Explore the vast range of titles available.

Radiotherapy can be limited by pneumonitis, which is impacted by innate immunity, including pathways regulated by TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from toxic effects of radiation and found that 2 different agonists, parenteral PEGylated trimeric TRAIL (TLY012) and oral TRAIL-inducing compound (TIC10/ONC201), could reduce pneumonitis, alveolar wall thickness, and oxygen desaturation. Lung protection extended to late effects of radiation including less fibrosis at 22 weeks in TLY012-rescued survivors versus unrescued surviving irradiated mice. Wild-type orthotopic breast tumor-bearing mice receiving 20 Gy thoracic radiation were protected from pneumonitis with disappearance of tumors. At the molecular level, radioprotection appeared to be due to inhibition of CCL22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. Treatment with anti-CCL22 reduced lung injury in vivo but less so than TLY012. Pneumonitis severity was worse in female versus male mice, and this was associated with increased expression of X-linked TLR7. Irradiated mice had reduced esophagitis characterized by reduced epithelial disruption and muscularis externa thickness following treatment with the ONC201 analog ONC212. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from pneumonitis, dermatitis, and esophagitis following high doses of thoracic radiation exposure has important translational implications.

Dermatofibrosarcoma protuberans (DFSP) is a rare soft tissue sarcoma with low potential for metastases. To date, only a few cases of DFSP in the breast have been reported, and none have reported comprehensive genetic signatures. We report, for the first time, the largest DFSP in the breast with multidisciplinary tumor board discussion and comprehensive molecular analysis. This DFSP is 18.5 cm with fibrosarcomatous transformation, distinct gene rearrangement translocation t(17;22) (q22;q13), COL1A1::PDGFB fusion, and subsequent segmental amplification of chromosomes 17q and 22q. The high-level of amplifications of genomic regions containing the COL1A1 and PDGFB genes (6 copies) compared to the reported DFSP cases (2-3 copies) supports the gene dosage effect correlated with aggressive behavior and high-grade tumor histology. This case highlights the importance of precise genetic alteration in the clinicopathological and phenotypic expression of DFSP with fibrosarcomatous transformation, and it helps guide clinical management and informs the role of targeted therapy.

Background Intergroup 0139 Trial suggests an increase in mortality after pneumonectomy in patients receiving preoperative chemotherapy and radiation. We evaluate our outcomes with pneumonectomy after neoadjuvant chemotherapy and radiation. Methods Neoadjuvant chemotherapy and radiation consisted of cisplatin 50 mg/m 2 on days 1, 8, 29, and 36 and etoposide 50 mg/m 2 on days 1–5 and 29–33 given concurrently with 5,040 cGy radiation. From a prospective database, results after pneumonectomy were compared between patients receiving and not receiving neoadjuvant chemotherapy and radiation during the same time period. Results Over 7 years, 50 pneumonectomies were performed for non-small-cell carcinoma; 18 received neoadjuvant chemotherapy and radiation (group A) and 32 did not (group B). Comparing group A with group B, there was no significant difference in patient demographics, blood loss, transfusion requirements or pneumonectomy side. Group A had more patients with stage III disease [17/18 (94%) versus 15/32 (47%), P  = 0.001] and also more often had vascularized flap for bronchial stump coverage [17/18 (94%) versus 4/32 (13%), P  < 0.001]. There was no significant difference in operative morbidity or mortality. Mortality for group A was 0/18 and for group B was 2/32 (6.3%) ( P  = 0.530). Group A patients with IIIA(N2) disease ( n  = 13) had median recurrence-free survival of 12.4 months, median overall survival of 25 months, and 3-year overall survival of 22.2%. Conclusions Using a multidisciplinary team approach at a tertiary care center, pneumonectomy can be performed successfully after neoadjuvant chemotherapy and radiation for advanced-stage lung cancer. Vascularized flap for bronchial stump coverage may be important in this regard.

