Publications by authors named "Chia-Jen Liu"

253 Publications

Histopathology and Genetic Causes of Primary Aldosteronism in Young Adults.

J Clin Endocrinol Metab 2022 Jul 2. Epub 2022 Jul 2.

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.

Context: Due to its rare incidence, molecular features of PA in young adults are largely unknown. Recently developed targeted mutational analysis identified aldosterone-driver somatic mutations in aldosterone-producing lesions, including aldosterone-producing adenomas (APAs), aldosterone-producing nodules (APNs), and aldosterone-producing micronodules, formerly known as aldosterone-producing cell clusters.

Objective: To investigate histologic and genetic characteristics of lateralized PA in young adults.

Methods: Formalin-fixed, paraffin-embedded (FFPE) adrenal tissue sections from 74 young patients with lateralized PA (<35 years-old) were used for this study. Immunohistochemistry (IHC) for aldosterone synthase (CYP11B2) was performed to define the histopathologic diagnosis. Somatic mutations in aldosterone-producing lesions were further determined by CYP11B2 IHC-guided DNA sequencing.

Results: Based on the CYP11B2 IHC results, histopathologic classification was made as follows: 48 APAs, 20 APNs, 2 multiple aldosterone-producing nodules (MAPNs), 1 double APN, 1 APA with MAPN, and 2 non-functioning adenomas (NFAs). Of 45 APAs with successful sequencing, 43 (96%) had somatic mutations, with KCNJ5 mutations being the most common genetic cause of young-onset APA (35/45, 78%). Of 18 APNs with successful sequencing, all of them harbored somatic mutations, with CACNA1D mutations being the most frequent genetic alteration in young-onset APN (8/18, 44%). Multiple CYP11B2-expressing lesions in patients with MAPN showed several aldosterone-driver mutations. No somatic mutations were identified in NFAs.

Conclusions: APA is the most common histologic feature of lateralized PA in young adults. Somatic KCNJ5 mutations are common in APAs, whereas CACNA1D mutations are often seen in APNs in this young PA population.
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http://dx.doi.org/10.1210/clinem/dgac408DOI Listing
July 2022

Aging accelerates while multiparity delays tumorigenesis in mouse models of high-grade serous carcinoma.

Gynecol Oncol 2022 06 9;165(3):552-559. Epub 2022 Apr 9.

Departments of Pathology, University of Michigan Medical School, USA; Departments of Internal Medicine, University of Michigan Medical School, USA. Electronic address:

Objectives: The "incessant ovulation" hypothesis links increased risk for tubo-ovarian high-grade serous carcinoma (HGSC) due to more ovulations and reduced risk conferred by pre-menopausal exposures like oral contraceptive use, multiparity, and breastfeeding. However, most women diagnosed with HGSC are postmenopausal, implying age is a major risk factor for HGSC. Our mouse model for HGSC, based on tamoxifen (TAM)-induced somatic inactivation of the Brca1, Trp53, Rb1, and Nf1 (BPRN) tumor suppressor genes in oviductal epithelium, recapitulates key genetic, histopathologic, and biological features of human HGSCs. We aimed to credential the model for future efforts to define biological and risk modification factors in HGSC pathogenesis.

Methods: BPRN mice were treated with TAM to induce tumors at defined ages and parity status.

Results: BPRN mice aged 9-months prior to tumor induction had markedly shorter survival than 6-8 week old mice induced to form tumors (median 46.5 weeks versus 61.5 weeks, log-rank test P = 0.0006). No significant differences in cancer phenotypes were observed between multiparous versus nulliparous BPRN mice. However, using a modified tumor model with one wild-type Nf1 allele (BPRN), nulliparous mice had more advanced tumors than multiparous mice (Mantel-Haenszel Chi-square test of association, P = 0.01).

Conclusions: Our findings show aging is associated with significantly shortened survival post tumor induction in the BRPN model and multiparity delays development and/or progression of HGSC in certain genetic contexts. The findings support relevance of our mouse model to gain mechanistic insights into how known factors exert their protective effects and to test novel approaches for HGSC prevention.
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http://dx.doi.org/10.1016/j.ygyno.2022.03.030DOI Listing
June 2022

Direct cellular reprogramming enables development of viral T antigen-driven Merkel cell carcinoma in mice.

J Clin Invest 2022 04;132(7)

Department of Dermatology.

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine skin cancer that frequently carries an integrated Merkel cell polyomavirus (MCPyV) genome and expresses viral transforming antigens (TAgs). MCC tumor cells also express signature genes detected in skin-resident, postmitotic Merkel cells, including atonal bHLH transcription factor 1 (ATOH1), which is required for Merkel cell development from epidermal progenitors. We now report the use of in vivo cellular reprogramming, using ATOH1, to drive MCC development from murine epidermis. We generated mice that conditionally expressed MCPyV TAgs and ATOH1 in epidermal cells, yielding microscopic collections of proliferating MCC-like cells arising from hair follicles. Immunostaining of these nascent tumors revealed p53 accumulation and apoptosis, and targeted deletion of transformation related protein 53 (Trp53) led to development of gross skin tumors with classic MCC histology and marker expression. Global transcriptome analysis confirmed the close similarity of mouse and human MCCs, and hierarchical clustering showed conserved upregulation of signature genes. Our data establish that expression of MCPyV TAgs in ATOH1-reprogrammed epidermal cells and their neuroendocrine progeny initiates hair follicle-derived MCC tumorigenesis in adult mice. Moreover, progression to full-blown MCC in this model requires loss of p53, mimicking the functional inhibition of p53 reported in human MCPyV-positive MCCs.
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http://dx.doi.org/10.1172/JCI152069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8970662PMC
April 2022

Prompt successful response to a COVID-19 outbreak: Performance of community-based rapid screening station.

J Formos Med Assoc 2022 Jan 24. Epub 2022 Jan 24.

Department of Otorhinolaryngology, Taipei City Hospital, Taipei, 10341, Taiwan; Graduate Institute of Gerontology and Health Care Management, Chang Gung University of Science and Technology, Taoyuan, 33303, Taiwan; Department of Exercise and Health Sciences, University of Taipei, Taipei, 111036, Taiwan. Electronic address:

An outbreak occurred in Wanhua District of Taipei City. It was traced to a cluster infection originating from a teahouse. To prevent further large-scaled community spread, the Taipei City Government established the first community rapid test screening station. This report describes the station's strategy and performance and key factors that contributed to its operation. The project involves collaboration among various departments of Taipei City Government, including the health, environmental, police, transportation, and fire departments. The station provides rapid screening, polymerase chain reaction (PCR) testing, and immediate isolation and follow-up medical services upon the detection of a positive case. These services are accessible to local residents and are intended to ease hospitals' burdens. In 36 days, a total of 8532 people were tested, and 419 confirmed cases were identified. Over the same period, the weekly number of positive cases in Wanhua District decreased from 356 to 40, and the PCR positive rate decreased from 21.7% to 1.2%. The policy of establishing rapid screening station, contact tracing and mask wearing policy are key strategies for interrupting chains of transmission of COVID-19. This intervention has become a model for preventing the spread of the epidemic and establishing community rapid screening stations in Taiwan.
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http://dx.doi.org/10.1016/j.jfma.2022.01.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8784669PMC
January 2022

Implementation of Compassionate Communities: The Taipei Experience.

