Sara E. Wobker

Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast cancer biology

Significance The identification of molecular subtype heterogeneity in breast cancer has allowed a deeper understanding of breast cancer biology. We present evidence that there are two intrinsic subtypes of high-grade bladder cancer, basal-like and luminal, which reflect the hallmarks of breast biology. Moreover, we have developed an accurate gene set predictor of molecular subtype, the BASE47, that should allow the incorporation of subtype stratification into clinical trials. Further clinical, etiologic, and therapeutic response associations will be of interest in future investigations. We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus clustering performed on gene expression data from a meta-dataset of high-grade, muscle-invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer, termed “luminal” and “basal-like,” which have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. A gene set predictor, bladder cancer analysis of subtypes by gene expression (BASE47) was defined by prediction analysis of microarrays (PAM) and accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer and validate the BASE47 as a subtype predictor. Future studies exploring the predictive value of the BASE47 subtypes for standard of care bladder cancer therapies, as well as novel subtype-specific therapies, will be of interest.

Racial differences in PSA screening interval and stage at diagnosis.

ObjectivesThis study examined PSA screening interval of black and white men aged 65 or older and its association with prostate cancer stage at diagnosis.MethodsSEER-Medicare data were examined for 18,067 black and white men diagnosed with prostate cancer between 1994 and 2002. Logistic regression was used to assess the association between race, PSA screening interval, and stage at diagnosis. Analysis also controlled for age, marital status, comorbidity, diagnosis year, geographic region, income, and receipt of surgery.ResultsCompared to whites, blacks diagnosed with prostate cancer were more likely to have had a longer PSA screening interval prior to diagnosis, including a greater likelihood of no pre-diagnosis use of PSA screening. Controlling for PSA screening interval was associated with a reduction in blacks’ relative odds of being diagnosed with advanced (stage III or IV) prostate cancer, to a point that the stage at diagnosis was not statistically different from that of whites (OR=1.12, 95% CI=0.98–1.29). Longer intra-PSA intervals were systematically associated with greater odds of diagnosis with advanced disease.ConclusionsMore frequent or systematic PSA screening may be a pathway to reducing racial differences in prostate cancer stage at diagnosis, and, by extension, mortality.

The Binding Site Barrier Elicited by Tumor-Associated Fibroblasts Interferes Disposition of Nanoparticles in Stroma-Vessel Type Tumors

The binding site barrier (BSB) was originally proposed to describe the binding behavior of antibodies to cells peripheral to blood vessels, preventing their further penetration into the tumors. Yet, it is revisited herein to describe the intratumoral cellular disposition of nanoparticles (NPs). Specifically, the BSB limits NP diffusion and results in unintended internalization of NPs by stroma cells localized near blood vessels. This not only limits the therapeutic outcome but also promotes adverse off-target effects. In the current study, it was shown that tumor-associated fibroblast cells (TAFs) are the major component of the BSB, particularly in tumors with a stroma-vessel architecture where the location of TAFs aligns with blood vessels. Specifically, TAF distance to blood vessels, expression of receptor proteins, and binding affinity affect the intensity of the BSB. The physical barrier elicited by extracellular matrix also prolongs the retention of NPs in the stroma, potentially contributing to the BSB. The influence of particle size on the BSB was also investigated. The strongest BSB effect was found with small (∼18 nm) NPs targeted with the anisamide ligand. The uptake of these NPs by TAFs was about 7-fold higher than that of the other cells 16 h post-intravenous injection. This was because TAFs also expressed the sigma receptor under the influence of TGF-β secreted by the tumor cells. Overall, the current study underscores the importance of BSBs in the delivery of nanotherapeutics and provides a rationale for exploiting BSBs to target TAFs.

Use of BRAF v600e immunocytochemistry on FNA direct smears of papillary thyroid carcinoma

Mutations of v‐Raf murine sarcoma viral oncogene homolog B1 (BRAF) are identified in almost half of all papillary thyroid carcinomas (PTCs). These mutations are specific for PTC and may confer a worse prognosis. An immunohistochemical (IHC) stain for BRAF is commercially available and has been validated in surgical specimens. Fine‐needle aspiration (FNA) is frequently used as a diagnostic tool for risk stratification of thyroid nodules. Therefore, the authors evaluated the performance of immunostaining with the anti‐BRAF antibody VE1 on FNA direct smears.

