Publications by authors named "Yu-Lin Lin"

69 Publications

Intrauterine administration of peripheral blood mononuclear cells activated by human chorionic gonadotropin in patients with repeated implantation failure: A meta-analysis.

J Reprod Immunol 2021 Jun 15;145:103323. Epub 2021 Apr 15.

Jinxin Research Institute for Reproductive Medicine and Genetics, Chengdu Jinjiang Hospital for Maternal and Child Health Care, Chengdu, China. Electronic address:

The purpose of this study was to assess whether intrauterine administration of peripheral blood mononuclear cells (PBMCs) activated by human chorionic gonadotropin (hCG) could improve the pregnancy and live birth rates in women with repeated implantation failure (RIF), and whether the parameters of co-culture of hCG and PBMCs would affect the clinical outcomes. Six databases (PubMed, Ovid, Medline, NCBI, Cqvip and Wanfang) were searched up to October 2020 by two independent reviewers. Seven studies were included according to specific inclusion and exclusion criteria. A meta-analysis showed that the pregnancy and live birth rates were significantly increased in the case group compared with the control group (odds ratio [OR]: 3.43, 95 % confidence interval [CI]: 1.78-6.61; P =  0.0002 and OR: 2.79, 95 % CI: 1.09-7.15; P =  0.03), especially when hCG was cultured with PBMCs for 48 h or PBMCs administration was performed two or three days before embryo transfer (ET). Neither the dosage of the hCG co-cultured with PBMCs nor the mean concentration of the administered PBMCs appeared to influence the therapeutic efficiency. In conclusion, intrauterine administration of PBMCs co-cultured with hCG for 48 h, conducted two or three days before ET, could be an effective therapy for women experiencing RIF. Due to the limitations of sample size and quality of the included studies, further high-quality studies with large sample sizes are warranted to optimize the parameters of hCG and PBMC co-culture to help more RIF patients benefit from this therapy.
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http://dx.doi.org/10.1016/j.jri.2021.103323DOI Listing
June 2021

Consensuses and controversies on pseudomyxoma peritonei: a review of the published consensus statements and guidelines.

Orphanet J Rare Dis 2021 02 13;16(1):85. Epub 2021 Feb 13.

Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, No. 10 Tieyi Road, Yangfangdian Street, Haidian District, Beijing, 100038, China.

Background: Pseudomyxoma peritonei (PMP) is a clinical malignant syndrome mainly originating from the appendix, with an incidence of 2-4 per million people. As a rare disease, an early and accurate diagnosis of PMP is difficult. It was not until the 1980s that the systematic study of this disease was started.

Main Body: As a result of clinical and basic research progress over the last 4 decades, a comprehensive strategy based on cytoreductive surgery (CRS) + hyperthermic intraperitoneal chemotherapy (HIPEC) has been established and proved to be an effective treatment for PMP. Currently, CRS + HIPEC was recommended as the standard treatment for PMP worldwide. There are several consensuses on PMP management, playing an important role in the standardization of CRS + HIPEC. However, controversies exist among consensuses published worldwide. A systematic evaluation of PMP consensuses helps not only to standardize PMP treatment but also to identify existing controversies and point to possible solutions in the future. The controversy underlying the consensus and vice versa promotes the continuous refinement and updating of consensuses and continue to improve PMP management through a gradual and continuous process. In this traditional narrative review, we systemically evaluated the consensuses published by major national and international academic organizations, aiming to get a timely update on the treatment strategies of CRS + HIPEC on PMP.

Conclusion: Currently, consensuses have been reached on the following aspects: pathological classification, terminology, preoperative evaluation, eligibility for surgical treatment, maximal tumor debulking, CRS technical details, and severe adverse event classification system. However, controversies still exist regarding the HIPEC regimen, systemic chemotherapy, and early postoperative intraperitoneal chemotherapy.
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http://dx.doi.org/10.1186/s13023-021-01723-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881689PMC
February 2021

Establishment and histopathological study of patient-derived xenograft models and primary cell lines of epithelioid malignant peritoneal mesothelioma.

Exp Anim 2021 May 21;70(2):225-235. Epub 2021 Jan 21.

Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, No. 10 Tieyi Road, Yangfangdian Street, Haidian District, Beijing 100038, China.

Malignant peritoneal mesothelioma (MPM) is a rare malignancy with few experimental models. This study used the human surgical specimen to establish MPM patient-derived xenograft (PDX) models and primary cell lines to provide a study platform for MPM in vitro and in vivo, and conducted histopathological analysis. Our study used the experimental peritoneal cancer index (ePCI) score to evaluate gross pathology, and the results showed that the ePCI score of the female and male nude mice were 8.80 ± 1.75 and 9.20 ± 1.81 (P=0.6219), respectively. The Hematoxylin and eosin (HE) staining of animal models showed that the tumor was epithelioid mesothelioma and invaded multiple organs. Immunohistochemistry (IHC) staining showed that Calretinin, Cytokeratin 5/6, WT-1 and Ki-67 were all positive. The Swiss-Giemsa and Immunofluorescence (IF) staining of primary cell lines were also consistent with the pathological characteristics of mesothelioma. We also performed the whole-exome sequencing (WES) to identify the mutant genes between models and the patient. And the results showed that 21 mutant genes were shared between the two groups, and the genes related to tumorigenesis and development including BAP1, NF2, MTBP, NECTIN2, CDC23, LRPPRC, TRIM25, and DHRS2. In conclusion, the PDX models and primary cell lines of MPM were successfully established with the epithelioid mesothelioma identity confirmed by histopathological evidence. Moreover, our study has also illustrated the shared genomic profile between models and the patient.
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http://dx.doi.org/10.1538/expanim.20-0119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150237PMC
May 2021

Downstaged ypT0-2N0 rectal cancer after neoadjuvant chemoradiation therapy may not need adjuvant chemotherapy: a retrospective cohort study.

Int J Colorectal Dis 2021 Mar 30;36(3):509-516. Epub 2020 Oct 30.

Division of Colorectal Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, Taipei, Taiwan, Republic of China.

Purpose: Current guidelines suggest that adjuvant chemotherapy (AC) be administered to all locally advanced (clinically T3-4 or N-positivity) rectal cancer patients undergoing neoadjuvant chemoradiotherapy (nCRT) and radical surgical resection regardless of the final pathological staging (yp staging). This study aimed to evaluate the necessity of AC for ypT0-2N0 rectal cancer.

Methods: Patients with ypT0-2N0 rectal cancer, who received nCRT and radical surgical resection, were recruited retrospectively at a university hospital. The main outcome was to evaluate the 5-year overall survival (OS) and disease-free survival (DFS) between ypT0-2N0 rectal cancer patients with AC and those without AC. We also identified potential independent prognostic factors associated with poor outcomes.

