Publications by authors named "Cheng Har Yip"

170 Publications

Polygenic risk scores for prediction of breast cancer risk in Asian populations.

Genet Med 2021 Dec 14. Epub 2021 Dec 14.

RIKEN Center for Integrative Medical Sciences (IMS), Yokohama, Japan.

Purpose: Non-European populations are under-represented in genetics studies, hindering clinical implementation of breast cancer polygenic risk scores (PRSs). We aimed to develop PRSs using the largest available studies of Asian ancestry and to assess the transferability of PRS across ethnic subgroups.

Methods: The development data set comprised 138,309 women from 17 case-control studies. PRSs were generated using a clumping and thresholding method, lasso penalized regression, an Empirical Bayes approach, a Bayesian polygenic prediction approach, or linear combinations of multiple PRSs. These PRSs were evaluated in 89,898 women from 3 prospective studies (1592 incident cases).

Results: The best performing PRS (genome-wide set of single-nucleotide variations [formerly single-nucleotide polymorphism]) had a hazard ratio per unit SD of 1.62 (95% CI = 1.46-1.80) and an area under the receiver operating curve of 0.635 (95% CI = 0.622-0.649). Combined Asian and European PRSs (333 single-nucleotide variations) had a hazard ratio per SD of 1.53 (95% CI = 1.37-1.71) and an area under the receiver operating curve of 0.621 (95% CI = 0.608-0.635). The distribution of the latter PRS was different across ethnic subgroups, confirming the importance of population-specific calibration for valid estimation of breast cancer risk.

Conclusion: PRSs developed in this study, from association data from multiple ancestries, can enhance risk stratification for women of Asian ancestry.
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http://dx.doi.org/10.1016/j.gim.2021.11.008DOI Listing
December 2021

Germline breast cancer susceptibility genes, tumor characteristics, and survival.

Genome Med 2021 Dec 2;13(1):185. Epub 2021 Dec 2.

Department of Surgery, University of Ulsan College of Medicine and Asan Medical Center, Seoul, Republic of Korea.

Background: Mutations in certain genes are known to increase breast cancer risk. We study the relevance of rare protein-truncating variants (PTVs) that may result in loss-of-function in breast cancer susceptibility genes on tumor characteristics and survival in 8852 breast cancer patients of Asian descent.

Methods: Gene panel sequencing was performed for 34 known or suspected breast cancer predisposition genes, of which nine genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, BARD1, RAD51C, RAD51D, and TP53) were associated with breast cancer risk. Associations between PTV carriership in one or more genes and tumor characteristics were examined using multinomial logistic regression. Ten-year overall survival was estimated using Cox regression models in 6477 breast cancer patients after excluding older patients (≥75years) and stage 0 and IV disease.

Results: PTV carriership (n = 690) was significantly associated (p < 0.001) with more aggressive tumor characteristics including high grade (poorly vs well-differentiated, odds ratio [95% confidence interval] 3.48 [2.35-5.17], moderately vs well-differentiated 2.33 [1.56-3.49]), as well as luminal B [HER-] and triple-negative subtypes (vs luminal A 2.15 [1.58-2.92] and 2.85 [2.17-3.73], respectively), adjusted for age at diagnosis, study, and ethnicity. Associations with grade and luminal B [HER2-] subtype remained significant after excluding BRCA1/2 carriers. PTV carriership (n = 289, excluding carriers of the nine genes associated with breast cancer) was not associated with tumor characteristics. However, PTV carriership, but not PTV carriership, was suggested to be associated with worse 10-year overall survival (hazard ratio [CI] 1.63 [1.16-2.28]).

Conclusions: PTV carriership is associated with more aggressive tumors. Variants in other genes might be associated with the survival of breast cancer patients. The finding that PTV carriership is not just associated with higher breast cancer risk, but also more severe and fatal forms of the disease, suggests that genetic testing has the potential to provide additional health information and help healthy individuals make screening decisions.
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http://dx.doi.org/10.1186/s13073-021-00978-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8638193PMC
December 2021

Baseline cardiovascular comorbidities, and the influence on cancer treatment decision-making in women with breast cancer.

Ecancermedicalscience 2021 21;15:1293. Epub 2021 Sep 21.

Department of Social and Preventive Medicine, Faculty of Medicine, Universiti Malaya, 50603 Lembah Pantai, Kuala Lumpur, Malaysia.

Purpose: To measure the baseline prevalence of cardiovascular disease (CVD), its modifiable and non-modifiable risk factors in breast cancer patients, and determine their association with adjuvant treatment decision-making.

Method: From 2016 to 2017, 2,127 women newly-diagnosed with breast cancer were prospectively recruited. Participants' cardiovascular biomarkers were measured prior to adjuvant treatment decision-making. Clinical data and medical histories were obtained from hospital records. Adjuvant treatment decisions were collated 6-8 months after recruitment. A priori risk of cardiotoxicity was predicted using the Cardiotoxicity Risk Score.

Results: Mean age was 54 years. Eighty-five patients had pre-existing cardiac diseases and 30 had prior stroke. Baseline prevalence of hypertension was 47.8%. Close to 20% had diabetes mellitus, or were obese. Dyslipidaemia was present in 65.3%. The proportion of women presenting with ≥2 modifiable CVD risk factors at initial cancer diagnosis was substantial, irrespective of age. Significant ethnic variations were observed. Multivariable analyses showed that pre-existing CVD was consistently associated with lower administration of adjuvant breast cancer therapies (odds ratio for chemotherapy: 0.32, 95% confidence interval: 0.17-0.58). However, presence of multiple risk factors of CVD did not appear to influence adjuvant treatment decision-making. In this study, 63.6% of patients were predicted to have high risks of developing cardiotoxicities attributed to a high baseline burden of CVD risk factors and anthracycline administration.

