Applicant and Program Director Perceptions of Second Look Events During the 2023 Radiation Oncology Residency Match.

Purpose: Virtual radiation oncology (RO) residency interviews may impair applicant and program evaluation. Second look events (SLEs) exist; however, the frequency, nature, and implications are unknown. We surveyed applicants and program directors (PDs) to characterize the 2023 RO Match SLEs and assess perspectives. Method and Materials: An online, anonymous survey was distributed to 2023 RO Match applicants and American College of Graduate Medical Education-accredited RO PDs post-Match. Number and percentage are reported as response per question. Likert-type scores (1, strongly agree; 5, strongly disagree) are reported as median, IQR. Results: Responses were received from 51 of 246 applicants (21%) and 52 of 88 PDs (59%). Forty applicants (87%) were offered in-person and virtual SLEs; 20 (51%) and 17 (44%) applicants were invited to 1 to 3 and 4 to 6 events, respectively. Most invited applicants attended none (21, 54%). Applicants reported that all (21, 54%) or some (16, 41%) programs communicated intentions to finalize rank order lists (ROLs) before SLEs. Most applicants (29, 74%) agreed that SLEs were optional without ROL consequences (median, 2, IQR 1-3). Applicants declined in-person SLEs due to city/facility indifference (10, 43%), finances (10, 43%), and logistics (9, 39%). Most (12, 86%) in-person SLE attendees agreed that SLEs influenced their ROL (median, 2, IQR 1-2). Nineteen PDs (40%) reported offering SLEs, with 18 of 19 being in-person. PDs who did not offer SLEs cited ethical concerns (13, 45%) and institutional policies (11, 38%). All PDs reported that SLEs were optional, and 18 of 19 explained that the SLE would be without ROL consequences. SLEs mostly occurred in February before (11, 58%) and after (15, 79%) ROL submission. Conclusions: In-person SLEs occurred during Match 2023. All PDs considered SLEs optional which was trusted by most applicants. Attendance at in-person SLEs influenced applicants' ROLs; however, finances and logistics impaired applicant attendance. Further work is needed to appreciate SLE implications and ensure equitable residency recruitment.

Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance.

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

Tyrosine Kinase Inhibitors With and Without Up-Front Stereotactic Radiosurgery for Brain Metastases From EGFR and ALK Oncogene-Driven Non-Small Cell Lung Cancer (TURBO-NSCLC).

PURPOSE: Newer-generation tyrosine kinase inhibitors (TKIs) for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements have demonstrated high CNS activity. The optimal use of up-front stereotactic radiosurgery (SRS) for brain metastases (BM) in patients eligible for CNS-penetrant TKIs is controversial, and data to guide patient management are limited. MATERIALS AND METHODS: Data on TKI-naïve patients with EGFR- and ALK-driven NSCLC with BM treated with CNS-penetrant TKIs with and without up-front SRS were retrospectively collected from seven academic centers in the United States. Time-to-CNS progression and overall survival (OS) were analyzed, with multivariable adjustment in Fine & Gray and Cox proportional hazards models for clinically relevant factors. RESULTS: From 2013 to 2022, 317 patients were identified (200 TKI-only and 117 TKI + SRS). Two hundred fifty (79%) and 61 (19%) patients received osimertinib and alectinib, respectively. Patients receiving TKI + SRS were more likely to have BM ≥1 cm (P < .001) and neurologic symptoms (P < .001) at presentation. Median OS was similar between the TKI and TKI + SRS groups (median 41 v 40 months, respectively; P = .5). On multivariable analysis, TKI + SRS was associated with a significant improvement in time-to-CNS progression (hazard ratio [HR], 0.63 [95% CI, 0.42 to 0.96]; P = .033). Local CNS control was significantly improved with TKI + SRS (HR, 0.30 [95% CI, 0.16 to 0.55]; P < .001), whereas no significant differences were observed in distant CNS control. Subgroup analyses demonstrated a greater benefit from TKI + SRS in patients with BM ≥1 cm in diameter for time-to-CNS progression and CNS progression-free survival. CONCLUSION: The addition of up-front SRS to CNS-penetrant TKI improved time-to-CNS progression and local CNS control, but not OS, in patients with BM from EGFR- and ALK-driven NSCLC. Patients with larger BM (≥1 cm) may benefit the most from up-front SRS.

