[Prevention of iodine deficiency diseases: focus on regional targeted programs].

The strategy for the elimination of diseases associated with iodine deficiency throughout the Russian Federation is based on the adoption of a federal law providing for the use of iodized salt as a means of mass (population) iodine prophylaxis. Chronic iodine deficiency that exists in Russia leads to dramatic consequences: the development of mental and physical retardation in children, cretinism, thyroid diseases, and infertility. Under conditions of iodine deficiency, the risk of radiation-induced thyroid cancer in children in the event of nuclear disasters increases hundreds of times. By definition, all iodine deficiency diseases (IDDs) can be prevented, while changes caused by iodine deficiency during fetal development and in early childhood are irreversible and practically defy treatment and rehabilitation. The actual average consumption of iodine by a resident of Russia is only 40-80 mcg per day, which is 3 times less than the established norm (150-250 mcg). Every year, more than 1.5 million adults and 650 thousand children with various thyroid diseases turn to medical institutions. The cause of 65% of cases of thyroid disease in adults and 95% in children is insufficient intake of iodine from the diet. At the stage of preparing the relevant legislative act, the development and implementation of regional programs for the prevention of IDD is of utmost importance. A typical draft of such a program is proposed in this article for its adaptation and use at the regional level.

Inhibition of c-MET reverses radiation-induced malignant potential in pancreatic cancer.

As a treatment option for PDAC, radiation therapy induces good local control. However, radiation also reportedly enhances the malignant potential (e.g., invasion and migration ability) in various cancers, thus increasing the risk of distant metastasis. It remains unclear how radiation induces malignant potential, and how such enhanced malignant potential can be suppressed. In the current study, we evaluated the sequential change of c-Met expression in pancreatic cancer cells following irradiation. We found that irradiation transiently induced c-Met expression in vitro. In an in vivo subcutaneous tumor mouse model, irradiation also enhanced downstream phosphorylated Met (p-Met). Furthermore, this enhancement of p-Met protein expression was suppressed by oral administration of the c-Met inhibitor INC280. Irradiated pancreatic cancer cells with enhanced c-Met expression exhibited higher malignant potential, including invasion and migration ability, compared with cells showing low c-Met expression. Pancreatic cancer cells that overexpressed c-met also showed enhanced malignant potential, which was reversed by c-Met inhibition. Additionally, c-Met inhibitor suppressed the metastatic potential in a liver metastasis mouse model using c-met-overexpressing cells. Overall, our present results revealed that irradiation could induce c-met expression in pancreatic cancer cells, leading to enhanced malignant potential (e.g., invasion and migration ability) and thus promoting distant metastasis. Moreover, a c-Met inhibitor could reverse this enhanced malignant potential.

Suppression of beta 2 adrenergic receptor actions prevent UVB mediated cutaneous squamous cell tumorigenesis through inhibition of VEGF-A induced angiogenesis.

Although beta 2 adrenergic receptors (ß2 ADR) are present in the keratinocytes, their role in cutaneous squamous cell tumorigenesis needs to be ascertained. For the first time, we report here that selective ß2 ADR antagonists by inhibiting ß2 ADR actions significantly retarded the progression of ultraviolet B (UVB) induced premalignant cutaneous squamous cell lesions. These antagonists acted by inhibiting vascular endothelial growth factor-A (VEGF) mediated angiogenesis to prevent UVB radiation-induced squamous cell carcinoma of the skin.

1O2 determined from the measured PDT dose and 3O2 predicts long-term response to Photofrin-mediated PDT.

Photodynamic therapy (PDT) that employs the photochemical interaction of light, photosensitizer and oxygen is an established modality for the treatment of cancer. However, dosimetry for PDT is becoming increasingly complex due to the heterogeneous photosensitizer uptake by the tumor, and complicated relationship between the tissue oxygenation ([3O2]), interstitial light distribution, photosensitizer photobleaching and PDT effect. As a result, experts argue that the failure to realize PDT's true potential is, at least partly due to the complexity of the dosimetry problem. In this study, we examine the efficacy of singlet oxygen explicit dosimetry (SOED) based on the measurements of the interstitial light fluence rate distribution, changes of [3O2] and photosensitizer concentration during Photofrin-mediated PDT to predict long-term control rates of radiation-induced fibrosarcoma tumors. We further show how variation in tissue [3O2] between animals induces variation in the treatment response for the same PDT protocol. PDT was performed with 5 mg kg-1 Photofrin (a drug-light interval of 24 h), in-air fluence rates (ϕ air) of 50 and 75 mW cm-2 and in-air fluences from 225 to 540 J cm-2. The tumor regrowth was tracked for 90 d after the treatment and Kaplan-Meier analyses for local control rate were performed based on a tumor volume ⩽100 mm3 for the two dosimetry quantities of PDT dose and SOED. Based on the results, SOED allowed for reduced subject variation and improved treatment evaluation as compared to the PDT dose.

