Normal Tissue Effects Research Articles

Treatment Planning Study for Microbeam Radiotherapy Using Clinical Patient Data.

Simple SummaryMicrobeam radiotherapy is a novel dose delivery technique in radiation oncology. Preclinical studies have demonstrated preferable dose distributions with reduced damage to normal tissue but similar tumor control compared to conventional radiotherapy. For future clinical applications, realistic treatment plans for patient data are required as well as a method for comparing the spatially fractionated MRT doses with conventional broad beam doses. In this study, we performed MRT treatment planning on real patient data for relevant clinical scenarios. We successfully implemented a sophisticated dose comparison concept based on the equivalent uniform dose. For most scenarios and parameters studied, the clinical dose constraints were met. However, limitations were caused by the lack of treatment plan optimization and dose optimization. Altogether, we demonstrated the feasibility of achieving clinically acceptable MRT dose distributions based on real patient data as a primary major step towards clinical application of MRT.Microbeam radiotherapy (MRT) is a novel, still preclinical dose delivery technique. MRT has shown reduced normal tissue effects at equal tumor control rates compared to conventional radiotherapy. Treatment planning studies are required to permit clinical application. The aim of this study was to establish a dose comparison between MRT and conventional radiotherapy and to identify suitable clinical scenarios for future applications of MRT. We simulated MRT treatment scenarios for clinical patient data using an inhouse developed planning algorithm based on a hybrid Monte Carlo dose calculation and implemented the concept of equivalent uniform dose (EUD) for MRT dose evaluation. The investigated clinical scenarios comprised fractionated radiotherapy of a glioblastoma resection cavity, a lung stereotactic body radiotherapy (SBRT), palliative bone metastasis irradiation, brain metastasis radiosurgery and hypofractionated breast cancer radiotherapy. Clinically acceptable treatment plans were achieved for most analyzed parameters. Lung SBRT seemed the most challenging treatment scenario. Major limitations comprised treatment plan optimization and dose calculation considering the tissue microstructure. This study presents an important step of the development towards clinical MRT. For clinical treatment scenarios using a sophisticated dose comparison concept based on EUD and EQD2, we demonstrated the capability of MRT to achieve clinically acceptable dose distributions.

Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells

Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-β (TGF-β) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells invivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.

In-silico characterization of phytochemicals identified from Vitex negundo (L) extract as potential therapy for Wnt-signaling proteins

BackgroundColorectal cancer is the third most diagnosed disease in the world population and current chemotherapy has been used for targeting the cell proliferation and metastasizing ability of tumor cells. Potent chemotherapeutic drugs for colorectal cancer are capecitabine, fluorouracil, irinotecan, etc. which have toxic effects in normal tissues and adverse effects in multiple organs leading to major obstacles in clinical use. The aim of the study is the use of plant-derived compounds that improve the effectiveness of chemotherapeutics with lower and alleviate toxic side effects and reduce the risk of tumor progression.ResultsThe current study is performed using Vitex negundo leaf which has been demonstrated to have positive effects against colorectal cancer. The use of computational approaches will help improve the identification and screening of lead molecules using AutoDock 4.2 and AutoDock Vina. Using computational approaches will help to improve lead identification and screening. Herein, we have retrieved six phytochemicals from published literature and investigated their inhibitory effect with Wnt-associated signaling proteins. Authentication of phytocompounds and Wnt-associated signaling proteins was done using AutoDock.4.2.ConclusionsThe results are screened based on the number of hydrogen bonds, binding energy, and interacting amino acids. The Isoorientin, luteolin, and Chrysophanol get the highest binding energy with target receptors. The binding energy is calculated with all target receptors from the range of − 6.0 to − 8.9 kcal/mol. The In-silico drug likeliness properties are predicted to be the best interacting compounds based on Lipinski Rule of 5 and ADMET analysis. Hence, we propose that Isoorientin, luteolin, and Chrysophanol are the potential inhibitors of Wnt signaling inhibitors, and preclinical studies are needed to confirm the promising therapeutic ability of colorectal cancer.

