Search

BACKGROUND AND OBJECTIVE: Radiation-induced lung injury (RILI) is often found in thoracic tumor patients after thoracic radiation therapy, and influences patient quality of life. However, systematic exploration of RILI, including its molecular biological mechanisms and standardized treatment, has not yet been fully elucidated. The main objective of the narrative review was to describe the available evidence concerning RILI, from the biological mechanism to the clinical management. The underlying causes of RILI are multifactorial, including gene-level changes, the influence of signaling pathways, the convergence of various cells, as well as the expression of cytokines and chemokines. Based on the various mechanisms of RILI, several novel treatment strategies have been proposed and gradually applied in clinical practice. METHODS: PubMed was used to collect articles about RILI from 1995 to 2021. The papers included clinical trials, reviews, as well as systematic reviews and meta-analyses. Based on the mechanism, diagnosis, and treatment, we synthesized and analyzed these papers to form a clearly logical and normative suggestion to guide clinical application. KEY CONTENT AND FINDINGS: RILI is a constantly developing and changing process including radiation pneumonitis and radiation lung fibrosis. Different kinds of inflammatory and immune cells such as macrophages, fibroblasts, and T cells play key roles in the development of RILI, and transforming growth factor-β (TGF-β), interleukin-4 (IL-4), IL-13, and interferon-γ (IFN-γ) are also participants in this process. At present, glucocorticoids are mainly therapeutic drugs for the early stage of RILI, and drugs treatment should abide early period, sufficient doses, and the individual principles. Other novel drugs such as Azithromycin also have been tried in clinical application. radiation dose, combination therapy modality, the condition of the tumor, and the age and underlying conditions of patients all effect the occurrence of RILI. Importantly, RILI has a relatively higher incidence in patients who received radiotherapy combined with other treatments, especially immunotherapy. CONCLUSIONS: The occurrence of RILI after radiotherapy will greatly affect the prognosis and quality of life of patients. In clinical practice, early intervention, active treatment, and more effective therapeutic drugs should be found.

The recently identified bilateral macroscopic tubarial salivary glands present a potential opportunity for further toxicity mitigation for patients receiving head and neck radiotherapy. Here, we show superior dosimetric sparing of the tubarial salivary glands with proton radiation therapy (PRT) compared to intensity-modulated radiotherapy (IMRT) for patients treated postoperatively for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC). This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved, equivalent IMRT plan to serve as a reference. The main end point was dose delivered to the tubarial salivary glands by modality, assessed via a 2-tailed, paired t-test. We also report disease outcomes for the entire cohort, via the Kaplan-Meier method. Sixty-four patients were identified. The mean RT dose to the tubarial salivary glands was 23.6 Gy (95% confidence interval (CI) 21.7 to 25.5) and 30.4 Gy (28.6 to 32.2) for PRT and IMRT plans (p0.0001), respectively. With a median follow-up of 25.2 months, the two-year locoregional control, progression-free survival and overall survival were 97.8% (95% CI 85.6% to 99.7%), 94.1% (82.8% to 98.1%) and 98.1% (87.4% to 99.7%), respectively. Our study suggests that meaningful normal tissue sparing of the recently identified tubarial salivary glands is achievable with PRT. The apparent gains with PRT did not impact disease outcomes, with only 1 observed locoregional recurrence (0 local, 1 regional). Further studies are warranted to explore the impact of the improved dosimetric sparing of the tubarial salivary glands conveyed by PRT on patient toxicity and quality of life.

Fbln5 and α5β1 integrin expression pattern in mouse and human (S1); Characterization of KIC and KPC mice (S2); Examination of ROS levels in normal pancreas and NAC-treated KIC and RGE KIC tumors (S3); Reduced microvessel density (MVD) in RGE KIC and RGE KPC tumors compared to KIC and KPC tumors (S4); Examination and quantification of MVD in pancreatic tissues from KIC and RGE KIC, WT and RGE mice (S5); Fbln5 expression in Fbln5 WT, KO and RGE MEFs (S6); NADPH oxidase (Nox) is not the source of ROS induction for RGE MEFs when plated on FN (S7).

Description of additional methods and procedures used in the study.

Elevated oxidative stress is an aberration seen in many solid tumors, and exploiting this biochemical difference has the potential to enhance the efficacy of anticancer agents. Homeostasis of reactive oxygen species (ROS) is important for normal cell function, but excessive production of ROS can result in cellular toxicity, and therefore ROS levels must be balanced finely. Here, we highlight the relationship between the extracellular matrix and ROS production by reporting a novel function of the matricellular protein Fibulin-5 (Fbln5). We used genetically engineered mouse models of pancreatic ductal adenocarcinoma (PDAC) and found that mutation of the integrin-binding domain of Fbln5 led to decreased tumor growth, increased survival, and enhanced chemoresponse to standard PDAC therapies. Through mechanistic investigations, we found that improved survival was due to increased levels of oxidative stress in Fbln5-mutant tumors. Furthermore, loss of the Fbln5–integrin interaction augmented fibronectin signaling, driving integrin-induced ROS production in a 5-lipooxygenase–dependent manner. These data indicate that Fbln5 promotes PDAC progression by functioning as a molecular rheostat that modulates cell–ECM interactions to reduce ROS production, and thus tip the balance in favor of tumor cell survival and treatment-refractory disease. Cancer Res; 75(23); 5058–69. ©2015 AACR.

Recent improvements in chemoimmunotherapies, targeted agents, hematopoietic stem cell transplants, and cellular therapies have revolutionized treatment paradigms for patients with diffuse large B-cell lymphoma (DLBCL). Even in the relapsed or refractory setting, contemporary treatment options are delivered with curative intent and can lead to lasting remissions. Although such therapies have improved overall outcomes, they have increasingly led to a wide variety of presentations of recurrent tumors in need of palliation. Here, we review the use of radiotherapy (RT) in the palliation of DLBCL. We draw particular attention to the evolving role for hypofractionated RT and low-dose RT for DLBCL. We review the available literature on these topics and focus on commonly encountered clinical scenarios.

