Late Radiation Side Effects Research Articles

Radiation Therapy for Stage IIA/B Seminoma: Modeling Secondary Cancer Risk for Protons and VMAT versus 3D Photons.

Radiation therapy (RT) is an effective treatment for stage IIA and select stage IIB seminomas. However, given the long life expectancy of seminoma patients, there are concerns about the risk of secondary cancers from RT. This study assessed differences in secondary cancer risk for stage II seminoma patients following proton pencil-beam scanning (PBS) and photon VMAT, compared to 3D conformal photon RT. Ten seminoma patients, five with a IIA staging who received 30 GyRBE and five with a IIB staging who received 36 GyRBE, had three RT plans generated. Doses to organs at risk (OAR) were evaluated, and secondary cancer risks were calculated as the Excess Absolute Risk (EAR) and Lifetime Attributable Risk (LAR). PBS reduced the mean OAR dose by 60% on average compared to 3D, and reduced the EAR and LAR for all OAR, with the greatest reductions seen for the bowel, liver, and stomach. VMAT reduced high doses but increased the low-dose bath, leading to an increased EAR and LAR for some OAR. PBS provided superior dosimetric sparing of OAR compared to 3D and VMAT in stage II seminoma cases, with models demonstrating that this may reduce secondary cancer risk. Therefore, proton therapy shows the potential to reduce acute and late side effects of RT for this population.

Immediate and long-term results of radiation therapy in combination with capecitabine and oxaliplatin in the treatment of patients with asquamous cell carcinoma of the anus

Introduction. The current standard of care is concurrent radiation therapy (RT) and chemotherapy with mitomycin or cisplatin in combination with fuoropyrimidine drugs. One possible option for effective chemotherapy regimens with a lower toxicity is the combination of oxaliplatin and capecitabine with RT. The purpose of the study: a retrospective evaluation of the results of combined treatment of 74 patients with squamous cell carcinoma of the anus (SCCA) with the use of oxaliplatin and capecitabine. Material and Methods. The study included 74 patients (men – 12.2 %, women – 87.8 %) with stage I–III SCCA. All patients underwent megavolt photon RT (2×25), a cumulative dose of 50 Gy and a boost of 10 Gy to the anal canal. From days 1 to 14 and from days 22 to 36 of RT, capecitabine was administered orally at a dose of 825 mg/m2 twice a day in combination with intravenous administration of oxaliplatin 50 mg/m2 on days 1, 8, 22, and 29 of RT. If a residual tumor 6 months after completion of chemoradiotherapy was found, patients underwent surgery. Results. All 74 patients underwent RT with a cumulative dose of 60 Gy. Chemotherapy, according to the protocol, was completed in 58 (78.4 %) patients. Grade 3-4 toxicity was noted in 11 (14.9 %) patients. In 64 patients (86.5 %), a complete clinical response was registered. At least one late radiation side effects according to the RTOG (LENT SOMA) scale was noted in 48 (98.0 %) patients, including grade 3-4 complications in 12 (24.5 %) patients. With a median follow-up of 40 months (3-82) cumulative three-year local recurrence rate, overall and relapse-free survival were 15.3 ± 4.5 %, 73.7 ± 5.7 % and 53.5 ± 6.4 %, respectively. Conclusion. Combined treatment of SCCA, based on the combination of RT with chemotherapy with oxaliplatin and capecitabine, is feasible and has acceptable acute toxicity. Additional clinical studies are needed using this chemotherapy regimen in combination with modern RT techniques.

