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.

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.

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.

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.

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.

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.

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.

CD38-Directed Therapies for Management of Multiple Myeloma.

The survival outcomes for multiple myeloma have improved several-fold in the past two decades, primarily due to the introduction of therapies with novel mechanisms of action including immunomodulatory agents, proteasome inhibitors, stem cell transplant and monoclonal antibodies in the schema of therapy. Antibody-based therapies targeting the surface marker CD38, namely daratumumab and isatuximab, have emerged as being highly effective as single agents as well as in combination regimens for both newly diagnosed and relapsed settings. Herein, the authors summarize the most recent data with both the current and emerging CD38-directed therapies in multiple myeloma.

A Living, Interactive Systematic Review and Network Meta-analysis of First-line Treatment of Metastatic Renal Cell Carcinoma.

CONTEXT: Identifying the most effective first-line treatment for metastatic renal cell carcinoma (mRCC) is challenging as rapidly evolving data quickly outdate the existing body of evidence, and current approaches to presenting the evidence in user-friendly formats are fraught with limitations. OBJECTIVE: To maintain living evidence for contemporary first-line treatment for previously untreated mRCC. EVIDENCE ACQUISITION: We have created a living, interactive systematic review (LISR) and network meta-analysis for first-line treatment of mRCC using data from randomized controlled trials comparing contemporary treatment options with single-agent tyrosine kinase inhibitors. We applied an advanced programming and artificial intelligence-assisted framework for evidence synthesis to create a living search strategy, facilitate screening and data extraction using a graphical user interface, automate the frequentist network meta-analysis, and display results in an interactive manner. EVIDENCE SYNTHESIS: As of October 22, 2020, the LISR includes data from 14 clinical trials. Baseline characteristics are summarized in an interactive table. The cabozantinib + nivolumab combination (CaboNivo) is ranked the highest for the overall response rate, progression-free survival, and overall survival, whereas ipilimumab + nivolumab (NivoIpi) is ranked the highest for achieving a complete response (CR). NivoIpi, and atezolizumab + bevacizumab (AteBev) were ranked highest (lowest toxicity) and CaboNivo ranked lowest for treatment-related adverse events (AEs). Network meta-analysis results are summarized as interactive tables and plots, GRADE summary-of-findings tables, and evidence maps. CONCLUSIONS: This innovative living and interactive review provides the best current evidence on the comparative effectiveness of multiple treatment options for patients with untreated mRCC. Trial-level comparisons suggest that CaboNivo is likely to cause more AEs but is ranked best for all efficacy outcomes, except NivoIpi offers the best chance of CR. Pembrolizumab + axitinib and NivoIpi are acceptable alternatives, except NivoIpi may not be preferred for patients with favorable risk. Although network meta-analysis provides rankings with statistical adjustments, there are inherent biases in cross-trial comparisons with sparse direct evidence that does not replace randomized comparisons. PATIENT SUMMARY: It is challenging to decide the best option among the several treatment combinations of immunotherapy and targeted treatments for newly diagnosed metastatic kidney cancer. We have created interactive evidence summaries of multiple treatment options that present the benefits and harms and evidence certainty for patient-important outcomes. This evidence is updated as soon as new studies are published.

Development of Nonbacterial Thrombotic Endocarditis While on Systemic Anticoagulation in Pancreatic Cancer: A Case Report.

Nonbacterial thromboembolic endocarditis (NBTE), or marantic endocarditis, is a rare complication associated with advanced cancer. Enoxaparin or unfractionated heparin is considered the standard treatment for NBTE. In this case report, we describe a 59-year-old female with metastatic pancreatic cancer who presented with embolic stroke and was found to have new NBTE of the mitral valve while she was receiving the therapeutic dose of enoxaparin. Of note, her recent echocardiogram one week ago was negative for mitral valve vegetations. Our case emphasized that for patients with advanced cancer presenting with stroke, the diagnosis of NBTE should be entertained even for those on systemic anticoagulation.

Betalains: Potential Drugs with Versatile Phytochemistry.

Currently, the demand for natural colorants is increasing instead of synthetic colorants for foodstuff, because they are harmless to human health. Betalain is group of compounds containing nitrogen and water soluble pigment. Betalain is classified into two main classes, betacyanin which is the condensation of betalamic acid with cyclo-DOPA and betaxanthin which is the conjugation of amino acid or amines with betalamic acid. They are used to color various foods and medicines. Betalain is different from anthocyanin because betalains contain nitrogen in their structures. It is interesting to hear that betalains and anthocyanins are individually significant but they have not seen together in the same plant. Their stability influenced by various factors such as, temperature, pH, water activity and light. In this review basic chemistry of betalains, classes, subclasses, their sources and biosynthesis, factors affecting their stability, health and food industry applications are discussed. Moreover, mentioned work signifies the potent anticancer, antioxidant and antimalarial activities of betalains, furthermore provides a help to do more scientific work on it.

Clinical and radiological characteristics of patients with pulmonary marginal zone lymphoma: A single center analysis.

