Changes in Telomere Length in Leukocytes and Leukemic Cells after Ultrashort Electron Beam Radiation.

Application of laser-generated electron beams in radiotherapy is a recent development. Accordingly, mechanisms of biological response to radiation damage need to be investigated. In this study, telomere length (TL) as endpoint of genetic damage was analyzed in human blood cells (leukocytes) and K562 leukemic cells irradiated with laser-generated ultrashort electron beam. Metaphases and interphases were analyzed in quantitative fluorescence in situ hybridization (Q-FISH) to assess TL. TLs were shortened compared to non-irradiated controls in both settings (metaphase and interphase) after irradiation with 0.5, 1.5, and 3.0 Gy in blood leukocytes. Radiation also caused a significant TL shortening detectable in the interphase of K562 cells. Overall, a negative correlation between TL and radiation doses was observed in normal and leukemic cells in a dose-dependent manner. K562 cells were more sensitive than normal blood cells to increasing doses of ultrashort electron beam radiation. As telomere shortening leads to genome instability and cell death, the results obtained confirm the suitability of this biomarker for assessing genotoxic effects of accelerated electrons for their further use in radiation therapy. Observed differences in TL shortening between normal and K562 cells provide an opportunity for further development of optimal radiation parameters to reduce side effects in normal cells during radiotherapy.

[Role of radiotherapy in haematology]. / Place de la radiothérapie en hématologie.

The management of myeloid and lymphoid disease is essentially based on chemotherapy and targeted therapies. Since radiotherapy could be responsible for severe late toxicities, essentially due to conventional bidimensional irradiation techniques, many trials have attempted to omit radiotherapy or to scale down the dose in their therapeutic strategy. Nevertheless, radiotherapy still plays a role for curative or symptomatic purposes.

Risk of cerebrovascular disease among 13 457 five-year survivors of childhood cancer: A population-based cohort study.

Survivors of childhood cancer treated with cranial irradiation are at risk of cerebrovascular disease (CVD), but the risks beyond age 50 are unknown. In all, 13457 survivors of childhood cancer included in the population-based British Childhood Cancer Survivor Study cohort were linked to Hospital Episode Statistics data for England. Risk of CVD related hospitalisation was quantified by standardised hospitalisation ratios (SHRs), absolute excess risks and cumulative incidence. Overall, 315 (2.3%) survivors had been hospitalised at least once for CVD with a 4-fold risk compared to that expected (95% confidence interval [CI]: 3.7-4.3). Survivors of a central nervous system (CNS) tumour and leukaemia treated with cranial irradiation were at greatest risk of CVD (SHR = 15.6, 95% CI: 14.0-17.4; SHR = 5.4; 95% CI: 4.5-6.5, respectively). Beyond age 60, on average, 3.1% of CNS tumour survivors treated with cranial irradiation were hospitalised annually for CVD (0.4% general population). Cumulative incidence of CVD increased from 16.0% at age 50 to 26.0% at age 65 (general population: 1.4-4.2%). In conclusion, among CNS tumour survivors treated with cranial irradiation, the risk of CVD continues to increase substantially beyond age 50 up to at least age 65. Such survivors should be: counselled regarding this risk; regularly monitored for hypertension, dyslipidaemia and diabetes; advised on life-style risk behaviours. Future research should include the recall for counselling and brain MRI to identify subgroups that could benefit from pharmacological or surgical intervention and establishment of a case-control study to comprehensively determine risk-factors for CVD.

Implementation of total body photon irradiation as part of an institutional bone marrow transplant program for the treatment of canine lymphoma and leukemias.

A total body irradiation (TBI) protocol was developed to support a bone marrow transplant (BMT) program for the treatment of canine hematologic malignancies. The purpose of this prospective study is to describe implementation of the protocol and resultant dosimetry. Nongraphic manual treatment planning using 6 MV photons, isocentric delivery, 40 × 40 cm field size, wall-mounted lasers to verify positioning, a lucite beam spoiler (without use of bolus material), a dose rate of 8.75 cGy/min at patient isocenter, and a source-to-axis distance of 338 cm were used for TBI. A monitor unit calculation formula was derived using ion chamber measurements and a solid water phantom. Five thermoluminescent dosimeters (TLDs) were used at various anatomic locations in each of four cadaver dogs, to verify fidelity of the monitor unit formula prior to clinical implementation. In vivo dosimetric data were then collected with five TLDs at various anatomic locations in six patients treated with TBI. A total dose of 10 Gy divided into two 5 Gy fractions was delivered approximately 16 h apart, immediately followed by autologous stem cell transplant. The mean difference between prescribed and delivered doses ranged from 99% to 109% for various sites in cadavers, and from 83% to 121% in clinical patients. The mean total body dose in cadavers and clinical patients when whole body dose was estimated by averaging doses measured by variably placed TLDs ranged from 98% to 108% and 93% to 102% of the prescribed dose, respectively, which was considered acceptable. This protocol could be used for institutional implementation of TBI.

