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PURPOSE: BRAF(V600E), a major driver of thyroid cancer, evaluated in the context of thyroid hormones and human relaxin. METHODS: Immunohistochemical expression of BRAF(V600E), TSH, TSH receptor (TSHR), T4, T3 receptor (T3R), RLNH2, and its receptor, RXFP1, were evaluated in thyroid tumors from a retrospective U.S. population of 481 cancer cases diagnosed in 1983-2004. RESULTS: BRAF(V600E) was expressed in 52% of all thyroid tumors; expression of other markers ranged from 25% for T4 to 98% for RLNH2. Tumors predominantly exhibited hypothyroid-like conditions characterized by elevated TSH and TSHR and reduced T4. BRAF(V600E) prevalence was significantly higher in tumors expressing TSH, TSHR, T3R, and RXFP1 and lower in tumors expressing T4. The proportion of BRAF(V600E) mutation in classic papillary tumors significantly increased from 56% to 72% over the 21-year period of diagnoses while expression of RXFP1, TSH, TSHR, and T3R decreased in non-tumor. Racial/ethnic differences were observed in thyroid hormone marker expression. Non-tumor expression of TSH, TSHR, and T3R were each associated with shorter overall survival but did not remain significant after adjustment for demographic and clinical factors. CONCLUSIONS: Our study provides the first evidence of the potential interaction of BRAF(V600E) mutation, relaxin, and thyroid hormones in thyroid carcinogenesis. Moreover, our results suggest that hypothyroidism, influenced by RLNH2 activity, may underlie the development of the majority of thyroid cancers and mediate the role of BRAF(V600E) in thyroid carcinogenesis. BRAF(V600E) mutation is increasing in papillary thyroid cancers and may be contributing to the rising incidence of this malignancy

BackgroundCombining an immune checkpoint inhibitor with a tumor vaccine may modulate the immune system to leverage complementary mechanisms of action that lead to sustained T-cell activation and a potent prolonged immunotherapeutic response in metastatic castration resistant prostate cancer (mCRPC).MethodsSubjects with asymptomatic or minimally symptomatic mCRPC were randomly assigned in a 1:1 ratio to receive either atezolizumab followed by sipuleucel-T (Arm 1) or sipuleucel-T followed by atezolizumab (Arm 2). The primary endpoint was safety, while secondary endpoints included preliminary clinical activity such as objective tumor response and systemic immune responses that could identify key molecular and immunological changes associated with sequential administration of atezolizumab and sipuleucel-T.ResultsA total of 37 subjects were enrolled. The median age was 75.0 years, median prostate specific antigen (PSA) was 21.9 ng/mL, and subjects had a median number of three prior treatments. Most subjects (83.8%) had at least one treatment-related adverse event. There were no grade 4 or 5 toxicities attributed to either study drug. Immune-related adverse events and infusion reactions occurred in 13.5% of subjects, and all of which were grade 1 or 2. Of 23 subjects with Response Evaluation Criteria in Solid Tumors measurable disease, only one subject in Arm 2 had a partial response (PR) and four subjects overall had stable disease (SD) at 6 months reflecting an objective response rate of 4.3% and a disease control rate of 21.7%. T-cell receptor diversity was higher in subjects with a response, including SD. Immune response to three novel putative antigens (SIK3, KDM1A/LSD1, and PIK3R6) appeared to increase with treatment.ConclusionsOverall, regardless of the order in which they were administered, the combination of atezolizumab with sipuleucel-T appears to be safe and well tolerated with a comparable safety profile to each agent administered as monotherapy. Correlative immune studies may suggest the combination to be beneficial; however, further studies are needed.Trial registration numberNCT03024216.

Objectives The role of HPV in oral cavity cancers was investigated using two markers of viral exposure. Materials and methods HPV DNA and p16INK4a expression were evaluated in tumor tissue from a U.S. population-based sample of 122 invasive oral cavity cancer cases. Results HPV DNA was detected in 38 of 122 (31%) oral cavity tumors. Seven genotypes were detected including HPV 16, which was found in 22% of tumors. p16INK4a was expressed in 30% of tumors and was poorly correlated with HPV DNA detection (Kappa Conclusions Based on both HPV DNA and p16INK4a, HPV is etiologically linked to a limited subset of oral cavity cancers. However, the role of HPV in oral cavity cancer may vary widely by subsite and may have increased over time, similar to trends observed for oropharyngeal cancer.

