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Background: Endocervical adenocarcinomas (ECAs) and endometrial adenocarcinomas (EMAs) are malignancies that affect uterus; however, their biological behaviors are quite different. This distinction has clinical significance, because the appropriate therapy may depend on the site of tumor origin. The purpose of this study is to evaluate 3 different scoring mechanisms of p16INK4a immunohistochemical (IHC) staining in distinguishing between primary ECAs and EMAs.Methods: A tissue microarray (TMA) was constructed using formalin-fixed, paraffin-embedded tissue from hysterectomy specimens, including 14 ECAs and 24 EMAs. Tissue array sections were immunostained with a commercially available antibody of p16INK4a. Avidin-biotin complex (ABC) method was used for antigens visualization. The staining intensity and area extent of the IHC reactions was evaluated using the semi-quantitative scoring system. The 3 scoring methods were defined on the bases of the following: (1) independent cytoplasmic staining alone (Method C), (2) independent nucleic staining alone (Method N), and (3) mean of the sum of cytoplasmic score plus nucleic score (Method Mean of C plus N).Results: Of the 3 scoring mechanisms for p16INK4a expression, Method N and Method Mean of C plus N showed significant (p-values < 0.05), but Method C showed non-significant (p = 0.245) frequency differences between ECAs and EMAs. In addition, Method Mean of C plus N had the highest overall accuracy rate (81.6%) for diagnostic distinction among these 3 scoring methods.Conclusion: According to the data characteristics and test effectiveness in this study, Method N and Method Mean of C plus N can significantly signal to distinguish between ECAs and EMAs; while Method C cannot do. Method Mean of C plus N is the most promising and favorable means among the three scoring mechanisms. [ABSTRACT FROM AUTHOR]

Recent clinical evidence shows that the antibody-drug conjugate (ADC) trastuzumab deruxtecan (T-DXd) can successfully treat patients with advanced HER2-mutant non-small cell lung cancer (NSCLC). We aimed to characterize HER2 mutations in cervical neuroendocrine carcinoma (NEC) among Taiwanese women to provide the rationale for exploring T-DXd as a tumor-agnostic targeted therapy option. We analyzed 12 archived primary cervical NEC samples from Taiwanese patients. Tumor-rich areas were marked for microdissection on 10 μm unstained sections. DNA was extracted, and HER2 hotspots were sequenced using a targeted panel on the Illumina MiSeq. HER2 missense mutations were identified in 5 of 12 cases (41.7%). Of the 5 cases with mutations, 2 patients (40%) had a single mutation, while 3 patients (60%) had double mutations. We detected 4 substitutions outside the tyrosine kinase domain (non-TKD), which were p.P1170A, p.S305C, p.I655V, and a novel T328K alteration. No mutations were found within the tyrosine kinase domain (TKD). The 41.7% HER2 mutation rate warrants expanded screening and future clinical investigation of the T-DXd targeting HER2 mutations in cervical NEC patients. Overall, this study contributes to the molecular understanding of cervical NEC and lays the groundwork for developing more effective treatment strategies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This document is the revised edition of the previously issued Shanghai Expert Consensus on Clinical Protocol for Traditional Chinese Medicine Treatment of COVID-19 among the Elderly Population. Based on the clinical experience and the Protocol for Diagnosis and Treatment of COVID-19 (Trial 9th Edition), this revised edition provides treatment approaches and recommendations to proactively cope with Omicron variant and increase the therapeutic efficacy for coronavirus disease 2019 among the elderly population in Shanghai, China., (Copyright © 2022 Journal of Integrative Medicine Editorial Office. Published by Elsevier B.V. All rights reserved.)

