Prevention of bone growth defects, increased bone resorption and marrow adiposity with folinic acid in rats receiving long-term methotrexate

The underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1b and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1b in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1b neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.Chia-Ming Fan, Bruce K. Foster, Susanta K. Hui and Cory J. Xia

Feasibility of a Novel Sparse Orthogonal Collimator–Based Preclinical Total Marrow Irradiation for Enhanced Dosimetric Conformality

Total marrow irradiation (TMI) has significantly improved radiation conditioning for hematopoietic cell transplantation in hematologic diseases by reducing conditioning-induced toxicities and improving survival outcomes in relapsed/refractory patients. Recently, preclinical three-dimensional image–guided TMI has been developed to enhance mechanistic understanding of the role of TMI and to support the development of experimental therapeutics. However, a dosimetric comparison between preclinical and clinical TMI reveals that the preclinical TMI treatment lacks the ability to reduce the dose to some of the vital organs that are very close to the skeletal system and thus limits the ability to evaluate radiobiological relevance. To overcome this limit, we introduce a novel Sparse Orthogonal Collimator (SOC)–based TMI and evaluate its ability to enhance dosimetric conformality. The SOC-TMI–based dose modulation technique significantly improves TMI treatment planning by reducing radiation exposures to critical organs that are close to the skeletal system that leads to reducing the gap between clinical and preclinical TMI

Fast, simple, and informative patient-specific dose verification method for intensity modulated total marrow irradiation with helical tomotherapy

BACKGROUND: Patient-specific dose verification for treatment planning in helical tomotherapy is routinely performed using a homogeneous virtual water cylindrical phantom of 30 cm diameter and 18 cm length (Cheese phantom). Because of this small length, treatment with total marrow irradiation (TMI) requires multiple deliveries of the dose verification procedures to cover a wide range of the target volumes, which significantly prolongs the dose verification process. We propose a fast, simple, and informative patient-specific dose verification method which reduce dose verification time for TMI with helical tomotherapy. METHODS: We constructed a two-step solid water slab phantom (length 110 cm, height 8 cm, and two-step width of 30 cm and 15 cm), termed the Whole Body Phantom (WB phantom). Three ionization chambers and three EDR-2 films can be inserted to cover extended field TMI treatment delivery. Three TMI treatment plans were conducted with a TomoTherapy HiArt Planning Station and verified using the WB phantom with ion chambers and films. Three regions simulating the head and neck, thorax, and pelvis were covered in a single treatment delivery. The results were compared to those with the cheese phantom supplied by Accuray, Inc. following three treatment deliveries to cover the body from head to pelvis. RESULTS: Use of the WB phantom provided point doses or dose distributions from head and neck to femur in a single treatment delivery of TMI. Patient-specific dose verification with the WB phantom was 62% faster than with the cheese phantom. The average pass rate in gamma analysis with the criteria of a 3-mm distance-to-agreement and 3% dose differences was 94% ± 2% for the three TMI treatment plans. The differences in pass rates between the WB and cheese phantoms at the upper thorax to abdomen regions were within 2%. The calculated dose agreed with the measured dose within 3% for all points in all five cases in both the WB and cheese phantoms. CONCLUSIONS: Our dose verification method with the WB phantom provides simple and rapid quality assurance without limiting dose verification information in total marrow irradiation with helical tomotherapy

CT-based analysis of dose homogeneity in total body irradiation

using lateral bea

Role of NK Cells in Cancer and Immunotherapy

Increasing knowledge of cancer immunology has led to the design of therapies using immune cells directly or manipulating their activity, collectively termed immunotherapy. In the field of immuno-oncology, research on adaptive immune T cells has led to the development of CAR-T cells. Innate immune cells such as NK cells can also eliminate oncogenically transformed cells and regulate cells of the immune system. Considering NK cells as a live drug, numerous methods for the isolation and activation of NK cells have been shown to be clinically and therapeutically relevant. In such processes, various cytokines and antibodies present a source of stimulation of NK cells and enhance the efficacy of such treatments. The ex vivo expansion and activation of NK cells, along with genetic modification with CAR, enhance their antitumor activity. Recent preclinical studies have shown an antitumor effect through extracellular vesicles (EVs) derived from NK cells. Work with autologous NK cells has provided insights for clinical applications. In this review, we outline the recent advances of NK-cell-based immunotherapies, summarizing CAR-NK cells, BiKEs, and TriKEs as treatment options against cancer. This review also discusses the challenges of NK cell immunotherapy

Emerging CAR T Cell Strategies for the Treatment of AML

Engineered T cells expressing chimeric antigen receptors (CARs) on their cell surface can redirect antigen specificity. This ability makes CARs one of the most promising cancer therapeutic agents. CAR-T cells for treating patients with B cell hematological malignancies have shown impressive results. Clinical manifestation has yielded several trials, so far five CAR-T cell therapies have received US Food and Drug Administration (FDA) approval. However, emerging clinical data and recent findings have identified some immune-related toxicities due to CAR-T cell therapy. Given the outcome and utilization of the same proof of concept, further investigation in other hematological malignancies, such as leukemias, is warranted. This review discusses the previous findings from the pre-clinical and human experience with CAR-T cell therapy. Additionally, we describe recent developments of novel targets for adoptive immunotherapy. Here we present some of the early findings from the pre-clinical studies of CAR-T cell modification through advances in genetic engineering, gene editing, cellular programming, and formats of synthetic biology, along with the ongoing efforts to restore the function of exhausted CAR-T cells through epigenetic remodeling. We aim to shed light on the new targets focusing on acute myeloid leukemia (AML)

Primer sequences used in this study.

<p>Primer sequences used in this study.</p

Effects of treatment with MTX alone or with supplementary folinic acid (FA) for 6 weeks on adipocyte density and mRNA expression of PPARγ.

<p>H&E-stained sections of tibia from a control (A), MTX-treated (B) and MTX+FA treated rat (C). Treatment effects on adipocyte density within bone marrow area of secondary spongiosa (D), and mRNA expression of PPARg relative to Cyclophilin-A (E). Scale bar on panel C = 250 µm, which applies to A and B.</p