Conclusion: While recent guidelines recommend routine assessment of cardiovascular comorbidities in cancer patients prior to initiation of anticancer therapies, this study highlights the prevailing gap in knowledge on how such data may be used to optimise cancer treatment decision-making.
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http://dx.doi.org/10.3332/ecancer.2021.1293DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8580595PMC
September 2021

Exploring Unmet Needs from an Online Metastatic Breast Cancer Support Group: A Qualitative Study.

Medicina (Kaunas) 2021 Jul 7;57(7). Epub 2021 Jul 7.

Breast Centre, Subang Jaya Medical Centre, Subang Jaya 47500, Malaysia.

: Despite the increasing treatment options for patients with metastatic breast cancer (MBC), unmet needs remain common, especially in low and middle-income countries where resources are limited and MBC patients face many challenges. They often join support groups to cope with their unmet needs. Currently, many MBC patients connect with each other via online support group in view of the constant availability of support and rapid information exchange. The objective of this study is to determine the unmet needs of women with MBC from an online support group. : Messages in an online support group of twenty-two MBC patients over a period of three years from August 2016 till August 2019 were thematically analyzed. : Three themes were generated, (1) unmet information needs (2) unmet financial needs (3) unmet support needs. Women needed information on side effects of treatment, new treatment options and availability of clinical trials. Although Malaysia has universal health care coverage, access to treatment remains a major challenge. When treatment was not available in the public hospitals, or waiting lists were too long, women were forced to seek treatment in private hospitals, incurring financial catastrophe. Insufficient private insurance and inadequate social security payments force many women to consider stopping treatment. Women felt that they were not getting support from their clinicians in the public sector, who were quick to stop active treatment and advise palliation. On the other hand, clinicians in the private sector advise expensive treatment beyond the financial capability of the patients. Women with families also face the challenge of managing their family and household in addition to coping with their illness. : There is a need for healthcare professionals, policy makers, and civil society to better address the needs of MBC patients through patient-centered, multidisciplinary and multi-organizational collaboration.
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http://dx.doi.org/10.3390/medicina57070693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305467PMC
July 2021

The Impact of Quality Improvement Interventions in Improving Surgical Infections and Mortality in Low and Middle-Income Countries: A Systematic Review and Meta-Analysis.

World J Surg 2021 10 3;45(10):2993-3006. Epub 2021 Jul 3.

Department of Surgery, University of Auckland, Auckland, 1010, New Zealand.

Background: Morbidity and mortality in surgical systems in low- and middle-income countries (LMICs) remain high compared to high-income countries. Quality improvement processes, interventions, and structure are essential in the effort to improve peri-operative outcomes.

Methods: A systematic review and meta-analysis of interventional studies assessing quality improvement processes, interventions, and structure in developing country surgical systems was conducted according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they were conducted in an LMIC, occurred in a surgical setting, and measured the effect of an implementation and its impact. The primary outcome was mortality, and secondary outcomes were rates of rates of hospital-acquired infection (HAI) and surgical site infections (SSI). Prospero Registration: CRD42020171542.

Result: Of 38,273 search results, 31 studies were included in a qualitative synthesis, and 28 articles were included in a meta-analysis. Implementation of multimodal bundled interventions reduced the incidence of HAI by a relative risk (RR) of 0.39 (95%CI 0.26 to 0.59), the effect of hand hygiene interventions on HAIs showed a non-significant effect of RR of 0.69 (0.46-1.05). The WHO Safe Surgery Checklist reduced mortality by RR 0.68 (0.49 to 0.95) and SSI by RR 0.50 (0.33 to 0.63) and antimicrobial stewardship interventions reduced SSI by RR 0.67 (0.48-0.93).

Conclusion: There is evidence that a number of quality improvement processes, interventions and structural changes can improve mortality, HAI and SSI outcomes in the peri-operative setting in LMICs.
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http://dx.doi.org/10.1007/s00268-021-06208-yDOI Listing
October 2021

Out-of-Pocket Costs of Complementary Medicine Following Cancer and the Financial Impact in a Setting With Universal Health Coverage: Findings From a Prospective Cohort Study.

JCO Oncol Pract 2021 10 2;17(10):e1592-e1602. Epub 2021 Jun 2.

Subang Jaya Medical Centre, Subang Jaya, Selangor, Malaysia.

Purpose: To determine household spending patterns on complementary medicine following cancer and the financial impact in a setting with universal health coverage.

Methods: Country-specific data from a multinational prospective cohort study, Association of Southeast Asian Nations Costs in Oncology Study, comprising 1,249 cancer survivors were included. Household costs of complementary medicine (healthcare practices or products that are not considered as part of conventional medicine) throughout the first year after cancer diagnosis were measured using cost diaries. Study outcomes comprised (1) shares of household expenditures on complementary medicine from total out-of-pocket costs and health costs that were respectively incurred in relation to cancer, (2) incidence of financial catastrophe (out-of-pocket costs related to cancer ≥ 30% of annual household income), and (3) economic hardship (inability to pay for essential household items or services).

Results: One third of patients reported out-of-pocket household expenditures on complementary medicine in the immediate year after cancer diagnosis, accounting to 20% of the total out-of-pocket costs and 35% of the health costs. Risk of financial catastrophe was higher in households reporting out-of-pocket expenditures on complementary medicine (adjusted odds ratio: 1.39 [95% CI, 1.05 to 1.86]). Corresponding odds ratio within patients from low-income households showed that they were substantially more vulnerable: 2.28 (95% CI, 1.41 to 3.68). Expenditures on complementary medicine were, however, not associated with economic hardship in the immediate year after cancer diagnosis.

