Long-Term Zidovudine Therapy and Whether It is a Trigger of Vitamin B12 Deficiency: A Case Study of Megaloblastic Anemia at the University of Zambia Teaching Hospital.

Macrocytic anemia is frequently observed in adult HIV-infected patients treated with nucleoside reverse transcriptase inhibitors and with vitamin B12 and folate deficiency. In this case report, we discuss a 52-year-old nonvegetarian male on long-term antiretroviral therapy for 5 years, presenting with severe macrocytic anemia (hemoglobin, 3.7 g/dL; mean corpuscular volume, 119.6 fL) and leukopenia (2.71∗109/L), who was diagnosed with megaloblastic anemia caused by vitamin B12 deficiency following laboratory investigations. Parenteral vitamin B12 replacement therapy was initiated, with an early response observed. Notwithstanding, the treatment response was not sustained as the patient later presented with refractory anemia and persistence of macrocytosis. Discontinuation of zidovudine with concurrent vitamin B12 administration promptly improved the patient's clinical deficiency symptoms. At the end of 3 months, the patient had a complete hematological recovery. The deficiency of vitamin B12 disrupts DNA synthesis inhibiting effective hematopoiesis in all cell lines, particularly erythroid precursors and further promotes reversible bone marrow failure. Long-term ART therapy with zidovudine causes cytotoxicity in myeloid and erythroid precursors and induces bone marrow suppression. Whether long-term zidovudine consumption induced lower levels of vitamin B12 and subsequent megaloblastic anemia requires in-depth research and exploration.

Development of a Risk Assessment Model for Early Grade ≥ 3 Infection During the First 3 Months in Patients Newly Diagnosed With Multiple Myeloma Based on a Multicenter, Real-World Analysis in China.

Purpose: The study aimed to assess factors associated with early infection and identify patients at high risk of developing infection in multiple myeloma. Methods: The study retrospectively analyzed patients with MM seen at two medical centers between January 2013 and June 2019. One medical center reported 745 cases, of which 540 of the cases were available for analysis and were further subdivided into training cohort and internal validation cohort. 169 cases from the other medical center served as an external validation cohort. The least absolute shrinkage and selection operator (Lasso) regression model was used for data dimension reduction, feature selection, and model building. Results: Bacteria and the respiratory tract were the most common pathogen and localization of infection, respectively. In the training cohort, PS≥2, HGB<35g/L of the lower limit of normal range, ß2MG≥6.0mg/L, and GLB≥2.1 times the upper limit of normal range were identified as factors associated with early grade ≥ 3 infections by Lasso regression. An infection risk model of MM (IRMM) was established to define high-, moderate- and low-risk groups, which showed significantly different rates of infection in the training cohort (46.5% vs. 22.1% vs. 8.8%, p<0.0001), internal validation cohort (37.9% vs. 24.1% vs. 13.0%, p=0.009) and external validation cohort (40.0% vs. 29.2% vs. 8.5%, p=0.0003). IRMM displayed good calibration (p<0.05) and discrimination with AUC values of 0.76, 0.67 and 0.71 in the three cohorts, respectively. Furthermore, IRMM still showed good classification ability in immunomodulatory (IMiD) based regimens, proteasome-inhibitors (PI) based regimens and combined IMiD and PI regimens. Conclusion: In this study, we determined risk factors for early grade ≥ 3 infection and established a predictive model to help clinicians identify MM patients with high-risk infection.

Upfront Treatment of Pediatric High-Risk Neuroblastoma With Chemotherapy, Surgery, and Radiotherapy Combination: The CCCG-NB-2014 Protocol.

PURPOSE: The Chinese Children's Cancer Group developed the CCCG-NB-2014 study to formulate optimal treatment strategies for high-risk (HR) neuroblastoma (NB). The safety and efficacy of this protocol were evaluated. METHOD: Patients with newly diagnosed neuroblastoma and defined as HR according to the Children's Oncology Group study were included. They were treated with a combination of chemotherapy, surgery, and radiotherapy. The treatment-related toxicities, response rate, 3-year progression-free survival (PFS), and overall survival (OS) were analyzed. RESULTS: Of 159 patients enrolled between 2014 and 2018, 80 were eligible, including 19 girls and 61 boys, with a median age of 3.9 years (range 0.9-11). After a median follow-up of 24 months (range 3-40), the median OS was 31.8 months, and 3-year OS was 83.8%. In multivariate analyses, the OS was affected by N-MYC amplification (hazard ratio 0.212, 95% confidence interval (CI) 0.049-0.910; p = 0.037) and giant tumor mass (hazard ratio 0.197, 95% CI 0.071-0.552; p = 0.002). The median 3-year PFS was 25.8 months, and 3-year PFS was 57.5%. The univariate analysis showed that only the giant tumor mass was associated with the outcome. Of the 13 deaths, 11 died from the rapid progression of the disease and two from treatment-related toxicities. The most common adverse reaction was chemotherapy-induced hematological toxicity. CONCLUSION: The PFS and OS reported in our study were similar to Western countries. The CCCG-NB-2014 protocol proved to be an efficient regimen with tolerable side-effect for the treatment of pediatric HR-NB.

