Transitional Carcinoma Research Articles

Single-fraction radiosurgery for the treatment of renal tumors in singular renal units.

368 Background: High-dose local radiation treatment (stereotactic radiosurgery [SRS]) was added for selected patients to improve local control and overall survival in metastases. We report on toxicity and local tumor control in patients with renal tumors who were treated with aggressive local irradiation using a single fraction SRS with the Cyberknife in singular renal units to avoid hemodialysis. Methods: n=18 patients with renal tumors and an eastern cooperative oncology group (ECOG) status of 0 or 1 were treated with SRS. Patients with surgically removable renal lesions were not included. Prior to SRS gold markers were planted into the renal parenchyma under ultrasonographic guidance. Results: Nine patients had transitional carcinoma of the renal pelvis, six patients had renal cell carcinoma and three had other tumor entities. No skin toxicity occurred after SRS, and SRS did not induce other side effects. Local tumor control 9 months after SRS was 98% (95% CI: 89-99%). There were no treatment related deaths, and late complications after SRS were not noted so far. Renal function so far remained stable without a change in serum creatinine. Conclusions: SRS for selected patients with renal tumors is safe and effective. Single-fraction delivery as an outpatient procedure allows for convenient integration of SRS into various oncological treatment concepts. Further studies are needed to determine the limits of SRS in this setting. No significant financial relationships to disclose.

Cutaneous metastasis of transitional cell bladder carcinoma: A rare presentation and literature review

Cutaneous metastasis from transitional cell bladder carcinoma is a rare clinical entity associated with poor prognosis. We present a case of cutaneous metastasis arising from a transitional cell bladder carcinoma in a male patient who had undergone a radical cystectomy and bilateral ureterostomy 17 months previously. The cutaneous metastasis became evident 3 months before the manifestations of generalized recurrent disease. An awareness of this rare clinical entity and high index of suspicion is needed to rule out metastatic spread in patients with a previous history of transitional cell bladder carcinoma presenting with cutaneous nodules. Definitive diagnosis requires a histological confirmation, but prognosis is generally poor.

Nuclear Matrix Protein-22 and Telomerase Reverse Transcriptase Are Diagnostic Markers for Bladder Carcinoma in Egypt

Bladder carcinoma is the foremost oncologic problem among males in Egypt. Here, we evaluated the possible diagnostic value of the urinary Nuclear Matrix Protein-22 “NMP-22” and Telomerase Reverse Transcriptase “hTERT” among histological subtypes of bladder cancer. 120 males with non-muscle invasive bladder cancer, 21 non malignant bladder conditions and 21 healthy volunteers were included in this study. Estimation of hTERT and NMP-22 was done by PCR-ELISA and ELISA, respectively, from voided urine and results were compared to those of urine cytology. Results showed that urinary hTERT and NMP-22 were significantly higher in all cancer patients compared to control group. NMP-22 was able to discriminate between transitional cell bladder carcinoma “TCC” patients and squamous cell bladder carcinoma “SqCC” ones. Both markers succeded to discriminate between some transitional cell bladder carcinoma grades. Additionally, hTERT discriminated between some Tumor stages in both TCC and SqCC. Our results demonstrated that urinary hTERT and NMP-22 could be efficient urinary markers for the differential diagnosis of bladder cancer.

Gallic acid induces G2/M phase cell cycle arrest via regulating 14‐3‐3β release from Cdc25C and Chk2 activation in human bladder transitional carcinoma cells

Cell cycle regulation is a critical issue in cancer treatment. Previously, gallic acid (GA) has been reported to possess anticancer ability. Here, we have evaluated the molecular mechanism of GA on cell cycle modulation in a human bladder transitional carcinoma cell line (TSGH-8301 cell). Using flow cytometer analysis, exposure of the cells to 40 μM GA resulted in a statistically significant increase in G2/M phase cells, which was accompanied by a decrease in G0/G1 phase cells. GA-treated cells resulted in significant growth inhibition in a dose-dependent manner accompanied by a decrease in cyclin-dependent kinases (Cdk1), Cyclin B1, and Cdc25C, but significant increases in p-cdc2 (Tyr-15) and Cip1/p21 by western blotting. Additional mechanistic studies showed that GA induces phosphorylation of Cdc25C at Ser-216. This mechanism leads to its translocation from the nucleus to the cytoplasm resulting in an increased binding with 14-3-3β. When treated with GA, phosphorylated Cdc25C can be activated by ataxia telangiectasia-mutated checkpoint kinase 2 (Chk2). This might be a DNA damage response as indicated by Ser-139 phosphorylation of histine H2A.X. Furthermore, treatment of the cells with a Chk2 inhibitor significantly attenuated GA-induced G2/M phase arrest. These results indicate that GA can induce cell cycle arrest at G2/M phase via Chk2-mediated phosphorylation of Cdc25C in a bladder transitional carcinoma cell line.

