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Fulltext Crosstalk Between microRNAs and the Pathological Features of Secondary Lymphedema

Yusof KM, Groen K, Rosli R, Avery-Kiejda KA

Front Cell Dev Biol, 2021;9:732415.
PMID: 34733847 DOI: 10.3389/fcell.2021.732415

Secondary lymphedema is characterized by lymphatic fluid retention and subsequent tissue swelling in one or both limbs that can lead to decreased quality of life. It often arises after loss, obstruction, or blockage of lymphatic vessels due to multifactorial modalities, such as lymphatic insults after surgery, immune system dysfunction, deposition of fat that compresses the lymphatic capillaries, fibrosis, and inflammation. Although secondary lymphedema is often associated with breast cancer, the condition can occur in patients with any type of cancer that requires lymphadenectomy such as gynecological, genitourinary, or head and neck cancers. MicroRNAs demonstrate pivotal roles in regulating gene expression in biological processes such as lymphangiogenesis, angiogenesis, modulation of the immune system, and oxidative stress. MicroRNA profiling has led to the discovery of the molecular mechanisms involved in the pathophysiology of auto-immune, inflammation-related, and metabolic diseases. Although the role of microRNAs in regulating secondary lymphedema is yet to be elucidated, the crosstalk between microRNAs and molecular factors involved in the pathological features of lymphedema, such as skin fibrosis, inflammation, immune dysregulation, and aberrant lipid metabolism have been demonstrated in several studies. MicroRNAs have the potential to serve as biomarkers for diseases and elucidation of their roles in lymphedema can provide a better understanding or new insights of the mechanisms underlying this debilitating condition.
Fulltext Cross-Cultural Adaptation of the Functional Assessment of Cancer Therapy-Breast (FACT-B) in Malaysian Breast Cancer Survivors

Md Yusof K, Mahmud R, Abdullah M, Avery-Kiejda KA, Rosli R

Asian Pac J Cancer Prev, 2021 Apr 01;22(4):1055-1061.
PMID: 33906296 DOI: 10.31557/APJCP.2021.22.4.1055

INTRODUCTION: The survival rate of female breast cancer survivors has been reported to be higher than other types of cancer in Malaysia. Nonetheless, breast cancer survivors face new challenges from unwanted side effects of treatment or management such as fatigue, psychological disturbance, or arm swelling, which can lead to the decline of quality of life (QOL). This study aims to adapt the Malay version of the Functional Assessment of Cancer Therapy-Breast (FACT-B) to evaluate the QOL and to test its reliability and validity in Malaysian breast cancer survivors.
METHODS: The Malay version of the FACT-B, with Disabilities of Arms, Shoulders and Hands (DASH), and Patient Health Questionnaire Anxiety-Depression Scale (PHQ-ADS) were distributed to female breast cancer survivors which were recruited on a voluntary basis, from cancer support groups based in selected states in Malaysia. Reliability was assessed based on internal consistency (Cronbach's α), whereas concurrent validity was examined by comparing domains in FACT-B with DASH and PHQ-ADS. Finally, total scores of each domain were analysed between lymphedema and without lymphedema groups for known-group validity.
RESULTS: A total of 113 breast cancer survivors agreed to participate (response rate = 100%) in the study. Our results showed that the Cronbach's α value for Malay FACT-B is 0.88, and each domain ranged from 0.62 to 0.88. A strong correlation was found between the physical well-being domain of FACT-B with DASH. Meanwhile, the breast cancer scale (BCS) displayed significant correlation with the instrument, Patient Health Questionnaire- Anxiety Depression Scale (PHQ-ADS), indicating that multiple factors including psychological distress were measured in the BCS domain. Furthermore, the instrument was able to detect differences in physical, functional and QOL between participants from lymphedema and without lymphedema groups.
CONCLUSION: The Malay version of the FACT-B demonstrated reliable properties and is effective in assessing QOL and can be applied in Malaysian breast cancer survivors.
Fulltext Evaluation of Circulating MicroRNAs and Adipokines in Breast Cancer Survivors with Arm Lymphedema

