Hematologic Malignant Neoplasms Research Articles

Abstract P2-16-05: Targeting EZH2 to overcome chemoresistance in Triple Negative Breast Cancers Employing Combinatorial Approach

Abstract Objective: Triple Negative Breast Cancers (TNBC) are highly invasive and 46% of patients develop distant metastases, leading to higher mortality. Chemotherapy remains the most efficacious option, however, there is still a largely unmet need to identify novel therapeutic targets in TNBC to increase treatment options and improve patient outcomes, survival. Enhancer of zeste homologue 2 (EZH2), a member of the catalytic subunit of the polycomb repressive complex 2, is a histone methyltransferase and its canonical function is to methylate lysine 27 of histone 3. EZH2 is a potential driver of TNBC metastasis, and its high expression strongly associates with the TNBC phenotype as compared with other molecular subtypes of breast cancer. Despite the advancement in the discovery of inhibitors for EZH2 that attenuate its catalytic activity. Currently, several EZH2 inhibitors are under development and undergoing clinical trials and these compounds have been proved to be effective in the treatment of hematological malignancies, sarcomas and malignant rhabdoid tumors. However these inhibitors do not affect the intrinsic protein stability of EZH2, but typically competes with the cofactor S-adenosylmethionine (SAM) and binds to the SET domain of EZH2. Hence, the EZH2 inhibitors are only effective for some malignant blood tumors, and have poor efficacy for solid tumors, such as TNBC. Several studies have shown the involvement of neurotransmitter dopamine in proliferation, apoptosis, tumor angiogenesis, and drug resistance among different cancers, including the breast1. Dopamine D1 receptor activation in TNBC cell line induces apoptosis, autophagy and phosphorylation of eukaryotic translation initiation factor 2-alpha (eIF2a)2. Also, D1R agonists inhibits the invasion of breast cancer cell lines MDA-MB-231 and BT-20 and regress mammary tumors3. The oncogenic nature of EZH2 in driving aggressiveness in TNBC cells led us to simultaneously target dopamine D1 receptor and EZH2 to completely ablate tumor growth and metastasis. Methods: Schrodinger protein modeling software was employed for docking studies. TNBC cells MDA-MB-231 cells were treated with the EZH2 inhibitor GSK126 and/or D1R agonists A77636 and SKF38393 for assessing cell viability, migration. Immuno precipitation to investigate if the combination could disrupt the PRC2 complex in TNBC cells. To model tumor burden and the effects of combination therapy on tumor growth in vitro, we tested the combinatory effect of GSK126 and D1R agonists in a 3D culture system of MDA-MB-231 cells encapsulated in calcium-alginate microgels seeded from a microfluidic droplet generator. Cell death was determined by Yo-pro-Propidium Iodide staining. Result: In silico analysis confirmed that D1R agonists exhibited strong stabilization of protein structures upon binding to the EZH2 catalytic active site, albeit with slightly weaker affinity than GSK126. Combination treatment with GSK126 and dopamine agonists A77636 or SKF 38393 led to significant and synergistic inhibition of cell viability (p< 0.01), migration, invasion, and EZH2 activity (p< 0.01) in TNBC cells. In addition, MDA-MB-231 cells formed tumor spheroids that were subjected to the EZH2 inhibitor alongside dopamine agonists, indicating tumor reduction relative to single agent treatment in 3D culture (p < 0.0001). The combination also led to increased necrotic cell death (p < 0.05). Immunoprecipitation of EZH2 in the presence of GSK126 and SKF38393 and A77636 dissociated the physical interaction between EZH2, EED, and SUZ12 in MDA-MB-231 cells. Conclusion: Our data suggest that the combination of GSK126 and Dopamine D1 agonists synergistically inhibits TNBC proliferation by disrupting EZH2 functions leading to necrotic cell death. (This work is supported by DOD: W81XWH2010065, for Eswar Shankar). 1) PMID: 21531818 2) PMID: 29773888 3) PMID: 26477316 Citation Format: Eswar Shankar, Sridhar SNC, Xilal Y. Rima, Prem Kushwaha, Shiv Verma, Gautam K. Sarathy, Anagh kulkarni, Dharmaraja Allimuthu, Eduardo Reátegui, Sanjay Gupta, Bhuvaneswari Ramaswamy. Targeting EZH2 to overcome chemoresistance in Triple Negative Breast Cancers Employing Combinatorial Approach. [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-16-05.

