The Impact of Tumor Hypoxia Modulation on sIL-2R Levels in Newly Diagnosed Diffuse Large B Cell Lymphoma (DLBCL) Patients Undergoing Chemotherapy: A Randomized Clinical Trial.

OBJECTIVE: Tumor hypoxia induces the production of Hypoxia-Inducible Factor (HIF)-1 alpha, which interacts with NF-kB, leading to cancer proliferation and metastasis. This study investigated the effect of tumor hypoxia modulation using carbogen (95% O2 and 5% CO2) and nicotinamide on reducing soluble interleukin-2 receptor (sIL-2R) levels in newly diagnosed DLBCL patients with tissue overexpression of HIF-1α ≥10%. MATERIAL AND METHODS: A prospective randomized controlled clinical trial was conducted at Dr. Kariadi Hospital in Semarang, Indonesia, from 2021 to 2022. Newly diagnosed DLBCL patients with tissue HIF-1α ≥10% were randomized into an intervention group (nicotinamide 2,000 mg + carbogen 10 liters/min during R-CHOP) and a control group (R-CHOP alone) for one cycle. sIL-2R levels were measured in the blood before and after intervention. RESULTS: The intervention group showed a significant reduction in sIL-2R levels after chemotherapy (p=0.026), with 85% of samples exhibiting a decrease. In contrast, only 45% of samples in the control group demonstrated a decrease in sIL-2R levels (p=0.184). The median sIL-2R level decreased from 139.50 pg/mL to 70.50 pg/mL in the intervention group, while the control group exhibited an increase from 182.50 pg/mL to 250.00 pg/mL following one cycle of chemotherapy. CONCLUSION: Tumor hypoxia modulation led to a significant decrease in serum sIL-2R levels, potentially through improvements in the crosstalk between hypoxia and inflammation pathways.

Medical thoracoscopy with cryobiopsy as diagnostic tool for pleural metastatic in cutaneous squamous cell carcinoma: a rare case report.

Introduction: Distance metastasis of cutaneous squamous cell carcinoma (cSCC) to pleural is rarely reported, and meets difficulties in diagnosing due to quality of pleural biopsy sample. This case presented a novel technique by using cryobiopsy to obtain adequate sample and was first conducted in our hospital. Case presentation: A 62-years-old man admitted to hospital with dyspnoea due to massive right pleural effusion. Lung multi-sliced computed tomography showed right lung pleural effusion with compression atelectasis as well as collapse of medial lobe and upper lobe, multiple solitary nodules on mediastinal, costal antero-posterior and right diaphragm pleural part. Medical thoracoscopy was performed to obtain pleural samples by using cryobiopsy and forceps biopsy. Pathological analysis with Immunohistochemistry (IHC) revealed metastatic squamous cell carcinoma. Discussion: Recurrence rate of cSCC remains high even after treatment, with worse prognosis. Distant metastasis to pleural is rarely reported. Clinical approach for malignant pleural effusion by using medical thoracoscopy has 80% sensitivity with minimal complication. Pleural cryobiopsy is a novel technique used for obtaining sample from pleural biopsy with significant larger size of the specimen, less crush artefacts, fragmented and better tissue integrity, although the diagnostic yield and bleeding severity between cryobiopsy and conventional forceps biopsy are not significant. Conclusion: Medical thoracoscopy with cryobiopsy should be considered as a preferrable diagnostic tool for obtaining better sample specimen, especially for pleural metastatic.

Efficacy and Safety of Ibrutinib for Chronic Graft-Versus-Host Disease: A Systematic Review.