Healthcare (Basel) 2022 Jan 17;10(1). Epub 2022 Jan 17.

Department of Health and Welfare, Tian-Mu Campus, College of City Management, University of Taipei, Taipei City 111036, Taiwan.

A worldwide movement to empower communities to support their members to care for each other at the end of life (EoL) has emerged since Kellehear published the Compassionate City Charter. This current report discusses the implementation experiences and preliminary outcomes of Compassionate Communities (CC) in Taipei City. Using the guidance of the Charter and international experiences, we have developed and multiplied a culturally sensitive, sustainable, and holistic CC program that composes municipal hospital, social, and other services, partnering with community leaders, non-governmental organizations, university students, and volunteers. Innovative campaigns, such as workshops, conferences, and the Life Issue Café, have been delivered to facilitate engagement, public education, and leadership with reverence to folk beliefs and the use of existing social networks. We have identified a model with strong collaborative leadership, high participation rates, and ongoing commitment. The gaps between asking/accepting and providing help were bridged when social connectedness was strengthened. We also integrated home-based medical care, home-based palliative care, and advance care planning to help the vulnerable who live alone, with poor status, or with limited resource access, and continue to support the community throughout the COVID-19 pandemic.
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http://dx.doi.org/10.3390/healthcare10010177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8776212PMC
January 2022

Efficacy of Postoperative Unilateral Neck Irradiation in Patients with Buccal Mucosa Squamous Carcinoma with Extranodal Extension: A Propensity Score Analysis.

Cancers (Basel) 2021 Nov 29;13(23). Epub 2021 Nov 29.

Department of Radiation Oncology, Linkou Chang Gung Memorial Hospital, Chang Gung University, Taoyuan 333, Taiwan.

Unilateral radiotherapy (RT) as a postoperative treatment for multiple ipsilateral lymph node (LN) metastases remains controversial. We investigated the efficacy of postoperative unilateral RT for buccal mucosa squamous cell carcinoma (BMSCC) with extranodal extensions (ENEs). We retrospectively reviewed the clinical records of 186 patients with ENE+ BMSCC who received postoperative RT during 1997-2016. Propensity score matching was used to establish comparable cohorts. The endpoints were contralateral nodal control (CLNC), overall survival (OS), disease-free survival (DFS), distant metastasis-free survival (DMFS), local control (LC), and regional control (RC). After matching, 123 patients were selected for analysis; 45 (36.6%) and 78 (63.4%) patients underwent unilateral and bilateral RT, respectively. The median follow-up was 36.27 months. The survival outcomes in the unilateral and bilateral RT groups were similar: 3-year CLNC (85.6% vs. 89.1%, = 0.748), OS (53.2% vs. 57.4%, = 0.229), DFS (46.5% vs. 48.6%, = 0.515), DMFS (70.7% vs. 72.0%, = 0.499), LC (78.0% vs. 75.6%, = 0.692), and RC (79.9% vs. 76.2%, = 0.465). On multivariable Cox regression analysis, unilateral and bilateral RT showed comparable outcomes; the number of ENEs ≥ 4 was the only significant prognostic factor for all clinical outcomes. Using decision tree analysis, we classified our patients to have a low, intermediate, or high risk of contralateral failure based on three factors: number of ENEs, margin status, and tumor stage. In conclusion, postoperative unilateral RT did not worsen outcomes in patients with ENE+ BMSCC in this cohort. The decision tree model may assist physicians in optimizing and tailoring radiation fields.
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http://dx.doi.org/10.3390/cancers13235997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8656711PMC
November 2021

Serial monitoring of genomic alterations in circulating tumor cells of ER-positive/HER2-negative advanced breast cancer: feasibility of precision oncology biomarker detection.

Mol Oncol 2022 05 20;16(10):1969-1985. Epub 2021 Dec 20.

Rogel Cancer Center, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA.

Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions.
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http://dx.doi.org/10.1002/1878-0261.13150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9120891PMC
May 2022

Molecular Characterization of Clear Cell Renal Cell Carcinoma Reveals Prognostic Significance of Epithelial-mesenchymal Transition Gene Expression Signature.

Eur Urol Oncol 2022 02 26;5(1):92-99. Epub 2021 Nov 26.

Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; Michigan Center for Translational Pathology, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA. Electronic address:

Background: There is an ongoing need to develop prognostic biomarkers to improve the management of clear cell renal cell carcinoma (ccRCC).

Objective: To leverage enriched pathways in ccRCC to improve risk-stratification.

Design, Setting, And Participants: We retrospectively identified two complementary discovery cohorts of patients with ccRCC who underwent (1) radical nephrectomy (RNx) with inferior vena cava tumor thrombectomy (patients = 5, samples = 24) and (2) RNx for localized disease and developed recurrence versus no recurrence (n = 36). Patients with localized ccRCC (M0) in The Cancer Genome Atlas (TCGA, n = 386) were used for validation.

Outcome Measurements And Statistical Analysis: A differential expression gene (DEG) analysis was performed on targeted RNA next-generation sequencing data from both discovery cohorts. Using TCGA for validation, Kaplan-Meier survival analysis and multivariable Cox proportional hazard testing were utilized to investigate the prognostic impact of DEGs, cell cycle proliferation (CCP), and a novel epithelial-mesenchymal transition (EMT) score on progression-free (PFS) and disease-specific (DSS) survival.

Results And Limitations: In the discovery cohorts, we observed overexpression of WT1 and CCP genes in the tumor thrombus versus the primary tumor, as well as in patients with recurrence versus those without recurrence. A hallmark pathway analysis demonstrated enrichment of the EMT- and CCP-related pathways in patients with high WT1 expression in the TCGA (validation) ccRCC cohort. CCP and EMT scores were derived in the validation cohort, which was stratified into four risk groups using Youden Index cut points: CCP/EMT, CCP/EMT, CCP/EMT, and CCP/EMT. The CCP/EMT risk group was associated with the worst PFS and DSS (both p < 0.001). In a multivariable analysis, CCP/EMT was independently associated with poor PFS and DSS (hazard ratio = 4.6 and 10.3, respectively; p < 0.001).

Conclusions: We demonstrate the synergistic prognostic impact of EMT in tumors with a high CCP score. Our novel EMT score has the potential to improve risk stratification and provide potential novel therapeutic targets.

