Hong-I Chen

THE EXPRESSION OF NEUROPEPTIDES IN HYPERPLASTIC AND MALIGNANT PROSTATE TISSUE AND ITS POSSIBLE CLINICAL IMPLICATIONS

PURPOSE We characterized the incidence and pattern of distribution of neuroendocrine differentiated tumor cells in prostatic hyperplastic and carcinomatous tissue, correlated neuroendocrine differentiation with prostate specific antigen (PSA) and assessed whether neuroendocrine cells have value as an independent indicator of poor prognosis in patients with prostate carcinoma. MATERIALS AND METHODS We immunohistochemically evaluated hyperplastic and carcinomatous prostate specimens for chromogranin A, neuron specific enolase and serotonin expressing tumor cells. The expression of various markers in cells was analyzed and correlated with tumor DNA ploidy, disease grade and stage, PSA and clinical course in patients with prostate cancer. RESULTS Enrolled in our study were 31 patients with hyperplastic prostate tissue and 30 with prostatic carcinoma. Followup in cancer cases was 1 to 9 years (mean 3.7). During followup 9 patients (30%) died of cancer. We noted DNA content aneuploidy in 5 cases (16.7%) of prostate carcinoma. Chromogranin A, neuron specific enolase and serotonin were expressed in 80%, 43% and 77% of cases of prostate carcinoma and in 29%, 10% and 36% of hyperplastic tissue, respectively. Larger prostates had no higher content of various neuroendocrine cells than smaller prostates. There was higher expression of neuropeptides in carcinomatous than in hyperplastic tissue. Of the 3 peptides chromogranin A was significantly related to all parameters, including Gleason score, tumor stage, PSA and patient survival. In addition to PSA, neuron specific enolase was also closely associated with other clinicopathological parameters. Serotonin was significantly related to patient survival only but we noted no correlation with Gleason score, tumor stage or PSA. In regard to factors predictive of patient prognosis expression of the 3 neuropeptides in tumor cells, Gleason score, tumor stage and PSA were closely related to patient survival in this study CONCLUSIONS The growth of hyperplastic prostate tissue is related to neuroendocrine cell activity. The chromogranin A marker has the highest expression in prostate cancer. Neuroendocrine cells may represent an independent indicator of poor prognosis in patients with prostate carcinoma.

Chromosomal Aberrations in Transitional Cell Carcinoma: Its Correlation with Tumor Behavior

Objective: Fluorescence in situ hybridization (FISH) was used to study numerical aberrations of chromosomes 1, 3, 7, 9, 11, 15, 17, X and Y in interphase nuclei of 16 transitional cell carcinoma (TCC) cell lines of the urinary tract. The number of chromosomal signal copies was compared with the DNA ploidy and correlated with the cellular grading and original tumor staging. Methods: The single-target FISH with the repetitive DNA probes for chromosomes 1, 3, 5, 7, 9, 11, 15, 17, X and Y were performed in 16 human TCC cell lines. For each test specimen, a minimum of 200 nuclei were analyzed. The number of fluorescent signals per nucleus was recorded. Tumor ploidy was analyzed using the DNA propidium iodide flow cytometric method. These results were correlated with tumor grade and stage. Results: In two diploid TCC cell lines, on average 67% of detected chromosomes were di-(i)somic. In 14 aneuploid TCC cell lines, on average only 10% (0–44%) of detected chromosomes were di-(i)somic. Chromosome X was completely changed into polysomism in 16 TCC cell lines (native male:female ratio = 12:4) but was unrelated to tumor grade or stage. Chromosome Y was lost in 10 out of 12 (83%) TCC cell lines which originated from male patients but was unrelated to tumor grade or stage too. 31% of chromosomes 11 and 15 were disomic in 16 TCC cell lines, 38% of chromosome 3 was monosomic, and 81–88% (83 in average) of chromosomes 1, 7, 9, 17 were polysomic. Disomic chromosome 11 associated with lower grade TCC and disomic chromosome 15 associated with higher grade TCC were noted (p < 0.01). Higher incidence of low stage tumors was observed in TCC cell lines with disomic chromosome 11 or chromosome 15 (p < 0.01). There was no correlation in somatic status of chromosomes 1, 7, 9, 17 with tumor grade and stage. Conclusions: The results of the study demonstrate that polysomism of chromosomes 1, 7, 9, 17 and X occurs in most of the TCC cells with aneuploidy. The stability of chromosomes 11 and 15 is closely related to tumor grade and stage. The role of chromosome Y loss and monosomism of chromosome 3 in oncogenic relevant of bladder cancer is still unclear.

