Thomas Jefferson University Hospital

BACKGROUND: Oropharyngeal squamous-cell carcinomas caused by human papillomavirus (HPV) are associated with favorable survival, but the independent prognostic significance of tumor HPV status remains unknown. METHODS: We performed a retrospective analysis of the association between tumor HPV status and survival among patients with stage III or IV oropharyngeal squamous-cell carcinoma who were enrolled in a randomized trial comparing accelerated-fractionation radiotherapy (with acceleration by means of concomitant boost radiotherapy) with standard-fractionation radiotherapy, each combined with cisplatin therapy, in patients with squamous-cell carcinoma of the head and neck. Proportional-hazards models were used to compare the risk of death among patients with HPV-positive cancer and those with HPV-negative cancer. RESULTS: The median follow-up period was 4.8 years. The 3-year rate of overall survival was similar in the group receiving accelerated-fractionation radiotherapy and the group receiving standard-fractionation radiotherapy (70.3% vs. 64.3%; P=0.18; hazard ratio for death with accelerated-fractionation radiotherapy, 0.90; 95% confidence interval [CI], 0.72 to 1.13), as were the rates of high-grade acute and late toxic events. A total of 63.8% of patients with oropharyngeal cancer (206 of 323) had HPV-positive tumors; these patients had better 3-year rates of overall survival (82.4%, vs. 57.1% among patients with HPV-negative tumors; P<0.001 by the log-rank test) and, after adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, had a 58% reduction in the risk of death (hazard ratio, 0.42; 95% CI, 0.27 to 0.66). The risk of death significantly increased with each additional pack-year of tobacco smoking. Using recursive-partitioning analysis, we classified our patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage. CONCLUSIONS: Tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer. (ClinicalTrials.gov number, NCT00047008.)

Task Group 101 of the AAPM has prepared this report for medical physicists, clinicians, and therapists in order to outline the best practice guidelines for the external-beam radiation therapy technique referred to as stereotactic body radiation therapy (SBRT). The task group report includes a review of the literature to identify reported clinical findings and expected outcomes for this treatment modality. Information is provided for establishing a SBRT program, including protocols, equipment, resources, and QA procedures. Additionally, suggestions for developing consistent documentation for prescribing, reporting, and recording SBRT treatment delivery is provided.

Disorders of the brain can exhibit considerable epidemiological comorbidity and often share symptoms, provoking debate about their etiologic overlap. We quantified the genetic sharing of 25 brain disorders from genome-wide association studies of 265,218 patients and 784,643 control participants and assessed their relationship to 17 phenotypes from 1,191,588 individuals. Psychiatric disorders share common variant risk, whereas neurological disorders appear more distinct from one another and from the psychiatric disorders. We also identified significant sharing between disorders and a number of brain phenotypes, including cognitive measures. Further, we conducted simulations to explore how statistical power, diagnostic misclassification, and phenotypic heterogeneity affect genetic correlations. These results highlight the importance of common genetic variation as a risk factor for brain disorders and the value of heritability-based methods in understanding their etiology.

