Rectal deformation management with IGRT in prostate radiotherapy: Can it be managed with rigid alignment alone?

PURPOSE: It is challenging to achieve appropriate target coverage of the prostate with Image Guided Radiation Therapy (IGRT) while simultaneously constraining rectal doses within planned values when there is significant variability in rectal filling and shape. We investigated if rectum planning goals can be fulfilled using rigid CBCT-based on-board alignment to account for interfraction rectal deformations. METHODS: Delivered rectal doses corresponding to prostate alignment ("PR") and anterior rectum alignment ("AR") for 239 daily treatments from 13 patients are reported. Rectal doses were estimated by rigidly mapping the planned dose on the daily CT derived from the daily CBCT according to respective alignment shifts. Rectum V95% (rV95%) was used for analyses. RESULTS: Compared to "PR", "AR" alignment increased rV95% for an average of 34.4% across all patients. rV95% (cc) averaged over all fractions was significant from planning values for 10/13 patients for "PR" and for 9/13 for "AR". 3/13 patients had reproducible anatomy. Of patients with non-reproducible anatomy, three had dosimetrically more favorable, while seven had less favorable anatomies. Most shift differences (82.3%) between the "PR" and "AR" alignments larger than 2 mm resulted in rV95% changes larger than 2 cc. Most shift differences (82.2%) of 2 mm or less between the "PR" and "AR" alignments resulted in rV95% changes less than 2 cc. The average percentage of fractions among patients in which anterior or posterior shifts for "AR" and "PR" alignment was larger than the PTV margins was 9.1% (0.0%-37.5%) and 1.3% (0%-10%). CONCLUSION: Rectal deformation and subsequent inconsistent interfraction separation between prostate and rectal wall translate into anatomical changes that cannot always be mitigated with rigid alignment. If systematic differences exist due to a non-reproducible planning anatomy, attempts to restore the planned rectal doses through anterior rectum alignment produce rather small improvements and may result in unacceptable target underdosage.

Melatonin Supplementation for Cancer-Related Fatigue in Patients With Early Stage Breast Cancer Receiving Radiotherapy: A Double-Blind Placebo-Controlled Trial.

BACKGROUND: Fatigue is common in patients undergoing radiotherapy (RT) and can significantly impact quality of life. Melatonin, a safe inexpensive natural supplement, may improve symptoms and attenuate the side effects of RT. The purpose of this randomized double-blind placebo-controlled phase III trial was to assess the effects of melatonin for preventing fatigue and other symptoms in patients with breast cancer undergoing RT. METHODS: Female early stage or Ductal carcinoma in situ patients with breast cancer ≥18 years of age with Eastern Cooperative Oncology Group (ECOG) performance status <3, hemoglobin ≥9 g/dL, planned for outpatient RT treatment with curative intent, were randomized 1:1 to melatonin 20 mg or placebo, orally, starting the night before RT initiation until 2 weeks post-RT. Randomization was stratified according to treatment duration (<3 weeks, ≥3 weeks) and prior chemotherapy. The primary endpoint was the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue scale), and secondary endpoints were FACIT-F subscales, Edmonton Symptom Assessment Scale (ESAS), and Patient-Reported Outcomes Measurement Information System (PROMIS) scores obtained at baseline, and 2 and 8 weeks post-RT. A 2-sided ANOVA F-test at a 4.5% significance level for the primary endpoint was used. Secondary analyses were reported using an F-test at a 5% significance level. The goal was to recruit approximately 140 patients with interim analysis planned mid-recruitment. RESULTS: Eighty-five patients were screened for eligibility; 79 patients were randomized: 40 to melatonin and 39 to placebo; 78 patients were treated and included in the interim analysis at the mid-recruitment point. Baseline patient characteristics of age, race, and ECOG performance status were similar in both arms. The treatment effect was studied using a longitudinal mixed effects model with the effect of treatment over time (treatment × time) as the primary outcome parameter. The treatment × time for FACIT-Fatigue did not demonstrate statistical significance (P-value .83) in the melatonin group compared to placebo. In addition, secondary analyses of FACIT physical, social, emotional, and functional well-being scores did not demonstrate statistical significance (P-values of .35, .06, .62, and .71, respectively). Total PROMIS scores, collected as secondary outcome reported by patients, did not demonstrate statistically significant change over time either (P-value is .34). The other secondary scale, ESAS, was analyzed for each individual item and found to be nonsignificant, anxiety (P = .56), well-being (.82), drowsiness (.83), lack of appetite (.35), nausea (.79), pain (.50), shortness of breath (.77), sleep (.45), and tiredness (.56). Depression was the only item demonstrating statistical significance with a decrease of 0.01 unit in the placebo group, a change not considered clinically significant. Melatonin was well-tolerated with no grade 3 or 4 adverse events reported. The most common side effects were headache, somnolence, and abdominal pain. No patients died while participating in this study. Two patients died within a year of study completion from breast cancer recurrence. Sixteen patients withdrew prior to study completion for various reasons including adverse events, hospitalizations unrelated to study drug, RT discontinuation, and COVID-19 precautions. CONCLUSIONS: In this double-blind placebo-controlled phase III trial, melatonin did not prevent or significantly improve fatigue and other symptoms in patients with early stage breast cancer undergoing RT. The analysis, showing little evidence of an effect, at mid-recruitment, assured early termination of the trial.