Intravesical BCG is active against non-muscle invasive bladder cancer (NMIBC), but bladder cancer will recur and even progress in a significant number of patients. To improve the response rate, N-803, an IL-15 superagonist was administered in combination with BCG. To evaluate the safety and efficacy associated with the use of intravesical N-803 and BCG in patients with BCG-naïve NMIBC. This phase 1b clinical trial used a 3 + 3 dose-escalation design. Participants were enrolled from July 2014 and July 2015, with follow-up and analyses through January 15, 2021. Eligibility criteria included histologically confirmed non-muscle invasive urothelial carcinoma of intermediate or high risk who had not received prior treatment with intravesical BCG (ie, BCG-naïve). All 9 participants met the eligibility criteria, received treatment according to the protocol, and were included in all analyses. Treatment was done once weekly for 6 consecutive weeks with bladder infusion of the standard dose of BCG, 50 mg/instillation, in combination with increasing doses of N-803 (100, 200, or 400 µg N-803 per instillation). No DLTs were noted in any of the dose cohorts. All adverse events (AEs) were manageable and less than grade 3. During the 2-year follow-up, all 9 participants were disease free. Furthermore, 6 y after treatment, all 9 participants (100%) were disease free with no evidence of disease progression and an intact bladder. This phase 1b trial found the combination of intravesical N-803 and BCG to be associated with modest toxic effects, low immunogenicity, and substantial prolonged antitumoral activity; phase 2 trials are in progress.

Background Accumulating evidence suggests that plasminogen activator inhibitor-1 (PAI-1) plays an important role in bladder tumorigenesis by regulating cell cycle. However, it remains unclear whether and how inhibition of PAI-1 suppresses bladder tumorigenesis. Methods To elucidate the therapeutic effect of PAI-1 inhibition, we tested its tumorigenicity in PAI-1 knockout (KO) mice exposed to a known bladder carcinogen. Results PAI-1 deficiency did not inhibit carcinogen-induced bladder cancer in mice although carcinogen-exposed wild type mice significantly increased PAI-1 levels in bladder tissue, plasma and urine. We found that PAI-1 KO mice exposed to carcinogen tended to upregulate protein C inhibitor (PAI-3), urokinase-type plasminogen activator (uPA) and tissue-type PA (tPA), and significantly increased PAI-2, suggesting a potential compensatory function of these molecules when PAI-1 is abrogated. Subsequent studies employing gene expression microarray using mouse bladder tissues followed by post hoc bioinformatics analysis and validation experiments by qPCR and IHC demonstrated that SERPING1 is further downregulated in PAI-1 KO mice exposed to BBN, suggesting that SERPING1 as a potential missing factor that regulate PAI-2 overexpression (compensation pathway). Conclusions These results indicate that serpin compensation pathway, specifically PAI-2 overexpression in this model, supports bladder cancer development when oncoprotein PAI-1 is deleted. Further investigations into PAI-1 are necessary in order to identify true potential targets for bladder cancer therapy.

We set out to expand on our previous work in which we reported the epithelial expression pattern of a urine-based bladder cancer-associated diagnostic panel (A1AT, ANG, APOE, CA9, IL8, MMP9, MMP10, PAI1, SDC1, and VEGFA). Since many of the analytes in the bladder cancer-associated diagnostic signature were chemokines, cytokines, or secreted proteins, we set out to report the stromal staining pattern of the diagnostic signature as well as CD3+ (T-cell) cell and CD68+ (macrophage) cell staining in human bladder tumors as a snapshot of the tumor immune landscape. Immunohistochemical staining was performed on 213 tumor specimens and 74 benign controls. Images were digitally captured and quantitated using Aperio (Vista, CA). The expression patterns were correlated with tumor grade, tumor stage, and outcome measures. We noted a positive correlation of seven of the 10 proteins (excluding A1AT and IL8 which had a negative association and VEGFA had no association) in bladder cancer. The overexpression of MMP10 was associated with higher grade disease, while overexpression of MMP10, PAI1, SDC1 and ANG were associated with high stage bladder cancer and CA9 was associated with low stage bladder cancer. Increased tumor infiltration of CD68+ cells were associated with higher stage disease. Overall survival was significantly reduced in bladder cancer patients&rsquo, whose tumors expressed eight or more of the 10 proteins that comprise the bladder cancer diagnostic panel. These findings confirm that the chemokines, cytokines, and secreted proteins in a urine-based diagnostic panel are atypically expressed, not only in the epithelial component of bladder tumors, but also in the stromal component of bladder tumors and portends a worse overall survival. Thus, when assessing immunohistochemical staining, it is important to report staining patterns within the stroma as well as the entire stroma itself.

