Pulmonary gangliocytic paraganglioma: An under-recognized mimic of carcinoid tumor.

Gangliocytic paragangliomas are rare neoplasms occurring almost exclusively in the ampullary region of the gastrointestinal tract. Although these tumors are not typically considered in the differential diagnosis of primary pulmonary neoplasia, 5 cases of primary pulmonary gangliocytic paragangliomas have been previously reported. Herein we report our experience with 3 additional examples, all referred to our Anatomic Pathology Consultation service. The patients (a 32-year-old man, a 69-year-old woman and a 55-year-old man) each presented with an endobronchial (2 cases) or upper lobe lung mass, ranging from 1.5 to 2.5 cm in maximum dimension. Biopsy and endobronchial debulking specimens demonstrated the classic triphasic morphology of gangliocytic paraganglioma, with epithelial, spindled and ganglion-like cells. By immunohistochemistry, the tumors were positive for keratin, synaptophysin and chromogranin A in the epithelial component, S100 protein and glial fibrillary acidic protein (GFAP) in the Schwannian spindled cells, and synaptophysin in ganglion cells. TTF1 expression was seen in the epithelial components of 2 cases. The Ki-67 labelling index was low (<2%). Primary pulmonary gangliocytic paragangliomas should be distinguished from carcinoid tumors, given the different natural histories and risk stratification approaches for these morphologically similar tumors. Awareness that gangliocytic paraganglioma may occur in the lung and appropriate immunohistochemical studies are key to correct diagnosis.

Inhibition of p38 MAPK attenuates renal atrophy and fibrosis in a murine renal artery stenosis model.

Renal artery stenosis (RAS) is an important cause of chronic renal dysfunction. Recent studies have underscored a critical role for CCL2 (MCP-1)-mediated inflammation in the progression of chronic renal damage in RAS and other chronic renal diseases. In vitro studies have implicated p38 MAPK as a critical intermediate for the production of CCL2. However, a potential role of p38 signaling in the development and progression of chronic renal disease in RAS has not been previously defined. We sought to test the hypothesis that inhibition of p38 MAPK ameliorates chronic renal injury in mice with RAS. We established a murine RAS model by placing a cuff on the right renal artery and treated mice with the p38 inhibitor SB203580 or vehicle for 2 wk. In mice treated with vehicle, the cuffed kidney developed interstitial fibrosis, tubular atrophy, and interstitial inflammation. In mice treated with SB203580, the RAS-induced renal atrophy was reduced (70% vs. 39%, P < 0.05). SB203580 also reduced interstitial inflammation and extracellular matrix deposition but had no effect on the development of hypertension. SB203580 partially blocked the induction of CCL2, CCL7 (MCP-3), CC chemokine receptor 2 (CCR2), and collagen 4 mRNA expression in the cuffed kidneys. In vitro, blockade of p38 hindered both TNF-α and TGF-ß-induced CCL2 upregulation. Based on these observations, we conclude that p38 MAPK plays a critical role in the induction of CCL2/CCL7/CCR2 system and the development of interstitial inflammation in RAS.

Axl regulated survival/proliferation network and its therapeutic intervention in mouse models of glomerulonephritis.

BACKGROUND: Lupus nephritis (LN) is the most common and serious complication of systemic lupus erythematosus (SLE). LN pathogenesis is not fully understood. Axl receptor tyrosine kinase is upregulated and contributes to the pathogenic progress in LN. We have reported that Axl disruption attenuates nephritis development in mice. METHODS: In this study, we analyzed the gene expression profiles with RNA-seq using renal cortical samples from nephritic mice. Axl-KO mice were bred onto a B6.lpr spontaneous lupus background, and renal disease development was followed and compared to the Axl-sufficient B6.lpr mice. Finally, anti-glomerular basement membrane (anti-GBM) Ab-induced nephritic mice were treated with Axl small molecule inhibitor, R428, at different stages of nephritis development. Blood urine nitrogen levels and renal pathologies were evaluated. RESULTS: Transcriptome analysis revealed that renal Axl activation contributed to cell proliferation, survival, and motility through regulation of the Akt, c-Jun, and actin pathways. Spontaneous lupus-prone B6.lpr mice with Axl deficiency showed significantly reduced kidney damages and decreased T cell infiltration compared to the renal damage and T cell infiltration in Axl-sufficient B6.lpr mice. The improved kidney function was independent of autoAb production. Moreover, R428 significantly reduced anti-GBM glomerulonephritis at different stages of GN development compared to the untreated nephritic control mice. R428 administration reduced inflammatory cytokine (IL-6) production, T cell infiltration, and nephritis disease activity. CONCLUSIONS: Results from this study emphasize the important role of Axl signaling in LN and highlight Axl as an attractive target in LN.

