Stromal Tumor Infiltrating Lymphocytes (sTILs) Were Associated with a Higher Grade and a Lower Stage of Indonesian Triple Negative Breast Cancers.

OBJECTIVE: This study aimed to investigate the association of sTILs with clinicopathological parameters and overall survival (OS) in patients with triple negative breast cancer (TNBC). METHODS: One hundred and twenty-five paraffin embedded tissue of patients with TNBC, collected from Dr. Sardjito General Hospital Yogyakarta, Indonesia, between 2008-2017, were used in this study. Stromal TILs were examined from hematoxylin and eosin (H&E)-stained samples, and classified as either low or high score using 20% cut-off. Analysis of the association of sTILs with clinicopathological parameters, relative risk (RR) and OS used 95% confidence interval (CI) with significance set as p<0.05. RESULTS: The higher proportion of TNBC patients in this study were ≥40 years old (83.3%), high tumor grade (68%), tumor stage >IIIa (56%), alive (50.4%), and with low sTILs (54.4%). The results showed significant association between sTILs and a higher grade or a lower stage of tumor (B = 0.259, 95%CI = 0.090-0.468, p = 0.004 and B = -0.255, 95%CI = -0.433 - -0.080, p = 0.005, respectively ). Meanwhile sTILs were not associated with age at diagnosis (B = 0.027, 95%CI = -0.193 - 0.264  p = 0.758 nor 3-year OS of patients (HR = 0.342, 95%CI = 0.41 - 1.43  p = 0.402). CONCLUSION: The results indicate that sTILs may serve as an additional pathological parameter for TNBC.

Survival outcome and prognostic factors of patients with nasopharyngeal cancer in Yogyakarta, Indonesia: A hospital-based retrospective study.

PURPOSE: This study aimed to determine the survival outcome and prognostic factors of patients with nasopharyngeal cancer accessing treatment in Yogyakarta, Indonesia. METHODS: Data on 759 patients with NPC diagnosed from 2007 to 2016 at Dr Sardjito General Hospital were included. Potential prognostic variables included sociodemographic, clinicopathology and treatment parameters. Multivariable analyses were implemented using semi-parametric Cox proportional hazards modelling and fully parametric survival analysis. RESULTS: The median time of observation was 14.39 months. In the whole cohort the median observed survival was 31.08 months. In the univariable analysis, age, education status, insurance type, BMI, ECOG index, stage and treatment strategy had an impact on overall survival (OS) (p values <0.01). Semi-parametric multivariable analyses with stage stratification showed that education status, ECOG index, and treatment modality were independent prognostic factors for OS (p values <0.05). In the fully parametric models age, education status, ECOG index, stage, and treatment modality were independent prognostic factors for OS (p values <0.05). For both multivariable analyses, all treatment strategies were associated with a reduced hazard (semi-parametric models, p values <0.05) and a better OS (parametric models, p values <0.05) compared with no treatment. Furthermore, compared with radiation alone or chemotherapy alone, a combination of chemotherapy and radiation either in a form of concurrent chemoradiotherapy (CCRT), sequential chemotherapy and radiation, or induction chemotherapy followed by CCRT demonstrated a reduced hazard (hazard ratio/HR 0.226, 95% confidence interval/CI 0.089-0.363, and HR 0.390, 95%CI 0.260-0.519) and a better OS (time ratio/TR 3.108, 95%CI 1.274-4.942 and TR 2.531, 95%CI 1.829-3.233) (p values < 0.01). CONCLUSIONS: Median OS for the cohort was low compared to those reported in both endemic and non-endemic regions. By combining the findings of multivariable analyses, we showed that age, education status, ECOG index, stage and first treatment modality were independent predictors for the OS.

Overexpression of Programmed Death-Ligand 1 Receptor mRNA as an Independent Negative Prognostic Factor for Triple Negative Breast Cancer.

