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Nicholas Borcherding,1– 4 Yogesh Jethava,1,5 Praveen Vikas1,5 1Holden Comprehensive Cancer Center, University of Iowa, College of Medicine, Iowa City, IA, USA; 2Department of Pathology, University of Iowa, College of Medicine, Iowa City, IA, USA; 3Cancer Biology Graduate Program, University of Iowa, College of Medicine, Iowa City, IA, USA; 4Medical Scientist Training Program, University of Iowa, College of Medicine, Iowa City, IA, USA; 5Department of Internal Medicine, University of Iowa, College of Medicine, Iowa City, IA, USACorrespondence: Praveen VikasHolden Comprehensive Cancer Center, 5983 JPP, 200 Hawkins Drive, Iowa City, Iowa 52242, USATel + 1 319-356-2757Email praveen-vikas@uiowa.eduAbstract: The novel coronavirus disease 2019 (COVID-19) pandemic has caused catastrophic damage to human life across the globe along with social and financial hardships. According to the Johns Hopkins University Coronavirus Resource Center, more than 41.3 million people worldwide have been infected, and more than 1,133,000 people have died as of October 22, 2020. At present, there is no available vaccine and a scarcity of efficacious therapies. However, there is tremendous ongoing effort towards identifying effective drugs and developing novel vaccines. Early data from Adaptive COVID-19 Treatment Trials (ACTT) sponsored by the National Institute of Allergy and Infectious Diseases (NIAID) and compassionate use study have shown promise for remdesivir, leading to emergency authorization by the Food and Drug Administration (FDA) for treatment of hospitalized COVID-19 patients. However, several randomized studies have now shown no benefit or increased adverse events associated with remdesivir treatment. Drug development is a time-intensive process and requires extensive safety and efficacy evaluations. In contrast, drug repurposing is a time-saving and cost-effective drug discovery strategy geared towards using existing drugs instead of de novo drug discovery. Treatments for cancer and COVID-19 often have similar goals of controlling inflammation, inhibiting cell division, and modulating the host microenvironment to control the disease. In this review, we focus on anti-cancer drugs that can potentially be repurposed for COVID-19 and are currently being tested in clinical trials.Keywords: COVID-19, drug-repurposing, anti-cancer drugs

Elranatamab is a humanized B-cell maturation antigen (BCMA)-CD3 bispecific antibody. In the ongoing phase 2 MagnetisMM-3 trial, patients with relapsed or refractory multiple myeloma received subcutaneous elranatamab once weekly after two step-up priming doses. After six cycles, persistent responders switched to biweekly dosing. Results from cohort A, which enrolled patients without prior BCMA-directed therapy (n = 123) are reported. The primary endpoint of confirmed objective response rate (ORR) by blinded independent central review was met with an ORR of 61.0% (75/123); 35.0% ≥complete response. Fifty responders switched to biweekly dosing, and 40 (80.0%) improved or maintained their response for ≥6 months. With a median follow-up of 14.7 months, median duration of response, progression-free survival and overall survival (secondary endpoints) have not been reached. Fifteen-month rates were 71.5%, 50.9% and 56.7%, respectively. Common adverse events (any grade; grade 3-4) included infections (69.9%, 39.8%), cytokine release syndrome (57.7%, 0%), anemia (48.8%, 37.4%), and neutropenia (48.8%, 48.8%). With biweekly dosing, grade 3-4 adverse events decreased from 58.6% to 46.6%. Elranatamab induced deep and durable responses with a manageable safety profile. Switching to biweekly dosing may improve long-term safety without compromising efficacy. ClinicalTrials.gov identifier: NCT04649359 ., (© 2023. The Author(s).)

