Publications by authors named "Young-Kyung Bae"

113 Publications

The dangers of using Cq to quantify nucleic acid in biological samples; a lesson from COVID-19.

Clin Chem 2021 Oct 11. Epub 2021 Oct 11.

National Measurement Laboratory, LGC, Queens Road, Teddington, Middlesex, TW11 0LY, United Kingdom.

Background: SARS-CoV-2 RNA quantities, measured by reverse transcription quantitative PCR (RT-qPCR), have been proposed to stratify clinical risk or determine analytical performance targets. We investigated reproducibility and how setting diagnostic cut-offs altered the clinical sensitivity of COVID-19 testing.

Methods: Quantitative SARS-CoV-2 RNA distributions (Cq and copies/mL) from more than 6000 patients from three clinical laboratories in UK, Belgium and the Republic of Korea were analyzed. Impact of Cq cut-offs on clinical sensitivity was assessed. The June/July 2020 INSTAND EQA scheme SARS-CoV-2 materials were used to estimate laboratory reported copies/mL and to estimate the variation in copies/mL for a given Cq.

Results: When the WHO suggested Cq cut-off of 25 was applied, the clinical sensitivity dropped to as little as about 16%. Clinical sensitivity also dropped to as little as about 27% when a simulated LOD of 106 copies/mL was applied. The inter-laboratory variation for a given Cq value was >1000 fold in copies/mL (99% CI).

Conclusion: While RT-qPCR has been instrumental in the response to COVID-19, we recommend Cq (Ct or Cp) values not be used to set clinical cut-offs, or diagnostic performance targets, due to poor inter-laboratory reproducibility; calibrated copy-based units (used elsewhere in virology) offer more reproducible alternatives. We also report a phenomenon where diagnostic performance may change relative to the effective reproduction number (R). Our findings indicate that the disparities between patient populations across time are an important consideration when evaluating or deploying diagnostic tests. This is especially relevant to the emergency situation of an evolving pandemic.
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http://dx.doi.org/10.1093/clinchem/hvab219DOI Listing
October 2021

Immunohistochemical Expressions of Senescence-Associated Secretory Phenotype and Its Association With Immune Microenvironments and Clinicopathological Factors in Invasive Breast Cancer.

Pathol Oncol Res 2021 29;27:1609795. Epub 2021 Jun 29.

Department of Pathology, Yeungnam University College of Medicine, Daegu, South Korea.

This study was undertaken to investigate immunohistochemical expression of the senescence-associated secretory phenotype (SASP) in invasive breast cancer (IBC) tissues and to determine relationships between SASP positivity and tumor microenvironments and the clinicopathological characteristics of IBC. Immunohistochemistry for senescence markers, that is, high mobility group box-1 (HMGB1), p16, p15, and decoy receptor 2 (DCR2), was performed in tissue microarrays of 1140 IBC samples. Cases positive for at least one of these four markers were considered SASP-positive. Relations between SASP and tumor characteristics, including immune microenvironments (stromal tumor-infiltrating lymphocytes [sTILs] density and numbers of intraepithelial CD103-positive [iCD103 + ] lymphocytes) and clinical outcomes were retrospectively evaluated. HMGB1, p16, p15, or DCR2 was positive in 6.7%, 26.6%, 21.1%, and 26.5%, respectively, of the 1,140 cases. Six hundred and five (53.1%) cases were SASP positive, and SASP positivity was significantly associated with histologic grade 3, high-sTIL and iCD103 + lymphocyte counts, absence of ER or PR, and a high Ki-67 index. Although SASP did not predict breast cancer-specific survival (BCSS) or disease-free survival (DFS) in the entire cohort, SASP positivity in luminal A IBC was associated with poor BCSS and DFS. However, patients with SASP-positive TNBC showed better survival than those with SASP-negative TNBC. In multivariate analysis, SASP positivity was an independent prognostic factor in both luminal A IBC and TNBC, although the effect on prognosis was the opposite. In conclusion, SASP would be involved in the modulation of immune microenvironments and tumor progression in IBC, and its prognostic significance depends on molecular subtype.
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http://dx.doi.org/10.3389/pore.2021.1609795DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8276694PMC
June 2021

Clinicopathologic features of cutaneous metastases from internal malignancies.

J Pathol Transl Med 2021 Jul 7;55(4):289-297. Epub 2021 Jul 7.

Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea.

Background: Cutaneous metastasis (CM) is the spread of cancer cells from a primary site to the skin and is rarely the first sign of silent cancer. We investigated the clinicopathological characteristics of CM from internal malignancies in Korean patients treated at our institution over 20 years.

Methods: The clinicopathological findings of 112 patients (62 females, 50 males) with CM diagnosed at Yeungnam University Hospital between 2000 and 2020 were retrospectively reviewed.

Results: Mean patient age was 58.6 years (range, 26 to 87 years), and the most common primary cancer site was breast (74.2%) in women and lung (36.0%) in men. Ninety-six patients (85.7%) presented with CM after primary tumor diagnosis. CM from the lung or biliary tract usually occurred within 2 years of primary tumor diagnosis, whereas metastases from the breast and kidney occurred several years later. The chest, abdomen, and scalp were common sites of CM. Breast cancer usually metastasized to chest skin, while gastrointestinal tract cancers commonly metastasized to the abdomen. The scalp was a common location for CM from various tumors. The most common dermatologic presentations were nodules and masses. Immunohistochemical studies helped identify underlying malignancies when primary tumors were unknown.

Conclusions: The relative frequency of CM parallels the overall incidence of primary malignant tumors, and CMs usually occur at anatomic sites close to the primary tumor. CM can be diagnosed based on clinical, radiological, and histological features; however, immunohistochemical study is required in some cases.
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http://dx.doi.org/10.4132/jptm.2021.05.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8353133PMC
July 2021

Comparison of two digital PCR methods for EGFR DNA and SARS-CoV-2 RNA quantification.

Clin Chim Acta 2021 Oct 16;521:9-18. Epub 2021 Jun 16.

