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Biomedical subjects

Joseph L Chin

Publications and source records attributed to Joseph L Chin.

30 records · Page 2Linked to original sources
PubMed2003

Correlation study showing no concordance between EPAS-1/HIF-2alpha mRNA and protein expression in transitional cellcancer of the bladder.

OBJECTIVES: Endothelial Per-ARNT-Sim (PAS) domain protein-1 (EPAS-1)/hypoxia-inducible factor (HIF)-2alpha is a recently identified, endothelial-specific, hypoxia-induced transcription factor and is reputed to have an important role in tumor angiogenesis and tumor progression. Only a few studies have reported on the clinical correlation with grade, stage, necrosis, and microvessel density in transitional cell carcinoma of the bladder. In vitro studies have reported no concordance of EPAS-1/HIF-2alpha mRNA and protein expression. We sought to elucidate these two issues. METHODS: Surgical specimens from 110 patients with transitional cell carcinoma comprised the study, including 51 from radical cystectomy and 59 from transurethral resection of bladder tumor. Immunohistochemistry and in situ hybridization were performed with antibodies against EPAS-1/HIF-2alpha, CD31, and a human EPAS-1/HIF-2alpha cDNA subclone probe. RESULTS: EPAS-1/HIF-2alpha protein expression was found almost exclusively in high-grade and high-stage tumors (P <0.0001). EPAS-1/HIF-2alpha mRNA expression was detectable only in high-grade (grade 3) and high-stage (pT3a or greater) cases with positive EPAS-1/HIF-2alpha protein expression (P = 0.0017). The presence of necrosis correlated with EPAS-1/HIF-2alpha expression, tumor grade, and tumor stage (P <0.0001). Microvessel density was much lower in invasive, larger tumor nodules in EPAS-1/HIF-2alpha-positive cases than in the negative cases (P <0.0001). CONCLUSIONS: EPAS-1/HIF-2alpha protein and mRNA levels correlate with higher grade and advanced bladder transitional cell carcinoma. In lower stage cases, no concordance was found between transcription and translation of EPAS-1/HIF-2alpha gene expression. Because EPAS-1/HIF-2alpha mRNA is only detectable in highly invasive cancer cases, it may serve as a therapeutic target (eg, by an antisense mRNA approach) for bladder cancer.

Adult↗
PubMed2003

Serial histopathology results of salvage cryoablation for prostate cancer after radiation failure.

PURPOSE: There has been a paucity of long-term followup reports of cryoablation for prostate cancer. In particular, little is known regarding the long-term histological results following salvage cryoablation. We report serial biopsy results of up to 43 months on 106 patients who underwent cryoablation after radical radiotherapy failed. MATERIALS AND METHODS: A total of 110 cryoablation procedures were done in 106 patients for biopsy proven, clinically localized radiation failure. Postoperatively transrectal ultrasound guided biopsy (usually 4 cores) was done at approximately 3, and/or 6, 12 and 24 months, and thereafter as indicated by prostate specific antigen, which was measured every 6 months. RESULTS: Of 818 biopsy cores a total of 23 (2.8%) from 15 patients (14.2%) were positive. Of the positive cores 73.9% were found within year 1 following cryoablation. Residual viable prostate glands and stroma were found in 42.4% and 27.4% of patients, respectively, at various time points. The frequency of various histological features, the most common being necrosis and fibrosis, was tabulated from the serial biopsy histology reports. CONCLUSIONS: The results of serial biopsies have improved our understanding of the histopathological changes as well as the capabilities and limitations of salvage cryoablation. The biopsy positivity rate is acceptable, although the finding of persistent viable prostatic tissue in a substantial proportion of patients implies that vigilant long-term followup is mandatory.

Aged↗
PubMed2003

The prognostic significance of metastatic perivesical lymph nodes identified in radical cystectomy specimens for transitional cell carcinoma of the bladder.

