The negative binomial-beta Weibull regression model to predict the cure of prostate cancer

In this article, for the first time, we propose the negative binomial-beta Weibull (BW) regression model for studying the recurrence of prostate cancer and to predict the cure fraction for patients with clinically localized prostate cancer treated by open radical prostatectomy. The cure model considers that a fraction of the survivors are cured of the disease. The survival function for the population of patients can be modeled by a cure parametric model using the BW distribution. We derive an explicit expansion for the moments of the recurrence time distribution for the uncured individuals. The proposed distribution can be used to model survival data when the hazard rate function is increasing, decreasing, unimodal and bathtub shaped. Another advantage is that the proposed model includes as special sub-models some of the well-known cure rate models discussed in the literature. We derive the appropriate matrices for assessing local influence on the parameter estimates under different perturbation schemes. We analyze a real data set for localized prostate cancer patients after open radical prostatectomy.

Cyclosporin A causes impairment of the ventral prostate tissue structure of Wistar rats

Cyclosporin A (CsA) is an immunosuppressive drug widely used in medicine to reduce the immune system activity and, therefore, the risk of organ rejection after transplantation. However, many side effects can be related to its use, such as, reduction in serum testosterone levels due to damage of the testis structure and, consequently, male infertility. The present study aims to evaluate the effects of chronic CsA administration on the ventral prostate tissue ( 1 5 mg/kg per d, for 56 days). Stereological, morphometrical, morphological and ultrastructural observations were employed. The plasmatic testosterone and glucose levels were measured. An androgen receptor (AR) immunohistochemical method was applied on ventral prostate sections. Apoptosis was detected with the terminal deoxynucleotidyl transferase dUTP nick end labeling technique. CsA treatment caused reduction in plasmatic testosterone levels and an increase in glycemia. The volume of all ventral prostate tissue components (lumen, epithelium and muscular and nonmuscular stroma) and ventral prostate weight were reduced in the CsA-treated group. Light and transmission electron microscopy confirmed epithelium atrophy of treated animals. There was no alteration of AR expression or apoptotic index. CsA chronic treatment in the therapeutic doses caused damage to prostate tissue of adult Wistar rats, probably due to increase in the glucose levels and reduction in the plasmatic testosterone levels.

Reprogramming of prostate cancer-associated stromal cells to embryonic stem-like

BACKGROUND CD90+ prostate cancer-associated (CP) stromal cells represent a diseased cell type found only in tumor tissue. They differ from their normal counterpart in gene expression and inductive signaling. Genetic reprogramming by induced pluripotent stem (iPS) cell technology can effectively change adult cells into stem-like cells through wholesale alteration of the gene expression program. This technology might be used to erase the abnormal gene expression of diseased cells. The resultant iPS cells would no longer express the disease phenotype, and behave like stem cells. METHODS CP stromal cells, isolated from tumor tissue of a surgically resected prostate by anti-CD90-mediated sorting and cultured in vitro, were transfected with in vitro packaged lentiviral expression vectors containing stem cell transcription factor genes POU5F1, LIN28, NANOG, and SOX2. RESULTS Alkaline phosphatase-positive iPS cells were obtained in about 3 weeks post-transfection at a frequency of 10-4. Their colony morphology was indistinguishable from that of human embryonic stem (ES) cells. Transcriptome analysis showed a virtually complete match in gene expression between the iPS and ES cells. CONCLUSIONS Genes of CP stromal cells could be fully inactivated by genetic reprogramming. As a consequence, the disease phenotype was cured. Prostate 72:14531463, 2012. (c) 2012 Wiley Periodicals, Inc.

Are we able to correctly identify prostate cancer patients who could be adequately treated by focal therapy?

