Comparable efficacy of oral bendamustine versus intravenous administration in treating hematologic malignancies.

PURPOSE: The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine and a novel orally administered (PO) bendamustine agent that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. METHODS: Pharmacokinetics of IV versus PO bendamustine were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO bendamustine. Plasma samples were analyzed using liquid chromatography-mass spectrometry following a liquid-liquid extraction to determine peak bendamustine concentration, area under the concentration-time curve, and the half-life in-vivo. In-vitro cytotoxicity of bendamustine against human non-Hodgkin Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo bendamustine cytotoxicity of IV versus PO bendamustine at two different doses. RESULTS: Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor activity between IV and novel PO bendamustine at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of bendamustine in mice to be 51.4%. CONCLUSIONS: The novel oral bendamustine agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV bendamustine. An oral bendamustine formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

The Hidden Toll of Psychological Distress in Australian Adults and Its Impact on Health-Related Quality of Life Measured as Health State Utilities.

BACKGROUND: Psychological distress (PD) is a major health problem that affects all aspects of health-related quality of life including physical, mental and social health, leading to a substantial human and economic burden. Studies have revealed a concerning rise in the prevalence of PD and various mental health conditions among Australians, particularly in female individuals. There is a scarcity of studies that estimate health state utilities (HSUs), which reflect the overall health-related quality of life in individuals with PD. No such studies have been conducted in Australia thus far. OBJECTIVE: We aimed to evaluate the age-specific, sex-specific and PD category-specific HSUs (disutilities) in Australian adults with PD to inform healthcare decision making in the management of PD. METHODS: Data on age, sex, SF-36/SF6D responses, Kessler psychological distress (K10) scale scores and other characteristics of N = 15,139 participants (n = 8149 female individuals) aged >15 years were derived from the latest wave (21) of the nationally representative Household, Income and Labor Dynamics in Australia survey. Participants were grouped into the severity categories of no (K10 score: 10-19), mild (K10: 20-24), moderate (K10: 25-29) and severe PD (K10: 30-50). Both crude and adjusted HSUs were calculated from participants' SF-36 profiles, considering potential confounders such as smoking, marital status, remoteness, education and income levels. The calculations were based on the SF-6D algorithm and aligned with Australian population norms. Additionally, the HSUs were stratified by age, sex and PD categories. Disutilities of PD, representing the mean difference between HSUs of people with PD and those without, were also calculated for each group. RESULTS: The average age of individuals was 46.130 years (46% male), and 31% experienced PD in the last 4 weeks. Overall, individuals with PD had significantly lower mean HSUs than those likely to be no PD, 0.637 (95% confidence interval [CI] 0.636, 0.640) vs 0.776 (95% CI 0.775, 0.777) i.e. disutility: -0.139 [95% CI -0.139, -0.138]). Mean disutilities of -0.108 (95% CI -0.110, -0.104), -0.140 (95% CI -0.142, -0.138), and -0.188 (95% CI -0.190, -0.187) were observed for mild PD, moderate PD and severe PD, respectively. Disutilities of PD also differed by age and sex groups. For instance, female individuals had up to 0.049 points lower mean HSUs than male individuals across the three classifications of PD. There was a clear decline in health-related quality of life with increasing age, demonstrated by lower mean HSUs in older population age groups, that ranged from 0.818 (95% CI 0.817, 0.818) for the 15-24 years age group with no PD to 0.496 (95% CI 0.491, 0.500) for the 65+ years age group with severe PD). Across all ages and genders, respondents were more likely to report issues in certain dimensions, notably vitality, and these responses did not uniformly align with ageing. CONCLUSIONS: The burden of PD in Australia is substantial, with a significant impact on female individuals and older individuals. Implementing age-specific and sex-specific healthcare interventions to address PD among Australian adults may greatly alleviate this burden. The PD state-specific HSUs calculated in our study can serve as valuable inputs for future health economic evaluations of PD in Australia and similar populations.

Comparable Efficacy of Oral Bendamustine versus Intravenous Administration in Treating Hematologic Malignancies.

