Anticancer Radiation Research Articles

Immune modulation during anti-cancer radio(immuno)therapy.

Cancer can affect all human organs and tissues and ranks as a prominent cause of death as well as an obstruction to increasing life expectancy. A notable breakthrough in oncology has been the inclusion of the immune system in fighting cancer, potentially prolonging life and providing long-term benefits. The concept of "immunotherapy" has been discussed from the 19th and early 20th centuries by Wilhelm Busch, William B. Coley and Paul Ehrlich. This involves distinct approaches, including vaccines, non-specific cytokines and adoptive cell therapies. However, despite the advances made in recent years, questions on how to select the best therapeutic options or how to select the best combinations to improve clinical outcomes are still relevant for scientists and clinicians. More than half of cancer patients receive radiotherapy (RT) as part of their treatment. With the advances in RT and immunotherapy approaches, it is reasonable to consider how to enhance immunotherapy with radiation and vice versa, and to investigate whether combinations of these therapies would be beneficial. In this chapter, we will discuss how the immune system responds to cancer cells and different cancer therapies with a focus on combination of RT and immunotherapy (radioimmunotherapy, RIT).

1224 A Systematic Review Exploring the Mechanisms Behind Autologous Lipotransfer for Radiation-Induced Fibrosis

Abstract Aim Radiation-induced fibrosis (RIF) is a recognised consequence of anti-cancer radiotherapy, especially after multiple and prolonged dosing regimens. There is no definitive treatment for late-stage RIF, although the use of autologous fat transfer (AFT) has shown promise. However, the exact mechanisms by which AFT improves RIF remain poorly understood. We aim to explore existing literature on the effects of AFT on both in-vitro and in-vivo RIF models, and to collate potential mechanisms of action. Method PubMed, Cochrane reviews and Scopus electronic databases from inception to January 2022 were searched. Our search strategy combined both free-text terms with Boolean operators, derived from synonyms of adipose tissue and RIF. Results The search strategy produced 2645 articles. Of these, 76 underwent full-text review for eligibility, yielding 26 for final analysis. Eight conducted in-vitro experiments utilising a co-culture model, whilst 21 conducted in-vivo experiments. AFT interventions included adipose-derived stem cells (ADSCs), stromal vascular function, whole fat and microfat. Notable findings include downregulation of fibroblast proliferation, collagen deposition, epithelial cell apoptosis, and proinflammatory processes. AFT suppressed hypoxia and pro-inflammatory interferon-γ signalling pathways, and ADSC-treated tissue stained strongly for anti-inflammatory M2 macrophages. Although largely proangiogenic initially, studies show varying effects on vascularisation. There is early evidence that ADSC subgroups may have different functional properties. Conclusions AFT functions through pro-angiogenic, anti-fibrotic, immunomodulatory, and extracellular matrix remodelling properties. By characterising these mechanisms, relevant drug targets can be identified and used to further improve clinical outcomes in RIF. Further research should focus on ADSC sub-populations and augmentation techniques such as cell-assisted lipotransfer.

Quantitative Correlations between Radiosensitivity Biomarkers Show That the ATM Protein Kinase Is Strongly Involved in the Radiotoxicities Observed after Radiotherapy.

