Nodal staging convergence for HPV- and HPV+ oropharyngeal carcinoma.

BACKGROUND: Modern disease staging systems have restructured human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) oropharyngeal carcinoma (OPC) into distinct pathologic nodal systems. Given that quantitative lymph node (LN) burden is the dominant prognostic factor in most head and neck cancers, we investigated whether HPV- and HPV+ OPC warrant divergent pathologic nodal classification. METHODS: Multivariable Cox regression models of OPC surgical patients identified via U.S. cancer registry data were constructed to determine associations between survival and nodal characteristics. Nonlinear associations between metastatic LN number and survival were modeled with restricted cubic splines. Recursive partitioning analysis (RPA) was used to derive unbiased nodal schema. RESULTS: Mortality risk escalated continuously with each successive positive LN in both OPC subtypes, with analogous slope. Survival hazard increased by 18.5% (hazard ratio [HR], 1.19 [95% CI, 1.16-1.21]; P < .001) and 19.1% (HR, 1.19 [95% CI, 1.17-1.21]; P < .001), with each added positive LN for HPV- and HPV+ OPC, respectively, up to identical change points of 5 positive LNs. Extranodal extension (ENE) was an independent predictor of HPV- OPC (HR, 1.55 [95% CI, 1.20-1.99]; P < .001) and HPV+ OPC (HR 1.73 [95% CI, 1.36-2.20]; P < .001) mortality. In RPA for both diseases, metastatic LN was the principal nodal covariate driving survival, with ENE as a secondary determinant. Given the similarities across analyses, we propose a concise, unifying HPV-/HPV+ OPC pathologic nodal classification schema: N1, 1-5 LN+/ENE-; N2, 1-5 LN+/ENE+; N3, >5 LN+. CONCLUSION: HPV- and HPV+ OPC exhibit parallel relationships between nodal characteristics and relative mortality. In both diseases, metastatic LN number represents the principal nodal covariate governing survival, with ENE being an influential secondary element. A consolidated OPC pathologic nodal staging system that is based on these covariates may best convey prognosis. LAY SUMMARY: The current nodal staging system for oropharyngeal carcinoma (OPC) has divided human papillomavirus (HPV)-negative (HPV-) and HPV-positive (HPV+) OPC into distinct systems that rely upon criteria that establish them as separate entities, a complexity that may undermine the core objective of staging schema to clearly communicate prognosis. Our large-scale analysis revealed that HPV- and HPV+ pathologic nodal staging systems in fact mirror each other. Multiple analyses produced conspicuously similar nodal staging systems, with metastatic lymph node number and extranodal extension delineating the highest risk groups that shape prognosis. We propose unifying HPV- and HPV+ nodal systems to best streamline prognostication and maximize staging accuracy.

Improved survival in women versus men with merkel cell carcinoma.

BACKGROUND: Studies have observed that women have better outcomes than men in melanoma, but less is known about the influence of sex differences on outcomes for other aggressive cutaneous malignancies. OBJECTIVE: To investigate whether women and men have disparate outcomes in Merkel cell carcinoma (MCC). METHODS: Patients with nonmetastatic MCC undergoing surgery and lymph node evaluation were identified from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analysis and Cox proportional hazards regression models were used for overall survival, and competing-risks analysis and Fine-Gray models were used for cause-specific and other-cause mortality. RESULTS: The NCDB cohort (n = 4178) included 1516 (36%) women. Women had a consistent survival advantage compared with men in propensity score-matched analysis (66.0% vs 56.8% at 5 years, P < .001) and multivariable Cox regression (hazard ratio, 0.68; 95% confidence interval, 0.61-0.75; P < .001). Similarly, women had a survival advantage in the SEER validation cohort (n = 1202) with 457 (38.0%) women, which was entirely due to differences in MCC-specific mortality (5-year cumulative incidence: 16.4% vs 26.7%, P = .002), with no difference in other-cause mortality (16.8% vs 17.8%, P = .43) observed in propensity score-matched patients. LIMITATIONS: Potential selection bias from a retrospective data set. CONCLUSION: In MCC, women have improved survival compared with men, driven by MCC-related mortality.