Biomolecular Measurement Team, Korea Research Institute of Standards and Science, Daejeon, Republic of Korea. Electronic address:

Background: The COVID-19 pandemic caused by the severe acute SARS-CoV-2 virus has undeniably highlighted the importance of reliable nucleic acid quantification. Digital PCR (dPCR) is capable of the absolute quantification of nucleic acids.

Method: By using the droplet dPCR (QX200) and the digital real-time PCR (LOAA), the copy numbers were compared via multiple assays for three distinct targerts; EGFR DNA, SARS-CoV-2 and HIV-1 RNA.

Results: The droplet dPCR and digital real-time PCR showed similar copy numbers for both DNA and RNA quantification. When the limit of detection (LOD) and limit of quantitation (LOQ) of each method were estimated for DNA and RNA targets, the digital real-time PCR showed a higher sensitivity and precision especially with low copy number targets.

Conclusion: The breath of nucleic acid testing in diagnostic applications continues to expand. In this study we applied common diagnostic targets to a novel digital real-time PCR methodology. It performed comparably to the established dPCR method with distinctive advantages and disadvantages for implementing in laboratories. These rapidly developing dPCR systems can be applied to benefit the accurate and sensitive nucleic acid testing for various clinical areas.
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http://dx.doi.org/10.1016/j.cca.2021.06.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8206622PMC
October 2021

Programmed Death Ligand 1 Immunohistochemistry in Triple-Negative Breast Cancer: Evaluation of Inter-Pathologist Concordance and Inter-Assay Variability.

J Breast Cancer 2021 Jun 26;24(3):266-279. Epub 2021 May 26.

Department of Pathology, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.

Purpose: The programmed death ligand 1 (PD-L1) SP142 assay with a 1% immune cell (IC) cutoff is approved for the selection of advanced triple-negative breast cancer (TNBC) patients for atezolizumab treatment. We aimed to evaluate the interobserver concordance of PD-L1 scoring and inter-assay variability of various PD-L1 assays in TNBC.

Methods: Thirty patients with primary TNBC were selected, and SP142, SP263, 22C3, and E1L3N assays were performed. PD-L1 staining in ICs and tumor cells (TCs) was scored by 10 pathologists who were blinded to the assay. The interobserver concordance among pathologists and the inter-assay variability of the four PD-L1 assays were analyzed. For SP142, the intraobserver concordance among the six pathologists was analyzed after training.

Results: The adjusted means of PD-L1 IC scoring ranged from 6.2% to 12.9% for the four assays; the intraclass correlations showed moderate (0.584-0.649) reader concordance. The PD-L1 IC scoring with a 1% cutoff resulted in identical scoring in 40.0%-66.7% of cases and a poor to moderate agreement (Fleiss κ statistic [FKS] = 0.345-0.534) for the four assays. The SP142 assay had the widest range of positive rate (56.5%-100.0%), lowest number of cases with identical scoring, and lowest FKS at 1% cutoff. Pairwise comparison of adjusted means showed significantly decreased PD-L1 staining in SP142 compared with the other assays in both ICs and TCs. As for the intraobserver concordance in the SP142 assay, the overall percent agreement was 87.8% with a 1% IC cutoff. After training, the proportion of cases with identical scoring at a 1% IC cutoff increased to 70.0%; the FKS also increased to 0.610.

Conclusion: The concordance of PD-L1 IC scoring among pathologists was low, at the 1% cutoff for the SP142 assay without training. SP142 showed the lowest PD-L1 expression in both IC and TC.
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http://dx.doi.org/10.4048/jbc.2021.24.e29DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8250096PMC
June 2021

Clinical Outcomes Following Letrozole Treatment according to Estrogen Receptor Expression in Postmenopausal Women: LETTER Study (KBCSG-006).

J Breast Cancer 2021 Apr 25;24(2):164-174. Epub 2021 Mar 25.

Department of Surgery, Pusan National University Hospital, Busan, Korea.

Purpose: In this trial, we investigated the efficacy and safety of adjuvant letrozole for hormone receptor (HR)-positive breast cancer. Here, we report the clinical outcome in postmenopausal women with HR-positive breast cancer treated with adjuvant letrozole according to estrogen receptor (ER) expression levels.

Methods: In this multi-institutional, open-label, observational study, postmenopausal patients with HR-positive breast cancer received adjuvant letrozole (2.5 mg/daily) for 5 years unless they experienced disease progression or unacceptable toxicity or withdrew their consent. The patients were stratified into the following 3 groups according to ER expression levels using a modified Allred score (AS): low, intermediate, and high (AS 3-4, 5-6, and 7-8, respectively). ER expression was centrally reviewed. The primary objective was the 5-year disease-free survival (DFS) rate.

Results: Between April 25, 2010, and February 5, 2014, 440 patients were enrolled. With a median follow-up of 62.0 months, the 5-year DFS rate in all patients was 94.2% (95% confidence interval [CI], 91.8-96.6). The 5-year DFS and recurrence-free survival (RFS) rates did not differ according to ER expression; the 5-year DFS rates were 94.3% and 94.1%in the low-to-intermediate and high expression groups, respectively ( = 0.6), and the corresponding 5-year RFS rates were 95.7% and 95.4%, respectively ( = 0.7). Furthermore, 25 patients discontinued letrozole because of drug toxicity.

Conclusion: Treatment with adjuvant letrozole showed very favorable treatment outcomes and good tolerability among Korean postmenopausal women with ER-positive breast cancer, independent of ER expression.

Trial Registration: ClinicalTrials.gov Identifier: NCT01069211.
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http://dx.doi.org/10.4048/jbc.2021.24.e17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8090806PMC
April 2021

Standardized Pathology Report for Breast Cancer.

J Breast Cancer 2021 Feb;24(1):1-21

Department of Pathology, Busan Paik Hospital, Inje University, Busan, Korea.

