Histopathology, mRNA expression profile, and donor-derived cell-free DNA for assessment of rejection in pediatric heart transplantation.

BACKGROUND: The relationship between histopathologic and molecular ("MMDx"®) assessments of endomyocardial biopsy (EMB) and serum donor-derived cell-free DNA (ddcfDNA) in acute rejection (AR) assessment following pediatric heart transplantation (HT) is unknown. METHODS: EMB sent for MMDx and histopathology from November 2021 to September 2022 were reviewed. MMDx and histopathology results were compared. DdcfDNA obtained ≤1 week prior to EMB were compared with histopathology and MMDx results. The discrimination of ddcfDNA for AR was assessed using receiver-operating curves. FINDINGS: In this study, 177 EMBs were obtained for histopathology and MMDx, 101 had time-matched ddcfDNA values. MMDx and Histopathology displayed moderate agreement for T-cell-mediated rejection (TCMR, Kappa = 0.52, p < .001) and antibody-mediated rejection (ABMR, Kappa = 0.41, p < .001). Discordant results occurred in 24% of cases, most often with ABMR. Compared with no AR, ddcfDNA values were elevated in cases of AR diagnosed by both histopathology and MMDx (p < .01 for all). Additionally, ddcfDNA values were elevated in injury patterns on MMDx, even when AR was not present (p = .01). DdcfDNA displayed excellent discrimination (AUC 0.83) for AR by MMDx and/or histopathology. Using a threshold of ≥0.135%, ddcfDNA had a sensitivity of 90%, specificity of 63%, PPV of 52%, and NPV of 94%. CONCLUSIONS: Histopathology and MMDx displayed moderate agreement in diagnosing AR following pediatric HT, with most discrepancies noted in the presence of ABMR. DdcfDNA is elevated with AR, with excellent discrimination and high NPV particularly when utilizing MMDx. A combination of all three tests may be necessary in some cases.

Assessment of the Impact of Carvedilol Administered Together with Dexrazoxan and Doxorubicin on Liver Structure and Function, Iron Metabolism, and Myocardial Redox System in Rats.

Late cardiotoxicity is a formidable challenge in anthracycline-based anticancer treatments. Previous research hypothesized that co-administration of carvedilol (CVD) and dexrazoxane (DEX) might provide superior protection against doxorubicin (DOX)-induced cardiotoxicity compared to DEX alone. However, the anticipated benefits were not substantiated by the findings. This study focuses on investigating the impact of CVD on myocardial redox system parameters in rats treated with DOX + DEX, examining its influence on overall toxicity and iron metabolism. Additionally, considering the previously observed DOX-induced ascites, a seldom-discussed condition, the study explores the potential involvement of the liver in ascites development. Compounds were administered weekly for ten weeks, with a specific emphasis on comparing parameter changes between DOX + DEX + CVD and DOX + DEX groups. Evaluation included alterations in body weight, feed and water consumption, and analysis of NADPH2, NADP+, NADPH2/NADP+, lipid peroxidation, oxidized DNA, and mRNA for superoxide dismutase 2 and catalase expressions in cardiac muscle. The iron management panel included markers for iron, transferrin, and ferritin. Liver abnormalities were assessed through histological examinations, aspartate transaminase, alanine transaminase, and serum albumin level measurements. During weeks 11 and 21, reduced NADPH2 levels were observed in almost all examined groups. Co-administration of DEX and CVD negatively affected transferrin levels in DOX-treated rats but did not influence body weight changes. Ascites predominantly resulted from cardiac muscle dysfunction rather than liver-related effects. The study's findings, exploring the impact of DEX and CVD on DOX-induced cardiotoxicity, indicate a lack of scientific justification for advocating the combined use of these drugs at histological, biochemical, and molecular levels.

Treatment patterns and costs among US patients with diffuse large B-cell lymphoma not treated with 2L stem cell transplantation.