Results: One hundred and ten ypT0-2N0 rectal cancer patients (ypT0: n = 6; ypT1: n = 44; ypT2: n = 60) were followed up for a median of 60 months. No significant difference was observed in DFS and 5-year OS between patients with AC and those without AC. The risk of recurrence was associated with the postoperative pathological staging (0% with ypT0, 2.4% with ypT1, and 10% with ypT2). In the multivariate analysis, retrieval of < 12 lymph nodes was an independent favorable prognostic factor, which correlated with a higher OS (HR: 2.263; 95% CI: 1.093-4.687, P = 0.028). Intra-tumor lymphovascular and perineural invasion were poor prognostic markers for shorter DFS (HR: 5.940; 95% CI: 1.150-30.696, P = 0.033).

Conclusion: Postoperative AC is not required for patients with ypT0-2N0 rectal cancer downstaged by nCRT, especially in those without poor prognostic factors.
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http://dx.doi.org/10.1007/s00384-020-03787-5DOI Listing
March 2021

Trifluridine/tipiracil in combination with local therapy may be a favorable option for refractory metastatic colorectal cancer patients: A case report.

Medicine (Baltimore) 2020 Oct;99(43):e22780

Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Rationale: Currently, the 5-year survival rate remains poor for patients with metastatic colorectal cancer (mCRC), and the purpose of therapy is to prolong survival while maintaining the quality of life. Trifluridine/tipiracil, an oral drug combining trifluorothymidine and a thymidine phosphorylase inhibitor, is indicated as salvage therapy for mCRC patients who have progressed after all available regimens. Combination of local treatments with systemic therapy such as trifluridine/tipiracil represents an apt management strategy for mCRC patients.

Patient Concerns: A 72-year-old man diagnosed with stage IV rectal adenocarcinoma (KRAS mutation) with peritoneal carcinomatosis and liver metastases developed resistance to 2 lines of treatment (bevacizumab/irinotecan/S-1 and bevacizumab/oxaliplatin/HDFL [high-dose 24-hour infusion of 5-fluorouracil and leucovorin regimen]) within 5 months.

Diagnosis: Refractory stage IV rectal adenocarcinoma.

Interventions: Systemic treatment of trifluridine/tipiracil has been given for approximately 15 months in addition to radiotherapy, Yttrium-90 radioembolization, and trans-arterial chemoembolization for peritoneal and liver metastases.

Outcomes: After 15 months, the patient was still taking trifluridine/tipiracil for disease control with a good quality of life.

Lessons: Trifluridine/tipiracil plus other appropriate local therapy may significantly prolong patients survival with a satisfactory quality of life for patients with refractory mCRC. The favorable safety profile of trifluridine/tipiracil renders it a suitable option to be combined with other local therapies for metastatic lesions.
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http://dx.doi.org/10.1097/MD.0000000000022780DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7581032PMC
October 2020

Study on the hepatocellular carcinoma model with metastasis.

Authors:
Yu-Lin Lin Yan Li

Genes Dis 2020 Sep 8;7(3):336-350. Epub 2020 Jan 8.

Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China.

Hepatocellular carcinoma (HCC) is one of the most common causes of cancer-related death around the world due to advanced clinical stage at diagnosis, high incidence of recurrence and metastasis after surgical treatment. It is in urgent need to create appropriate animal models to explore the mechanism, patterns, risk factors, and therapeutic strategies of HCC metastasis and recurrence. However, most of the established models lack the phenotype of invasion and metastasis in patient, or have unstable phenotype. To establish HCC models with stable metastasis phenotype requires profound understanding in cancer metastasis biology and scientific methodology. Over the past 3 decades, HCC models with stable metastasis have been extensively studied. This paper reviewed the history and development of HCC animal models and cell models, focusing on the screening and maintaining of metastatic potential and phenotype. In-depth studies using these models vastly promote the understanding of cellular and molecular mechanisms and development of therapeutic strategies on HCC metastasis.
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http://dx.doi.org/10.1016/j.gendis.2019.12.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7452459PMC
September 2020

Molecular structure and phylogenetic analyses of the complete chloroplast genomes of three original species of Pyrrosiae Folium.

Chin J Nat Med 2020 Aug;18(8):573-581

Key Lab of Chinese Medicine Resources Conservation, State Administration of Traditional Chinese Medicine of the People's Republic of China, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China; Engineering Research Center of Chinese Medicine Resources, Ministry of Education, Beijing 100193, China. Electronic address:

Pyrrosia petiolosa, Pyrrosia lingua and Pyrrosia sheareri are recorded as original plants of Pyrrosiae Folium (PF) and commonly used as Chinese herbal medicines. Due to the similar morphological features of PF and its adulterants, common DNA barcodes cannot accurately distinguish PF species. Knowledge of the chloroplast (cp) genome is widely used in species identification, molecular marker and phylogenetic analyses. Herein, we determined the complete cp genomes of three original species of PF via high-throughput sequencing technologies. The three cp genomes exhibited a typical quadripartite structure with sizes ranging from 158 165 to 163 026 bp. The cp genomes of P. petiolosa and P. lingua encoded 130 genes, whilst that of P. sheareri encoded 131 genes. The complete cp genomes were compared, and five highly divergent regions of petA-psbJ, matK-rps16, ndhC-trnM, psbM-petN and psaC-ndhE were screened as potential DNA barcodes for identification of Pyrrosia genus species. The phylogenetic tree we obtained indicated that P. petiolosa and P. lingua are clustered in a single clade and, thus, share a close relationship. This study provides invaluable information for further studies on the species identification, taxonomy and phylogeny of Pyrrosia genus species.
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http://dx.doi.org/10.1016/S1875-5364(20)30069-8DOI Listing
August 2020

The biological basis and function of GNAS mutation in pseudomyxoma peritonei: a review.

J Cancer Res Clin Oncol 2020 Sep 22;146(9):2179-2188. Epub 2020 Jul 22.

Department of Peritoneal Cancer Surgery and Pathology, Beijing Shijitan Hospital, Capital Medical University, No. 10 Tieyi Road, Yangfangdian Street, Haidian District, Beijing, 100038, China.

Purpose: Pseudomyxoma peritonei (PMP) is a rare clinical malignancy syndrome characterized by the uncontrollable accumulation of copious mucinous ascites in the peritoneal cavity, resulting in "jelly belly". The mechanism of tumor progression and mucin hypersecretion remains largely unknown, but GNAS mutation is a promising contributor. This review is to systemically summarize the biological background and variant features of GNAS, as well as the impacts of GNAS mutations on mucin expression, tumor cell proliferation, clinical-pathological characteristics, and prognosis of PMP.

Methods: NCBI PubMed database (in English) and WAN FANG DATA (in Chinese) were used for literature search. And NCBI Gene and Protein databases, Ensembl Genome Browser, COSMIC, UniProt, and RCSB PDB database were used for gene and protein review.

Results: GNAS encodes guanine nucleotide-binding protein α subunit (Gsα). The mutation sites of GNAS mutation in PMP are relatively stable, usually at Chr20: 57,484,420 (base pair: C-G) and Chr20: 57,484,421 (base pair: G-C). Typical GNAS mutation results in the reduction of GTP enzyme activity in Gsα, causing failure to hydrolyze GTP and release phosphoric acid, and eventually the continuous binding of GTP to Gsα. The activated Gsα could thus continuously promote mucin secretion through stimulating the cAMP-PKA signaling pathway, which is a possible mechanism leading to elevated mucin secretion in PMP.

