Intercontinental Comparison of Immunohistochemical Subtypes Among Individuals With Breast Cancer in South-East Asia and South America: A Scoping Systematic Review and Meta-Analysis of Observational Studies.

Background: Breast cancer (BC) remains a significant global concern, particularly among developing countries in South-East Asia (SEA) and South America (SA). The socioeconomic burdens of oncologic care in those countries were often originated from limited accessibility on attainable therapeutic options and reliability on identifying essential information of cancer cells, i.e., immunohistochemical (IHC) subtyping to determine suitable approaches. The triple-negative breast cancer (TNBC) is among the most aggressive category in breast malignancy, therefore, requiring more specific molecular pathway blocking to exhaust the cells. However, large-scale epidemiological investigation on its rate among BC remains unavailable to date. This study aimed to describe the prevalence of TNBC in the SEA and SA continents since it may guide the future direction of oncologic research and trials. Methods: This review focuses on observational studies from the SEA and SA continents from the last decade. Each study represents its country or cities, period of observation, population size, and the TNBC-BC rate as the main outcomes. Therefore, we may also limit the reporting bias originated from same-patient data on the specific occasions. The analysis will be derived to SEA-SA comparison, plus SEA/SA-specific session as processed in Comprehensive Meta-Analysis (CMA) version 3.0. The statistical analysis will be performed in random effects model (REM) within 95% confidence interval (CI). Results: From 46 studies included in the final analysis with a total enlisted population of 34,346 unique individuals with BC, the TNBC rate was higher in the SEA compared to the SA region (19.3% vs. 15.7%; P < 0.05 in 95% CI), with the highest prevalence observed in Vietnam (22.4%) and Peru (17.8%), if it was restricted on countries with two or more studies. Interestingly, both Laos and Argentina possessed significant differences compared to other countries within their respective continents, with the highest and lowest TNBC rates (P < 0.05). Conclusions: The IHC characteristics in SEA differ from those in the SA continent as mainly represented by TNBC prevalence, possibly shaping the course of future trials in the respective region based on IHC expressivity status.

Sociodemographic disparities associated with advanced stages and distant metastatic breast cancers at diagnosis in Indonesia: a cross-sectional study.

Background: The global health burden of breast cancer is increasing with 5-year survival rates being much shorter in low-income and middle-income countries. Sociodemographic and clinical disparities in early cancer detection affect long-term outcome. Methods: The authors compared social, demographic, and pathological characteristics associated with metastatic and late stages of breast cancer diagnosis using data collected from a special registry developed by Perhimpunan Bedah Onkologi Indonesia (PERABOI) in 2015. Results: Of 4959 patients recruited in this study, 995 women (20.1%) were diagnosed with metastatic breast cancer. Lower education status and living in rural areas were significantly associated with Stage IV at diagnosis [odds ratio (OR)=1.256, 95% CI=1.093-1.445, P=0.001; and OR=1.197, 95% CI=1.042-1.377, P=0.012; respectively). Main complaints other than lump (ulceration, breast pain, and discharge) and occupation as a housewife were also associated with the presentation of metastatic diseases (OR=2.598, 95% CI=2.538-3.448, P<0.001 and OR=1.264, 95% CI=1.056-1.567, P=0.030, respectively). Having lower education and living outside Java and Bali islands were associated with the diagnosis of late-stage breast cancers (OR=1.908, 95% CI=1.629-2.232, P<0.001 and OR=3.039, 95% CI=2.238-4.126, P<0.001; respectively). A higher proportion of breast cancer patients were relatively younger with bigger tumour size, positive axillary nodal involvement, and more frequent Human epidermal growth factor receptor 2 overexpression. Conclusion: The authors identified sociodemographic disparities in the metastatic and late-stage diagnosis of breast cancers among Indonesian women. The subsequent action is required to reduce disparities faced by women with lower social and educational levels for early diagnosis and better healthcare access.

Incidence of COVID-19 in cancer patients in a teaching hospital faculty of medicine, in Medan, Indonesia.