Financial conflicts of interest (FCOIs) could bias the potentially practice-changing oncologic randomized clinical trials (RCTs) of tomorrow. This investigation characterized the FCOIs of the principal investigators (PIs) of all currently accruing trials of the four (adult) cooperative groups of the National Clinical Trials Network. For this study, the PI list was first compiled, and each name was then searched in the CMS Open Payments database. For each transaction (general payments (GPs) or research funding (RF)), the amount/number/source of payments was recorded. Results showed that from 2014-2019, the 91 PIs collectively accepted nearly one-third of a billion dollars ($10 477 023 GPs and $320 096 233 RF). The mean and median GP was $6505 and $945 respectively, and $301 693 and $49 824 RF respectively. Multivariable Gamma regression analysis revealed that higher GP sums were associated with RCTs involving any type of systemic therapy, and higher RF sums with medical oncologist PIs, trials with phase III components, and RCTs involving radiotherapy (P < 0.05 for all). Both higher-volume GPs and RF were predicted by PIs having accepted payment(s) from the manufacturer of the drug utilized in their RCT (P < 0.001 GP, P = 0.008 RF). Taken together, the main message of this investigation is that FCOIs may be particularly high in PIs of phase III systemic therapy trials, especially if the PI accepted payments from the manufacturer of the drug utilized in their trial. Such RCTs should be thoroughly scrutinized by medical journals, the FDA, and insurance companies for potential “industry bias” that could influence the integrity of their conclusions. This article is protected by copyright. All rights reserved.

Background Despite accounting for a minority of malignant pleural mesothelioma (MPM) diagnoses, females may experience differential survival relative to males. It is unclear if there are gender-based differences in receipt of treatment or disease-related outcomes for patients with MPM. We therefore utilized the National Cancer Database (NCDB) to assess patterns-of-care and overall survival (OS) among patients with MPM by gender. Materials and Methods Patients with histologically confirmed MPM treated from 2004 to 2013 were identified from the NCDB. The association between female gender and OS was assessed using multivariable Cox proportional hazards models with propensity score matching. Patterns-of-care were assessed using multivariable logistic regression. The overall treatment effect was tested in subsets of patients by treatment strategy, histology, and clinical stage. Results A total of 18,799 patients were identified, of whom 14,728 (78%) were male and 4071 (22%) were female. Females were statistically more likely to present at a younger age, with fewer comorbidities, and with epithelioid histology. Despite these favorable prognostic features, women were less likely to receive surgery (P ≤ .001) or chemotherapy (P ≤ .001) compared with males. On multivariable analysis, female gender was associated with improved OS (hazard ratio, 0.83; 95% confidence interval, 0.80-0.86; P ≤ .001). Gender-based survival differences were seen across all stages, but only among patients with epithelioid (P ≤ .001) and not biphasic (P = .17) or sarcomatoid (P = 1.00) histology. Conclusions Surgery and chemotherapy are disproportionately underutilized in female patients with MPM. Despite this concerning disparity, female gender is independently associated with improved survival relative to males. Further research to understand factors that lead to gender disparities in MPM is warranted.

Background Radiation therapy (RT) can provide effective symptomatic palliation in patients with malignant pleural mesothelioma (MPM). Advances in RT technology, including intensity-modulated RT (IMRT) and volumetric-modulated arc therapy (VMAT), have improved treatment conformality, potentially improving the therapeutic ratio of RT. A novel 6-MV flattening-filter-free O-ring linear accelerator, HalcyonTM (Varian Medical Systems, Palo Alto, CA, USA), was built to provide such advanced therapies, while possibly reducing treatment time. Here, we report the initial clinical experience using HalcyonTM to deliver palliative RT for patients with MPM. Methods We retrospectively assessed consecutive patients with MPM who received thoracic RT on HalcyonTM. Their electronic medical records were reviewed for clinical, RT planning, treatment timing, and image-guidance RT (IGRT) data. Results Four patients with metastatic MPM received palliative RT on HalcyonTM between 1/2017-1/2020 for severe pain (50%), dysphagia (25%), or dyspnea (25%). Targets included a combination of pleura, chest wall, lung, hilum, and mediastinum, with patient-specific dose and fractionation regimens ranging from 20-45 Gy in 5-15 fractions, and 75% of patients receiving concurrent systemic therapy. Pre-specified target and organ-at-risk constraints were met for nearly all plans. At a median follow-up of 2.2 months (range, 1.6-7.1 months), all patients experienced either improved (75%) or stable (25%) tumor-related symptoms following palliative RT. The mean 3D vector couch correction was 0.67±0.15 cm. The mean beam-on, treatment (beam-on plus cone-beam computed tomography times), and approximated total room usage times were 1.6±0.2, 1.8±0.2, and 9.8±0.2 min, respectively. Grade 2 fatigue and cough occurred in 25% and 25% of patients, and no patients experienced Grade ≥3 toxicity. Conclusions In this initial clinical experience treating patients with palliative RT for MPM on HalcyonTM, treatment provided symptom palliation and local control across multiple palliative scenarios, with minimal toxicity, acceptable dosimetry, and setup corrections and treatment times that compared favorably with other published experiences of MPM RT. Palliative RT on HalcyonTM can provide patients with MPM quick and safe tumor-related symptom relief, even in a frail, elderly population.

Although dose de-escalation is one proposed strategy to mitigate long-term toxicity in human papillomavirus associated oropharyngeal cancer, applying more stringent normal tissue constraints may be a complementary approach to further reduce toxicity. Our study demonstrates that in a postoperative setting, improving upon nationally accepted constraints is achievable and leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease control.We identified 92 patients at our institution between 2015 and 2019 with p16+ oropharyngeal cancer who were treated with adjuvant volumetric modulated arc therapy. We included patients treated to postoperative doses and standard volumes (including bilateral neck). Doses delivered to organs at risk were compared with recommended dose constraints from a recent cooperative group head and neck cancer trial of radiation therapy to 60 Gy. We applied validated and published NTCP models for dysphagia, dysgeusia, esophagitis, oral mucositis, and xerostomia relevant to oropharyngeal cancer.Achievable and delivered mean doses to most normal head and neck tissues were well below national recommended constraints. This translates to notable absolute NTCP reductions for salivary flow (10% improvement in contralateral parotid, 35% improvement in submandibular gland), grade ≥ 2 esophagitis (23% improvement), grade ≥ 3 mucositis (17% improvement), dysgeusia (10% improvement), and dysphagia (8% improvement). Locoregional control at a median follow-up of 26.3 months was 96.7%, with only 3 patients experiencing locoregional recurrence (1 local, 2 regional).Modern radiation therapy planning techniques allow for improved normal tissue sparing compared with currently established dose constraints without compromising disease control. These improvements may lead to reduced toxicity in a patient population expected to have favorable long-term outcomes. Stricter constraints can be easily achieved and should be used in conjunction with other evolving efforts to mitigate toxicity.