Aim: To assess treatment patterns, healthcare resource utilization (HCRU), and costs for patients with diffuse large B-cell lymphoma (DLBCL) who did not receive stem cell transplantation in second-line. Patients & methods: An administrative MarketScan® database study to assess DLBCL claims from 01/01/2009-30/09/2020. Results: Most patients (n = 750) received rituximab plus cyclophosphamide, doxorubicin, vincristine and prednisone in first-line (86.8%) and rituximab (39.5%) or bendamustine ± rituximab ± other (16.3%) in second-line. Over half were hospitalized (mean duration: 16.5 (standard deviation [SD]: 25.8) days per patient per year). Mean medical/pharmacy costs were US$141,532 per patient per year (SD: $189,579), driven by DLBCL-related claims. Conclusion: Healthcare resource utilization and costs for DLBCL-related claims were due to hospitalizations and outpatient visits. Novel therapies to reduce clinical and economic burdens are needed.

Pulmonary lesions in early response assessment in pediatric Hodgkin lymphoma: prevalence and possible implications for initial staging.

BACKGROUND: Disseminated pulmonary involvement in pediatric Hodgkin lymphoma (pHL) is indicative of Ann Arbor stage IV disease. During staging, it is necessary to assess for coexistence of non-malignant lung lesions due to infection representing background noise to avoid erroneously upstaging with therapy intensification. OBJECTIVE: This study attempts to describe new lung lesions detected on interim staging computed tomography (CT) scans after two cycles of vincristine, etoposide, prednisolone, doxorubicin in a prospective clinical trial. Based on the hypothesis that these new lung lesions are not part of the underlying malignancy but are epiphenomena, the aim is to analyze their size, number, and pattern to help distinguish true lung metastases from benign lung lesions on initial staging. MATERIALS AND METHODS: A retrospective analysis of the EuroNet-PHL-C1 trial re-evaluated the staging and interim lung CT scans of 1,300 pediatric patients with HL. Newly developed lung lesions during chemotherapy were classified according to the current Fleischner glossary of terms for thoracic imaging. Patients with new lung lesions found at early response assessment (ERA) were additionally assessed and compared to response seen in hilar and mediastinal lymph nodes. RESULTS: Of 1,300 patients at ERA, 119 (9.2%) had new pulmonary lesions not originally detectable at diagnosis. The phenomenon occurred regardless of initial lung involvement or whether a patient relapsed. In the latter group, new lung lesions on ERA regressed by the time of relapse staging. New lung lesions on ERA in patients without relapse were detected in 102 (7.8%) patients. Pulmonary nodules were recorded in 72 (5.5%) patients, the majority (97%) being<10 mm. Consolidations, ground-glass opacities, and parenchymal bands were less common. CONCLUSION: New nodules on interim staging are common, mostly measure less than 10 mm in diameter and usually require no further action because they are most likely non-malignant. Since it must be assumed that benign and malignant lung lesions coexist on initial staging, this benign background noise needs to be distinguished from lung metastases to avoid upstaging to stage IV disease. Raising the cut-off size for lung nodules to ≥ 10 mm might achieve the reduction of overtreatment but needs to be further evaluated with survival data. In contrast to the staging criteria of EuroNet-PHL-C1 and C2, our data suggest that the number of lesions present at initial staging may be less important.

Real-world treatment patterns, healthcare resource utilization and costs among patients with peripheral T-cell lymphoma.

Objective: To evaluate treatment patterns, healthcare resource utilization (HRU) and costs among peripheral T-cell lymphoma (PTCL) patients in the USA. Methods: A retrospective cohort study, using the IQVIA PharMetrics® Plus claims database from 1 April 2011 to 30 November 2021, identified PTCL patients receiving systemic treatments. Three mutually exclusive subcohorts were created based on line of therapy (LOT): 1LOT, 2LOT and ≥3LOT. Common treatment regimens, median time on treatment, all-cause and PTCL-related HRU and costs were estimated. Results: Among 189 PTCL patients identified, 61.9% had 1LOT, 21.7% had 2LOT and 16.4% had ≥3LOT. The most common treatment regimens in the 1LOT were CHOP/CHOP-like, CHOEP/CHOEP-like and brentuximab vedotin; monotherapies were most common in the 2LOT and ≥3LOT. All-cause and PTCL-related hospitalizations and prescriptions PPPM increased with increasing LOT. Nearly 70% of total treatment costs were PTCL related. Conclusion: Higher utilization of combination therapies in the 1LOT and monotherapies in subsequent LOTs were observed, alongside high PTCL-related costs.

