Exosomal microRNA-92b Is a Diagnostic Biomarker in Breast Cancer and Targets Survival-Related MTSS1L to Promote Tumorigenesis.

Exosomal microRNAs (miRNAs) are novel, non-invasive biomarkers for facilitating communication and diagnosing cancer. However, only a few studies have investigated their function and role in the clinical diagnosis of breast cancer. To address this gap, we established a stable cell line, MDA-MB-231-CD63-RFP, and recruited 112 female participants for serum collection. We screened 88 exosomal miRNAs identified through microarray analysis of 231-CD63 and literature screening using real-time PCR; only exosomal miR-92b-5p was significantly increased in patients with breast cancer. It had a significant correlation with stage and discriminated patients from the control with an AUC of 0.787. Exosomal miR-92b-5p impacted the migration, adhesion, and spreading ability of normal human mammary epithelial recipient cells through the downregulation of the actin dynamics regulator MTSS1L. In clinical breast cancer tissue, the expression of MTSS1L was significantly inversely correlated with tissue miR-92b-5p, and high expression of MTSS1L was associated with better 10-year overall survival rates in patients undergoing hormone therapy. In summary, our studies demonstrated that exosomal miR-92b-5p might function as a non-invasive body fluid biomarker for breast cancer detection and provide a novel therapeutic strategy in the axis of miR-92b-5p to MTSS1L for controlling metastasis and improving patient survival.

Next-Generation Sequencing in Lung Cancers-A Single-Center Experience in Taiwan.

Background and Objectives: Lung cancer is a leading cause of cancer mortality in Taiwan. With rapid advancement of targeted therapeutics in non-small cell lung cancers, next-generation sequencing (NGS) is becoming an important tool for biomarker testing. In this study, we describe institutional experience of NGS analysis in non-small cell carcinoma (NSCLC). Materials and Methods: A cohort of 73 cases was identified from the institutional pathology archive in the period between November 2020 and December 2022. Results: Adenocarcinoma was the most common histologic type (91.8%). Most patients presented with stage IIIB and beyond (87.7%). Twenty-nine patients (39.7%) were evaluated at the time of initial diagnosis, while the others had received prior chemotherapy or targeted therapy. The most frequently mutated gene was EGFR (63%), and this was followed by TP53 (50.7%), KRAS (13.7%), RB1 (13.7%), and CDKN2A (13.7%). Clinically actionable mutations associated with a guideline-suggested targeted therapy were identified in 55 cases (75.3%) overall, and in 47.1% of cases excluding EGFR TKI-sensitizing mutation. Biomarkers other than EGFR TKI-sensitizing mutations were compared. Cases without TKI-sensitizing EGFR mutation had more level 1 or 2 biomarkers (excluding EGFR TKI-sensitizing mutations) than cases with TKI-sensitizing EGFR mutations (47.1% versus 20.1%, p = 0.016). Progressive disease was associated with co-occurrence of clinically actionable mutations (20.5% versus 0%, p < 0.05). Eight of the nine cases with co-occurring actionable genetic alternations had an EGFR mutation. After an NGS test, 46.1% of actionable or potentially actionable genetic alternations led to patients receiving a matched therapy. Conclusions: Our study demonstrated that NGS analysis identifies therapeutic targets and may guide treatment strategies in NSCLC. NGS tests may be advantageous over multiple single-gene tests for optimization of treatment plans, especially for those with non-EGFR mutations or those with progressive disease.

Correlation between Cancer Stem Cells, Inflammation and Malignant Transformation in a DEN-Induced Model of Hepatic Carcinogenesis.

