Adaptive Region-Specific Loss for Improved Medical Image Segmentation.

Defining the loss function is an important part of neural network design and critically determines the success of deep learning modeling. A significant shortcoming of the conventional loss functions is that they weight all regions in the input image volume equally, despite the fact that the system is known to be heterogeneous (i.e., some regions can achieve high prediction performance more easily than others). Here, we introduce a region-specific loss to lift the implicit assumption of homogeneous weighting for better learning. We divide the entire volume into multiple sub-regions, each with an individualized loss constructed for optimal local performance. Effectively, this scheme imposes higher weightings on the sub-regions that are more difficult to segment, and vice versa. Furthermore, the regional false positive and false negative errors are computed for each input image during a training step and the regional penalty is adjusted accordingly to enhance the overall accuracy of the prediction. Using different public and in-house medical image datasets, we demonstrate that the proposed regionally adaptive loss paradigm outperforms conventional methods in the multi-organ segmentations, without any modification to the neural network architecture or additional data preparation.

Investigating and modeling positron emission tomography factors associated with large cell transformation from low-grade lymphomas.

Low-grade lymphomas have a 1%-3% annual risk of transformation to a high-grade histology, and prognostic factors remain undefined. We set to investigate the role of positron emission tomography (PET) metrics in identification of transformation in a retrospective case-control series of patients matched by histology and follow-up time. We measured PET parameters including maximum standard uptake value (SUV-max) and total lesion glycolysis (TLG), and developed a PET feature and lactate dehydrogenase (LDH)-based model to identify transformation status within discovery and validation cohorts. For our discovery cohort, we identified 53 patients with transformation and 53 controls with a similar distribution of follicular lymphoma (FL). Time to transformation and control follow-up time was similar. We observed a significant incremental increase in SUV-max and TLG between control, pretransformation and post-transformation groups (P < 0.05). By multivariable analysis, we identified a significant interaction between SUV-max and TLG such that SUV-max had highest significance for low volume cases (P = 0.04). We developed a scoring model incorporating SUV-max, TLG, and serum LDH with improved identification of transformation (area under the curve [AUC] = 0.91). Our model performed similarly for our validation cohort of 23 patients (AUC = 0.90). With external and prospective validation, our scoring model may provide a specific and noninvasive tool for risk stratification for patients with low-grade lymphoma.

Radiation Oncology Virtual Education Rotation (ROVER) 2.0 for Residents: Implementation and Outcomes.

The COVID-19 pandemic catalyzed the integration of a virtual education curriculum to support radiation oncologists in training. We report outcomes from Radiation Oncology Virtual Education Rotation (ROVER) 2.0, a supplementary virtual educational curriculum created for radiation oncology residents globally. A prospective cohort of residents completed surveys before and after the live virtual webinar sessions (pre- and post-surveys, respectively). Live sessions were structured as complex gray-zone cases across various core disease sites. Resident demographics and responses were summarized using means, standard deviations, and proportions. Nine ROVER sessions were held from October 2020 to June 2021. A total of 1487 registered residents completed the pre-survey, of which 786 attended the live case discussion and 223 completed post-surveys. A total of 479 unique radiation oncology residents (of which 95, n = 19.8%, were international attendees) from 147 institutions (national, n = 81, 55.1%; international, n = 66, 44.9%) participated in the sessions. There was similar participation across post-graduate year (PGY) 2 through 5 (range n = 86 to n = 105). Of the 122 unique resident post-surveys, nearly all reported learning through the virtual structure as "very easy" or "easy" (97.5%, n = 119). A majority rated the ROVER 2.0 educational sessions to be "valuable or "very valuable" (99.2%, n = 121), and the panelists-attendee interaction as "appropriate" (97.5%, n = 119). Virtual live didactics aimed at radiation oncology residents are feasible. These results suggest that the adoption of the ROVER 2.0 curricula may help improve radiation oncology resident education.

Radiation Oncology Virtual Education Rotation (ROVER) for Medical Students.