Conclusion: GNAS mutation is one of the most important molecular biological features in PMP, with major functions to promote mucin hypersecretion.
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http://dx.doi.org/10.1007/s00432-020-03321-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382651PMC
September 2020

Revealing the Impact of the Environment on : From Global Ecological Regionalization to Soil Microbial Community Characteristics.

J Agric Food Chem 2020 Aug 28;68(32):8720-8731. Epub 2020 Jul 28.

Key Research Laboratory of Traditional Chinese Medicine Resources Protection, Administration of Traditional Chinese Medicine, National Administration of Traditional Chinese Medicine, Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100193, China.

To understand the regulatory relationship between the environment and , here we integrated the macro- and microdimension methods. From a macroperspective, the MaxEnt model indicated that countries along the Belt and Road Initiative, such as China, Egypt, and Libya, were particularly suitable for growth of from ancient times (Last Glacial Maximum and mid-Holocene) to the future (2050 and 2070). The Jackknife test revealed that precipitation is an important ecological factor that affects 's distribution. From a microperspective, 16S rRNA amplicon sequencing data showed that the soil microbial communities of three ecotypes (desert-steppe, grassland, and gravel-desert) were significantly different ( < 0.001). Core microbiome analysis demonstrated that the bacterial genera , , and were enriched core taxa of . LEfSe and random forest were used to excavate the (desert-steppe), (grassland), and (gravel-desert) as biomarkers that can distinguish among microbial communities from the three ecotypes. The prediction profile showed that the metabolic function of the microbial community was enriched in metabolic pathways and environmental information processing. Correlation analyses revealed that the altitude, precipitation of the warmest quarter (bio18), mean diurnal range (bio2), and mean temperature of the warmest quarter (bio10) were important ecological factors that affect the composition of soil microbial communities. This work provided new insights into the regulatory relationship among the suitable distribution of , soil microbial communities, and ecological drivers. Moreover, it deepened the understanding of the interaction between desert plants and ecological factors in arid environments.
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http://dx.doi.org/10.1021/acs.jafc.0c01568DOI Listing
August 2020

Expression profile, subcellular localization and signaling pathway analysis of fish-specific TLR25 in Nile tilapia (Oreochromis niloticus).

Fish Shellfish Immunol 2020 Sep 2;104:141-154. Epub 2020 Jun 2.

Department of Aquaculture, National Taiwan Ocean University, Keelung, Taiwan.

The Nile tilapia (Oreochromis niloticus) is one of the major food fish species produced in tropical and subtropical regions. However, this industry has been facing significant challenges from microbial infections. Understanding how hosts initiate immune responses against invading microbes is the first requirement for addressing disease outbreak prevention and disease resistance. Toll-like receptors (TLRs) are a family of evolutionarily conserved proteins that can recognize pathogen-associated molecular patterns (PAMPs). They thus play an essential role in innate immunity. TLR25 is a newly identified fish-specific member of the TLR1 subfamily. In this study, we investigate the molecular and functional characteristics of O. niloticus TLR25 (OnTLR25) via tissue expression patterns, gene expression modulation after challenge with bacteria and TLR ligands, subcellular localization in human and fish cells, and the signaling pathways TLR25 may induce. Transcriptional levels of OnTLR25 are high in immune-related organs such as the spleen and head kidney, and are increased following bacterial challenges. In addition, we show that OnTLR25 preferentially localizes to the intracellular compartment in transfected tilapia head kidney (THK) cell line. Furthermore, overexpression of the truncated form of OnTLR25 in THK cell line induced the expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin (IL)-1β, IL-8, IL-12a, and interferon-d2.13. Combined, our results suggest that TLR25 is likely to play an important role in the antimicrobial responses of the innate immune system of Nile tilapia.
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http://dx.doi.org/10.1016/j.fsi.2020.05.028DOI Listing
September 2020

Perioperative safety after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy for pseudomyxoma peritonei from appendiceal origin: Experience on 254 patients from a single center.

Eur J Surg Oncol 2020 04 15;46(4 Pt A):600-606. Epub 2020 Jan 15.

Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, PR China. Electronic address:

Objective: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is a standard treatment for pseudomyxoma peritonei (PMP) recommended by Peritoneal Surface Oncology Group International (PSOGI). The study is to analyze the incidence of perioperative serious adverse events (SAEs) of CRS + HIPEC to treat PMP patients, and identify the risk factors, for guiding the prevention of SAEs.

Methods: This is a retrospective study on the PMP database established at our center. The clinicopathological features, treatment details and SAEs information on the PMP patients are systematically established in this database. The incidence, organ system distribution and severity of perioperative SAEs are analyzed. Univariate and multivariate analyses are performed to identify the independent risk factors.

Results: Among the 272 CRS + HIPEC procedures for 254 PMP patients, there are 93 (34.2%) SAEs. Six systems are involved in the SAEs, including infections (9.6%), digestive system (8.1%), respiratory system (6.3%), cardiovascular system (5.5%), hematological system (2.9%), and urinary system (1.5%), in terms of frequency. In terms of severity, the majority is grade III SAEs (27.9%), followed by grade IV SAEs (4.8%) and grade V SAEs (1.5%). Univariate analysis reveals 4 risk factors for perioperative SAEs: HIPEC regimens (P = 0.020), PCI (P = 0.025), intraoperative red blood cell transfusion volume (P = 0.004), and intraoperative blood loss volume (P = 0.002). Multivariate and logistic regression model analysis identifies only one independent risk factor for perioperative SAEs: intraoperative blood loss volume (P = 0.001, OR = 0.344, 95%CI: 0.182-0.649).

Conclusions: PMP patients treated by CRS + HIPEC at experienced centers could have acceptable safety. Improving the surgical techniques and developing the integrated hemostasis techniques are essential to reduce intraoperative blood loss and decrease SAEs rate.
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http://dx.doi.org/10.1016/j.ejso.2020.01.017DOI Listing
April 2020

Establishment of patient-derived xenograft model of peritoneal mucinous carcinomatosis with signet ring cells and in vivo study on the efficacy and toxicity of intraperitoneal injection of 5-fluorouracil.

Cancer Med 2020 02 8;9(3):1104-1114. Epub 2019 Dec 8.

Department of Peritoneal Cancer Surgery, Beijing Shijitan Hospital, Capital Medical University, Beijing, China.

Background: Pseudomyxoma peritonei (PMP) is an indolent malignancy and insensitive to systemic chemotherapy. The authors established patient-derived xenograft (PDX) model of PMP, and evaluated the efficacy and toxicity of intraperitoneal (i.p.) administration of 5-fluorouracil (5-FU) in this model.

Methods: Human PMP sample was collected to establish subcutaneous (s.c.) and i.p.