Peripheral T-cell lymphomas (PTCL) are a rare and fast-growing form of blood cancer. About 8000­12,000 people in the USA are diagnosed with PTCL every year. As it is a rare disease and has many types, and there is a limited understanding of the patients who have PTCL and the treatments they receive in the real world. The purpose of this study was to evaluate how these patients are treated, what are they treated with and what are the costs of these treatments in the USA. The data collected on these patients was divided into three groups based upon the number of lines of treatment/therapy (LOT) they received: 1LOT, 2LOT and ≥3LOT. This study researched different treatments and their duration in each line of therapy. Among 189 PTCL patients included in the study, the average age of patients was 55 years and 62% were male. Among these patients, 62% had 1LOT, 22% had 2LOT and 16% had ≥3LOT. The most common treatments in the 1LOT were traditional chemotherapy regimens followed by targeted therapies: CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) or CHOP-like, CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone) or CHOEP-like, and brentuximab vedotin. Treatment regimens with only one drug were most common in the 2LOT and ≥3LOT. The total cost of PTCL treatment in the USA is very high; 70% of this cost is related to their treatment with various drugs. More research is needed to better understand the treatment and cost of this rare cancer.

Assessment of early anthracycline-induced cardiotoxicity and liver injury with T2 and T2* mapping in rabbit models.

OBJECTIVES: To evaluate the early prevalence of anthracycline-induced cardiotoxicity (AIC) and anthracycline-induced liver injury (AILI) using T2 and T2* mapping and to explore their correlations. MATERIALS AND METHODS: The study included 17 cardiotoxic rabbits that received weekly injections of doxorubicin and magnetic resonance imaging (MRI) every 2 weeks for 10 weeks. Cardiac function and T2 and T2* values were measured on each period. Histopathological examinations for two to five rabbits were performed after each MRI scan. The earliest sensitive time and the threshold of MRI parameters for detecting AIC and AILI based on these MRI parameters were obtained. Moreover, the relationship between myocardial and liver damage was assessed. RESULTS: Early AIC could be detected by T2 mapping as early as the second week and focused on the 7th, 11th, and 12th segments of left ventricle. The cutoff value of 46.64 for the 7th segment had the best diagnostic value, with an area under the curve (of 0.767, sensitivity of 100%, and specificity of 52%. T2* mapping could detect the change in iron content for early AIC at the middle interventricular septum and AILI as early as the sixth week (p = 0.014, p = 0.027). The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver (r = 0.39, p = 0.002). CONCLUSION: T2 and T2* mapping showed value one-stop assessment of AIC and AILI and could obtain the earliest MRI diagnosis point and optimal parameter thresholds for these conditions. CLINICAL RELEVANCE STATEMENT: Anthracycline-induced cardiotoxicity could be detected by T2 mapping as earlier as the second week, mainly focusing on the 7th, 11th, and 12th segments of left ventricle. Combined with T2* mapping, hepatoxicity and supplementary cardiotoxicity were assessed by one-stop scan. KEY POINTS: • MRI screening time of cardiotoxicity was as early as the second week with focusing on T2 values of the 7th, 11th, and 12th segments of left ventricle. • T2* mapping could be used as a complement to T2 mapping to evaluate cardiotoxicity and as an effective index to detect iron change in the early stages of chemotherapy. • The T2* values of the middle interventricular septum showed a significant positive association with the T2* values of the liver, indicating that iron content in the liver and heart increased with an increase in the chemotherapeutic drugs.

Adding a Gene Expression Profile Test to Aid Differential Diagnosis and Treatment in Aggressive Large B-Cell Lymphoma: An Early Exploratory Economic Evaluation.