Secondary Budd-Chiari syndrome occurred after adjuvant radiotherapy for perihilar cholangiocarcinoma: a case report

BackgroundBudd–Chiari syndrome (BCS) is a rare vascular disorder of the liver, and acute and secondary BCS is even rarer.Case presentationA 62-year-old man with perihilar cholangiocarcinoma of Bismuth type IIIa underwent right hemi-hepatectomy with caudate lobectomy and pancreatoduodenectomy. Adjuvant chemoradiotherapy was performed due to a positive hepatic ductal margin. Subsequently, the disease passed without recurrence. The patient visited for acute onset abdominal pain at the 32nd postoperative month. Multidetector-row computed tomography (MDCT) showed stenosis of the left hepatic vein (LHV) root, which was the irradiated field, and thrombotic occlusion of the LHV. The patient was diagnosed with acute BCS caused by adjuvant radiotherapy. Although anticoagulation therapy was performed, the patient complained of sudden upper abdominal pain again. MDCT showed an enlarged LHV thrombus and hepatomegaly. The patient was diagnosed with exacerbated acute BCS, and stenting for the stenotic LHV root was performed with a bare stent. Although stenting for the LHV root was very effective, restenosis occurred twice due to thrombus in the existing stent, so re-stenting was performed twice. The subsequent clinical course was acceptable without recurrence or restenosis of the LHV root as of 6 months after the last stenting using a stent graft.ConclusionAlthough no case of BCS caused by radiotherapy has yet been reported, the present case showed that late side effect of radiotherapy can cause hepatic vein stenosis and secondary BCS.

Исследование возможных радиопротекторных свойств деанола ацеглумата при действии ионизирующего излучения на клетки человека

One of the effective methods to mitigate late side effects of radiotherapy is to use radioprotectors that reduce harmful effects of ionizing radiation on living cells. Nowadays there are no ideal and multifunctional radioprotectors. In this connection, the research priority is the search for new radioprotectors able to protect healthy cells from side effects of radiation therapy. A promising compound that can be used as a radioprotector is deanol aceglumate. Deanol aceglumate is known as a low-toxic nootropic drug. In addition, there is evidence of its hepatoprotective and antioxidant activity. The aim of the study is to investigate the potential properties of deanol aceglumate to protect human fibroblasts (hTERT) from gamma-radiation and C-12 ions and to select the optimal time of cell incubation with deanol aceglumate prior to irradiation. The effect of radiation was evaluated by the criteria of the time of cells doubling and cells clonogenic activity. It is shown that deanol aceglumate at a concentration of 1000 mcM has a radioprotective effect on human fibroblasts exposed to gamma radiation. The optimal time of the cells incubation prior to irradiation is 24 hours in order to achieve the highest radioprotective effect. Deanol aceglumate at a concentration of 1000 mcM does not protect normal cells when exposed to C-12 ions beyond Bragg Peak. It has been found that deanol aceglumate radioprotective properties depend significantly on the quality of ionizing radiation. The use of deanol aceglumate can be a promising way to reduce the ionizing radiation-induced diverse effect on normal human cells during radiation therapy of cancer patients.

P096: Polymorphisms in SETD7 may predispose the risk of developing late cardiac side effects after radiotherapy including the mediastinum in Hodgkin’ s lymphoma.

Background: In Hodgkin’s lymphoma (HL) radiation therapy including the mediastinum is known to cause long time cardiac side effects. Method: A cohort of 183 previous HL patients who received radiotherapy involving the mediastinum during the period of 1965–1995 were dichotomized into patients with or without known cardiac complications. This was done after a separate study visit performed with a range of 13–43 years from diagnosis (median 23 years). A complication was defined as having a medical record of any of the following clinical conditions: angina, myocardial infarction, congestive heart failure or valvular disease. DNA was extracted from whole blood and analyzed using Infinum OncoArray-500K. We analyzed a set of 4341 single nucleotide polymorphisms (SNPs) representing 167 genes previously associated with late side effects of radiotherapy or associated with the normal myocyte function, ischemic heart disease, primary restrictive cardiomyopathy or valvular disease. The association between cardiac status and alterations in SNPs was examined. Forty-six of the patients had also received doxorubicin, an anthracycline associated with late cardiotoxic side effects. Results: A SNP of SETD7 (intron), rs2725790, significantly differed between the two groups (allelic test, p = 9.2E-6, maxT permutation test p=0.024, logistic regression p=0.00013). To take prior anthracycline therapy into account, logistic regression was performed adjusting for anthracycline therapy (logistic regression p=0.00020). Conclusion: This study indicates that constitutional differences in SETD7, a gene associated with epigenetic regulation of cardiomyogenesis and response to cardiac hypoxia may be involved in the risk of developing late cardiac side effect after radiation therapy of the mediastinum in the treatment of HL.

