Citations

Fibrosing mediastinitis (FM) and IgG4-related disease (IgG4-RD) are two fibroinflammatory disorders with potentially overlapping clinical and radiological features. In this paper, we looked for histopathologic features of IgG4-RD and enumerated infiltrating IgG4-positive plasma cells within mediastinal tissue biopsies from FM patients. We identified 15 consecutive FM surgical mediastinal tissue biopsies between 1985 and 2006. All patients satisfied the clinical and radiological diagnostic criteria for FM. All patients had either serological or radiological evidence of prior histoplasmosis or granulomatous disease, respectively. Formalin-fixed paraffin-embedded tissue sections of all patients were stained for H&E, IgG, and IgG4. Three samples met the predefined diagnostic criteria for IgG4-RD. In addition, characteristic histopathologic changes of IgG4-RD in the absence of diagnostic numbers of tissue infiltrating IgG4-positive plasma cells were seen in a number of additional cases (storiform cell-rich fibrosis in 11 cases, lymphoplasmacytic infiltrate in 7 cases, and obliterative phlebitis/arteritis in 2 cases). We conclude that up to one-third of histoplasmosis or granulomatous-disease-associated FM cases demonstrate histopathological features of IgG4-RD spectrum. Whether these changes occur as the host immune response against Histoplasma or represent a manifestation of IgG4-RD remains to be determined. Studies to prospectively identify these cases and evaluate their therapeutic responses to glucocorticoids and/or other immunosuppressive agents such as rituximab are warranted.

Abstract Purpose: miRNA plays an important role in human disease and cancer. We seek to investigate the expression status, clinical relevance, and functional role of miRNA in non–small cell lung cancer. Experimental Design: We conducted miRNA expression profiling in matched lung adenocarcinoma and uninvolved lung using 56 pairs of fresh-frozen (FF) and 47 pairs of formalin-fixed, paraffin-embedded (FFPE) samples from never smokers. The most differentially expressed miRNA genes were evaluated by Cox analysis and log-rank test. Among the best candidate, miR-708 was further examined for differential expression in two independent cohorts. Functional significance of miR-708 expression in lung cancer was examined by identifying its candidate mRNA target and through manipulating its expression levels in cultured cells. Results: Among the 20 miRNAs most differentially expressed between tested tumor and normal samples, high expression level of miR-708 in the tumors was most strongly associated with an increased risk of death after adjustments for all clinically significant factors including age, sex, and tumor stage (FF cohort: HR, 1.90; 95% CI, 1.08–3.35; P = 0.025 and FFPE cohort: HR, 1.93; 95% CI, 1.02–3.63; P = 0.042). The transcript for TMEM88 gene has a miR-708 binding site in its 3′ UTR and was significantly reduced in tumors high of miR-708. Forced miR-708 expression reduced TMEM88 transcript levels and increased the rate of cell proliferation, invasion, and migration in culture. Conclusions: miRNA-708 acts as an oncogene contributing to tumor growth and disease progression by directly downregulating TMEM88, a negative regulator of the Wnt signaling pathway in lung cancer. Clin Cancer Res; 18(13); 3658–67. ©2012 AACR.

What's known on the subject? and What does the study add? There is great variability in the utilization of partial nephrectomy, but the causes of these variations are not well understood. The present study underscores the already observed phenomenon of surgical volume influencing surgical planning and outcomes, but it gets at why this might be so. We observe that high‐volume renal surgeons have different thresholds of ‘technical feasibility’. Objective To investigate why there continues to be wide variability in the application of partial nephrectomy ( PN ) for treating small renal masses despite guidelines in the US and E urope stating that a PN is a standard of care for a patient with a T 1 renal mass. Patients and Methods In June 2009, 764 surgeon‐members of the A merican U rologic A ssociation ( AUA ) participated in a survey evaluating the management of renal masses. Renal mass complexity was graded by nephrometry score ( NS ). Multivariable logistic regression models with generalized estimating equations were constructed to evaluate how tumour, surgeon and practice‐setting characteristics influence the use of PN . Results The survey response rate was 19%. Each urological surgeon responded to eight scenarios, providing 6112 evaluable cases. Tumour NS ranged from 4 to 10, and each unit increase in NS was associated with 59% increased likelihood of a surgeon offering RN on multivariable analysis (odds ratio [ OR ] = 1.59; 95% CI : 1.52–1.64). When holding patient and tumour characteristics constant, the following surgeon and practice‐setting characteristics significantly increased the odds of offering a PN: increasing renal case volume ( OR = 1.57; 95% CI : 1.27–1.95), academic practice ( OR = 1.80; 95% CI : 1.42–2.29), increasing PN % volume ( OR = 3.7; 95% CI : 2.46–5.55) and younger surgeon age (≤40 vs >50 years) ( OR = 1.64; 95% CI : 1.35–1.96). Conclusion The characteristics of a surgeon and the setting in which he or she practices influence the utilization of PN , the adherence to professional guidelines, and the threshold of tumour complexity at which a surgeon stops offering PN .