PURPOSE: We describe the implementation of a novel virtual educational program for medical students, Radiation Oncology Virtual Education Rotation (ROVER), and its effect on student interest and knowledge in radiation oncology. METHODS AND MATERIALS: ROVER comprised a series of virtual educational panels with case-based discussions across disease sites tailored to medical students. The panels were moderated by radiation oncology residents and included faculty panelists from academic radiation oncology programs across the country. Student pre- and postsession surveys were collected. Paired t tests were used to compare the pre- and postsession assessment results. RESULTS: Six ROVER sessions were held from June 4, 2020, to August 20, 2020, with a total of 427 medical students registering for at least 1 session. Of these, 231 students attended at least 1 session, with 140 completing at least 1 postsession survey (60.6% response rate). Fourth-year medical students were the largest group represented among attendees (32.0%). Most attendees had exposure to radiation oncology (78.8%) before the sessions. The majority of students signed up for these sessions for education (90.6%). Some students signed up for the sessions to help with specialty selection (30.9%) and to network (30.4%). Medical students' understanding of the role of radiation oncology in each disease site (breast, sarcoma, central nervous system, pediatrics, gastrointestinal, genitourinary, gynecologic, lymphoma, lung, and head and neck) was improved by attending each session (pre- vs postsession; P < .0001 for all disease sites). Over three-quarters of respondents stated they were considering applying or were likely to apply to radiation oncology both before and after the sessions. CONCLUSIONS: ROVER improved medical student perceived knowledge of radiation oncology across all disease sites covered. ROVER fulfills a need for a national medical student education platform for radiation oncology. Future work is warranted to augment virtual and open educational platforms to improve access to radiation oncology education.

Networking and Applying to Radiation Oncology During A Pandemic: Cross-Sectional Survey of Medical Student Concerns.

PURPOSE: We assessed the effectiveness of a virtual networking session tailored for third- and fourth-year medical students interested in radiation oncology, and report students' concerns about applying to radiation oncology during the pandemic. METHODS AND MATERIALS: A multi-institutional networking session was hosted on Zoom and included medical students, faculty, and residents from across the country. The breakout room feature was used to divide participants into smaller groups. Participants were randomly shuffled into new groups every 10 to 15 minutes. Students completed pre- and post-session surveys. RESULTS: Among the 134 students who registered, 69 students participated in the session, and 53 students completed a post-session survey. Most students reported the session was valuable or very valuable (79%), and it was easy or very easy to network through the virtual format (66%). After the session, 18 (33.9%) students reported their interest in radiation oncology increased, and 34 (64.2%) reported their interest remained the same. Most students believed COVID-19 (55%) and virtual interviews and platforms (55%) negatively or somewhat negatively affected their ability to select a residency program. Most students (62%) were concerned they will be inaccurately evaluated as an interviewee on a virtual platform. Although 30% agreed or strongly agreed the cost-savings and convenience of virtual interviews outweigh potential downsides, 66% of students were planning to visit cities of interest in person before rank list submission. CONCLUSIONS: Medical students reported significant concerns with their ability to be accurately evaluated and to choose among residency programs on a virtual platform. Students found the networking session to be a valuable resource for most students, and programs could continue similar efforts during the residency application cycle to better represent their program while maintaining certain financial and geographic advantages of a virtual environment.

Virtual Radiation Oncology Clerkship During the COVID-19 Pandemic and Beyond.