BACKGROUND AND OBJECTIVE: Adding gene expression profiles (GEPs) to the current diagnostic work-up of aggressive large B-cell lymphomas may lead to the reclassification of patients, treatment changes and improved outcomes. A GEP test is in development using TempO-Seq® technology to distinguish Burkitt lymphoma (BL) and primary mediastinal large B-cell lymphoma (PMBCL) from diffuse large B-cell lymphoma (DLBCL), and to classify patients with DLBLC and to predict the benefit of (e.g.) adding bortezomib to R-CHOP therapy (RB-CHOP). This study aims to estimate the potential impact of a GEP test on costs and health outcomes to inform pricing and evidence generation strategies. METHODS: Three decision models were developed comparing diagnostic strategies with and without GEP signatures over a lifetime horizon using a UK health and social care perspective. Inputs were taken from a recent clinical trial, literature and expert opinion. We estimated the maximum price of the test using a threshold of Great Britain Pound (GBP) 30,000 per quality-adjusted life-year (QALY). Sensitivity analyses were conducted. RESULTS: The estimated maximum threshold price for a combined test to be cost effective is GBP 15,352. At base-case values, the BL signature delivers QALY gains of 0.054 at an additional cost of GBP 275. This results in a net monetary benefit at a threshold of GBP 30,000 per QALY of GBP 1345. For PMBCL, the QALY gain was 0.0011 at a cost saving of GBP 406 and the net monetary benefit was GBP 437. The hazard ratio for the impact of treating BL less intensively must be at least 1.2 for a positive net monetary benefit. For identifying patients with the DLBCL subtype responsive to bortezomib, QALY gain was 0.2465 at a cost saving of GBP 6175, resulting in a net monetary benefit of GBP 13,570. In a probabilistic sensitivity analysis using 1000 simulations, a testing strategy was superior to a treat all with R-CHOP strategy in 81% of the simulations and with a cost saving in 92% assuming a cost price of zero. CONCLUSIONS: Our estimates show that the combined test has a high probability of being cost effective. There is good quality evidence for the benefit of subtyping DLBCL but the evidence on the number of patients reclassified to or from BL and PMBCL and the impact of a more precise diagnosis and the cost of treatment is weak. The developers can use the price estimate to inform a return on investment calculations. Evidence will be required of how well the TempO-Seq® technology performs compared to the testing GEP technology used for subtyping in the recent clinical trial. For BL and PMBCL elements of the test, evidence would be required of the number of patients reclassified and improved costing information would be useful. The diagnostic and therapeutic environment in haematological malignancies is fast moving, which increases the risk for developers of diagnostic tests.

Circulating-tumor DNA Assessment in Diffuse Large B-cell Lymphoma to Determine Up-front Stem Cell Transplantation: A Pilot Study.

BACKGROUND/AIM: This study evaluated the possibility of clinical use of circulating-tumor DNA (ctDNA) as a biomarker to determine up-front autologous stem cell transplantation (auto-SCT) for patients with high-risk diffuse large B-cell lymphoma (DLBCL) in practice. PATIENTS AND METHODS: To explore the dynamics of ctDNA in DLBCL, blood samples were collected sequentially before and after treatment from patients with newly diagnosed DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy. To conduct ctDNA genotyping and ctDNA monitoring simultaneously, targeted sequencing by cancer personalized profiling using deep sequencing was used. RESULTS: Ten patients between the ages of 50 and 60 years were enrolled. Based on the international prognostic index (IPI), seven patients were classified as high-IPI-risk group, and three patients were classified as low-IPI-risk group. The IPI risk group correlated with total metabolic tumor volume. All patients completed six cycles of R-CHOP chemotherapy, and seven patients achieved complete response. Changes in ctDNA mutation numbers did not correlate with changes in PET scan images and treatment response. In most high-risk patients, new mutations appeared in ctDNA after completion of chemotherapy that conceivably marked resistant clones. Notably, disease relapse did not occur in high-risk patients with poor prognostic mutations who underwent autologous SCT. CONCLUSION: ctDNA monitoring was meaningful in high-risk patients. Moreover, ctDNA and well-known prognostic factors should be considered in the decision making for auto-SCT. If a new genetic mutation in ctDNA with a negative prognosis would emerge during treatment, high-risk patients should consider auto-SCT.

Molecular assessment of drug-phospholipid interactions consequent to cancer treatment: a study of anthracycline-induced cardiotoxicity.

