Therapeutic Targeting of Thioredoxin Reductase 1 Causes Ferroptosis while Potentiating Anti-PD-1 Efficacy in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) faces low response rates to anti-PD-1 immunotherapies, highlighting the need for enhanced treatment strategies. Auranofin, which inhibits thioredoxin reductase (TrxR) through its gold-based composition, has shown potential in cancer treatment. It targets the TrxR system, essential for safeguarding cells from oxidative stress. The overproduction of TrxR in cancerous cells supports their proliferation. However, auranofin's interference with this system can upset the cellular redox equilibrium, boost levels of reactive oxygen species, and trigger the death of cancer cells. This study is the first to highlight TXNRD1 as a crucial factor contributing to resistance to anti-PD-1 treatment in HNSCC. In this study, we identified targetable regulators of resistance to immunotherapy-induced ferroptosis in HNSCC. We observed a link of thioredoxin reductase 1 (TXNRD1) with tumoral PD-L1 expression and ferroptosis suppression in HNSCC. Moreover, HNSCC tumors with aberrant TXNRD1 expression exhibited a lack of PD-1 response, NRF2 overexpression, and PD-L1 upregulation. TXNRD1 inhibition promoted ferroptosis in HNSCC cells with NRF2 activation and in organoid tumors derived from patients lacking a PD-1 response. Mechanistically, TXNRD1 regulated PD-L1 transcription and maintained the redox balance by binding to ribonucleotide reductase regulatory subunit M2 (RRM2). TXNRD1 expression disruption sensitized HNSCC cells to anti-PD-1-mediated Jurkat T-cell activation, promoting tumor killing through ferroptosis. Moreover, TXNRD1 inhibition through auranofin cotreatment synergized with anti-PD-1 therapy to potentiate immunotherapy-mediated ferroptosis by mediating CD8+ T-cell infiltration and downregulating PD-L1 expression. Our findings indicate that targeting TXNRD1 is a promising therapeutic strategy for improving immunotherapy outcomes in patients with HNSCC.

Patient-reported outcomes and symptom clusters pattern of chemotherapy-induced toxicity in patients with early breast cancer.

OBJECTIVE: This study aims to characterize patient-reported chemotherapy-induced toxicity in patients with breast cancer, determine its association with treatment regimens and patient characteristics, identify toxicity symptom clusters within a specific chemotherapy timeframe and analyze the correlation between symptom clusters within and between the timeframe to understand the changes and influences across chemotherapy. METHODS: Forty-six patient-reported toxicities during neoadjuvant/adjuvant chemotherapy for breast cancer were evaluated using adapted CTCAE version 4.0. Chi-Square/Fisher's Exact test was performed to analyze the difference in the incidence of toxicity symptoms by chemotherapy regimens. Poisson regression performed to assess factors associated with patient's total chemotherapy toxicity. Exploratory factor analysis (EFA) conducted to identify symptom clusters at T1 (first half) and T2 (second half of planned cycle). Factor scores were generated and Spearman correlation performed to explore the factor scores correlation between symptom clusters. RESULTS: A total of 142 patients with stage I-III breast cancer were included. The incidence of several toxicities differed significantly among three chemotherapy regimens. Subjects age ≥51 years are associated with lower number of reported toxicity (IRR/incidence rate ratio = 0.94, 95% confidence interval/CI 0.88 to 0.99, p = 0.042). Receiving more chemotherapy cycles are associated with higher number of reported toxicity (IRR = 1.06, 95% CI 1.03 to 1.10, p<0.001). Two symptom clusters identified at T1 (psychoneurological-pain/PNP-T1 and gastrointestinal-psychological/GIP-T1 cluster) and three at T2 (psychoneurological-pain/PNP-T2, epithelial/EPI-T2, and gastrointestinal cluster/GI-T2), with moderate-strong positive correlation between PNP-T1 and GIP-T2 (p<0.001), PNP-T1 and PNP-T2 (p<0.001), and GIP-T1 and PNP-T2 (p<0.001). CONCLUSIONS: This study investigated 46 patient-reported toxicities prospectively during adjuvant/neoadjuvant chemotherapy for early breast cancer. Anthracycline-taxane combination regimen had higher proportions of toxicity incidence. Subject's age and number of chemotherapy cycles significantly associated with total number of toxicity symptoms. Two symptom clusters at T1 and three at T2 were identified, with significant correlation between symptom clusters within and between chemotherapy timeframe.