Air Medical Transport for Acute Ischemic Stroke Patients: A Retrospective Cohort Study of National Trends Over an 8-Year Period.

OBJECTIVE: Optimal management of ischemic stroke is time dependent. An understanding of patterns of air medical transport may identify disparities that could affect patient care. METHODS: In this 8-year (2007-2014) observational, retrospective, cohort study, we abstracted a 20% national sample of Medicare data from patients ≥ 66 years of age hospitalized with a primary diagnosis of acute ischemic stroke who presented to the emergency department by ambulance (air or ground). RESULTS: Among 149,751 hospitalized stroke patients who arrived by ambulance, the mean age was 81.6 years (standard deviation = 8.0 years), 62.1% were female (n = 93,007), and 86.3% were White (n = 129,268). Of these, 5,534 patients (3.7%) used any form of air ambulance. Air ambulance use (2007: 2.5%, 2014: 4.9%; P < .001) and arrival at certified stroke centers (2007: 40.3%, 2014: 63.2%; P < .001) increased over time. Air ambulance use was less likely among older patients (76-85 years and >85 years vs. 66-75 years; odds ratio [OR] = 0.68; 95% confidence interval [CI], 0.64-0.72 and OR = 0.34; 95% CI, 0.32-0.37, respectively) and all racial minorities except American Natives (OR = 2.07; 95% CI, 1.57-2.73) and more likely among sicker patients (Charlson Comorbidity Index ≥ 2 vs. 1, OR = 1.23; 95% CI, 1.09-1.38) and rural residents (OR = 1.34; 95% CI, 1.09-1.64). After adjustment for covariates, air ambulance use was associated with higher odds of thrombolysis (adjusted OR = 2.57; 95% CI, 2.38-2.79). CONCLUSION: Air ambulance use is independently associated with increased thrombolysis use for stroke, but disparities exist in both air ambulance and thrombolysis use. Further research into underlying causes for these disparities would be beneficial for systems and public health-based interventions for improving outcomes for ischemic stroke.

Association of an Emergency Critical Care Program With Survival and Early Downgrade Among Critically Ill Medical Patients in the Emergency Department.

OBJECTIVES: To determine whether implementation of an Emergency Critical Care Program (ECCP) is associated with improved survival and early downgrade of critically ill medical patients in the emergency department (ED). DESIGN: Single-center, retrospective cohort study using ED-visit data between 2015 and 2019. SETTING: Tertiary academic medical center. PATIENTS: Adult medical patients presenting to the ED with a critical care admission order within 12 hours of arrival. INTERVENTIONS: Dedicated bedside critical care for medical ICU patients by an ED-based intensivist following initial resuscitation by the ED team. MEASUREMENTS AND MAIN RESULTS: Primary outcomes were inhospital mortality and the proportion of patients downgraded to non-ICU status while in the ED within 6 hours of the critical care admission order (ED downgrade <6 hr). A difference-in-differences (DiD) analysis compared the change in outcomes for patients arriving during ECCP hours (2 pm to midnight, weekdays) between the preintervention period (2015-2017) and the intervention period (2017-2019) to the change in outcomes for patients arriving during non-ECCP hours (all other hours). Adjustment for severity of illness was performed using the emergency critical care Sequential Organ Failure Assessment (eccSOFA) score. The primary cohort included 2,250 patients. The DiDs for the eccSOFA-adjusted inhospital mortality decreased by 6.0% (95% CI, -11.9 to -0.1) with largest difference in the intermediate illness severity group (DiD, -12.2%; 95% CI, -23.1 to -1.3). The increase in ED downgrade less than 6 hours was not statistically significant (DiD, 4.8%; 95% CI, -0.7 to 10.3%) except in the intermediate group (DiD, 8.8%; 95% CI, 0.2-17.4). CONCLUSIONS: The implementation of a novel ECCP was associated with a significant decrease in inhospital mortality among critically ill medical ED patients, with the greatest decrease observed in patients with intermediate severity of illness. Early ED downgrades also increased, but the difference was statistically significant only in the intermediate illness severity group.

