Elevated LDH Levels Research Articles

Bone marrow necrosis in paediatric patients: a diagnostic dilemma

Bone marrow necrosis (BMN) is regarded as an infrequent and rare pathological finding in the aspirates and the trephine biopsies. It is a rare histological finding which may be associated with infections, sickle cell disease, leukemia and other diseases. Its postmortem prevalence ranges from 0.3% to 2.2%., BMN might also be seen prior to, or following a diagnosis of neoplasia, ordering subsequent treatments with chemotherapy or radiotherapy. Cellular elements can be masked by the extensive necrosis, leading to a non-diagnosis and can also precede the disease pathology before its presentation, which can lead to delay in accurate diagnosis. This study was done to highlight the rare findings of BMN and to scrutinize the underlying disease producing BMN after evaluating medical history, clinical presentation, laboratory findings and morphological analysis of bone marrow aspirations and biopsy. A cross-sectional observational study was done for a period of 3 years and this rare finding was observed only in five cases. This study indicates that the conditions associated with BMN are varied and malignancy remains common. BMN may precede or obscure the diagnosis, and repeat biopsies are indicated to secure a diagnosis. Pyrexia, bone pain, pancytopenia, elevated LDH and alkaline phosphatase levels are common associates of BMN.

Primary tumour category, site of metastasis, and baseline serum S100B and LDH are independent prognostic factors for survival in metastatic melanoma patients treated with anti-PD-1.

Prognostic classification of metastatic melanoma patients treated with anti-PD-1 is of great interest to clinicians. We aimed to determine the anti-PD-1 treatment related prognostic performance of demographics, clinical and histological prognostic markers and baseline serum S100B and LDH levels in advanced melanoma. A total of 200 patients with unresectable metastatic melanoma were included in this retrospective study. 34.5% had stage M1c disease and 11.5% had stage M1d disease at the start of therapy. 30% had pT4b primary melanoma. 55.5% had elevated baseline serum S100B levels and 62.5% had elevated baseline serum LDH levels. We analysed the risk of death using univariate and multivariate Cox proportional-hazards models and the median overall (OS) and progression-free (PFS) survival using the Kaplan-Meier estimator. The median follow-up time from the start of anti-PD-1 treatment in patients who were alive at the end of the study (N=81) was 37 months (range: 6.1-95.9). The multivariate Cox regression analysis showed that M1c stage (vs. M1a, p=0.005) or M1d stage at the start of therapy (vs. M1a, p=0.001), pT4b category (vs. pT1a, p=0.036), elevated baseline serum S100B levels (vs. normal S100B, p=0.008) and elevated LDH levels (vs. normal LDH, p=0.049) were independently associated with poor survival. The combination of M1d stage, elevated baseline serum S100B and LDH levels and pT4b category was associated with a very high risk of death (HR 4.72 [1.81; 12.33]). In the subgroup of patients with pT4b primary melanoma, the median OS of patients with normal serum S100B levels was 37.25 months [95% CI 11.04; 63.46]), while the median OS of patients with elevated serum S100B levels was 8.00 months [95% CI 3.49; 12.51]) (p<0.001); the median OS of patients with normal serum LDH levels was 41.82 months [95% CI 11.33; 72.32]), while the median OS of patients with elevated serum LDH levels was 12.29 months [95% CI 4.35; 20.23]) (p=0.002). Our real-world study indicates that the prognostic role of primary melanoma parameters is preserved in anti-PD-1 treated stage IV patients. Furthermore, there seems to be perspective in combining clinical, histological and serum prognostic markers in a prognostic model.

Value of the HFA-PEFF diagnostic algorithms for heart failure with preserved ejection fraction to the inflammatory myopathy population

ObjectivesThe HFA-PEFF score has been validated to hold great diagnostic and prognostic utility for heart failure with preserved ejection fraction (HFpEF). Idiopathic inflammatory myopathy (IIM) is recognized as one of the potential etiologies underlying HFpEF. Here, we intended to investigate the real prevalence of HFpEF in IIM via the HFA-PEFF score and explore the prognostic value of this score.MethodsTwo hundred twenty IIM patients were enrolled for assessment. The cohort was divided into low, intermediate and high tertiles of the HFA-PEFF score. Spearman’s correlation analysis was used to explore the association between the score and disease activity. Chi-square test was applied to investigate the distribution discrepancy of HFA-PEFF tertiles among patients with different myositis-specific antibodies (MSAs) or myositis-associated antibodies (MAAs). Univariate and multivariate ordinal regression analyses were performed to screen risk factors for high HFA-PEFF scores. Survival curves were obtained using the Kaplan–Meier method and log-rank tests.ResultsIn total, 79 (35.9%), 107 (48.6%) and 34 (15.5%) patients were rated low, intermediate and high probability of HFpEF, respectively. The HFA-PEFF score correlated well with disease activity. Patients with positive AMA-M2 scored higher in the HFA-PEFF score (p = 0.011). During follow-up, patients with positive AMA-M2 or anti-SRP antibody developed an inclination towards concentric hypertrophy on echocardiography. Additionally, palpitation symptom, AMA-M2 positivity and elevated serum levels of LDH, cTnI were independent risk factors for high HFA-PEFF scores. Finally, a high-tertile HFA-PEFF score was related to lower overall survival rate (p < 0.001). Patients with positive AMA-M2 had poorer outcomes (p = 0.002).ConclusionHFpEF was prevailing in IIM patients according to the HFA-PEFF score. The HFA-PEFF score correlated well with disease activity and held significant prognostic value. Patients with AMA-M2 antibody were prone to have poor outcomes.