Introduction and Objective: Because of the improvements on detection of early stage prostate cancer over the last decade, focal therapy for localized prostate cancer (PC) has been proposed for patients with low-risk disease. Such treatment would allow the control of cancer, thereby diminishing side effects, such as urinary incontinence and sexual dysfunction, which have an enormous impact on quality of life. The critical issue is whether it is possible to preoperatively predict clinically significant unifocal or unilateral prostate cancer with sufficient accuracy. Our aim is to determine whether there is any preoperative feature that can help select the ideal patient for focal therapy. Material and methods: A total of 599 patients who underwent transrectal ultrasound, (TRUS)-guided prostate biopsy followed by radical prostatectomy to treat PC were examined in our laboratory between 2001 and 2009. We established very restricted criteria to select patients with very-low-risk disease for whom focal therapy would be suitable (only I biopsy core positive, tumor no larger than 80% of a single core, no perineural invasion, PSA serum level < 10 ng/ml, Gleason score < 7 and clinical stage T1c, T2a-b). We defined 2 groups of patients who would be either adequately treated or not treated by focal therapy. The primary endpoint was the evaluation of preoperative features in order to identify which parameters should be considered when choosing good candidates for focal therapy. Results: Fifty-six out of 599 patients met our criteria. The mean age was 59 years, and the mean number of biopsy cores was 14.4. Forty-seven (83.9%) were staged T1c, and 9 (16.1%) were staged T2a-b. Forty-four (78.6%) patients could be considered to have been adequately treated by focal therapy, and 12 (21.4%) could not. There was no statistical difference between the 2 groups considering age, clinical stage, PSA levels, Gleason score, and tumor volume in the biopsy. All 12 patients who could be considered inadequately treated had a bilateral, significant secondary tumor, 58.3% had Gleason >= 7, and 25% were staged pT3. Conclusion: Although focal therapy might be a good option for patients with localized prostate cancer, we are so far unable to select which of them would benefit from it based on preoperative data, even using very restricted criteria, and a considerable proportion of men would still be left undertreated. (c) 2012 Elsevier Inc. All rights reserved.

Gene expression down-regulation in CD90+ prostate tumor-associated stromal cells involves potential organ-specific genes

Abstract Background The prostate stroma is a key mediator of epithelial differentiation and development, and potentially plays a role in the initiation and progression of prostate cancer. The tumor-associated stroma is marked by increased expression of CD90/THY1. Isolation and characterization of these stromal cells could provide valuable insight into the biology of the tumor microenvironment. Methods Prostate CD90+ stromal fibromuscular cells from tumor specimens were isolated by cell-sorting and analyzed by DNA microarray. Dataset analysis was used to compare gene expression between histologically normal and tumor-associated stromal cells. For comparison, stromal cells were also isolated and analyzed from the urinary bladder. Results The tumor-associated stromal cells were found to have decreased expression of genes involved in smooth muscle differentiation, and those detected in prostate but not bladder. Other differential expression between the stromal cell types included that of the CXC-chemokine genes. Conclusion CD90+ prostate tumor-associated stromal cells differed from their normal counterpart in expression of multiple genes, some of which are potentially involved in organ development.

Quantification of fractal dimension and Shannon’s entropy in histological diagnosis of prostate cancer

Background: Prostate cancer is a serious public health problem that affects quality of life and has a significant mortality rate. The aim of the present study was to quantify the fractal dimension and Shannon’s entropy in the histological diagnosis of prostate cancer. Methods: Thirty-four patients with prostate cancer aged 50 to 75 years having been submitted to radical prostatectomy participated in the study. Histological slides of normal (N), hyperplastic (H) and tumor (T) areas of the prostate were digitally photographed with three different magnifications (40x, 100x and 400x) and analyzed. The fractal dimension (FD), Shannon’s entropy (SE) and number of cell nuclei (NCN) in these areas were compared. Results: FD analysis demonstrated the following significant differences between groups: T vs. N and H vs. N groups (p < 0.05) at a magnification of 40x; T vs. N (p < 0.01) at 100x and H vs. N (p < 0.01) at 400x. SE analysis revealed the following significant differences groups: T vs. H and T vs. N (p < 0.05) at 100x; and T vs. H and T vs. N (p < 0.001) at 400x. NCN analysis demonstrated the following significant differences between groups: T vs. H and T vs. N (p < 0.05) at 40x; T vs. H and T vs. N (p < 0.0001) at 100x; and T vs. H and T vs. N (p < 0.01) at 400x. Conclusions: The quantification of the FD and SE, together with the number of cell nuclei, has potential clinical applications in the histological diagnosis of prostate cancer.

