Jorge L. Yao

Immediate versus deferred androgen deprivation treatment in patients with node-positive prostate cancer after radical prostatectomy and pelvic lymphadenectomy

BACKGROUND Appropriate timing of androgen deprivation treatment (ADT) for prostate cancer is controversial. Our aim was to determine whether immediate ADT extends survival in men with node-positive prostate cancer who have undergone radical prostatectomy and pelvic lymphadenectomy compared with those who received ADT only once disease progressed. METHODS Eligible patients from 36 institutes in the USA were randomly assigned in 1988-93 to receive immediate ADT (n=47) or to be observed (n=51), with ADT to be given on detection of distant metastases or symptomatic recurrences. Patients were followed up every 3 months for the first year and every 6 months thereafter. The primary endpoint was progression-free survival; secondary endpoints were overall and disease-specific survival. Analysis was by intention to treat. To ensure that the treatment groups were comparable, we did a retrospective central pathology review of slides and regraded the Gleason scores for available samples. This trial predates the requirement for clinical trial registration. FINDINGS At median follow-up of 11.9 years (range 9.7-14.5 for surviving patients), men assigned immediate ADT had a significant improvement in overall survival (hazard ratio 1.84 [95% CI 1.01-3.35], p=0.04), prostate-cancer-specific survival (4.09 [1.76-9.49], p=0.0004), and progression-free survival (3.42 [1.96-5.98], p<0.0001). Of 49 histopathology slides received (19 immediate ADT, 30 observation), 16 were downgraded from the original Gleason score (between groups < or = 6, 7, and > or = 8) and five were upgraded. We recorded similar proportions of score changes in each group (p=0.68), and no difference in score distribution by treatment (p=0.38). After adjustment for score, associations were still significant between treatment and survival (overall, p=0.02; disease-specific, p=0.002; progression-free survival, p<0.0001). INTERPRETATION Early ADT benefits patients with nodal metastases who have undergone prostatectomy and lymphadenectomy, compared with those who receive deferred treatment. The beneficial effects of early ADT, rather than an imbalance in risk factors, are likely to explain the differences in outcomes between treatments.

Androgen receptor is a tumor suppressor and proliferator in prostate cancer.

Targeting androgens/androgen receptor (AR) functions via androgen deprivation therapy (ADT) remains the standard treatment for prostate cancer. However, most tumors eventually recur despite ADT. Here we demonstrate that the prostate AR may function as both a suppressor and a proliferator to suppress or promote prostate cancer metastasis. Results from orthotopically recombining stromal WPMY1 cells with epithelial PC3 prostate cancer cells in mice demonstrated that restoring AR in epithelial PC3 cells or knockdown of AR in stromal WPMY1 cells suppressed prostate cancer metastasis. Knockdown of the AR in epithelial CWR22rv1 prostate cancer cells also resulted in increased cell invasion in vitro and in vivo. Restoring AR in PC3 cells (PC3-AR9) results in decreased invasion in bone lesion assays and in vivo mouse models. Mice lacking the prostate epithelial AR have increased apoptosis in epithelial luminal cells and increased proliferation in epithelial basal cells. The consequences of these two contrasting results led to the expansion of CK5/CK8-positive intermediate cells, and mice developed larger and more invasive metastatic tumors in lymph nodes and died earlier than wild-type littermates. Mechanistic dissection suggested that androgens/AR might directly or indirectly modulate metastasis-related genes and suppression of TGFβ1 signals results in the partial inhibition of AR-mediated metastasis. Collectively, our understanding of these opposing roles of prostatic AR may revolutionize the way we combat prostate cancer, and allow the development of new and better therapies by targeting only the proliferative role of AR.

Small cell carcinoma of the prostate: An immunohistochemical study

Small cell carcinoma of the prostate (SCPC) is morphologically similar to small cell carcinoma of the lung (SCLC) and maybe misinterpreted as Gleason pattern 5b prostate adenocarcinoma (HGPC). Recognition of SCPC is important because of its different clinical behavior. This study aims to characterize the immunophenotype of histologically classic SCPC using a comprehensive panel of markers, to better understand its histogenesis, aid in its classification, and evaluate potential therapeutic targets. Using the World Health Organization morphologic criteria for SCLC, 18 SCPC cases were identified; and studied for the following tumor marker groups: prostate specific/related, neuroendocrine, sex steroid hormone receptors, and prognostic/treatment target-related. Ten cases of UPC were used as controls. PSA was positive in 17% of SCPC and neuroendocrine markers were expressed in HGPC. PSA, TTF-1 and CD56 were the most helpful markers in differentiating between SCPC and HGPC (P<0.01), whereas bombesin/GRP, c-kit, bcl-2, and EGFR expression was more frequent in SCPC. SCPC is best diagnosed by following the World Health Organization diagnostic criteria for SCLC. Immunohistochemical markers can help separate SCPC from HGPC and may be useful in histologically borderline cases. Potential therapeutic targets are identified immunohistochemically in SCPC (Bombesin/GRP, c-kit, bcl-2, and EGFR).