The successful experiences of HER2 inhibitors in patients with HER2 ( +) breast cancer (BC) and advanced gastroesophageal adenocarcinoma (GEA) have encouraged us to continuously explore the HER2 status and its potential as a therapeutic target in primary mucinous ovarian carcinoma (mOC). Using 49 primary mOC samples, we compared the assay characteristics of HER2 status between both 2017 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) for GEA and 2018 ASCO/CAP for BC guideline recommendations. We demonstrated moderate to strong agreement between their HER2 IHC results (Weighted Kappa = 0.78) and perfect agreement between their HER2 FISH results (Kappa = 1.00). The overall concordance of non-equivocal HER2 IHC and HER2 FISH results was 97.56% (kappa = 0.93) by 2017 ASCO/CAP for GEA criteria and 100% (kappa = 1.00) by 2018 ASCO/CAP for BC criteria. The number (n = 8; 16.32%) of HER2 IHC equivocal (score + 2) by 2017 ASCO/CAP for GEA criteria was twofold higher than that (n = 4; 8.16%) by 2018 ASCO/CAP for BC criteria. Additionally, we identified one false-positive (FP) case (n = 1; 2.04%) that was HER2 IHC positive (score + 3), but HER2 FISH non-amplified result by the 2017 ASCO/CAP for GEA criteria. In conclusion, owing to the absence of FP/ FN and fewer equivocal cases of HER2 IHC, we recommend that the 2018 ASCO/CAP for BC are more appropriate than 2017 ASCO/CAP for GEA criteria in appraising the HER2 status in mOC and justifying the inclusion of eligible subjects for basket clinical trials of the newly developmental anti-HER2 treatments., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: Considering the clinical evidence of BRAF inhibitors that can treat melanoma patients successfully, we aimed to investigate the status of BRAF mutations of primary mucinous ovarian carcinomas (MOC) in Taiwanese women, and apply the emerging paradigm classification of BRAF mutation groups., Materials and Methods: 20 archived primary MOC samples were analyzed. The BRAF mutations of activation segment (exon 15), CR3 (conserved regions 3), kinase domain of the BRAF gene were analyzed using the highly sensitive BRAF mutant enriched kit (FemtoPath®) with Sanger sequencing method. Additionally, we extended our prior reported data of HER2 aberrations and KRAS mutation into this study in order to compare with the status of BRAF mutation., Results: Of them (n = 20), 16 (80%) harbored BRAF missense mutations. Their mutation profile and case number (n) were categorized as (1) class I: V600E (n=1), V600M (n = 1); (2) class II: A598V (n = 1), T599I (n = 10); (3) class III: none (n = 0); and (4) unclassified variants: S602F (n = 2), T599I/S602F (n = 1). The BRAF S602F is novel. The prevalence of BRAF mutation is significantly higher than either HER2 mutation (80% vs. 35%; p = 0.022) or HER2 amplification (80% vs. 35%; p = 0.022). However, the mutation rates of BRAF and KRAS were not significantly different (80% vs. 60%; p = 0.289)., Conclusion: Activating BRAF mutation, HER2 amplification, HER2 mutation and KRAS mutation were not mutually exclusive. However, they may even have a synergistic effect in tumorigenesis. BRAF mutation is not uncommon in primary MOC of Taiwanese. The BRAF mutant (T599I) stands the majority. We suggested that there was a lower potential response to the existing V600 BRAF inhibitors, but may be responsive to dual BRAF plus MEK inhibitors or single MEK inhibitor. Further studies are warranted to investigate the clinical benefits of newly targeted therapy in recurrent or advanced stage primary MOC patients carrying different classes of BRAF mutation., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2021. Published by Elsevier B.V.)

Background: Dexmedetomidine (Dexm), a selective alpha-2 adrenoceptor agonist, and dexamethasone (Dexa), a very potent and highly selective glucocorticoid, have both been proven effectively to prolong the duration of local anesthetics (LA) in regional anesthesia. However, data comparing the efficacy of Dexm and Dexa as perineural adjuvants are inconsistent. Therefore, this systematic review and meta-analysis of randomized and quasi-randomized controlled trials (RCTs) was conducted to compare the effects of Dexm and Dexa when used as LA adjuvants on peripheral nerve block (PNB)., Methods: We systematically searched PubMed, Cochrane Library, EMBASE, Web of Science, and ScienceDirect databases up to October, 2020. The primary outcome was the duration of analgesia. Secondary outcomes included incidence of rescue analgesia, cumulative opioid consumption, time required for onset of sensory and motor blockades, duration of sensory and motor blockades, incidence of postoperative nausea and vomiting (PONV), and side effect-associated outcomes (e.g., bradycardia, sedation, hypotension, rates of infection, and neurological complications). The study was registered on PROSPERO, number CRD42020188796., Results: After screening of full-text relevant articles, 13 RCTs that met the inclusion criteria were retrieved for this systematic review. It was revealed that perineural Dexm provided equivalent analgesic duration to perineural Dexa. Besides, the intake of Dexm increased the incidence of rescue analgesia in limbs surgery, as well as the cumulative opioid consumption, and decreased the time required for onset of sensory and motor blockades for long-acting LA (all P < .05). Other analysis revealed insignificant difference between the 2 groups in terms of the incidence of PONV (P > .05). Additionally, 2 studies demonstrated that Dexm possesses more sedative properties than Dexa (P < .05)., Conclusions: This meta-analysis indicated that the analgesic duration of Dexm and Dexa as LA adjuvants in PNB is the same. Meanwhile, the effects of perineural Dexm and Dexa on some secondary outcomes, including the incidence of rescue analgesia, cumulative opioid consumption, and time required for onset of sensory and motor blockades, are associated with the surgical site and type of LA., Competing Interests: The authors have no funding and conflicts of interests to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose . The optimal surgical approach for full-thickness rectal prolapse (FTRP) remains controversial. In China, patients with limited FTRP (<5 cm in length) are usually managed by perineal surgery. We retrospectively assessed the outcome of Delorme's procedure and compared it with modified stapled transanal rectal resection (STARR). Methods . The study was conducted in 2 public tertiary referral centers in China with modified STARR or Delorme's procedure performed by experienced surgeons. Outcomes assessed recurrence, operative times, blood loss, complications, length of hospital stay, and continence and constipation scoring. Results . Between December 2012 and May 2019, 65 patients were assessed, including 48 with modified STARR (group 1) and 17 with Delorme's procedure (group 2). The median follow-up was 22 months (range, 3-86 months). The mean operative time for group 1 was 37.4 ± 17.5 minutes vs 74.3 ± 30.6 minutes for group 2 ( P < .001). The blood loss for group 1 was significantly lower than that for group 2 (17.4 ± 15.9 mL vs 27.8 ± 16.7 mL, respectively; P = .028). There was no significant difference between groups in recurrence (group 1 18.8% vs group 2 23.5%; P = .944) with no effect of operation type. Both procedures showed improvement in constipation and continence scoring with a similar impact. Conclusions . Modified STARR and the Delorme operation are comparable in managing limited FTRP with superior results in operative time and blood loss for STARR.

