Far Ultraviolet Fluorescence of Molecular Hydrogen in IC 63

We present observations of H_2 fluorescence at wavelengths between 1000 and 1200 A from the bright reflection nebula IC 63. Observations were performed with the Berkeley spectrograph on the ORFEUS-SPAS II mission. To the best of our knowledge, this is the first detection of astrophysical H_2 fluorescent emission at these wavelengths (excluding planetary atmospheres). The shape of the spectrum is well described by the model of Sternberg (1989). The absolute intensity, however, is fainter than an extrapolation from observations at longer ultraviolet wavelengths (Witt et al. 1989) by a factor of ten. Of the mechanisms that might help reconcile these observations, optical depth effects in the fluorescing H_2 itself are the most promising (or at least the most difficult to rule out).Comment: LaTeX file, 7 pages, 1 encapsulated PostScript figure. Uses aaspp4.sty and astrobib.sty. (Astrobib is available from http://www.stsci.edu/software/TeX.html .) The ORFEUS telescope is described at http://sag-www.ssl.berkeley.edu/orfeus/ . To appear in The Astrophysical Journal (Letters

Hyperthermia and immunotherapy: clinical opportunities.

Hyperthermia holds great promise to advance immunotherapy in the treatment of cancer. Multiple trials have demonstrated benefit with the addition of hyperthermia to radiation or chemotherapy in the treatment of wide-ranging malignancies. Similarly, pre-clinical studies have demonstrated the ability of hyperthermia to enhance each of the 8 steps in the cancer-immunotherapy cycle including stimulation of tumor-specific immunity. While there has been an extensive recent focus on augmenting immunotherapy with radiation, surprisingly to date, there have been no clinical trials assessing the combination of hyperthermia with immunotherapy. The study of hyperthermia with immunotherapy is particularly compelling when considered in the context of a new treatment paradigm for this anti-neoplastic modality. Novel concepts include ease of treatment including elicitation of the tumor-specific response of not requiring whole tumor heating, potentially shorter treatment time, better treatment tolerance as opposed to other multi-agent approaches to immunotherapy and the ability to apply heat repeatedly with immunotherapies, unlike ionizing radiation. Several questions remained with regard to clinical integration which can be readily addressed with thoughtful clinical trial design building upon lessons learned at the bench and from clinical trials combining radiation and immunotherapy. Examples of promising avenues for clinical investigation of hyperthermia and immunotherapy including melanoma, bladder, and head and neck cancers are reviewed. In summary, there is a present convergence of factors in oncology that compel further investigation of the integration of hyperthermia with immunotherapy for the benefit of cancer patients

Combined Hyperthermia and Radiotherapy for the Treatment of Cancer

Radiotherapy is used to treat approximately 50% of all cancer patients, with varying success. Radiation therapy has become an integral part of modern treatment strategies for many types of cancer in recent decades, but is associated with a risk of long-term adverse effects. Of these side effects, cardiac complications are particularly relevant since they not only adversely affect quality of life but can also be potentially life-threatening. The dose of ionizing radiation that can be given to the tumor is determined by the sensitivity of the surrounding normal tissues. Strategies to improve radiotherapy therefore aim to increase the effect on the tumor or to decrease the effects on normal tissues, which must be achieved without sensitizing the normal tissues in the first approach and without protecting the tumor in the second approach. Hyperthermia is a potent sensitizer of cell killing by ionizing radiation (IR), which can be attributed to the fact that heat is a pleiotropic damaging agent, affecting multiple cell components to varying degrees by altering protein structures, thus influencing the DNA damage response. Hyperthermia induces heat shock protein 70 (Hsp70; HSPA1A) synthesis and enhances telomerase activity. HSPA1A expression is associated with radioresistance. Inactivation of HSPA1A and telomerase increases residual DNA DSBs post IR exposure, which correlates with increased cell killing, supporting the role of HSPA1A and telomerase in IR-induced DNA damage repair. Thus, hyperthermia influences several molecular parameters involved in sensitizing tumor cells to radiation and can enhance the potential of targeted radiotherapy. Therapy-inducible vectors are useful for conditional expression of therapeutic genes in gene therapy, which is based on the control of gene expression by conventional treatment modalities. The understanding of the molecular response of cells and tissues to ionizing radiation has lead to a new appreciation of the exploitable genetic alterations in tumors and the development of treatments combining pharmacological interventions with ionizing radiation that more specifically target either tumor or normal tissue, leading to improvements in efficacy

