ABSTRACT
CD19-targeted chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for patients with relapsed/refractory large B-cell lymphoma (LBCL). However, data available concerning the impact of the prognostic value of quantitative 18F-fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET/CT) parameters on the CAR T-related outcomes and toxicities are limited. Therefore, we aimed to evaluate the predictive value of pre- and post-CAR T metabolic parameters on survival and toxicities following CAR T-cell therapy. Fifty-nine patients with PET/CT scans done pre-and post-CAR T infusion were retrospectively identified and analyzed in a single institution database of LBCL patients treated with commercial CD19-targeted CAR T-cell therapy. The median follow-up was 10.7 months [interquartile range (IQR): 2.6-25.5 months]. The overall response (complete response-CR and partial response) and CR rates post-CAR T were 76% (n = 45) and 53% (n = 31), respectively. On univariate analysis, low pre-CAR T total lesion glycolysis (TLG) and metabolic tumor volume (MTV) predicted improved overall response post-CAR T (OR = 4.7, p = 0.01, OR = 9.5, p = 0.03, respectively) and CR post-CAR T (OR = 12.4, p = 0.0004, OR = 10.9, p = 0.0001, respectively). High TLG pre-CAR T was correlated with cytokine release syndrome (CRS, OR = 3.25, p = 0.04). High MTV pre-CAR T was correlated with developing immune effector cell neurotoxicity syndrome (ICANS) events (OR = 4.3, p = 0.01), and high SUV pre-CAR T was associated with grade 3-4 neurological events (OR = 12, p = 0.01). High MTV/TLG/SUVmax post-CAR T were significantly associated with inferior Overall survival (OS). On multivariate analysis, high TLG pre-CAR T (HR = 2.4, p = 0.03), age ≥60 (HR = 2.7, p = 0.03), and bulky disease (≥5 cm) at the time of apheresis (HR = 2.5, p = 0.02) were identified to be independent prognostic factors for inferior PFS. High MTV post-CAR T was identified as the most prognostic factor associated with inferior OS.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Receptors, Chimeric Antigen , Humans , Positron Emission Tomography Computed Tomography/methods , Radiopharmaceuticals , Immunotherapy, Adoptive/adverse effects , Retrospective Studies , Fluorodeoxyglucose F18/metabolism , Prognosis , Cell- and Tissue-Based TherapyABSTRACT
Pathways leading to osteoarthritis (OA) are diverse depending on the risk factors involved; thus, developing OA therapeutics has been challenging. Here we report that nuclear protein-1 (Nupr1), a stress-inducible protein/transcription factor, is activated by pathways associated with obesity and aging in chondrocytes. Treatment of human chondrocytes with free fatty acids (palmitate and oleate; a model for high-fat diet/obesity) induced PERK signaling and increased expression of caspase-3, TRB3, and Nupr1. On the other hand, treatment of chondrocytes with menadione (oxidative stress inducer) induced oxidation of IRE1, activated antioxidant response (higher Nrf2 expression), and increased expression of Nupr1 and matrix metalloproteinases. Experimental OA was induced by destabilization of the medial meniscus (DMM) in the knee joints of Nupr1+/+ and Nupr1-/- mice. Loss of Nupr1 expression reduced the severity of cartilage lesions in this model. Together, our findings suggest that Nupr1 is a common factor activated by signaling pathways activated by obesity (ER stress) and age (oxidative stress) and a potential drug target for OA resulting from various risk factors.
Subject(s)
Cartilage, Articular , Osteoarthritis , Animals , Humans , Mice , Aging , Cartilage, Articular/metabolism , Chondrocytes/metabolism , Nuclear Proteins/metabolism , Obesity/metabolism , Osteoarthritis/metabolismABSTRACT
Despite the success of CD19-targeted chimeric antigen receptor (CAR T)-cell therapy in patients with relapsed/refractory large B-cell lymphoma (LBCL), there is a need for effective salvage strategies post-CAR T-cell therapy failure. We conducted a multi-institutional retrospective study of patients who relapsed following CAR T-cell therapy (axicabtagene ciloleucel [axi-cel] or tisagenlecleucel [tisa-cel]) and received salvage therapies (radiation therapy [RT] alone, systemic therapy alone, or combined modality therapy [CMT]). A total of 120 patients with post-CAR T relapsed LBCL received salvage therapies (RT alone, 25 patients; CMT, 15 patients; systemic therapy alone, 80 patients). The median follow-up from CAR T-cell infusion was 10.2 months (interquartile range, 5.2-20.9 months). Failure occurred in previously involved sites prior to CAR T-cell therapy in 78% of patients (n=93). A total of 93 sites were irradiated in 54 patients who received any salvage RT post-CAR T failure. The median dose/fractionation were 30 Gy (range, 4-50.4 Gy) and 10 fractions (range, 1-28 fractions). The 1-year local control rate for the 81 assessable sites was 84%. On univariate analysis, the median overall survival (OS) from the start date of RT was significantly higher among patients who received comprehensive RT versus focal RT (19.1 months vs. 3.0 months; P=<0.001). Twenty-three of 29 patients who received comprehensive RT had limited-stage disease. Among these, there was no difference in median OS among the patients who received RT alone versus those who received RT followed by additional therapies (log-rank P=0.2). On multivariate survival analysis, achieving PR or CR post-CAR T (hazard ratio =0.5; 95% confidence interval: 0.3-0.9; P=0.01) was independently associated with superior OS. Our findings suggest that RT can provide local control for LBCL relapsed post-CAR T-cell therapy, particularly in patients with limited-stage relapsed disease treated with comprehensive RT.
