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.

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.

Preliminary study of hypoxia markers in diffuse large B-cell lymphoma.

While the association of hypoxia has been established in various types of solid cancers, little is known about its presence and existence in diffuse large B-cell lymphoma (DLBCL). The purpose of the present study was to evaluate the expression of hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGF-A) in DLBCL and to analyze the association of these factors with several clinical and pathological characteristics. The immunohistochemical protein expression of HIF-1α and VEGF-A was investigated in 34 de novo DLBCL tumor samples from January 2017 to December 2017 from the Department of Hematology/Medical Oncology and Anatomical Pathology at Dr Kariadi Hospital (Semarang, Indonesia). The present study revealed by using immunohistochemistry (IHC), that hypoxic markers were overexpressed (88.2% for both HIF-1α and VEGF-A) in the vast majority of patients with DLBCL. Only in 4 tumors, was HIF-1α expression normal, and interestingly VEGF-A was negative as well. There was a significant correlation in the intensity of staining of HIF-1α and VEGF-A using our custom scoring system in surgically resected tissues (r=0.475; P=0.005). Both HIF-1α and VEGF-A were also associated to serum LDH and tumor diameter. Collectively, HIF-1α and VEGF-A were predominantly expressed in the majority of DLBCL tumor cells. The findings of the present study indicate the existence of hypoxia in DLBCL tumors similar to numerous solid cancers, and thus warrants further investigation to clarify its role as a potential pathogenic or prognostic marker in this type of hematological cancer.

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 Use of Etoposide, Ara-Cytarabine, and Melphalan (EAM) Conditioning Chemotherapy in Autologous Stem Cell Transplantation (ASCT) for a Patient with Relapsed Hodgkin's Lymphoma.

Up to 20-40% of patients with Hodgkin's lymphoma will eventually relapse after treatment, among which early relapse confers a poor outcome. With salvage chemotherapy followed by autologous stem cell transplantation (ASCT), the long-term remission rate is 30%. We report our experience of using a modified-BEAM conditioning regimen without BCNU consisting of etoposide, cytarabine, and melphalan (EAM) in a patient with relapsed Hodgkin's lymphoma. Before transplantation, the patient achieved second complete remission (CR2) using brentuximab vedotin and ESHAP (BR-ESHAP) chemotherapy. The ASCT went well without significant complications. This case demonstrated the considerable efficacy of EAM protocol as a conditioning regimen in terms of sufficient ablative capabilities, and the patient showed a successful hematopoietic engraftment. Although durability of the disease-free survival needs further observation, it had nearly 18 months of complete remission and the patient was in good performance status at the time of writing this manuscript.

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.

Biventricular Cardiac Hypertrophy in a Patient with Primary Aldosteronism and Atrial Septal Defect.

BACKGROUND Primary aldosteronism can be caused by adrenocortical adenoma and is usually associated with left ventricular hypertrophy. Biventricular cardiac hypertrophy and heart failure in the presence of a pre-existing atrial septal defect (ASD) are a rare association of primary aldosteronism. CASE REPORT A 33-year-old woman with resistant hypertension and refractory hypokalemia presented with signs and symptoms of heart failure. She had previously been diagnosed having a right adrenal tumor and ostium secundum type ASD. Transthoracic echocardiography confirmed the location of the ASD, with a left-to-right cardiac shunt, moderate to severe tricuspid insufficiency, moderate pulmonary hypertension (60 mm Hg), four chamber dilatation and biventricular hypertrophy. The left ventricular ejection fraction was 17%. Endocrine function tests showed a raised plasma aldosterone concentration (PAC) to plasma renin activity (PRA) ratio, which supported a diagnosis of primary aldosteronism. A captopril suppression test failed to suppress the patient's PAC, which confirmed the diagnosis. The patient underwent a right adrenalectomy with subsequent normalization of hypokalemia, PAC, and PAC to PRA ratio and her hypertension was managed successfully with monotherapy. Surgical pathology examination of the tumor revealed an adrenocortical adenoma. At follow-up at 18 months, the patient had a normal potassium level, and her cardiac function and ventricular geometries were improved. CONCLUSIONS Reversible cardiac hypertrophy is rarely associated with primary aldosteronism, however, it should be recognized. Present findings suggest that aldosteronism contributes to cardiac remodelling and biventricular hypertrophic changes. Administering appropriate treatment in a timely manner, can reverse cardiac changes along with the other symptoms of primary aldosteronism.

