Stereotactic Radiosurgery in the Management of Brain Metastases: A Case-Based Radiosurgery Society Practice Guideline.

Purpose: Brain metastases are common among adult patients with solid malignancies and are increasingly being treated with stereotactic radiosurgery (SRS). As more patients with brain metastases are becoming eligible for SRS, there is a need for practical review of patient selection and treatment considerations. Methods and Materials: Two patient cases were identified to use as the foundation for a discussion of a wide and representative range of management principles: (A) SRS alone for 5 to 15 lesions and (B) a large single metastasis to be treated with pre- or postoperative SRS. Patient selection, fractionation, prescription dose, treatment technique, and dose constraints are discussed. Literature relevant to these cases is summarized to provide a framework for treatment of similar patients. Results: Treatment of brain metastases with SRS requires many considerations including optimal patient selection, fractionation selection, and plan optimization. Conclusions: Case-based practice guidelines developed by the Radiosurgery Society provide a practical guide to the common scenarios noted above affecting patients with metastatic brain tumors.

Palliative radiotherapy for hepatic tumors: a narrative review of indications and recommendations.

BACKGROUND AND OBJECTIVE: Primary and metastatic liver cancer presents heterogeneously. New radiotherapy techniques have reduced toxicity concerns, leading to increased use of liver radiotherapy. This review synthesizes available evidence and offers recommendations for palliative radiotherapy for liver cancer. METHODS: PubMed, Ovid Medline, Embase, Cochrane Central, and Web of Science were searched from inception to December 28th, 2022. Articles reporting local control (LC), survival, toxicity, symptom control, and response after stereotactic body radiotherapy (SBRT), partial-liver, or whole-liver radiotherapy (WLRT) techniques were reviewed. We also identified nomograms identifying patients who may benefit from radiotherapy. KEY CONTENT AND FINDINGS: Nine randomized-controlled trials were found, in addition to many retrospective, feasibility, and phase I or II studies. Patients with favorable prognosis may receive SBRT using 30-50 Gray (Gy) in 3-5 fractions for primary cancer and up to 60 Gy for metastases, provided normal-tissue constraints are met. Select patients with multiple (>5) or large (>10 cm) lesions or macrovascular invasion (MVI) may be considered, but with potentially reduced LC and increased toxicity. Lower SBRT doses (i.e., 25 Gy in 5 fractions) can be considered on a cautionary basis for patients with poorer liver function or health. Patients with larger tumor burden, poor performance status (PS), or inability to tolerate SBRT positioning or motion-management can consider partial-liver three-dimensional conformal radiotherapy (3DCRT). For patients with extremely guarded prognosis and/or extremely poor performance, WLRT provides pain and symptom relief over several weeks. Combining radiotherapy and systemic therapy may allow radiotherapy de-escalation while maintaining good outcomes. CONCLUSIONS: Radiotherapy has a definite role for palliation of liver cancer with practical research providing guidance in the use of techniques and different regimens in various patient subgroups. Future investigation, including randomized trials, is needed to optimize patient selection, radiotherapy techniques, and integration with other therapies.

Proton Bragg Peak FLASH Enables Organ Sparing and Ultra-High Dose-Rate Delivery: Proof of Principle in Recurrent Head and Neck Cancer.

Proton pencil-beam scanning (PBS) Bragg peak FLASH combines ultra-high dose rate delivery and organ-at-risk (OAR) sparing. This proof-of-principle study compared dosimetry and dose rate coverage between PBS Bragg peak FLASH and PBS transmission FLASH in head and neck reirradiation. PBS Bragg peak FLASH plans were created via the highest beam single energy, range shifter, and range compensator, and were compared to PBS transmission FLASH plans for 6 GyE/fraction and 10 GyE/fraction in eight recurrent head and neck patients originally treated with quad shot reirradiation (14.8/3.7 CGE). The 6 GyE/fraction and 10 GyE/fraction plans were also created using conventional-rate intensity-modulated proton therapy techniques. PBS Bragg peak FLASH, PBS transmission FLASH, and conventional plans were compared for OAR sparing, FLASH dose rate coverage, and target coverage. All FLASH OAR V40 Gy/s dose rate coverage was 90-100% at 6 GyE and 10 GyE for both FLASH modalities. PBS Bragg peak FLASH generated dose volume histograms (DVHs) like those of conventional therapy and demonstrated improved OAR dose sparing over PBS transmission FLASH. All the modalities had similar CTV coverage. PBS Bragg peak FLASH can deliver conformal, ultra-high dose rate FLASH with a two-millisecond delivery of the minimum MU per spot. PBS Bragg peak FLASH demonstrated similar dose rate coverage to PBS transmission FLASH with improved OAR dose-sparing, which was more pronounced in the 10 GyE/fraction than in the 6 GyE/fraction. This feasibility study generates hypotheses for the benefits of FLASH in head and neck reirradiation and developing biological models.