CXCL8, MMP1, MMP2, and FN1 Gene Expression and Tumor Extension in Nasopharyngeal Cancer Patients: A Cross-sectional Study.

BACKGROUND: There are correlations between tumor staging, lymph node involvement, and patient survival in Nasopharyngeal cancer (NPC) which is one of the most common types of cancer in Indonesia.  The inflammation process plays a role in tumor progression over the long term and this marked by increased proinflammatory cytokine and gene overexpression. This study aims to identify differentially expressed genes (DEGs) in NPC using T and N staging. METHODS: This is a cross-sectional study of NPC patients in Cipto Mangunkusumo, Jakarta, between 2018 and 2022. DEGs were identified based on the amount of mRNA detected on paraffin blocks with a 1.5- to -1.5-fold change and an adjusted p-value of <0.05. RESULTS: We included 48 subjects. The mean age of subjects was 47.75 (10.48) years, and most were male (77.1%). Non-keratinized squamous cell carcinoma was the most common histopathology type. Differences in the tumor size of the T4 and non-T4 in metastatic (33.3%) group when compared to the non-metastatic (37.5%) group were insignificant (p = 0.763). The proportion of N3 subjects in the metastatic vs non-metastatic group was different significantly (83.3% vs. 50%, p = 0.030). Gene expression analysis showed that C-X-C motif ligand 8 (CXCL8), matrix metalloproteinase-1 (MMP1), matrix metalloproteinase-1 (MMP2), and fibronectin-1 (FN1) genes of the T4 and non-T4 group to be different significantly. CONCLUSION: There was significant finding in the N3 subjects of the metastatic and non-metastatic groups. The DEGs of CXCL8, MMP1, MMP2, and FN1 were statistically significant in the T4 when compared to the non-T4 group.

Physician Perceptions of the Clinical, Economic and Humanistic Burden of Disease and Unmet Needs in Myelofibrosis: Preliminary Findings from the MPN Landmark Survey in Indonesia.

Background/ Objective: Myelofibrosis (MF) is a severe form of Myeloproliferative Neoplasms (MPNs). It is a rare disease in Indonesia and is reportedly associated with symptoms resulting in poor quality-of-life, pre-mature mortality, disability, and loss of productivity. As the disease is rare, there are limited published information around MF, particularly in Indonesia. METHODS: A cross-sectional survey was designed and administered between November and December 2021 among practicing Haematologists-Medical Oncologists who are experienced in treating patients with MF. The objectives of the survey were to assess physician's understanding of the overall diagnosis of MF, the disease burden, current treatment practices and remaining unmet needs. Outcomes were analysed descriptively. RESULT: The survey was completed by 30 respondents. The findings suggest that symptom burden is high and has a significant negative impact on quality-of-life. Treatment burden is also high which can result in high healthcare resource utilisation. Physicians expressed need for novel therapeutic options and improved access and coverage for such options. There is also a need to improve access and coverage for JAK V617F testing locally and local hospital infrastructures should be upgraded to ensure MF is accurately diagnosed. Patient may benefit from information on MPN, which may result in earlier presentation, diagnosis and treatment which can improve outcomes. CONCLUSION: The findings align with previous international research reporting that symptoms and treatment burden are high, and that novel therapeutic options are needed. Additional patient research might be required to better understand the patient experience of MF and how this can be improved.

Prognostic Value of Vimentin in Triple Negative Breast Cancer Patients Depends on Chemotherapy Regimen and p53 Mutant Expression.