PURPOSE: We determined the prognostic significance of metastatic perivesical lymph nodes (PVLN) in transitional cell carcinoma of the bladder (TCC). MATERIALS AND METHODS: A retrospective review of 198 consecutive patients who underwent radical cystectomy for clinically organ confined TCC identified 32 patients with PVLN in pathology specimens. Patient characteristics were compared. Overall survival, disease-specific survival (DSS) and disease-free survival were estimated using Kaplan-Meier actuarial methodology. The log-rank test was used to compare the differences between patients with and without metastatic TCC to PVLN. Cox multivariate regression analysis was used to determine whether the effect of metastatic PVLN on survival was independent of pathological stage. RESULTS: Metastatic TCC was found in the PVLN of 14 patients. Median followup and age were 13.5 months and 66.5 years, respectively. Patients with and without metastatic PVLN had similar characteristics and pathological disease staging. The overall survival, DSS and disease-free survival were significantly less for patients with metastatic TCC in PVLN (p = 0.002, p = 0.013 and p <0.001, respectively), and involvement of PVLN and pelvic nodes (p = 0.001, p = 0.010 and p = 0.041, respectively). Metastatic PVLN was an independent predictor of OS and DSS (p = 0.016 and p = 0.025, respectively). CONCLUSIONS: Metastases to PVLN appear to confer a significantly worse prognosis for patients undergoing radical cystectomy. Patients with identifiable metastatic PVLN may benefit from early adjuvant therapies.

Aged↗
PubMed2003

Management of bacillus Calmette-Guerin (BCG) refractory superficial bladder cancer: results with intravesical BCG and Interferon combination therapy.

INTRODUCTION AND OBJECTIVE: BCG is the most efficacious intravesical treatment for superficial bladder cancer. However, 30%-40% of tumors are refractory. BCG failure is an indication for cystectomy but several salvage intravesical (IVe) strategies have been proposed. Early results with reduced dose BCG in combination with IFN-a in patients are currently the most promising. We have adopted this approach and now report our preliminary results. This is the first report of this salvage therapy from Canada, the birthplace of IVe BCG therapy for superficial bladder cancer. METHODS: The "O'Donnell protocol" of reduced dose IVe BCG plus IFN-a was followed in 12 patients with BCG refractory superficial transitional cell carcinoma. A retrospective review of the efficacy and toxicity of the treatment was conducted. RESULTS: One year from induction therapy with salvage BCG/IFN-a, 6 of the 12 (50%) of patients were tumor free. Of the six recurrences, 3(50%) did not respond to the IVe therapy and had residual/recurrent tumor at the first follow-up visit. Risk factors for treatment failure were identified. The combinative therapy was well tolerated with minimal toxicity compared to previous full dose BCG. CONCLUSION: Our 12 month data with reduced dose IVe BCG plus IFN-a salvage therapy for BCG refractory superficial TCC confirm previous reports of >50% complete response rates. We need longer follow up in a larger patient population to determine the durability of this promising therapy in patients who would otherwise undergo radical cystectomy.

Antineoplastic Agents↗
PubMed2003

Clinical impact of adjunctive donor microvascular reconstruction on renal transplantation.