Exploring causes and consequences of early discontinuation of durvalumab after chemoradiotherapy for non-small cell lung cancer.

Introduction: For most locally advanced non-small cell lung cancer (LA-NSCLC) patients who complete definitive chemoradiotherapy (CRT) and do not experience disease progression, one year of adjuvant durvalumab is recommended. Here, we explore causes and consequences of early durvalumab discontinuation. Materials and Methods: We reviewed patients treated for LA-NSCLC with definitive CRT who began adjuvant durvalumab between 2017 and 2021. Duration of durvalumab receipt and causes for early discontinuation were tabulated. Logistic regression models were utilized to evaluate predictors of early durvalumab discontinuation. Landmark analyses were performed to explore associations between early durvalumab discontinuation and clinical outcomes (progression-free survival (PFS), overall survival (OS)). Results: Fifty-nine patients were included. Forty-one patients (69%) discontinued durvalumab early, most commonly for disease progression (n = 14) or lung toxicity (n = 10). Multivariable analysis revealed mean heart radiotherapy dose (MHD) was associated with risk of durvalumab discontinuation from progression (HR = 2.34 per 10 Gy, p = 0.052), and there was a trend suggesting an association between MHD and risk of durvalumab discontinuation from lung toxicity (HR = 2.16 per 10 Gy, p = 0.126). Median PFS duration following durvalumab initiation was 14 months, and median OS duration was 32 months. Landmark analyses that excluded patients with progression or death within one year of durvalumab initiation demonstrated improved outcomes for patients who completed one year of durvalumab (2-year PFS 100% v. 40%, p < 0.001; 2-year OS 100% v. 67%, p = 0.862). Improved outcomes were observed for patients who received MHD below the cohort median (9.3 Gy) compared to patients with higher MHD (median PFS 32 months v. 8 months, p < 0.001; 2-year OS 69% v. 44%, p = 0.088). Conclusion: For LA-NSCLC patients treated with CRT followed by immunotherapy, extent of cardiac irradiation may be a risk factor for immunotherapy discontinuation, disease recurrence, and death.

Commissioning a 250 MeV research beamline for proton FLASH radiotherapy preclinical experiments.

