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D Theodorescu

Publications and source records attributed to D Theodorescu.

At least 55 records · Page 3Linked to original sources
PubMed1999

Unusual case of non-exophytic invasive penile squamous cell cancer arising from a chronic sinus tract.

We present an unusual case of an extremely well-differentiated but deeply invasive squamous cell carcinoma of the penis without an obvious external lesion, arising from a chronic draining sinus tract. This case highlights how a confounding clinical history, physical examination and initial biopsies may lead to a significant delay in diagnosis. This delay may have resulted in tumour growth and the need for a more extensive partial penectomy than would have occurred had the diagnosis been made more promptly. Finally, this case demonstrates the key diagnostic utility of deep core biopsies of the penis in situations where a cutaneous lesion does not exist.

Adult↗
PubMed1999

Molecular determination of surgical margins using fossa biopsies at radical prostatectomy.

PURPOSE: Status of the surgical margins after radical prostatectomy is a key factor for predicting postoperative outcome. Current methods used to determine margin status are tedious, costly and vary among institutions. Sensitive and inexpensive detection of prostate cells in the circulation of patients with prostate cancer has been achieved using reverse transcriptase (RT) polymerase chain reaction (PCR) for prostate specific antigen and prostate specific membrane antigen. Therefore, we designed and tested a novel and objective molecular assay for assessing surgical margins at radical prostatectomy based on the detection of prostate specific markers using RT-PCR. We also compared this assay to standard pathological examination. MATERIALS AND METHODS: A total of 30 consecutive patients with local prostate cancer underwent radical prostatectomy. At the completion of gland excision 5 biopsies of the prostatic fossa were obtained for histopathological and molecular analysis. We performed RT-PCR analysis for prostate specific antigen and prostate specific membrane antigen messenger ribonucleic acid in these biopsy specimens, and compared the results with pathological stage. Men free of prostate cancer who underwent radical cystoprostatectomy for bladder cancer or abdominoperineal resection for rectal cancer served as controls. RESULTS: There were positive molecular margins in all patients with positive margins and/or extracapsular extension. No controls had a positive molecular assay. In 4 of 16 patients (25%) histopathological evaluation revealed organ confined disease but biopsies were positive by the molecular assay, including those in 2 (50%) who had been treated with neoadjuvant hormonal therapy before surgery because of a higher estimated risk of extracapsular disease. Results in 4 cases were uninformative. CONCLUSIONS: Our results with an objective molecular assay aimed at assessing surgical margins after radical prostatectomy reveal an excellent correlation with conventional pathological analysis. In addition, molecular assessment of the prostatic fossa identifies patients in whom extracapsular disease may have been unidentified by conventional pathological examination. In addition, this assay yields clues to why neoadjuvant hormonal treatment before radical prostatectomy does not seem to decrease the biochemical failure rate in these patients. Larger studies with longer followup are required to determine the prognostic significance of these positive molecular margins.

Adenocarcinoma↗
PubMed1998

Inhibition of human bladder cancer cell motility by genistein is dependent on epidermal growth factor receptor but not p21ras gene expression.

A significant portion of patients who present with non-muscle invasive "superficial" bladder cancer develop the muscle "invasive" life-threatening form of the disease during subsequent follow-up. In clinical studies, overexpression of the epidermal growth factor receptor (EGFR) and the p21 ras oncogene have been strongly associated with this phenotypic tumor transition. The marked difference in incidence of invasive bladder cancer in Asia compared to the United States has made us hypothesize that, among other factors, dietary influences have an impact on such tumor progression. A significantly higher dietary consumption of soy products exists in Asia and has led to the notion that the isoflavones present in this diet may contribute to a reduction in the number of invasive transitional cell bladder cancers. In this regard, we sought to determine the effect of genistein, a naturally occurring dietary protein tyrosine kinase (PTK) inhibitor, on the growth and motility of human bladder cancer cell lines with diverse EGFR and p21ras expression phenotypes and corresponding invasive behaviors. These effects were compared with those of tyrphostin, a pure synthetic EGFR inhibitor. Our results indicate that both genistein and tyrphostin are effective inhibitors of bladder cancer motility and growth, key factors in the development of muscle invasive disease. In addition, the growth and motility inhibitory effects of genistein and tyrphostin are observed preferentially in cells that overexpress the EGFR. Cells that have a mutated p21ras but do not overexpress the EGFR are less inhibited by these 2 compounds, suggesting that their effect is primarily directed at the EGFR signal transduction pathways proximal to the p21ras gene. Our results would seem to corroborate the notion that a high dietary intake of isoflavones is a likely explanation for the decreased incidence of invasive bladder cancer.

