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Hypofractionated particle beam therapy for hepatocellular carcinoma–a brief review of clinical effectiveness

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World Journal of Gastrointestinal Oncology 2019年第8期11卷 579-588页

作者： Che-Yu Hsu Chun-Wei Wang ann-lii cheng Sung-Hsin Kuo Division of Radiation Oncology Department of OncologyNational Taiwan University Hospital and National Taiwan University College of MedicineTaipei 100Taiwan National Taiwan University Cancer Center National Taiwan University College of MedicineTaipei 100Taiwan Cancer Research Center National Taiwan University College of MedicineTaipei 100Taiwan Department of Internal Medicine and Department of Oncology National Taiwan University HospitalTaipei 100Taiwan Graduate Institute of Oncology National Taiwan University College of MedicineTaipei 100Taiwan

Hepatocellular carcinoma(HCC)is the fifth most common malignancy and the second leading cause of cancer mortality *** cornerstone to improving the prognosis of HCC patients has been the control of loco-regional disease progression and the lesser toxicities of local *** radiotherapy has not been considered a preferred treatment modality for HCC,charged particle therapy(CPT),including proton beam therapy(PBT)and carbon ion radiotherapy(CIRT),possesses advantages(for example,it allows ablative radiation doses to be applied to tumors but simultaneously spares the normal liver parenchyma from radiation)and has emerged as an alternative treatment option for *** the technological advancements in CPT,various radiation dosages of CPT have been used for HCC treatment via ***,the efficacy and safety of the evolving dosages remain *** assess the association between locoregional control of HCC and the dose and regimen of CPT,we provide a brief overview of selected literature on dose regimens from conventional to hypofractionated short-course CPT in the treatment of HCC and the subsequent determinants of clinical ***,CPT provides a better local control rate compared with photon beam therapy,ranging from 80%to 96%,and a 3-year overall survival ranging from 50%to 75%,and it results in rare grade 3 toxicities of the late gastrointestinal tract(including radiation-induced liver disease).Regarding CPT for the treatment of locoregional HCC,conventional CPT is preferred to treat central tumors of HCC to avoid late toxicities of the biliary *** contrast,the hypo-fractionation regimen of CPT is suggested for treatment of larger-sized tumors of HCC to overcome potential radio-resistance.

关键词： Hepatocellular carcinoma Proton beam therapy Carbon ion radiotherapy Local control Toxicity Overall survival

Topoisomerase I Inhibition Radiosensitizing Hepatocellular Carcinoma by RNF144A-mediated DNA-PKcs Ubiquitination and Natural Killer Cell Cytotoxicity

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Journal of Clinical and Translational Hepatology 2023年第3期11卷 614-625页

作者： Chiao-Ling Tsai Po-Sheng Yang Feng-Ming Hsu ann-lii cheng Wan-Ni Yu Jason Chia-Hsien cheng Graduate Institute of Clinical Medicine National Taiwan University College of MedicineChina Taipei Division of Radiation Oncology Department of OncologyNational Taiwan University HospitalChina Taipei Department of General Surgery Mackay Memorial HospitalChina Taipei Graduate Institute of Oncology National Taiwan University College of MedicineChina Taipei Cancer Center National Taiwan UniversityChina Taipei Taiwan Liposome Company China Taipei

