Toll-Like Receptor 9 Deficiency Breaks Tolerance to RNA-Associated Antigens and Up-Regulates Toll-Like Receptor 7 Protein in Sle1 Mice.

OBJECTIVE: Toll-like receptors (TLRs) 7 and 9 are important innate signaling molecules with opposing roles in the development and progression of systemic lupus erythematosus (SLE). While multiple studies support the notion of a dependency on TLR-7 for disease development, genetic ablation of TLR-9 results in severe disease with glomerulonephritis (GN) by a largely unknown mechanism. This study was undertaken to examine the suppressive role of TLR-9 in the development of severe lupus in a mouse model. METHODS: We crossed Sle1 lupus-prone mice with TLR-9-deficient mice to generate Sle1TLR-9-/- mice. Mice ages 4.5-6.5 months were evaluated for severe autoimmunity by assessing splenomegaly, GN, immune cell populations, autoantibody and total Ig profiles, kidney dendritic cell (DC) function, and TLR-7 protein expression. Mice ages 8-10 weeks were used for functional B cell studies, Ig profiling, and determination of TLR-7 expression. RESULTS: Sle1TLR-9-/- mice developed severe disease similar to TLR-9-deficient MRL and Nba2 models. Sle1TLR-9-/- mouse B cells produced more class-switched antibodies, and the autoantibody repertoire was skewed toward RNA-containing antigens. GN in these mice was associated with DC infiltration, and purified Sle1TLR-9-/- mouse renal DCs were more efficient at TLR-7-dependent antigen presentation and expressed higher levels of TLR-7 protein. Importantly, this increase in TLR-7 expression occurred prior to disease development, indicating a role in the initiation stages of tissue destruction. CONCLUSION: The increase in TLR-7-reactive immune complexes, and the concomitant enhanced expression of their receptor, promotes inflammation and disease in Sle1TLR9-/- mice.

Prospective validation of %p2PSA and the Prostate Health Index, in prostate cancer detection in initial prostate biopsies of Asian men, with total PSA 4-10 ng ml-1.

Despite its widespread use for prostate cancer screening, low specificity makes PSA a suboptimal biomarker, especially in the diagnostic "gray zone" of 4-10 ng ml-1 . False-positives lead to unnecessary biopsies with attendant morbidities. This is the first prospective validation study of %p2PSA and the Prostate Health Index (PHI) in Asian men presenting with a total PSA between 4.0 and 10 ng ml-1 . We studied 157 Asian men between 50 and 75 years old, with normal per rectal prostate examinations, undergoing their first prostate biopsy, using a standardized biopsy protocol, for PSA levels of 4-10 ng ml-1 . Thirty (19.1%) were found to have prostate cancer on biopsy. Statistically significant differences between patients with and without prostate cancer were found for total PSA, p2PSA, %p2PSA, and PHI. The areas under the curve of the receiver operating characteristic curve for total PSA, %fPSA, %p2PSA, and PHI were 0.479, 0.420, 0.695, and 0.794, respectively. PHI predicts prostatic biopsies results best. At a sensitivity of 90%, the specificity (95% CI) of PHI was 58.3%, more than triple the specificity of total PSA at 17.3%, potentially avoiding 77 (49%) unnecessary biopsies. Similar to studies in mainly Caucasian populations, we have prospectively shown that %p2PSA and PHI greatly outperform total and free to total PSA ratio, in the detection of prostate cancer at first biopsy. Higher PHI levels also correspond to increasing the risk of detecting GS ≥7 cancers. We have validated the use of PHI to aid decision-making regarding prostate biopsies in Asian men with serum PSA between 4 and 10 ng ml-1 .

RNA sensing by conventional dendritic cells is central to the development of lupus nephritis.

Glomerulonephritis is a common and debilitating feature of systemic lupus erythematosus (SLE). The precise immune mechanisms that drive the progression from benign autoimmunity to glomerulonephritis are largely unknown. Previous investigations have shown that a moderate increase of the innate Toll-like receptor 7 (TLR7) is sufficient for the development of nephritis. In these systems normalization of B-cell TLR7 expression or temporal depletion of plasmacytoid dendritic cells (pDCs) slow progression; however, the critical cell that is responsible for driving full immunopathology remains unidentified. In this investigation we have shown that conventional DC expression of TLR7 is essential for severe autoimmunity in the Sle1Tg7 model of SLE. We show that a novel expanding CD11b(+) conventional DC subpopulation dominates the infiltrating renal inflammatory milieu, localizing to the glomeruli. Moreover, exposure of human myeloid DCs to IFN-α or Flu increases TLR7 expression, suggesting they may have a role in self-RNA recognition pathways in clinical disease. To our knowledge, this study is the first to highlight the importance of conventional DC-TLR7 expression for kidney pathogenesis in a murine model of SLE.