Cardiotoxicity limits the use of anthracyclines as potent chemotherapeutics. We employ classical molecular dynamics to explore anthracycline interactions with a realistic myocardial membrane and compare to an ideal membrane widely used in literature. The interaction of these two membranes with four anthracyclines; doxorubicin, epirubicin, daunorubicin, and idarubicin are studied. Careful analysis was conducted on three forms of each drug; pristine, primary metabolite, and cationic salt. By examining the molecular residence time near the membrane's surface, the average number of molecule/membrane hydrogen bonds, the immobilization of the molecules near the membrane, and the location of those molecules relative to the mid-plane of the membrane we found out that salt forms exhibit the highest cardiotoxic probability, followed by the metabolites and pristine forms. Additionally, all forms have more affinity to the upper layer of the realistic myocardial membrane. Meanwhile, an ideal membrane consisting of a single type of phospholipids is not capable of capturing the specific interactions of each drug form. These findings confirm that cardiotoxic mechanisms are membrane-layer and drug-form dependent.

Spindle Monitor: A Tool for Real-Time Assessment and Concurrent Treatment of Postoperative Tumor Prognosis.

Cancer surgery remains a mainstay in clinical treatment. However, the efficacy of subsequent therapies largely depends on the precise evaluation of postoperative prognoses, underscoring the critical need for a comprehensive and accurate assessment of surgical outcomes. Nanoprobes targeting tumors offer a promising solution for visual prognostic assessment. In this study, we developed a "Spindle Monitor" system, designated as APPADs (Au NBPs@PDA-pep-AS1411-Dox), composed of core-shell nanoparticles. The core was made up of gold nanobipyramids (Au NBPs), coated with polydopamine (PDA), and subsequently loaded with peptide chains, AS1411, and doxorubicin (Dox). Upon deployment in the acidic tumor microenvironment (TME), APPADs released substantial amounts of Dox, initiating the apoptotic process. This triggered the activity of caspase-3, which is a crucial executor in the apoptotic pathway. Consequently, DEVD, a specific recognition site for caspase-3, was cleaved, enabling the disconnection of FITC-conjugated peptide chains and the recovery of fluorescence. Through assessing this fluorescence imaging effect, local laser irradiation could be precisely guided to the postoperative site, facilitating a synergistic combination of photothermal therapy and chemotherapy. Specifically, our "Spindle Monitor" APPADs had been validated to achieve accurate fluorescence imaging in vitro and in vivo, which demonstrated its potential value as a versatile tool for evaluating postoperative prognosis in surgical treatments, such as thyroid cancer, and assessing chemotherapy efficacy in difficult cases, like late-stage osteosarcoma. This promising tool lays a good foundation for development in visual prognosis evaluation after tumor surgery.

Estimated impact of ECHELON-1 overall survival on productivity costs in stage III/IV classical Hodgkin lymphoma in the United States.

BACKGROUND: A 2010 study on the impact of cancer mortality on productivity costs found Hodgkin lymphoma to have the second largest productivity cost lost per death in the United States. The ECHELON-1 trial demonstrated that frontline brentuximab vedotin, doxorubicin, vinblastine, and dacarbazine (A+AVD) improves overall survival (OS) vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) in stage III/IV classical Hodgkin lymphoma (cHL), reducing the risk of death to 41% (hazard ratio = 0.59; 95% CI = 0.40-0.88; P = 0.009). OBJECTIVES: To assess the estimated impact of frontline treatment choice on mortality and productivity using an oncology simulation model informed by ECHELON-1 data. METHODS: Individual productivity was estimated using the human capital approach and reported via present value lifetime earnings (PVLE) estimates. Deaths avoided and lifeyears saved without and with A+AVD were calculated using a model informed by realworld treatment use, treatment-specific OS, and expert clinicians' opinions. A+AVD use in the base case was 27% (range: 0%-80%). Stage III/IV cHL prevalence over a 10-year period was estimated; downstream lifetime productivity costs were projected without and with A+AVD. RESULTS: In 2031, 3,645 patients were estimated to be newly diagnosed with stage III/IV cHL. Over 10 years with 27% A+AVD vs no A+AVD use, estimates predicted 14% fewer deaths (2,290 vs 2,650) and 14% less total PVLE losses ($1.438 vs $1.664 billion). Results from scenario analyses (40%-80% vs no A+AVD use) showed 20% to 32% decreases in PVLE losses ($1.331-$1.137 billion vs $1.664 billion), saving up to $527 million over 10 years. CONCLUSIONS: Productivity cost losses due to mortality in stage III/IV cHL are high. Increasing A+AVD use for patients with stage III/IV cHL would reduce productivity cost losses as deaths are avoided, based on ECHELON-1 OS results.

