Design and standard utilization of safety devices for the radiation treatment management of heavy patients.

PURPOSE: Increasing number of heavy cancer patients has created challenges in diagnostic imaging and radiation oncology. Practical weight limits of the equipment can become an obstacle both for imaging and treatment of these patients. Most magnetic resonance imaging and computed tomography (CT) tables' static load capacities are between 450 and 500 pounds, and linear accelerator tables can support similar weights depending on the type of the table and manufacturer. One recurring issue we encountered was failure of the treatment couch's longitudinal drive belt due to heavy patients' sudden movement. In several cases, snapping of the longitudinal drive belt occurred when the patient's weight was under 300 lbs (below the rated weight limit). Additionally, we observed vertical deflection of the couch when extended/cantilevered with heavy patients. The purpose of this work was to implement immobilization methods and safety devices for radiation treatment management of heavy patients in order to increase patient/provider safety, prevent treatment couch damage, and reduce treatment disruptions. MATERIALS AND METHODS: We created three safety devices for treatment management of heavy patients. Wooden brace and Scissor jack were used to lock the couch longitudinal axis (while the couch longitudinal drive was floated) during the setup of a heavy patient and absorb the mechanical impulse applied to the couch longitudinal drive belt. Wooden brace was built in house and positioned in between the wall and treatment couch to lock the longitudinal axis. Commercially available 10 in × 10 in scissor jack lift with adjustable height 3 ½ in - 13 in was modified to increase effectiveness and safety. An additional stand was created with adjustable height and rolling rubber wheels to support the couch when extended/cantilevered with heavy patients. RESULTS: Using these devices prevented the longitudinal belt from breaking and improved the patient/therapist safety at eight treatment sites within our network. No farther couch belt failures were observed since devices were introduced for clinical use. All three devices can be used and removed without any modifications done to the treatment couch.

A Simulation-Free Replacement Solution for Radiation Therapy Immobilization Devices Using Computer Numerical Control (CNC) -Milled Polystyrene Molds.

Purpose: In radiation therapy (RT), if an immobilization device is lost or damaged, the patient may need to be brought back for resimulation, device fabrication, and treatment planning, causing additional imaging radiation exposure, inconvenience, cost, and delay. We describe a simulation-free method for replacing lost or damaged RT immobilization devices. Methods and Materials: Replacement immobilization devices were fabricated using existing simulation scans as design templates by computer numerical control (CNC) milling of molds made from extruded polystyrene (XPS). XPS material attenuation and bolusing properties were evaluated, a standard workflow was established, and 12 patients were treated. Setup reproducibility was analyzed postfacto using Dice similarity coefficient (DSC) and mean distance to agreement (MDA) calculations comparing onboard treatment imaging with computed tomography (CT) simulations. Results: Results showed that XPS foam material had less dosimetric impact (attenuation and bolusing) than materials used for our standard immobilization devices. The average direct cost to produce each replacement mold was $242.17, compared with over $2000 for standard resimulation. Hands-on time to manufacture was 86.3 minutes, whereas molds were delivered in as little as 4 hours and mostly within 24 hours, compared with a week or more required for standard resimulation. Each mold was optically scanned after production and was measured to be within 2-mm tolerance (pointwise displacement) of design input. All patients were successfully treated using the CNC-milled foam mold replacements, and pretreatment imaging verified satisfactory clinical setup reproduction for each case. The external body contours from the setup cone beam CT and the original CT simulation with matching superior-inferior extent were compared by calculating the DSC and MDA. DSC average was 0.966 (SD, 0.011), and MDA average was 2.694 mm (SD, 0.986). Conclusions: CNC milling of XPS foam is a quicker and more convenient solution than traditional resimulation for replacing lost or damaged RT immobilization devices. Satisfactory patient immobilization, low dosimetric impact compared with standard immobilization devices, and strong correlation of onboard contours with CT simulations are shown. We share our clinical experience, workflow, and manufacturing guide to help other clinicians who may want to adopt this solution.

3D Printing in a hospital: Centralized clinical implementation and applications for comprehensive care.

This educational article discusses the use of 3D printing or additive manufacturing in hospitals, not just for rapid prototyping but also for creating end-use products, such as clinical, diagnostic, and educational tools. The flexibility of 3D printing is valuable for creating patient-specific medical devices, custom surgical tools, anatomical models, implants, research tools and on-demand parts, among others. The advantages of and requirements for implementing a clinical 3D printing service in a hospital environment are discussed, including centralized 3D printing management, technology, example use cases, and considerations for implementation. The article provides an overview for other institutions to reference in setting up or organizing their clinical 3D printing services and is applicable to general hospitals or various sub-specialty practices.