Patient Summary: Genes involved in epithelial-mesenchymal transition provides important prognostic information for patients with clear cell renal cell carcinoma.
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http://dx.doi.org/10.1016/j.euo.2021.10.007DOI Listing
February 2022

Genomic evidence suggests that cutaneous neuroendocrine carcinomas can arise from squamous dysplastic precursors.

Mod Pathol 2022 04 30;35(4):506-514. Epub 2021 Sep 30.

Department of Dermatology, University of Michigan, Ann Arbor, MI, USA.

Merkel cell carcinoma (MCC) is an aggressive cutaneous neuroendocrine carcinoma without a known dysplastic precursor. In some cases, MCC is associated with SCCIS in the overlying epidermis; however, the MCC and SCCIS populations display strikingly different morphologies, and thus far a relationship between these components has not been demonstrated. To better understand the relationship between these distinct tumor cell populations, we evaluated 7 pairs of MCC-SCCIS for overlapping genomic alterations by cancer profiling panel. A subset was further characterized by transcriptional profiling and immunohistochemistry. In 6 of 7 MCC-SCCIS pairs there was highly significant mutational overlap including shared TP53 and/or RB1 mutations. In some cases, oncogenic events previously implicated in MCC (MYCL gain, MDM4 gain, HRAS mutation) were detected in both components. Although FBXW7 mutations were enriched in MCC, no gene mutation was unique to the MCC component across all cases. Transcriptome analysis identified 2736 differentially expressed genes between MCC and SCCIS. Genes upregulated in the MCC component included Polycomb repressive complex targets; downregulated transcripts included epidermal markers, and immune genes such as HLA-A. Immunohistochemical studies revealed increased expression of SOX2 in the MCC component, with diminished H3K27Me3, Rb, and HLA-A expression. In summary, MCC-SCCIS pairs demonstrate clonal relatedness. The shift to neuroendocrine phenotype is associated with loss of Rb protein expression, decrease in global H3K27Me3, and increased expression of Merkel cell genes such as SOX2. Our findings suggest an epidermal origin of MCC in this setting, and to our knowledge provide the first molecular evidence that intraepithelial squamous dysplasia may represent a direct precursor for small cell carcinoma.
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http://dx.doi.org/10.1038/s41379-021-00928-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8964828PMC
April 2022

Comparative Molecular Analysis of Primary Central Nervous System Lymphomas and Matched Vitreoretinal Lymphomas by Vitreous Liquid Biopsy.

Int J Mol Sci 2021 Sep 16;22(18). Epub 2021 Sep 16.

W.K. Kellogg Eye Center, Department of Ophthalmology and Visual Science, University of Michigan, Ann Arbor, MI 48109, USA.

Primary Central Nervous System Lymphoma (PCNSL) is a lymphoid malignancy of the brain that occurs in ~1500 patients per year in the US. PCNSL can spread to the vitreous and retina, where it is known as vitreoretinal lymphoma (VRL). While confirmatory testing for diagnosis is dependent on invasive brain tissue or cerebrospinal fluid sampling, the ability to access the vitreous as a proximal biofluid for liquid biopsy to diagnose PCNSL is an attractive prospect given ease of access and minimization of risks and complications from other biopsy strategies. However, the extent to which VRL, previously considered genetically identical to PCNSL, resembles PCNSL in the same individual with respect to genetic alterations, diagnostic strategies, and precision-medicine based approaches has hitherto not been explored. Furthermore, the degree of intra-patient tumor genomic heterogeneity between the brain and vitreous sites has not been studied. In this work, we report on targeted DNA next-generation sequencing (NGS) of matched brain and vitreous samples in two patients who each harbored VRL and PCSNL. Our strategy showed enhanced sensitivity for molecular diagnosis confirmation over current clinically used vitreous liquid biopsy methods. We observed a clonal relationship between the eye and brain samples in both patients, which carried clonal deep deletions, a highly recurrent alteration in VRL patients, as well as p.L265P activating mutation in one patient. Several subclonal alterations, however, in the genes , , , and broad chromosomal regions showed heterogeneity between the brain and the eyes, between the two eyes, and among different regions of the PCNSL brain lesion. Taken together, our data show that NGS of vitreous liquid biopsies in PCNSL patients with VRL highlights shared and distinct genetic alterations that suggest a common origin for these lymphomas, but with additional site-specific alterations. Liquid biopsy of VRL accurately replicates the findings for PCNSL truncal (tumor-initiating) genomic alterations; it can also nominate precision medicine interventions and shows intra-patient heterogeneity in subclonal alterations. To the best of our knowledge, this study represents the first interrogation of genetic underpinnings of PCNSL with matched VRL samples. Our findings support continued investigation into the utility of vitreous liquid biopsy in precision diagnosis and treatment of PCNSL/VRL.
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http://dx.doi.org/10.3390/ijms22189992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8471952PMC
September 2021

Targeted Mutational Analysis of Cortisol-Producing Adenomas.

J Clin Endocrinol Metab 2022 01;107(2):e594-e603

Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.

Context: Somatic gene mutations have been identified in only about half of cortisol-producing adenomas (CPAs). Affected genes include PRKACA, GNAS, PRKAR1A, and CTNNB1.

Objective: This work aims to expand our understanding of the prevalence of somatic mutations in CPAs from patients with overt Cushing syndrome (OCS) and "subclinical" mild autonomous cortisol excess (MACE), with an immunohistochemistry (IHC)‒guided targeted amplicon sequencing approach using formalin-fixed paraffin-embedded (FFPE) tissue.

Methods: We analyzed FFPE adrenal tissue from 77 patients (n = 12 men, 65 women) with either OCS (n = 32) or MACE (n = 45). Using IHC for 17α-hydroxylase/17,20-lyase (CYP17A1) and 3β-hydroxysteroid dehydrogenase (HSD3B2), we identified 78 CPAs (32 OCS CPAs and 46 MACE CPAs). Genomic DNA was isolated from the FFPE CPAs and subjected to targeted amplicon sequencing for identification of somatic mutations.

Results: Somatic mutations were identified in 71.8% (56/78) of the CPAs. While PRKACA was the most frequently mutated gene in OCS CPAs (14/32, 43.8%), somatic genetic aberrations in CTNNB1 occurred in 56.5% (26/46) of the MACE CPAs. Most GNAS mutations were observed in MACE CPAs (5/7, 71.4%). No mutations were observed in PRKAR1A. In addition to the known mutations, we identified one previously unreported mutation in PRKACA. Two patients with MACE harbored 2 adjacent tumors within the same adrenal gland - one patient had 2 CPAs, and the other patient had a CPA and an aldosterone-producing adenoma (identified by IHC for aldosterone synthase).

Conclusion: A comprehensive FFPE IHC-guided gene-targeted sequencing approach identified somatic mutations in 71.8% of the CPAs. OCS CPAs demonstrated a distinct mutation profile compared to MACE CPAs.
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http://dx.doi.org/10.1210/clinem/dgab682DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8764218PMC
January 2022

Molecular Characterization of a Rare Case of Bilateral Vitreoretinal T Cell Lymphoma through Vitreous Liquid Biopsy.

