Proton therapy in the most common pediatric non-central nervous system malignancies: an overview of clinical and dosimetric outcomes.

Radiation therapy represents an important approach in the therapeutic management of children and adolescents with malignant tumors and its application with modern techniques - including Proton Beam Therapy (PBT) - is of great interest. In particular, potential radiation-induced injuries and secondary malignancies - also associated to the prolonged life expectancy of patients - are still questions of concern that increase the debate on the usefulness of PBT in pediatric treatments. This paper presents a literary review of current applications of PBT in non-Central Nervous System pediatric tumors (such as retinoblastoma, Hodgkin Lymphoma, Wilms tumor, bone and soft tissues sarcomas). We specifically reported clinical results achieved with PBT and dosimetric comparisons between PBT and the most common photon-therapy techniques. The analysis emphasizes that PBT minimizes radiation doses to healthy growing organs, suggesting for reduced risks of late side-effects and radiation-induced secondary malignancies. Extended follow up and confirms by prospective clinical trials should support the effectiveness and long-term tolerance of PBT in the considered setting.

B-type natriuretic peptide plasma level in 5-year breast cancer survivors after radiotherapy.

BACKGROUND: Left-sided breast cancer patients treated with radiotherapy (RT) are at risk for late radiation-induced cardiovascular complications. AIM: The aim of this study was to investigate the BNP plasma levels in long-term breast cancer survivors who received only RT as well to assess whether cardiac dose was associated with BNP values. METHODS: Plasma samples for BNP measurement were repeated in 29 patients (63 ± 11 years) who were alive at 5 years after radiotherapy, free of heart disease and available to provide new blood sample. All patients had BNP measurements at baseline. The ΔBNP was measured to analyze the role of marker variations. No patients received chemotherapy. RESULTS: The mean cardiac and ventricle dose were 2.1 ± 1.0 (range 0.02-4.5) Gy and 3.0 ± 1.7 (range 0.02-7.6), respectively. Median value of BNP was 47 pg/mL (interquartile ranges, 26-58.2 pg/mL) at baseline, and 34 pg/mL (interquartile ranges, 17.5-54 pg/mL) at 5 years after radiotherapy. There was no significantly different between two measurements (p = ns). Fifteen (52%) reported an improvement in BNP levels, 1 (3%) no changes and 13 (45%) reported a worsening. There was no correlation between ΔBNP and age (p = ns). When patients were stratified according to the median value of dose-volume data, ΔBNP was significantly higher in patients with increased cardiac Dmean (p = .02) and left ventricle Dmean (p = .009). CONCLUSION: At 5 years after radiotherapy, median plasma BNP levels remained within the normal range, but the delta-BNP levels are directly related to the heart and ventricular dose received.

Ultrasound B-lines for detection of late lung fibrosis in breast cancer patients after radiation therapy.

BACKGROUND AND PURPOSE: Radiation therapy (RT) for breast cancer after conservative surgery can be life-saving but remains associated with significant late side effects, including lung fibrosis, detected by chest CT. Aim of this study was to assess whether lung ultrasound (LUS) may detect late lung fibrosis through the biomarker of B-lines. MATERIALS AND METHODS: We evaluated 30 women (median age 67 years, range 46-80 years) about 3-8 years after RT (follow up 38-101 months, median 58 months) for left (n = 12) or right (n = 18) breast cancer (stage 1, n = 24; stage 2, n = 6), treated with total dose 40.5 - 50.00 Gy with/without boost dose). In all, both treated and contralateral hemithorax were evaluated. LUS was performed and B-lines evaluated with a 28-region antero-lateral scan, from second to fifth intercostal spaces, along the mid-axillary, anterior axillary, mid-clavicular, and parasternal lines. In each space, the B-lines were counted from 0 = black lung to 10 = white lung. The sum of B-lines in all spaces generated the B-line score of each hemithorax. RESULTS: Median B-line score was higher in the irradiated site than in the contralateral control hemithorax (9, 1st-3rd quartiles: 2-23 vs 3, 1st-3rd quartiles: 1-4; P < 0.05). In the treated hemithorax, higher mean lung doses ( > median value of 2.7 Gy) were associated with more B-lines when compared to lower doses (< 2.7 Gy): 9 vs 5, p <0.001. CONCLUSION: RT in female breast cancer survivors is associated with increase in B-lines in the targeted hemithorax, likely due to lung fibrosis, and related to the lung mean dose. LUS can provide a simple "echo-marker" of lung fibrosis.

The Potential Role of Lung Ultrasound B-Lines for Detection of Lung Radio-Induced Toxicity in Breast Cancer Patients after Radiation Therapy.