Conclusion: In settings with universal health coverage, integration of subsidized evidence-based complementary medicine into mainstream cancer care may alleviate catastrophic expenditures. However, this must go hand in hand with interventions to reduce the use of nonevidence-based complementary therapies following cancer.
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http://dx.doi.org/10.1200/OP.20.01052DOI Listing
October 2021

Breast-Gynaecological & Immuno-Oncology International Cancer Conference (BGICC) Consensus and Recommendations for the Management of Triple-Negative Breast Cancer.

Cancers (Basel) 2021 May 8;13(9). Epub 2021 May 8.

Russian Association of Oncological Mammology, Department of Breast Tumours of Federal State Budgetary Institution "Petrov Research Institute of Oncology", 197758 Saint Petersburg, Russia.

: The management of patients with triple-negative breast cancer (TNBC) is challenging with several controversies and unmet needs. During the 12th Breast-Gynaecological & Immuno-oncology International Cancer Conference (BGICC) Egypt, 2020, a panel of 35 breast cancer experts from 13 countries voted on consensus guidelines for the clinical management of TNBC. The consensus was subsequently updated based on the most recent data evolved lately. : A consensus conference approach adapted from the American Society of Clinical Oncology (ASCO) was utilized. The panellists voted anonymously on each question, and a consensus was achieved when ≥75% of voters selected an answer. The final consensus was later circulated to the panellists for critical revision of important intellectual content. : These recommendations represent the available clinical evidence and expert opinion when evidence is scarce. The percentage of the consensus votes, levels of evidence and grades of recommendation are presented for each statement. The consensus covered all the aspects of TNBC management starting from defining TNBC to the management of metastatic disease and highlighted the rapidly evolving landscape in this field. Consensus was reached in 70% of the statements (35/50). In addition, areas of warranted research were identified to guide future prospective clinical trials.
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http://dx.doi.org/10.3390/cancers13092262DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125909PMC
May 2021

Characterisation of PALB2 tumours through whole-exome and whole-transcriptomic analyses.

NPJ Breast Cancer 2021 Apr 23;7(1):46. Epub 2021 Apr 23.

Cancer Research Malaysia, Subang Jaya, Malaysia.

Rare protein-truncating variants (PTVs) in PALB2 confer increased risk to breast cancer, but relatively few studies have reported the characteristics of tumours with PALB2 PTVs. In this study, we describe molecular characteristics of tumours with either germline or somatic alterations in PALB2. DNA from fresh frozen tumour tissues and matched peripheral blood lymphocytes for 560 breast cancer patients was subjected for whole-exome sequencing (WES), and RNA from tumour tissues was subjected to RNA sequencing (RNA-seq). We found six cases with germline and three with somatic protein-truncating variants in PALB2. The characteristics of tumours in patients with PALB2 PTVs were similar to those with BRCA1 and BRCA2 PTVs, having significantly more somatic alterations, and a high proportion of the mutational signature and genomic scar scores characteristic of deficiencies in homologous recombination (HR), compared to tumours arising in non-carriers. Unlike tumours arising in patients with BRCA1 and BRCA2 PTVs, PALB2 tumours did not have high prevalence of TP53 somatic alterations or an enriched immune microenvironment. In summary, PALB2 tumours show the homologous recombination deficiencies characteristic of BRCA1 and BRCA2 tumours, and highlight the potential clinical relevance of PALB2 mutational status in guiding therapeutic choices.
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http://dx.doi.org/10.1038/s41523-021-00254-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065101PMC
April 2021

Effectiveness of Quality Improvement Processes, Interventions, and Structure in Trauma Systems in Low- and Middle-Income Countries: A Systematic Review and Meta-analysis.

World J Surg 2021 07 9;45(7):1982-1998. Epub 2021 Apr 9.

Department of Surgery, The University of Auckland, Auckland, New Zealand.

Background: Trauma mortality in low- and middle-income countries (LMICs) remains high compared to high-income countries. Quality improvement processes, interventions, and structure are essential in the effort to decrease trauma mortality.

Methods: A systematic review and meta-analysis of interventional studies assessing quality improvement processes, interventions, and structure in developing country trauma systems was conducted from November 1989 to August 2020 according to the Preferred Reporting Items of Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Studies were included if they were conducted in an LMIC population according to World Bank Income Classification, occurred in a trauma setting, and measured the effect of implementation and its impact. The primary outcome was trauma mortality.

Results: Of 37,575 search results, 30 studies were included from 15 LMICs covering five WHO regions in a qualitative synthesis. Twenty-seven articles were included in a meta-analysis. Implementing a pre-hospital trauma system reduced overall trauma mortality by 45% (risk ratio (RR) 0.55, 95% CI 0.4 to 0.75). Training first responders resulted in an overall decrease in mortality (RR 0.47, 95% CI 0.28 to 0.78). In-hospital trauma training with certified courses resulted in a reduction of mortality (RR 0.71, 95% CI 0.62 to 0.78). Trauma audits and trauma protocols resulted in varying improvements in trauma mortality.

Conclusion: There is evidence that quality improvement processes, interventions, and structure can improve mortality in the trauma systems in LMICs.
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http://dx.doi.org/10.1007/s00268-021-06065-9DOI Listing
July 2021

Characterisation of protein-truncating and missense variants in in 15 768 women from Malaysia and Singapore.