Correlation of CD44v5 Expression with Invasiveness and Prognosis in Renal Cell Carcinoma

BACKGROUND AND PURPOSE The expression of specific CD44 isoforms is associated with metastasis and poor prognosis in human malignant tumors. We retrospectively investigated the expression of the CD44 variant isoform v5 (CD44v5) in human renal cell carcinoma (RCC) specimens by immunohistochemistry. METHODS We studied the expression of CD44v5 immunohistochemistry in archival tissue specimens from 72 RCC patients (47 men and 25 women) with a mean age of 60.1 years (range, 30 to 83 years) who underwent resection in our hospital from 1986 to 1996. The patients were divided into non-invasive (pT1, pT2, and pT3a; n = 49) and invasive groups (pT3b, pT3c, and any T with N+; n = 23). Among the 72 patients, 67 were followed for at least 60 months (up to 190 months) after radical nephrectomy. Twenty nine renal specimens, including 15 of normal renal parenchyma and 14 of inflammatory or immune renal diseases, were used as controls. RESULTS All control group tissues expressed CD44v5. CD44v5 expression was detected in 66 of 72 RCC specimens (91.7%). In general, the expression of CD44v5 was higher in the non-invasive group [47/49 (95.9%) vs 19/23 (82.6%), p < 0.05]. Five cases were lost to follow-up. Thirty three of 67 patients (49.3%) died of RCC-related causes during the follow-up period. The CD44v5 non-expression group had a higher mortality rate than the expression group [4/5 (80%) vs 29/62 (46.8%), p < 0.001]. The 5-year and 10-year survival rates were significantly higher in patients with CD44v5 expression than in those without (p < 0.001). CONCLUSIONS This study found that CD44v5 expression was greater in early stage than in advanced stage RCC and was associated with tumor progression and long-term survival. Although the survival analysis showed both tumor stage and CD44v5 expression were significant prognostic factors in RCC, only tumor stage remained an independent factor.

Congenital Seminal Vesicle Cyst Associated with Ipsilateral Renal Agenesis Mimicking Bladder Outlet Obstruction: A Case Report and Review of the Literature

Seminal vesicle cysts combined with genitourinary anomalies are uncommon. We present a 43‐year‐old married man who suffered from difficulty in urination and irritating voiding symptoms for 3 years. The symptoms worsened in the last 6 months. Digital rectal examination revealed a palpable large soft mass behind the prostate. Diagnostic imaging showed a left seminal vesicle cyst with an intravesical protrusion. The ipsilateral kidney and ureter were absent. Transrectal aspiration of the cyst was performed, which improved the clinical genitourinary symptoms. The maximal and mean urinary flow rates increased from 18 to 37 mL/s and from 6 to 16 mL/s, respectively.

Fibrosarcoma of the Kidney:A Case Report and Literature Review

Primary renal sarcomas of the kidney in adults are unusual, accounting for approximately 1% to 3% of all primary renal malignancies. Pathologically, leiomyosarcomas are the most frequent tumors of primary renal sarcomas, and fibrosarcomas of the kidney are rare. We report on a 46-yr-old male admitted to our hospital due to right side renal tumor. He received radical nephrectomy, and the histopathological report revealed primary fibrosarcoma of the right kidney. He received adjuvant radiotherapy with 5000 cGy due to invasion of the retroperitoneal muscle. Multiple organs metastases of lung, liver and bone developed 2 mo after nephrectomy. He died of the disease 6 mo after surgery. Prognoses of fibrosarcomas. Chemotherapy or radiotherapy is not helpful for survival. Herein, we present this case and review the literature.