Hyperthyroidism After Radiation Therapy for Childhood Cancer: A Report from the Childhood Cancer Survivor Study.

PURPOSE: The association of hyperthyroidism with exposure to ionizing radiation is poorly understood. This study addresses the risk of hyperthyroidism in relation to incidental therapeutic radiation dose to the thyroid and pituitary glands in a large cohort of survivors of childhood cancer. METHODS AND MATERIALS: Using the Childhood Cancer Survivor Study's cohort of 5-year survivors of childhood cancer diagnosed at hospitals in the United States and Canada between 1970 and 1986, the occurrence of hyperthyroidism through 2009 was ascertained among 12,183 survivors who responded to serial questionnaires. Radiation doses to the thyroid and pituitary glands were estimated from radiation therapy records, and chemotherapy exposures were abstracted from medical records. Binary outcome regression was used to estimate prevalence odds ratios (ORs) for hyperthyroidism at 5 years from diagnosis of childhood cancer and Poisson regression to estimate incidence rate ratios (RRs) after the first 5 years. RESULTS: Survivors reported 179 cases of hyperthyroidism, of which 148 were diagnosed 5 or more years after their cancer diagnosis. The cumulative proportion of survivors diagnosed with hyperthyroidism by 30 years after the cancer diagnosis was 2.5% (95% confidence interval [CI], 2.0%-2.9%) among those who received radiation therapy. A linear relation adequately described the thyroid radiation dose response for prevalence of self-reported hyperthyroidism 5 years after cancer diagnosis (excess OR/Gy, 0.24; 95% CI, 0.06-0.95) and incidence rate thereafter (excess RR/Gy, 0.06; 95% CI, 0.03-0.14) over the dose range of 0 to 63 Gy. Neither radiation dose to the pituitary gland nor chemotherapy was associated significantly with hyperthyroidism. Radiation-associated risk remained elevated >25 years after exposure. CONCLUSIONS: Risk of hyperthyroidism after radiation therapy during childhood is positively associated with external radiation dose to the thyroid gland, with radiation-related excess risk persisting for >25 years. Neither radiation dose to the pituitary gland nor chemotherapy exposures were associated with hyperthyroidism among childhood cancer survivors through early adulthood.

Simultaneous integrated boost with helical arc radiotherapy of total skin (HEARTS) to treat cutaneous manifestations of advanced, therapy-refractory cutaneous lymphoma and leukemia - dosimetry comparison of different regimens and clinical application.

BACKGROUND: Helical irradiation of the total skin (HITS) was modified as simultaneous integrated boost (SIB)-helical arc radiotherapy of total skin (HEARTS) technique and applied to an acute myeloid leukemia (AML) patient with disseminated leukemia cutis. METHODS: The original HITS plan was revised for different regimens, i.e. HEARTS, low-dose HEARTS and SIB-HEARTS. The uniformity index (UI), conformity index (CI), and dose of organs at risk (OARs) were used to evaluate the plans. Additionally, the SIB-HEART (21/15 Gy) was delivered to the total skin and chloromas. RESULTS: No significant differences were observed for the CI and UI between HITS and HEARTS regimens. Compared with HITS, the reduced mean doses to various bone marrows ranged from 17 to 88%. The mean OARs doses for the head, chest and abdomen of a patient with AML treated with SIB-HEARTS (21/15 Gy) were 2.1 to 21.9 Gy, 1.8 to 7.8 Gy and 1.7 to 3.3 Gy, respectively. No severe adverse effects were noted except for grade 4 leukocytopenia and thrombocytopenia. CONCLUSION: HEARTS and different regimens reduced the dose to OARs and bone marrow while maintaining the uniformity and conformity. SIB-HEARTS deliveries different doses to the total skin and enlarged tumors simultaneously. TRIAL REGISTRATION: Retrospectively registered and approved by the Institutional Review Board of our hospital ( FEMH-106151-C ).

Hematopoietic stem and progenitor cell responses to low radiation doses - implications for leukemia risk.