BACKGROUND: Triple negative breast cancer (TNBC) (represents roughly 25% of all breast cancers in Yogyakarta) still has the worst survival compared to other breast cancer subtypes. Results from recent studies have shown that inhibition of programmed death-ligand 1 receptor (PD-L1) in TNBC patients is associated with better prognosis. Currently, data on PD-L1 expression and its prognostic value in Indonesian TNBC patients are still relatively unknown. This study aimed to investigate the expression of PD-L1 in Indonesian TNBC patients as preliminary proof to support PD-L1 inhibitor as a possible treatment option near in the future. METHODS: We retrospectively included stage I-III TNBC patients diagnosed between 2014 and 2017 in Dr. Sardjito Hospital, Yogyakarta, Indonesia. Clinical variables were collected from medical record. Paraffin blocks of biopsy specimen were retrieved to examine mRNA level of PD-L1. RESULTS: We included 48 subjects with mean age of 51.09 years and mean body mass index (BMI) of 24.58. The 3-year overall survival (OS) was 58.3%. Overexpression of PD-L1 mRNA in TNBC patients is associated with worse prognosis (P < 0.01). There were no statistically significant associations between PD-L1 mRNA expression and any of the clinicopathologic variables examined. CONCLUSIONS: In summary, PD-L1 mRNA overexpression is associated with worse survival in Indonesian TNBC patients, independent of other established risk factors. PD-L1 mRNA is expressed in all of our samples, presenting as a feasible alternative or complementary method in deciding which patient might benefit from receiving PD-L1 inhibitor.

Complete Remission of Relapsed Hodgkin's Lymphoma following Brentuximab Vedotin and Gemcitabine Combination Therapy with Severe Hypotension as Possible Treatment-Related Adverse Event: A Case Report.

A 40-year-old Asian female with heavily treated relapsed Hodgkin's lymphoma showed complete remission (CR) after receiving 8 cycles of brentuximab vedotin (BV) in combination with gemcitabine as 4th line treatment. The patient remained in CR at the 18-month post-treatment follow-up. She developed severe hypotension (50/36 mm Hg) with upper and lower limb petechiae and edema after the addition of gemcitabine on the 6th cycle of BV. This adverse event resolved after 3 days of treatment with vasopressor and high-dose corticosteroid. The addition of dexamethasone for the subsequent 2 cycles successfully prevented this adverse event from recurring.

Effects of Omega-3 Supplementation on Ki-67 and VEGF Expression Levels and Clinical Outcomes of Locally Advanced Breast Cancer Patients Treated with Neoadjuvant CAF Chemotherapy: A Randomized Controlled Trial Report

Background: Omega-3 is a polyunsaturated fatty acid with an ability to regulate cell proliferation and apoptosis through interaction with inflammatory mediators. The potential additional beneficial effects of Omega-3 on chemotherapy patients with breast cancer is not yet completely revealed. Methods: A double-blind randomized control trial (RCT) involving a total of 48 locally advanced breast cancer patients was conducted. Ki-67 and VEGF expressions, as well as overall survival of patients receiving neoadjuvant cyclophosphamide-doxorubicin-5'fluorouracyl (CAF) chemotherapy plus Omega-3 (intervention group) or placebo (control group), were compared. Kaplan-Meier curve and Cox-regression tests were used to assess conditional disease-free survival (DFS) and overall survival (OS) between the two groups. Results: Decreased Ki-67 expression was observed in the intervention group compared to control (42.4±4.8 versus 39.2±5.3; T-test p=0.032). Decreased Ki-67 expression was observed in intervention compared to control group (42.4±4.8 versus 39.2±5.3; T-test p=0.032). Decreased VEGF expression was also seen in the intervention group compared to control (32.7±5.2 versus 29.5±5.4; T-test p=0.041). VEGF expression positively correlated with Ki-67 expression (Spearman's test p<0.001, R2=0.541). Overall survival in the intervention group was significantly longer in comparison to the control group (mean survival: 30.9 ± 3.71 versus 25.9 ± 3.6 weeks, Mantel-Cox test p=0.048; HR=0.411, 95%CI: 0.201-0.840). Disease-free survival was significantly longer in the intervention group compared to the control group (mean survival: 28.5 ± 3.3 versus 23.7 ± 3.6, respectively; Mantel-Cox test p=0.044, HR= 0.439, 95%CI: 0.222-0.869). Conclusion: Omega-3 fatty acid supplementation improved overall survival and progression-free survival of locally advanced breast cancer treated with CAF neoadjuvant chemotherapy and mastectomy.