PURPOSE: We evaluated the impact of a virtual radiation oncology clerkship. METHODS AND MATERIALS: We developed a 2-week virtual radiation oncology clerkship that launched on April 27, 2020. Clerkship components included a virtual clinic with radiation oncology faculty and residents, didactic lectures, student talks, and supplemental sessions such as tumor boards and chart rounds. Medical students completed pre- and post-clerkship self-assessments. Faculty and resident participants also completed surveys on their experience with virtual lectures and clinics. Pre- and post-clerkship results were compared using a 2-sided paired t test. An analysis of variance model was used to analyze the clerkship components. RESULTS: Twenty-six medical students, including 4 visiting students, enrolled over 2 clerkship periods (4 weeks). All students completed the pre- and post-clerkship self-assessments and agreed that the clerkship improved their understanding of radiation oncology. Compared with 3 (11.5%) students who agreed that they understood the daily responsibilities of a radiation oncologist before the clerkship, 22 (84.6%) students agreed and 3 (11.5%) strongly agreed that they understood the daily responsibilities of a radiation oncologist after the clerkship (P < .0001). Although 15 students (57.7%) reported an increased interest in radiation oncology because of the clerkship, the mean level of interest in radiation oncology as a career remained the same, with pre- and post-clerkship scores of 3.0 (±0.9) and 3.0 (±1.1) on a 5-point scale, respectively (P = .7). Students found virtual clinic and didactic lectures to be the most valuable components of the clerkship. Most respondents agreed (30.8%) or strongly agreed (65.4%) to recommend the clerkship to their classmates. CONCLUSIONS: Our virtual clerkship was effective in increasing medical student interest in and knowledge about radiation oncology. These data will help optimize a new paradigm of virtual radiation oncology education for medical students during COVID-19 and beyond.

Continuing Medical Student Education During the Coronavirus Disease 2019 (COVID-19) Pandemic: Development of a Virtual Radiation Oncology Clerkship.

PURPOSE: Our institution cancelled all in-person clerkships owing to the coronavirus disease 2019 pandemic. In response, we designed a virtual radiation oncology medical student clerkship. METHODS AND MATERIALS: We convened an advisory panel to design a virtual clerkship curriculum. We implemented clerkship activities using a cloud-based learning management system, video web conferencing systems, and a telemedicine portal. Students completed assessments pre- and postclerkship to provide data to improve future versions of the clerkship. RESULTS: The virtual clerkship spans 2 weeks and is graded pass or fail. Students attend interactive didactic sessions during the first week and participate in virtual clinic and give talks to the department during the second week. Didactic sessions include lectures, case-based discussions, treatment planning seminars, and material adapted from the Radiation Oncology Education Collaborative Study Group curriculum. Students also attend virtual departmental quality assurance rounds, cancer center seminars, and multidisciplinary tumor boards. The enrollment cap was met during the first virtual clerkship period (April 27 through May 8, 2020), with a total of 12 students enrolling. CONCLUSIONS: Our virtual clerkship can increase student exposure and engagement in radiation oncology. Data on clerkship outcomes are forthcoming.

E6-Associated Protein Dependent Estrogen Receptor Regulation of Protein Kinase A Regulatory Subunit R2A Expression in Neuroblastoma.

E6ap is a known transcriptional coregulator for estrogen receptor alpha (Er, Erα) in the presence of estrogen. Protein kinase A (PKA) contains two regulatory subunits derived from four genes. Recent evidence demonstrates that PKA regulates E6ap activity. Data generated in our lab indicated estrogen dependent regulation of Pkar2a levels. Our project sets to investigate a possible feedback mechanism constituting of Erα and E6ap transcriptional regulation of Pkar2a expression. Western blot evaluated protein regulation correlations with E2 in mouse neuroblastoma lines. Bioinformatics detected estrogen response element (ERE) sequences. quantitative polymerase chain reaction (qPCR) validated the western blot results. ERE oligonucleotides were synthesized. Reporter gene transcriptional activity was evaluated via Luciferase assay output. Electromobility shift assay (EMSA) assessed direct binding between Erα relevant sequences. Chromatin immunoprecipitation (ChIP) and Re-ChIP were conducted in quantifying protein complex recruitment levels. Pkar2a protein expression directly correlated with E2, and four putative ERE sequences were identified. Pkar2a mRNA expression reverted to baseline with either E2 or E6ap absent. In the presence of E2, ERE-1 and ERE-4 possessed Luciferase reporter gene transcriptional capabilities. ERE-1 portrayed band shifts, representing direct binding to Erα with E2 supplementation. With E2, ERE-1 significantly enhanced Erα and E6ap recruitment levels to the Pkar2a promoter. Pkar2a is directly regulated by Erα and E6ap in the presence of estrogen stimulus. This work indicates a feedback mechanism in the interplay between PKA and E6ap, which may prove crucial for the role of both proteins in cancers and neurogenetic diseases like Angelman syndrome.