BACKGROUND: The potential reduction of normal tissue toxicities during FLASH radiotherapy (FLASH-RT) has inspired many efforts to investigate its underlying mechanism and to translate it into the clinic. Such investigations require experimental platforms of FLASH-RT capabilities. PURPOSE: To commission and characterize a 250 MeV proton research beamline with a saturated nozzle monitor ionization chamber for proton FLASH-RT small animal experiments. METHODS: A 2D strip ionization chamber array (SICA) with high spatiotemporal resolution was used to measure spot dwell times under various beam currents and to quantify dose rates for various field sizes. An Advanced Markus chamber and a Faraday cup were irradiated with spot-scanned uniform fields and nozzle currents from 50 to 215 nA to investigate dose scaling relations. The SICA detector was set up upstream to establish a correlation between SICA signal and delivered dose at isocenter to serve as an in vivo dosimeter and monitor the delivered dose rate. Two off-the-shelf brass blocks were used as apertures to shape the dose laterally. Dose profiles in 2D were measured with an amorphous silicon detector array at a low current of 2 nA and validated with Gafchromic films EBT-XD at high currents of up to 215 nA. RESULTS: Spot dwell times become asymptotically constant as a function of the requested beam current at the nozzle of greater than 30 nA due to the saturation of monitor ionization chamber (MIC). With a saturated nozzle MIC, the delivered dose is always greater than the planned dose, but the desired dose can be achieved by scaling the MU of the field. The delivered doses exhibit excellent linearity with R 2 > 0.99 ${R^2} > 0.99$ with respect to MU, beam current, and the product of MU and beam current. If the total number of spots is less than 100 at a nozzle current of 215 nA, a field-averaged dose rate greater than 40 Gy/s can be achieved. The SICA-based in vivo dosimetry system achieved excellent estimates of the delivered dose with an average (maximum) deviation of 0.02 Gy (0.05 Gy) over a range of delivered doses from 3 to 44 Gy. Using brass aperture blocks reduced the 80%-20% penumbra by 64% from 7.55 to 2.75 mm. The 2D dose profiles measured by the Phoenix detector at 2 nA and the EBT-XD film at 215 nA showed great agreement, with a gamma passing rate of 95.99% using 1 mm/2% criterion. CONCLUSION: A 250 MeV proton research beamline was successfully commissioned and characterized. Challenges due to the saturated monitor ionization chamber were mitigated by scaling MU and using an in vivo dosimetry system. A simple aperture system was designed and validated to provide sharp dose fall-off for small animal experiments. This experience can serve as a foundation for other centers interested in implementing FLASH radiotherapy preclinical research, especially those equipped with a similar saturated MIC.

Correlation between Venous Thromboembolism Risk and Venous Congestion in Microvascular Reconstruction of the Lower Extremity.

BACKGROUND: Risk for venous thromboembolism formation and the relationship to postoperative free flap venous congestion and flap failure have not been adequately evaluated in a trauma population. The authors aim to use the Caprini Risk Assessment Model to evaluate the association between venous thromboembolism risk and postoperative flap venous congestion following lower extremity free tissue transfer. METHODS: A retrospective analysis was conducted of all patients who underwent lower extremity free flap reconstruction of traumatic defects at a single institution between 2007 and 2016. A Wilcoxon rank sum test was used for nonparametric analysis of aggregate Caprini Risk Assessment Model scores and flap outcomes. Flap venous congestion and failure rates as associated with the categorical variables underlying the Caprini Risk Assessment Model were further studied. Logistic regression was used to evaluate each of these outcomes and other flap-related covariates relative to the Caprini Risk Assessment Model categorical variables that had the greatest effect on our patient sample. RESULTS: One hundred twelve patients underwent lower extremity free flap reconstruction. One hundred eight free flaps were analyzed. Eight patients were excluded. The majority of patients were male (75.9 percent) and required reconstruction because of acute trauma (68.1 percent versus 31.9 percent for chronic wounds). There was no statistically significant association found between age, body mass index, or timing of trauma versus venous congestion, flap failure, or other flap-related covariates. CONCLUSION: In patients with significantly elevated Caprini Risk Assessment Model scores, there was no significant association between venous thromboembolism risk and flap failure following free tissue reconstruction of lower extremities. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

A Case of External Auditory Canal Sebaceous Carcinoma: Literature Review and Treatment Discussion.

Sebaceous neoplasms are a rare type of skin cancer that may occur in any area with sebaceous glands, including the outer third of the external auditory canal. However, documentation of the tumor originating in this location is limited to scarce case reports. In this location, malignancies can invade the temporal bone, typically requiring en bloc resection and radiation therapy. We describe a case managed with limited surgical excision based on criteria for primary squamous cell carcinoma of the external auditory canal with only close observation following surgery. Margins were free of disease following excision and histology demonstrated a favorable prognosis. The patient was disease free after a follow-up period of over 3 years postoperatively. A review of relevant literature is utilized to discuss clinical characteristics, staging, treatment, and prognosis to assist in clinical decision making for these patients.

Completion of an Individualized Learning Plan for Otology-Related Milestone Subcompetencies Leads to Improved Otology Section Otolaryngology Training Exam Scores.