Dosimetric comparison between intensity modulated radiotherapy and three-dimensional conformal radiotherapy in adjuvant setting after radical cystectomy in high-risk urothelial bladder cancer

Objective: To compare the 4-field 3D conformal radiotherapy technique (3DCRT) to the intensity-modulated radiotherapy (IMRT) 9-field technique for adjuvant radiotherapy post radical cystectomy in high-risk urothelial bladder cancer cases. Patients and Methods: A dosimetric analysis of 11 urothelial bladder cancer patients who underwent radical cystectomy was performed. These patients were presented to the radiotherapy department, National Cancer Institute, Cairo, between 2018 and 2020 with adjuvant radiotherapy using the IMRT technique. Two plans were designed for each patient, one using 9-field IMRT and the second using 4-field 3DCRT. The two techniques were compared, including the PTV, bowel bag, rectum, neobladder, and pelvic bone marrow. Results: Comparing different DVHs, the planning target volume (PTV) was adequately covered in both plans, while the 9-field IMRT technique delivered significantly lower doses to OARs (bowel, rectum, and pelvic bone marrow). Conclusion: The IMRT technique incredibly spared the OARs more than that obtained by the 3DCRT technique, while both techniques covered the PTV adequately. The IMRT technique, through sparing OARs, was expected to decrease early and late radiation side effects.

Pencil-beam scanning proton therapy for the treatment of glomus jugulare tumours.

Glomus jugulare tumours (GJT) are benign tumours that arise locally and destructively in the base of the skull and can be successfully treated with radiotherapy. Patients have a long-life expectancy and the late effects of radiotherapy can be serious. Proton radiotherapy reduces doses to critical organs and can reduce late side effects of radiotherapy. The aim of this study was to report feasibility and early clinical results of 12 patients treated using proton therapy. Between December 2013 and June 2019, 12 patients (pts) with GJT (median volume 20.4 cm3 ; range 8.5-41 cm3 ) were treated with intensity modulated proton therapy (IMPT). Median dose was 54 GyE (Gray Equivalents) (50-60 GyE) with daily fractions of 2 GyE. Twelve patients were analysed with a median follow-up time of 42.2 months (11.3-86.7). Feasibility, dosimetric parameters, acute and late toxicity and local effect on tumour were evaluated in this retrospective study. All patients finished treatment without interruption, with excellent dosimetric parameters and mild acute toxicity. Stabilisation of tumour size was detected on MRI in all patients. No changes in symptoms were observed in comparison with pre-treatment conditions. No late effects of radiotherapy were observed. Pencil-beam scanning proton radiotherapy is highly feasible in the treatment of large GJT with mild acute toxicity and promising short-term results. Longer follow-up and larger patient cohorts are required to further identify the role of pencil-beam scanning (PBS) for this indication.

MicroRNAs in Prostate Cancer Following Radiotherapy: Towards Predicting Response to Radiation Treatment.