Primary squamous carcinoma of the ovary likely arising from a monodermal cystic mucinous teratoma

We present a 58-year-old woman with primary squamous carcinoma of the ovary likely arising from a monodermal cystic mucinous teratoma. Noninvolved ovary showed no Brenner tumor, endometriosis, transitional carcinoma, endometrioid adenocarcinoma, or typical multigerm layer classic mature teratoma. Moreover, no other primary site was possible because there were no prior or concomitant squamous carcinomas, or history of cervical intraepithelial neoplasia. The tumor showed strong positivity for p63 and CK5/6, reactivity that also extended from the squamous carcinoma into the basal-cell lining of the mucinous cyst of a likely monodermal teratoma. This basal-cell pattern was absent in a series of conventional benign and borderline cystic mucinous cystadenomas of the ovary, but clearly present in the mucinous cysts part of mature teratomas. We present this as a unique case of squamous carcinoma likely arising from a monodermal cystic mucinous teratoma. Moreover, we submit that the p63 and CK5/6 staining pattern may help to differentiate monodermal cystic mucinous teratoma from conventional cystic mucinous tumors.

Neuroendocrine Small-Cell Bladder Cancer: Our Experience

Introduction Neuroendocrine bladder cancer is extremely rare, with an estimated incidence of 0.35–0.70% of all bladder tumors. The small-cell carcinoma represents the most frequent histologic variant described. Small-cell carcinoma is an epithelial tumor associated with a more aggressive behavior and poorer prognosis than transitional cell bladder carcinoma. The overall survival rate at 5 years does not exceed 8%. At the time of presentation 59% of patients have clinical stage >T2 and 56% show metastatic disease. In 50% of the patients, fatal progression occurrs within 6 months. Local recurrence after radical surgery occurred in 50–70% of cases. Patients and Methods We report three cases of pure neuroendocrine small-cell bladder cancer. Hematuria was the most common presenting symptom. Local advanced disease was present in all the cases with stage >T2, metastatic disease in 1 case, lymph node involvement and ureteral bilateral obstruction in 2. Two patients were treated by radical cystectomy, bilateral pelvic limph node resections and urinary derivation. Platinum-based adjuvant chemotherapy was proposed but only two patients received the treatment. One patient with liver metastasis was managed only by extensive TUR and support regimen. Results In 2 patients residual or relapsed cancer reappered within 2 months after surgery. All of the three patients died of metastatic disease at 5, 7, and 13 months. Median overall survival was 7 months. The most common site of relapse and spread of disease was the peritoneum and intestinal tract, and the reason of death was uncontrolled acute hemorrhage from gastro-intestinal district. Conclusions In the absence of a prospective study, and because of the rarity of the disease, the best treatment for small-cell bladder cancer remains uncertain. Neoadjuvant chemoterapy with platinum regimen plus aggressive surgical approach will be the treatment of choice. The association of chemotherapy and radiotherapy should also be considered.

S148 ENDOSCOPIC URETERECTOMY DURING NEPHROURETERECTOMY FOR UPPER URINARY TRACT TRANSITIONAL CELL CARCINOMA

Introduction: Radical nephroureterectomy with resection of a bladder cuff remains the “gold standard” in the treatment of upper urinary tract transitional cell tumors. McDonald is the first to describe a ureteral stripping technique with subsequent endoscopic resection of the bladder cuff around the ureteral orifice during nephroureterectomy, which is called transurethral endoscopic ureterectomy and is a less invasive alternative of open surgical ureterectomy in patients with transitional cell renal pelvic carcinoma. Objective: To evaluate the clinical outcome of transurethral endoscopic ureterectomy during nephroureterectomy for transitional cell carcinoma of the renal pelvis and calyces.