Chronic inflammation and cancer stem cells are known risk factors for tumorigenesis. The aetiology of hepatocellular carcinoma (HCC) involves a multistep pathological process that is characterised by chronic inflammation and hepatocyte damage, but the correlation between HCC, inflammation and cancer stem cells remains unclear. In this study, we examined the role of hepatic progenitor cells in a mouse model of chemical-induced hepatocarcinogenesis to elucidate the relationship between inflammation, malignant transformation and cancer stem cells. We used diethylnitrosamine (DEN) to induce liver tumour and scored for H&E and reticulin staining. We also scored for immunohistochemistry staining for OV-6 expression and analysed the statistical correlation between them. DEN progressively induced inflammation at week 7 (40%, 2/5); week 27 (75%, 6/8); week 33 (62.5%, 5/8); and week 50 (100%, 12/12). DEN progressively induced malignant transformation at week 7 (0%, 0/5); week 27 (87.5%, 7/8); week 33 (100%, 8/8); and week 50 (100%, 12/12). The obtained data showed that DEN progressively induced high-levels of OV-6 expression at week 7 (20%, 1/5); week 27 (37.5%, 3/8); week 33 (50%, 4/8); and week 50 (100%, 12/12). DEN-induced inflammation, malignant transformation and high-level OV-6 expression in hamster liver, as shown above, as well as applying Spearman's correlation to the data showed that the expression of OV-6 was significantly correlated to inflammation (p = 0.001) and malignant transformation (p < 0.001). There was a significant correlation between the number of cancer stem cells, inflammation and malignant transformation in a DEN-induced model of hepatic carcinogenesis in the hamster.

Perineural Invasion is a Powerful Prognostic Factor for Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy.

BACKGROUND: Taiwan has the highest incidence of upper tract urothelial carcinoma (UTUC) worldwide. Although many pathological factors can predict the prognosis of UTUC, previous studies have rarely discussed perineural invasion (PNI). Therefore, we aimed to investigate the effect of PNI on a well-established cohort of patients with UTUC. METHODS: This retrospective study included 803 patients with non-metastatic UTUC who underwent radical nephroureterectomy between June 2000 and August 2019. Demographic and clinicopathological parameters, including PNI, were collected for analysis. Using the Kaplan-Meier method and Cox proportional hazards model, we evaluated the significance of PNI with respect to progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS). RESULTS: The median follow-up was 30.9 months, and there were 83 cases of PNI (10.3%). PNI-positive patients had unfavorable pathological features, including high pT stage, positive lymph node involvement, high tumor grade, and more lymphovascular invasion (all p < 0.001). Kaplan-Meier analysis showed that PNI was significantly associated with PFS, CSS, and OS (all p < 0.00001), and when combined with lymphovascular invasion, patients could be divided into groups with distinct survival rates (all p < 0.00001). In multivariate analysis, PNI was an independent factor leading to worse PFS (hazard ratio [HR] 1.72, 95% confidence interval [CI] 1.19-2.50; p = 0.004), CSS (HR 2.54, 95% CI 1.58-4.10; p = 0.0001), and OS (HR 1.78, 95% CI 1.19-2.65; p = 0.005). CONCLUSIONS: We demonstrated an association between PNI and the prognosis of UTUC. Routine assessment of PNI in UTUC with standardized protocols may help achieve better risk stratification and subject selection for perioperative treatment.

Interethnic differences in the impact of body mass index on upper tract urothelial carcinoma following radical nephroureterectomy.