Prostate cancer (PCa) is the second most frequently diagnosed male cancer worldwide. Early diagnosis of PCa, response to therapy, and prognosis still represent a challenge. Nearly 60% of PCa patients undergo radiation therapy (RT) which might cause side effects. Despite numerous researches in this field, predictive biomarkers for radiation toxicity are still not elucidated. MicroRNAs as posttranscriptional regulators of gene expression are shown to be changed during and after irradiation. MicroRNA level changes might be utilized to predict response to RT in the near future, which might help clinicians to make the decision on treatment regimens if needed. Individual radiation response results from the interactions among radiation treatment parameters and the biological background of each patient. In this review, we have listed and described miRNAs involved in response to RT in PCa and highlighted potential candidates for future biological tests predicting radiation response to RT, with the special focus on side effects of RT. According to described literature, we concluded that let-7, miR-21, miR-34a, miR-146a, miR-155, and members of miR-17/92 cluster might be promising candidates for biological tests predicting radiosensitivity of PCa patients undergoing radiation treatment. Predictive miRNA panels, especially for acute and late side effects of RT, can serve as a starting point for decisions for individualized RT planning. We believe that this review might be one step closer to understanding molecular mechanisms underlying individual radiation response of patients with PCa.

The impact of hyperbaric oxygen therapy on late radiation toxicity and quality of life in breast cancer patients

PurposeTo evaluate symptoms of late radiation toxicity, side effects, and quality of life in breast cancer patients treated with hyperbaric oxygen therapy (HBOT).MethodsFor this cohort study breast cancer patients treated with HBOT in 5 Dutch facilities were eligible for inclusion. Breast cancer patients with late radiation toxicity treated with ≥ 20 HBOT sessions from 2015 to 2019 were included. Breast and arm symptoms, pain, and quality of life were assessed by means of the EORTC QLQ-C30 and -BR23 before, immediately after, and 3 months after HBOT on a scale of 0–100. Determinants associated with persistent breast pain after HBOT were assessed.Results1005/1280 patients were included for analysis. Pain scores decreased significantly from 43.4 before HBOT to 29.7 after 3 months (p < 0.001). Breast symptoms decreased significantly from 44.6 at baseline to 28.9 at 3 months follow-up (p < 0.001) and arm symptoms decreased significantly from 38.2 at baseline to 27.4 at 3 months follow-up (p < 0.001). All quality of life domains improved at the end of HBOT and after 3 months follow-up in comparison to baseline scores. Most prevalent side effects of HBOT were myopia (any grade, n = 576, 57.3%) and mild barotrauma (n = 179, 17.8%). Moderate/severe side effects were reported in 3.2% (n = 32) of the patients. Active smoking during HBOT and shorter time (i.e., median 17.5 vs. 22.0 months) since radiotherapy were associated with persistent breast pain after HBOT.ConclusionBreast cancer patients with late radiation toxicity reported reduced pain, breast and arm symptoms, and improved quality of life following treatment with HBOT.

Proton Radiotherapy to Reduce Late Complications in Childhood Head and Neck Cancers.

In most childhood head and neck cancers, radiotherapy is an essential component of treatment; however, it can be associated with problematic long-term complications. Proton beam therapy is accepted as a preferred radiation modality in pediatric cancers to minimize the late radiation side effects. Given that childhood cancers are a rare and heterogeneous disease, the support for proton therapy comes from risk modeling and a limited number of cohort series. Here, we discuss the role of proton radiotherapy in pediatric head and neck cancers with a focus on reducing radiation toxicities. First, we compare the efficacy and expected toxicities in proton and photon radiotherapy for childhood cancers. Second, we review the benefit of proton radiotherapy in reducing acute and late radiation toxicities, including risks for secondary cancers, craniofacial development, vision, and cognition. Finally, we review the cost effectiveness for proton radiotherapy in pediatric head and neck cancers. This review highlights the benefits of particle radiotherapy for pediatric head and neck cancers to improve the quality of life in cancer survivors, to reduce radiation morbidities, and to maximize efficient health care use.

Late radiation effects in survivors of head and neck cancer: State of the science.