Ferroptosis-related STEAP3 acts as predictor and regulator in diffuse large B cell lymphoma through immune infiltration.

Diffuse large B cell lymphoma (DLBCL) is a usual-seen hematological malignant tumor possessing molecular and genetic heterogeneity. Ferroptosis induction has been increasingly acknowledged to be an advantageous therapeutic method in tumor treatment by triggering cell death of tumor cells. However, studies on the function of ferroptosis in DLBCL remain scarce, especially the interaction with the tumor immune microenvironment (TIME). The clinical and biological functions of ferroptosis-related genes in DLBCL were still warranted to be explored. A ferroptosis-related risk model was constructed, followed by functional enrichment analyses and evaluation of immune profile. Quantitative real-time PCR, western blotting, and immunohistochemistry were conducted to examine the RNA and protein levels. Dysregulated expression of the major ferroptosis-related genes was found in DLBCL. A prognostic risk model based on 10 ferroptosis-related genes was constructed. The risk score served as an independent prognostic indicator for DLBCL patients in univariate and multivariate Cox regression analysis. Patients with low-risk scores presented a more favorable prognosis. Functional enrichment analysis revealed that immune-related pathways were significantly enriched, and the high-risk group exhibited less immunocyte infiltration, lower immunoscore, and downregulated PD-L1 expression relative to the low-risk group. Two molecular subtypes were determined through consensus clustering of the expression of ferroptosis-related genes. Cluster 1 was relevant to favorable prognosis, higher immunoscore, and elevated PD-L1 expression. More importantly, STEAP3 was screened as a reliable biomarker for DLBCL, and its enhanced expression levels of mRNA and protein were verified in public databases and clinical specimens. Our study demonstrated the crucial role of ferroptosis-related genes including STEAP3 in the TIME of DLBCL and identified promising novel molecular targets for DLBCL treatment.

Immune Microenvironment and Immunotherapies for Diffuse Intrinsic Pontine Glioma.

Diffuse intrinsic pontine glioma (DIPG) is a primary glial glioma that occurs in all age groups but predominates in children and is the main cause of solid tumor-related childhood mortality. Due to its rapid progression, the inability to operate and insensitivity to most chemotherapies, there is a lack of effective treatment methods in clinical practice for DIPG patients. The prognosis of DIPG patients is extremely poor, with a median survival time of no more than 12 months. In recent years, there have been continuous breakthroughs for immunotherapies in various hematological tumors and malignant solid tumors with extremely poor prognoses, which provides new insights into tumors without effective treatment strategies. Meanwhile, with the gradual development of stereotactic biopsy techniques, it is gradually becoming easier and safer to obtain live DIPG tissue, and the understanding of the immune properties of DIPG has also increased. On this basis, a series of immunotherapy studies of DIPG are under way, some of which have shown encouraging results. Herein, we review the current understanding of the immune characteristics of DIPG and critically reveal the limitations of current immune research, as well as the opportunities and challenges for immunological therapies in DIPG, hoping to clarify the development of novel immunotherapies for DIPG treatment.

Design, synthesis and biological evaluation of novel quinazolinone derivatives as CRBN E3 ligase modulators

CRBN E3 ligase modulators, also anteriorly called immunomodulatory drugs (IMiDs), exhibit excellent pharmacological activity by degrading cereblon (CRBN) associated multiple substrates and have become an important field for drug development. These modulators such as Thalidomide, Lenalidomide and CC-122 abduct CRBN to adhere to IKZF1/3 and other neosubstrates, and then induce the degradation of these substrates, thus retarding the further development of related diseases. Herein, we reported a series of CC-122 derivatives that inhibit the proliferation of hematological malignant tumor cell lines. Studies further confirmed that several derivatives which exhibit strong anti-proliferation effect induce the significant degradation of IKZF1/3. In addition, we found that the best compound 14 (SIAIS355035) exhibits better degradation activity and better anti-proliferation activities than CC-122, especially in diffuse large B lymphoma cell lines. Moreover, the PK properties of compound 14 are pretty promising with excellent oral bioavailability. These results clarified the SAR of CC-122 derivatives preliminarily and suggested that compound 14 has great value for further studies as an ideal novel CRBN E3 ligase modulation drug.