PURPOSE: Inconsistent prognostic implications of body mass index (BMI) in upper tract urothelial carcinoma (UTUC) have been reported across different ethnicities. In this study, we aimed to analyze the oncologic role of BMI in Asian and Caucasian patients with UTUC. METHODS: We retrospectively collected data from 648 Asian Taiwanese and 213 Caucasian American patients who underwent radical nephroureterectomy for UTUC. We compared clinicopathologic features among groups categorized by different BMI. Kaplan-Meier method and Cox regression model were used to examine the impact of BMI on recurrence and survival by ethnicity. RESULTS: According to ethnicity-specific criteria, overweight and obesity were found in 151 (23.2%) and 215 (33.2%) Asians, and 79 (37.1%) and 78 (36.6%) Caucasians, respectively. No significant association between BMI and disease characteristics was detected in both ethnicities. On multivariate analysis, overweight and obese Asians had significantly lower recurrence than those with normal weight (HR 0.631, 95% CI 0.413-0.966; HR 0.695, 95% CI 0.493-0.981, respectively), and obesity was an independent prognostic factor for favorable cancer-specific and overall survival (HR 0.521, 95% CI 0.342-0.794; HR 0.545, 95% CI 0.386-0.769, respectively). There was no significant difference in outcomes among normal, overweight and obese Caucasians, but obese patients had a relatively poorer 5-year RFS, CSS, and OS rates of 52.8%, 60.5%, and 47.2%, compared to 54.9%, 69.1%, and 54.9% for normal weight patients. CONCLUSION: Higher BMI was associated with improved outcomes in Asian patients with UTUC. Interethnic differences could influence preoperative counseling or prediction modeling in patients with UTUC.

Medulla oblongata germinoma with Klinefelter syndrome.

Intracranial germinomas mostly occur in teenagers and young adults. The common sites are pineal and suprasellar regions. Males with Klinefelter syndrome, compared with males without chromosomal abnormalities, are known to have a higher incidence of developing pineal or suprasellar germinomas. As for germinoma in the medulla oblongata, this is rare, with only 21 previous cases reported. Due to the rarities, any relationship between people with Klinefelter syndrome and medulla oblongata germinomas remains undetermined. We present a rare case of medulla oblongata germinoma in a 25-year-old man. It is the second case of medulla oblongata germinoma in association with Klinefelter syndrome. We emphasize the importance of karyotyping in every case of germinoma, especially those with intracranial germinomas at atypical locations.

Primary effusion lymphoma in Taiwan shows two distinctive clinicopathological subtypes with rare human immunodeficiency virus association.

AIMS: To investigate the clinicopathological and molecular features of primary effusion lymphoma (PEL) in Taiwan and the association with human immunodeficiency virus (HIV), human herpesvirus 8 (HHV8) and Epstein-Barr virus (EBV). METHODS AND RESULTS: We investigated retrospectively 26 cases with a median age of 76.5. Only one (4%) patient was infected with HIV. Cytologically, all lymphoma cells revealed typical immunoblastic to plasmablastic morphology. Immunohistochemically, HHV8 was positive in eight (32%) tumours and negative in 17 (68%) cases. All 23 tested cases examined were of the non-germinal-centre B cell phenotype. MYC proto-oncogene (MYC) and Epstein-Barr encoding mRNA (EBER) were positive in 43% (nine of 21) and 17% (four of 23) cases, respectively. Immunoglobulin heavy chain (IGH), B cell lymphoma (BCL)2, BCL6 and MYC were rearranged in 71%, 11%, 12% and 18% cases, respectively. By univariate analysis, the overall survival (OS) was associated statistically with MYC expression (P = 0.012) and BCL2 rearrangement (P = 0.035), but not with the others. By multivariate analysis, no factor was statistically significant. Compared to the HHV8-negative cases, the HHV8-positive cases were mainly of the plasmablastic immunophenotype expressing CD30 and CD138, and with a less frequent expression of pan-B cell markers. CONCLUSIONS: Apart from the phenotypical difference, our HHV8-positive neoplasms were not distinct from the HHV8-negative group. Literature review of 256 cases, including our cases, revealed that HHV8-positive cases were associated more frequently with HIV and EBV infection, with rare MYC rearrangement, and a poorer prognosis than HHV8-negative cases. We propose to name the HHV8-positive cases as 'classical' or 'type I PEL' and the HHV8-negative cases as 'type II PEL', stressing the similarities and the distinctive features between these two groups.

B-type natriuretic peptide prevents postnatal closure of ductus arteriosus by both vasodilation and anti-remodeling in neonatal rats.