Head and neck squamous cell carcinoma is one of the most common neoplasms. Radiotherapy (RT) plays an essential role in the management of such cases. Despite advances in the technique, hyposalivation, xerostomia, dysphagia, trismus, radiation caries, and osteoradionecrosis remain significant late complications of RT. The aim of this narrative review was to summarize and update the main findings related to late side effects of radiotherapy in survivors of head and neck cancer (HNC). Such effects limit the ability to speak, ingest food and medications, and breathe and also exert a negative impact on social well-being and quality of life. This review highlights research in the field for both researchers and clinicians, assisting in the prevention and management of these adverse conditions. The findings can contribute to improving preventive management and multidisciplinary interventions for HNC patients.

The role of c-MYC expression in the diagnostic and clinical confirmation of radiation-induced angiosarcoma

Introduction. Angiosarcomas (ASs) arising from vascular tissue, account for 3.3% of all sarcomas and have a poor prognosis. Radiation-induced AS is a rare late complication of radiotherapy (RT) treatment and is characterized by a gene expression profile such as amplification of the MYC oncogene, by which we can distinguish primary from secondary induced tumor. Case report. For a 77-year-old female patient with early-stage endometrial adenocarcinoma, a radical hysterectomy with bilateral salpingo-oophorectomy was initially done. According to pathological risk factors, the postoperative external beam conformal RT (CRT) of the pelvis was administered with concomitant brachytherapy. Six years after the treatment, on the anterior abdominal wall, in the region of the postoperative irradiation field and surgical scar, an infiltrative AS of the skin and subcutaneous adipose tissue was histologically confirmed. The patient received six cycles of mono-adriamycin chemotherapy with verified partial regression. Additional immunohistochemical analysis (IHC) of c-MYC, Ki67, and CD34 expression showed a high proliferative index (Ki67 around 60%) and c-MYC positivity indicating the molecular pattern of radiation-induced AS. Furthermore, the high proliferative index could explain the positive response to chemotherapy. Conclusion. The novel postoperative RT techniques provide better survival and local control in risk-endometrial cancer groups with a decrease in irradiation complications. These patients with longer survival are at a higher risk of developing radiation-induced tumors as late side-effects of RT. When assessing the probability of radiation-induced AS, IHC analysis of c-MYC expression could distinguish secondary from other AS if Cahan?s criteria are fulfilled.

Late Intervention with Radiation-Induced Lung Fibrosis - Comparing Pamrevlumab Anti-CTGF Therapy vs. Pirfenidone vs. Nintedanib as Mono-, Dual- and Triple-therapy Combinations

Radiation-induced lung fibrosis (RILF) is a major late side effect of radiotherapy of thoracic malignancies. The severity of RILF depends on irradiated lung volume and prescribed dose/fractionation scheme. In contrast to acute and subacute pneumonitis that are responsive to steroids, RILF is a dose-limiting factor for curative treatment of tumors and is an unmet medical need for potential anti-fibrosis therapy. We investigated the impact of pamrevlumab (FG-3019), an anti-CTGF antibody, and compared it to approved IPF (idiopathic pulmonary fibrosis) drugs, pirfenidone and nintedanib, or to their combinations. Late intervention, after fibrosis begins (15-16-week post radiation in mice), is challenging for anti-fibrotic treatment. Therefore, we evaluated if dual or triple combinations of the antifibrotic drugs may elicit superior effects. C57Bl/6 mice received single dose 14.5 Gy whole thoracic irradiation (RT) and the antifibrotic treatments started 16 weeks after RT, when lung remodeling was evident by CT, for 8 weeks. Pamrevlumab or placebo IgG were administered IP 2/wk at 40 mg/kg. Pirfenidone or nintedanib were administered PO at a daily target dose of 300 or 100 mg/kg, either formulated into chow or by gavage. Lung density changes were assessed by CT, and lung function was assessed by blood gas analysis. Gene expression changes were assessed by RNAseq. Pamrevlumab was the only monotherapy to inhibit lung remodeling and to normalize a substantial number of RT-altered transcripts when the IPF drugs were administered in chow. Interestingly, pirfenidone appeared to antagonize some of the benefits of pamrevlumab, which was also supported by transcriptome analysis. Based on the known short plasma half-life of pirfenidone and nintedanib and their possible insufficient exposure in chow, both drugs were administered by gavage for the next experiments to ensure that mice received a full daily dose. Neither drug was tolerable at the full dose, so the daily doses were divided into two parts and administered 2/d. With gavage administration, both pirfenidone and nintedanib inhibited lung remodeling measured by CT (p< 0.05), but pamrevlumab remained the superior monotherapy (p< 0.001). Combining pirfenidone with pamrevlumab did not appear to alter the benefit of pamrevlumab, but the combination of nintedanib with pamrevlumab significantly decreased lung remodeling at 24 weeks after RT compared to pamrevlumab alone (p< 0.01). Pamrevlumab was the only monotherapy to significantly increase median survival (p< 0.01). Addition of pirfenidone or nintedanib to pamrevlumab resulted in non-significant changes of median survival. At late stage RILF development, pamrevlumab monotherapy exhibits potent antifibrotic activity that warrants further clinical evaluation.

