Extramedullary T-lymphoblastic Crisis in a Myelodysplastic/Myeloproliferative Neoplasm with a t(12;22)/MN1::ETV6 Translocation.

Myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are not a single disease, but rather a heterogenous group of entities which are increasingly subclassified according to recurrent genetic abnormalities. Chromosomal translocations involving meningioma 1 (MN1) and ETS variant 6 (ETV6) genes are extremely rare, but recurrent in myeloid neoplasms. We describe the case of a patient with a myelodysplastic/myeloproliferative neoplasm with neutrophilia, who developed an extramedullary T-lymphoblastic crisis with the t(12;22)(p13;q12) translocation as the only cytogenetic abnormality. This case shares several clinical and molecular features with myeloid/lymphoid neoplasms with eosinophilia. The treatment of this patient was challenging, as the disease proved to be highly refractory to chemotherapy, with allogenic stem cell transplantation as the only curative option. This clinical presentation has not been reported in association with these genetic alterations and supports the concept of a hematopoietic neoplasm originating in an early uncommitted precursor cell. Additionally, it stresses the importance of molecular characterization in the classification and prognostic stratification of these entities.

The UGT1A9*22 genotype identifies a high-risk group for irinotecan toxicity among gastric cancer patients.

Several studies have shown associations between irinotecan toxicity and UGT1A genetic variations in colorectal and lung cancer, but only limited data are available for gastric cancer patients. We evaluated the frequencies of UGT1A polymorphisms and their relationship with clinicopathologic parameters in 382 Korean gastric cancer patients. Polymorphisms of UGT1A1*6, UGT1A1*27, UGT1A1*28, UGT1A1*60, UGT1A7*2, UGT1A7*3, and UGT1A9*22 were genotyped by direct sequencing. In 98 patients treated with irinotecan-containing regimens, toxicity and response were compared according to the genotype. The UGT1A1*6 and UGT1A9*22 genotypes showed a higher prevalence in Korean gastric cancer patients, while the prevalence of the UG1A1*28 polymorphism was lower than in normal Koreans, as has been found in other studies of Asian populations. The incidence of severe diarrhea after irinotecan-containing treatment was more common in patients with the UGT1A1*6, UGT1A7*3, and UGT1A9*22 polymorphisms than in controls. The presence of the UGT1A1*6 allele also showed a significant association with grade III-IV neutropenia. Upon haplotype and diplotype analyses, almost every patient bearing the UGT1A1*6 or UGT1A7*3 variant also had the UGT1A9*22 polymorphism, and all severe manifestations of UGT1A polymorphism-associated toxicity were related to the UGT1A9*22 polymorphism. By genotyping UGT1A9*22 polymorphisms, we could identify high-risk gastric cancer patients receiving irinotecan-containing chemotherapy, who would experience severe toxicity. When treating high-risk patients with the UGT1A9*22 polymorphism, clinicians should closely monitor them for signs of severe toxicity such as intense diarrhea or neutropenia.

[Expression comparison and clinical significance of PD-L1 (22C3) and PD-L1 (SP142) in triple negative breast cancer].