Quantitative metastatic lymph node burden and survival in Merkel cell carcinoma.

BACKGROUND: Current lymph node (LN) staging for Merkel cell carcinoma (MCC) does not account for the number of metastatic LNs, which is a primary driver of survival in multiple cancers. OBJECTIVE: To determine the impact of the number of metastatic LNs on survival in MCC. METHODS: Patients with MCC undergoing surgery were identified from the National Cancer Database (NCDB). The association between metastatic LN number and survival was modeled with restricted cubic splines. A novel nodal classification system was derived by using recursive partitioning analysis. MCC patients undergoing surgery in the Surveillance, Epidemiology, and End Results (SEER) Program were used as validation cohort. RESULTS: Among 3670 patients in the NCDB, increasing metastatic LN number was associated with decreased survival (P < .001). Mortality risk increased continuously with each additional positive LN when using multivariable, nonlinear modeling. According to a novel staging system derived via recursive partitioning analysis, the hazard ratio for death in multivariable regression compared with patients without LN involvement was 1.24 (P = .049), 2.08 (P < .001), 3.24 (P < .001), and 6.13 (P < .001) for the proposed N1a (1-3 metastatic LNs with microscopic detection), N1b (1-3 metastatic LNs with macroscopic detection), N2 (4-8 metastatic LNs), and N3 (≥9 metastatic LNs), respectively. This system was validated in the SEER cohort and showed improved concordance compared with the American Joint Committee on Cancer, Eighth Edition. LIMITATIONS: Retrospective design. CONCLUSIONS: Number of metastatic LNs is the dominant nodal factor driving survival in patients with MCC.

Stage I HPV-positive oropharyngeal cancer: Should all patients receive similar treatments?

BACKGROUND: Patients with clinical stage I human papillomavirus (HPV)-positive oropharyngeal squamous cell cancer (OPSCC) according to the American Joint Committee on Cancer (AJCC) eighth edition classification comprise a heterogeneous group formerly classified as stage I to stage IVA according to the seventh edition of the AJCC classification. These patients historically were treated with disparate treatment regimens, particularly with respect to the use of concurrent chemotherapy. METHODS: The National Cancer Data Base was queried for patients with AJCC eighth edition clinical stage I HPV-positive OPSCC (AJCC seventh edition stage T1-2N0-2bM0) who were diagnosed from 2010 to 2014 and underwent definitive radiotherapy. Concurrent chemotherapy with definitive radiotherapy was defined as chemotherapy administered within 7 days of the initiation of radiotherapy. RESULTS: The current analysis included 4473 patients with HPV-positive stage I OPSCC with a median follow-up of 36.3 months. A total of 3127 patients (69.9%) received concurrent chemotherapy. Concurrent chemotherapy was found to be associated with improved overall survival on multivariable analyses (hazard ratio [HR], 0.782; 95% CI, 0.645-0.948 [P = .012]). The effect of chemotherapy on survival varied based on lymph node involvement (P for interaction = .001). Specifically, chemotherapy was associated with improved survival for patients with lymph node-positive stage I disease (stage III-IVA according to the AJCC seventh edition: HR, 0.682; 95% CI, 0.557-0.835 [P < .001]), but not for patients with N0 disease (stage I-II according to the AJCC seventh edition: HR, 1.646; 95% CI, 1.011-2.681 [P = .05]). Similar results were noted among propensity score-matched cohorts. CONCLUSIONS: Treatment with concurrent chemotherapy was associated with improved overall survival for patients with lymph node-positive, but not lymph node-negative, AJCC eighth edition stage I HPV-positive OPSCC undergoing definitive radiotherapy, thereby supporting different treatment paradigms for these patients.

Effects of aging and environmental tobacco smoke exposure on ocular and plasma circulatory microRNAs in the Rhesus macaque.

