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.

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.

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.

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.

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.

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.

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.

Clinical cancer research: the past, present and the future.

In the past decade, we have witnessed unprecedented changes and some remarkable advances that have enabled true personalized medicine. Nevertheless, many challenges in clinical cancer research remain and need to be overcome if we are to witness similar progress in the next decade. Such hurdles include, but are not limited to, clinical development and testing of multiple agents in combination, design of clinical trials to best accommodate the ever increasing knowledge of heterogeneity of the disease, regulatory challenges relating to drug development and trial design, and funding for basic research. With this in mind, we asked four leading cancer researchers from around the world, and who have been associated with the journal since its launch in November 2004 what, in their opinion, we have learnt over the past 10 years and how we should progress in the next 10 years.

Learning while caring: medicine's epistemology.

An essential epistemic consideration is the conditional nature of medical knowledge. This uncertainty must be understood when acquiring new knowledge or designing treatments. We must value all sources of information, neither discarding those deemed lower on the current value scale, nor slavishly accepting randomized clinical trials or their meta-analyses as the fount of all knowledge. Generally, the tension between clinical investigation and individual care can be framed in a utilitarian versus deontologic or rights-based philosophy. The utilitarian is clearly appropriate to public health considerations, but what is learned for public health may not necessarily be in the best interest of an individual patient. In utilitarianism, the distribution of goods-in this case, health-is not important; rather, it is the amount of total good gained that is to be maximized. Too often we assume that survival or cure is a sufficient metric, with no similar quantitative measure of other factors. This often leads to the so-called best treatment being not what the patient wants. All personal care requires consideration of both the helpful and harmful consequences of treatment in the context of individual patient comorbidity, preferences, and fears. Knowledge of patients in general is not what is required; rather, it is how to apply the information to the particular patient that is the heart of medical practice. Each patient's episode of illness is the consequence of a unique interaction of that individual with the disease. Good patient care considers the disease and its management in the context of each patient's values.

Towards a molecular basis of oligometastatic disease: potential role of micro-RNAs.

Oligometastasis is a cancer disease state characterized by a limited number of metastatic tumors involving single or few organs and with biological properties that make them potentially amenable to locoregional antitumor therapy. Current clinical data show that they are potentially curable with surgical resection or/and radiotherapy. Yet, mechanisms of progression from primary tumor to oligometastasis, rather than to polymetastases, is lacking in detail. In the current review we focus on the role of micro-RNAs in the regulation of metastases development and the role they may play in the differentiation of oligometastatic from polymetastatic progression. We also discuss the analyses of metastatic samples from oligo-and polymetastatic patients, which suggest that oligometastasis is a distinct biologic entity regulated in part by micro-RNAs. In addition, a review of the known functions of oligometastatic-specific micro-RNAs suggest that they regulate multiple steps in the metastatic cascade, including epithelial-mesenchymal transition, tumor invasion, intravasation, distant vascular extravasation and proliferation in a distant organ. Understanding the role of micro-RNAs and their target genes in oligometastatic disease may allow for the development of targeted therapies to effectively conrol the spread of metastases.

Oligo- and polymetastatic progression in lung metastasis(es) patients is associated with specific microRNAs.

RATIONALE: Strategies to stage and treat cancer rely on a presumption of either localized or widespread metastatic disease. An intermediate state of metastasis termed oligometastasis(es) characterized by limited progression has been proposed. Oligometastases are amenable to treatment by surgical resection or radiotherapy. METHODS: We analyzed microRNA expression patterns from lung metastasis samples of patients with ≤ 5 initial metastases resected with curative intent. RESULTS: Patients were stratified into subgroups based on their rate of metastatic progression. We prioritized microRNAs between patients with the highest and lowest rates of recurrence. We designated these as high rate of progression (HRP) and low rate of progression (LRP); the latter group included patients with no recurrences. The prioritized microRNAs distinguished HRP from LRP and were associated with rate of metastatic progression and survival in an independent validation dataset. CONCLUSION: Oligo- and poly- metastasis are distinct entities at the clinical and molecular level.

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.

MicroRNA expression characterizes oligometastasis(es).

BACKGROUND: Cancer staging and treatment presumes a division into localized or metastatic disease. We proposed an intermediate state defined by ≤ 5 cumulative metastasis(es), termed oligometastases. In contrast to widespread polymetastases, oligometastatic patients may benefit from metastasis-directed local treatments. However, many patients who initially present with oligometastases progress to polymetastases. Predictors of progression could improve patient selection for metastasis-directed therapy. METHODS: Here, we identified patterns of microRNA expression of tumor samples from oligometastatic patients treated with high-dose radiotherapy. RESULTS: Patients who failed to develop polymetastases are characterized by unique prioritized features of a microRNA classifier that includes the microRNA-200 family. We created an oligometastatic-polymetastatic xenograft model in which the patient-derived microRNAs discriminated between the two metastatic outcomes. MicroRNA-200c enhancement in an oligometastatic cell line resulted in polymetastatic progression. CONCLUSIONS: These results demonstrate a biological basis for oligometastases and a potential for using microRNA expression to identify patients most likely to remain oligometastatic after metastasis-directed treatment.

Oligometastases revisited.

We previously proposed a clinical state of metastasis termed 'oligometastases' that refers to restricted tumor metastatic capacity. The implication of this concept is that local cancer treatments are curative in a proportion of patients with metastases. Here we review clinical and laboratory data that support the hypothesis that oligometastasis is a distinct clinical entity. Investigations of the prevalence, mechanism of occurrence, and position in the metastatic cascade, as well as the determination of molecular markers to distinguish oligometastatic from polymetastatic disease, are ongoing.