Pain and quality of life in patients undergoing radiotherapy for spinal metastatic disease treatment

Abstract Background Radiotherapy is an important tool in the control of pain in patients with spinal metastatic disease. We aimed to evaluate pain and of quality of life of patients with spinal metastatic disease undergoing radiotherapy with supportive treatment. Methods The study enrolled 30 patients. From January 2008 to January 2010, patients selection included those treated with a 20 Gy tumour dose in five fractions. Patients completed the visual analogue scale for pain assessment and the SF-36 questionnaire for quality of life assessment. Results The most frequent primary sites were breast, multiple myeloma, prostate and lymphoma. It was found that 14 spinal metastatic disease patients (46.66%) had restricted involvement of three or fewer vertebrae, while 16 patients (53.33%) had cases involving more than three vertebrae. The data from the visual analogue scale evaluation of pain showed that the average initial score was 5.7 points, the value 30 days after the end of radiotherapy was 4.60 points and the average value 6 months after treatment was 4.25 points. Notably, this final value was 25.43% lower than the value from the initial analysis. With regard to the quality of life evaluation, only the values for the functional capability and social aspects categories of the questionnaire showed significant improvement. Conclusion Radiotherapy with supportive treatment appears to be an important tool for the treatment of pain in patients with spinal metastatic disease.

Underexpression of MMP-2 and its regulators, TIMP2, MT1-MMP and IL-8, is associated with prostate cancer

OBJECTIVE: Extracellular matrix homeostasis is strictly maintained by a coordinated balance between the expression of metalloproteinases (MMPs) and their regulators. The purpose of this study was to investigate whether MMP-2 and its specific regulators, TIMP-2, MT1-MMP and IL-8, are expressed in a reproducible, specific pattern and if the profiles are related to prognosis and clinical outcome of prostate cancer (PCa). MATERIALS AND METHODS: MMP-2, TIMP-2, MT1-MMP and IL-8 expression levels were analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) in freshly frozen malignant and benign tissue specimens collected from 79 patients with clinically localized PCa who underwent radical prostatectomies. The control group consisted of 11 patients with benign prostate hyperplasia (BPH). The expression profile of the MMP-2 and its regulators were compared using Gleason scores, pathological stage, pre-operative PSA levels and the final outcome of the PCa. RESULTS: The analysis of 79 specimens of PCa revealed that MMP-2, TIMP-2, MT1-MMP and IL-8 were underexpressed at 60.0%, 72.2%, 62.0% and 65.8%, respectively, in malignant prostatic tissue in relation to BPH samples. Considering the prognostic parameters, we demonstrated that high Gleason score tumors (> 7) overexpressed MMP-2 (p = 0.048) and TIMP-2 (p = 0.021), compared to low Gleason score tumors (< 7). CONCLUSION: We have demonstrated that MMP-2 and its regulators are underexpressed in PCa. Alternatively, overexpression of MMP-2 and TIMP-2 was related to higher Gleason score tumors. We postulate that alterations in metalloproteinase expression may be important in the control of tissue homeostasis related to prostate carcinogenesis and tumor behavior.

Analysis of cone-beam ct dose in image-guided radiation therapy for brain and prostate cancer patients via gpu-based Monte Carlo simulations

La radioterapia guidata da immagini (IGRT), grazie alle ripetute verifiche della posizione del paziente e della localizzazione del volume bersaglio, si è recentemente affermata come nuovo paradigma nella radioterapia, avendo migliorato radicalmente l’accuratezza nella somministrazione di dose a scopo terapeutico. Una promettente tecnica nel campo dell’IGRT è rappresentata dalla tomografia computerizzata a fascio conico (CBCT). La CBCT a kilovoltaggio, consente di fornire un’accurata mappatura tridimensionale dell’anatomia del paziente, in fase di pianificazione del trattamento e a ogni frazione del medisimo. Tuttavia, la dose da imaging attribuibile alle ripetute scansioni è diventata, negli ultimi anni, oggetto di una crescente preoccupazione nel contesto clinico. Lo scopo di questo lavoro è di valutare quantitativamente la dose addizionale somministrata da CBCT a kilovoltaggio, con riferimento a tre tipici protocolli di scansione per Varian OnBoard Imaging Systems (OBI, Palo Alto, California). A questo scopo sono state condotte simulazioni con codici Monte Carlo per il calcolo della dose, utilizzando il pacchetto gCTD, sviluppato sull’architettura della scheda grafica. L’utilizzo della GPU per sistemi server di calcolo ha permesso di raggiungere alte efficienze computazionali, accelerando le simulazioni Monte Carlo fino a raggiungere tempi di calcolo di ~1 min per un caso tipico. Inizialmente sono state condotte misure sperimentali di dose su un fantoccio d’acqua. I parametri necessari per la modellazione della sorgente di raggi X nel codice gCTD sono stati ottenuti attraverso un processo di validazione del codice al fine di accordare i valori di dose simulati in acqua con le misure nel fantoccio. Lo studio si concentra su cinquanta pazienti sottoposti a cicli di radioterapia a intensità modulata (IMRT). Venticinque pazienti con tumore al cervello sono utilizzati per studiare la dose nel protocollo standard-dose head e venticinque pazienti con tumore alla prostata sono selezionati per studiare la dose nei protocolli pelvis e pelvis spotlight. La dose media a ogni organo è calcolata. La dose media al 2% dei voxels con i valori più alti di dose è inoltre computata per ogni organo, al fine di caratterizzare l’omogeneità spaziale della distribuzione.