Cost-effectiveness of Axicabtagene Ciloleucel and Tisagenlecleucel as Second-line or Later Therapy in Relapsed or Refractory Diffuse Large B-Cell Lymphoma

Chimeric antigen receptor (CAR) T cell therapies are approved as a third-line or later therapy for several hematological malignant neoplasms. Recently, randomized clinical trials have investigated their efficacy as a second-line treatment in high-risk relapsed or refractory diffuse large B-cell lymphoma (DLBCL) compared with salvage chemotherapy followed by hematopoietic stem cell transplantation (HSCT). To evaluate the cost-effectiveness of axicabtagene ciloleucel and tisagenlecleucel vs standard care (SC) as second-line or later therapy for relapsed or refractory DLBCL, from both US health care sector and societal perspectives at a cost-effectiveness threshold of $150 000 per quality-adjusted life-year (QALY). This economic evaluation assessed cost-effectiveness using a partitioned survival model with 2021 US dollars and QALYs over a lifetime horizon. Model inputs were derived from 2 randomized clinical trials (ZUMA-7 and BELINDA) and published literature. In the trials, patients who did not respond to SC received CAR T cells (treatment switching or crossover), either outside the protocol (ZUMA-7) or as part of the protocol (BELINDA). A separate scenario analysis compared second-line axicabtagene ciloleucel with SC alone without treatment crossover to CAR T cell therapy. Data analysis was performed from December 18, 2021, to September 13, 2022. CAR T cell therapy (axicabtagene ciloleucel and tisagenlecleucel) compared with salvage chemotherapy followed by HSCT. Costs and QALYs were used to derive incremental cost-effectiveness ratios (ICERs) for the health care sector and societal perspectives. Cost and QALYs were discounted at 3.0% annually. Univariate and multivariate probabilistic sensitivity analysis using 10 000 Monte Carlo simulations were applied to test model uncertainty on the ICER. Second-line axicabtagene ciloleucel was associated with an ICER of $99 101 per QALY from the health care sector perspective and an ICER of $97 977 per QALY from the societal perspective, while second-line tisagenlecleucel was dominated by SC (incremental costs of $37 803 from the health care sector and $39 480 from the societal perspective with decremental QALY of -0.02). Third-line or later tisagenlecleucel was associated with an ICER of $126 593 per QALY from the health care sector perspective and an ICER of $128 012 per QALY from the societal perspective. Based on the scenario analysis of no treatment switching, second-line axicabtagene ciloleucel yielded an ICER of $216 790 per QALY from the health care sector perspective and an ICER of $218 907 per QALY from the societal perspective, compared with SC. When accounting for patients achieving prolonged progression-free survival who would not incur progression-related costs, in this scenario ICER changed to $125 962 per QALY from the health care sector perspective and $122 931 per QALY from the societal perspective. These results were most sensitive to increased list prices of CAR T cell therapy and QALY losses associated with axicabtagene ciloleucel and tisagenlecleucel. These findings suggest that second-line axicabtagene ciloleucel and third-line or later tisagenlecleucel were cost-effective in treating patients with relapsed or refractory DLBCL at the cost-effectiveness threshold of $150 000 per QALY. However, uncertainty remains regarding the best candidates who would experience value gains from receiving CAR T cell therapy.

CAR NK-сells for the treatment of hematological malignancies: A review

Hematological malignant neoplasms include more than a hundred different subtypes and account for about 4.8% of all neoplastic diseases in Russia. Despite significant advances in diagnosis and treatment, many of them remain incurable. In recent years, cell-based therapy appears to be a promising approach to the treatment of these incurable hematologic malignancies, showing striking results in various clinical trials. The most studied and advanced cell therapy is the therapy with T-lymphocytes modified with chimeric antigen receptors (CAR). However, although the US Food and Drug Administration has approved CAR T cells for the treatment of B-cell lymphoma and acute lymphoblastic leukemia, significant problems remain in terms of production, cost, and serious side effects. An alternative to the use of T cells can be the use of innate immune cells, in particular natural killer cells (NK), which have a high antitumor potential. Recent studies have shown the antitumor efficacy of a therapy that uses genetically modified natural killer cells CAR NK cells. The purpose of this review was to describe and systematize the experience of using CAR NK cells for the treatment of hematological neoplasms. The review presents the advantages and disadvantages of this method, as well as the problems that still have to be solved for its widespread introduction into clinical practice.

