Barriers and shortcomings in access to cardiovascular management and prevention for familial hypercholesterolemia during the COVID-19 pandemic.

Familial hypercholesterolemia (FH) is a hereditary condition caused by mutations in the lipid pathway. The goal in managing FH is to reduce circulating low-density lipoprotein cholesterol and, therefore, reduce the risk of developing atherosclerotic cardiovascular disease (ASCVD). Because FH patients were considered high risk groups due to an increased susceptible for contracting COVID-19 infection, we hypothesized whether the effects of the pandemic hindered access to cardiovascular care. In this review, we conducted a literature search in databases Pubmed/Medline and ScienceDirect. We included a comprehensive analysis of findings from articles in English related and summarized the effects of the pandemic on cardiovascular care through direct and indirect effects. During the COVID-19 pandemic, FH patients presented with worse outcomes and prognosis, especially those that have suffered from early ASCVD. This caused avoidance in seeking care due to fear of transmission. The pandemic severely impacted consultations with lipidologists and cardiologists, causing a decline in lipid profile evaluations. Low socioeconomic communities and ethnic minorities were hit the hardest with job displacements and lacked healthcare coverage respectively, leading to treatment nonadherence. Lock-down restrictions promoted sedentary lifestyles and intake of fatty meals, but it is unclear whether these factors attenuated cardiovascular risk in FH. To prevent early atherogenesis in FH patients, universal screening programs, telemedicine, and lifestyle interventions are important recommendations that could improve outcomes in FH patients. However, the need to research in depth on the disproportionate impact within different subgroups should be the forefront of FH research.

CAR T-cell therapies in China: rapid evolution and a bright future.

Chimeric antigen receptor (CAR) T-cell therapies have achieved remarkable success in the treatment of haematological malignancies. Over the past 9 years, the use of CAR T-cell therapies has expanded throughout China, from the first clinical trials of CAR T cells conducted in 2013, to the world's largest number of CAR T-cell-related clinical trials in 2017, to a cumulative US$2·37 billion in funding for cell therapy companies in 2021, and a significant growth in the number of CAR T-cell-related clinical trials and basic research. This strong increase in activity is the result of a culmination of factors in China: strong government support, capital inflow, large patient demand, a unique health-care system, and the efforts of Chinese physicians and scientists. This Series paper provides an overview of the scope of CAR T-cell clinical trials in China (especially in the field of haematological malignancies), analyses the relevant policies, summarises the characteristics of corporate and capital support, and explores the achievements and challenges of CAR T-cell therapy in China to provide a better understanding for further promoting the development of cellular therapy and its clinical application.

Successful BCMA CAR-T Therapy for Multiple Myeloma With Central Nervous System Involvement Manifesting as Cauda Equina Syndrome-A Wandering Road to Remission.

Multiple myeloma (MM) with central nervous system (CNS) involvement is rare with only 1% incidence. So far, there is no standard or effective treatment for CNS MM, and the expected survival time is fewer than 6 months. Here, we report a case of MM with CNS involvement presented with cauda equina syndrome (CES) who achieved complete remission after anti-B-cell maturation antigen (BCMA) chimeric antigen receptor T (CAR-T) cell therapy (Chictr.org.cn, ChiCTR1800017404). The expansion of BCMA CAR-T cells was observed in both peripheral blood (PB) and cerebrospinal fluid (CSF). The CAR-T cells peaked at 2.4 × 106/l in CSF at day 8 and 4.1 × 109/l in PB at day 13. The peak concentration of interleukin (IL)-6 in CSF was detected 3 days earlier, and almost five times higher than that in PB. Next, morphological analysis confirmed the elimination of nucleated cells in CSF 1 month after CAR-T cell treatment from 300 cells/µl, and the patient achieved functional recovery with regressed lesion shown in PET-CT. The case demonstrated that BCMA CAR-T cells are effective and safe in this patient population.

The role of pre-treatment and mid-treatment 18F-FDG PET/CT imaging in evaluating prognosis of peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS).