Near infrared fluorescence imaging with robotic assisted laparoscopic partial nephrectomy: initial clinical experience for renal cortical tumors.

PURPOSE We evaluated the utility of near infrared fluorescence of intravenously injected indocyanine green in performing robotic assisted laparoscopic partial nephrectomy. In addition, we evaluated the initial performance of a novel near infrared fluorescence imaging system integrated into the da Vinci® Si Surgical System during robotic assisted laparoscopic nephrectomy. MATERIALS AND METHODS Fluorescence imaging for the da Vinci Si Surgical System was used for all cases. Indocyanine green was injected before near infrared imaging. Immediate imaging assessed the renal vasculature while delayed imaging differentiated renal cortical tumors from normal parenchyma. The intraoperative performance of near infrared fluorescence of intravenous indocyanine green was evaluated for tumor appearance relative to surrounding renal parenchyma as well as identification of the renal vasculature. RESULTS A total of 11 patients underwent robotic assisted laparoscopic nephrectomy with 2 converted to robotic assisted laparoscopic radical nephrectomy. Indocyanine green injections were repeated up to a total of 5 times depending on the goal of visualization. Of the 11 patients 10 demonstrated malignancy on final pathology. Of the malignant tumors 7 were hypofluorescent and 3 were isofluorescent compared to the surrounding renal parenchyma. Near infrared fluorescence imaging delineated the vascular anatomy in all cases. All surgical margins were negative on final pathology. CONCLUSIONS Intraoperative imaging of indocyanine green with near infrared fluorescence is a safe and effective method to accurately identify the renal vasculature and to differentiate renal tumors from surrounding normal parenchyma. The capacity for multimodal imaging within the surgical console further facilitates this imaging. Further study is needed to determine if this technique will help improve outcomes of robotic assisted laparoscopic nephrectomy.

Expression of androgen and oestrogen receptors and its prognostic significance in urothelial neoplasm of the urinary bladder

Whats known on the subject? and What does the study add?

Tocopherol-Associated Protein Suppresses Prostate Cancer Cell Growth by Inhibition of the Phosphoinositide 3-Kinase Pathway

Epidemiologic studies suggested that vitamin E has a protective effect against prostate cancer. We showed here that tocopherol-associated protein (TAP), a vitamin E-binding protein, promoted vitamin E uptake and facilitated vitamin E antiproliferation effect in prostate cancer cells. Interestingly, without vitamin E treatment, overexpression of TAP in prostate cancer cells significantly suppressed cell growth; knockdown of endogenous TAP by TAP small interfering RNA (siRNA) in nonmalignant prostate HPr-1 cells increased cell growth. Further mechanism dissection studies suggested that the tumor suppressor function of TAP was via down-regulation of phosphoinositide 3-kinase (PI3K)/Akt signaling, but not by modulating cell cycle arrest or androgen receptor signaling. Immunoprecipitation results indicated that TAP inhibited the interaction of PI3K subunits, p110 with p85, and subsequently reduced Akt activity. Constitutively active Akt could negate the TAP-suppressive activity on prostate cancer cell growth. Moreover, stable transfection of TAP in LNCaP cells suppressed LNCaP tumor incidence and growth rate in nude mice. Furthermore, TAP mRNA and protein expression levels were significantly down-regulated in human prostate cancer tissue samples compared with benign prostate tissues as measured by reverse transcription-PCR, in situ hybridization, and immunohistochemistry. Together, our data suggest that TAP not only mediates vitamin E absorption to facilitate vitamin E antiproliferation effect in prostate cancer cells, but also functions like a tumor suppressor gene to control cancer cell viability through a non-vitamin E manner. Therefore, TAP may represent a new prognostic marker for prostate cancer progression.