INTRODUCTION: Microvascular reconstruction was incorporated into our donor organ harvesting algorithm for kidneys with anatomic anomalies or injury of the vasculature. The impact of adjunctive microsurgery was appraised in terms of organ availability and graft quality procedures. METHODS: Out of a total of 441 renal transplant procedures performed by one surgeon (JLC) between 1984 and 1997, 104 allografts (83 cadaveric, 21 living related) required ex-vivo microvascular reconstruction. Micro-reconstruction using 2.5-10 X magnification was employed to create a single artery and vein for subsequent in-situ anastomosis. Side-to-side or end-to-side anastomosis was performed, depending on the vascular arrangement. Multiple vessels and those injured during harvesting were reconstructed with a combination of the above techniques. RESULTS: Eleven kidneys had two or more arterial anastomoses; 12 had combination (arterial and venous) anastomoses while 74 required a single micro-reconstruction. In addition, seven kidneys with severely traumatized vessels were salvaged. Average bench surgery times were 30 and 50 minutes for single and multiple reconstructions respectively. Mean warm ischemic time was 29 minutes. Three kidneys were lost due to vascular thrombosis (two venous, one arterial) where in-situ technical difficulties were encountered in all three cases. With mean follow-up of 30 months, 23 kidneys had been lost due to chronic rejection with the remainder functioning. CONCLUSION: Extensive microvascular reconstruction salvaged 30 suboptimal or previously deemed unusable grafts (30/439 = 7%) and facilitated the vascular anastomosis in another 74 cases (17%). The warm ischemic time and the possibility of in-situ technical errors with small-calibre vessels were minimized. This report affirms the contention that microvascular reconstruction should be available as an adjunctive technique for renal transplantation, to maximize the quantity and quality of donor kidneys.

Adult↗
PubMed2003

The Canadian Urology Fair: a model for minimizing the financial and academic costs of the residency selection process.

INTRODUCTION: In 1994, the Canadian urology residency training programs designed the "Canadian Urology Fair"--a single-site (Toronto, Ont.), 1-day fair to conduct the personal interview portion of the residency selection process. The objective of the current study was to evaluate the success of the Urology Fair in achieving its original goals of decreasing the financial burden and minimizing time away from medical training for applicants and faculty. METHODS: Both candidates and Canadian urology training programs were surveyed regarding the financial and academic costs (days absent) of attending the 2001 Urology Fair. Data from the 2001 Canadian Resident Matching Service (CaRMS) was used to compare the financial and academic costs of attending personal interviews incurred by candidates declaring urology as their first-choice discipline to candidates interviewing with other surgical specialties throughout Canada. RESULTS: Financial costs incurred by candidates to attend the Urology Fair (mean Can dollar 367) were significantly lower than candidates' estimated costs of attending on-site interviews at the individual programs (mean Can dollar 2065). The financial costs of attending personal interviews by CaRMS applicants declaring urology as their first-choice discipline (mean Can dollar 2002) were significantly lower than the costs incurred by applicants interviewing with other surgical disciplines (mean Can dollar 2744). Financial costs to urology programs attending the fair (mean Can dollar 1931) were not significantly greater than the programs' estimated costs of conducting on-site interviews at their respective program locations (mean Can dollar 1825). Days absent from medical school to attend interviews were significantly lower among CaRMS applicants declaring urology as their first-choice discipline (3 d) compared with applicants who interviewed with other surgical specialties (9.1 d). CONCLUSION: The Canadian Urology Fair represents an innovative and efficient method for residency programs to conduct the personal interview portion of the residency selection process and should serve as a model for making the interview process less expensive and time-consuming for both candidates and faculty.

Absenteeism↗
PubMed2002

A randomized, placebo-controlled trial of zoledronic acid in patients with hormone-refractory metastatic prostate carcinoma.