Background and Aims: Topoisomerase I (TOP1) partici-pates the repair of DNA double-strand breaks (DSBs) upon radiation therapy (RT). RNF144A mediates ubiquitination of catalytic subunit of DNA protein kinase (DNA-PKcs), a critical factor in DSB repair. This study aimed to investigate the natural killer (NK) cell-mediated radiosensitization with TOP1 inhibition and the mechanism by DNA-PKcs/RNF144A. Methods: In vitro synergism with TOP1i or cocultured NK cells and RT were evaluated in human hepatocellular car-cinoma (HCC) cell lines (Huh7/PLC5) by clonogenic surviv-als. Orthotopic xenografts were treated with Lipotecan and/or RT. Protein expression was analyzed by western blotting, immunoprecipitation, subcellular fractionation, and confocal microscopy. Results: Lipotecan/RT had a superior synergis-tic effect to RT on HCC cells. Combined RT/Lipotecan reduced the xenograft size by 7-fold than RT (p<0.05). Lipotecan caused more radiation-induced DNA damage and DNA-PKcs signaling. The expression of major histocompatibility com-plex class I-related chain A and B (MICA/B) on tumor cells is associated with the sensitivity to NK cell-mediated lysis. Cocultured NK and HCC cells with Lipotecan radiosensitized HCC cells/tissues with the expression of MICA/B. RNF144A increased more in Huh7 cells with combined RT/TOP1i, and reduced the prosurvival function of DNA-PKcs. The effect was reversed by inhibiting the ubiquitin/proteasome system. In comparison, RNF144A decreased through nuclear transloca-tion with the cumulated DNA-PKcs and radio-resistance of PLC5 cells. Conclusions: TOP1i reinforces NK cell-activated anti-HCC effect of RT through RNF144A mediated DNA-PKcs ubiquitination. RNF144A provides a reason for differentiating radiosensitization effect between HCC cells.

关键词： Hepatocellular carcinoma Radiotherapy DNA topoisomerase I Li-potecan RNF144A.

Fractionated evaluation of immunohistochemical hormone receptor expression enhances prognostic prediction in breast cancer patients treated with tamoxifen as adjuvant therapy

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Journal of Zhejiang University-Science B(Biomedicine & Biotechnology) 2010年第1期11卷 1-9页

作者： Ching-hung LIN Huang-chun LIEN Fu-chang HU Yen-shen LU Sung-hsin KUO Ling-chu WE San-lin YOU ann-lii cheng King-jen CHANG Department of Oncology National Taiwan University Hospital Taiwan Taipei 10016 Department of Pathology National Taiwan University Hospital Taiwan Taipei 10016 National Center of Excellence for General Clinical Trial and Research National Taiwan University Hospital Taiwan Taipei 1001 6 Graduate Institute of Epidemiology College of Public Health National Taiwan University Taiwan Taipei 10055 Department of Surgery National Taiwan University Hospital Taiwan Taipei 10016

Objective： To compare the prognostic prediction between dichotomized and fractionated evaluations of hormone receptor expressions. Methods： Patients with stages Ⅰ-Ⅲ breast cancers, who received adjuvant tamoxifen, were enrolled. The expression of estrogen receptor （ER） and progesterone receptor （PR） was evaluated by immu- nohistochemistry （IHC）. A fractionated score （F score）, the percentage of positive-staining nuclei （0=none, 1=1%-10% 2= 11%-30%, 3=31%-50%, 4=51%-70%, and 5=71%-100%）, was assigned to each case. The dichotomized scoring method defines an F score 〉1 as positive. The prognostic values of both scores were compared by multiple Cox＇s proportional hazard models of disease-free survival （DFS） and overall survival （OS）. Results： Four hundred and six- teen patients with a median follow-up of 78.0 months were included. F scores for ER and PR correlated directly with DFS and OS. Although both the dichotomized and fractionated ER and PR scores were significantly associated with DFS and OS in univariate analyses, only fractionated ER and PR scores remained as independent prognostic factors of DFS and OS in the final multiple Cox＇s proportional hazard models. Conclusion： Fractionated IHC hormone receptor expression evaluation enhances the prognostic prediction compared with a dichotomized assessment.

