Monica P. Revelo

Incidence and Location of Prostate and Urothelial Carcinoma in Prostates From Cystoprostatectomies: Implications for Possible Apical Sparing Surgery

PURPOSE Prostatic carcinoma (Pca) at cystoprostatectomy is usually an incidental finding with the majority thought to be clinically insignificant. Most studies have not specifically addressed the location of Pca or the incidence and location of in situ or invasive urothelial carcinoma (Uca) in prostates of cystoprostatectomy specimens. The frequency of involvement of the apex with these processes has clinical implications. Specifically urinary continence following orthotopic diversion may be enhanced by prostate apical sparing. In this study the pathological features of Pca and Uca, and the frequency of apical involvement were investigated in prostates from cystoprostatectomy specimens. MATERIALS AND METHODS Whole mounted prostates from 121 consecutive cystoprostatectomy specimens were analyzed. Pca location, tumor volume, grade, stage, surgical margin and pelvic lymph node status of Pcas were assessed. Clinically insignificant Pcas had a volume of less than 0.5 cc without Gleason pattern 4, extracapsular extension, seminal vesicle invasion, lymph node involvement or positive surgical margins. Prostate involvement by Uca or urothelial carcinoma in situ (CIS)/severe dysplasia and its location were assessed. RESULTS Of 121 prostates 50 (41%) had unsuspected Pca, of which 24 (48%) were clinically significant. Of Pcas 30 of 50 (60%) involved the apex, including 19 of 24 (79%) that were significant and 11 of 26 (42%) that were insignificant. Of 121 prostates 58 (48%) had Uca involving the prostatic stroma, noninvasive Uca or urothelial CIS/severe dysplasia in the prostatic urethra or periurethral ducts, of which 19 (33%) had apical involvement. Overall only 32 of 121 patients (26%) had no Pca or prostate Uca/CIS and only 45 (37%) had no clinically significant Pca or Uca/CIS in the prostate. However, 74 of the 121 patients (61%) had no prostatic apical involvement by Pca or Uca/CIS and 85 (70%) had no apical involvement by clinically significant Pca or Uca/CIS. Patients with prostatic apical involvement by invasive or in situ Uca uniformly had involvement of more proximal (toward the base) portions of the prostate. CONCLUSIONS The majority of prostates from cystoprostatectomies had no involvement of the prostatic apex by Uca or clinically significant Pca. Hence, most patients may be candidates for prostate apical sparing. However, involvement of the apex by Uca in any patient raises concern about procedures that leave portions of the prostate urethra after cystectomy in an effort to improve continence. In candidates for orthotopic neobladder reconstruction removing all of the prostatic urethra and sparing the remainder of the prostatic apex may allow improved preservation of urinary continence with an acceptable low risk of clinical Pca progression. Whether future strategies for preoperative exclusion of apical Pca and intraoperative assessment of more proximal prostate to help exclude apical urothelial disease may identify patients suitable for prostatic apical sparing remains to be determined. The impact on functional outcomes and cancer control also require additional study.

The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation

During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers.

The ISHLT working formulation for pathologic diagnosis of antibody-mediated rejection in heart transplantation: Evolution and current status (2005-2011)

From the Department of Pathology, Stanford University, Stanford, California; Universita of Padua Medical School, Padua, Italy; Royal Brompton and Harefield NHS Trust, London, United Kingdom; Hopital Europeen Georges Pompidou, Paris, France; David Geffen School of Medicine at the University of California-Los Angeles, Los Angeles, California; Intermountain Medical Center, Salt Lake City, Utah; Queen Elizabeth Hospital, Birmingham, United Kingdom; University of Utah, Salt Lake City, Utah; Cleveland Clinic, Cleveland, Ohio; Papworth Hospital, Papworth, United Kingdom; Brigham & Women’s Hospital, Boston, Massachusetts; Cedars Sinai Heart Institute, Los Angeles, California; University of Maryland School of Medicine, Baltimore, Maryland.

Altered TGF-β Signaling in a Subpopulation of Human Stromal Cells Promotes Prostatic Carcinogenesis

Carcinoma-associated fibroblasts (CAF) play a critical role in malignant progression. Loss of TGF-β receptor II (TGFβR2) in the prostate stroma is correlated with prostatic tumorigenesis. To determine the mechanisms by which stromal heterogeneity because of loss of TGFβR2 might contribute to cancer progression, we attenuated transforming growth factor beta (TGF-β) signaling in a subpopulation of immortalized human prostate fibroblasts in a model of tumor progression. In a tissue recombination model, loss of TGFβR2 function in 50% of the stromal cell population resulted in malignant transformation of the nontumorigenic human prostate epithelial cell line BPH1. Mixing fibroblasts expressing the empty vector and dominant negative TGFβR2 increased the expression of markers of myofibroblast differentiation [coexpression of vimentin and alpha smooth muscle actin (αSMA)] through elevation of TGF-β1 and activation of the Akt pathway. In combination, these two populations of stromal cells recapitulated the tumor inductive activity of CAFs. TGFβR2 activity in mixed stromal cell populations cultured in vitro caused secretion of factors that are known to promote tumor progression, including TGF-β1, SDF1/CXCL12, and members of the fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) families. In vivo, tissue recombination of fibroblasts overexpressing TGF-β1 and SDF1/CXCL12 not only induced transformation of BPH1 cells, but also promoted a robust growth of highly invasive cells, similar to effects produced by CAFs. While the precise nature and/or origin of the particular stromal cell populations in vivo remain unknown, these findings strongly link heterogeneity in TGF-β signaling to tumor promotion by tumor stromal cells.