BACKGROUND: It has been reported the prognostic value of MTV in predicting the disease prognosis of peripheral T-cell lymphoma (PTCL) through pre-treatment PET/CT imaging. However, these are limited data on pretreatment evaluation and prognosis assessments of peripheral T-cell lymphoma-not otherwise specified (PTCL-NOS). This study aimed to determine the prognostic values of pre-treatment and mid-treatment total metabolic tumor volume (MTV), total lesion glycolysis (TLG), and Deauville 5-Point Scale (D-5PS) in accessing the prognosis of PTCL-NOS. METHODS: A retrospective analysis was conducted in 31 patients with pathologically diagnosed PTCL-NOS. These patients have undergone positron emission PET/CT scanning before and during chemotherapy. Follow-ups were also done to investigate the 2-year progression-free survival (PFS) and Overall Survival (OS) of these patients. During [Formula: see text]F-fluorodeoxyglucose ([Formula: see text]F-FDG) PET/CT scans, the MTV and TLG were recorded. Meanwhile, [Formula: see text]MTV and [Formula: see text]TLG were calculated. Furthermore, the receiver operating characteristic (ROC) curve was employed to classify and to define the threshold values. On the other hand, the mid-chemotherapy assessment and staging of these 31 patients were done by utilizing D-5PS. Subsequently, based on the D-5PS scores obtained, these patients were grouped into two categories: a group of patients with a score of <4 and another group with [Formula: see text]4 points. For these two groups of patients, the survival analysis was done by Kaplan-Meier analysis and a multivariate COX regression model. Moreover, Pearson's chi-square test ([Formula: see text] test) and Spearman rank correlation coefficient were used to comparing the collected data, respectively. RESULTS: During the 2-year follow-up period, 15 out of the 31 patients experienced disease progression. The optimal threshold values for both baseline MTV and TLG were 158.16 cm[Formula: see text] and 677.40.Additionally, the difference in 2-year PFS between the progressive and non-progressive groups was statistically significant ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text]), significant between-group difference was detected for MTV and for TLG ([Formula: see text], [Formula: see text]; [Formula: see text], [Formula: see text]). On the other hand, when these patients were classified into two groups according to the mid-chemotherapy Deauville score of <4 and [Formula: see text]4, the statistical difference of 2-year PFS between these two groups was significant, too ([Formula: see text], [Formula: see text]),but there is no significant between-group difference in OS ([Formula: see text], [Formula: see text]). COX analysis revealed that D-5PS are the independent factors influencing PFS, while MTV is the independent influencing factor of OS. CONCLUSION: The baseline total MTV obtained by PET/CT scanning, and D-5PS are crucial prognostic factors in evaluating the prognosis of PTCL-NOS.

Tumor Burden Measured by 18F-FDG PET/CT in Predicting Efficacy and Adverse Effects of Chimeric Antigen Receptor T-Cell Therapy in Non-Hodgkin Lymphoma.

Chimeric antigen receptor (CAR) T-cell therapy has exhibited promising clinical outcomes in treating relapsed/refractory (R/R) B-cell hematologic malignancies. Current studies have shown a close correlation between baseline tumor burden and therapeutic response in CAR-T cell therapy. However, the roles of PET/CT metabolic parameters, such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG), remain unclear in this setting. In this study, we retrospectively reviewed 41 R/R NHL patients. 18F-FDG PET/CT was used to measure the average standardized uptake value (SUVavg), MTV, and TLG of the lymphomatous lesions. These patients were divided into two groups according to the optimal cutoff values of respective PET/CT metabolic parameters. The multivariate analysis depicted that early post-therapy SUVavg (HR: 1.418, 95% CI: 1.029, 1.955; p = 0.033) and MTV (HR: 1.001, 95% CI: 1.000, 1.002; p = 0.041) were independent risk factors associated with OS and PFS, respectively. Patients with baseline SUVavg < 4.36 achieved a superior 1-year OS rate than the SUVavg ≥ 4.36 group (100.0% vs. 44.9%, p = 0.019). For the patients with lower values in early post-therapy SUVavg (<2.60) (51.1% vs. 0%, p < 0.001), MTV (<0.55 cm3) (53.6% vs. 0.0%, p = 0.001), and TLG (<1.54) (53.6% vs. 0.0%, p = 0.001), their 1-year PFS rates were higher than the compared groups. Moreover, patients with higher baseline tumor burdens were found to have significantly increased CRS incidence and cytokine levels. In conclusion, the PET/CT metabolic parameters are closely related to OS, PFS, and CRS in R/R NHL patients treated with CAR-T cells. This study may pave the way for building a comprehensive assessment system of tumor burden using 18F-FDG PET/CT, which can optimize therapeutic and supportive approaches in CAR-T cell therapy.