Given the recent advances in management and understanding of breast cancer, a standardized pathology report reflecting these changes is critical. To meet this need, the Breast Pathology Study Group of the Korean Society of Pathologists has developed a standardized pathology reporting format for breast cancer, consisting of 'standard data elements,' 'conditional data elements,' and a biomarker report form. The 'standard data elements' consist of the basic pathologic features used for prognostication, while other factors related to prognosis or diagnosis are described in the 'conditional data elements.' In addition to standard data elements, all recommended issues are also presented. We expect that this standardized pathology report for breast cancer will improve diagnostic concordance and communication between pathologists and clinicians, as well as between pathologists inter-institutionally.
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http://dx.doi.org/10.4048/jbc.2021.24.e5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920867PMC
February 2021

Standardized pathology report for breast cancer.

J Pathol Transl Med 2021 Jan 11;55(1):1-15. Epub 2021 Jan 11.

Department of Pathology, Busan Paik Hospital, Inje University, Busan, Korea.

Given the recent advances in management and understanding of breast cancer, a standardized pathology report reflecting these changes is critical. To meet this need, the Breast Pathology Study Group of the Korean Society of Pathologists has developed a standardized pathology reporting format for breast cancer, consisting of 'standard data elements,' 'conditional data elements,' and a biomarker report form. The 'standard data elements' consist of the basic pathologic features used for prognostication, while other factors related to prognosis or diagnosis are described in the 'conditional data elements.' In addition to standard data elements, all recommended issues are also presented. We expect that this standardized pathology report for breast cancer will improve diagnostic concordance and communication between pathologists and clinicians, as well as between pathologists inter-institutionally.
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http://dx.doi.org/10.4132/jptm.2020.11.20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829577PMC
January 2021

Recurrence prediction for breast phyllodes tumours: validation of the Singapore nomogram in Korean women.

J Clin Pathol 2020 Dec 29. Epub 2020 Dec 29.

Deparment of Pathology, Yeungnam University College of Medicine, Daegu, The Republic of Korea

Aim: The Singapore nomogram was developed to predict recurrence risk of phyllodes tumours (PTs) of the breast based on histological features of stromal atypia, stromal mitoses, stromal overgrowth and surgical margin status. We aimed to validate the utility of the Singapore nomogram in a Korean PT cohort.

Methods: One hundred and twenty-four patients with Korean PT who underwent surgical resection between 1996 and 2015 were included in this study. Pathology reports and slides were reviewed to obtain histopathologic features and acquire Singapore nomogram scores. The probability of concordance between predicted and observed survivals by means of the Singapore nomogram was evaluated using a concordance index (C-index).

Results: Of the 124 cases, 57 (46%) were diagnosed as benign, 50 (40.3%) as borderline and 17 (13.7%) as malignant. Recurrences occurred in 25 (20.2%) patients. Univariate analysis showed PTs with higher stromal mitotic counts, marked stromal cellularity, stromal overgrowth, positive surgical margin, marked stromal atypia or a malignant grade presented higher risks of recurrence. Multivariate analysis showed stromal mitoses and surgical margin status independently predicted recurrence-free survival. Patients with high nomogram scores were at greater risk of recurrence (HR=1.05, 95% CI: 1.02 to 1.07, p<0.001) with a C-index of 0.762.

Conclusion: The Singapore nomogram provided a useful means of predicting PT outcomes in a Korean PT cohort.
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http://dx.doi.org/10.1136/jclinpath-2020-207093DOI Listing
December 2020

Particulate-Based Single-Dose Local Immunosuppressive Regimen for Inducing Tolerogenic Dendritic Cells in Xenogeneic Islet Transplantation.

Adv Healthc Mater 2021 01 29;10(2):e2001157. Epub 2020 Nov 29.

College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk, 38541, Republic of Korea.

Recent studies emphasize on developing immune tolerance by an interim administration of various immunosuppressive drugs. In this study, a robust protocol is reported for local immunomodulation using a single-dose of FK506 microspheres and clodronate liposomes (mFK+CLO) in a xenogeneic model of islet transplantation. Surprisingly, the single-dose treatment with mFK+CLO induce tolerance to the islet xenograft. The recipient mice display tolerogenic dendritic cells (tDCs) with decreased antigen presenting ability and T cell activation capacity. Furthermore, a reduced percentage of CD4 and CD8 T cells and an impaired differentiation of naïve CD4 T cells into interferon-γ producing Th1 and interleukin-17 producing Th17 cells are observed. In addition, the immunosuppressive protocol leads to the generation of Foxp3 regulatory T cells (Tregs) which are required for the long-term graft survival. The enhanced generation of tDCs and Tregs by the single treatment of mFK+CLO cause xenograft tolerance, suggesting a possible clinical strategy which may pave the way towards improving therapeutic outcomes of clinical islet transplantation.
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http://dx.doi.org/10.1002/adhm.202001157DOI Listing
January 2021

Pancreatic metastasis from malignant phyllodes tumor of the breast.

Yeungnam Univ J Med 2021 Jan 27;38(1):78-82. Epub 2020 Nov 27.

Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea.

Pancreatic metastasis from malignant phyllodes tumor (PT) of the breast is rare, and only a few cases have been reported in the literature. Here, we report a case of pancreatic metastasis from malignant PT of the breast in a 48-year-old woman. She had had three episodes of recurrence of malignant PT in her right breast. She presented with epigastric pain for 2 months. Computed tomography and magnetic resonance imaging revealed a 6 cm-sized, well-defined, heterogeneous mass with peripheral enhancement in the body of the pancreas. Endoscopic ultrasonography-guided fine-needle aspiration was performed, and the pathologic report suggested spindle cell mesenchymal neoplasm. Subsequently, surgical excision was performed, and the mass was confirmed as a metastatic malignant PT. The imaging findings are discussed and the literature is briefly reviewed in this report.
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http://dx.doi.org/10.12701/yujm.2020.00759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7787903PMC
January 2021

A High Quality Asian Genome Assembly Identifies Features of Common Missing Regions.

Genes (Basel) 2020 11 13;11(11). Epub 2020 Nov 13.

Bioinformatics Institute, Macrogen Inc., Seoul 08511, Korea.