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative option for many hematologic conditions and is associated with considerable morbidity and mortality. Therefore, prognostic tools are essential to navigate the complex patient, disease, donor, and transplant characteristics that differentially influence outcomes. We developed a novel, comprehensive composite prognostic tool. Using a lasso-penalized Cox regression model (n = 273), performance status, HCT-CI, refined disease-risk index (rDRI), donor and recipient CMV status, and donor age were identified as predictors of disease-free survival (DFS). The results for overall survival (OS) were similar except for recipient CMV status not being included in the model. Models were validated in an external dataset (n = 378) and resulted in a c-statistic of 0.61 and 0.62 for DFS and OS, respectively. Importantly, this tool incorporates donor age as a variable, which has an important role in HSCT outcomes. This needs to be further studied in prospective models. An easy-to-use and a web-based nomogram can be accessed here: https://allohsctsurvivalcalc.iowa.uiowa.edu/ ., (© 2021. The Author(s).)

Diagnosing the cause of hypoxemia and dyspnea can be complicated in complex patients with multiple comorbidities. This "Case Study in Physiology" describes an man with obesity admitted to the hospital for relapse of acute lymphoblastic leukemia, who experienced progressive hypoxemia, shortness of breath, and dyspnea on exertion during his hospitalization. After initial empirical treatment with diuresis and antibiotics failed to improve his symptoms and because an arterial blood gas measurement was not readily available, we applied a novel, recently described physiological method to estimate the arterial partial pressure of oxygen from the peripheral saturation measurement and calculate the alveolar-arterial oxygen difference to discern the source of his hypoxemia and dyspnea. Using basic physiological principles, we describe how hypoventilation, anemia, and the use of a β blocker and furosemide, collaborated to create a "perfect storm" in this patient that impaired oxygen delivery and limited utilization. This case illustrates the application of innovative physiology methodology in medicine and provides a strong rationale for continuing to integrate physiology education in medical education. NEW & NOTEWORTHY Discerning the cause of dyspnea and hypoxemia in complex patients can be difficult. We describe the "real world" application of an innovative methodology to untangle the underlying physiology in a patient with multiple comorbidities. This case further demonstrates the importance of applying physiology to interrogate the underlying cause of a patient's symptoms when treatment based on probability fails.

Hematopoietic stem cell transplant (HSCT) is a potentially curative treatment for hematopoietic malignancies, complicated by decreased performance status and quality of life. Exercise therapy improves outcomes in HSCT, but several barriers have prevented exercise from becoming routine clinical practice. Based on existing data that wearable technologies facilitate exercise participation in other sedentary and chronic illness populations, we propose the novel hypothesis that wearable technologies are a valuable tool in transcending barriers and developing exercise therapy programs for HSCT patients., (Copyright © 2021 by the American College of Sports Medicine.)

At the end of 2019, a novel coronavirus was identified as the cause of pneumonia cases in Wuhan, a city in the Hubei Province of China. On January 30, 2020, the World Health Organization (WHO) declared the COVID-19 outbreak a public health emergency of international concern and, in March 2020, began to characterize it as a pandemic. The virus that causes COVID-19 is designated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) In February 2020, the World Health Organization designated the disease COVID-19, which stands for coronavirus disease 2019., Competing Interests: Dr Yogesh S Jethava: none. Dr Rafael Fonseca: none. Dr. Landgren reports grants from NIH, FDA, MMRF, IMF, LLS, Perelman Family Foundation, Rising Tide Foundation, Janssen, Takeda, Glenmark, Seattle Genetics, Karyopharm; personal fees from Adaptive Biotech, Binding Site, BMS, Cellectis, Juno, and Pfizer; and IDMC from Takeda, Merck, and Janssen.”, (© 2020 Published by Elsevier Ltd.)

