An unusual cause of back pain: a case of large nonfunctioning retroperitoneal paraganglioma presented as a large cystic lesion. A case report and review of literature.

Pheochromocytoma arising from outside the adrenal glands is also called paraganglioma. When it occurs below the diaphragm, in the organ of Zuckerkandl or retroperitoneum, it is also called extra-adrenal pheochromocytoma. Paragangliomas are rare tumors which arise from neuroendocrine cells and extra-adrenal paragangliomas (EAPs) account for only 10-15% if all paragangliomas and may present incidentally as a symptomless mass. Typical triad of sweating, headache and fluctuating hypertension if not present makes preoperative diagnosis difficult. Surgical excision is the treatment of choice. Definitive diagnosis is usually made with histological findings. We report a case of large retroperitoneal tumor with size >10 cm which was a high risk depicting malignancy.

Inflammatory myofibroblastic tumours of the urinary bladder: multi-centre 18-year experience.

OBJECTIVE: To review a series of inflammatory myofibroblastic tumours (IMTs) of the urinary bladder in 10 hospitals in Hong Kong. METHODS: A database search in the pathology archives of 10 hospitals in Hong Kong from 1995 to 2013 was performed using the key words 'inflammatory myofibroblastic tumour', 'inflammatory pseudotumour' and 'spindle cell lesion'. Patient characteristics, clinical features, histological features, immunohistochemical staining results and treatment outcomes were reviewed. RESULTS: Nine cases of IMT of the urinary bladder were retrieved. The mean age was 45.4 ± 22.8 years (range 11-78). Eight patients (88.9%) presented with haematuria and 5 patients (55.6%) had anaemia with a mean haemoglobin level of 6.8 ± 1.3 g/dl. Histologically, the majority of patients (77.8%) had a compact spindle cell pattern. Anaplastic lymphoma kinase staining was positive in 75% of cases. During a mean follow-up period of 43.4 months (range 8-94), none of them developed any local recurrence or distant metastasis. CONCLUSIONS: A high index of suspicion of IMT should be maintained for young patients presenting with bleeding bladder tumours and significant anaemia. IMTs of the urinary bladder run a benign disease course, and good prognosis can be achieved after surgical resection.

Methylation of miR-155-3p in mantle cell lymphoma and other non-Hodgkin's lymphomas.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma (NHL). In cancers, tumor suppressive microRNAs may be silenced by DNA hypermethylation. By microRNA profiling of representative EBV-negative MCL cell lines before and after demethylation treatment, miR-155-3p was found significantly restored. Methylation-specific PCR, verified by pyrosequencing, showed complete methylation of miR-155-3p in one MCL cell line (REC-1). 5-aza-2'-deoxycytidine treatment of REC-1 led to demethylation and re-expression of miR-155-3p. Over-expression of miR-155-3p led to increased sub-G1 apoptotic cells and reduced cellular viability, demonstrating its tumor suppressive properties. By luciferase assay, lymphotoxin-beta (LT-ß) was validated as a miR-155-3p target. In 31 primary MCL, miR-155-3p was found hypermethylated in 6(19%) cases. To test if methylation of miR-155-3p was MCL-specific, miR-155-3p methylation was tested in an additional 191 B-cell, T-cell and NK-cell NHLs, yielding miR-155-3p methylation in 66(34.6%) including 36(27%) non-MCL B-cell, 24(53%) T-cell and 6(46%) of NK-cell lymphoma. Moreover, in 72 primary NHL samples with RNA, miR-155-3p methylation correlated with miR-155-3p downregulation (p=0.024), and LT-ß upregulation (p=0.043). Collectively, miR-155-3p is a potential tumor suppressive microRNA hypermethylated in MCL and other NHL subtypes. As miR-155-3p targets LT-ß, which is an upstream activator of the non-canonical NF-kB signaling, miR-155-3p methylation is potentially important in lymphomagenesis.

Epigenetic inactivation of the MIR129-2 in hematological malignancies.