The current human reference genome (GRCh38), with its superior quality, has contributed significantly to genome analysis. However, GRCh38 may still underrepresent the ethnic genome, specifically for Asians, though exactly what we are missing is still elusive. Here, we juxtaposed GRCh38 with a high-contiguity genome assembly of one Korean (AK1) to show that a part of AK1 genome is missing in GRCh38 and that the missing regions harbored ~1390 putative coding elements. Furthermore, we found that multiple populations shared some certain parts in the missing genome when we analyzed the "unmapped" (to GRCh38) reads of fourteen individuals (five East-Asians, four Europeans, and five Africans), amounting to ~5.3 Mb (~0.2% of AK1) of the total genomic regions. The recovered AK1 regions from the "unmapped reads", which were the estimated missing regions that did not exist in GRCh38, harbored candidate coding elements. We verified that most of the common (shared by ≥7 individuals) missing regions exist in human and chimpanzee DNA. Moreover, we further identified the occurrence mechanism and ethnic heterogeneity as well as the presence of the common missing regions. This study illuminates a potential advantage of using a pangenome reference and brings up the need for further investigations on the various features of regions globally missed in GRCh38.
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http://dx.doi.org/10.3390/genes11111350DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697454PMC
November 2020

Impact of the Updated Guidelines on Human Epidermal Growth Factor Receptor 2 (HER2) Testing in Breast Cancer.

J Breast Cancer 2020 Oct 29;23(5):484-497. Epub 2020 Sep 29.

Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea.

Purpose: In 2007, the American Society of Clinical Oncology and the College of American Pathologists had established a human epidermal growth factor receptor 2 (HER2) testing guideline, which was updated in 2013 and subsequently in 2018. We assessed the clinical impact of the recent update by comparing the hybridization (ISH) results based on the 2007, 2013, and 2018 guidelines.

Methods: We assessed 2 cohorts. The first cohort included 1,161 primary invasive breast cancer (IBC) samples including 18 bilateral IBC cases, with both immunohistochemistry (IHC) and silver-enhanced ISH (SISH) results available for the HER2 status. The second cohort included 160 IBC cases with equivocal HER2 IHC, assessed using SISH. We retrospectively evaluated and compared the HER2 SISH results.

Results: There were 22 (1.9%) and 20 (12.5%) cases with altered SISH results according to the 2013 guidelines in cohorts 1 and 2, respectively. As per the 2018 guidelines, final HER2 statuses of 16 (1.4%) and 14 (8.5%) cases changed in cohorts 1 and 2, respectively. The 2013 guidelines increased the positive rate compared to the 2007 guidelines, in both cohorts (0.6% and 6.2%, respectively). Most equivocal cases in cohorts 1 (92.3%) and 2 (100%) as per the 2013 guidelines were reclassified as HER2-negative according to the 2018 guidelines. The 2018 guidelines increased the negative rates (1.3% in cohort 1 and 8.7% in cohort 2) and slightly decreased the positive rates (-0.2% in cohort 1 and -3.1% in cohort 2), compared to the 2013 guidelines. With each update, minor changes in the positive and negative rates were observed in whole breast cancer samples (cohort 1). However, the 2018 guidelines affected previously defined HER2-positive IBC with equivocal IHC results.

Conclusion: Under the 2013 guidelines, the positive and equivocal cases increased. However, the 2018 guidelines eliminated ambiguous cases by reclassifying them as HER2-negative.
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http://dx.doi.org/10.4048/jbc.2020.23.e53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604374PMC
October 2020

Breast lesions during pregnancy and lactation: a pictorial essay.

Ultrasonography 2020 Jul 23;39(3):298-310. Epub 2020 Jan 23.

Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea.

A wide range of breast lesions can arise during pregnancy and lactation, from benign or Epub ahead of print inflammatory diseases to malignant tumors. Hormone-influenced physiological changes of the breast make the radiological evaluation of breast lesions challenging. Knowledge of the imaging features of normal physiological changes and common breast lesions during this period can help radiologists accurately diagnose and appropriately manage conditions. As such, this pictorial essay illustrates normal physiological changes related to pregnancy and lactation, as well as common benign and malignant breast lesions encountered during those periods.
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http://dx.doi.org/10.14366/usg.19070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7315302PMC
July 2020

Necrobiotic Xanthogranuloma Coexists with Diffuse Normolipidemic Plane Xanthoma and Multiple Myeloma.

Ann Dermatol 2020 Feb 27;32(1):53-56. Epub 2019 Dec 27.

Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea.

Necrobiotic xanthogranuloma (NXG), is a rare multisystem disease that manifests as cutaneous inflammatory lesions, and is commonly associated with lymphoproliferative disease. Diffuse normolipemic plane xanthoma (NX), is also a rare, acquired disease that is often associated with systemic diseases such as lymphoproliferative disease. Both of these diseases have been reported to be associated with monoclonal gammopathy (MG). However, there are few cases in which these diseases co-exist. A 78-year-old female, who had a known case of NX on the neck and axillary area, presented with an asymptomatic erythematous plaque on her left supraclavicular area. Histopathological examination showed lymphoid aggregates, necrobiotic areas, and granulomatous inflammation in the dermis. Numerous foreignbody and Touton type giant cells were noticed. Serum protein immunoelectrophoresis showed an IgG kappa type MG. Lipid profile of the patient was normal. Bone marrow examination showed plasma cell myeloma. Based on these histologic and laboratory results, we diagnosed this lesion as NXG coexisting with NX and multiple myeloma. She was started on treatment with bortezomib and melphalan for multiple myeloma, and high-dose systemic corticosteroid and triamcinolone intralesional injection for the skin lesion. After 3 months of treatment, the NXG skin lesion and MG improved.
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http://dx.doi.org/10.5021/ad.2020.32.1.53DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7992639PMC
February 2020

NDRG3 protein expression is associated with aggressive biologic phenotype and unfavorable outcome in patients with invasive breast cancer.

Int J Clin Exp Pathol 2019 1;12(10):3886-3893. Epub 2019 Oct 1.

Department of Pathology, Yeungnam University College of Medicine Daegu, South Korea.