The physiologic process of postnatal ductus arteriosus (DA) closure consists of vasoconstriction followed by vascular remodeling. We have recently reported that B-type natriuretic peptide (BNP), a potent vasodilator, also has anti-remodeling effects in pulmonary vasculature. However, its effects on DA have not been elucidated. We investigated whether BNP can prevent DA closure, and if so, the underlying mechanisms. Using in vivo studies, we examined effects of BNP (10 mg/kg, ip at birth) on DA closure in neonatal rats within 4 h after birth. We found that in control rats, the DA spontaneously closed at 4 h with a decreased DA diameter, enhanced intimal thickening, and luminal occlusion. BNP prevented DA closure at 4 h with a preserved DA diameter, attenuated intimal thickening, and preserved luminal patency. Ex vivo, BNP attenuated oxygen-induced vasoconstriction of isolated DA rings of newborn rats. These vasodilating effects were blunted by Rp-8-Br-PET-cGMPS, a cGMP inhibitor. In vitro, BNP inhibited angiotensin II (Ang II)-induced proliferation and migration of DA smooth muscle cells (DASMCs). BNP inhibited Ang II-induced mitochondrial reactive oxygen species (ROS) production and calcium overload in DASMCs. Finally, BNP inhibited Ang II-induced ERK1/2 activation. These in vitro effects were antagonized by Rp-8-Br-PET-cGMPS. In conclusion, BNP prevents postnatal DA closure by both vasodilation and anti-remodeling through the cGMP pathway. The mechanisms underlying anti-remodeling effects include anti-poliferation and anti-migration, with attenuation of mitochondrial ROS production and intracellular calcium and ERK1/2 signaling. Therefore, the BNP/cGMP pathway can be a promising therapeutic target for clinical management of DA patency.

Prognostic value of protein inhibitor of activated STAT3 in breast cancer patients receiving hormone therapy.

BACKGROUND: Deregulated signal transducer and activator of transcription 3 (STAT3) signaling has been well documented in certain cancers. Alterations in specific negative regulators, such as protein inhibitor of activated STAT3 (PIAS3), may contribute to cancer development. METHODS: The expression of total PIAS3 was determined in 100 paired cancerous and non-cancerous breast tissues by immunoblotting and was statistically analyzed along with the clinicopathological characteristics and overall survival of the patients. XTT, immunoblotting, and chromatin immunoprecipitation (Chip) were used to examine the biological effect of PIAS3 in breast cancer cells. RESULTS: Hormone therapy failed to improve the overall survival in patients presenting with increased PIAS3 expression. Ectopic PIAS3 overexpression increased the proliferation and expression of cyclin D1 in estrogen receptor (ER)-positive MCF-7 and T47D cells, but decreased those in ER-negative MDA-MB-231 and SKBR3 cells. Furthermore, PIAS3 overexpression attenuated cytotoxicity of tamoxifen and increased proliferation and cyclin D1 expression in MCF-7 cells. PIAS3 also decreased the binding of itself on the cyclin D1 promoter and this decreased binding was not affected by tamoxifen. CONCLUSION: PIAS3 may serve as a biomarker for predicting hormone therapy stratification, although it is limited to those breast cancer patients receiving hormone therapy.

Prognostic Relevance of Methylenetetrahydrofolate Reductase Polymorphisms for Prostate Cancer.

Folate metabolism has been associated with cancers via alterations in nucleotide synthesis, DNA methylation, and DNA repair. We hypothesized that genetic variants in methylenetetrahydrofolate reductase (MTHFR), a key enzyme of folate metabolism, would affect the prognosis of prostate cancer. Three haplotype-tagging single-nucleotide polymorphisms (SNPs) across the MTHFR gene region were genotyped in a cohort of 458 patients with clinically localized prostate cancer treated with radical prostatectomy. One SNP, rs9651118, was associated with disease recurrence, and the association persisted after multivariate analyses adjusting for known risk factors. Public dataset analyses suggested that rs9651118 affects MTHFR expression. Quantitative real-time polymerase chain reaction analysis revealed that MTHFR expression is significantly upregulated in prostate tumor tissues when compared with adjacent normal tissues. Furthermore, overexpression of MTHFR correlates with cancer recurrence and death in two independent publicly available prostate cancer datasets. In conclusion, our data provide rationale to further validate the clinical utility of MTHFR rs9651118 as a biomarker for prognosis in prostate cancer.

