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Biomedical subjects

Michael R Pins

Publications and source records attributed to Michael R Pins.

16 recordsLinked to original sources
PubMed2006

Alteration of proliferation and apoptotic markers in normal and premalignant tissue associated with prostate cancer.

BACKGROUND: Molecular markers identifying alterations in proliferation and apoptotic pathways could be particularly important in characterizing high-risk normal or pre-neoplastic tissue. We evaluated the following markers: Ki67, Minichromosome Maintenance Protein-2 (Mcm-2), activated caspase-3 (a-casp3) and Bcl-2 to determine if they showed differential expression across progressive degrees of intraepithelial neoplasia and cancer in the prostate. To identify field effects, we also evaluated whether high-risk expression patterns in normal tissue were more common in prostates containing cancer compared to those without cancer (supernormal), and in histologically normal glands adjacent to a cancer focus as opposed to equivalent glands that were more distant. METHODS: The aforementioned markers were studied in 13 radical prostatectomy (RP) and 6 cystoprostatectomy (CP) specimens. Tissue compartments representing normal, low grade prostatic intraepithelial neoplasia (LGPIN), high grade prostatic intraepithelial neoplasia (HGPIN), as well as different grades of cancer were mapped on H&E slides and adjacent sections were analyzed using immunohistochemistry. Normal glands within 1 mm distance of a tumor focus and glands beyond 5 mm were considered "near" and "far", respectively. Randomly selected nuclei and 40 x fields were scored by a single observer; basal and luminal epithelial layers were scored separately. RESULTS: Both Ki-67 and Mcm-2 showed an upward trend from normal tissue through HGPIN and cancer with a shift in proliferation from basal to luminal compartment. Activated caspase-3 showed a significant decrease in HGPIN and cancer compartments. Supernormal glands had significantly lower proliferation indices and higher a-casp3 expression compared to normal glands. "Near" normal glands had higher Mcm-2 indices compared to "far" glands; however, they also had higher a-casp3 expression. Bcl-2, which varied minimally in normal tissue, did not show any trend across compartments or evidence for field effects. CONCLUSION: These results demonstrate that proliferation and apoptosis are altered not only in preneoplastic lesions but also in apparently normal looking epithelium associated with cancer. Luminal cell expression of Mcm-2 appears to be particularly promising as a marker of high-risk normal epithelium. The role of apoptotic markers such as activated caspase-3 is more complex, and might depend on the proliferation status of the tissue in question.

Adenocarcinoma↗
PubMed2006

Prognostic value of DNA ploidy, bcl-2 and p53 in localized prostate adenocarcinoma incidentally discovered at transurethral prostatectomy.

PURPOSE: Discovery of prostatic adenocarcinoma limited to transurethral resection material generates a treatment dilemma. We investigated the usefulness of parameters shown to be associated with prognosis in prostate cancer (p53 and bcl-2 immuno-expression, DNA cell cycle analysis and Gleason score) to stratify these incidentally identified tumors to guide clinical decision making. MATERIALS AND METHODS: Paraffin embedded tissues from transurethral prostate resection specimens containing T1a prostate adenocarcinoma from 44 patients who underwent resection between 1980 and 1990 were immunostained for p53 and bcl-2, and subjected to flow cytometry to determine DNA ploidy. Gleason score was determined by 2 pathologists independently. Statistical relationships among these 4 variables, tumor progression and cancer specific survival were analyzed. RESULTS: Six of 44 patients in the study population had cancer progression. Time to clinical progression was 4.5 years (range 7 months to 11 years). Most tumors stained negative for p53 and bcl-2. Only 2 tumors studied were aneuploid and neither of these 2 patients had cancer progression. Only Gleason score was a significant predictor of cancer progression on univariate and multivariate Cox regression analysis (p = 0.045 and 0.046, respectively). No tumor characteristics correlated with time to disease progression, including p53 and bcl-2 immuno-expression, and Gleason score (p = 0.182, 0.563 and 0.346, respectively). Positive immunostaining for p53 and bcl-2 did not occur together in the same tumor in significant fashion (p = 0.334), nor did either significantly occur more with aneuploidy (p = 0.237 and 0.307 respectively). CONCLUSIONS: For T1a prostate cancer incidentally detected on transurethral prostate resection p53 and bcl-2 immuno-expression, and DNA ploidy do not predict survival or disease progression.