An Ethical Anaylsis of the Arguments Both For and Against COVID-19 Vaccine Mandates for Healthcare Workers.

BACKGROUND: Since the development of the first U.S. Food and Drug Administration-approved vaccine for the prevention of serious disease and death associated with the SARS-CoV-2 virus, health care workers have been expected to comply with mandatory immunization requirements or face potential termination of employment and censure by their state medical boards. Although most accepted this mandate, there have been several who have felt this was an unnecessary intrusion and violation of their right to choose their own health care mitigation strategies, or an infringement on their autonomy and other civil liberties. Others have argued that being a health care professional places your duties above your own self-interests, so-called fiduciary duties. As a result of these duties, there is an expected obligation to do the best action to achieve the "most good" for society. A so-called "utilitarian argument." DISCUSSION: We explore arguments both for and against these mandatory vaccine requirements and conclude using duty- and consequence-based moral reasoning to weigh the merits of each. CONCLUSIONS: Although arguments for and against vaccine mandates are compelling, it is the opinion of the Ethics Committee of the American Academy of Emergency Medicine that vaccine mandates for health care workers are ethically just and appropriate, and the benefit to society far outweighs the minor inconvenience to an individual's personal liberties.

Call of Duty - What are Physicians' Obligations During Crises?

BACKGROUND: Society allows physicians the privilege and responsibility of caring for patients. Those responsibilities demand that their knowledge and technical expertise meet standards defined and policed by their colleagues, through medical societies or governmental entities. However, the fiduciary duty that patients' interests are held above those of the physicians' is an ethical precept that is tested when society is under threat. DISCUSSION: Disasters that stress society are a constant and can present themselves in a myriad of ways to include medical, meteorological, or political. Minimizing the potential damage to the quality and quantity of life of the population is dependent upon public safety personnel and health care professionals who may put their health and safety in harm's way to care for patients. These acts may be taken for granted or assumed to be part of the professional obligations of physicians and other health care workers who work at the bedside. The obligations of physicians to their patients and society may differ from those not in the medical field, and the level of risk deemed acceptable by the physician and by society should be clearly delineated. CONCLUSION: Despite the conflict between normative and descriptive ethics, in times of disaster, physicians must respond to the call of duty. This duty is contingent on the responsibility being shared with governmental agencies and health care facilities, to mitigate the risks borne by those who answer the call.

PSA and PSA Kinetics as Predictors for 18F-Fluciclovine PET/CT Positivity in Biochemically Recurrent Prostate Cancer.

INTRODUCTION: 18F-Fluciclovine PET/CT is one of the imaging techniques currently employed to restage prostate cancer (PCa). Due to the conflicting results reported in the literature, it is not yet known at what PSA threshold 18F-fluciclovine PET/CT could reliably demonstrate the presence of recurring disease. We explored the association between 18F-fluciclovine PET/CT positivity and prescan PSA, PSA doubling time, and PSA velocity in patients with biochemical recurrence (BCR) of PCa after curative-intent treatment. METHODS: Data from 59 patients who underwent 18F-fluciclovine PET/CT for BCR after radical prostatectomy or radiotherapy were retrieved from a single institution database. Patients already undergone salvage treatments at the time of PET/CT, with newly diagnosed PCa or with initial diagnosis of metastatic PCa were excluded. A 2-sided independent samples Bayesian t test and Bayesian Mann-Whitney U test were used to assess the association between PET/CT and prescan PSA, PSA doubling time, and PSA velocity. RESULTS: Evidence for no difference between PET/CT-positive and -negative patients for log-transformed PSA was found (BF01 3.61, % error: 0.01). Robustness check and sequential analysis showed stability across a wide range of prior distribution specifications. The hypothesis of no difference in terms of PSA-dt and for PSA-vel between groups was found to be more likely compared to the alternative hypothesis (BF01 of 3.44 and 3.48, respectively). CONCLUSION: PSA and PSA kinetics are unlikely to be associated with 18F-fluciclovine PET/CT positivity in patients with BCR, and none of these serum biomarkers might be used as single predictors of PET/CT detection. Larger studies might be needed to evaluate the role of different predictors.