BACKGROUND: Bone metastases are a common cause of morbidity in patients with prostate carcinoma. We studied the effect of a new bisphosphonate, zoledronic acid, which blocks bone destruction, on skeletal complications in prostate cancer patients with bone metastases. METHODS: Patients with hormone-refractory prostate cancer and a history of bone metastases were randomly assigned to a double-blind treatment regimen of intravenous zoledronic acid at 4 mg (N = 214), zoledronic acid at 8 mg (subsequently reduced to 4 mg; 8/4) (N = 221), or placebo (N = 208) every 3 weeks for 15 months. Proportions of patients with skeletal-related events, time to the first skeletal-related event, skeletal morbidity rate, pain and analgesic scores, disease progression, and safety were assessed. All statistical tests were two-sided. RESULTS: Approximately 38% of patients who received zoledronic acid at 4 mg, 28% who received zoledronic acid at 8/4 mg, and 31% who received placebo completed the study. A greater proportion of patients who received placebo had skeletal-related events than those who received zoledronic acid at 4 mg (44.2% versus 33.2%; difference = -11.0%, 95% confidence interval [CI] = -20.3% to -1.8%; P =.021) or those who received zoledronic acid at 8/4 mg (38.5%; difference versus placebo = -5.8%, 95% CI = -15.1% to 3.6%; P =.222). Median time to first skeletal-related event was 321 days for patients who received placebo, was not reached for patients who received zoledronic acid at 4 mg (P =.011 versus placebo), and was 363 days for those who received zoledronic acid at 8/4 mg (P =.491 versus placebo). Compared with urinary markers in patients who received placebo, urinary markers of bone resorption were statistically significantly decreased in patients who received zoledronic acid at either dose (P =.001). Pain and analgesic scores increased more in patients who received placebo than in patients who received zoledronic acid, but there were no differences in disease progression, performance status, or quality-of-life scores among the groups. Zoledronic acid at 4 mg given as a 15-minute infusion was well tolerated, but the 8-mg dose was associated with renal function deterioration. CONCLUSION: Zoledronic acid at 4 mg reduced skeletal-related events in prostate cancer patients with bone metastases.

Adenocarcinoma↗
PubMed2002

Hypoxia-induced, perinecrotic expression of endothelial Per-ARNT-Sim domain protein-1/hypoxia-inducible factor-2alpha correlates with tumor progression, vascularization, and focal macrophage infiltration in bladder cancer.

Endothelial Per-ARNT-Sim (PAS) domain protein-1 (EPAS-1)/hypoxia-inducible factor-2alpha (HIF-2alpha) is a member of the basic helix-loop-helix/PAS domain protein family and is considered to be an endothelial-specific, hypoxia-inducible transcription factor. Because hypoxia is a fundamental element of tumor biology determining clinical outcome, we performed an immunohistochemical study of EPAS-1 expression in a cohort of bladder cancer cases and assessed the possible correlation of EPAS-1 expression with tumor hypoxia and growth. In the 67 cases (37 radical cystectomy and 30 transurethral resection) studied, overexpression of EPAS-1/HIF-2alpha protein was not found in cancer cells or in normal tissues but was mostly found in stroma around cancer cells, and strong positive staining was noted in perinecrotic regions. The perinecrotic/tumorous expression of EPAS-1/HIF-2alpha was correlated statistically with higher histological grade (P < 0.001), advanced pathological T stage (P < 0.001), and presence of necrosis (P < 0.001). A parallel immunohistochemical analysis of a marker gene of vascular endothelial growth factor demonstrated its positive correlation with tumor grade, stage, and EPAS-1/HIF-2alpha overexpression, supporting the correlation of EPAS-1/HIF-2alpha up-regulation with tumor angiogenesis. To further clarify the relationship between hypoxia and vascularity in the perinecrotic/tumorous area with EPAS-1/HIF-2alpha expression, tissue microvessel density (MVD) was assessed. No significant correlation (P = 0.442) was found between EPAS-1/HIF-2alpha expression and MVD if the 67 tumors of different stages were all included. However, EPAS-1/HIF-2alpha-positive cases had lower MVD than EPAS-1/HIF-2alpha-negative cases (P = 0.001) if only invasive cancer cases were analyzed. In addition, in all EPAS-1/HIF-2alpha-positive staining cases, EPAS-1/HIF-2alpha-positive foci had lower MVD than EPAS-1/HIF-2alpha-negative foci (P < 0.001). Finally, using serial sections, the location of EPAS-1/HIF 2alpha expression was identified mainly in tumor-associated macrophage (TAM) as well as in some fibroblast cells. Focal TAM infiltration was identified at a higher level in EPAS-1-positive cases than EPAS-1-negative cases (P < 0.001). This is the first clinical report suggesting that hypoxia-induced, perinecrotic EPAS-1/HIF-2alpha expression is correlated with tumor progression and angiogenesis at higher grade and stage through focal TAM infiltration in invasive bladder cancer.