CYP17A1 polymorphisms and clinical outcome of patients with metastatic castration-resistant prostate cancer treated with abiraterone

Background. Abiraterone acetate is a potent inhibitor of cytochrome P450 17 α-hydrolase (CYP17A1) that causes a reduction in the synthesis of testosterone in the adrenal glands, testes and tumor microenvironment. Blocking androgen production, abiraterone has been shown to prolong progression-free survival (PFS) and overall survival (OS) in patients with metastatic castration-resistant prostate cancer (CRPC) previously submitted to chemotherapy. The aim of our study was to verify the role of single nucleotide polymorphisms (SNPs) in predicting clinical outcome in CRPC patients treated with abiraterone after chemotherapy. Methods. We analyzed 48 CRPC consecutive patients treated with abiraterone after at least one chemotherapeutic regimen with docetaxel. DNA was extracted from peripheral blood and genotyped for four polymorphisms in the CYP17A1 gene (rs743572, rs10883783, rs17115100, rs284849). PFS and OS survival curves were used to identify statistical associations between haplotypes and clinical outcome. Results. Forty-eight Caucasian patients with metastatic CRPC treated with abiraterone were genotyped for polymorphisms in the CYP17A1 gene. All samples were evaluable for both sequencing and TaqMan Genotyping assay. The CRPC patients treated with abiraterone had a median PFS and OS of 7.6 months (95% CI: 4.3-10.5) and 17.6 months (95% CI: 10.5-19.0), respectively Statistical analyses highlighted a difference approaching statistical significance (log-rank test p = 0.0534) between rs10883783 and PFS. Other polymorphisms were not associated with a benefit from treatment with abiraterone. Conclusions. In our case series of 48 treated patients, rs10883783 only was identified as a possible predictive marker, results showing a trend toward statistical significance. Further analysis of this polymorphism is needed in larger series of patients to confirm our findings.

IGF system, CD99 and tumor-specific chromosomal translocations: evaluation of their cross-talk and definition of their role in Ewing sarcoma and prostate cancer

Aberrant expression of ETS transcription factors, including FLI1 and ERG, due to chromosomal translocations has been described as a driver event in initiation and progression of different tumors. In this study, the impact of prostate cancer (PCa) fusion gene TMPRSS2-ERG was evaluated on components of the insulin-like growth factor (IGF) system and the CD99 molecule, two well documented targets of EWS-FLI1, the hallmark of Ewing sarcoma (ES). The aim of this study was to identify common or distinctive ETS-related mechanisms which could be exploited at biological and clinical level. The results demonstrate that IGF-1R represents a common target of ETS rearrangements as ERG and FLI1 bind IGF-1R gene promoter and their modulation causes alteration in IGF-1R protein levels. At clinical level, this mechanism provides basis for a more rationale use of anti-IGF-1R inhibitors as PCa cells expressing the fusion gene better respond to anti-IGF-1R agents. EWS-FLI1/IGF-1R axis provides rationale for combination of anti-IGF-1R agents with trabectedin, an alkylator agent causing enhanced EWS-FLI1 occupancy on the IGF-1R promoter. TMPRSS2-ERG also influences prognosis relevance of IGF system as high IGF-1R correlates with a better biochemical progression free survival (BPFS) in PCa patients negative for the fusion gene while marginal or no association was found in the total cases or TMPRSS2-ERG-positive cases, respectively. This study indicates CD99 is differentially regulated between ETS-related tumors as CD99 is not a target of ERG. In PCa, CD99 did not show differential expression between TMPRSS2-ERG-positive and –negative cells. A direct correlation was anyway found between ERG and CD99 proteins both in vitro and in patients putatively suggesting that ERG target genes comprehend regulators of CD99. Despite a little trend suggesting a correlation between CD99 expression and a better BPFS, no clinical relevance for CD99 was found in the field of prognostic biomarkers.