OBJECTIVE: To examine the relationships among self-assessment of knowledge in otology via an individualized learning plan (ILP), otology milestone achievement rate, and otolaryngology training exam (OTE) otology scores. STUDY DESIGN: Prospective study. SETTING: One otolaryngology residency covering a tertiary care facility, trauma and hospital center, outpatient ambulatory surgery center, and outpatient clinics. PARTICIPANTS: Twenty otolaryngology residents, four from each class. METHODS: Residents identified four milestones from otology-related sub-competencies to achieve in a 3-month rotation via an ILP. During the same rotation, the residents sat for the OTE, and their overall and otology scores were analyzed. MAIN OUTCOME MEASURES: Completion of an ILP before and at the end of the rotation, self-reported achievement of otology milestones, and OTE score components including total percent correct, scaled score, group stanine, national stanine, and residency group weighted scores. RESULTS: Group stanine OTE otology scores were higher for those residents who completed pre- and post-rotation ILPs compared with those who did not, 4.0 (±0.348) versus 2.75 (±0.453), respectively (p = 0.04). Residents who self-reported achieving all four otology milestones had significantly higher otology group stanine scores than the residents who achieved less, 4.1 (±0.348) versus 2.9 ±â€Š0.433, respectively (p = 0.045). Residents who performed well in their PGY program cohort on the otology OTE 1 year were less inclined to complete an ILP for otology in the subsequent year (Pearson correlation -0.528, p = 0.035). CONCLUSION: In the otology subspecialty, residents who completed ILPs scored better on OTE examinations independent of resident class. Consequently, programs may find ILPs useful in other otolaryngology subspecialties and across residencies.

Policy Flight Simulators: Accelerating Decisions to Adopt Evidence-Based Health Interventions.

EXECUTIVE SUMMARY: In this study, the authors used simulation to explore factors that might influence hospitals' decisions to adopt evidence-based interventions. Specifically, they developed a simulation model to examine the extent to which hospitals would benefit economically from the transitional care model (TCM). The TCM is designed to transition high-risk older adults from hospitals back to communities using interventions focused on preventing readmissions.The authors used qualitative methods to identify and validate simulation facets. Four simulation experiments explored the economic impact of the TCM on more than 3,000 U.S. hospitals: (1) magnitude of readmission penalty, (2) application to specific diagnosis-related groups, (3) level of cost sharing between payer and provider, and (4) capitated versus fee-for-service payments. The simulator projected hospital-specific economic effects. The authors used Monte Carlo methods for the simulations, which were parameterized with public data sets from the Centers for Medicare & Medicaid Services (CMS) and TCM data from randomized controlled trials and comparative effectiveness studies.Under current conditions, the simulation indicated that only 10 of more than 3,000 Medicare-certified hospitals would benefit financially from the TCM. If current readmission penalties were doubled, the number of hospitals projected to benefit would increase to 300. Targeting selected diagnosis cohorts would also increase the number of hospitals to 300. If payers reimbursed providers for 100% of the TCM costs, 2,000 hospitals would benefit financially. Under a capitated payment model, 1,500 hospitals would benefit from the TCM.Current CMS penalties-or reasonable increases-have little economic effect on the TCM. In the current environment, two strategies are likely to facilitate adoption: (1) persuading payers to reimburse TCM costs and (2) focusing on hospitals with higher bed occupancies and higher revenue patients.

Developing a Policy Flight Simulator to Facilitate the Adoption of an Evidence-Based Intervention.

While the use of evidence-based interventions (EBIs) has been advocated by the medical research community for quite some time, uptake of these interventions by healthcare providers has been slow. One possible explanation is that it is challenging for providers to estimate impacts of a specific EBI on their particular organization. To address that concern, we developed and evaluated a type of simulation called a policy flight simulator to determine if it could improve the adoption decision about a specific EBI, the transitional care model (TCM). The TCM uses an advanced practice nurse-led model of care to transition older adults with multiple chronic conditions from a hospitalization to home. An evaluation by a National Advisory Committee, made up of senior representatives from various stakeholders in the U.S. healthcare system, found the policy flight simulator to be a useful tool that has the potential to better inform adoption decisions. This paper describes the simulation development effort and documents lessons learned that may be useful to the healthcare modeling community and those interested in using simulation to support decisions based on EBIs.

Baroreceptor reflex failure: Review of the literature and the potential impact on patients with head and neck cancer.