Optimization of Chest Wall Hyperthermia Treatment Using a Virtual Human Chest Model

This work explores different coupling configurations (direct contact, air and water coupling) between a single 915 MHz waveguide applicator and human tissue in the setting of chest wall recurrence (CWR) of breast cancer. The objective is to treat chest wall tumours with microwave hyperthermia, while avoiding hot spots in critical areas such as scars and ribs. The best coupling configuration was a customized 24×29 cm water bolus developed by our team. It helps the applicator deliver an effective field size of 268 cm2 at 1 cm depth and a penetration depth of 2-3 cm. Water bolus thickness can be adjusted during treatment (0.5-4 cm) to shift hot spot locations and thus homogenize thermal dose delivered over a 60 min hyperthermia treatment. The virtual human chest model is easily customized so it can be used as a tool for treatment planning and quality assurance testing of microwave applicator configurations

GHRS and ORFEUS-II Observations of the Highly Ionized Interstellar Medium Toward ESO141-055

We present Goddard High Resolution Spectrograph and ORFEUS-II measurements of Si IV, CIV, N V, and O VI absorption in the interstellar medium of the Galactic disk and halo toward the nucleus of the Seyfert galaxy ESO141-055. The high ionization absorption is strong, with line strengths consistent with the spectral signature expected for hot (log T = 5-6) collisionally ionized gas in either a ``Galactic fountain'' or an inhomogeneous medium containing a mixture of conductive interfaces and turbulent mixing layers. The total O VI column density of log N ~ 15 suggests that the scale height of O VI is large (>3 kpc) in this direction. Comparison of the high ion column densities with measurements for other sight lines indicates that the highly ionized gas distribution is patchy. The amount of O VI perpendicular to the Galactic plane varies by at least a factor of ~4 among the complete halo sight lines thus far studied. In addition to the high ion absorption, lines of low ionization species are also present in the spectra. With the possible exception of Ar I, which may have a lower than expected abundance resulting from partial photoionization of gas along the sight line, the absorption strengths are typical of those expected for the warm, neutral interstellar medium. The sight line intercepts a cold molecular cloud with log N(H2) ~ 19. The cloud has an identifiable counterpart in IRAS 100-micron emission maps of this region of the sky. We detect a Ly-alpha absorber associated with ESO141-055 at z = 0.03492. This study presents an enticing glimpse into the interstellar and intergalactic absorption patterns that will be observed at high spectral resolution by the Far Ultraviolet Spectroscopic Explorer.Comment: 24 pages + 8 figures, uses aaspp4.sty. Accepted for publication in Ap

A Telehealth Clinical Workflow for Academic Radiation Oncology Programs During the COVID19 Pandemic

COVID19 has resulted in drastic measures to decrease exposure risks within healthcare systems, with cancer patients at increased risk of infection and death (Liang. Lancet Oncol. 2020). Telehealth is the delivery of medical care via interactive audio and/or video telecommunication services. Telehealth was previously used sparingly within the department of radiation oncology but has suddenly become the preferred method of contact. In order to maintain quality of care, patient satisfaction, resident learning, and reimbursement, a robust telehealth clinical workflow is critical. Our department engaged various stakeholder to quickly develop a clinical workflow

Blood-based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin-binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment-by-marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild-type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild-type (WT) patients (chemo HR = 0.98, 95% CI = 0.74-1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05-2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02-2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67-1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68-13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31-2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88-1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32-1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab

Quality assurance guidelines for superficial hyperthermia clinical trials: II. Technical requirements for heating devices

Quality assurance (QA) guidelines are essential to provide uniform execution of clinical trials with uniform quality hyperthermia treatments. This document outlines the requirements for appropriate QA of all current superficial heating equipment including electromagnetic (radiative and capacitive), ultrasound, and infrared heating techniques. Detailed instructions are provided how to characterize and document the performance of these hyperthermia applicators in order to apply reproducible hyperthermia treatments of uniform high quality. Earlier documents used specific absorption rate (SAR) to define and characterize applicator performance. In these QA guidelines, temperature rise is the leading parameter for characterization of applicator performance. The intention of this approach is that characterization can be achieved with affordable equipment and easy-to-implement procedures. These characteristics are essential to establish for each individual applicator the specific maximum size and depth of tumors that can be heated adequately. The guidelines in this document are supplemented with a second set of guidelines focusing on the clinical application. Both sets of guidelines were developed by the European Society for Hyperthermic Oncology (ESHO) Technical Committee with participation of senior Society of Thermal Medicine (STM) members and members of the Atzelsberg Circle