PurposeRadiation therapy (RT) with doses ranging from 24 Gray (Gy) to 40 Gy is a proven treatment modality for indolent orbital adnexal lymphoma (IOAL), but recently the use of low dose RT (LDRT, defined as 2 Gy x 2 fractions) has become a notable alternative. However, limited data exists comparing outcomes following LDRT to moderate-dose RT (MDRT, RT dose 4 – 36 Gy). We present a single institution retrospective analysis comparing outcomes of patients with IOALs following LDRT or MDRT.MethodsA total of 36 patients treated with 38 consecutive courses of RT were identified; LDRT was delivered for 14 courses and MDRT for 24 courses. Overall response rates (ORR) were recorded according to Deauville or RECIST criteria with a response characterized as a complete response (CR) or partial response. Local control (LC), orbital control (OC), and overall survival (OS) rates were estimated with the Kaplan-Meier method. RT toxicity was graded per CTCAEv5 and compared with the Fisher’s exact test.ResultsMedian follow-up time was 29 months (m) (range, 4-129m), and median MDRT dose used was 24 Gy (range 21-36 Gy). Overall response rates (ORR) were 100% (CR 50%) and 87.5% (CR 58.3%) following LDRT and MDRT, respectively. OS at 2 years was 100% and 95% for the LDRT and MDRT groups, respectively (p=0.36). LC rates at 2 years was 100% for both LDRT and MDRT groups and at 4 years was 100% and 89% for the LDRT and MDRT groups, respectively (p=0.56). The 4-year OC rate (including both ipsilateral and contralateral relapses) was 80% and 85% for the LDRT and MDRT groups, respectively (p=0.79). No patient required treatment with RT to a previously irradiated orbit. Acute toxicities were reported following 6 LDRT courses compared to 20 MDRT courses (p=.014). No Grade 3 or higher acute toxicities occurred in either group. Late toxicities were reported following 2 LDRT courses compared to 10 MDRT courses (p=0.147).ConclusionsLDRT produced similar ORR, LC, OC, and OS rates compared to MDRT with fewer acute and minimal late toxicities reported. Future multi-center studies with larger patient numbers are warranted to show significant associations.

Purpose One significant advantage of proton therapy is its ability to improve normal tissue sparing and toxicity mitigation, which is relevant in the treatment of oropharyngeal squamous cell carcinoma (OPSCC). Here, we report our institutional experience and dosimetric results with adjuvant proton radiation therapy (PRT) versus intensity-modulated radiotherapy (IMRT) for Human Papilloma Virus (HPV)-associated OPSCC. Materials and Methods This was a retrospective, single institutional study of all patients treated with adjuvant PRT for HPV-associated OPSCC from 2015 to 2019. Each patient had a treatment-approved equivalent IMRT plan to serve as a reference. Endpoints included dosimetric outcomes to the organs at risk (OARs), local regional control (LRC), progression-free survival (PFS), and overall survival (OS). Descriptive statistics, a 2-tailed paired t test for dosimetric comparisons, and the Kaplan-Meier method for disease outcomes were used. Results Fifty-three patients were identified. Doses delivered to OARs compared favorably for PRT versus IMRT, particularly for the pharyngeal constrictors, esophagus, larynx, oral cavity, and submandibular and parotid glands. The achieved normal tissue sparing did not negatively impact disease outcomes, with 2-year LRC, PFS, and OS of 97.0%, 90.3%, and 97.5%, respectively. Conclusion Our study suggests that meaningful normal tissue sparing in the postoperative setting is achievable with PRT, without impacting disease outcomes.

Gingival myeloid sarcoma (MS) refractory to induction chemotherapy is a rare clinical entity and can be treated with palliative radiation therapy (RT). However, there are few previously published reports of RT approaches for the treatment of gingival MS. We present a single institution retrospective observational study of adult patients treated with palliative RT for chemotherapy refractory gingival MS. A total of six patients diagnosed with gingival MS in the setting of relapsed or refractory acute myeloid leukemia treated with palliative RT were identified, with a median age of 66 (range 52–77). Patients were treated with radiation doses ranging from 5 to 20 Gy in 2–10 fractions. Two patients had adequate follow-up time to assess treatment response. One patient who was simulated with PET/CT experienced a local complete response, while the other patient required retreatment 2 months after initial treatment and experienced an eventual local partial response. Three patients experienced radiation mucositis, with one patient experiencing grade 5 toxicity attributed to concomitant treatment with the radiosensitizer hydroxyurea. We believe that this study can provide a practical reference point for other clinicians given the rarity of gingival MS requiring palliative radiation therapy as a clinical entity.