BACKGROUND: Baroreceptor dysfunction and reflex failure may occur after surgery affecting the carotid artery. The implications for patients undergoing treatment for head and neck cancer are not well described. METHODS: A literature search of PubMed was performed between March 2016 and May 2016. Search terms used individually and in combination included: "baroreflex failure," "carotid sinus sensitivity," "carotid endarterectomy," "carotid body tumor," and "head and neck cancer." Bibliographies of included articles were also reviewed for additional pertinent articles. RESULTS: There is evidence of baroreceptor failure in certain patients after interventions associated with the carotid artery, including carotid endarterectomy and carotid body tumor excision. Few studies have been performed investigating the potential effect of head and neck surgery treatment, including surgery and/or radiation, on baroreflex function. CONCLUSION: Head and neck cancer treatment has the potential to cause baroreflex failure, and this is likely an underrecognized and underdiagnosed condition.

Interactive visualizations for decision support: Application of Rasmussen's abstraction-aggregation hierarchy.

Data visualization has of late received an enormous amount of attention from both researchers and practitioners. Even the popular press often includes impressive visualizations of various data sets. Interactive visualizations frequently include data visualizations, but they differ in that users employ the visualizations to make inferences, reach conclusions, and make decisions that result in changed and/or new visualizations. Data visualizations emphasize "what is," but interactive visualizations address "what if." In this way, interactive visualizations are often intended for decision support. This article addresses the design of interactive visualizations for decision support. An overall methodology is presented; central to this methodology is Jens Rasmussen's abstraction-aggregation hierarchy. The results of two applications and evaluations of the outcomes of using this methodology are discussed. The first application focused on interactive visualizations for helicopter maintenance. The second application addressed "enterprise diagnostics" in the automobile industry where subjects were asked to diagnose the cause of failed automobile brands. The results of these two applications are used to assess the efficacy of the proposed methodology.

The effects of amphetamine, butorphanol, and their combination on cocaine self-administration.

There have been recent calls to examine the efficacy of drug-combination therapies in the treatment of substance use disorders. The purpose of the present study was to examine the ability of a novel stimulant-opioid combination to reduce cocaine self-administration, and to compare these effects to those of each drug administered alone. To this end, male Long-Evans rats were implanted with intravenous catheters and trained to self-administer cocaine under positive reinforcement contingencies. Once self-administration was acquired, rats were divided into four different groups and treated chronically for 20 days with (1) saline, (2) the psychomotor stimulant and monoamine releaser amphetamine, (3) the mu/kappa opioid agonist butorphanol, or (4) a combination of amphetamine and butorphanol. During chronic treatment, cocaine self-administration was examined on both fixed ratio (FR) and progressive ratio (PR) schedules of reinforcement. On the FR schedule, butorphanol significantly decreased cocaine self-administration, but this effect was not enhanced by amphetamine. On the PR schedule, amphetamine and butorphanol non-significantly decreased cocaine self-administration when administered alone but significantly decreased cocaine self-administration when administered in combination. These data suggest that under some conditions (e.g., when the response requirement of cocaine is high), a dual stimulant-opioid pharmacotherapy may be more effective than a single-drug monotherapy.

Access to a running wheel decreases cocaine-primed and cue-induced reinstatement in male and female rats.

BACKGROUND: Relapse to drug use after a period of abstinence is a persistent problem in the treatment of cocaine dependence. Physical activity decreases cocaine self-administration in laboratory animals and is associated with a positive prognosis in human substance-abusing populations. The purpose of this study was to examine the effects of long-term access to a running wheel on drug-primed and cue-induced reinstatement of cocaine-seeking behavior in male and female rats. methods: Long-Evans rats were obtained at weaning and assigned to sedentary (no wheel) and exercising (access to wheel) groups for the duration of the study. After 6 weeks, rats were implanted with intravenous catheters and trained to self-administer cocaine for 14 days. After training, saline was substituted for cocaine and responding was allowed to extinguish, after which cocaine-primed reinstatement was examined in both groups. Following this test, cocaine self-administration was re-established in both groups for a 5-day period. Next, a second period of abstinence occurred in which both cocaine and the cocaine-associated cues were withheld. After 5 days of abstinence, cue-induced reinstatement was examined in both groups. RESULTS: Sedentary and exercising rats exhibited similar levels of cocaine self-administration, but exercising rats responded less than sedentary rats during extinction. In tests of cocaine-primed and cue-induced reinstatement, exercising rats responded less than sedentary rats, and this effect was apparent in both males and females. CONCLUSIONS: These data indicate that long-term access to a running wheel decreases drug-primed and cue-induced reinstatement, and that physical activity may be effective at preventing relapse in substance-abusing populations.