Topical simvastatin promotes healing of Staphylococcus aureus-contaminated cutaneous wounds.

Cutaneous wounds are prompt to be contaminated by bacteria, but the clinical benefits of applying antibiotics and antiseptics in wound management have not been proven. Statins are 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors commonly used to lower cholesterol levels. Studies indicated that statins, especially simvastatin, promote wound healing in experimental models. As Staphylococcus aureus is one of the most important microorganism responsible for wound infections, the aims of this study were to characterise the anti-staphylococcal activity of simvastatin and to evaluate the application of simvastatin as a topical therapy for S. aureus-contaminated wounds. In the present study, simvastatin was bacteriostatic against S. aureus at sub-inhibitory concentrations up to 8 hours after exposure. Further increased concentrations of simvastatin above the minimal inhibitory concentration (MIC) did not enhance the growth inhibitory effect. By contrast, the ability of simvastatin to inhibit S. aureus biofilm formation was concentration dependent. Topical application of simvastatin at its MIC against S. aureus accelerated the healing and bacterial clearance of S. aureus-contaminated wounds in an excisional mice wound model. This effective concentration is well below the safe concentration for topical use. Collectively, topical application of simvastatin has the potential as a novel modality for managing wound infections and promoting wound healing.

Prognostic significance of lymphovascular invasion in upper urinary tract urothelial carcinoma is influenced by tumor location.

BACKGROUND: To examine the prognostic value of lymphovascular invasion (LVI) in different tumor locations (i.e., renal pelvis and ureter) of upper urinary tract urothelial carcinoma (UTUC). METHODS: Data from a total of 250 patients with nonmetastatic UTUC who received radical nephroureterectomy between 2004 and 2010 at our institution were analyzed retrospectively. The significance of LVI and other relevant factors on cancer-specific survival (CSS), metastasis-free survival (MFS), and intraluminal recurrence-free survival (IRFS) were evaluated. RESULTS: Lymphovascular invasion was present in 60 patients (24 %) and was related to advanced pathological T stage (P < 0.001), higher tumor grade (P < 0.001), lymph node metastasis (P = 0.005), and pyelocaliceal tumor location (P = 0.002). By Kaplan-Meier analysis, LVI was found to be significantly correlated with worse CSS and MFS but not with IRFS. Multivariate analysis showed that high pathological T stage and regional lymph node involvement were significant prognostic factors for CSS and MFS, and LVI was an independent predictor for MFS (hazard ratio 1.71, 95 % confidence interval 1.00-2.93, P = 0.049). In patients with ureteral tumors, LVI represented the only significant prognosticator for both CSS and MFS in multivariate analysis. The prognostic value of LVI was not observed in pyelocaliceal tumors. CONCLUSIONS: The implication of LVI on prognosis, particularly in ureteral tumors but not in pyelocaliceal tumors, may imply diverse disease characteristics between different tumor locations among UTUC. LVI is essential to identify patients at high risk for metastasis/mortality and can facilitate treatment planning and surveillance strategies, especially in patients with ureteral tumors.

Autophagy is deficient and inversely correlated with COX-2 expression in nasal polyps: a novel insight into the inflammation mechanism.