Differential Expression of Interleukin-8 and Its Receptors in the Neuroendocrine and Non-Neuroendocrine Compartments of Prostate Cancer

Hormonal therapy (androgen ablation and/or inhibition of androgen action) is the treatment of choice for advanced prostate cancer. After an initial response in most patients, tumors invariably progress to an androgen-independent state. It is unclear how prostate cancer cells proliferate without androgen. Recent studies suggest that interleukin-8 may promote androgen-independent proliferation, but the source of interleukin-8 in the prostate is unknown. Using immunohistochemistry, we show that interleukin-8 was expressed by the neuroendocrine tumor cells in human prostate cancer tissue. Expression of the interleukin-8 receptor CXCR1 was negative or low in benign prostatic tissue and was frequently increased in malignant cells of high-grade prostatic intraepithelial neoplasia and prostate cancer; however, CXCR1 was not detected in the neuroendocrine tumor cells, suggesting a paracrine mechanism by which interleukin-8 produced by neuroendocrine tumor cells stimulates androgen-independent proliferation of prostate cancer. Neuroendocrine tumor cells expressed another type of interleukin-8 receptor, CXCR2, suggesting an autocrine mechanism by which interleukin-8 regulates the differentiation or function of the neuroendocrine cells. These results, combined with previous reports that neuroendocrine differentiation is induced by hormonal therapy, suggest that neuroendocrine cells play an important role in promoting androgen-independent growth of prostate cancer through interleukin-8 signaling.

Loss of androgen receptor expression is not associated with pathological stage, grade, gender or outcome in bladder cancer: a large multi‐institutional study

Study Type – Prognosis (multi‐centre cohort) 
Level of Evidence 1b

Mitochondrial DNA depletion in prostate epithelial cells promotes anoikis resistance and invasion through activation of PI3K/Akt2

Neoplastic transformation of prostate epithelium involves aberrant activation of anti-apoptotic and pro-invasive pathways triggered by multiple poorly understood genetic events. We demonstrated earlier that depletion of mitochondrial DNA (mtDNA) induces prostate cancer progression. Here, using normal prostate epithelial PNT1A cells we demonstrate that mtDNA depletion prevents detachment-induced apoptosis (anoikis) and promotes migratory capabilities onto basement membrane proteins through upregulation of p85 and p110 phosphatidylinositol 3-kinase (PI3K) subunits, which results in Akt2 activation and phosphorylation of downstream substrates GSK3β, c-Myc, MMP-9, Mdm2, and p53. Pharmacological or genetic PI3K inhibition, siRNA-mediated Akt2 depletion, as well as mtDNA reconstitution were sufficient to restore sensitivity to anoikis and curtail cell migration. Moreover, Akt2 activation induced glucose transporter 1 (GLUT1) expression, glucose uptake, and lactate production, common phenotypic changes seen in neoplastic cells. In keeping with these findings, several prostate carcinoma cell lines displayed reduced mtDNA content and increased PI3K/Akt2 levels when compared to normal PNT1A cells, and Akt2 downregulation prevented their survival, migration and glycolytic metabolism. On a tissue microarray, we also found a statistically significant decrease in mtDNA-encoded cytochrome oxidase I in prostate carcinomas. Taken together, these results provide novel mechanistic evidence supporting the notion that mtDNA mutations may confer survival and migratory advantage to prostate cancer cells through Akt2 signaling.

Combination of napsin A and TTF-1 immunohistochemistry helps in differentiating primary lung adenocarcinoma from metastatic carcinoma in the lung.

Differentiation of primary from metastatic adenocarcinoma in the lung can be challenging, and it demands sensitive and specific biomarkers, especially when the tissue for diagnosis is limited. Thyroid transcription factor-1 (TTF-1) has been considered a reliable marker for adenocarcinoma of lung origin. However, several recent studies have shown that TTF-1 immunostaining is also positive in adenocarcinomas arising in different organs including colon, endometrium, endocervix, and ovary. In addition, approximately 20% of lung primary adenocarcinomas are negative for TTF-1 immunostaining, and napsin A immunostaining has slightly higher sensitivity in detecting lung primary adenocarcinoma. We performed TTF-1 and napsin A immunostaining on 120 cases of primary lung adenocarcinomas and 37 cases of metastatic carcinomas in the lung. The results showed that 95 (79.2%) of 120 lung primary adenocarcinomas showed napsin A(+)/TTF-1(+) double-positive immunostaining pattern. TTF-1(−)/napsin A(+), TTF-1(+)/napsin A(−), and TTF-1(−)/napsin A(−) were seen in 8.3%, 3.3%, and 9.2% lung primary adenocarcinomas, respectively. Eight (21.6%) of the 37 metastatic carcinomas were positive for TTF-1 and they include clear-cell renal cell carcinomas completely negative for napsin A although napsin A was detected in 12 (80.0%) of 15 primary papillary and 3 (33.3%) of 9 primary clear-cell renal cell carcinomas. All renal epithelial neoplasms were TTF-1 negative. These findings indicate that double napsin A and TTF-1-positive immunostaining is highly specific for lung primary adenocarcinoma and the combination of these 2 biomarkers is warranted to help segregating primary lung adenocarcinoma from metastatic carcinoma in the lung.