Objective: The aim of this study was to determine the incidence of COVID-19 in cancer patients in the Teaching Hospital Faculty of Medicine, Universitas Sumatera Utara, Medan, Indonesia. Methods: This descriptive study was conducted at H. Adam Malik Hospital and USU General Hospital, Medan, from March 2020 to August 2021. The main inclusion criteria for the participants were COVID-19 and confirmed cancer. A total sampling technique was used. Results: Among the 3308 COVID-19 patients studied, the mean age was 44 years, ranging from 1 day to 92 years. Male participants were slightly more prevalent (51.8% vs 48.2%). Twenty-five of these patients (0.75%) had both COVID-19 and cancer, and thus met the inclusion criteria. The most common types of cancer were leukemia (20.0%), breast cancer (20.0%), ovarian cancer (16.0%), lymphoma (8.0%), and osteosarcoma (8.0%). The proportions of patients with mild, moderate, and severe degrees of COVID-19 where 48.0%, 24.0%, and 28.0%, respectively. Seven patients required intensive care, and five died. Conclusion: The incidence of COVID-19 in patients with cancer was relatively low. Nevertheless, almost a third of cancer patients with COVID-19 developed severe disease and had poor prognoses. Vaccination among cancer patients is important to protect them from poor outcomes if exposed to COVID-19.

High platelet count as a predicting factor of histopathological grading among invasive breast cancer individuals: a single centre experience from Indonesia.

Background: The interplay between platelet and breast cancer (BC) pathology may have the potential to represent the malignancy status itself, evidently through predicting the histopathological results of each individual. This study aims to elaborate on the diagnostic value of a higher platelet count or thrombocytosis and the histopathological status of invasive BC in our center, explaining its correlation from the diagnostic perspective. Materials and methods: A retrospective cohort study was conducted using breast cancer patients' medical records from January to March 2022 at the Haji Adam Malik General Hospital, Medan, Indonesia. The patients' histopathological records and complete blood counts were collected from the hospital's medical records. We analyzed the risk analysis model in receiver operator characteristics analysis and diagnostic parameters, e.g., sensitivity and specificity, which we analyzed further using the correlation test to fulfill our objective. Result: The mean age of the 69 subjects we included, in the final analysis, was 49.0 ± 11.1 years old, of whom 35 (50.7%) individuals were histologically confirmed to be high-grade BC. By applying the cut-off value of 299 × 103 cells/µL, the diagnostic value of a platelet count was 60.0 % in sensitivity, 61.8% in specificity, and an area under the curve (AUC) value of 0.597 (0.462-0.732) in 95% confidence interval (CI) as presented by receiver operating characteristic (ROC). We also found that a higher platelet count may also predict the diagnosis of invasive BC by 2.423 times as shown in the odd ratio (OR) analysis. Conclusion: Platelet counts investigation is an applicable yet potential hematological biomarker to predict invasive BC histopathological grading.

Combination Curcuma longa and Phyllanthus niruri Extract Potentiate Antiproliferative in Triple Negative Breast Cancer MDAMB-231 Cells.