Introduction Periprosthetic joint infection (PJI) is one of the most challenging and frequent complications after lower-extremity joint (hip and knee) arthroplasty. However, there is no single accepted set of diagnostic criteria for PJI. Various definitions have been proposed; however, none have been widely adopted. Furthermore, some of these definitions disagree with each other [14]. Therefore, a workgroup convened by the Musculoskeletal Infection Society (MSIS) analyzed the available evidence to propose a new definition for PJI. A summary of recommendations of those in attendance at a premeeting workshop of the 21st Annual Meeting of the MSIS on August 4, 2011, pertaining to the definition of PJI is outlined below. Existing published data on the definition of PJI was discussed by e-mail in the preceding 6 months by the executive members of the MSIS and a group of experts with known interest in this field. The intention of this proposal is to have a “gold standard” definition for PJI that can be universally adopted by all physicians, surveillance authorities (including the Centers for Disease Control, medical and surgical journals, the medicolegal community), and all involved in management of PJI. The panel acknowledged, in certain low-grade infections (ie, Propionibacterium acnes), several of these criteria may not be routinely met despite the presence of PJI. Using this definition, clinicians can be confident in their diagnosis and therefore provide appropriate treatment. Additionally, adoption of this definition for research purposes will allow for consistency between studies and potential improvement of the quality of the published body of evidence. Definition of Periprosthetic Joint Infection Based on the proposed criteria, definite PJI exists when: There is a sinus tract communicating with the prosthesis; or A pathogen is isolated by culture from at least two separate tissue or fluid samples obtained from the affected prosthetic joint; or Four of the following six criteria exist: Elevated serum erythrocyte sedimentation rate (ESR) and serum C-reactive protein (CRP) concentration, Elevated synovial leukocyte count, Elevated synovial neutrophil percentage (PMN%), Presence of purulence in the affected joint, Isolation of a microorganism in one culture of periprosthetic tissue or fluid, or Greater than five neutrophils per high-power field in five high-power fields observed from histologic analysis of periprosthetic tissue at ×400 magnification. PJI may be present if fewer than four of these criteria are met. Considerations Microbiologic Testing It is imperative that tissue for culture be obtained from representative periprosthetic tissue or fluid. To limit the risk of contamination, each sample should be taken with separate, sterile instruments. The definition of phenotypically identical organisms should be based on phenotypic similarities and in vitro antimicrobial susceptibility testing since confirmation of genetic identity is not routinely performed on clinical isolates. We recommend that at least three and no more than five periprosthetic specimen culture samples are taken and incubated in an aerobic and anaerobic environment. Fungal and mycobacterial cultures should not be performed routinely and reserved to higher-risk scenarios. The time of culture incubation has not been standardized yet. Isolation of a single low-virulence pathogen such as coagulase-negative Staphylococcus, P. acnes, or Corynebacteria in the absence of other criteria is not believed to represent a definite infection. Isolation of a single virulent organism such as S. aureus may represent a PJI. Furthermore, recent evidence has identified that certain tests, such as Gram stain, of periprosthetic tissue or fluid are not sensitive in diagnosing PJI [7]. Serum Tests Based on previous publications, an ESR of greater than 30 mm/hour and a CRP of greater than 10 mg/L would represent elevated levels [11, 15]. However, it is important to note there are variations in measuring these markers between laboratories. Furthermore, the level of these serum markers is affected by age, sex, and medical comorbidities of the patient. It has also been reported these markers can be elevated for approximately 30 to 60 days in the immediate postoperative period [3, 9]. Synovial Tests Multiple studies have provided thresholds for synovial leukocyte count and PMN% in the differential. In the chronically infected knee arthroplasty, these values have been reported from 1100 to 4000 cells/μL and 64% to 69%, respectively [5, 8, 16]. In patients with acute infections, the levels of synovial cell count and PMN% are much higher (approximately 20,000 cells/μL and 89%, respectively). Acute infections are defined as less than 3 months from index surgery or from the onset of symptoms [1]. The levels of synovial cell count and PMN% in the infected hip arthroplasty are not well delineated. A sole study has provided a threshold of 3000 cells/μL for leukocytes and 80% for PMN% for the infected hip arthroplasty [15]. None of these studies have included patients with underlying inflammatory arthropathies and related diseases. Current research is proceeding to provide more definitive thresholds for all patients. Histology Examination of periprosthetic tissues for evidence of neutrophils has been traditionally conducted by specially trained musculoskeletal pathologists. Histologic examination consequently may be operator dependent. It is therefore incumbent on surgeons to ensure their pathologists are in agreement with the diagnostic criteria for PJI. When examining for the presence of neutrophils, the histopathologist should disregard neutrophils entrapped in superficial fibrin or adherent to endothelium or small veins. Also, caution should be exercised in analyzing this test in cases where elevated neutrophil count might be expected, such as recent periprosthetic fractures or inflammatory arthropathy. Future Developments This proposed definition was based on current evidence supporting the role of various tests in diagnosis of PJI that are available in the literature. We recognize there are numerous other tests currently being evaluated, including measurement of CRP from the synovial fluid [12], synovial leukocyte esterase [13], sonication of explanted prosthetics [17], and molecular techniques such as PCR [10] and other molecular markers such as IL-6 [2, 4, 6]. As these or other techniques become validated and widely available, the currently proposed definition may require modification. Acknowledgments We thank the following individuals for their involvement and invaluable input throughout the development of this document: Robert Barrack MD, Keith Berend MD, Sandra Berrios-Torres (from Centers for Disease Control and Prevention), Kevin Bozic MD, John Esterhai MD, Ryan Fagan (from Centers for Disease Control and Prevention), Thomas Fehring MD, Terry Gioe MD, Teresa Horan (from Centers for Disease Control and Prevention), Steven Kurtz PhD, Bas Masri MD, Arvind Nana MD, Douglas Osmon MD, John Segreti MD, and Mark Spangehl MD.