PURPOSE/OBJECTIVE(S) Orbital low grade non-Hodgkin Lymphomas (LGNHLs) are a common tumor of the ocular adnexa. Courses of low-dose radiotherapy (LDRT), previously defined as 2 Gray (Gy) x 2 fractions, have resulted in excellent short-term outcomes for orbital LGNHLs. Recent data, however, suggests that higher doses are associated with improvements in response rates and progression free survival. RT is a proven treatment modality for this entity, but no prior data exists comparing outcomes following LDRT to moderate-dose RT (MDRT, RT dose > 4 Gy). Herein, we compare outcomes including overall response rates (ORR), local control (LC) and overall survival (OS) for patients treated with LDRT vs MDRT. MATERIALS/METHODS We reviewed 38 consecutive courses of RT for 36 patients treated for orbital LGNHL at a single institution. Bilateral disease was present in 15 patients. Nine patients had advanced stage disease or secondary orbital lymphoma following systemic dissemination. Indolent histologies included marginal zone lymphoma (20 patients), follicular lymphoma (11 patients), and mantle cell lymphoma (MCL, 5 patients). ORR were recorded according to Deauville or RECIST criteria with a response characterized as a complete response (CR) or partial response. Time to orbital recurrence (TTOR) and OS were estimated with the Kaplan-Meier (KM) method from start of RT to event or last follow-up. Univariate and multivariate Cox regression analysis was performed for characteristics associated with the studied outcomes. RT toxicity was graded per CTCAEv5. RESULTS Median follow-up time for all patients was 29 months (m) (range, 4-129m) and median MDRT dose used was 24 Gy (range 21-36 Gy) in 1.5-2 Gy fractions. LDRT was delivered for 14 courses and MDRT for 24 courses. Advanced stage (odds ratio (OR) 7, P = 0.021) and year of RT ≥2016 (OR 24, P = 0.008) were associated with increased use of LDRT as compared to MDRT. Acute grade 1 (G1) and G2 RT toxicities occurred following 22 (58%) and 5 (13%) courses, respectively. No ≥G3 acute toxicities occurred. Late toxicities included 6 patients with G1 dry eye (4 MDRT, 2 LDRT), 3 patients with G2 dry eye (3 MDRT) and one patient with a G1 cataract (1 MDRT). ORR were 100% (CR 50%) and 87.5% (CR 58.3%) following LDRT and MDRT, respectively. No evaluated characteristics, including the use of LDRT, were significantly associated with inferior ORR, TTOR or OS. LC at 2 years was 100% and 95% for the LDRT and MDRT groups, respectively. CONCLUSION RT for orbital LGNHL is associated with excellent outcomes in terms of response rates and local control. Due to the exquisite radiosensitivity of orbital LGNHL, LDRT produces similar response rates and TTOR as compared to more protracted RT courses. Present data suggests that LDRT should be considered for patients with orbital LGNHL; however, further multi-center studies with larger patient numbers are warranted to show significant associations.

PURPOSE/OBJECTIVE(S) Toxicity mitigation is a salient focus in the treatment of HPV-associated oropharyngeal cancer. As the standard of care evolves, toxicity mitigation can be facilitated by adopting more stringent normal tissue constraints. We hypothesize that further reduction in currently accepted constraints leads to reductions in normal tissue complication probabilities (NTCP) without compromising disease outcomes. MATERIALS/METHODS This was a retrospective, single-institution study of patients with oropharynx cancer treated with adjuvant volumetric modulated arc therapy to standard doses (60-66 Gy) and volumes (i.e., bilateral neck) from 2015-2018. Doses delivered to organs at risk were compared to recommended dose acceptance criteria from a recent, cooperative trial of RT to 60 Gy (NRG HN002). We applied validated, published NTCP models for xerostomia, dysphagia, dysgeusia, oral mucositis and esophagitis relevant to oropharyngeal cancer. RESULTS 92 patients were identified. Median follow-up was 2.2 years. The doses achieved and corresponding estimates of NTCP are shown in Table 1, as compared to a nationally recognized standard (NRG HN002). Notable NTCP reductions were observed for salivary flow, dysphagia, dysgeusia, mucositis, and esophagitis. The use of more stringent constraints did not impact disease outcome, with only a total of 3 patients having experienced locoregional recurrence (1 local, 2 regional), for an overall locoregional control of 96.7%. CONCLUSION Improved normal tissue sparing compared to current dose constraint standards is achievable with contemporary RT planning techniques. These improved constraints may lead to decreased toxicity, while preserving excellent disease outcomes. Our constraints can easily be adopted as standard of care and used in conjunction with other efforts to mitigate toxicity.

Purpose/Objective(s) This study aims to address a question on the potential role of omics in machine learning (ML) interpretability. Materials/Methods We performed a retrospective study to investigate the association between clinical features and overall survival (OS) in 778 patients with stage III or IV head and neck squamous cell carcinoma (HNSCC), who participated in the RTOG 0522 randomized trial, by using an interpretable ML model known as the Explainable Boosting Machine (EBM). By extracting and adding omics (radiomics and dosiomics) features to the clinical features, we attempted to determine the potential role of omics with respect to the interpretability of the ML model for predicting OS. Results The EBM model showed clear details of the contribution of each feature to OS prediction and supported the primary findings in RTOG 0522 that the primary tumor site, N2b-3 category, T4 tumor, smoking history ≥ 10 pack-years of cigarette, age > 50 years, and Zubrod performance status are strong predictors of poor OS. The interpretable model also predicted a 2-year survival with 69% and a 5-year survival with 72% in accuracy in the test dataset, despite not having certain critical features such as human papillomavirus status due to significant missing values. The performance of the EBM model for predicting 2-year and 5-year survival achieved the area under the curve of 0.69 and 0.73, respectively. When dosiomics information was added to the dose-volume histogram parameters, we observed a clearer trend in the model's explanations on risk scores for clinical features, illustrating that omics could promote the development of personalized medicine. Conclusion Our findings contribute to the evidence that the addition of omics in prognostic models can improve ML interpretability.