Studies of the responses of hematopoietic stem and progenitor cells (HSPCs) to low doses of ionizing radiation formed an important aspect of the RISK-IR project ( www.risk-ir.eu ). A brief overview of these studies is presented here. The findings confirm the sensitivity of HSPCs to radiation even at low doses, and illustrate the substantial impact that differentiation state has upon cell sensitivity. The work provides mechanistic support for epidemiological findings of leukemia risk at dose levels used in diagnostic CT imaging, and further suggests that low-dose irradiation may facilitate bone marrow transplantation, a finding that could lead to refinements in clinical practice.

Use of Radiation in Extramedullary Leukemia/Chloroma: Guidelines From the International Lymphoma Radiation Oncology Group.

Survival times for patients with leukemia generally have improved in recent decades, and this improvement has been attributed to an enhanced understanding of the genetics driving the cause of the disease and improved combinations of chemotherapy and targeted therapy. Durable control of systemic disease in blood and bone marrow has significantly improved survival, but extramedullary relapse can pose therapeutic challenges for which radiation therapy can have an important role. This report discusses the current role of radiation therapy for patients with leukemia, specifically the extramedullary manifestations of leukemia.

The Children's Oncology Group Radiation Oncology Discipline: 15 Years of Contributions to the Treatment of Childhood Cancer.

PURPOSE: Our aim was to review the advances in radiation therapy for the management of pediatric cancers made by the Children's Oncology Group (COG) radiation oncology discipline since its inception in 2000. METHODS AND MATERIALS: The various radiation oncology disease site leaders reviewed the contributions and advances in pediatric oncology made through the work of the COG. They have presented outcomes of relevant studies and summarized current treatment policies developed by consensus from experts in the field. RESULTS: The indications and techniques for pediatric radiation therapy have evolved considerably over the years for virtually all pediatric tumor types, resulting in improved cure rates together with the potential for decreased treatment-related morbidity and mortality. CONCLUSIONS: The COG radiation oncology discipline has made significant contributions toward the treatment of childhood cancer. Our discipline is committed to continuing research to refine and modernize the use of radiation therapy in current and future protocols with the goal of further improving the cure rates and quality of life of children with cancer.

Fertility after cryopreservation of ovarian tissue due to cancer treatment. / Fertilitet etter kryopreservering av ovarialvev ved kreftbehandling.

BAKGRUNN: Kryopreservering av ovarialvev som fertilitetsbevarende metode tilbys prepubertale jenter og kvinner i reproduktiv alder med høy risiko for å utvikle prematur ovarialsvikt i forbindelse med medisinsk eller kirurgisk behandling. I denne studien ønsket vi å kartlegge fertilitet og prematur ovarialsvikt hos kvinner som har fått gjort kryopreservering av ovarialvev i forbindelse med kreftbehandling. MATERIALE OG METODE: Et spørreskjema ble i 2014 sendt til 94 kvinner over 18 år som i perioden 2004-12 hadde fått kryopreservert ovarialvev i forbindelse med behandling for en malign tilstand. Skjemaet inneholdt spørsmål om menstruasjonsfrekvens, prevensjonsbruk, fertilitet, fremtidig barneønske og sannsynlighet for at de ville benytte ovarialvevet senere. Av de 77 kvinnene som returnerte spørreskjemaet, ble 74 kvinner inkludert i studien. RESULTATER: Totalt 20 av 74 kvinner (27 %) hadde prematur ovarialsvikt definert som opphør av ovarialfunksjonen før 40 års alder. Risikoen var lavest hos kvinner behandlet for brystkreft (5 %) og høyest hos kvinner behandlet for leukemi (75 %). Størst risiko for prematur ovarialsvikt fant man i pasientgruppene som hadde gjennomgått stamcelletransplantasjon, strålebehandling mot helkropp og/eller abdomen og bekken. Til sammen hadde 22 kvinner født 31 barn etter kreftbehandlingen, hvorav to etter reimplantasjon av ovarialvev. FORTOLKNING: Risikoen for å utvikle prematur ovarialsvikt er avhengig av pasientens kreftdiagnose. Hvilke fertilitetsbevarende tiltak som anbefales, bør differensieres avhengig av pasienten kreftdiagnose og planlagt behandling.

Use of speckle tracking in the evaluation of late subclinical myocardial damage in survivors of childhood acute leukaemia.