Purpose: The purpose of this study was to analyze potential differences in antitumor efficacy and pharmacokinetics between intravenous (IV) bendamustine (BEN) and a novel orally administered bendamustine agent (PO) that is utilizing the beneficial properties of superstaturated solid dispersions formulated in nanoparticles. Methods: Pharmacokinetics of IV versus PO BEN were determined by analysis of plasma samples collected from NSG mice treated with either IV or PO BEN. Plasma samples were analyzed using liquid chromatography-mass spectrometry (LC/MS/MS) following a liquid-liquid extraction to determine peak BEN concentration (Cmax), area under the concentration-time curve (AUC) and the half-life (t1/2) in-vivo. in-vitro cytotoxicity of BEN against human non-Hodgkin's Burkitt's Lymphoma (Raji), multiple myeloma (MM.1s), and B-cell acute lymphoblastic leukemia (RS4;11) cell lines was determined over time using MTS assays. Luciferase-tagged versions of the aforementioned cell lines were used to determine in-vivo BEN cytotoxicity of IV versus PO BEN at two different doses. Results: Bendamustine at a high dose in-vitro causes cell death. There was no significant difference in antitumor efficacy between IV and novel PO BEN at a physiologically relevant concentration in all three xenograft models. In-vivo pharmacokinetics showed the oral bioavailability of BEN in mice to be 51.4%. Conclusions: The novel oral BEN agent tested exhibits good oral bioavailability and systemic exposure for in-vivo antitumor efficacy comparable to IV BEN. An oral BEN formulation offers exciting clinical potential as an additional method of administration for bendamustine and warrants further evaluation in clinical studies.

An environmental perspective of energy consumption, overpopulation, and human capital barriers in South Asia.

Prior literature is substantive in highlighting the nexus between pollutant and socio-economic predictors; however, the role of human interaction has not been sufficiently explored. Thus, the present study examines the validity of the environmental Kuznets Curve (EKC) hypothesis in the presence of energy consumption, overpopulation, and human capital index in five South Asian countries. It employs fixed effects, random effects, and dynamic panel causality techniques with a set of panel data from 1972 to 2021. The baseline results validate the existence of the EKC hypothesis in the recipient panel. Nevertheless, the findings reveal that energy consumption and population density have positive effects, while human capital has negative impacts on CO2 emissions. Furthermore, the study observes that energy consumption and per capita GDP have a significant causal link with CO2 emissions, whereas CO2 emissions are evident to have causality with population density and human capital index. The results are robust and suggest that the consolidation of an effective regulatory framework and technological improvements are substantial measures to improve environmental quality in South Asia. Moreover, allocating sufficient resources to uplift contemporary educational and health status would be imperative to improving environmental quality as aspired to by the Paris Agreement.

Has the shortage of fludarabine altered the current paradigm of lymphodepletion in favor of bendamustine?

The most common lymphodepletion regimen used prior to infusion of chimeric antigen receptor-T cells (CAR-T) is cyclophosphamide (CY) in combination with fludarabine (Flu) (CY-FLU). While cyclophosphamide (CY) possesses lymphotoxic effects, it concurrently preserves regulatory T cell activity, potentially affecting the efficacy of CAR-T cells. Moreover, the use of fludarabine (FLU) has been linked to neurotoxicity, which could complicate the early detection of immune effector cell-associated neurotoxicity syndrome (ICANS) observed in CAR-T cell therapy. Given the ongoing shortage of FLU, alternative lymphodepleting agents have become necessary. To date, only a limited number of studies have directly compared different lymphodepleting regimens, and most of these comparisons have been retrospective in nature. Herein, we review the current literature on lymphodepletion preceding CAR-T cell therapies for lymphoid hematologic malignancies, with a specific focus on the use of bendamustine (BEN). Recent evidence suggests that administering BEN before CAR-T cell infusion yields comparable efficacy, possibly with a more favorable toxicity profile when compared to CY-FLU. This warrants further investigation through randomized prospective studies.

Examining the impact of environmental technologies, environmental taxes, energy consumption, and natural resources on GHG emissions in G-7 economies.