RSNA, 2017.

IMPORTANCE: Cerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies. OBJECTIVE: To use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI). DATA SOURCES: Relevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators. STUDY SELECTION: Studies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity. DATA EXTRACTION AND SYNTHESIS: Individual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies. MAIN OUTCOMES AND MEASURES: Prevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations. RESULTS: The prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality. CONCLUSIONS AND RELEVANCE: Among persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.

UNLABELLED: Periprosthetic joint infection is one of the most challenging complications of joint arthroplasty. We identified current risk factors of periprosthetic joint infection after modern joint arthroplasty, and determined the incidence and timing of periprosthetic joint infection. We reviewed prospectively collected data from our database on 9245 patients undergoing primary hip or knee arthroplasty between January 2001 and April 2006. Periprosthetic joint infections developed in 63 patients (0.7%). Sixty-five percent of periprosthetic joint infections developed within the first year of the index arthroplasty. The infecting organism was isolated in 57 of 63 cases (91%). The most common organisms identified were Staphylococcus aureus and Staphylococcus epidermidis. We identified the following independent predictors for periprosthetic joint infection: higher American Society of Anesthesiologists score, morbid obesity, bilateral arthroplasty, knee arthroplasty, allogenic transfusion, postoperative atrial fibrillation, myocardial infarction, urinary tract infection, and longer hospitalization. This study confirmed some previously implicated factors and identified new variables that predispose patients to periprosthetic joint infection. LEVEL OF EVIDENCE: Level II, prognostic study.

The incidence of failure after knee replacement is low, yet it has been reported that more than 22,000 knee replacements are revised yearly. The purpose of the current study was to determine current mechanisms of failure of total knee arthroplasties. A retrospective review was done on all patients who had revision total knee arthroplasty during a 3-year period (September 1997-October 2000) at one institution. The preoperative evaluation in conjunction with radiographs, laboratory data, and intraoperative findings were used to determine causes of failure. Two hundred twelve surgeries were done on 203 patients (nine patients had bilateral surgeries). The reasons for failure listed in order of prevalence among the patients in this study include polyethylene wear, aseptic loosening, instability, infection, arthrofibrosis, malalignment or malposition, deficient extensor mechanism, avascular necrosis in the patella, periprosthetic fracture, and isolated patellar resurfacing. The cases reviewed included patients who had revision surgery within 9 days to 28 years (average, 3.7 years) after the previous surgery. More than half of the revisions in this group of patients were done less than 2 years after the index operation. Fifty percent of early revision total knee arthroplasties in this series were related to instability, malalignment or malposition, and failure of fixation.

Observational studies of necrotic core progression identify intraplaque hemorrhage as a critical factor in atherosclerotic plaque growth and destabilization. The rapid accumulation of erythrocyte membranes causes an abrupt change in plaque substrate characterized by increased free cholesterol within the lipid core and excessive macrophage infiltration. Neoangiogenesis is associated closely with plaque progression, and microvascular incompetence is a likely source of intraplaque hemorrhage. Intimal neovascularization is predominantly thought to arise from the adventitia, where there are a plethora of pre-existing vasa vasorum. In lesions that have early necrotic cores, the majority of vessels invading from the adventitia occur at specific sites of medial wall disruption. A breech in the medial wall likely facilitates the rapid in-growth of microvessels from the adventitia, and exposure to an atherosclerotic environment stimulates abnormal vascular development characterized by disorganized branching and immature endothelial tubes with "leaky" imperfect linings. This network of immature blood vessels is a viable source of intraplaque hemorrhage providing erythrocyte-derived phospholipids and free cholesterol. The rapid change in plaque substrate caused by the excessive accumulation of erythrocytes may promote the transition from a stable to an unstable lesion. This review discusses the potential role of intraplaque vasa vasorum in lesion instability as it relates to plaque rupture.