The Expression of Cyclooxygenase in Transitional Cell Carcinoma Cell Lines: Its Correlation with Tumor Differentiation, Invasiveness and Prostanoids Production

OBJECTIVE To evaluate the isozyme activities of COX-1 and COX-2 in TCC cells and correlate with cellular differentiation and tumor behavior. MATERIAL AND METHODS Various TCC cell lines were characterized through several aspects: (1). to measure the content and the mRNA amount of COX-1 and COX-2, (2). to characterize the proteins of COX-1 and COX-2 by Western immunoblotting, (3). to measure the production of prostaglandin E2 and thromboxane B2 in culture media, and (4). to correlate these parameters with tumor differentiation and invasiveness. RESULTS Seven out of 10 cell lines (70%) had significantly higher COX expression than normal urothelium. Tumors with lower-grade differentiation and less invasiveness had significantly higher content of COX-1 and COX-2 than those tumors with higher-grade differentiation and more invasive behavior (p<0.01). The expression of COX mRNA in TSGH8301, TCC8702 and RT4 were much higher than J82 which has minimal expression of COXs. Similarly, the COX-2 protein was much higher in TSGH8301, TCC8702 and RT4 when compared with J82. TSGH8301, TCC8702, and RT4 had high production of PGE2 and thromboxane B2 in their culture media. Increased secretions of PGE2 and thromboxane B2 were also observed in TCC8701, TCC9101, HT1376, and T24. The production of prostanoids is closely related to cytoplasmic COX expression of tumor cells. CONCLUSIONS The expression of COX-1 and COX-2 is a common phenomenon in TCC cells and closely related to cellular differentiation and tumor invasiveness. The COX-2 inhibitors may play an important role in the control of TCC growth.

Cost-effective homemade specimen retrieval bag for use in laparoscopic surgery: Experience at a single center

BACKGROUND To offer an easily produced and cost-effective specimen retrieval bag that can be used to reduce the cost of laparoscopic surgery. METHODS From January 2005 to October 2009, 135 patients underwent laparoscopic surgery for adrenalectomy or prostatectomy, during which a homemade specimen retrieval bag was used. The retrieval bag was produced from a large sterile surgical glove, 2-0 nylon thread, and 1-0 RB-1 needle Vicryl thread. A purse-string suture at the opening of the bag was made using the nylon thread, and the bottom of the bag was double-tied using the tail of the Vicryl thread. The bag was introduced into the peritoneal cavity via a 12-mm port, and the specimen was enclosed with the use of two laparoscopic instruments. The bag was then extracted by extending the port incisional wound. RESULTS We used a homemade retrieval bag to extract specimens from 110 patients who underwent robot-assisted laparoscopic radical prostatectomy and 25 patients who underwent laparoscopic adrenalectomy. The procedure was performed safely, and no bags were broken. No complications were observed after the operations such as wound infection, ileus, or intestinal adhesion. In our experience, our homemade endobag can be easily used by surgeons to extract specimens from the abdominal cavity. The total cost of hospitalization was also reduced for the patients. CONCLUSION The homemade specimen retrieval bag is cost-effective and useful for the retrieval of intact specimens. It is also easy to make and safe to use.

Combining prostrate-specific antigen and Gleason score increases the diagnostic power of endorectal coil magnetic resonance imaging in prostate cancer pathological stage.

Background: The proper use of endorectal coil MRI (eMRI) images provide detailed information for the real extent of locally prostate cancer invasion and involvement of pelvic lymph nodes. This study evaluated the accuracy of endorectal coil magnetic resonance imaging (eMRI) results, combining the preoperative prostate‐specific antigen (PSA), and the biopsy Gleason score to improve the diagnostic accuracy of prostate cancer (PCa) with organ‐confined disease (OCD) or extracapsular extension (ECE)/seminal vesicle invasion (SVI). Methods: Between 2001 and 2007, 94 PCa patients received eMRI testing during presurgical evaluation and underwent radical prostatectomy. As a part of routine patient workup, serum PSA level and Gleason score after pathology examination were recorded. The eMRI images were used to help assess patient PCa staging status regarding OCD or ECE/SVI. These stage assessments as evaluated through the use of MRI were compared with the final specimen pathological stage after the patients underwent radical prostatectomy. Results: Of the total 94 patients in our study, 65 had stage pT2, 12 had stage pT3a, and 17 had stage pT3b PCa. In patients with clinical stage T2 PCa, the Gleason score significantly improved the discriminative ability of eMRI to successfully predict PCa at the OCD stage. Otherwise, in cases of clinical stage T3 PCa, accurate determination of PSA levels significantly improved eMRI predictive ability to assess ECE or SVI staging. Conclusion: In clinical stage T2 PCa patients, integrating the biopsy Gleason score improved the discriminative ability to assess OCD PCa staging. Additionally, combining the preoperative PSA levels of clinical T3 prostate cancer cases with Gleason scores significantly improved the sensitivity and accuracy of eMRI diagnosis to distinguish ECE from SVI.