Factors Affecting Hospitalization Length and in-Hospital Death Due to COVID-19 Infection in Saudi Arabia: A Single-Center Retrospective Analysis.

The emerging COVID-19 coronavirus disease has widely spread, causing a serious worldwide pandemic. Disease severity and mortality risk can be predicted using an analysis of COVID-19 clinical characteristics. Finding out what influences patients' hospitalization length and in-hospital mortality is crucial for decision-making and planning for emergencies. The goal of this study is to identify the factors that influence hospital stay length and in-hospital death due to COVID-19 infection. This cross-sectional study was conducted from August to October 2020 and included 630 patients with a confirmed diagnosis of COVID-19 infection. Using odds ratios (OR) and 95% confidence intervals (CI), a multivariable logistic regression model was used to assess the variables that are linked to longer hospital stays and in-hospital deaths. Most patients were male (64.3%), and most were older than 40 years (81.4%). The mean length of hospital stay (LoHS) was 10.4±11.6 days. The overall death rate among these COVID-19 cases was 14.3%. Non-survivors were older, had more comorbidities, had prolonged LoHS with increased ICU admission rates and mechanical ventilation usage, and had a more severe condition than survivors. ICU admission, low serum albumin, and elevated LDH levels were associated with longer LoHS, while ICU admission, DM, and respiratory diseases as comorbidities, total leukocytic count, and serum albumin were predictors of mortality. Longer LoHS due to COVID-19 infection was linked to ICU admission, low serum albumin, and elevated LDH levels, while the independent predictors of in-hospital death were ICU admission, DM, and respiratory diseases as comorbidities, total leukocytic count, and serum albumin.

Clinical Profile and Determinants of Mortality in Patients with Interstitial Lung Disease Admitted for COVID-19.

Concern has risen about the effects of COVID-19 in interstitial lung disease (ILD) patients. The aim of our study was to determine clinical characteristics and prognostic factors of ILD patients admitted for COVID-19. Ancillary analysis of an international, multicenter COVID-19 registry (HOPE: Health Outcome Predictive Evaluation) was performed. The subgroup of ILD patients was selected and compared with the rest of the cohort. A total of 114 patients with ILDs were evaluated. Mean ± SD age was 72.4 ± 13.6 years, and 65.8% were men. ILD patients were older, had more comorbidities, received more home oxygen therapy and more frequently had respiratory failure upon admission than non-ILD patients (all p < 0.05). In laboratory findings, ILD patients more frequently had elevated LDH, C-reactive protein, and D-dimer levels (all p < 0.05). A multivariate analysis showed that chronic kidney disease and respiratory insufficiency on admission were predictors of ventilatory support, and that older age, kidney disease and elevated LDH were predictors of death. Our data show that ILD patients admitted for COVID-19 are older, have more comorbidities, more frequently require ventilatory support and have higher mortality than those without ILDs. Older age, kidney disease and LDH were independent predictors of mortality in this population.