Optimizing NK Cell-Based Immunotherapy in Myeloid Leukemia: Abrogating an Immunosuppressive Microenvironment.

Natural killer (NK) cells are prominent cytotoxic and cytokine-producing components of the innate immune system representing crucial effector cells in cancer immunotherapy. Presently, various NK cell-based immunotherapies have contributed to the substantial improvement in the reconstitution of NK cells against advanced-staged and high-risk AML. Various NK cell sources, including haploidentical NK cells, adaptive NK cells, umbilical cord blood NK cells, stem cell-derived NK cells, chimeric antigen receptor NK cells, cytokine-induced memory-like NK cells, and NK cell lines have been identified. Devising innovative approaches to improve the generation of therapeutic NK cells from the aforementioned sources is likely to enhance NK cell expansion and activation, stimulate ex vivo and in vivo persistence of NK cells and improve conventional treatment response of myeloid leukemia. The tumor-promoting properties of the tumor microenvironment and downmodulation of NK cellular metabolic activity in solid tumors and hematological malignancies constitute a significant impediment in enhancing the anti-tumor effects of NK cells. In this review, we discuss the current NK cell sources, highlight ongoing interventions in enhancing NK cell function, and outline novel strategies to circumvent immunosuppressive factors in the tumor microenvironment to improve the efficacy of NK cell-based immunotherapy and expand their future success in treating myeloid leukemia.

Leukapheresis and Hyperleukocytosis, Past and Future.

Hyperleukocytosis is a hematologic crisis caused by excessive proliferation of leukemic cells and has a relatively high early mortality due to a series of severe complications. Therefore, prompt and effective intervention is required. Leukapheresis performed using apheresis equipment to separate leukocytes from peripheral blood, at the same time returns autologous plasma, platelets and erythrocytes to the patient, is applied clinically for the treatment of hyperleukocytosis. Leukapheresis not only removes excessive leukocytes rapidly and corrects metabolic abnormalities but also alleviates the symptoms of leukostasis. In addition, the procedure of leukapheresis is generally well tolerated. Leukapheresis has become one of the most imperative adjuvant therapies to treat hyperleukocytosis, especially in the patient who was not inappropriate to cytoreduce with Ara-C or hydroxyurea. In this review, we present the background of leukapheresis development and highlight its clinical application in hyperleukocytic leukemia patients.

Impact of Treatment Regimens on Antibody Response to the SARS-CoV-2 Coronavirus.

The coronavirus disease 2019 (COVID-19) is widely spread and remains a global pandemic. Limited evidence on the systematic evaluation of the impact of treatment regimens on antibody responses exists. Our study aimed to analyze the role of antibody response on prognosis and determine factors influencing the IgG antibodies' seroconversion. A total of 1,111 patients with mild to moderate COVID-19 symptoms admitted to Leishenshan Hospital in Wuhan were retrospectively analyzed. A serologic SARS-CoV-2 IgM/IgG antibody test was performed on all the patients 21 days after the onset of symptoms. Patient clinical characteristics were compared. In the study, 42 patients progressed to critical illness, with 6 mortalities reported while 1,069 patients reported mild to moderate disease. Advanced age (P = 0.028), gasping (P < 0.001), dyspnea (P = 0.024), and IgG negativity (P = 0.006) were associated with progression to critical illness. The mortality rate in critically ill patients with IgG antibody was 6.45% (95% CI 1.12-22.84%) and 36.36% (95% CI 12.36-68.38%) in patients with no IgG antibody (P = 0.003). Symptomatic patients were more likely to develop IgG antibody responses than asymptomatic patients. Using univariable analysis, fever (P < 0.001), gasping (P = 0.048), cancer (P < 0.001), cephalosporin (P = 0.015), and chloroquine/hydroxychloroquine (P = 0.021) were associated with IgG response. In the multivariable analysis, fever, cancer, cephalosporins, and chloroquine/hydroxychloroquine correlated independently with IgG response. We determined that the absence of SARS-CoV-2 antibody IgG in the convalescent stage had a specific predictive role in critical illness progression. Importantly, risk factors affecting seropositivity were identified, and the effect of antimalarial drugs on antibody response was determined.