High R.E.N.A.L. Nephrometry scores are associated with pathologic upstaging of clinical T1 renal-cell carcinomas in radical nephrectomy specimens: implications for nephron-sparing surgery.

BACKGROUND AND PURPOSE: The R.E.N.A.L. Nephrometry Score (RNS) was developed to standardize the reporting of anatomic information of a renal mass. This study aimed to identify the association of preoperative clinical and tumor features assessed by the RNS with pathologic upstaging of clinical T1 renal-cell carcinomas (RCCs) in complete en bloc radical nephrectomy (RN) specimens. PATIENTS AND METHODS: A review was performed for 65 consecutive patients (2005-2013) who underwent RNs for a unilateral clinical T1N0M0 RCC. The RNS was measured in all patients based on preoperative CT scans. Pathologic review was performed to identify patients with final pathologic upstaging. Associations were assessed with the Fisher exact test, Student t test, and Wilcoxon rank sum test. RESULTS: Of the 65 patients (41 male, mean age 59 years), 4 (6%) patients were upstaged to pT2 and 16 (25%) were upstaged to pT3a and above in the final histologic evaluation. Upstaged patients were not significantly different from those without in terms of age, sex, race, surgical approach, side of surgery, Fuhrman grade, and histologic cell type. Independent tumor features associated with pathologic upstaging were (R) tumor diameter (P=0.021), and (L) central location within polar lines (P=0.010). Tumors that were upstaged had a higher median total RNS than those without (10 vs 9, P=0.010). Complex tumors, with RNS≥10, were associated with significantly increased risk of upstaging compared with low and intermediate complexity categories (RNS<10) (relative risk=2.56, 95% confidence interval 1.22-5.37, P=0.014). CONCLUSIONS: A higher RNS was associated with an increased risk of upstaging in clinical T1 cancers, predominantly from perinephric or sinus fat invasion in RN pathologic specimens. This may have implications on the selection of surgical option for the clinical T1 renal mass.

Pharyngoesophageal diverticulum resembling a thyroid nodule on ultrasound.

BACKGROUND: Ultrasound is routinely used in evaluating thyroid nodules and performing fine-needle aspiration cytology (FNAC). Occasionally, nonthyroidal lesions can mimic thyroid nodules on imaging and get wrongly aspirated. METHODS: A 63-year-old woman was reported to have an incidental left thyroid "nodule" on neck ultrasound scan. It was isoechoic with a surrounding hypoechoic rim and contained tiny foci of echogenicity. Similar findings were noted in a second surgeon-performed ultrasound scan. RESULTS: An ultrasound-guided FNAC showed abundant squamous cells, bacteria, and vegetable cells with no evidence of thyroid cells or colloid. The suspicion of a pharyngoesophageal diverticulum was confirmed on barium swallow. She remained asymptomatic with no increase in size at 6 months follow-up. CONCLUSION: A pharyngoesophageal diverticulum can be mistaken for a posteriorly placed "thyroid nodule" on ultrasound scan if the subtle differentiating signs are missed. An awareness of this condition is important to avoid unnecessary needle biopsies.

Mucinous cystadenocarcinoma of the breast with amplification of the HER2-gene confirmed by FISH: The first case reported.

We present the first case of a primary mucinous cystadenocarcinoma of the breast that, in addition to the characteristic immunophenotype (CK7(+), CK20(-), ER(-), PR(-), and cdx2(-)), showed a strong membranous HER2-protein expression and HER2-gene amplification documented by fluorescence in situ hybridization.

Acute abdominal pain secondary to retroperitoneal bleeding from a giant adrenal lipoma with review of literature.

Adrenal lipomas are rare, non-functioning benign tumours, which are primarily detected during autopsy or imaging, as asymptomatic incidentalomas. Occasionally, they can present with abdominal pain due to their large size. Imaging studies help to determine the origin, volume, composition of the lesion and presence of bleeding. Histopathology, however, is necessary to differentiate an adrenal lipoma from other fatty tumours such as myelolipoma, angiomyolipomas, teratomas and liposarcomas. We report a case of spontaneous bleeding from a giant adrenal lipoma that presented as an acute abdomen, and was initially mistaken on imaging for the more common myelolipoma. The literature is reviewed to discuss the clinical, pathological and radiological features, and the optimum therapeutic management.

Kimura disease of the eyelid in an Indian man.

Kimura disease is a rare idiopathic chronic inflammatory disease, characterized by subcutaneous nodular lesions in the head and neck area. Ophthalmic manifestation of Kimura disease involves orbital and eyelid lesions mostly in Asian patients, but it has been described in White patients and Black Caribbean patients. Kimura disease is usually associated with eosinophilia and occasionally with renal disease. Here, we report a case of Kimura disease of the eyelid in a 50-year-old Indian man with eosinophilia. The main differential diagnosis was angiolymphoid hyperplasia with eosinophilia. Histology is crucial to separate these two entities, and our case was shown to be Kimura disease by histology. To our knowledge, this is the first report of a person of Indian origin to develop Kimura disease involving the eyelid.