BACKGROUND AND PURPOSE: Breast cancer patients exposed to doses of radiation after radiotherapy could develop toxicity to lung. Lung ultrasound (LUS) is able to detect interstitial lung disease by the evaluation of B-lines. The aim of our study was to assess the number of B-lines to diagnose lung involvement after chest radiotherapy. MATERIALS AND METHODS: We measured LUS B-lines in the treated and contralateral lung of 20 breast cancer patients, 1-3 months after the end of radiotherapy and 1 year after previous LUS. The sum of the B-lines number in the 72 sites on anterior and posterior chest yielded a global B-lines score. RESULTS: B-lines were more numerous in treated (median: 21; 1st-3rd quartiles: 11-31) versus untreated hemithorax (median: 3; 1st-3rd quartiles: 1-5) in both examination at T1-3 months (Kolmogorov-Smirnov test P < 0.001) and T1 year (median: 21; 1st-3rd quartiles: 12-28 vs. median: 4; 1st-3rd quartiles: 1-10; Kolmogorov-Smirnov test P < 0.01). Within the treated hemithorax, B-lines were more frequent in the anterior than in the posterior chest in both examination at T1-3 months (Kolmogorov-Smirnov test: P < 0.0001) and T1 year (Kolmogorov-Smirnov test: P < 0.01). Abnormal scores (B-lines>5) were present in 17/20 treated versus 7/20 untreated hemithoraxes (85.0 vs. 35.0%, P < 0.01) in the first LUS and likewise in 16/17 treated versus 7/17 in untreated hemithorax (94.1% vs. 41.2%, P < 0.01) after 1-year follow-up. CONCLUSION: Among women receiving radiotherapy after breast cancer, B-lines are present predominantly in the irradiated lung. These data suggest that B-lines by LUS could provide, at a subclinical stage, a radiation-free biomarker of radiotherapy-induced lung damage.

Kinetics of B-type natriuretic peptide plasma levels in patients with left-sided breast cancer treated with radiation therapy: Results after one-year follow-up.

PURPOSE: To analyze temporal changes of B-type natriuretic peptide (BNP) used as index of heart remodeling in left-sided breast cancer patients after radiotherapy (RT) and its relationship with dosimetric parameters. METHODS AND MATERIALS: BNP and dose-volume parameters for heart and ventricle were collected in 59 patients (median age 58.0 years) during a 1-year follow-up. Biochemical measurements were performed before the RT treatment (T0), at 15 days during RT (T(15day)), at the end of RT (T(endRT)), and then at 1, 3, 6, 9, 12 months (T1, T3, T6, T9 and T12). A logistical regression analysis was performed to identify demographic characteristics, dosimetric variables and risk factors associated with increased values of BNP. RESULTS: The ratio between the BNP value at T12 and the BNP value at T0 (BNP(T12)/BNP(T0)) increased significantly (p < 0.01). A significant association was found between the variation of BNP values after 1 year and the isodose received by 50% of the volume (D50% [Gy]) both to the heart (p = 0.03) and ventricle (p = 0.04). CONCLUSIONS: BNP plasma levels could provide additional information about subclinical RT-induced cardiotoxicity earlier than traditional ecocardiographic data.

Genetic risk score and acute skin toxicity after breast radiation therapy.

Genetic predisposition has been shown to affect the severity of skin complications in breast cancer patients after radiotherapy. Limited data exist regarding the use of a genetic risk score (GRS) for predicting risk of tissue radiosensitivity. We evaluated the impact of different single-nucleotide polymorphisms (SNPs) in genes related to DNA repair mechanisms and oxidative stress response combined in a GRS on acute adverse effects induced by breast radiation therapy (RT). Skin toxicity was scored according to the Radiation Therapy Oncology Group (RTOG) criteria in 59 breast cancer patients who received RT. After genotyping, a multilocus GRS was constructed by summing the number of risk alleles. The hazard ratio (HR) for GSTM1 was 2.4 (95% confidence intervals [CI]=1.1-5.3, p=0.04). The other polymorphisms were associated to an increased adverse radiosensitivity, although they did not reach statistical significance. GRS predicted roughly 40% risk for acute skin toxicity per risk allele (HR 1.37, 95% CI=1.1-1.76, p<0.01). Patients in the top tertile had a fivefold higher risk of skin reaction (HR 5.1, 95% CI=1.2-22.8, p=0.03). Our findings demonstrate that the joint effect of SNPs from oxidative stress and DNA damage repair genes may be a promising approach to identify patients with a high risk of skin reaction after breast RT.