Combination of CRISPR/Cas9 System and CAR-T Cell Therapy: A New Era for Refractory and Relapsed Hematological Malignancies.

Chimeric antigen receptor T (CAR-T) cell therapy is the novel treatment strategy for hematological malignancies such as acute lymphoblastic leukemia (ALL), lymphoma and multiple myeloma. However, treatment-related toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) have become significant hurdles to CAR-T treatment. Multiple strategies were established to alter the CAR structure on the genomic level to improve efficacy and reduce toxicities. Recently, the innovative gene-editing technology-clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated nuclease9 (Cas9) system, which particularly exhibits preponderance in knock-in and knockout at specific sites, is widely utilized to manufacture CAR-T products. The application of CRISPR/Cas9 to CAR-T cell therapy has shown promising clinical results with minimal toxicity. In this review, we summarized the past achievements of CRISPR/Cas9 in CAR-T therapy and focused on the potential CAR-T targets.

A giant step forward: chimeric antigen receptor T-cell therapy for lymphoma.

The combination of the immunotherapy (i.e., the use of monoclonal antibodies) and the conventional chemotherapy increases the long-term survival of patients with lymphoma. However, for patients with relapsed or treatment-resistant lymphoma, a novel treatment approach is urgently needed. Chimeric antigen receptor T (CAR-T) cells were introduced as a treatment for these patients. Based on recent clinical data, approximately 50% of patients with relapsed or refractory B-cell lymphoma achieved complete remission after receiving the CD19 CAR-T cell therapy. Moreover, clinical data revealed that some patients remained in remission for more than two years after the CAR-T cell therapy. Other than the CD19-targeted CAR-T, the novel target antigens, such as CD20, CD22, CD30, and CD37, which were greatly expressed on lymphoma cells, were studied under preclinical and clinical evaluations for use in the treatment of lymphoma. Nonetheless, the CAR-T therapy was usually associated with potentially lethal adverse effects, such as the cytokine release syndrome and the neurotoxicity. Therefore, optimizing the structure of CAR, creating new drugs, and combining CAR-T cell therapy with stem cell transplantation are potential solutions to increase the effectiveness of treatment and reduce the toxicity in patients with lymphoma after the CAR-T cell therapy.

CAR-T cells: the Chinese experience.

INTRODUCTION: Chimeric antigen receptor T (CAR-T) cells are harnessed to identify and lyse malignant cells specifically, efficiently, and independently of the major histocompatibility complex (MHC). As a result, prognoses of relapsed or refractory (R/R) B cell hematological malignancies as well as limited types of solid tumors, have been ameliorated to a great extent. In China, a rising number of clinical trials that contribute to the development of novel CAR-T therapeutic strategies have been conducted on an extensive scale. AREAS COVERED: We summarize registered clinical trials related to CAR-T therapy conducted in China by evaluating various parameters such as distribution, study phase, CAR structure, target antigen, and disease. The efficacy, toxicity, and, more importantly, the new strategies for optimization of CAR-T therapy of Chinese studies and clinical trials are elaborated in detail. EXPERT OPINION: In terms of the number of CAR-T clinical trials, China is second to the USA, registering approximately 33% of trials worldwide. China's extensive explorations and breakthroughs in the search of novel target antigens, optimization of CAR structure, cocktail CAR-T therapy, combination therapy, and extension of CAR-T cell applications, imply that we are currently on the verge of a revolution in CAR-T therapy.