The relative importance of various human leukocyte antigen (HLA) loci and the resolution level at which they are matched has not been fully defined for unrelated donor transplantation. To address this question, National Marrow Donor Program data from 3857 transplantations performed from 1988 to 2003 in the United States were analyzed. Patient-donor pairs were fully typed for HLA-A, -B, -C, -DRB1, -DQB1, -DQA1, -DPB1, and -DPA1 alleles. High-resolution DNA matching for HLA-A, -B, -C, and -DRB1 (8/8 match) was the minimum level of matching associated with the highest survival. A single mismatch detected by low- or high-resolution DNA testing at HLA-A, -B, -C or -DRB1 (7/8 match) was associated with higher mortality (relative risk, 1.25; 95% CI, 1.13-1.38; P < .001) and 1-year survival of 43% compared with 52% for 8/8 matched pairs. Single mismatches at HLA-B or HLA-C appear better tolerated than mismatches at HLA-A or HLA-DRB1. Mismatching at 2 or more loci compounded the risk. Mismatching at HLA-DP or -DQ loci and donor factors other than HLA type were not associated with survival. In multivariate modeling, patient age, race, disease stage, and cytomegalovirus status were as predictive of survival as donor HLA matching. High-resolution DNA matching for HLA-A, -B, -C, and -DRB1 alleles is associated with higher rates of survival.

PURPOSE: Hippocampal neural stem-cell injury during whole-brain radiotherapy (WBRT) may play a role in memory decline. Intensity-modulated radiotherapy can be used to avoid conformally the hippocampal neural stem-cell compartment during WBRT (HA-WBRT). RTOG 0933 was a single-arm phase II study of HA-WBRT for brain metastases with prespecified comparison with a historical control of patients treated with WBRT without hippocampal avoidance. PATIENTS AND METHODS: Eligible adult patients with brain metastases received HA-WBRT to 30 Gy in 10 fractions. Standardized cognitive function and quality-of-life (QOL) assessments were performed at baseline and 2, 4, and 6 months. The primary end point was the Hopkins Verbal Learning Test-Revised Delayed Recall (HVLT-R DR) at 4 months. The historical control demonstrated a 30% mean relative decline in HVLT-R DR from baseline to 4 months. To detect a mean relative decline ≤ 15% in HVLT-R DR after HA-WBRT, 51 analyzable patients were required to ensure 80% statistical power with α = 0.05. RESULTS: Of 113 patients accrued from March 2011 through November 2012, 42 patients were analyzable at 4 months. Mean relative decline in HVLT-R DR from baseline to 4 months was 7.0% (95% CI, -4.7% to 18.7%), significantly lower in comparison with the historical control (P < .001). No decline in QOL scores was observed. Two grade 3 toxicities and no grade 4 to 5 toxicities were reported. Median survival was 6.8 months. CONCLUSION: Conformal avoidance of the hippocampus during WBRT is associated with preservation of memory and QOL as compared with historical series.

The Liver Imaging Reporting and Data System (LI-RADS) is composed of four individual algorithms intended to standardize the lexicon, as well as reporting and care, in patients with or at risk for hepatocellular carcinoma in the context of surveillance with US; diagnosis with CT, MRI, or contrast material-enhanced US; and assessment of treatment response with CT or MRI. This report provides a broad overview of LI-RADS, including its historic development, relationship to other imaging guidelines, composition, aims, and future directions. In addition, readers will understand the motivation for and key components of the 2018 update.

SCOPUS: ar.j

BACKGROUND: Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. METHODS: Clinical data from patients with candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis. RESULTS: The incidence of candidemia caused by non-Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P<.001) and were less likely to be neutropenic (5.1%; P<.001) and to receive corticosteroids (33.5%; P<.001) or other immunosuppressive drugs (7.9%; P=.002), compared with patients infected with other Candida species. Candida krusei candidemia was most commonly associated with prior use of antifungal agents (70.6%; P<.001), hematologic malignancy (52.9%; P<.001) or stem cell transplantation (17.7%; P<.001), neutropenia (45.1%; P<.001), and corticosteroid treatment (60.8%; P<.001). Patients with C. krusei candidemia had the highest crude 12-week mortality in this series (52.9%; P<.001). Fluconazole was the most commonly administered antimicrobial, followed by the echinocandins, and amphotericin B products were infrequently administered. CONCLUSIONS: The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen.