CNS RELAPSE OF DIFFUSE LARGE B‐CELL LYMPHOMA AND ROLE OF UPFRONT PROPHYLAXIS: A 10‐YEAR SINGLE CENTER EXPERIENCE

Introduction: Central nervous system (CNS) relapse of diffuse large B-cell lymphoma (DLBCL) is a rare event, occurring in about 5% of patients (pts) and correlating with a very dismal prognosis. Much debate has surrounded the use of strategies to avert CNS disease recurrence. Nowadays, CNS prophylaxis is mostly based on high-dose intravenous (iv) methotrexate (HD-MTX), but its effectiveness is controversial. Our study focuses on pts with CNS relapse of DLBCL in order to evaluate their clinical and biological features, the validity of known prognostic scores, the efficacy of CNS prophylaxis, prognosis and treatment at the time of relapse. Methods: All pts with DLBCL diagnosed between January 2010 and December 2021 at AOU Città della Salute e della Scienza di Torino and treated with curative intent were selected: 498 cases with at least 12 months of follow-up were identified. Pts with primary mediastinal lymphoma, primary testicular lymphoma or CNS disease at diagnosis were excluded. Results: The case series included 406 pts. Mean age was 67 years, 56/400 had ECOG PS ≥ 2 (14%), 231/400 elevated LDH levels (58%), 251/404 were stage IV (62%), 192/374 IPI score ≥ 3 (51%), 189/373 CNS-IPI 2–3 (51%), 91/373 CNS-IPI 4–6 (24%). 95/397 pts received CNS prophylaxis (24%): 59 by intrathecal (IT) route only (15%) (n 26 CNS-IPI 2-3; n 29 CNS-IPI 4-6), 25 by iv MTX only (6%) (n 17 HD-MTX ≥3 g/mq; n 6 CNS-IPI 2-3; n 16 CNS-IPI 4-6), and 11 by combined route (3%) (n 5 CNS-IPI 2-3, n 6 CNS-IPI 3–6). 12 pts experienced CNS relapse; 8/12 exclusively CNS and 4/12 along with systemic recurrence. The cumulative incidence at 3 years was 2.8%. In univariate analysis CNS relapse risk was significantly influenced by ECOG PS and elevated LDH levels, while the use of prophylaxis was not shown to impact the risk of CNS recurrence. However, none of the pts who received systemic MTX prophylaxis had subsequent CNS disease, while 2/59 pts who received exclusive IT prophylaxis had CNS relapse with an incidence superimposable to the whole cohort (3.3%). In multivariate analysis, only ECOG PS confirmed significant correlation with the risk of such disease recurrence (Figure 1). With a mean follow-up of 36 months, the 3-year overall survival for pts with SNC recurrence was 30%. Encore Abstract—previously submitted to EHA 2023 Keyword: aggressive B-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

EXCELLENT OUTCOMES OF SUBCUTANEOUS PANNICULITIS‐LIKE T‐CELL LYMPHOMA TREATED WITH CYCLOSPORIN‐BASED REGIMEN, A MULTICENTER RETROSPECTIVE STUDY IN THAILAND

Background: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma, characterized by primary cutaneous tissue involvement mimicking inflammatory panniculitis. Treatment for this disease is still under debated between conventional chemotherapy or immunosuppressive agents like cyclosporin and prednisolone. Material and Methods: A multicenter retrospective study was conducted among adult patients who was diagnosed as subcutaneous panniculitis-like T-cell lymphoma from January 2013 to December 2020, in 15 medical centers in Thailand. The patient demographic data, treatment regimens which divided into conventional chemotherapy or immunosuppressive agents, and treatment outcomes were retrieved from the Thai lymphoma registry database. All of aspects were analyzed and compared between the treatment group. Results: A total of 34 patients were reviewed in this cohort. The median age was 30 years (range;16–64) with female predominance (67.6%). The majority of patients was diagnosed as advanced stage of disease as Ann Arbor stage IV (58.8%). All patients presented with skin and subcutaneous involvement while one-fourth of them had extra-cutaneous lesions including liver (14.7%) and bone marrow (11%). B symptom was observed in 64% and elevated LDH level in 70.6% of the patients which represented the high disease burden. However, almost all of our patients were in good performance status (ECOG 1–2). For treatment options, 41% of the patients received conventional chemotherapy, mostly CHOP, while 38% received cyclosporin containing regimens. The overall response rate (ORR) was 64% in chemotherapy group and 76% in cyclosporin group, which was comparable. Precisely 57% and 76% of the patients in conventional chemotherapy and cyclosporin treatment, respectively, had complete remission. Patients with Ann Arbor stage IV were received conventional chemotherapy as first-line treatment for 69%, on the other hand, 31% received cyclosporin-based treatment, which was in complete remission around 60% on both groups. With median follow up time of 35.2 months, the overall survival and progression free survival were not reached in both groups. Conclusions: Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma which predominantly affects young female and usually presents with extranodal lesions especially skin and subcutaneous tissues, bone marrow, and liver. Patients were responded well to cyclosporin-based treatment both limited and advanced stages of the disease. Keywords: chemotherapy, cyclosporin, Subcutaneous panniculitis-like T-cell lymphoma Keyword: Cutaneous non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

Clinical benefit of personalized treatment following high throughput sequencing in metastatic melanoma: A national retrospective study.