BACKGROUND: Triple negative breast cancer cells (TNBC) are a small part of cancer-inducing cells in breast cancer, which are characterized by high metastatic and self-renewal. Self-renewal has the ability to renew itself and loses control of proliferation. Curcuma longa extract (CL) and Phyllanthus niruri extract (PN) known to have anti-proliferative effects on cancer cells. However, the effects of combination CL and PN on TNBC proliferation still unclear. AIMS: This study aimed to evaluate the antiproliferative effects of the combination CL and PN on TNBC MDAMB-231 and attempted to elucidate the underlying molecular mechanisms. SUBJECTS AND METHODS: The dried rhizomes of Curcuma longa and the herbs of Phyllanthus niruri were macerated with ethanol for 72 h.The antiproliferative and synergistic effects of combination CL and PN were investigated using 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide (MTT) assay. Combination index values were calculated using CompuSyn (ComboSyn, Inc, Paramus, NJ). The cell cycle and apoptosis assay were determined by propidium iodide (PI) and PI-AnnexinV assay under flow cytometer, respectively. The intracellular ROS levels were evaluated using 2',7'-Dichlorodihydrofluorescein diacetate (DCFDA) assay. The mRNA expressions of proliferation-related genes in the cells were determined using bioinformatic assay. RESULTS: The CL and PN single treatment caused a potent and dose-dependent decrease in the percentage of viable cells with IC50 value of 13 µg/mL and 45 µg/mL for 24 h, respectively. The combination index values of the different combinations ranged from 0.08 - 0.90, indicating slightly strong to very strong synergistic effects. The combination of CL and PN also remarkably induced the S- and G2/M-phases cell cycle arrest that leading to apoptosis induction. Furthermore, the combination of CL and PN treatment induced the intracellular reactive oxygen species (ROS) levels. Mechanistically, the AKT1, EP300, STAT3 and EGFR signaling as potential targets of combination CL and PN in antiproliferation and antimetastatic of TNBC. CONCLUSIONS: The combination of CL and PN exerted promising antiproliferative effects in TNBC. Therefore, CL and PN may be considered a potential source for the development of potent anticancer drugs for breast cancer treatment.

Tamoxifen-associated Endometrial Cancer after Treatment in Young Premenopausal Women with Breast Cancer: A Case Report.

Background: Tamoxifen has been successfully administered as adjunctive therapy for breast cancer. However, the effect of tamoxifen as an estrogen agonist and antagonist can cause pathological changes in the uterus. The agonist effect may stimulate endometrial proliferation leading to endometrial polyps, hyperplasia, and, rarely, endometrial cancer. Objective: We present the case of tamoxifen-treated breast cancer case to better understand one of the most serious consequences, endometrial cancer. Case presentation: A 37-year-old woman came to our centre with complaints of abnormal vaginal bleeding. She has diagnosed with grade I infiltrative ductal carcinoma in 2018, with primary complaints of right breast mass and axillary lymphadenopathy. During this period, adjuvant chemotherapy was given tamoxifen 20 mg once daily. There were no complaints or relapses at a six-month follow-up over three years. In the fourth year, the patient complained of vaginal bleeding. A vaginal biopsy was performed, and the results showed low-grade endometrioid-type endometrial carcinoma. Total hysterectomy and bilateral salpingo-oophorectomy were performed with the resultant mass of up to half of the myometrial lining with metastatic negative parallax lymph nodes. Conclusion: Following tamoxifen therapy, endometrial cancer is more likely to occur in patients. Patients who experience irregular vaginal hemorrhage should have hysteroscopy or uterine ultrasound performed, and if the cause is unknown, a biopsy should be performed.

The PD-L1 Expression Among Triple-Negative Breast Cancer Patients in Universitas Sumatera Utara Teaching Hospital, Indonesia.

Background: The emerging role of precision medicine among in oncologic science is a potentially explorable area to solve long-standing implication of triple-negative breast cancer (TNBC)'s management, especially by identifying programmed cell death ligand-1 (PD-L1) in its population. Objective: To describe the PD-L1's expression among TNBC populations in our Indonesia-based centers. Methods: This descriptive study was conducted in the teaching hospitals of Universitas Sumatera Utara ranging from April 2019 to July 2020. Our investigation encompassed female individuals with histopathologically confirmed TNBC and complete medical record data, especially the status of PD-L1 expression to be reported in this study. We use Daco 22C3 antibodies to confirm the latter protein immunohistochemical positivity after thorough specimen preparation and staining. Results: This study included 60 females with TNBC of which 40 participants were issued in the final report. Our populations were dominated by middle-aged individuals (41-50 years old; 45%), and remarkable presentation of LVSI, angioinvasion, or lymph-node metastatic status. In PD-L1 expression status, our study reported that 45.0% patients were confirmed with confirmed PD-L1 positivity. Conclusion: PD-L1 expression among TNBC patients is concordant with the global report hence anti-PD-1-based treatment trial in Asia or even Indonesia region should be considered.

The Combination of CDK 4/6 Inhibitors plus Endocrine Treatment versus Endocrine Treatment Alone in Hormone-receptor (HR)-Positive breast Cancer: a Systematic Review and Meta-analysis.

