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Funda Vakar-Lopez

Publications and source records attributed to Funda Vakar-Lopez.

12 recordsLinked to original sources
PubMed2026

Evolution and heterogeneity of lethal metastatic bladder cancer subtypes.

Histological variation is a prognostic feature of metastatic urothelial cancer1-3, but its evolutionary trajectory remains poorly defined. We developed a metastatic bladder cancer rapid autopsy programme enriched in histological subtypes4 to profile individuals with terminal disease. Here by reconstructing the evolutionary histories of patient tumours, we show that metastasis-to-metastasis seeding is the dominant pattern of cancer spread and that increased polyclonal migration predicts poor prognosis. The burden, heterogeneity and timing of genomic alterations differ markedly among histological subtypes. Plasmacytoid and neuroendocrine variants develop early driver alterations associated with shorter survival. Mutational signature analyses and experimental models demonstrated that plasmacytoid tumours uniquely use the Fanconi anaemia pathway to mitigate chemotherapy-induced genomic scarring. Single-nucleus profiling revealed mixed cell states in histological subtypes and an association between transcriptional heterogeneity and patient survival. Characterization of the tumour microenvironment uncovered distinct immune states across subtypes, with plasmacytoid tumours exhibiting immune-inflamed profiles, whereas squamous tumours are predominantly immunosuppressive. Last, we demonstrate that post-mortem cell-free DNA captures genomic and transcriptional heterogeneity of the subtypes, which provides a potential strategy for noninvasive assessment of tumour identity and aggressiveness. Our results provide new insights into how tumour heterogeneity shapes the evolutionary history of disease progression in bladder cancer histological subtypes.

Journal Article↗
PubMed2006

Histological changes in prostate biopsies after salvage cryotherapy: effect of chronology and the method of biopsy.

OBJECTIVES: To examine changes in prostate biopsies at different intervals after salvage cryotherapy and the effect of biopsy type (transrectal ultrasonography-guided vs transurethral resection, TUR), as the sequence and extent of histological changes occurring in the prostate after salvage cryotherapy for local failure of prostate cancer treatment are unknown. PATIENTS AND METHODS: In all, 158 prostate biopsies from 150 patients were examined histologically after salvage cryotherapy for prostate cancer after radiotherapy had failed. Specimens were grouped by time from cryotherapy and biopsy technique. RESULTS: Biopsies showed hyalinization, necrosis, inflammation and residual cancer. Hyalinization became predominant over time, most notably in biopsies with no residual cancer. Core biopsies showed more hyalinization and regenerating glands, while TUR biopsies showed more necrosis and inflammation. CONCLUSIONS: Tissue cryo-injury and reactive changes last for >1 year; more extensive cryo-injury suggests more effective cancer ablation. A long-term follow-up is necessary, as prostate cancer might remain indolent for >1 year.

Analysis of Variance↗
PubMed2006

Primary angiosarcoma of the bladder.

CONTEXT: Primary bladder angiosarcomas are extremely rare, and their clinical and pathologic features are not well described. OBJECTIVE: To further refine the clinical features of primary bladder angiosarcomas and define their pathologic spectra. DATA SOURCES: Relevant sources were identified using MEDLINE and a subsequent bibliographic search of all pertinent reports and reviews. We also searched the M. D. Anderson pathology archives. STUDY SELECTION: After excluding 4 cases that likely secondarily involved the bladder, we identified 9 true primary bladder angiosarcomas. DATA EXTRACTION: Data were extracted on the following: demographics, clinical presentation, predisposing factors, gross pathology, microscopic pathology, immunophenotype, therapy, and outcomes. DATA SYNTHESIS: Primary bladder angiosarcomas were found at a mean age of 64.2 years, with a male-female ratio of 8:1. Two cases arose in a postirradiation setting. Primary bladder angiosarcomas typically presented with hematuria and were grossly hemorrhagic, raised masses (mean size, 6.7 cm) of the trigone and/or dome. Histologically, most showed classic anastomosing channels lined by plump hyperchromatic cells, though many showed variant histology such as solid growth and epithelioid cytology. Three (43%) of 7 patients died within a year, but only 1 patient died with evidence of disease. The remaining patients were alive at the time of publication of their respective cases (mean, 22 months). CONCLUSIONS: Primary angiosarcomas of the bladder are typically rare tumors of middle-aged and elderly men that present with locally advanced disease and show a wide histologic spectrum. However, their prognosis may be better than previously thought.