CAR T-cell treatment during the COVID-19 pandemic: Management strategies and challenges.

The pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is spreading rapidly across the world. Currently, the COVID-19 pandemic is affecting the continuity of essential routine healthcare services and procedures, including chimeric antigen receptor T-cell (CAR-T) therapy, a life-saving option for patients with relapsed/refractory (R/R) hematologic malignancies. Due to the rapid disease progression of hematological malignancies, there is an urgent need to manufacture and utilize CAR T-cells. However, CAR-T treatment has become extraordinarily challenging during this COVID-19 pandemic. Thus, many medical and technical factors must now be taken into consideration before, during, and after CAR-T therapy. The purpose of this review is to provide brief suggestions for rational decision-making strategies in evaluating and selecting CAR T-cell treatment and appropriate CAR T-cell products, and protective strategies for medical staff and patients to prevent infection in the midst of the current COVID-19 pandemic.

Pre-transplant MRD negativity predicts favorable outcomes of CAR-T therapy followed by haploidentical HSCT for relapsed/refractory acute lymphoblastic leukemia: a multi-center retrospective study.

BACKGROUND: Consolidative allogeneic hematopoietic stem cell transplantation is a controversial option for patients with relapsed/refractory acute lymphoblastic leukemia after chimeric antigen receptor T cell (CAR-T) therapy. We performed a multicenter retrospective study to assess whether patients can benefit from haploidentical hematopoietic stem cell transplantation after CAR-T therapy. METHODS: A total of 122 patients after CAR-T therapy were enrolled, including 67 patients without subsequent transplantation (non-transplant group) and 55 patients with subsequent haploidentical hematopoietic stem cell transplantation (transplant group). Long-term outcome was assessed, as was its association with baseline patient characteristics. RESULTS: Compared with the non-transplant group, transplantation recipients had a higher 2-year overall survival (OS; 77.0% versus 36.4%; P < 0.001) and leukemia-free survival (LFS; 65.6% versus 32.8%; P < 0.001). Multivariate analysis showed that minimal residual disease (MRD) positivity at transplantation is an independent factor associated with poor LFS (P = 0.005), OS (P = 0.035), and high cumulative incidence rate of relapse (P = 0.045). Pre-transplant MRD-negative recipients (MRD- group) had a lower cumulative incidence of relapse (17.3%) than those in the non-transplant group (67.2%; P < 0.001) and pre-transplant MRD-positive recipients (MRD+ group) (65.8%; P = 0.006). The cumulative incidence of relapse in MRD+ and non-transplant groups did not differ significantly (P = 0.139). The 2-year LFS in the non-transplant, MRD+, and MRD- groups was 32.8%, 27.6%, and 76.1%, respectively. The MRD- group had a higher LFS than the non-transplantation group (P < 0.001) and MRD+ group (P = 0.007), whereas the LFS in the MRD+ and non-transplant groups did not differ significantly (P = 0.305). The 2-year OS of the MRD- group was higher than that of the non-transplant group (83.3% versus 36.4%; P < 0.001) but did not differ from that of the MRD+ group (83.3% versus 62.7%; P = 0.069). The OS in the non-transplant and MRD+ groups did not differ significantly (P = 0.231). CONCLUSION: Haploidentical hematopoietic stem cell transplantation with pre-transplant MRD negativity after CAR-T therapy could greatly improve LFS and OS in patients with relapsed/refractory acute lymphoblastic leukemia. TRIAL REGISTRATION: The study was registered in the Chinese clinical trial registry (ChiCTR1900023957).

Weathering the storm: COVID-19 infection in patients with hematological malignancies.