Cell Movement↗
PubMed1998

Early prostate-specific antigen failure following radical perineal versus retropubic prostatectomy: the importance of seminal vesicle excision.

OBJECTIVES: Because of renewed interest in the radical perineal prostatectomy, we chose to evaluate factors influencing differences in biochemical failure as measured by prostate-specific antigen (PSA) between radical perineal and the radical retropubic prostatectomies. METHODS: We undertook a retrospective review of 87 men with clinically localized prostate cancer who underwent radical retropubic (64%) or radical perineal (36%) prostatectomy, noting age, race, preoperative PSA, Gleason score, clinical stage, capsular penetration, surgical approach, and completeness of seminal vesicle (SV) excision. The two groups were comparable with respect to tumor factors such as preoperative PSA, Gleason score, clinical stage, and capsular penetration. Time to postoperative PSA failure (0.2 ng/mL or greater) was evaluated with univariate and multivariate analysis of multiple contributing factors. RESULTS: Twenty-eight percent of patients had a PSA level rising to 0.2 ng/mL or greater in the follow-up period. Patients who underwent perineal prostatectomy had a higher PSA failure rate (45%) than those treated by the retropubic approach (18%) and patients with incomplete SV excision had a higher failure rate (69%) than patients with bilateral SV excision (20%). When time to PSA failure was examined by multivariate analysis, completeness of SV excision, clinical stage, and Gleason score had a statistically significant impact on this outcome. In perineal prostatectomy patients, bilateral SV excision had a significantly longer time to PSA failure than in patients with incomplete excision. There was no significant difference in time to PSA failure between patients who underwent radical retropubic prostatectomy and the patients who underwent perineal prostatectomy with bilateral SV excision. CONCLUSIONS: Incomplete excision of SVs during a radical perineal prostatectomy contributes to an earlier postoperative biochemical recurrence as measured by a rising PSA, and may explain the higher disease recurrence rate for radical perineal prostatectomies as opposed to radical retropubic prostatectomies in this study.

Adult↗
PubMed1998

Urethral replacement with vascularized tunica vaginalis: defining the optimal form of use.

PURPOSE: Residual urethral defects after failed hypospadias surgery present difficulties in reconstruction. In these situations, repair using vascularized tissue flaps remains ideal, yet challenging. In order to offer more surgical alternatives in these cases, the use of vascularized tunica vaginalis flaps as urethral replacements has recently been established in an animal model. We undertook the following studies to further define the role of tunica vaginalis in urethral reconstruction. MATERIALS AND METHODS: A vascularized flap of tunica vaginalis was used to replace an experimentally created 25-30 mm. gap in the anterior urethra of 26 rabbits, either as an onlay or tube flap. A control group consisting of 7 animals underwent only a segmental anterior urethral resection and primary re-anastomosis. RESULTS: Satisfactory urethral healing occurred in all control animals that survived the procedure. All 8 animals which had tunica vaginalis tube flap reconstruction underwent contracture of the neourethra probably secondary to the presence of striated cremasteric muscle elements brought with the tunica during mobilization. All 16 animals available for long term study in the onlay flap group had excellent flap viability and 100% urethral patency rates. The mesothelial lining of the tunica was seen to be replaced by a stratified epithelial lining similar to the urothelial lining of the native urethra. CONCLUSION: The tunica vaginalis is a viable alternative to other tissues presently used for urethral replacement and can be used successfully as a vascularized onlay flap.

Animals↗
PubMed1998

Epidermal growth factor receptor-regulated human bladder cancer motility is in part a phosphatidylinositol 3-kinase-mediated process.

Although overexpression of the epidermal growth factor receptor (EGFR) has been strongly associated with the transition from superficial to invasive human bladder cancer, the exact molecular pathways by which this gene effectively triggers or facilitates the invasive process are not completely understood. Because enhanced cellular motility is a prerequisite for invasion, we chose to determine how EGFR signaling impacts cellular motility of human bladder cancer in vitro in a cell model of human bladder cancer that closely mimics the human disease. Using a stable antisense approach to diminish EGFR expression, we obtained data that support the role of EGFR in mediating bladder cancer motility. These results also demonstrate that EGFR plays an important role in bladder cancer motility, even in the presence of a mutated and overexpressing Ras protein, and suggest the possibility that Ras-independent EGFR motility signaling is a significant pathway used by bladder cancer cells. In support of this concept, using specific pharmacological inhibition of phosphatidylinositol 3-kinase, we show that this mediator is involved in EGFR motility signaling in this system. Knowledge of the pathways used by EGFR to induce motility and subsequent invasion may lead to development of methods to prevent or retard the progression of aggressive superficial bladder tumors.