The N-myc downstream regulated gene (NDRG) protein family consists of 4 members (NDRG1, NDRG2, NDRG3, and NDRG4), that have been reported to be aberrantly expressed in human cancers. Furthermore, NDRG3 protein expression is known to promote tumor angiogenesis and cell growth. The aim of this study was to investigate the clinical significance of NDRG3 expression in invasive breast cancer (IBC). NDRG3 expression was evaluated immunohistochemically in tissue microarrays of 1339 IBC samples, and associations between NDRG3 expression and clinicopathologic parameters, including prognosis, were examined. NDRG3 protein expression was observed in 194 (14.5%) cases, and found to be associated with an age of ≥ 50 yrs (=0.043), a high histologic grade ( < 0.001), high Ki-67 index ( < 0.001), negatively for estrogen or progesterone receptor (both < 0.001), and positive HER2 status ( < 0.001). No significant association was found between NDRG3 expression and tumor size, lymph node status, lymphovascular invasion, or androgen receptor status. NDRG3-positive tumors were found to be associated with poorer overall survival (OS, =0.035), and multivariate analyses showed NDRG3 expression independently predicted OS (=0.011) and disease-free survival (=0.051). This study shows NDRG3 protein expression is a promising prognostic marker in IBC.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6949768PMC
October 2019

Colorectal cancer cells differentially impact migration and microRNA expression in endothelial cells.

Oncol Lett 2019 Dec 5;18(6):6361-6370. Epub 2019 Nov 5.

Center for Bioanalysis, Division of Chemical and Medical Metrology, Korea Research Institute of Standards and Science, Daejeon 34113, Republic of Korea.

Angiogenesis is an essential step in cancer progression and metastasis. Changes in the microRNA (miRNA or miR) expression profiles of endothelial cells (ECs) elicited by cancer cells promote angiogenesis. Vascular endothelial growth factor (VEGF), a key pro-angiogenic factor, influences miRNA expression in ECs; however, the exact role that VEGF serves in miRNA regulation during angiogenesis is poorly defined. The present study aimed to demonstrate the differential angiogenic effects on human umbilical vein endothelial cells (HUVECs) of five different colorectal cancer (CRC) cell lines by HUVEC migration and angiogenesis assays in response to CRC-conditioned medium (CM). Among the tested CMs, LoVo was the most effective cell line in eliciting HUVEC angiogenic phenotypes, at least partially due to its high VEGF level. It was also observed that pro-angiogenesis-regulatory miRNAs (angio-miRNA) miR-296, miR-132, miR-105 and miR-200 were upregulated in the VEGF-rich LoVo CM compared with the VEGF-scarce SW620 CM. In addition, treatment with VEGF receptor 2 inhibitor downregulated the pro-angio-miRNAs, with the exception of miR-132, suggesting that VEGF, as well as additional signaling, is required for angio-miRNA expression. Quantitative analyses on pro-angio-miRNA target expression suggested that independent pathways may be involved in the regulation of their expression. Overall, the data from the present study indicated that multiple paracrine factors, including VEGF secreted by CRCs, effectively modulated angio-miRNA expression, thus impacting their target expression and the angiogenic phenotypes of HUVECs.
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http://dx.doi.org/10.3892/ol.2019.11055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888185PMC
December 2019

Author Correction: An ADAMTS Sol narae is required for cell survival in Drosophila.

Sci Rep 2019 Nov 14;9(1):17116. Epub 2019 Nov 14.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, Korea.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41598-019-53741-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6854092PMC
November 2019

High mobility group A1 (HMGA1) protein and gene expression correlate with ER-negativity and poor outcomes in breast cancer.

Breast Cancer Res Treat 2020 Jan 17;179(1):25-35. Epub 2019 Sep 17.

Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, MD, 21205, USA.

Purpose: The high mobility group A1 (HMGA1) chromatin remodeling protein is required for metastatic progression and cancer stem cell properties in preclinical breast cancer models, although its role in breast carcinogenesis has remained unclear. To investigate HMGA1 in primary breast cancer, we evaluated immunoreactivity score (IRS) in tumors from a large cohort of Asian women; HMGA1 gene expression was queried from two independent Western cohorts.

Methods: HMGA1 IRS was generated from breast tumors in Korean women as the product of staining intensity (weak = 1, moderate = 2, strong = 3) and percent positive cells (< 5% = 0, 5-30% = 1, 30-60% = 2, > 60% = 3), and stratified into three groups: low (< 3), intermediate (3-6), high (> 6). We assessed HMGA1 and estrogen receptor (ESR1) gene expression from two large databases (TCGA, METABRIC). Overall survival was ascertained from the METABRIC cohort.

Results: Among 540 primary tumors from Korean women (181 ER-negative, 359 ER-positive), HMGA1 IRS was < 3 in 89 (16.5%), 3-6 in 215 (39.8%), and > 6 in 236 (43.7%). High HMGA1 IRS was associated with estrogen receptor (ER)-negativity (χ = 12.07; P = 0.002) and advanced nuclear grade (χ = 12.83; P = 0.012). In two large Western cohorts, the HMGA1 gene was overexpressed in breast cancers compared to non-malignant breast tissue (P < 0.0001), including Asian, African American, and Caucasian subgroups. HMGA1 was highest in ER-negative tumors and there was a strong inverse correlation between HMGA1 and ESR1 gene expression (Pearson r = - 0.60, P < 0.0001). Most importantly, high HMGA1 predicted decreased overall survival (P < 0.0001) for all women with breast cancer and further stratified ER-positive tumors into those with inferior outcomes.

Conclusions: Together, our results suggest that HMGA1 contributes to estrogen-independence, tumor progression, and poor outcomes. Moreover, further studies are warranted to determine whether HMGA1 could serve as a prognostic marker and therapeutic target for women with breast cancer.
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http://dx.doi.org/10.1007/s10549-019-05419-1DOI Listing
January 2020

A novel population of extracellular vesicles smaller than exosomes promotes cell proliferation.

Cell Commun Signal 2019 08 15;17(1):95. Epub 2019 Aug 15.

Center for Bioanalysis, Korea Research Institute of Standards and Science, 267 Gajeong-ro, Yuseong-gu, Daejeon, Korea.