Subject(s)
Lymphoma, Large B-Cell, Diffuse , Receptors, Chimeric Antigen , Humans , Immunotherapy, Adoptive/adverse effects , Retrospective Studies , Lymphoma, Large B-Cell, Diffuse/radiotherapy , Survival Analysis , Antigens, CD19ABSTRACT
The NCCN Guidelines for Survivorship are intended to help healthcare professionals address the complex and varied needs of cancer survivors. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for psychosocial and physical problems resulting from adult-onset cancer and its treatment; recommendations to help promote healthy behaviors and immunizations in survivors; and a framework for care coordination. These NCCN Guidelines Insights summarize recent guideline updates and panel discussions pertaining to sleep disorders, fatigue, and cognitive function in cancer survivors.
Subject(s)
Cancer Survivors , Neoplasms , Adult , Humans , Survivorship , Neoplasms/diagnosis , Neoplasms/therapy , Neoplasms/psychology , Survivors , Cancer Survivors/psychology , ImmunizationABSTRACT
The NCCN Guidelines for Survivorship are intended to help healthcare professionals who work with survivors to ensure that the survivors' complex and varied needs are addressed. The NCCN Guidelines provide screening, evaluation, and treatment recommendations for the consequences of adult-onset cancer and its treatment; recommendations to help promote physical activity, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes updates to the NCCN Guidelines pertaining to preventive health for cancer survivors, including recommendations about alcohol consumption and vaccinations.
Subject(s)
Cancer Survivors , Neoplasms , Adult , Humans , Immunization , Neoplasms/diagnosis , Neoplasms/therapy , Survivors , SurvivorshipABSTRACT
The NCCN Guidelines for Survivorship are intended to help healthcare professionals working with cancer survivors to ensure that each survivor's complex and varied needs are addressed. The Guidelines provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment; recommendations to help promote healthful lifestyle behaviors, weight management, and immunizations in survivors; and a framework for care coordination. This article summarizes the recommendations regarding employment and return to work for cancer survivors that were added in the 2021 version of the NCCN Guidelines.
Subject(s)
Cancer Survivors , Neoplasms , Adult , Humans , Mass Screening , Neoplasms/diagnosis , Neoplasms/therapy , Survivors , SurvivorshipABSTRACT
INTRODUCTION: Low-dose total skin electron beam therapy provides a durable treatment response for skin lesions caused by cutaneous T-cell lymphoma. We prospectively assessed the durability of response and quality of life for patients receiving low-dose total skin electron beam therapy using a novel rotational technique and dosing regimen. METHODS: Patients completed baseline Skindex-29 quality-of-life surveys and had baseline Modified Severity-Weighted Assessment Tool score recorded. Patients received 12 Gy in 12 fractions with a dual-field rotational technique. The primary outcome was overall response rate, with the secondary outcomes being time to treatment response, duration of clinical benefit, and quality-of-life change. RESULTS: We enrolled 20 patients and recorded an overall response rate of 90%. The median time to treatment response was 6.5 weeks. The baseline Modified Severity-Weighted Assessment Tool score was 55.6 and it declined to a median of 2.2 at last follow-up (P < .001). The median duration of clinical benefit was 21 months. There was a decline in the Skindex-29 total score and every subdomain when each follow-up visit was compared (P = .004). CONCLUSIONS: This prospective study demonstrated a very high overall response rate and improvement in skin-related quality of life. Low-dose rotational total skin electron beam therapy can be implemented routinely in clinical practice.