Surgical outcomes and prognostic factors of non-metastatic radiation-induced sarcoma of bone.

BACKGROUND: The survival and prognostic factors in non-metastatic, radiation-induced bone sarcomas of bone have not been described. Moreover, the quantitative data about surgical outcomes and complications after limb-salvage surgery versus amputation are quite limited. METHODS: Twenty-five patients with non-metastatic, radiation-induced sarcoma of bone who underwent definitive surgery were analysed. Histological diagnosis was osteosarcoma in 19 and undifferentiated pleomorphic sarcoma in six. The definitive surgery was limb-salvage surgery in 15 patients and an amputation in 10. RESULTS: The 5-year overall survival rate (OS) and the 5-year event-free survival rate (EFS) were 53% (95% CI 31%-70%) and 40% (21%-59%), respectively. Patients with wide or radical surgical margins (n = 13) showed significantly better OS compared with those with marginal (n = 8) or intralesional (n = 2) margins (5-year OS, radical or wide = 74%, marginal = 17%, intralesional = 0%, p = 0.044). The risk of local recurrence was significantly higher in the limb-salvage group compared to the amputation group (49% vs 0%, p = 0.011). OS and EFS were not significantly different between limb-salvage group and an amputation group (p = 0.188 and 0.912, respectively). CONCLUSIONS: We believe non-metastatic, radiation-induced sarcoma of bone should be resected with the aim of achieving wide or radical margins. Although limb-salvage surgery was related to higher rates of local recurrence compared with those of the amputation group, OS and EFS were not different among two groups. Surgeons need to discuss the higher risk of local recurrence in limb-salvage surgery.

Treatment of consistent BRAF/HRAS gene mutation and MYC amplification radiation-induced abdominal wall angiosarcoma with low-dose apatinib: a case report.

BACKGROUND: An extremely rare condition, radiation-induced angiosarcoma is characterized by a poor prognosis, high recurrence rate and lack of effective treatment. Herein, we present a case report of a 48-year-old female patient with radiation-induced abdominal wall angiosarcoma who showed a dramatic response to low-dose apatinib. CASE PRESENTATION: The patient, who was diagnosed with cervical squamous cell carcinoma 20 years ago, had received radiotherapy and chemotherapy after operation. Angiosarcomas of the abdominal wall appeared 9 years later. After repeated surgical operations and intravenous chemotherapy for the angiosarcomas, the patient developed tumor recurrence and pulmonary metastasis. The abdominal wall tumors showed repeated rupture and bleeding, with poor wound healing. On evaluation, laboratory findings detected the negative serum tumor markers CEA, CA 125, CA 15-3 and CA 19-9. Imaging showed multiple subcutaneous nodules and masses in the abdominal wall, accompanied by suspected small subpleural nodule at the lower lobe of the right lung. Immunohistochemistry of previous surgical pathology indicated that CD31, ERG and Vim were positive. The result of whole exome sequencing suggested the mutations of BRAF and HRAS, and the amplification of MYC. Based on the above results, the patient was clinically diagnosed with radiation-induced angiosarcoma of the abdominal wall with pulmonary metastasis. The patient was treated with low-dose apatinib and rejected reoperation or chemotherapy. RESULTS: At the 6-month follow-up visit, the abdominal wall lesions that had previously ruptured stopped bleeding and showed significant shrinkage. Imaging showed that most of the abdominal wall lesions had partially regressed, and some of the lesions on the abdominal wall and the suspected lesion of subpleural nodule at the lower lobe of the right lung had disappeared. CONCLUSIONS: We described this case and reviewed the literature on radiation-related angiosarcoma. Importantly, this case suggests that apatinib may be an effective and sensitive treatment for radiation-induced angiosarcoma even at the lowest dosage, without aggravating the bleeding of lesions.