"It's a feel. That's what a lot of our evidence would consist of ": public health practitioners' perspectives on evidence.

This article describes how evidence is defined and used in two British Columbia public health departments during the implementation of a Healthy Living initiative in 2009. Through interviews with 21 public health staff and decision makers, the author sought to investigate how "evidence" was defined by both frontline and management staff and how it was used in decision making. The authors found public health staff, particularly frontline practitioners, to be drawn to grassroots and local "lived experience" evidence. This tacit wisdom, in combination with evidence from academia and clinical evidence accessed through disciplinary or professional networks, offered a knowledge transition opportunity to inform decision making, rather than what can be characterized in the literature as unidirectional knowledge translation. It is often difficult for staff to digest and interpret research as part of their work day because of the volume and density of information that typically counts as evidence. Moreover, there exist challenges to identify and gather indicators as evidence of their work.

TPH2 in the ventral tegmental area of the male rat brain.

This study surveyed the distribution of tryptophan hydroxylase 2 (TPH2) mRNA, protein, and enzymatic activity throughout the male Sprague-Dawley rat brain. TPH2 is the genetic isoform of TPH that catalyzes the rate-limiting step in serotonin biosynthesis within the central nervous system. Although cell bodies of serotonergic neurons are located mainly in the raphe, serotonin-containing axons innervate many regions of the brain. In the present study, we assessed the levels of mRNA, protein expression, and enzyme activity of TPH2 in the rat raphe, ventral tegmental area (VTA), substantia nigra, hippocampus, cerebellum, dorsal striatum, nucleus accumbens, amygdala, and medial prefrontal cortex to more fully understand the distribution of this enzyme throughout the central nervous system. The pineal gland was used as a control tissue that expresses TPH1 (the peripheral enzyme), but not TPH2. As expected, the raphe showed the highest brain TPH2 activity and protein expression. In the contrast to other reports, however, the VTA followed the raphe as the region with the second-highest amount of TPH2 activity, mRNA and protein expression. There were significantly lower TPH activities and levels of TPH2 protein in the other regions. In addition, TPH2 immunocytochemistry demonstrated the presence of TPH-positive cell bodies within the VTA. The results of this study indicate that TPH2 and serotonergic signaling may play an important role in the mesolimbic/mesocortical reward pathway.

Social assistance, lone parents and health: what do we know, where do we go?

BACKGROUND: A mounting body of evidence indicates that lone mothers and their children are at higher risk of a variety of health problems. The dynamics of the relationship between social assistance, poverty and health are not well understood, and the study of this population presents substantial challenges. The purpose of this paper is to present an analysis of the state of research on lone parents, social assistance and health in an effort to make recommendations that will move the research forward. METHODS: Reviews of the relevant literature and social policies were conducted to identify (1) trends in social assistance policy and the extent of interprovincial variation in policy, and (2) research gaps. A series of interviews were conducted with key informants in government, non-governmental organizations and academia to gather information regarding research obstacles, opportunities and priorities. Finally, a consensus-building workshop was held to form research recommendations. RESULTS: A substantial degree of variation exists among provinces and territories with regard to social assistance policies. The nature of the variation, however, is complex and does not fall into tightly defined categories. This variation creates the possibility for "natural experiments" to examine the health implications of policies and practices. The pace of policy change, however, creates problems with respect to evaluation of specific policy initiatives. Interviewees and workshop participants recognized substantial impediments to research in this area, particularly regarding the availability of appropriate data. CONCLUSION: A research agenda, data development and dissemination activities were proposed to increase the research activity; these would be based upon multi-disciplinary, multi-sectoral collaborations using multiple methodologies. The creation of a multi-disciplinary, multi-sectoral national consortium in social assistance and health, reflecting the appropriate mix of urban, rural, anglophone, francophone and First Nations communities, is proposed.