Are Pivotal Trials for Drug Approval for Chimeric Antigen Receptor-T Cell Therapy for Hematological Malignant Neoplasms Representative of the Population Affected By These Diseases?

Are Pivotal Trials for Drug Approval for Chimeric Antigen Receptor-T Cell Therapy for Hematological Malignant Neoplasms Representative of the Population Affected By These Diseases?

Factors Associated With Patients Not Receiving Oral Anticancer Drugs

Oral anticancer drugs (OACDs) are increasingly prescribed for cancer treatment and require significant coordination of care. Retrospective studies suggest that 10% to 20% of OACD prescriptions are never received by the patients, but the reasons behind this are poorly understood. To estimate the rate of failure to receive OACD prescriptions among patients with cancer and to examine the underlying reasons for this failure. A prospective cohort study was conducted among patients with cancer who were prescribed a new OACD from January 1, 2018, to December 31, 2019, at an urban academic medical center. Data analysis was conducted between 2021 and 2022. Patient demographic, clinical, and insurance data and OACD delivery dates were collected. The reasons for a failure to receive a prescribed OACD within 3 months were confirmed by manual review of medical records and were classified into 7 categories: clinical deterioration, financial access, clinician-directed change in decision-making, patient-directed change in decision-making, transfer of care, loss to follow-up, and unknown or other. A multivariable random-effects model was developed to identify factors associated with failure to receive a prescribed OACD. The cohort included 1024 patients (538 men [53%]; mean [SD] age, 66.2 [13.9] years; 463 non-Hispanic White patients [45%], 140 non-Hispanic Black patients [14%], and 300 Hispanic patients [29%]), representing 1197 new OACD prescriptions. Of the 1197 prescriptions, 158 (13%) were categorized as having not been received by the patient. The most common reason for the failure to receive a prescribed OACD was due to patient and clinician decision-making (73 of 158 [46%]), and 20 cases (13%) in which prescriptions were not received were associated with financial access issues. In multivariable analysis, patients with a nonmetastatic solid malignant neoplasm were significantly less likely to not receive their OACDs than those with a hematologic malignant neoplasm (odds ratio, 0.57 [95% CI, 0.33-1.00]; P = .048). This cohort study of patients prescribed a new OACD found that 13% of prescriptions were not received. The failure to receive a prescribed OACD was most frequently due to a change in clinical decision-making or patient choice. Ultimately, the reasons for the failure to receive a prescribed OACD were multifactorial and may have been appropriate in some cases.

From iron chelation to overload as a therapeutic strategy to induce ferroptosis in hematologic malignancies

ABSTRACT Objectives Ferroptosis is an iron-dependent, non-apoptotic mode of cell death characterized by excessive accumulation of reactive oxygen species (ROS). It plays an important role in the occurrence, development and treatment of various cancers, but little is known regarding the role of ferroptosis in hematologic malignancies. This review elaborates the regulatory mechanism of ferroptosis and the treatment opportunities for targeting ferroptosis in hematologic malignancies. Methods: A systematic literature review through PubMed was conducted to summarize the published evidence on the therapeutic potential of targeting ferroptosis in hematological malignant tumors. Literature sources published in English were searched, using the terms ferroptosis, leukemia, myelodysplastic syndrome, lymphoma and multiple myeloma. Results: More and more small molecules have been found to induce ferroptosis in hematologic malignancies through targeted iron metabolism and lipid peroxidation, and some ferroptosis inducers have been proved to have synergistic effect with other chemotherapeutic drugs. Conclusion: This paper discusses the significance of ferroptosis in hematologic malignancies and provides a new way for the treatment of hematologic malignancies, and more experimental studies should be conducted in future.