Objective: To investigate the expression of programmed death ligand-1 (PD-L1, SP142) and PD-L1 (22C3) in triple-negative breast cancer (TNBC), and analyze their correlation with the clinicopathological factors and prognosis. Methods: The clinicopathologic data of 259 patients with TNBC treated in Cancer Hospital from August 2010 to December 2013 were collected. Whole section of surgical tissue samples were collected to conduct PD-L1 (SP142) and PD-L1 (22C3) immunohistochemical (IHC) staining. The PD-L1 expression in tumor cells and tumor infiltrating immune cells were visually assessed respectively, the relationship between PD-L1 expression and clinicopathologic characterizes were analyzed. Univariable and multivariable Cox proportional hazards regression models were used to test the correlations between PD-L1 expression and disease-free survival (DFS) and overall survival (OS). Results: The positive rates of SP142 (immune cell score, ICs≥1%) and 22C3 (combined positive score, CPS≥1) were 42.1%(109/259) and 41.3%(107/259) in TNBC tissues, respectively, with a total coincidence rate of 82.3%. The Kappa value of positive expression cases was 0.571 and the distribution difference of SP142 and 22C3 positive expression cases was statistically significant (P<0.001). The PD-L1 positive patients were less likely to have vascular invasion (P<0.05), but with higher histological grade and Ki-67 proliferation index (P<0.05). The recurrence/metastasis cases(8) of the patients with positive PD-L1 (SP142) was significantly lower than that of patients with negative PD-L1(SP142, 27, P=0.016). The positive expression of PD-L1 (SP142) patients were longer DFS (P=0.019). The OS of patients with positive PD-L1 (SP142) were longer than those with negative PD-L1 (SP142), but without significance (P=0.116). The positive expression of PD-L1 (22C3) was marginally associated with DFS and OS of patients (P>0.05). Conclusions: The expression of PD-L1 (22C3) is different from that of PD-L1 (SP142) in TNBC, and the two antibodies can't be interchangeable for each other in clinical tests. PD-L1 (SP142) status is an independent prognostic factor of DFS in TNBC. The DFS is significantly prolonged in patients with positive expression of PD-L1 (SP142).

Diagnostic accuracy of NMP 22 and urine cytology for detection of transitional cell carcinoma urinary bladder taking cystoscopy as gold standard.

OBJECTIVE: To determine diagnostic accuracy of NMP 22 and urine cytology in the detection of transitional cell carcinoma (TCC) urinary bladder taking cystoscopy as a gold standard in patients having provisional diagnosis of bladder cancer (BC). METHODS: This cross sectional validational study enrolled 380 patients fulfilling selection criteria and was conducted at Armed Forces Institute of Urology (AFIU) Rawalpindi, Pakistan form July 2018 to July 2019. The urine sample collected underwent NMP22 and cytological analysis followed by rigid cystoscopy. Reports of all three tests divided patients into positive or negative for malignancy as per defined criteria. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy of NMP 22, urine cytology and their combination was determined. Receiver operating characteristic (ROC) curve analysis performed and area under the curve (AUC) compared among these tests. RESULTS: The average age of patients was 53.08 ± 12.41 years having male to female ratio 3.75:1(300 males and 80 females). NMP 22 had better sensitivity and comparable specificity to cytology (81.9 & 81.2% vs 54 & 93.9%). Combination of NMP 22 / cytology outperformed both in terms of sensitivity (91.63 vs 81.83 vs 53.96), NPV (87.59 vs 77.46 vs 61.02) and diagnostic accuracy (85.26 vs 81.58 vs 71.32) but at the cost of specificity (76.97 vs 81.21 vs 93.94) and PPV (83.83 vs 85.02 vs 92.06). ROC curve revealed statistically significant higher AUC (0.843 vs .815 vs .73) for combination as compared to NMP 22 and Cytology (p < 0.001). CONCLUSION: NMP22 is a quick, point of care test having higher sensitivity, NPV and accuracy but similar specificity and PPV to urine cytology for detection of TCC urinary bladder. Combination outperformed both in terms of sensitivity while having modest specificity.

PD-L1 Testing in Gastric Cancer by the Combined Positive Score of the 22C3 PharmDx and SP263 Assay with Clinically Relevant Cut-offs.