Pygo2 as a novel biomarker in gastric cancer for monitoring drug resistance by upregulating MDR1.

Chemotherapy is the main therapy for gastric cancer (GC) both before and after surgery, but the emergence of multidrug resistance (MDR) often leads to disease progression and recurrence. P-glycoprotein, encoded by MDR1, is a well-known multidrug efflux transporter involved in drug resistance development. Pygo2 overexpression has been identified in several cancers. Previous studies have shown that abnormal expression of Pygo2 is related to tumorigenesis, chemoresistance, and tumor progression. In this study, to evaluate the underlying relationship between Pygo2 and MDR1 in GC, we constructed GC drug-resistant cell lines, SGC7901/cis-platinum (DDP), and collected tissue from GC patients' pre-and post-chemotherapy. We found that Pygo2 was overexpressed in GC, especially in GC drug-resistant cell lines and GC patients who underwent neoadjuvant DDP-based chemotherapy. Pygo2 overexpression may precede MDR1 and correlates with MDR1 in GC patients. Furthermore, knock-down of Pygo2 induced downregulation of MDR1 and restored SGC7901/DDP's sensitivity to DDP. Further mechanistic analysis demonstrated that Pygo2 could modulate MDR1 transcription by binding to the MDR1 promoter region and promoting MDR1 activation. The overall findings reveal that Pygo2 may be a promising biomarker for monitoring drug resistance in GC by regulating MDR1.

Approaches and Challenges in the Management of Multiple Myeloma in the Very Old: Future Treatment Prospects.

The increasing incidence of geriatric patients with multiple myeloma has elevated concerns in clinical practice. While the introduction of novel therapeutic agents has substantially improved outcomes in younger patients with myeloma, poorer outcomes remain in older patients. Managing older patients requires a multidisciplinary team approach to consider factors that may influence both treatment selection and outcomes. Aging is associated with remodeling of vital organs, physiological downregulations of basal metabolism, susceptibility to multiple comorbidities with ultimate frailty, thereby contributing to the underrepresentation and exclusion of very old patients from clinical trials. Therefore, timely confirmation of a precise diagnosis is crucial for prompt initiation of treatment if the desired outcome is to be achieved. Adequate and judicious assessment using comprehensive geriatric assessment tools minimizes toxicities and treatment discontinuation. Initiating treatment with combinational therapy requires knowledge of indications and anticipated outcomes, as well as individualized therapy with appropriate dose-adjustment. Individualized therapy based on good clinical acumen and best practices obverts unwanted polypharmacy, preventing iatrogenic harm. This review will therefore address the approaches and challenges faced in managing myeloma in geriatric patients aged 80 years and older, highlighting recommended therapeutic strategies and future prospective regimens.

The significant role of redox system in myeloid leukemia: from pathogenesis to therapeutic applications.

BACKGROUND: Excessive generation of reactive oxygen species (ROS) in the presence of a defective antioxidant system can induce cellular damage and disrupt normal physiological functions. Several studies have revealed the unfavorable role of ROS in promoting the growth, proliferation, migration, and survival of leukemia cells. In this review study, we summarize the mechanisms of ROS production and its role in leukemogenesis, counteractive effects of antioxidants, and implicate the current ROS-dependent anticancer therapies in acute myeloid leukemia. BODY: The dysregulation of the redox system is known to play a significant role in the pathogenesis of leukemia. Leukemia cells generate high levels of ROS, which further increases the levels through extra pathways, including mitochondrial deoxyribonucleic mutation, leukemic oncogene activation, increased nicotinamide adenine phosphate hydrogen (NADPH), and cytochrome P450 activities. Aforementioned pathways once activated have shown to promote genomic instability, induce drug resistance to leukemia medical therapy, disease relapse and reduce survival period. The current standard of treatment with chemotherapy employs the pro-oxidant approach to induce apoptosis and promote tumor regression. However, this approach retains several deleterious effects on the subject resulting in degradation of the quality of life. Nevertheless, the addition of an antioxidant as an adjuvant drug to chemotherapy alleviates treatment-related toxicity, increases chemotherapeutic efficacy, and improves survival rates of a patient. CONCLUSION: Acute myeloid leukemia remains a daunting challenge to clinicians. The desire to achieve the maximum benefit of chemotherapy but also improve patient outcomes is investigated. ROS generated through several pathways promotes leukemogenesis, drug resistance, and disease relapse. Chemotherapy, the mainstay of treatment, further upregulates ROS levels. Therefore, the addition of an antioxidant to leukemia medical therapy alleviates toxicity and improves patient outcomes.