J Med Genet 2021 Apr 2. Epub 2021 Apr 2.

Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia

Background: Rare protein-truncating variants (PTVs) in partner and localiser of BRCA2 () confer increased risk to breast cancer, but relatively few studies have reported the prevalence in South-East Asian populations. Here, we describe the prevalence of rare variants in in a population-based study of 7840 breast cancer cases and 7928 healthy Chinese, Malay and Indian women from Malaysia and Singapore, and describe the functional impact of germline missense variants identified in this population.

Methods: Mutation testing was performed on germline DNA (n=15 768) using targeted sequencing panels. The functional impact of missense variants was tested in mouse embryonic stem cell based functional assays.

Results: PTVs in were found in 0.73% of breast cancer patients and 0.14% of healthy individuals (OR=5.44; 95% CI 2.85 to 10.39, p<0.0001). In contrast, rare missense variants in were not associated with increased risk of breast cancer. Whereas PTVs were associated with later stage of presentation and higher-grade tumours, no significant association was observed with missense variants in . However, two novel rare missense variants (p.L1027R and p.G1043V) produced unstable proteins and resulted in a decrease in homologous recombination-mediated repair of DNA double-strand breaks.

Conclusion: Despite genetic and lifestyle differences between Asian and other populations, the population prevalence of PTVs and associated relative risk of breast cancer, are similar to those reported in European populations.
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http://dx.doi.org/10.1136/jmedgenet-2020-107471DOI Listing
April 2021

Insights on emotional distress following cancer, sources of support and the unmet needs in a setting with limited supportive care services for people living with cancer.

Support Care Cancer 2021 Oct 19;29(10):5811-5819. Epub 2021 Mar 19.

Centre for Epidemiology and Evidence-Based Practice, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.

Introduction: Delivery of supportive cancer care is often deemed a low priority in resource-limited settings. We aimed to explore the sources of emotional distress, the related support and the unmet needs of cancer survivors in Malaysia, where cancer survivorship services are presently limited.

Method: Twenty focus group discussions were conducted with 102 cancer patients from diverse ethnic and socioeconomic backgrounds. Thematic analyses were performed.

Results: Patient narratives suggested that emotional distress arose from direct and indirect stressors. Direct stressors comprised physical and cognitive side effects of cancer surgery and therapies, and fear of recurrence. Indirect stressors included worry over dependent family members, financial distress following cancer, working with cancer and lack of practical support at home. Distress from altered physical appearances, fear of recurrence and lack of practical support were mainly raised by women, implying that men and women may have disproportionate emotional needs. Emotional support largely came from informal sources including self, family, friends and religion. While formal emotional support from professional counsellors and cancer support groups was acknowledged as important, it appeared to be largely lacking. Unmet needs in coping with fear of recurrence, financial distress, workplace discrimination and household chores were particularly highlighted.

Conclusion: The unmet needs revealed in this study provide insights to initiate actionable changes to improve the emotional wellbeing of people living with cancer in settings where cancer survivorship services are still in its infancy.
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http://dx.doi.org/10.1007/s00520-021-06148-2DOI Listing
October 2021

The first BGICC consensus and recommendations for breast cancer awareness, early detection and risk reduction in low- and middle-income countries and the MENA region.

Int J Cancer 2021 08 21;149(3):505-513. Epub 2021 Feb 21.

Clinical Oncology Department, Ain shams University, Cairo, Egypt.

In low-middle income countries (LMICs) and the Middle East and North Africa (MENA) region, there is an unmet need to establish and improve breast cancer (BC) awareness, early diagnosis and risk reduction programs. During the 12th Breast, Gynecological & Immuno-oncology International Cancer Conference - Egypt 2020, 26 experts from 7 countries worldwide voted to establish the first consensus for BC awareness, early detection and risk reduction in LMICs/MENA region. The panel advised that there is an extreme necessity for a well-developed BC data registries and prospective clinical studies that address alternative modalities/modified BC screening programs in areas of limited resources. The most important recommendations of the panel were: (a) BC awareness campaigns should be promoted to public and all adult age groups; (b) early detection programs should combine geographically distributed mammographic facilities with clinical breast examination (CBE); (c) breast awareness should be encouraged; and (d) intensive surveillance and chemoprevention strategies should be fostered for high-risk women. The panel defined some areas for future clinical research, which included the role of CBE and breast self-examination as an alternative to radiological screening in areas of limited resources, the interval and methodology of BC surveillance in women with increased risk of BC and the use of low dose tamoxifen in BC risk reduction. In LMICs/MENA region, BC awareness and early detection campaigns should take into consideration the specific disease criteria and the socioeconomic status of the target population. The statements with no consensus reached should serve as potential catalyst for future clinical research.
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http://dx.doi.org/10.1002/ijc.33506DOI Listing
August 2021

American Society of Clinical Oncology, American Society for Radiation Oncology, and Society of Surgical Oncology Guideline for Management of Hereditary Breast Cancer.

JAMA Surg 2021 03;156(3):284-285

Breast Surgery Section, International Center for the Study of Breast Cancer Subtypes, Weill Cornell Medicine, New York, New York.

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http://dx.doi.org/10.1001/jamasurg.2020.6254DOI Listing
March 2021

Germline APOBEC3B deletion increases somatic hypermutation in Asian breast cancer that is associated with Her2 subtype, PIK3CA mutations, and immune activation.

Int J Cancer 2021 Jan 7. Epub 2021 Jan 7.

Cancer Research Malaysia, Subang Jaya, Malaysia.