Tissue overreactions (OR), whether called adverse effects, radiotoxicity, or radiosensitivity reactions, may occur during or after anti-cancer radiotherapy (RT). They represent a medical, economic, and societal issue and raise the question of individual response to radiation. To predict and prevent them are among the major tasks of radiobiologists. To this aim, radiobiologists have developed a number of predictive assays involving different cellular models and endpoints. To date, while no consensus has been reached to consider one assay as the best predictor of the OR occurrence and severity, radiation oncologists have proposed consensual scales to quantify OR in six different grades of severity, whatever the organ/tissue concerned and their early/late features. This is notably the case with the Common Terminology Criteria for Adverse Events (CTCAE). Few radiobiological studies have used the CTCAE scale as a clinical endpoint to evaluate the statistical robustness of the molecular and cellular predictive assays in the largest range of human radiosensitivity. Here, by using 200 untransformed skin fibroblast cell lines derived from RT-treated cancer patients eliciting OR in the six CTCAE grades range, correlations between CTCAE grades and the major molecular and cellular endpoints proposed to predict OR (namely, cell survival at 2 Gy (SF2), yields of micronuclei, recognized and unrepaired DSBs assessed by immunofluorescence with γH2AX and pATM markers) were examined. To our knowledge, this was the first time that the major radiosensitivity endpoints were compared together with the same cohort and irradiation conditions. Both SF2 and the maximal number of pATM foci reached after 2 Gy appear to be the best predictors of the OR, whatever the CTCAE grades range. All these major radiosensitivity endpoints are mathematically linked in a single mechanistic model of individual response to radiation in which the ATM kinase plays a major role.

Does burning fat make tumor immune hot? Discovery of CD47 overexpression by radiation induced fatty acid oxidation

Although extensively studied, it is unknown what is the major cellular energy driving tumor metastasis after anti-cancer radiotherapy. Metabolic reprogramming is one of the fundamental hallmarks in carcinogenesis and tumor progression featured with the increased glycolysis in solid tumors. However, accumulating evidence indicates that in addition to the rudimentary glycolytic pathway, tumor cells are capable of reactivating mitochondrial OXPHOS under genotoxic stress condition to meet the increasing cellular fuel demand for repairing and surviving anti-cancer radiation. Such dynamic metabolic rewiring may play a key role in cancer therapy resistance and metastasis. Interestingly, data from our group and others have demonstrated that cancer cells can re-activate mitochondrial oxidative respiration to boost an annexing energy to meet the increasing cellular fuel demand for tumor cells surviving genotoxic anti-cancer therapy with metastatic potential.

Synthesis and Characterization of Magnetic Drug Carriers Modified with Tb3+ Ions.

The study aimed to synthesize and characterize the magnetic drug carrier modified with terbium (III) ions. The addition of terbium extends the possibilities of their applications for targeted anticancer radiotherapy as well as for imaging techniques using radioisotopes emitting β+, β−, α, and γ radiation. The synthesis of iron oxide nanoparticles stabilized with citrates using the co-precipitation method (IONP @ CA) was carried out during the experimental work. The obtained nanoparticles were used to synthesize a conjugate containing terbium ions and guanosine-5′-monophosphate as an analog of drugs from the thiopurine group. Conjugates and their components were characterized using Transmission Electron Microscopy, infrared spectroscopy, X-ray microanalysis, spectrofluorimetry, and thermogravimetric analysis. The hybrid was also investigated with Langmuir layers to check the interaction with analogs of biological membranes.

Stereotactic Ablative Brachytherapy: Recent Advances in Optimization of Radiobiological Cancer Therapy.

Simple SummaryEmerging studies involving ablative brachytherapy with curative effect have been published, but the evidence was not comprehensively discussed. This study will provide an overview of stereotactic ablative brachytherapy, focusing on the advances in stereotactic ablative brachytherapy optimization, and provide insights on the future benefits of the combined application of stereotactic ablative brachytherapy with cancer immunotherapies.Brachytherapy (BT), a type of focal anti-cancer radiotherapy, delivers a highly focused radiation dose to localized tumors, sparing surrounding normal tissues. Recent technological advances have helped to increase the accuracy of BT and, thus, improve BT-based cancer treatment. Stereotactic ablative brachytherapy (SABT) was designed to improve the ablative effect of radiation, which was achieved via improved image guidance, and calculation of ablative dose, shorter treatment duration, and better organ preservation. Recently collected data characterized SABT as having the potential to cure various early-stage cancers. The method provides higher tumor control rate levels that were previously achievable only by surgical resection. Notably, SABT is suitable for application with unresectable malignancies. However, the pathological assessment of SABT irradiated tumors is limited due to difficulties in specimen acquisition. Prostate, lung, liver, and gynecological cancers are the most commonly reported SABT-treated malignancies. This study will give an overview of SABT, focusing on the advances in SABT optimization, and provide insights on the future benefits of the combined application of SABT with cancer immunotherapies.