Background: The identification of the novel targeted therapy i.e., cyclin-dependent kinases (CDKs) 4/6 inhibitor as combined with the endocrine regimen revealed a considerable capability to increase the managements' effectivity of hormone-receptor-positive (HR+) and HER2- breast cancer (BC). Objective: This study aims to compare the latter combination strategies versus hormonal therapy alone to determine its applicability in the treatment of HR+/HER2- BC. Methods: We established the review based on the clinical trials as collected from several scientific databases from January 2011 to April 2021. RevMan 5.4 was utilized in statistical analysis and risk of bias (RoB) measurement. 5110 participants from 9 different trials were included in this review with similar baseline characteristics. Results: According to our analysis of the intention-to-treat (ITT) group, CDK 4/6 inhibitor arms exhibited better overall response rate (ORR) as indicated by the relative risk (RR) (randomized-effect model (REM), 1.59 [1.37, 1.86]; 95% confidence interval (CI); P <0.00001) and higher clinical benefit rate (CBR) (RR, 1.22 [1.13, 1.32]; 95% CI; REM; P <0.00001). The combination regiment also proved to be effective in reducing the rate of progressive disease (PD) in the ITT group (RR 0.46 [0.39, 0.54]; CI 95%; FEM; P <0.00001. Although the rate of adverse effects especially the hematological reactions was significantly lower in the endocrine alone arm, other system reactions were fairly comparable. Conclusion: The introduction of CDK 4/6 inhibitor to the endocrine-based regiment is proved beneficial to patients with HR+/HER2- BC even though the most recommended anti-hormonal to be combined remains questionable.

D-dimer as a Predictive Factor of Axillary Lymph Node Metastases in Operable Breast Cancer Patients in the Teaching Hospital of Universitas Sumatera Utara.

Background: Axillary lymph node (ALN) involvement in breast cancer (BC) is considered to be a significant factor in determining the diseases' extent at the moment. The spreading capacity of cancerous cells may linearly correlate with its activity level, which in turn alter the coagulation function as commonly represented by fibrin degradation biomarker i.e., D-dimer. Although ALN metastatic status is eventually should be perceptible in physical examinations or other diagnostic modalities, an additional marker to estimate the lymph node extent should be considered in the pre-operative sessions. Objective: To provide the correlation between elevated D-dimer level and ALN metastatic status positivity among BC patients. Methods: This cross-sectional study was conducted at the Teaching Hospital of Universitas Sumatera Utara by retrieving outpatients' medical records from June 2018 to January 2019, encompassing 111 female patients. The ALN involvement status was recorded along with plasma D-dimer level in which the value of 500 ng/mL was considered to be elevated. Results: From the 102 eligible participants, 47.1% and 70.6% were confirmed with elevated D-dimer level and ALN involved respectively. Further analysis of those variables demonstrated a considerable diagnostic performance for sensitivity (64.4%), specificity (79.1%), PPV (80.9%), NPV (61.8%), accuracy (70.6%) and statistically significant results (P = .001). Conclusion: Elevated D-dimer level may be influenced by cancerous spread capacity in the lymphatic system, as it also eventually correlated with coagulation system dysregulation. Therefore, it is suggested that the role of D-dimer measurement is recommended to be explored further in BC diagnostic workup.

Regulation of p53 and survivin by Curcuma longa extract to caspase-3 dependent apoptosis in triple negative breast cancer cells.