Rhizopus microsporus typhlitis in a patient with acute myelogenous leukemia.

While patients undergoing treatment for hematologic malignancies are at risk for a variety of infections, gastrointestinal mucormycosis is a rare and feared complication. Diagnosis requires a high index of suspicion and timely evaluation. Prompt treatment improves patient outcomes.

Mucinous Cystadenoma of the Urachus and Review of Current Classification of Urachal Mucinous Cystic Neoplasms.

Urachal neoplasms are uncommon and represent a minor portion of bladder tumors. According to the recently updated World Health Organization classification (2016), these tumors are classified as adenomas, adenocarcinomas, nonglandular neoplasms, and mixed carcinomas. The mucinous cystic neoplasms represent a small percentage of urachal tumors with morphologic spectrum ranging from benign mucinous cystadenoma to borderline mucinous cystic tumor of low malignant potential and to malignant mucinous cystadenocarcinoma. Benign urachal mucinous cystic adenomas are exceedingly rare, and only a few cases have been reported in the literature to date. The goal of this review is to summarize the clinical features, histopathologic characteristics, treatment, and prognosis of urachal mucinous cystadenoma in light of differentiating them from mucinous cystic tumor of low malignant potential and mucinous cystadenocarcinoma.

Noninvasive Contrast-Free 3D Evaluation of Tumor Angiogenesis with Ultrasensitive Ultrasound Microvessel Imaging.

Ultrasound microvessel imaging (UMI), when applied with ultrafast planewave acquisitions, has demonstrated superior blood signal sensitivity in comparison to conventional Doppler imaging. Here we propose a high spatial resolution and ultra-sensitive UMI that is based on conventional line-by-line high-frequency ultrasound imagers and singular value decomposition (SVD) clutter filtering for the visualization and quantification of tumor microvasculature and perfusion. The technique was applied to a chicken embryo tumor model of renal cell carcinoma that was treated with two FDA-approved anti-angiogenic agents at clinically relevant dosages. We demonstrate the feasibility of 3D evaluation with UMI to achieve highly sensitive detection of microvasculature using conventional line-by-line ultrasound imaging on a preclinical and commercially available high-frequency ultrasound device without software or hardware modifications. Quantitative parameters (vascularization index and fractional moving blood volume) derived from UMI images provide significantly improved evaluation of anti-angiogenic therapy response as compared with conventional power Doppler imaging, using histological analysis and immunohistochemistry as the reference standard. This proof-of-concept study demonstrates that high-frequency UMI is a low-cost, contrast-agent-free, easily applicable, accessible, and quantitative imaging tool for tumor characterization, which may be very useful for preclinical evaluation and longitudinal monitoring of anti-cancer treatment.

Well-Differentiated Laryngeal/Hypopharyngeal Liposarcoma in the MDM2 Era Report of Three Cases and Literature Review.

Laryngeal/hypopharyngeal liposarcomas are very rare, fewer than 40 cases have been reported. These tumors are polypoid, with a male predisposition, and usually cause hoarseness and difficulty breathing. Their clinical course is characterized by multiple local recurrences. No distant metastasis has been reported, and dedifferentiation is extremely rare. In sum, the prognosis of these tumors is excellent; the 5-year survival rate is essentially 100 %. Pathologic diagnosis of these well-differentiated liposarcomas can be challenging. Many of them were initially diagnosed as benign lipoma, fibrovascular polyp, or "inflammatory polyp". The correct diagnosis is usually made after multiple recurrences. On the other hand, the literature bears out that these incorrect diagnoses do not impact disease-specific survival. Here, we report three patients with laryngeal/hypopharyngeal well-differentiated liposarcomas; this is the first documentation of MDM2 amplification in liposarcomas at this site.

Pregnancy outcomes in autosomal dominant polycystic kidney disease: a case-control study.

