ß-Endorphin mediates radiation therapy fatigue.

Fatigue is a common adverse effect of external beam radiation therapy in cancer patients. Mechanisms causing radiation fatigue remain unclear, although linkage to skin irradiation has been suggested. ß-Endorphin, an endogenous opioid, is synthesized in skin following genotoxic ultraviolet irradiation and acts systemically, producing addiction. Exogenous opiates with the same receptor activity as ß-endorphin can cause fatigue. Using rodent models of radiation therapy, exposing tails and sparing vital organs, we tested whether skin-derived ß-endorphin contributes to radiation-induced fatigue. Over a 6-week radiation regimen, plasma ß-endorphin increased in rats, paralleled by opiate phenotypes (elevated pain thresholds, Straub tail) and fatigue-like behavior, which was reversed in animals treated by the opiate antagonist naloxone. Mechanistically, all these phenotypes were blocked by opiate antagonist treatment and were undetected in either ß-endorphin knockout mice or mice lacking keratinocyte p53 expression. These findings implicate skin-derived ß-endorphin in systemic effects of radiation therapy. Opioid antagonism may warrant testing in humans as treatment or prevention of radiation-induced fatigue.

Demographics of ASTRO Student Members and Potential Implications for Future U.S. Radiation Oncology Workforce Diversity.

PURPOSE: The radiation oncology workforce in the United States is comparatively less diverse than the U.S. population and U.S. medical school graduates. Workforce diversity correlates with higher quality care and outcomes. The purpose of this study was to determine whether student members of the American Society for Radiation Oncology (ASTRO) are any more diverse than resident members-in-training using the recently established medical student membership category. METHODS AND MATERIALS: Self-reported sex, race and Hispanic ethnicity, medical school, and degree(s) earned for all medical students (n = 268) and members-in-training (n = 713) were collected from the ASTRO membership database. International members were excluded. The χ2 test was used to assess for differences between subgroups. RESULTS: Compared with members-in-training, student members were more likely to be female (40.0% vs 31.5%, P = .032), black or African American (10.7% vs 4.8%, P = .009), candidates for or holders of a DO rather than MD degree (5.2% vs 1.5%, P = .002), and from a U.S. medical school that is not affiliated with a radiation oncology residency program (30.5% vs 20.9%, P = .001). There was no significant difference in self-reported Hispanic ethnicity (7.3% vs 5.4%, P = .356). There were no indigenous members in either category assessed. CONCLUSIONS: Medical student members of ASTRO are more diverse in terms of black race, female sex, and osteopathic training, though not in terms of Hispanic ethnicity or nonmultiracial indigenous background, than the members-in-training. Longitudinal engagement with these students and assessment of the factors leading to specialty retention versus attrition may increase diversity, equity, and inclusion in radiation oncology.

US Radiation Oncologists (Re)Defined: An American Society for Radiation Oncology Scope of Practice Study.

PURPOSE: To assess US radiation oncologists' views on practice scope and the ideal role of the radiation oncologist (RO), the American Society for Radiation Oncology (ASTRO) conducted a scope of practice survey. METHODS AND MATERIALS: In spring 2019, ASTRO distributed an online survey to 3822 US RO members. The survey generated 984 complete responses (26% response rate) for analysis. Face validity testing confirmed respondents were representative of ASTRO's RO membership. RESULTS: Nearly all respondents agreed that "ROs should be leaders in oncologic care." Respondents indicated the ideal approach to patient care was to provide "an independent opinion on radiation therapy and other treatment options" (82.5%) or "an independent opinion on radiation therapy but not outside of it" (16.1%), with only 1.4% favoring provision of "radiation therapy at the request of the referring physician" as the ideal approach. Actual practice fully matched the ideal approach in 18.2% of respondents. For the remaining majority, actual practice did not always match the ideal and comprised a mix of approaches that included providing radiation at the referring physician's request 24.0% of the time on average. Reasons for the mismatch included fear of alienating referring physicians and concern for offering an unwelcome opinion. One-fifth of respondents expressed a desire to expand the scope of service though interspecialty politics and insufficient training were potential barriers. Respondents interested in expanding scope of practice were on average earlier in their career (average years in practice 13.3) than those who were not interested (average years in practice 17.2, P < .001). Radiopharmaceuticals administration, medical marijuana and anticancer medications prescribing, and RO inpatient service represented areas of interest for expansion but also knowledge gaps. CONCLUSIONS: These results provide insight regarding US ROs' scope of practice and attitudes on the ideal role of the RO. For most ROs, to provide an independent opinion on treatment options represented the ideal approach to care, but barriers such as concern of alienating referring physicians prevented many from fully adhering to their ideal in practice. Actual practice commonly comprised a mixed approach, including the least favored scenario of delivering radiation at the referring physician's request one-quarter of the time, highlighting the influence of interspecialty politics on practice behavior. Advocacy for open communication and meaningful interdisciplinary collaboration presents an actionable solution toward a more balanced relationship with other specialties as ROs strive to better fulfill the vision of being leaders in oncologic care and being our best for our patients. The study also identified interest in expanding into nontraditional domains that offer opportunities to address unmet needs in the cancer patient's journey and elevate radiation oncology within the increasingly value-based US health care system.