Purpose: To determine the prognostic value of vimentin in triple negative breast cancer (TNBC) patients, specifically in relation to chemotherapy regimen and p53 mutant expression. Patient and Methods: We retrospectively analyzed the association of pre-treatment tumor expression of vimentin with 48-month overall survival (OS) of 72 all stages TNBC patients diagnosed between 2014 and 2018 in relation to chemotherapy regimen and expression of p53 mutant. Vimentin and p53 mutant expressions were examined using immunohistochemistry. Analysis was conducted on all patients collectively, then repeated on two cohorts divided according to the chemotherapy regimen. Sub-analysis was performed to determine the effect of p53 mutant expression on the prognostic value of vimentin. Results: Vimentin was expressed in 43.1% of patients and was not associated with clinicopathologic characteristics. Vimentin was associated with improved 48-month OS in all patients in univariate analysis but not significant in multivariate analysis. When analyzed according to chemotherapy regimen, vimentin was independently associated with improved 48-month OS in patients receiving non-platinum-based chemotherapy (80% vs 15.8%; HR: 0.17, 95% CI: 0.05-0.58, p: 0.005). Other independent prognostic factors include T (HR: 6.18, 95% CI: 1.38-27.7, p: 0.017) and M (HR: 5.64, 95% CI: 1.2-26.33, p: 0.028). On subanalysis, vimentin was significantly associated with improved 48-month OS in patients expressing p53 mutant (69.2% vs 22.2%, p: 0.006) but was not significant in patients not expressing p53 mutant. Conclusion: Vimentin expression was independently associated with improved 48-month OS in TNBC patients treated with non-platinum-based chemotherapy. Expression of p53 mutant significantly affected the prognostic value of vimentin.

Synergistic disruption of BTK and BCL-2 causes apoptosis while inducing ferroptosis in double-hit lymphoma.

Double-hit lymphoma (DHL) is an aggressive subset of Diffuse Large B-cell Lymphoma (DLBCL) with poor outcomes and without satisfying treatment options. BTK inhibitor monotherapy is ineffective to suppress aggressive lymphoma. Hence, combination with other potential agents is warranted. Here, we demonstrated the second generation of BTK inhibitor, zanubrutinib, and a BCL-2 inhibitor, navitoclax, worked in synergistic manner to suppress DHL. Comprehensive in silico approach by interrogating single-cell to bulk-level profiling was employed along with in vitro and in vivo validation in DHL cell lines. Ablation of BTK enhanced sensitivity to navitoclax and suppressed proliferation of DHL cells. Combination of second generation of BTK inhibitor with navitoclax synergistically suppressed DLBCL cells with higher synergy score in DHL subset. The drug combination triggered apoptosis and ferroptosis, with the latter being characterized by reactive oxygen species (ROS) accumulation, extensive lipid peroxidation, and depletion of reduced glutathione. Moreover, ablation of BTK sensitized DHL cells to ferroptosis. Mechanistically, disruption of BTK and BCL-2 triggered ferroptosis by downregulating NRF2 and HMOX1, while deactivating GPX4. Combination of zanubrutinib and navitoclax effectively suppressed tumor growth in vivo. Our data suggest that zanubrutinib and navitoclax synergistically suppressed DHL by inducing apoptosis and ferroptosis.

The occurrence and risk factors of chemotherapy-induced neutropenia in patients with breast cancer not receiving primary G-CSF prophylaxis.