The Tendency of Having MSH2 and MSH6 Microsatellite Instability among Clinicopathological Features in Patients with Colorectal Cancer

Objective: This study aimed to identify micro-satellite instability (MSI) based on the expression of MMRp (MSH2 and MSH6) and to evaluate the association of MSI and with clinicopathological features in patients with colorectal cancer (CRC). Methods: MMRp expression in 80 tissue samples from patients with adenocarcinoma CRC were evaluated by using anti-MSH2 and -MSH6 antibodies. Loss of MSH2 and/or MSH6 expression was stated as MSI. The association between MSI status and clinicopathological features were analyzed by using binary logistic regression (p<0.05). Results: The frequency of MSI in patients with CRC varied, corresponding to 8.3% (6/72) MSH2 MSI, 36.1% (26/72) MSH6 MSI and 6.9% (5/72) MSH2-MSH6 MSI. Male patients (OR=1.98), with tumor located in colon (OR=1.47) and late stage tumor (OR=1.48) have a tendency of having MSH2 MSI. Male patients (OR=1.4), with tumor located in colon (OR=2.53) and poor tumor differentiation (OR=3.02) have a tendency to encounter MSH6 MSI. Male patients (OR=4.93) with late stage tumor (OR=1.69) have a tendency of having MSH2-MSH6 MSI. Conclusion: Patients more likely to have MSH2 MSI are males, and/or having tumor located in colon, and /or having late stage tumor. Patients more likely to have MSH6 MSI are males, and/or having tumor located in colon, and/or having tumor with poor differentiation. Patients who have greater tendency to have MSH2 and MSH6 MSI are males, and/or having late stage tumor.

Mediastinal Ectopic Pancreas with Abundant Endocrine Cells Coexisting with Mediastinal Cyst and Thymic Hyperplasia.

Mediastinal ectopic pancreas is a rare condition with only 28 cases reported in the literature. Here we report a 21-year-old female patient who presented with dyspnea and intermittent severe chest pain of 7 years' duration. Computerized tomography scan (CT-scan) of the chest revealed a mediastinal cyst. The cyst was resected and it demonstrated on histopathological examination the presence of pancreatic tissue with increased number of islets of Langerhans, coexistent with mediastinal cyst and thymic hyperplasia. We made a review of all previously reported cases of this entity.

Upregulation of Endothelin-1/Endothelin A Receptor Expression Correlates with Heparanase Expression in Ovarian Carcinoma.

BACKGROUND: Heparanase and endothelin-1/endothelin A receptor (ET-1/ETAR) expressions increase in cancer. This condition enhances tumor progression and correlates with poor survival. Limited data are documented regarding the role of heparanase and ET-1/ETAR in epithelial ovarian cancer (EOC). We sought to characterize the correlation between heparanase and ET-1/ETAR in EOC. METHODS: Thirty patients with benign and malignant ovarian neoplasms were recruited in this study. Neoplasm subtypes were diagnosed by pathologists. RNA extraction was done in fresh frozen neoplasms while immunohistochemical (IHC) staining was done on ETAR, heparanase, and proliferation (Ki-67 antigen) in paraffin sections. Reverse transcriptase PCR was done to quantify the expression of preproET-1 (ppET-1), ETAR, and heparanase. ETAR and heparanase histoscores were done based on IHC staining. The Independent Samples t Test, ANOVA, and correlations were used for statistical analysis. RESULTS: Heparanase and ETAR histoscores, ppET-1 and ETAR mRNA levels, and Ki-67 were significantly higher in the group with EOC than in the benign or borderline group, regardless of the histopathological types. The heparanase histoscore correlated with the ETAR histoscore (r=0.484, P=0.007) and the ETAR mRNA level (r=0.551, P=0.003). The level of ppET-1 mRNA correlated with both ETAR mRNA level and ETAR histoscore (r=0.603, P=0.001 and r=0.455, P=028, respectively). The ovarian neoplasms with high ppET-1 mRNA levels also tended to have high heparanase mRNA levels; however, the correlation was weak (r=0.354, P=0.07). Ki-67 correlated with the heparanase and ETAR histoscores (r=0.381, P=0.038 and r=0.477, P=0.008, respectively). CONCLUSION: Heparanase and ETAR were upregulated in EOC, and the correlation between heparanase and ETAR expressions was also elucidated in the current study.