Human Endogenous Retroviruses and Hematological Malignant Tumors

Abstract Human endogenous retrovirus (HERV) gene sequences are remnants of retroviruses that infected the ancestors of humans millions of years ago and were integrated into human chromosomes, accounting for approximately 8%–9% of the human genome. Most integrated HERVs have lost their coding capacity and remain silent due to frame shifts, mutations, and sequence deletions or insertions over the millions of years, but their expression is highly regulated by epigenetic and host defense mechanisms. However, there are still some HERV genes that have intact open reading frames due to recent integration into the human genome or positive selective pressure. The abnormal activation of HERVs may contribute to diseases or their pathology, such as malignant tumors, autoimmune diseases, and nervous system diseases. The occurrence and development of hematological malignant tumors (HMTs) is a complex process involving interactions of multiple genetic and environmental factors. The abnormal activation of HERVs may contribute to the pathology of HMTs via indirect mechanisms. In this review, we address the discovery of endogenous retroviruses in vertebrates, and the classification and genomic structure of HERVs. Among HERV family members, HERV-K is the latest type of HERV integrated into the human genome and it has the strongest transcriptional activity. We explore the currently known expression of HERV-K proto-oncogenes in HMTs and further address potential research and therapeutic approaches. However, much remains to be learned about not only the impact of HERVs on the occurrence of HMTs, but also the potential value of HERVs as diagnostic and therapeutic targets for HMTs.

Enrollment of Black Participants in Pivotal Clinical Trials Supporting US Food and Drug Administration Approval of Chimeric Antigen Receptor–T Cell Therapy for Hematological Malignant Neoplasms

Disparities that affect Black persons with various hematological malignant neoplasms are substantial, yet little is known about disparities related to the use of US Food and Drug Administration (FDA)-approved chimeric antigen receptor-T cell (CAR-T) therapy. To examine the enrollment of Black participants in clinical trials that resulted in a subsequent FDA approval of CAR-T products in hematological malignant neoplasms. A cross-sectional study was performed using publicly available data on drug products and demographic subgroups from Drugs@fda in the period of August 2017 to May 2021. Data analysis included patients with large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, acute lymphoblastic leukemia, and multiple myeloma who were enrolled into 7 clinical trials that investigated various CAR-T products. The study was conducted from July 1, 2021, to November 30, 2021. Frequencies of participation of Black participants were calculated with adjustment for disease prevalence. Of the 1057 enrolled patients included in the study, CAR-T products were given to 746 patients (71%), and efficacy was reported for 729 enrolled patients (69%) across all the approved CAR-T products and indications. Most patients (1015 patients [96%]) were enrolled in the US. Black participants were included in the racial category other in the study that supported tisagenlecleucel approval in acute lymphoblastic leukemia; otherwise, their enrollment was specified either in the study publication and/or the demographic subgroup information available under the FDA product labeling information. The number of Black participants who received the CAR-T product and had reported efficacy varied between studies (range, 1-12 participants [2%-5%]). Adjusted prevalence measures showed the lowest participation to prevalence ratio of 0.2 for multiple myeloma and 0.6 for large B cell lymphoma. The findings of this study suggest that there are substantial disparities affecting Black patients across all approved CAR-T products used to treat hematological malignant neoplasms with otherwise limited effective treatment options. The study findings might aid policy discussions regarding the immediate need of regulations that enforce certain thresholds of Black patients' enrollment before granting FDA approval.

Multiparametric Flow Cytometry versus Conventional Cytology in the Study of Leptomeningeal Involvement in Malignant Hematological Diseases

CNS involvement is a complication in hematologic malignant neoplasms. The advantage of multiparametric flow cytometry (MFC) over conventional cytology (CC) in detecting occult leptomeningeal disease in CSF has been proven previously, as reported in the literature. In this study, we reviewed the experience of our laboratory in evaluating CSF specimens by MFC and CC after refinement of technical procedures. MFC analysis was performed in 159 specimens. In 91 specimens, simultaneous CC and MFC analysis was requested and results compared. Neoplastic cells were identified in 27 (17.0%) of the total samples and in 17 (18.7%) of the paired specimens group by MFC, compared with 2 (2.2%) specimens with positive results as determined by CC. MFC enabled identification of malignant cells in low-cellularity specimens (<5 cells/μL) and all neoplasm categories. MFC allowed the detection of minimal numbers of tumor cells in CSF specimens from individuals with leukemia and lymphoma in whom CC had not been able to identify those tumor cells.