Intractable haematuria: long‐term results after selective embolization of the internal iliac arteries

Study Type – Therapy (case series) Level of Evidence 4OBJECTIVETo determine the feasibility and efficacy of transarterial embolization (TAE) in haemorrhagic urological emergencies, and to assess the perioperative morbidity, effect of timing of intervention on the requirement for blood transfusion, and the long‐term follow‐up.PATIENTS AND METHODSBetween October 1997 and March 2009, 44 patients (30 men and 14 women; mean age 79 years, range 51–95) with intractable haematuria secondary to advanced pelvic tumour arising from or invading the bladder, underwent internal iliac TAE. Twenty‐four patients had transitional carcinoma of the urinary bladder, 12 adenocarcinoma of the prostate, five carcinoma of the uterus, one cancer of the vagina, two carcinoma of the rectum, three carcinoma of the kidney, two simultaneous carcinoma of prostate and bladder, one simultaneous carcinoma of prostate and kidney and one had haemorrhagic cystitis after radiotherapy.RESULTSTAE of the internal iliac arteries produced initial complete control of bleeding in 36 of the 44 patients (82%). At a mean (range) follow‐up of 10.5 (1–97) months TAE there was permanent control of bleeding in 19 (43%) patients. A second TAE session was use in five (11%) patients and it was successful in two of them. There were 24 patients (55%) who required a mean of 4 (1–17) transfusion units before embolization; only 13 (30%) required more blood products after TAE. The mean haematocrit level before and after TAE was 27% and 31% (P < 0001), and the respective haemoglobin level were 8.7 and 10.3 g/dL (P < 0001). During the follow‐up there were no major complications related to TAE; minor complications were post‐TAE syndrome in 12 (27%) patients, fever (11%), gluteus pain (14%), nausea (2%), and exterior genital oedema (5%). The 6‐ and 12‐month mortality rates were 66% (29 patients) and 18% (eight), respectively.CONCLUSIONSTAE should be considered as an alternative less‐invasive palliative measure and the treatment of choice in these situations. TAE should always be bilateral, the catheter should advance distally to the origin of the superior gluteal artery and the artery embolized with unresorbable particles. Our study confirms the efficacy and safety of TAE in patients with pelvic malignancy, and indicates that this technique should be considered before surgery. The procedure combines the benefits of a minimally invasive approach in decreasing the cost of surgery and operating time, while maintaining low blood loss and analgesia requirement.

Voided Urine Fluorescence In Situ Hybridization Testing for Upper Tract Urothelial Carcinoma Surveillance

Fluorescence in situ hybridization is gaining popularity for transitional cell carcinoma screening. We determined the accuracy of fluorescence in situ hybridization for identifying upper tract transitional cell carcinoma. A retrospective review of our upper tract transitional cell carcinoma database from 2005 to 2008 identified 35 patients with upper tract transitional cell carcinoma who submitted voided urine specimens for fluorescence in situ hybridization at commercial laboratory during a routine office visit. Each patient was evaluated endoscopically in the operating room within 3 months of sampling. Suspicious lesions were biopsied and treated. Transitional cell carcinoma in the lower or upper tract was proved by direct visualization, positive biopsy or upper tract cytology read as positive or highly suspicious for malignancy. Of the patients 35 satisfied study inclusion criteria. A total of 67 fluorescence in situ hybridization specimens were submitted. Upper tract transitional cell carcinoma was identified on 51 operative evaluations, of which 23 showed concurrent bladder tumor. For all encounters the sensitivity of fluorescence in situ hybridization was 56% and specificity was 80%. Sensitivity for low and high grade lesions was 68% and 67%, respectively. Only upper tract tumors were noted in 28 patients, in whom there were 2 false-positive and 13 false-negative voided fluorescence in situ hybridization results. In these cases sensitivity was 54% and specificity was 78% compared to the 18% sensitivity and 100% specificity of bladder cytology. Sensitivity for low and high grade upper tract transitional cell carcinoma was 60% and 50%, respectively. Voided fluorescence in situ hybridization has become an adjunct for bladder transitional cell carcinoma surveillance. However, it has limited value for upper tract tumor surveillance.

Clear Cell Carcinoma of the Bladder in a Patient With a Earlier Clear Cell Renal Cell Carcinoma

Clear cell transitional carcinoma of the bladder is a subtype of transitional carcinoma that morphologically resembles a clear cell renal cell carcinoma. Although kidney tumors do not frequently metastasize to the bladder, the recurrence after a clear cell renal cell carcinoma has been reported even several years after nephrectomy. We report the case of a male patient to whom radical nephrectomy for a clear cell renal cell carcinoma has been done, with a bladder tumor featuring polygonal cells with abundant clear cytoplasm deeply infiltrating the vesical wall. We discuss the morphologic features, the immunohistochemical staining with a new marker and the UroVysion FISH analysis to achieve a definitive diagnosis.