Trimodal therapy in muscle invasive bladder cancer management.

INTRODUCTION: Radical cystectomy (RC) is the current mainstay for muscle-invasive bladder cancer (MIBC). Concerns regarding morbidity, mortality and quality of life have favored the introduction of bladder sparing strategies. Trimodal therapy, combining transurethral resection, chemotherapy and radiotherapy is the current standard of care for bladder preservation strategies in selected patients with MIBC. EVIDENCE ACQUISITION: A comprehensive search of the Medline and Embase databases was performed. A total of 19 studies were included in a systematic review of bladder sparing strategies in MIBC management was carried out following the preferred reporting items for systematic reviews and meta-analysis (PRISMA). EVIDENCE SYNTHESIS: The overall median complete response rate after trimodal therapy (TMT) was 77% (55-93). Salvage cystectomy rate with TMT was 17% on average (8-30). For TMT, the 5-year cancer-specific survival and overall survival rates range from 42-82% and 32-74%, respectively. Currently data supporting neoadjuvant or adjuvant chemotherapy in bladder sparing approaches are emerging, but robust definitive conclusions are still lacking. Gastrointestinal toxicity rates are low around 4% (0.5-16), whereas genitourinary toxicity rates reached 8% (1-24). Quality of life outcomes are still underreported. CONCLUSIONS: Published data and clinical experience strongly support trimodal therapy as an acceptable bladder sparing strategy in terms of oncological outcomes and quality of life in selected patients with MIBC. A strong need exists for specialized centers, to increase awareness among urologists, to discuss these options with patients and to stress the increased participation of patients and their families in treatment path decision-making.

Cutting Edge Acute Ischemic Stroke Management.

Acute ischemic stroke (AIS) is a medical emergency that requires prompt recognition and streamlined work-up to ensure that time-dependent therapies are initiated to achieve the best outcomes. This article discusses frequently missed AIS in the emergency department, the role of various imagining modalities in the work-up of AIS, updates on the use of intravenous thrombolytics and endovascular therapy for AIS, pearls on supportive care management of AIS, and prehospital and hospital process improvements to shorten door-to-needle time.

Current Status of Targeted Radioprotection and Radiation Injury Mitigation and Treatment Agents: A Critical Review of the Literature.

As more cancer patients survive their disease, concerns about radiation therapy-induced side effects have increased. The concept of radioprotection and radiation injury mitigation and treatment offers the possibility to enhance the therapeutic ratio of radiation therapy by limiting radiation therapy-induced normal tissue injury without compromising its antitumor effect. Advances in the understanding of the underlying mechanisms of radiation toxicity have stimulated radiation oncologists to target these pathways across different organ systems. These generalized radiation injury mechanisms include production of free radicals such as superoxides, activation of inflammatory pathways, and vascular endothelial dysfunction leading to tissue hypoxia. There is a significant body of literature evaluating the effectiveness of various treatments in preventing, mitigating, or treating radiation-induced normal tissue injury. Whereas some reviews have focused on a specific disease site or agent, this critical review focuses on a mechanistic classification of activity and assesses multiple agents across different disease sites. The classification of agents used herein further offers a useful framework to organize the multitude of treatments that have been studied. Many commonly available treatments have demonstrated benefit in prevention, mitigation, and/or treatment of radiation toxicity and warrant further investigation. These drug-based approaches to radioprotection and radiation injury mitigation and treatment represent an important method of making radiation therapy safer.

Radiographic and Clinical Predictors of Cardiac Dysfunction Following Isolated Traumatic Brain Injury.