PURPOSE: We provide a comparison between 22C3 pharmDx and SP263 assay, for evaluating programmed death ligand 1 (PD-L1) expression in advanced gastric cancer (GC) patients. MATERIALS AND METHODS: The PD-L1 immunohistochemistry by 22C3 pharmDx and SP263 assays was performed in the center of the tumor (CT) and invasive margin (IM) in 379 GC tissues using tissue microarrays and interpreted as combined positive score (CPS) and tumor proportion score (TPS). Of the total samples, 55 samples were independently reviewed by five pathologists. RESULTS: The two assays showed a high correlation in both the CPS and TPS. At a CPS ≥ 1 cut-off, 219 (57.8%) and 231 (60.9%) GCs were positive for PD-L1 with the 22C3 and SP263 assays, and at ≥ 10 cut-off, 37 (9.8%) and 36 (9.5%) GCs were positive, respectively. The overall percent agreement (OPA) was greater than 90% with CPS ≥ 1 and ≥ 10 cut-offs, and TPS ≥ 1% and ≥ 10% cut-offs. There was higher OPA between the two assays with a CPS cut-off ≥ 10 (99.2%) than ≥ 1 (94.7%). The percent agreement between the CT and IM was higher with a CPS cut-off ≥ 10 (92.9%) than ≥ 1 (77.6%). Patient with positive expression at CPS ≥ 5 cut-off had a significantly better outcomes in both assays. Interobserver variability among five pathologists was higher than the assay variability. CONCLUSION: Two assays for PD-L1 expression in GC showed high agreement. These results provide guidance for selecting eligible patients with GC for pembrolizumab treatment.

Myeloid/Lymphoid Neoplasm with PDGFRB Rearrangement with t (5;10) (q33;q22) Harboring a Novel Breakpoint of the CCDC6-PDGFRB Fusion Gene.

Myeloid/lymphoid neoplasms with PDGFRB rearrangement are a distinct type of myeloid neoplasms that occur in association with rearrangement of PDGFRB at 5q32. The hematological features most often show prominent eosinophilia. We herein report a patient with myeloid/lymphoid neoplasms with PDGFRB rearrangement with t (5;10) (q33;q22) who showed atypical chronic myeloid leukemia-like clinical features without eosinophilia and achieved an optimal response to imatinib. A sequence analysis showed a CCDC6-PDGFRB fusion gene with a new break point in the PDGFRB gene. This is the sixth case of myeloid/lymphoid neoplasm with PDGFRB rearrangement harboring a CCDC6-PDGFRB fusion gene, and it has a new breakpoint in the PDGFRB fusion gene.

Solid pseudopapillary neoplasms of the pancreas do not express major pancreatic markers in pediatric patients.

Solid pseudopapillary neoplasms (SPNs) of the pancreas are classified as "exocrine" pancreatic tumors by the World Health Organization. However, despite numerous studies using immunohistochemistry, electron microscopy, animal models, and molecular biology, the histogenesis of SPN remains unclear. At the same time, our knowledge of human pancreas development has significantly increased. It is now well known that the undifferentiated PDX1+ pancreatic progenitors proliferate and differentiate into endocrine, ductal, and acinar cells, thanks to the expression of numerous transcription factors, which can be used to better characterize pancreatic tumors. In a series of 14 pediatric SPN, we investigated the expression of 4 transcription factors associated with pancreatic development (PDX1, SOX9, PTF1A, and NKX2.2) to obtain new insights into the pathogenesis of SPN. In addition, we tested the expression of different markers of epithelial, endocrine, exocrine, and neural differentiation using both immunohistochemical and immunofluorescence analyses. All tumors displayed the typical histologic features of SPN, with both pseudopapillary and solid patterns. The immunoprofile was characterized by immunoreactivity for ß-catenin (100%), progesterone receptor (100%), cyclin D1 (100%), synaptophysin (65%), and S100 (15%). In all cases, tumor cells were negative for the following markers: PDX1, SOX9, PTF1A, NKX2.2, chromogranin A, glucagon, insulin, somatostatin, ghrelin, pancreatic polypeptide, amylase, GFAP, calretinin, EPCAM, and estrogen receptor α. To conclude, SPNs do not express major transcription factors involved in pancreatic development and differentiation, which does not allow for precise pancreatic lineage of tumor cells. Thus, additional studies are still required to determine the origin of SPN.

The Prevalence and Impact of Urinary Marker Testing in Patients with Bladder Cancer.

