Koo Foundation Sun Yat Sen Cancer Center

Taipei, Taiwan

Koo Foundation Sun Yat Sen Cancer Center

Taipei, Taiwan
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Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center | Pui N.N.M.,Sunny Pharmtech Inc.
Supportive Care in Cancer | Year: 2017

Purpose: The aim of this study was to identify patient-centered, mucositis-associated adverse impact factors and events that might confound physician-assessed oral mucositis (OM) in head and neck cancer (HNC) patients receiving chemoradiotherapy. Methods: This was a post hoc analysis of a previously conducted randomized trial to determine the efficacy of 5% phenylbutyrate mouthwash in preventing chemoradiotherapy-induced OM. This analysis identified patient-centered symptomatic, observable, and measurable factors that may confound physician scoring of the severity of OM during chemoradiotherapy. Confounding factors were then combined with physician-rated OM scores according to World Health Organization (WHO) and OM Assessment Scale (OMAS) criteria to investigate the therapeutic implications of OM treatment. Results: The original analysis found no significant differences between experimental and placebo groups with respect to the cumulative incidence of physician-recorded severe OM (WHO ≥3 or OMAS ≥2), patient-reported adverse events, and opioid use. However, patients in the experimental arm had relatively lower rates of OM-associated adverse clinical issues including unplanned short radiation breaks, skipping of chemotherapy, nausea/vomiting, late loss of body weight, and early opioid use, all of which could potentially interfere with physician-assessed OM scoring. When WHO OM grade (functional impact and pain), OMAS ulceration size (organic impact), and prolonged radiation treatment time (cancer treatment impact) were combined, there were significantly fewer interruptions of chemoradiotherapy treatment in symptomatic OM patients in the experimental compared to the placebo group. The benefits conferred by reducing the amount of chemoradiotherapy-related, OM-associated adverse impacts in the experimental group were reflected by better 5-year locoregional recurrence-free survival. Conclusions: This exploratory study raises questions as to whether the severity reflected by physician-rated OM scores is in concordance with OM-induced adverse impacts on HNC patients. Further investigations are warranted to identify patient-related and cancer-associated symptom burdens that may affect tolerance, compliance, and outcome of chemoradiotherapy and confound the evaluation of therapeutic effects on chemoradiotherapy-induced OM. © 2017 Springer-Verlag Berlin Heidelberg

Kau H.-C.,Koo Foundation Sun Yat Sen Cancer Center | Tsai C.-C.,Taipei Veterans General Hospital
Cutaneous and Ocular Toxicology | Year: 2016

Erlotinib is a tyrosine kinase inhibitor of the epidermal growth factor receptor. Since there is a wide expression of the epidermal growth factor receptors in the epithelial tissues of ocular surface and adnexa, ocular adverse reactions may happen during systemic administration of erlotinib. Previously reported ocular adverse reactions of erlotinib include trichomegaly, periorbital rash, ectropion, blepharitis, persistent corneal epithelial defect, corneal ulcer and perforation. We report the first case of erlotinib-related keratopathy in a patient who had received laser in situ keratomileusis. The patient presented a special picture of flap striae related to erlotinib. Improvement of keratopathy after cessation of erlotinib was demonstrated. © 2015 Taylor & Francis.

ABSTRACT: Autologous cord blood transplantations are rarely applied in patients with hematologic as well as metastatic solid cancers since contamination of malignant clones is a concern.We report a case of therapy-related myelodysplasia after metastatic neuroblastoma who suffered from graft rejection and life-threatening infections after a myeloablative unrelated cord blood transplantation.The patient experiences long-term survival, free from leukemia/neuroblastoma after infusion of autologous cord blood cells.It suggests that autologous cord blood transplantation after high dose therapy might be a curative strategy for certain hematologic or metastatic solid cancers. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.