OBJECTIVES: To determine whether autosomal dominant polycystic kidney disease (ADPKD) is associated with adverse fetal outcomes and maternal complications. METHODS: We identified a cohort of 146 patients seen for pregnancy and cystic kidney disease at Mayo Clinic from 1975 to 2010. From this cohort, 54 patients met the ultrasound diagnostic criteria for ADPKD (ADPKD group), while the other 92 patients were diagnosed as "Simple Cyst" (control group). We compared the fetal and maternal outcomes of pregnancy and long-term maternal prognoses between these two groups. RESULTS: Overall, the fetal complication rates were similar between the ADPKD and control groups. Rates of spontaneous abortion (15.1% versus 14%, p = 0.77) and premature birth (11.1% versus 6.8%, p = 0.44) were comparable between groups, while the rate of fetal distress (3.4% versus 0.7%, p < 0.01) was increased in the ADPKD group. The rate of preeclampsia in the patients with simple cysts (2%) was similar to that of the general population. In contrast, the pregnant ADPKD patients had higher risks for hypertension, proteinuria, edema, urinary tract infection, renal dysfunction and preeclampsia during their pregnancies. CONCLUSION: ADPKD is associated with increased maternal complications during pregnancy, but only has a slight potential of increased rates of fetal complications.

Androgens regulate TRAIL-induced cell death in prostate cancer cells via multiple mechanisms.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising therapeutic agent for prostate cancer because it selectively induces apoptosis in cancer cells but not in normal cells. Previous reports have suggested that androgens regulate TRAIL-induced apoptosis in prostate cancer cells. However, there are discrepancies between these reports of how androgens affect TRAIL-induced cell death. To clarify the role of androgens on TRAIL-induced apoptosis in prostate cancer cells, we investigated the effects of androgen on TRAIL-induced cell death in a dose-response manner. Our results showed that although androgens sensitize LNCaP cells to TRAIL-induced apoptosis, this effect is dose-dependent and biphasic. We found that low levels of androgen are superior to high levels of androgen in term of sensitizing LNCaP cells to TRAIL. We also found that upregulation of DR5 (TRAIL-R2) expression by androgens is critical for sensitizing LNCaP cells to TRAIL. However, low levels of androgen are sufficient to induce DR5 expression and sensitize LNCaP cells to TRAIL-induced cell death. High levels of androgen alter the TRADD/RIP1 ratio, which may contribute to NF-κB activation and sequentially inhibit TRAIL-induced apoptosis.

Androgen action during prostate carcinogenesis.

Androgens are critical for normal prostate development and function, as well as prostate cancer initiation and progression. Androgens function mainly by regulating target gene expression through the androgen receptor (AR). Many studies have shown that androgen-AR signaling exerts actions on key events during prostate carcinogenesis. In this review, androgen action in distinct aspects of prostate carcinogenesis, including (i) cell proliferation, (ii) cell apoptosis, and (iii) prostate cancer metastasis will be discussed.

Reduced tumor necrosis factor receptor-associated death domain expression is associated with prostate cancer progression.

By using LNCaP and its derivative cell lines, we first observed an association between tumor necrosis factor-alpha (TNF-alpha) resistance and hormone independence. Moreover, we found that the expression of tumor necrosis factor receptor-associated death domain (TRADD) was reduced in androgen deprivation-independent cells compared with that in androgen deprivation-dependent cells. TRADD is a crucial transducer for TNF-alpha-induced nuclear factor-kappaB (NF-kappaB) activation. Knocking down TRADD expression in LNCaP cells impaired TNF-alpha-induced NF-kappaB activation and androgen receptor repression, whereas overexpression of TRADD in C4-2B cells restored their sensitivity to TNF-alpha. Finally, we found that androgen deprivation reduces TRADD expression in vitro and in vivo, suggesting that androgen deprivation therapy may promote the development of TNF-alpha resistance by reducing TRADD expression during prostate cancer progression.

Skp2 inhibits FOXO1 in tumor suppression through ubiquitin-mediated degradation.

Forkhead transcription factors FOXO1 (FKHR), FOXO3a (FKHRL1), and FOXO4 (AFX) play a pivotal role in tumor suppression by inducing growth arrest and apoptosis. Loss of function of these factors due to phosphorylation and proteasomal degradation has been implicated in cell transformation and malignancy. However, the ubiquitin ligase necessary for the ubiquitination of the FOXO factors and the relevance of this regulation to tumorigenesis have not been characterized. Here we demonstrate that Skp2, an oncogenic subunit of the Skp1/Cul1/F-box protein ubiquitin complex, interacts with, ubiquitinates, and promotes the degradation of FOXO1. This effect of Skp2 requires Akt-specific phosphorylation of FOXO1 at Ser-256. Moreover, expression of Skp2 inhibits transactivation of FOXO1 and abolishes the inhibitory effect of FOXO1 on cell proliferation and survival. Furthermore, expression of the FOXO1 protein is lost in a mouse lymphoma model, where Skp2 is overexpressed. These data suggest that the Skp2-promoted proteolysis of FOXO1 plays a key role in tumorigenesis.