The focus areas for COP-27 include fast-tracking our worldwide evolution to decarbonization in the energy industry and clean energy as the stockholder's effort to restrict global warming to 1.5 °C (2.7 °F) above the levels of pre-industrial. After this COP-27 summit, most of the developing countries will provoke challenges in accomplishing their targets of a carbon neutrality and sustainable economy with the minimum possible greenhouse gas (GHG) emissions. In this regard, the G-7 countries, despite prosperous cautiously, have not prospered in certifying ecological welfare in tandem. Nevertheless, these economies cannot endure their green growth attainments without instantaneously safeguarding their ecological features. To do this, green technologies and environmental taxes are vital apparatuses that can assist in accomplishing carbon neutrality objectives. Consequently, the current study investigates the influence of green technologies, environmental taxes, natural resources, renewable, and fossil fuel energy on GHG emissions in G-7 nations from 1994 to 2020. After confirming the cross-sectional dependency issue, this study uses a battery of second-generation panel methods to estimate the empirical findings. The estimated evidences discovered that green technologies, environmental taxes, and renewable protect environmental quality in the long run. However, natural resources and fossil fuel energy increase the GHG emissions levels. Furthermore, this study suggests that G-7 economies should be more focus on green technologies, imposing environmental taxes eco-innovation related developments, and promote renewable energy projects through the sustainable alteration of their consumption and production processes.

Waldenström macroglobulinemia: a review of pathogenesis, current treatment, and future prospects.

Waldenström macroglobulinemia (WM) is a chronic B-cell lymphoproliferative disorder characterized by lymphoplasmacytic cell overgrowth in the bone marrow and increased secretion of IgM immunoglobulins into the serum. Patients with WM have a variety of clinical outcomes, including long-term survival but inevitable recurrence. Recent advances in disease knowledge, including molecular and genetic principles with the discovery of MYD88 and CXCR4 mutations, have rapidly increased patient-tolerable treatment options. WM patients may benefit from chemotherapy regimens that include rituximab-based regimens, alkylating drugs, proteasome inhibitors, monoclonal antibodies, and drugs targeting Bruton tyrosine kinase inhibitors. In light of these advancements, patients can now receive treatment customized to their specific clinical characteristics, focusing on enhancing the depth and durability of their response while limiting the adverse effects. Despite the rapidly developing therapeutic armament against WM, a lack of high-quality evidence from extensive phase 3 trials remains a significant challenge in the research. We believe clinical outcomes will keep improving when new medicines are introduced while preserving efficacy and minimizing toxicity.

Incidence of second primary malignancies in patients with multiple myeloma receiving anti-CD38 monoclonal antibodies: A systematic review and meta-analysis.

Anti-CD38 monoclonal antibodies (mAbs) are commonly used for treating newly diagnosed and relapsed/refractory (r/r) multiple myeloma (MM). However, concerns have been raised about the occurrence of second primary malignancies (SPMs) in patients receiving anti-CD38 mAbs. Assessing the safety data for rare adverse events like SPMs is challenging because individual clinical trials are typically focused on the primary endpoint. Therefore, we conducted a meta-analysis of randomized controlled trials (RCTs) published between January 2005 and April 2022, including patients with newly diagnosed or r/r MM. Our aim was to compare SPM rate with the use of anti-CD38 mAb-based regimens with other anti-myeloma regimens. After a median follow-up of 35.3 months (range: 8.2-56.2), we found that exposure to anti-CD38 mAbs was associated with an increased risk of developing SPMs compared to the control group (6.8% vs. 5.2%; Peto odds ratio [OR]: 1.53 [95% confidence interval (CI): 1.20-1.95]; I2= 0%, p-value for heterogeneity= 0.44). This increased risk was primarily driven by non-melanoma cutaneous cancers (92 vs. 47; Peto OR: 1.77 [95% CI: 1.25-2.51]; I2 = 0%, p-value for heterogeneity = 0.54). However, there was no significant difference in the incidence of solid tumors (including malignant melanoma) (OR: 1.28 [95% CI: 0.85-1.95]) or hematologic SPMs (OR: 1.86; [95% CI: 0.81-4.27]). In conclusion, the use of anti-CD38 mAb-based combination regimens is associated with a higher risk of non-invasive cutaneous SPMs, but not solid tumors or hematologic SPMs. The increased occurrence of non-invasive cutaneous SPMs may be due to enhanced monitoring resulting from longer treatment duration with anti-CD38 mAbs.