Objective: To explore the changes in signal intensity (SI) ratios of globus pallidus (GP) on unenhanced T(1)-weighted(T(1)WI)magnetic resonance imaging (MRI) scans between the first and last MRI using the linear gadolinium-based contrast agent (GBCAs) intravenously. Methods: Clinical and imaging data of 114 patients who underwent at least 4 consecutive enhanced MRI examinations at the Affiliated Hospital of Xuzhou Medical University between January 2016 and April 2018 were analyzed. The SI ratio of GP, thalamus and cerebrospinal fluid (CSF) were measured on unenhanced T(1)WI. The GP to thalamus SI ratio was calculated by dividing the SI in the GP by that in the thalamus, and so was the GP to CSF SI ratio. The difference of SI ratio in the same patient was analyzed by nonparametric tests, linear regression analysis was used to analyze clinical factors. Results: The SI ratio of GP-to-thalamus and GP-to-CSF after multiple enhancement were higher than before, and the difference was statistically significant. The SI ratio of GP-to-thalamus and GP-to-CSF before and after repeated contrast-enhanced were 1.036(1.010, 1.075), 1.104(1.074, 1.168); 4.215(3.590, 5.614), 5.409(4.213, 6.502), all P <0.01. The SI ratio differences showed a significant positive correlation with the number of enhanced examination(pons: b =0.023, P< 0.01,CSF: b =0.279, P= 0.034), and a significant negative correlation with the interval (pons: b =-0.002, P< 0.01, CSF: b =-0.023, P= 0.039). There was no correlation with other clinical factors (all P >0.05). Conclusions: There is an increase in SI in the GP after serial injections of linear GBCAs, and there is a positive correlation with the times of enhanced examination, and a negative correlation with time interval.

In the present report, vertically-aligned graphene nanowalls are grown on Ni foam (VA-G/NF) using plasma-enhanced chemical vapor deposition method at room temperature. Optimization of the growth conditions provides graphene sheets with controlled defect sites. The unique architecture of the vertically-aligned graphene sheets allows sufficient space for the ionic movement within the sheets and hence enhancing the catalytic activity. Further modification with ruthenium nanoparticles (Ru NPs) drop-casted on VA-G/NF improves the charge overpotential for lithium-oxygen (Li-O 2 ) battery cycles. Such reduction we believe is due to the easier passage of ions between the perpendicularly standing graphene sheets thereby providing ionic channels.

Objective: Desmoglein-2 (Dsg2) plays a crucial role in the assembly and adhesion of desmosomes. The absent or aberrant expression of Dsg2 was reported to be associated with the progression of varies human cancers. However, the expression of Dsg2 in hepatocellular carcinoma (HCC) and its association with tumor prognosis is still unknown. The aim of this study was to evaluate the expression level of Dsg2 in HCC and of the correlation between Dsg2 expression and clinicopathological variables., Patients and Methods: A total of 104 patients diagnosed with HCC were enrolled in this study. Real time-quantitative PCR (RT-qPCR) and Western blot were performed to determine the expression level of Dsg2 in HCC tumor tissues and matched noncancerous tissues. Cell proliferation and cell cycle were measured by cell counting kit-8 (CCK-8) assay and flow-cytometry assay, respectively., Results: Our results revealed that Dsg2 expression was significantly higher in HCC tumor tissues than in matched noncancerous tissues (p < 0.01), positively correlated with tumor size (p = 0.035) and tumor stage (p = 0.021). Univariate and multivariate analyses demonstrated Dsg2 expression was an independent prognostic factor for overall survival. Meanwhile, we found knockdown the expression of Dsg2 using small interfering RNA (siRNA) could efficiently impaired HCC cell proliferation rate and cell cycle progression (p < 0.05)., Conclusions: Taken together, our results suggest that increased Dsg2 expression was associated with tumor progression in HCC and may function as a promising biomarker for unfavorable prognosis of HCC.