Cell Division↗
PubMed1997

Cathepsin D and chromogranin A as predictors of long term disease specific survival after radical prostatectomy for localized carcinoma of the prostate.

BACKGROUND: The accumulation of chromogranin A (Chr A) and cathepsin D (Cath D) gene products may be important in prostate carcinoma progression. This study assessed whether the levels of immunoreactivity for Chr A and Cath D are better predictors of disease specific survival than conventional pathologic parameters of the primary tumor such as Gleason score, capsular penetration, seminal vesicle invasion, and percent tumor in the specimen for patients with clinically localized prostate carcinoma managed by radical prostatectomy. METHODS: Seventy-one patients with modified Jewett clinical stages A1 to B2 adenocarcinoma of the prostate underwent a radical prostatectomy after a negative metastatic workup. No neoadjuvant or adjuvant treatments were given and all disease recurrences and causes of death were recorded. Analysis of prostatectomy specimens was undertaken to determine the conventional pathologic parameters of the primary tumor and Chr A and Cath D immunohistochemical staining. Univariate and multivariate analyses were performed to determine the independent contributions of Chr A and Cath D in predicting survival. RESULTS: On univariate analysis Chr A was the only variable that reached statistical significance for disease specific survival (P = 0.035). Cath D nearly reached significance with a P value of 0.079 for disease specific survival. On multivariate analysis, the only independent factor predicting disease specific survival was the Chr A staining score (P < 0.05). In patients with unequivocal foci of Chr A immunoreactivity, the 14-year disease specific survival was 50% compared with 68% for patients lacking such foci. CONCLUSIONS: The level of Chr A immunohistochemical staining is a strong predictor of disease specific survival and is superior to standard pathologic prognostic factors. Such findings lay the groundwork for future prospective study of the utility of such markers on biopsy specimens to predict patient outcome.

Carcinoma↗
PubMed1997

p53, bcl-2 and retinoblastoma proteins as long-term prognostic markers in localized carcinoma of the prostate.

PURPOSE: The accumulation of p53 and bcl-2 gene products as well as the loss of the retinoblastoma (Rb) gene product have been associated with prostate cancer progression. We assessed whether the levels of immunoreactivity for p53, Rb and bcl-2 are better long-term predictors of disease specific survival than conventional pathological parameters of the primary tumor, such as Gleason score, capsular penetration, seminal vesicle invasion and percent tumor in the specimen, in patients with clinically localized prostate cancer treated with radical prostatectomy. MATERIALS AND METHODS: A total of 71 patients with clinical stages A1 to B2 adenocarcinoma of the prostate underwent radical prostatectomy after a negative metastatic evaluation. No neoadjuvant or adjuvant treatments were given and causes of death were recorded. Prostatectomy specimens were analyzed to determine the conventional pathological parameters, and p53, Rb and bcl-2 immunohistochemical staining. Univariate and multivariate analyses were done to determine the independent contributions of p53, Rb and bcl-2 in predicting survival. RESULTS: On multivariate analysis the independent factors predicting disease specific survival were p53 staining score (p < 0.001) and Rb staining score (p < 0.001). In patients with p53 immunoreactive tumors the 15-year disease specific survival was 38% compared to 87% for those with less immunoreactivity. Analysis of Rb immunoreactivity for 15-year disease specific survival yielded 92 and 66% high and low staining levels, respectively. Best subset analysis revealed that the combination of p53 score and Rb score yielded the best predictive value for disease specific survival. CONCLUSIONS: p53 and Rb immunohistochemical staining scores were independent predictors of disease specific survival and were superior to conventional pathological prognostic factors of the primary tumor. These findings lay the groundwork for the prospective study of these markers in patients treated with radical prostatectomy.

Adenocarcinoma↗
PubMed1997

gamma-Glutamyl transpeptidase in normal and neoplastic prostate glands.