The dynamic impact of renewable energy consumption, trade, and financial development on carbon emissions in low-, middle-, and high-income countries.

The present study confronts potential theoretical argument of dynamic and non-linear relationship between [Formula: see text] emissions, renewable energy consumption, trade, and financial development by using quantile regression that accounts for the role of development in explaining the stated nexus. The results show that renewable energy consumption reduces [Formula: see text] emissions in the short run in low-, middle-, and high-income countries. [Formula: see text] emissions plumet as country open up for trade and expand financial services for their people. It is found that trade openness and financial development decrease [Formula: see text] emissions at upper quantile in low-income countries. In the middle-income countries, the findings are not much different as reported in case of low-income countries. In the high-income countries, renewable energy consumption and trade openness lead to decrease in [Formula: see text] emissions at all income quantiles. The Dumitrescu-Hurlin (D-H) panel causality test draws a sturdy support of bi-directional causation between renewable energy and [Formula: see text] emissions in low-income countries. Based on this analysis, some important policy implications can be drawn. First, in advanced countries, restrictions on renewable energy do not have significant effect on environmental condition. However, in low-income countries, adoption of renewable energy can significantly reduce [Formula: see text] emissions. Second, low-income countries may combat rise in [Formula: see text] emissions by introducing new technologies in exploiting trade potentials that are necessary to acquire resources to adopt clean energy. Third, energy policies should be framed based on the stage of development of a country, share of renewable energy in its total energy mix, and environmental condition of the country.

Investigating the energy-environmental Kuznets curve under panel quantile regression: a global perspective.

Energy is regarded as an engine of economic growth and an important ingredient of human survival and development, but it can lead to deterioration of environmental quality. The study investigates the energy environmental Kuznets curve (EEKC) during the 1990-2017 period for 144 countries using models for total energy, renewable energy, and non-renewable energy consumptions. We employ panel mean and quantile regressions, accounting for individual and distributional heterogeneities. It is found that the EEKC sustains among the higher middle-income countries while it cannot be verified at some lower-income quantiles due to the heterogeneous nature of the different groups of countries. The relationship between economic growth, total energy, and non-renewable energy consumption is positive and non-linear. The quantile estimations revealed mixed (positive and non-linear, inverted U-shape, U-shape, and N-shape) EEKC. The maximum and minimum turning values of GDP per capita for total energy consumption (is 43,201.58 and 89,630.49), for renewable energy consumption (53,535.07 and 89,869.41), and for non-renewable energy consumption (42,188.16 and 89,487.71). Urbanization and population growth had positive impacts on energy consumption while these effects become more significant as moving from low to high-income quantiles. The study implies that while the developed nations can adopt energy-efficient policies without compromising on the growth momentum and environment, this might be not recommended for the developing nations and it would be preferable for these countries to "grow first and clean up later." The study indicates the importance of the developed nations to support the developing countries to achieve economic growth along the EEKC by transferring energy-efficient technologies.

Chimeric Antigen Receptor T-Cell (CAR T-Cell) Therapy for Primary and Secondary Central Nervous System Lymphoma: A Systematic Review of Literature.

Relapsed/refractory central nervous system (CNS) lymphoma, whether primary or secondary, is associated with poor prognosis with currently available treatment modalities, including high-dose chemotherapy-autologous stem cell transplantation. The pivotal ZUMA-1 and JULIET trials that led to FDA approval of Axicabtagene ciloleucel and Tisagenlecleucel for relapsed refractory large cell lymphoma excluded patients with CNS involvement due to concerns of increased toxicity. However, TRANSCEND study for Lisocabtagene maraleucel in relapsed refractory large cell lymphoma allowed patients with CNS involvement and reported manageable CNS toxicities in these patients. In the real-world experience, chimeric antigen receptor T-cell (CAR T) therapy has been deemed safe and effective for these patients with poor prognosis. In this systematic review, we analyzed available literature to evaluate the role of CAR T-cell therapy in both primary and secondary CNS lymphoma using Embase, Cochrane, and PubMed databases. A total of 14 studies, including 8 retrospective analyses and 6 prospective studies/clinical trials, were included in the qualitative synthesis to study the safety and efficacy of CAR T. Based on our analysis, CAR T-cell therapy appears to be associated with reasonable efficacy and a manageable safety for primary and secondary CNS lymphoma.