BACKGROUND: Nasal polyposis is characterised by persistent inflammation of the upper airways. Autophagy has been implicated in many chronic inflammatory diseases. Whether autophagy plays a role in nasal polyp (NP) inflammation is completely unknown and deserves investigation. METHODS: LC3 and COX-2 expression, the common autophagy and inflammation indicators, respectively, was analysed by immunoblotting in fresh tissues of NP and control nasal mucosa (NM). Primary cultures of NP-derived fibroblasts (NPDFs) and NMDFs were established for in vitro studies. Autophagy was induced by amino acid starvation and LC3 ectopic overexpression or inhibited by 3-methyladenine in the fibroblasts. Inflammation was induced by IL1-ß and TNF-α. LC3 and COX-2 expression was confirmed in NP specimens by immunohistochemistry. RESULTS: LC3 expression was decreased while COX-2 expression was significantly increased in fresh NP tissues compared with the NM control. In NMDFs and NPDFs, autophagy induction by starvation and LC3 overexpression downregulated COX-2 expression. Conversely, autophagy inhibition by 3-methyladenine enhanced COX-2 expression. However, IL1-ß and TNF-α had no effect on autophagy. Immunohistochemical studies on the NP specimens showed that most displayed low LC3 expression, whereas COX-2 was highly expressed in >50% of the specimens. Examination of two consecutive NP sections from the same tissue blocks revealed a negative correlation between LC3 and COX-2 expression. CONCLUSION: Autophagy is deficient in NP tissues and COX-2 is negatively regulated by autophagy in NP-derived fibroblasts. Since COX-2 is essential for the production of pro-inflammatory mediators, this study might help interpret persistent mucosal inflammation in NP. Attenuation of inflammation by restoring autophagy might be a therapeutic strategy for treating NP.

Comparison of Confirmed Cytology Smears and Cell Blocks for Epidermal Growth Factor Receptor Mutation Testing in Non-Small Cell Lung Cancer.

INTRODUCTION: Various cytologic specimens have been used to diagnose epidermal growth factor receptor (EGFR) gene mutations in non-small cell lung cancer (NSCLC). However, insufficient samples and lengthy DNA extraction procedures have led to inconsistent diagnostic results. To reduce manipulation losses and improve DNA extraction quality, we provide an improved procedure for DNA extraction from smear samples containing rare tumor cells in NSCLC. PATIENTS AND METHODS: The effectiveness of this new method for DNA extraction and diagnosis was validated in 8 patients with pleural effusion smears and formalin-fixed paraffin-embedded cell blocks, and another with 2 smears. Smear samples with <5% tumor cells were collected, and visible particles were selected for DNA extraction after centrifugation. Qiagen formalin-fixed paraffin-embedded DNA extraction kit (Qiagen) was used for DNA extraction and the procedure was modified. The EGFR mutation analysis in both types of material used the EGFR mutation analysis kit (Therascreen EGFR RGQ PCR) and real-time polymerase chain reaction (Rotor-Gene Q). RESULTS: The DNA extraction amount of the smear was 2.6 to 258.8 ng/µL, and that of the cell block was 1.4 to 139.9 ng/µL. The DNA quantity and purity of DNA extracts isolated from both sample sources were sufficient for subsequent EGFR mutation detection, where mutation rates were similar and diagnostic results were consistent when smears or cell blocks were used. CONCLUSION: This improved method demonstrates that cytology smears can be used as a test material for the detection of EGFR mutations in patients with NSCLC with sparse cells.

An Optimized Melanin Depigmentation Method for Histopathological and Immunohistochemical Staining of Formalin-Fixed Paraffin-Embedded Tissues.