Background: Extracellular vesicles (EVs) play important roles in intercellular communication by delivering RNA, lipid, and proteins to neighboring or distant cells. Identification and classification of EVs secreted from diverse cell types are essential for understanding their signaling properties.

Methods: In this study, EVs from the culture media were isolated by ultracentrifugation and analyzed by electron microscopy (EM) and nanoparticle tracking analyses. Conditioned media (CM) from HEK293 cells culture grown either in serum-free (SF) or 10% fetal bovine serum (FBS) containing media were centrifuged at 100,000×g to separate the SN supernatant and the P100 pellet in which exosomes are enriched. Then, the SN fraction was centrifuged at 200,000×g to yield the P200 pellet fraction containing novel EVs smaller than exosomes. The exosomal markers in the EV subgroups were examined by western blotting and immune-EM, and the functional analyses of EVs were conducted on HEK293 and THP-1 cell culture.

Results: We identified a new group of EVs in the P200 fraction that was smaller than exosomes in size. Typical exosome markers such as Hsp70, TSG101, and CD63 were found in both P100 exosomes and the P200 vesicles, but CD81 was highly enriched in exosomes but not in the P200 vesicles. Furthermore, chemicals that inhibit the major exosome production pathway did not decrease the level of P200 vesicles. Therefore, these small EVs indeed belong to a distinguished group of EVs. Exosomes and the P200 vesicles were found in CM of human cell lines as well as FBS. Addition of the exosomes and the P200 vesicles to human cell cultures enhanced exosome production and cell proliferation, respectively.

Conclusions: Our study identifies a novel population of EVs present in the P200 fraction. This EV population is distinguished from exosomes in size, protein contents, and biogenesis pathway. Furthermore, exosomes promote their own production whereas the P200 vesicles support cell proliferation. In sum, we report a new group of EVs that are distinct physically, biologically and functionally from exosomes.
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http://dx.doi.org/10.1186/s12964-019-0401-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6694590PMC
August 2019

ADAMTS Sol narae cleaves extracellular Wingless to generate a novel active form that regulates cell proliferation in Drosophila.

Cell Death Dis 2019 07 22;10(8):564. Epub 2019 Jul 22.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, Korea.

Wnt/ Wingless (Wg) is essential for embryonic development and adult homeostasis in all metazoans, but the mechanisms by which secreted Wnt/Wg is processed remain largely unknown. A Drosophila Sol narae (Sona) is a member of A Disintegrin And Metalloprotease with ThromboSpondin motif (ADAMTS) family, and positively regulates Wg signaling by promoting Wg secretion. Here we report that Sona and Wg are secreted by both conventional Golgi and exosomal transports, and Sona cleaves extracellular Wg at the two specific sites, leading to the generation of N-terminal domain (NTD) and C-terminal domain (CTD) fragments. The cleaved forms of extracellular Wg were detected in the extracellular region of fly wing discs, and its level was substantially reduced in sona mutants. Transient overexpression of Wg-CTD increased wing size while prolonged overexpression caused lethality and developmental defects. In contrast, Wg-NTD did not induce any phenotype. Moreover, the wing defects and lethality induced by sona RNAi were considerably rescued by Wg-CTD, indicating that a main function of extracellular Sona is the generation of Wg-CTD. Wg-CTD stabilized cytoplasmic Armadillo (Arm) and had genetic interactions with components of canonical Wg signaling. Wg-CTD also induced Wg downstream targets such as Distal-less (Dll) and Vestigial (Vg). Most importantly, Cyclin D (Cyc D) was induced by Wg-CTD but not by full-length Wg. Because Sona also induces Cyc D in a cell non-autonomous manner, Wg-CTD generated by Sona in the extracellular region activates a subset of Wg signaling whose major function is the regulation of cell proliferation.
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http://dx.doi.org/10.1038/s41419-019-1794-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646336PMC
July 2019

Application of digital PCR for assessing DNA fragmentation in cytotoxicity response.

Biochim Biophys Acta Gen Subj 2019 08 7;1863(8):1235-1242. Epub 2019 May 7.

Center for Bioanalysis, Korea Research Institute of Standards and Science, 267 Gajeong-ro, Yuseong-gu, Daejeon, Republic of Korea. Electronic address:

Background: Regulated cell death plays an essential role in various biological processes, leading to the development of a number of methods to detect and quantitatively measure cells exhibiting decreased viability due to either apoptosis or necrosis.

Methods And Results: When cytotoxicity is induced by anti-cancer chemicals, human cell lines exhibit specific features, including dampened cell proliferation and lost plasma membrane asymmetry, presenting distinct sensitivity. In this study, we report a set of novel digital PCR (dPCR) assays to quantitatively measure the degree of cell death. These dPCR assays are designed to quantify targets of increasing sizes within the RNase P (RP) gene locus. The ratio between short and long target copy numbers implies the degree of DNA fragmentation, which we name the RP fragmentation index.

Conclusions: Compared to other conventional quantitative methods, the RP fragmentation index using cellular DNA represents a valid indicator in the measurement of the degree of cell death.

General Significance: The demonstrated dPCR assays can precisely assess DNA fragmentation that quantitatively reflects the degree of cytotoxicity.
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http://dx.doi.org/10.1016/j.bbagen.2019.05.001DOI Listing
August 2019

CD9 Expression in Tumor Cells Is Associated with Poor Prognosis in Patients with Invasive Lobular Carcinoma.

J Breast Cancer 2019 Mar 1;22(1):77-85. Epub 2019 Feb 1.

Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea.

Purpose: We investigated the prognostic significance of CD9 expression in tumor cells of patients with invasive lobular carcinoma (ILC).

Methods: CD9 expression was evaluated by immunohistochemistry in 113 ILC tissue samples. Correlation of CD9 expression with the patients' clinicopathological parameters and overall survival was assessed.