关键词： Breast cancer Fractionated evaluation Estrogen receptor Progesterone receptor

Perspectives on the combination of radiotherapy and targeted therapy with DNA repair inhibitors in the treatment of pancreatic cancer

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World Journal of Gastroenterology 2016年第32期22卷 7275-7288页

作者： Shih-Hung Yang Ting-Chun Kuo Hsu Wu Jhe-Cyuan Guo Chiun Hsu Chih-Hung Hsu Yu-Wen Tien Kun-Huei Yeh ann-lii cheng Sung-Hsin Kuo Department of Oncology National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan Department of Internal Medicine National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan Institute of Clinical Medicine National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan Department of Traumatology National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan Department of Oncology National Taiwan University Hospital Yun-Lin Branch Yunlin 655 Taiwan Graduate Institute of Oncology National Taiwan University College of Medicine Taipei 100 Taiwan Department of Surgery National Taiwan University Hospital and National Taiwan University Cancer Center Taipei 100 Taiwan

Pancreatic cancer is highly lethal. Current research that combines radiation with targeted therapy may dramatically improve prognosis. Cancerous cells are characterized by unstable genomes and activation of DNA repair pathways, which are indicated by increased phosphorylation of numerous factors, including H2 AX, ATM, ATR, Chk1, Chk2, DNA-PKcs, Rad51, and Ku70/Ku80 heterodimers. Radiotherapy causes DNA damage. Cancer cells can be made more sensitive to the effects of radiation(radiosensitization) through inhibition of DNA repair pathways. The synergistic effects, of two or more combined non-lethal treatments, led to coadministration of chemotherapy and radiosensitization in BRCA-defective cells and patients, with promising results. ATM/Chk2 and ATR/Chk1 pathways are principal regulators of cell cycle arrest, following DNA doublestrand or single-strand breaks. DNA double-stranded breaks activate DNA-dependent protein kinase, catalytic subunit(DNA-PKcs). It forms a holoenzyme with Ku70/Ku80 heterodimers, called DNA-PK, which catalyzes the joining of nonhomologous ends. This is the primary repair pathway utilized in human cells after exposure to ionizing radiation. Radiosensitization, induced by inhibitors of ATM, ATR, Chk1, Chk2, Wee1, PP2 A, or DNA-PK, has been demonstrated in preclinical pancreatic cancer studies. Clinical trials are underway. Development of agents that inhibit DNA repair pathways to be clinically used in combination with radiotherapy is warranted for the treatment of pancreatic cancer.

关键词： Radiotherapy Pancreatic cancer DNA damage DNA repair Molecular targets

Anti-CD 20 monoclonal antibodies and associated viral hepatitis in hematological diseases

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World Journal of Hematology 2014年第2期3卷 29-43页

作者： Shih-Hung Yang Chiun Hsu ann-lii cheng Sung-Hsin Kuo Graduate Institute of Clinical Medicine National Taiwan University College of Medicine Department of Oncology National Taiwan University Hospital Cancer Research Center National Taiwan University College of Medicine Graduate Institute of Oncology National Taiwan University College of Medicine Department of Internal Medicine National Taiwan University Hospital

Over the past decade, the administration of anti-CD20 monoclonal antibodies such as rituximab has demonstrated various degrees of effectiveness and has improved patients' outcomes during the treatment of autoimmune hematological disorders and hematological malignancies. However, the depletion of B-cells, the distribution of T-cell populations, and the reconstruction of host immunity resulting from the use of anti-CD20 monoclonal antibodies potentially lead to severe viral infections, such as hepatitis B virus(HBV), hepatitis C virus(HCV), parvovirus B19, and herpes viruses, in patients who are undergoing immune therapy or immunochemotherapy. Of these infections, HBV- and HCV-related hepatitis are a great concern in endemic areas because of the high morbidity and mortality rates in untreated patients. As a result, prophylaxis against HBV infection is becoming a standard of care in these areas. Parvovirus B19, a widespread pathogen that causes red blood cell aplasia in immunocompromised hosts, also causes hepatitis in healthy individuals. Recently, its association with hepatitis was recognized in a patient treated with rituximab. In addition, adenovirus, varicella-zoster virus hepatitis E virus, and rituximab itself have been linked to the occurrence of hepatitis during or after rituximab treatments. The epidemiologies and pathogeneses of these etiologies remain unknown. Because of the increasing use of anti-CD20 monoclonal antibodies for the treatment of hematological malignancies or autoimmune hematological disorders, it is imperative that physicians understand and balance the risks of hepatotropic virusassociated hepatitis against the benefits of using antiCD20 monoclonal antibodies.