Model: In vivo study of i.p. injection of 5-FU was performed in i.p. model, with experimental peritoneal cancer index (ePCI) score and pathological examinations for evaluating the efficacy and toxicity.

Results: Both s.c. and i.p. models were constructed. The average passage interval of s.c. model was 44.2 ± 5.2 days, and the i.p. model was characterized by disseminated solid tumor nodules in abdominal-pelvic cavity. Both models were diagnosed as peritoneal mucinous carcinomatosis with signet ring cells (PMCA-S). Immunohistochemical characteristics was similar to human. GNAS mutation was detected in both model and patient. In the in vivo study, average ePCI of treatment group was lower than control and vehicle group (P = .004). Histopathology revealed obvious tumor necrosis in treatment group, and decreased Ki67 positive rate (P = .010). In toxicity study, 5-FU significantly influenced body weight (P = .010) and 1 animal from treatment group died on day 14. Congestive splenomegaly was observed (88.9%). Hepatotoxicity presented as acidophilic body (55.6%), cholestasis (100%), bile canaliculus hyperplasia and obstruction (22.2%), and lymphocyte accumulation (77.8%).

Conclusions: PDX model of PMCA-S was established successfully, and i.p. 5-FU could inhibit tumor proliferation and progression, with decreased Ki67 positive rate and ePCI score. Hepatotoxicity was the main side effect.
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http://dx.doi.org/10.1002/cam4.2766DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6997068PMC
February 2020

A multicenter, phase I/II trial of biweekly S-1, leucovorin, oxaliplatin and gemcitabine in metastatic pancreatic adenocarcinoma-TCOG T1211 study.

Eur J Cancer 2020 01 22;124:123-130. Epub 2019 Nov 22.

National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan; Division of Hematology and Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Internal Medicine, Kaohsiung Medical University Hospital and Kaohsiung Medical University, Kaohsiung, Taiwan. Electronic address:

Background: This phase I/II study evaluated the feasibility and efficacy of S-1, leucovorin, oxaliplatin and gemcitabine (SLOG), a triplet regimen, for treating patients with metastatic pancreatic ductal adenocarcinoma (PDAC).

Methods: Patients with chemo-naive, metastatic PDAC were eligible to receive fixed-rate infusion (10 mg/m/min) of gemcitabine of 800 mg/m followed by oxaliplatin of 85 mg/m on day 1 plus oral S-1 and leucovorin (20 mg/m) twice daily from days 1 to 7 in a 2-week cycle. The dose of S-1 would be escalated from 20, 30, 35 to 40 mg/m2 in a 3 + 3 designed phase I part to determine the maximum tolerated dose (MTD) for phase II study, in which the primary end-point was objective response rate (ORR). The recommended dose of S-1 was from phase I. This trial is registered at ClinicalTrials.gov: NCT01415713.

Results: Seventy-three patients were enrolled. In the phase I study (n = 19), the MTD of S-1 was 35 mg/m twice daily. Of 54 patients in phase II, the ORR was 40.7% (95% confidence interval [CI], 28%-55%). The median progression-free survival and overall survival were 7.6 (95% CI, 5.6-11.0) and 11.4 (95% CI, 8.1-16.3) months, respectively. The most common grade III/IV adverse event was neutropenia (40.7%). Twenty-four percent of patients had SLOG treatment for more than 1 year. The mean relative dose intensities of gemcitabine, oxaliplatin, and S-1 were 92%, 92% and 89%, respectively.

Conclusion: Biweekly SLOG is a feasible regimen with promising activity and safety profiles. A randomised study comparing SLOG versus modified folinic acid, fluorouracil, irinotecan, and oxaliplatin (FOLFIRINOX) in advanced PDAC is ongoing (ClinicalTrials.gov: NCT03443492).
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http://dx.doi.org/10.1016/j.ejca.2019.10.023DOI Listing
January 2020

Traditional Serrated Pathway-associated Colorectal Carcinoma: Morphologic Reappraisal of Serrated Morphology, Tumor Budding, and Identification of Frequent PTEN Alterations.

Am J Surg Pathol 2019 08;43(8):1042-1051

Departments of Pathology.

The phenotypic characteristics of traditional serrated adenoma (TSA)-associated malignancies remain obscure. This study was a morphologic reappraisal of 27 colorectal carcinomas arising from TSA (TSA-CRCs) and 53 BRAF-mutated/microsatellite-stable colorectal carcinomas (BRAF-mut/MSS CRCs). Makinen's criteria for serrated adenocarcinoma were applied to assess the morphologic similarity of the 2 entities. Tumor budding, another histologic feature of serrated adenocarcinoma, was also evaluated. Phosphatase and tensin homologue deleted on chromosome 10 (PTEN), a commonly mutated gene in the serrated pathway, was assessed with immunohistochemistry. Tumors with aberrant PTEN expression were subjected to molecular analysis using quantitative methylation assay, exon sequencing, and fluorescence in situ hybridization. Most cases (>90%) of TSA-CRCs and BRAF-mut/MSS CRCs exhibited a constellation of serrated morphology, including epithelial serrations, abundant eosinophilic cytoplasm, and discernible/vesicular nuclei. A majority (65%) of them qualified for the diagnosis of serrated adenocarcinoma. High-grade tumor budding was closely associated with serrated morphology and was a significant independent factor for poor patient survival in multivariate analysis (P=0.008). Aberrant PTEN expression was detected in nearly half of the cases of both entities (P=0.501). Among the 44 samples with aberrant PTEN expression, 8 harbored PTEN somatic mutations, which were characterized by random distribution without hotspot clustering, 12 had promoter hypermethylation, and 14 had deleted alleles. These findings support a unique model of colorectal carcinogenesis that is similar between TSA-CRCs and BRAF-mut/MSS CRCs. Both entities exhibited common histologic patterns and similar molecular alterations and may well constitute the TSA pathway.
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http://dx.doi.org/10.1097/PAS.0000000000001274DOI Listing
August 2019

CpG Island Methylator Phenotype May Predict Poor Overall Survival of Patients with Stage IV Colorectal Cancer.

Oncology 2019 12;96(3):156-163. Epub 2018 Dec 12.

Department of Oncology, National Taiwan University Hospital, Taipei City, Taiwan,

Objective: We aimed to study the prognostic role of CpG island methylator phenotype (CIMP) in patients with different stages of colorectal cancer (CRC).

Material And Methods: We analyzed CIMP in stage I-IV CRC specimens from patients who were diagnosed between 2005 and 2013. CIMP status was determined using a 5-gene MethyLight-based assay. The clinicopathologic characteristics were reviewed and the overall survival (OS) was compared between patients with CIMP-high CRC and those with CIMP-low/negative CRC.

Results: Among 450 CRC specimens with successfully determined CIMP statuses, 74 (16.4%) were CIMP-high CRC. Although there was no difference in OS between patients with CIMP-high and CIMP-low/negative CRC across all stages (p = 0.4526), intriguingly, patients with stage IV CIMP-high CRC had significantly worse OS than those with stage IV CIMP-low/negative CRC (p = 0.0047). In a multivariate analysis, CIMP status remained an independent prognostic factor for overall mortality (HR = 5.60, 95% CI: 2.12-14.79, p = 0.0005) in metastatic CRC after adjusting for clinicopathologic variables and anti-cancer therapies.