INTRODUCTION: Although cardiac dysfunction after traumatic brain injury (TBI) has been described, there is little data regarding the association of radiographic severity and particular lesions of TBI with the development of cardiac dysfunction. We hypothesize that the Rotterdam or Marshall scores and particular TBI lesions are associated with the development of cardiac dysfunction after isolated TBI. METHODS: We performed a retrospective cohort study. Adult patients with isolated TBI who underwent echocardiography between 2003 and 2010 were included. A board-certified neuroradiologist assessed the first computed tomography head, assigning the Rotterdam and Marshall scores and the type of TBI. Cardiac dysfunction was defined as either systolic or all cause based on the first echocardiogram after TBI. Demographic, radiological, and clinical variables were used in our analysis. RESULTS: A total of 139 patients were identified, with 20 having isolated systolic dysfunction. The Marshall and Rotterdam scores were not associated with the development of cardiac dysfunction. Only head Abbreviated Injury Scale was found to be an independent predictor of systolic cardiac dysfunction (relative risk: 2.70, 95% confidence interval: 1.19-6.13; P = .02). CONCLUSIONS: No specific radiographic variable was found to be an independent predictor of cardiac dysfunction. Further study into clinical or radiological features that would warrant an echocardiogram is warranted, as it may direct patient management.

The role of androgen deprivation therapy plus radiation therapy in patients with non-metastatic prostate cancer.

INTRODUCTION: Androgen deprivation therapy (ADT) has a long and illustrious history in the treatment for prostate cancer and continues to be a mainstay treatment for locally advanced and high-risk patients. Because the survival for even high-risk prostate patients is lengthy, details of treatment such as duration and timing must be considered carefully and weighed against the various side effects. AREAS COVERED: In the following article, we discuss the evolution of ADT from its initial applications in metastatic prostate cancer to its more recent incorporation into front line treatment in conjunction with radiation therapy (RT) for intermediate and high risk disease. We emphasize the results of phase III trials, which have defined the role of ADT in combination with RT in this patient population. We emphasize not only the potential benefits of ADT with RT, but also the potential risks, and underscore the need to consider both in order to maximize the therapeutic ration for each patient. Studies were identified via a search of PubMed as well as the bibliographies of articles discussed herein. Expert commentary: Even with advanced radiation techniques and dose escalation, adjuvant ADT continues to confer an overall survival benefit in intermediate and high-risk patients, although some evidence suggest that duration of treatment may be shortened, particularly for the high-risk group. The coming years will shed further information on this complicated topic with maturing of results from several ongoing trials.

Management of Postprostatectomy Biochemical Relapse With Salvage Radiotherapy: Results of an International Survey.

OBJECTIVES: The management of patients with postprostatectomy salvage radiotherapy (SRT) presents radiation oncologists (ROs) with multiple treatment decisions that may impact outcomes. As the evidence addressing these issues is limited to retrospective data, it was hypothesized that widely disparate treatment paradigms exist. METHODS: A 21-question survey was sent through SurveyMonkey to members of the American Society of Radiation Oncology. RESULTS: A total of 999 ROs responded. Threshold rPSA values to initiate SRT ranged from 0.1 to 1 ng/mL. The highest dose prescribed by ROs ranged from <60 to >70.2 Gy. Elective lymph node irradiation was offered by 74%, and the majority (64%) referenced the Roach formula, Kattan nomogram, or D'Amico risk stratification to decide when it was appropriate. There was variability in pelvic field design with a preference to place the superior field border at either the upper, middle, or lower sacroiliac joint by 57.6%, 28.8%, and 13.6% of respondents, respectively. Adjuvant androgen deprivation therapy (ADT) was offered by 74%. CONCLUSIONS: Disparate treatment paradigms exist for SRT that may impact patient outcomes. Variability includes patient selection, treatment design, and recommendations for ADT. Many reference formulas to predict the benefit of pelvic lymph node irradiation that are not yet validated in the postprostatectomy setting. These data make it clear that well-designed, prospective clinical trials are needed to better evaluate the role of larger treatment fields, dose escalation, and ADT for the thousands of patients who are treated with postprostatectomy SRT each year.

Cervical spine injury: analysis and comparison of patients by mode of transportation.