AbstractRecently, we have identified serum response factor (SRF) as a mediator of clinically relevant androgen receptor (AR) action in prostate cancer (PCa). Genes that rely on SRF for androgen responsiveness represent a small fraction of androgen-regulated genes, but distinguish benign from malignant prostate, correlate with aggressive disease, and are associated with biochemical recurrence. Thus, understanding the mechanism(s) by which SRF conveys androgen regulation to its target genes may provide novel opportunities to target clinically relevant androgen signaling. Here, we show that the small GTPase ras homolog family member A (RhoA) mediates androgen-responsiveness of more than half of SRF target genes. Interference with expression of RhoA, activity of the RhoA effector Rho-associated coiled-coil containing protein kinase 1 (ROCK), and actin polymerization necessary for nuclear translocation of the SRF cofactor megakaryocytic acute leukemia (MAL) prevented full androgen regulation of SRF target genes. Androgen treatment induced RhoA activation, increased the nuclear content of MAL, and led to MAL recruitment to the promoter of the SRF target gene FHL2. In clinical specimens RhoA expression was higher in PCa cells than benign prostate cells, and elevated RhoA expression levels were associated with aggressive disease features and decreased disease-free survival after radical prostatectomy. Overexpression of RhoA markedly increased the androgen-responsiveness of select SRF target genes, in a manner that depends on its GTPase activity. The use of isogenic cell lines and a xenograft model that mimics the transition from androgen-stimulated to castration-recurrent PCa indicated that RhoA levels are not altered during disease progression, suggesting that RhoA expression levels in the primary tumor determine disease aggressiveness. Androgen-responsiveness of SRF target genes in castration-recurrent PCa cells continued to rely on AR, RhoA, SRF, and MAL and the presence of intact SRF binding sites. Silencing of RhoA, use of Rho-associated coiled-coil containing protein kinase 1 inhibitors, or an inhibitor of SRF-MAL interaction attenuated (androgen-regulated) cell viability and blunted PCa cell migration. Taken together, these studies demonstrate that the RhoA signaling axis mediates clinically relevant AR action in PCa.

Abstract Background: Genome-wide association studies (GWAS) identified variants at 19p13.1 and ZNF365 (10q21.2) as risk factors for breast cancer among BRCA1 and BRCA2 mutation carriers, respectively. We explored associations with ovarian cancer and with breast cancer by tumor histopathology for these variants in mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). Methods: Genotyping data for 12,599 BRCA1 and 7,132 BRCA2 mutation carriers from 40 studies were combined. Results: We confirmed associations between rs8170 at 19p13.1 and breast cancer risk for BRCA1 mutation carriers [HR, 1.17; 95% confidence interval (CI), 1.07–1.27; P = 7.42 × 10−4] and between rs16917302 at ZNF365 (HR, 0.84; 95% CI, 0.73–0.97; P = 0.017) but not rs311499 at 20q13.3 (HR, 1.11; 95% CI, 0.94–1.31; P = 0.22) and breast cancer risk for BRCA2 mutation carriers. Analyses based on tumor histopathology showed that 19p13 variants were predominantly associated with estrogen receptor (ER)-negative breast cancer for both BRCA1 and BRCA2 mutation carriers, whereas rs16917302 at ZNF365 was mainly associated with ER-positive breast cancer for both BRCA1 and BRCA2 mutation carriers. We also found for the first time that rs67397200 at 19p13.1 was associated with an increased risk of ovarian cancer for BRCA1 (HR, 1.16; 95% CI, 1.05–1.29; P = 3.8 × 10−4) and BRCA2 mutation carriers (HR, 1.30; 95% CI, 1.10–1.52; P = 1.8 × 10−3). Conclusions: 19p13.1 and ZNF365 are susceptibility loci for ovarian cancer and ER subtypes of breast cancer among BRCA1 and BRCA2 mutation carriers. Impact: These findings can lead to an improved understanding of tumor development and may prove useful for breast and ovarian cancer risk prediction for BRCA1 and BRCA2 mutation carriers. Cancer Epidemiol Biomarkers Prev; 21(4); 645–57. ©2012 AACR.

AbstractBackgroundIndications and survival benefit for adrenalectomy (ADX) in the setting of metastasis are not clearly defined. We aimed to determine which patients with primary malignancies may benefit from ADX performed for metastasis. Mayo Clinic institutional outcomes in patients with metastatic disease to the adrenal(s) treated by adrenalectomy were compared to stage‐matched historical controls from the Surveillance Epidemiology and End Results (SEER) database.MethodsA retrospective review (1992–2010) was conducted to identify patients treated with ADX for metastatic cancer at Mayo Clinic, Rochester. Associations of clinical, surgical, and pathologic features with overall survival (OS) were evaluated using Cox proportional regression models. OS for those treated with ADX was compared with that for SEER database stage‐matched patients who underwent primary resection without resection of distant disease using log‐rank tests.ResultsA total of 166 patients underwent ADX for metastatic primaries involving the kidney 60, lung 24, sarcoma 19, colon 15, pancreas 13, and other‐35. Patients with sarcoma and kidney, lung, and pancreatic tumors who underwent ADX had better OS at 1, 2, and 3 years than did the SEER‐matched controls. Respectively, the rates were for sarcoma (100, 93, 86% vs. 57, 36, 30%), kidney (86, 80, 72% vs. 55, 37, 27%), lung (91, 69, 52% vs. 52, 34, 25%), and pancreas (79, 56, 45% vs. 33, 20, 12%). Univariate analysis identified primary diagnosis <2 years before ADX, other distant site, pancreatic primary, palliative operation, and persistent disease as risk factors for death.ConclusionsAn aggressive surgical approach results in improved OS in patients with metastatic disease arising from soft tissues, kidney, lung, and pancreas. Other tumors may benefit, but larger study cohorts are needed for a meaningful comparison.