Genetski prediktori radijacione toksičnosti kod pacijenata sa karcinomom prostate

Cancer survivors often face adverse effects of treatment, which have a significant impact on morbidity and mortality. Normal-tissue side effects following radiotherapy (RT), as one of therapeutic modalities, are common and may seriously affect quality of life which is especially important in long-term prostate cancer (PC) survivors. Upgrading in our knowledge in radiation biology have led to the better understanding that genetics plays a significant role in determining a patient's predisposition to developing late RT toxicity, leading to the new field of research called "radiogenomics". With the evolution of DNA sequencing technologies and genomic analysis, radiogenomics made an appearance as a state-of-the-art science in the field of personalized medicine with the goal of detection the genetic determinants RT adverse reactions. A single-nucleotide polymorphism (SNPs) - based assay could be used to predict the risk of RT side effects along with clinical features and treatment factors. Several SNPs have been identified that are associated with late radiation-induced morbidity in PC patients. Most importantly, these SNPs make up genes expressed in the tissues that are likely at the root of these symptoms, including the bladder, rectum, and small intestine, which are most exposed in PC RT. Furthermore, genome-wide association studies are likely to lead to an increasing number of genetic polymorphisms that can predict long-term RT complications. Finally, radiogenomics attempts to predict which PC patients will show radiosensitivity, so that radiation oncologists, as well as surgeons, can change treatment accordingly in order to reduce side effects or increase the RT effectiveness.

COMPARISON OF TWO RADIOTHERAPY TECHNIQUES IN TREATMENT OF PATIENTS WITH DIAGNOSED INOPERABLE CERVICAL CANCER

Advanced cervical cancer is treated with radiotherapy, target therapy, chemotherapy or a combination of those. Standardized accepted treatment of inoperable cervical cancer is concurrent chemo-radiotherapy (CCRT) followed by brachytherapy. Radiotherapy techniques used are three-dimensional conformal radiotherapy (3D-CRT) and intensity modulated radiation therapy (IMRT). In this study participated 30 female patients, average age of 52 at the time of irradiation.3D-CRT plans were made, patients were treated on linear accelerator (LINAC) with 3D-CRT. IMRT plans were made additionally. Planning target volume (PTV) dose coverage was 105.36% for 3D-CRT and 105.64% for IMRT. Homogeneity index (HI) was 0.062 for 3D-CRT and 0.048 for IMRT. Conformity index (CI) for 3D-CRT was 1.93 for PTV of 2990.77 ccm. CI for IMRT  was 1.305 for PTV of 2019.83 ccm. Bladder V40 (%) for 3D-CRT averaged 96.61%, while IMRT averaged 73.11%. Rectal V50 (%) for 3D-CRT was 72.55% and for IMRT was 17.80%. Rectal V40 (%) for 3D-CRT and IMRT averaged 92.12% and 73.49% respectively. Quantitative Analysis of normal Tissue Effects in the Clinic (QUANTEC) – V45 for 3D-CRT was 228.80ccm and for IMRT was 104.55ccm. Femoral heads dose for 3D-CRT was 51.50Gy for left and 51.29Gy for right. Absorbed doses for IMRT were 47.28Gy for left and 47.32Gy for right femoral head, respectively. 13 patients had grade 1 cystitis and urethritis, 2 with grade 2. 7 patients developed grade 1 diarrhea, 1 with grade 2. It can be concluded that dosimetrically IMRT is superior to 3D-CRT in patients treating cervical cancer. Keywords: cervical cancer, 3D-CRT, IMRT.  

Total Body Irradiation in Haematopoietic Stem Cell Transplantation for Paediatric Acute Lymphoblastic Leukaemia: Review of the Literature and Future Directions.