Adenocarcinoma↗
PubMed2006

Tumor necrosis factor promotes differential trafficking of bladder mast cells in neurogenic cystitis.

PURPOSE: IC is often considered neurogenic cystitis, in which mast cells are involved in a positive feedback loop that results in sustained urothelial inflammation. To characterize these processes we developed a murine model of neurogenic cystitis using Bartha's strain of PRV based on a similar model in the rat. MATERIALS AND METHODS: Female C57BL/6 mice (National Cancer Institute, Bethesda, Maryland) were used in the study. Neurogenic cystitis was induced by the injection of Bartha's strain of PRV (2.2 x 10 pfu) into the abductor caudalis dorsalis tail base muscle. Bladder inflammation was assessed by leukocyte influx and Evans blue dye extravasation. Mast cells were visualized in bladder tissue by staining with 0.1% toluidine blue. RESULTS: Inoculation with PRV in the abductor caudalis dorsalis resulted in cystitis within 3 days. Coincident with the induction of cystitis mast cells accumulated in the lamina propria due to mast cell trafficking from the proximal detrusor (relative to the lumen), whereas mast cells from the distal detrusor were unchanged and total mast cell counts were not increased. Degranulated mast cells increased approximately 20-fold in the lamina propria of infected mice relative to controls. In TNF receptor 1/2 deficient mice (Jackson Laboratory, Bar Harbor, Maine) mast cell trafficking was not observed in response to PRV and mast cells were not degranulated. CONCLUSIONS: These data indicate that neurogenic cystitis is associated with the differential trafficking and activation of distinct mast cell pools in the bladder. Since TNF mediates these events, anti-TNF therapy may mitigate the pathogenesis of neurogenic cystitis.

Animals↗
PubMed2005

Mammary serine protease inhibitor (Maspin) binds directly to interferon regulatory factor 6: identification of a novel serpin partnership.

Since its reported discovery in 1994, maspin (mammary serine protease inhibitor) has been characterized as a class II tumor suppressor by its ability to promote apoptosis and inhibit cell invasion. Maspin is highly expressed in normal mammary epithelial cells but reduced or absent in aggressive breast carcinomas. However, despite efforts to characterize the mechanism(s) by which maspin functions as a tumor suppressor, its molecular characterization has remained somewhat elusive. Therefore, in an attempt to identify maspin-interacting proteins and thereby gain insight into the functional pathways of maspin, we employed a maspin-baited yeast two-hybrid system and subsequently identified Interferon Regulatory Factor 6 (IRF6) as a maspin-binding protein. IRF6 belongs to the IRF family of transcription factors, which is best known for its regulation of interferon and interferon-inducible genes following a pathogenic stimulus. Although many of the IRF family members have been well characterized, IRF6 remains poorly understood. We report that IRF6 is expressed in normal mammary epithelial cells and that it directly associates with maspin in a yeast two-hybrid system and in vitro. The interaction occurs via the conserved IRF protein association domain and is regulated by phosphorylation of IRF6. We have shown that, similar to maspin, IRF6 expression is inversely correlated with breast cancer invasiveness. We further demonstrated that the transient re-expression of IRF6 in breast cancer cells results in an increase of N-cadherin and a redistribution of vimentin commensurate with changes in cell morphology, suggestive of an epithelial-to-mesenchymal transition event. Concomitantly, we showed that maspin acts as a negative regulator of this process. These findings help to elucidate the molecular mechanisms of maspin and suggest an interactive role between maspin and IRF6 in regulating cellular phenotype, the loss of which can lead to neoplastic transformation.