Blood�based markers of efficacy and resistance to cetuximab treatment in metastatic colorectal cancer: results from CALGB 80203 (Alliance)

Circulating protein markers were assessed in patients with colorectal cancer (CRC) treated with cetuximab in CALGB 80203 to identify prognostic and predictive biomarkers. Patients with locally advanced or metastatic CRC received FOLFOX or FOLFIRI chemotherapy (chemo) or chemo in combination with cetuximab. Baseline plasma samples from 152 patients were analyzed for six candidate markers [epidermal growth factor (EGF), heparin�binding EGF (HBEGF), epidermal growth factor receptor (EGFR), HER2, HER3, and CD73]. Analyte levels were associated with survival endpoints using univariate Cox proportional hazards models. Predictive markers were identified using a treatment�by�marker interaction term in the Cox model. Plasma levels of EGF, HBEGF, HER3, and CD73 were prognostic for overall survival (OS) across all patients (KRAS mutant and wild�type). High levels of EGF predicted for lack of OS benefit from cetuximab in KRAS wild�type (WT) patients (chemo HR = 0.98, 95% CI = 0.74–1.29; chemo+cetuximab HR = 1.54, 95% CI = 1.05–2.25; interaction P = 0.045) and benefit from cetuximab in KRAS mutant patients (chemo HR = 1.72, 95% CI = 1.02–2.92; chemo+cetuximab HR = 0.90, 95% CI = 0.67–1.21; interaction P = 0.026). Across all patients, higher HER3 levels were associated with significant OS benefit from cetuximab treatment (chemo HR = 4.82, 95% CI = 1.68–13.84; chemo+cetuximab HR = 0.95, 95% CI = 0.31–2.95; interaction P = 0.046). CD73 was also identified as predictive of OS benefit in KRAS WT patients (chemo HR = 1.28, 95% CI = 0.88–1.84; chemo+cetuximab HR = 0.60, 95% CI = 0.32–1.13; interaction P = 0.049). Although these results are preliminary, and confirmatory studies are necessary before clinical application, the data suggest that HER3 and CD73 may play important roles in the biological response to cetuximab

Feasibility of removable balloon implant for simultaneous magnetic nanoparticle heating and HDR brachytherapy of brain tumor resection cavities.

AIM: Hyperthermia (HT) has been shown to improve clinical response to radiation therapy (RT) for cancer. Synergism is dramatically enhanced if HT and RT are combined simultaneously, but appropriate technology to apply treatments together does not exist. This study investigates the feasibility of delivering HT with RT to a 5-10mm annular rim of at-risk tissue around a tumor resection cavity using a temporary thermobrachytherapy (TBT) balloon implant. METHODS: A balloon catheter was designed to deliver radiation from High Dose Rate (HDR) brachytherapy concurrent with HT delivered by filling the balloon with magnetic nanoparticles (MNP) and immersing it in a radiofrequency magnetic field. Temperature distributions in brain around the TBT balloon were simulated with temperature dependent brain blood perfusion using numerical modeling. A magnetic induction system was constructed and used to produce rapid heating (\u3e0.2°C/s) of MNP-filled balloons in brain tissue-equivalent phantoms by absorbing 0.5 W/ml from a 5.7 kA/m field at 133 kHz. RESULTS: Simulated treatment plans demonstrate the ability to heat at-risk tissue around a brain tumor resection cavity between 40-48°C for 2-5cm diameter balloons. Experimental thermal dosimetry verifies the expected rapid and spherically symmetric heating of brain phantom around the MNP-filled balloon at a magnetic field strength that has proven safe in previous clinical studies. CONCLUSIONS: These preclinical results demonstrate the feasibility of using a TBT balloon to deliver heat simultaneously with HDR brachytherapy to tumor bed around a brain tumor resection cavity, with significantly improved uniformity of heating over previous multi-catheter interstitial approaches. Considered along with results of previous clinical thermobrachytherapy trials, this new capability is expected to improve both survival and quality of life in patients with glioblastoma multiforme