Background: Chemotherapy-induced neutropenia (CIN) is a substantial side effect in chemotherapy of breast cancer patients. Administration of granulocyte colony stimulating factor (G-CSF) that may reduce CIN occurrence is not commonly available to many local cases. Objectives: To investigate the occurrence of grade 4 CIN and the influencing factors in breast cancer patients not receiving G-CSF prophylaxis. Methods: One-hundred and eighty-six newly diagnosed breast cancer patients who received a 3-weekly (neo)adjuvant or palliative chemotherapy without primary G-CSF prophylaxis were included. Grade 4 CIN was defined as absolute neutrophil count (ANC) <0.5 × 103/mm3 during any chemotherapy cycle. We used logistic regression to explore the association of clinical, pathological and treatment factors with the risk of grade 4 CIN in the first cycle and in any given cycle. Results: Fifty-seven (30.6%) patients experienced grade 4 CIN in the first cycle and 145 (78%) had it at least once during chemotherapy. In the first cycle, haemoglobin, ANC, and albumin levels were associated with grade 4 CIN (OR = 1.48, p = 0.031; OR = 0.68, p = 0.006; and OR = 2.07, p = 0.042). In any cycle, pre-treatment ANC levels and anthracycline-taxane combination regimen were associated with grade 4 CIN (OR = 0.78, p = 0.032 and OR = 3.64, p = 0.012). Conclusions: A significant proportion of the local breast cancer cases undergoing chemotherapy without primary G-CSF prophylaxis experienced grade 4 CIN. Haemoglobin, ANC, and albumin levels are the risk factors for first cycle CIN, while pre-treatment ANC levels and anthracycline-taxane chemotherapy regimen are associated with CIN in any given cycle. These risk factors may be used to direct a recommendation of G-CSF prophylaxis to the most at-risk individuals in the local setting or other settings in similar situations.

Vitamin D status in breast cancer cases following chemotherapy: A pre and post observational study in a tertiary hospital in Yogyakarta, Indonesia.

OBJECTIVES: To observe pre- and post-treatment vitamin D level and its association with treatment and concomitant factors in breast cancer patients treated with chemotherapy. METHODS: We performed a pre-post observational analysis that nested in an ongoing prospective cohort study of breast cancer patients at Dr. Sardjito General Hospital, Yogyakarta, Indonesia. 136 subjects were recruited from the main study. Information on subjects' socio-demographic characteristics clinical status, and tumour profile was assessed at baseline. Number of chemotherapy cycles and chemotherapy-induced nausea vomiting (CINV) were also recorded. Vitamin D concentration was measured using ELISA methods at baseline and post-treatment. Vitamin D level of <20 ng/ml and <12 ng/ml were defined as deficiency and severe deficiency. Correlation between socio-demographic and clinical profile with baseline vitamin D was tested using Spearman correlation. Paired t-test was used to evaluate changes in post-treatment vitamin D concentration. The odds ratio for a subject to experience post-treatment vitamin D decrease was assessed based on number of chemotherapy cycles and CINV severity. RESULTS: The mean vitamin D level before chemotherapy was very low (8.80±3.64 ng/ml) in the whole panel. Higher AST level were associated with lower vitamin D level at baseline (r = -0.188, p = 0.028). Severe deficiency was found in 82.4% subjects at baseline and the rate increased to 89.0% after chemotherapy. Eighty-five cases showed a decrease level whereas 51 showed a slight improvement. Overall, a significant decrease of the vitamin D level was observed after chemotherapy (median change 3.13±4.03 ng/ml, p <0.001). Subjects who received >6 cycles of chemotherapy were less likely to experience a decreased level of post-treatment vitamin D (OR = 0.436, 95% CI = 0.196-0.968, p = 0.039). CONCLUSIONS: Indonesian breast cancer patients showed pre-existing severe vitamin D deficiency and deterioration of vitamin D after chemotherapy. Future research is needed to explore its implication towards patients' survival in the local setting. Evidence-based approach also needs to be taken to address this modifiable condition, including increasing awareness of the importance of maintaining vitamin D sufficiency both in patients and the general population.

Delays in the presentation and diagnosis of women with breast cancer in Yogyakarta, Indonesia: A retrospective observational study.