Amino Acid Sequence↗
PubMed2005

Alpha-methylacyl-CoA racemase (AMACR) expression in normal prostatic glands and high-grade prostatic intraepithelial neoplasia (HGPIN): association with diagnosis of prostate cancer.

BACKGROUND: Alpha-methylacyl-CoA racemase (AMACR) is strongly expressed in prostate cancer with variable expression in high-grade prostatic intraepithelial neoplasia (HGPIN) and low expression in normal prostate. We examined whether AMACR expression in HGPIN and normal tissue was associated with subsequent diagnosis of cancer or proximity to a cancer focus. METHODS: Needle core biopsies from 45 patients with isolated HGPIN, 12 radical prostatectomy (RP) specimens with prostatic carcinoma and 6 cystoprostatectomies without prostatic carcinoma were immunostained for AMACR. Among patients with HGPIN, 23 (cases) showed cancer on a later biopsy and 22 (controls) had no cancer with at least 3 consecutive negative biopsies. RESULTS: In the biopsy set, the mean AMACR expression per gland in the normal compartment of the cases (0.29) was significantly higher than the controls (0.21) (P = 0.0006). In the RP set, normal glands near a cancer focus had higher mean AMACR expression than those that were distant (P = 0.0006). There was no difference within the HGPIN compartment between cases and controls in the biopsies, or between near and distant glands in the RP set. Mean AMACR staining of normal glands in the cystoprostatectomy specimens was significantly lower than in normal glands in close proximity to a cancer focus. CONCLUSIONS: Higher expression of AMACR in normal glands near a focus of cancer, as well as in the subjects eventually showing cancer, suggests a possible field effect in prostatic carcinogenesis. AMACR expression in normal glands therefore might be a useful predictor for repeat biopsy outcomes or as an intermediate endpoint in chemoprevention studies.

Aged↗
PubMed2005

Histopathology of human renal tumors after laparoscopic renal cryosurgery.

PURPOSE: Laparoscopic renal cryoablation is a nephron sparing treatment alternative for selected patients with small renal tumors. The acute tumoricidal effects of cryosurgery on human renal tumors and in experimental models have been reported previously. For cryoablation to be a viable option in the treatment of renal tumors, it must induce not only acute tissue injury but also sustain permanent tissue necrosis and cellular death, in addition to affording an adequate surgical margin free of viable tumor. We report on the longer term effects of in vivo human tumor tissue destruction by cryosurgery and describe the histopathology of a cryoablated renal lesion. MATERIALS AND METHODS: Three patients in our series who were treated with laparoscopic renal cryosurgery subsequently underwent radical nephrectomy of the cryoablated renal unit. RESULTS: All patients underwent uneventful cryosurgery. Two patients were found to have positive post-cryosurgery biopsies, while a new, metachronous lesion developed in 1 patient. All 3 patients elected to undergo radical nephrectomy. Mean time from cryosurgery to nephrectomy was 275 days. The cryoablated lesions demonstrated coagulative necrosis as evidenced by numerous histiocytes, cholesterol crystals and dystrophic calcification. There was no evidence of viable tumor within the cryoablated field. CONCLUSIONS: The longer term tumoricidal effects of laparoscopic renal cryosurgery in human renal tissue have been demonstrated. However, careful patient selection with lesions less than 3.0 cm and vigilant monitoring of the iceball under strict radiographic guidance are imperative to ensure successful oncological outcomes.

Aged↗
PubMed2004

Xanthogranulomatous orchitis.

Xanthogranulomatous inflammation is an uncommon process that is usually associated with severe renal infection. We report a case of a 64-year-old man with xanthogranulomatous inflammation in the testis who presented with contralateral epididymoorchitis and a painless testicular mass. Only two prior cases of xanthogranulomatous orchitis have been reported. This case highlights the need for a broad differential diagnosis when approaching testicular masses, particularly in the setting of coincident infection.