e21534 Background: Despite the approval of effective therapies in metastatic melanoma, durable benefit concerns only a fraction of patients and new therapeutic options are still needed. Next generation sequencing is now widely available to screen for targetable genomic alterations. Clinical impact of personalized medicine strategies in melanoma, outside classical targeting, have little been reported yet. Methods: By means of the Group of Cutaneous Oncology of the French Society of Dermatology, we retrospectively included all metastatic melanoma patients, aged 18 and over, for whom a molecular testing has identified one, or more, actionable molecular alterations and who received molecularly matched therapy accordingly, between 2018 and 2022. We excluded patients with only BRAF, NRAS or CKIT alterations and patients who received molecularly matched therapy for less than 15 days. Response was evaluated using RECIST 1.1 criteria. Results: We included 26 patients, median age was 63 years [24-89] and sex ratio 2.7. They had been heavily pretreated (58% have received 3 or more previous lines of treatment); 77% had 3 or more metastatic sites; 58% elevated LDH levels; and 42% and 35% had brain and liver metastasis respectively; 69 % had an ECOG PS 0 or 1. Actionable molecular alterations affected MAP kinase pathway in 12/26 cases: 10 of them received trametinib for GNA11 mutations (n = 4), MAP2K1 mutations (n = 2), CBL mutation (n = 1), NF1 loss (n = 1), FYCO1-RAF1 fusion (n = 1) and KRAS amplification (n = 1) while tipifarnib was given for an HRAS mutation and sunitinib for a CBL mutation. Cell cycle pathway was targeted in 7/26 cases with abemaciclib for a CDKN2A/B mutation, palbociclib for CDKN2A deletion, ribociclib and binimetinib for concurrent loss of CDKN2A and NRAS mutations (n = 2) and siremaldin and ribociclib for CCND1 amplification and MDM2/ CDK4 amplification (n = 2). PIK3CA pathway was targeted with alpelisib (n = 1) and with sirolimus for 1 PTEN mutation. EGFR, ALK and MET mutations were targeted using afatinib, alectinib and cabozantanib respectively. BRCA spectrum ( ATM and BRCA1) was targeted with olaparib in 2 patients in combination with dabrafenib and trametinib for one patient who had relapsed under this therapy. 11/26 patients responded to this molecularly matched strategy with 4 partial responses and 7 stable diseases including 5 ≥ 6 months stable diseases, with a median follow-up of 8 months [1-54]. Among responders, median duration of response was 6.5 months [2.5-13] and 3 are still ongoing. Responding patients had GNA11 (n = 2), MAP2K1, FYCO1-RAF1, HRAS, ATM, CCND1 (n = 2), MDM2/ CDK4 and CDKN2A/NRAS (n = 2) alterations. Conclusions: High throughput sequencing followed by matched targeted therapy is a promising approach in metastatic melanoma patients refractory to approved treatments, underlying the importance of access to molecular testing and molecular tumor boards.

17th International Conference on Malignant Lymphoma, Palazzo dei Congressi, Lugano, Switzerland, 13 - 17 June, 2023.

Introduction: Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type I (HTLV-1), endemic in some areas of the world, such as Brazil. Between 3% and 5% of HTLV-1-infected individuals develop ATL after a long latency. The clinical features are heterogeneous and classified into acute, lymphoma, chronic and smoldering types. Acute and lymphoma types are defined as aggressive whereas the others as indolent ATL. On April 2017, the T-cell Brazil project was launched. Methods: Ambispective observational study design collected 90 ATL patients from 606 registered cases in the T-Cell Brazil Project. Its main goal is to describe demographic and clinical features, analyze the overall and progression-free survival (OS and PFS), and try to identify factors that could influence them. REDcap Platform has been used to collect and store data, and the IBM-SPSS version 24 for statistical analysis. Results: The median age was 50 years (23–88), 59% female; 50% was lymphoma subtype, followed by 33% acute (both aggressive), 12% chronic and 5% smoldering (indolent); 87% had advanced stage disease (III-IV, Ann Arbor), 57% had B symptoms and 11% had Central Nervous System involved. Both indolent and aggressive had elevated serum LDH levels. 25% received chemotherapy plus immunotherapy, whilst 46% took chemotherapy alone with anthracycline-based regimens (46% CHOEP; 33% CHOP; 21% others). The best response (complete plus partial) after 1st line of treatment reached 50%; 31% had no response or progression; 13% was undetermined due early death; 5% were on treatment, and 1% had stable disease (without treatment). Median follow-up was ten months (0–78) and 18 months for 35% of alive cases. OS for 24 months was 34% (95% CI: 24%–44%), whereas 24-month PFS was 20% (95% CI: 12%–28%). Indolent presented better OS and PFS when compared with Aggressive; 86% versus 33%, P = 0.001 for OS and 45% versus 12%, P = 0.002 for PFS. Public medical care had worst OS and PFS than private (P = 0.14 and P = 0.05). The multivariate Cox Regression for OS resulted hypoalbuminemia - albumin <3.5 g/dL (HR 2.13 CI95% 1.10–4.12, P = 0.024) plus LDH twice the normal value (HR 2.49 CI95% 1.17–5.32, P = 0.018) as predictors. And for PFS were male (HR 1.83 CI95% 1.03–3.24, P = 0.037), ECOG > 1 (HR 2.01 CI95% 1.10–3.70, P = 0.023) and hypoalbuminemia (HR 3.35 CI95% 1.82–6.17, P < 0.0001). The research was funded by: Educational Support by Takeda Keyword: aggressive T-cell non-Hodgkin lymphoma No conflicts of interests pertinent to the abstract.