关键词： CD20 Monoclonal antibody Hepatitis Hepatitis B virus Hepatitis C virus

Effects of glucocorticoids on the growth and chemosensitivity of carcinoma cells are heterogeneous and require high concentration of functional glucocorticoid receptors

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World Journal of Gastroenterology 2005年第40期11卷 6373-6380页

作者： Yen-Shen Lu Huang-Chun Lien Pei-Yen Yeh Kun-Huei Yeh Min-Liang Kuo Sung-Hsin Kuo ann-lii cheng Department ofOncology National Taiwan University Hospital Graduate Instituteof Clinical Medicine National Taiwan University College ofMedicine Taipei Taiwan China Departments of Pathology National TaiwanUniversity Hospital Taipei Taiwan China Department of Oncology National Taiwan UniversityHospital Taipei Taiwan Department of Oncology and Departments of InternalMedicine National Taiwan University Hospital Departments ofInternal Medicine and Medical Research Far Eastern MemorialHospital Taipei Taiwan China Department of Oncology and Department ofInternal Medicine National Taiwan University Hospital TaipeiTaiwan China

AIM： To determine how glucocorticoids （GCs） may affect the growth and chemosensitivity of common carcinoma cells. METHODS： The effect of dexamethasone （DEX） on growth and chemosensitivity was assessed in 14 carcinoma cell lines. The function of GC receptors （GR） was assessed by MMTV reporter assay. Overexpression of GR was done by in vitro transfection and expression of a GR-expressing vector. Immunohistochemical stain of tissues and ceils were done by PA1-511A, an anti-GR monodonal antibody. RESULTS： DEX inhibited cell growth of four （MCF-7, MCF- 7/MXR1, MCF-7/TPT300, and HeLa）, increased cisplatin cytoxicity of one （SiHa）, and decreased dsplatin cytotoxicity of two （H460 and Hep3B） cell lines. The GR content of the seven cell lines affected by DEX was significantly higher than those of the seven cell lines unaffected by DEX （5.2±2.5×10^4 sites/cell vs1.3±1.4×10^4 sites/cell, P= 0.005）. Only two DEX-unresponsive cell lines {NPC-TW01 and NPC- TW04） oontained high GR amounts in the range （1.9-8.1×10^4 sites/cell） of the seven DEX-responsive cell lines. The GR function of NPC-TW01 and NPC-TW04, however, was foundto be impaired. The importance of high cellular amount of GR in mediating DEX susceptibility of the cells was further exemplified by GR dose-dependent drug resistance to cisplatin of AGS, a cell line with low GR content and was unaffected by DEX before transfection of GR-expressing vector. Immunohistochemical studies of human cancer tissues showed that 5 of the 45 （11.1%） breast cancer and 43 of the 85 （50.6%） non-small cell lung cancer had high GR contents at the ranges of the GC-responsive carcinoma cell lines. CONCLUSION： The growth and chemosensitivity of human carcinomas with high GR contents may be affected by GC. However, in light of the heterogeneous and even contradictive effects of GC on these cells, routine examination of GR contents of human carcinoma tissues may not be clinically useful until other markers that help predict the ultimate effect of

关键词： Glucocorticoids Glucocorticoid receptor Carcinoma Cell growth Chemosensitivility Drug resistance

Expression of CD86 and increased infiltration of NK cells are associated with Helicobacter pylori-dependent state of early stage high-grade gastric MALT lymphoma

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World Journal of Gastroenterology 2005年第28期11卷 4357-4362页