Role of Liraglutide Use in Patients With Heart Failure.

Heart failure is a clinical condition in which the heart is unable to maintain adequate cardiac output. Liraglutide is a glucagon-like peptide 1 (GLP-1) analogue that is used for the treatment of type 2 diabetes mellitus, but recent evidence suggests that it might have a beneficial role in treating heart failure. We conducted a review of existing literature and found five relevant studies. Data from these studies were extracted and then extrapolated into results following analysis. Four of the five studies found an increase in heart rate in heart failure patients. All five studies reported an increased rate of hospitalization. The five studies also showed an increased risk of adverse effects such as arrhythmia, ventricular tachycardia, atrial fibrillation, and worsening of heart failure. Given the scarcity of evidence in the available literature on liraglutide in heart failure, more research on this population is required.

Refractory Pure Red Blood Cell Aplasia Secondary to Major ABO-Incompatible Allogeneic Stem Cell Transplantation Successfully Treated With Daratumumab.

Pure red cell aplasia (PRCA) is a rare hematologic phenomenon that is usually associated with inherited genetic mutations such as in Diamond-Blackfan anemia. However, due to the emergence of allogenic stem cell transplantation in the treatment of various malignant and non-malignant disorders, the incidence of PRCA has increased. PRCA following hematopoietic stem cell transplant (HSCT) is more commonly seen in the setting of a major ABO-incompatible transplant. Treatment of allo-HSCT induced PRCA can be initially supportive as it takes time for the bone marrow to fully recover. However, prolonged and/or failure of the bone marrow to recover, significantly increases patient's risk of iron overload in the setting of frequent transfusions. Iron deposition can potentially lead to severe life-threatening multiorgan involvement which can be fatal. Therefore, earlier recognition and intervention with immunomodulators in patients who undergo frequent transfusions can be beneficial to mitigate this risk. Here, we present a case with severe transfusion-dependent PRCA following major ABO-incompatible allo-HSCT successfully treated with daratumumab.

Corporate Business Strategy and Tax Avoidance Culture: Moderating Role of Gender Diversity in an Emerging Economy.

Tax payments stimulate business enterprises to choose tax management through tax avoidance activities, which is the legal practice to reduce the amount of tax payable. In developing economies, taxation is considered more critical for budget and revenues of a country. This paper investigates whether various business strategies influence corporate tax avoidance decisions of firms by adopting business strategies. Besides, it explores how gender diversity can ease this relationship. This study has chosen a sample of organizations from non-financial sector in Pakistan. The time frame is 5 years, including once a year. The present model employed a generalized moment method (GMM) and tested the proposed hypothesis to draw the results. The study has taken the size, leverage, and business profitability as control variables of firms. The study outcomes by using the GMM method demonstrate that the presence of female directors reduces tax avoidance behavior in prospector companies. This study provides insight into future research for stakeholders, government officials, tax authorities, and policymakers. The findings offer valuable recommendations and practical insights and implications. The findings provide future directions for research to test different frameworks to attain beneficial results to promote the responsibility of tax payment culture.

A gender-specific assessment of tobacco use risk factors: evidence from the latest Pakistan demographic and health survey.