Purpose To determine the relationship between hepatic uptake at preoperative fluorine 18 (18F) fluorocholine combined positron emission tomography (PET) and computed tomography (CT) and the histopathologic features of chronic liver disease in patients with Child-Pugh class A or B disease who are undergoing hepatic resection for liver cancer. Materials and Methods Forty-eight patients with resectable liver tumors underwent preoperative 18F fluorocholine PET/CT. Mean liver standardized uptake value (SUVmean) measurements were obtained from PET images, while histologic indexes of inflammation and fibrosis were applied to nontumor liver tissue from resection specimens. Effects of histopathologic features on liver SUVmean were examined with analysis of variance. Results Liver SUVmean ranged from 4.3 to 11.6, correlating significantly with Knodell histologic activity index (ρ = -0.81, P < .001) and several clinical indexes of liver disease severity. Liver SUVmean also differed significantly across groups stratified by necroinflammatory severity and Metavir fibrosis stage (P < . 001). The area under the receiver operating characteristic curve for 18F fluorocholine PET/CT detecting Metavir fibrosis stage F1 or higher was 0.89 ± 0.05, with an odds-ratio of 3.03 (95% confidence interval: 1.59, 5.88) and sensitivity and specificity of 82% and 93%, respectively. Conclusion Correlations found in patients undergoing hepatic resection for liver cancer between liver 18F fluorocholine uptake and histopathologic indexes of liver fibrosis and inflammation support the use of 18F fluorocholine PET/CT as a potential imaging biomarker for chronic liver disease. © RSNA, 2018.

Rectal squamous cell carcinoma (SCC) is a rare tumor with unresolved etiology. Human immunodeficiency virus-infected individuals and solid organ transplant recipients experience >30-fold and approximately 3-fold elevated rates of rectal SCC, respectively, suggesting immunosuppression plays a role.1 Human immunodeficiency virus-infected homosexual men have >60-fold higher rates of rectal SCC, similar to anal SCC. These patterns, which differ from the more common rectal adenocarcinoma (AdCA), raise the possibility of shared etiology between rectal and anal SCC, with human papillomavirus type 16 (HPV16) being a likely candidate.2.

Aberrant sphingolipid metabolism has been reported to promote breast cancer progression. Sphingosine kinase 1 (SphK1) is a key metabolic enzyme for the formation of pro-survival S1P from pro-apoptotic ceramide. The role of SphK1 in breast cancer has been well studied in estrogen receptor (ER)-positive breast cancer; however, its role in human epidermal growth factor 2 (HER2)-positive breast cancer remains unclear. Here, we show that genetic deletion of SphK1 significantly reduced mammary tumor development with reduced tumor incidence and multiplicity in the MMTV-neu transgenic mouse model. Gene expression analysis revealed significant reduction of claudin-2 (CLDN2) expression in tumors from SphK1 deficient mice, suggesting that CLDN2 may mediate SphK1's function. It is remarkable that SphK1 deficiency in HER2-positive breast cancer model inhibited tumor formation by the different mechanism from ER-positive breast cancer. In vitro experiments demonstrated that overexpression of SphK1 in ER-/PR-/HER2+ human breast cancer cells enhanced cell proliferation, colony formation, migration and invasion. Furthermore, immunostaining of SphK1 and CLDN2 in HER2-positive human breast tumors revealed a correlation in high-grade disease. Taken together, these findings suggest that SphK1 may play a pivotal role in HER2-positive breast carcinogenesis. Targeting SphK1 may represent a novel approach for HER2-positive breast cancer chemoprevention and/or treatment.