Diagnosis, Differential↗
PubMed2004

Expression of RON Proto-oncogene in Renal Oncocytoma and Chromophobe Renal Cell Carcinoma.

Recently, it was reported that RON proto-oncogene, encoding a receptor tyrosine kinase, was strongly expressed in renal oncocytomas but not in any renal cell carcinomas, including 5 chromophobe renal cell carcinomas, which morphologically resemble oncocytomas. To determine its diagnostic value, we studied Ron protein expression by immunohistochemistry in a larger number of renal cell neoplasms with emphasis on chromophobe renal cell carcinomas. Tissue microarrays containing 141 renal cell neoplasms, including 55 oncocytomas and 52 chromophobe renal cell carcinomas, were constructed. In addition, conventional sections from 15 cases of oncocytoma and 5 cases of chromophobe renal cell carcinoma were analyzed. Immunohistochemistry was carried out with a monoclonal mouse anti-human Ron-alpha antibody. Staining intensity was scored on a 0 to 3 scale. Ninety-nine percent of oncocytomas (69 of 70) and 96% of chromophobe renal cell carcinomas (55 of 57) showed moderate to strong, diffuse cytoplasmic Ron immunoreactivity with intensities > or =2, while only 17% of other renal cell carcinoma subtypes stained with intensities > or =2. Our study indicates that Ron immunostaining cannot be used to distinguish oncocytoma from chromophobe renal cell carcinoma.

Adenoma, Oxyphilic↗
PubMed2004

Expression of alpha-methylacyl-coenzyme A racemase in nephrogenic adenoma.

Nephrogenic adenoma is a benign lesion composed of small glandular structures that develops along the urothelium with uncertain pathogenesis. Some investigators believe that nephrogenic adenoma develops by a metaplastic process in response to injury to the urothelium, while others believe that it arises from detached renal tubules. Nephrogenic adenoma may be present in the prostatic urethra and morphologically mimic prostatic adenocarcinoma. Alpha-methylacyl-coenzyme A racemase (AMACR), a recently identified prostate cancer marker, is typically negative in normal urothelium and prostatic glands, and positive in distal convoluted renal tubules in addition to prostatic adenocarcinomas. Therefore, evaluation of AMACR expression in nephrogenic adenoma will have significance in the pathologic diagnosis and in understanding pathogenesis of this lesion. We studied 38 nephrogenic adenomas by clinical, histologic, and immunohistochemical analyses for AMACR (P504S) and high molecular weight cytokeratin (34betaE12). Twenty-two of 38 nephrogenic adenomas (58%) demonstrated strong cytoplasmic positivity for AMACR, ranging from patchy, focal to diffuse staining. In addition, 16 of 26 (62%) nephrogenic adenomas were negative for 34betaE12. To our knowledge, this is one of the first report of a completely benign lesion, which can be found in the prostate, showing strong AMACR immunoreactivity. Our findings suggest using caution when interpreting positive AMACR immunostaining in prostatic specimens. These findings could be explained by possible renal tubular origin or renal differentiation, at least in a subset, of nephrogenic adenomas.

Adenoma↗
PubMed2003

Pigment epithelium-derived factor regulates the vasculature and mass of the prostate and pancreas.

Angiogenesis sustains tumor growth and metastasis, and recent studies indicate that the vascular endothelium regulates tissue mass. In the prostate, androgens drive angiogenic inducers to stimulate growth, whereas androgen withdrawal leads to decreased vascular endothelial growth factor, vascular regression and epithelial cell apoptosis. Here, we identify the angiogenesis inhibitor pigment epithelium-derived factor (PEDF) as a key inhibitor of stromal vasculature and epithelial tissue growth in mouse prostate and pancreas. In PEDF-deficient mice, stromal vessels were increased and associated with epithelial cell hyperplasia. Androgens inhibited prostatic PEDF expression in cultured cells. In vivo, androgen ablation increased PEDF in normal rat prostates and in human cancer biopsies. Exogenous PEDF induced tumor epithelial apoptosis in vitro and limited in vivo tumor xenograft growth, triggering endothelial apoptosis. Thus, PEDF regulates normal pancreas and prostate mass. Its androgen sensitivity makes PEDF a likely contributor to the anticancer effects of androgen ablation.