Age Distribution↗
PubMed2005

Therapy tolerance in selected patients with androgen-independent prostate cancer following strontium-89 combined with chemotherapy.

PURPOSE: Clinicians may have reservations about using strontium-89 for the treatment of bone metastases because of concerns that it may limit future use of chemotherapy. We assessed the rate of bone marrow failure in patients with prostate cancer who had received a dose of strontium-89. PATIENTS AND METHODS: This subgroup analysis involved 34 patients with androgen-independent prostate cancer who had been given a dose of strontium-89 and six weekly doses of doxorubicin after response to induction chemotherapy. We assessed subsequent hematotoxicity in terms of bone marrow failure and the ability to tolerate additional treatments during a median of 25 months (range, 7 to 76 months) after the strontium-89 was administered. RESULTS: No patients developed bone marrow failure within 6 months of receiving strontium-89. Five (15%) of 34 patients developed bone marrow failure at a median 23 months (range, 6 to 53 months) after the strontium-89 treatment. Bone marrow biopsy performed in two of these five patients showed complete replacement of the marrow by tumor. Thirty-one patients (91%) received subsequent cytotoxic treatments at a median 11 months (range, 1 to 33 months) after the strontium-89 treatment. CONCLUSION: This analysis demonstrated that a single dose of strontium-89 combined with chemotherapy did not affect the delivery of subsequent courses of chemotherapy in a select group of patients. However, a majority of these therapies were given off protocol and were administered at a dose schedule that might be considered inappropriate or inadequate. The clinical role and safety profile of radiopharmaceuticals combined with chemotherapy in prostate cancer therapy deserve further exploration.

Aged↗
PubMed2005

Port-site metastasis: the influence of biology.

OBJECTIVE: Several surgical and technical mechanisms have been proposed for the development of port-site metastasis, but the influence of tumor and host biologic factors has not been emphasized. We present a case of a pelvic chordoma that metastasized to a prior laparoscopic radical nephrectomy port-site. METHODS: A 62-year-old woman underwent laparoscopic radical nephrectomy (LRN) for a pT1b grade 3 renal cell carcinoma, followed 6 weeks later by resection of a sacral chordoma. The incisions and areas of dissection for the two procedures were discontinuous. RESULTS: Eight months following the LRN she developed a nodule in one of the laparoscopic port-sites. The port-site metastasis was treated with wide surgical resection, which was confirmed as metastatic chordoma on histologic examination. CONCLUSION: Based on the chronological sequence and physical distance between surgical sites, only biological factors could have contributed to this port-site metastasis. This unusual case highlights the important role that tumor and host biologic mechanisms play in the development of port-site metastasis.

Carcinoma, Renal Cell↗
PubMed2004

Identification of Sp2 as a transcriptional repressor of carcinoembryonic antigen-related cell adhesion molecule 1 in tumorigenesis.

Down-regulation of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) tumor suppressor gene expression is common in several malignancies including prostate, colon, and breast cancer. The mechanism that mediates this down-regulation is not known. Here, we report that down-regulation of CEACAM1 expression in prostate cancer cells occurs primarily at the transcriptional level and is mediated by Sp2, a member of the Sp family of transcription factors. Sp2 binds to the CEACAM1 promoter in vitro and in vivo, and transient overexpression of Sp2 down-regulates endogenous CEACAM1 expression in normal prostate epithelial cells. Sp2 appears to repress CEACAM1 gene expression by recruiting histone deacetylase activity to the CEACAM1 promoter. In human prostate cancer specimens, Sp2 expression is high in prostate cancer cells but low in normal prostate epithelial cells and is inversely correlated with CEACAM1 expression. Our studies show that transcriptional repression by Sp2 represents one mechanism by which CEACAM1 tumor suppressor gene is down-regulated in prostate cancer.

Acetyltransferases↗
PubMed2004

Glycogen synthase kinase-3 beta is involved in the phosphorylation and suppression of androgen receptor activity.

