Evaluation of a Radiation Oncology Microclerkship as a Component of Medical Student Education.

Compared to most oncologic subspecialties, radiation oncology (RO) lacks a natural pathway for incorporation into the clinical clerkships, and few students ever complete a formal rotation in RO. The feasibility, and perceived value, of a 1-day "microclerkship" exposure in RO during other related clerkships was evaluated in this study. At a single institution, the RO clerkship director partnered with clerkship directors in medical oncology, palliative care, and radiology so that every 3rd or 4th year student would spend 1 day in RO during those clerkships. Afterwards, students completed an electronic survey containing multiple choice and 5-point Likert-type questions describing their experience. Descriptive statistics are reported. Ninety-seven students completed the RO microclerkship over 2 years, and 81 completed the survey (response rate 84%). Only 8 students (10%) had ever been in a RO department previously. During the microclerkship, 73 students (90%) saw at least one new patient consultation; 77 (95%) were involved in contouring or treatment planning; 76 (94%) saw treatment delivery; and 38 (47%) saw a brachytherapy procedure. Seventy-nine students (98%) felt that the microclerkship was at least moderately valuable (mean Likert-type rating 4.01, SD 0.73). Forty students (49%) were either somewhat or much more interested in participating in a longer (2-4 week) rotation in radiation oncology (mean Likert-type rating 3.59, SD 0.83). This study demonstrated the feasibility of incorporating a 1-day RO microclerkship into other related elective clerkships. Students viewed the experience favorably and found it valuable in their education.

Patterns of failure in pediatric medulloblastoma and implications for hippocampal sparing.

BACKGROUND: Hippocampal avoidance (HA) has been shown to preserve cognitive function in adult patients with cancer treated with whole-brain radiation therapy for brain metastases. However, the feasibility of HA in pediatric patients with brain tumors has not been explored because of concerns of increased risk of relapse in the peri-hippocampal region. Our aim was to determine patterns of recurrence and incidence of peri-hippocampal relapse in pediatric patients with medulloblastoma (MB). METHODS AND MATERIALS: We identified pediatric patients with MB treated with protons between 2002 and 2016 and who had recurrent disease. To estimate the risk of peri-hippocampal recurrence, three hippocampal zones (HZs) were delineated corresponding to ≤5 mm (HZ-1), 6 to 10 mm (HZ-2), and >10 mm (HZ-3) distance of the recurrence from the contoured hippocampi. To determine the feasibility of HA, three standard-risk patients with MB were planned using either volumetric-modulated arc therapy (VMAT) or intensity-modulated proton therapy (IMPT) plans. RESULTS: Thirty-eight patients developed a recurrence at a median of 1.6 years. Of the 25 patients who had magnetic resonance imaging of the recurrence, no patients failed within the hippocampus and only two patients failed within HZ-1. The crude incidence of peri-hippocampal failure was 8%. Both HA-VMAT and HA-IMPT plans were associated with significantly reduced mean dose to the hippocampi (p < .05). HA-VMAT and HA-IMPT plans were associated with decreased percentage of the third and lateral ventricles receiving the prescription craniospinal dose of 23.4 Gy. CONCLUSIONS: Peri-hippocampal failures are uncommon in pediatric patients with MB. Hippocampal avoidance should be evaluated in a prospective cohort of pediatric patients with MB. PLAIN LANGUAGE SUMMARY: In this study, the patterns of disease recurrence in patients with a pediatric brain tumor known as medulloblastoma treated with proton radiotherapy were examined. The majority of failures occur outside of an important structure related to memory formation called the hippocampus. Hippocampal sparing radiation plans using proton radiotherapy were generated and showed that dose to the hippocampus was able to be significantly reduced. The study provides the rationale to explore hippocampal sparing in pediatric medulloblastoma in a prospective clinical trial.

Radiation Necrosis with Proton Therapy in a Patient with Aarskog-Scott Syndrome and Medulloblastoma.