Results: CD9 expression was detected in 48 (42.5%) ILC patients. However, no significant relation could be determined between CD9 expression and the clinicopathological parameters of the patient including tumor size, lymph node metastasis, lymphovascular invasion, histologic grade, expression of hormone receptors, human epidermal growth factor receptor 2 status, and Ki-67 labeling index. Patients with CD9 expression had worse overall survival ( = 0.051) and disease-free survival (DFS, = 0.014) compared to patients without CD9 expression. Multivariate analysis revealed that CD9 expression was an independent prognostic factor for DFS ( = 0.049).

Conclusion: CD9 expression in tumor cells could be a significant prognostic marker in patients with ILC.
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http://dx.doi.org/10.4048/jbc.2019.22.e9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438839PMC
March 2019

Stable Isotope Labeled DNA: A New Strategy for the Quantification of Total DNA Using Liquid Chromatography-Mass Spectrometry.

Anal Chem 2019 03 7;91(6):3936-3943. Epub 2019 Mar 7.

Department of Bio-Analytical Science , University of Science and Technology , 217 Gajeong-ro , Yuseong-gu, Daejeon 34113 , Republic of Korea.

Conventional DNA quantification methods require a DNA purification step that limits their reliability in estimating the original DNA amount, especially in complex matrix. To overcome this limitation, we developed a method to calibrate the variable DNA extraction efficiencies during the purification process, allowing for the accurate quantification of DNA in complex matrix. This method is based on isotope dilution-liquid chromatography-mass spectrometry using stable isotope labeled DNA (SILD) as an internal standard. Steps include spiking prepared SILD into samples, purification, enzymatic hydrolysis, and detection of DNA monomers via mass spectrometry, where the spiked SILD is expected to behave the same as the target DNA throughout the entire procedure. We show that the mean recoveries of four different DNA purification kits were dramatically improved by using the SILD internal standard, both for Escherichia coli and human genomic DNA. As standards for calibration, deoxyribonucleoside monophosphates and purified genomic DNA were tested, with genomic DNA from corresponding species found to calibrate the variable extraction efficiencies more effectively. With this successful calibration, our newly developed procedure enables International System of Units-traceable quantification of total DNA in complex matrix.
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http://dx.doi.org/10.1021/acs.analchem.8b04940DOI Listing
March 2019

An ADAMTS Sol narae is required for cell survival in Drosophila.

Sci Rep 2019 02 4;9(1):1270. Epub 2019 Feb 4.

Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Yuseong-gu, Daejeon, Korea.

Cell survival is essential for all living organisms to cope against multiple environmental insults. Intercellular signaling between dying and surviving cells plays an important role to ensure compensatory proliferation, preventing tissue loss after environmental stresses. Here, we show that Sol narae (Sona), a Disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) in Drosophila is required for cell survival. sona exhibited a positive genetic interaction with Death-associated inhibitor of apoptosis 1 (Diap1), and a negative genetic interaction with reaper (rpr). Transcription patterns of sona, Diap1, and rpr genes in the pouch region of wing discs were coordinately changed after irradiation. Interestingly, there was a negative correlation in the expression levels of Sona and DIAP1, and both cell types, one with high Sona level and the other with high Diap1 level, were resistant to irradiation-induced cell death. The sona-expressing cells rarely entered into cell cycle themselves but promoted the nearby cells to proliferate in irradiation conditions. We found that these sona-expressing cells are able to upregulate Cyclin D (Cyc D) and increase tissue size. Furthermore, transient Sona overexpression increased survival rate and promoted development of flies in irradiation conditions. We propose that the two types of radiation-resistant cells, one with high Sona level and the other with high Diap1 level, communicate with dying cells and between each other for cell survival and proliferation in response to irradiation.
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http://dx.doi.org/10.1038/s41598-018-37557-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362049PMC
February 2019

Validation of the pathological prognostic staging system proposed in the revised eighth edition of the AJCC staging manual in different molecular subtypes of breast cancer.

Virchows Arch 2019 Feb 24;474(2):193-200. Epub 2018 Nov 24.

Department of Pathology, Yeungnam University College of Medicine, Daegu, South Korea.

The authors investigated the clinical utility of the revised prognostic staging system proposed in the eighth edition of the American Joint Committee on Cancer (AJCC) staging manual in breast cancer (BC) patients. We retrospectively reviewed the data of 714 BC patients that received surgical treatment and standard adjuvant therapy from January 2005 to December 2007. All patients were restaged for anatomic TNM stage and pathological prognostic (PP) stage as defined in the revised eighth edition of the AJCC manual. Compared with anatomic stage, PP stage was different from anatomic stage in 325 (45.5%) patients, 254 were down-staged and 71 were upstaged. There were significant differences in overall survival (OS) and disease-free survival (DFS) according to different anatomic stages or PP stages (all, p < 0.001). In anatomic stage I patients, OS was significantly different between PP stages IA and IB (p < 0.001), but no significant difference was observed between anatomic stages IA and IB (p = 0.413). PP stages exhibited significant OS differences in anatomic stage IIB (p = 0.011), but survival differences according to PP stages were not observed in anatomic stage IIA, IIIA, or IIIC. PP stages were found to have prognostic value with respect to OS and DFS for luminal (p < 0.001 and p < 0.001), HER2-positive (p = 0.001 and p = 0.013), and triple-negative (p = 0.008 and p = 0.03) subtypes. The prognostic staging system proposed in the eighth edition of the AJCC more accurately predicts the clinical outcomes of BC patients than the traditional anatomic staging system.
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http://dx.doi.org/10.1007/s00428-018-2495-xDOI Listing
February 2019

Ovarian Gynandroblastoma with a Juvenile Granulosa Cell Tumor Component in a Postmenopausal Woman: A Case Report and Literature Review.

J Pathol Transl Med 2018 Sep 17;52(5):344-348. Epub 2018 Jul 17.

Department of Pathology, Yeungnam University School of Medicine, Daegu, Korea.