P435 THE IMPORTANCE OF CORRELATION BETWEEN HEART FAILURE AND THYROID: A CASE REPORT

Abstract A 39–year–old African man was admitted to our department within a four days symptoms of short of breath, cough, tachycardia and lower limb edema. He also complained headache for about a month. He denied fever, chest pain and loss of consciousness. Clinical and family history were unremarkable. Blood tests showed moderate microcytic anemia ( Hb 9.6 g/dl, MCV 93.3 fL), hypoalbuminemia ( Albumin: 3.20 g/dl), elevated levels of LDH ( LDH: 246 U/L), mild C–reactive protein (CRP) and pro–Brain Natriuretic Peptide (pro–BNP) increase (CRP: 1.14 mg/dl); (PRO–BNP: 1133 pg/mL) and negative troponin. Given the clinical picture suggestive of heart failure, we immediately started diuretic therapy with benefit. Chest–x ray revealed a modest thickening of the pulmonary interstitium, electrocardiogram (ECG) a sinus rhythm and early repolarization changes. Chest CT highlighted a bilateral apical–basal pleural effusion, a bilateral hilar ectasia and interstitial markings due to stasis. He underwent an ultrasound of the abdomen that was normal. Thyroid function tests showed high levels of thyroid hormones with suppressed TSH and elevated levels of Ab anti–receptor TSH ( FT3: 8.73 pg/mL; FT4: 2.35 ng/dL; TSH&amp;lt;0.01 mUI/ml; TRAB: 3.62 UI/L). Thyroid ultrasound showed a multinodular goiter. The patient began therapy with Tapazole. Echocardiogram didn’t show any evidence of acute heart disease and systolic function was normal. After discharge he performed a heart MRI with evidence of no alteration of global systolic function, of regional left and right ventricular kinetics or of pathological areas of delayed enhancement in relation to myocardial edema/fibrosis/necrosis. Hyperthyroid patients can show signs and symptoms of heart failure that are due to the hyperdynamic circulatory state and/or to the frequent pulmonary arterial hypertension and our case report demonstrates that this clinical status tends to improve with the restoration of euthyroidism, but if left untreated, can worsen over the time leading to heart failure.

Towards Predicting Length of Stay and Identification of Cohort Risk Factors Using Self-Attention-Based Transformers and Association Mining: COVID-19 as a Phenotype.

Predicting length of stay (LoS) and understanding its underlying factors is essential to minimizing the risk of hospital-acquired conditions, improving financial, operational, and clinical outcomes, and better managing future pandemics. The purpose of this study was to forecast patients' LoS using a deep learning model and to analyze cohorts of risk factors reducing or prolonging LoS. We employed various preprocessing techniques, SMOTE-N to balance data, and a TabTransformer model to forecast LoS. Finally, the Apriori algorithm was applied to analyze cohorts of risk factors influencing hospital LoS. The TabTransformer outperformed the base machine learning models in terms of F1 score (0.92), precision (0.83), recall (0.93), and accuracy (0.73) for the discharged dataset and F1 score (0.84), precision (0.75), recall (0.98), and accuracy (0.77) for the deceased dataset. The association mining algorithm was able to identify significant risk factors/indicators belonging to laboratory, X-ray, and clinical data, such as elevated LDH and D-dimer levels, lymphocyte count, and comorbidities such as hypertension and diabetes. It also reveals what treatments have reduced the symptoms of COVID-19 patients, leading to a reduction in LoS, particularly when no vaccines or medication, such as Paxlovid, were available.

Abstract 2004: Selective cytotoxicity of multiple myeloma using novel cell membrane lipid-extracted nanoliposomes