Heart disease is the leading cause of non-cancer death in childhood cancer survivors. to determine the prevalence of subclinical cardiac dysfunction using speckle tracking and compare its results with those obtained by classical methods of assessing left ventricular function and its relationship with different factors to identify the population at higher risk. Echocardiographic assessment of left ventricular function included ejection fraction, tissue Doppler, longitudinal/circumferential strains and biochemical parameters (troponin-T and Pro-BNP) in a cohort of 57 survivors of childhood acute leukaemia with at least 10 years since diagnosis. Ventricular dysfunction was found in 5.2% of patients in M-mode (ejection fraction-EF < 53% with a reduction in the EF ≥ 10%) and in 7% of patients with Simpson's method, compared with 21.05 and 8.8% with suboptimal global longitudinal strain (GLS) and global circumferential strain, respectively. The GLS alteration was significantly correlated with lower values of left ventricular systolic function and was associated with high tumour risk (odds ratio [OR] 13.8), cumulative doses of anthracyclines ≥ 250 mg/m2 (OR 7.6) and radiotherapy (OR 7.19). Biomarkers were not useful for the diagnosis of subclinical cardiomyopathy. Good reproducibility was obtained, with an intraobserver correlation of 93.6% and an interobserver correlation of 89.2% in the GLS. The alteration of the GLS was more prevalent than the alteration in the EF and was associated with the treatment received and high tumour risk. strain imaging seems to be a powerful tool to identify an increased number of survivor with an early myocardial injury.

Overweight in childhood cancer survivors: the Swiss Childhood Cancer Survivor Study.

Background: An increased risk of becoming overweight has been reported for childhood cancer survivors (CCSs), in particular leukemia survivors, although the evidence is inconclusive. Objective: We assessed the prevalence of overweight in CCSs, with a focus on leukemia survivors, compared it with their peers, and determined potential risk factors. Design: As part of the Swiss Childhood Cancer Survivor Study, we sent a questionnaire between 2007 and 2013 to all Swiss resident CCSs aged <21 y at diagnosis who had survived ≥5 y. We calculated body mass index (BMI) from medical records at diagnosis and self-reported heights and weights at survey. We calculated BMI z scores by using Swiss references for children and compared overweight prevalence in CCSs, their siblings, and the general population with the use of the Swiss Health Survey (SHS) and assessed risk factors for being overweight by using multivariable logistic regression. Results: The study included 2365 CCSs, 819 siblings, and 9591 SHS participants. At survey, at an average of 15 y after diagnosis, the prevalence of overweight in CCSs overall (26%) and in leukemia survivors (26%) was similar to that in siblings (22%) and the general population (25%). Risk factors for being overweight in CCSs were male sex (OR: 1.8; 95% CI: 1.5, 2.1), both young (OR for ages 5-14 y: 1.6; 95% CI: 1.2, 2.3) and older (range-OR for ages 25-29 y: 1.7; 95% CI: 1.2, 2.4; OR for ages 40-45 y: 4.0; 95% CI: 2.5, 6.5) age at study, lower education (OR: 1.4; 95% CI: 1.1, 1.8), migration background (OR: 1.3; 95% CI: 1.1, 1.7), and no sports participation (OR: 1.4; 95% CI: 1.1, 1.7). Risk factors for overweight were similar in peers. CCSs treated with cranial radiotherapy (≥20 Gy) were more likely to be overweight than their peers (OR: 1.6; 95% CI: 1.2, 2.2). Conclusions: The prevalence of and risk factors for being overweight are similar in long-term CCSs and their peers. This suggests that prevention methods can be the same as in the general population. An important exception is CCSs treated with cranial radiotherapy ≥20 Gy who may need extra attention during follow-up care. This study was registered at clinicaltrials.gov as NCT03297034.

Pregnancy and child health outcomes in pediatric and young adult leukemia and lymphoma survivors: a systematic review.

As long-term survival is high for children and young adults diagnosed with leukemia and lymphoma, delineating maternal, fetal and offspring health risks is important to their family planning. This systematic review examined data comparing these health risks between leukemia and lymphoma survivors and women without a history of cancer. Following a search of Embase, PubMed, CINAHL, Cochrane, and Web of Science, 142 articles were screened and 18 were included in this review. No higher risks of spontaneous abortion, maternal diabetes and anemia, stillbirth, birth defects, or childhood cancer in offspring were observed in survivors compared to controls. Important to counseling and clinical care, live birth rates were lower, while preterm birth and low birth weight risks were modestly higher in survivors compared to controls. Findings were largely reassuring but highlight the lack of data on maternal cardiopulmonary risks, differential risk by cancer treatment type, and interventions to decrease these risks.

Genome-Wide Association Study to Identify Susceptibility Loci That Modify Radiation-Related Risk for Breast Cancer After Childhood Cancer.