作者： Sung-Hsin Kuo Li-Tzong Chen Chi-Long Chen Shin-Lian Doong Kun-Huei Yeh Hui-Chen Hsu Ming-Shiang Wu Jaw-Town Lin Hsiu-Po Wang ann-lii cheng Departments of Oncology National Taiwan University Hospital Taipei Cancer Research Center and Graduate Institute of Clinical Medicine National Taiwan University College of Medicine Taipei Taiwan China Division of Cancer Research National Health Research Institutes Taipei Department of Internal Medicine Kaohsiung Medical University Hospital Kaohsiung Taipei Taiwan China Department of Pathologyl Taipei MedicalUniversity Taipei Taiwan China Graduate Institute of Microbiology National Taiwan University College of Medicine Taipei Taiwan China Departments of Oncology National Taiwan University Hospital Taipei Cancer Research Center National Taiwan University College of Medicine Taipei Taiwan China Department of Internal Mcclicine National Taiwan University Hospital Taipei Taiwan China Department of Emergency Medicine National Taiwan University Hospital Taipei Taiwan China Department of internal Medicine and Department of Oncology National Taiwan University Hospital Taipei Cancer Research Center National Taiwan University College of MedicineTaipei Division of Cancer Research National Health Research Institutes Taipei Taiwan China

AIM： A high percentage of early-stage high-grade gastric mucosa-associated lymphoid tissue （MALT） lymphomas remain Helicobacter pylori （ H pylori）-dependent. However,unlike their low-grade counterparts, high-grade gastric MALT lymphomas may progress rapidly if unresponsive to H pylori eradication. It is mandatory to identify markers that may predict the H pylori-dependent status of these tumors. Proliferation of MALT lymphoma cells depends on cognate help and cell-to-cell contact of H pylori- spedfic intratumoral T-cells. To examine whether the expression of co-stimulatory marker CD86 （B7.2） and the infiltration of CD56 （＋） natural killer （NK） cells can be useful markers to predict Hpylori-dependent status of high-grade gastric MALT iymphoma.METHODS： Lymphoma biopsies from 26 patients who had participated in a prospective study of Hpylori-eradication for stage IE high-grade gastric MALT lymphomas were evaluated. Tumors that resolved to Wotherspoon grade Ⅱ or less alter H pylori eradication were dassified as H pylori-dependent; others were dassified as H *** infiltration of NK cells and the expression of CD86 in pre-treatment paraffin-embedded lymphoma tissues were determined by immunohistochemistry. RESULTS： There were 16 H pylori-dependent and 10 H pylori-independent cases. CD86 expression was detected in 11 （68.8%） of 16 H pylori-dependent cases but in none of 10 H pylori-independent cases （P = 0.001）.H pylori-dependent high-grade gastric MALT lymphomas contained significantly higher numbers of CD56 （＋） NK cells than H pylori-independent cases （2.8±1.4% vs 1.1±0.8%, P = 0.003）. CD86 positive MALT lymphomas also showed significantly increased infiltration of CD56 （＋） NK cells compared to CD86-negative cases （2.9±1.1% vs 1.4±1.3%; P= 0.005）.CONCLUSION： These results suggest that the expression of co-stimulatory marker CD86 and the increased infiltration of NK cells are associated with Hpylori-dependent state of early-stage high-grade gastric M

关键词： MALT lymphoma Hpylori CD86 CD56

Long-term hepatic consequences of chemotherapy-related HBV reactivation in lymphoma patients

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World Journal of Gastroenterology 2005年第34期11卷 5283-5288页