Conclusion: Our results revealed that the presence of CIMP independently predicts poor OS in patients with stage IV CRC.
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http://dx.doi.org/10.1159/000493387DOI Listing
March 2019

Strong opioid prescription in cancer patients in their final year of life: A population-based analysis using a Taiwanese health insurance database.

Asia Pac J Clin Oncol 2018 Oct 2;14(5):e498-e504. Epub 2018 Mar 2.

School of Health Care Administration, College of Management, Taipei Medical University, Taipei, Taiwan.

Aim: Pain assessment and management have been important criteria in hospital accreditation in Taiwan since 2007. We used a Taiwanese health insurance database to determine factors influencing patterns of strong opioid use in cancer patients in their final 12 months of life.

Methods: Data from patients with cancer in Taiwan outpatient clinics with cancer-related deaths between 2008 and 2011 were included in the analysis. Strong opioid prescription data from the last 12 months of each patient's life, as well as patient, physician, and hospital characteristics, were collected from the National Health Insurance Research Database.

Results: Among 162 679 patients, more were male (63.6%) than female (36.4%) and almost half (49.3%) were ≥70 years old. Most (44.9%) patients had gastrointestinal cancer. More than one-third (35.4%) of patients were prescribed strong opioids during the 12 months before death, and more than half (53.2%) of those prescribed opioids received them in the 3 months before death. Median duration of strong opioid use was 81 days before death. Patients with head/neck cancer (52.8%) or who were treated in hematology and oncology departments (45.8%) were most likely, and patients with gastrointestinal cancer (hazard ratio = 0.65; 95% confidence interval, 0.64-0.67) or treated in gastroenterology departments (hazard ratio = 0.88; 95% confidence interval, 0.84-0.93) were least likely to be prescribed strong opioids.

Conclusion: Strong opioid prescriptions varied among patients with different cancer diagnoses and physicians. Information from this study can guide efforts to improve patient and physician education about cancer pain management.
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http://dx.doi.org/10.1111/ajco.12865DOI Listing
October 2018

Bisphenol A Initiates Excessive Premature Activation of Primordial Follicles in Mouse Ovaries via the PTEN Signaling Pathway.

Reprod Sci 2018 04 5;25(4):609-620. Epub 2017 Oct 5.

7 West China School of Medicine, Sichuan University, Sichuan, Chengdu, China.

The essence of primary ovarian insufficiency (POI) is the premature exhaustion of primordial follicles in the follicle pool, which is caused by the excessive premature activation of primordial follicles after birth. Bisphenol A (BPA) exposure promotes the transition of primordial follicles to primary follicles, thus the number of primordial follicles in the primordial follicle pool decreases significantly. However, the molecular mechanisms underlying abnormal follicle activation are poorly understood. Phosphatase and tensin homologue (PTEN) signal system is a negative regulator of follicle activation, which is called the brake of follicle activation. Besides, BPA induces Michigan Cancer Foundation-7 breast cancer cells proliferation by dysregulating PTEN/serine/threonine kinase/p53 axis. Whether BPA initiates the excessive premature activation of primordial follicles in the mouse ovaries via PTEN signaling pathway is unclear. In this study, we treated 6-week-old female CD-1 mice with different concentrations of BPA to study the effect of BPA on follicular activation and development in vivo, as well as the role of PTEN signaling in this process. We observed that BPA in concentrations from 1 μg/kg to 10 mg/kg groups downregulated PTEN expression and initiated excessive premature activation of primordial follicles in the mouse ovaries, and this effect was partly reversible by PTEN overexpression. Our results improve the understanding of both the effect of BPA in occurrence of POI and molecular mechanisms underlying initiation of primordial follicle pool activation, thus providing insight for POI treatment and theoretical basis for reducing the risk of POI.
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http://dx.doi.org/10.1177/1933719117734700DOI Listing
April 2018

NRASQ61R immunohistochemistry detects both NRASQ61R and KRASQ61R mutations in colorectal cancer.

Pathology 2017 Jun 19;49(4):387-390. Epub 2017 Apr 19.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan; Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan. Electronic address:

The NRASQ61R monoclonal antibody (clone sp174) is a mutation-specific antibody that is increasingly being used to detect the NRAS mutation in melanomas. This antibody has been reported to be highly correlated with the NRAS mutation status in melanomas and follicular neoplasms of the thyroid gland. However, its utility in colorectal carcinoma (CRC) has remained largely unknown. In this study, we assessed the sensitivity, specificity, and diagnostic utility of NRASQ61R immunohistochemistry in a cohort consisting of tissue sections of 113 CRCs, which were molecularly profiled for the KRAS, NRAS, and BRAF mutations. Five CRCs tested positive for NRASQ61R immunohistochemistry. Four of these CRCs exhibited the NRAS mutation and one exhibited the KRAS mutation. All of the other 108 colorectal carcinomas lacking the NRAS or KRAS mutation tested negative for NRASQ61R immunohistochemistry. In the positively stained cases, we observed a diffuse staining pattern in >90% of the tumour cells with a moderate-to-strong intensity. By contrast, the staining was essentially entirely negative in cases negative for the NRAS or KRAS mutations. We concluded that although it cross-reacts with the mutant KRAS protein, the NRASQ61R antibody is a useful diagnostic tool that assists in the molecular testing of CRCs and facilitates patient management.
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http://dx.doi.org/10.1016/j.pathol.2017.01.008DOI Listing
June 2017

The Changes of Cytoskeletal Proteins Induced by the Fast Effect of Estrogen in Mouse Blastocysts and Its Roles in Implantation.

Reprod Sci 2017 12 16;24(12):1639-1646. Epub 2017 Mar 16.