This is the first study to investigate the relationships among fibroblast growth factor receptor 4 (FGFR4) genetic polymorphisms, development of uterine cervical cancer, clinicopathological variables, and patient prognosis in Taiwanese women. Real-time polymerase chain reaction and genotyping were used to detect the genotype frequencies of 4 FGFR4 single-nucleotide polymorphisms (SNPs), rs351855 (C/T, Gly388Arg), rs2011077 (G/A), rs7708357 (G/A), and rs1966265 (Ile10Val), in 138 patients with invasive cancer, 89 with precancerous lesions of uterine cervix, and 335 normal controls. The results showed that there is no significant difference in the frequencies of FGFR4 SNPs rs351855, rs2011077, rs7708357, and 1966265 between women with cervical invasive cancer and normal controls even after controlling for age. However, significant differences existed in the distributions of the FGFR4 genetic polymorphism rs2011077, when mutant homozygotes (AA) were compared using other genotypes (GG/GA) as a reference, as well as rs1966265, when mutant homozygotes (AA) were compared using GG/GA as a reference, between women with cervical precancerous lesions and normal women even after controlling for age. In multivariate analysis, lymph node metastasis was associated with cancer recurrence, and lymph node metastasis and FGFR4 rs351855 were associated with patient survival. In conclusion, our study demonstrated that FGFR4 rs2011077 and rs1966265 are associated with the progression of cervical normal tissues to precancerous lesions in Taiwanese women. Moreover, rs351855 (Gly388Arg) is the only FGFR4 genetic polymorphism that is associated with patient survival.

Objective: To investigate the feasibility of contrast-enhanced computer tomography (CT) texture analysis in predicting early recurrence after transarterial chemoembolization (TACE) in patients with liver cancer. Methods: A retrospective analysis was performed for 47 patients with liver cancer confirmed by liver biopsy and digital subtraction angiography who underwent upper abdominal contrast-enhanced CT scan before TACE, and according to the presence or absence of focal recurrence within half a year, these patients were divided into early recurrence (ER) group and non-early recurrence (NER) group. The texture analysis was used to delineate tumor boundary layer by layer on the axial contrast-enhanced CT image before liver cancer surgery, and related parameters of tumor heterogeneity, including entropy, mean, non-uniformity, skewness, and kurtosis, were obtained. The independent samples t-test was used for comparison of texture parameters between the two groups. The receiver operating characteristic (ROC) curve was used for the analysis of entropy, mean, and non-uniformity, and the area under the ROC curve (ROC), optical cut-off value, sensitivity, and specificity were calculated to evaluate the efficiency of texture analysis in predicting early focal recurrence after TACE. Results: There were 20 patients in the ER group and 27 in the NER group. The ER group had a maximum major axis length of 88.2±36.3 mm and a maximum minor axis length of 41.4±21.4 mm, and the NER group had a maximum major axis length of 66.9±30.2 mm and a maximum minor axis length of 29.3±19.8 mm; the ER group had significantly higher maximum major and minor axis lengths than the NER group ( t = 4.89 and 4.62, P < 0.001). The ER group had significantly higher entropy and non-uniformity values than the NER group, and there were no significant differences in skewness and kurtosis between the two groups. Entropy, non-uniformity, and mean had high efficiency in predicting early recurrence after TACE, and the optimal cut-off value of entropy was 4.135. Conclusion: Volumetric texture analysis of contrast-enhanced CT images before liver cancer surgery has a high value in predicting early recurrence after TACE.