Purpose/objective(s) Radiotherapy is curative for the majority of patients with IOAL. Some reports suggest inferior outcomes for bilateral IOAL, leading to uncertainty regarding optimal management for this presentation. This retrospective, international study evaluated long-term outcomes of bilateral IOAL treated with radiotherapy alone, with the current analysis limited to synchronous presentations (defined as ≤90 days between diagnoses). Materials/methods Ninety patients with bilateral synchronous IOAL were treated with radiotherapy to both orbits at 13 centers. Overall (OS), progression-free survival (PFS), freedom from local (FFLF) and freedom from distant (FFDF) failure were measured from the commencement of treatment of the second orbit. The study met local institutional review board requirements. Results The median age at diagnosis was 55 years (range 15-83), with 47% males. Histology was marginal zone lymphoma in 90% and disease was conjunctival in 65% of orbits. Sixty-three percent had bilateral conjunctival disease. The radiotherapy dose (per orbit) was 20-25.2 Gy for 46%, 27-30.6 Gy for 33%, 33-40 Gy for 8% and 13% had 4 Gy. Radiotherapy was given to the whole orbit for 62% of orbits, conjunctiva only for 29% and other partial orbit for 9%. Median follow-up was 6.6 years. The 10-year OS and PFS were 99% (95% CI: 92-100) and 73% (95% CI: 60-82), respectively. Ten-year FFLF and FFDF were 88% (95% CI: 78-94) and 83% (95% CI: 70-91), respectively. PFS was lower for the 33 patients with one or both orbits having non-conjunctival disease (HR 3.7 (1.4-9.3), P = 0.004). Three-year FFLP was 91% (95% CI: 81-95) for orbits receiving ≥ 20 Gy and 61% (95% CI: 27-84) after 4Gy (P Conclusion In this large, multicenter experience, patients with bilateral, synchronous IOAL treated with radiotherapy alone appeared to have outcomes comparable to historical series of unilateral disease. These results would suggest bilateral IOAL can be considered a localized process and support the use of curative intent radiotherapy in this setting.

The origin of the inner dust cavities observed in transition discs remains unknown. The segregation of dust and size of the cavity is expected to vary depending on which clearing mechanism dominates grain evolution. We present the results from the Discs Down Under program, an 8.8 mm continuum Australia Telescope Compact Array (ATCA) survey targeting 15 transition discs with large (> 20 au) cavities, and compare the resulting dust emission to Atacama Large millimetre/sub-millimetre Array (ALMA) observations. Our ATCA observations resolve the inner cavity for 8 of the 14 detected discs. We fit the visibilities and reconstruct 1D radial brightness models for 10 sources with a S/N > 5sigma. We find that, for sources with a resolved cavity in both wavebands, the 8.8 mm and sub-mm brightness distributions peak at the same radius from the star. We suggest that a similar cavity size for 8.8 mm and sub-mm dust grains is due to a dust trap induced by the presence of a companion., 18 pages, 11 figures

BACKGROUND: For malignant pleural mesothelioma (MPM), the benefit of resection, as well as the optimal surgical technique, remain controversial. In efforts to better refine patient selection, this retrospective observational cohort study queried the National Cancer Database in an effort to quantify and evaluate predictors of 30- and 90-day mortality between extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D), as well as nonoperative management. METHODS: After applying selection criteria, cumulative incidences of mortality by treatment paradigm were graphed for the unadjusted and propensity-matched populations, as well as for six a priori age-based intervals (≤60, 61–65, 66–70, 71–75, 76–80, and ≥81 years). The interaction between age and hazard ratio (HR) for mortality between treatment paradigms was also graphed. Cox multivariable analysis ascertained factors independently associated with 30- and 90-day mortality. RESULTS: Of 10,723 patients, 2,125 (19.8%) received resection (n=438 EPP, n=1,687 P/D) and 8,598 (80.2%) underwent nonoperative management. The unadjusted 30/90-day mortality for EPP, P/D, and all operated cases was 3.0%/8.0%, 5.4%/14.1%, and 4.9%/12.8%, respectively. There were no short-term mortality differences between EPP and P/D following propensity-matching, within each age interval, or between age subgroups on interaction testing (P>0.05 for all). Nonoperative patients had a crude 30- and 90-day mortality of 9.9% and 24.6%, respectively. Several variables were identified as predictors of short-term mortality, notably patient age (HR 1.022, P

Introduction Modern technologies, like intensity-modulated radiotherapy (IMRT) and volumetric-modulated arc therapy (VMAT), have improved the therapeutic ratio of thoracic radiotherapy (TRT) for lung cancer (LC). Halcyon™ (Varian Medical Systems, Palo Alto, CA, USA), a novel 6MV-flattening-filter-free O-ring linear accelerator (6X-FFF ORL), was designed to deliver IMRT and VMAT with greater speed than a C-arm linac. Herein, we report our initial clinical experience treating patients with LC on this linac. Methods All patients who received TRT for LC on the 6X-FFF ORL at our institution were retrospectively identified. Patients' clinicopathologic data, radiotherapy details, early disease-control and toxicity outcomes, dosimetric data, couch corrections, and treatment times are reported. Results Between 10/2018-12/2019, 30 consecutive patients (median age 66 years, range 54-94 years) received definitive or post-operative TRT for LC (median 66 Gy/33 fractions; range 5-70 Gy/2-37 fractions) following four-dimensional computed tomography (CT) simulation (97%) using daily kilovoltage KV cone-beam CT (CBCT) (100%) on a 6X-FFF ORL for non-small cell LC (84%) or small cell LC (16%), with 53% receiving VMAT, 43% receiving static-field IMRT, and 77% receiving concurrent systemic therapy. All plans were approved through institutional peer review. The average three-dimensional vector couch correction based on CBCT guidance was 0.90 ± 0.50 cm. The average beam-on and beam on plus CBCT times were 1.7 ± 1.1 min, and 5.0 ± 3.2 min, respectively. Grade 3 dyspnea and fatigue occurred in 3% and 3% of patients, respectively. There were no grade ≥4 toxicities. Conclusion In this first clinical report of TRT for LC on a 6X-FFF ORL, daily CBCT-guided treatment was fast and safe with respect to dosimetry and clinical outcomes. Thus, use of this linac for TRT may increase LC patient throughput without a detriment in radiotherapy quality.