Introduction. The difficulty in diagnosis of severe melanocytic lesions is a problem to be overcome in pathological practice. Melanin bleaching is an effective approach to ameliorate melanin disturbances in severely pigmented lesions. Although various methods for improving melanin pigmentation in immunohistochemical staining have been reported, these depigmentation methods still need to be optimized and standardized. In this study, the coloring efficiency of 3,3'-diaminobenzidine (DAB) and alkaline phosphatase (AP) after melanin depigmentation was compared under the automatic immunohistochemical staining platform. Methods. The applicability of the optimized depigmentation method was validated in 10 formalin-fixed paraffin-embedded (FFPE) blocks of ocular melanoma tissues. Specimens were demelaninized with 10% hydrogen peroxide at 60°C for immunohistochemical staining (Melan-A and SOX10), and tissue chromogenic staining was performed with DAB and AP detection systems, respectively. Results. The optimized depigmentation method including immunohistochemistry (IHC) could be completed in 3 h, effectively preserving cell morphology and immunoreactivity. Among these, the color-rendering effect and contrast of AP are better than DAB. Conclusion. This optimized method can effectively remove melanin and improve the accuracy of IHC staining interpretation. AP staining has better visibility and readability without the interference of residual melanin. The comparison results showed that after melanin depigmentation, the immunohistochemical staining agent was replaced with red AP, which avoided the misjudgment caused by brown DAB when melanin depigmentation was incomplete. This improved method can be applied to future histopathological and immunohistochemical staining of melanin-deposited tissues.

Clinicopathologic Analysis of Micropapillary Urothelial Carcinoma of the Upper Urinary Tract: Implications for HER2-Targeted Therapy.

Introduction/Background To determine the clinical significance of micropapillary urothelial carcinoma (MPUC) of the upper urinary tract (UTUC) and a potential therapeutic strategy. Patients and Methods A retrospective cohort study was conducted to examine the incidence of micropapillary UTUC from 2010 to 2018 and its clinicopathological characteristics. Clinical outcomes and cancer-specific survival (CSS) were compared between MPUC and conventional UTUC matched by stage within a 6-month variation of receiving surgery. Results A total of 24 MPUC cases were identified out of 901 cases (2.7%) of urothelial carcinoma (UC) of the renal pelvis and ureter. MPUC was significantly smaller (<3 cm) and associated with nodal metastasis compared with conventional UTUC (P = .017 & 0.021, respectively); however, no significant difference was observed for lymphovascular invasion, distant metastasis, or CSS (P > 0.50, respectively) compared with match controls. Six MPUC patients (25%) developed metastasis to the liver, lymph nodes, and lung during follow-up. Patients with HER2-positive MPUC (3 of 4) had a significantly higher risk of metastasis compared with HER2-negative MPUC (3 of 20; P = 0.035). Conclusions MPUC is an aggressive variant of UTUC and usually presents as a small locally advanced disease. HER2 immunohistochemistry may identify the subset of patients with micropapillary UTUC that are candidates for targeted therapy.

Decreased total MKP-1 protein levels predict poor prognosis in breast cancer.

BACKGROUND: MKP-1 dephosphorylates and inactivates MAPKs, whose constitutive activations have been associated with human cancers. RESULTS: We found that total MKP-1 protein levels were decreased in 63.7 % of breast cancer tissues compared with the paired noncancerous breast tissues. Decreased MKP-1 protein levels were correlated with increased tumor stage and positive recurrence and were associated with poor survival, even when using a multivariate Cox regression model. Intriguingly, nuclear MKP-1 staining was positively correlated with ER status. In vitro, tamoxifen increased MKP-1 expression in ER-positive but not ER-negative breast cancer cells. ER-specific siRNA was able to attenuate tamoxifen-induced MKP-1 expression. Furthermore, tamoxifen prolonged the duration of MKP-1 elevation and the binding time of ER to the promoter of the MKP-1/DUSP-1 gene compared with estrogen. CONCLUSIONS: Our results suggest that alterations of MKP-1 may serve as a prognostic factor in breast cancer. In addition, the regulation of MKP-1 may be related to the ER.

Distinctive patterns of marrow involvement by classic Hodgkin lymphoma are clues for diagnosis and subtyping.