MR spectroscopy in human prostate: in vitro and in vivo measurements to optimize new quantification algorithms

Il cancro della prostata (PCa) è il tumore maligno non-cutaneo più diffuso tra gli uomini ed è il secondo tumore che miete più vittime nei paesi occidentali. La necessità di nuove tecniche non invasive per la diagnosi precoce del PCa è aumentata negli anni. 1H-MRS (proton magnetic resonance spectroscopy) e 1H-MRSI (proton magnetic resonance spectroscopy imaging) sono tecniche avanzate di spettroscopia in risonanza magnetica che permettono di individuare presenza di metaboliti come citrato, colina, creatina e in alcuni casi poliammine in uno o più voxel nel tessuto prostatico. L’abbondanza o l’assenza di uno di questi metaboliti rende possibile discriminare un tessuto sano da uno patologico. Le tecniche di spettroscopia RM sono correntemente utilizzate nella pratica clinica per cervello e fegato, con l’utilizzo di software dedicati per l’analisi degli spettri. La quantificazione di metaboliti nella prostata invece può risultare difficile a causa del basso rapporto segnale/rumore (SNR) degli spettri e del forte accoppiamento-j del citrato. Lo scopo principale di questo lavoro è di proporre un software prototipo per la quantificazione automatica di citrato, colina e creatina nella prostata. Lo sviluppo del programma e dei suoi algoritmi è stato portato avanti all’interno dell’IRST (Istituto Romagnolo per lo Studio e la cura dei Tumori) con l’aiuto dell’unità di fisica sanitaria. Il cuore del programma è un algoritmo iterativo per il fit degli spettri che fa uso di simulazioni MRS sviluppate con il pacchetto di librerie GAMMA in C++. L’accuratezza delle quantificazioni è stata testata con dei fantocci realizzati all’interno dei laboratori dell’istituto. Tutte le misure spettroscopiche sono state eseguite con il nuovo scanner Philips Ingenia 3T, una delle machine di risonanza magnetica più avanzate per applicazioni cliniche. Infine, dopo aver eseguito i test in vitro sui fantocci, sono stati acquisiti gli spettri delle prostate di alcuni volontari sani, per testare se il programma fosse in grado di lavorare in condizioni di basso SNR.

Human prostate fibroblasts induce growth and confer castration resistance and metastatic potential in LNCaP Cells

The tumor microenvironment is important for progressive and metastatic disease.

Oncocytic ependymoma: a new morphological variant of high-grade ependymal neoplasm composed of mitochondrion-rich epithelioid cells

Oncocytomas are defined as tumors containing in excess of 50% large mitochondrion-rich cells, irrespective of histogenesis and dignity. Along the central neuraxis, oncocytomas are distinctly uncommon but relevant to the differential diagnosis of neoplasia marked by prominent cytoplasmic granularity. We describe an anaplastic ependymoma (WHO grade III) with a prevailing oncocytic component that was surgically resected from the right fronto-insular region of a 43-year-old female. Preoperative imaging showed a fairly circumscribed, partly cystic, contrast-enhancing mass of 2 cm × 2 cm × 1.7 cm. Histology revealed a biphasic neoplasm wherein conventional ependymal features coexisted with plump epithelioid cells replete with brightly eosinophilic granules. Whereas both components displayed an overtly ependymal immunophenotype, including positivity for S100 protein and GFAP, as well as "dot-like" staining for EMA, the oncocytic population also tended to intensely react with the antimitochondrial antibody 113-1. Conversely, failure to bind CD68 indicated absence of significant lysosomal storage. Negative reactions for both pan-cytokeratin (MNF 116) and low molecular weight cytokeratin (CAM 5.2), as well as synaptophysin and thyroglobulin, further assisted in ruling out metastatic carcinoma. In addition to confirming the presence of "zipper-like" intercellular junctions and microvillus-bearing cytoplasmic microlumina, electron microscopy allowed for the pervasive accumulation of mitochondria in tumor cells to be directly visualized. A previously not documented variant, oncocytic ependymoma, is felt to add a reasonably relevant novel item to the differential diagnosis of granule-bearing central nervous system neoplasia, in particular oncocytic meningioma, granular cell astrocytoma, as well as metastatic deposits by oncocytic malignancies from extracranial sites.