A 30-kb deletion that eliminates the coding region of APOBEC3B (A3B) is >5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with the APOBEC3A (A3A) coding region and A3B 3'UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between the A3B deletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germline A3B deletion polymorphism leads to expression of the A3A-B hybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless of A3B germline status, were associated with the Her2 molecular subtype and PIK3CA mutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germline A3B deletion polymorphism, via the A3A-B hybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless of A3B background, may be an important clinical biomarker for Asian breast cancers. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33463DOI Listing
January 2021

The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences.

Nat Commun 2020 12 22;11(1):6433. Epub 2020 Dec 22.

Cancer Research Malaysia, No. 1, Jalan SS12/1A, 47500, Subang Jaya, Malaysia.

Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.
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http://dx.doi.org/10.1038/s41467-020-20173-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755902PMC
December 2020

Epidemiological and ES cell-based functional evaluation of BRCA2 variants identified in families with breast cancer.

Hum Mutat 2021 02 31;42(2):200-212. Epub 2020 Dec 31.

Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702, USA.

The discovery of high-risk breast cancer susceptibility genes, such as Breast cancer associated gene 1 (BRCA1) and Breast cancer associated gene 2 (BRCA2) has led to accurate identification of individuals for risk management and targeted therapy. The rapid decline in sequencing costs has tremendously increased the number of individuals who are undergoing genetic testing world-wide. However, given the significant differences in population-specific variants, interpreting the results of these tests can be challenging especially for novel genetic variants in understudied populations. Here we report the characterization of novel variants in the Malaysian and Singaporean population that consist of different ethnic groups (Malays, Chinese, Indian, and other indigenous groups). We have evaluated the functional significance of 14 BRCA2 variants of uncertain clinical significance by using multiple in silico prediction tools and examined their frequency in a cohort of 7840 breast cancer cases and 7928 healthy controls. In addition, we have used a mouse embryonic stem cell (mESC)-based functional assay to assess the impact of these variants on BRCA2 function. We found these variants to be functionally indistinguishable from wild-type BRCA2. These variants could fully rescue the lethality of Brca2-null mESCs and exhibited no sensitivity to six different DNA damaging agents including a poly ADP ribose polymerase inhibitor. Our findings strongly suggest that all 14 evaluated variants are functionally neutral. Our findings should be valuable in risk assessment of individuals carrying these variants.
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http://dx.doi.org/10.1002/humu.24154DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7919386PMC
February 2021

Communication about positive BRCA1 and BRCA2 genetic test results and uptake of testing in relatives in a diverse Asian setting.

J Genet Couns 2021 06 27;30(3):720-729. Epub 2020 Nov 27.

Cancer Research Malaysia, Selangor, Malaysia.

The vast majority of studies assessing communication of BRCA1/2 results with relatives and family uptake of BRCA1/2 testing have been conducted in Western societies, and a dearth of studies have been conducted in Asia among relatives of diverse carriers of pathogenic BRCA1/2 germline variants. This study aimed to present rates of BRCA1/2 result disclosure by probands and probands' motivators and barriers of family communication and predictive testing uptake among eligible relatives. It also examined patterns of disclosure and testing uptake among different types of relatives. Eighty-seven carriers with either breast or ovarian cancer, who had previously been found to be carriers of a pathogenic variant in BRCA1/2, were interviewed over the phone using a semi-structured interview guide. Fifty-six percent of patients were Chinese, 21% were Indian, and 23% were Malay. It was found that 62.0% of eligible first- and second-degree relatives were informed by the proband about the testing result and that 11.5% of eligible first- and second-degree relatives had genetic testing. First-degree relatives were more likely to have been informed and tested compared to second-degree relatives, as were sisters compared to brothers. The low rates of family communication and testing uptake documented in this study suggest that interventions should focus on encouraging probands to inform male and second-degree relatives and targeting such relatives to increase informed decisions and accessibility to testing. Promotion strategies should be culturally sensitive to optimize outcomes.
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http://dx.doi.org/10.1002/jgc4.1360DOI Listing
June 2021

Working after cancer: in-depth perspectives from a setting with limited employment protection policies.

J Cancer Surviv 2021 10 22;15(5):706-712. Epub 2020 Oct 22.

Centre for Epidemiology and Evidence-Based Practice, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Lembah Pantai, 50603, Kuala Lumpur, Malaysia.

Purpose: A considerable proportion of individuals who are diagnosed with cancer are at a working age. We aimed to gain an in-depth understanding of the challenges, and arising needs related to working after cancer in a setting with limited employment protection policies.

Methods: Focus group discussions were conducted with cancer patients who were diagnosed at least 1 year prior to recruitment, and either had paid work, were self-employed, currently unemployed, or currently retired (N = 66).

Results: Three main themes were identified: (1) loss of income: While some participants were entitled for a 1-year cancer-specific sick leave, many other participants recounted having insufficient paid sick leave, forcing them to take prolonged unpaid leave to complete treatment; (2) dealing with side effects of cancer and its treatment: The need for workplace accommodations was highlighted including flexible working hours, lighter workloads, and dedicated rest areas to enable patients to cope better; (3) Discrimination and stigma at workplace: Some participants mentioned being passed over on a promotion, getting demoted, or being forced to resign once their cancer diagnosis was disclosed, highlighting an urgent need to destigmatize cancer in the workplace.

Conclusion: In settings with limited employment protection policies, a cancer diagnosis severely impacts the working experiences of patients, leading to financial loss. Urgent interventions and legislative reforms are needed in these settings to address the unmet employment needs of cancer survivors.