Mortality Among Adults With Cancer Undergoing Chemotherapy or Immunotherapy and Infected With COVID-19

Large cohorts of patients with active cancers and COVID-19 infection are needed to provide evidence of the association of recent cancer treatment and cancer type with COVID-19 mortality. To evaluate whether systemic anticancer treatments (SACTs), tumor subtypes, patient demographic characteristics (age and sex), and comorbidities are associated with COVID-19 mortality. The UK Coronavirus Cancer Monitoring Project (UKCCMP) is a prospective cohort study conducted at 69 UK cancer hospitals among adult patients (≥18 years) with an active cancer and a clinical diagnosis of COVID-19. Patients registered from March 18 to August 1, 2020, were included in this analysis. SACT, tumor subtype, patient demographic characteristics (eg, age, sex, body mass index, race and ethnicity, smoking history), and comorbidities were investigated. The primary end point was all-cause mortality within the primary hospitalization. Overall, 2515 of 2786 patients registered during the study period were included; 1464 (58%) were men; and the median (IQR) age was 72 (62-80) years. The mortality rate was 38% (966 patients). The data suggest an association between higher mortality in patients with hematological malignant neoplasms irrespective of recent SACT, particularly in those with acute leukemias or myelodysplastic syndrome (OR, 2.16; 95% CI, 1.30-3.60) and myeloma or plasmacytoma (OR, 1.53; 95% CI, 1.04-2.26). Lung cancer was also significantly associated with higher COVID-19-related mortality (OR, 1.58; 95% CI, 1.11-2.25). No association between higher mortality and receiving chemotherapy in the 4 weeks before COVID-19 diagnosis was observed after correcting for the crucial confounders of age, sex, and comorbidities. An association between lower mortality and receiving immunotherapy in the 4 weeks before COVID-19 diagnosis was observed (immunotherapy vs no cancer therapy: OR, 0.52; 95% CI, 0.31-0.86). The findings of this study of patients with active cancer suggest that recent SACT is not associated with inferior outcomes from COVID-19 infection. This has relevance for the care of patients with cancer requiring treatment, particularly in countries experiencing an increase in COVID-19 case numbers. Important differences in outcomes among patients with hematological and lung cancers were observed.

Research Progress of Intercellular Mitochondrial Transfer in the Development of Hematological Malignant Tumors --Review

In recent years, studies have found that mitochondrial transfer between leukemic cells and different types of cells in their bone marrow microenvironment, especially mesenchymal stem cells, plays a key role in the occurrence, development and drug resistance of hematological malignant tumors. This paper mainly introduces the role and latest research progress of mitochondrial transfer in acute and chronic myeloid leukemia, acute lymphoblastic leukemia and multiple myeloma, and briefly describes the mechanism of drug resistance caused by mitochondrial transfer in leukemic cells during chemotherapy. The aim is to provide a new idea and theoretical basis for using intercellular mitochondrial transfer as a potential therapeutic target.

Risk of Hematologic Malignant Neoplasms from Head CT Radiation in Children and Adolescents Presenting with Minor Head Trauma: A Nationwide Population-Based Cohort Study

Risk of Hematologic Malignant Neoplasms from Head CT Radiation in Children and Adolescents Presenting with Minor Head Trauma: A Nationwide Population-Based Cohort Study

Metabolic Volume Measurements in Multiple Myeloma.

Multiple myeloma (MM) accounts for 10–15% of all hematologic malignancies, as well as 20% of deaths related to hematologic malignant tumors, predominantly affecting bone and bone marrow. Positron emission tomography/computed tomography with 18F-fluorodeoxyglucose (FDG-PET/CT) is an important method to assess the tumor burden of these patients. It is often challenging to classify the extent of disease involvement in the PET scans for many of these patients because both focal and diffuse bone lesions may coexist, with varying degrees of FDG uptake. Different metrics involving volumetric parameters and texture features have been proposed to objectively assess these images. Here, we review some metabolic parameters that can be extracted from FDG-PET/CT images of MM patients, including technical aspects and predicting MM outcome impact. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) are volumetric parameters known to be independent predictors of MM outcome. However, they have not been adopted in clinical practice due to the lack of measuring standards. CT-based segmentation allows automated, and therefore reproducible, calculation of bone metabolic metrics in patients with MM, such as maximum, mean and standard deviation of the standardized uptake values (SUV) for the entire skeleton. Intensity of bone involvement (IBI) is a new parameter that also takes advantage of this approach with promising results. Other indirect parameters obtained from FDG-PET/CT images, such as visceral adipose tissue glucose uptake and subcutaneous adipose tissue radiodensity, may also be useful to evaluate the prognosis of MM patients. Furthermore, the use and quantification of new radiotracers can address different metabolic aspects of MM and may have important prognostic implications.