BACKGROUND: Cervical spine injury (CSI) studies have identified different factors contributing to CSI, but none compares the incidence and pattern of injury of patients arriving at the Emergency Department (ED) by private vehicle (PV). OBJECTIVE: We compared the characteristics and injury patterns in CSI patients who were transported to the ED via Emergency Medical Services (EMS) versus PV. METHODS: We conducted a three-hospital retrospective review of patients with CSI from January 1, 2000 to December 31, 2007. We excluded transfers and follow-up visits. Using a standardized data collection form, we reviewed demographics, mode of transport, mechanism of injury, imaging results, injury type and level, and neurologic deficits. Means and proportions were compared using t-tests and chi-squared as appropriate. RESULTS: Of 1174 charts identified, 718 met all study criteria; 671 arrived by EMS and 47 by PV. There was no difference between groups in age or gender. Ground-level fall was more likely in PV patients (32%, 95% confidence interval [CI] 20-46% vs. 6%, 95% CI 4-9%), whereas motor vehicle collision was less likely (32%, 95% CI 20-46% vs. 67%, 95% CI 63-70%). PV patients more often sustained a stable injury (66%, 95% CI 52-78% vs. 40%, 95% CI 36-44%), and were more often triaged to a lower-acuity area (25%, 95% CI 15-40% vs. 4%, 95% CI 3-6%). The incidence of neurologic deficit was similar (32%, 95% CI 20-46% vs. 24%, 95% CI 21-28%), though more PV patients had spinal cord injury without radiographic abnormality (21%, 95% CI 12-35% vs. 5%, 95% CI 4-7%). CONCLUSION: A small proportion of patients with CSI present to the ED by PV. Although most had stable injuries, a surprising number had unstable injuries with neurologic deficits, and were triaged to lower-acuity areas in the ED.

Population based cancer registry analysis of primary tracheal carcinoma.

INTRODUCTION: Primary carcinomas of the trachea are rare tumors, occurring at a rate of 2.6 new cases per 1,000,000 people per year. This study investigates the large observational cohort of patients recorded in the NCI Surveillance, Epidemiology, and End Results (SEER) 1973-2004 database, and provides information regarding epidemiology, treatment, and prognosis. METHODS: The SEER database was investigated, and all patients for whom primary tracheal carcinoma was the first and only cancer were investigated. Demographic information was investigated. The cohort was analyzed for variables effecting survival, including age, gender, race, histology, extent of disease, extent of surgery, use of radiation, and year of diagnosis. RESULTS: Between 1973 and 2004, 578 cases of primary tracheal carcinomas were reported in the SEER database. There were 322 men (55.7%) and 256 women (44.3%). Squamous cell carcinoma was the predominant histology, representing 259 tumors (44.8%). Adenoid cystic carcinoma (ACC) was the second most common tumor (16.3%). Localized, regional and distant disease was found in 140 (24.2%), 212 (36.7%), and 108 (18.7%), respectively. Twenty percent of the patients did not undergo staging. Patients with localized disease had a better prognosis than those with regional (P = 0.001) or distant disease (P = <0.001).A significant fraction of patients did not receive cancer directed local therapy; 34.3% did not undergo surgery and 29.1% did not receive any kind of radiation therapy. There was a statistically significant improved survival for patients who underwent any type of surgery in comparison with patients who did not undergo cancer directed surgery. There was no statistical benefit for patients who underwent radiation therapy.General overall 5-year survival for all patients was 27.1% (95% CI: 23.1-33.3%). Patients with localized disease had a better outcome than patients with regional or distant disease with an overall 5-year survival of 46% (95% CI: 37.3%-55.8%). Squamous cell carcinoma tumors had worse outcomes than any other histologic type, with a 5 year overall survival of 12.6% (95% CI: 8.4-17.6%). In contrast, 5-year overall survival for AACs was relatively good at 74.3% (95% CI: 63.1-82.5). For localized disease, 5-year survival was 24.7% (95% CI: 12.8-38.7%) for squamous cell carcinoma versus 90.5% (95% CI: 73.3-96.8%) for ACCs (P < 0.001). CONCLUSION: Primary tracheal tumors are very uncommon; squamous cell carcinoma is the most common histologic type, followed by ACCs. General 5-year overall survival is poor, though localized disease has better survival when compared with regional or distant disease. There is a remarkable difference in survival between squamous cell carcinoma and ACC.