gamma-Glutamyl transpeptidase (GGT) is a cytoplasmic membrane-bound enzyme important in the metabolism of glutathione and other gamma-glutamyl compounds. It is present in highest levels in the kidney and is also expressed prominently in reproductive organs such as the prostate gland. Because GGT has never been examined in prostatic carcinoma, we used a new polyclonal antibody (GGT 129) for immunohistochemical localization of GGT in normal prostate gland and 72 prostatic carcinomas. The normal lining secretory cells of ducts and acini showed apical immunoreactivity for GGT, but the basal epithelial cells were negative. Most of the prostatic adenocarcinomas had GGT staining patterns and intensity similar to those of normal prostatic secretory cells, because the majority of neoplastic cells showed immunopositivity in more than 80% of the adenocarcinomas. In comparing the percentage of cells staining for GGT with clinicopathologic parameters, there was no correlation between the number of positive cells and the Gleason score, the percentage of intraglandular carcinoma, capsule penetration, or seminal vesicle invasion. Immunostaining for GGT lacks value as a prognostic factor and does not correlate with standard clinicopathologic parameters. GGT may be important, however, for growth and maintenance of both normal and neoplastic prostatic cells. Modulating GGT levels or administering drugs that can be activated by GGT may have therapeutic value.

Adenocarcinoma↗
PubMed1997

Staging pelvic lymphadenectomy for localized carcinoma of the prostate: a comparison of 3 surgical techniques.

PURPOSE: Pelvic lymph node dissection continues to be the most effective method of staging extracapsular adenocarcinoma of the prostate. Three principal methods of pelvic lymph node dissection are currently available: intraperitoneal laparoscopic, minilaparotomy and the standard open modified pelvic lymph node dissection. In the hope of determining some of the relative advantages and disadvantages associated with each technique a comparison of these approaches was made. MATERIALS AND METHODS: Of 68 patients with histologically proved clinical stage T3N0M0 adenocarcinoma of the prostate who underwent staging pelvic lymph node dissection 38 underwent modified open, 19 laparoscopic and 11 minilaparotomy procedures. The efficacy of node sampling, resource expenditure and complication rates were compared among the 3 groups. RESULTS: No statistically significant difference was observed in terms of the number of nodes harvested with each technique. Resource expenditure analysis revealed significantly increased operative and procedural time requirements for laparoscopic pelvic lymph node dissection compared to modified open and minilaparotomy procedures. Total hospital stay was significantly longer for the modified open pelvic lymph node dissection (mean plus or minus standard deviation 6.5 +/- 0.9 days) compared to the laparoscopic (mean 2.7 +/- 1.1 days) and minilaparotomy (mean 3.3 +/- 0.2 days) groups. Multiple complications, such as ileus, lymphocele and urinary retention, were observed in the modified open pelvic lymph node dissection group. No complications were noted in the other 2 groups. CONCLUSIONS: Comparison of laparoscopic and minilaparotomy procedures to modified open pelvic lymph node dissection revealed similar staging efficacy, and decreased total hospital stay and complications. Laparoscopic pelvic lymph node dissection required increased operative time. Minilaparotomy should become the open surgical procedure of choice for pelvic lymph node dissection, particularly at institutions where the laparoscopy learning curve, equipment expense and time disadvantages cannot be overcome.

Adenocarcinoma↗
PubMed1997

The Hautmann neobladder with a chimney: a versatile modification.

PURPOSE: We describe a modification to the popular Hautmann ileal neobladder comprised of a chimney for the ureterointestinal anastomosis in order to enhance its flexibility, reduce its pitfalls and hence make more patients candidates for this type of diversion. MATERIALS AND METHODS: The Hautmann ileal neobladder is prepared in the standard fashion except that an additional 5 to 10 cm. (or more if needed in the case of a short ureter) of small bowel are selected to be added for either a left or right "chimney" (depending on which side the ureter may be shorter or if there is a solitary kidney). The V segment of the W which will be anastomosed to the urethra is made longer than the contralateral V segment. A neobladder neck is created by sewing together the cut edges of a 5 cm. lip in the lowermost W configuration of the neobladder, allowing an end-to-end urethrointestinal anastomosis. RESULTS: Between March and October 1996, 3 patients have undergone this procedure at the University of Virginia. Two had right chimneys and 1 had a left chimney. Followup is short, but there have been no complications except for a transient postoperative partial small bowel obstruction in 1 patient. Two patients have no urinary incontinence, the third has only occasional nocturnal incontinence. CONCLUSIONS: This modification of the Hautmann ileal neobladder provides greater versatility for short ureters, minimizes tension from the mesentery on the urethrointestinal anastomosis, simplifies the ureterointestinal anastomosis and provides easy postoperative access for ureterointestinal anastomosis revision or resection in case of recurrent disease.

Female↗
PubMed1996

Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes.