Background Prone breast positioning reduces skin reaction and heart and lung dose, but may also reduce radiation dose to axillary lymph nodes (ALNs). Methods Women with early stage breast cancer treated with whole breast irradiation (WBI) in the prone position were identified. Patients treated in the supine position were matched for treating physician, laterality, and fractionation. Ipsilateral breast, tumor bed, and Level I, II, and III ALNs were contoured according to the RTOG breast atlas. Clips marking surgically removed sentinel lymph nodes (SLN)s were contoured. Treatment plans developed for each patient were retrospectively analyzed. V90 % and V95 % was calculated for each axillary level. When present, dose to axillary surgical clips was calculated. Results Treatment plans for 46 women (23 prone and 23 supine) were reviewed. The mean V90 % and V95 % of ALN Level I was significantly lower for patients treated in the prone position (21% and 14%, respectively) than in the supine position (50% and 37%, respectively) ( p  < 0.0001 and p  < 0.0001, respectively). Generally, Level II & III ALNs received little dose in either position. Sentinel node biopsy clips were all contained within axillary Level I. The mean V95 % of SLN clips was 47% for patients treated in the supine position and 0% for patients treated in the prone position ( p  < 0.0001). Mean V90 % to SLN clips was 96% for women treated in the supine position but only 13% for women treated in the prone position. Conclusions Standard tangential breast irradiation in the prone position results in substantially reduced dose to the Level I axilla as compared with treatment in the supine position. For women in whom axillary coverage is indicated such as those with positive sentinel lymph node biopsy who do not undergo completion axillary dissection, treatment in the prone position may be inappropriate.

Cancer therapy is often limited by toxicity from pneumonitis. This often-lethal side effect is known to be impacted by innate immunity, and in particular the pathways regulated by the TRAIL death receptor DR5. We investigated whether DR5 agonists could rescue mice from the lethal effects of radiation. We found that two different agonists, parenteral PEGylated trimeric-TRAIL (TLY012) and oral TRAIL-Inducing Compound #10 (TIC10/ONC201), could achieve this goal. Both compounds could completely protect mice from lethality by reducing pneumonitis, alveolar-wall thickness, and oxygen desaturation. At the molecular level, this protection appeared to be due to the inhibition of CCl22, a macrophage-derived chemokine previously associated with radiation pneumonitis and pulmonary fibrosis. The discovery that short-term treatment with TRAIL pathway agonists effectively rescues animals from high doses of radiation exposure has important translational implications. Prevention of lethality, pneumonitis, lung fibrosis and skin dermatitis post-ψ-irradiation by short- term treatment with innate immune TRAIL pathway agonists

The standard treatment of stage I non-small cell lung cancer (NSCLC) is surgical resection. Some patients are poor surgical candidates due to severe comorbid medical conditions. Radiotherapy alone has historically been used in this patient population with limited success. Radiofrequency ablation (RFA) is an image-guided, thermally mediated ablative technique recently applied to lung tumors. Combination therapy with both these treatments has not been previously performed. We report our experience with combined CT-guided RFA and conventional radiotherapy in 24 medically inoperable patients with a minimum of 2-year study follow-up in surviving patients. Twenty-four consecutive, medically inoperable patients with biopsy-proven, stage I NSCLC were treated with CT-guided RFA followed by radiotherapy to a dose of 66 Gy. RFA was performed with a single or cluster cool-tip F electrode; 21 patients were staged before therapy using fluorodeoxyglucose-positron emission tomography. There were 14 women and 10 men (median age, 76 years; range, 58 to 85 years). The histologic subtypes were squamous cell (n = 13), adenocarcinoma (n = 5), and undifferentiated (n = 6). All patients received RFA followed by three-dimensional conformal radiotherapy. There were no treatment-related deaths or grade 3/4 toxicities. Pneumothorax requiring chest tubes developed in three patients (12.5%). At a mean follow-up period of 26.7 months (range, 6 to 65 months), 14 patients (58.3%) died, with cumulative survival rates of 50% and 39% at the end of 2 years and 5 years, respectively. Ten of the deaths were cancer related. Two patients had local recurrence (8.3%), while nine patients had systemic metastatic disease. Three patients died of respiratory failure with no evidence of active disease, and one patient died of a cerebrovascular accident at 18-month follow-up. Pleural effusions developed after treatment in six patients (25%), which proved to be malignant in one patient. RFA followed by conventional radiotherapy is feasible in this population of medically inoperable stage I NSCLC patients. Procedural complication rates are low, and no additional major toxicities were seen despite the addition of RFA. Local control and survival rates appear to be better than with radiotherapy alone.