BACKGROUND: Traumatic spinal cord injuries (SCI) have devastating consequences for the physical, financial, and psychosocial well-being of patients and their caregivers. Expediently delivering interventions during the early postinjury period can have a tremendous impact on long-term functional recovery. PATHOPHYSIOLOGY: This is largely due to the unique pathophysiology of SCI where the initial traumatic insult (primary injury) is followed by a progressive secondary injury cascade characterized by ischemia, proapoptotic signaling, and peripheral inflammatory cell infiltration. Over the subsequent hours, release of proinflammatory cytokines and cytotoxic debris (DNA, ATP, reactive oxygen species) cyclically adds to the harsh postinjury microenvironment. As the lesions mature into the chronic phase, regeneration is severely impeded by the development of an astroglial-fibrous scar surrounding coalesced cystic cavities. Addressing these challenges forms the basis of current and upcoming treatments for SCI. MANAGEMENT: This paper discusses the evidence-based management of a patient with SCI while emphasizing the importance of early definitive care. Key neuroprotective therapies are summarized including surgical decompression, methylprednisolone, and blood pressure augmentation. We then review exciting neuroprotective interventions on the cusp of translation such as Riluzole, Minocycline, magnesium, therapeutic hypothermia, and CSF drainage. We also explore the most promising neuroregenerative strategies in trial today including Cethrin™, anti-NOGO antibody, cell-based approaches, and bioengineered biomaterials. Each section provides a working knowledge of the key preclinical and patient trials relevant to clinicians while highlighting the pathophysiologic rationale for the therapies. CONCLUSION: We conclude with our perspectives on the future of treatment and research in this rapidly evolving field.

OBJECTIVES: Concise "synthetic" review of the state of the art of management of acute ischemic stroke. DATA SOURCES: Available literature on PubMed. STUDY SELECTION: We selected landmark studies, recent clinical trials, observational studies, and professional guidelines on the management of stroke including the last 10 years. DATA EXTRACTION: Eligible studies were identified and results leading to guideline recommendations were summarized. DATA SYNTHESIS: Stroke mortality has been declining over the past 6 decades, and as a result, stroke has fallen from the second to the fifth leading cause of death in the United States. This trend may follow recent advances in the management of stroke, which highlight the importance of early recognition and early revascularization. Recent studies have shown that early recognition, emergency interventional treatment of acute ischemic stroke, and treatment in dedicated stroke centers can significantly reduce stroke-related morbidity and mortality. However, stroke remains the second leading cause of death worldwide and the number one cause for acquired long-term disability, resulting in a global annual economic burden. CONCLUSIONS: Appropriate treatment of ischemic stroke is essential in the reduction of mortality and morbidity. Management of stroke involves a multidisciplinary approach that starts and extends beyond hospital admission.

Rhabdomyolysis ranges from an asymptomatic illness with elevation in the creatine kinase level to a life-threatening condition associated with extreme elevations in creatine kinase, electrolyte imbalances, acute renal failure and disseminated intravascular coagulation. Muscular trauma is the most common cause of rhabdomyolysis. Less common causes include muscle enzyme deficiencies, electrolyte abnormalities, infectious causes, drugs, toxins and endocrinopathies. Weakness, myalgia and tea-colored urine are the main clinical manifestations. The most sensitive laboratory finding of muscle injury is an elevated plasma creatine kinase level. The management of patients with rhabdomyolysis includes early vigorous hydration.