Cell cycle arrest and apoptosis in TP53 subtypes of bladder carcinoma cell lines treated with cisplatin and gemcitabine

Currently, the combination of cisplatin and gemcitabine is considered a standard chemotherapeutic protocol for bladder cancer. However, the mechanism by which these drugs act on tumor cells is not completely understood. The aim of the present study was to investigate the effects of these two antineoplastic drugs on the apoptotic index and cell cycle kinetics of urinary bladder transitional carcinoma cell lines with wild-type or mutant TP53 (RT4: wild type for TP53; 5637 and T24: mutated TP53). Cytotoxicity, cell survival assays, clonogenic survival assays and flow cytometric analyses for cell cycle kinetics and apoptosis detection were performed with three cell lines treated with different concentrations of cisplatin and gemcitabine. G(1) cell cycle arrest was observed in the three cell lines after treatment with gemcitabine and gemcitabine plus cisplatin. A significant increase in cell death was also detected in all cell lines treated with cisplatin or gemcitabine. Lower survival rates occurred with the combined drug protocol independent of TP53 status. TP53-wild type cells (RT4) were more sensitive to apoptosis than were mutated TP53 cells when treated with cisplatin or gemcitabine. Concurrent treatment with cisplatin and gemcitabine was more effective on transitional carcinoma cell lines than either drug alone; the drug combination led to a decreased cell survival that was independent of TP53 status. Therefore, the synergy between low concentrations of cisplatin and gemcitabine may have clinical relevance, as high concentrations of each individual drug are toxic to whole organisms.

435 LOXL2 as a new marker of basal-like phenotype in breast cancer

The aim of the present study was to investigate the biological and molecular basis of intraepithelial spreading (IES) of carcinomas in situ (CIS) of the urinary bladder, which were considered to be precursors of nodular invasive carcinomas.The propensity for IES of human transitional carcinoma cells was examined by inoculation into murine renal pelvis and urinary bladder, and the biological character of the cells with a high propensity for IES was explored in vitro.Three of 6 cell lines exhibited a high propensity for IES. When cultured on laminin, these IES cells scattered, whereas 3 non-IES cells and 2 immortalized transitional epithelial cells did not. IES cells showed strong adhesiveness, haptotaxis and enhanced migration on laminin compared with both non-IES and immortalized transitional epithelial cells. In IES cells, expression of the integrin beta4 subunit was markedly reduced and the integrin alpha6 beta1 complex was predominant compared with the integrin alpha6 beta4 complex. Transfection of IES cells with integrin beta4 subunit cDNA inhibited their ability to migrate on laminin and their propensity for IES. In addition, expression of the integrin beta4 subunit was reduced in surgically resected specimens of CIS of the urinary bladder.The results indicate that a reduction in integrin beta4 plays a role in IES of CIS of the urinary bladder through enhanced migration on laminin.

Antitumor effects of recombinant human Interleukin-6 on mouse bladder carcinoma through Fas-mediated apoptosis