INTRODUCTION: Allogeneic hematopoietic cell transplantation (allo-HCT) serves as a potentially curative intervention for various hematologic disorders. However, its utility can be limited by the emergence of chronic graft-versus-host disease (cGVHD). The clinical manifestations of cGVHD result from a complex immune response characterized by the involvement of both B and T cells. Ibrutinib, a pharmacological agent, acts as an inhibitor of Bruton's tyrosine kinase (BTK) pathway, which becomes activated through the B-cell receptor and regulates B-cell survival. By exerting inhibitory effects on both BTK and inhibitor of interleukin-2 inducible T-cell kinase (ITK), ibrutinib exhibits promise as a therapeutic approach for managing cGVHD. Ibrutinib may be considered as a viable treatment option for active cGVHD in cases where patients exhibit an inadequate response to corticosteroid-based therapies. This systematic review seeks to assess the efficacy and safety of ibrutinib in the context of cGVHD patient management. METHOD: We incorporated search engines from PubMed, Embase, Cochrane Library, Scopus, Web of Science, and ClinicalTrials.gov. The study was performed following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 and Assessing The Methodological Quality of Systematic Review (AMSTAR). We used Risk of Bias- 2 (RoB-2) tool for assess the risk of bias in randomized controlled studies (RCTs) and Newcastle Ottawa Scale (NOS) for observational and open-label studies. RESULTS: A total of 7 studies were included in this study consisted of four open-label studies, two retrospective cohort studies, and one RCT study. These studies compared Ibrutinitib with standard therapies. Two studies investigated the pediatric population, and five studies investigated the adult population. Overall, these studies reported the overall response rate (ORR) of ibrutinib for cGVHD were 54%-78%. The results showed that in pediatric patients, the ORR were 54-78%. The results also showed that in adult patients, the ORR were 67%-76%. The most common adverse effects observed across the seven studies included pyrexia, diarrhea, abdominal pain, cough, nausea, stomatitis, vomiting, headache, bleeding and bruising, infection, muscle aches, fatigue, oral bleeding, elevated transaminases, lower gastrointestinal bleeding, persistent dizziness, sepsis, pneumonia, reduced platelet count, exhaustion, sleeplessness, peripheral edema, and fatigue. CONCLUSION: The majority of studies have indicated that ibrutinib exhibits a high ORR and provides long-lasting responses, while also having manageable side effects.

The expression of hypoxia inducible factor-1 alpha in diffuse large B-cell lymphoma (DLBCL) patients: a cross-sectional study in Indonesia.

Introduction: Hypoxia fuels cancer growth by supporting blood vessel formation, suppressing immune response, and helping cancer cells adapt to harsh surroundings. This happens when cancer cells react to low oxygen levels by activating hypoxia inducible factor-1 alpha (HIF-1α). High levels of HIF-1α can indicate an aggressive form of cancer and resistance to treatment in diffuse large B-cell lymphoma (DLBCL) patients. This study aimed to identify which factors are linked to HIF-1α distribution using immunohistochemistry in DLBCL patients. Method: This study conducted at a hospital in Indonesia between 2020 and 2022 aimed to investigate factors associated with HIF-1α expression in DLBCL patients. Newly diagnosed DLBCL patients were categorized into two groups based on HIF-1α distribution (<40% and ≥40%). Various factors were analyzed between the two groups using statistical tests such as χ2, Mann-Whitney U, and Spearman correlation tests. Results: In this study, 40 participants diagnosed with DLBCL were divided into two groups based on their HIF-1α distribution. The group with HIF-1α distribution greater than or equal to 40% had a higher incidence of extranodal involvement, including primary extranodal disease, compared to the group with less than 40% distribution. This difference was statistically significant. The authors also found that haemoglobin level statistically significant (P=0.041) in this research. The Spearman test analysis showed negative correlation between haemoglobin (P = <0.05, r = -0.44) and positive correlation of soluble interleukin-2 receptor (sIL-2R) (P = <0.05, r = 0.5) with vascular endothelial growth factor (VEGF), as well as between tumour volume (P = <0.05, r = 0.37) with sIL-2R. Additionally, there was a positive correlation between VEGF and sIL-2R (P = <0.05, r= 0.5). Conclusion: Patients with higher HIF-1α expression (≥40%) had more extranodal involvement and primary extranodal disease in this study of 40 DLBCL patients. Haemoglobin level, sIL-2R, and VEGF were also identified as potential biomarkers.