Int J Mol Sci 2021 Jun 5;22(11). Epub 2021 Jun 5.

Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA.

Vitreoretinal lymphoma (VRL) is an uncommon eye malignancy, and VRLs of T cell origin are rare. They are difficult to treat, and their molecular underpinnings, including actionable genomic alterations, remain to be elucidated. At present, vitreous fluid liquid biopsies represent a valuable VRL sample for molecular analysis to study VRLs. In this study, we report the molecular diagnostic workup of a rare case of bilateral T cell VRL and characterize its genomic landscape, including identification of potentially targetable alterations. Using next-generation sequencing of vitreous-derived DNA with a pan-cancer 126-gene panel, we found a copy number gain of and copy number loss of tumor suppressor . To the best of our knowledge, this represents the first exploration of the T cell VRL cancer genome and supports vitreous liquid biopsy as a suitable approach for precision oncology treatments.
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http://dx.doi.org/10.3390/ijms22116099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8201094PMC
June 2021

The influence of high-efficiency particulate air filtration on mortality among multiple myeloma patients receiving autologous stem cell transplantation.

Sci Rep 2021 06 3;11(1):11789. Epub 2021 Jun 3.

Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201 Shipai Road, Sec. 2, Taipei, 11217, Taiwan.

Autologous stem cell transplantation (ASCT) continues to be the standard treatment for transplant-eligible multiple myeloma (MM) patients. A portion of MM patients received ASCT in an isolation room with high-efficiency particulate air (HEPA) filtration. The effectiveness of the HEPA filtration on reducing treatment-related mortality (TRM) is controversial. We enrolled patients with newly diagnosed MM in Taiwan between 2000 and 2017. The primary endpoint of the study was TRM, which was defined as death within 100 days after ASCT. A total of 961 MM patients received ASCT. Of them, 480 patients (49.9%) received ASCT in an isolation room with HEPA filtration (HEPA group). The median overall survival from ASCT was 7.52 years for the HEPA group and 5.88 years for the remaining patients (non-HEPA group) (p = 0.370). The 100-day mortality rate was 1.5% and 1.0% for the HEPA and non-HEPA groups, respectively. In the multivariate analysis, the 100-day mortality had no difference between the HEPA and non-HEPA groups (adjusted hazard ratio 1.65, 95% CI 0.52-5.23). The median cost for ASCT inpatient care was $13,777.6 and $6527.6 for the HEPA and non-HEPA groups, respectively (p < 0.001). Although half of MM patients in Taiwan received ASCT in HEPA room, it didn't affect 100-day mortality.
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http://dx.doi.org/10.1038/s41598-021-91135-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175695PMC
June 2021

Targeted RNA sequencing of adrenal zones using immunohistochemistry-guided capture of formalin-fixed paraffin-embedded tissue.

Mol Cell Endocrinol 2021 06 26;530:111296. Epub 2021 Apr 26.

Michigan Center for Translational Pathology, Ann Arbor, MI, USA; Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA. Electronic address:

Adequate access to fresh or frozen normal adrenal tissue has been a primary limitation to the enhanced characterization of the adrenal zones via RNA sequencing (RNAseq). Herein, we describe the application of targeted RNAseq to formalin-fixed paraffin-embedded (FFPE) normal adrenal gland specimens. Immunohistochemistry (IHC) was used to visualize and guide the capture of the adrenocortical zones and medulla. Following IHC-based tissue capture and isolation of RNA, high-throughput targeted RNAseq highlighted clear transcriptomic differences and identified differentially expressed genes among the adrenal zones. Our data demonstrate the ability to capture FFPE adrenal zone tissue for targeted transcriptomic analyses. Future comparison of normal adrenal zones will improve our understanding of transcriptomic patterns and help identify potential novel pathways controlling zone-specific steroid production.
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http://dx.doi.org/10.1016/j.mce.2021.111296DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8456741PMC
June 2021

Development of a Whole-urine, Multiplexed, Next-generation RNA-sequencing Assay for Early Detection of Aggressive Prostate Cancer.

Eur Urol Oncol 2022 Aug 31;5(4):430-439. Epub 2021 Mar 31.

Michigan Center for Translational Pathology, University of Michigan Medical School, Ann Arbor, MI, USA; Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA; Department of Urology, University of Michigan Medical School, Ann Arbor, MI, USA. Electronic address:

Background: Despite biomarker development advances, early detection of aggressive prostate cancer (PCa) remains challenging. We previously developed a clinical-grade urine test (Michigan Prostate Score [MiPS]) for individualized aggressive PCa risk prediction. MiPS combines serum prostate-specific antigen (PSA), the TMPRSS2:ERG (T2:ERG) gene fusion, and PCA3 lncRNA in whole urine after digital rectal examination (DRE).

Objective: To improve on MiPS with a novel next-generation sequencing (NGS) multibiomarker urine assay for early detection of aggressive PCa.

Design, Setting, And Participants: Preclinical development and validation of a post-DRE urine RNA NGS assay (Urine Prostate Seq [UPSeq]) assessing 84 PCa transcriptomic biomarkers, including T2:ERG, PCA3, additional PCa fusions/isoforms, mRNAs, lncRNAs, and expressed mutations. Our UPSeq model was trained on 73 patients and validated on a held-out set of 36 patients representing the spectrum of disease (benign to grade group [GG] 5 PCa).

Outcome Measurements And Statistical Analysis: The area under the receiver operating characteristic curve (AUC) of UPSeq was compared with PSA, MiPS, and other existing models/biomarkers for predicting GG ≥3 PCa.

Results And Limitations: UPSeq demonstrated high analytical accuracy and concordance with MiPS, and was able to detect expressed germline HOXB13 and somatic SPOP mutations. In an extreme design cohort (n = 109; benign/GG 1 vs GG ≥3 PCa, stratified to exclude GG 2 cancer in order to capture signal difference between extreme ends of disease), UPSeq showed differential expression for T2:ERG.T1E4 (1.2 vs 78.8 median normalized reads, p < 0.00001) and PCA3 (1024 vs 2521, p = 0.02), additional T2:ERG splice isoforms, and other candidate biomarkers. Using machine learning, we developed a 15-transcript model on the training set (n = 73) that outperformed serum PSA and sequencing-derived MiPS in predicting GG ≥3 PCa in the held-out validation set (n = 36; AUC 0.82 vs 0.69 and 0.69, respectively).

Conclusions: These results support the potential utility of our novel urine-based RNA NGS assay to supplement PSA for improved early detection of aggressive PCa.

Patient Summary: We have developed a new urine-based test for the detection of aggressive prostate cancer, which promises improvement upon current biomarker tests.
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http://dx.doi.org/10.1016/j.euo.2021.03.002DOI Listing
August 2022

The dynamics of patient visits to traditional Chinese medicine during the 2019 coronavirus pandemic.

