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.

Role of hyaluronidase in diplopia after peribulbar anesthesia for cataract surgery.

OBJECTIVE: To determine the protective action of hyaluronidase on peribulbar anesthesia-related diplopia in patients undergoing cataract surgery. DESIGN: Single-center observational case series. PARTICIPANTS: All patients undergoing elective phacoemulsification and intraocular lens implantation under peribulbar anesthesia between February 2001 and January 2003. METHODS: We compared the incidence of postoperative diplopia between 2 periods--February 2001 to January 2002 (P1) and February 2002 to January 2003 (P2)--which differed by the presence (P1) or absence (P2) of hyaluronidase in the anesthetic solution. MAIN OUTCOME MEASURES: All patients were examined on the first and fifth postoperative days during both periods. When diplopia was diagnosed, we recorded the characteristics of the patient, peribulbar anesthesia, and diplopia (orthoptic examination, and magnetic resonance imaging in some cases). RESULTS: Seven thousand two hundred five patients were studied. During P1, 3582 patients received peribulbar anesthesia, and no cases of diplopia occurred. During P2, 3623 patients received peribulbar anesthesia, and 27 cases of diplopia occurred (incidence, 0.75%; P = 0.0002 vs. P1). Diplopia involved the inferior rectus (40%) and the external rectus (37%) muscles. Diplopia was persistent in 54% of the cases. CONCLUSIONS: Peribulbar anesthesia-related diplopia was significantly more frequent when hyaluronidase was not added to the anesthetic solution.

Vertical diplopia following peribulbar anesthesia: the role of hyaluronidase.

PURPOSE: To estimate the incidence of vertical diplopia following peribulbar anesthesia in otherwise uncomplicated cataract surgery and to establish whether the use of hyaluronidase in the peribulbar injection mixture affected the likelihood of this complication. METHODS: Nine hundred forty consecutive phacoemulsification procedures using peribulbar anesthesia were retrospectively reviewed to identify cases of postoperative vertical diplopia. Case notes were reviewed to establish the nature and timing of the onset of diplopia, the anesthetic technique, and whether hyaluronidase was used. The patterns of progression as demonstrated by serial Hess charts were compared. RESULTS: There were 6 cases of vertical diplopia (incidence, 0.64%). All showed an immediate postoperative hypertropia in the injected eye changing during a 4- to 6-week period to hypotropia with restriction of upgaze. All applications of anesthesia were administered by consultant anesthetists, associate specialists, or residents under their direct supervision using 25-mm, 25-gauge needles with 2% lidocaine. Hyaluronidase was included in the injection mixture for 435 (46%) of the cases and was not included for 505 (54%) of the cases. All 6 cases of vertical diplopia occurred in the group in which hyaluronidase was not used, which has a significant association (chi-square test, 5.22; P = .023). CONCLUSION: Hyaluronidase should be included in peribulbar anesthetics to reduce the risk of postoperative vertical diplopia.