PURPOSE: We determined factors predictive of inguinal nodal relapse in patients with stages T1 to 3NOMO squamous cell penile cancer treated initially with surveillance of inguinal nodes. MATERIALS AND METHODS: Between 1980 and 1994, in 42 patients with stages T1 to 3NOMO squamous cell penile cancer of 60 with invasive disease seen at our center the inguinal nodes were surveyed after definitive treatment of the primary tumor. Clinical inguinal nodal recurrences were treated with inguinal lymphadenectomy. RESULTS: A total of 26 patients (62%) had inguinal nodal recurrences during followup, with 50% occurring within 1.4 years and 75% within 2.8 years of resection of the primary tumor. The only factor predicting nodal relapse was grade of the primary tumor at initial treatment. Patients with grade 1 tumors had a 45% long-term actuarial relapse-free survival rate. All other groups had a 100% actuarial nodal relapse rate. Of the patients 10% had metastatic disease without nodal recurrence. CONCLUSIONS: Invasive penile cancer may be associated with inguinal lymph node and hematogenous metastasis. A strong case for prophylactic bilateral inguinal lymphadenectomy can be made in patients with primary tumors other than grade 1, since surveillance of these patients will not spare them eventual lymphadenectomy and may potentially compromise survival by delaying surgery. Patients with grade 1 tumors may be offered either careful surveillance or prophylactic bilateral inguinal lymphadenectomy depending on the clinical circumstances and patient preference.

Adult↗
PubMed1995

Transforming growth factor beta 1 (TGF beta 1) is an autocrine positive regulator of colon carcinoma U9 cells in vivo as shown by transfection of a TGF beta 1 antisense expression plasmid.

A transforming growth factor beta1 (TGF beta1) antisense expression plasmid under constitutive control of the Rous sarcoma virus promoter was introduced into the highly tumorigenic and invasive colon carcinoma U9A cell line, which uses its autocrine TGF beta1 as a growth-stimulating factor. Stable transfectants were infrequent, and only the K6 transfectant exhibited 39 and 33%, respectively, of the levels of TGF beta1 mRNA and active, secreted TGF beta1 protein of the parental line. K6 exhibited no change in TGF beta2 expression, and TGF beta3 expression was not detected in either parental or transfectant cells. Compared to the parental line, the K6 antisense transfectant exhibited a 3-fold increase in lag time in anchorage-dependent colony formation. The parental line was 44 times as invasive through a collagen l-coated polycarbonate membrane in vitro as K6 cells and, after s.c. injection at low-cell inocula, U9A cells induced tumors 75 times as large in vivo as did the K6 antisense transfectant. The decreases in in vitro invasion and anchorage-dependent colony formation seen in K6 cells were largely reversed by the addition of TGF beta1. Tumors that did arise from the K6 antisense transfectant cells had lost antisense TGF beta1 expression and expressed the same TGF beta1 mRNA levels as controls. U9A cells were more metastatic to the liver after intrasplenic injection than K6 cells. These findings demonstrate a role for autocrine TGE beta1 in colon cancer tumorigenicity and invasion. They also show that a relatively small decrease in TGF beta1 levels was enough to markedly decrease colon carcinoma cell aggressiveness. This is not unprecedented, as we had found in an earlier study that a small, 2-4-fold increase in TGF beta1 protein levels in human colon cancers correlated with disease progression to metastases (E. Friedman et al., Cancer Epidemiol, Biomarkers & Prev., 4:549-554, 1995).

Animals↗
PubMed1993

Altered growth and spontaneous transformation of cells cultured from v-jun transgenic mice recapitulate wound-induced multistage tumorigenesis.

H-2K/v-jun transgenic mice develop sarcomas at sites of wounding via a multistep process characterized by discrete pathological stages. To study this progression in vitro, cells from different stages of tumorigenesis were cultured and examined for their growth properties. The results show that whereas transgenic fibroblasts do not manifest enhanced proliferative potential in vivo in the absence of wounding, they do show obvious proliferative advantage relative to nontransgenic fibroblasts in vitro, including the capacity for indefinite growth. In addition, relative to nontransgenic fibroblasts, transgenic cells show altered sensitivity to platelet-derived growth factor and tumor necrosis factor alpha, both of which are known to be mobilized during wounding. No obvious differences in growth potential are observed between transgenic fibroblasts and cells cultured from wound-induced premalignant lesions, and confluent cultures of both cell populations give rise to spontaneous foci of transformed myogenic and nonmyogenic cells that resemble those of late-stage malignant wound sarcomas. Relative to transgenic fibroblast cultures, however, premalignant lesion cultures segregate transformed cells at a greater frequency and after shorter intervals of in vitro growth. The results suggest that wound-induced multistage tumorigenesis can be recapitulated in vitro and that cells cultured from different stages of tumorigenesis retain biological properties that reflect the pathological stage from which they are derived.

Animals↗