BMC Complement Med Ther 2021 Feb 19;21(1):70. Epub 2021 Feb 19.

School of Chinese Medicine, College of Chinese Medicine, China Medical University, No.91, Hsueh-Shih Road, Taichung, 40402, Taiwan, Republic of China.

Background: Large-scale epidemics have changed people's medical behavior, and patients tend to delay non-urgent medical needs. However, the impact of the pandemic on the use of complementary and alternative medicine remains unknown.

Methods: This retrospective study aimed to analyze the changes in the number of traditional Chinese medicine (TCM) patients and examine the epidemic prevention policy during the coronavirus disease 2019 (COVID-19) pandemic. We analyzed the number of TCM patients in Taipei City Hospital from January 2017 to May 2020. We tallied the numbers of patients in each month and compared them with those in the same months last year. We calculated the percentage difference in the number of patients to reveal the impact of the COVID-19 pandemic on TCM utilization. We used the Mann-Whitney U test to examine whether there was a significant difference in the number of patients during the COVID-19 pandemic.

Results: We included a total of 1,935,827 TCM visits of patients from January 2017 to May 2020 in this study. During the COVID-19 pandemic, the number of patients decreased significantly, except in February 2020. The number of patients during the COVID-19 pandemic had fallen by more than 15% compared with those in the same months last year. March and April had the greatest number of patient losses, with falls of 32.8 and 40% respectively. TCM patients declined significantly during the COVID-19 pandemic, and mobile medicine provided to rural areas fell considerably. Among all the TCM specialties, pediatrics and traumatology, as well as infertility treatment, witnessed the most significant decline in the number of patients. However, the number of cancer patients has reportedly increased.

Conclusions: The COVID-19 pandemic decreased the utilization rate of TCM, especially for mobile healthcare in rural areas. We suggest that the government pay attention to the medical disparity between urban and rural areas, which are affected by the pandemic, as well as allocate adequate resources in areas deprived of medical care.
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http://dx.doi.org/10.1186/s12906-021-03245-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7895508PMC
February 2021

Patient-sharing relationship between Chinese medicine doctors and other physicians: costs and outcomes of breast cancer survivorship care.

J Cancer Surviv 2021 12 18;15(6):922-932. Epub 2021 Feb 18.

Institute of Public Health, National Yang-Ming University, Taipei, Taiwan.

Purpose: Breast cancer survivors represent a unique group of patients who need complex and continuous care after their cancer treatment. These patients often see several providers in various specialties. This study aimed to analyze how traditional Chinese medicine (TCM) integration within care networks of patients with breast cancer might be related to health care costs and patient outcomes under the National Health Insurance program in Taiwan.

Methods: We enrolled all patients who underwent definitive mastectomy for newly diagnosed breast cancer between 2007 and 2015. We analyzed the presence of TCM physicians and the patient-sharing relationship between TCM physicians and other physicians during the first year after mastectomy. The outcomes included all-cause mortality, avoidable hospitalization, and medical expenditures.

Results: There were 68,987 patients with breast cancer, with a median age of 53 years. After propensity score matching, patients whose TCM doctors had the highest connectedness with other physicians had the lowest odds of avoidable hospitalization (adjusted odds ratio 0.86; 95% confidence interval [CI], 0.78-0.96) and lowest hazard of mortality (adjusted hazard ratio, 0.82; 95% CI, 0.72-0.93), followed by those with TCM doctors with medium connectedness, then low connectedness, and lastly those patients with no TCM doctor in their care network.

Conclusions: A dose-response pattern was observed regarding the relationship between TCM doctor's connectedness with other physicians within a patient's care network and patient outcomes.

Implications For Cancer Survivors: The findings demonstrated that stronger connectedness between TCM and other physicians could help improve the health outcomes of breast cancer survivors.
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http://dx.doi.org/10.1007/s11764-020-00985-6DOI Listing
December 2021

Single-cell RNA sequencing reveals compromised immune microenvironment in precursor stages of multiple myeloma.

Nat Cancer 2020 05 27;1(5):493-506. Epub 2020 Apr 27.

Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.

Precursor states of Multiple Myeloma (MM) and its native tumor microenvironment need in-depth molecular characterization to better stratify and treat patients at risk. Using single-cell RNA sequencing of bone marrow cells from precursor stages, MGUS and smoldering myeloma (SMM), to full-blown MM alongside healthy donors, we demonstrate early immune changes during patient progression. We find NK cell abundance is frequently increased in early stages, and associated with altered chemokine receptor expression. As early as SMM, we show loss of GrK memory cytotoxic T-cells, and show their critical role in MM immunosurveillance in mouse models. Finally, we report MHC class II dysregulation in CD14 monocytes, which results in T cell suppression . These results provide a comprehensive map of immune changes at play over the evolution of pre-malignant MM, which will help develop strategies for immune-based patient stratification.
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http://dx.doi.org/10.1038/s43018-020-0053-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7785110PMC
May 2020

Underweight as a risk factor of mortality in patients with newly diagnosed multiple myeloma.

Support Care Cancer 2021 Jul 4;29(7):3991-3999. Epub 2021 Jan 4.

Division of Hematology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Purpose: Multiple myeloma (MM), a clonal plasma cell malignancy, composes around 10% of hematologic malignancies. Though recent advances in treatment have dramatically improved MM survival, some aggressive courses of disease and dismal outcomes still exist. Low body weight, undernutrition, and cachexia are noted at MM diagnosis. We aim to evaluate the impact of low body mass index (BMI) and undernutrition in MM patients.

Methods: We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 1, 2006 and October 31, 2018. Being underweight is defined as having a BMI of under 18.5 kg/m. The patient's baseline characteristics, including BMI, serum albumin level, and comorbidities, etc., were recorded. The primary endpoint of the study was all-cause mortality. A Cox regression model was used to estimate the risk factors of mortality.

Results: A total of 378 newly diagnosed MM patients were enrolled in this study. The median age of the patients was 69. Thirty patients (7.9%) were underweight at diagnosis. The median overall survival was 1.3 years (95% CI 0.3-5.7) and 5.0 years (95% CI 3.1-5.9) for patients with low BMI and for patients with normal or higher BMI, respectively. In the multivariate analysis, low BMI (95% CI 1.07-4.44), ECOG ≥2 (95% CI 1.02-2.89), hypoalbuminemia (95% CI 1.21-4.01), high LDH (95% CI 1.22-3.49), and light chain ratio > 100 (95% CI 1.06-2.77) were independent risk factors of mortality.

Conclusion: MM patients who were underweight, with hypoalbuminemia, poor performance status, higher LDH, and light chain ratio > 100 were associated with poor overall survival.
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http://dx.doi.org/10.1007/s00520-020-05849-4DOI Listing
July 2021

A clinical trial with valproic acid and hydralazine in combination with gemcitabine and cisplatin followed by doxorubicin and dacarbazine for advanced hepatocellular carcinoma.