PURPOSE: Medulloblastoma is known to be associated with multiple cancer-predisposition syndromes. In this article, we explore a possible association among a patient's Aarskog-Scott syndrome, development of medulloblastoma, and subsequent brainstem radiation necrosis. CASE PRESENTATION: A 5-year-old male with Aarskog-Scott syndrome initially presented to his pediatrician with morning emesis, gait instability, and truncal weakness. He was ultimately found to have a posterior fossa tumor with pathology consistent with group 3 medulloblastoma. After receiving a gross total resection and standard proton beam radiation therapy with concurrent vincristine, he was noted to develop brainstem radiation necrosis, for which he underwent therapy with high-dose dexamethasone, bevacizumab, and hyperbaric oxygen therapy with radiographic improvement and clinical stabilization. CONCLUSION: Based on several possible pathologic correlates in the FDG1 pathway, there exists a potential association between this patient's Aarskog-Scott syndrome and medulloblastoma, which needs to be investigated further. In patients with underlying, rare genetic syndromes, further caution should be taken when evaluating chemotherapy and radiation dosimetry planning.

Variation in Proton Craniospinal Irradiation Practice Patterns in the United States: A Pediatric Proton Consortium Registry (PPCR) Study.

PURPOSE: Craniospinal irradiation (CSI) is commonly used for pediatric brain tumors with a propensity for spread in craniospinal fluid, principally medulloblastoma. Evolving technology has led to the use of highly conformal radiation therapy (RT) techniques for CSI, including proton therapy. Target delineation and plan coverage are critical for CSI, but there is ongoing controversy and variability in these realms, with little available data on practice patterns. We sought to characterize proton CSI practice patterns in the United States by examining CSI plans in the Pediatric Proton/Photon Consortium Registry (PPCR). MATERIALS AND METHODS: PPCR was queried for data on proton CSI patients from 2015 to early 2020. Each plan was manually reviewed, determining patient position; prescription dose; and coverage of optic nerves, vertebral bodies, spinal nerve roots, sacral nerves, and cranial foramina, among other variables. Two radiation oncologists blinded to clinical data and treating institution assessed coverage at the 95% prescription isodose line and per published European Society for Paediatric Oncology guidelines. Variability in coverage was assessed with nonparametric tests and univariate and multivariate logistic regression. RESULTS: PPCR supplied data for 450 patients, 384 of whom had an evaluable portion of a CSI plan. Most patients (90.3%) were supine. Optic nerves were fully covered in 48.2%; sacral nerves in 87.7%; cranial foramina in 69.3%; and spinal nerves in 95.6%. Vertebral body (VB) sparing was used in 18.6% of skeletally immature cases, increasing over time (P < .001). Coverage in all categories was significantly different among treating institutions, on univariate and multivariate analyses. Cribriform plate deficits were rare, with marginal misses of the foramen ovale (17.4%) and frontal lobe (12%) most common. CONCLUSION: We found consistent variation based on treating institution in proton CSI practices including optic nerve, VB, sacral nerve, cranial, and spinal nerve coverage. These data may serve as a baseline quantification of current proton CSI practices in the United States as they continue to evolve.

Modern Radiotherapy for Pediatric Brain Tumors.

Cancer is a leading cause of death in children with tumors of the central nervous system, the most commonly encountered solid malignancies in this population. Radiotherapy (RT) is an integral part of managing brain tumors, with excellent long-term survival overall. The tumor histology will dictate the volume of tissue requiring treatment and the dose. However, radiation in developing children can yield functional deficits and/or cosmetic defects and carries a risk of second tumors. In particular, children receiving RT are at risk for neurocognitive effects, neuroendocrine dysfunction, hearing loss, vascular anomalies and events, and psychosocial dysfunction. The risk of these late effects is directly correlated with the volume of tissue irradiated and dose delivered and is inversely correlated with age. To limit the risk of developing these late effects, improved conformity of radiation to the target volume has come from adopting a volumetric planning process. Radiation beam characteristics have also evolved to achieve this end, as exemplified through development of intensity modulated photons and the use of protons. Understanding dose limits of critical at-risk structures for different RT modalities is evolving. In this review, we discuss the physical basis of the most common RT modalities used to treat pediatric brain tumors (intensity modulated radiation therapy and proton therapy), the RT planning process, survival outcomes for several common pediatric malignant brain tumor histologies, RT-associated toxicities, and steps taken to mitigate the risk of acute and late effects from treatment.