Purpose CD19-targeting chimeric antigen receptor T-cell (CART) therapy has emerged as a promising treatment for relapsed/refractory aggressive B-cell lymphoma (r/rABL), culminating in 2 US Food and Drug Administration–approved therapies: tisagenlecleucel (tisa-cel) and axicabtagene ciloleucel (axi-cel). Following leukapheresis and in preparation for CART infusion, contemporary bridging and lymphodepletion regimens rely mostly on cytotoxic chemotherapy. Here, in a cohort of patients treated with commercial tisa-cel and axi-cel, we show that bridging-RT may offer a supplemental approach. Methods and Materials Thirty-one patients receiving commercial tisa-cel (n = 13) or axi-cel (n = 18) between August 2018 and February 2019 for r/rABL were retrospectively reviewed. Patients were categorized into 2 groups: (1) bridging-RT within 30 days of CART infusion or (2) nonbridging-RT (NBRT), in which patients received either remote RT greater than 30 days before CART infusion or no prior RT. Results Five patients received bridging-RT within 30 days of CART infusion. Median bridging-RT dose was 37.5 Gy and was completed a median of 13 days before infusion. No grade 3 (G3) or higher RT-toxicities occurred. No patients in the bridging-RT group experienced G3 or higher CART-related toxicities (CRS or neurotoxicity), and 23% (n = 6) and 15% (n = 4) experienced G3-5 CRS and G3-5 neurotoxicity in the NBRT group, respectively. Overall treatment response in the bridging-RT and NBRT groups was 80% and 64%, respectively. The axi-cel CART product was associated with CRS (odds ratio [OR] = 26.67, P = .001) and CRS correlated with neurotoxicity (OR = 12.22, P = .028). There was a trend toward an association for CRS with metabolic tumor volume (OR = 1.06/mL, P = .141) and TLG (OR = 1.01/mL x standard uptake value, P = .099). Conclusions Bridging-RT before commercial CART does not appear to increase the risk for CART-related toxicities or negatively affect outcomes in r/rABL patients. No G3 or higher RT-toxicities occurred in this series. Pretreatment metabolic tumor burden may be associated with CART-associated CRS; however, larger patient numbers are required to elucidate significant associations. Future work to prospectively assess the value of bridging-RT is warranted.

This article offers a new analysis of radionuclide and hydroacoustic data to support a low-yield nuclear weapon test as a plausible explanation for the still contentious 22 September 1979 Vela Inci...

Purpose/Objective(s) Patients with HPV+ oropharyngeal squamous cell carcinoma (OPSCC) generally have a good prognosis, though those with locally advanced (LA) disease are at increased risk of locoregional failure (LRF) and distant metastases (DM). A recent SEER study suggested improvement in overall survival and cancer-specific mortality with trimodality therapy compared to definitive chemoradiation (dCRT) for LA HPV+ OPSCC, but is prone to confounding and lacks pattern of failure data. We therefore performed this retrospective analysis of oncologic outcomes for patients with T3/T4 HPV+ OPSCC treated at a high-volume TORS center with surgery +/- adjuvant therapy compared to dCRT alone. Materials/Methods Included were patients with cT3/T4 HPV+ OPSCC treated with dCRT or upfront TORS +/- adjuvant therapy from 2010-2019 with ≥1 year of follow-up. Patients with DM at diagnosis were excluded. Primary outcomes were freedom from LRF (FF-LRF) and LRF leading to death, defined as LRF directly resulting in death or occurring at the same time or before DM resulting in death. Secondary outcomes were freedom from DM (FF-DM) and cancer-specific survival (CSS). Patients were risk stratified based on criteria in the secondary analysis of RTOG 0129 by Ang et al (NEJM 2010): Low-risk: ≤10 pack-year (py) smoking, or > 10 py and N0–N2a disease (AJCC 7th ed.); Intermediate-risk: > 10 py and N2b-N3 disease. Fisher's exact test was used to compare demographics and Kaplan-Meier estimates to compare endpoints. Results 78 patients were treated with dCRT and 44 with upfront TORS. Significantly more dCRT patients were Intermediate-risk (per RTOG 0129 criteria) compared to TORS patients (35.9% vs 6.8%, P Conclusion This large, single-institution series of patients with T3/T4 HPV+ OPSCC treated with either dCRT or upfront TORS +/- adjuvant therapy shows high FF-LRF and low rates of LRF leading to death regardless of treatment. Even in patients with advanced T stage, dCRT was able to obtain excellent disease outcomes. Future prospective studies are warranted to determine which combinations of multimodality therapy are optimal for LA HPV+ OPSCC, incorporating both oncologic and functional outcome endpoints.

PURPOSE/OBJECTIVE(S) Recent landmark trials have suggested a survival benefit to definitive tumor directed therapies (DTDT) for selected patients with metastatic disease for various malignancies. We sought 1) to confirm the prognostic significance of metachronous oligometastatic burden for human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and 2) to evaluate disease outcomes for oligometastatic HPV-associated OPSCC after upfront DTDT versus upfront systemic therapy. MATERIALS/METHODS This was a single institution retrospective observational cohort study of patients with HPV-associated OPSCC who developed metachronous metastases ≥3 months after primary treatment with trans-oral robotic surgery (TORS) from 2008-2017. At metastatic presentation, patients were classified as oligometastatic (≤5 metastases) or polymetastatic (> 5 metastases). Treatment was classified as DTDT (all metastases initially treated with surgery/radiotherapy) or as upfront systemic therapy. Overall survival (OS) was compared using log-rank tests at a significance of P < 0.05. Univariable and multivariable (MV) Cox proportional hazard models were used to assess the association of patient, disease, and treatment characteristics with survival. Variables with P < 0.15 on univariable analysis (initial metastatic treatment, metastatic site, and number of metastases) were included in the multivariable model. RESULTS Of 676 patients undergoing primary surgical management for HPV-associated OPSCC, 36 patients subsequently developed metachronous metastases. For those 36 patients, the median follow-up time after surgery was 27.5 months (range 4.5-127.0), and the median OS was 42.8 months. The median age at distant metastasis was 62 (range 32-86), and most patients were male (86.1%) and Caucasian (97.2%). Overall, 27 patients presented with oligometastasis and 9 with polymetastasis. Oligometastatic patients had improved median OS compared to polymetastatic patients (47.9 vs. 22.7 months, P = 0.020). For the 27 oligometastatic patients, 12 were initially treated with DTDT while 15 received systemic therapy. DTDT was associated with an improved median OS when compared to systemic therapy (median OS not reached for DTDT vs 40.7 months, P = 0.021), with 3 year OS of 90.0% and 55.0% respectively. DTDT was also associated with improved OS on MV Cox regression (hazard ratio = 0.06, 95% CI 0.004-0.73, P = 0.027) compared to systemic therapy when controlling for number of metastases and metastatic site. CONCLUSION Our study findings suggest that the extent of metastatic disease at metastatic presentation is related to prognosis, with oligometastasis associated with improved overall survival compared to polymetastasis. Among patients with oligometastatic disease, initial DTDT is associated with superior overall survival when compared to upfront systemic therapy.