DNA methylome and transcriptome alterations and cancer prevention by triterpenoid ursolic acid in UVB-induced skin tumor in mice.

Nonmelanoma skin cancers (NMSCs) are the most common type of skin cancers. Major risk factors for NMSCs include exposure to ultraviolet (UV) irradiation. Ursolic acid (UA) is a natural triterpenoid enriched in blueberries and herbal medicinal products, and possess anticancer activities. This study focuses on the impact of UA on epigenomic, genomic mechanisms and prevention of UVB-mediated NMSC. CpG methylome and RNA transcriptome alterations of early, promotion and late stages of UA treated on UVB-induced NMSC in SKH-1 hairless mice were conducted using CpG methyl-seq and RNA-seq. Samples were collected at weeks 2, 15, and 25, and integrated bioinformatic analyses were performed to identify key pathways and genes modified by UA against UVB-induced NMSC. Morphologically, UA significantly reduced NMSC tumor volume and tumor number. DNA methylome showed inflammatory pathways IL-8, NF-κB, and Nrf2 pathways were highly involved. Antioxidative stress master regulator Nrf2, cyclin D1, DNA damage, and anti-inflammatory pathways were induced by UA. Nrf2, cyclin D1, TNFrsf1b, and Mybl1 at early (2 weeks) and late (25 weeks) stages were identified and validated by quantitative polymerase chain reaction. In summary, integration of CpG methylome and RNA transcriptome studies show UA alters antioxidative, anti-inflammatory, and anticancer pathways in UVB-induced NMSC carcinogenesis. Particularly, UA appears to drive Nrf2 and its upstream/downstream genes, anti-inflammatory (at early stages) and cell cycle regulatory (both early and late stages) genes, of which might contribute to the overall chemopreventive effects of UVB-induced MNSC. This study may provide potential biomarkers/targets for chemoprevention of early stage of UVB-induced NMSC in human.

Investigation into the use of histone deacetylase inhibitor MS-275 as a topical agent for the prevention and treatment of cutaneous squamous cell carcinoma in an SKH-1 hairless mouse model.

Cutaneous squamous cell carcinomas are a common form of highly mutated keratinocyte skin cancers that are of particular concern in immunocompromised patients. Here we report on the efficacy of topically applied MS-275, a clinically used histone deacetylase inhibitor, for the treatment and management of this disease. At 2 mg/kg, MS-275 significantly decreased tumor burden in an SKH-1 hairless mouse model of UVB radiation-induced skin carcinogenesis. MS-275 was cell permeable as a topical formulation and induced histone acetylation changes in mouse tumor tissue. MS-275 was also effective at inhibiting the proliferation of patient derived cutaneous squamous cell carcinoma lines and was particularly potent toward cells isolated from a regional metastasis on an immunocompromised individual. Our findings support the use of alternative routes of administration for histone deacetylase inhibitors in the treatment of high-risk squamous cell carcinoma which may ultimately lead to more precise delivery and reduced systemic toxicity.

Tranexamic Acid Ameliorates Nonmelanoma Skin Cancer Induced by Long-term Ultraviolet A Irradiation.

To date, there have been no treatments developed to ameliorate nonmelanoma skin cancer induced by long-term exposure to ultraviolet A (UVA) irradiation. In this study, we examined the effects of tranexamic acid (trans-4-aminomethyl cyclohexanecarboxylic acid) on long-term UVA-induced skin cancer. We exposed the dorsal skin of male hairless mice to UVA at a dose of 110 kJ m-2 using an FL20SBLB-A lamp three times weekly for 15 weeks after application of 7,12-dimethylbenz [a] anthracene (DMBA). During the experimental period, the mice were administered tranexamic acid (750 mg kg-1 day-1 ) three times weekly. We found that cancer development was ameliorated by administration of tranexamic acid. Furthermore, tranexamic acid treatment was observed to suppress increases in the plasma levels of matrix metalloproteinase-9 and interleukin (IL)-6, and skin expression of plasmin, CC chemokine 2, macrophages, signal transducer and activator of transcription (STAT)3, cyclin D and vascular endothelial growth factor (VEGF)-A that occurred in mice subjected to long-term UVA irradiation. These results indicated that the nonmelanoma skin cancer induced by DMBA+UVA long-term irradiation is ameliorated by tranexamic acid through regulation of the plasmin/macrophage/IL-6/STAT3/cyclin D signal transmission pathway. In addition, this ameliorative effect against skin cancer may be mediated via inhibition of the IL-6-induced expression of VEGF-A.