1 Department of Physiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu, Sichuan, China.

It is necessary for estrogen to activate mouse blastocysts, so that they can attach to endometrial epithelium in implantation and in our previous research, we have proved estrogen can induce a fast increase in intracellular calcium of mouse blastocysts through acting on G protein-coupled receptor 30 (GPR30), which further promotes their implantation. Moreover, there has been evidence that cytoskeletal proteins are involved in integrin-mediated adhesion of many kinds of cells, which also plays an important role in implantation. To prove estrogen induces rapidly the changes of cytoskeletal proteins in mouse blastocysts and its roles in implantation, we first used immunofluorescence staining and laser confocal microscopy to investigate the fast effect of estrogen on the expression and localization of cytoskeletal proteins in mouse blastocysts. Second, we used electroporation associated with RNA interference to knock down one of the important cytoskeletal proteins, talin, in the mouse blastocyst cells to investigate the fast effect of estrogen on the localization of integrins and the binding activity of integrins with their ligand fibronectin (FN). At last, mouse blastocysts with different treatments were cultured with FN or uterine epithelial cell line Ishikawa in vitro, respectively, and transferred into the bilateral uterine horns of recipient mice, to study the role of the fast effect of estrogen on cytoskeletal proteins in blastocysts adhesion and implantation. Our results indicated that estradiol (E), E conjugated with bovine serum album (E-BSA) and G-1 (a GPR30-specific agonist) could induce cytoskeletal protein talin, vinculin, and actin to cluster in the mouse blastocysts, while G15 (a GPR30-specific antagonist) and BAPTA (a calcium chelator) may block this effect induced by E-BSA. Furthermore, E-BSA could induce the clustering and relocalization of integrin β1 and β3 and increase the FN-binding activity of integrins in blastocyst cells, while E-BSA could not induce these effects in the blastocysts pretreated with talin-small interfering RNA (siRNA). Meanwhile, the adhesion rate and implantation rate of blastocysts pretreated with talin-siRNA were significantly lower than those pretreated with control-siRNA. We provided the first evidence that the fast effect of estrogen might cause the clustering of the cytoskeletal proteins in mouse blastocyst cells and further induce the changes of localization and functional activity of integrins in the blastocyst cells, which play important roles in blastocyst implantation.
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http://dx.doi.org/10.1177/1933719117697126DOI Listing
December 2017

[Progress of non-genomic action of estrogen and its impact on female reproduction].

Sheng Li Xue Bao 2016 Aug;68(4):547-56

Department of Physiology, West China School of Preclinical and Forensic Medicine, Sichuan University, Chengdu 610041, China.

Estrogen is one of the steroid hormones. Besides the genomic action mediated by its intracellular receptor on target cells, there is now increasing body of evidence indicating that estrogen also has non-genomic action. For the non-genomic action, estrogen binds to its receptor on cell membrane, subsequently rapidly activates various intracellular signaling pathways, such as PLC/Ca(2+), ERK/MAPK, cAMP-PKA, PI3K-AKT-NOS, and finally induces biological effects. The non-genomic effects of estrogen on physiologic and pathologic processes have been found in many tissues within the reproductive, nervous and cardiovascular systems and bone etc. In reproductive system, it has been demonstrated that estrogen plays important roles in follicle development, fertilization and embryo implantation, and it is involved in the genesis and development of genital tract tumors and breast cancer. In this review, we focus on the general characteristics of non-genomic action of estrogen, its main nonnuclear signaling pathways and physiological and pathological significance, especially its influences in female reproductive functions.
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August 2016

RNF43 Is an Early and Specific Mutated Gene in the Serrated Pathway, With Increased Frequency in Traditional Serrated Adenoma and Its Associated Malignancy.

Am J Surg Pathol 2016 10;40(10):1352-9

Departments of *Pathology ‡Oncology ∥Medical Genetics, National Taiwan University Hospital †Graduate Institute of Pathology §Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan.

RNF43 is an E3 ligase that suppresses the Wnt/β-catenin signaling pathway and is frequently mutated in microsatellite-unstable colorectal carcinoma. To investigate the pathogenetic role of RNF43 in the serrated pathway, we conducted mutation analysis of RNF43 in several types of colorectal neoplasms. RNF43 mutation was found in 2 of 20 (10%) sessile serrated adenomas, 10 of 36 (28%) traditional serrated adenomas, 7 of 37 (19%) traditional serrated adenomas with cytologic dysplasia, and 9 of 31 (29%) BRAF-mutated/microsatellite-stable colorectal carcinomas; however, no mutation was found in 30 tubulovillous/villous adenomas. All mutations were located upstream of the ring finger domain of RNF43 without clustering, which is distinct from the pattern described for microsatellite-unstable colorectal carcinoma. RNF43 mutation was closely associated with BRAF mutation but inversely associated with KRAS mutation in traditional serrated adenoma with or without cytologic dysplasia (P=0.018 and 0.045, respectively). The finding of RNF43 mutation in sessile serrated adenoma and traditional serrated adenoma, but not in tubulovillous/villous adenoma, indicated that RNF43 mutation is an early and specific molecular aberration in the serrated pathway. The frequency of RNF43 mutation was significantly higher in traditional serrated adenoma with or without cytologic dysplasia and BRAF-mutated/microsatellite-stable colorectal carcinoma than sessile serrated adenoma. The unique molecular spectrum of these tumors suggests a stepwise neoplastic progression from sessile serrated adenoma to traditional serrated adenoma and BRAF-mutated/microsatellite-stable colorectal carcinoma, which should be recognized as the traditional serrated pathway to distinguish from the sessile serrated pathway.
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http://dx.doi.org/10.1097/PAS.0000000000000664DOI Listing
October 2016

Primary tumor site is a useful predictor of cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 non-mutant) metastatic colorectal cancer: a nationwide cohort study.

BMC Cancer 2016 05 24;16:327. Epub 2016 May 24.

Department of Oncology, National Taiwan University Hospital, 7, Chun-Shan S Rd, Taipei, 10002, Taiwan.

Background: Previous studies have shown left-sided colorectal cancer (LCRC) and right-sided colorectal cancer (RCRC) exhibit different molecular and clinicopathological features. We explored the association between the primary tumor site and cetuximab efficacy in KRAS wild-type colorectal cancer (CRC).

Methods: This study enrolled a cohort of patients, who had received cetuximab treatment after two or more lines of chemotherapy for KRAS wild-type (exon 2 nonmutant) metastatic CRC, from the databases of Taiwan Cancer Registry (2004-2010) and National Health Insurance (2004-2011). Survival data were obtained from the National Death Registry. Time to treatment discontinuation (TTD) and overall survival (OS) after the start of cetuximab treatment were compared between patients with LCRC (splenic flexure to rectum) and RCRC (cecum to hepatic flexure).

Results: A total of 969 CRC patients were enrolled. Among them, 765 (78.9 %) and 136 (14.0 %) patients had LCRC and RCRC, respectively. Patients with LCRC, compared to patients with RCRC, had longer TTD (median, 4.59 vs. 2.75 months, P = .0005) and OS (median, 12.62 vs. 8.07 months, P < .0001) after the start of cetuximab treatment. Multivariate analysis revealed a right-sided primary tumor site was an independent predictor of shorter TTD (adjusted hazard ratio [HR] = 1.32, using the LCRC group as a reference, 95 % confidence interval: 1.08-1.61, P = .0072) and OS (adjusted HR = 1.45, 95 % CI: 1.18-1.78, P = .0003).

Conclusion: Our findings demonstrate that a left-sided primary tumor site is a useful predictor of improved cetuximab efficacy in the third-line or salvage treatment of KRAS wild-type (exon 2 nonmutant) metastatic CRC.
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http://dx.doi.org/10.1186/s12885-016-2358-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4879738PMC
May 2016

Local Control by Radiofrequency Thermal Ablation Increased Overall Survival in Patients With Refractory Liver Metastases of Colorectal Cancer.