Gianni L.,San Raffaele Cancer Center | Pienkowski T.,Centrum Onkologii | Im Y.-H.,Samsung | Roman L.,Leningrad Regional Oncology Dispensary | And 15 more authors.
The Lancet Oncology | Year: 2012

Background: Studies with pertuzumab, a novel anti-HER2 antibody, show improved efficacy when combined with the established HER2-directed antibody trastuzumab in breast cancer therapy. We investigated the combination of pertuzumab or trastuzumab, or both, with docetaxel and the combination of pertuzumab and trastuzumab without chemotherapy in the neoadjuvant setting. Methods: In this multicentre, open-label, phase 2 study, treatment-naive women with HER2-positive breast cancer were randomly assigned (1:1:1:1) centrally and stratified by operable, locally advanced, and inflammatory breast cancer, and by hormone receptor expression to receive four neoadjuvant cycles of: trastuzumab (8 mg/kg loading dose, followed by 6 mg/kg every 3 weeks) plus docetaxel (75 mg/m 2, escalating, if tolerated, to 100 mg/m 2 every 3 weeks; group A) or pertuzumab (loading dose 840 mg, followed by 420 mg every 3 weeks) and trastuzumab plus docetaxel (group B) or pertuzumab and trastuzumab (group C) or pertuzumab plus docetaxel (group D). The primary endpoint, examined in the intention-to-treat population, was pathological complete response in the breast. Neither patients nor investigators were masked to treatment. This study is registered with ClinicalTrials.gov, number NCT00545688. Findings: Of 417 eligible patients, 107 were randomly assigned to group A, 107 to group B, 107 to group C, and 96 to group D. Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate (49 of 107 patients; 45·8% [95% CI 36·1-55·7]) compared with those given trastuzumab plus docetaxel (group A; 31 of 107; 29·0% [20·6-38·5]; p=0·0141). 23 of 96 (24·0% [15·8-33·7]) women given pertuzumab plus docetaxel (group D) had a pathological complete response, as did 18 of 107 (16·8% [10·3-25·3]) given pertuzumab and trastuzumab (group C). The most common adverse events of grade 3 or higher were neutropenia (61 of 107 women in group A, 48 of 107 in group B, one of 108 in group C, and 52 of 94 in group D), febrile neutropenia (eight, nine, none, and seven, respectively), and leucopenia (13, five, none, and seven, respectively). The number of serious adverse events was similar in groups A, B, and D (15-20 serious adverse events per group in 10-17% of patients) but lower in group C (four serious adverse events in 4% of patients). Interpretation: Patients given pertuzumab and trastuzumab plus docetaxel (group B) had a significantly improved pathological complete response rate compared with those given trastuzumab plus docetaxel, without substantial differences in tolerability. Pertuzumab and trastuzumab without chemotherapy eradicated tumours in a proportion of women and showed a favourable safety profile. These findings justify further exploration in adjuvant trials and support the neoadjuvant approach for accelerating drug assessment in early breast cancer. Funding: F Hoffmann-La Roche. © 2012 Elsevier Ltd.

Chang L.,I - Shou University | Chui C.-S.,Koo Foundation Sun Yat Sen Cancer Center | Ding H.-J.,I - Shou University | Hwang I.-M.,Kaohsiung Medical University | Ho S.-Y.,Sinlau Christian Hospital
Physics in Medicine and Biology | Year: 2012

The EBT2 film together with a flatbed scanner is a convenient dosimetry QA tool for verification of clinical radiotherapy treatments. However, it suffers from a relatively high degree of uncertainty and a tedious film calibration process for every new lot of films, including cutting the films into several small pieces, exposing with different doses, restoring them back and selecting theproper region of interest (ROI) for each piece for curve fitting. In this work, we present a percentage depth dose (PDD) method that can accurately calibrate the EBT2 film together with the scanner non-uniformity correction and provide an easy way to perform film dosimetry. All films were scanned before and after the irradiation in one of the two homemade 2mm thick acrylic frames (one portrait and the other landscape), which was located at a fixed position on the scan bed of an Epson 10000XL scanner. After the pre-irradiated scan, the film was placed parallel to the beam central axis and sandwiched between six polystyrene plates (5cm thick each), followed by irradiation of a 20×20cm 26 MV photon beam. Two different beams on times were used on two different films to deliver a dose to the film ranging from 32 to 320 cGy. After the post-irradiated scan, the net optical densities for a total of 235 points on the beam central axis on the films were auto-extracted and compared with the corresponding depth doses that were calculated through the measurement of a 0.6 cc farmer chamber and the related PDD table to perform the curve fitting. The portrait film location was selected for routine calibration, since the central beam axis on the film is parallel to the scanning direction, where non-uniformity correction is not needed (Ferreira et al 2009 Phys. Med. Biol. 54 1073-85). To perform the scanner non-uniformity calibration, the cross-beam profiles of the film were analysed by referencing the measured profiles from a Profiler™. Finally, to verify our method, the films were exposed to 60° physical wedge fields and the compositive fields, and their relative dose profiles were compared with those from the water phantom measurement. The fitting uncertainty was less than 0.5% due to the many calibration points, and the overall calibration uncertainty was within 3% for doses above 50 cGy, when the average of four films were used for the calibration. According to our study, the non-uniformity calibration factor was found to be independent of the given dose for the EBT2 film and the relative dose differences between the profiles measured by the film and the Profiler were within 1.5% after applying the non-uniformity correction. For the verification tests, the relative dose differences between the measurements by films and in the water phantom, when the average of three films were used, were generally within 3% for the 60° wedge fields and compositive fields, respectively. In conclusion, our method is convenient, time-saving and cost-effective, since no film cutting is needed and only two films with two exposures are needed. © 2012 Institute of Physics and Engineering in Medicine.