The coronavirus disease 2019 (COVID-19) is an emerging infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Within a matter of months, this highly contagious novel virus has led to a global outbreak and is still spreading rapidly across continents. In patients with COVID-19, underlying chronic diseases and comorbidities are associated with dismal treatment outcomes. Owing to their immunosuppressive status, patients with hematological malignancies (HMs) are at an increased risk of infection and have a worse prognosis than patients without HMs. Accordingly, intensive attention should be paid to this cohort. In this review, we summarize and analyze specific clinical manifestations for patients with coexisting COVID-19 and HMs. Furthermore, we briefly describe customized management strategies and interventions for this susceptible cohort. This review is intended to guide clinical practice.

Does Partial Meal Replacement During Pregnancy Reduce 12-Month Postpartum Weight Retention?

OBJECTIVE: This randomized trial tested whether a behavioral intervention with meal replacements in pregnancy could increase the proportion of women who returned to prepregnancy weight and reduce postpartum weight retention by 12 months after delivery. METHODS: Women (N = 264; 13.7 weeks' gestation) with overweight or obesity were randomly assigned to usual care or intervention. The intervention reduced excess gestational weight gain and was discontinued at delivery. At follow-up, 83.7% completed the 12-month assessment. RESULTS: Compared with usual care, prenatal intervention had no significant effect on odds of achieving prepregnancy weight (38/128 [29.7%] vs. 41/129 [31.8%]; P = 0.98) or in reducing the magnitude of weight retained (3.3 vs. 3.1 kg; P = 0.82) at 12 months. After delivery, significant (P < 0.0001) declines in meal replacements, practice of weight control behaviors, and dietary restraint were observed in the intervention group. Independent of group, lower gestational weight gain was the strongest predictor of achieving prepregnancy weight at 12 months (P = 0.0008). CONCLUSIONS: A prenatal behavioral intervention with meal replacements that reduced pregnancy weight gain had no significant effect on 12-month postpartum weight retention.

Randomized controlled clinical trial of behavioral lifestyle intervention with partial meal replacement to reduce excessive gestational weight gain.

Background: Behavioral lifestyle interventions during pregnancy can prevent excessive gestational weight gain (GWG) in women with normal weight; however, effective interventions to reduce GWG in ethnically diverse women with obesity are lacking. Objective: A randomized controlled trial was conducted to test whether a behavioral lifestyle intervention with partial meal replacement reduces GWG rate in Hispanic and non-Hispanic women with overweight or obesity relative to enhanced usual care. Design: Participants (n = 257) were recruited in San Luis Obispo, California, and Providence, Rhode Island, between November 2012 and May 2016. Participants were pregnant (mean ± SD: 13.6 ± 1.8 wk of gestation) with overweight or obesity and had a mean age of 30.3 y; 41.6% of participants were Hispanic. Women were randomly assigned within site and by ethnicity to enhanced usual care (n = 128) or to a behavioral lifestyle intervention with partial meal replacement (n = 129). The primary outcome was GWG per week of observation. Secondary outcomes were proportions exceeding Institute of Medicine (IOM) guidelines for total GWG, changes in weight-control behaviors and cardiovascular disease risk factors, and incidence of pregnancy complications. Study retention was 99.6% (256 of 257). Results: The intervention compared with usual care resulted in less mean ± SD weekly GWG (0.33 ± 0.25 compared with 0.39 ± 0.23 kg/wk; P = 0.02) and total GWG (9.4 ± 6.9 compared with 11.2 ± 7.0 kg; P = 0.03) and reduced the proportion of women who exceeded IOM guidelines for total GWG (41.1% compared with 53.9%; P = 0.03). No significant group × time × demographic subgroup (ethnicity, BMI, age, parity, and income) interactions were observed. Among intervention participants, greater meal replacement intake was related to reduced GWG rate (ß = -0.07; 95% CI:-0.12, -0.03; P = 0.002). The intervention compared with usual care increased weight-control strategies (P < 0.0001) and cognitive restraint (P < 0.0001) and reduced triglycerides (P = 0.03). Conclusion: Prenatal behavioral intervention with partial meal replacement significantly reduced GWG in Hispanic and non-Hispanic women with overweight or obesity. This trial was registered at www.clinicaltrials.gov as NCT01545934.