A physiologically-based pharmacokinetic model for predicting doxorubicin disposition in multiple tissue levels and quantitative toxicity assessment.

Doxorubicin is a widely-used chemotherapeutic drug, however its high toxicity poses a significant challenge for its clinical use. To address this issue, a physiologically-based pharmacokinetic (PBPK) model was implemented to quantitatively assess doxorubicin toxicity at cellular scale. Due to its unique pharmacokinetic behavior (e.g. high volume of distribution and affinity to extra-plasma tissue compartments), we proposed a modified PBPK model structure and developed the model with multispecies extrapolation to compensate for the limitation of obtaining clinical tissue data. Our model predicted the disposition of doxorubicin in multiple tissues including clinical tissue data with an overall absolute average fold error (AAFE) of 2.12. The model's performance was further validated with 8 clinical datasets in combined with intracellular doxorubicin concentration with an average AAFE of 1.98. To assess the potential cellular toxicity, toxicity levels and area under curve (AUC) were defined for different dosing regimens in toxic and non-toxic scenarios. The cellular concentrations of doxorubicin in multiple organ sites associated with commonly observed adverse effects (AEs) were simulated and calculated the AUC for quantitative assessments. Our findings supported the clinical dosing regimen of 75 mg/m2 with a 21-day interval and suggest that slow infusion and separated single high doses may lower the risk of developing AEs from a cellular level, providing valuable insights for the risk assessment of doxorubicin chemotherapy. In conclusion, our work highlights the potential of PBPK modelling to provide quantitative assessments of cellular toxicity and supports the use of clinical dosing regimens to mitigate the risk of adverse effects.

Assessment of doxorubicin toxicity using human cardiac organoids: A novel model for evaluating drug cardiotoxicity.

Cardiovascular diseases pose a huge threat to global human health and are also a major obstacle to drug development and disease treatment. Drug-induced cardiotoxicity remains an important clinical issue. Both traditional two-dimensional (2D) monolayer cell models and animal models have their own limitations and are not fully suitable for the study of human heart physiology or pathology. Cardiac organoids are three-dimensional (3D) and self-organized structures that accurately retain the biological characteristics and functions of heart tissue. In this study, we successfully established a human cardiac organoid model by inducing the directed differentiation of human embryonic stem cells, which recapitulates the patterns of early myocardial development. Moreover, this model accurately characterized the cardiotoxic damage caused by the anticancer drug doxorubicin, including clinical cardiac injury and cardiac function indicators, cell apoptosis, inflammation, fibrosis, as well as mitochondrial damage. In general, the cardiac organoid model can be used to evaluate the cardiotoxicity of drugs, opening new directions and ideas for drug screening and cardiotoxicity research.

Influence of treatment intensity and medical comorbidities in older adults with peripheral T cell lymphoma.

We conducted a population-based study of patients >65 years, diagnosed 2008-2017, with peripheral T-cell lymphoma (PTCL) using SEER-Medicare. Associations between PTCL subtype, treatment regimen, comorbidity, and mortality were assessed using the Kaplan-Meier method and multivariable Cox regression. Amongst the 2,546 patients, the median age was 77 years (interquartile range, 71-83). 5-year overall survival (OS) ranged from 22.2% to 37.3% depending on PTCL subtype. The most common frontline regimen was cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). 5-year OS rate was 47.0% for patients treated with etoposide + CHOP (N = 67; CHOEP), 33.7% for those treated with CHOP (N = 732), and 23.8% for patients treated with non-anthracycline-containing regimens (N = 105; p < 0.001). In patients without comorbidities, CHOEP remained independently associated with improved OS (HR 0.52, 95% CI,0.30-0.91). Median OS was 1.2 years from initiation of second-line therapy (N = 228) independent of treatment regimen. Frontline but not second-line treatment regimen is associated with OS in older patients with PTCL.

US cost-effectiveness analysis of polatuzumab vedotin in previously untreated diffuse large B-cell lymphoma.