Purpose: To identify changes induced by environmental tobacco smoke (ETS) in circulatory microRNA (miRNA) in plasma and ocular fluids of the Rhesus macaque and compare these changes to normal age-related changes. Tobacco smoke has been identified as the leading environmental risk factor for age-related macular degeneration (AMD). Methods: All Rhesus macaques were housed at the California National Primate Research Center (CNPRC), University of California, Davis. Four groups of animals were used: Group 1 (1-3 years old), Group 2 (19-28 years old), Group 3 (10-16 years old), and Group 4 (middle aged, 9-14 years old). Group 4 was exposed to smoke for 1 month. Ocular fluids and plasma samples were collected, miRNAs isolated, and expression data obtained using Affymetrix miRNA GeneTitan Array Plates 4.0. Bioinformatics analysis was done on the Affymetrix Expression Console (EC), Transcriptome Analysis Software (TAS) using ANOVA for candidate miRNA selection, followed by Ingenuity Pathway Analysis (IPA). Results: The expression of circulatory miRNAs showed statistically significant changes with age and ETS. In the plasma samples, 45 miRNAs were strongly upregulated (fold change >±1.5, p<0.05) upon ETS exposure. In the vitreous, three miRNAs were statistically significantly downregulated with ETS, and two of them (miR-6794 and miR-6790) were also statistically significantly downregulated with age. Some retinal layers exhibited a thinning trend measured with optical coherence tomography (OCT) imaging. The pathways activated were IL-17A, VEGF, and recruitment of eosinophils, Th2 lymphocytes, and macrophages. Conclusions: ETS exposure of Rhesus macaques resulted in statistically significant changes in the expression of the circulatory miRNAs, distinct from those affected by aging. The pathways activated appear to be common for ETS and AMD pathogenesis. These data will be used to develop an animal model of early dry AMD.

Surveillance outcomes of small abdominal aortic aneurysms identified from a large screening program.

OBJECTIVE: Surveillance of patients identified with small abdominal aortic aneurysm (AAA) from an AAA screening program poses a challenge for health systems because of numerous patient follow-ups. This study evaluates the surveillance outcomes of patients identified with small AAA from a large screening program. METHODS: A retrospective chart review of all patients screened for small AAA (3.0-5.4 cm) from 2007 to 2011 was conducted. Patients with small AAA and no previous history of repair were tracked for follow-up using the 2013 RESCAN follow-up guidelines according to aortic diameter (3.0-3.9 cm, 3 years; 4.0-4.4 cm, 2 years; 4.5-5.4 cm, 1 year). Socioeconomic factors that may influence the follow-up rate and all-cause mortality after screening, including marital status, distance to hospital from residence, estimated household income, and employment disability status, were also evaluated. RESULTS: A total of 568 patients (mean ± standard deviation, 73.4 ± 7.2 years old) with small AAA (3.6 ± 0.6 cm) were analyzed. Patient follow-up rate was 65.1% (n = 370 of 568). Reasons for follow-up failure were lack of the physician's ordering a scan (n = 139; 70.2%), delayed ordering of scans (n = 36; 18.2%), patient no-show (n = 18; 9.1%), or patient death before follow-up (n = 5; 2.5%). Of all patient-specific factors, patients with smaller diameters were unlikely to achieve follow-up scans (P < .001). A significantly higher risk of all-cause mortality was found for patients with no ultrasound follow-up scan (hazard ratio [HR], 0.369; P < .001), assisted living (HR, 0.381; P < .001), older age (HR, 1.04; P = .001), and lower household incomes (HR, 0.989; P = .01). CONCLUSIONS: The follow-up rate of patients with small AAA was poor at 65.1%. The data indicate that socioeconomic factors do not significantly affect follow-up success. Therefore, physician ordering of scans may exert the greatest influence on follow-up rates in patients with small AAA. Automatic ordering of follow-up scans for patients with small AAAs is proposed to improve follow-up rates.

Localization of complement factor H gene expression and protein distribution in the mouse outer retina.