BACKGROUND: The high prevalence of tobacco use in Pakistan poses a substantial health and economic burden to Pakistani individuals, families, and society. However, a comprehensive assessment of the key risk factors of tobacco use in Pakistan is very limited in the literature. A better understanding of the key risk factors of tobacco use is needed to identify and implement effective tobacco control measures. OBJECTIVES: To investigate the key socioeconomic, demographic, and psychosocial determinants of tobacco smoking in a recent large nationally representative sample of Pakistani adults. METHODS: N = 18,737 participants (15,057 females and 3680 males) from the 2017-18 Pakistan Demographic Health Survey, aged 15-49 years, with data on smoking use and related factors were included. Characteristics of male and female participants were compared using T-tests (for continuous variables) and χ2-tests (for categorical variables). Multivariable logistic regression models were used to identify gender-specific risk factors of tobacco use. The Receiver Operating Characteristic Curve test was used to evaluate the predictive power of models. RESULTS: We found that the probability of smoking for both males and females is significantly associated with factors such as their age, province/region of usual residence, education level, wealth, and marital status. For instance, the odds of smoking increased with age (from 1.00 [for ages 15-19 years] to 3.01 and 5.78 respectively for females and males aged 45-49 years) and decreased with increasing education (from 1.00 [for no education] to 0.47 and 0.50 for females and males with higher education) and wealth (from 1.00 [poorest] to 0.43 and 0.47 for richest females and males). Whilst the odd ratio of smoking for rural males (0.67) was significantly lower than that of urban males (1.00), the odds did not differ significantly between rural and urban females. Finally, factors such as occupation type, media influence, and domestic violence were associated with the probability of smoking for Pakistani females only. CONCLUSIONS: This study identified gender-specific factors contributing to the risk of tobacco usage in Pakistani adults, suggesting that policy interventions to curb tobacco consumption in Pakistan should be tailored to specific population sub-groups based on their sociodemographic and psychosocial features.

Secondary Immune Thrombocytopenia Due to Mycoplasma pneumoniae Without Clinically Significant Evidence of Active Infection.

Immune thrombocytopenia (ITP) is a leading cause of isolated thrombocytopenia characterized by autoantibody-mediated destruction of platelets, impaired megakaryocyte function, and pathologic T-cell recognition of platelet antigens. Several triggers for ITP have been identified. Treatment of the inciting cause decreases the antibodies responsible for molecular mimicry, and these cases are usually associated with a better outcome with a decreased probability of progression to chronic ITP. Mycoplasma pneumoniae infection is known to have extrapulmonary manifestations, and growing evidence suggests it can be a cause of secondary ITP. Many of the described cases report evidence of a pulmonary infection with severe mucosal bleeding. Here, we describe an interesting case of a patient presenting with isolated thrombocytopenia with mild mucosal bleeding, later found to be positive for Mycoplasma immunoglobulin M without clinically significant evidence of active infection. Currently, mycoplasma testing is not routinely performed as a workup for ITP. However, clinicians may consider this before proceeding with more aggressive treatment for refractory ITP (i.e., prolonged immunosuppression, splenectomy). This case illustrates that mild/asymptomatic Mycoplasma infection can also be associated with ITP.

Feasibility and Efficacy of Partially Replacing Post-Transplantation Cyclophosphamide with Bendamustine in Pediatric and Young Adult Patients Undergoing Haploidentical Bone Marrow Transplantation.

Post-transplantation cyclophosphamide (PT-CY) is the most widely applied graft-versus-host disease (GVHD) prophylaxis regimen in T-cell replete haploidentical bone marrow transplantation (haplo-BMT). Although PT-CY has met with great success in the haplo-BMT arena by suppressing GVHD, patients without acute GVHD have high relapse rates. One strategy to reduce relapse rates being explored by others is a dosage reduction of PT-CY. We have taken a different approach in evaluating whether partially replacing PT-CY with post-transplantation bendamustine (PT-BEN) would be advantageous, an idea based on our preclinical research identifying several beneficial immunomodulatory properties of BEN. We therefore initiated and completed a Phase Ia trial to evaluate the progressive substitution of PT-CY with PT-BEN (ClinicalTrials.gov identifier NCT02996773). We compared outcomes between 13 patients with high-risk hematologic malignancies who received PT-CY/BEN and 31 contemporaneous haplo-BMT recipients treated with the same myeloablative conditioning regimens but receiving only PT-CY. We found that partial replacement of PT-CY with PT-BEN (PT-CY/BEN) on day +4 was well tolerated and associated with significantly earlier trilineage engraftment. We also report favorable trends toward significant improvements on univariate and multivariate analyses with PT-CY/BEN compared with PT-CY with respect to rates of chronic GVHD (hazard ratio [HR], .08; 95% confidence interval [CI], .005 to 1.11; P = .06), and GVHD-free relapse-free survival (GRFS) (HR, .22; 95% CI, .05 to .86; P = .039). Our human trial has now transitioned to Phase Ib, which will further evaluate the safety and potential benefits of PT-CY/BEN. Herein we also expand our pediatric, adolescent, and young adult experience to 31 patients, demonstrating overall survival, progression-free survival, and GRFS at 3 years of 85.6%, 76.1%, and 58.2%, respectively, in a largely racial/ethnic minority cohort. PT-CY/BEN appears to be a promising treatment option that requires further evaluation.