Implications For Cancer Survivors: This study may facilitate planning of local solutions to fulfill the unmet employment needs following cancer, such as return-to-work navigation services.
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http://dx.doi.org/10.1007/s11764-020-00962-zDOI Listing
October 2021

Primary Breast Angiosarcoma: Utilisation of Pre-surgical Magnetic Resonance Imaging (MRI) for Accurate Tumour Characterization and Planning - A Case Report and Literature Review.

Curr Med Imaging 2021 ;17(4):552-558

Department of Surgery, Subang Jaya Medical Centre, Kuala Lumpur, Malaysia.

Background: Primary breast angiosarcoma is a rare malignancy with non-specific clinical and radiological findings.

Case Report: A 30-year-old lady presented with left breast pain and lumpiness for over one year. She has had several breast ultrasounds (US) and was treated for acute mastitis and abscess. Subsequently, in view of the rapid growth of the lump and worsening pain, she was re-investigated with US, elastography, digital breast tomosynthesis (DBT) and MRI. MRI raised the suspicion of angiosarcoma. The diagnosis was confirmed after biopsy and she underwent mastectomy.

Discussion: Literature review on imaging findings of breast angiosarcoma, especially on MRI, is discussed. MRI features showed heterogeneous low signal intensity on T1 and high signal intensity on T2. Dynamic contrast enhancement (DCE) features included either early enhancement with or without washout in the delayed phase, and some reported central areas of non-enhancement.

Conclusion: This case report emphasises on the importance of MRI in clinching the diagnosis of breast angiosarcoma, and hence, should be offered sooner to prevent diagnostic delay.
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http://dx.doi.org/10.2174/1573405616666201007161119DOI Listing
October 2021

Breaking News of Cancer Diagnosis: A Qualitative Study on the Experiences and Emotional Needs of Patients With Cancer in a Multiethnic Asian Setting.

JCO Oncol Pract 2021 04 28;17(4):e548-e555. Epub 2020 Sep 28.

Centre for Epidemiology and Evidence-Based Practice, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

Purpose: The breaking of news of a cancer diagnosis is an important milestone in a patient's cancer journey. We explored the emotional experiences of patients with cancer during the breaking of news of a cancer diagnosis and the arising needs in a multiethnic Asian setting with limited supportive cancer care services.

Methods: Twenty focus group discussions were conducted with 102 Asian patients with cancer from diverse sociodemographic backgrounds. Thematic analysis was performed.

Results: While most participants, especially younger patients with young children, experienced intense emotional distress upon receiving a cancer diagnosis, those with a family history of cancer were relatively calm and resigned. Nonetheless, the prior negative experience with cancer in the family made affected participants with a family history less eager to seek cancer treatment and less hopeful for a cure. Although a majority viewed the presence of family members during the breaking of bad news as important, a minority opted to face it alone to lessen the emotional impact on their family members. Difficulties disclosing the news of a cancer diagnosis to loved ones also emerged as an important need. Sensitive and empathetic patient-physician communication during the breaking of news of a cancer diagnosis was stressed as paramount.

Conclusion: A patient-centered communication approach needs to be developed to reduce the emotional distress to patients and their families after the breaking of bad news of a cancer diagnosis. This is expected to positively affect the patients' subsequent coping skills and attitudes toward cancer, which may improve adherence to cancer therapy.
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http://dx.doi.org/10.1200/JOP.20.00002DOI Listing
April 2021

Implementing Society of Surgical Oncology and the American Society for Radiation Oncology Margin Guidelines to Reduce Reoperations After Lumpectomy for Early Breast Cancer.

Authors:
Cheng-Har Yip

JAMA Surg 2020 10 21;155(10):e203026. Epub 2020 Oct 21.

Department of Surgery, Subang Jaya Medical Centre, Subang Jaya, Malaysia.

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http://dx.doi.org/10.1001/jamasurg.2020.3026DOI Listing
October 2020

European polygenic risk score for prediction of breast cancer shows similar performance in Asian women.

Nat Commun 2020 07 31;11(1):3833. Epub 2020 Jul 31.

Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, 117597, Singapore, Singapore.

Polygenic risk scores (PRS) have been shown to predict breast cancer risk in European women, but their utility in Asian women is unclear. Here we evaluate the best performing PRSs for European-ancestry women using data from 17,262 breast cancer cases and 17,695 controls of Asian ancestry from 13 case-control studies, and 10,255 Chinese women from a prospective cohort (413 incident breast cancers). Compared to women in the middle quintile of the risk distribution, women in the highest 1% of PRS distribution have a ~2.7-fold risk and women in the lowest 1% of PRS distribution has ~0.4-fold risk of developing breast cancer. There is no evidence of heterogeneity in PRS performance in Chinese, Malay and Indian women. A PRS developed for European-ancestry women is also predictive of breast cancer risk in Asian women and can help in developing risk-stratified screening programmes in Asia.
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http://dx.doi.org/10.1038/s41467-020-17680-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7395776PMC
July 2020

The Breast Health Global Initiative 2018 Global Summit on Improving Breast Healthcare Through Resource-Stratified Phased Implementation: Methods and overview.

Cancer 2020 05;126 Suppl 10:2339-2352

Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington.

Background: The Breast Health Global Initiative (BHGI) established a series of resource-stratified, evidence-based guidelines to address breast cancer control in the context of available resources. Here, the authors describe methodologies and health system prerequisites to support the translation and implementation of these guidelines into practice.