The effectiveness of atorvastatin for the prevention of deep vein thrombosis in cancer patients undergoing chemotherapy : A randomised controlled trial: open label.

BACKGROUND: Deep vein thrombosis (DVT) is a common complication in cancer. Although thromboprophylaxis in cancer patients is recommended by the guidelines, clinicians' use of thromboprophylaxis remains limited due to cost, bleeding complications, and reluctance to give injectable anticoagulants. Inflammation plays essential roles in the pathogenesis of cancer-associated thrombosis. Owing to its ability to decrease proinflammatory cytokines, statins have anti-inflammatory properties. Thus, statins can be possibly utilized as thromboprophylaxis therapy in cancer patients undergoing chemotherapy. OBJECTIVE: To compare the effectiveness of atorvastatin and rivaroxaban for DVT prevention in high-risk thrombosis patients with cancer undergoing chemotherapy. METHODS: Double-blind, randomized controlled trial involving cancer patients with high-risk of thrombosis undergoing chemotherapy. We randomly assigned patients without deep-vein thrombosis at screening to receive atorvastatin 20 mg or rivaroxaban 10 mg daily for up to 90 days. Doppler ultrasonography was performed 90 days following chemotherapy to diagnose DVT. Average cost-effectiveness analysis was performed to analyze the cost of atorvastatin compared to rivaroxaban. RESULTS: Of the eighty six patients who underwent randomization, primary efficacy end point was observed in 1 of 42 patients (2.3%) in the atorvastatin group and in 1 of 44 (2.2%) in the rivaroxaban group (Odds Ratio [OR], 0.953; 95% confidence interval [CI], 0.240 to 3.971; p = 1.000). There was a significant difference in the incidence of major bleeding, 2 of 42 patients (4.8%) in the atorvastatin group and 12 of 44 (27.3%) in the rivaroxaban group (OR, 0.257; 95% CI, 0.07 to 0.94; p = 0.007). The average cost-effectiveness ratio of using atorvastatin was lower than that of rivaroxaban. CONCLUSION: Atorvastatin did not differ significantly from rivaroxaban in reducing the incidence of DVT, lower bleeding risk, and cost-effectiveness for thromboprophylaxis in high-risk thrombosis patients with cancer undergoing chemotherapy. The presence of limited statistical power and wide confidence intervals in this study needs further study to strengthen the efficacy of atorvastatin as DVT prophylaxis in cancer patients. TRIAL REGISTRATION: ISRCTN71891829, Registration Date: 17/12/2020.

Evaluation of Usability and User Experience of Oncodoc 's M-Health Application for Early Detection of Cancer.

OBJECTIVE: Cancer is a non-communicable disease that accounts for 71% of deaths globally. The prevalence of people living with cancer in Indonesia increased from 1.4/1000 population (2013) to 1.8/1,000 population (2018). This study aims to evaluate usability, user experience, and user feedback on the use of the Oncodoc m-health application. METHODS:  The research method uses mixed methods with a cross-sectional approach and online survey sampling techniques (677 respondents), in December 2021-January 2022 in Indonesia. The instruments used are the System Usability Scale and User Experience Questionnaire. The variables measured include the characteristics of respondents, usability, user experience, and responses to using applications qualitatively. Quantitative data were analysed descriptively and the User Experience Questionnaire's analysis tool. Qualitative data were analysed thematically. RESULTS: Evaluation of the usability of Oncodoc's m-health application is in the "acceptable" category (70.88), and the adjective rating is in the "Good" category. Evaluations of the relative quality of user experience are in the "good" and "very good" types. The average user experience scale is (mean; SD): attractiveness (1.80; 0.99), perspicuity (1.82; 1.05), efficiency (1.78; 1.09), dependability (1.56; 1.01), stimulation (1.81; 1.06), and novelty (1.32; 1.10). The findings of this study are 1) the ability to accommodate user needs, 2) usage barriers, and 3) user expectations for the Oncodoc application. CONCLUSION: Overall, the Oncodoc m-health application is acceptable to users. We recommend developing a cancer early detection application with an approach that refers to user needs for further research.