TPGS2000-DOX Prodrug Micelles for Improving Breast Cancer Therapy

BackgroundDoxorubicin (DOX) is an anthracycline antibiotic that inhibits the growth of several solid and hematologic malignant tumors. Increasing the targeting ability of DOX and reducing the multi-drug resistance (MDR) of tumor cells to DOX are major aims for researchers.PurposeIn this study, to increase therapeutic efficiency, reduce the side effects and the MDR of tumor cells to DOX, D-alpha-tocopheryl polyethylene glycol 2000 succinate monoester (TPGS2000)-DOX prodrug micelles were developed by grafting DOX to TPGS2000 via an amide bond that release DOX in the slightly acidic conditions in tumor tissue.Materials and MethodsThe TPGS2000-DOX micelles were constructed using polyethylene glycol 12-hydroxy stearate (Solutol HS15) as the carrier. The in vitro drug release profile and dilution stability of the nanomicelles were determined. The in vitro cytotoxicity and distribution of the nanomicelles in the tumor cells were also investigated. Moreover, we explored the therapeutic outcomes using the MCF-7/ADR tumor-bearing murine model.ResultsThe average particle size was approximately 30 nm with a narrow distribution, which was conducive for solid tumor accumulation. The results of in vivo imaging and in vitro cellular uptake assays demonstrated that the TPGS2000-DOX micelles increased the tumor-targeting ability and cellular uptake of DOX. The anticancer potential of TPGS2000-DOX micelles was higher than that of DOX, as revealed by in vitro cytotoxic assays with MCF-7/ADR cells and in vivo antitumor assays with MCF-7 tumor-bearing nude mice.ConclusionTPGS2000-DOX prodrug micelles reverse the MDR of tumor cells, achieve passive targeting by forming nanomicelles, and subsequently enhance the efficacy and reduce the toxicity of DOX.

Evaluation of COVID-19 Mortality and Adverse Outcomes in US Patients With or Without Cancer

As the COVID-19 pandemic continues, understanding the clinical outcomes of patients with cancer and COVID-19 has become critically important. To compare the outcomes of patients with or without cancer who were diagnosed with COVID-19 and to identify the factors associated with mortality, mechanical ventilation, intensive care unit (ICU) stay, and hospitalization. This cohort study obtained data from the Optum de-identified COVID-19 electronic health record data set. More than 500 000 US adults who were diagnosed with COVID-19 from January 1 to December 31, 2020, were analyzed. The patient groups were (1) patients without cancer, (2) patients with no recent cancer treatment, and (3) patients with recent cancer treatment (within 3 months before COVID-19 diagnosis) consisting of radiation therapy or systemic therapy. Mortality, mechanical ventilation, ICU stay, and hospitalization within 30 days of COVID-19 diagnosis were the main outcomes. Unadjusted rates and adjusted odds ratios (ORs) of adverse outcomes were presented according to exposure group. A total of 507 307 patients with COVID-19 were identified (mean [SD] age, 48.4 [18.4] years; 281 165 women [55.4%]), of whom 493 020 (97.2%) did not have cancer. Among the 14 287 (2.8%) patients with cancer, 9991 (69.9%) did not receive recent treatment and 4296 (30.1%) received recent treatment. In unadjusted analyses, patients with cancer, regardless of recent treatment received, were more likely to have adverse outcomes compared with patients without cancer (eg, mortality rate: 1.6% for patients without cancer, 5.0% for patients with no recent cancer treatment, and 7.8% for patients with recent cancer treatment). After adjustment, patients with no recent cancer treatment had similar or better outcomes than patients without cancer (eg, mortality OR, 0.93 [95% CI, 0.84-1.02]; mechanical ventilation OR, 0.61 [95% CI, 0.54-0.68]). In contrast, a higher risk of death (OR, 1.74; 95% CI, 1.54-1.96), ICU stay (OR, 1.69; 95% CI, 1.54-1.87), and hospitalization (OR, 1.19; 95% CI, 1.11-1.27) was observed in patients with recent cancer treatment. Compared with patients with nonmetastatic solid tumors, those with metastatic solid tumors and hematologic malignant neoplasms had worse outcomes (eg, mortality OR, 2.36 [95% CI, 1.96-2.84]; mechanical ventilation OR, 0.87 [95% CI, 0.70-1.08]). Recent chemotherapy and chemoimmunotherapy were also associated with worse outcomes (eg, chemotherapy mortality OR, 1.84 [95% CI, 1.51-2.26]). This cohort study found that patients with recent cancer treatment and COVID-19 had a significantly higher risk of adverse outcomes, and patients with no recent cancer treatment had similar outcomes to those without cancer. The findings have risk stratification and resource use implications for patients, clinicians, and health systems.