Radiation Therapy for Small Cell Lung Cancer: An ASTRO Clinical Practice Guideline.

PURPOSE: Several sentinel phase III randomized trials have recently been published challenging traditional radiation therapy (RT) practices for small cell lung cancer (SCLC). This American Society for Radiation Oncology guideline reviews the evidence for thoracic RT and prophylactic cranial irradiation (PCI) for both limited-stage (LS) and extensive-stage (ES) SCLC. METHODS: The American Society for Radiation Oncology convened a task force to address 4 key questions focused on indications, dose fractionation, techniques and timing of thoracic RT for LS-SCLC, the role of stereotactic body radiation therapy (SBRT) compared with conventional RT in stage I or II node negative SCLC, PCI for LS-SCLC and ES-SCLC, and thoracic consolidation for ES-SCLC. Recommendations were based on a systematic literature review and created using a consensus-building methodology and system for grading evidence quality and recommendation strength. RESULTS: The task force strongly recommends definitive thoracic RT administered once or twice daily early in the course of treatment for LS-SCLC. Adjuvant RT is conditionally recommended in surgically resected patients with positive margins or nodal metastases. Involved field RT delivered using conformal advanced treatment modalities to postchemotherapy volumes is also strongly recommended. For patients with stage I or II node negative disease, SBRT or conventional fractionation is strongly recommended, and chemotherapy should be delivered before or after SBRT. In LS-SCLC, PCI is strongly recommended for stage II or III patients who responded to chemoradiation, conditionally not recommended for stage I patients, and should be a shared decision for patients at higher risk of neurocognitive toxicities. In ES-SCLC, radiation oncologist consultation for consideration of PCI versus magnetic resonance surveillance is strongly recommended. Lastly, the use of thoracic RT is strongly recommended in select patients with ES-SCLC after chemotherapy treatment, including a conditional recommendation in those responding to chemotherapy and immunotherapy. CONCLUSIONS: RT plays a vital role in both LS-SCLC and ES-SCLC. These guidelines inform best clinical practices for local therapy in SCLC.

Second Primary Non-Small-Cell Lung Cancer After Head and Neck Cancer: A Population-Based Study of Clinical and Pathologic Characteristics and Survival Outcomes in 3597 Patients.

INTRODUCTION: Retrospective studies have shown an increased risk of second primary lung cancer in patients with a history of head and neck cancer (HNC). No population-based study has examined the overall survival (OS) outcomes of patients with second primary non-small-cell lung cancer (NSCLC) after HNC comparison with patients with first primary NSCLC. PATIENTS AND METHODS: Individuals with histologically confirmed NSCLC diagnosed after nonmetastatic squamous-cell carcinoma of the head and neck (HNC-NSCLC; n = 3597) were identified in Surveillance, Epidemiology, and End Results 18 registries (1988-2013). OS and baseline characteristics were compared in patients with first primary NSCLC (NSCLC-1; n = 365,551) in the same registries. RESULTS: Squamous NSCLC was more common in HNC-NSCLC (n = 745 [64.1%] localized, n = 833 [71.9%] regional, and n = 811 [63.5%] distant) than in the NSCLC-1 (n = 30,901 [38.3%] localized, n = 50,557 [48.2%] regional, and n = 53,720 [29.8%] distant; P < .001). The leading cause of death in HNC-NSCLC was NSCLC (n = 2183; 60.6%), and median OS after localized, regional, and distant NSCLC diagnosis was 2.50 years, 1.17 years, and 5 months, respectively. For NSCLC-1, median OS was 4.58 years, 1.58 years, and 6 months, respectively. These differences were significant (P < .001). In multivariable analysis, a history of HNC remained associated with worse OS for localized (hazard ratio [HR], 1.40; 95% confidence interval [CI], 1.29-1.51; P < .001), regional (HR, 1.26; 95% CI, 1.19-1.35; P < .001) and distant (HR, 1.11; 95% CI, 1.04-1.18; P < .01) stage NSCLC. CONCLUSION: A history of HNC adversely affects OS in patients who subsequently develop NSCLC. This OS decrement might have implications for NSCLC surveillance and NSCLC therapy selection in this population.