Abstract PO040: High-throughput vascularized tumor array for In-vitro natural killer cell cytotoxicity testing

Abstract Colorectal cancer is second leading cause of cancer death. There have been many approaches proposed, such as anti-cancer drugs, chemotherapy and radiotherapy, however, there are still lack of breakthrough therapy designation. Cancer immunotherapies hold great promise, where the mechanism of interaction between immune cell and tumor remains poorly understood. Understanding of immune cell infiltration in solid tumor plays an important role in cancer immunotherapy. This paper describes injection molded plastic chip to mimic complex three-dimensional tumor-vasculature for evaluating immune cell infiltration and their cytotoxicity. Our device facilities simple and high-throughput screening, constituting of 28 wells per device. Using our system, Co-culture conditions that both tumors and blood vessels were adequately benefited were established. Also, we characterized the aberrant vasculature according to the colorectal tumor subtypes and confirmed increased blood vessel the permeability, which is the major feature of aberrant tumor vasculature. Moreover, we evaluated Natural killer(NK) cell infiltration and cytotoxicity according CMS subtypes. NK cell showed higher cytotoxicity to CMS 1 type colorectal cancer compared to the other subtypes. This result confirmed that NK cell is the crucial effector in innate immune system as a first line of defense against pathogens. Therefore, we propose our plastic microfluidic chip as a high-throughput screening platform to evaluate lymphocyte cytotoxicity to various solid tumor including immune infiltration. Citation Format: Jiyoung Song, Hyeri Choi, Dohyun Park, James Yu, Nooli Jeon. High-throughput vascularized tumor array for In-vitro natural killer cell cytotoxicity testing [abstract]. In: Abstracts: AACR Virtual Special Conference: Tumor Immunology and Immunotherapy; 2020 Oct 19-20. Philadelphia (PA): AACR; Cancer Immunol Res 2021;9(2 Suppl):Abstract nr PO040.

THE EFFECTIVENESS OF MELATONIN IN REDUCING PAIN RESULTING FROM RADIATION INDUCED ORAL MUCOSITIS: A RANDOMIZED CLINICAL TRIAL

BACKGROUND: Oral mucositis is a common side effect of anticancer radiotherapy causing severe ulceration of the mucosal tissues. Recently, melatonin supplements have been proposed as a new therapeutic modality for oral mucositis due to its antioxidant effects, anti-inflammatory, and anti-cancer properties.OBJECTIVES: evaluation of the effectiveness of melatonin in reducing pain resulting from radiation induced oral mucositisMATERIALS AND METHODS: Forty patients were randomly assigned to receive either: conventional treatment of oral mucositis, or 20 mg melatonin treatment in combination with the conventional treatment before irradiation, and for six weeks. All patients were evaluated for pain resulting from oral mucositis at three and six weeks after the start of radiotherapy.RESULTS: Oral mucositis patients in the melatonin group have experienced significantly lower pain scores oral mucositis compared to the control group.CONCLUSION: Adjuvant melatonin reduced the pain of oral mucositis, and the amount of analgesics used for pain treatment.

Positive Effects of Preventive Nutrition Supplement on Anticancer Radiotherapy in Lung Cancer Bearing Mice.