Kras mutation is a common phenomenon in many human neoplasms. We aimed to assess the Kras mutational status along the histological continuum from normal ovaries to the development of benign, borderline and malignant ovarian mucinous neoplasms. We analyzed 41 cases of malignant, 10 cases of borderline, 7 cases of benign mucinous ovarian tumors and 7 cases of normal ovarian tissue. The prevalence of Kras mutations in the normal ovary was 0.00% (n=0/7), while the prevalence in benign, borderline and malignant mucinous neoplasms was 57.14% (n=4/7), 90.00% (n=9/10) and 75.61% (n=31/41), respectively. Multiple Kras mutations were detected in 6 cases of mucinous carcinoma, including 5 double mutations with G13D/V14I (n=1), G12V/G13S (n=1), G12D/G13S (n=3) and one triple mutation with A11V/G13N/V14I (n=1). We identified six cases with 3 novel Kras mutations not previously described in the COSMIC database, which included A11V (n=3) and V14I (n=2) in mucinous carcinomas, and A11T (n=1) in a mucinous borderline tumor. In conclusion, Kras mutation appears to be one of the imperative events in the ovarian mucinous adenoma-borderline tumor-carcinoma sequence, as increased numbers of Kras mutations have been shown to be the strongest predictor of unequivocal malignancy in ovarian mucinous neoplasms.

To date, no study associated the genetic polymorphisms of high-mobility group box 1 protein (HMGB1) with the development of uterine cervical cancer. We therefore conducted this study to investigate the associations of HMGB1 single-nucleotide polymorphisms (SNPs) with cervical carcinogenesis and clinicopathological characteristics of cancer patients. Five hundred two women, including 112 with invasive cancer, 85 with precancerous lesions of the uterine cervix, and 305 normal controls, were consecutively enrolled into this study. Analysis of HMGB1 SNPs was done by real-time polymerase chain reaction and genotyping. Our results found that the risk of susceptibility to cervical invasive cancer was 1.85 (95 % CI 1.12-3.04; p = 0.016) in women with TC and 1.99 (95 % CI 1.24-3.23; p = 0.005) in women with TC/CC after adjusting for age, using TT as a comparison reference in HMGB1 SNP rs1412125. In rs2249825, the increased risk was also seen for the development of cervical invasive cancer in women with CG [adjusted odds ratio (AOR) 2.04, 95 % CI 1.22-3.40; p = 0.006] or CG/GG (AOR 2.02, 95 % CI 1.22-3.32; p = 0.006) using CC as a comparison reference. An additional integrated in silico analysis confirmed that rs2249825 creates a binding site for v-Myb, which may affect HMGB1 expression. In conclusion, Taiwanese women with TC or TC/CC in HMGB1 SNP rs1412125 as well as CG or CG/GG in rs2249825 were susceptible to the development of cervical invasive cancer.

We recently reported one interesting case showing mutation-free c-KIT proto-oncogene overexpression and paradoxical hypermethylation in 54 cases of primary squamous cell carcinoma of uterine cervix (SCC). However, its molecular mechanisms still remain unknown. We propose the hypothesis that increased methylation at the CpG islands on the promoter near the first exon region might interfere with the binding of CTCF repressor with c-KIT promoter that regulates c-KIT proto-oncogene expression in such case. Further studies focusing on the status of epigenetic modifications of mutation-free c-KIT (+) tumors are encouraged.

We aimed to compare the assay performance characteristics of HER2 status in mucinous epithelial ovarian cancer (EOC) by ToGA (Trastuzumab for Gastric Cancer) biopsy versus ToGA surgical specimen methods. Forty-nine tissue microarray (TMA) samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using ToGA trial HER2 scoring methods. The overall concordance between IHC and FISH by the ToGA surgical specimen method is 97.56% and by the ToGA biopsy specimen method is 97.14%. The agreements of HER2 IHC results under both biopsy and surgical specimen methods were nearly perfect (weighted kappa = 0.845). Additionally, the percentage of Her2 FISH amplification showed increasing trend with increasing HER2 IHC ordinals (negative, equivocal, positive) by both TOGA biopsy (P<0.001) and surgical specimen method (P<0.001). After excluding equivocal cases, the sensitivity (100%), PPV (88.89%) and NPV (100%) of HER2 IHC were unchanged under either surgical specimen method or biopsy method. However, the specificity (96.97%) and accuracy (97.56%) of HER2 IHC was slightly higher under the surgical specimen method than those (specificity 96.30%, accuracy 97.14%) under the biopsy method. Of the total 49 cases, the number (n = 14) of HER2 IHC equivocal results under the ToGA biopsy method was 1.75-fold higher than those (n = 8) under the ToGA surgical specimen method (28.57% vs. 16.32%). Therefore, compared to ToGA surgery specimen method, the ToGA biopsy method caused more equivocal IHC cases to be referred to FISH testing and did not increase the detection rates of Her2 FISH amplification.