Oligometastases: Characterizing the Role of Epigenetic Regulation of Epithelial-Mesenchymal Transition.

The "oligometastasis" hypothesis proposes that metastases exist as a spectrum and are not always disseminated. According to this theory, a subset of patients with metastatic disease could benefit from aggressive local therapies. However, the identification of patients most likely to exhibit an oligometastatic phenotype remains challenging. Recent literature focusing on basic and translational studies has identified novel epigenetic regulators of epithelial-mesenchymal transition (EMT) and the emergence of a spectrum of metastatic behavior. Herein, we review these scientific advances and suggest that the spectrum of metastatic virulence produced by these epigenetic mechanisms broadly contributes to the emergence of clinically evident "oligometastases." Epigenetic regulation of EMT programs can result in a spectrum of cell trajectories (e.g., quasi-mesenchymal and highly mesenchymal states) with differential propensity to develop metastases. We propose that quasi-mesenchymal cell states may be associated with a polymetastatic phenotype, whereas highly mesenchymal cell states may be associated with a more oligometastatic phenotype. The mechanisms governing epigenetic regulation of EMT and its array of intermediate states are multifaceted and may contribute to the development of the metastatic spectrum observed clinically. Within this context, translational studies that support the role of EMT and its epigenetic regulation are discussed. Continued translation of these mechanistic discoveries into novel biomarkers may help optimally select patients most likely to exhibit an oligometastatic phenotype and benefit from aggressive local therapies, such as surgery, radiotherapy, and other ablative procedures.

Stereotactic body radiotherapy for multisite extracranial oligometastases: final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease.

BACKGROUND: A subset of patients with metastatic cancer in limited organs may benefit from metastasis-directed therapy. The authors investigated whether patients with limited metastases could be safely treated with metastasis-directed radiotherapy. METHODS: Patients with 1 to 5 metastatic cancer sites with a life expectancy of >3 months received escalating stereotactic body radiotherapy (SBRT) doses to all known cancer sites. Patients were followed radiographically with CT scans of the chest, abdomen, and pelvis and metabolically with fluorodeoxyglucose-positron emission tomography, 1 month after treatment, and then every 3 months. Acute toxicities were scored using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0, and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system. RESULTS: Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 on a prospective radiation dose escalation study. Median follow-up was 20.9 months. Patients tolerated treatment well; the maximal tolerated dose was not reached in any cohort. Eleven patients (18.3%) have not progressed. One and 2-year progression-free survival are 33.3% (95% confidence interval [CI], 22.8-46.1) and 22.0% (95% CI, 12.8-34.4); 1-year and 2-year overall survival are 81.5% (95% CI, 71.1-91.1) and 56.7% (95% CI, 43.9-68.9). Seventy-two percent of patients whose tumors progressed did so in limited (1-3) metastatic sites. CONCLUSIONS: Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT. Further investigation should focus on patient selection.

Sizing of airborne particles in an operating room.

Medical procedures that produce aerosolized particles are under great scrutiny due to the recent concerns surrounding the COVID-19 virus and increased risk for nosocomial infections. For example, thoracostomies, tracheotomies and intubations/extubations produce aerosols that can linger in the air. The lingering time is dependent on particle size where, e.g., 500 µm (0.5 mm) particles may quickly fall to the floor, while 1 µm particles may float for extended lengths of time. Here, a method is presented to characterize the size of <40 µm to >600 µm particles resulting from surgery in an operating room (OR). The particles are measured in-situ (next to a patient on an operating table) through a 75mm aperture in a ∼400 mm rectangular enclosure with minimal flow restriction. The particles and gasses exiting a patient are vented through an enclosed laser sheet while a camera captures images of the side-scattered light from the entrained particles. A similar optical configuration was described by Anfinrud et al.; however, we present here an extended method which provides a calibration method for determining particle size. The use of a laser sheet with side-scattered light provides a large FOV and bright image of the particles; however, the particle image dilation caused by scattering does not allow direct measurement of particle size. The calibration routine presented here is accomplished by measuring fixed particle distribution ranges with a calibrated shadow imaging system and mapping these measurements to the in-situ imaging system. The technique used for generating and measuring these particles is described. The result is a three-part process where 1) particles of varying sizes are produced and measured using a calibrated, high-resolution shadow imaging method, 2) the same particle generators are measured with the in-situ imaging system, and 3) a correlation mapping is made between the (dilated) laser image size and the measured particle size. Additionally, experimental and operational details of the imaging system are described such as requirements for the enclosure volume, light management, air filtration and control of various laser reflections. Details related to the OR environment and requirements for achieving close proximity to a patient are discussed as well.