PURPOSE: To investigate factors associated with delays in presentation and diagnosis of women with confirmed breast cancer (BC). METHODS: A cross-sectional study nested in an ongoing prospective cohort study of breast cancer patients at Dr Sardjito Hospital, Yogyakarta, Indonesia, was employed. Participants (n = 150) from the main study were recruited, with secondary information on demographic, clinical, and tumor variables collected from the study database. A questionnaire was used to gather data on other socioeconomic variables, herbal consumption, number of healthcare visits, knowledge-attitude-practice of BC, and open-ended questions relating to initial presentation. Presentation delay (time between initial symptom and first consultation) was defined as ≥3 months. Diagnosis delay was defined as ≥1 month between presentation and diagnosis confirmation. Impact on disease stage and determinants of both delays were examined. A Kruskal-Wallis test was used to assess the length and distribution of delays by disease stage. A multivariable logistic regression analysis was conducted to explore the association between delays, cancer stage and factors. RESULTS: Sixty-five (43.3%) patients had a ≥3-month presentation delay and 97 (64.7%) had a diagnosis confirmation by ≥1 month. Both presentation and diagnosis delays increased the risk of being diagnosed with cancer stage III-IV (odds ratio/OR 2.21, 95% CI 0.97-5.01, p = 0.059 and OR 3.03, 95% CI 1.28-7.19, p = 0.012). Visit to providers ≤3 times was significantly attributed to a reduced diagnosis delay (OR 0.15, 95% CI 0.06-0.37, p <0.001), while having a family history of cancer was significantly associated with increased diagnosis delay (OR 2.28, 95% CI 1.03-5.04, p = 0.042). The most frequent reasons for delaying presentation were lack of awareness of the cause of symptoms (41.5%), low perceived severity (27.7%) and fear of surgery intervention (26.2%). CONCLUSIONS: Almost half of BC patients in our setting had a delay in presentation and 64.7% experienced a delay in diagnosis. These delays increased the likelihood of presentation with a more advanced stage of disease. Future research is required in Indonesia to explore the feasibility of evidence-based approaches to reducing delays at both levels, including educational interventions to increase awareness of BC symptoms and reducing existing complex and convoluted referral pathways for patients suspected of having cancer.

Two Cases of Hemophagocytic Lymphohistiocytosis Associated with Disseminated Histoplasmosis Presented with Transient Pancytopenia.

Transient pancytopenia due to reactive bone marrow suppression often occurs in hemophagocytic lymphohistiocytosis (HLH), a syndrome resulting from excessive immune activation following a severe infection. We reported two cases with pancytopenia and disseminated histoplasmosis accompanied by HLH, initially suspected to be blood malignancies. Our first case documented the relevance between the improvement of pancytopenia and the clearance of Histoplasma capsulatum in serial bone marrow aspirations. The second case showed immense Histoplasma engulfment by the macrophage in relation to a severe clinical condition, followed by improvement of clinical symptoms in accordance with the recovery of pancytopenia. These two cases highlighted the importance of comprehensive and critical analysis for cases with concurrent pancytopenia and severe infection, since it may be that the pancytopenia underlies the severe infection or vice versa.

Fatty Liver in Hormone Receptor-Positive Breast Cancer and Its Impact on Patient's Survival.

PURPOSE: Long-term estrogen inhibition may cause fatty liver disease (non-alcoholic fatty liver disease; NAFLD) among other adverse conditions such as osteoporosis, climacteric symptoms, thromboembolism, dyslipidemia, and metabolic syndrome. The prevalence of NAFLD among breast cancer patients ranges from 2.3%-45.2%. This study aimed to determine the risk factors for newly developed NAFLD among breast cancer patients after hormonal treatment and whether it influences survival outcomes. METHODS: This retrospective study investigated hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-), nonmetastatic breast cancer patients diagnosed between January 2010 and December 2018. All patients received adjuvant hormonal treatment for at least 6 months. Clinical data on metabolic profile indicators such as body mass index (BMI), waist circumference, serum cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C), diabetes, and presence of metabolic syndrome (MetS) were collected. In total, 160 eligible patients with complete covariate data and survival follow-up were included. RESULTS: NAFLD was diagnosed in 35% of patients. There were significant associations of being overweight (BMI ≥ 25 kg/m²), waist circumference > 80 cm, triglycerides ≥ 150 mg/dL, HDL-C ≤ 50 mg/dL, LDL-C < 150 mg/dL, and presence of MetS with the development of NAFLD. However, unlike other factors, MetS and HDL-C were not independently associated with NAFLD. Patients with breast cancer who developed NAFLD had longer disease-free survival (DFS). The median DFS was not reached in the NAFLD group, whereas it was 59.3 (45.6-73.0) months in the non-NAFLD group. No worsening of overall survival was observed in patients with breast cancer and NAFLD. CONCLUSION: The development of NAFLD during treatment in patients with HR+/HER2- breast cancer was associated with several independent risk factors: being overweight, waist circumference, triglycerides, and LDL-C. Interestingly, breast cancer patients with NAFLD during treatment had longer DFS than those without NAFLD.