AIMS: We evaluated the pharmacoeconomic value of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) in previously untreated diffuse large B-cell lymphoma (DLBCL) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). MATERIALS AND METHODS: A 3-state partitioned survival model was used to estimate life years (LYs), quality-adjusted LYs (QALYs), and cost impacts of Pola-R-CHP versus R-CHOP. Analyses utilized mixture-cure survival modelling, assessed a lifetime horizon, discounted all outcomes at 3% per year, and examined both payer and societal perspectives. Progression-free survival, overall survival (OS), drug utilization, treatment duration, adverse reactions, and subsequent treatment inputs were based on data from the POLARIX study (NCT03274492). Costs included drug acquisition/administration, adverse reaction management, routine care, subsequent treatments, end-of-life care, and work productivity. RESULTS: Incremental cost-effectiveness ratios of Pola-R-CHP versus R-CHOP were $70,719/QALY gained and $88,855/QALY gained from societal and payer perspectives, respectively. The $32,824 higher total cost of Pola-R-CHP versus R-CHOP was largely due to higher drug costs ($122,525 vs $27,694), with cost offsets including subsequent treatment (-$52,765), routine care (-$1,781), end-of-life care (-$383), and work productivity (-$8,418). Pola-R-CHP resulted in an increase of 0.47 LYs and 0.46 QALYs versus R-CHOP. Pola-R-CHP was cost-effective in 60.9% and 58.0% of simulations at a willingness-to-pay threshold of $150,000/QALY gained from societal and payer perspectives, respectively. LIMITATIONS: There was uncertainty around the OS extrapolation in the model, and costs were derived from different sources. Recommended prophylactic medications were not included; prophylactic use of granulocyte colony-stimulating factor for all patients was assumed to be equal across treatment arms in POLARIX. Work productivity loss was estimated from a general population and was not specific to patients with DLBCL. CONCLUSION: Pola-R-CHP was projected to be cost-effective versus R-CHOP in previously untreated DLBCL, suggesting that Pola-R-CHP represents good value relative to R-CHOP in this setting.

Use of Deep-Learning Assisted Assessment of Cardiac Parameters in Zebrafish to Discover Cyanidin Chloride as a Novel Keap1 Inhibitor Against Doxorubicin-Induced Cardiotoxicity.

Doxorubicin-induced cardiomyopathy (DIC) brings tough clinical challenges as well as continued demand in developing agents for adjuvant cardioprotective therapies. Here, a zebrafish phenotypic screening with deep-learning assisted multiplex cardiac functional analysis using motion videos of larval hearts is established. Through training the model on a dataset of 2125 labeled ventricular images, ZVSegNet and HRNet exhibit superior performance over previous methods. As a result of high-content phenotypic screening, cyanidin chloride (CyCl) is identified as a potent suppressor of DIC. CyCl effectively rescues cardiac cell death and improves heart function in both in vitro and in vivo models of Doxorubicin (Dox) exposure. CyCl shows strong inhibitory effects on lipid peroxidation and mitochondrial damage and prevents ferroptosis and apoptosis-related cell death. Molecular docking and thermal shift assay further suggest a direct binding between CyCl and Keap1, which may compete for the Keap1-Nrf2 interaction, promote nuclear accumulation of Nrf2, and subsequentially transactivate Gpx4 and other antioxidant factors. Site-specific mutation of R415A in Keap1 significantly attenuates the protective effects of CyCl against Dox-induced cardiotoxicity. Taken together, the capability of deep-learning-assisted phenotypic screening in identifying promising lead compounds against DIC is exhibited, and new perspectives into drug discovery in the era of artificial intelligence are provided.

Cost-effectiveness of brentuximab vedotin in Hodgkin lymphoma: a systematic review.