Abstract Background: Multiple Myeloma (MM) is a highly malignant hematologic disease that originates in the bone marrow from tumorigenic plasma cells that rapidly proliferate and often metastasize before detection or symptom manifestation. Due to the enhanced anaerobic metabolism of cancer vis-a-vis normal cells, elevated media levels of LDH following cell death can serve as a reliable benchmark for in-vitro targeted MM treatment efficacy. Cell membrane Lipid Extracted Nanoliposomes (CLENs) are novel drug delivery vehicles that demonstrate preferential uptake by neoplastic cells. By varying the composition of CLENs, they can be tailored to optimize liposomal uptake by MM cells. This study evaluates the degree to which optimized in-vitro cellular uptake of CLENs translates to cytotoxicity by comparing the attrition rate of doxorubicin hydrochloride (DOX)-loaded MM CLENs compared to relevant liposomal and cellular controls. Methods: The RPMI 8226 cell line was this study’s cellular model for MM. RPMI-8226 cells were seeded at 10,000 cells/mL in 48 well plates. The Y79 (retinoblastoma) cell line served as the negative control for all in vitro experiments. Both cell lines were exposed to two different liposome preparations loaded with 3 mol% doxorubicin hydrochloride (DOX), a MM targeted CLENs preparation of 95% DOPC and 5 mol% RPMI-8226 cell lipid extract (LE) and a non-specific, 100 % DOPC liposome. Liposome preparations were separated from free drug by centrifugation and overnight dialysis. Following overnight liposome exposure, the CyQUANTTM LDH Cytotoxicity Assay Kit (Invitrogen) was utilized to assess extracellular LDH activity and evaluate cytotoxicity of DOX-loaded RPMI-8226 LE in vitro. Results: The mean diameter for the DOX-loaded DOPC (100%) and DOPC/LE (95/5) nanoliposomes was 203 ± 24.3 nm (n=4) and 235 ± 24.6 nm (n=4), respectively. The average zeta potential was -15.79 ± 0.33 mV (n=2) and 0.26 ± 0.19 mV (n=2) for DOPC (100%) and DOPC/LE (95/5), respectively. The mean percent of doxorubicin incorporated into DOPC (100%) and DOPC/LE (95/5) was 72% (n=4) and 84% (n=4), respectively. Following overnight exposure of RPMI 8226 cells to DOX-loaded DOPC (100%) and DOX-loaded DOPC/LE (95/5) at 50 nM and 150 nM, preliminary results showed that the inclusion of LE significantly improved cytotoxicity when compared to the DOX-loaded DOPC control. Additionally, DOX-loaded DOPC/LE (95/5) displayed enhanced extracellular LDH activity compared to the DOX-loaded DOPC control, indicated by higher red formazan fluorescence intensity. There was no difference in LDH activity or cytotoxicity between the two DOX-loaded preparations against Y79 (negative control) cells. Conclusions: Preliminary results suggest that RPMI 8226-CLENs represent an improvement over the use of more conventional nanoliposome preparations. Future studies will evaluate additional drug-loaded CLENs in vitro. Citation Format: Matthew Amorin, Peter Daley, William Smullen, Robert Campbell. Selective cytotoxicity of multiple myeloma using novel cell membrane lipid-extracted nanoliposomes [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 2004.

SARS-CoV-2 immune complex triggers human monocyte necroptosis.

We analyzed the ability of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) itself and SARS-CoV-2-IgG immune complexes to trigger human monocyte necroptosis. SARS-CoV-2 was able to induce monocyte necroptosis dependently of MLKL activation. Necroptosis-associated proteins (RIPK1, RIPK3 and MLKL) were involved in SARS-CoV-2N1 gene expression in monocytes. SARS-CoV-2 immune complexes promoted monocyte necroptosis in a RIPK3- and MLKL-dependent manner, and Syk tyrosine kinase was necessary for SARS-CoV-2 immune complex-induced monocyte necroptosis, indicating the involvement of Fcγ receptors on necroptosis. Finally, we provide evidence that elevated LDH levels as a marker of lytic cell death are associated with COVID-19 pathogenesis.

Niclosamide does not modulate airway epithelial function through blocking of the calcium activated chloride channel, TMEM16A.

Niclosamide and benzbromarone have been described as inhibitors of the calcium activated chloride channel, TMEM16A, and on this basis have been considered and tested as clinical candidates for the treatment of airway diseases. However, both compounds have previously demonstrated activity on a range of additional biological targets and it is unclear from the literature to what extent any activity on TMEM16A may contribute to efficacy in these models of airway disease. The aim of the present study was therefore to examine the pharmacology and selectivity of these clinical candidates together with a structurally unrelated TMEM16A blocker, Ani9, in a range of functional assays to better appreciate the putative role of TMEM16A in the regulation of both epithelial ion transport and the development of an airway epithelial mucus secretory phenoptype. Benzbromarone and Ani9 both attenuated recombinant TMEM16A activity in patch clamp studies, whereas in contrast, niclosamide induced a paradoxical potentiation of the TMEM16A-mediated current. Niclosamide and benzbromarone were also demonstrated to attenuate receptor-dependent increases in intracellular Ca2+ levels ([Ca2+]i) which likely contributed to their concomitant attenuation of the Ca2+-stimulated short-circuit current responses of FRT-TMEM16A and primary human bronchial epithelial (HBE) cells. In contrast, Ani9 attenuated the Ca2+-stimulated short-circuit current responses of both cell systems without influencing [Ca2+]i which supports a true channel blocking mechanism for this compound. Additional studies using HBE cells revealed effects of both niclosamide and benzbromarone on global ion transport processes (absorptive and secretory) as well as signs of toxicity (elevated LDH levels, loss of transepithelial resistance) that were not shared by Ani9. Ani9 also failed to influence the IL-13 induced differentiation of HBE towards a goblet cell rich, mucus hypersecreting epithelium, whereas niclosamide and benzbromarone attenuated numbers of both goblet and multiciliated cells, that would be consistent with cellular toxicity. Together these data challenge the description of niclosamide as a TMEM16A blocker and illustrate a range of off-target effects of both niclosamide and benzbromarone which may contribute to the reported activity in models of airway function.