Liu C.-C.,Koo Foundation Sun Yat Sen Cancer Center | Shih C.-S.,Koo Foundation Sun Yat Sen Cancer Center | Pennarun N.,Koo Foundation Sun Yat Sen Cancer Center | Cheng C.-T.,Koo Foundation Sun Yat Sen Cancer Center | Cheng C.-T.,Chung Cheng Institute of Technology
European Journal of Cardio-thoracic Surgery | Year: 2015

OBJECTIVES: The feasibility and radicalism of lymph node dissection for lung cancer surgery by a single-port technique has frequently been challenged. We performed a retrospective cohort study to investigate this issue. METHODS: Two chest surgeons initiated multiple-port thoracoscopic surgery in a 180-bed cancer centre in 2005 and shifted to a singleport technique gradually after 2010. Data, including demographic and clinical information, from 389 patients receiving multiport thoracoscopic lobectomy or segmentectomy and 149 consecutive patients undergoing either single-port lobectomy or segmentectomy for primary non-small-cell lung cancer were retrieved and entered for statistical analysis by multivariable linear regression models and Box-Cox transformed multivariable analysis. RESULTS: The mean number of total dissected lymph nodes in the lobectomy group was 28.5 ± 11.7 for the single-port group versus 25.2 ± 11.3 for the multiport group; the mean number of total dissected lymph nodes in the segmentectomy group was 19.5 ± 10.8 for the single-port group versus 17.9 ± 10.3 for the multiport group. In linear multivariable and after Box-Cox transformed multivariable analyses, the single-port approach was still associated with a higher total number of dissected lymph nodes. CONCLUSIONS: The total number of dissected lymph nodes for primary lung cancer surgery by single-port video-assisted thoracoscopic surgery (VATS) was higher than by multiport VATS in univariable, multivariable linear regression and Box-Cox transformed multivariable analyses. This study confirmed that highly effective lymph node dissection could be achieved through single-port VATS in our setting. © The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.

Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center | Wu M.-L.,Foundation Medicine
Oncotarget | Year: 2016

Proteasome-mediated degradation of promyelocytic leukemia tumor suppressor (PML) is upregulated in many viral infections and cancers. We previously showed that PML knockdown promotes early-onset hepatocellular carcinoma (HCC) in hepatitis B virus surface antigen (HBsAg)-transgenic mice. Here we report the effects of PML restoration on late-onset HBsAg-induced HCC. We compared protein expression patterns, genetic mutations and the effects of pharmacologically targeting PML in wild-type, PML-/-, PML+/+HBsAgtg/o and PML-/-HBsAgtg/o mice. PML-/- mice exhibited somatic mutations in DNA repair genes and developed severe steatosis and proliferative disorders, but not HCC. PML-/-HBsAgtg/o mice exhibited early mutations in cancer driver genes and developed hyperplasia, fatty livers and indolent adiposelike HCC. In PML+/+HBsAg-transgenic mice, HBsAg expression declined over time, and HBsAg-associated PML suppression was concomitantly relieved. Nevertheless, these mice accumulated mutations in genes contributing to oxidative stress pathways and developed aggressive late-onset angiogenic trabecular HCC. PML inhibition using non-toxic doses of arsenic trioxide selectively killed long-term HBsAg-affected liver cells in PML+/+HBsAgtg/o mice with falling HBsAg and rising PML levels, but not normal liver cells or early-onset HCC cells in PML-/-HBsAgtg/0 mice. These findings suggest dual roles for PML as a tumor-suppressor lost in early-onset HBsAg-induced hepatocarcinogenesis and as an oncogenic promoter in late-onset HBsAg-related HCC progression.

Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center | Wu M.-L.,Foundation Medicine
Journal of Pathology | Year: 2013

DNA damage response and repair pathways are important barriers to carcinogenesis. Here, we show that promyelocytic leukaemia (PML, also known as TRIM19), involved in sensing DNA damage and executing homologous recombination repair, is down-regulated in non-tumour liver cells surrounding hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). No PML mutation or deletion was found in HBV-infected liver or HCC cells. Immunohistochemical analysis of liver biopsies from patients with breast or liver cancer and HBV reactivation after chemotherapy revealed PML up-regulation and HBV exacerbation in normal liver tissue in response to DNA damage (functional PML), PML down-regulation in HCC peritumour cells associated with high HBsAg accumulation and low HBV replication activity (suppressive PML), and heterogeneous nuclear PML expression in HCC cells that lost HBV DNA and HBsAg and were non-reactive to DNA damage (dysregulated PML). Loss of PML in HBsAg-transgenic mice promoted chromosome breaks in liver cells and accelerated the accumulation of body and liver fat and the development of a liver steatosis-dysplasia-adenoma-carcinoma sequence in an inflammation-independent and male-predominant manner, compared to PML knock-out or HBsAg-transgenic mice during the same time period. These results indicate that PML deficiency facilitates genomic instability and promotes HBsAg-related hepatocarcinogenesis, which also involves androgen and lipid metabolism. These findings uncover a novel PML link between HBV-related tumourigenesis, DNA repair, and metabolism. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center | Pui N.N.M.,ASAN Laboratories Inc.
Wound Repair and Regeneration | Year: 2015

We hypothesized the histone deacetylase inhibitor phenylbutyrate (PB) has beneficial effects on radiation-induced injury by modulating the expression of DNA repair and wound healing genes. Hamsters received a radiosurgical dose of radiation (40 Gy) to the cheek and were treated with varying PB dosing regimens. Gross alteration of the irradiated cheeks, eating function, histological changes, and gene expression during the course of wound healing were compared between treatment groups. Pathological analysis showed decreased radiation-induced mucositis, facilitated epithelial cell growth, and preventing ulcerative wound formation, after short-term PB treatment, but not after vehicle or sustained PB. The radiation-induced wound healing gene expression profile exhibited a sequential transition from the inflammatory and DNA repair phases to the tissue remodeling phase in the vehicle group. Sustained PB treatment resulted in a prolonged wound healing gene expression profile and delayed the wound healing process. Short-term PB shortened the duration of inflammatory cytokine expression, triggered repeated pulsed expression of cell cycle and DNA repair-regulating genes, and promoted earlier oscillatory expression of tissue remodeling genes. Distinct gene expression patterns between sustained and short-term treatment suggest dynamic profiling of wound healing gene expression can be an important part of a biological therapeutic strategy to mitigate radiation-related tissue injury. © 2015 by the Wound Healing Society.

Chung Y.-L.,Koo Foundation Sun Yat Sen Cancer Center
FASEB Journal | Year: 2013

Hepatitis B virus (HBV) is implicated in liver cancer. The aim of this study was to find out whether HBV or its components [HBV surface antigen (HBsAg), HBV core protein (HBc), and HBV X protein (HBx)] could interfere with the host DNA damage response and repair pathway. The full HBV genome or individual HBV open-reading frame (ORF) was introduced into HepG2 cells to examine the effect on host genomic stability, DNA repair efficacy in response to double-strand DNA damage, and DNA damage-induced cell death. Responses to apoptosis induction in the HBV ORF-transfected HepG2 cells were also compared with those in HBVpositive and HBV-negative human hepatocellular carcinoma (HCC) cells. In the absence of HBV replication, accumulation of HBsAg in liver cells without other HBV proteins enhanced DNA repair protein and tumor suppressor promyelocytic leukemia (PML) degradation, which resulted in resistance to apoptosis induction and deficient double-strand DNA repair. However, HBsAg-positive cells exhibited increased cell death with exposure to the poly(ADP-ribose) polymerase inhibitor that blocks single-strand DNA repair. These results indicate that suppression of PML by HBsAg disrupts cellular mechanisms that respond to double-strand DNA damage for DNA repair or apoptosis induction, which may facilitate hepatocarcinogenesis and open up a synthetic lethality strategy for HBsAg-positive HCC treatment. © FASEB.

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