Pulmonary epithelioid hemangioendothelioma presenting with vertebral metastases: a case report.

INTRODUCTION: Epithelioid hemangioendothelioma is a rare vascular tumor that has an epithelioid and histiocytoid appearance, originates from vascular endothelial or pre-endothelial cells and comprises less than 1% of all vascular tumors. It was described for the first time in 1975 as pulmonary epithelioid hemangioendothelioma, because initially it was believed to be an aggressive form of bronchoalveolar cell carcinoma with a remarkable propensity to invade adjacent blood vessels and small airways. Only a few cases have been reported in the literature to date. Tumor cells expressing Fli-1 and CD31 have been identified as relatively specific endothelial markers. Epithelioid hemangioendothelioma may affect multiple organs and may vary considerably in its clinical and radiological presentation. More than 50% to 76% of pulmonary epithelioid hemangioendothelioma patients are asymptomatic. They are usually incidentally diagnosed on the basis of abnormal chest radiography during routine physical examinations. Hematologic and gastrointestinal disorders and weakness or numbness may also be observed, in addition to respiratory symptoms, in cases of disseminated pulmonary epithelioid hemangioendothelioma. Pain and swelling, pathological fractures, spine compression or paresthesia, loss of muscular strength and paraplegia may be present when bone metastases occur. Because of the rarity of this disease, there is no standard for treatment. CASE PRESENTATION: A 46-year-old Caucasian woman presented to our institution in November 2009 with metastases of pulmonary epithelioid hemangioendothelioma from the L3 and L4 vertebrae. A course of radiotherapy at a dosage of 3,000 cGy delivered in individual doses of 200 cGy/day for 5 days/wk to the L3 and L4 vertebrae led to the disappearance of the patient's lumbar pain without any detectable side effects. Percussion of the patient's vertebral spine was negative, and no radiological progression of bone disease was found at her 1-year follow-up examination. CONCLUSION: Since epithelioid hemangioendothelioma was first correctly defined, several research groups have reported their experiences with epithelioid hemangioendothelioma irradiation. Further studies are needed to establish a standard radiation dose to be used for such a complex and extremely rare disease. In our present case, a radiotherapy dosage of 3,000 cGy delivered in individual doses 200 cGy/day for 5 days/wk allowed us to reach our goals: local pain control with good tolerance and better quality of life by the 1-year follow-up examination.

Epithelioid hemangioendothelioma: an overview and update on a rare vascular tumor.

Epithelioid hemangioendothelioma is a rare vascular tumor, described for the first time in 1975 by Dail and Liebow as an aggressive bronchoalveolar cell carcinoma. The etiology is still a dilemma. Studies about suggestive hypothesis are ongoing. Most of the times it affects lung, liver and bones, although this kind of tumor may involve the head and neck area, breast, lymph nodes, mediastinum, brain and meninges, the spine, skin, abdomen and many other sites. Because of its heterogeneous presentation, as it represents less than 1% of all the vascular tumors, it is often misdiagnosed and not suitably treated, leading to a poor prognosis in some cases. Over 50-76% of the patients are asymptomatic. A small number of them complains respiratory symptoms. Bone metastases might cause pathological fractures or spine compression, if they arise in vertebrae. Imaging is necessary to determine morphological data, the involvement of surrounding tissues, and potentially the cleavage plan. It is important to recognize the expression of vascular markers (Fli-1 and CD31 are endothelial-specific markers), and the microscopic evidence of vascular differentiation to make a correct diagnosis, as many pulmonary diseases show multiple nodular lesions. Because of its rarity, there is no standard for treatment. We focused on radiotherapy as a good therapeutic option: despite the poor prognosis, evidence is in favor of radiotherapy which offers local pain control with good tolerance and better quality of life at least at a one-year follow-up in most of cases. Further studies are needed to establish the standard radiation dose to be used for locoregional control of such a complex and extremely rare disease.

Radiation-induced cardiac damage in early left breast cancer patients: risk factors, biological mechanisms, radiobiology, and dosimetric constraints.

Today there is general awareness of the potential damage to the heart in left-sided (more than in right-sided) breast cancer radiotherapy (RT). Historical changes in tumor and heart doses are presented here along with the impact of different RT techniques and volumes. Individual and pharmacological risk factors are also examined with respect to radiation damage. The biological mechanisms of harm are only partially understood, such as the radiobiology of heart damage due to the presence of various radiosensitive structures and their topographic heterogeneity. Furthermore, individual variability may expose patients to higher or lower risks of late cardiac damage or death. Damage mechanisms and radiobiological characteristics in heart irradiation are presented in relation to dosimetric and biological parameters.