The effect of CT-based cardiothoracic ratio on survival of COVID-19 patients

Objectives: We aimed to investigate the relationship between computed tomography (CT)- based cardiothoracic ratio (CTR) with mortality rates of COVID-19 patients. Methods: Our study was a single-center retrospective analysis of 484 patients (aged ≥ 18) who were admitted to our hospital’s emergency department. We included only laboratory-confirmed COVID-19 patients who underwent chest CT. Data of demographic information, laboratory findings, survivals, and chest CT imaging findings were recorded. The radiologist calculated CTR by dividing the greatest transverse cardiac diameter by the greatest transverse thoracic diameter on the initial chest CT. Cardiomegaly was defined if “CTR &amp;gt; 0.5”. Results: Thirty (6.2%) patients were treated as outpatients, and 135/484 (%27.9) patients were treated in the intensive care unit (ICU). A total of 147 /484 (30.4%) patients died. We found a statistical association between cardiomegaly with mortality rates (p &amp;lt; 0.001) and ICU admission (p = 0.008). In multivariate analysis, older age was 1.07-fold (p &amp;lt; 0.001), cardiomegaly 1.75-fold (p = 0.015), history of cerebrovascular diseases 2.929-fold (p = 0.018), and elevated serum LDH level 1.003-fold (p = 0.011) associated with higher risks of mortality. Conclusions: Since the presence of cardiomegaly on chest CT is associated with a worse prognosis for COVID-19 patients, more caution should be exercised in the evaluation, follow-up, and treatment of COVID-19 patients with cardiomegaly.

Efficacy of immunotherapy (Prolgolimab) and targeted therapy (Trametinib and Dabrafenib, Cobimetinib and Vemurafenib) in adult patients with metastatic or unresectable skin melanoma: matching-adjusted indirect comparison

Aim. To assess the comparative clinical efficacy of Prolgolimab monotherapy versus combination therapy with BRAF/MEK inhibitors (Dabrafenib and Trametinib, Vemurafenib and Cobimetinb) in adult patients with metastatic or unresectable skin melanoma implementing a matching-adjusted indirect comparison (MAIC).&#x0D; Materials and methods. We conducted a systematic search for randomized clinical trials of Prolgolimab, combinations of Dabrafenib and Trametinib, Cobimetinib and Vemurafenib. Unanchored MAIC was applied due to the absence of common comparator between trials. We determined effect modifiers based on an expert survey. The population from Prolgolimab studies was weighted using defined effect modifiers, followed by the approximation of survival curves.&#x0D; Results. Systematic literature search revealed 4 RCTs that met the inclusion criteria: MIRACULUM, coBRIM, combi-v and combi-d. To increase the power of prolgolimab comparison, data from the observational study FORA were included in evidence synthesis and combined with data from MIRACULUM. We selected M staging and the proportion of patients with elevated LDH levels as effect modifiers. No significant differences (all p0.05) were established between Prolgolimab and combination therapy with BRAF/MEK inhibitors for both OS after 1 year and PFS outcomes after 2 years from initiation.&#x0D; Discussion. Despite the inclusion of observational data and the limitations of adjusted indirect comparison method, the results of this analyses are consistent with both other comparisons of anti-PD1 inhibitors with BRAF/MEK inhibitors, and with real world data. It is necessary to recompare targeted therapy and immunotherapy after five-year follow-up period due to peculiarities of time of onset of their effect with the presence of a primary failure with a gradual exit to a long plateau on anti-PD1 inhibitors therapy.&#x0D; Conclusion. In these unanchored MAICs, Prolgolimab monotherapy showed comparable efficacy with combinations of BRAF/MEK inhibitors (Dabrafenib + Trametinib, Vemurafenib + Cobimetinib) in first line therapy of patients with metastatic or unresectable melanoma. This analysis may be relevant for clinical decision-making about the choice of the first line therapy for patients with BRAF mutation.

Risk Factors for and Outcomes of Follicular Lymphoma Histological Transformation at First Progression in the GALLIUM Study.

Although advanced‑stage follicular lymphoma (FL) is considered incurable, survival has improved with the introduction of the anti-CD20 antibodies, rituximab (R) and obinutuzumab (G). However, FL can undergo histological transformation (HT) to a more aggressive disease, and a validated model for predicting HT risk is not yet available. We assessed HT incidence, risk factors and outcomes in the phase III, GALLIUM study evaluating R- or G-chemotherapy in patients with previously untreated, advanced-stage FL (ClinicalTrials.gov NCT01332968). HT rates were assessed by repeat tumour biopsy at disease progression or relapse, at the investigator's discretion. Of 1202 patients enrolled, 315 (26.2%) experienced progressive disease; 46 (14.6%) had a biopsy at first progression, 40 of whom had biopsy-confirmed HT. HT risk factors were male sex (subdistribution hazard ratio [sHR], 2.21; 95% confidence interval [CI], 1.16-4.20), elevated baseline serum lactate dehydrogenase (sHR, 3.97; 95% CI, 2.03-7.76), and elevated baseline serum β2-microglobulin (sHR, 1.96; 95% CI, 1.02-3.79). Patients with HT at first progression had poorer post-progression survival than those with relapsed FL (2-year rate: 55.9% vs. 83.1%). Relapse with HT occurred earlier than FL relapse (median time from randomisation: 0.8 vs. 2.3 years). HT was a low-frequency event associated with poor survival outcomes in the GALLIUM study. Male sex and elevated baseline levels of serum LDH and B2M were significant risk factors for HT. Further research is required to develop validated prognostic indices for HT risk and guide treatment decisions.