BACKGROUND: MIR129-2 has been shown to be a tumor suppressor microRNA hypermethylated in epithelial cancers. PATIENTS AND METHODS: Epigenetic inactivation of MIR129-2 was studied by methylation-specific PCR (MSP) in 13 cell lines (eight myeloma and five lymphoma), 15 normal controls and 344 primary samples including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myeloid leukemia (CML), chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), multiple myeloma (MM) at diagnosis, MM at relapse/progression, and monoclonal gammopathy of undetermined significance (MGUS). Expression of MIR129 and its target, SOX4, in cell lines was measured before and after hypomethylating treatment and MIR129 overexpression. MIR129 expression was correlated with MIR129-2 methylation status in primary lymphoma samples. Tumor suppressor function of MIR129 was demonstrated by MTT and trypan blue exclusion assay after MIR129 overexpression. RESULTS: The sensitivity of the methylated-MSP was one in 10(3). Different MSP statuses, including complete methylation, partial methylation, and complete unmethylation, were verified by quantitative bisulfite pyrosequencing. All five lymphoma and seven of eight myeloma cell lines showed complete and partial MIR129-2 methylation. In primary samples, MIR129-2 methylation was absent in AML and CML, but detected in 5% ALL, 45.9% CLL, 49.5% MM at diagnosis, and 59.1% NHL. In CLL, MIR129-2 methylation adversely impacted on survival (p=0.004). In MM, MIR129-2 methylation increased from 27.5% MGUS to 49.5% MM at diagnosis and 41.5% at relapse/progression (p=0.023). In NHL, MIR129-2 methylation was associated with MIR124-1 and MIR203 methylation (p<0.001), and lower MIR129 expression (p=0.009). Hypomethylation treatment of JEKO-1, homozygously methylated for MIR129-2, led to MIR129-2 demethylation and MIR129 re-expression, with downregulation of SOX4 mRNA. Moreover, MIR129 overexpression in both mantle cell lines, JEKO-1 and GRANTA-519, inhibited cellular proliferation and enhanced cell death, with concomitant SOX4 mRNA downregulation. CONCLUSIONS: MIR129-2 is a tumor suppressive microRNA frequently methylated in lymphoid but not myeloid malignancies, leading to reversible MIR129-2 silencing. In CLL, MIR129-2 methylation was associated with an inferior survival. In MM, MIR129-2 methylation might be acquired during progression from MGUS to symptomatic MM. In NHL, MIR129-2 methylation might collaborate with MIR124-1 and MIR203 methylation in lymphomagenesis.

Epigenetic inactivation of the hsa-miR-203 in haematological malignancies.

miR-203 is a tumour suppressor microRNA (miRNA). We studied the methylation of hsa-miR-203 in 150 samples including acute myeloid leukaemia (AML), acute lymphoblastic leukaemia (ALL), chronic myeloid leukaemia (CML), chronic lymphocytic leukaemia (CLL) and non-Hodgkin's lymphoma (NHL) by methylation-specific PCR, and miRNA expression by stem-loop RT-qPCR. hsa-miR-203 promoter was unmethylated in normal controls but homozygously methylated in two AML and four lymphoma cell lines, in which 5-Aza-2'-deoxycytidine treatment led to promoter demethylation and miR-203 re-expression. Restoration of miR-203 expression in lymphoma cells inhibited cellular proliferation and increased cell death, suggesting an inherent tumour suppressor activity. In primary samples, hsa-miR-203 methylation was absent in CML but detected in 5.0% ALL, 10.0% AML, 42.0% CLL and 38.8% of NHL (including six [60.0%] natural killer-cell, nine [40.9%] B-cell and four [23.5%] T cell NHL). Moreover, hsa-miR-203 methylation was associated with hypermethylation of hsa-miR-34a, -124a and -196b in NHL but not CLL. In CLL, hsa-miR-203 methylation was associated with a higher presenting Hb level (P = 0.033). The projected 10 year overall survival of the CLL patients was 58.2%, which was impacted by Rai stage and high-risk karyotypes but not hsa-miR-203 methylation. hsa-miR-203 was more frequently methylated in lymphoid than myeloid malignancies (P = 0.002). In conclusion, miR-203, a tumour suppressor gene, was hypermethylated in a tumour-specific manner with gene silencing. hsa-miR-203 was more frequently hypermethylated in lymphoid than myeloid malignancies. In NHL, hsa-miR-203 methylation was associated with concomitant methylation of other tumour suppressor miRNAs. The frequent hsa-miR-203 methylation in lymphoid malignancies suggested a pathogenetic role of hsa-miR-203 methylation.