PURPOSE: To determine the localization of complement factor H (Cfh) mRNA and its protein in the mouse outer retina. METHODS: Quantitative real-time PCR (qPCR) was used to determine the expression of Cfh and Cfh-related (Cfhr) transcripts in the RPE/choroid. In situ hybridization (ISH) was performed using the novel RNAscope 2.0 FFPE assay to localize the expression of Cfh mRNA in the mouse outer retina. Immunohistochemistry (IHC) was used to localize Cfh protein expression, and western blots were used to characterize CFH antibodies used for IHC. RESULTS: Cfh and Cfhr2 transcripts were detected in the mouse RPE/choroid using qPCR, while Cfhr1, Cfhr3, and Cfhrc (Gm4788) were not detected. ISH showed abundant Cfh mRNA in the RPE of all mouse strains (C57BL/6, BALB/c, 129/Sv) tested, with the exception of the Cfh(-/-) eye. Surprisingly, the Cfh protein was detected by immunohistochemistry in photoreceptors rather than in RPE cells. The specificity of the CFH antibodies was tested by western blotting. Our CFH antibodies recognized purified mouse Cfh protein, serum Cfh protein in wild-type C57BL/6, BALB/c, and 129/Sv, and showed an absence of the Cfh protein in the serum of Cfh(-/-) mice. Greatly reduced Cfh protein immunohistological signals in the Cfh(-/-) eyes also supported the specificity of the Cfh protein distribution results. CONCLUSIONS: Only Cfh and Cfhr2 genes are expressed in the mouse outer retina. Only Cfh mRNA was detected in the RPE, but no protein. We hypothesize that the steady-state concentration of Cfh protein is low in the cells due to secretion, and therefore is below the detection level for IHC.

Age-dependent increase in miRNA-34a expression in the posterior pole of the mouse eye.

PURPOSE: MicroRNA-34a (miR-34a) has been implicated in neurodegeneration. MiR-34a belongs to a signaling network involving p53 and Sirt-1. This network responds to DNA damage with further downstream signals that induce senescence or apoptosis. Our goal was to measure the expression level of miR-34a in the mouse retina and RPE as a function of age. METHODS: The age-dependent change in miR-34a expression was quantified using a real-time PCR (RT-PCR) assay on microRNA isolates from eye tissue: the retina and RPE/choroid (4, 18, 24, and 32 months of age). Tissue localization of miR-34a was determined by in situ hybridization (ISH) for a series of time points. Expression of the miR-34a target gene Sirt1 was analyzed using RT-PCR and immunohistochemistry. RESULTS: MiR-34a examined with real-time PCR showed a linear increase in expression with age when compared to that of 4-month-old mice. However, the level of expression between the 24 and 32-month-old animals showed mild downregulation. An age-related increase in miR-34a expression was confirmed in the mouse eye using in situ hybridization. An inverse relationship between the levels of expression of miR-34a and its target Sirt1 mRNA was found at 18 and 24 months of age. CONCLUSIONS: Our data showed that miR-34a expression increased in the retina and RPE with age. The level of DNA damage in mitochondria in the retina and RPE followed a similar time course. This suggests that miR-34a may play a role in the senescence and apoptosis of the retina and RPE cells in the aging eye.

Monocyte activity is linked with abdominal aortic aneurysm diameter.