// Owen T.M. Chan 1, * , Hideki Furuya 1, * , Ian Pagano 2 , Yoshiko Shimizu 1, 3 , Kanani Hokutan 1, 3 , Lars Dyrskjot 4 , Jorgen Bjerggaard Jensen 5 , Per-Uno Malmstrom 6 , Ulrika Segersten 6 , Filip Janku 7 and Charles J. Rosser 1 1 Clinical and Translational Research Program University of Hawaii Cancer Center, Honolulu, HI, USA 2 Cancer Prevention and Control Program Research Program University of Hawaii Cancer Center, Honolulu, HI, USA 3 Department of Molecular Biosciences and Bioengineering, University of Hawaii at Manoa, Honolulu, HI, USA 4 Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark 5 Department of Urology, Aarhus University Hospital, Aarhus, Denmark 6 Departments of Surgical Sciences, Uppsala University, Uppsala, Sweden 7 Department of Investigational Cancer Therapeutics, University of Texas MD Anderson Cancer Center, Houston, TX, USA * Co-first authors Correspondence to: Charles J. Rosser, email: cjrosser@hawaii.edu Keywords: angiogenin, bladder cancer, IHC, MMP-2, PAI-1 Received: May 07, 2017 Accepted: July 12, 2017 Published: September 06, 2017 ABSTRACT Background: We previously reported an accurate urine-based bladder cancer (BCa)-associated diagnostic signature that can be used to non-invasively detect BCa. In this study, we investigated whether a component of this signature could risk stratify patients with BCa. Methods: Utilizing immunohistochemistry, we investigated angiogenin, MMP-2, p53, RB and PAI-1 expression from 939 patients with BCa. The expression levels were scored by assigning a proportion score and an intensity score to yield a total staining score for each protein. The expressions of each protein individually and as an aggregate were then correlated with progression-free survival (PFS), cancer-specific survival (CSS) and overall survival (OS). Results: Differential expressions of these markers were noted in BCa. With multivariate analysis in non-muscle invasive bladder cancer (NMIBC) age, tumor grade portended a worse PFS, while age, tumor grade, nodal status, MMP2, RB and PAI-1 expression portended a worse OS. As for multivariate analysis in muscle invasive bladder cancer (MIBC), age MMP-2 and RB were associated with a worse PFS, while age, nodal status, MMP-2, RB and PAI-1 were associated with a worse OS. Using Kaplan-Meier survival analysis, we noted a significant reduction in OS as more of the five biomarkers were expressed in a tumor. Thus, overall, high expressions of MMP-2, RB and/or PAI-1 in bladder tumors were markers of poor prognosis. Conclusion: Individually, MMP-2, RB and PAI-1, as well as in aggregate correlated with poor survival in patients with BCa. Thus, patients whose bladder tumors express these biomarkers may benefit from early radical treatment and/or neoadjuvant or adjuvant therapies.

OBJECTIVES: The role of HPV in oral cavity cancers was investigated using two markers of viral exposure. MATERIALS AND METHODS: HPV DNA and pl6(INK4a) expression were evaluated in tumor tissue from a U.S. population-based sample of 122 invasive oral cavity cancer cases. RESULTS: HPV DNA was detected in 38 of 122 (31%) oral cavity tumors. Seven genotypes were detected including HPV 16, which was found in 22% of tumors. pl6(INK4a) was expressed in 30% of tumors and was poorly correlated with HPV DNA detection (Kappa < 0.1). Joint positivity for HPV 16 and/or 18 and pl6(INK4a) was observed in only 7% of cases. When comparing cases diagnosed in 1993–1999 and in 2000–2004, positivity for HPV DNA 16/18 increased from 19% to 39% (p = 0.02) and joint HPV 16/18 - pl6(INK4a) positivity increased from 0% to 12% (p = 0.01). For gingival tumors, HPV 16 and/or 18 positivity was 67% compared to 11–38% for other sites (p = 0.02); joint HPV 16/18 - pl6(INK4a) positivity was 33% compared to 0–8% for other sites (p = 0.01). The association of HPV with gingival tumors and more recent diagnosis period remained after adjustment for age and stage (p < 0.05). Neither HPV DNA nor pl6(INK4a) were associated with overall survival. CONCLUSIONS: Based on both HPV DNA and pl6(1NK4a), HPV is etiologically linked to a limited subset of oral cavity cancers. However, the role of HPV in oral cavity cancer may vary widely by subsite and may have increased over time, similar to trends observed for oropharyngeal cancer.

PURPOSE: To determine the relationship between hepatic uptake at preoperative fluorine 18 ((18)F) fluorocholine combined positron emission tomography (PET) and computed tomography (CT) and the histopathologic features of chronic liver disease in patients with Child-Pugh class A or B disease who are undergoing hepatic resection for liver cancer. MATERIALS AND METHODS: Forty-eight patients with resectable liver tumors underwent preoperative (18)F fluorocholine PET/CT. Mean liver standardized uptake value (SUV(mean)) measurements were obtained from PET images, while histologic indexes of inflammation and fibrosis were applied to nontumor liver tissue from resection specimens. Effects of histopathologic features on liver SUV(mean) were examined with analysis of variance. RESULTS: Liver SUV(mean) ranged from 4.3 to 11.6, correlating significantly with Knodell histologic activity index (ρ = −0.81, P < .001) and several clinical indexes of liver disease severity. Liver SUV(mean) also differed significantly across groups stratified by necroinflammatory severity and Metavir fibrosis stage (P < . 001). The area under the receiver operating characteristic curve for (18)F fluorocholine PET/CT detecting Metavir fibrosis stage F1 or higher was 0.89 ± 0.05, with an odds-ratio of 3.03 (95% confidence interval: 1.59, 5.88) and sensitivity and specificity of 82% and 93%, respectively. CONCLUSION: Correlations found in patients undergoing hepatic resection for liver cancer between liver (18)F fluorocholine uptake and histopathologic indexes of liver fibrosis and inflammation support the use of (18)F fluorocholine PET/CT as a potential imaging biomarker for chronic liver disease. (©) RSNA, 2018