Conversion of ciclosporin A to tacrolimus in kidney transplant recipients with chronic allograft nephropathy.

BACKGROUND: Tacrolimus and ciclosporin might have different effects on intra-renal fibrosis and allograft function in chronic allograft nephropathy (CAN). It is difficult to predict the response to calcineurin inhibitor minimization in patients with CAN. METHODS: This prospective randomized study compared ciclosporin A (CsA)-to-tacrolimus conversion (group A, target tacrolimus trough level 6-8 ng/ml) vs CsA minimization (group B, target CsA trough level 80-100 ng/ml) with regard to efficacy and safety in patients with CAN and deteriorating allograft function. The primary efficacy endpoint was improvement in the slope of inverse serum creatinine (1/SCr) vs time plot. RESULTS: There were 34 evaluable patients (n=16 in group A; n=18 in group B), with similar baseline characteristics. Both groups reached target drug levels after a 3-month run-in period. Over the ensuing 12 months, nine (56.3%) subjects in group A and 10 (55.6%) in group B reached the primary end point (P=0.968). Both groups showed considerable improvement in the slope of 1/SCr vs time plot. There was no significant difference in the slope between groups before and after intervention. Graft survival was 87% in group A and 100% in group B (P=0.121). Acute rejection was encountered in two group A subjects. There was no significant change or difference in blood glucose, lipids, and blood pressure between groups. CONCLUSION: Our results suggest that in patients with CAN and deteriorating allograft function, CsA-to-tacrolimus conversion or CsA minimization achieved comparable efficacies in retarding the decline of graft function. Such contention may be biased by the low patient number. Further studies with a larger cohort are needed for validation.

Predictors and outcome of renal flares after successful cyclophosphamide treatment for diffuse proliferative lupus glomerulonephritis.

OBJECTIVE: To study the incidence, predictors, and outcome of renal flares after successful cyclophosphamide (CYC) treatment for diffuse proliferative glomerulonephritis (DPGN) in patients with systemic lupus erythematosus (SLE). METHODS: Between 1988 and 2001, patients with biopsy-proven SLE DPGN who were treated initially with prednisone and CYC were studied. Those who responded to CYC were followed up for the occurrence of renal flares. The cumulative risk, predictors, and outcome of renal flares were evaluated. RESULTS: We studied 189 patients (167 women; and 22 men) with SLE DPGN. All were initially treated with prednisone and CYC (49% orally; 51% by intravenous pulse). At the last dose of CYC, 103 patients (55%) and 52 patients (28%) had achieved complete and partial renal responses, respectively. Azathioprine (AZA) was given as maintenance therapy in 117 patients (75%). After a mean followup of 96.5 months, 59 patients (38%) experienced renal flares (42% nephritic; 58% proteinuric). The median time to relapse was 32 months. The cumulative risk of renal flare was 28% at 36 months and 44% at 60 months. Independent predictors of nephritic flares were persistently low C3 levels after CYC treatment and absence of AZA maintenance therapy. At the last clinic visit, 16 patients (10.3%) had developed doubling of the serum creatinine level (cumulative risk of creatinine doubling 7.4% at 5 years after renal biopsy and 14.3% at 10 years). Ten patients (6.5%) developed end-stage renal disease (ESRD). Renal survival rates at 5 and 10 years were 94.9% and 87.5%, respectively. Increasing histologic chronicity scores, failure to achieve complete response, persistent hypertension after CYC treatment, and nephritic renal flares were unfavorable factors for doubling of the serum creatinine level and for ESRD by univariate analysis. The occurrence of nephritic flares was the only predictor of creatinine doubling by Cox regression analysis. CONCLUSION: In patients with SLE DPGN, renal flares are common despite initial responses to CYC. Nephritic renal flares are associated with a decline in renal function. Maintenance therapy with AZA reduces, but does not completely prevent, renal flares. More effective maintenance treatment for SLE DPGN after an initial response to CYC should be evaluated.