CAR T-cell therapy and the onco-nephrologist.

Cell therapy, specifically the revolutionary chimeric antigen receptor (CAR) T-cell therapy, has transformed the landscape of oncology, making substantial strides in practical treatment approaches. Today, established guidelines for diseases such as lymphomas, myelomas, and leukemias actively advocate the utilization of these once-unconventional therapies. The practical impact of these therapies is underscored by their unparalleled efficacy, reshaping the way we approach and implement treatments in the realm of oncology. However, CAR T-cell therapy, with its performance in anti-tumor aggression through cellular action and inflammatory response, also comes with various adverse events, one of which is kidney injury. Therefore, the management of these side effects is extremely important. The integration of knowledge between oncologists and specialized nephrologists has led to the emergence of a new sub-area of expertise for onco-nephrologists specializing in managing kidney complications from immune effector therapies.

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.

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.

Impact of independent multidisciplinary work on the survival rate of stage 3 and 4 nasopharyngeal cancer in Indonesia: a retrospective cohort study.

Background: The utilization of a multidisciplinary team (MDT) strategy is a beneficial approach in integrating the knowledge and proficiencies of various fields to produce thorough and advantageous cancer treatment plans for patients. Nevertheless, MDT has yet to be widely adopted in Indonesia. In this study, the authors examined an early form of MDT in Indonesia that does not involve dedicated meetings, referred as independent multidisciplinary work (IMW). The objective is to investigate the differences in survival rates of nasopharyngeal cancer (NPC) patients who underwent treatment with and without IMW. Materials and methods: This study has a retrospective cohort design. Data were collected from the medical records of newly diagnosed stage 3 and 4 NPC patients between 2016 and 2018. The subjects were divided into two groups: the IMW group and the non-IMW group. The primary end point of the study is overall survival rate between the two groups. Kaplan-Meier survival analysis, log-rank test, and cox proportional hazard analysis were used for statistical analysis. Results: This study included a total of 124 patients with NPC, 81 patients in the IMW group and 43 patients in the non-IMW group. At the end of the 36-month follow-up period, the median survival of the IMW group was not reached, while in the non-IMW, it was 12 months [95% confidence intervals (95% CI), 8.78-15.22], hazard ratio (HR): 0.47 (95% CI, 0.28-0.78; P<0.01). The 1-year survival rate was 66.7% in the IMW group versus 46.5% in the non-IMW group (HR=0.7, 95% CI 0.49-0.99; P=0.03); the 2-year survival rate was 40.7% in the IMW group versus 16.3% in the non-IMW group (HR=0.4, 95% CI 0.19-0.83; P<0.01). Daniel Rizky, Vina Yunarvika, and Yasjudan Rastrama Putra, these authors contributed equally to this work. In the multivariate analysis, the IMW approach, ECOG (The Eastern Cooperative Oncology Group) status, distant metastasis, and treatment approach were significantly associated with survival outcome. Conclusion: The use of IMW approach in the treatment of NPC was associated with a better survival outcome compared to non-IMW treatment.

The effect of multidisciplinary team on survival rates of women with breast cancer: a systematic review and meta-analysis.

Breast cancer is quite frequent all around the world. This disease was responsible for an estimated 2.1 million malignancies in 2022, making it the seventh-highest cause of cancer deaths globally. A multidisciplinary team (MDT) care policy was developed in the United Kingdom (UK) in 1995 to enhance the quality of care for cancer patients. The purpose of this systematic review and meta-analysis study is to assess the effects of MDT on breast cancer survival rates. Methods: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. Systematic search was conducted in several international databases including Google Scholar, PubMed, EBSCOhost, and Proquest from 2012 to 2022. The authors used RevMan 5.4 to do the meta-analysis of the pooled hazard ratio. Newcastle-Ottawa Scale to measure the risk of bias. Newcastle-Ottawa Scale evaluated participant selection, comparability, and reporting of results using eight subscale items. Egger's test funnel plot was used to assess the potential publication bias for this study. Results: A total of 1187 studies were identified from research database. The authors found a total of six studies from six different countries (China, the UK, Taiwan, Australia, Africa, and France) included for this study. Based on the meta-analysis of the pooled hazard ratio of the included studies, the authors found that the overall effect size of the study was 0.80 (CI 95%: 0.73-0.88). Conclusions: Breast cancer patients who participated in well-organized MDT discussions had a greater survival rate than those who did not.

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.

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.

A full-term pregnant woman with secondary Evans syndrome caused by severe coronavirus disease 2019: a case report.

BACKGROUND: In this report, we describe a very challenging case of a patient with secondary Evans syndrome caused by severe coronavirus disease 2019 infection in a pregnant full-term woman. CASE PRESENTATION: A 29-year-old full-term pregnant Indonesian woman presented with gross hematuria, dry cough, fever, dyspnea, nausea, anosmia, and fatigue 5 days after confirmation of coronavirus disease 2019 infection. Laboratory examinations showed very severe thrombocytopenia, increased indirect bilirubin, and a positive direct Coombs' test. From peripheral blood, there was an increased number of spherocytes, which indicated an autoimmune hemolytic process. Antinuclear antibody and anti-double-stranded DNA test results were negative, and her virology serological markers are also negative for human immunodeficiency virus, cytomegalovirus, and hepatitis B and C. Despite aggressive treatment with platelet transfusion, high-dose steroid, and thrombopoietin receptor agonists, the platelet count did not recover, and a speculative cesarean delivery had to be done with a very low platelet count.