An investigation into the prognostic significance of necrosis and hypoxia in high grade and invasive bladder cancer.

PURPOSE: We investigated hypoxia and necrosis in high grade and invasive bladder cancer, and related this to prognosis. MATERIALS AND METHODS: We performed a retrospective observational study of 98 primary cystectomy specimens scored for necrosis, and the hypoxia associated markers carbonic anhydrase IX, hypoxia-inducible factor 1 alpha and 2 alpha, and Bcl2/adenovirus EIB 19 kDa interacting protein 3. Tumor tissue array was used with cores taken from representative and perinecrotic tumor regions. Necrosis was scored on whole sections as absent, less than 5 mm (comedo) or more than 5 mm (gross). RESULTS: Of the 98 cases analyzed followup data were available on 91. Median followup was 22 months (IQR 8-35). Stage was T0/1 to T4 in 18, 20, 41 and 12 cases, respectively. The prevalence of necrosis in bladder cancer was high and it increased with stage (17%, 30%, 70% and 71% at stages T0/1 to T4, respectively). Necrosis was significantly associated with stage (p = 0.0001) and nodal status (p = 0.016). Hypoxia-inducible factor 1 alpha showed no association with stage, grade or nodal status. Hypoxia-inducible factor 1 alpha and carbonic anhydrase IX showed a significant association with necrosis, whereas hypoxia-inducible factor 2 alpha and Bcl2/adenovirus EIB 19 kDa interacting protein 3 did not. Stage (p <0.0001), necrosis (p <0.0001) and intense hypoxia-inducible factor 1 positivity (p = 0.048) were the only significant prognostic factors on univariate analysis. Stage (HR 3.29, 95% CI 1.80-6.04, p <0.001) and necrosis (HR 1.92, 95% CI 1.05-3.51, p = 0.04) were independent prognostic factors on multivariate analysis, while hypoxia-inducible factor 1 lost significance (HR 1.36, 95% CI 0.98-1.88, p = 0.07). Node status was only reported in 45% of cases. CONCLUSIONS: Necrosis (the presence and amount) in high grade and invasive bladder cancer is an independent prognostic risk factor.

Urine cytology screening for polyoma virus infection following renal transplantation: the Oxford experience.

OBJECTIVE: To review the first year of a monthly urine cytology screening service, introduced to identify renal transplant patients at risk of polyoma virus nephropathy (PVN), at an early, potentially treatable, stage. METHODS AND RESULTS: Monthly urine samples (n = 392) were received from 97/108 transplant recipients in 2005. Of 56 patients with follow-up >6 months, 20% and 9% had significant (>10 decoy cells/cytospin) and non-significant positive cytology, respectively. The first positive urine samples occurred most commonly in the second and third month post-transplantation and patients with significantly positive samples had higher 3-month and 6-month serum creatinine levels than patients with negative urine cytology (p<0.01). Four patients with positive urine cytology had a subsequent positive plasma BK virus PCR; 3/97 patients had biopsy-proven PVN, all in the third month, 1-6 weeks after first positive urine samples. CONCLUSIONS: Significant PV viruria is common following renal transplantation with onset usually within the first 3 months. Viruria is associated with worse graft function at 3 and 6 months. The time between urine positivity and clinical PVN is short. More frequent early urine screening would be required to achieve clinical benefit.

Expression of Bcl-x in normal skin and benign cutaneous adnexal tumors.

BACKGROUND: Bcl-x appears to have an antiapoptotic role in the epidermis. Little is known about the expression of Bcl-x in cutaneous adnexal structures and benign cutaneous adnexal tumors. METHODS: Tissues from 31 cases of benign cutaneous adnexal tumors (five trichofolliculomas, five trichoepitheliomas, two sebaceous adenomas, five apocrine hidradenomas, five eccrine poromas, five eccrine spiradenomas, and four syringomas) were immunostained for Bcl-x. RESULTS: Strong staining for Bcl-x was seen in cells of the epidermal granular layer and inner root sheath of hair follicles. Sebaceous gland cells showed strong staining. Apocrine gland cells showed weak to moderate staining. No staining was seen in eccrine gland cells. The basaloid cells of trichofolliculomas and trichoepitheliomas showed no staining. In sebaceous adenomas, the sebaceous cells showed strong staining while the basaloid cells were negative. The cells of apocrine hidradenomas showed patchy weak staining. No staining was seen in eccrine poromas, eccrine spiradenomas, and syringomas. CONCLUSIONS: The degree of Bcl-x expression in cutaneous adnexal glandular structures appears to be related to their mode of secretion, being strongest in cells with apoptotic degradation of the entire cell (sebocytes). This pattern is recapitulated in the corresponding benign cutaneous adnexal tumors. Bcl-x may be useful in identifying cells with sebaceous differentiation in poorly differentiated adnexal tumors.