Total body irradiation (TBI) has been a pivotal component of the conditioning regimen for allogeneic myeloablative haematopoietic stem cell transplantation (HSCT) in very-high-risk acute lymphoblastic leukaemia (ALL) for decades, especially in children and young adults. The myeloablative conditioning regimen has two aims: (1) to eradicate leukaemic cells, and (2) to prevent rejection of the graft through suppression of the recipient's immune system. Radiotherapy has the advantage of achieving an adequate dose effect in sanctuary sites and in areas with poor blood supply. However, radiotherapy is subject to radiobiological trade-offs between ALL cell destruction, immune and haematopoietic stem cell survival, and various adverse effects in normal tissue. To diminish toxicity, a shift from single-fraction to fractionated TBI has taken place. However, HSCT and TBI are still associated with multiple late sequelae, leaving room for improvement. This review discusses the past developments of TBI and considerations for dose, fractionation and dose-rate, as well as issues regarding TBI setup performance, limitations and possibilities for improvement. TBI is typically delivered using conventional irradiation techniques and centres have locally developed heterogeneous treatment methods and ways to achieve reduced doses in several organs. There are, however, limitations in options to shield organs at risk without compromising the anti-leukaemic and immunosuppressive effects of conventional TBI. Technological improvements in radiotherapy planning and delivery with highly conformal TBI or total marrow irradiation (TMI), and total marrow and lymphoid irradiation (TMLI) have opened the way to investigate the potential reduction of radiotherapy-related toxicities without jeopardising efficacy. The demonstration of the superiority of TBI compared with chemotherapy-only conditioning regimens for event-free and overall survival in the randomised For Omitting Radiation Under Majority age (FORUM) trial in children with high-risk ALL makes exploration of the optimal use of TBI delivery mandatory. Standardisation and comprehensive reporting of conventional TBI techniques as well as cooperation between radiotherapy centres may help to increase the ratio between treatment outcomes and toxicity, and future studies must determine potential added benefit of innovative conformal techniques to ultimately improve quality of life for paediatric ALL patients receiving TBI-conditioned HSCT.

Apigenin Enhanced Radiation-Induced Apoptosis/Necrosis by Sensitization of LNCaP Prostate Cancer Cells to 6 MV Photon Beams.

Objective Whereas prostate cancer (PrCa) may be unresponsive or moderately responsive to radiation therapy (RT)- most common modality for treatment of PrCa- patients must receive a high dose of RT In order to achieve appropriate tumour control. However, this increase in radiation dose may lead to severe adverse effects in normal tissues. Sensitization of PrCa to radiation provides an alternate approach to improve the therapeutic efficacy of RT. This study aims to assess the radiosensitisation effect of apigenin (Api) on a prostate cancer cell line (LNCaP). Materials and Methods In this experimental study, LNCaP cells were treated with 0-80 µM Api to investigate its effect on LNCaP cell viability and determine its half-maximal inhibitory concentration (IC50). Next, the cells were divided into four groups: i. Control, ii. Cells treated with the IC50 concentration of Api, iii. Cells treated with 2 Gy ionizing radiation (IR), and cells co-treated with Api and IR. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, real-time polymerase chain reaction (PCR), and an Annexin V-FITC/PI assay were performed to assess cell survival, Bax and Bcl-2 expressions, and presence of apoptosis and necrosis. Results Api inhibited cell survival in a dose-dependent, but not time-dependent manner. Cells treated with Api had increased amounts of early apoptosis, late apoptosis, and secondary necrosis compared to the control group. This group also had decreased Bcl-2 gene expression and up-regulated Bax gene expression. Co-treatment with Api and IR significantly inhibited cell survival, and increased early apoptosis, late apoptosis and secondary necrosis compared to the other groups. There was a significant decrease in Bcl-2 gene expression along with up-regulation of Bax gene expression, and Bax/Bcl-2 ratio changes that favoured apoptosis. ConclusionApi inhibited PrCa cell survival and induced apoptosis as a single agent. In addition, Api significantly sensitized the LNCaP cells to IR and enhanced radiation-induced apoptosis.

Effect of Lactobacillus species on apoptosis-related genes BCL2, BAX, and caspase 3 in the testes of gamma-irradiated rats.

Ionizing radiation has various applications, including uses in medicine, industry, agriculture, and research. However, ionizing radiation is accompanied by side effects in normal radiosensitive tissues. Probiotics as natural radioprotective agents can protect normal tissues from ionizing radiation. In this regard, this study aimed to investigate the effect of Lactobacillus species on apoptosis-related genes BCL2, BAX, and caspase 3 (CASP3) in the testes of gamma-irradiated rats. A total of 30 male Wistar rats were involved in this study. The animals received the whole- body radiation with the dose rate of 2 Gy gamma-ray and were orally gavaged with 0.2 mL of 1×1010 Lactobacillus species in phosphate-buffered saline (PBS) for 4 weeks. Then, the relative gene expression levels of BCL2, BAX, and CASP3 in the testis were assessed by using the quantitative real-time polymerase chain reaction (qRT-PCR). Compared with the control group, radiation significantly downregulated the BCL2 and upregulated the BAX and CASP3 genes (p<0.0001). However, Lactobacillus species significantly reversed these effects. All in all, according to our results, employing Lactobacilli probiotics as a natural radioprotector may protect radiosensitive tissue from damage.