BACKGROUND: Systemic inflammation and increased matrix metalloproteinase (MMP) cause elastin degradation leading to abdominal aortic aneurysm (AAA) expansion. Several prospective studies report that statin therapy can reduce AAA expansion through anti-inflammation. We hypothesize that monocyte activity plays a pivotal role in this AAA development and this study examines patient peripheral blood monocyte cell adhesion, transendothelial migration, and MMP concentrations between AAA and non-AAA patients. MATERIALS AND METHODS: Peripheral blood was collected and monocytes isolated from control (n=15) and AAA (n=13) patients. Monocyte adhesion, transmigration, and permeability assays were assessed. Luminex assays determined MMP-9 and tissue inhibitor of metalloproteinase-4 (TIMP-4) concentrations from cell culture supernatant and patient serum. RESULTS: AAA patient monocytes showed increased adhesion to the endothelium relative fluorescence units (RFU, 0.33±0.17) versus controls (RFU, 0.13±0.04; P=0.005). Monocyte transmigration was also increased in AAA patients (RFU, 0.33±0.11) compared with controls (RFU, 0.25±0.04, P=0.01). Greater numbers of adhesive (R2=0.66) and transmigratory (R2=0.86) monocytes were directly proportional to the AAA diameter. Significantly higher serum levels of MMP-9 (2149.14±947 pg/mL) were found in AAA patients compared with controls (1189.2±293; P=0.01). TIMP-4 concentrations were significantly lower in AAA patients (826.7±100 pg/mL) compared with controls (1233±222 pg/mL; P=0.02). Cell culture supernatant concentrations of MMP and TIMP from cocultures were higher than monocyte-only cultures. CONCLUSIONS: Monocytes from AAA patients have greater adhesion and transmigration through the endothelium in vitro, leading to elevated MMP-9 levels and the appropriate decrease in TIMP-4 levels. The ability to modulate monocyte activity may lead to novel medical therapies to decrease AAA expansion.

Patterns of Failure in Patients With Borderline Resectable/Locally Advanced Pancreatic Cancer After Preoperative Chemotherapy and Stereotactic Body Radiation Therapy.

Purpose: The role of preoperative stereotactic body radiation therapy (SBRT) in pancreatic cancer is controversial, and questions regarding the optimal dose and radiation treatment field remain. To better inform future investigations of SBRT dose and radiation fields, we evaluated the patterns of failure in patients with borderline resectable/locally advanced pancreatic cancer (BR/LAPC) after preoperative chemotherapy and SBRT in patients who underwent surgical resection. Methods and Materials: We performed a single-institution retrospective review of consecutive patients treated from September 2017 to January 2022 with BR/LAPC. Patients who underwent preoperative chemotherapy and SBRT followed by surgical resection were reviewed. SBRT was delivered to a dose of 33 Gy in 5 fractions. Kaplan-Meier overall survival and progression-free survival estimates were calculated. Results: In total, 18 patients (12 BRPC, 6 LAPC) were included. Median age was 69 years (range 41-84 years). Median follow-up was 30 months (range 13-59 months). Seventeen patients (94%) had a R0 resection and 13 (72%) underwent vascular reconstruction. Median overall survival and progression-free survival was 42 months (range 13-59 months) and 23 months (range 1-45 months), respectively. In total, 61% (11/18) patients experienced progression at any point during follow-up. Of the patients who experienced recurrence, 27% (3/11) experienced local progression as component of their first recurrence, whereas 100% (11/11) experienced distant progression as a component of their first recurrence. When examining all recurrences that occurred at any point in follow-up, 28% (5/18) of patients experienced local or locoregional recurrence and 61% (11/18) experienced distant progression. Conclusions: Local control and margin negative resection rates were excellent with preoperative chemotherapy and nondose-escalated SBRT in surgically resected patients with BR/LAPC. Distant recurrence was the predominant site of failure with lower incidences of isolated locoregional recurrences. Additional research is needed to determine the ideal treatment volume and patients who may benefit from dose escalation.

A "scoping" review of prostate brachytherapy and immune responses.

PURPOSE: Whether prostate brachytherapy (BT) results in opportunistic biological changes that can improve clinical outcomes is not well studied. We sought to investigate the impact of prostate BT on the immune system. MATERIALS AND METHODS: A scoping review was performed using PubMed/Scopus for papers published between 2011-2021. Search terms were "brachytherapy" AND "immune" AND "prostate". A total of 81 records were identified and 6 were selected for further review. RESULTS: 2 low-dose-rate BT papers (n=68) evaluated changes in the peripheral blood following I-125 monotherapy. Both showed significant increases in peripheral CD3+ and CD4+ T cells post-BT. One also demonstrated significant increases in Treg subsets up to 150 days post-BT. 4 high-dose-rate (HDR) studies (n=37) were identified, and all were done in combination with EBRT. The largest study (n=24) showed a single 10 Gy fraction of HDR converted 80% of "cold" tumors into an "intermediate" or "hot" state, based on a tumor inflammation signature when comparing a pre-BT biopsy to one prior to a second HDR fraction. CONCLUSION: Prostate BT can invoke an immune activating phenotype; however, changes in immunosuppressive cells are also seen. Additional data is needed to understand how to promote synergy between BT and the immune system.