The Radiation Oncology Mentorship Initiative: Analysis of a Formal Mentoring Initiative for Medical Students Interested in Radiation Oncology.

The importance of mentorship in medicine and its impact on academic and professional development has been widely studied. However, mentorship for medical students in the field of radiation oncology is limited. Our radiation oncology department developed a formal medical student mentorship program in 2004. This program included both clinical and research mentoring pathways. Our study aims to gain feedback and perspective from former medical student participants who subsequently entered into a radiation oncology residency program. An anonymous survey was sent to 22 former students in the mentorship program from 2005 to 2016 who entered a radiation oncology residency program. The survey included Likert scales (1-5), multiple choice, strength category rankings, and free responses. Data was compiled and analyzed with Qualtrics data software. The survey response rate was 100%. Seventeen (77.3%) participants reported that the mentorship program strongly affected their career choice and a majority reported that their research experience strongly (45.5%) or moderately affected (31.8%) their career choice. Fourteen (63.6%) respondents reported that the mentorship program was very effective and 8 (36.4%) reported it as being effective. Eighteen (81.8%) respondents reported that mentorship was extremely important to their career. Students participating in the research pathway also reported improvement in valuable skills such as presentations, abstract writing, manuscript writing, statistical analysis, and coordination with colleagues. A total of 66.7% of attending radiation oncologists who previously participated in this program now practice in an academic setting. Our institution successfully developed a formalized mentorship program for medical students interested in radiation oncology. Participants in this program reported high levels of satisfaction and emphasized the importance of mentorship in the development of valuable research competencies and on their overall career path. This program can serve as a model for future mentorship initiative in medical school.

Medical student mentorship in radiation oncology at a single academic institution: A 10-year analysis.

PURPOSE: Mentorship has been identified by medical students, residents, and faculty as an important component of specialty selection and research productivity in radiation oncology. This study quantitatively analyzes the impact of a mentorship program in radiation oncology targeted to medical students at our institution. METHODS AND MATERIALS: We performed a retrospective review of 76 current or former medical students who were mentored by faculty radiation oncologists at our institution between 2004 and 2013. Data were collected from the medical school's Office of Student Affairs and from internal departmental records. Mentees were organized by mentorship tracks, which included a clinical track and a research track. For each track, data were compiled and analyzed for student specialty selection, and Fisher exact tests were used to determine the relative significance of exposure to clinical, research, or both tracks on student likelihood of pursuing residency in radiation oncology relative to other specialties. We further tracked the research productivity of mentees in the program, as determined by the number publications that were coauthored by mentees and mentors each year. RESULTS: The absolute number of mentees has grown each year, with a total of 76 mentees, including 58 alumni, at the end of 2013. Mentees in the program have produced a total of 53 manuscripts, given 75 presentations at national conferences, and received numerous national and internal medical school research awards. Of the 58 alumni, 17 (29.3%) applied to and matched into radiation oncology residencies. Alumni of both the research and the clinical track were 5.76 (P < .01) times more likely to enter a radiation oncology residency program than the average single-track alumnus. CONCLUSIONS: Mentorship in medical school is an important factor in the development of future radiation oncologists. These results demonstrate the positive impact mentorship has on specialty selection and research productivity.