Simple SummaryThe supplement of TNuF, a total nutrition formula, before cancer diagnosis significantly enhanced the anticancer effect of radiotherapy against primary tumor and lung metastasis in tumor-bearing mice. Meanwhile, TNuF improved cancer related sarcopenia. We supposed that these benefits are related to the regulations of cell proliferation, angiogenesis, and immunity in tumor microenvironment.(1) Background: Radiotherapy (RT) is one of the major treatments for non-small cell lung cancer, but RT-associated toxicities usually impede its anticancer effect. Nutrient supplementation has been applied for cancer prevention or a complementary measure to anticancer therapy. Here, we explored the influence of total nutrition supplementation before and after cancer occurrence on the anticancer benefit and side effects of RT. (2) Methods: C57BL/6JNarl mice were inoculated with Lewis lung carcinoma cells and then treated with radiotherapy. TNuF, a total nutrition formula, was prescribed by oral gavage. In the preventive groups, TNuF supplementation started from seven days before tumor inoculation. In the complementary groups, TNuF supplementation began after tumor inoculation. (3) Results: TNuF successfully enhanced the anticancer effect of RT against primary tumor and lung metastasis. Additionally, the complementary supplement improved the high serum TNF-α level and the wasting of sartorius muscle in mice receiving RT. In histologic and molecular analysis, TNuF was observed to modulate EGFR, apoptosis, and VEGF and PD-1/PD-L1 pathways. Furthermore, the anticancer benefit of the preventive supplement was comparable to that of the complementary administration. (4) Conclusions: Our results demonstrated that the prescription of the TNuF total nutrition formula before and after cancer diagnosis attains similar benefits in testing subjects with typical anticancer RT. TNuF is also a potential sensitizer to anti-PD-1 immune therapy.

Changes in Cancer Treatment Practice During the COVID-19 Pandemic: An Egyptian Multi-Institution Study

Background: In many countries, especially the lower-income ones, the COVID-19 pandemic had a significant negative impact on the services provided to cancer patients. This necessitated setting guidelines for the management of cancer during the pandemic and resulted in changes in its practice. Aim:To explore the change in practice of cancer treatment in cancer centers during the COVID-19 pandemic in Egypt, a lower-income country. Methods: Oncologists from six geographically-distributed Egyptian cancer centers were invited to complete a semi-structured questionnaire evaluating their cancer treatment practice changes. This included systemic anti-cancer treatment, radiotherapy, surgery and supportive and palliative care. Results: Regarding systemic chemotherapy, there was a switch from weekly to 3-4 weekly schedules, from longer to shorter courses and from parenteral to oral administration whenever possible in the majority of centers. Single agents were encouraged and regimens more likely to cause neutropenia were avoided. Hormonal and palliative care treatments were prescribed for longer durations. For many indications, especially the palliative, a switch to hypofractionated radiotherapy regimens was adopted. Excluding emergencies, surgeries were postponed in many centers. The number of elective hospital admissions was minimized and the time interval of follow up visits was prolonged. The majority used phone calls to follow up patients. Conclusion: The COVID-19 pandemic has been associated with many changes in cancer treatment practice in Egyptian cancer care facilities. These changes are likely to minimize the risk of exposure of patients and health care professionals and to utilize the limited resources in a better way.

Nanoparticles in medicine

Nanotechnology is a new, interdisciplinary field of science, the products of which are nanoparticles, i.e. structures that, thanks to their unique physical and chemical properties conditioned by their nanometric dimensions, have found wide application in medicine, pharmacy and biotechnology. Currently, they play a particularly important role as drug carriers, antibacterial and antiviral substances. They are also used in diagnostics, genetic tests, and increasing the accuracy of biological tests. The enormous possibilities of nanoparticles concern their potential use as drug delivery systems, factors improving the quality of anticancer radiotherapy and supporting molecular imaging, as well as compounds with highly bactericidal, fungicidal and antiviral properties. Therefore, it is crucial to implement therapies based on nanoparticles into clinical trials, as they can be an excellent diagnostic and therapeutic tool for many diseases, including cancer. However, it is necessary to overcome certain barriers due to the nature of some nanoparticles, such as problems with biodegradability and porosity. Despite the benefits of using nanostructures, the possibility of side effects caused by the action of metal nanoparticles absorbed by organisms has not been ruled out.