Adolescent↗
PubMed2003

Renal cell carcinoma, chromophobe type, with collecting duct carcinoma and sarcomatoid components.

We report a case of a 72-year-old man with a chromophobe renal cell carcinoma that had both sarcomatoid and collecting duct carcinoma components. The 7-cm tumor occupied the entire lower pole of the kidney and infiltrated the renal parenchyma and the pelvic-calyceal system. Histologically, it had an area of classic chromophobe renal cell carcinoma that merged into a sarcomatoid component. Closely intermixed with the sarcomatoid component was a collecting duct carcinoma component characterized by highly pleomorphic, epithelioid cells arranged in cords, nests, and tubulomicrocystic structures. The cords, nests, and tubules were associated with a florid desmoplastic stromal response and numerous inflammatory cells. In addition, dysplastic changes were noted in adjacent nonneoplastic collecting duct epithelium. Immunohistochemical studies confirmed the presence of 3 distinct components in this patient's tumor. To the best of our knowledge, this is the first reported case of a chromophobe renal cell carcinoma with sarcomatoid and collecting duct carcinoma components.

Aged↗
PubMed2002

Biochemical disease-free survival following adjuvant and salvage irradiation after radical prostatectomy.

PURPOSE: To present the biochemical cure rates (biochemically no evidence of disease) after external irradiation (RT) in patients with high-risk prostate cancer after radical prostatectomy. METHODS AND MATERIALS: Seventy-six patients who underwent radical prostatectomy and subsequent RT were included in this analysis. No patient received hormonal therapy. Adjuvant RT was administered in 35 patients (46%), and 41 patients (54%) underwent salvage RT. After prostatectomy, the Gleason score was <7 in 87%, and 24% had seminal vesicle invasion. The median RT dose in the adjuvant RT and salvage RT groups was 60 Gy and 65 Gy, respectively. The biochemical cure rate was defined as a serum prostate-specific antigen of < or =0.2 ng/mL. RESULTS: The overall 5-year Kaplan-Meier biochemical control rate from the end of RT was 70%. The 5-year biochemical cure rate for adjuvant RT was significantly superior to that after salvage RT (86% vs. 57%). The significant predictors of biochemical failure were seminal vesicle invasion in the adjuvant RT group and the presence of Gleason grade 4 or 5 in the salvage RT group. The clinical local control rate in the prostate bed was 100%. CONCLUSION: This report demonstrates the efficacy of RT in achieving high biochemical cure rates after radical prostatectomy. Additional clinical studies are required to determine the optimal treatment of patients at high risk of biochemical failure after postprostatectomy RT.

Aged↗
PubMed2002

Long-term survival after "drop metastases" of renal cell carcinoma to the bladder.

Renal cell carcinoma can metastasize to virtually any organ, yet isolated bladder metastases are exceedingly rare, and most of these patients die within 1 year of diagnosis. Proposed mechanisms of renal cell carcinoma metastases to the bladder include hematogenous spread, lymphatic dissemination, and "drop metastases" by way of the urinary tract. We present the longest reported survival after isolated "drop metastases" of renal cell carcinoma to the bladder.

Adult↗
PubMed2002

Juxtaglomerular apparatus tumor: a rare, surgically correctable cause of hypertension.

Although uncommon, presentation of juxtaglomerular cell tumor is distinct and should allow a correct preoperative diagnosis in most patients. Typical clinical presentations include headaches, polyuria, or isolated, asymptomatic, severe hypertension. The diagnosis of a juxtaglomerular apparatus (JGA) tumor typically results from identification of plasma renin levels two- to sevenfold greater than the normal value. Although JGA tumors are considered benign, with no reports of metastases or recurrence, they are potentially lethal if left untreated. Surgical excision is curative.

Case Reports↗