Medicine (Baltimore) 2016 Apr;95(14):e3338

From the Department of Surgery, National Taiwan University Hospital Hsinchu Branch, Hsinchu (P-CY); Department of Surgery (B-RL, H-SL, K-WH, J-TL); Department of Medical Imaging (Y-CC); and Department of Oncology, National Taiwan University Hospital and College of Medicine, National Taiwan University, Taipei, Taiwan, ROC (Y-LL).

Radiofrequency thermal ablation (RFA) is widely used for local solitary liver tumor control. However, the benefit of RFA for colorectal cancer with liver metastases, which is refractory to chemotherapy, remains unknown.We retrospectively enrolled 70 consecutive colorectal adenocarcinoma patients, who had synchronous liver metastases, who were refractory to chemotherapy, and whose life expectancy was >6 months, into this study to investigate the outcomes of RFA and associated prognostic factors. RFA was introduced to all of these patients during the enrollment. The time interval from RFA to recurrence of liver metastases and overall survival was recorded. Age, sex, carcinoembryonic antigen level, primary tumor location, postoperative adjuvant chemotherapy regimens, and the size and number of metastatic liver lesions were recorded. Cox regression analysis was used to determine the prognostic significance.Thirty-nine patients accepted RFA during chemotherapy, whereas 31 chose to receive chemotherapy alone. Patients with ≤5 and >5 liver metastases had median survival durations of 28 and 17 months, respectively (P = 0.018). The dominant liver tumor size (<5 vs ≥5 cm) was significantly associated with median survival (30 vs 17 months, respectively; P = 0.038), as was the carcinoembryonic antigen level (35 vs 16 months for ≤200 vs >200 ng/mL respectively; P = 0.029). Besides, radiofrequency thermal ablation plus chemotherapy was associated with a better median overall survival than chemotherapy alone (29 vs 12 months, respectively; P = 0.002). In multivariate analysis, only radiofrequency thermal ablation treatment and number of liver tumors were significant prognostic factors for survival. Our result further revealed that patients treated with radiofrequency thermal ablation had longer progression-free intervals than those treated with chemotherapy alone (18 vs 9 months, respectively; P = 0.001). Hence, radiofrequency thermal ablation is a safe and effective adjunct treatment to chemotherapy.
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http://dx.doi.org/10.1097/MD.0000000000003338DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4998829PMC
April 2016

BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer.

Med Oncol 2016 May 31;33(5):39. Epub 2016 Mar 31.

Department of Oncology, National Taiwan University Hospital, No 7, Chung-Shan South Rd, Taipei, 10002, Taiwan.

The prognostic implication of BRAF mutant colorectal cancer remains paradoxical. Records of BRAF mutant and wild-type colorectal cancer patients at all stages were reviewed. Clinicopathologic features, including microsatellite instability, CpG islands methylator phenotype, and overall survival, of these patients were analyzed. Between 2005 and 2013, 428 colorectal cancer patients were enrolled in this study. The overall survival between BRAF mutant and wild-type patients with early-stage (stages I and II) colorectal cancer differed nonsignificantly (P = 0.99). By contrast, in late-stage (stages III and IV) patients, the median overall survival of BRAF mutant patients (N = 25) was significantly poorer than that of BRAF wild-type (N = 207) patients (BRAF mutant: 21.3 months (95% confidence interval [CI] 7.1-35.5); BRAF wild-type: 53.5 months (95% CI 37.5-69.5), P < 0.0001). In early-stage patients, we found that BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P < 0.001), and microsatellite instability-high status (P = 0.0013). Conversely, in late-stage patients, BRAF mutation was significantly associated with CpG island methylator phenotype-positive (P = 0.0015) and the right-side colon (P = 0.014). BRAF mutation may have different prognostic implications in early- and late-stage colorectal cancer.
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http://dx.doi.org/10.1007/s12032-016-0756-6DOI Listing
May 2016

Frequent BRAF mutation in early-onset colorectal cancer in Taiwan: association with distinct clinicopathological and molecular features and poor clinical outcome.

J Clin Pathol 2016 Apr 23;69(4):319-25. Epub 2015 Oct 23.

Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan Graduate Institute of Pathology, College of Medicine, National Taiwan University, Taipei, Taiwan.

Background: Occurrence of early-onset colorectal cancer (EOCRC) under the age of 30 is very rare and the molecular characteristics are poorly understood. A low BRAF mutation rate has been noted in several studies of EOCRC from Western countries.

Aims: To determine the clinicopathological and molecular features of EOCRCs in Taiwan.

Methods: KRAS/BRAF gene mutation, mismatch repair protein immunohistochemistry, microsatellite instability and CpG island methylation phenotype analyses were examined to determine the molecular characteristics of EOCRC.

Results: Sixty-six patients with EOCRC at our hospital between 2000 and 2012 were studied. BRAF mutation was detected in 11 of the 59 tumours analysed (19%) and the rate was significantly higher than the overall BRAF mutation rate of colorectal cancer in patients older than 30 years (p<0.001). Clinically, 9 of 11 patients with BRAF-mutated tumours presented with advanced-stage diseases and they presented significantly more frequently with stage IV disease than those with BRAF wild-type tumours (p=0.042). Histologically, BRAF mutation was associated with a poorly differentiated histology, a serrated precursor polyp and focal signet ring cell differentiation (p=0.042, 0.008 and 0.008, respectively). None of the BRAF-mutated tumours was mismatch repair protein-deficient and/or microsatellite instability-high. Overall survival of patients with BRAF-mutated tumours was significantly worse than that of patients with BRAF wild-type tumours, despite adjustment for the disease stages and tumour differentiation.

Conclusions: BRAF mutation was frequent in EOCRCs in Taiwan and was associated with distinct clinicopathological and molecular features.
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http://dx.doi.org/10.1136/jclinpath-2015-203335DOI Listing
April 2016

Traditional serrated adenoma with BRAF mutation is associated with synchronous/metachronous BRAF-mutated serrated lesions.

Histopathology 2016 May 25;68(6):810-8. Epub 2015 Oct 25.

Department of Pathology, National Taiwan University, Taipei, Taiwan.

Aims: To determine whether traditional serrated adenoma (TSA) results in an increased risk of developing subsequent serrated polyps or colorectal cancer (CRC).

Methods And Results: We recruited 111 patients with an index TSA, and analysed the pathological and molecular features of their synchronous/metachronous serrated lesions. Fifty hyperplastic polyps, 14 sessile serrated adenomas, an additional 27 TSAs and 17 CRCs were identified from 46 patients. Twenty-seven percent of TSAs showed a precursor serrated polyp in the periphery and were strongly correlated with BRAF mutation (P < 0.001). Serrated polyps occurred more commonly in patients with BRAF-mutated index TSAs than in patients with KRAS-mutated index TSAs. BRAF-mutated index TSAs were strongly associated with a right-sided location and BRAF mutation of synchronous/metachronous serrated polyps (P = 0.013 and P = 0.005, respectively). The 17 CRCs occurred more frequently in women, and were characterized by a high BRAF mutation rate (59%), a positive CpG island methylator phenotype (59%), and stable or low levels of microsatellite instability (77%).