PURPOSE: This study aimed to systematically review and critically appraise cost-effectiveness studies on Brentuximab vedotin (BV) in patients with Hodgkin lymphoma (HL). METHODS: The PubMed, Scopus, Web of Science core collection, and Embase databases were searched until July 3, 2022. We included published full economic evaluation studies on BV for treating patients with HL. The methodological quality of the studies was assessed using the Quality of Health Economic Studies (QHES) checklist. Meanwhile, we used qualitative synthesis to analyze the findings. We converted the incremental cost-effectiveness ratios (ICERs) to the value of the US dollar in 2022. RESULTS: Eight economic evaluations met the study's inclusion criteria. The results of three studies that compared BV plus doxorubicin, vinblastine, and dacarbazine (BV + AVD) front-line therapy with doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) showed that BV is unlikely to be cost-effective as a front-line treatment in patients advanced stage (III or IV) HL. Four studies investigated the cost-effectiveness of BV in patients with relapsed or refractory (R/R) HL after autologous stem cell transplantation (ASCT). BV was not cost-effective in the reviewed studies at accepted thresholds. In addition, the adjusted ICERs ranged from $65,382 to $374,896 per quality-adjusted life-year (QALY). The key drivers of cost-effectiveness were medication costs, hazard ratio for BV, and utilities. CONCLUSION: Available economic evaluations show that using BV as front-line treatment or consolidation therapy is not cost-effective based on specific ICER thresholds for patients with HL or R/R HL. To decide on this orphan drug, we should consider other factors such as existence of alternative treatment options, clinical benefits, and disease burden.

Cost-effectiveness of combination therapy of polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone for previously untreated diffuse large B-cell lymphoma in Japan.

AIM: The POLARIX trial showed that Pola + R-CHP (polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisolone) prolongs progression-free survival (PFS) in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) compared with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone), the conventional standard of care, with a similar safety profile. However, Pola + R-CHP has not been evaluated from the viewpoint of health economics in Japan. This study evaluates the cost-effectiveness of Pola + R-CHP for previously untreated DLBCL from a Japanese public healthcare payer's perspective. METHODS: A partitioned survival analysis model was constructed to estimate lifetime costs and effectiveness of Pola + R-CHP and R-CHOP in previously untreated DLBCL who had an International Prognostic Index score (IPI) score of ≥2. A parametric survival model was applied to data analyzed in the POLARIX trial to estimate the lifetime overall survival (OS) and PFS for each treatment. The parameters required for the model were based on the results of a literature search and expert opinion. RESULTS: The incremental cost-effectiveness ratio (ICER) of Pola + R-CHP vs. R-CHOP was JPY2,710,238 per quality-adjusted life year (QALY), less than the ICER of JPY7.5 million per QALY that is considered to be cost-effective based on the threshold of the Japanese cost-effectiveness evaluation system. One-way sensitivity analysis showed that the parameters influencing the results of the analysis were median PFS and the total cost per regimen of salvage chemotherapy, patient weight, and patient age. Probabilistic sensitivity analysis showed that the probability of Pola + R-CHP having superior cost-effectiveness was 99.2% when the reference value was JPY7.5 million. The results of scenario analysis suggested that prolongation of PFS was an important factor in the evaluation of cost-effectiveness in previously untreated DLBCL with or without prolongation of OS. CONCLUSIONS: This study suggests that Pola + R-CHP is a cost-effective treatment for previously untreated DLBCL in Japan under the public health insurance system.

Cost-effectiveness of response-adapted therapy (RAT) for advanced Hodgkin's Lymphoma compared with conventional treatment in India: a Markov-model based analysis.

Cost effectiveness analysis of interim positron emission tomography (PET-2, done after 2 cycles of chemotherapy) based response adaptive therapy (RAT) approaches in advanced Hodgkin lymphoma (aHL) are not available from an Indian perspective. We used a five-year decision analytics model to assess the cost-effectiveness of the two RAT approaches [(escalation (RAT-1) or de-escalation (RAT-2)] compared with standard care (SOC) in aHL (mean age:35 years). Modelling data was derived from secondary sources and sensitivity analyses were performed to assess the robustness of the model. Net monetary benefit (NMB) gained from RAT2 in Indian rupees (INR) (INR 2,26,896) was higher than the RAT1 (INR 1,83,138) when compared with SOC. Proportion achieving the complete response after initial treatment (CR1) was the key determining factor for the RAT1/2 dominance over SOC. Despite higher initial input costs, response-adapted therapy of aHL was cost-effective by minimizing the cost incurred and disutility experienced during relapse and salvage.

Despite higher initial costs, response-adapted therapy based on the interim PET scan after 2 cycles of chemotherapy was more cost-effective when compared to standard therapy with 6 cycles of ABVD in patients with advanced Hodgkin's lymphoma. Among the RAT approaches, de-escalation (RAT-2) had better cost-effectiveness than the escalation approach (RAT-1).