Gynandroblastoma is an extremely rare sex cord-stromal tumor with both female (granulosa cell tumor) and male (Sertoli-Leydig cell tumor) elements. Juvenile granulosa cell tumors are also very rare and are so named because they usually occur in children and adolescents. A 71-year-old woman with right upper quadrant abdominal pain visited our hospital. Pelvic computed tomography showed a large multilocular cystic mass, suspected to be of ovarian origin. We performed a total abdominal hysterectomy (total abdominal hysterectomy was performed) with bilateral salpingooophorectomy. A 13-cm multilocular cystic mass with serous fluid was observed in her right ovary. Upon microscopic examination, the solid component of the mass showed both Sertoli-Leydig cell and juvenile granulosa cell differentiation, which we diagnosed as gynandroblastoma. Gynandroblastoma with a juvenile granulosa cell tumor component is extremely rare and, until now, only six cases have been reported in the English literature. We report the first gynandroblastoma with a juvenile granulosa cell tumor component diagnosed in an elderly patient, along with a literature review.
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http://dx.doi.org/10.4132/jptm.2018.06.28DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166011PMC
September 2018

Mammary Paget's disease without underlying malignancy of the breast.

Yeungnam Univ J Med 2018 06 30;35(1):99-103. Epub 2018 Jun 30.

Department of Pathology, Yeungnam University College of Medicine, Daegu, Korea.

Mammary Paget's disease (MPD) is usually accompanied by underlying breast malignancy; however, a few cases have been reported as only skin lesions without any evidence of malignancy of the breast on imaging tests and microscopic examination of surgical specimen. Here, we describe a 47-year-old woman who visited our hospital who had an eczematous lesion on right nipple and areola for over 10 years. The lesion was diagnosed as Paget's disease by punch biopsy; however, imaging studies demonstrated no breast malignancy or lymph node metastasis. The patient underwent surgery of on the nipple and areola including underlying breast tissue. No underlying malignancy was found upon microscopic examination, except for Paget's disease. Immunohistochemical stains revealed that the tumor cells were positive for cytokeratin 7, and negativity for p63, cytokeratin 5/6, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. We report a case of MPD without underlying malignancy. To the best of our knowledge, this is the third case reported in Korea.
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http://dx.doi.org/10.12701/yujm.2018.35.1.99DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6784678PMC
June 2018

Interleukin-13 receptor alpha 2 expression in tumor cells is associated with reduced disease-free survival in patients with luminal subtype invasive breast cancer.

Tumour Biol 2018 Jun;40(6):1010428318783657

1 Department of Pathology, College of Medicine, Yeungnam University, Daegu, South Korea.

Interleukin-13 receptor alpha 2 is one of the subunits of transmembrane receptor for interleukin-13. The aim of this study was to investigate the prognostic value of interleukin-13 receptor alpha 2 expression in invasive breast cancer. Interleukin-13 receptor alpha 2 expressions were assessed by immunohistochemistry in tissue microarrays of 1283 invasive breast cancer samples, and associations between these expressions and clinicopathological variables and clinical outcomes were investigated. Interleukin-13 receptor alpha 2 expression was observed in 138 (10.8%) samples, and found to be associated with positive estrogen receptor (p < 0.001) and progesterone receptor (p < 0.001) and with the luminal subtype (p < 0.001). No significant association was found between interleukin-13 receptor alpha 2 expression and other clinicopathological variables including age, tumor size, lymph node metastasis, histologic types, histologic grade, HER2 status, Ki-67 labeling index, or tumor-infiltrating lymphocytes levels. Patients with interleukin-13 receptor alpha 2 expression tended to have poorer disease-free survival, but the difference was not statistically significant (p = 0.069). Subgroup analysis showed luminal breast cancer patients positive for interleukin-13 receptor alpha 2 expression had significantly poorer disease-free survival (p = 0.018) than luminal breast cancer patients negative for interleukin-13 receptor alpha 2 expression. However, no association between interleukin-13 receptor alpha 2 expression and clinical outcome was observed in HER2-positive and triple-negative subgroups (p = 0.574 and p = 0.936, respectively). Multivariate analysis showed interleukin-13 receptor alpha 2 expression was an independent poor prognostic factor for luminal breast cancer (p = 0.03). This study shows interleukin-13 receptor alpha 2 expression could be a useful prognostic marker for selecting patients with luminal breast cancer likely to follow a clinically aggressive course despite receiving systemic therapy.
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http://dx.doi.org/10.1177/1010428318783657DOI Listing
June 2018

Assessment of Digital PCR as a Primary Reference Measurement Procedure to Support Advances in Precision Medicine.

Clin Chem 2018 09 14;64(9):1296-1307. Epub 2018 Jun 14.

Molecular and Cell Biology Team, LGC, Teddington, Middlesex, UK;

Background: Genetic testing of tumor tissue and circulating cell-free DNA for somatic variants guides patient treatment of many cancers. Such measurements will be fundamental in the future support of precision medicine. However, there are currently no primary reference measurement procedures available for nucleic acid quantification that would support translation of tests for circulating tumor DNA into routine use.

Methods: We assessed the accuracy of digital PCR (dPCR) for copy number quantification of a frequently occurring single-nucleotide variant in colorectal cancer ( c.35G>A, p.Gly12Asp, from hereon termed G12D) by evaluating potential sources of uncertainty that influence dPCR measurement.

Results: Concentration values for samples of G12D and wild-type plasmid templates varied by <1.2-fold when measured using 5 different assays with varying detection chemistry (hydrolysis, scorpion probes, and intercalating dyes) and <1.3-fold with 4 commercial dPCR platforms. Measurement trueness of a selected dPCR assay and platform was validated by comparison with an orthogonal method (inductively coupled plasma mass spectrometry). The candidate dPCR reference measurement procedure showed linear quantification over a wide range of copies per reaction and high repeatability and interlaboratory reproducibility (CV, 2%-8% and 5%-10%, respectively).

Conclusions: This work validates dPCR as an SI-traceable reference measurement procedure based on enumeration and demonstrates how it can be applied for assignment of copy number concentration and fractional abundance values to DNA reference materials in an aqueous solution. High-accuracy measurements using dPCR will support the implementation and traceable standardization of molecular diagnostic procedures needed for advancements in precision medicine.
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http://dx.doi.org/10.1373/clinchem.2017.285478DOI Listing
September 2018
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