An apoptosis-inducing therapy is gradually becoming a new strategy for cancer treatment. The aim of this study was to investigate the mechanism of growth-inhibitory effects of recombinant human interleukin-6 (rhIL-6) on bladder tumor-bearing T739 mice in vivo. Murine bladder transitional carcinoma cells (BTT739) were inoculated subcutaneously into T739 mice as a tumor model for evaluating the antitumor effects of rhIL-6. Then the mice were divided randomly into 5 groups: A, B, C, D and E. Different doses (0, 2, 4, 8 x 10(6) IU/kg body weight) of rhIL-6 were injected intraperitoneally twice per day and administered for 14 days, and 1 mg/kg/d mitomycin-C(MMC) was used as control. Tumor size was measured and determined as the mean of the largest diameter and the diameter at right angle. Animals were killed by CO(2) inhalation on the 15th day after tumor cell inoculation. Then, tumors were removed, weighed and collected. The tumor growth inhibition rate of rhIL-6 was calculated. The morphological characteristic changes of tumor cells were observed under electron microscope, and cell cycle analysis was determined by flow cytometry. The expressions of Fas, FasL and Bcl-2 protein on tumor cells were qualitatively detected by immunofluorescence cell staining, and their relative contents (rate of positive cells, RPC) were quantitatively determined with flow cytometry. rhIL-6 could inhibit bladder tumor growth in a dose-dependent manner in vivo. The tumor growth-inhibitory rates of 2, 4, 8 x 10(6) IU/kg rhIL-6 and 1 mg/kg MMC were 11.8, 39.5, 39.7 and 68.8%, respectively. Flow cytometry results showed that a hypodiploid peak before G1 phase could be found in tumor cells treated with rhIL-6. Moreover, the cells treated with rhIL-6 displayed disappearance of nucleoli, chromatin gathering under the nuclear membrane in mass or ring-shape under transmission electron microscopy. The rates of Fas, FasL protein-positive cells estimated by flow cytometry in rhIL-6-treated mice were (12.57 +/- 0.83) and (20.1 +/- 0.87) %, respectively, significantly higher than that (4.66 +/- 0.17) and (14.1 +/- 0.83) % in control mice (P < 0.01). There was no significant difference in the rate of Bcl-2 protein-positive cells between the mice in these two groups (P > 0.05). rhIL-6 had obvious antitumor effects on mouse bladder carcinoma in vivo, and the Fas signaling pathway might play an important role in rhIL-6-induced bladder carcinoma cell apoptosis.

Gli2 Expression and Human Bladder Transitional Carcinoma Cell Invasiveness

Hedgehog signaling regulates Gli transcription factors. Aberrant hedgehog signaling can be oncogenic and drugs that block hedgehog are being tested as anticancer agents. We considered whether hedgehog/Gli signaling may be involved in human bladder transitional cell carcinoma proliferative or invasive behavior. We stratified the human bladder transitional cell carcinoma lines RT4 (ATCC), 253JP, 253BV, UMUC6 and UMUC3 for relative growth rate by cell counting and for in vitro invasiveness by Matrigel invasion assay. Cells were tested for growth inhibition by the hedgehog blocking drug cyclopamine or the inactive mimic tomatidine. Cell RNA was characterized for hedgehog signaling component expression, including ligands, receptors and signaling mediators, by quantitative reverse transcriptase-polymerase chain reaction. Gli2 expression or activity was modified by Gli2 expression lentiviruses or the Gli inhibitor GANT61. We measured effects on proliferation and invasiveness. Cell growth rates and invasiveness were stratified into an equivalent order (RT4 <243JP <253BV <UMUC6 <UMUC3). All cells were weakly growth inhibited by tomatidine and cyclopamine. Gli2 was the only hedgehog signaling molecule of which expression correlated with stratification. Manipulation of Gli2 expression or activity significantly affected cell invasiveness. Weak growth suppression by cyclopamine suggests that hedgehog signaling is not involved in bladder cancer cell proliferation but Gli2 expression strongly correlated with invasive behavior. Increased Gli2 expression increased low Gli2 cell invasiveness while Gli inhibition by GANT61 decreased high Gli2 cell invasiveness. Results suggest that Gli2 expression by noncanonical signaling contributes to bladder cancer cell invasiveness.

Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

The Role of Tumor-Free Status in Repeat Resection Before Intravesical Bacillus Calmette-Guerin for High Grade Ta, T1 and CIS Bladder Cancer

We evaluated the outcome of repeat transurethral bladder tumor resection for high risk nonmuscle invasive bladder cancer before induction and maintenance bacillus Calmette-Guerin. Included in the study were 151 consecutive patients with a mean age of 68.6 years (range 32 to 86) with primary high grade, nonmuscle invasive (Ta, T1 or CIS) bladder cancer. All patients underwent repeat transurethral bladder tumor resection and were shown by repeat resection to be tumor-free or have residual tumor before bacillus Calmette-Guerin. The bacillus Calmette-Guerin response was evaluated by disease recurrence and progression. A total of 70 tumor-free patients and 47 with residual tumor received bacillus Calmette-Guerin induction and maintenance therapy after repeat transurethral bladder tumor resection, of whom 84 (71.8%) were disease-free during followup. In the tumor-free group 11.4% of tumors recurred compared with 27.7% in the residual tumor group (p <0.05). Progression was noted in 5.7% of tumor-free cases vs 17.0% of residual tumor cases (p <0.05). Time to recurrence was significantly less in the residual tumor group than in the tumor-free group (17.8 vs 23.9 months, p <0.001). Tumor-free status at repeat transurethral bladder tumor resection improves the bacillus Calmette-Guerin response rate and delays tumor recurrence. During followup recurrence in residual tumor-free patients develop more likely as low grade lesions than in patients with residual tumor at repeat transurethral bladder tumor resection.