Neck Dissection for Cervical Lymph Node Metastases from Remote Primary Malignancies

Background and Objectives: Patients with cervical lymph node metastases from remote primary tumours have poor prognoses because of the advanced stage of their cancer. Owing to recent progress in the nonsurgical management of various cancer types, options for surgical treatment to reduce tumour volume are increasing, and may help improve survival rates. For example, neck dissection may be a good option as a definitive therapy for some patients with resectable cervical metastases. We assessed patients who underwent neck dissection with curative intent and discuss the effectiveness of this approach for cervical metastases from remote malignancies. Material and Methods: We retrospectively reviewed the data of 18 patients (10 males and 8 females in an age range of 30–79 years) who underwent neck dissections for neck lymph node metastases from a remote primary tumour between 2010 and 2019. Patient clinical characteristics, preoperative accuracy of positive node localisation using fluorodeoxyglucose positron emission tomography–computed tomography (FDG/PET-CT), and patient survival rates were estimated. Results: Primary sites included ten lungs, two mammary glands, one thymus, one thoracic oesophagus, one stomach, one uterine cervix, one ovary, and one testis per patient. There were 19 levels with FDG/PET-CT positive nodes in 17 out of 18 patients. Conversely, there were 28 pathological positive levels out of 50 dissected levels. The sensitivity, specificity, positive and negative predictive values, and accuracy of FDG-PET/CT in predicting positive nodes were 69%, 88%, 95%, 47%, and 74%, respectively. The three-year overall survival (OS) rate for all patients was 70%. The three-year OS rate of the group with zero or one pathological positive nodes was 81%, which was significantly higher than that of the group with more than two positive nodes (51%) (p = 0.03). Conclusions: Neck dissection for cervical lymph node metastases from remote primary malignancies may improve prognoses, especially considering anticancer agents and radiotherapy advancements.

The Influence of Single, Tandem, and Clustered DNA Damage on the Electronic Properties of the Double Helix: A Theoretical Study.

Oxidatively generated damage to DNA frequently appears in the human genome as the effect of aerobic metabolism or as the result of exposure to exogenous oxidizing agents, such as ionization radiation. In this paper, the electronic properties of single, tandem, and clustered DNA damage in comparison with native ds-DNA are discussed as a comparative analysis for the first time. A single lesion—8-oxo-7,8-dihydro-2′-deoxyguanosine (Goxo), a tandem lesion—(5′S) and (5′R) 5′,8-cyclo-2′-deoxyadenosine (cdA), and the presence of both of them in one helix turn as clustered DNA damage were chosen and taken into consideration. The lowest vertical and adiabatic potential (VIP ~ 5.9 and AIP ~ 5.5 eV, respectively) were found for Goxo, independently of the discussed DNA lesion type and their distribution within the double helix. Moreover, the VIP and AIP were assigned for ds-trimers, ds- dimers and single base pairs isolated from parental ds-hexamers in their neutral and cationic forms. The above results were confirmed by the charge and spin density population, which revealed that Goxo can be considered as a cation radical point of destination independently of the DNA damage type (single, tandem, or clustered). Additionally, the different influences of cdA on the charge transfer rate were found and discussed in the context of tandem and clustered lesions. Because oligonucleotide lesions are effectively produced as a result of ionization factors, the presented data in this article might be valuable in developing a new scheme of anticancer radiotherapy efficiency.

Irradiation-induced senescence of bone marrow mesenchymal stem cells aggravates osteogenic differentiation dysfunction via paracrine signaling.