Aim Triple negative breast cancer cells (TNBC) are the population of breast cancer cells that are responsible for cancer recurrence and apoptosis resistance. Unfortunately, current therapies have limited efficacy to TNBC population due to apoptosis resistance and chemoresistance. Tumour suppressor p53 and survivin are primary targets for TNBC therapy. Consequently, a search for a natural compound which targets p53 and survivin is needed to further advance TNBC treatment. Curcuma longa extract (CL), a natural compound induces apoptosis in several cancer cells by targeting various molecules and possess fewer side effects. However, a possible potential of CL as p53- and survivin modulating agent in TNBC cells has not been investigated. Methods MDAMB-231 cells were treated with several concentration of CL, after which, viability, p53 gene expression, surviving protein expression, and caspase-3 protein expression were evaluated. Results After 24-h treatment, CL possessed cytotoxic effect with IC50 value of 13 µg/mL. Treatment with 1.625, 3.25, 6.5, and 13 µg/mL of CL resulted in 2.70-25.80% increase in caspase-3 expression levels followed by 94.60 - 21.60% decrease in survivin protein levels. CL induced remarkably p53 gene expression ratio up to 5-fold at 13 µg/mL. Survivin protein levels were inversely proportional to p53 accumulation levels. Low survivin protein levels combined with high levels of p53 accumulation were correlated to higher apoptotic rates. Conclusion p53 and survivin as molecular targets of CL contribute to caspase-3-dependent apoptosis in TNBC cells and this compound represents an attractive p53- and survivin modulating agent in TNBC.

The Potential Use of Propolis as an Adjunctive Therapy in Breast Cancers.

Propolis is a resinous beehive product that has a wide range of biological activities, namely antimicrobial, antioxidant, and anti-inflammatory properties. Propolis is collected by the bees from plant resin and exudates to protect hives and maintain hive homeostasis. The aim of the present systematic scoping review is to explore the potential and suitability of propolis as an adjunctive treatment in breast cancers, based on the latest available experimental evidence (2012-2021). After applying the exclusion criteria, a total of 83 research publications were identified and retrieved from Scopus, Web of Science, and Pubmed. Several relevant key themes identified from the included studies were cytotoxicity, synergistic/combination treatment, improvement in bioavailability, human clinical trials, and others. A majority of the studies identified were still in the in vitro and in vivo stages. Nonetheless, we managed to identify 4 human clinical trials that demonstrated the successful use of propolis in alleviating side effects of chemotherapy and radiotherapy while increasing the quality of life of breast cancer patients, with minimal adverse effects. In conclusion, propolis, as an adjunctive treatment, may have therapeutic benefits in alleviating symptoms related to breast cancers. However, further clinical trials, preferably with higher number of participants/subjects/patients, are urgently needed.

Role of Hormonal Receptor in Predicting Sentinel Lymph Node Metastasis in Early Breast Cancer.

Background: Sentinel lymph node biopsy is one of the minimally invasive techniques that can confirm the presence of metastasis of regional lymph nodes in cancer. Sentinel lymph node biopsy can be done with a lymph mapping technique using blue-dye, radiotracer, or a combination of both. In developing countries, sentinel lymph node biopsy is often done with a single agent, which is the blue dye. The limitation of conducting SLNB in Indonesia is the availability of patent blue dye and radioisotope tracer. To overcome that, a hormonal receptor is expected to aid in predicting sentinel lymph node metastasis. Objective: The aim of this study was to investigate the hormonal receptor as a prognostic factor of sentinel lymph node metastasis in breast cancer. Methods: This study was conducted in Universitas Sumatera Utara Teaching Hospital with the acknowledgment from the Ethics Committee of the respected hospital by the number of 116/KEP/USU/2020. Total of 51 patients participated in this research. Results: Statistically, the p-value in each immunohistochemistry group is > 0.05 in all ER (+) / PR (+); ER (+) / PR (-); ER (-) / PR (+) groups. This shows that there is no significant relationship between hormonal receptors on sentinel lymph node metastases. Conclusion: The statistical evaluation showed that there is no significant correlation between the hormonal receptor and sentinel lymph node metastasis (p>0.05), but is found clinically significant. Therefore, hormonal receptors should be considered as a predicting factor for sentinel lymph node metastasis.

Cat-Scratch Lymphadenitis Presenting with Right Upper Arm and Axillary Masses: a Case Report Mimicking Lymphoma and Potential Diagnostic Pitfall.