Impact of autologous transplantation on survival in patients with newly diagnosed multiple myeloma who have high-risk cytogenetics: A meta-analysis of randomized controlled trials.

BACKGROUND: Despite routine evaluation of cytogenetics in myeloma, little is known regarding the impact of high-dose therapy (HDT) consolidation on overall survival (OS) or progression-free survival (PFS) in patients who have high-risk cytogenetics. The authors performed a meta-analysis of randomized controlled trials (RCTs) to assess the heterogeneity of HDT efficacy according to cytogenetic risk. METHODS: All RCTs in patients who had newly diagnosed myeloma from 2000 to 2021 that compared upfront HDT versus standard-dose therapy (SDT) consolidation were included. The primary objective was to assess the difference in HDT efficacy between standard-risk and high-risk cytogenetics in terms of the OS or PFS log(hazard ratio) (HR). The pooled OS and PFS HR was calculated according to cytogenetic-risk subgroup using a random-effects model, and heterogeneity (I2 ) (the percentage of total observed variability explained by between-study differences) was assessed using an interaction test. RESULTS: After screening 3307 citations, 6 RCTs were included for PFS analysis, and 4 were included for OS analysis. The median follow-up ranged from 3.1 to 7.8 years. The pooled OS HR for HDT versus SDT consolidation in patients with standard-risk and high-risk cytogenetics was 0.90 (95% confidence interval [CI], 0.70-1.17; I2 = 0%) and 0.66 (95% CI, 0.45-0.97; I2 = 0%), respectively. The difference in HDT efficacy in terms of OS between standard-risk and high-risk patients was statistically significant in favor of the high-risk group (P for interaction = .03). The pooled PFS HR for HDT versus SDT was 0.65 (95% CI 0.56-0.76; I2 = 0%) versus 0.52 (95% CI, 0.33-0.83; I2 = 55%), respectively. The difference in HDT efficacy in terms of PFS between standard-risk and high-risk patients was not significant (P for interaction = .25). CONCLUSIONS: The magnitude of OS benefit with upfront HDT is cytogenetics-dependent. Patients with high-risk cytogenetics should preferably receive upfront rather than delayed HDT consolidation. LAY SUMMARY: Upfront autologous stem cell transplantation improves overall survival in patients with newly diagnosed myeloma harboring high-risk cytogenetics.

Do geopolitical risk and energy consumption contribute to environmental degradation? Evidence from E7 countries.

Environmental degradation is frequently cited as one of the eminent issues in the modern era. To limit environmental degradation, prior literature discerns several macroeconomic, socio-economic, and institutional factors that affect environmental degradation. However, the relationship between geopolitical risk and environmental degradation is understudied in the previous literature. To fill this gap, the inquiry at hand aims to scrutinize the influence of geopolitical risk on environmental degradation for E7 countries while controlling the effect of renewable energy, non-renewable energy, and GDP. Further, we utilize both the ecological footprint and CO2 emissions as proxies of environmental degradation and employ second-generation panel methods for robust findings. In addition to this, the present study uses augmented mean group (AMG) estimator to provide long-run relationship among the selected variables. The findings from the AMG estimator expound that there exists environmental Kuznets curve (EKC) for E7 countries. Moreover, renewable energy ameliorates environmental quality because it plunges both ecological footprint and CO2 emissions. On the contrary, non-renewable energy consumption escalates both ecological footprint and CO2 emissions. Finally, geopolitical risk tends to decrease CO2 emissions as well as ecological footprint. Our findings deduce a few policy implications to replenish environmental quality. For instance, the share of renewables in the energy mix should be surged to ameliorate the environmental quality. Further, to control both the geopolitical risk and environmental degradation at the same time, policymakers should put forward reforms and initiatives (e.g., policies to escalate R&D, technological innovations, and tax exemptions on imports of renewables) that can help to improve environmental quality without affecting geopolitical risk. At times of low geopolitical risk, environmental degradation will surge; therefore, the rate of environmental control taxes should be increased by the policymakers.