DEXTRAN-CHITOSAN-nTIO2 TAILORED HYDROGELS (DEXCH-nTIO2-HGS) AS VERSATILE TOOL IN EXPLORING THE POTENTIAL OF KAEMPFEROL FOR EFFECTIVE DIABETIC WOUND HEALING

Grafts made from synthetic polymers perform poorly in wound healing applications. In these applications, dextranchitosan based materials can be produced and fabricated to present a novel scaffold for wound healing engineering. The aim of this study was to evaluate in-vitro the mechanical properties of a novel dextran-chitosan based hydrogel formulation to examine its potential for this scaffold. Kaempferol (KMF) (obtained from leaves of Ipomea carnea Jacq) loaded hydrogel (HGs) was prepared using dextran-chitosan (Dex-CH) and PEG as a cross linking agent with nano titanium dioxide (nTiO2). Subsequently Dex and CH solution were blended together to form a homogeneous DexCH binary blend mixture with the PEG as crosslinker and characterized for various paramters like AFM (Atomic Force Microscopy), mechanical (tensile) strength of hydrogel, swelling property, entrapment efficiency and drug release. The role of hydrogel was assessed by wound healing activity tested beside wound contraction, collagen content, dried granuloma weights and antioxidant property. Percent entrapment efficiency of optimized hydrogel found to be 89.36 ± 1.19%. KMF loaded DexCH- nTiO2-HGs were able to release 95.36%, KMF in 24 hrs. The level of superoxide dismutase (SOD) and catalase were found increased significantly in granuloma tissue of KMF treated group. The significant wound healing effect in normal wound tissues as well as diabetic with higher antioxidant activity founded in KMF-DexCH-nTiO2-HGs. Prepared hydrogel formulations (KMF loaded DexCH- nTiO2-HGs) were proved to be highly suitable on grounds of moist nature, biocompatibility, biodegradability and antioxidant effectiveness.

Apoptosis and DNA Repair in Irradiated Cerebral Organoids

In the treatment of CNS neoplasms, radiation therapy to high biologically effective doses is performed in both fractionated and single fraction schemes. Inevitably, normal CNS tissues are irradiated, leading to both acute and late toxicities, and demanding greater insight into normal tissue effects and development of innovative strategies for radioprotection and mitigation. For this purpose, the cerebral organoid, which recapitulates many cell types and complex architectures of the human brain, is proposed as a model system. The objective of our study was to characterize the response of cerebral organoids to high single fraction doses of photon irradiation in terms of apoptosis, DNA damage, and activation of DNA repair.Cerebral organoids were prepared from human embryonic stem cells as previously described. CNS tissue differentiation was verified by histopathology. Irradiation of organoids was accomplished using a 160 kV x-ray irradiator. Apoptosis was characterized by immunofluorescence of cleaved caspase 3 and TUNEL assay. DNA damage and repair was determined by immunofluorescence of γH2Ax foci and 53BP1.While cerebral organoids demonstrated no gross morphologic changes to high single dose radiation up to 40 Gy even when incubated for several months following treatment, individual apoptotic cells were readily apparent at 72 hours after 20 Gy. High levels of γH2Ax foci and 53BP1 were observed within hours. While characterization of the kinetics of DNA repair showed significant resolution of DNA damage foci by 24 hours, many foci persisted at 72 hours alongside activation of apoptotic pathways. Choroid plexus tissue was highly resistant to radiation-induced apoptosis.Cerebral organoids provide a viable experimental platform to study effects of radiation in normal CNS tissues, and may potentially aid in the development of neuroprotective strategies.

Breast Hypoplasia and Decreased Lactation From Radiation Therapy in Survivors of Pediatric Malignancy: A PENTEC Comprehensive Review