Background Accumulating evidence suggests that sphingosine kinase 1 (SphK1)/sphingosine 1-phosphate pathway plays a pivotal role in colon carcinogenesis. Methods To further support the evidence, we investigated the effects of SphK1 using three separate animal models: SphK1 knockout mice, SphK1 overexpressing transgenic mice, and SphK1 overexpression in human colon cancer xenografts. Using azoxymethane (AOM, colon carcinogen), we analyzed colon tumor development in SphK1 KO and SphK1 overexpression in intestinal epithelial cells regulated by a tet-on system. Then, we analyzed subcutaneous tumor growth using xenografts of HT-29 human colon cancer cell. Finally, immunohistochemical analyses for SphK1 and COX-2 were performed on human colon cancer tissue microarray. Results SphK1 KO mice, compared to wild-type mice, demonstrated a significant inhibition in colon cancer development induced by AOM (58.6% vs. 96.4%, respectively, P

Background: Hepatocellular carcinoma (HCC) incidence is increasing in the United States. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of HCC. Hepatitis infection in patients with HCC is generally diagnosed by serology, which is not always consistent with the presence of HBV and HCV in the liver. The relationship of liver viral status to serostatus in hepatocarcinogenesis is not fully understood. Methods: HBV and HCV were evaluated in formalin-fixed, paraffin-embedded liver tissue specimens in a retrospective study of 61 U.S. HCC cases of known serologic status. HBV DNA and HCV RNA were detected by PCR, reverse transcription PCR (RT-PCR), and pyrosequencing, and HBsAg and HBcAg were evaluated by immunohistochemistry. Results: Viral markers were detected in the liver tissue of 25 of 61 (41%) HCC cases. Tissue viral and serologic status were discordant in 27 (44%) cases, including those with apparent “occult” infection. Specifically, HBV DNA was detected in tissue of 4 of 39 (10%) serum HBsAg (−) cases, including 1 anti-HCV(+) case; and HCV RNA was detected in tissue of 3 of 42 (7%) anti-HCV seronegative cases, including two with serologic evidence of HBV. Conclusions: Viral hepatitis, including HBV-HCV coinfection, may be unrecognized in up to 17% of patients with HCC when based on serology alone. Further research is needed to understand the clinical significance of viral makers in liver tissue of patients with HCC in the absence of serologic indices. Impact: The contribution of HBV and HCV to the increasing incidence of HCC in the United States may be underestimated. Cancer Epidemiol Biomarkers Prev; 22(11); 2016–23. ©2013 AACR.

There are conflicting studies associating twin pregnancies derived from assisted reproductive technology (ART) with preterm birth, low birthweight, and other negative outcomes. This work investigates whether ART is linked with any placental pathology, given that placentation significantly influences fetal development. A 5-year, retrospective cohort study was conducted on placentas from twin pregnancies. The placental information from 417 patients was divided into two groups: placentas derived from ART and placentas derived from spontaneous pregnancies (non-ART). Available clinical information and pathologic findings from both groups then were compared. There was no statistical difference in the prevalence of placental pathology between the non-ART and ART cohorts (i.e., cord insertion, single umbilical artery, cord knot, retroplacental hemorrhage, infarction, vasculopathy, vascular anastomoses, chorangiosis, villitis, deciduitis, chorioamnionitis, meconium staining). However, 8% of ART multiple pregnancies were monochorionic. While monochorionicity is a known risk factor for adverse obstetric and neonatal outcomes, the rate of monochorionic placentation did not increase as a result of ART. Nevertheless, it is interesting to note that this small percentage of monochorionic placentation occurred in the ART cohort despite the implantation of individual embryos. Overall, the data suggests that ART does not have a role in the pathologic placentation of twin pregnancies.