Epigenetic reprogramming shapes the cellular landscape of schwannoma.

Mechanisms specifying cancer cell states and response to therapy are incompletely understood. Here we show epigenetic reprogramming shapes the cellular landscape of schwannomas, the most common tumors of the peripheral nervous system. We find schwannomas are comprised of 2 molecular groups that are distinguished by activation of neural crest or nerve injury pathways that specify tumor cell states and the architecture of the tumor immune microenvironment. Moreover, we find radiotherapy is sufficient for interconversion of neural crest schwannomas to immune-enriched schwannomas through epigenetic and metabolic reprogramming. To define mechanisms underlying schwannoma groups, we develop a technique for simultaneous interrogation of chromatin accessibility and gene expression coupled with genetic and therapeutic perturbations in single-nuclei. Our results elucidate a framework for understanding epigenetic drivers of tumor evolution and establish a paradigm of epigenetic and metabolic reprograming of cancer cells that shapes the immune microenvironment in response to radiotherapy.

Patterns of recurrence after radiotherapy for high-risk neuroblastoma: Implications for radiation dose and field.

BACKGROUND: Prognosis for patients with high-risk neuroblastoma (HR-NBL) is guarded despite aggressive therapy, and few studies have characterized outcomes after radiotherapy in relation to radiation treatment fields. METHODS: Multi-institutional retrospective cohort of 293 patients with HR-NBL who received autologous stem cell transplant (ASCT) and EBRT between 1997-2021. LRR was defined as recurrence at the primary site or within one nodal echelon beyond disease present at diagnosis. Follow-up was defined from the end of EBRT. Event-free survival (EFS) and OS were analyzed by Kaplan-Meier method. Cumulative incidence of locoregional progression (CILP) was analyzed using competing risks of distant-only relapse and death with Gray's test. RESULTS: Median follow-up was 7.0 years (range: 0.01-22.4). Five-year CILP, EFS, and OS were 11.9 %, 65.2 %, and 77.5 %, respectively. Of the 31 patients with LRR and imaging review, 15 (48.4 %) had in-field recurrences (>12 Gy), 6 (19.4 %) had marginal failures (≤12 Gy), and 10 (32.3 %) had both in-field and marginal recurrences. No patients receiving total body irradiation (12 Gy) experienced marginal-only failures (p = 0.069). On multivariable analyses, MYCN amplification had higher risk of LRR (HR: 2.42, 95 % CI: 1.06-5.50, p = 0.035) and post-consolidation isotretinoin and anti-GD2 antibody therapy (HR: 0.42, 95 % CI: 0.19-0.94, p = 0.035) had lower risk of LRR. CONCLUSIONS: Despite EBRT, LRR remains a contributor to treatment failure in HR-NBL with approximately half of LRRs including a component of marginal failure. Future prospective studies are needed to explore whether radiation fields and doses should be defined based on molecular features such as MYCN amplification, and/or response to chemotherapy.

Precision based approach to tailoring radiotherapy in the multidisciplinary management of pediatric central nervous system tumors.

Modern day survivorship from childhood malignancies is estimated to be over 80%. However, central nervous system tumors remain the leading cause of cancer mortality in children and is the most common solid tumor in this population. Improved survivorship is, in part, a result of improved multidisciplinary care, often with a combination of surgery, radiation therapy, and systemic therapy. With improved survival, long term effects of treatment and quality of life impacts have been recognized and pose a challenge to maximize the therapeutic ratio of treatment. It has been increasingly more apparent that precise risk stratification, such as with the inclusion of molecular classification, is instrumental in efforts to tailor radiotherapy for appropriate treatment, generally towards de-intensification for this vulnerable patient population. In addition, advances in radiotherapy techniques have allowed greater conformality and accuracy of treatment for those who do require radiotherapy for tumor control. Ongoing efforts to tailor radiotherapy, including de-escalation, omission, or intensification of radiotherapy, continue to improve as increasing insight into tumor heterogeneity is recognized, coupled with advances in precision medicine employing novel molecularly-targeted therapeutics.