Asia Pac J Clin Oncol 2022 Feb 22;18(1):19-27. Epub 2020 Sep 22.

School of Medicine, National Yang-Ming University, Taipei, Taiwan.

Background: Survival benefit from chemotherapy in advanced hepatocellular carcinoma (HCC) was limited till now. New chemoregimens with cytotoxicity modulators were explored to improve efficacy. Chemotherapy modulated with valproic acid (VA) as a deacetylation inhibitor of histone and DNA damage response proteins, and hydralazine (HZ) as a DNA hypomethylating agent, hypothetically suppressing DNA repair, were used in phase II trial here for advanced HCC.

Methods: Between July 2008 and March 2016, patients with chemo-naive advanced HCC, regardless of previous sorafenib treatment, not amenable to local therapy and with Child Pugh score ≤7, were treated with VA (200 mg thrice per day) and HZ (12.5 mg twice per day) in conjunction with gemcitabine and cisplatin (GCGG): gemcitabine (1000 mg/m , D1; 800 mg/m D8, 15) and cisplatin (70 mg/m , D1) every 28 days till disease progression and then with Dox-DTIC: doxorubicin (45 mg/m ) and dacarbazine (450 mg/m ) every 28 days. The primary endpoint was overall survival (OS); the secondary endpoints were safety, progression-free survival (PFS) and response rate (RR).

Results: Thirty-seven patients with 16 sorafenib-experienced, underwent GCGG treatment, and 30 of them underwent the following Dox-DTIC treatment. The median OS was 14.6 months (95% confidence interval: 6.0-23.1). The median PFSs for patients treated with VA- and HZ-combined GCGG and Dox-DTIC were 3.7 and 4.2 months, respectively; the RRs were 10/37 (27.0%) and 7/30 (23.3%); and grade 3/4 neutropenia were 54% and 51%. However, there were no chemotherapy-related deaths.

Conclusion: VA- and HZ-combined sequential chemotherapy was effective in advanced HCC with manageable toxicities.
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http://dx.doi.org/10.1111/ajco.13443DOI Listing
February 2022

Prognostic significance of dynamic changes in lymphocyte-to-monocyte ratio in patients with head and neck cancer treated with radiotherapy: results from a large cohort study.

Radiother Oncol 2021 01 14;154:76-86. Epub 2020 Sep 14.

Department of Radiation Oncology, Linkou Chang Gung Memorial Hospital and Chang Gung University, Taoyuan City, Taiwan; School of Traditional Chinese Medicine, Chang Gung University, Taoyuan City, Taiwan; Department of Radiation Oncology, Fangliao General Hospital, PingTung Hsien, Taiwan. Electronic address:

Background And Purpose: We sought to investigate whether dynamic changes in lymphocyte-to-monocyte ratio (LMR) occurring during the course of radiotherapy (RT) may have prognostic value in patients with head and neck cancer (HNC).

Materials And Methods: We retrospectively reviewed the clinical records of patients with HNC who underwent RT at our center between 2005 and 2013. Generalized estimating equations were used to longitudinally assess changes in LMR through the course of RT. Delta-LMR was calculated as the difference between LMR measured during treatment and baseline LMR values. Freedom from metastasis (FFM) and overall survival (OS) served as the main outcome measures.

Results: A total of 1431 patients with HNC were enrolled. After a median follow-up of 9 years, 636 (44.4%) patients died and 240 (16.8%) had distant metastases. Compared with patients with low delta-LMR at two weeks, those with high delta-LMR experienced less favorable outcomes (five-year OS: 73% versus 59%, respectively, p < 0.001; five-year FFM: 87% versus 80%, respectively, p = 0.015). Similar findings were observed for delta-LMR measured at four weeks (five-year OS: 72% versus 60%, p < 0.001; five-year FFM: 86% versus 79%, respectively, p = 0.002) and six weeks (five-year OS: 72% versus 57%, p < 0.001; five-year FFM: 87% versus 79%, respectively, p = 0.002). Multivariate analysis identified delta-LMR as an independent prognostic factor for both FFM and OS.

Conclusion: Delta-LMR is a simple and inexpensive biomarker that may be clinically useful for predicting FFM and OS in patients with HNC treated with RT.
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http://dx.doi.org/10.1016/j.radonc.2020.09.012DOI Listing
January 2021

Targeted RNAseq of Formalin-Fixed Paraffin-Embedded Tissue to Differentiate Among Benign and Malignant Adrenal Cortical Tumors.

Horm Metab Res 2020 Aug 13;52(8):607-613. Epub 2020 Aug 13.

Michigan Center for Translational Pathology, Ann Arbor, Michigan, USA.

Lack of routine fresh or frozen tissue is a barrier to widespread transcriptomic analysis of adrenal cortical tumors and an impediment to translational research in endocrinology and endocrine oncology. Our group has previously pioneered the use of targeted amplicon-based next-generation sequencing for archival formalin-fixed paraffin-embedded (FFPE) adrenal tissue specimens to characterize the spectrum of somatic mutations in various forms of primary aldosteronism. Herein, we developed and validated a novel 194-amplicon targeted next-generation RNA sequencing (RNAseq) assay for transcriptomic analysis of adrenal tumors using clinical-grade FFPE specimens. Targeted RNAseq-derived expression values for 27 adrenal cortical tumors, including aldosterone-producing adenomas (APA; n=8), cortisol-producing adenomas (CPA; n=11), and adrenal cortical carcinomas (ACC; n=8), highlighted known differentially-expressed genes (DEGs; i. e., , , etc.) and tumor type-specific transcriptional modules (i. e., high cell cycle/proliferation transcript expression in ACC, etc.), and a subset of DEGs was validated orthogonally using quantitative reverse transcription PCR (qRT-PCR). Finally, unsupervised hierarchical clustering using a subset of high-confidence DEGs revealed three discrete clusters representing APA, CPA, and ACC tumors with corresponding unique gene expression signatures, suggesting potential clinical utility for a transcriptomic-based approach to tumor classification. Overall, these data support the use of targeted amplicon-based RNAseq for comprehensive transcriptomic profiling of archival FFPE adrenal tumor material and indicate that this approach may facilitate important translational research opportunities for the study of these tumors.
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http://dx.doi.org/10.1055/a-1212-8803DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880170PMC
August 2020

Hospital volume and physician volume in association with survival in patients with nasopharyngeal cancer after radiation therapy.

Radiother Oncol 2020 10 25;151:190-199. Epub 2020 Jul 25.