On first looking into Kutcher's "Contested Medicine": ethical tensions in clinical research.

Contested Medicine examines the experiments done at the University of Cincinnati by Eugene Saenger and his colleagues during the 1960s, a time of great fear that the Cold War between the United States and the Soviet Union would become a hot war using nuclear weapons. These studies were to provide the Department of Defense information relevant to the consequences of exposure of military personnel to ionizing radiation in such circumstances. Kutcher, a radiation physicist turned historian of science, is especially well prepared to put these studies into the context of the evolving bioethics of the time. He reviews the essential ethical reviews, beginning with the Nuremberg Code and extending to those of the Advisory Committee on Human Radiation Experiments appointed by President Clinton. These evolving ethical standards provide a cautionary note to today's methods of clinical experimentation in search of proper evidence-based medicine. There has been an ascendance of the priority of patient rights over societal good except in increasingly limited special circumstances. Some of what was considered good and necessary science in the 1960s and 1970s is no longer considered proper. Similarly, future ethical norms may well find current trial methodology to be flawed.

Effects of Optical Turbulence and Density Gradients on Particle Image Velocimetry.

Particle image velocimetry (PIV) is a well-established tool to collect high-resolution velocity and turbulence data in the laboratory, in both air and water. Laboratory experiments are often performed under conditions of constant temperature or salinity or in flows with only small gradients of these properties. At larger temperature or salinity variations, the changes in the index of refraction of water or air due to turbulent microstructure can lead to so-called optical turbulence. We observed a marked influence of optical turbulence on particle imaging in PIV. The effect of index of refraction variations on PIV has been described in air for high Mach number flows, but in such cases the distortion is directional. No such effect has previously been reported for conditions of isotropic optical turbulence in water. We investigated the effect of optical turbulence on PIV imaging in a large Rayleigh-Bénard tank for various path lengths and turbulence strengths. The results show that optical turbulence can significantly affect PIV measurements. Depending on the strength of the optical turbulence and path length, the impact can be mitigated in post-processing, which may reduce noise and recover the mean velocity signal, but leads to the loss of the high-frequency turbulence signal.

An initial report of a radiation dose-escalation trial in patients with one to five sites of metastatic disease.

PURPOSE: Previous investigations have suggested that a subset of patients with metastatic cancer in a limited number of organs may benefit from local treatment. We investigated whether cancer patients with limited sites of metastatic disease (oligometastasis) who failed standard therapies could be identified and safely treated at one to five known sites of low-volume disease with radiotherapy. EXPERIMENTAL DESIGN: Patients with one to five sites of metastatic cancer with a life expectancy of >3 months and good performance status received escalating doses of radiation to all known sites of cancer with hypofractionated radiation therapy. Patients were followed radiographically with computed tomography scans of the chest, abdomen, and pelvis and metabolically with [18F]fluorodeoxyglucose-positron emission tomography 1 month following treatment and then every 3 months. Acute toxicities were scored using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0 and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system. RESULTS: Twenty-nine patients with 56 metastatic lesions were enrolled from November 2004 to March 2007, with a median follow-up of 14.9 months. Two patients experienced acute (radiation pneumonitis and nausea) and one experienced chronic (gastrointestinal hemorrhage) grade > or =3 toxicity. Fifty-nine percent of patients responded to protocol therapy. Twenty-one percent of patients have not progressed following protocol treatment. Fifty-seven percent of treated lesions have not progressed at last follow-up. Progression was amenable to further local therapy in 48% of patients. CONCLUSIONS: Patients with low-volume metastatic cancer can be identified, safely treated, and may benefit from radiotherapy.

Early prostate cancer: hedonic prices model of provider-patient interactions and decisions.