1283 COULD WE IMPROVE THE BIOPSY QUALITY OF THE UPPER URINARY TRACT TRANSITIONAL CARCINOMA (UUT-TCC)? (EVALUATION OF A NEW BIOPSY FORCEPS)

You have accessJournal of UrologyTechnology & Instruments: Ureteroscopy1 Apr 20101283 COULD WE IMPROVE THE BIOPSY QUALITY OF THE UPPER URINARY TRACT TRANSITIONAL CARCINOMA (UUT-TCC)? (EVALUATION OF A NEW BIOPSY FORCEPS) Saeed Al-Qahtani, Dorian Legraverand, Sixtina Gil-Diez de Medina, Mathilde Sibony, and Olivir Traxer Saeed Al-QahtaniSaeed Al-Qahtani More articles by this author , Dorian LegraverandDorian Legraverand More articles by this author , Sixtina Gil-Diez de MedinaSixtina Gil-Diez de Medina More articles by this author , Mathilde SibonyMathilde Sibony More articles by this author , and Olivir TraxerOlivir Traxer More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2010.02.854AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES We aim to evaluate the biopsy quality for the upper tract urothelial tumors using new biopsy forceps (Bigopsy cook Medical) in comparing with classic biopsy forceps (Piranha Boston Scientific). METHODS 15 patients with upper tract urothelial tumors were been treated by conservative treatment using Flexible-Ureterorenoscopy. The histopathology specimens had been obtained by the (Piranha Boston Scientific) and by the (Bigopsy Cook Medical). All the specimens were been analyzed blindly by a single pathologist to determine the best specimen for each patient. RESULTS From our date the tumor location was found to be in renal pelvis(8), renal pelvis and upper calyx(2), middle calyx(1), lower and middle calyx(1), lower and upper calyx(1), upper third ureter (1), middle third ureter (1). One patient with no valid biopsies whether obtained by the classic or the new forceps. Among those 14 patients, all of the histopathology results of the biopsies performed by the (Bigopsy cook Medical) were better in 9 patients (60%) or equal in 5 patients (33.3%) comparing to the (Piranha Boston Scientific) especially for the stage of the tumor. CONCLUSIONS Our study demonstrates the advantage of this new forceps (Bigopsy Cook Medical) and we strongly recommend it for the evaluation of the (UUT-TCC) especially in case of conservative treatment. Paris, France© 2010 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 183Issue 4SApril 2010Page: e497 Advertisement Copyright & Permissions© 2010 by American Urological Association Education and Research, Inc.MetricsAuthor Information Saeed Al-Qahtani More articles by this author Dorian Legraverand More articles by this author Sixtina Gil-Diez de Medina More articles by this author Mathilde Sibony More articles by this author Olivir Traxer More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

The Origin and Pathogenesis of Epithelial Ovarian Cancer: A Proposed Unifying Theory