Breast hypoplasia and impaired lactation are poorly studied sequelae of chest radiation therapy (RT) in children. The Pediatric Normal Tissue Effects in the Clinic female breast task force aimed to quantitate the radiation dose-volume effects on these endpoints. A literature search was conducted of peer-reviewed manuscripts evaluating breast hypoplasia and lactation after chest RT in children, yielding 789 abstracts. Only 2 studies on children irradiated at <4 years of age for angioma of the breast provided dosimetric data correlated with breast hypoplasia. For patients who received brachytherapy, the dose was converted to external beam RT in equivalent 2 Gy fractions (DEBRT), although the limitations of this type of mathematical conversion need to be recognized. We calculated relative risks (RR) and 95% confidence intervals (95% CIs) based on these data. Only 1 study was relevant to the lactation endpoint, in which patients were given RT for Hodgkin lymphoma at age 14 to 40 years. The 3 studies involved 206 patients in total. In patients <4 years old at the time of RT, the prevalence of patient-perceived breast hypoplasia was 38% (RR 2.5; 95% CI, 1.3-4.6) after DEBRT of <0.34 Gy, 61% (RR 4.0; 95% CI, 2.1-7.4) after DEBRT 0.34-0.97 Gy, and 97% (RR 6.3; 95% CI, 3.6-10.8) after DEBRT ≥0.97 Gy to the breast anlage. A simple linear regression model (r = 0.72; P < .001) showed that the treated breast was smaller than the untreated breast by 13% at DEBRT = 0.5 Gy, 20% at DEBRT = 1 Gy, 32% at DEBRT = 2 Gy, 51% at DEBRT = 4 Gy, 66% at DEBRT = 6 Gy, 79% at DEBRT = 8 Gy, and 90% at DEBRT = 10 Gy. The risk of unsuccessful breastfeeding was 39% after a median mediastinal dose of 41 Gy, compared with 21% in a sibling control group (P = .04). RT dose of ≥42 Gy was not associated with less breastfeeding success compared with <42 Gy, and data on lower doses were unavailable. Based on extremely limited data, young adults exposed to thoracic RT as children seem to be at significant risk of breast hypoplasia and impaired lactation. Doses as low as 0.3 Gy to immature breasts can cause breast hypoplasia. Additional studies are needed to quantify dose and technique effects with modern RT indications. Prospective collection of clinical outcomes and dosimetric factors would enhance our understanding of RT-induced breast hypoplasia and impaired lactation.

Vascular damage mechanism and parameter optimization under alexandrite laser irradiation: a theoretical study.

The 755-nm Alexandrite Laser has a good clinical effect in treating resistant port wine stain, without causing thermal damage of normal tissue and side effects such as purpura. However, little is known about the mechanism of vascular damage induced by 755-nm laser irradiation, which restricts the optimization of laser parameters. In this work, the thermal damage model and the pressure damage model were used to study the damage mechanism of 755-nm laser irradiation on vessels, and the incident energy density and pulse width required for vascular damage were determined according to the damage mode. Under the irradiation of 755-nm laser, the vascular injury pattern was the co-occurrence of vessel rupture and vessel constriction, and the energy density required for the treatment of vessels with a diameter of 200μm to reach the damage threshold was the lowest.

Renal Clearable Ultrasmall Single-Crystal Fe Nanoparticles for Highly Selective and Effective Ferroptosis Therapy and Immunotherapy.

Iron-based nanoparticles have attracted much attention because of their ability to induce ferroptosis via a catalyzing Fenton reaction and to further potentiate immunotherapy. However, current iron-based nanoparticles need to be used in cooperation with other treatments or be applied in a high dose for effective therapy because of their low reactive oxygen species production efficacy. Here, we synthesized ultrasmall single-crystal Fe nanoparticles (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of an Fe3O4 shell and the exposure of the Fe(0) core. The bcc-USINPs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. Intravenous injection of iRGD-bcc-USINPs at three doses of 1 mg/kg could effectively suppress the tumor growth, promote the maturation of dendritic cells, and trigger the adaptive T cell response. Combined with programmed death-ligand 1 (PD-L1) immune checkpoint blockade immunotherapy, the iRGD-bcc-USINP-mediated ferroptosis therapy greatly potentiated the immune response and developed strong immune memory. In addition, these USINPs were quickly renal excreted with no side effects in normal tissues. These iRGD-bcc-USINPs provide a simple, safe, effective, and selectively tumor-responsive Fe(0) delivery system for ferroptosis-based immunotherapy.

The Critical Role of Tetrahydrobiopterin (BH4) Metabolism in Modulating Radiosensitivity: BH4/NOS Axis as an Angel or a Devil.