Optimizing tumor immune response through combination of radiation and immunotherapy.

Radiation therapy and immunotherapy are two highly evolving modalities for the treatment of solid tumors. Immunotherapeutic drugs can either stimulate the immune system via immunogenic pathways or target co-inhibitory checkpoints. An augmented tumor cell recognition by host immune cells can be achieved post-irradiation, as irradiated tissues can release chemical signals which are sensed by the immune system resulting in its activation. Different strategies combining both treatment modalities were tested in order to achieve a better therapeutic response and longer tumor control. Both regimens act synergistically to one another with complimentary mechanisms. In this review, we explore the scientific basis behind such a combination, starting initially with a brief historical overview behind utilizing radiation and immunotherapies for solid tumors, followed by the different types of these two modalities, and the biological concept behind their synergistic effect. We also shed light on the common side effects and toxicities associated with radiation and immunotherapy. Finally, we discuss previous clinical trials tackling this multimodality combination and highlight future ongoing research.

Intraoperative Radiation Therapy: A Promising Treatment Modality in Head and Neck Cancer.

Every year, almost 62,000 are diagnosed with a head and neck cancer (HNC) and 13,000 will succumb to their disease. In the primary setting, intraoperative radiation therapy (IORT) can be used as a boost in select patients in order to optimize local control. Addition of external beam radiation to limited volumes results in improved disease control over surgery and IORT alone. In the recurrent setting, IORT can improve outcomes from salvage surgery especially in patients previously treated with external beam radiation. The use of IORT remains limited to select institutions with various modalities being currently employed including orthovoltage, electrons, and high-dose rate brachytherapy. Practically, execution of IORT requires a coordinated effort and careful planning by a multidisciplinary team involving the head and neck surgeon, radiation oncologist, and physicist. The current review summarizes common uses, outcomes, toxicities, and technical aspects of IORT in HNC patients.

Ubiquitination of nuclear receptors.

Nuclear receptors (NRs) are cellular proteins, which upon ligand activation, act to exert regulatory control over transcription and subsequent expression. Organized via systemic classification into seven subfamilies, NRs partake in modulating a vast expanse of physiological functions essential for maintenance of life. NRs display particular characteristics towards ubiquitination, the process of addition of specific ubiquitin tags at appropriate locations. Orchestrated through groups of enzymes harboring a diverse array of specialized structural components, the ubiquitination process emphatically alters the fate or downstream effects of NRs. Such influence is especially prominent in transcriptional processes such as promoter clearing for optimization and degradation pathways eliminating or recycling targeted proteins. Ultimately, the ubiquitination of NRs carries significant implications in terms of generating pathological clinical manifestations. Increasing evidence from studies involving patients and disease models suggests a role for ubiquitinated NRs in virtually every organ system. This supports the broad repertoire of roles that NRs play in the body, including modulatory conductors, facilitators, responders to external agents, and critical constituents for pharmacological or biological interventions. This review aims to cover relevant background and mechanisms of NRs and ubiquitination, with a focus towards elucidating subsequent pathophysiology and therapeutics in clinical disorders encompassing such ubiquitinated NRs.

Steroid Hormone Receptor Coregulators in Endocrine Cancers.

Coregulators span a broad and extensive domain in modulating cellular transcriptional activity. Studies have established a dynamic role for such coregulators in various endocrine cancers. Steroid hormone receptors (SHRs) play a pivotal role in such endocrine cancers, and interact abundantly with transcriptional coregulators in altering gene expression. Several families of coregulators have implications in propagating the development, progression and invasion of breast, prostate, and other hormone-responsive cancers. This mini-review aims to discuss different classes of coregulators involved in endocrine cancers and highlight unique information regarding each family with relevance to mechanism, intervention, and novel directions being investigated. © 2016 IUBMB Life, 68(7):504-515, 2016.