Clinical profile and outcome of diabetic foot ulcer, a view from tertiary care hospital in Semarang, Indonesia.

Background: This study attempted to determine the disease burden in terms of clinical profile and outcome of diabetic foot ulcer (DFU) admissions at a tertiary care hospital in a developing country. Methods: In this descriptive study, the data were collected from the medical record of diabetic patients with foot ulcer who were treated in Dr. Kariadi General Hospital during a 3-year period. The demographic characteristic, type of foot lesion, etiology, isolated microorganism, treatment, and outcome were reviewed. Results: Foot problems accounted for 16.2% of total diabetic admission (n = 1429). All patients had type 2 diabetes with no gender predominance. The mean age was 54.3 ± 8.6 years and diabetes control was very poor. Before admission, the ulcers had already developed for 4.7 ± 2.9 weeks; however, the majority of patients were unaware of the preceding causes. Ulcers were neuropathic in 42.2% of cases, neuroischemic in 29.9%, and pure ischemic at lesser percentage. More than 70% of ulcers were in Wagner grade ≥3 with infection event in nearly all patients. The most common isolates from culture were Gram-negative bacteria. A total of 98 (36.3%) lower extremity amputations (LEAs) at various level of the foot were carried out, including major LEA in 24 patients and multiple amputations in seven patients. Mortality rate due to DFU reached 10.7%. Conclusions: Diabetic foot problems constitute a source of morbidity, a reason for LEA surgery as well as being a cause of death among patients with diabetes mellitus.

Risk factors for lower extremity amputation in patients with diabetic foot ulcers: a hospital-based case-control study.

BACKGROUND: Diabetic foot ulcers (DFU) may cause significant morbidity and lower extremity amputation (LEA) due to diabetic foot problems can occur more often compared to the general population. The purpose of the present study was to use an epidemiological design to determine and to quantify the risk factors of subsequent amputation in hospitalized DFU patients. METHODS: We performed a hospital-based, case-control study of 47 DFU patients with LEA and 47 control DFU patients without LEA. The control subjects were matched to cases in respect to age (±5 years), sex, and nutritional status, with ratio of 1:1. This study was conducted in Dr. Kariadi General Hospital Semarang between January 2012 and December 2014. Patients' demographical data and all risk factors-related information were collected from clinical records using a short structural chart. Using LEA as the outcome variable, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) by logistic regression. Univariate and stepwise logistic regression analyses were used to assess the independent effect of selected risk factors associated with LEA. The data were analyzed in SPSS version 21. RESULTS: There were 47 case-control pairs, all of which were diagnosed with type 2 diabetes mellitus. Seven potential independent variables show a promise of influence, the latter being defined as p≤0.15 upon univariate analysis. Multivariable logistic regression identified levels of HbA1c ≥8% (OR 20.47, 95% CI 3.12-134.31; p=0.002), presence of peripheral arterial disease (PAD) (OR 12.97, 95% CI 3.44-48.88; p<0.001), hypertriglyceridemia (OR 5.58, 95% CI 1.74-17.91; p=0.004), and hypertension (OR 3.67, 95% CI 1.14-11.79; p=0.028) as the independent risk factors associated with subsequent LEA in DFU. CONCLUSIONS: Several risk factors for LEA were identified. We found that HbA1c ≥8%, PAD, hypertriglyceridemia, and hypertension have been recognized as the predictors of LEA in this study. Good glycemic control, active investigation against PAD, and management of comorbidities such as hypertriglyceridemia and hypertension are considered important to reduce amputation risk.