Yusof KM, Groen K, Rosli R, Abdullah M, Mahmud R, Avery-Kiejda KA

Int J Mol Sci, 2022 Sep 26;23(19).
PMID: 36232660 DOI: 10.3390/ijms231911359

Breast cancer-related lymphedema (BCRL) is a form of secondary lymphedema that is characterized by abnormal swelling of one or both arms due to the accumulation of lymph fluid in the interstitial tissue spaces, resulting from obstruction of the lymphatic vessels due to surgery insults, radiotherapy, or chemotherapy. Due to the multifactorial nature of this condition, the pathogenesis of secondary lymphedema remains unclear and the search for molecular factors associated with the condition is ongoing. This study aimed to identify serum microRNAs and adipokines associated with BCRL. Blood was collected from 113 breast cancer survivors and processed to obtain serum for small RNA-sequencing (BCRL vs. non-BCRL, n = 7 per group). MicroRNAs that were differentially expressed (fold change >1.5, p < 0.05) between lymphedema cases and those without lymphedema were further quantified in a validation cohort through quantitative reverse transcription PCR (BCRL n = 16, non-BCRL, n = 83). Leptin and adiponectin levels were measured in a combined cohort (BCRL n = 23, non-BCRL n = 90) using enzyme-linked immunosorbent assays. Two of the most significantly upregulated microRNAs, miR-199a-3p and miR-151a-3p, were strongly correlated with the onset of lymphedema and diabetes mellitus in the BCRL group. Leptin levels were higher in the BCRL cohort compared to the non-BCRL cohort (p < 0.05). A metabolic syndrome biomarker, the adiponectin/leptin ratio, was found to be lower in the BCRL group than in the non-BCRL group (median: 0.28 vs. 0.41, p < 0.05). Extensive studies on the mechanisms of the identified microRNAs and association of leptin with arm lymphedema may provide new insights on the potential biomarkers for lymphedema that should be followed up in a prospective cohort study.
Association of psychological distress with arm morbidity symptoms in breast cancer survivors: outcomes from the use of PHQ-9 and GAD-7 questionnaires

Yusof KM, Mohd Sidik S, Mahmud R, Abdullah M, Avery-Kiejda KA, Rosli R

Breast Cancer, 2023 Sep;30(5):810-819.
PMID: 37306933 DOI: 10.1007/s12282-023-01475-0

BACKGROUND: Although higher survival rates of breast cancer are achieved these days, breast cancer survivors are challenged with unwanted side effects from treatment or management that affect physical, functional, and psychological well-being of an individual. This study aimed to assess psychological distress status in Malaysian breast cancer survivors and factors that affected the condition.
METHODS: A cross-sectional study design was conducted on 162 breast cancer survivors from various breast cancer support groups in Malaysia. Psychological distress status was assessed based on depression and anxiety scores by applying the Malay version of Patient Health Questionnaire (PHQ-9) and General Anxiety Disorder (GAD-7). Both instruments were self-administered along with a set of questionnaires comprising demographic, medical history, quality of life, and upper extremity function assessment. Outcomes from the PHQ-9 and GAD-7 were analyzed for severity level of psychological distress, and its association with relevant variables, arm morbidity symptoms, as well as the duration of cancer survivorship.
RESULTS: The univariate analysis showed that breast cancer survivors with arm morbidities after breast surgery had a higher score of depression (5.0 vs 4.0, p = 0.011) and anxiety (3.0 vs 1.0, p = 0.026) than those who did not. Besides that, receiving fewer post-rehabilitation treatments (p = 0.049) and having a family history of cancer (p = 0.022) were correlated with higher anxiety level. The level of depression and anxiety was inversely proportionate with quality of life and positively correlated with greater disability of the arm function (p
Fulltext Assessment of Potential Risk Factors and Skin Ultrasound Presentation Associated with Breast Cancer-Related Lymphedema in Long-Term Breast Cancer Survivors

Yusof KM, Avery-Kiejda KA, Ahmad Suhaimi S, Ahmad Zamri N, Rusli MEF, Mahmud R, et al.

Diagnostics (Basel), 2021 Jul 21;11(8).
PMID: 34441238 DOI: 10.3390/diagnostics11081303

Breast cancer has been reported to have the highest survival rate among various cancers. However, breast cancer survivors face several challenges following breast cancer treatment including breast cancer-related lymphedema (BCRL), sexual dysfunction, and psychological distress. This study aimed to investigate the potential risk factors of BCRL in long term breast cancer survivors. A total of 160 female breast cancer subjects were recruited on a voluntary basis and arm lymphedema was assessed through self-reporting of diagnosis, arm circumference measurement, and ultrasound examination. A total of 33/160 or 20.5% of the women developed BCRL with significantly higher scores for upper extremity disability (37.14 ± 18.90 vs. 20.08 ± 15.29, p < 0.001) and a lower score for quality of life (103.91 ± 21.80 vs. 115.49 ± 16.80, p = 0.009) as compared to non-lymphedema cases. Univariate analysis revealed that multiple surgeries (OR = 5.70, 95% CI: 1.21-26.8, p < 0.001), axillary lymph nodes excision (>10) (OR = 2.83, 95% CI: 0.94-8.11, p = 0.047), being overweight (≥25 kg/m2) (OR = 2.57, 95% CI: 1.04 - 6.38, p = 0.036), received fewer post-surgery rehabilitation treatment (OR = 2.37, 95% CI: 1.05-5.39, p = 0.036) and hypertension (OR = 2.38, 95% CI: 1.01-5.62, p = 0.043) were associated with an increased risk of BCRL. Meanwhile, multivariate analysis showed that multiple surgeries remained significant and elevated the likelihood of BCRL (OR = 5.83, 95% CI: 1.14-29.78, p = 0.034). Arm swelling was more prominent in the forearm area demonstrated by the highest difference of arm circumference measurement when compared to the upper arm (2.07 ± 2.48 vs. 1.34 ± 1.91 cm, p < 0.001). The total of skinfold thickness of the affected forearm was also significantly higher than the unaffected arms (p < 0.05) as evidenced by the ultrasound examination. The continuous search for risk factors in specific populations may facilitate the development of a standardized method to reduce the occurrence of BCRL and provide better management for breast cancer patients.