作者： Chi-Chung Wen Chao A.Hsiung Ih-Jen Su ann-lii cheng Ming-Chih Chang Chao-Jung Tsao Woei-Yao Kao Wu-Ching Uen Chiun Hsu Chih-Hung Hsu Yen-Shen Lu Hwei-Fan Tien Tsu-Yi Chao Li-Tzong Chen Jacqueline Whang-Peng Pei-Jer Chen Division of Biostatics and Bioinformatics National Health Research Institutes Taipei Taiwan China Division of Clinical Research National Health Research Institutes Taipei Taiwan China Department of Oncology National Taiwan University Hospital Taipei Taiwan China Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan China Department of Internal Medicine Mackay Memorial Hospital Taipei Taiwan China Department of Internal Medicine Chi-Mei Hospital Tainan Taiwan China Department of Internal Medicine Tri-Service General Hospital Taipei Taiwan China Department of Internal Medicine Shin Kong Memorial Hospital Taipei Taiwan China Department of Oncology National Taiwan University Hospital Taipei Taiwan China Department of Internal Medicine National Taiwan University Hospital Taipei Taiwan China Division of Cancer Research National Health Research Institutes Taipei Taiwan China

AIM: To investigate the long-term consequences of chemotherapy-related HBV reactivation in patients with ***: This study was based on the database of published prospective study evaluating HBV reactivation in HBV lymphoma patients during *** liver reserve (DLR) was defined as development of either one of the following conditions during follow-up: (1) newly onset parenchyma liver disease, splenomegaly or ascites without evidence of lymphoma involvement; (2) decrease of the ratio (albumin/globulin ratio) to less than 0.8 or increase of the ratio of INR of prothrombin time to larger than 1.2 without evidence of malnutrition or infection. Liver cirrhosis was diagnosed by imaging ***: A total of 49 patients were included. The median follow-up was 6.2 years (range, 3.9-8.1 years).There were 31 patients with and 18 patients without HBV reactivation. Although there was no difference of overall survival (OS) and chemotherapy response rate between the two groups, DLR developed more frequently in patients with HBV reactivation (48.4% vs 16.7%; P= 0.0342). Among the HBV reactivators, HBV genotype C was associated with a higher risk of developing DLR (P = 0.0768) and liver cirrhosis (P = 0.003). Four of five patients with sustained high titer of HBV DNA and two of three patients with multiple HBV reactivation developed DLR. Further, patients with a sustained high titer of HBV DNA had the shortest OS among the HBV reactivators (P= 0.0000). No patients in the non-HBV reactivation group developed hepatic failure or liver ***: Chemotherapy-related HBV reactivation is associated with the long-term effect of deterioration of hepatic function.

关键词： HBV reactivation Liver function Non-HodgkJn'slymphoma, Chemotherapy

Fanlian Huazhuo formula:A promising therapeutic approach for metabolic associated steatotic liver disease

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World Journal of Gastroenterology 2025年第1期31卷 167-171页

作者： Chun-Han cheng Wen-Rui Hao Tzu-Hurng cheng Department of Medical Education Linkou Chang Gung Memorial HospitalTaoyuan 33305Taiwan Division of Cardiology Department of Internal MedicineShuang Ho HospitalMinistry of Health and WelfareTaipei Medical UniversityNew Taipei 23561Taiwan Division of Cardiology Department of Internal MedicineSchool of MedicineCollege of MedicineTaipei Medical UniversityTaipei 11002Taiwan Department of Biochemistry School of MedicineCollege of MedicineChina Medical UniversityTaichung 404328Taiwan

This article reviews the study,“Fanlian huazhuo formula alleviates high-fat-dietinduced nonalcoholic fatty liver disease by modulating autophagy and lipid synthesis signaling pathway”published in the World Journal of *** study explores the therapeutic potential of Fanlian Huazhuo formula(FLHZF)in treating metabolic-associated steatotic liver disease(MASLD),demonstrating that FLHZF reduces lipid accumulation,oxidative stress,and liver injury in MASLD models by modulating key signaling pathways involved in lipid metabolism and *** editorial emphasizes the potential of FLHZF as a treatment for MASLD and calls for further research to verify its clinical efficacy.

关键词： Fanlian Huazhuo formula Metabolic associated steatotic liver disease Autophagy Lipid metabolism Oxidative stress