Conclusions: BRAF-mutated TSA is distinct from KRAS-mutated TSA in predisposing to the acquisition of subsequent serrated neoplasia. This indicates the presence of an intestinal field defect in the tumour microenvironment that results in tumour initiation and malignant progression.
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http://dx.doi.org/10.1111/his.12814DOI Listing
May 2016

Overall Survival of Stage III Colon Cancer with Only One Lymph Node Metastasis Is Independently Predicted by Preoperative Carcinoembryonic Antigen Level and Lymph Node Sampling Status.

PLoS One 2015 18;10(9):e0137053. Epub 2015 Sep 18.

Division of Colorectal Surgery, Department of Surgery, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei, Taiwan, ROC.

Background: This study identified predictors of favorable overall survival (OS) for stage III colon cancer patients who had only one lymph node (LN) metastasis (N1a).

Methods: Variables, including preoperative carcinoembryonic antigen (CEA) level, LN sampling status, and the choices of postoperative adjuvant chemotherapy, were recorded. Prognostic significance was determined using the log-rank test and multivariate Cox regression analysis.

Results: The median 42-month follow-up period included 363 eligible patients. Among them, 230 (63.3%) received only 5-flurouracil (5-FU) adjuvant chemotherapy; 76 (20.9%) underwent oxaliplatin-based regimens; and 57 (15.7%) chose surgery alone. The 5-year survival rate of these evaluated patients was 75%, 63%, and 77%, respectively (P = 0.823). Multivariate analysis revealed that normal preoperative CEA level (≦5 ng/mL) and adequate LN sampling (LN ≧ 12) were significant predictors for higher 5-year OS (P < 0.001; P = 0.007, respectively). However, the use of postoperative adjuvant chemotherapy in these N1a colon cancer patients did not significantly affect their 5-year OS.

Conclusions: A preoperative CEA level of less than or equal to 5 ng/mL, and curative surgery with an adequate lymphadenectomy determined a favorable OS outcome in stage III colon cancer with only one LN metastasis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0137053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4575069PMC
May 2016

Cetuximab Might Be Detrimental to Metastatic Colorectal Cancer Patients with KRAS Codon 12 Mutations.

Anticancer Res 2015 Jul;35(7):4207-14

Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan, R.O.C. Graduate Institute of Oncology, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C. Graduate Institute of Clinical Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan, R.O.C.

Background: Anti-epidermal growth factor receptor (EGFR) monoclonal antibodies benefit patients with wild-type KRAS exon 2 metastatic colorectal cancer (mCRC). However, their effect in KRAS-mutant mCRC remains unclear.

Patients And Methods: This was a retrospective study enrolling 163 patients with unresectable KRAS-mutant mCRC diagnosed at the National Taiwan University Hospital between 2007 and 2011.

Results: The median overall survival (mOS) was 29.5 months in patients who had never used cetuximab and 19.0 months in those who had (p=0.040). The mOS was 32.0 months in patients with mutant KRAS codon 12 who had never used cetuximab and 17.5 months in those who had (p=0.017). In patients with mutant KRAS codon 13, the mOS was not significantly different. Univariate and multivariate Cox proportional hazards analysis revealed that absence of cetuximab treatment was an independent prognostic factor for longer mOS in patients with unresectable KRAS-mutant mCRC.

Conclusion: Cetuximab usage might be detrimental to patients with mCRC with mutant KRAS codon 12.
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July 2015

Relocalisation and activation of integrins induced rapidly by oestrogen via G-protein-coupled receptor 30 in mouse blastocysts.

Reprod Fertil Dev 2015 May 8. Epub 2015 May 8.

Integrins are the dominant and final adhesion molecules in the attachment process between the blastocysts and endometrium. It is necessary for oestrogen to rapidly activate mouse blastocysts so that they attach to the endometrial epithelium. Our previous study suggested that oestrogen can rapidly induce an increase in intracellular calcium in mouse blastocysts via G-protein-coupled receptor 30 (GPR30). Thus, we deduced that integrins may be involved in GPR30 mediation of the fast effect of oestrogen on mouse blastocysts in implantation. To prove our hypothesis, we used immunofluorescence staining and in vitro coculture of mouse blastocysts and endometrial epithelial cell line (EECs), Ishikawa cells, in the present study. We found that αv and β1 integrin clustered in mouse blastocysts, and that β3 integrin was relocalised to the apical membrane of blastocyst cells when embryos were treated with 1 μM 17β-estradiol (E2), 1 μM E2 conjugated to bovine serum albumin (E2-BSA) and 1 μM G-1, a specific GPR30 agonist, for 30 min respectively, whereas pretreatment with 1 μM G15, a specific GPR30 antagonist, and 5 μM 1,2-Bis(2-aminophenoxy)ethane-N,N,N'',N''-tetraacetic acid tetrakis (acetoxymethyl ester)(BAPTA/AM), a cellular Ca2+ chelator, blocked the localisation of integrins induced by oestrogen via GPR30 in mouse blastocyst cells. E2, E2-BSA and G-1 increased the fibronectin (FN)-binding activity of integrins in blastocysts, whereas G15 and BAPTA/AM blocked the activation of integrins induced by oestrogen via GPR30 in mouse blastocysts. Inhibition of integrins by Arg-Gly-Asp peptide in blastocysts resulted in their failure to adhere to EECs in vitro, even if oestrogen or G-1 was provided. Together, the results indicate the fast effect of oestrogen via the GPR30 membrane receptor further induces relocalisation and activation of integrins in mouse blastocysts, which play important roles in the adhesion of blastocysts to EECs.
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http://dx.doi.org/10.1071/RD14227DOI Listing
May 2015

[Estrogen induced rapid increase of intracellular calcium plays important role in the implantation of mouse blastocysts].

Sichuan Da Xue Xue Bao Yi Xue Ban 2015 Mar;46(2):205-8

Objective: To study the roles of the increased intracellular calcium induced rapidly by estrogen in the implantation of mouse blastocysts.

Methods: The mouse blastocysts were collected from the female mice on the pregnant day 4, divided into 3 groups: control, E2-BSA and BAPTA +E2-BSA. Immunofluorescence staining, confocal microscopy, embryo and endometrial epithenial cells co-culture and embryo transfer were used to investigate the effect of increased intracellular calcium induced by E2-BSA on the expression and localization of integrins in blastocysts and their adhesion to endometrial epithenial calls (EECs) and implantation into the endometrium.

Results: The increase of intracellular calcium induced rapidly by estrogen could cause the cluster and relocation of integrin av and beta3, and BAPTA might block this effect, the adhesion rate of blastocysts in contol group was 35.5%, BAPTA +E2-BSA group was 26.7% and significantly lower than 65.6% of E2-BSA group (P<0.05), and the implantation rate in BAPTA+E2-BSA group was 11.8%, which was significantly lower than 52.9% of E2-BSA group (P<0.05).

Conclusion: The rapid increase of intracellular calcium induced by estrogen may cause the relocalization of integrin in blastocysts and their adhesion to ECCs, which is important in the process of implantation.
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March 2015