MYC activation cooperates with Vhl and Ink4a/Arf loss to induce clear cell renal cell carcinoma

Renal carcinoma is a common and aggressive malignancy whose histopathogenesis is incompletely understood and that is largely resistant to cytotoxic chemotherapy. We present two mouse models of kidney cancer that recapitulate the genomic alterations found in human papillary (pRCC) and clear cell RCC (ccRCC), the most common RCC subtypes. MYC activation results in highly penetrant pRCC tumours (MYC), while MYC activation, when combined with Vhl and Cdkn2a (Ink4a/Arf) deletion (VIM), produce kidney tumours that approximate human ccRCC. RNAseq of the mouse tumours demonstrate that MYC tumours resemble Type 2 pRCC, which are known to harbour MYC activation. Furthermore, VIM tumours more closely simulate human ccRCC. Based on their high penetrance, short latency, and histologic fidelity, these models of papillary and clear cell RCC should be significant contributions to the field of kidney cancer research.

Differential Diagnosis of Intraductal Lesions of the Prostate.

The category of intraductal lesions of the prostate includes a range of primary prostatic and nonprostatic processes with wide variation in prognosis and recommended follow-up. Studies have shown that pathologists are uncomfortable with the diagnosis of these lesions and that the diagnostic reproducibility is low in this category. Despite the diagnostic difficulty, their accurate and reproducible diagnosis is critical for patient management. This review aims to highlight the diagnostic criteria, prognosis, and treatment implications of common intraductal lesions of the prostate. It focuses on the recognition of intraductal carcinoma of the prostate (IDC-P) in prostate needle biopsies and how to distinguish it from its common mimickers, including high-grade prostatic intraepithelial neoplasia, invasive cribriform prostatic adenocarcinoma, urothelial carcinoma extending into prostatic ducts, and prostatic ductal adenocarcinoma. IDC-P is independently associated with higher risk disease, and its identification in a needle biopsy, even in the absence of invasive carcinoma, should compel definitive treatment. Conversely, high-grade prostatic intraepithelial neoplasia has a much better prognosis and in limited quantities does not even warrant a repeat biopsy. IDC-P must be distinguished from urothelial carcinoma involving prostatic ducts, as recommended treatment varies markedly. Ductal adenocarcinoma may confuse the pathologist and clinician by overlapping terminology, and morphology may also mimic IDC-P on occasion. The use of ancillary testing with immunohistochemistry and molecular markers has also been reviewed.

Renal oncocytoma with vascular invasion: a series of 22 cases

Renal oncocytomas are benign neoplasms that are often excised, as clinically they cannot be distinguished with certainty from renal cell carcinoma. One of the least common findings in oncocytomas is vascular invasion, and their behavior is not well characterized with only reports of isolated examples and smaller case series. Whether vascular invasion is acceptable for the diagnosis of oncocytoma still remains controversial, even amongst genitourinary pathologists with expertise in renal tumor pathology. Of 1474 cases of renal oncocytoma identified at 3 large medical centers, 22 (1.5%) had vascular invasion. Patients included 12 men and 10 women with an average age at diagnosis of 67.5 years (range, 48-91 years). Thirteen cases showed large vessel invasion, and the remainder involved medium or small vessels. Tumor was grossly visible in the renal vein in 2 cases. Clinical data were available on 16 of the 22 cases with an average follow-up time of 29.9 months (range, 7.5-94.5 months). Of the cases with clinical follow-up, all but one individual was alive. All living individuals were free of recurrence or metastatic disease at the time of last follow-up. Our cohort showed no metastasis or recurrence and overall survival of 94.7% at 2.5 years following diagnosis, supporting the finding that vascular invasion does not alter the favorable prognosis of oncocytoma. The presence of vascular invasion should not lead to any uncertainty about the diagnosis in an otherwise typical oncocytoma.