Serine Protease 3 Promotes Progression of Diffuse Large B-Cell Lymphoma and Serves as a Novel Prognostic Predictor.

Diffuse large B-cell lymphoma (DLBCL) ranks among the most prevalent malignancies of the lymphohematopoietic system in adults. The PRSS (Serine Protease) protein family members had been reported to be involved in carcinogenesis as well as tumor progression. Here, we aimed to explore the expression profile of PRSS3 in DLBCL and investigate its clinical significance as well as detailed functions. We retrospectively enrolled 155 DLBCL patients from our hospital and tested protein expression level of PRSS3 through immunohistochemical staining. Accordingly, PRSS3 was highly expressed in certain DLBCL tissues. Chi-square test revealed that higher PRSS3 expression was correlated with advanced Ann Arbor stage, elevated serum LDH level, and higher International Prognostic Index. Moreover, univariate and multivariate analyses confirmed that higher PRSS3 can act as an independent unfavorable prognostic predictor for DLBCL. Two human DLBCL cell lines, SUDHL10 and OCI-LY3, were subjected for knockdown assays, followed by phonotype tests including proliferation and invasion. According to the cellular experiments, PRSS3-knockdown resulted in impaired DLBCL proliferation in the two cell lines above. Taken together, PRSS3 is a novel prognostic factor for DLBCL, which functions by multiple signaling pathways.

The impacts of contact lenses on the short- and long-term biochemical parameters of tear films and corneal thickness

Introduction: To investigate the effects of long- and short-term use of different types of contact lenses on corneal metabolism and corneal thickness. Materials and Method: The participants were divided into two groups in the study. In the first group, 20 of the 42 patients were administered a rigid gas-permeable lens (RGPL) with a Dk value of 92x10-11, while the remaining wore a soft contact lens with a water content of 38%. We then explored their Lactate Dehydrogenase (LHD) levels to evaluate the hypoxic effect on tear films in short- (8 hours) and long-term (2nd, 3rd, 5th months) and albumin levels to assess mechanical trauma. In the second group, the corneal thickness was measured using a Haag-Streit optical pachymeter before and at the 8th hour and 2nd month following the first set of lenses, and LDH and albumin values were simultaneously evaluated in tear film. Results: The results yielded no significant increase in tear film LDH and albumin levels in the short- and long-term in both the RGPL and the soft contact lens groups with similar age and sex distribution. In the second part, the corneal thickness measurements resulted in an increase of 5.5% in the RGPL group and 3.63% in the soft lens group at the 8th hour of lens use. However, the groups did not significantly differ by baseline corneal thickness at the 2nd-month follow-up. Similarly, there was no significant increase in LDH and albumin levels in the tear film samples of the same group. Conclusion: The absence of a long-term increase in corneal thickness and no elevated levels of albumin and LDH in tear films indicate that contact lenses fit corneal physiology.

SARS-CoV-2 infection of companion animals in Egypt and its risk of spillover.

Reverse zoonoses occur because of interactions between humans and animals. Homology of ACE-2 cell receptors in different hosts and high mutation rate of SARS-CoV-2 enhance viral transmission among species. This study aimed to investigate spillover of SARS-CoV-2 between humans and companion animals. A cross-sectional study was constructed using nasopharyngeal/oropharyngeal swabs, serum and blood samples collected from 66 companion animals (33 cats and 33 dogs) that were in contact with SARS-CoV-2-positive owners from December 2020 to March 2021. Swabs were screened by rRT-PCR and some positive cases were confirmed by partial spike gene sequencing. Clinical pathology and pathological studies were also performed. Our findings revealed that 30% of cats (10/33) and 24% of dogs (8/33) were SARS-CoV-2 positive. While 33% of these animals were asymptomatic (6/18), 28% showed mild respiratory signs (5/18) and 39% displayed severe respiratory signs (7/18) including 4 dead cats 40% (4/10). Partial spike gene sequencing of 6 positive samples collected in December 2020 were identical to SARS-CoV-2 that was detected in humans in Egypt in that time frame. Clinical pathology findings revealed thrombocytopenia, lymphocytopenia, as well as elevated levels of D-dimer, LDH, CRP, and ferritin. Post-mortem and histopathological examinations illustrated multisystemic effects. There is a potential occurrence of SARS-CoV-2 spillover between humans and pet animals. The present study highlighted the potential occurrence of SARS-CoV-2 spillover between humans and their companion animals. Biosecurity measures should be applied to decrease spread of SARS-CoV-2 among humans and pet animals.