Division of Hematology and Oncology, Department of Internal Medicine, Taipei Veterans General Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University, Taipei, Taiwan; Institute of Public Health, National Yang-Ming University, Taipei, Taiwan. Electronic address:

Background: Cancer patients treated at higher-volume hospitals or by more experienced physicians have better outcomes. However, little is known about the effect of these provider volumes on the prognosis of patients receiving definitive radiotherapy (RT). This study aims to examine the independent association between hospital volume and physician volume in relation to the overall survival (OS) of nasopharyngeal cancer (NPC) patients after RT.

Methods: Patients with newly diagnosed NPC receiving definitive RT between 2001 and 2017 were identified from Taiwan's National Health Insurance Research Database. We collected demographic characteristics of patients, physicians and hospitals, as well as cancer treatment and comorbidities. Patients were categorized into quartiles according to cumulative hospital and physician volumes of their treatment providers. The effects of hospital and physician volumes on OS was examined by the frailty Cox regression model.

Results: A total of 16,315 NPC patients treated by 258 physicians in 92 hospitals were identified. When the effects of hospital volume and physician volume on survival were separately examined, both of them were positively associated with OS. In a fully adjusted model considering patient and provider characteristics, hospital volume, physician volume, and clustering effects, it showed that hospital volume significantly predicted OS, while physician volume did not. In patients treated with advanced technique RT, hospital volume was significantly associated with OS. However, volume effect was not observed in 2-D RT subgroup.

Conclusions: NPC patients receiving RT at higher-volume hospitals saw better survival. Treatment for NPC should be centralized to high-volume hospitals rather than high-volume physicians.
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http://dx.doi.org/10.1016/j.radonc.2020.07.039DOI Listing
October 2020

Serial Molecular Profiling of Low-grade Prostate Cancer to Assess Tumor Upgrading: A Longitudinal Cohort Study.

Eur Urol 2021 04 3;79(4):456-465. Epub 2020 Jul 3.

Department of Urology, Michigan Medicine, Ann Arbor, MI, USA; University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA; Department of Urology, Medical University of Vienna, Vienna, Austria.

Background: The potential for low-grade (grade group 1 [GG1]) prostate cancer (PCa) to progress to high-grade disease remains unclear.

Objective: To interrogate the molecular and biological features of low-grade PCa serially over time.

Design, Setting, And Participants: Nested longitudinal cohort study in an academic active surveillance (AS) program. Men were on AS for GG1 PCa from 2012 to 2017.

Intervention: Electronic tracking and resampling of PCa using magnetic resonance imaging/ultrasound fusion biopsy.

Outcome Measurements And Statistical Analysis: ERG immunohistochemistry (IHC) and targeted DNA/RNA next-generation sequencing were performed on initial and repeat biopsies. Tumor clonality was assessed. Molecular data were compared between men who upgraded and those who did not upgrade to GG ≥ 2 cancer.

Results And Limitations: Sixty-six men with median age 64 yr (interquartile range [IQR], 59-69) and prostate-specific antigen 4.9 ng/mL (IQR, 3.3-6.4) underwent repeat sampling of a tracked tumor focus (median interval, 11 mo; IQR, 6-13). IHC-based ERG fusion status was concordant at initial and repeat biopsies in 63 men (95% vs expected 50%, p <  0.001), and RNAseq-based fusion and isoform expression were concordant in nine of 13 (69%) ERG patients, supporting focal resampling. Among 15 men who upgraded with complete data at both time points, integrated DNA/RNAseq analysis provided evidence of shared clonality in at least five cases. Such cases could reflect initial undersampling, but also support the possibility of clonal temporal progression of low-grade cancer. Our assessment was limited by sample size and use of targeted sequencing.

Conclusions: Repeat molecular assessment of low-grade tumors suggests that clonal progression could be one mechanism of upgrading. These data underscore the importance of serial tumor assessment in men pursuing AS of low-grade PCa.

Patient Summary: We performed targeted rebiopsy and molecular testing of low-grade tumors on active surveillance. Our findings highlight the importance of periodic biopsy as a component of monitoring for cancer upgrading during surveillance.
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http://dx.doi.org/10.1016/j.eururo.2020.06.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7779657PMC
April 2021

Risk and impact of invasive fungal infections in patients with multiple myeloma.

Ann Hematol 2020 Aug 1;99(8):1813-1822. Epub 2020 Jul 1.

Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201 Shipai Road, Sec. 2, Taipei, 11217, Taiwan.

Infection is associated with great morbidity and mortality in patients with multiple myeloma (MM), but evidence for invasive fungal infections (IFIs) is lacking. We aimed to investigate risk factors for IFI in MM patients and to determine its impact on patients' survival. We retrospectively analyzed MM patients at Taipei Veterans General Hospital in Taiwan between January 2002 and October 2018. MM was diagnosed according to the International Myeloma Working Group criteria. IFI was defined according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. All risk factors of IFI in MM patients were estimated using Cox regression models in the univariate and multivariate analyses. Of the 623 patients recruited, 22 (3.5%) were diagnosed with proven or probable IFI. Light chain disease (adjusted hazard ratio [HR] 6.74, 95% confidence interval [CI] 2.10-21.66), hemoglobin less than 8 g/dl (adjusted HR 3.34, 95% CI 1.32-8.42), serum albumin < 3.5 g/dl (adjusted HR 3.24, 95% CI 1.09-9.68), and having received allogeneic stem cell transplantation (allo-SCT) (adjusted HR 5.98, 95% CI 1.62-22.03) were significantly associated with IFI in the multivariate analysis. Contracting IFI was in turn associated with early mortality (adjusted HR 11.60, 95% CI 1.26-106.74). Light chain disease, anemia, hypoalbuminemia, and receiving allo-SCT were independent predictors of IFI in MM patients. The early mortality risk is much higher in those encountering IFI. Physicians must be aware of the rare but potentially lethal infections.
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http://dx.doi.org/10.1007/s00277-020-04125-zDOI Listing
August 2020

Clonal hematopoiesis is associated with adverse outcomes in multiple myeloma patients undergoing transplant.

Nat Commun 2020 06 12;11(1):2996. Epub 2020 Jun 12.

Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02115, USA.

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003-2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p = 0.02) and progression free survival (PFS) (HR:1.45, p < 0.001) due to an increase in MM progression.
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http://dx.doi.org/10.1038/s41467-020-16805-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7293239PMC
June 2020

Molecular characterization of uterine and ovarian tumors with mixed epithelial and germ cell features confirms frequent somatic derivation.

Mod Pathol 2020 10 13;33(10):1989-2000. Epub 2020 May 13.

Department of Pathology, University of Michigan, Ann Arbor, MI, USA.