The remarkable success of trastuzumab and other newly developed anti-HER2 (human epidermal growth factor receptor 2) therapies in breast, gastric, or gastroesophageal junction cancer patients has supported us to investigate the HER2 status and its possible therapeutic implication in mucinous epithelial ovarian cancer (EOC). However, there is currently no standardization of HER2 scoring criteria in mucinous EOC. In this study, we aimed to compare both the assay performance characteristics of the 2007 and the 2013 American Society for Clinical Oncology and College of American Pathologists scoring methods. Forty-nine tissue microarray samples of mucinous EOC from Asian women were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests using the 2007 and the 2013 criteria, respectively. The overall concordance between IHC and FISH by the 2007 criteria was 97.92 % (kappa = 0.921), and that by the 2013 criteria was 100% (kappa = 1.000). The percentage of Her2 FISH-amplified cases showed an increasing trend significantly through their corresponding HER2 IHC ordinals by the 2007 and the 2013 criteria, respectively (P < 0.001, P < 0.001). After excluding equivocal cases, the specificity (100%) and positive predictive value (100%) were unchanged under either the 2007 or the 2013 criteria. The sensitivity (100%), negative predictive value (NPV) (100%), and accuracy (100%) of HER2 IHC were higher under the 2013 criteria than those (sensitivity 87.5%, NPV 97.6%, and accuracy 97.9%) under the 2007 criteria. Of the total 49 cases, the number (n = 4) of HER2 IHC equivocal results under the 2013 criteria was 4-fold higher than that (n = 1) under the 2007 criteria (8.16% vs 2.04%). Conclusively, if first tested by IHC, the 2013 criteria caused more equivocal HER2 IHC cases to be referred to Her2 FISH testing than the 2007 criteria. That decreased the false-negative rate of HER2 status and increased the detection rates of HER2 positivity in mucinous EOC.

Her2 gene amplification and protein overexpression are important factors in predicting clinical sensitivity to anti-HER2 monoclonal antibody therapy in breast, gastric, or gastro-esophageal junction cancer patients. The purpose of this study was to evaluate the HER2 status in the mucinous epithelial ovarian cancer (EOC). Adopting the 2013 American Society for Clinical Oncology and the College of American Pathologists guideline update for HER2 testing, 49 tissue microarray samples of mucinous EOC were analyzed by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) tests. The prevalence of HER2 positivity in Asian mucinous EOC was 9 of 49 Asian women (18.37%). The overall concordance was 100% between IHC and FISH results. Her2 gene copies before chromosome-17 correction increased significantly in a stepwise order through the negative, equivocal, and positive IHC result categories (P<0.001), as did the Her2 gene copies after chromosome-17 correction (P<0.001). Of the Taiwanese cohort (n=21), HER2 heterogeneity was 4.76% (1/21) in all but 14.26% (1/7) in HER2-positive cancer. In conclusion, we demonstrated that the prevalence of HER2 positivity in both Asian and white women was comparable; complete HER2 concordance existed between IHC and FISH tests for the Her2 gene copies per tumor cell either before or after correction of chromosome-17, and this can be applied as a potentially valuable tool to analyze the HER2 status. Polysomy-17 was absent under the CEP17 cutoff ≥3. The existence of HER2 heterogeneity can be discerned in certain HER2-expressed primary mucinous EOC in Taiwanese women.

The hemiascomycetes yeast Yarrowia lipolytica is a dimorphic yeast with alternating yeast and mycelia forms. Bioinformatic analysis revealed the presence of three putative chitinase genes, YlCTS1, YlCTS2, and YlCTS3, in the Y. lipolytica genome. Here, we demonstrated that the protein of YlCTS1 (YlCts1p), which contains an N-terminal secretion signal peptide, a long C-terminal Ser/Thr-rich domain, and a chitin-binding domain, is a homologue to Saccharomyces cerevisiae chitinase 1 (ScCts1p). Deletion of YlCTS1 remarkably reduced extracellular endochitinase activity in the culture supernatant of Y. lipolytica and enhanced cell aggregation, suggesting a role of YlCts1p in cell separation as ScCts1p does in S. cerevisiae. However, loss of YlCts1p function did not affect hyphal formation induced by fetal bovine serum addition. The mass of YlCts1p was dramatically decreased by jack bean α-mannosidase digestion but not by PNGase F treatment, indicating that YlCts1p is modified only by O-mannosylation without N-glycosylation. Moreover, the O-glycan profile of YlCts1p was identical to that of total cell wall mannoproteins, supporting the notion that YlCts1p can be used as a good model for studying O-glycosylation in this dimorphic yeast.