The role of cellular senescence induced by radiation in bone loss has attracted much attention. As one of the common complications of anticancer radiotherapy, irradiation-induced bone deterioration is common and clinically significant, but the pathological mechanism has not been elucidated. This study was performed to explore the cellular senescence and senescence-associated secretory phenotype (SASP) induction of bone marrow-derived mesenchymal stem cells (BMSCs) by irradiation and its role in osteogenic differentiation dysfunction. It was observed that irradiated BMSCs lost typical fibroblast-like morphology, exhibited suppressed viability and differentiation potential accompanied with senescence phenotypes, including an increase in senescence-associated β-galactosidase (SA-β-gal) staining-positive cells, and upregulated senescence-related genes p53/p21, whereas no changes happened to p16. Additionally, DNA damage γ-H2AX foci, G0/G1 phase of cell cycle arrest, and cellular and mitochondrial reactive oxygen species (ROS) increased in an irradiation dose-dependent manner. Meanwhile, the JAK1/STAT3 pathway was activated and accompanied by an increase in SASP secretion, such as IL-6, IL-8, and matrix metalloproteinase-9 (MMP9), whereas 0.8 μM JAK1 inhibitor (JAKi) treatment effectively inhibited the JAK pathway and SASP production. Furthermore, conditioned medium (CM) from irradiation-induced senescent (IRIS) BMSCs exhibited a markedly reduced ability in osteogenic differentiation and marker gene expression of osteoblasts, whereas CM with JAKi intervention may effectively improve these deterioration effects. In conclusion, irradiation could provoke BMSC senescence and SASP secretion and further aggravate osteogenic differentiation dysfunction via paracrine signaling, whereas SASP targeting may be a possible intervention strategy for alleviating irradiation-induced bone loss.

FLASH Irradiation Spares Lung Progenitor Cells and Limits the Incidence of Radio-induced Senescence.

One of the main limitations to anticancer radiotherapy lies in irreversible damage to healthy tissues located within the radiation field. "FLASH" irradiation at very high dose-rate is a new treatment modality that has been reported to specifically spare normal tissue from late radiation-induced toxicity in animal models and therefore could be a promising strategy to reduce treatment toxicity. Lung responses to FLASH irradiation were investigated by qPCR, single-cell RNA sequencing (sc-RNA-Seq), and histologic methods during the acute wound healing phase as well as at late stages using C57BL/6J wild-type and Terc-/- mice exposed to bilateral thorax irradiation as well as human lung cells grown in vitro. In vitro studies gave evidence of a reduced level of DNA damage and induced lethality at the advantage of FLASH. In mouse lung, sc-RNA-seq and the monitoring of proliferating cells revealed that FLASH minimized the induction of proinflammatory genes and reduced the proliferation of progenitor cells after injury. At late stages, FLASH-irradiated lungs presented less persistent DNA damage and senescent cells than after CONV exposure, suggesting a higher potential for lung regeneration with FLASH. Consistent with this hypothesis, the beneficial effect of FLASH was lost in Terc-/- mice harboring critically short telomeres and lack of telomerase activity. The results suggest that, compared with conventional radiotherapy, FLASH minimizes DNA damage in normal cells, spares lung progenitor cells from excessive damage, and reduces the risk of replicative senescence.

Current research analysis and prospects on sensitization effect of artesunate on anti-cancer radiotherapy and chemotherapy

The wide application of artemisinins in the treatment of multiple cancers reflects the advantages of traditional Chinese medicine used in this field. The existing basic and clinical studies have revealed that artesunate can effectively suppress the malignant progression of breast cancer,colon cancer,leukemia,melanoma,ovarian cancer,prostate cancer,kidney cancer and various tumors in central nervous system. The pharmacological mechanisms of artesunate against cancers are reflected in many aspects,such as inhibiting tumor cell proliferation,invasion and metastasis,inducing tumor cell apoptosis and autophagy,regulating cell signal transduction and inhibiting tumor angiogenesis. Meanwhile,growing experimental evidences have indicated that artesunate has been used for the sensitization of radiotherapy with X-ray,β-ray,γ-ray and~(60)Co γ-ray,as well as chemotherapy with cisplatin,carboplatin and doxorubicin.This review collected basic and clinical studies on the sensitization effect of artesunate on anti-cancer radiotherapy and chemotherapy published on PubMed and CNKI during April 2000 and February 2019,and summarized the clinical positioning and application of artesunate,with the aim to provide a more comprehensive explanation on the sensitization effect of artesunate on anti-cancer radiotherapy and chemotherapy,and offer the inspiration and ideas for the development of radiotherapy and chemotherapy sensitizers,as well as cancer resistance reversal agents.

5-Iodo-4-thio-2'-Deoxyuridine as a Sensitizer of X-ray Induced Cancer Cell Killing.