The American Society for Radiation Oncology 2017 Radiation Oncologist Workforce Study.

PURPOSE: The aim of this study is to report the American Society for Radiation Oncology 2017 radiation oncologist (RO) workforce survey results; identify demographic, technology utilization, and employment trends; and assess the profession's ability to meet patients' needs, offer job satisfaction, and attract high-caliber trainees. METHODS: In spring 2017, the American Society for Radiation Oncology distributed an online survey to 3856 US RO members. The questionnaire was patterned after the 2012 workforce survey for trend analysis. The 31% response rate yielded 1174 individual responses (726 practices) for analysis. RESULTS: ROs' mean age was 50.9 years. Compared to 2012, female representation (28.9%) increased and white representation (69.8%) dropped. The proportion in rural practice (12.6%) decreased, whereas the number of suburban ROs (40.6%) increased and urban ROs (46.8%) remained high. Most ROs worked full-time, averaging 51.4 h/wk. Stereotactic body radiation therapy, cone beam computed tomography, and magnetic resonance/positron emission tomography-computed tomography fusion utilization increased, whereas low-dose-rate brachytherapy decreased by >15 percentage points. Hypofractionation utilization was 95.3% and was highest in academic/university systems and lowest in private solo practices (P < .001). More respondents were concerned about an RO oversupply rather than shortage. ROs reported 250 consults (median) and 20 on-treatment patients (median) in 2016 and greater time allocation to electronic health record management compared with 3 years earlier. Approximately 15% of ROs reported job vacancies, which were more prevalent in urban practices and academic/university systems. ROs were employed by academic/university systems, private practices, and nonacademic hospitals in a respective ratio of 2:2:1. Comparison with 2012 survey findings showed a shift from private practice toward academic/university systems and nonacademic hospitals. Compensation was predominantly productivity-based at private practices and a fixed salary or a base salary at academic/university systems and nonacademic hospitals. Practice merger/buyout was the lead reason for ROs to change employers. CONCLUSIONS: Since 2012, race and gender gaps narrowed, but geographic disparities persisted, with ROs gravitating toward resource-rich suburban and urban locations over rural practices. The workforce has shifted from predominantly private practice to more equal balance with academic/university systems. These findings reflect the current US RO landscape and serve to underscore the need for collective action to ensure equitable RO care for all patients.

Illness in the Returned International Traveler.

Familiarity with the distribution, mode of transmission, and risk factors for acquisition of illnesses commonly transmitted to travelers to low-income nations can help guide clinicians in their work-up of an ill returned traveler. The 3 most common categories of illness in returned international travelers are gastrointestinal illness, fever, and dermatoses. Diarrhea is the most common illness reported in returned international travelers. Fever is a marker of a potentially significant illness; work-up of the ill febrile returned traveler should be conducted promptly.

An assessment of the current US radiation oncology workforce: methodology and global results of the American Society for Radiation Oncology 2012 Workforce Study.

PURPOSE: To determine the characteristics, needs, and concerns of the current radiation oncology workforce, evaluate best practices and opportunities for improving quality and safety, and assess what we can predict about the future workforce. METHODS AND MATERIALS: An online survey was distributed to 35,204 respondents from all segments of the radiation oncology workforce, including radiation oncologists, residents, medical dosimetrists, radiation therapists, medical physicists, nurse practitioners, nurses, physician assistants, and practice managers/administrators. The survey was disseminated by the American Society for Radiation Oncology (ASTRO) together with specialty societies representing other workforce segments. An overview of the methods and global results is presented in this paper. RESULTS: A total of 6765 completed surveys were received, a response rate of 19%, and the final analysis included 5257 respondents. Three-quarters of the radiation oncologists, residents, and physicists who responded were male, in contrast to the other segments in which two-thirds or more were female. The majority of respondents (58%) indicated they were hospital-based, whereas 40% practiced in a free-standing/satellite clinic and 2% in another setting. Among the practices represented in the survey, 21.5% were academic, 25.2% were hospital, and 53.3% were private. A perceived oversupply of professionals relative to demand was reported by the physicist, dosimetrist, and radiation therapist segments. An undersupply was perceived by physician's assistants, nurse practitioners, and nurses. The supply of radiation oncologists and residents was considered balanced. CONCLUSIONS: This survey was unique as it attempted to comprehensively assess the radiation oncology workforce by directly surveying each segment. The results suggest there is potential to improve the diversity of the workforce and optimize the supply of the workforce segments. The survey also provides a benchmark for future studies, as many changes in the healthcare field exert pressure on the workforce.