Positron emission tomography (PET) using the radiopharmaceutical tracer fluorine-18 fluorocholine (FCh) can elucidate tumors based on differences in choline phospholipid metabolism between tumor and surrounding tissue. The feasibility of detecting hepatocellular carcinoma (HCC) using FCh PET has been shown despite constitutively high parenchymal choline metabolism in the liver. Since HCC frequently develops in the setting of chronic liver disease, we comparatively evaluated FCh PET/CT between cirrhotic and non-cirrhotic patients with HCC to investigate the effects of hepatic dysfunction on tumor detection and the tumor-to-background ratio (TBR) of FCh uptake. FCh PET/CT was performed prospectively in 22 consecutive patients with HCC (7 newly diagnosed, 15 previously treated). Of these 22 patients, 14 were cirrhotic and 8 non-cirrhotic. Standardized uptake value (SUV) measurements were obtained by region of interest analysis of the PET images. Tumor FCh uptake and the TBR were compared between cirrhotic and non-cirrhotic patients. Liver lesions were confirmed to be HCC by biopsy in 10 patients and by Barcelona criteria in 4 patients. There was correspondingly increased liver tumor FCh uptake in 13/14 of those patients, and iso-intense tumor FCh uptake (TBR 0.94) in one non-cirrhotic patient with newly diagnosed HCC. FCh PET/CT also showed metastatic disease without local tumor recurrence in 2 previously treated patients, and was negative in 6 treated patients without tumor recurrence by radiographic and clinical follow-up. Tumor maximum SUV ranged from 6.4 to 15.3 (mean 12.1) and liver TBR ranged from 0.94 to 2.1 (mean 1.6), with no significant differences between cirrhotic and non-cirrhotic patients (SUVmax 11.9 vs. 12.2, p = 0.83, TBR 1.71 vs. 1.51, p = 0.29). Liver parenchyma mean SUV was significantly lower in cirrhotic patients (6.4 vs. 8.7, p &lt, 0.05). This pilot study supports the general feasibility of HCC detection by FCh PET/CT. However, a broad range of tumor FCh uptake was observed, and lower liver parenchymal uptake of FCh was noted in cirrhotic patients as compared to non-cirrhotic patients. Incorporating tissue profiling into future liver imaging trials of FCh PET may help determine the molecular basis of the observed variations in tumor and hepatic FCh uptake.

In a previously published study, we showed that expression of theABCD3gene increased with increasing metastatic potential in a panel of prostate cancer cell lines derived from African American and Caucasian American men. Given importance of identifying biomarker(s) that can distinguish indolent versus aggressive prostate tumors, we conducted an immunohistochemical analysis ofABCD3expression Caucasian and African American prostate tumors.ABCD3expression in each patient population was compared with clinicopathologic characteristics, Gleason score, and age.ABCD3expression increased with increasing Gleason score (P=0.0094), age (P=0.0014), and pathology grade (P=0.0007) in Caucasian patients. Interestingly, in the AA patients,ABCD3expression highly increased to the same degree in both low and high Gleason score tumors. Similarly,ABCD3expression was elevated to the same degree in BPH derived from AA. Our findings demonstrate that increasedABCD3expression correlates with Gleason Score in CA prostate tumors. However, in AA prostate tumors,ABCD3expression was higher and was sustained in both low Gleason and high Gleason AA tumors. While the functional role ofABCD3in prostate cancer is not completely elucidated, this gene warrants further study as a potential biomarker for aggressive prostate.

Objective To compare the effects of combined administration of cyclophosphamide (CYC) and CTLA-4Ig with the effects of these agents alone on the immunopathology and progression of renal damage in (NZB × NZW)F1 (B/W) lupus-prone mice, and to explore the clinical implications of this combination by evaluating the ability of CTLA-4Ig to sustain the benefit of CYC in patients with lupus nephritis. Methods We carried out a detailed, prospective pathologic and immunohistochemical analysis of the effects of CYC and CTLA-4Ig, alone and in combination, in kidney tissue from B/W mice. The acute effects of these agents on immune cells in the kidney were evaluated by fluorescence-activated cell sorting. We also compared the effect of brief CYC plus sustained CTLA-4Ig administration with the effect of sustained administration of both agents on the progression of renal disease in B/W mice. Results As a single agent, CTLA-4Ig was generally as effective, and in some cases more effective, than CYC in slowing progression of renal disease. Combined therapy with these two agents very effectively arrested the progression of renal damage and, in some respects, reversed renal pathology. Induction therapy with both CTLA-4Ig and CYC precluded the need for continuous administration of CYC. Conclusion Our results indicate that the combination of CTLA-4Ig and CYC very effectively arrests the progression of murine lupus nephritis. These findings have direct implications for the treatment of lupus nephritis.

Spontaneous CD8+ T cell activation in MRL-Faslpr mice is B cell dependent. It is unclear whether this B-dependent activation is mediated by direct Ag presentation via MHC class I proteins (i.e., cross-presentation) or whether activation occurs by an indirect mechanism, e.g., via effects on CD4+ cells. To determine how CD8+ T cell activation is promoted by B cells, we created mixed bone marrow chimeras where direct MHC class I Ag presentation by B cells was abrogated while other leukocyte compartments could express MHC class I. Surprisingly, despite the absence of B cell class I-restricted Ag presentation, CD8+ T cell activation was intact in the chimeric mice. Therefore, the spontaneous B cell-dependent CD8+ T cell activation that occurs in systemic autoimmunity is not due to direct presentation by B cells to CD8+ T cells.