Ovarian germ cell tumors, including yolk sac tumors, are most commonly diagnosed in children and young women. Most so-called yolk sac tumors reported in women >35 years old have been associated with an epithelial proliferation (endometriosis or carcinoma). Here, we describe eight cases clinically diagnosed as uterine or ovarian germ cell tumors in women >35 years old. In addition to routine morphologic examination and immunohistochemical evaluation, we present data from targeted next-generation sequencing (NGS) and isochromosome (12p) fluorescence in situ hybridization (FISH). We identified two groups of tumors with mixed germ cell and epithelial features: (1) tumors with background endometriosis and endometrioid carcinoma-like mutations (PTEN, PIK3CA, FGFR2, and CTNNB1), and (2) high-grade morphology, presumptive presence of isochromosome (12p) by FISH, and TP53 or PIK3CA mutations. These findings support the notion that the "germ cell tumor" component of these tumors is often somatically derived. Two tumors in our cohort were from premenopausal women; one showed no detectable mutations by NGS (suggestive of germ cell derivation), whereas the other showed PIK3CA, PTEN, and CTNNB1 mutations (suggestive of somatic derivation). Accurate classification of these tumors is likely important for selection of appropriate chemotherapy.
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http://dx.doi.org/10.1038/s41379-020-0548-6DOI Listing
October 2020

Pralatrexate as a bridge to allogeneic hematopoietic stem cell transplantation in a patient with advanced-stage extranodal nasal-type natural killer/T cell lymphoma refractory to first-line chemotherapy: a case report.

J Med Case Rep 2020 Mar 17;14(1):43. Epub 2020 Mar 17.

Division of Haematology, Department of Medicine, Taipei Veterans General Hospital, No. 201, Section 2, Shipai Road, Beitou District, Taipei City, 112, Taiwan.

Background: Extranodal natural killer/T cell lymphoma, nasal type, is one of the more common subtypes of mature T cell lymphoma, especially in the Far East Asian population. This aggressive histologic subtype of peripheral T cell lymphomas is frequently susceptible to exposure of Epstein-Barr virus infection. The optimal treatment is not well elucidated. For stage IV disseminated extranodal natural killer/T cell lymphoma, induction chemotherapy with consolidative autologus or allogeneic hematopoietic stem cell transplantation is recommended as the major first-line treatment. However, there is controversy over which type of chemotherapy is most appropriate and effective as a bridge to autologus or allogeneic hematopoietic stem cell transplantation in patients with newly diagnosed disseminated advanced-stage or relapsed extranodal natural killer/T cell lymphoma because of cancer chemoresistance or associated complications. Pralatrexate is the first US Food and Drug Administration-approved novel agent for the treatment of refractory/recurrent peripheral T cell lymphomas. In our case, pralatrexate was used as a successful bridge to allogeneic hematopoietic stem cell transplantation in a patient with advanced-stage disseminated extranodal natural killer/T cell lymphoma refractory to first-line chemotherapy.

Case Presentation: We presented a case report of a 29-year-old Asian man diagnosed as having stage IV disseminated extranodal natural killer/T cell lymphoma, nasal type, with skin and bone marrow involvement, whose disease was primary refractory to first-line dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy, but obviously responded to treatment with two cycles of single-agent pralatrexate treatment. Monitoring Epstein-Barr virus viremia revealed dramatic downregulation. In addition to complete remission of the involvement of bone marrow and nasal cavity, skin involvement also obtained partial remission. The extranodal natural killer/T cell lymphoma successfully achieved complete remission after a bridge to allogeneic hematopoietic stem cell transplantation.

Conclusions: This is the first study to present pralatrexate as a successful bridge to allogeneic hematopoietic stem cell transplantation in a 29-year-old Asian male patient with advanced-stage extranodal natural killer/T cell lymphoma refractory to first-line dexamethasone, methotrexate, ifosfamide, L-asparaginase, and etoposide chemotherapy. This case provides a novel treatment opinion for extranodal natural killer/T cell lymphoma, especially for the Far East Asian population.
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http://dx.doi.org/10.1186/s13256-020-02363-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7079354PMC
March 2020

A new prognostic score for disease progression and mortality in patients with newly diagnosed primary CNS lymphoma.

Cancer Med 2020 03 3;9(6):2134-2145. Epub 2020 Feb 3.

Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan.

Background: Although various prognostic models for primary central nervous system lymphoma (PCNSL) have been developed, there is no consensus regarding the optimal prognostic index. We aimed to evaluate potential prognostic factors and construct a novel predictive model for PCNSL patients.

Methods: We enrolled newly diagnosed PCNSL patients between 2003 and 2015. The primary endpoint was progression-free survival (PFS), and the secondary endpoint was overall survival (OS). The prognostic factors identified using multivariate Cox proportional hazards models were used to develop a predictive model. We subsequently validated the prognostic model in an independent cohort. We also evaluated the validity of the existing scores: the International Extranodal Lymphoma Study Group (IELSG), the Nottingham/Barcelona (NB), and the Memorial Sloan-Kettering Cancer Center models (MSKCC).

Results: We identified 101 patients with newly diagnosed PCNSL at our center. Multivariate analysis showed that age ≥80, deep brain lesions, and ECOG ≥2 were independent risk factors of PFS. Assigning one point for each factor, we constructed a novel prognostic model, the Taipei Score, with four distinct risk groups (0-3 points). The performances of the Taipei Score in discriminating both PFS and OS in the training cohort were significant, and the score was validated in the external validation cohort. The IELSG, NB and MSKCC models had insufficient discriminative ability for either PFS or OS in both cohorts.

Conclusion: The Taipei Score is a simple model that discriminates PFS and OS for PCNSL patients. The score may offer disease risk stratification and facilitate clinical decision-making.
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http://dx.doi.org/10.1002/cam4.2872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064125PMC
March 2020

Somatic Mutation As a Cause of Aldosterone-Producing Adenoma.

Hypertension 2020 03 27;75(3):645-649. Epub 2020 Jan 27.

From the Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor (K.N., A.R.B., J.R., W.E.R.).

Driver somatic mutations for aldosterone excess have been found in ≈90% of aldosterone-producing adenomas (APAs) using an aldosterone synthase (CYP11B2)-guided sequencing approach. In the present study, we identified a novel somatic mutation (c.T4289C, p.I1430T) in an APA without any currently known aldosterone-driver mutations using CYP11B2 immunohistochemistry-guided whole exome sequencing. The gene encodes a voltage-dependent T-type calcium channel alpha-1H subunit. Germline variants in this gene are known as a cause of familial hyperaldosteronism IV. Targeted next-generation sequencing detected identical variants in 2 additional APAs in a cohort of the University of Michigan, resulting in a prevalence of 4% (3/75) in APAs. We tested the functional effect of the variant on adrenal cell aldosterone production and mRNA expression using the human adrenocortical HAC15 cell line with a doxycycline-inducible mutation. Doxycycline treatment increased mRNA levels as well as aldosterone production, supporting a pathological role of the p.I1430T mutation on the development of primary aldosteronism. In conclusion, somatic mutation is a genetic cause of APAs. Although the prevalence of this mutation is low, this study will provide better understanding of molecular mechanism of inappropriate aldosterone production in APAs.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.119.14349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7059016PMC
March 2020
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