On 22 September 1979 two optical sensors on U.S. satellite Vela 6911 detected a double-flash of light that appeared characteristic of an atmospheric nuclear explosion conducted over the southern Atlantic or Indian Ocean. It became known as the Vela Incident, Event 747, or Alert 747. An anomaly between the amplitude of the two signals during the second pulse led a U.S. government expert panel established to assess the event to conclude in mid-1980 that a more likely explanation was the impact of a small meteoroid on the satellite, the debris from which reflected sunlight into the sensors' field of view. No model was presented to support the contention, and a similar anomaly--known as background modulation--was a given for the second pulse of all confirmed explosions detected by Vela, though beginning later. Nonetheless, this event has remained the subject of intense debate. This article reviews the evidence and presents an updated analysis of the original Vela signal based on recently declassified literature and on modern knowledge of interplanetary dust and hyper velocity impact. Given the geometry of the satellite, and that the bulk of the surface comprised solar panels, much of the debris from any collision would be carried away from the sensors' field of view. Thus, a meteoroid collision appears much less likely than previously assumed. The double flash is instead consistent with a nuclear explosion, albeit detected by an aged satellite for which background modulation was abnormal and/or commenced earlier, also seen in post-event system tests. A companion paper to be published in 2018 presents radionuclide and hydroacoustic evidence supporting the conclusion that the Vela Incident was a nuclear weapon test explosion.

An absorption feature is occasionally reported around 11 microns in astronomical spectra, including those of forming stars. Candidate carriers include water ice, polycyclic aromatic hydrocarbons (PAHs), silicon carbide, crystalline silicates or even carbonates. All are known constituents of cosmic dust in one or more types of environments, though not necessarily together. In this paper we present new ground-based 8-13 micron spectra of one evolved star, several embedded young stellar objects (YSOs) and a background source lying behind a large column of the interstellar medium (ISM) toward the Galactic Centre. Our observations, obtained at a spectral resolution of approximately 100, are compared with previous lower resolution data, as well as data obtained with the Infrared Space Observatory (ISO) on these and other targets. By presenting a subset of a larger sample our aim is to establish the reality of the feature and subsequently speculate on its carrier. All evidence points toward crystalline silicate. For instance, the 11 micron band profile is well matched with the emissivity of crystalline olivine. Furthermore, the apparent association of the absorption feature with a sharp polarisation signature in the spectrum of two previously reported cases suggests a carrier with a relatively high band strength compared to amorphous silicates. If true, this would either set back the evolutionary stage in which silicates are crystallised, either to the embedded phase or even before within the ISM, or else the silicates ejected from the outflows of evolved stars retain some of their crystalline identity during their long residence in the ISM., 36 pages, 23 figures. Accepted for publication in Monthly Notices of the Royal Astronomical Society

For the past 100 years, oncologists have relentlessly pursued the destruction of tumor cells by surgical, chemotherapeutic or radiation oncological means. Consistent with this focus, treatment plans are typically based on key characteristics of the tumor itself such as disease site, histology and staging based on local, regional and systemic dissemination. Precision medicine is similarly built on the premise that detailed knowledge of molecular alterations of tumor cells themselves enables better and more effective tumor cell destruction. Recently, host factors within the tumor microenvironment including the vasculature and immune systems have been recognized as modifiers of disease progression and are being targeted for therapeutic gain. In this review, we argue that—to optimize the impact of old and new treatment options—we need to take account of an epidemic that occurs independently of—but has major impact on—the development and treatment of malignant diseases. This is the rapidly increasing number of patients with excess weight and its’ attendant metabolic consequences, commonly described as metabolic syndrome. It is well established that patients with altered metabolism manifesting as obesity, metabolic syndrome and chronic inflammation have an increased incidence of cancer. Here, we focus on evidence that these patients also respond differently to cancer therapy including radiation and provide a perspective how exercise, diet or pharmacological agents may be harnessed to improve therapeutic responses in this patient population.

We report new imaging polarimetry observations of the Galactic compact HII region K3-50 using CanariCam at the Gran Telescopio Canarias. We use a standard polarimetric analysis technique, first outlined by Aitken, to decompose the observed polarisation images centred at 8.7, 10.3, and 12.5 $\mu$m into the emissive and absorptive components from silicate grains that are aligned with the local magnetic field. These components reveal the spatially-resolved magnetic field structures across the mid-infrared emission area of K3-50. We examine these structures and show that they are consistent with previously observed features and physical models of K3-50, such as the molecular torus and the ionised outflow. We propose a 3D geometry for all the structures seen at different wavelengths. We also compute relevant physical quantities in order to estimate the associated magnetic field strengths that would be implied under various physical assumptions. We compare these results with MHD simulations of protostar formation that predict the magnetic field strength and configuration. We find that the magnetic field may be dynamically important in the innermost 0.2 pc of the molecular torus, but that the torus is more likely to be rotationally-supported against gravity outside this radius. Similarly, magnetic fields are unlikely to dominate the {\em global} physics of the ionised outflow, but they may be important in helping confine the flow near the cavity wall in some locations. Ours is the first application of the Aitken technique to spatially-resolved magnetic field structures in multiple layers along the line of sight, effectively a method of "polarisation tomography.", Comment: 15 pages, 12 figures, accepted by MNRAS