B cells are required for both the expression of lupus nephritis and spontaneous T cell activation/memory cell accumulation in MRL-Faslpr mice (MRL/lpr). Autoimmunity in the MRL/lpr strain is the result of Fas-deficiency and multiple background genes; however, the precise roles of background genes vs Fas-deficiency have not been fully defined. Fas-deficiency (i.e., the lpr defect) is required in B cells for optimal autoantibody expression, raising the possibility that the central role for B cells in MRL/lpr mice may not extend to MRL/+ mice and, thus, to lupus models that do not depend on Fas-deficiency (“polygenic lupus”). To address this issue, B cell-deficient, Fas-intact MRL/+ mice (JHd-MRL/+) were created; and disease was evaluated in aged animals (>9 mo). The JHd-MRL/+ animals did not develop nephritis or vasculitis at a time when the B cell-intact littermates had severe disease. In addition, while activated/memory CD4+ and CD8+ T cells accumulated in B cell-intact mice, such accumulation was substantially inhibited in the absence of B cells. This effect appeared to be restricted to the MRL strain because it was not seen in B cell-deficient BALB/c mice (JHd-BALB) of similar ages. The results indicate that B cells are essential in promoting systemic autoimmunity in a Fas-independent model. Therefore, B cells have an important role in pathogenesis, generalizable to lupus models that depend on multiple genes even when Fas expression is intact. The results provide further rationale for B cell suppression as therapy for systemic lupus erythematosus.

The precise role of B cells in systemic autoimmunity is incompletely understood. Although B cells are necessary for expression of disease (Chan, O., and M.J. Shlomchik. 1998. J. Immunol. 160:51–59, and Shlomchik, M.J., M.P. Madaio, D. Ni, M. Trounstine, and D. Huszar. 1994. J. Exp. Med. 180:1295–1306), it is unclear whether autoantibody production, antigen presentation, and/or other B cell functions are required for the complete pathologic phenotype. To address this issue, two experimental approaches were used. In the first, the individual contributions of circulating antibodies and B cells were analyzed using MRL/MpJ-Faslpr (MRL/lpr) mice that expressed a mutant transgene encoding surface immunoglobulin (Ig), but which did not permit the secretion of circulating Ig. These mice developed nephritis, characterized by cellular infiltration within the kidney, indicating that B cells themselves, without soluble autoantibody production, exert a pathogenic role. The results indicate that, independent of serum autoantibody, functional B cells expressing surface Ig are essential for disease expression, either by serving as antigen-presenting cells for antigen-specific, autoreactive T cells, or by contributing directly to local inflammation.

Pseudosarcomatous reactive myofibroblastic proliferations have been described following surgery or trauma at a variety of anatomical sites. These types of reactions have not been previously described at injection sites. Here we evaluated prevalence, morphologic patterns and clinical resolution of such lesions.We analyzed 266 surgical resection specimens obtained during the definitive treatment of piriformis syndrome. Three cases showed exuberant reactive fibroblastic/myofibroblastic intramuscular proliferations, mimicking a sarcoma. In all three cases the surgeries were found to be preceded by local injections of cortisone and bupivacaine. Clinical follow-up revealed no uncontrolled growth.As the clinical history of injections is often not provided, it is important to be aware of this pitfall when reviewing skeletal muscle resections for entrapment syndromes.

Current methods that assay hemoglobin beta-globin chain variants can have limited clinical sensitivity when applied techniques identify only a predefined panel of mutations. Even sequence-based assays may be limited depending on which gene regions are investigated. We sought to develop a clinically practical yet inclusive molecular assay to identify beta-globin mutations in multicultural populations. We highlight the beta-globin mutation detection assay (beta-GMDA), an extensive gene sequencing assay. The polymerase chain reaction (PCR) primers are located to encompass virtually all hemoglobin beta locus (HBB) mutations. In addition, this assay is able to detect, by gap PCR, a common large deletion (Delta619 base pair), which would be missed by sequencing alone. We describe our 5-year experience with the beta-GMDA and indicate its capability for detecting homozygous, heterozygous, and compound heterozygous sequence changes, including previously unknown HBB variants. The beta-GMDA offers superior sensitivity and ease of use with comprehensive detection of HBB mutations that result in beta-globin chain variants.