Background: Cat scratch disease (CSD) is an infectious disease caused by a cat's scratch, hard enough to break the skin's surface. Clinical manifestations include inflammatory lymphadenopathy and papular lesions at the site of the injury. However, it may be mistaken for a neoplasm-related process e.g., lymphoma due to its similar clinical presentation. Objective: To report a CSD case in an Indonesian male presenting with mass-like symptoms in the oncologic ward of our center. Case report: A 24-year-old male presented with painful and swelling masses in the right upper arm and right armpit for the last 4 months, enlarged progressively, and feverish for two days. Our initial differential diagnosis was lymphoma by history and routine physical examination, however. The patient reported a history of sleeping with his cat and recently experiencing a cat bite. We conducted the ultrasonography and lymph node biopsy to establish the final diagnosis and it was revealed to be related to CSD. The patient was treated with lymphadenectomy and azithromycin 500 mg bd for 7 days. The patient was completely treated with no additional complaints after two weeks of follow-up. Conclusion: The differential diagnosis for CSD is relatively broad, including active infection, an ongoing inflammatory process, or a metastatic process; hence, thorough diagnostic approaches should be made in approaching CSD cases to avoid the pitfall or mistreatment in advance.

Accuracy of Methylene Blue Test as Single Technique for Sentinel Lymph Node Biopsy in Early Stages Breast Cancer.

AIM: Sentinel Lymph Node Biopsy (SLNB) establishes as a gold standard for diagnostic lymph node involvement in early breast cancer. Most of the developed country does not have radiotracer and nuclear medicine facilities. Unless in Indonesia there is Methylene Blue as an alternative agent for SLNB. This study measure accuracy of sentinel lymph node biopsy as a single technique using the Methylene Blue test. METHODS: This cross-sectional study enrolled 60 female patients with breast cancer stage I-II. We performed SNB using 2-5 cc of 1% Methylene-blue dye (MBD) injected to periareolar tissue and proceeded with axillary lymph nodes dissection (ALND). The histopathology results of sentinel nodes (SNs) and axillary lymph nodes (ALNs) analyze for diagnostic value assessments. RESULTS: The identification rate of SN was 97.62 %, and the median number of identified SNs was 4 (2-7). Sentinel node metastasis was found in (19/60) % cases and % of them were macrometastases. The sensitivity and specificity of MBD were 91.67% and 96.67% respectively. The negative predictive value (NPV) of SNs to predict axillary metastasis was 96.67% (95% CI, 81-99%). CONCLUSION: Injection of 1% MBD as a single technique in breast cancer SNB has a favorable identification rate and predictive value.

Mesenchymal Stem Cells Suppress TGF-ß Release to Decrease α-SMA Expression in Ameliorating CCl4-Induced Liver Fibrosis.

INTRODUCTION: Liver fibrosis (LF) is the excessive deposition of extracellular matrix (ECM), produced by overactivated hepatic stellate cells, following prolonged transforming growth factor-ß (TGF-ß) stimulation. The ability of mesenchymal stem cells (MSCs) to improve LF has been reported. However, the mechanisms of MSCs to ameliorate LF through suppressing TGF-ß and α-smooth muscle actin (α-SMA) remains unclear. AIM: To investigate the effects of MSCs treatment on suppressing TGF-ß levels and decreasing α-SMA expression in an LF model. METHODS: In this study, wenty-four male Wistar rats were injected intraperitoneal (IP) with carbon tetrachloride (CCL4), twice weekly, for eight weeks, to induce LF. Rats were randomly assigned to six groups: Sham, Control, Sham-lo, Sham-hi, and MSC-treated groups, at doses of 1 x 106 (T1) and 2x106 (T2) cells. TGF-ß levels were analyzed by enzyme-linked immunosorbent assay (ELISA), whereas α-SMA expression was determined by immunohistochemistry staining. RESULTS: MSCs decreased the expression of TGF-ß in T1 and T2 groups on day 3 and 14. The T2 group showed lower TGF-ß levels than that in the T1 group. This finding was in line with the observed decrease in α-SMA expression and the number of collagen. CONCLUSION: MSCs treatment ameliorated LF by suppressing TGF-ß production, leading to decreased α-SMA expression in a CCL4-induced LF animal model.