A pilot study evaluating chemotherapy tolerability for breast cancer patients who have received prior treatment and chest radiation for Hodgkin Lymphoma.

MICROABSTRACT: Women treated with chest radiation for Hodgkin lymphoma (HL) have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer. This small retrospective study identified 15 patients, noting that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation. PURPOSE: Women treated for Hodgkin lymphoma (HL) with chest radiation have significantly higher risk of developing breast cancer, and little is known about how these patients tolerate chemotherapy for breast cancer. METHODS: Women with breast cancer diagnosed from 1986-2015 after radiation for HL were identified from hospitals and clinics in St. Paul and Minneapolis, Minnesota. Patient, tumor and treatment characteristics, and clinical outcomes were abstracted from medical records and summarized using descriptive statistics. Chemotherapy was defined as tolerated if all scheduled doses and cycles were completed without deviation from the initial plan, with lack of grade 3 or higher toxicity attributable to chemotherapy in categories including blood, cardiac, gastrointestinal, fatigue and pain. RESULTS: Forty-two patients with breast cancer and prior radiation for HL were identified, 15 of which received chemotherapy for breast cancer. We noted 75% tolerability of taxane-based and 100% tolerability of anthracycline-based chemotherapy, suggesting that most patients with prior radiation for HL tolerate chemotherapy for breast cancer. A subset of patients (N = 7) in this study were also treated with chemotherapy for HL prior to breast cancer diagnosis, and 86% (6 of 7) also tolerated chemotherapy for breast cancer. CONCLUSIONS: Treatment of breast cancer is strongly influenced by prior treatment of HL. Although this study was small and did not meet statistical significance, the data suggest that these patients tolerate proposed chemotherapy regimens for breast cancer in rates similar to those without prior HL and therapeutic radiation. Larger studies comparing specific chemotherapy dosing schedules are needed to address this complicated population.

The Mechanisms of Carnosol in Chemoprevention of Ultraviolet B-Light-Induced Non-Melanoma Skin Cancer Formation.

Carnosol is a natural compound extracted from rosemary and sage, which has been demonstrated to have anti-inflammatory, anti-oxidant, and anti-cancer properties. In this report, we evaluated the therapeutic potential and elucidated the potential mechanism of action of carnosol in chemoprevention of ultraviolet B-light (UVB) induced non-melanoma skin cancer formation. Our data indicated that carnosol could partially reduce UVB-induced reactive oxygen species (ROS) elevation and thus reduce DNA damage. It could also reduce UVB-induced formation of cyclobutane pyrimidine dimers (CDP) in keratinocytes possibly through its ability in absorbing UVB radiation. In addition, carnosol could inhibit the UVB-induced activation of NF-κB and also reduce UVB-induced transformation of keratinocytes. Taken together, the results indicate the role of carnosol as a potential chemopreventive agent upon UVB radiation.

Ultraviolet light and melanoma.

Melanoma is a clinically heterogeneous disease, and current strategies for treatment of the primary tumour are based on pathological criteria alone. In the recent past, several DNA-sequencing and RNA-sequencing studies of primary and advanced melanoma samples have identified unique relationships between somatic mutations, genomic aberrations, and the genetic fingerprint of ultraviolet radiation (UVR). The recurrent patterns of genomic alterations reveal different disease pathways, drug targets and mechanisms limiting drug response. Here, we examine the known associations between the molecular categories of melanoma and the multidimensional UVR damage. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Radiation-associated breast cancer and gonadal hormone exposure: a report from the Childhood Cancer Survivor Study.