PURPOSE: Novel urinary tumor markers for bladder cancer may permit early detection and improved oncologic outcomes but data on use is limited. We sought to identify trends in the application of urinary markers and long-term outcomes of urinary tumor marker use in patients with bladder cancer. MATERIALS AND METHODS: Data from the SEER (Surveillance, Epidemiology and End Results)-Medicare database from 2001 to 2011 were used to identify a cohort of 64,450 patients with bladder cancer who underwent urinary marker testing with UroVysion® fluorescence in situ hybridization, or the NMP22® or BTA Stat® test. We assessed the prevalence of urinary marker testing and urine cytology. Characteristics of patients who did and did not undergo urinary marker testing were analyzed by the chi-square test. Urinary marker testing predictors were analyzed with a multivariable logistic regression model and Cox proportional hazards were used to determine unadjusted cancer specific and overall mortality risks. RESULTS: The rate of urinary marker testing increased from 17.8% to a peak of 28.2% during the study years (p <0.0001). Predictors of marker use included female gender, younger age and lower Charlson score. Overall and cancer specific survival improved on Kaplan-Meier and Cox proportional hazards analyses with urinary marker testing. CONCLUSIONS: Increased urinary marker testing was documented over all stages and grades of bladder cancer, and in certain patient and provider variables. This increase may have contributed to improved overall and cancer specific survival. Additional investigation is necessary to further characterize this benefit.

Acute myeloid leukemia with t(3;21)(q26.2;q22) developing following low-dose methotrexate therapy for rheumatoid arthritis and expressing two AML1/MDS1/EVI1 fusion proteins: A case report.

The t(3;21)(q26.2;q22) translocation is a rare chromosomal abnormality exhibited almost exclusively in therapy-related myelodysplastic syndrome/acute myeloid leukemia (t-MDS/AML) or in the blastic crisis phase of chronic myelogenous leukemia, which results in the fusion of the runt related transcription factor 1 (RUNX1, also called AML1) gene at 21q22 to the myelodysplasia syndrome 1 (MDS1)-ecotropic virus integration site 1 (EVI1) complex locus (MECOM) at 3q26.2, generating various fusion transcripts, including AML1/MDS1/EVI1 (AME). The present study examined the case of an 84-year-old Japanese woman who developed t-MDS/AML with t(3;21)(q26.2;q22) subsequent to receiving low-dose methotrexate (MTX) treatment for rheumatoid arthritis. Following treatment with MTX for 6 years, the patient developed anemia and neutropenia, and MTX was discontinued. A total of 3 years later, the patient was diagnosed with MDS with t(3;21)(q26.2;q22) and del (5q), which progressed rapidly to AML within 3 months. The patients was subsequently treated with azacitidine and cytarabine chemotherapy, but succumbed to the disease 6 months after diagnosis. Sequencing analysis of the nested reverse transcription-PCR products from the leukemic cells revealed the expression of two types of alternatively-spliced AME transcripts with or without RUNX1 exon 6 sequences. Western blot analysis of the leukemic cells of the patient additionally revealed that the corresponding AME fusion protein products were expressed at high levels, and that these cells also prominently expressed CCAAT/enhancer-binding protein α, the repression of which has been reported to be involved in leukemogenesis mediated by AME. To the best of our knowledge, the case discussed in the present study represents the first report of MDS/AML with t(3;21)(q26.2;q22) developing following low-dose MTX therapy for rheumatoid arthritis. Nonetheless, the clinical and molecular features of the patient in the present study were representative of those patients who typically develop this disease following exposure to chemotherapy or radiotherapy for primary malignancy, which implicates MTX in the pathogenesis of t-MDS/AML. Moreover, we confirmed the expression of two AME fusion proteins for the first time in primary leukemic cells and analyzed several cellular factors implicated in AME-mediated leukemogenesis to gain some insight into its molecular mechanisms.

Evaluation of miR-22 and miR-20a as diagnostic biomarkers for gastric cancer.