Methods: In October 2018, the BHGI convened the Sixth Global Summit on Improving Breast Healthcare Through Resource-Stratified Phased Implementation. The purpose of the summit was to define a stepwise methodology (phased implementation) for guiding the translation of resource-appropriate breast cancer control guidelines into real-world practice. Three expert consensus panels developed stepwise, resource-appropriate recommendations for implementing these guidelines in low-income and middle-income countries as well as underserved communities in high-income countries. Each panel focused on 1 of 3 specific aspects of breast cancer care: 1) early detection, 2) treatment, and 3) health system strengthening.

Results: Key findings from the summit and subsequent article preparation included the identification of phased-implementation prerequisites that were explored during consensus debates. These core issues and concepts are key components for implementing breast health care that consider real-world resource constraints. Communication and engagement across all levels of care is vital to any effectively operating health care system, including effective communication with ministries of health and of finance, to demonstrate needs, outcomes, and cost benefits.

Conclusions: Underserved communities at all economic levels require effective strategies to deploy scarce resources to ensure access to timely, effective, and affordable health care. Systematically strategic approaches translating guidelines into practice are needed to build health system capacity to meet the current and anticipated global breast cancer burden.
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http://dx.doi.org/10.1002/cncr.32891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482869PMC
May 2020

Breast cancer early detection: A phased approach to implementation.

Cancer 2020 05;126 Suppl 10:2379-2393

Department of Global Health, University of Washington, Seattle, Washington.

When breast cancer is detected and treated early, the chances of survival are very high. However, women in many settings face complex barriers to early detection, including social, economic, geographic, and other interrelated factors, which can limit their access to timely, affordable, and effective breast health care services. Previously, the Breast Health Global Initiative (BHGI) developed resource-stratified guidelines for the early detection and diagnosis of breast cancer. In this consensus article from the sixth BHGI Global Summit held in October 2018, the authors describe phases of early detection program development, beginning with management strategies required for the diagnosis of clinically detectable disease based on awareness education and technical training, history and physical examination, and accurate tissue diagnosis. The core issues address include finance and governance, which pertain to successful planning, implementation, and the iterative process of program improvement and are needed for a breast cancer early detection program to succeed in any resource setting. Examples are presented of implementation, process, and clinical outcome metrics that assist in program implementation monitoring. Country case examples are presented to highlight the challenges and opportunities of implementing successful breast cancer early detection programs, and the complex interplay of barriers and facilitators to achieving early detection for breast cancer in real-world settings are considered.
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http://dx.doi.org/10.1002/cncr.32887DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237065PMC
May 2020

Options for Addressing the Dilemma of Managing Dense Breasts.

JAMA Surg 2020 04;155(4):279-280

Breast Centre, Subang Jaya Medical Centre/Parkcity Medical Centre, University Malaya, Kuala Lumpur, Malaysia.

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http://dx.doi.org/10.1001/jamasurg.2020.0280DOI Listing
April 2020

The association between methods of biopsy and survival following breast cancer: A hospital registry based cohort study.

Medicine (Baltimore) 2020 Feb;99(6):e19093

Subang Jaya Medical Centre, Subang Jaya, Selangor, Malaysia.

Percutaneous biopsy in breast cancer has been associated with an increased risk of malignant cell seeding. However, the importance of these observations remains obscure due to lack of corroborating evidence from clinical studies. We determined whether method of biopsy is associated with breast cancer survival. This hospital registry-based cohort study included 3416 non-metastatic breast cancer patients diagnosed from 1993 to 2011 in a tertiary setting. Factors associated with biopsy methods were assessed. Multivariable Cox regression analysis was used to determine the independent prognostic impact of method of biopsy. Overall, 990 patients were diagnosed by core needle biopsy (CNB), 1364 by fine needle aspiration cytology (FNAC), and 1062 by excision biopsy. Excision biopsy was significantly associated with more favorable tumor characteristics. Radiotherapy modified the prognostic impact of biopsy method (Pinteraction < .001). Following multivariable analysis, excision biopsy was consistently associated with lower risk of mortality compared to FNAC in women receiving adjuvant radiotherapy (adjusted hazard ratio: 0.81, 95%CI: 0.66-0.99), but not in those who did not receive adjuvant radiotherapy (adjusted hazard ratio: 0.87, 95%CI: 0.65-1.17). While the risk of mortality was not different between patients undergoing FNAC and CNB when radiotherapy is administered, in the absence of radiotherapy, CNB was associated with higher risk of mortality than FNAC (adjusted hazard ratio: 1.57, 95%CI: 1.16-2.12). Given that our results contradict with findings of previous clinical studies assessing the prognostic impact of method of biopsy in women with breast cancer, further studies are warranted.
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http://dx.doi.org/10.1097/MD.0000000000019093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7015568PMC
February 2020

Understanding the Financial Needs Following Diagnosis of Breast Cancer in a Setting with Universal Health Coverage.

Oncologist 2020 06 10;25(6):497-504. Epub 2020 Jan 10.

Centre for Epidemiology and Evidence-Based Practice, Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

Background: A diagnosis of cancer negatively impacts the financial wellbeing of affected individuals as well as their households. We aimed to gain an in-depth understanding of the financial needs following diagnosis of breast cancer in a middle-income setting with universal health coverage.

Materials And Methods: Twelve focus group discussions (n = 64) were conducted with women with breast cancer from two public and three private hospitals. This study specifically focused on (a) health costs, (b) nonhealth costs, (c) employment and earnings, and (d) financial assistance. Thematic analysis was used.