Background: Treatment failures in cancers, including multiple myeloma (MM), are most likely due to the persistence of a minor population of tumor-initiating cells (TICs), which are noncycling or slowly cycling and very drug resistant., Methods: Gene expression profiling and real-time quantitative reverse transcription polymerase chain reaction were employed to define genes differentially expressed between the side-population cells, which contain the TICs, and the main population of MM cells derived from 11 MM patient samples. Self-renewal potential was analyzed by clonogenicity and drug resistance of CD24+ MM cells. Flow cytometry (n = 60) and immunofluorescence (n = 66) were applied on MM patient samples to determine CD24 expression. Therapeutic effects of CD24 antibodies were tested in xenograft MM mouse models containing three to six mice per group., Results: CD24 was highly expressed in the side-population cells, and CD24+ MM cells exhibited high expression of induced pluripotent or embryonic stem cell genes. CD24+ MM cells showed increased clonogenicity, drug resistance, and tumorigenicity. Only 10 CD24+ MM cells were required to develop plasmacytomas in mice (n = three of five mice after 27 days). The frequency of CD24+ MM cells was highly variable in primary MM samples, but the average of CD24+ MM cells was 8.3% after chemotherapy and in complete-remission MM samples with persistent minimal residual disease compared with 1.0% CD24+ MM cells in newly diagnosed MM samples (n = 26). MM patients with a high initial percentage of CD24+ MM cells had inferior progression-free survival (hazard ratio [HR] = 3.81, 95% confidence interval [CI] = 5.66 to 18.34, P < .001) and overall survival (HR = 3.87, 95% CI = 16.61 to 34.39, P = .002). A CD24 antibody inhibited MM cell growth and prevented tumor progression in vivo., Conclusion: Our studies demonstrate that CD24+ MM cells maintain the TIC features of self-renewal and drug resistance and provide a target for myeloma therapy., (© The Author(s) 2019. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Multiple myeloma is an invariably fatal cancer of plasma cells. Despite tremendous advances in treatment, this malignancy remains incurable in most individuals. We postulate that strategies aimed at prevention have the potential to be more effective in preventing myeloma-related death than additional pharmaceutical strategies aimed at treating advanced disease. Here, we present a rationale for the development of prevention therapy and highlight potential target areas of study.

Background Neutropenic fever (NF) is a known and common complication of autologous hematopoietic stem cell transplantation (ASCT). Early risk assessment may help direct treatment. We retrospectively analyzed the role of serial serum C-reactive protein (CRP) levels in predicting NF and assessed the clinical value of CRP within 14 days after transplantation. Methods One hundred twenty-one multiple myeloma (MM) patients received 170 first and/or second ASCT between January 2014 and March 2017. A Cox regression model was applied to assess the prognostic value of CRP as a time-dependent covariate at the onset of NF within 14 days post-transplant. Results Forty-seven of 170 patients developed NF. High CRP levels (4.0-43.2 mg/dL) were associated with a 5.45-fold increased risk of NF (P = 0.02). Patients had a nearly three-fold increased risk of NF after the second transplant (P < 0.01), but this was not associated with increased mortality. Those with NF had higher maximum values of CRP (P < 0.01) which tended to occur at or after the onset of NF. Conclusion CRP monitoring provides important information about the risk for NF immediately after first MM ASCT, and even more so after the second., Competing Interests: The authors have declared that no competing interests exist.

Drug resistance remains the key problem in cancer treatment. It is now accepted that each myeloma patient harbors multiple subclones and subclone dominance may change over time. The coexistence of multiple subclones with high or low chromosomal instability (CIN) signature causes heterogeneity and drug resistance with consequent disease relapse. In this study, using a tandem affinity purification-mass spectrometry (TAP-MS) technique, we found that NEK2, a CIN gene, was bound to the deubiquitinase USP7. Binding to USP7 prevented NEK2 ubiquitination resulting in NEK2 stabilization. Increased NEK2 kinase levels activated the canonical NF-κB signaling pathway through the PP1α/AKT axis. Newly diagnosed myeloma patients with activated NF-κB signaling through increased NEK2 activity had poorer event-free and overall survivals based on multiple independent clinical cohorts. We also found that NEK2 activated heparanase, a secreted enzyme, responsible for bone destruction in an NF-κB-dependent manner. Intriguingly, both NEK2 and USP7 inhibitors showed great efficacy in inhibiting myeloma cell growth and overcoming NEK2-induced and -acquired drug resistance in xenograft myeloma mouse models.