HER2 gene amplification and protein over-expression are important factors in predicting clinical sensitivity to anti-HER2 therapies in breast, gastric or gastroesophageal junction cancer patients. The aim of this study was to evaluate the correlation between HER2 gene copy numbers and HER2 protein expressions in mucinous epithelial ovarian cancer (EOC). Of the 49 tissue microarray samples of mucinous EOC, we applied 2010 ToGA trial (Trastuzumab for Gastric Cancer) surgical specimen scoring criteria to analyze the HER2 protein expression by an immunohistochemistry (IHC) test with Dako (Carpenteria, CA), c-erb-B2 antibody, and the HER2 gene amplification by the fluorescence in situ hybridization (FISH) test with Abbott/Vysis PathVysion HER2 DNA Probe Kit (Abbott Molecular Inc., Des Plaines, IA). We achieved a high overall concordance of 97.56% between nonequivocal HER2 results by IHC and FISH tests. In addition, HER2 gene copies before chromosome-17 correction increased significantly in a stepwise order through the negative, equivocal and positive IHC result categories (P<.001), as did the HER2 gene copies after chromosome-17 correction (P<.001). On the other hand, HER2 IHC results correlated significantly with both chromosome-17-uncorrected HER2 gene copy numbers (ρ=0.630, P<.001) and chromosome-17 corrected HER2 gene copy numbers (ρ=0.558, P<.001). We concluded that both chromosome-17 corrected and uncorrected HER2 gene copies correlated significantly with HER2 IHC results. Tests for the HER2 gene copies per tumor cell either before or after correction of chromosome-17 can be applied as a potentially valuable tool to analyze the HER2 status in mucinous EOC., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Objective: Over-expression of the aldo-keto reductase family 1 member C3 (AKR1C3) has been demonstrated in many human cancers. Lipocalin 2 (LCN2) is reported to inhibit cervical cancer metastasis but little is known regarding its relationship with AKR1C3 in the development and progression of uterine cervical cancer. This study aimed to investigate the involvement of AKR1C3 and its relationship with LCN2 in cervical cancer., Methods: The roles of AKR1C3 and LCN2 were investigated using the lentivirus shRNA system in SiHa and Caski cervical cancer cells. LCN2 and matrix metalloproteinase-2 (MMP-2) promoters were constructed to demonstrate transcriptional regulation by shAKR1C3 and shLCN2, respectively. The influences of metastatic phenotypes were analyzed by wound healing, Boyden chamber, and immunofluorescence assays. The activity of MMP-2 was determined by zymography assay. The impacts of AKR1C3 and LCN2 on patient prognosis were evaluated using tissue microarrays by Cox regression and Kaplan-Meier models., Results: Silencing of the AKR1C3 gene increased the expression of LCN2 and decreased the migratory and invasive abilities and changed the cytoskeleton of cervical cancer cells. When AKR1C3 was over-expressed, it decreased LCN2 promoter activity and LCN2 expression and increased cell migration. The mRNA level and enzyme activity of MMP-2 increased in silenced LCN2 cells. Positive AKR1C3 and negative LCN2 were correlated with higher recurrence and poorer survival of cervical cancer patients., Conclusions: Silencing of AKR1C3 increases LCN2 expression and inhibits metastasis in cervical cancer. Both AKR1C3 and LCN2 serve as molecular targets for cancer therapy to improve the clinical outcome of cervical cancer patients., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Membrane type 1-matrix metalloproteinase (MT1-MMP) participates in the activity of MMP-2, which correlates with cancer of uterine cervix. Single-nucleotide polymorphisms (SNPs) in promoter and exon of MT1-MMP may influence their binding with transcription factors and gene transcription. To date, no study reports the association of the MT1-MMP polymorphisms with cervical neoplasia. Therefore, we investigated the influence of the MT1-MMP gene polymorphisms on the susceptibility and clinicopathological variables of cervical neoplasia for women in Taiwan. We recruited 72 patients with cervical squamous cell carcinoma and 63 with high-grade dysplasia as 1 subgroup. Meanwhile, 280 control women were included as another subgroup. The SNPs rs1003349 (site -165), rs2236307 (+7096), and rs3751489 (+8153) as well as rs2236302 (site +6727) of MT1-MMP gene were determined by polymerase chain reaction (PCR)-restriction fragment length polymorphism and real-time PCR genotyping, respectively. Then, we correlated these SNPs and haplotypes with the development of cervical neoplasia and cancer clinicopathological variables. We found that women with CC genotype in rs2236307 SNP exhibited a more risk to develop cervical neoplasia as compared with those with wild genotype TT. Haplotypes -165 T, +6727 C, +7096 C, +8153 G or -165 G, +6727 G, +7096 T, and +8153 G and diplotypes including at least 1 type of these haplotypes of MT1-MMP gene showed a higher risk of cervical neoplasia. However, both haplotypes were not significantly correlated with the clinicopathological characteristics of cervical cancer. In conclusion, Taiwan women with variant homozygote CC (+7096) and haplotypes, TCCG and GGTG, of MT1-MMP exhibit more risk in developing cervical neoplasia.