Clinicopathologic Significance of CXCL12 and CXCR4 Expressions in Patients with Colorectal Cancer.

BACKGROUND: Colorectal cancer (CRC) is both a global and national burden, being the third most common malignancy in men and the second in women, worldwide. The prognosis of CRC is affected by various factors like the histological grade, angiolymphatic invasion, and distant metastases. Metastasis is an intricate process; one of the possible mechanisms is through the interaction of the chemokines CXCL12 and CXCR4. This study aims to reveal the expression patterns of CXCL12 and CXCR4 in CRC. METHODS: The quantitative expressions of CXCL12 and CXCR4 messenger RNA (mRNA) were evaluated in 32 patients with adenocarcinoma-type CRC. Real-time polymerase chain reaction (qRT-PCR) was performed on formalin-fixed tissues. CXCL12 and CXCR4's expressions, clinicopathologic features, and the treatment response to the CRC were analysed. RESULTS: All tumour tissues showed higher levels of both chemokines compared to normal colonic tissue. The expression of CXCL12 mRNA was higher in rectal location (p = 0.04) with a tendency to be higher in later stages (p = 0.15), while the expression of CXCR4 was lower in tumours with a lymphatic invasion (p = 0.02), compared to their counterparts. There was no difference in the expression of CXCL12 and CXCR4 according to the patients' ages, gender, tumour differentiation, or response to chemotherapy. CONCLUSION: Our study demonstrated that the mRNA expression of CXCL12 was significantly correlated with rectal location. CXCR4 mRNA expression was inversely correlated in tumours with a lymphatic invasion.

The Association between Molecular Subtypes of Breast Cancer with Histological Grade and Lymph Node Metastases in Indonesian Woman

Objective: Breast carcinoma is a heterogeneous disease which is rich in diversity. Molecular subtypes of breast cancer, histological grade and lymph node metastases are strong prognostic and predictive factors. In Indonesia, only a limited number of studies have investigated the correlation between molecular subtypes with histological grade and lymph node metastases. Methods: We analyzed 247 invasive breast carcinoma cases from the Anatomic Pathology Installation of Dr. Sardjito General Hospital Yogyakarta between 2012-2015. The slides were stained for estrogen receptors (ER), progesterone receptors (PR), HER2, Ki-67 and CK5/6 for classification into breast cancer subtypes (BCS). Histological grade using the Nottingham system and lymph node status were obtained from anatomic pathology records. The association between histological grade and lymph node status with BCS was examined with Chi-square tests. Results: The immunohistochemical features of 247 cases of women with invasive breast carcinoma were examined. There were 102 (41.3%) patients with Luminal A, 34 (13.8%) patients with Luminal B, 48 (19.4%) patients with HER2-positive, and 63 (25.5%) patients with triple negative breast cancer (TNBC). There were 148 (59.9%) patients with negative lymph node status and 99 (40.1%) with positive status. Among 63 TNBC cases, 37 (58.7%) patients were positive for CK5/6 staining (basal-like). Statistically, there were significant differences between histological grade and subtypes (p=0.013). However, no significant differences were found for lymph node metastases (p=0.540). Conclusion: Among subtypes, Luminal A has the highest frequency, followed by TNBC, HER2-positive and Luminal B. Histological grade was associated with molecular subtypes of breast carcinoma in Yogyakarta. Grade I was associated with Luminal A, while Grade III was associated with Luminal B, HER2 and TNBC subtypes.