A Single-Institution Retrospective Study of Three-Fraction HDR Accelerated Partial Breast Irradiation.

PURPOSE: Accelerated partial breast irradiation (APBI) delivered with high-dose-rate brachytherapy is a standard of care treatment typically delivered over 10 fractions. The TRIUMPH-T multi-institutional study recently demonstrated promising results using a shorter three fraction regimen, however there are limited additional published series using this regimen. Here, we report our experience and outcomes for patients treated as per the TRIUMPH-T regimen. METHODS AND MATERIALS: This study was a retrospective single-institution analysis of patients who underwent lumpectomy followed by APBI (22.5 Gy in 3 fractions delivered over 2-3 days) using a Strut Adjusted Volume Implant (SAVI) applicator between November 2016 and January 2021. Dose-volume metrics were obtained from the clinically treated plan. Chart review was performed to determine locoregional recurrence and toxicities according to CTCAE v5.0. RESULTS: Between 2016 and 2021, 31 patients were treated per the TRIUMPH-T protocol. Median followup was 31 months from completion of brachytherapy. There were no acute/late Grade 3 or higher toxicities. Cumulative late Grade 1 and 2 toxicities were seen in 58.1% and 9.7% of patients, respectively. Of note, four patients experienced locoregional recurrence: three ipsilateral breast tumor recurrences and one nodal recurrence. All three ipsilateral breast tumor recurrences occurred in patients who would be classified as "cautionary" based on ASTRO consensus guidelines due to age ≤50, lobular histology, or high grade. CONCLUSIONS: Three-fraction HDR brachytherapy APBI was well-tolerated with no grade 3 or higher toxicities and an acceptably small percentage of grade 2 toxicities. Given the small sample size, the number of recurrences suggests that attention to appropriate patient selection is necessary until more long-term followup data is available.

Feasibility and acceptability of ChatGPT generated radiology report summaries for cancer patients.

Objective: Patients now have direct access to their radiology reports, which can include complex terminology and be difficult to understand. We assessed ChatGPT's ability to generate summarized MRI reports for patients with prostate cancer and evaluated physician satisfaction with the artificial intelligence (AI)-summarized report. Methods: We used ChatGPT to summarize five full MRI reports for patients with prostate cancer performed at a single institution from 2021 to 2022. Three summarized reports were generated for each full MRI report. Full MRI and summarized reports were assessed for readability using Flesch-Kincaid Grade Level (FK) score. Radiation oncologists were asked to evaluate the AI-summarized reports via an anonymous questionnaire. Qualitative responses were given on a 1-5 Likert-type scale. Fifty newly diagnosed prostate cancer patient MRIs performed at a single institution were additionally assessed for physician online portal response rates. Results: Fifteen summarized reports were generated from five full MRI reports using ChatGPT. The median FK score for the full MRI reports and summarized reports was 9.6 vs. 5.0, (p < 0.05), respectively. Twelve radiation oncologists responded to our questionnaire. The mean [SD] ratings for summarized reports were factual correctness (4.0 [0.6], understanding 4.0 [0.7]), completeness (4.1 [0.5]), potential for harm (3.5 [0.9]), overall quality (3.4 [0.9]), and likelihood to send to patient (3.1 [1.1]). Current physician online portal response rates were 14/50 (28%) at our institution. Conclusions: We demonstrate a novel application of ChatGPT to summarize MRI reports at a reading level appropriate for patients. Physicians were likely to be satisfied with the summarized reports with respect to factual correctness, ease of understanding, and completeness. Physicians were less likely to be satisfied with respect to potential for harm, overall quality, and likelihood to send to patients. Further research is needed to optimize ChatGPT's ability to summarize radiology reports and understand what factors influence physician trust in AI-summarized reports.