Background: Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. Methods: We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Results: Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8 ; <10 gray: rs17020562, 1q32.3, RPS6KC1 , RAF controls = 0.0005, P = 6.68 × 10 -8 ). Associations were restricted to these dose subgroups, with consistent findings in the two survivor cohorts. Conclusions: Our study provides strong evidence that germline genetics outside high-risk syndromes could modify the effect of radiation exposure on breast cancer risk after childhood cancer.

Therapeutic radiation for childhood cancer drives structural aberrations of NF2 in meningiomas.

Cranial radiotherapy improves survival of the most common childhood cancers, including brain tumors and leukemia. Unfortunately, long-term survivors are faced with consequences of secondary neoplasia, including radiation-induced meningiomas (RIMs). We characterized 31 RIMs with exome/NF2 intronic sequencing, RNA sequencing and methylation profiling, and found NF2 gene rearrangements in 12/31 of RIMs, an observation previously unreported in sporadic meningioma (SM). Additionally, known recurrent mutations characteristic of SM, including AKT1, KLF4, TRAF7 and SMO, were not observed in RIMs. Combined losses of chromosomes 1p and 22q were common in RIMs (16/18 cases) and overall, chromosomal aberrations were more complex than that observed in SM. Patterns of DNA methylation profiling supported similar cell of origin between RIMs and SMs. The findings indicate that the mutational landscape of RIMs is distinct from SMs, and have significant therapeutic implications for survivors of childhood cranial radiation and the elucidation of the molecular pathogenesis of meningiomas.Radiation-induced meningiomas are often more aggressive than sporadic ones. In this study, the authors perform an exome, methylation and RNA-seq analysis of 31 cases of radiation-induced meningioma and show NF2 rearrangement, an observation previously unreported in the sporadic tumors.

Craniospinal irradiation prior to stem cell transplant for hematologic malignancies with CNS involvement: Effectiveness and toxicity after photon or proton treatment.

PURPOSE/OBJECTIVE(S): Craniospinal irradiation (CSI) improves local control of leukemia/lymphoma with central nervous system (CNS) involvement; however, for adult patients anticipating stem cell transplant (SCT), cumulative treatment toxicity is a major concern. We evaluated toxicities and outcomes for patients receiving proton or photon CSI before SCT. METHODS AND MATERIALS: We identified 37 consecutive leukemia/lymphoma patients with CNS involvement who received CSI before SCT at our institution. Photon versus proton toxicities during CSI, transplant, and through 100 days posttransplant were compared using Fisher exact and Wilcoxon rank sum tests. Long-term neurotoxicity, disease response, and overall survival were analyzed. RESULTS: Thirty-seven patients (23 photon, 14 proton) underwent CSI for CNS involvement of acute lymphoblastic leukemia (49%), acute myeloblastic leukemia (22%), chronic lymphocytic leukemia (3%), chronic myelocytic leukemia (14%), lymphoma (11%), and myeloma (3%). CSI was used for consolidation (30 patients, 81%) and gross disease treatment (7 patients, 19%). Median radiation dose (interquartile range) was 24 Gy (23.4-24) for photons and 21.8 Gy (21.3-23.6) for protons (P = .03). Proton CSI was associated with lower rates of Radiation Therapy Oncology Group grade 1-3 mucositis during CSI (7% vs 44%, P = .03): 1 grade 3 with protons versus 5 grade 1, 3 grade 2, and 2 grade 3 with photons. During CSI, other toxicities (infection, gastrointestinal symptoms) did not differ. Allogeneic stem cell transplant (SCT) was used in 95% of patients, with 53% of patients in remission before SCT. Myeloablative conditioning was used for 76%. During SCT admission and 100 days post-SCT, toxicities did not differ by CSI technique. Successful engraftment occurred in 95% of patients (P = .67). Progression or death occurred for 47% of patients, with only 1 CNS relapse. CONCLUSION: In our cohort, CSI offered excellent local control for CNS-involved hematologic malignancies in the pre-SCT setting. Acute mucositis occurred less frequently with proton CSI with comparable peritransplant/long-term toxicity profile, suggesting the need to further explore the benefit/toxicity profile of this technique.

Findings May Lead to New Strategies for GVHD.

A new study in mice demonstrates that activating the RIG-I and STING signaling pathways, normally associated with antiviral immunity, can help protect the intestinal epithelium from damage caused by chemotherapy and radiation following stem cell transplantation. The findings may help in developing strategies to prevent graft-versus-host disease in patients with leukemia and other blood disorders.