Beyond the standard curriculum: a review of available opportunities for medical students to prepare for a career in radiation oncology.

PURPOSE: To review currently available opportunities for medical students to supplement their standard medical education to prepare for a career in radiation oncology. METHODS AND MATERIALS: Google and PubMed were used to identify existing clinical, health policy, and research programs for medical students in radiation oncology. In addition, results publicly available by the National Resident Matching Program were used to explore opportunities that successful radiation oncology applicants pursued during their medical education, including obtaining additional graduate degrees. RESULTS: Medical students can pursue a wide variety of opportunities before entering radiation oncology. Several national specialty societies, such as the American Society for Radiation Oncology and the Radiological Society of North America, offer summer internships for medical students interested in radiation oncology. In 2011, 30% of allopathic senior medical students in the United States who matched into radiation oncology had an additional graduate degree, including PhD, MPH, MBA, and MA degrees. Some medical schools are beginning to further integrate dedicated education in radiation oncology into the standard 4-year medical curriculum. CONCLUSIONS: To the authors' knowledge, this is the first comprehensive review of available opportunities for medical students interested in radiation oncology. Early exposure to radiation oncology and additional educational training beyond the standard medical curriculum have the potential to create more successful radiation oncology applicants and practicing radiation oncologists while also promoting the growth of the field. We hope this review can serve as guide to radiation oncology applicants and mentors as well as encourage discussion regarding initiatives in radiation oncology opportunities for medical students.

Neutron diffraction studies towards deciphering the protonation state of catalytic residues in the bacterial KDN9P phosphatase.

The enzyme 2-keto-3-deoxy-9-O-phosphonononic acid phosphatase (KDN9P phosphatase) functions in the pathway for the production of 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid, a sialic acid that is important for the survival of commensal bacteria in the human intestine. The enzyme is a member of the haloalkanoate dehalogenase superfamily and represents a good model for the active-site protonation state of family members. Crystals of approximate dimensions 1.5 × 1.0 × 1.0 mm were obtained in space group P2(1)2(1)2, with unit-cell parameters a = 83.1, b = 108.9, c = 75.7 Å. A complete neutron data set was collected from a medium-sized H/D-exchanged crystal at BIODIFF at the Heinz Maier-Leibnitz Zentrum (MLZ), Garching, Germany in 18 d. Initial refinement to 2.3 Šresolution using only neutron data showed significant density for catalytically important residues.

Devising the optimal preclinical oncology curriculum for undergraduate medical students in the United States.

A third of women and a near majority of men in the United States will be diagnosed with cancer in their lifetimes. To prepare future physicians for this reality, we have developed a preclinical oncology curriculum that introduces second-year medical students to essential concepts and practices in oncology to improve their abilities to appropriately care for these patients. We surveyed the oncology and education literature and compiled subjects important to students' education including basic science and clinical aspects of oncology and addressing patients' psychosocial needs. Along with the proposed curriculum content, scheduling, independent learning exercises, and case studies, we discuss practical considerations for curriculum implementation based on experience at our institution. Given the changing oncology healthcare landscape, all (new) physicians must competently address their cancer patients' needs, regardless of chosen specialty. A thorough and logically organized cancer curriculum for preclinical medical students should help achieve these aims. This new model curriculum, with accompanying strategies to evaluate its efforts, is essential to update how medical students are educated about cancer.

Quantitatively and qualitatively augmenting medical student knowledge of oncology and radiation oncology: an update on the impact of the oncology education initiative.