Pulmonary marginal zone lymphoma (PMZL) is the most common non-Hodgkin lymphoma affecting the lung. PMZL is usually an indolent disease. Clinical and radiological variables associated with shorter survival are largely unknown and no consensus exists on preferred treatment strategy in PMZL. Herein we aimed to identify clinical and radiological features associated with shorter survival and inferior treatment outcomes. Forty patients with PMZL were analyzed. FDG-avid disease was evident in most patients (93%) with staging PET/CT (n = 15). With a median follow-up in treated patients (n = 38) of 8.4 years (range 0.07-18.44), the median progression-free survival (PFS) and overall survival (OS) were 7.5 years (95% CI 1.8-9.5) and 15.7 years (95% CI 9.3-NE) respectively. Shorter PFS was observed in patients who presented at diagnosis with elevated LDH, B symptoms, advanced stage and failed to achieve complete response (CR) after initial treatment. Patients with multifocal lung disease, extrapulmonary MZL and cavitary lesions on CT scans exhibited shorter PFS. Nevertheless, no clinical or radiologic findings were associated with shorter OS. All patients treated with surgery (n = 4) and radiation therapy (n = 3) achieved and remained in CR. No higher grade transformations occurred during the follow-up period. PMZL exhibited excellent outcomes with a 15-year PMZL-related OS of 94.9% (95% CI: 81.25%-98.7%). Radiation therapy and surgery are potentially curative strategies in localized PMZL.

Growth Performance of Broilers as Influenced by Different Levels and Sources of Methionine Plus Cysteine.

The objective of this work was to evaluate the utilization of methionine from DL-methionine (DL-Met) and L-methionine (L-Met) with different levels of dietary methionine plus cystine (Met + Cyst) in broilers. The experimental diets were formulated by using three levels of Met + Cyst, i.e., 74%, 77% and 80% of digestible lysine. Met + Cyst was provided either from DL-Met or L-Met. A total of 450 day-old broilers were divided into six groups (five replicates of 15 birds each) in a 3 × 2 factorial arrangement under completely randomized design. Weight gain (WG), feed intake (FI) and feed conversion ratio (FCR) was determined. At the end of the experiment (35 days), two birds from each replicate were slaughtered to determine carcass characteristics and serum homocysteine. Results indicate that the combined effect of L-Met and DL-Met significantly affected (p < 0.05) the WG in the starter period and FI in the finisher period. Neither source nor level of methionine influenced (p > 0.05) the FI, WG and FCR of broilers during the starter, finisher or overall phase of growth. The interaction between sources and levels of methionine did not influence (p > 0.05) the feed intake, weight gain and FCR during the overall phase of growth. Source of methionine had no (p > 0.05) effect on carcass characteristics. Methionine levels had a significant effect (p < 0.05) on carcass weight, chest weight and thigh weight. The interaction between sources and levels of methionine had a significant (p < 0.05) effect on the liver weight. The sources of methionine had significant (p < 0.05) effects on the liver and heart weight, while methionine levels significantly influenced (p < 0.05) the liver and gizzard weight. Finally, it was concluded that if DL-Met and L-Met are included in feed at a standard level, they are equally effective as a source of methionine for broilers.

Multiple Myeloma in a Patient with ANKRD26-Related Thrombocytopenia Successfully Treated with Combination Therapy and Autologous Stem Cell Transplant.

Ankyrin repeat domain-containing protein 26- (ANKRD26-) related thrombocytopenia is a rare, autosomal dominant condition caused by ANKRD26 gene mutation. ANKRD26-related thrombocytopenia is characterized by moderate thrombocytopenia with minimal bleeding, normal platelet size, and dysmegakaryopoiesis on bone marrow evaluation. ANKRD26 mutation has been previously associated with myeloid malignancies, including acute myeloid leukemia, myelodysplastic syndrome, and chronic myeloid leukemia. We report the first case of multiple myeloma in a patient with ANKRD26 related thrombocytopenia. The patient was successfully treated with contemporary combination therapy followed by melphalan-conditioned autologous stem cell transplant for his multiple myeloma despite preexisting thrombocytopenia.

Adjuvant Therapy in High-Risk Renal Cell Cancer: A Systematic Review and Meta-analysis.

OBJECTIVE: To perform a systematic review and meta-analysis of randomized controlled trials (RCTs) evaluating risk-benefit for adjuvant postoperative treatments in high-risk renal cell carcinoma by assessing reported disease-free survival (DFS), overall survival (OS), toxicity, and quality of life. METHODS: A literature search was performed in PubMed, Embase, Web of Science, and Cochrane Central Register of Controlled Trials to identify relevant RCTs (from database inception through May 15, 2018). The results of the ATLAS trial were published while writing this manuscript, and the manuscript was updated accordingly. A generic variance-weighted random effects model was used to derive estimates for efficacy and common adverse effects. Heterogeneity was assessed using the Cochran Q statistic and was quantified using the I2 test. RESULTS: Adjuvant therapy with tyrosine kinase inhibitors compared with placebo was observed to have a DFS hazard ratio [HR] of 0.92 (95% CI, 0.83-1.01) and an OS HR of 1.01 (95% CI, 0.89-1.15) (4 RCTs; 4417 patients). Analysis of DFS for sunitinib compared with placebo (n=1909) in the adjuvant setting detected an HR of 0.90 (95% CI, 0.67-1.19). Increased risk of grade 3 or 4 adverse events (relative risk [RR]=2.6; 95% CI, 2.28-2.97), diarrhea (RR=9.89; 95% CI, 4.22-23.14), fatigue (RR=3.11; 95% CI, 1.86-5.18), hypertension (RR=3.63; 95% CI, 2.99-4.41), and palmar/plantar dysesthesia (RR=2.70; 95% CI, 2.47-2.96) was observed. CONCLUSION: Adjuvant vascular endothelial growth factor tyrosine kinase inhibitors in high-risk renal cell carcinoma did not improve OS or DFS, and there was a significant increased risk of toxicity in greater than half of the patients, leading to a decline in quality of life.