Kinases can phosphorylate and regulate androgen receptor activity during prostate cancer progression. In particular, we showed that glycogen synthase kinase-3 beta phosphorylates the androgen receptor, thereby inhibiting androgen receptor-driven transcription. Conversely, the glycogen synthase kinase-3 beta inhibitor lithium chloride suppressed the glycogen synthase kinase-3 beta-mediated phosphorylation of the androgen receptor, thereby enabling androgen receptor-driven transcription to occur. The androgen receptor hinge and ligand-binding domains were important for both the phosphorylation and the inhibition of transcriptional activity of the receptor by glycogen synthase kinase-3 beta. Furthermore, androgen receptor phosphorylation was augmented by LY294002, an indirect inhibitor of protein kinase B/Akt that inhibits glycogen synthase kinase-3 beta. We also showed that the mutation of various phosphorylation sites on glycogen synthase kinase-3 beta affected the ability of these mutants to co-distribute with the androgen receptor in the cell nucleus, also that both glycogen synthase kinase-3beta and androgen receptor proteins can be found in cell nuclei of prostate cancer tissue samples. Because glycogen synthase kinase-3 beta activity is suppressed after the enzyme is phosphorylated by protein kinase B/Akt and Akt activity frequently increases during the progression of prostate cancer, nullification of the glycogen synthase kinase-3 beta-mediated suppression of androgen receptor activity by Akt likely contributes to prostate cancer progression.

Androgen Receptor Antagonists↗
PubMed2004

Up-regulation of MDA-BF-1, a secreted isoform of ErbB3, in metastatic prostate cancer cells and activated osteoblasts in bone marrow.

Prostate cancer (PCa) has a propensity to metastasize to bone. The identification of molecules that mediate the biological interactions between PCa cells and the bone environment is crucial to the understanding of PCa bone metastasis. The present study has used protein purification to identify bone metastasis-related factors present in bone marrow aspirates from PCa patients with bone metastasis. MDA-BF-1 was the first bone metastasis factor to be identified and is a secreted isoform of the ErbB3 growth factor receptor. To determine which cell types in PCa bone metastases express MDA-BF-1, MDA-BF-1 expression was studied in both primary and metastatic PCa cells, using an antibody to the extracellular domain (Ab10) and another to the cytoplasmic domain (RTJ.2) of ErbB3 to distinguish MDA-BF-1 from p180-ErbB3. It was found that epithelial cells in primary PCa did not express MDA-BF-1. In contrast, epithelial cells in 41 of 45 PCa metastases (18 of 19 lymph node metastases and 23 of 26 bone metastases), and activated osteoblasts in bone metastases, expressed MDA-BF-1. In addition, newly formed bone matrices adjacent to activated osteoblasts were also immunopositive for MDA-BF-1, suggesting that activated osteoblasts secrete MDA-BF-1. These observations indicate that MDA-BF-1 is up-regulated in metastatic PCa and raise the interesting possibility that MDA-BF-1 may play a role in the metastasis and progression of PCa, particularly in bone.

Antibodies↗
PubMed2003

Bcl-2 is significantly overexpressed in localized radio-recurrent prostate carcinoma, compared with localized radio-naive prostate carcinoma.

PURPOSE: We set out to determine whether patients who underwent prostatectomy for recurrence after external-beam radiotherapy for prostate cancer had a higher incidence of alterations in the apoptotic pathway than did patients who underwent surgery as initial treatment. MATERIALS AND METHODS: Twenty patients who underwent unsuccessful full-dose external-beam radiotherapy for prostate cancer and subsequently underwent salvage radical surgery (radio-recurrent group), and 20 patients matched for various clinical parameters who underwent only radical prostatectomy for localized or locally advanced prostate cancer (radio-naive group), were studied. Tissue samples were examined for immunoreactivity for p53, p21, Bcl-2, and Ki-67 proteins. Statistically, the two groups were compared using exact logistic regression. RESULTS: Fifty-five percent of the tumors from patients initially treated with radiotherapy were noted to overexpress Bcl-2; whereas, in the radio-naive group, no patient had Bcl-2 overexpression (p = 0.0004). More patients who underwent salvage radical surgery were found to have a higher mean proliferative index (Ki-67 staining) (39.6%), compared with patients undergoing prostatectomy alone (22.1%), p = 0.0800. No significant difference was noted in immunohistochemical expression of p53 and p21 between the two groups. CONCLUSIONS: Patients undergoing radical prostatectomy after radiotherapy had a significantly higher rate of Bcl-2 overexpression than did patients who underwent surgery as the initial treatment. Alterations in the apoptotic pathway may be important in the development of local recurrence after radiation therapy.