PURPOSE: To determine the relative influence of treatment features and treatment availabilities on final treatment decisions in early prostate cancer. METHODS AND MATERIALS: We describe and apply a model, based on hedonic prices, to understand provider-patient interactions in prostate cancer. This model included four treatments (observation, external beam radiotherapy, brachytherapy, and prostatectomy) and five treatment features (one efficacy and four treatment complication features). We performed a literature search to estimate (1) the intersections of the "bid" functions and "offer" functions with the price function along different treatment feature axes, and (2) the treatments actually rendered in different patient subgroups based on age. We performed regressions to determine the relative weight of each feature in the overall interaction and the relative availability of each treatment modality to explain differences between observed vs. predicted use of different modalities in different patient subpopulations. RESULTS: Treatment efficacy and potency preservation are the major factors influencing decisions for young patients, whereas preservation of urinary and rectal function is much more important for very elderly patients. Referral patterns seem to be responsible for most of the deviations of observed use of different treatments from those predicted by idealized provider-patient interactions. Specifically, prostatectomy is used far more commonly in young patients and radiotherapy and observation used far more commonly in elderly patients than predicted by a uniform referral pattern. CONCLUSIONS: The hedonic prices approach facilitated identifying the relative importance of treatment features and quantification of the impact of the prevailing referral pattern on prostate cancer treatment decisions.

Author Correction: Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis.

In the originally published version of this Article, the affiliation details for Kevin P. White inadvertently omitted 'Tempus Labs, Chicago, IL, 60654, USA'. This has now been corrected in both the PDF and HTML versions of the Article.

Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis.

The oligometastasis hypothesis suggests a spectrum of metastatic virulence where some metastases are limited in extent and curable with focal therapies. A subset of patients with metastatic colorectal cancer achieves prolonged survival after resection of liver metastases consistent with oligometastasis. Here we define three robust subtypes of de novo colorectal liver metastasis through integrative molecular analysis. Patients with metastases exhibiting MSI-independent immune activation experience the most favorable survival. Subtypes with adverse outcomes demonstrate VEGFA amplification in concert with (i) stromal, mesenchymal, and angiogenic signatures, or (ii) exclusive NOTCH1 and PIK3C2B mutations with E2F/MYC activation. Molecular subtypes complement clinical risk stratification to distinguish low-risk, intermediate-risk, and high-risk patients with 10-year overall survivals of 94%, 45%, and 19%, respectively. Our findings provide a framework for integrated classification and treatment of metastasis and support the biological basis of curable oligometastatic colorectal cancer. These concepts may be applicable to many patients with metastatic cancer.

Transcriptional control of viral gene therapy by cisplatin.

Ionizing radiation (IR) and radical oxygen intermediates (ROIs) activate the early growth response-1 (Egr1) promoter through specific cis-acting sequences termed CArG elements. Ad.Egr.TNF.11D, a replication-deficient adenoviral vector containing CArG elements cloned upstream of the cDNA for human recombinant TNF-alpha was used to treat human esophageal adenocarcinoma and rat colon adenocarcinoma cells in culture and as xenografts in athymic nude mice. Cisplatin, a commonly used chemotherapeutic agent, causes tumor cell death by producing DNA damage and generating ROIs. The present studies demonstrate induction of TNF-alpha production in tumor cells and xenografts treated with the combination of Ad.Egr.TNF.11D and cisplatin. The results show that the Egr1 promoter is induced by cisplatin and that this induction is mediated in part through the CArG elements. These studies also demonstrate an enhanced antitumor response without an increase in toxicity following treatment with Ad.Egr.TNF.11D and cisplatin, compared with either agent alone. Chemo-inducible cancer gene therapy thus provides a means to control transgene expression while enhancing the effectiveness of commonly used chemotherapeutic agents.

Advanced Animal Model of Colorectal Metastasis in Liver: Imaging Techniques and Properties of Metastatic Clones.

Patients with a limited number of hepatic metastases and slow rates of progression can be successfully treated with local treatment approaches1,2. However, little is known about the heterogeneity of liver metastases, and animal models capable of evaluating the development of individual metastatic colonies are needed. Here, we present an advanced model of hepatic metastases that provides the ability to quantitatively visualize the development of individual tumor clones in the liver and estimate their growth kinetics and colonization efficiency. We generated a panel of monoclonal derivatives of HCT116 human colorectal cancer cells stably labeled with luciferase and tdTomato and possessing different growth properties. With a splenic injection followed by a splenectomy, the majority of these clones are able to generate hepatic metastases, but with different frequencies of colonization and varying growth rates. Using the In Vivo Imaging System (IVIS), it is possible to visualize and quantify metastasis development with in vivo luminescent and ex vivo fluorescent imaging. In addition, Diffuse Luminescent Imaging Tomography (DLIT) provides a 3D distribution of liver metastases in vivo. Ex vivo fluorescent imaging of harvested livers provides quantitative measurements of individual hepatic metastatic colonies, allowing for the evaluation of the frequency of liver colonization and the growth kinetics of metastases. Since the model is similar to clinically observed liver metastases, it can serve as a modality for detecting genes associated with liver metastasis and for testing potential ablative or adjuvant treatments for liver metastatic disease.