BACKGROUND: Gastric cancer (GC) is the fourth most common cancers and the second reason for cancer-related death around the world, particularly in East Asian countries. Diagnosing GC in its early stages is followed by more successful treatment. Unfortunately, there is no accurate method for GC diagnosis in its early stages. Recently, miRNAs have been investigated in the most cancer researches which have demonstrated that they have been dysregulated in many cancers. METHODS: This case-control study aims to investigate the expression rate of miR-22 and miR-20a in 32 cancerous tissues as well as 32 healthy adjacent tissues. Quantitative reverse transcriptase PCR (q-RT PCR) was used for investigating the expression rate of these miRNAs. RESULTS: The expression rate of miR-20a in cancerous tissues was significantly increased (8.9 times) in comparison with their healthy tissues (P<0.001), while the expression rate of miR-22 in cancerous tissues was significantly decreased (1.9 times) (P<0.05). CONCLUSIONS: The obtained results suggest miR-22 and miR-20a as good diagnostic biomarkers for early detection of GC. However more research is needed to investigate their efficacy.

USP22 knockdown enhanced chemosensitivity of hepatocellular carcinoma cells to 5-Fu by up-regulation of Smad4 and suppression of Akt.

USP22, a member of the deubiquitinases (DUBs) family, is known to be a key subunit of the human Spt-Ada-Gcn5 acetyltransferase (hSAGA) transcriptional cofactor complex. Within hSAGA, USP22 removes ubiquitin from histone proteins, thus regulating the transcription and expression of downstream genes. USP22 plays important roles in many cancers; however, its effect and the mechanism underlying HCC chemoresistance remain unclear. In the present study, we found that USP22 was highly expressed in chemoresistant HCC tissues and cells and was correlated with the prognosis of HCC patients who received chemotherapy. Silencing USP22 in chemoresistant HCC Bel/Fu cells dramatically inhibited proliferation, migration, invasion and epithelial-mesenchymal transition in vitro; suppressed tumorigenic and metastatic capacities in vivo; and inhibited drug resistance-related proteins (MDR1, LRP, MRP1). Mechanistically, we found that USP22 knockdown exerts its function through down-regulating PI3K and activating Smad4, which inhibited phosphorylation of Akt. Silencing Smad4 blocked USP22 knockdown-induced Akt inhibition in Bel/Fu cells. Our results, for the first time, provide evidence that USP22 plays a critical role in the development of chemoresistant HCC cells and that high USP22 expression serves as a molecular marker for the prognosis of HCC patients who undergo chemotherapy.

[The role of CD4 ⁺ CD25 ⁺ T regs and CCL17, CCL22 in the pathogenesis of head and neck squamous cell carcinoma].

Objective:To investigate the role of CD4 ⁺ CD25 ⁺ T regs and CCL17 and CCL22 in the pathogenesis of HNSCC.Method:Twenty cases of HNSCC were enrolled. All patients were primary or recurrent after treatment (chemotherapy, surgery). The primary tumor was taken as the experimental group, and the adjacent normal tissues from the primary tumor 1-3 cm were taken as control group. CD4 ⁺ /Foxp3 and CD25⁺/Foxp3 were detected by immunofluorescence, while CCL17 and CCL22 were detected by ELISA. The difference and correlation between the amount of CD4⁺,CD25⁺ and the expression of CCL17, CCL22 were observed and analyzed.Result:The difference of mean optical density between CD4⁺/Foxp3 and CD25⁺/Foxp3 was statistically significant between the experimental group and the control group (P<0.05). The concentration of CCL17 and CCL22 was statistically different between the two groups (P<0.01). There was a positive correlation between CD25⁺and CCL17,CCL22(r=0.595, 0.720,P<0.01).Conclusion:CD4⁺CD25⁺T regs and CCL17,CCL22 played an important role in the pathogenesis of head and neck squamous cell carcinoma,both of which interacted with each other,and promoted the recurrence and metastasis of HNSCC.

Genetic Polymorphisms of CCL22 and CCR4 in Patients with Lung Cancer.

