured in muscle-invasive bladder cancer (MIBC) specimens by qRT-PCR and IHC. HYAL-4 wild-type (Wt) and V1 were stably expressed or silenced in normal urothelial and three bladder cancer cell lines. Transfectants were analyzed for chemoresistance and associated mechanism in preclinical models. RESULTS: V1 levels in MIBC specimens of patients who developed metastasis, predicted response to gemcitabine + cisplatin adjuvant/salvage treatment and disease-specific mortality. V1-expressing bladder cells were resistant to gemcitabine but not to cisplatin. V1 expression neither affected gemcitabine influx nor the drug-efflux transporters. Instead, V1 increased gemcitabine metabolism and subsequent efflux of difluorodeoxyuridine, by upregulating cytidine deaminase (CDA) expression through increased CD44-JAK2/STAT3 signaling. CDA inhibitor tetrahydrouridine resensitized V1-expressing cells to gemcitabine. While gemcitabine (25-50 mg/kg) inhibited bladder cancer xenograft growth, V1-expressing tumors were resistant. Low-dose combination of gemcitabine and tetrahydrouridine abrogated the growth of V1 tumors with minimal toxicity. CONCLUSIONS: V1/Chase drives gemcitabine resistance and potentially predicts gemcitabine + cisplatin failure. CDA inhibition resensitizes V1-expressing tumors to gemcitabine. Because several chemotherapy regimens include gemcitabine, our study could have broad significance.

Pain perception in sequential cataract surgery: comparison of first and second procedures.

PURPOSE: To compare pain and anxiety between first and second cataract extractions under topical anesthesia with monitored anesthesia care. SETTING: University ophthalmology clinic. DESIGN: Cohort study. METHODS: Consecutive adults having bilateral sequential clear corneal cataract extraction using phacoemulsification under topical anesthesia with monitored anesthesia care were recruited. Exclusion criteria included baseline eye pain, poor comprehension, and complicated cataract extraction. Patients completed 4 short perioperative surveys with each cataract extraction as follows: the Amsterdam Preoperative Anxiety and Information Scale (APAIS) and the State-Trait Anxiety Scale (STAI) preoperatively and a 0-to-10 visual analog scale pain survey twice after surgery. Pain and difference in pain were the primary outcomes. RESULTS: Of the 65 patients who completed the study, 26 (40%) reported higher visual analog scale pain scores for the second cataract extraction. Overall, the median pain score was 0 (range 0 to 6) for the first cataract extraction and 1 (range 0 to 9) for the second (P = .004). By 1 day postoperatively, the pain scores were similar (median 0; range 0 to 9; P = .58). Both APAIS and STAI anxiety scores decreased between surgeries (P = .003 and P < .001, respectively). CONCLUSIONS: Although cataract extraction remained relatively painless under topical anesthesia with monitored anesthesia care, there was a subtle increase in pain in the second surgery relative to the first. This appears to be associated with decreased preoperative anxiety and may be related to the amnestic effects of intravenous sedation. These data may explain a common operative observation. FINANCIAL DISCLOSURE: No author has a financial or proprietary interest in any material or method mentioned.