MRI- and CT-determined changes of dysphagia / aspiration-related structures (DARS) during and after radiotherapy.

The concept of dysphagia/aspiration-related structures (DARS) was developed against the background of severe late side effects of radiotherapy (RT) for head and neck cancer (HNC). DARS can be delineated on CT scans, but with a better morphological discrimination on magnetic resonance imaging (MRI). Swallowing function was analyzed by use of patient charts and prospective investigations and questionnaires. Seventeen HNC patients treated with intensity-modulated radiotherapy (IMRT) ± chemotherapy between 5/2012 - 8/2015 were included. Planning CT (computed tomography) scans and MRIs (magnetic resonance imaging) prior, during 40 Gray (Gy) radiotherapy and posttreatment were available and co-registered to delineate DARS. The RT dose of each DARS was calculated. Five patients were investigated posttreatment for swallowing function and assessed by means of various questionnaires for quality of life (QoL), swallowing, and voice function. By retrospective comparison of DARS volume, a significant change in four of eight DARS was detected over time. Three increased and one diminished. The risk of posttreatment dysphagia rose by every 1Gy above the mean dose (D mean) of RT to DARS. 7.5 was the risk factor for dysphagia in the first 6 months, reducing to 4.7 for months 6-12 posttreatment. For all five patients of the prospective part of swallowing investigations, a function disturbance was detected. These results were in contrast to the self-assessment of patients by questionnaires. There was neither a dose dependency of D mean DARS volume changes over time nor of dysphonia and no correlation between volume changes, dysphagia or dysphonia. Delineation of DARS on MRI co-registered to planning CT gave the opportunity to differentiate morphology better than by CT alone. Due to the small number of patients with complete MRI scans over time, we failed to detect a dose dependency of DARS and swallowing and voice disorder posttreatment.

Role and toxicity of radiation therapy in neuroblastoma patients: A literature review.

Neuroblastoma is the most common extracranial solid tumor, arising from primitive sympathetic ganglion cells, in pediatric patients. The unique features of neuroblastoma include variable clinical behaviors, such as rapid progression to death and maturation to benign ganglioneuroma, followed by regression. Radiation therapy (RT) is usually administered to both the primary tumor bed and persistent metastatic sites after induction chemotherapy for high-risk neuroblastoma. RT to the tumor bed after surgical resection contributes significantly to local disease control and prevention of local relapse, confirming the role of RT. Palliative radiotherapy for metastatic neuroblastoma is also effective and safe and mainly provides symptomatic relief. The late side effects of RT in neuroblastoma patients include growth and developmental failure, hypothyroidism, gastrointestinal dysfunction, neurocognitive defects, pulmonary and cardiac abnormalities, infertility, and secondary cancers. In this article, we reviewed the role and toxicity of RT in neuroblastoma patients.