Classic Hodgkin lymphoma (CHL) is a lymphoid neoplasm deriving from B cells in a rich inflammatory background. There are four histological subtypes with different epidemiological features. Bone marrow involvement by CHL is infrequent, and subtyping CHL from the bone marrow is not suggested as there might be discordant histopathology between the primary tumors and bone marrow specimens. In this study, we aimed to identify the histopathological features of bone marrow involved by CHL and tried to correlate these features with their subtypes. Among the 23 recruited cases, the frequencies of mixed cellularity (MC; 48%, 11/23) and nodular sclerosis (NS; 44%, 10/23) were similar. There were two patterns of marrow involvement: pattern A (fibrous), space-occupying lesions with alternating hypo- and hypercellular areas against a fibrotic background with dilated sinusoids and pattern B (histiocyte-rich), ill-defined granuloma-like lesions in which histiocytes merged with normal hematopoietic and inflammatory cells. Pattern A was more frequent in patients with CHL-NS than CHL-MC (100% vs. 18.2%; p < 0.001). Diagnostic Hodgkin cells and Reed-Sternberg (HRS) cells were identified in all cases, while HRS variant lacunar cells were occasionally discovered, particularly in the CHL-NS subtype (NS 100% vs. MC 9%; p < 0.001). The frequency of EBV association was higher in MC (64%) than that in NS (36%) subtype, but not statistically significant. Of the two patterns of marrow involvement, pattern A was more commonly associated with the NS subtype and less frequently associated with EBV. Recognizing the patterns of marrow involvement is important for diagnosis and may contribute to the subtyping of CHL.

Surgical treatment of the synkinetic eyelid closure in Marin-Amat syndrome.

Marin-Amat syndrome is a synkinesis which develops following facial nerve palsy and manifests as an involuntary eyelid closure when the jaw is opened. We presented 2 patients with Marin-Amat syndrome. One patient developed this syndrome after Bell palsy and the other after cross-facial nerve graft and free functional muscle transfer. Surgery was planned with an attempt to resect the target muscle innervated by the aberrant nerve to eliminate the paradoxical synkinesis. We developed a new surgical technique by resection of the upper or lower preseptal orbicularis oculi muscle (OOM) to treat the synkinetic eyelid closure effectively in both cases. Since the pretarsal and orbital OOM remain intake, patients can close their eyes smoothly. No recurrence or any sequela was noted after long-term follow-up. Careful preoperative electromyography study and detailed dynamic facial image analysis of both upper and lower lid OOM are very important to locate the synkinetic muscle. To the best of our knowledge, this is the first report to treat Marin-Amat syndrome successfully with surgical resection of preseptal OOM.

Pediatric follicular lymphoma: a report of the first 3 cases from Taiwan and literature review.

Follicular lymphoma (FL) is a common lymphoma entity in adults but is rare in children. As opposed to adult cases, pediatric FL is characterized by a high-grade histology, low-stage disease, a lower frequency of both bcl-2 protein expression and BCL2 gene rearrangement, and a more favorable prognosis. During the authors' previous study of pediatric Burkitt lymphoma, they identified 3 cases of pediatric FL. Here the authors present the first series of pediatric FL from Taiwan. The patients were 2 boys and 1 girl, aged from 7 to 14. The presentation sites were cervical lymph node in 2 and tonsil in 1. All cases showed large neoplastic nodules comprising sheets of centroblasts, corresponding to grade 3b FL. Two of the 3 tumors weakly expressed bcl-2 protein. Fluorescence in situ hybridization for IGH, BCL2, BCL6, CCND1, and MYC loci showed that the only chromosomal translocation was rearranged IGH in 1 case. Two patients were at stage I, and 1 at stage III. All were treated with combination chemotherapy and achieved long-term complete remission. Literature review including the current cases showed that 45% cases of pediatric FL expressed bcl-2 protein and 9% cases carried BCL2 gene rearrangement, suggesting an alternate molecular pathogenesis of pediatric FL as compared to their adult counterparts.