Ionizing radiation and radioactive materials have been widely used in industry, medicine, science and military. The efficacy of radiotherapy and adverse effects of normal tissues are closed related to cellular radiosensitivity. Molecular mechanisms underlying radiosensitivity are of significance to tumor cell radiosensitization as well as normal tissue radioprotection. 5,6,7,8-Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide synthases (NOS) and aromatic amino acid hydroxylases, and its biosynthesis involves de novo biosynthesis and a pterin salvage pathway. In this review we overview the role of BH4 metabolism in modulating radiosensitivity. BH4 homeostasis determines the role of NOS, affecting the production of nitric oxide (NO) and oxygen free radicals. Under conditions of oxidative stress, such as UV-radiation and ionizing radiation, BH4 availability is diminished due to its oxidation, which subsequently leads to NOS uncoupling and generation of highly oxidative free radicals. On the other hand, BH4/NOS axis facilitates vascular normalization, a process by which antiangiogenic therapy corrects structural and functional flaws of tumor blood vessels, which enhances radiotherapy efficacy. Therefore, BH4/NOS axis may serve as an angel or a devil in regulating cellular radiosensitivity. Finally, we will address future perspectives, not only from the standpoint of perceived advances in treatment, but also from the potential mechanisms. These advances have demonstrated that it is possible to modulate cellular radiosensitivity through BH4 metabolism.

Pulmonary dose tolerance in hemithorax radiotherapy for Ewing sarcoma of the chest wall: Are we overestimating the risk of radiation pneumonitis?

Children with chest wall Ewing sarcoma with malignant pulmonary effusion or pleural stranding require hemithorax radiation, often with plans that exceed lung constraints. We investigated disease control and pneumonitis in children requiring hemithorax radiation. Eleven children (median age 13years) received hemithorax radiotherapy. Symptomatic radiation pneumonitis was considered National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 1+ with respiratory symptoms. Mean lung dose (MLD), volume of lung exposed to a dose ≥5Gy (V5), ≥20Gy (V20), and ≥35Gy (V35) were recorded. Adult and pediatric lung constraints were obtained from Quantitative Analysis of Normal Tissue Effects in the Clinic (QUANTEC) guidelines and Children's Oncology Group (COG) protocols, respectively. Median hemithorax dose was 15Gy (1.5Gy/fraction). Median total dose was 51Gy (1.8Gy/fraction). Most plans delivered both protons and photons. The ipsilateral MLD, V5, and V20 were 27.2Gy, 100%, and 48.3%; the bilateral MLD, V20, and V35 were 14.1Gy, 22.8%, and 14.3%, respectively. One hundred percent, 36%, and 91% of treatments exceeded recommended adult ipsilateral lung constraints of V5 <65%, V20 <52%, and MLD of 22Gy; 64%, 45%, and 82% exceeded COG bilateral lung constraints of V20 <20%, MLD <15Gy, and MLD <12Gy, respectively; 82% of treatments exceeded the COG ipsilateral lung constraint of V20 <30%. At a median 36months (range 12-129), the symptomatic radiation pneumonitis incidence was 0%. Two patients progressed with nonpulmonary metastatic disease and died at a median 12months following radiotherapy. Existing guidelines may overestimate pneumonitis risk, even among young children receiving multiagent chemotherapy. For children with chest wall Ewing sarcoma and other thoracic malignancies, more data are needed to refine pediatric dose-effect models for pulmonary toxicity.

Neuropathological Effects of Chemotherapeutic Drugs.

Novel treatments, screening, and detection methods have prolonged the lives of numerous cancer patients worldwide. Unfortunately, existing and many promising new chemotherapeutics can cause deleterious, off-target side effects in normal tissue and organ systems. The central and peripheral nervous systems are widely recognized as frequent off-target effectors of anticancer drugs which can produce persistent neurological and neuropsychiatric symptoms collectively termed "chemobrain". Following chemotherapy, patients report several forms of cognitive impairment occurring acutely and sometimes persisting years after treatment. There are no effective treatments for cognitive decline induced by chemotherapeutics, and the underlying molecular mechanisms are poorly characterized and understood. In this study, we find that chronic treatment with two common chemotherapeutic agents, cisplatin and gemcitabine, impairs brain region-specific metabolism, hippocampus-dependent memory formation, and stress response behavior. This corresponds to reduced hippocampal synaptic excitability, altered neuronal signal transduction, and neuroinflammation. These findings underline that a better understanding of the basic pathological consequences of chemotherapy-induced cognitive impairment is the first step toward improving cancer treatment survivorship.