Results: Financial needs related to cancer treatment and health care varied according to the participant's socioeconomic background and type of medical insurance. Although having medical insurance alleviated cancer treatment-related financial difficulties, limited policy coverage for cancer care and suboptimal reimbursement policies were common complaints. Nonhealth expenditures were also cited as an important source of financial distress; patients from low-income households reported transport and parking costs as troublesome, with some struggling to afford basic necessities, whereas participants from higher-income households mentioned hired help, special food and/or supplements and appliances as expensive needs following cancer. Needy patients had a hard time navigating through the complex system to obtain financial support. Irrespective of socioeconomic status, reductions in household income due to loss of employment and/or earnings were a major source of economic hardship.

Conclusion: There are many unmet financial needs following a diagnosis of (breast) cancer even in settings with universal health coverage. Health care professionals may only be able to fulfill these unmet needs through multisectoral collaborations, catalyzed by strong political will.

Implications For Practice: As unmet financial needs exist among patients with cancer across all socioeconomic groups, including for patients with medical insurance, financial navigation should be prioritized as an important component of cancer survivorship services, including in the low- and middle-income settings. Apart from assisting survivors to understand the costs of cancer care, navigate the complex system to obtain financial assistance, or file health insurance claims, any planned patient navigation program should also provide support to deal with employment-related challenges and navigate return to work. It is also echoed that costs for essential personal items (e.g., breast prostheses) should be covered by health insurance or subsidized by the government.
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http://dx.doi.org/10.1634/theoncologist.2019-0426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288648PMC
June 2020

Cancer Risks Associated With Germline Pathogenic Variants: An International Study of 524 Families.

J Clin Oncol 2020 03 16;38(7):674-685. Epub 2019 Dec 16.

Biopathologie, Centre Léon Bérard, Lyon, France.

Purpose: To estimate age-specific relative and absolute cancer risks of breast cancer and to estimate risks of ovarian, pancreatic, male breast, prostate, and colorectal cancers associated with germline pathogenic variants (PVs) because these risks have not been extensively characterized.

Methods: We analyzed data from 524 families with PVs from 21 countries. Complex segregation analysis was used to estimate relative risks (RRs; relative to country-specific population incidences) and absolute risks of cancers. The models allowed for residual familial aggregation of breast and ovarian cancer and were adjusted for the family-specific ascertainment schemes.

Results: We found associations between PVs and risk of female breast cancer (RR, 7.18; 95% CI, 5.82 to 8.85; = 6.5 × 10), ovarian cancer (RR, 2.91; 95% CI, 1.40 to 6.04; = 4.1 × 10), pancreatic cancer (RR, 2.37; 95% CI, 1.24 to 4.50; = 8.7 × 10), and male breast cancer (RR, 7.34; 95% CI, 1.28 to 42.18; = 2.6 × 10). There was no evidence for increased risks of prostate or colorectal cancer. The breast cancer RRs declined with age ( for trend = 2.0 × 10). After adjusting for family ascertainment, breast cancer risk estimates on the basis of multiple case families were similar to the estimates from families ascertained through population-based studies ( for difference = .41). On the basis of the combined data, the estimated risks to age 80 years were 53% (95% CI, 44% to 63%) for female breast cancer, 5% (95% CI, 2% to 10%) for ovarian cancer, 2%-3% (95% CI females, 1% to 4%; 95% CI males, 2% to 5%) for pancreatic cancer, and 1% (95% CI, 0.2% to 5%) for male breast cancer.

Conclusion: These results confirm as a major breast cancer susceptibility gene and establish substantial associations between germline PVs and ovarian, pancreatic, and male breast cancers. These findings will facilitate incorporation of into risk prediction models and optimize the clinical cancer risk management of PV carriers.
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http://dx.doi.org/10.1200/JCO.19.01907DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049229PMC
March 2020

Financial Toxicity After Cancer in a Setting With Universal Health Coverage: A Call for Urgent Action.

J Oncol Pract 2019 06 21;15(6):e537-e546. Epub 2019 May 21.

5 Subang Jaya Medical Centre, Subang Jaya, Malaysia.

Background: Financial toxicity negatively affects the well-being of cancer survivors. We examined the incidence, cost drivers, and factors associated with financial toxicity after cancer in an upper-middle-income country with universal health coverage.

Methods: Through the Association of Southeast Asian Nations Costs in Oncology study, 1,294 newly diagnosed patients with cancer (Ministry of Health [MOH] hospitals [n = 577], a public university hospital [n = 642], private hospitals [n = 75]) were observed in Malaysia. Cost diaries and questionnaires were used to measure incidence of financial toxicity, encompassing financial catastrophe (FC; out-of-pocket costs ≥ 30% of annual household income), medical impoverishment (decrease in household income from above the national poverty line to below that line after subtraction of cancer-related costs), and economic hardship (inability to make necessary household payments). Predictors of financial toxicity were determined using multivariable analyses.

Results: One fifth of patients had private health insurance. Incidence of FC at 1 year was 51% (MOH hospitals, 33%; public university hospital, 65%; private hospitals, 72%). Thirty-three percent of households were impoverished at 1 year. Economic hardship was reported by 47% of families. Risk of FC attributed to conventional medical care alone was 18% (MOH hospitals, 5%; public university hospital, 24%; private hospitals, 67%). Inclusion of expenditures on nonmedical goods and services inflated the risk of financial toxicity in public hospitals. Low-income status, type of hospital, and lack of health insurance were strong predictors of FC.

Conclusion: Patients with cancer may not be fully protected against financial hardships, even in settings with universal health coverage. Nonmedical costs also contribute as important drivers of financial toxicity in these settings.
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http://dx.doi.org/10.1200/JOP.18.00619DOI Listing
June 2019
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