Adenocarcinoma↗
PubMed2002

Amplification/overexpression of a mitotic kinase gene in human bladder cancer.

BACKGROUND: The mitotic kinase-encoding gene STK15/BTAK/ AuroraA is associated with aneuploidy and transformation when overexpressed in mammalian cells. STK15 overexpression activates an unknown oncogenic pathway that involves centrosome amplification and results in missegregation of chromosomes. Because clinical prognosis and tumor aneuploidy are tightly linked in human bladder cancer, we examined whether increased STK15 copy number and protein levels are linked to aneuploidy in bladder cancers. METHODS: STK15 protein was visualized by immunohistochemistry in 205 formalin-fixed, paraffin-embedded human bladder tumors. STK15 gene copy number was evaluated in 61 tumors by Southern blot hybridization and in 21 of these 61 tumors by fluorescence in situ hybridization (FISH). Copy numbers of chromosomes 3, 17, 20, and 21 were evaluated by FISH with chromosome-specific probes. STK15 expression levels were related to histologic grade, stage, and DNA ploidy of the tumors and to the patients' follow-up data. The chi-square test for association was used to analyze the relationship between STK15 expression and pathologic features. All statistical tests were two-sided. RESULTS: Tumors with low levels of STK15 amplification (3-4 copies) showed minimal deviation in their chromosome copy number and diploid or near-diploid total nuclear DNA content. Tumors with higher levels of STK15 amplification (>4 copies) had a major increase of chromosome copy number and of their total nuclear DNA content, i.e., exhibited pronounced aneuploidy. Elevated expression of STK15 was strongly associated with parameters of clinical aggressiveness including high histologic grade (P<.001), invasion (P<.001), increased rate of metastasis (P<.001), and decreased metastasis-free (P<.001) and overall (P<.001) survival of patients with bladder cancer. CONCLUSION: STK15 gene amplification and associated increased expression of the mitotic kinase it encodes are associated with aneuploidy and aggressive clinical behavior in human bladder cancer.

Adult↗
PubMed2002

Predictors of cancer in repeat extended multisite prostate biopsy in men with previous negative extended multisite biopsy.

OBJECTIVES: To evaluate the factors influencing the cancer detection rate in men whose initial and repeat biopsies were both performed using an extended multisite biopsy scheme. Sextant biopsy of the prostate is associated with a significant false-negative rate, as evident from the high cancer detection rate after repeat prostate biopsy. Extended multisite biopsy schemes have therefore been recommended to maximize cancer detection. METHODS: Between June 1997 and August 2001, 939 men underwent prostate biopsy for early detection of prostate cancer using the extended multisite scheme (10 or 11 cores incorporating the anterior horn of the peripheral zone with or without midline peripheral zone and/or the transition zone). Of these 939 men, 89 (9.5%) underwent a repeat extended multisite prostate biopsy. The median prostate-specific antigen level was 6.9 ng/mL (range 0.7-36.1). Twenty-four men (27%) had an abnormal digital rectal examination at presentation. Most men (86%) in the group undergoing repeat biopsy had two or more risk factors for a positive biopsy. The median interval between biopsies was 4 months. RESULTS: Of the 89 men, 15 (17%) had prostate cancer in the repeat biopsy specimen. Seven cancers (47%) were found only in the alternate biopsy sites, 5 (33%) cancers were found only in the sextant sites, and 3 in both sextant and alternate sites. Cancer was present in only one biopsy core in 11 (73%) of the 15 men, and the median Gleason score was 6 (range 6-8). On multivariate analysis, the presence of atypical glands suspicious for carcinoma (AGSC) was the only independent predictor of cancer in repeat biopsy (P <0.004). Of the 79 men without AGSC in the initial biopsy, 8 (10%) had a positive repeat biopsy. The total and percent free prostate-specific antigen level, digital rectal examination, ultrasound findings, and presence of high-grade prostatic intraepithelial neoplasia were not predictive of cancer detection. CONCLUSIONS: The probability of a positive result for a repeat prostate biopsy is lower after an initial extended multisite biopsy compared with an initial sextant biopsy. The presence of AGSC was the only significant predictor of cancer in the repeat biopsy. Because nearly 50% of cancers detected in the repeat biopsy were in alternate sites only, using a sextant biopsy scheme for repeat biopsy would have missed these cancers.

Adult↗