Oncolytic Adenovirus H101 Synergizes with Radiation in Cervical Cancer Cells.

A major challenge in cervical cancer radiotherapy is tailoring the radiation doses efficiently to eliminate malignant cells and reduce the side effects in normal tissues. Oncolytic adenovirus drug H101 was recently tested and approved as a topical adjuvant treatment for several malignancies. This study aimed to evaluate the potential neoadjuvant radiotherapy benefits of H101 by testing the inhibitory function of H101 in combination with radiation in different cervical cancer cells. Human cervical cancer cell lines C33a, SiHa, CaSki, and HeLa were treated with varying concentrations of H101 alone or in combination with radiation (2 Gy or 4 Gy). Cell viability and apoptosis were measured at the indicated time intervals. HPV16 E6 and cellular p53 mRNA expression alteration was measured by qRT-PCR. In situ RNA scope was used to determine HPV E6 status. P53 protein alterations were detected by Western blot. Cell viability and apoptosis assays revealed that the combination of a high dose of H101 (MOI=1000, 10000) with radiation yielded a synergistic anticancer effect in all tested cervical cancer cell lines (P<0.05), with the greatest effect achieved in HPV-negative C33a cells (P<0.05). Low-HPV16-viral-load SiHa cells were more sensitive to the combination therapy than high-HPV16- viral-load CaSki cells (P<0.05). The combined treatment reduced HPV16 E6 expression and increased cellular P53 levels compared to those observed with radiation alone in SiHa and CaSki cells (P<0.05). Oncolytic adenovirus H101 effectively enhances the antitumor efficacy of radiation in cervical cancer cells and may serve as a novel combination therapy for cervical cancer.

SP-0238 Normal tissue effects of radiation combined with vascular targeting agents

SP-0238 Normal tissue effects of radiation combined with vascular targeting agents

The Multifaceted Role of Flavonoids in Cancer Therapy: Leveraging Autophagy with a Double-Edged Sword.

Flavonoids are considered as pleiotropic, safe, and readily obtainable molecules. A large number of recent studies have proposed that flavonoids have potential in the treatment of tumors by the modulation of autophagy. In many cases, flavonoids suppress cancer by stimulating excessive autophagy or impairing autophagy flux especially in apoptosis-resistant cancer cells. However, the anti-cancer activity of flavonoids may be attenuated due to the simultaneous induction of protective autophagy. Notably, flavonoids-triggered protective autophagy is becoming a trend for preventing cancer in the clinical setting or for protecting patients from conventional therapeutic side effects in normal tissues. In this review, focusing on the underlying autophagic mechanisms of flavonoids, we hope to provide a new perspective for clinical application of flavonoids in cancer therapy. In addition, we highlight new research ideas for the development of new dosage forms of flavonoids to improve their various pharmacological effects, establishing flavonoids as ideal candidates for cancer prevention and therapy in the clinic.

Salivary and Dental Complications in Childhood Cancer Survivors Treated With Radiation Therapy to the Head and Neck: A PENTEC Comprehensive Review

Radiation therapy (RT) to the head and neck (H&N) region is critical in the management of various pediatric malignancies; however, it may result in late toxicity. This comprehensive review from the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative focused on salivary dysfunction and dental abnormalities in survivors who received RT to the H&N region as children. This systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. Of the 2,164 articles identified through a literature search, 40 were included in a qualitative synthesis and 3 were included in a quantitative synthesis. The dose-toxicity data regarding salivary function demonstrate that a mean parotid dose of 35 to 40 Gy is associated with a risk of acute and chronic grade ≥2 xerostomia of approximately 32% and 13% to 32%, respectively, in patients treated with chemo-radiation therapy. This risk increases with parotid dose; however, rates of xerostomia after lower dose exposure have not been reported. Dental developmental abnormalities are common after RT to the oral cavity. Risk factors include higher radiation dose to the developing teeth and younger age at RT. This PENTEC task force considers adoption of salivary gland dose constraints from the adult experience to be a reasonable strategy until more data specific to children become available; thus, we recommend limiting the parotid mean dose to ≤26 Gy. The minimum toxic dose for dental developmental abnormalities is unknown, suggesting that the dose to the teeth should be kept as low as possible particularly in younger patients, with special effort to keep doses <20 Gy in patients <4 years old.