Introduction: To date, no study reports the implication of YKL-40 in pelvic inflammatory disease (PID). Therefore, we investigate the levels of plasma YKL-40 in patients with PID and further associate its expression with the severity of disease., Methods: We designed a hospital-based case-control study with approximate 1:1 ratio and consecutively recruited 64 patients with PID and 70 control women. We collected blood samples from 64 women with PID before and after they received treatment and 70 control women to detect levels of plasma YKL-40 and C-reactive protein (CRP) as well as white blood cell and neutrophil counts., Results: The results revealed that levels of plasma YKL-40 were significantly elevated in patients with PID as compared to those in controls (38.36 vs. 21.69 ng/ml, P = 0.001) but the significant difference was restricted to women aged 30 years or old after age stratification (56.75 vs. 23.61 ng/ml, P ≤ 0.001). It declined significantly after they received treatment (median: 38.36 vs. 27.54 ng/ml; P ≤ 0.001). Although both plasma YKL-40 and CRP were elevated in patients with tubo-ovarian abscess, PID patients with surgery exhibited higher YKL-40 concentration than those without surgery (median: 82.05 vs. 30.19 ng/ml, P = 0.005) and only plasma YKL-40 was significantly associated with the length of the hospital stay (P ≤ 0.001, R = 0.604)., Conclusion: We conclude that once individuals are diagnosed to have PID, YKL-40 may act as a biomarker to predict the severity and clinical outcome of the disease., (© 2012 Wiley Periodicals, Inc.)

Background: HER2 gene amplification and HER2 protein overexpression are important factors in predicting clinical sensitivity to anti-HER2 monoclonal antibody therapy in breast cancer patients. The purpose of this study is to evaluate the correlation between HER2 protein expressions and the HER2 gene copies per tumor cell either before or after chromosome-17 correction in epithelial ovarian cancer (EOC)., Methods: Adopting 2007 ASCO/CAP guideline recommendations for HER2 testing, 27 tissue microarray (TMA) samples from EOC patients were analyzed by immunohistochemistry (IHC) using Dako, c-erb-B2 antibody and subsequently examined by fluorescence in situ hybridization (FISH) using Abbott/Vysis, PathVysion HER2 DNA Probe Kit., Results: The overall concordance revealed 81.5% between HER2 IHC and HER2 FISH results. Additionally, HER2 gene copies prior to chromosome-17 correction increased significantly in a stepwise order through the negative, equivocal, and positive IHC result categories (P = 0.026), as did the HER2 gene copies after chromosome-17 correction (P = 0.028). On the other hand, HER2 IHC results correlated significantly with both chromosome-17 uncorrected HER2 gene copy numbers (ρ = 0.430, P = 0.025) and chromosome-17 corrected HER2 gene copy numbers (ρ = 0.524, P = 0.027)., Conclusion: We demonstrated that both chromosome-17 corrected and uncorrected HER2 gene copies correlated significantly with HER2 IHC result categories; and tests for the HER2 gene copies per tumor cell either before or after correction for chromosome-17 can be applied as a potentially valuable tool in analyzing the HER2 status in EOC.

Background: Although overexpression, amplification, and somatic mutation of the HER2 gene have been noted in various types of human cancers, we report here for the first time that novel mutations and amplification of the HER2 gene occurred concomitantly in mucinous epithelial ovarian cancer (EOC)., Methods: Twenty-seven tissue microarray samples from EOC patients were analyzed by immunohistochemistry (IHC) with Dako c-erb-B2 antibody and subsequently were examined by fluorescence in situ hybridization (FISH) with the Abbott PathVysion HER2 DNA Probe Kit. HER2 gene, exon 18-24, encoding a tyrosine kinase domain, was analyzed by polymerase chain reaction (PCR) and direct sequencing., Results: The FISH-IHC paired results confirmed 19 concordant negative results and 3 concordant positive results. Moreover, all 4 HER2-amplified cases were of the mucinous type, whereas the remaining 23 HER2-nonamplified cases were of the nonmucinous type. The 4 mucinous EOC cases with HER2 gene amplification were selected and further analyzed for HER2 gene mutations. Data revealed that somatic mutations were present in 2 cases (R970W and E971G), but absent in the other 2 cases., Conclusions: HER2 protein overexpression correlated significantly with HER2 gene amplification in EOC (P = 0.027). It is surprising that all 4 cases of mucinous EOC showed HER2 gene amplification confirmed by FISH testing. However, we suppose that increasing the number of cases would possibly modify the results. This study also showed that both HER2 gene amplification and somatic mutations are not mutually exclusive in mucinous EOC. Further studies are warranted to investigate the potential role of anti-HER2 therapy.