Molecular Subtypes of Indonesian Breast Carcinomas - Lack of Association with Patient Age and Tumor Size

Objective: Breast carcinoma (BC) is a heterogeneous disease that exhibits variation in biological behaviour, prognosis and response to therapy. Molecular classification is generally into Luminal A, Luminal B, HER2+ and triple negative/basal-like, depending on receptor characteristics. Clinical factors that determined the BC prognosis are age and tumor size. Since information on molecular subtypes of Indonesian BCs is limited, the present study was conducted, with attention to subtypes in relation to age and tumor size. Methods: A retrospective cross-sectional study of 247 paraffin-embedded samples of invasive BC from Dr. Sardjito General Hospital Yogyakarta in the year 2012- 2015 was performed. Immunohistochemical staining using anti- ER, PR, HER2, Ki-67 and CK 5/6 antibodies was applied to classify molecular subtypes. Associations with age and tumor size were analyzed using the Chi Square Test. Results: The Luminal A was the most common subtype of Indonesian BC (41.3%), followed by triple negative (25.5%), HER2 (19.4%) and luminal B (13.8%). Among the triple negative lesions, the basal-like subtype was more frequent than the non basal-like (58.8 % vs 41.2%). Luminal B accounted for the highest percentage of younger age cases (< 40 years old) while HER2+ was most common in older age (> 50 years old) patients. Triple negative/basal-like were commonly large in size. Age (p = 0.080) and tumor size (p = 0.462) were not significantly associated with molecular subtypes of BC. Conclusion: The most common molecular subtype of Indonesian BC is luminal A, followed by triple-negative, HER2+ and luminal B. The majority of triple-negative lesions are basal-like. There are no association between age and tumor size with molecular subtypes of Indonesian BCs.

Correlation between vascular endothelial growth factor-A expression and tumor location and invasion in patients with colorectal cancer.

BACKGROUND: Vascular endothelial growth factor-A (VEGF-A) has been observed as the predominant angiogenic factor in colorectal cancer (CRC) and the assessment of microvessel density (MVD) has been used to quantify tumor neoangiogenesis. This study aimed to determine clinicopathological and prognostic significance of both angiogenic markers in the local CRC patients. METHODS: We analyzed tissue samples obtained from 81 cases with CRC. VEGF-A expression and MVD counts were immunohistochemically detected using anti VEGF-A and CD31. The assessments of both markers were classified as low and high. Correlation between VEGF-A expression and MVD value and clinicopathological characteristics were examined using Chi-square test. The overall survival (OS) was plotted using the Kaplan-Meier method. RESULTS: High VEGF-A expression was found more frequently in the rectal location (P=0.042) and T4 tumors (P=0.041) compared to their counterparts. Older patients tended to show a higher MVD value compared to younger cases (P=0.062). In addition, survival analysis showed that males had a worse OS compared to females (P=0.029), and VEGF-A expression and MVD count did not correlate with patients' survival. CONCLUSIONS: There were significant differences of VEGF-A expression according to tumor location and T invasion. Sex, but not angiogenic markers, had an influence on the survival of CRC patients.

Histochemical and Immunohistochemical Study of α-SMA, Collagen, and PCNA in Epithelial Ovarian Neoplasm