Subject(s)
Mycosis Fungoides/radiotherapy , Quality of Life , Skin Neoplasms/radiotherapy , Aged , Female , Humans , Male , Middle Aged , Prospective Studies , Radiotherapy/methods , Radiotherapy Dosage , Severity of Illness Index , Surveys and Questionnaires , Time-to-Treatment , Treatment OutcomeABSTRACT
Bone metastasis remains a major cause of death in cancer patients, and current therapies for bone metastatic disease are mainly palliative. Bone metastases arise after cancer cells have colonized the bone and co-opted the normal bone remodeling process. In addition to bone-targeted therapies (e.g., bisphosphonate and denosumab), hormone therapy, chemotherapy, external beam radiation therapy, and surgical intervention, attempts have been made to use systemic radiotherapy as a means of delivering cytocidal radiation to every bone metastatic lesion. Initially, several bone-seeking beta-minus-particle-emitting radiopharmaceuticals were incorporated into the treatment for bone metastases, but they failed to extend the overall survival in patients. However, recent clinical trials indicate that radium-223 dichloride (223RaCl2), an alpha-particle-emitting radiopharmaceutical, improves the overall survival of prostate cancer patients with bone metastases. This success has renewed interest in targeted alpha-particle therapy development for visceral and bone metastasis. This review will discuss (i) the biology of bone metastasis, especially focusing on the vicious cycle of bone metastasis, (ii) how bone remodeling has been exploited to administer systemic radiotherapies, and (iii) targeted radiotherapy development and progress in the development of targeted alpha-particle therapy for the treatment of prostate cancer bone metastasis.
Subject(s)
Alpha Particles/therapeutic use , Bone Neoplasms/secondary , Prostatic Neoplasms/drug therapy , Radiopharmaceuticals/therapeutic use , Humans , Ligands , Male , Prostate-Specific Antigen/metabolism , Radiopharmaceuticals/chemistryABSTRACT
The NCCN Guidelines for Survivorship provide screening, evaluation, and treatment recommendations for consequences of adult-onset cancer and its treatment, with the goal of helping healthcare professionals who work with survivors, including those in primary care. The guidelines also provide recommendations to help clinicians promote physical activity, weight management, and proper immunizations in survivors and facilitate care coordination to ensure that all of the survivors' needs are addressed. These NCCN Guidelines Insights summarize additions and changes made to the guidelines in 2020 regarding cardiovascular disease risk assessment and screening for subsequent primary malignancies.
Subject(s)
Neoplasms , Survivorship , Adult , Body Weight Maintenance , Exercise , Humans , Immunization , Mass Screening , Neoplasms/diagnosis , Neoplasms/therapy , Practice Guidelines as Topic , SurvivorsABSTRACT
To assess the utilization and outcomes of adjuvant monotherapy with hypofractionated radiation (RT) among elderly patients not receiving traditional adjuvant chemoradiotherapy (cRT) for glioblastoma multiforme (GBM). A retrospective analysis using the National Cancer Data Base with GBM patients aged 65 years or older treated between 2005 and 2012 was conducted. Patients who underwent hypofractionated RT (40 Gy), conventional RT (60 Gy), chemotherapy, or best supportive care alone were included. Statistical methods included logistic regression for utilization and Cox regression for survival analysis. A total of 9556 patients were analyzed. On multivariate analysis (compared to those receiving conventional RT), patients more likely to be treated with hypofractionated RT were older (75-84 years old OR 2.05; p < 0.01 and ≥ 85 years old OR 3.32; p < 0.01), with a Charlson/Deyo score of 2 or higher (OR 1.80; p = 0.05), from communities > 50 miles from their treatment facility (50-100 miles OR 8.03; p < 0.01 and > 100 miles OR 7.16; p < 0.01), treated at an Academic/Research facility (OR 2.85; p = 0.04), and diagnosed between 2011 and 2012 (OR 4.15; p < 0.01). On Cox regression, hypofractionated RT (HR 0.65; p < 0.01), conventional RT (HR 0.60; p < 0.01), and chemotherapy alone (HR 0.69; p < 0.01) were all associated with decreased risk of death compared to no adjuvant therapy. Among patients receiving adjuvant treatment, utilization of hypofractionated RT increased from 7 to 19% during the study period. Among elderly patients with GBM not receiving cRT, the utilization of adjuvant monotherapy with hypofractionated RT has increased over time. Retrospective evidence suggests it may be better than best supportive care alone and as good as conventionally fractionated RT alone.