Pencil Beam Scanning Proton Therapy for Paediatric Neuroblastoma with Motion Mitigation Strategy for Moving Target Volumes

AimsMore efforts are required to minimise late radiation side-effects for paediatric patients. Pencil beam scanning proton beam therapy (PBS-PT) allows increased sparing of normal tissues while maintaining conformality, but is prone to dose degradation from interplay effects due to respiratory motion. We report our clinical experience of motion mitigation with volumetric rescanning (vRSC) and outcomes of children with neuroblastoma. Materials and methodsNineteen patients with high-risk (n = 16) and intermediate-risk (n = 3) neuroblastoma received PBS-PT. The median age at PBS-PT was 3.5 years (range 1.2–8.6) and the median PBS-PT dose was 21 Gy (relative biological effectiveness). Most children (89%) were treated under general anaesthesia. Seven patients (37%) underwent four-dimensional computed tomography for motion assessment and were treated with vRSC for motion mitigation. ResultsThe mean result of maximum organ motion was 2.7 mm (cranial–caudal), 1.2 mm (left–right), 1.0 mm (anterior–posterior). Four anaesthetised children (21%) showing <5 mm motion had four-dimensional dose calculations (4DDC) to guide the number of vRSC. The mean deterioration or improvement to the planning target volume covered by 95% of the prescribed dose compared with static three-dimensional plans were: 4DDC no vRSC, –0.6%; 2 vRSC, +0.3%; 4 vRSC, +0.3%; and 8 vRSC, +0.1%. With a median follow-up of 14.9 months (range 2.7–49.0) there were no local recurrences. The 2-year overall survival was 94% and distant progression-free survival was 76%. Acute grade 2–4 toxicity was 11%. During the limited follow-up time, no late toxicities were observed. ConclusionsThe early outcomes of mainly high-risk patients with neuroblastoma treated with PBS-PT were excellent. With a subset of our cohort undergoing PBS-PT with vRSC we have shown that it is logistically feasible and safe. The clinical relevance of vRSC is debatable in anaesthetised children with small pre-PBS-PT motion of <5 mm.

Outcome of a rabbit model for late irradiation effects in mandibular oral mucosa and bone: a pilot study

Late side effects of radiotherapy (RT) in the treatment for head and neck (HN) malignancies involve an inadequate healing response of the distressed tissue due to RT-induced hypovascularity. The aim of this study was to develop a pilot model in which vascular alterations associated with the onset of late irradiation (IR) injury could be measured in rabbit oral mucosa and mandibular bone. Eight male New Zealand white rabbits were divided over four treatment groups. Group I-III received four fractions of RT (5.6 Gy, 6.5 Gy, and 8 Gy, respectively) and Group IV received 1 fraction of 30 Gy. Oral microcirculatory measurements were performed at baseline (before RT) and once a week during 11 consecutive weeks after RT assessing perfusion parameters, that is, total vessel density (TVD), perfused vessel density (PVD), proportion of perfused vessels (PPV), and microvascular flow index (MFI). Post-mortem histopathology specimens were analyzed. Five weeks after RT, TVD, and PVD in all groups showed a decrease of >10% compared to baseline, a significant difference was observed for Groups I, II, and IV (P<0.05). At T11, no lasting effect of decreased vessel density was observed. PPV and MFI remained unaltered at all-time points. Group IV showed a marked difference in scattered telangiectasia such as microangiopathies, histological necrosis, and loss of vasculature. No significant lasting effect in mucosal microcirculation density due to IR damage was detected. Observed changes in microcirculation vasculature and histology may align preliminary tissue transition towards clinical pathology in a very early state associated with late IR injury in the oral compartment. Enhancing knowledge on the onset of late vascular IR injury in the HN region could help the development, monitoring, and timing of therapies that act on prevention, discontinuation, or repair of radiation pathology.