Patients with follicular lymphoma (FL) experiencing early therapy failure (ETF) within 2 years of frontline chemoimmunotherapy have poor overall survival (OS). We analyzed data from the Center for International Blood and Marrow Transplant Research (CIBMTR) and the National LymphoCare Study (NLCS) to determine whether autologous hematopoietic cell transplant (autoHCT) can improve outcomes in this high-risk FL subgroup. ETF was defined as failure to achieve at least partial response after frontline chemoimmunotherapy or lymphoma progression within 2 years of frontline chemoimmunotherapy. We identified 2 groups: the non-autoHCT cohort (patients from the NLCS with ETF not undergoing autoHCT) and the autoHCT cohort (CIBMTR patients with ETF undergoing autoHCT). All patients received rituximab-based chemotherapy as frontline treatment; 174 non-autoHCT patients and 175 autoHCT patients were identified and analyzed. There was no difference in 5-year OS between the 2 groups (60% versus 67%, respectively; P = .16). A planned subgroup analysis showed that patients with ETF receiving autoHCT soon after treatment failure (≤1 year of ETF; n = 123) had higher 5-year OS than those without autoHCT (73% versus 60%, P = .05). On multivariate analysis, early use of autoHCT was associated with significantly reduced mortality (hazard ratio, .63; 95% confidence interval, .42 to .94; P = .02). Patients with FL experiencing ETF after frontline chemoimmunotherapy lack optimal therapy. We demonstrate improved OS when receiving autoHCT within 1 year of treatment failure. Results from this unique collaboration between the NLCS and CIBMTR support consideration of early consolidation with autoHCT in select FL patients experiencing ETF., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)

Background: Myeloid sarcoma (MS) is characterized by extramedullary infiltration by immature myeloid cells. Owing to rarity of this disease, the clinical features and overall outcomes are yet to be clarified., Objective: To define clinical characteristics, epidemiology, pathologic findings, treatment options and outcomes in MS., Methods: We conducted a retrospective review of 23 patients diagnosed with MS at our institute over a period of 13 years (2002-2015)., Results: MS presented mostly as a manifestation of relapsed acute myeloid leukemia, seen in 39% of patients. Skin and subcutaneous soft tissues were the most common sites of anatomic involvement (69.5%). Ninety five percent (n = 19) were positive for classical myeloid markers with either cytochemical staining (chloracetate-esterase, MPO), flow-cytometry (CD33, CD34, CD13 and CD117), or immunohistochemistry (CD34, CD43, CD68 and lysozyme). Of these, 52% were positive for CD33 (n = 12), 35% for CD68 (n = 8), 30% for CD34 (n = 7), and 26% for lysozyme (n = 6). Cytogenetic abnormalities were seen in 63% (n = 12/19) patients on bone-marrow aspirate, with five patients displaying a complex (n = 3) or monosomal (n = 2) karyotype. Twenty seven percent patients with a normal karyotype had presence of deleterious mutations (FLT3, ASXL, STAG and JAK2) on further testing with myeloid mutation panel. The Median overall survival (OS) of the entire cohort was 15.9 months (95% CI, 7.4-24.4 months). The OS was significantly better for patients <65 years (24.6 vs. 3.4 months, p = 0.009) of age, and for those attaining a complete remission (CR) to induction therapy (25.7 vs. 0.8 months, p < 0.001). All patients who underwent allogeneic hematopoietic stem cell transplant attained long-term remissions, with a median follow-up of 54 (range 32-120) months., Conclusion: Failure to achieve CR with induction therapy, and age >65 years are associated with poor outcomes in MS. Allogeneic stem-cell transplant in first remission appears to be the most effective modality for achieving long-term remissions.

Many cancers, including multiple myeloma (MM), retain more cytosolic iron to promote tumor cell growth and drug resistance. Higher cytosolic iron promotes oxidative damage due to its interaction with reactive oxygen species generated by mitochondria. The variation of mitochondrial biogenesis in different stages of MM disease was evaluated using gene expression profiles in a large clinical dataset. Sixteen of 18mitochondrial biogenesis related gene sets, including mitochondrial biogenesis signature and oxidative phosphorylation, were increased in myeloma cells compared with normal plasma cells and high expression was associated with an inferior patient outcome. Relapsed and drug resistant myeloma samples had higher expression of mitochondrial biogenesis signatures than newly diagnosed patient samples. The expression of mitochondrial biogenesis genes was regulated by the cellular iron content, which showed a synergistic effect in patient outcome in MM. Pharmacological ascorbic acid induced myeloma cell death by inhibition of mitochondria oxidative phosphorylation in an in vivo model. Here, we identify that dysregulated mitochondrial biogenesis and iron homeostasis play a major role in myeloma progression and patient outcome and that pharmacological ascorbic acid, through cellular iron content and mitochondrial oxidative species, should be considered as a novel treatment in myeloma including drug-resistant and relapsed patients., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.