Subject(s)
Brain Neoplasms/radiotherapy , Glioblastoma/radiotherapy , Radiation Dose Hypofractionation , Aged , Aged, 80 and over , Databases, Factual , Female , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Radiotherapy, Adjuvant/statistics & numerical data , Retrospective Studies , Treatment OutcomeABSTRACT
To investigate the determinants of radiation therapy refusal in pediatric cancer, we used the Surveillance, Epidemiology, and End Results registry to identify 24,421 patients who met the eligibility criteria, diagnosed between 1974 and 2012. Patients had any stage of cancer, were aged 0 to 19, and received radiation therapy or refused radiation therapy when it was recommended. One hundred twenty-eight patients (0.52%) refused radiation therapy when it was recommended. Thirty-two percent of patients who refused radiation therapy ultimately died from their cancer, at a median of 7 months after diagnosis (95% confidence interval, 3-11 mo), as compared with 29.0% of patients who did not refuse radiation therapy died from their cancer, at a median of 17 months after diagnosis (95% confidence interval, 17-18 mo). On multivariable analysis, central nervous system (CNS) site, education, and race were associated with radiation refusal. The odds ratio for radiation refusal for patients with CNS disease was 1.62 (P=0.009) as compared with patients without CNS disease. For patients living in a county with ≥10% residents having less than ninth grade education, the odds ratio for radiation refusal was 1.71 (P=0.008) as compared with patients living in a county with <10% residents having less than ninth grade education. Asian, Pacific Islander, Alaska Native, and American Indian races had an odds ratio of 2.12 (P=0.002) for radiation refusal as compared with black or white race. Although the radiation refusal rate in the pediatric cancer population is low, we show that CNS site, education level, and race are associated with a significant difference in radiation refusal.
Subject(s)
Central Nervous System Diseases , Education , Neoplasms/radiotherapy , Racial Groups , Treatment Refusal , Adolescent , Child , Humans , Infant , Neoplasms/mortality , Radiotherapy , Treatment Refusal/ethnology , Treatment Refusal/psychology , Young AdultABSTRACT
Although in vitro models have been a cornerstone of anti-cancer drug development, their direct applicability to clinical cancer research has been uncertain. Using a state-of-the-art Taqman-based quantitative RT-PCR assay, we investigated the multidrug resistance (MDR) transcriptome of six cancer types, in established cancer cell lines (grown in monolayer, 3D scaffold, or in xenograft) and clinical samples, either containing >75% tumor cells or microdissected. The MDR transcriptome was determined a priori based on an extensive curation of the literature published during the last three decades, which led to the enumeration of 380 genes. No correlation was found between clinical samples and established cancer cell lines. As expected, we found up-regulation of genes that would facilitate survival across all cultured cancer cell lines evaluated. More troubling, however, were data showing that all of the cell lines, grown either in vitro or in vivo, bear more resemblance to each other, regardless of the tissue of origin, than to the clinical samples they are supposed to model. Although cultured cells can be used to study many aspects of cancer biology and response of cells to drugs, this study emphasizes the necessity for new in vitro cancer models and the use of primary tumor models in which gene expression can be manipulated and small molecules tested in a setting that more closely mimics the in vivo cancer microenvironment so as to avoid radical changes in gene expression profiles brought on by extended periods of cell culture.
Subject(s)
Antineoplastic Agents/therapeutic use , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor/methods , Gene Expression Regulation, Neoplastic , Cell Line, Tumor , Cell Survival , Female , Gene Expression Profiling , Humans , Ovarian Neoplasms/metabolism , Ovary/metabolism , Reverse Transcriptase Polymerase Chain Reaction , Translational Research, Biomedical/methods , Tumor Cells, Cultured , Tumor Suppressor Protein p53/metabolismABSTRACT
Radiation therapy (RT) is utilized as a bridging strategy for patients with aggressive B-cell lymphoma prior to CD19-targeted chimeric antigen receptor (CAR T)-cell therapy. RT has been shown to provide local control without exacerbating the toxicities associated with subsequent CAR T-cell infusion. However, a consensus on the optimal radiation dose and fractionation for bridging purposes has yet to be established. We present a case of a patient with relapsed aggressive B-cell lymphoma who underwent bridging adaptive RT on a CT-linac prior to receiving CAR T-cell therapy. At month 6 post-CAR T infusion, the patient demonstrates no signs of disease recurrence or relapse, nor any unexpected toxicities attributable to the combined treatment. This underscores the feasibility and success of this innovative approach in treating lymphoma patients undergoing CAR T-cell therapy.