Ovarian cancer is the most lethal gynecologic malignancy. Efforts at early detection and new therapeutic approaches to reduce mortality have been largely unsuccessful, because the origin and pathogenesis of epithelial ovarian cancer are poorly understood. Despite numerous studies that have carefully scrutinized the ovaries for precursor lesions, none have been found. This has led to the proposal that ovarian cancer develops de novo. Studies have shown that epithelial ovarian cancer is not a single disease but is composed of a diverse group of tumors that can be classified based on distinctive morphologic and molecular genetic features. One group of tumors, designated type I, is composed of low-grade serous, low-grade endometrioid, clear cell, mucinous and transitional (Brenner) carcinomas. These tumors generally behave in an indolent fashion, are confined to the ovary at presentation and, as a group, are relatively genetically stable. They lack mutations of TP53, but each histologic type exhibits a distinctive molecular genetic profile. Moreover, the carcinomas exhibit a shared lineage with the corresponding benign cystic neoplasm, often through an intermediate (borderline tumor) step, supporting the morphologic continuum of tumor progression. In contrast, another group of tumors, designated type II, is highly aggressive, evolves rapidly and almost always presents in advanced stage. Type II tumors include conventional high-grade serous carcinoma, undifferentiated carcinoma, and malignant mixed mesodermal tumors (carcinosarcoma). They displayTP53 mutations in over 80% of cases and rarely harbor the mutations that are found in the type I tumors. Recent studies have also provided cogent evidence that what have been traditionally thought to be primary ovarian tumors actually originate in other pelvic organs and involve the ovary secondarily. Thus, it has been proposed that serous tumors arise from the implantation of epithelium (benign or malignant) from the fallopian tube. Endometrioid and clear cell tumors have been associated with endometriosis that is regarded as the precursor of these tumors. As it is generally accepted that endometriosis develops from endometrial tissue by retrograde menstruation, it is reasonable to assume that the endometrium is the source of these ovarian neoplasms. Finally, preliminary data suggest that mucinous and transitional (Brenner) tumors arise from transitional-type epithelial nests at the tubal-mesothelial junction by a process of metaplasia. Appreciation of these new concepts will allow for a more rationale approach to screening, treatment, and prevention that potentially can have a significant impact on reducing the mortality of this devastating disease.

Hypofractionated Whole-Brain Radiotherapy for Multiple Brain Metastases From Transitional Cell Carcinoma of the Bladder

Brain metastases in bladder cancer patients are extremely rare. Most patients with multiple lesions receive longer-course whole-brain radiotherapy (WBRT) with 10 × 3 Gy/2 weeks or 20 × 2 Gy/4 weeks. Because its radiosensitivity is relatively low, metastases from bladder cancer may be treated better with hypofractionated radiotherapy. This study compared short-course hypofractionated WBRT (5 × 4 Gy/1 week) to longer-course WBRT. Data for 33 patients receiving WBRT alone for multiple brain metastases from transitional cell bladder carcinoma were retrospectively analyzed. Short-course WBRT with 5 × 4 Gy (n = 12 patients) was compared to longer-course WBRT with 10 × 3 Gy/20 × 2 Gy (n = 21 patients) for overall survival (OS) and local (intracerebral) control (LC). Five additional potential prognostic factors were investigated: age, gender, Karnofsky performance score (KPS), number of brain metastases, and extracranial metastases. The Bonferroni correction for multiple tests was used to adjust the p values derived from the multivariate analysis. p values of <0.025 were considered significant. At 6 months, OS was 42% after 5 × 4 Gy and 24% after 10 × 3/20 × 2 Gy (p = 0.31). On univariate analysis, improved OS was associated with less than four brain metastases (p = 0.021) and almost associated with a lack of extracranial metastases (p = 0.057). On multivariate analysis, both factors were not significant. At 6 months, LC was 83% after 5 × 4 Gy and 27% after 10 × 3/20 × 2 Gy (p = 0.035). Improved LC was almost associated with a KPS of ≥70 (p = 0.051). On multivariate analysis, WBRT regimen was almost significant (p = 0.036). KPS showed a trend (p = 0.07). Short-course WBRT with 5 × 4 Gy should be seriously considered for most patients with multiple brain metastases from bladder cancer, as it resulted in improved LC.

Androgen Receptor Is a Potential Therapeutic Target for Bladder Cancer

To investigate whether androgen receptor (AR) could serve as a potential molecular target for the treatment of bladder cancer. Cell proliferation, apoptosis, and migration capacity were determined in human transitional carcinoma cell lines T24 and 253-J treated with small interfering RNA directed against AR, and expression levels of growth- and metastasis-related genes were assessed using quantitative reverse transcriptase-polymerase chain reaction. Tumor cell growth and apoptosis were also evaluated in vivo in T24 tumor-bearing nude mice receiving electroporation-assisted administration of anti-AR small interfering RNA. AR expression knockdown produced increased apoptosis, decreased proliferation, and migration of bladder cancer cells. Cyclin D1, Bcl-x(L), and matrix metallopeptidase-9 gene expression were also reduced with AR knockdown, which might have contributed to the altered biological behavior of cancer cells. In vivo experiments showed that silencing AR expression, by interference aided by electroporation, significantly suppressed AR-positive bladder tumor growth with decreased cell proliferation and increased apoptotic rates. Downregulation of AR expression inhibits bladder cancer cell growth in vitro and in vivo, implying that its use might be a potential therapeutic target for the treatment of bladder cancer.