We present the case of a young man with acute lymphoblastic leukemia who developed cytomegalovirus (CMV) appendicitis after receiving alemtuzumab for acute refractory graft-versus-host disease after allogeneic hematopoietic stem cell transplantation (HSCT). CMV appendicitis is a rare complication; and we are reporting the first case to our knowledge of CMV appendicitis following HSCT. Our case highlights the importance of recognition of CMV viral reactivation following the use of alemtuzumab. Using a preemptive strategy of checking CMV PCR, with initiation of early effective treatment on detection of CMV replication, may be appropriate following use of alemtuzumab in hematologic malignancies in patients after HSCT., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Blastic plasmacytoid dendritic cell neoplasm is rare myeloid malignancy clinically characterized by non-pruritic, violaceous and papulo-nodular skin lesions, together with bone marrow and lymph node involvement. Histologically, there is infiltration of dermis by neoplastic mono-nuclear CD4, CD56, CD123 co-expressing cells with epidermal sparing. Most commonly blastic plasmacytoid dendritic cell neoplasm presents as a de-novo condition, and treatment-related blastic plasmacytoid dendritic cell neoplasm is a rare phenomenon. Due to rarity of the disease, there is no established standard of care treatment. Both acute myeloid leukemia and acute lymphoid leukemia type induction regimens have been used for treatment of blastic plasmacytoid dendritic cell neoplasm, with initial response rate of 50%-80%. We present a rare case of therapy-associated blastic plasmacytoid dendritic cell neoplasm in a patient with remote history alkylating agent systemic therapy. A lag period of five to seven years and presence of deletion 7q.31 seen in bone marrow biopsy specimen in our patient are consistent with a likely therapy-associated etiology of his blastic plasmacytoid dendritic cell neoplasm.

Relapse of Hodgkin lymphoma after autologous hematopoietic cell transplantation (autologous HCT) is a major therapeutic challenge. Its management, at least in younger patients, traditionally involves salvage chemotherapy aiming to achieve disease remission followed by consolidation with allogeneic hematopoietic cell transplantation (allogeneic HCT) in eligible patients. The efficacy of salvage therapy is variable and newer combination chemotherapy regimens have improved the outcomes. Factors such as shorter time to relapse after autologous HCT and poor performance status have been identified as predictors of poor outcome. Newer agents such as immunoconjugate brentuximab vedotin, checkpoint inhibitors (e.g., pembrolizumab, nivolumab), lenalidomide, and everolimus are available for the treatment of patients relapsing after autologous HCT. With the availability of reduced intensity conditioning allogeneic HCT, more patients are eligible for this therapy with lesser toxicity and better efficacy due to graft versus lymphoma effects. Alternative donor sources such as haploidentical stem cell transplantation and umbilical cord blood transplantation are expanding this procedure to patients without HLA-matched donors. However, strategies aimed at reduction of disease relapse after reduced intensity conditioning allogeneic HCT are needed to improve the outcomes of this treatment. This review summarizes the current data on salvage chemotherapy and HCT strategies used to treat patients with relapsed Hodgkin lymphoma after prior autologous HCT., (Copyright © 2017 King Faisal Specialist Hospital & Research Centre. Published by Elsevier B.V. All rights reserved.)

The authors present a case of a 51-year-old woman with endometriosis who developed immune thrombocytopenic purpura. Her platelets dropped to 2×10(9)/l, and she had haemorrhage into her right endometrioma causing a large pelvic haematoma. She also had renal failure secondary to endometriosis compressing the right ureter. She was treated with immunoglobulin and steroids with subsequent recovery of platelet count and underwent ureteric stenting to prevent worsening renal function.