Background: Alpha-smooth muscle actin (α-SMA) is an isoform of actin, positive in myofibroblasts and is an epithelial to mesenchymal transition (EMT) marker. EMT is a process by which tumor cells develop to be more hostile and able to metastasize. Progression of tumor cells is always followed by cell composition and extracellular matrix component alteration. Increased α-SMA expression and collagen alteration may predict the progressivity of ovarian neoplasms. Objective: The aim of this research was to analyse the characteristic of α-SMA and collagen in tumor cells and stroma of ovarian neoplasms. In this study, PCNA (proliferating cell nuclear antigen) expression was also investigated. Methods: Thirty samples were collected including serous, mucinous, endometrioid, and clear cell subtypes. The expression of α-SMA and PCNA were calculated in cells and stroma of ovarian tumors. Collagen was detected using Sirius Red staining and presented as area fraction. Results: The overexpressions of α-SMA in tumor cells were only detected in serous and clear cell ovarian carcinoma. The histoscore of α-SMA was higher in malignant than in benign or borderline ovarian epithelial neoplasms (105.3±129.9 vs. 17.3±17.1, P=0.011; mean±SD). Oppositely, stromal α-SMA and collagen area fractions were higher in benign than in malignant tumors (27.2±6.6 vs 20.5±8.4, P=0.028; 31.0±5.6 vs. 23.7±6.4, P=0.04). The percentages of epithelial and stromal PCNA expressions were not significantly different between benign and malignant tumors. Conclusion: Tumor cells of serous and clear cell ovarian carcinoma exhibit mesenchymal characteristic as shown by α-SMA positive expression. This expression might indicate that these subtypes were more aggressive. This research showed that collagen and α-SMA area fractions in stroma were higher in benign than in malignant neoplasms.

Disseminated Histoplasmosis in an Indonesian HIV-Positive Patient: A Case Diagnosed by Fine Needle Aspiration Cytology.

A 30-year-old Javanese-Indonesian man was admitted with complaints of 3 months persistent fever, weight loss, and fatigue. He had never known his past history of unprotected HIV until the admission. His only risk factor is unsafe sex. The patient seemed well nourished. Physical examination revealed blood pressure 100/60 mmHg, pulse 100 beats per minute, respiratory rate 20 times per minute, and temperature 38.8°C. Multiple cervical and inguinal lymphadenopathies were also found. Electrocardiogram showed anterolateral ischemic finding, whereas chest X-ray were normal. Laboratory test results revealed pancytopenia with hemoglobin of 8.2 g/dL, leucocyte count 2000 cells/mm3, platelet 78000 cells/mm3, hematocrit 25.8%, AST 162 IU/L, ALT 81 IU/L, decreased albumin of 2.72 g/dL. The clinical differential diagnosis were lymphoma or tuberculosis lymphadenopathy.

p63 cytoplasmic aberrance is associated with high prostate cancer stem cell expression.

INTRODUCTION: Prostate cancer in Indonesia is the 3rd ranking cancer among males and the 5th rank for their cancer mortality. Prognostic markers that can identify aggressive prostate cancer in early stages and help select appropriate therapy to finally reduce the mortality are therefore urgently needed. It has been suggested that stem cells in the prostate gland have a role in initiation, progression, and metastasis of cancer, although controversy continues to exist. Maintenance of normal stem cell or reserve cell populations in several epithelia including prostate has been shown to be regulated by p63 and alteration of p63 expression is considered to have an oncogenic role in prostate cancer. We hypothesize that the expression of cytoplasmic aberrance of p63 is associated with high ALDH1A1 expression as a cancer stem cell marker, thus leading to progression of prostate cancer. METHODS: Using a cross-sectional study during two years (2009-2010), a total of 79 paraffin embedded tissues of benign prostatic hyperplasia, PIN prostatic intraepithelial neoplasia, low and high Gleason score prostate cancer were investigated using immunohistochemistry. Associations between cytoplasmic p63 and ALDH1A1, as well as with pathological diagnosis, were analyzed by Chi-Square test using SPSS 15.0. Links of both markers with cell proliferation rate (KI-67) and apoptotic rate (cleaved caspase 3) were also analyzed by Kruskal-Wallis test. RESULTS: The mean age of patient at the diagnosis is 70.0 years. Cytoplasmic aberrance of p63 was associated with ALDH1A1 expression (p<0.001) and both were found to have significant relationships with pathological diagnosis (including Gleason score), (p=0.006 and p<0.001 respectively). Moreover, it was also found that higher levels of cytoplasmic p63 were significantly associated with the frequency of proliferating cells and cells undergoing apoptosis in prostate cancers (p=0.001 and p=0.016 respectively). CONCLUSION: p63 cytoplasmic aberrance is associated with high ALDH1A1 expression. These components are suggested to have an important role in prostate cancer progression and may be used as molecular markers.