Humoral Immune Response in Hematooncological Patients and Health Care Workers Who Received SARS-CoV-2 Vaccinations

To our knowledge, little is known about antibody development after SARS-CoV-2 vaccination in immunocompromised individuals, such as patients with cancer. To determine whether hematooncological patients develop anti-SARS-CoV-2 antibodies after vaccination. This retrospective cohort study included 2 independent cohorts of patients who were treated for hematological and solid malignant tumors between October 2020 and May 2021, comprising 901 samples from 595 patients and 58 health care workers (HCWs). Serum samples were collected from patients who were treated at an academic center and a community hospital in a rural area and a control group of HCWs, all of whom received SARS-CoV-2 vaccination. Total anti-SARS-CoV-2 nucleocapsid (anti-NC) and antispike protein (anti-S) antibodies were measured retrospectively. In total, 595 patients (320 women [53.8%] and 275 men [46.2%]; median [range] age, 67 [19-96] years) and 58 HCWs (40 women [69.0%] and 18 men [31.0%]; median [range] age, 42 [24-60] years) were included. Previous SARS-CoV-2 infection was documented in 43 of 595 (7.2%), while anti-NC antibodies that suggested previous infections were observed in 49 of 573 evaluable patients (8.6%). In both cohorts, anti-S antibody levels were higher in fully vaccinated patients compared with patients who received 1 dose. After the first vaccination, patients with hematological cancer who received B cell-targeting agents had lower anti-S levels (median, 1.6 AU/mL; range: 0-17 244 AU/mL) than patients who received other therapies (median, 191.6 AU/mL; range, 0-40 000; P < .001) or patients with solid tumors (median, 246.4 AU/mL; range, 0-40 000 AU/mL; P < .001). Anti-S levels after the first vaccination differed according to ongoing antineoplastic treatment modalities, with the lowest median levels in patients who received chemotherapy alone (157.7 AU/mL; range, 0-40 000 AU/mL) or in combination with immunotherapy (118.7 AU/mL; range, 14.1-38 727 AU/mL) and the highest levels in patients with no ongoing antineoplastic treatment (median, 634.3 AU/mL; range, 0-40 000 AU/mL; P = .01). Antibody levels after full immunization were higher in HCWs (median, 2500 U/mL; range, 485-2500 U/mL) than in patients with cancer (median, 117.0 U/mL; range, 0-2500 U/mL; P < .001). In this cohort study of patients with hematooncological diseases and a control group of HCWs, anti-SARS-CoV-2 antibodies after vaccination could be detected in patients with cancer. Lower antibody levels compared with HCWs and differences in seroconversion in specific subgroups underscore the need for further studies on SARS-CoV-2 vaccination in patients with hematooncological disease.

Beyond the AJR: "Risk of Hematologic Malignant Neoplasms From Abdominopelvic Computed Tomographic Radiation in Patients Who Underwent Appendectomy".

Beyond the AJR: "Risk of Hematologic Malignant Neoplasms From Abdominopelvic Computed Tomographic Radiation in Patients Who Underwent Appendectomy".