Curcumin as adjuvant therapy to improve remission in myeloma patients: A pilot randomized clinical trial.

Background: The treatment for ineligible transplant multiple myeloma is melphalan prednisone. Curcumin has an anti-inflammatory and antiangiogenesis in cancer-directed to nuclear factor-kappa B (NF-kB) pathway. Interleukin 6 (IL-6), vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and lactate dehydrogenase (LDH) were also involved in the pathogenesis of myeloma. No clinical study has evaluated the efficacy of curcumin in myeloma patients. To evaluate the efficacy of curcumin as adjuvant into melphalan prednisone in myeloma patients. Methods: 33 myeloma patients at Dr. Kariadi General Hospital, Semarang, Indonesia during 2016-2017 were randomly assigned single-blindedly into MPC (n=17) and control group (n=16). The MPC group was treated with melphalan 4 mg/m2, prednisone 40 mg/m2 for 7 days, and curcumin 8 gram daily for 28 days. The MP control group was treated with melphalan, prednisone, and placebo. The primary endpoint was the overall remission. Pre- and post-treatment was examined for NF-κB, VEGF, TNF-α, IL-6, LDH, and CRP levels All data analyses were per protocol. Results: There was a significant difference in overall remission between the MPC and MP control groups [75%vs 33.3%, x2=6.89, P=0.009]. A significant decrease of NF-κB, VEGF, TNF-α levels were shown in the MPC group compared with the MP control group. There was a significant decrease in IL-6 levels in a subgroup analysis of the MPC group. TNF-α levels had a significant correlation with remission [OR=1.35; (95%CI=1.03-1.76); P=0.03]. Conclusion: Curcumin has an efficacy in improving overall remission and decreasing NF-κB, VEGF, TNF-α, and IL-6 levels in myeloma patients.

Correlation of Inflammation and Coagulation Markers with the Incidence of Deep Vein Thrombosis in Cancer Patients with High Risk of Thrombosis.

Background: Deep vein thrombosis (DVT) is a common complication and the second leading cause of death in cancer patients. Pro-inflammatory stimuli in the cancer microenvironment induce nuclear factor kappa B (NF-κB) signaling pathway that plays an integral role in immunothrombosis mechanism. Objective: To investigate the role of inflammatory and coagulation biomarkers in the development of DVT in cancer patients with high risk of thrombosis (Khorana score ≥2). Subjects and methods: This study was a cross-sectional study at Dr. Kariadi General Hospital. The serum levels of proinflammatory cytokines, ie, NF-κB, interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), and coagulation biomarkers, ie, tissue factor (TF), prothrombin fragment F1+2 (F1+2), fibrinogen and D-dimer were measured in newlydiagnosed cancer patients with a highrisk of thrombosis. Color duplex sonography was used for DVT screening. Results: From January to November 2021, there were 83 eligible patients. DVT was confirmed in 8 subjects (9.63%). Univariate analysis revealed a significant difference between the median age of patients with DVT compared to non-DVT patients, 49.5 years (range: 23-60 years) and 42 years (range: 19-60 years), with p=0.046. D-dimer level was higher in DVT patients [(6.020 µg/L, range 2.090-20.000) vs (1.940 µg/L, range 270-20.000), p=0.005]. Multivariate analysis revealed age and D-dimer were significantly correlated with DVT incidence. In all patients, there were significant positive correlations between several inflammatory and coagulation activation parameters, which were IL-6 with D-dimer and F1+2, CRP with F1+2 and D-dimer as well as TNF-α with F1+2. However, these findings were not shown in DVT patients. Conclusion: In cancer patients with a high risk of thrombosis, age and D-dimer level are the significant variables towards the incidence of DVT. In patients with DVT, there was no significant correlation between inflammatory and coagulation activation parameters.