American Society for Radiation Oncology (ASTRO) 2012 Workforce Study: the radiation oncologists' and residents' perspectives.

PURPOSE: The American Society for Radiation Oncology (ASTRO) conducted the 2012 Radiation Oncology Workforce Survey to obtain an up-to-date picture of the workforce, assess its needs and concerns, and identify quality and safety improvement opportunities. The results pertaining to radiation oncologists (ROs) and residents (RORs) are presented here. METHODS: The ASTRO Workforce Subcommittee, in collaboration with allied radiation oncology professional societies, conducted a survey study in early 2012. An online survey questionnaire was sent to all segments of the radiation oncology workforce. Respondents who were actively working were included in the analysis. This manuscript describes the data for ROs and RORs. RESULTS: A total of 3618 ROs and 568 RORs were surveyed. The response rate for both groups was 29%, with 1047 RO and 165 ROR responses. Among ROs, the 2 most common racial groups were white (80%) and Asian (15%), and the male-to-female ratio was 2.85 (74% male). The median age of ROs was 51. ROs averaged 253.4 new patient consults in a year and 22.9 on-treatment patients. More than 86% of ROs reported being satisfied or very satisfied overall with their career. Close to half of ROs reported having burnout feelings. There was a trend toward more frequent burnout feelings with increasing numbers of new patient consults. ROs' top concerns were related to documentation, reimbursement, and patients' health insurance coverage. Ninety-five percent of ROs felt confident when implementing new technology. Fifty-one percent of ROs thought that the supply of ROs was balanced with demand, and 33% perceived an oversupply. CONCLUSIONS: This study provides a current snapshot of the 2012 radiation oncology physician workforce. There was a predominance of whites and men. Job satisfaction level was high. However a substantial fraction of ROs reported burnout feelings. Perceptions about supply and demand balance were mixed. ROs top concerns reflect areas of attention for the healthcare sector as a whole.

Central role of p53 in the suntan response and pathologic hyperpigmentation.

UV-induced pigmentation (suntanning) requires induction of alpha-melanocyte-stimulating hormone (alpha-MSH) secretion by keratinocytes. alpha-MSH and other bioactive peptides are cleavage products of pro-opiomelanocortin (POMC). Here we provide biochemical and genetic evidence demonstrating that UV induction of POMC/MSH in skin is directly controlled by p53. Whereas p53 potently stimulates the POMC promoter in response to UV, the absence of p53, as in knockout mice, is associated with absence of the UV-tanning response. The same pathway produces beta-endorphin, another POMC derivative, which potentially contributes to sun-seeking behaviors. Furthermore, several instances of UV-independent pathologic pigmentation are shown to involve p53 "mimicking" the tanning response. p53 thus functions as a sensor/effector for UV pigmentation, which is a nearly constant environmental exposure. Moreover, this pathway is activated in numerous conditions of pathologic pigmentation and thus mimics the tanning response.

Lymphoma of the ocular adnexa: A study of 353 cases.

We studied the cases of 353 patients with lymphoma involving the ocular adnexa diagnosed at the Massachusetts General Hospital between 1974 and 2005. The patients included 153 males and 200 females, aged 7 to 95 years, with a mean age of 64 years. In 277 cases, there was no known history of lymphoma. Seventy-six patients had a history of lymphoma, with the ocular adnexa being involved at relapse or with progression of the previously diagnosed lymphoma. The patients had marginal zone lymphoma (182 cases), follicular lymphoma (80 cases), mantle cell lymphoma (18 cases), small lymphocytic lymphoma/chronic lymphocytic leukemia (13 cases), lymphoplasmacytic lymphoma (4 cases), splenic marginal zone lymphoma (2 cases), low-grade B cell, not subclassified (19 cases), precursor B lymphoblastic lymphoma (3 cases), diffuse large B-cell lymphoma (26 cases), and 1 case each of high-grade B-cell lymphoma, not subclassified, peripheral T-cell lymphoma, unspecified type, extranodal NK/T-cell lymphoma, nasal type, and Hodgkin lymphoma, nodular sclerosis type. Almost all marginal zone lymphoma patients (168 of 182, 92%) had primary ocular adnexal lymphoma. Fourteen marginal zone lymphoma patients (8%) had a prior history of lymphoma, usually arising in another extranodal site. Twenty-five of 80 (31%) follicular lymphoma patients had a prior history of lymphoma, usually arising in lymph nodes. Patients with mantle cell lymphoma, chronic lymphocytic leukemia, lymphoplasmacytic lymphoma, and splenic marginal zone lymphoma almost always had a prior history of lymphoma or were known to have widespread disease at the time of diagnosis of ocular adnexal lymphoma. A subset of the diffuse large B-cell lymphomas were associated with large destructive masses involving adjacent structures such as paranasal sinuses, raising the possibility that they may have arisen from one of the adjacent structures and involved the ocular adnexa by direct extension. The relatively high proportion of low-grade lymphoma, not subclassified, highlights the difficulty that may arise in distinguishing different types of low-grade lymphoma, particularly when biopsies are small and artifactually distorted. Ocular adnexal lymphoma is primarily a disease of older adults, with a slight female preponderance. Most lymphomas are low-grade B-cell lymphomas, with marginal zone lymphoma being by far the most common type. Marginal zone lymphoma typically involves the ocular adnexa primarily, whereas other types of low-grade B-cell lymphoma often involve the ocular adnexa secondarily. High-grade B-cell lymphomas only occasionally involve the ocular adnexa, and T-cell lymphoma, NK-cell lymphoma, and Hodgkin lymphoma are only rarely encountered in this site.