Nucleosides, especially pyrimidines modified in the C5-position, can act as radiosensitizers via a mechanism that involves their enzymatic triphosphorylation, incorporation into DNA, and a subsequent dissociative electron attachment (DEA) process. In this paper, we report 5-iodo-4-thio-2′-deoxyuridine (ISdU) as a compound that can effectively lead to ionizing radiation (IR)-induced cellular death, which is proven by a clonogenic assay. The test revealed that the survival of cells, pre-treated with 10 or 100 µM solution of ISdU and exposed to 0.5 Gy of IR, was reduced from 78.4% (for non-treated culture) to 67.7% and to 59.8%, respectively. For a somewhat higher dose of 1 Gy, the surviving fraction was reduced from 68.2% to 54.9% and to 40.8% for incubation with 10 or 100 µM ISdU, respectively. The cytometric analysis of histone H2A.X phosphorylation showed that the radiosensitizing effect of ISdU was associated, at least in part, with the formation of double-strand breaks. Moreover, the cytotoxic test against the MCF-7 breast cancer cell line and human dermal fibroblasts (HDFa line) confirmed low cytotoxic activity of ISdU. Based on the results of steady state radiolysis of ISdU with a dose of 140 Gy and quantum chemical calculations explaining the origin of the MS detected radioproducts, the molecular mechanism of sensitization by ISdU was proposed. In conclusion, we found ISdU to be a potential radiosensitizer that could improve anticancer radiotherapy.

Abstract OT2-07-04: A phase 1b study of poziotinib in combination with T-DM1 in women with advanced or metastatic HER2-positive breast cancer

Abstract Background:Poziotinib represents a new class of irreversible quinazoline inhibitors of ErbB receptor tyrosine kinases that inhibit the proliferation of tumor cells in culture and in vivo by inhibiting HER-1 (EGFR), HER-2, HER-4. ErbB signaling plays important roles in the progression of HER2+ breast cancer. Poziotinib has promising clinical activity in breast cancer, and other solid tumors including lung, gastric, and colorectal cancers. Study SPI-POZ-101, is being conducted to evaluate the safety and efficacy of the combination of daily poziotinib and T-DM1, HER2 antibody-drug-conjugate every three weeks in patients with HER2+ advanced or metastatic breast cancer. Trial Objectives and Design: The primary objectives of the study are to determine the maximum tolerated dose (MTD) or maximum administered dose (MAD) of daily poziotinib plus T-DM1 (every 3 weeks) in women with advanced or metastatic HER2 positive breast cancer; and to evaluate the Objective Response Rate (ORR) in these patients. The secondary objectives include disease control rate (DCR), progression-free-survival (PFS), safety and pharmacokinetics at the MTD/MAD dose level of poziotinib plus T-DM1. In Part 1, the dose of poziotinib plus standard dose of T-DM1 (3.6 mg/kg IV) on Day 1 of each cycle will be determined using a “3+3” design with up to 3 escalating dose levels, 8, 10 and 12 mg with no DLT or to de-escalate to 6 mg with DLT observed in Cycle 1. Patients in current dose cohort, if not discontinued, will continue treatment until discontinuation of therapy. In Part 2 of the study, approximately 10 patients will be treated at the MTD/MAD to confirm dose for safety of the combination and to evaluate preliminary efficacy. Eligibility Criteria: The study will enroll female patients between 18 and 90 years with confirmed HER2 overexpression or gene-amplified tumor via immunohistochemistry [IHC] with IHC 3+ or IHC 2+ with confirmatory fluorescence in situ hybridization [FISH]+ or [ISH]+ and must have had at least 2 lines of anti-HER2 directed therapies either in the metastatic or early-stage disease setting. Patients must have adequate hematologic, hepatic, cardiac and renal functions and have at least one measurable lesion per RECIST 1.1 criteria. Exclusion criteria includes unstable CNS metastases or seizure disorder; anticancer chemotherapy, TKIs, biologics, immunotherapy, radiotherapy, or investigational treatment within 15 days; ≥ Grade 2 adverse events; known hypersensitivity to receptor tyrosine kinase inhibitors or any of the components of poziotinib tablets or T-DM1 IV solution. Statistical Methods: Part 1 of the study will enroll 3 to 6 patients at each dose using 3+3 design. Part 2 will enroll 10 patients at the MTD/MAD. The efficacy analysis will be conducted using the Evaluable Population based on RECIST 1.1. The Clopper-Pearson 95% confidence interval will be estimated using exact method based on binomial distribution. Target Accrual:Part 1: 6-18 patients Part 2: 10 patients ClinicalTrials.gov Identifier: NCT03429101 Contact Information: Spectrum Pharmaceuticals. SPI-POZ-101@sppirx.com Poziotinib is currently under clinical investigation and has not been approved for use in breast cancer. Citation Format: Bhat G, Potter D, Bharadwaj J, Khan N, Shabazz L, Tache J, Yang Z. A phase 1b study of poziotinib in combination with T-DM1 in women with advanced or metastatic HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr OT2-07-04.