Impact of Mechanical Unloading on Microvasculature and Associated Central Remodeling Features of the Failing Human Heart

OBJECTIVES This study investigates alterations in myocardial microvasculature, fibrosis, and hypertrophy before and after mechanical unloading of the failing human heart. BACKGROUND Recent studies demonstrated the pathophysiologic importance and significant mechanistic links among microvasculature, fibrosis, and hypertrophy during the cardiac remodeling process. The effect of left ventricular assist device (LVAD) unloading on cardiac endothelium and microvasculature is unknown, and its influence on fibrosis and hypertrophy regression to the point of atrophy is controversial. METHODS Hemodynamic data and left ventricular tissue were collected from patients with chronic heart failure at LVAD implant and explant (n = 15) and from normal donors (n = 8). New advances in digital microscopy provided a unique opportunity for comprehensive whole-field, endocardium-to-epicardium evaluation for microvascular density, fibrosis, cardiomyocyte size, and glycogen content. Ultrastructural assessment was done with electron microscopy. RESULTS Hemodynamic data revealed significant pressure unloading with LVAD. This was accompanied by a 33% increase in microvascular density (p = 0.001) and a 36% decrease in microvascular lumen area (p = 0.028). We also identified, in agreement with these findings, ultrastructural and immunohistochemical evidence of endothelial cell activation. In addition, LVAD unloading significantly increased interstitial and total collagen content without any associated structural, ultrastructural, or metabolic cardiomyocyte changes suggestive of hypertrophy regression to the point of atrophy and degeneration. CONCLUSIONS The LVAD unloading resulted in increased microvascular density accompanied by increased fibrosis and no evidence of cardiomyocyte atrophy. These new insights into the effects of LVAD unloading on microvasculature and associated key remodeling features might guide future studies of unloading-induced reverse remodeling of the failing human heart.

Monoclonal gammopathy: significance and possible causality in renal disease

BACKGROUND Patients with monoclonal gammopathy can develop a variety of related renal lesions or possibly have kidney disease unrelated to their monoclonal gammopathy. We characterized the spectrum of renal diseases associated with monoclonal gammopathy and renal diseases. METHODS Patients who underwent renal biopsy and had monoclonal gammopathy on serum and/or urine electrophoresis and/or had a renal biopsy diagnosis related to paraprotein (cryoglobulinemic glomerulonephritis [CG], monoclonal immunoglobulin deposition disease [MIDD], light chain cast nephropathy [CN], or light chain amyloidosis [AL]) were identified. RESULTS One hundred twenty-one patients met the inclusion criteria and were classified as having renal disease related or unrelated to monoclonal gammopathy. Among 66 cases of renal disease related to monoclonal gammopathy, diagnoses were CG (30.3%), MIDD (28.8%), CN (19.7%), AL (19.7%), and CN plus MIDD (1.5%). Among patients with monoclonal gammopathy in serum and/or urine (n = 87), 32 patients (36.8%, included in listing above) had related renal disease. Among 55 patients with monoclonal gammopathy and unrelated renal disease (63.2% of all patients with monoclonal gammopathy), various lesions were found, including diabetic nephropathy (18.1%), focal segmental glomerulosclerosis (18.1%), arterionephrosclerosis (12.7%), membranous glomerulonephritis (9.0%), minimal change disease (7.3%), various immune complex diseases, interstitial nephritis, or nonspecific changes. CONCLUSION The majority of patients with serum and/or urine monoclonal gammopathy who undergo renal biopsy have disease unrelated to monoclonal gammopathy deposition. This likely reflects the high frequency of monoclonal gammopathy of undetermined significance in older patients and the frequent use of serum and/or urine protein electrophoresis as screening tools in adult patients with renal disease.