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.

MicroRNA-223 is Associated with Resistance Towards Platinum-based Chemotherapy and Worse Prognosis in Indonesian Triple-negative Breast Cancer Patients.

PURPOSE: Determining the optimal strategy to implement systemic treatment modalities has been challenging in triple-negative breast cancer (TNBC). We aim to investigate the role of microRNA-223 (miR-223) as prognostic factor and predictor of response toward chemotherapy in TNBC. PATIENTS AND METHODS: We retrospectively analyzed the association of pretreatment miR-223 expression with clinicopathologic characteristics and 36-month overall survival (OS) of 53 all stages TNBC patients. Tumor level of miR-223 was measured using real-time quantitative polymerase chain reaction (expressed in fold change). Cutoff value for miR-223 was determined by using receiver operating curve (ROC). Kaplan-Meier curve was used to perform survival analysis. RESULTS: The optimum cutoff value for miR-223 was 23.435 (AUC: 0.706, 95%CI: 0.565-0.848; p:0.01; sensitivity: 78.6%; specificity: 56%) and was used to categorize mir-223 expression into over- and underexpressed group. Overexpression of miR-223 was associated with increased expression of EGFR (69.7% vs 35%, p: 0.022) and lower 36-month OS (33.3% vs 70%; median OS±SE (months): 25.66±1.58 vs 30.23±1.99; log rank p<0.05). Worse survival is observed in miR-223 overexpressed group receiving platinum-based chemotherapy compared to miR-223 underexpressed group (mean OS (95%CI) months: 24.7 (20.3-29.1) vs 34.3 (31.2-37.4); p<0.01), while no significant difference observed in non-platinum containing regimen. No significant association was observed between miR-223 expression with other clinicopathologic characteristics. CONCLUSION: Overexpression of miR-223 is associated with increased expression of EGFR, worse prognosis, and resistance toward platinum-based chemotherapy in Indonesian TNBC patients.

Histopathological Features of Lymphoma in Yogyakarta, Indonesia.

The incidence and prevalence, the second most common lymphoid malignancy after leukemia, are both increasing. The distribution of lymphoma varies among sexes, age groups, and sites. In Indonesia, information about the incidence of lymphoma and its characteristics are insufficient. Therefore, this study was performed to evaluate the incidence of lymphoma and features based on age group, sex, site, clinical diagnosis, and histopathological type in Indonesia. This study is an observational analytical study with a cross-sectional design aimed to evaluate the histopathological profile of lymphoma in Yogyakarta from 2010-2014. It was based on secondary data from Anatomic Pathology Department's medical records from several hospitals and laboratories. The result showed an increased incidence of lymphoma in Yogyakarta in 2010-2014 (p=0.039). Lymphoma mostly occurred in age range 45-64 years (p=0.004), dominated by male with ratio 1.6:1. DLBCL was found to be the most common histopathological type (44.4%). Sex, age, and clinical diagnosis demonstrated statistically significant correlations with the histopathological type (p<0.001). In conclusion, the incidence of lymphoma has significantly increased from 2010-2014. There are statistically significant correlations between gender, age, and clinical diagnosis with the histopathological type of lymphoma.

Elevation of vascular endothelial growth factor in Indonesian advanced stage nasopharyngeal carcinoma.