BACKGROUND: An association between lung cancer and chemokines has been advocated in the recent years. This study aims at investigating the association between lung cancer and 16C/A single nucleotide polymorphism (SNP) (rs. 4359426) in C-C motif chemokine 22 (CCL22) as well as C1014T SNP (rs. 2228428) in C-C chemokine receptor type 4 (CCR4), which serves as the receptor for CCL22. METHODS: Genotyping was performed in 148 lung cancer patients and 148 normal controls using Polymerase Chain Reaction-Restriction-Fragment Length Polymorphism (PCR-RFLP). The data were verified by direct automated sequencing. RESULTS: Frequencies of CC, CA and AA genotypes of 16C/A SNP in CCL22 gene were 112 (75.7%), 33 (22.3%) and 3 (2.0%) in patients, and 119 (80.4%), 24 (16.2%) and 5 (3.4%) in controls respectively. No significant differences were observed in genotype frequencies at this position between cases and controls (P=0.34). Moreover, there was no significant association between CCL22 polymorphism and types of lung cancer in patients. The distribution of CC, CT and TT genotypes of C1014T SNP in CCR4 gene, was 76 (51.4%), 60 (40.5%) and 12 (8.1%) in patients, and 80 (54.1%), 49 (33.1%) and 19 (12.8%) in controls respectively. No statistically significant differences were observed in genotypes frequencies of CCR4 gene between patients and controls (P=0.24). The genotype inherited by patients observed not to be associated with the type of lung cancer (P>0.05). CONCLUSION: RESULTS reveal that CCL22 gene polymorphism at position 16C/A and CCR4 gene polymorphism at position C1014T, appear not to be associated with susceptibility to lung cancer.

Prospective external validation of a bladder cancer detection model.

PURPOSE: Few studies have combined clinical prognostic factors with urinary biomarkers into risk profiles that can be used to predict the likelihood of bladder cancer. We previously developed and internally validated a bladder cancer detection nomogram that combines clinical features with the NMP22® BladderChek® test. To consider extensive use of the model the nomogram was tested in a prospective cohort of patients who presented with hematuria. MATERIALS AND METHODS: Patients referred for hematuria evaluation were prospectively enrolled at 3 centers. Each patient underwent complete urological evaluation, including history, examination, cystoscopy, cytology and NMP22. A logistic regression model to predict urothelial bladder carcinoma was also developed to compare the performance of clinical data with and without adding NMP22 and urinary cytology. RESULTS: The study included 381 patients (50.7% women) with a median age of 58 years. Urothelial bladder carcinoma was detected in 23 patients (6%). It was associated with age greater than 65 (11.1% vs 4% of patients, p = 0.012), male gender (10.1% vs 2%, p = 0.003), white ethnicity (9.2% vs 3.1%, p = 0.016), gross hematuria (9.9% vs 2.5%, p = 0.005), positive NMP22 (37% vs 3.7%, p <0.001) and positive cytology (83.3% vs 3.9%, p <0.001). Predictive accuracy of the bladder cancer detection nomogram was 80.2%. The calibration plot indicated that the previously published nomogram was well calibrated in patients with a less than 15% predicted probability of urothelial bladder carcinoma. CONCLUSIONS: We prospectively validated a highly accurate tool that combines clinical factors and a urinary biomarker to detect bladder cancer. This tool can help prioritize urological referrals for patients with hematuria.

Patients with a negative cystoscopy and negative Nmp22® Bladderchek® test are at low risk of missed transitional cell carcinoma of the bladder: a prospective evaluation