Hormone therapy and radiotherapy for early prostate cancer: a utility-adjusted number needed to treat (NNT) analysis.

PURPOSE: To quantify, using the number needed to treat (NNT) methodology, the benefit of short-term (< or =6 months) hormone therapy adjuvant to radiotherapy in the group of patients with early (clinical stage T1-T2c) prostate cancer. METHODS AND MATERIALS: The absolute biochemical control benefit for the use of hormones adjuvant to radiotherapy in early-stage disease was determined by literature review. A model was developed to estimate the utility-adjusted survival detriment due to the side effects of hormone therapy. The NNTs before and after the incorporation of hormone sequelae were computed; the sign and magnitude of the NNTs were used to gauge the effect of the hormones. RESULTS: The absolute NNT analysis, based on summarizing the results of 8 reports including a total of 3652 patients, demonstrated an advantage to the addition of hormones for the general early-stage prostate cancer population as well as for all prognostic groups. After adjustment for hormone-induced functional loss, the advantage of hormones remained considerable in the high- and intermediate-risk groups, with the utility-adjusted NNT becoming weakened in the low-risk group when the utility compromise from complications of hormones was assumed to be considerable. CONCLUSIONS: Short-term hormone therapy seems to be beneficial for selected early-stage prostate cancer patients. The advantage seems to be greatest in the intermediate- and high-risk groups; with current follow-up, the side effects of hormones may outweigh their benefit in certain clinical situations in the favorable group. The present investigation demonstrates the significant role of the NNT technique for oncologic and radiotherapeutic management decisions when treatment complications need to be considered and balanced with the beneficial effects of the treatment.

Chemoinducible gene therapy: a strategy to enhance doxorubicin antitumor activity.

A replication-defective adenoviral vector, Ad.Egr-TNF.11D, was engineered by ligating the CArG (CC(A/T)6GG) elements of the Egr-1 gene promoter upstream to a cDNA encoding human tumor necrosis factor-alpha. We report here that Ad.Egr-TNF.11D is activated by the clinically important anticancer agents cisplatin, cyclophosphamide, doxorubicin, 5-fluorouracil, gemcitabine, and paclitaxel. N-acetylcysteine, a free radical scavenger, blocked induction of tumor necrosis factor-alpha by anticancer agents, supporting a role for reactive oxygen intermediates in activation of the CArG sequences. Importantly, resistance of PC-3 human prostate carcinoma and PROb rat colon carcinoma tumors to doxorubicin in vivo was reversed by combining doxorubicin with Ad.Egr-TNF and resulted in significant antitumor effects. Treatment with Ad.Egr-TNF.11D has been associated with inhibition of tumor angiogenesis. In this context, a significant decrease in tumor microvessel density was observed following combined treatment with doxorubicin and Ad.Egr-TNF.11D as compared with either agent alone. These data show that Ad.Egr-TNF.11D is activated by diverse anticancer drugs.

Imaging of tumor clones with differential liver colonization.

We present a model of hepatic colorectal metastases which represents monoclonal cell lines double-labeled by luciferase and tdTomato. These cells form liver metastasis in varying numbers and patterns similar to those observed in patients. Using in vivo and ex vivo luminescent and fluorescent imaging we determine the growth kinetics and clonogenic frequency of tumor cells colonizing liver. Molecular profiling detected stable expressional differences between clones consistent with their phenotypes. The data indicate that clinically relevant phenotypes of liver metastases can be modeled in vivo.

14q32-encoded microRNAs mediate an oligometastatic phenotype.

Oligometastasis is a clinically distinct subset of metastasis characterized by a limited number of metastases potentially curable with localized therapies. We analyzed pathways targeted by microRNAs over-expressed in clinical oligometastasis samples and identified suppression of cellular adhesion, invasion, and motility pathways in association with the oligometastatic phenotype. We identified miR-127-5p, miR-544a, and miR-655-3p encoded in the 14q32 microRNA cluster as co-regulators of multiple metastatic pathways through repression of shared target genes. These microRNAs suppressed cellular adhesion and invasion and inhibited metastasis development in an animal model of breast cancer lung colonization. Target genes, including TGFBR2 and ROCK2, were key mediators of these effects. Understanding the role of microRNAs expressed in oligometastases may lead to improved identification of and interventions for patients with curable metastatic disease, as well as an improved understanding of the molecular basis of this unique clinical entity.