Preventing Thrombosis in Cancer Patients.

Thromboembolism events, either venous (VTE) or arterial thromboembolism (ATE) remain a highly prevalent complication in cancer patients. Thrombosis is a leading cause of death, contributor to significant morbidity, the reason of delayed cancer treatment, leading to increased cancer financing and expenses. Both cancer and its treatment are recently found to be related to vascular inflammation through the induction of tissue factor (TF) expression and promoting a procoagulant state which triggers the activation of coagulation system. Several risk factors may also coexist such as dehydration, immobilization, smoking, obesity, previous DVT, etc. Even in patients with asymptomatic deep vein thrombosis (DVT), they have a three-fold increase in mortality. The high morbidity and mortality of VTE raises the need for thromboprophylaxis to reduce the incidence of overt thrombosis, albeit against its possible side effects related to anticoagulant prescription. This article highlighted the clinical perspectives for thromboprophylaxis while counting on the risk stratification in a particular cancer patient.

The Association Between Triglyceride-Glucose Index as a Marker of Insulin Resistance and the Risk of Breast Cancer.

Background: This study aims to evaluate the association and dose-response between triglyceride-glucose (TyG) index and breast cancer. Method: This is a multicenter case-control study conducted in six public referral hospitals in Indonesia. Cases are individuals aged 19 years or above who were diagnosed with breast cancer within 1 year of diagnosis, based on histopathology and immunohistochemistry. Controls were recruited from corresponding hospitals. TyG index was determined by the formula: ln (fasting TG [mg/dl] × fasting glucose [mg/dl]). Results: There were 212 participants in the breast cancer group and 212 participants in the control group. TyG index was higher in patients with breast cancer (median 8.65 [7.38, 10.9] vs. 8.30 [7.09, 10.84], p < 0.001). When compared with TyG quartile of Q1, Q4 was associated with an OR of 2.42 (1.77, 3.31), p < 0.001, Q3 was associated with an OR of 1.53 (1.21, 1.93), p < 0.001, Q2 was associated with an OR of 1.39 (1.12, 1.73), p = 0.002 for the risk of breast cancer. The dose-response relationship was nonlinear (p < 0.001). On univariate analysis, smoking (OR 2.15 [1.44, 3.22], p < 0.001), use of contraception (1.73 [1.15, 2.60], p = 0.008), alcohol consumption (OR 2.04 [0.96, 4.35], p = 0.064), and TyG Index >8.87 (OR 3.08 [1.93, 4.93], p < 0.001) were associated with risk of breast cancer. Independently associated with increased risk of breast cancer included smoking (OR 1.93 [1.23, 3.01], p = 0.004), use of contraception (OR 1.59 [1.02, 2.48], p = 0.039), and TyG Index >8.87 (OR 2.93 [1.72, 4.98], p < 0.001). Conclusion: TyG index was associated with breast cancer in a nonlinear dose-response fashion.

Von Willebrand factor:antigen and ADAMTS-13 level, but not soluble P-selectin, are risk factors for the first asymptomatic deep vein thrombosis in cancer patients undergoing chemotherapy.