The Role of Particle Therapy in the Risk of Radio-induced Second Tumors: A Review of the Literature.

One of the most important late side-effects of radiation therapy is the development of radiation-induced secondary malignancies. In the last years, this topic has significantly influenced treatment decision-making as the number of long-term cancer survivors has significantly increased with advances in treatment modalities. All efforts are being made to prevent the incidence of tumors induced by radiation. In this review article we summarize the current knowledge about treatment-related secondary cancers with a particular attention to hadrontherapy.

Heparan Sulfate Mimetics: A New Way to Optimize Therapeutic Effects of Hydrogel-Embedded Mesenchymal Stromal Cells in Colonic Radiation-Induced Damage

Clinical expression of gastrointestinal radiation toxicity on non-cancerous tissue could be very life threatening and clinicians must deal increasingly with the management of late side effects of radiotherapy. Cell therapy, in particular mesenchymal stromal cell (MSC) therapy, has shown promising results in numerous preclinical animal studies and thus has emerged as a new hope for patient refractory to current treatments. However, many stem cell clinical trials do not confer any beneficial effect suggesting a real need to accelerate research towards the successful clinical application of stem cell therapy. In this study, we propose a new concept to improve the procedure of MSC-based treatment for greater efficacy and clinical translatability. We demonstrated that heparan sulfate mimetic (HS-m) injections that restore the extracellular matrix network and enhance the biological activity of growth factors, associated with local injection of MSC protected in a hydrogel, that increase cell engraftment and cell survival, improve the therapeutic benefit of MSC treatment in two animal models relevant of the human pathology. For the first time, a decrease of the injury score in the ulcerated area was observed with this combined treatment. We also demonstrated that the combined treatment favored the epithelial regenerative process. In this study, we identified a new way, clinically applicable, to optimize stem-cell therapy and could be proposed to patients suffering from severe colonic defect after radiotherapy.

Melatonin as an adjuvant in radiotherapy for radioprotection and radiosensitization.

It is estimated that more than half of cancer patients undergo radiotherapy during the course of their treatment. Despite its beneficial therapeutic effects on tumor cells, exposure to high doses of ionizing radiation (IR) is associated with several side effects. Although improvements in radiotherapy techniques and instruments could reduce these side effects, there are still important concerns for cancer patients. For several years, scientists have been trying to modulate tumor and normal tissue responses to IR, leading to an increase in therapeutic ratio. So far, several types of radioprotectors and radiosensitizers have been investigated in experimental studies. However, high toxicity of chemical sensitizers or possible tumor protection by radioprotectors creates a doubt for their clinical applications. On the other hand, the protective effects of these radioprotectors or sensitizer effects of radiosensitizers may limit some type of cancers. Hence, the development of some radioprotectors without any protective effect on tumor cells or low toxic radiosensitizers can help improve therapeutic ratio with less side effects. Melatonin as a natural body hormone is a potent antioxidant and anti-inflammatory agent that shows some anti-cancer properties. It is able to neutralize different types of free radicals produced by IR or pro-oxidant enzymes which are activated following exposure to IR and plays a key role in the protection of normal tissues. In addition, melatonin has shown the ability to inhibit long-term changes in inflammatory responses at different levels, thereby ameliorating late side effects of radiotherapy. Fortunately, in contrast to classic antioxidants, some in vitro studies have revealed that melatonin has a potent anti-tumor activity when used alongside irradiation. However, the mechanisms of its radiosensitive effect remain to be elucidated. Studies suggested that the activation of pro-apoptosis gene, such as p53, changes in the metabolism of tumor cells, suppression of DNA repair responses as well as changes in biosynthesis of estrogen in breast cancer cells are involved in this process. In this review, we describe the molecular mechanisms for radioprotection and radiosensitizer effects of melatonin. Furthermore, some other proposed mechanisms that may be involved are presented.