Various factors contribute to the development of porphyria cutanea tarda (PCT). In this case report, we describe a patient with hepatitis C infection and chronic renal failure. The individual mechanisms, which promote cutaneous disease, are discussed. Finally, we propose that each factor may have an additive effect in prolonging the skin lesions of PCT.

Intestinal ganglioneuromas comprise benign, hamartomatous polyps characterized by an overgrowth of nerve ganglion cells, nerve fibers, and supporting cells in the gastrointestinal tract. This polyposis has been divided into 3 subgroups, each with a different degree of ganglioneuroma formation: polypoid ganglioneuroma, ganglioneuromatous polyposis, and diffuse ganglioneuromatosis. The ganglioneuromatous polyposis subgroup is not known to coexist with systemic disorders that often have an associated intestinal polyposis, such as multiple endocrine neoplasia type IIb, neurofibromatosis type I, and Cowden syndrome. We report a case of ganglioneuromatous polyposis plus cutaneous lipomatosis in a 41-year-old man with no established systemic disease. However, he possessed unique anatomic findings in addition to his ganglioneuromatosis, suggesting that the ganglioneuromatosis-lipomatosis in our patient may represent an unrecognized syndrome. This case report and brief review of the literature provide an overview of intestinal ganglioneuromatosis in relation to the hereditary polyposis syndromes and describe the individual ganglioneuromatosis subgroups.

Cockroaches are known carriers of bacteria and fungi that produce disease in humans. However, the link between pathogenic helminths and cockroaches has not been fully explored. This preliminary study demonstrates Trichinella and Enterobius (also known as human "pinworm") infestation in cockroaches obtained from a grade school and hospitals in Hawaii. This is the first report of Trichinella and Enterobius infestation in naturally occurring cockroaches. These results suggest that roachs are an unappreciated hosts for these human pathogens and are potential reservoirs for these nematodes, supporting their persistence and transmissibility in the environment. Given the ubiquitous nature of the cockroach and the human-occupied settings in which the infested roaches were found, public health concerns are apparent. Furthermore, this information may have diagnostic value when examining Trichinella and Enterobius-infected individuals.

When mutations that inactivate molecules that function in the immune system have been crossed to murine lupus strains, the result has generally been a uniform up-regulation or down-regulation of autoimmune disease in the end organs. In the current work we report an interesting dissociation of target organ disease in β2-microglobulin (β2m)-deficient MRL-Faslpr (MRL/lpr) mice: lupus skin lesions are accelerated, whereas nephritis is ameliorated. β2m deficiency affects the expression of classical and nonclassical MHC molecules and thus prevents the normal development of CD8- as well as CD1-dependent NK1+ T cells. To further define the mechanism by which β2m deficiency accelerates skin disease, we studied CD1-deficient MRL/lpr mice. These mice do not have accelerated skin disease, excluding a CD1 or NK1+ T cell-dependent mechanism of β2m deficiency. The data indicate that the regulation of systemic disease is not solely governed by regulation of initial activation of autoreactive lymphocytes in secondary lymphoid tissue, as this is equally relevant to renal and skin diseases. Rather, regulation of autoimmunity can also occur at the target organ level, explaining the divergence of disease in skin and kidney in β2m-deficient mice.

A standard view of B cells in systemic autoimmunity is that they promote lupus by producing autoantibodies (autoAb). However, this view is incomplete because recent studies have revealed that autoimmune disease can be dissociated from autoAb deposition. Furthermore, the spontaneous T-cell activation and organ infiltration in systemic lupus erythematosus patients and animal models are difficult to explain entirely via a direct autoAb-mediated mechanism. In this review, we describe work addressing the B-cell functions of autoantigen presentation and autoAb production in lupus pathogenesis. In the JHD-MRL-Faslpr strain (JHD/lpr), a B-cell-deficient version of the lupus-prone MRL-Faslpr (MRL/lpr) mouse, spontaneous nephritis and dermatitis is abrogated, demonstrating that B cells have a primary role in disease. B cells play a similar role in Fas-intact, lupus-prone MRL mice. To address the role of autoantigen presentation, we analyzed transgenic mice which have B cells that cannot secrete immunoglobulin (mIgM transgenic mice). The restoration of B cells without antibody caused substantial interstitial nephritis and vasculitis although less marked than the intact MRL/lpr controls. To address the role of autoAb, we infused serum from aged MRL/lpr mice into JHD/lpr mice. At most, mild to no nephritis was observed in the infused mice. These results indicate that B cells are promoting autoimmunity in mechanisms other than autoAb secretion, and we describe a model depicting these B-cell roles in the context of other inflammatory events in lupus.