BACKGROUND: There is a high incidence of deep vein thrombosis (DVT) among cancer patients undergoing chemotherapy. Chemotherapy-induced vascular endothelial cell activation (VECA) is characterized by increased plasma levels of von Willebrand factor (vWF) and soluble P-selectin (sP-selectin), leading to the activation of endothelial cells and signaling cascades. The biological role of a disintegrin-like and metalloproteinase with thrombospondin type 1 motif, member 13 (ADAMTS-13) is to control the activity of vWF and consequently the risk of thrombosis. The objective of this study was to investigate the roles of sP-selectin, vWF, and ADAMTS-13 as risk factors for the first episode of DVT in cancer patients undergoing chemotherapy. METHODS: This prospective cohort study was conducted at Dr. Kariadi Hospital, Indonesia, on 40 cancer patients. Prechemotherapy (baseline) and postchemotherapy sP-selectin, vWF antigen (vWF:Ag), and ADAMTS-13 plasma levels were determined with ELISAs before and 3 months after chemotherapy. The clinical characteristics of the patients, cancer type, cancer stage, chemotherapy regimen, ABO blood type, D-dimer level and Khorana risk score were also analyzed using logistic regression. Patients were observed for the possibility of developing DVT during chemotherapy. RESULTS: DVT was confirmed in 5 patients (12.5%) after a period of 3 months. In patients with DVT, sP-selectin and vWF were significantly higher while ADAMTS-13 was lower than in their counterparts. The levels of baseline vWF:Ag and ADAMTS-13, with cut-off points ≥ 2.35 IU/mL and ≤ 1.03 IU/mL, respectively, were found to independently predict the incidence of DVT. In the multivariate logistic regression analysis, the relative risk (RR) for DVT in patients with high vWF:Ag was 3.80 (95% CI 1.15-12.48, p = 0.028), and that for patients with low ADAMTS-13 was 2.67 (95% CI 1.22-23.82, p = 0.005). The vWF:Ag/ADAMTS-13 ratio and both vWF:Ag and ADAMTS-13 dynamics during treatment were also able to differentiate those with prospective DVT. However, sP-selectin and other covariates showed no statistical significance. CONCLUSION: We found that prechemotherapy plasma levels of vWF:Ag ≥ 2.35 IU/mL and ADAMTS-13 ≤ 1.03 IU/mL are independent risk factors for DVT incidence among cancer patients.

Clinical Evaluation for the Role of High-Sensitivity C-Reactive Protein in Combination with D-Dimer and Wells Score Probability Test to Predict the Incidence of Deep Vein Thrombosis Among Cancer Patients.

BACKGROUND: Deep vein thrombosis (DVT) is a frequent complication in cancer patients and is the second leading cause of death. The high level of C-reactive protein (CRP) is an acute phase reactant that induces tissue factor (TF) expression in monocytes, smooth muscle cells, and endothelial cells. The CRP level positively correlates with the incidence, extension, and volume of thrombus. TF expression triggers the coagulation system including the formation of thrombin and circulating fibrin such as prothrombin fragment 1+2 (F1 + 2) and D-dimer. OBJECTIVE: To determine the diagnostic value of high-sensitivity (hs)-CRP, D-dimer, and Wells score combination to predict the incidence of DVT on clinically suspected DVT (Wells score ≥2) cancer patients. SUBJECTS AND METHODS: This study was a cross-sectional study on a diagnostic test to determine the diagnostic value of hs-CRP and D-dimer for early detection of DVT on clinically suspected DVT (Wells score ≥2) cancer patients. It was conducted in Dr. Kariadi Hospital, Semarang Indonesia on 35 subjects. The diagnosis of DVT was confirmed by color duplex sonography. The diagnostic accuracy of combination of hs-CRP, D-dimer, and Wells score was analyzed by logistic regression. RESULTS: DVT was confirmed in 10 subjects (28,6%). The cut-off point of hs-CRP levels for probable DVT was ≥51.05 mg/L and for D-dimer was ≥5030 µg/L. The median levels of both variables were higher in the subjects with DVT compared with the subjects without DVT, but it was not statistically significant. The combination of hs-CRP (≥51.05 mg/L), D-dimer (≥5030 µg/L), and Wells score ≥3 had the high accuracy (94.1%) to predict the incidence of DVT compared with hs-CRP (65.0%), D-dimer (54.7%), and combination of hs-CRP and D-dimer (71.0%). CONCLUSION: The combination of hs-CRP (≥51.05 mg/L), D-dimer (≥5030 µg/L), and Wells score ≥3 can predict the incidence of DVT in cancer.