Studies on the role of vascular endothelial growth factor (VEGF) as the most potent angiogenic factor in disease progression of nasopharyngeal carcinoma (NPC) remain limited, partly be due to the geographical distribution of the disease. However, it has never been reported from Indonesian population despite its common incidence. Therefore, we aimed to study the possible prognostic value of VEGF in Indonesian advanced stage NPC. A clinical examination, CT scan, and the tumor tissue and plasma collection were performed before a combined therapy, and a local control rate was reassessed every 3 months to determine progression-free survival (PFS). Plasma VEGF-A was measured in 40 patients by ELISA, and VEGF and vWF expressions were examined in 30 patients by immunohistochemistry. Survival curves were plotted based on plasma VEGF-A level, VEGF, and microvessel density (MVD) count indicated by vWF expressions vs PFS. The median follow up was 16 months. Patients with high VEGF-A level (≥ 834pg/ml) presented shorter survival rate, as compared to those of low level (< 834pg/ml) (41.2% vs 82.6%; p=0.009, log rank 6.81). Patients with overexpressed VEGF (≥ 25%) showed shorter survival than those with low expression (<25%) (45.5% vs 79.6%; p=0.05, log rank 3.84). Patients with higher MVD count (≥ 25%) also had shorter survival than those with lower MVD count (53.4% vs 80%; p=0.101, log rank=2.70). In conclusion, an elevated plasma VEGF level predicts shorter survival for Indonesian advanced stage NPC in this study. However, more samples may be required to draw a better conclusion on a possible role of VEGF as a prognostic factor in the disease progression of NPC. This data is also substantial for the development of anti-VEGF as a possible targeted therapy for NPC.

Presence of somatic hypermutation and activation-induced cytidine deaminase in acute lymphoblastic leukemia L2 with t(14;18)(q32;q21).

AIM: Acute lymphoblastic leukemia (ALL) with L2 (FAB) morphology has rarely been reported to show t(14;18)(q32;q21). We aimed to delineate the stage at which this type of ALL is derived in B-lineage differentiation. METHODS: The somatic hypermutation (SHM) of the variable region of immunoglobulin heavy chain (IgV(H)) gene and the expression of terminal deoxynucleotidyl transferase (TdT), recombination-activating gene 1 and 2 (RAG-1 and -2), and activation-induced cytidine deaminase (AID) were investigated in three cell lines and two fresh samples, including a pair of matched fresh and cell line cells. RESULTS: TdT, RAG-1, and RAG-2 were variably expressed. AID was expressed in four of five samples. SHM of the IgV(H) gene was found in all samples with high average frequency (11.84%) comparable with that in follicular lymphoma. Ongoing mutation was seen in two fresh samples. CONCLUSION: As AID and SHM are generally regarded as properties exhibited by mature B cells, the presence of AID and SHM in this study seems to be incompatible with the general understanding of the early stage derivation of ALL in B-lineage differentiation. The results here give some insight into the relationship between disease type (ALL or lymphoma) and derivation stage, the overlapping of the early stage phenotype and the mature genomic characteristics, and the probable relationship between the mechanism of the occurrence of t(14;18)(q32;q21) and the machinery causing SHM.

Expression of activation-induced cytidine deaminase (AID) in Burkitt lymphoma cells: rare AID-negative cell lines with the unmutated rearranged VH gene.

Activation-induced cytidine deaminase (AID) is an enzyme that catalyzes somatic hypermutation (SHM) and class switch recombination (CSR) of the immunoglobulin (Ig) gene. The expression of AID was reported to be confined to the germinal center (GC). Burkitt lymphoma (BL) cells are regarded as being derived from GC cells. BL cells have been reported to have SHM in the Ig gene with variety in terms of degree, antigen selection and ongoing mutation characteristic. We investigated the expression of AID in 15 BL cell lines by RT-PCR. In only 2 BL cell lines, Tree92 and Black93, AID expression was not detected, and the 1gVH gene of these 2 cell lines was not mutated. Tree92 expresses terminal deoxy-nucleotidyl transferase (TdT) and recombination activating gene (RAG)1, but Black93 does not, as is typical of the BL phenotype. BL cells are generally derived from GC B-cell expressing AID, but are rarely derived from the stage of B-lineage differentiation in which AID is not yet expressed, causing the absence of mutation in the IgVH.