PURPOSE: The Oncology Education Initiative was established in 2007 in an effort to advance oncology and radiation oncology education at the undergraduate level. As a continuation of the initiative, the aim of this study was to determine whether these structured didactics would continue to increase overall medical student knowledge about oncologic topics. METHODS: Preclerkship and postclerkship tests examining concepts in general oncology, radiation oncology, breast cancer, and prostate cancer were administered. The 21-question, multiple-choice examination was administered at the beginning and end of the radiology clerkship, during which a 1.5-hour didactic session was given by an attending radiation oncologist. Changes in individual question responses, student responses, and overall categorical responses were analyzed. All hypothesis tests were two tailed with a significance level of .05. RESULTS: In the 2009-2010 academic year, 155 third-year and fourth-year students had average examination score improvements from 62% to 68.9% (P < .0001). Every topic (100%) showed improvement in scores, with the largest absolute improvement seen in the radiation oncology category, which increased from 56.5% to 71.8% (P < .0001). As the year proceeded, average examination scores increased among third-year students and decreased among fourth-year students. CONCLUSIONS: In the successive years since its inception, the Oncology Education Initiative continues to show a significant improvement in medical students' knowledge of cancer. The initiative has also succeeded in providing radiation oncology education to all graduating medical students at the authors' institution. Dedicated oncology education in the undergraduate medical curriculum provides students with a better understanding of multidisciplinary oncology management.

A cross-over inhibitor of the botulinum neurotoxin light chain B: a natural product implicating an exosite mechanism of action.

Clostridium botulinum produces the most lethal toxins known to man, as such they are high risk terrorist threats, and alarmingly there is no approved therapeutic. We report the first cross-over small molecule inhibitor of these neurotoxins and propose a mechanism by which it may impart its inhibitory activity.

Engineering encodable lanthanide-binding tags into loop regions of proteins.

Lanthanide-binding tags (LBTs) are valuable tools for investigation of protein structure, function, and dynamics by NMR spectroscopy, X-ray crystallography, and luminescence studies. We have inserted LBTs into three different loop positions (denoted L, R, and S) of the model protein interleukin-1ß (IL1ß) and varied the length of the spacer between the LBT and the protein (denoted 1−3). Luminescence studies demonstrate that all nine constructs bind Tb3+ tightly in the low nanomolar range. No significant change in the fusion protein occurs from insertion of the LBT, as shown by two X-ray crystallographic structures of the IL1ß-S1 and IL1ß-L3 constructs and for the remaining constructs by comparing the 1H−15N heteronuclear single-quantum coherence NMR spectra with that of the wild-type IL1ß. Additionally, binding of LBT-loop IL1ß proteins to their native binding partner in vitro remains unaltered. X-ray crystallographic phasing was successful using only the signal from the bound lanthanide. Large residual dipolar couplings (RDCs) could be determined by NMR spectroscopy for all LBT-loop constructs and revealed that the LBT-2 series were rigidly incorporated into the interleukin-1ß structure. The paramagnetic NMR spectra of loop-LBT mutant IL1ß-R2 were assigned and the Δχ tensor components were calculated on the basis of RDCs and pseudocontact shifts. A structural model of the IL1ß-R2 construct was calculated using the paramagnetic restraints. The current data provide support that encodable LBTs serve as versatile biophysical tags when inserted into loop regions of proteins of known structure or predicted via homology modeling.

Further evidence for BRCA1 communication with the inactive X chromosome.

BRCA1, a breast and ovarian cancer-suppressor gene, exerts tumor-suppressing functions that appear to be associated, at least in part, with its DNA repair, checkpoint, and mitotic regulatory activities. Earlier work from our laboratory also suggested an ability of BRCA1 to communicate with the inactive X chromosome (Xi) in female somatic cells (Ganesan et al., 2002). Xiao et al. (2007) (this issue of Cell) have challenged this conclusion. Here we discuss recently published data from our laboratory and others and present new results that, together, provide further support for a role of BRCA1 in the regulation of XIST concentration on Xi in somatic cells.