Getting cancer prevalence right: using state cancer registry data to estimate cancer survivors.

ObjectiveCancer incidence and mortality statistics provide limited insight regarding the cancer survivor population and its needs. Cancer prevalence statistics enumerate cancer survivors—those currently living with cancer. Commonly used limited-duration prevalence (LDP) methods yield biased estimates of the number of survivors. National estimates may not allow sufficient granularity to inform local survivorship programs. In this study, complete prevalence (CP) methods are applied to actual North Carolina Central Cancer Registry (NCCCR) data to generate better, more informative prevalence estimates than previous methods.MethodsData included all incident cases for 1995–2007 from the NCCCR and US Census population data. SEER*Stat software was used to calculate 13-year LDP. ComPrev software was used to estimate CP for each cancer site, gender, and race combination.ResultsCP methods estimated 362,810 survivors in North Carolina on January 1, 2008, 40% more than LDP estimates of 258,556, with substantial racial, regional, and gender differences in prevalence rankings of several cancers.ConclusionCP estimates are substantially higher than previous prevalence estimates. This study found previously unrecognized racial, regional, and gender differences. State and local programs may apply these methods using their own data to develop better, more detailed estimates to improve planning for their specific survivor populations’ needs.

Obesity is associated with worse overall survival in women with low-grade papillary serous epithelial ovarian cancer.

Objective The objective of this study was to evaluate prognostic risk factors for survival in women with low-grade serous epithelial ovarian cancer (LGSC). Methods A multicenter retrospective analysis of patients with LGSC was conducted. Potential epidemiologic risk factors evaluated included obesity, age, parity, race, smoking, oral contraceptive pill and/or hormonal replacement therapy use, and previous hysterectomy or surgery on fallopian tubes and/or ovaries. Additional factors included stage, extent of debulking, residual disease, and disease status. Results Eighty-one patients were identified, and pathologic diagnosis was independently confirmed. Median age at diagnosis was 56 years (range, 21–86 years). Thirty-four percent were obese, and 80% had optimally debulked disease. Forty-six percent were alive, 14% with disease, whereas 25% were dead of disease, 2% died of intercurrent disease, and 27% had an unknown status. In a univariate analysis, optimal surgical debulking was associated with improved progression-free survival (P = 0.01), disease-specific survival (P = 0.03), and overall survival (OS) (P < 0.001) and body mass index with worse OS (P = 0.05). On multivariate analysis, obesity (hazard ratio, 2.8; 95% confidence interval, 1.05–7.3; P = 0.04) and optimal tumor debulking (hazard ratio, 0.05; 95% confidence interval, 0.008–0.29; P = 0.001) were a significant predictor of OS. Conclusions In a multivariate analysis, obesity and optimal tumor cytoreduction were significant predictors of OS. However, obesity was not associated with worse disease-specific survival, suggesting that mortality of obese patients with LGSC may result from other comorbidities. Interventions addressing obesity may improve survival for women diagnosed with LGSC, and further study is warranted to address the role of obesity in LGSC.

Sav1 Loss Induces Senescence and Stat3 Activation Coinciding with Tubulointerstitial Fibrosis.

ABSTRACT Tubulointerstitial fibrosis (TIF) is recognized as a final phenotypic manifestation in the transition from chronic kidney disease (CKD) to end-stage renal disease (ESRD). Here we show that conditional inactivation of Sav1 in the mouse renal epithelium resulted in upregulated expression of profibrotic genes and TIF. Loss of Sav1 induced Stat3 activation and a senescence-associated secretory phenotype (SASP) that coincided with the development of tubulointerstitial fibrosis. Treatment of mice with the YAP inhibitor verteporfin (VP) inhibited activation of genes associated with senescence, SASPs, and activation of Stat3 as well as impeded the development of fibrosis. Collectively, our studies offer novel insights into molecular events that are linked to fibrosis development from Sav1 loss and implicate VP as a potential pharmacological inhibitor to treat patients at risk for developing CKD and TIF.