Approach to cardio-oncologic patients with special focus on patients with cardiac implantable electronic devices planned for radiotherapy: results of the European Heart Rhythm Association survey.

The aim of this European Heart Rhythm Association (EHRA) survey was to evaluate clinical practice regarding cardio-oncologic patients, with special focus on patients with cardiac implantable electronic devices (CIEDs) planned for anticancer radiotherapy (RT), among members of the EHRA electrophysiology research network. Of the 36 responding centres, 89% managed patients who were diagnosed or treated oncologically, and this diagnosis affected 1-5% of cardiovascular patients in majority of centres (57%). The main side effects of anticancer therapy in patients treated by cardiologists were thromboembolic complications and left ventricular dysfunction (both reported as 'frequent' by 43% of the centres). The main agents associated with complications were anthracyclines, RT, and monoclonal antibodies. Echocardiography was the most common method of screening for cardiovascular complications (93%), and 10% of the centres did not routinely screen for treatment-induced cardiotoxicity. Opinions on the safe radiation dose, methods of device shielding, and risk calculation prior to RT in CIED patients differed among centres. Precaution measures in high-risk CIED patients were very heterogeneous among centres. Our survey has shown that the awareness of cardiac consequences of anticancer therapy is high, despite relatively low proportion of patients treated oncologically among all cardiovascular patients. There is a consensus of which screening methods should be used for cardiotoxicity of anticancer treatment, but the apprehension of screening necessity is low. Methods of risk assessment and safety measures in CIED patients undergoing RT are very heterogeneous among the European centres, underscoring the need for standardization of the approach to cardio-oncologic patients.

Establishment of a mouse model of 70% lethal dose by total-body irradiation.

Whereas increasing concerns about radiation exposure to nuclear disasters or side effects of anticancer radiotherapy, relatively little research for radiation damages or remedy has been done. The purpose of this study was to establish level of LD70/30 (a lethal dose for 70% of mice within 30 days) by total-body γ irradiation (TBI) in a mouse model. For this purpose, at first, 8-week-old male ICR and C57BL/6N mice from A and B companies were received high dose (10, 11, 12 Gy) TBI. After irradiation, the body weight and survival rate were monitored for 30 days consecutively. In next experiment, 5-week-old male ICR and C57BL/6N mice from B company were received same dose irradiation. Results showed that survival rate and body weight change rate in inbred C57BL/6N mice were similar between A and B company. In ICR mice, however, survival rate and body weight change rate were completely different among the companies. Significant difference of survival rate both ICR and C57BL6N mice was not observed in between 5-week-old and 8-week-old groups receiving 10 or 12 Gy TBI. Our results indicate that the strain and age of mice, and even purchasing company (especially outbred), should be matched over experimental groups in TBI experiment. Based on our results, 8-week-old male ICR mice from B company subjected to 12 Gy of TBI showed LD70/30 and suitable as a mouse model for further development of new drug using the ideal total-body irradiation model.