BACKGROUND: The relationship between hormone exposure and breast cancer risk in women treated with chest radiotherapy for childhood cancer is uncertain. METHODS: Participants included 1108 females from the Childhood Cancer Survivor Study who were diagnosed with childhood cancer 1970-1986, treated with chest radiotherapy, and survived to ages ⩾20 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) from Cox models adjusted for chest radiation field, delivered dose, anthracycline exposure, and age at childhood cancer estimated risk. RESULTS: Among 195 women diagnosed with breast cancer, 102 tumours were oestrogen-receptor positive (ER+). Breast cancer risk increased with ⩾10 years of ovarian function after chest radiotherapy vs <10 years (HR=2.89, CI 1.56-5.53) and for radiotherapy given within 1 year of menarche vs >1 year from menarche (HR=1.80, CI 1.19-2.72). Risk decreased with decreasing age at menopause (Ptrend=0.014). Risk factors did not differ for ER+ breast cancer. Survivors with an age at menopause <20 years treated with hormone therapy had a lower breast cancer risk than premenopausal survivors (HR=0.47, CI 0.23-0.94). CONCLUSIONS: Endogenous hormones are key contributors to breast cancer observed among childhood cancer survivors. Hormone therapy given for premature ovarian insufficiency does not fully replace the function that endogenous hormones have in breast cancer development.

A Comparison of Dose Metrics to Predict Local Tumor Control for Photofrin-mediated Photodynamic Therapy.

This preclinical study examines light fluence, photodynamic therapy (PDT) dose and "apparent reacted singlet oxygen," [1 O2 ]rx , to predict local control rate (LCR) for Photofrin-mediated PDT of radiation-induced fibrosarcoma (RIF) tumors. Mice bearing RIF tumors were treated with in-air fluences (50-250 J cm-2 ) and in-air fluence rates (50-150 mW cm-2 ) at Photofrin dosages of 5 and 15 mg kg-1 and a drug-light interval of 24 h using a 630-nm, 1-cm-diameter collimated laser. A macroscopic model was used to calculate [1 O2 ]rx and PDT dose based on in vivo explicit dosimetry of the drug concentration, light fluence and tissue optical properties. PDT dose and [1 O2 ]rx were defined as a temporal integral of drug concentration and fluence rate, and singlet oxygen concentration consumed divided by the singlet oxygen lifetime, respectively. LCR was stratified for different dose metrics for 74 mice (66 + 8 control). Complete tumor control at 14 days was observed for [1 O2 ]rx ≥ 1.1 mm or PDT dose ≥1200 µm J cm-2 but cannot be predicted with fluence alone. LCR increases with increasing [1 O2 ]rx and PDT dose but is not well correlated with fluence. Comparing dosimetric quantities, [1 O2 ]rx outperformed both PDT dose and fluence in predicting tumor response and correlating with LCR.

[18F-FDG PET/CT contributes to diagnostics and therapy monitoring of radiation-induced angiosarcoma].

Angiosarcomas are rare, aggressive malignant mesenchymal tumours with a poor prognosis. Radiation therapy is an independent risk factor for the development of secondary angiosarcoma. The onset of angiosarcoma may resemble benign lesions, leading to delayed diagnosis. It has been suggested that 18F-fluorodeoxyglucose (FDG) PET/CT scan may be useful in the early diagnosis in differentiating angiosarcoma from benign lesions and in therapy monitoring. We report the utility of 18F-FDG PET/CT scan in the diagnosis and follow-up of radiation-induced angiosarcoma in a patient previously treated for uterine cancer.

Radiation-induced osteosarcoma of the skull base after radiation therapy in a patient with nasopharyngeal carcinoma: a case report and review of the literature.

BACKGROUND: Radiation-induced osteosarcomas are a recognized complication of radiation therapy. Owing to the fact that it is rare, publications on radiation-induced osteosarcoma of the skull base are limited to a small series and some case reports. CASE PRESENTATION: We describe a rare case of a patient with a skull base radiation-induced osteosarcoma treated 11 years before with ionizing radiation for an undifferentiated carcinoma of the nasopharynx. The patient was treated with chemotherapy alone, but he died after the third cycle. CONCLUSIONS: Radiation-induced osteosarcoma of the skull base after treatment of nasopharyngeal carcinoma is a very rare but very aggressive complication with a poor prognosis. Chemotherapy gives bad results, and regular follow-up of treated patients should be considered.