Adult↗
PubMed2002

New technologies for ablation of small renal tumors: current status.

The diagnostic rate of small, "incidental" tumors which are amenable to local excision or ablation has increased significantly due to widespread use of non-invasive body imaging tests. The role of nephron-sparing tumor-ablative surgery has expanded beyond the traditional circumstances of neoplasms in solitary/functionally solitary kidneys or tumors present bilaterally. Due to technologic advances, possible therapeutic options now include open surgery, laparoscopic, percutaneous and extraciorporeal approaches, in addition to surveillance in some cases. This review will concentrate on the new energy sources available for tumor ablation rather than the different surgical approaches, with a detailed review of renal cryoablation, radiofrequency and high intensity focused ultrasound. The emphasis is on the experimental data and the limited clinical data available to date, and challenges and current limitations of the various modalities.

Animals↗
PubMed2002

Adjuvant chemotherapy for deep muscle-invasive transitional cell bladder carcinoma - a practice guideline.

BACKGROUND AND PURPOSE: To examine the role of adjuvant chemotherapy in the treatment of patients with deep muscle-invasive transitional cell carcinoma (TCC) of the bladder who have undergone cystectomy. MATERIALS AND METHODS: A systematic review of the published literature was combined with a consensus process, involving the interpretation of evidence within the context of conventional practice, to develop an evidence-based practice guideline for use in Ontario. RESULTS: Five randomized controlled trials (RCTs) comparing adjuvant chemotherapy with observation were found that reported data on survival. Sample sizes of the trials were small, and each of the trials evaluated a cisplatin-based chemotherapy regimen; however, none studied less toxic combination chemotherapy regimens such as gemcitabine-cisplatin or dose-intensive methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) with granulocyte-colony stimulating factor (G-CSF). One trial was excluded due to inadequate reporting of outcomes. The remaining four studies failed to demonstrate an overall survival benefit in favor of adjuvant chemotherapy, although three of the four trials showed statistically significant benefits for adjuvant chemotherapy with respect to disease-free survival. CONCLUSIONS: As randomized trials have not proven a benefit in overall survival, adult patients with deep muscle-invasive TCC of the bladder should not be routinely offered adjuvant chemotherapy following cystectomy. Disease-free survival may be improved by adjuvant chemotherapy, but it is unclear whether this improvement compensates for the detrimental effects of chemotherapy. If a patient chooses adjuvant chemotherapy to improve disease-free survival they should be made aware of the lack of proven overall survival benefit, and a cisplatin-based combination chemotherapy regimen such as MVAC or CMV is recommended. RCTs of gemcitabine-cisplatin and dose-intensive MVAC plus G-CSF in the setting of metastatic TCC of the bladder provide indirect evidence that these regimens could offer equivalent benefit to MVAC and CMV but with less toxicity in patients with muscle-invasive disease. The use of these regimens in the adjuvant setting after cystectomy is currently being evaluated in a randomized trial (EORTC trial 30994).

Adult↗
PubMedDate not supplied

Tumor exosomes expressing Fas ligand mediate CD8+ T-cell apoptosis.

Tumor-derived immune suppression is considered to be a major mechanism of tumor evasion from the immune system destruction, however, little is known regarding the induction of T-cell functional suppression by tumor-derived exosomes. Herein, we investigate tumor-derived exosomes involved in normal immunological communications as means of inhibiting an antitumor T-cell response. Exosomes derived from LNCaP, a human prostate cancer cell line, were visualized by FACS and identified based on size (80-200 nm) in comparison to marker beads. Exosomes from tumor cell line inhibited T-cell proliferation. Dose-dependent apoptosis of T cells was induced by co-culture with tumor exosomes. Addition of anti-FasL antibody blocked the apoptosis induction by tumor exosomes. This study suggests that induction of T-cell apoptosis by tumor-derived exosomes appears to be a novel mechanism of tumor immune evasion.

Antigens, Neoplasm↗