We present $N$-band (8$-$13 $\mu$m) spectroscopic observations of the low-mass, embedded pre-main-sequence close binary system SVS13. Absorption features are clearly detected which are attributable to amorphous silicates, crystalline forsterite, crystalline enstatite and annealed SiO$_{2}$. Most intriguingly, a major component of the dust in the envelope or disc around SVS13 appears to be SiC, required to model adequately both the total intensity and polarisation spectra. Silicon carbide is a species previously detected only in the spectra of C-rich evolved star atmospheres, wherein it is a dust condensate. It has not been unambiguously identified in the interstellar medium, and never before in a molecular cloud, let alone in close proximity to a forming star. Yet pre-Solar grains of SiC have been identified in meteorites, possibly suggesting an interesting parallel between SVS13 and our own Solar-System evolution. The uniqueness of the spectrum suggests that we are either catching SVS13 in a short-lived evolutionary phase and/or that there is something special about SVS13 itself that makes it rare amongst young stars. We speculate on the physical origin of the respective dust species and why they are all simultaneously present toward SVS13. Two scenarios are presented: a disc-instability-induced fragmentation, with subsequent localised heating and orbital evolution firstly annealing initially amorphous silicates and then dispersing their crystalline products throughout a circumstellar disc; and a newly discovered shock-heating mechanism at the interface between the circumstellar and circumbinary discs providing the crystallisation process. One or both of these mechanisms acting on carbon-rich grain material can also feasibly produce the SiC signature., Comment: 15 pages, 6 figures, to be published in Monthly Notices of the Royal Astronomical Society

Somatic mitochondrial DNA (mtDNA) mutations contribute to the pathogenesis of age-related disorders, including myelodysplastic syndromes (MDS). The accumulation of mitochondria harboring mtDNA mutations in patients with these disorders suggests a failure of normal mitochondrial quality-control systems. The mtDNA-mutator mice acquire somatic mtDNA mutations via a targeted defect in the proofreading function of the mtDNA polymerase, PolgA, and develop macrocytic anemia similar to that of patients with MDS. We observed an unexpected defect in clearance of dysfunctional mitochondria at specific stages during erythroid maturation in hematopoietic cells from aged mtDNA-mutator mice. Mechanistically, aberrant activation of mechanistic target of rapamycin signaling and phosphorylation of uncoordinated 51-like kinase (ULK) 1 in mtDNA-mutator mice resulted in proteasome-mediated degradation of ULK1 and inhibition of autophagy in erythroid cells. To directly evaluate the consequence of inhibiting autophagy on mitochondrial function in erythroid cells harboring mtDNA mutations in vivo, we deleted Atg7 from erythroid progenitors of wild-type and mtDNA-mutator mice. Genetic disruption of autophagy did not cause anemia in wild-type mice but accelerated the decline in mitochondrial respiration and development of macrocytic anemia in mtDNA-mutator mice. These findings highlight a pathological feedback loop that explains how dysfunctional mitochondria can escape autophagy-mediated degradation and propagate in cells predisposed to somatic mtDNA mutations, leading to disease.

We measured mid-infrared polarization of protoplanetary discs to gain new insight into their magnetic fields. Using CanariCam at the 10.4 m Gran Telescopio Canarias, we detected linear polarization at 8.7, 10.3, and 12.5 $\mu$m from discs around eight Herbig Ae/Be stars and one T-Tauri star. We analyzed polarimetric properties of each object to find out the most likely interpretation of the data. While the observed mid-infrared polarization from most objects is consistent with polarized emission and/or absorption arising from aligned dust particles, we cannot rule out polarization due to dust scattering for a few objects in our sample. For those objects for which polarization can be explained by polarized emission and/or absorption, we examined how the derived magnetic field structure correlates with the disc position angle and inclination. We found no preference for a certain type of magnetic field. Instead, various configurations (toroidal, poloidal, or complex) are inferred from the observations. The detection rate (64 per cent) of polarized mid-infrared emission and/or absorption supports the expectation that magnetic fields and suitable conditions for grain alignment are common in protoplanetary discs around Herbig Ae/Be stars., Comment: 14 pages, 4 figures; accepted for publication in MNRAS

Protoplanetary disc systems observed at radio wavelengths often show excess emission above that expected from a simple extrapolation of thermal dust emission observed at short millimetre wavelengths. Monitoring the emission at radio wavelengths can be used to help disentangle the physical mechanisms responsible for this excess, including free-free emission from a wind or jet, and chromospheric emission associated with stellar activity. We present new results from a radio monitoring survey conducted with Australia Telescope Compact Array over the course of several years with observation intervals spanning days, months and years, where the flux variability of 11 T Tauri stars in the Chamaeleon and Lupus star forming regions was measured at 7 and 15 mm and 3 and 6 cm. Results show that for most sources are variable to some degree at 7 mm, indicating the presence of emission mechanisms other than thermal dust in some sources. Additionally, evidence of grain growth to cm-sized pebbles was found for some sources that also have signs of variable flux at 7 mm. We conclude that multiple processes contributing to the emission are common in T Tauri stars at 7 mm and beyond, and that a detection at a single epoch at radio wavelengths should not be used to determine all processes contributing to the emission., Comment: Accepted 2017 January 4, Monthly Notices of the Royal Astronomical Society

Reactivity controlled compression ignition (RCCI) has been shown in single- and multi-cylinder engine research to achieve high thermal efficiencies with ultra-low NOX and soot emissions. The nature of the particulate matter (PM) produced by RCCI operation has been shown in recent research to be different than that of conventional diesel combustion and even diesel low-temperature combustion. Previous research has shown that the PM from RCCI operation contains a large amount of organic material that is volatile and semi-volatile. However, it is unclear if the organic compounds are stemming from fuel or lubricant oil. The PM emissions from dual-fuel RCCI were investigated in this study using two engine platforms, with an emphasis on the potential contribution of lubricant. Both engine platforms used the same base General Motors (GM) 1.9-L diesel engine geometry. The first study was conducted on a single-cylinder research engine with primary reference fuels (PRFs), n-heptane, and iso-octane. The second study was conducted on a four-cylinder GM 1.9-L ZDTH engine which was modified with a port fuel injection (PFI) system while maintaining the stock direct injection fuel system. Multi-cylinder RCCI experiments were run with PFI gasoline and direct injection of 2-ethylhexyl nitrate (EHN) mixed with gasoline at 5 % EHN by volume. In addition, comparison cases of conventional diesel combustion (CDC) were performed. Particulate size distributions were measured, and PM filter samples were collected for analysis of lube oil components. Triplicate PM filter samples (i.e., three individual filter samples) for both gas chromatography-mass spectroscopy (GC-MS; organic) analysis and X-ray fluorescence (XRF; metals) were obtained at each operating point and queued for analysis of both organic species and lubricant metals. The results give a clear indication that lubricants do not contribute significantly to the formation of RCCI PM.