The SWI/SNF ATPase Brm Is a Gatekeeper of Proliferative Control in Prostate Cancer

Factors that drive prostate cancer progression remain poorly defined, thus hindering the development of new therapeutic strategies. Disseminated tumors are treated through regimens that ablate androgen signaling, as prostate cancer cells require androgen for growth and survival. However, recurrent, incurable tumors that have bypassed the androgen requirement ultimately arise. This study reveals that the Brm ATPase, a component of selected SWI/SNF complexes, has significant antiproliferative functions in the prostate that protect against these transitions. First, we show that targeted ablation of Brm is causative for the development of prostatic hyperplasia in mice. Second, in vivo challenge revealed that Brm-/- epithelia acquire the capacity for lobe-specific, castration-resistant cellular proliferation. Third, investigation of human specimens revealed that Brm mRNA and protein levels are attenuated in prostate cancer. Fourth, Brm down-regulation was associated with an increased proliferative index, consistent with the mouse model. Lastly, gene expression profiling showed that Brm loss alters factors upstream of E2F1; this was confirmed in murine models, wherein Brm loss induced E2F1 deregulation in a tissue-specific manner. Combined, these data identify Brm as a major effector of serum androgen-induced proliferation in the prostate that is disrupted in human disease, and indicate that loss of Brm confers a proliferative advantage in prostate cancer.

Targeting the BAF57 SWI/SNF Subunit in Prostate Cancer: A Novel Platform to Control Androgen Receptor Activity

The androgen receptor (AR) is critical for disseminated prostate cancer proliferation and survival. AR activity is targeted either through prevention of ligand synthesis or through the use of antagonists that bind the COOH-terminal ligand-binding domain. Although initially effective, treatment fails due to restored AR activity in the presence of therapeutics. Thus, new means must be developed to target AR activity. The SWI/SNF chromatin remodeling complex is critical for AR transcriptional activity, and the BAF57 SWI/SNF subunit facilitates direct interaction with the receptor. Although selected SWI/SNF subunit expression is reduced in prostate cancer, we show that BAF57 is retained in human disease and is elevated in a subset of tumors. Functional analyses showed that BAF57 contributes uniquely to androgen-mediated stimulation of transcription without compromising the effectiveness of AR antagonists. Subsequent studies revealed that BAF57 is recruited to the AR DNA-binding domain/hinge region, which occurs concomitant with receptor activation. These data provided the basis for a novel inhibitor derived from BAF57 [BAF57 inhibitory peptide (BIPep)], which blocked AR residence on chromatin and resultant AR-dependent gene activation. Importantly, BIPep expression was sufficient to inhibit androgen-dependent prostate cancer cell proliferation in AR-positive cells. In summary, these data identify blockade of AR-BAF57 interaction as a novel means to target agonist-induced AR function in prostate cancer, and provide the first evidence that abrogation of SWI/SNF function can be developed as a point of therapeutic intervention in prostate cancer.

Down-regulation of p57Kip2 Induces Prostate Cancer in the Mouse

p57(Kip2) has been considered a candidate tumor suppressor gene because of its location in the genome, biochemical activities, and imprinting status. However, little is known about the role of p57(Kip2) in tumorigenesis and cancer progression. Here, we show that the expression of p57(Kip2) is significantly decreased in human prostate cancer, and the overexpression of p57(Kip2) in prostate cancer cells significantly suppressed cell proliferation and reduced invasive ability. In addition, overexpression of p57(Kip2) in LNCaP cells inhibited tumor formation in nude mice, resulting in well-differentiated squamous tumors rather than adenocarcinoma. Furthermore, the prostates of p57(Kip2) knockout mice developed prostatic intraepithelial neoplasia and adenocarcinoma. Remarkably, this mouse prostate cancer is pathologically identical to human prostate adenocarcinoma. Therefore, these results strongly suggest that p57(Kip2) is an important gene in prostate cancer tumorigenesis, and the p57(Kip2) pathway may be a potential target for prostate cancer prevention and therapy.

Cyclin D3 action in androgen receptor regulation and prostate cancer.

Prostate cancer (PCa) cell proliferation is dependent on activation of the androgen receptor (AR), a ligand-dependent transcription factor. AR activation controls G1–S phase progression through fostering enhanced translation of the D-type cyclins, which promote cell cycle progression through activation of CDK4/6. However, the D-type cyclins harbor additional, CDK4/6 kinase-independent, functions through manipulation of transcription factors, including AR. It was previously established that cyclins D1 and D3 have the potential to modulate AR, and with regard to cyclin D1, disruption of this function occurs in human tumors. Therefore, it was essential to interrogate cyclin D3 function in this tumor type. Here, we show that cyclin D3 is found in association with AR in PCa cells, as mediated through a conserved motif. Cyclin D3 functions to attenuate AR activity through defined mechanisms that include modulation of ligand-dependent conformational changes and modulation of chromatin binding activity. Accumulated cyclin D3 slows cell proliferation in AR-dependent cells, thus suggesting that androgen-induced D-type cyclin production serves to temper the mitogenic response to androgen. Supporting this hypothesis, it is shown that cyclin D3 expression is reduced in primary PCas as a function of tumor grade, and inversely correlates with the proliferative index. In total, these data identify cyclin D3 as a critical modulator of the androgen response, whose deregulation may foster unchecked AR activity in PCa.