ABSTRACT
BACKGROUND CONTEXT: Conventional external beam radiation therapy (cEBRT) is used in multiple myeloma (MM) to treat severe pain, spinal cord compression, and disease-related bone disease. However, radiation may be associated with an increased risk of vertebral compression fractures (VCFs), which could substantially impair survival and quality of life. Additionally, the use of the Spinal Instability Neoplastic Score (SINS) in MM is debated in MM. PURPOSE: To determine the incidence of VCFs after cEBRT in patients with MM and to assess the applicability of the SINS score in the prediction of VCFs in MM. STUDY DESIGN: Retrospective multicenter cohort study. PATIENT SAMPLE: MM patients with spinal myeloma lesions who underwent cEBRT between January 2010 and December 2021. OUTCOME MEASURES: Frequency of new or progressed VCFs and subdistribution hazard ratios for potentially associated factors. METHODS: Patient and treatment characteristics were manually collected from the patients' electronic medical records. Computed tomography (CT) scans from before and up to 3 years after the start of radiation were used to score radiographic variables at baseline and at follow-up. Multivariable Fine and Gray competing risk analyses were performed to evaluate the diagnostic value of the SINS score to predict the postradiation VCF rate. RESULTS: A total of 127 patients with 427 eligible radiated vertebrae were included in this study. The mean age at radiation was 64 years, and 66.1% of them were male. At the start of radiation, 57 patients (44.9%) had at least one VCF. There were 89 preexisting VCFs (18.4% of 483 vertebrae). Overall, 39 of 127 patients (30.7%) reported new fractures (number of vertebrae (n)=12) or showed progression of existing fractures (n=36). This number represented 11.2% of all radiated vertebrae. Five of the 39 (12.8%) patients with new or worsened VCFs received an unplanned secondary treatment (augmentation [n=2] or open surgery [n=3]) within 3 years. Both the total SINS score (SHR 1.77; 95% confidence interval (CI) 1.54-2.03; p<.001) and categorical SINS score (SHR 10.83; 95% CI 4.20-27.94; p<.001) showed an independent association with higher rates of new or progressed VCFs in adjusted analyses. The use of bisphosphonates was independently associated with a lower rate of new or progressed VCFs (SHR 0.47 [95% CI 0.24-0.92; p=.027]). CONCLUSIONS: This study demonstrated that new or progressed VCFs occurred in 30.7% of patients within 3 years, in a total of 11.2% of vertebrae. The SINS score was found to be independently associated with the development or progression of VCFs and could thus be applied in MM for fracture prediction and possibly prevention.
Subject(s)
Fractures, Compression , Multiple Myeloma , Spinal Fractures , Humans , Male , Female , Spinal Fractures/diagnostic imaging , Spinal Fractures/epidemiology , Spinal Fractures/etiology , Fractures, Compression/diagnostic imaging , Fractures, Compression/epidemiology , Fractures, Compression/etiology , Multiple Myeloma/epidemiology , Multiple Myeloma/radiotherapy , Multiple Myeloma/complications , Cohort Studies , Quality of Life , Spine , Retrospective StudiesABSTRACT
STUDY DESIGN: Retrospective cohort study. OBJECTIVE: In general, Multiple Myeloma (MM) patients are treated with systemic therapy including chemotherapy. Radiation therapy can have an important supportive role in the palliative management of MM-related osteolytic lesions. Our study aims to investigate the degree of radiation-induced remineralization in MM patients to gain a better understanding of its potential impact on bone mineral density and, consequently, fracture prevention. Our primary outcome measure was percent change in bone mineral density measured in Hounsfield Units (Δ% HU) between pre- and post-radiation measurements, compared to non-targeted vertebrae. METHODS: We included 119 patients with MM who underwent radiotherapy of the spine between January 2010 and June 2021 and who had a CT scan of the spine at baseline and between 3-24 months after radiation. A linear mixed effect model tested any differences in remineralization rate per month (ßdifference) between targeted and non-targeted vertebrae. RESULTS: Analyses of CT scans yielded 565 unique vertebrae (366 targeted and 199 non-targeted vertebrae). In both targeted and non-targeted vertebrae, there was an increase in bone density per month (ßoverall = .04; P = .002) with the largest effect being between 9-18 months post-radiation. Radiation did not cause a greater increase in bone density per month compared to non-targeted vertebrae (ßdifference = .67; P = .118). CONCLUSION: Our results demonstrate that following radiation, bone density increased over time for both targeted and non-targeted vertebrae. However, no conclusive evidence was found that targeted vertebrae have a higher remineralization rate than non-targeted vertebrae in patients with MM.