The Feasibility of BCG and Sunitinib Combination Therapy for Transitional Cell Carcinoma

Objective Currently, intravesical bacille Calmette-Guerin (BCG) instillation is the standard treatment for patients with an intermediate to high risk of bladder cancer. Nevertheless, BCG-refractory generation is a common process during treatment. We hypothesized that sunitinib, a vascular endothelial growth factor (VEGF) receptor inhibitor, can synergistically enhance the immunotherapeutic effect of BCG on bladder tumor growth. Materials and Methods The 50% inhibitory concentration (IC 50 ) of BCG and sunitinib in various transitional cell carcinoma (TCC) cell lines was determined by the MTT method. The therapeutic effects of BCG, sunitinib, and their combination on MBT-2 tumors were investigated in both orthotopic bladder cancer and subcutaneously inoculated tumor models in mice. Evaluated parameters included the tumor growth rate and tumor burden in the bladder, tumor volume in the subcutaneous site, survival rate, serum cytokine changes, and mean vascular density in tumor tissues. Results BCG and sunitinib showed in vitro cytotoxicity to tested TCC cell lines with slight variations in IC 50 . Sunitinib had an in vitro synergistic effect on BCG cytotoxicity in TCC cells. BCG and sunitinib had individual tumor suppression activities in mice MBT-2 tumors in both the orthotopic and subcutaneous models. Surprisingly, synchronous combination treatment using BCG and sunitinib did not demonstrate synergistic suppression efficacy in animal tumor models. Inhibition of tumor growth, increased survival rate, and decreased mean vascular density were observed in mice treated with BCG, sunitinib, and synchronous cotreatment. In contrast, no therapeutic efficacy was seen in mice treated with BCG and sunitinib metachronously. Conclusions BCG and the VEGF receptor inhibitor sunitinib had significant suppressive effects in mice bladder cancer models when administered individually. The underlying mechanisms by which they counteract cytotoxicity and the interaction of BCG and sunitinib during cotreatment require further investigation.

Synergism of Fas-mediated apoptosis and tumor necrosis factor on adriamycin cytotoxicity to transitional cell carcinoma.

Objective: To explore the accurate Fas antigenic expression in transitional cell carcinoma (TCC) cells and and compare its synergistic modulation on adriamycin cytotoxicity with α-tumor necrosis factor (TNF-α). Methods: The expression of Fas antigen in normal urothelium and TCC cell lines was measured by flow cytometry. The Fas/Fas ligand reaction-induced cytotoxic changes in tumor cells were evaluated by microculture MTT technique. The synergism efficacy of Fas-mediated apoptosis and TNF-α on adriamycin cytotoxicity of TCC cells was analyzed. The Fas/Fas ligand-induced apoptosis in tumor cells was studied by annexin-V apoptotic cell expression and DNA ladder fragmentation analysis. Results: 75% of TCC cell lines showed Fas antigen expression. The Fas expression was not influenced by in vitro growth density of tumor cells. Apoptosis of TCC cells was observed during 48 h of treatment after activation of the Fas/Fas ligand pathway. TNF-α had a higher cytotoxicity activity on TCC cells than Fas ligand (17 vs. 0.7%) while combination of both reagents had 30% increased synergistic cytotoxicity. The increasing rate of apoptotic body after 3 days of treatment was 74% in adriamycin, 32% in Fas ligand, 60% in TNF-α, 69% in Fas and adriamycin combination and Fas and TNF-α combination, 103% in combination of TNF-α and adriamycin, and 136% in combination of these three reagents individually. In the DNA ladder analysis, Fas ligand had a 1.5-fold increase of DNA fragmentation when compared with adriamycin while TNF-α had a 4.4-fold increase and triple combination had a 5.5-fold increase after 3 days of treatment. Conclusions: Although the Fas antigen expression is common in TCC cells and apoptosis can be activated by the Fas/Fas ligand pathway activation, the synergistic cytotoxicity of adriamycin by the Fas/Fas ligand pathway is lower than that of TNF-α.