OBJECTIVES: Urine based tumor markers have uncertain utility in diagnosis or surveillance of patients with bladder cancer while cytology is commonly used. We evaluated whether cytology provides additional diagnostic information in patients with a negative NMP22® BladderChek® test (BladderChek) and negative cystoscopy. MATERIALS AND METHODS: We performed subset analyses of 2 large prospective multi-center databases evaluating BladderChek for UCB detection and surveillance. These cohorts were analyzed for presence of cancer and result of urine cytology in setting of a negative cystoscopy and negative BladderChek. Subsequently, we prospectively performed cystoscopy, cytology and BladderChek on 434 patients at our institution being evaluated for UCB. RESULTS: In the detection database (n = 1331), 1065 patients had a negative cystoscopy and BladderChek. There were 3 cancers (stages Ta, Tis and T1) and cytology was atypical in one and reactive in two. In the surveillance cohort (n = 668) patients, 437 patients had negative cystoscopy and BladderChek. Cancer was found in 2 patients (stages Tis and Ta). The patient with Tis has dysplastic cytology and Ta tumor had reactive cytology. In our cohort of 434 patients, 288 pts had negative cystoscopy and BladderChek. One cancer was missed, a Ta ureteral urothelial carcinoma with a reactive cytology. CONCLUSIONS: In patients with negative cystoscopy and BladderChek, very few cancers are missed and cytology was not effective in detection. Use of a point-of-care test in conjunction with cystoscopy in lieu of cytology could decrease cost, provide immediate results, improve negative predictive value and reduce the uncertainty that results from inconclusive cytologic results.

Usefulness of the NMP22BladderChek Test for Screening and Follow-up of Bladder Cancer.

PURPOSE: We evaluated the usefulness of the nuclear matrix protein 22 BladderChek (NMP22BC) test for the screening and follow-up of bladder cancer. MATERIALS AND METHODS: From February 2006 to September 2009, we enrolled 1,070 patients who had hematuria or who were being followed up for bladder cancer. We compared the sensitivity and specificity of the NMP22BC test with those of urine cytology. RESULTS: The sensitivity of the NMP22BC test (77.5%) was significantly higher than that of urine cytology (46.3%). The specificity of the NMP22BC test was 88.8%, compared with 97.9% for urine cytology. The sensitivity of the NMP22BC test (81.8%) in non-muscle-invasive bladder cancer was higher than that of cytology (36.4%). However, the sensitivity of the NMP22BC test and of urine cytology in invasive bladder cancer were 57.1% and 92.9%, respectively. The sensitivity of the NMP22BC test was higher for low-grade bladder cancer (83.9%) than for high-grade (62.5%), and the sensitivity of cytology was higher for high-grade bladder cancer (66.7%) than for low-grade (37.5%). Follow-up bladder cancer was detected in 262 patients. The sensitivity of the NMP22BC test in that group (72.7%) was decreased and the specificity (91.7%) was increased. The sensitivity of cytology (54.5%) in the follow-up group was increased and the specificity (95.6%) was decreased. The presence of pyuria was significantly associated with the lower specificity of the NMP22BC test. CONCLUSIONS: The greater sensitivity of the NMP22BC test may be more useful for the diagnosis of non-muscle-invasive bladder cancer and low-grade bladder cancer than for the diagnosis of invasive or high-grade bladder cancer. If the NMP22BC test is performed in the absence of pyuria, it may play a compensatory role for urine cytology.

EMP3 overexpression in primary breast carcinomas is not associated with epigenetic aberrations.

Epithelial membrane protein 3 (EMP3) is a trans-membrane signaling molecule with important roles in the regulation of apoptosis, differentiation and invasion of cancer cells, but the detailed is largely still unknown. We analyzed the mRNA levels and methylation statuses of EMP3 in 63 primary breast carcinomas and assessed their correlations with clinicopathologic variables. The expression of EMP3 mRNA in primary breast carcinomas was significantly higher than the expression of 20 normal breast tissues (p<10(-7)). EMP3 overexpression in breast carcinomas was significantly related to histological grade III (p=3.9 x 10(-7)), lymph node metastasis (p=0.003), and strong Her-2 expression (p=3.3 x 10(-6)). Hypermethylation frequencies of EMP3 were detected in 36.5% of breast carcinomas by methylation-specific polymerase chain reaction. However, no significant correlations were found between methylation status of EMP3 and mRNA expression levels as well as other clinical parameters. In conclusion, EMP3 may be a novel marker of tumor aggressiveness. Overexpression of EMP3 in primary breast carcinoma is not associated with DNA methylation.