BACKGROUND: Physicians, particularly trainees and those in surgical subspecialties, are at risk for burnout. Mistreatment (i.e., discrimination, verbal or physical abuse, and sexual harassment) may contribute to burnout and suicidal thoughts. METHODS: A cross-sectional national survey of general surgery residents administered with the 2018 American Board of Surgery In-Training Examination assessed mistreatment, burnout (evaluated with the use of the modified Maslach Burnout Inventory), and suicidal thoughts during the past year. We used multivariable logistic-regression models to assess the association of mistreatment with burnout and suicidal thoughts. The survey asked residents to report their gender. RESULTS: Among 7409 residents (99.3% of the eligible residents) from all 262 surgical residency programs, 31.9% reported discrimination based on their self-identified gender, 16.6% reported racial discrimination, 30.3% reported verbal or physical abuse (or both), and 10.3% reported sexual harassment. Rates of all mistreatment measures were higher among women; 65.1% of the women reported gender discrimination and 19.9% reported sexual harassment. Patients and patients' families were the most frequent sources of gender discrimination (as reported by 43.6% of residents) and racial discrimination (47.4%), whereas attending surgeons were the most frequent sources of sexual harassment (27.2%) and abuse (51.9%). Proportion of residents reporting mistreatment varied considerably among residency programs (e.g., ranging from 0 to 66.7% for verbal abuse). Weekly burnout symptoms were reported by 38.5% of residents, and 4.5% reported having had suicidal thoughts during the past year. Residents who reported exposure to discrimination, abuse, or harassment at least a few times per month were more likely than residents with no reported mistreatment exposures to have symptoms of burnout (odds ratio, 2.94; 95% confidence interval [CI], 2.58 to 3.36) and suicidal thoughts (odds ratio, 3.07; 95% CI, 2.25 to 4.19). Although models that were not adjusted for mistreatment showed that women were more likely than men to report burnout symptoms (42.4% vs. 35.9%; odds ratio, 1.33; 95% CI, 1.20 to 1.48), the difference was no longer evident after the models were adjusted for mistreatment (odds ratio, 0.90; 95% CI, 0.80 to 1.00). CONCLUSIONS: Mistreatment occurs frequently among general surgery residents, especially women, and is associated with burnout and suicidal thoughts.

Intensity-modulated radiation therapy (IMRT) represents one of the most significant technical advances in radiation therapy since the advent of the medical linear accelerator. It allows the clinical implementation of highly conformal nonconvex dose distributions. This complex but promising treatment modality is rapidly proliferating in both academic and community practice settings. However, these advances do not come without a risk. IMRT is not just an add-on to the current radiation therapy process; it represents a new paradigm that requires the knowledge of multimodality imaging, setup uncertainties and internal organ motion, tumor control probabilities, normal tissue complication probabilities, three-dimensional (3-D) dose calculation and optimization, and dynamic beam delivery of nonuniform beam intensities. Therefore, the purpose of this report is to guide and assist the clinical medical physicist in developing and implementing a viable and safe IMRT program. The scope of the IMRT program is quite broad, encompassing multileaf-collimator-based IMRT delivery systems, goal-based inverse treatment planning, and clinical implementation of IMRT with patient-specific quality assurance. This report, while not prescribing specific procedures, provides the framework and guidance to allow clinical radiation oncology physicists to make judicious decisions in implementing a safe and efficient IMRT program in their clinics.

BACKGROUND: Uveal melanoma is a disease that is distinct from cutaneous melanoma, with a low tumor mutational burden and a 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. Data showing a proven overall survival benefit with a systemic treatment are lacking. Tebentafusp is a bispecific protein consisting of an affinity-enhanced T-cell receptor fused to an anti-CD3 effector that can redirect T cells to target glycoprotein 100-positive cells. METHODS: In this open-label, phase 3 trial, we randomly assigned previously untreated HLA-A*02:01-positive patients with metastatic uveal melanoma in a 2:1 ratio to receive tebentafusp (tebentafusp group) or the investigator's choice of therapy with single-agent pembrolizumab, ipilimumab, or dacarbazine (control group), stratified according to the lactate dehydrogenase level. The primary end point was overall survival. RESULTS: A total of 378 patients were randomly assigned to either the tebentafusp group (252 patients) or the control group (126 patients). Overall survival at 1 year was 73% in the tebentafusp group and 59% in the control group (hazard ratio for death, 0.51; 95% confidence interval [CI], 0.37 to 0.71; P<0.001) in the intention-to-treat population. Progression-free survival was also significantly higher in the tebentafusp group than in the control group (31% vs. 19% at 6 months; hazard ratio for disease progression or death, 0.73; 95% CI, 0.58 to 0.94; P = 0.01). The most common treatment-related adverse events in the tebentafusp group were cytokine-mediated events (due to T-cell activation) and skin-related events (due to glycoprotein 100-positive melanocytes), including rash (83%), pyrexia (76%), and pruritus (69%). These adverse events decreased in incidence and severity after the first three or four doses and infrequently led to discontinuation of the trial treatment (2%). No treatment-related deaths were reported. CONCLUSIONS: Treatment with tebentafusp resulted in longer overall survival than the control therapy among previously untreated patients with metastatic uveal melanoma. (Funded by Immunocore; ClinicalTrials.gov number, NCT03070392; EudraCT number, 2015-003153-18.).