Trastuzumab is a monoclonal antibody against HER2 (also known as ERBB2). The primary objective of the NRG Oncology/RTOG-1010 trial was to establish whether trastuzumab improves disease-free survival when combined with trimodality treatment (paclitaxel plus carboplatin and radiotherapy, followed by surgery) for patients with untreated HER2-overexpressing oesophageal adenocarcinoma. NRG Oncology/RTOG-1010 was an open label, randomised, phase 3 trial for which patients were accrued from 111 NRG-affiliated institutions in the USA. Eligible patients were adults (aged ≥18 years) with newly diagnosed pathologically confirmed oesophageal adenocarcinoma, American Joint Committee on Cancer 7th edition T1N1–2 or T2–3N0–2 stage disease, and a Zubrod performance status of 0–2. Patients were stratified by adenopathy (no vs yes [coeliac absent] vs yes [coeliac present ≤2 cm]) and randomly assigned (1:1) to receive weekly intravenous paclitaxel (50 mg/m2 intravenously over 1 h) and carboplatin (area under the curve 2, intravenously over 30–60 min) for 6 weeks with radiotherapy 50·4 Gy in 28 fractions (chemoradiotherapy) followed by surgery, with or without intravenous trastuzumab (4 mg/kg in week one, 2 mg/kg per week for 5 weeks during chemoradiotherapy, 6 mg/kg once presurgery, and 6 mg/kg every 3 weeks for 13 treatments starting 21–56 days after surgery). The primary endpoint, disease-free survival, was defined as the time from randomisation to death or first of locoregional disease persistence or recurrence, distant metastases, or second primary malignancy. Analyses were done by modified intention to treat. This study is registered with Clinicaltrials.gov, NCT01196390; it is now closed and in follow-up. 606 patients were entered for HER2 assessment from Dec 30, 2010 to Nov 10, 2015, and 203 eligible patients who were HER2-positive were enrolled and randomly assigned to chemoradiotherapy plus trastuzumab (n=102) or chemoradiotherapy alone (n=101). Median duration of follow-up was 2·8 years (IQR 1·4–5·7). Median disease-free survival was 19·6 months (95% CI 13·5–26·2) with chemoradiotherapy plus trastuzumab compared with 14·2 months (10·5–23·0) for chemoradiotherapy alone (hazard ratio 0·99 [95% CI 0·71–1·39], log-rank p=0·97). Grade 3 treatment-related adverse events occurred in 41 (43%) of 95 patients in the chemoradiotherapy plus trastuzumab group versus 52 (54%) of 96 in the chemoradiotherapy group and grade 4 events occurred in 20 (21%) versus 21 (22%). The most common grade 3 or worse treatment-related adverse events for both groups were haematological (53 [56%] of 95 patients in the chemoradiotherapy plus trastuzumab group vs 55 [57%] of 96 patients in the chemotherapy group) or gastrointestinal disorders (28 [29%] vs 20 [21 %]). 34 (36%) of 95 patients in the chemoradiotherapy plus trastuzumab group and 27 (28%) of 96 patients in the chemoradiotherapy only group had treatment-related serious adverse events. There were eight treatment-related deaths: five (5%) of 95 patients in the chemoradiotherapy plus trastuzumab group (bronchopleural fistula, oesophageal anastomotic leak, lung infection, sudden death, and death not otherwise specified), and three (3%) of 96 in the chemoradiotherapy group (two multiorgan failure and one sepsis). The addition of trastuzumab to neoadjuvant chemoradiotherapy for HER2-overexpressing oesophageal cancer was not effective. Trastuzumab did not lead to increased toxicities, suggesting that future studies combining it with or using other agents targeting HER2 in oesophageal cancer are warranted. National Cancer Institute and Genentech.