Comprehensive mapping of receptor-functioning domains in feline leukemia virus subgroup C receptor FLVCR1.

Infection of cells by the highly anemogenic feline leukemia virus subgroup C (FeLV-C) is mediated by the heme exporter FLVCR1, a cell surface protein containing 12 potential transmembrane segments with six presumptive extracellular loops (ECLs). To identify FLVCR1 residues critical for mediating FeLV-C infection, we first independently isolated a human cDNA encoding the FLVCR2 protein that shares 52% identity to human FLVCR1, and we show that FLVCR2 does not function as a receptor for FeLV-C. Then, by generating specific hybrids between FLVCR1 and FLVCR2 and testing susceptibility of mouse cells expressing these hybrids to beta-galactosidase encoding FeLV-C, we identify FLVCR1 ECLs 1 and 6 as critical for mediating FeLV-C infection. Mouse cells expressing a hybrid protein containing FLVCR2 backbone with the ECL6 sequence from FLVCR1 were highly susceptible to FeLV-C infection. Using site-directed mutagenesis, we show that a single mutation of Asn463 in FLVCR2 ECL6 to an acidic Asp residue (a residue present in the corresponding position 487 in FLVCR1 ECL6) is sufficient to render FLVCR2 functional as an FeLV-C receptor. However, an Asp487Asn mutation in FLVCR1 ECL6 or substitution of the entire FLVCR1 ECL6 sequence for FLVCR2 ECL6 sequence does not disrupt receptor function. Subsequent substitutions show that residues within FLVCR1 ECL1 also contribute to mediating FeLV-C infection. Furthermore, our results suggest that FLVCR1 regions that mediate FeLV-C surface unit binding are distinct from ECL1 and ECL6. Our results are consistent with previous conclusions that infection of cells by gammaretroviruses involves interaction of virus with multiple receptor regions.

Ocular adnexal lymphoma: clinical behavior of distinct World Health Organization classification subtypes.

PURPOSE: To evaluate the clinical behavior and treatment outcome of ocular adnexal lymphomas classified by the World Health Organization system, with emphasis on marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT). MATERIALS AND METHODS: The clinicopathologic materials from 98 consecutive patients treated for ocular adnexal lymphoma were reviewed. Fourteen patients had prior lymphoma and 84 patients had primary disease (75% Stage I, 6% Stage III, and 19% Stage IV). Radiation (photons/electrons) was administered to 102 eyes to a median dose of 30.6 Gy. The mean follow-up was 82 months. RESULTS: The most common subtypes among the primary patients were MALT (57%) and follicular (18%) lymphoma. The 5-year actuarial local control rate in 102 irradiated eyes was 98%. Among the low-grade lymphomas, the 5-year local control rate correlated with the radiation dose in the MALT lymphoma subgroup (n = 53): 81% for <30 Gy and 100% for > or =30 Gy (p <0.01). For the non-MALT low-grade lymphomas such as follicular lymphoma (n = 30), the local control rate was 100% regardless of dose. For 39 Stage I MALT lymphoma patients treated with radiation alone, the distant relapse-free survival rate was 75% at 5 years and 45% at 10 years. Distant relapses were generally isolated and successfully salvaged by local therapy. The overall survival for this subgroup was 81% at 10 years, with no deaths from lymphoma. CONCLUSIONS: Dose-response data suggest that the optimal radiation dose for MALT lymphoma of the ocular adnexa is 30.6-32.4 Gy in 1.8-Gy fractions and follicular lymphoma is adequately controlled with doses in the mid-20 Gy range. The substantial risk of distant relapse in Stage I ocular adnexal MALT lymphoma underscores the importance of long-term follow-up for this disease and the need for additional comparative studies of MALT lymphoma of different anatomic sites.