Evaluation of burnout in physician members of the American Brachytherapy Society.

PURPOSE: To evaluate the prevalence of burnout among brachytherapy specialists and to identify factors associated with burnout. METHODS AND MATERIALS: An anonymous, online, cross-sectional survey was administered to non-trainee physician members of the American Brachytherapy Society. Burnout was evaluated using the validated Maslach Burnout Inventory-Human Services Survey (MBI-HSS). Demographic and practice-specific questions were collected from respondents. Univariate and multivariable analysis of outcomes were performed using probabilistic index models. RESULTS: Overall, 51 of 400 physicians responded (13% response rate). Fifty-seven percent of respondents demonstrated at least one symptom of professional burnout. However, only 6% of respondents met strict criteria for high burnout. Analysis of the individual MBI-HSS subdomains demonstrated higher subscale scores for emotional exhaustion and depersonalization, but also higher scores for personal accomplishment. On multivariable analysis after adjusting for increased feelings of burnout due to the COVID-19 pandemic or total hours of work per week, younger age was associated with both increased subscale scores for emotional exhaustion (p = 0.026) and lower personal accomplishment (p = 0.010). Lastly, nearly half of all respondents (47%) reported increased feelings of burnout due to the COVID-19 pandemic. Respondents from academic facilities were significantly more likely to report increased burnout due to COVID-19 compared to those from non-academic facilities (odds ratio, 7.04; 95% CI 1.60-31.0; p = 0.010). CONCLUSIONS: Nearly 60% of brachytherapists demonstrated symptoms of professional burnout, which is higher than other radiation oncology groups (academic chairs, program directors, residents). Managing stressors related to workload, COVID and support for junior physicians are potential areas for improving feelings of burnout.

Nodal Metastasis Count and Oncologic Outcomes in Head and Neck Cancer: A Secondary Analysis of NRG/RTOG 9501, NRG/RTOG 0234, and EORTC 22931.

PURPOSE: A better understanding of the relationship between the spread of head and neck squamous cell carcinoma (HNSCC) to regional lymph nodes (LNs) and the frequency and manner of treatment failure should help design better treatment intensification strategies. In this study, we evaluated the relationship between recurrence patterns, mortality, and number of pathologically positive (+) LNs in HNSCC in 3 prospective randomized controlled trials. METHODS AND MATERIALS: We performed a secondary analysis of 947 patients with HNSCC enrolled in RTOG 9501 (n = 410), RTOG 0234 (n = 203), and EORTC 22931 (n = 334) undergoing surgery and postoperative radiation ± systemic therapy. Multivariable models were constructed for overall survival (OS), disease-free survival (DFS), locoregional relapse (LRR), and distant metastases (DM). Restricted cubic splines were used to model the nonlinear relationship between +LN number and outcomes. RESULTS: In multivariable analysis, OS and DFS decreased with each +LN without plateau, most pronounced up to 5 +LNs (OS: hazard ratio [HR], 1.21 per +LN; 95% confidence interval [CI], 1.10-1.34; P < .001; DFS: HR per +LN, 1.19; 95% CI, 1.08-1.30; P < .001) and more gradually beyond this (OS: HR per +LN, 1.02; 95% CI, 1.01-1.06; P < .001; DFS: HR per +LN, 1.04; 95% CI, 1.02-1.06; P < .001). In contrast to LRR risk, which increased sharply up to 5 +LNs (HR per +LN, 1.28; 95% CI, 1.10-1.50; P < .001) but plateaued beyond this (HR per +LN, 1.00; 95% CI, 0.96-1.04; P = .98), DM risk increased continuously with increasing +LNs (≤5 +LNs: HR per +LN, 1.10; 95% CI, 1.01-1.20; P = .04; >5 +LNs: HR per +LN, 1.05; 95% CI, 1.02-1.08; P = .003). CONCLUSIONS: In high-risk resected HNSCC, increased mortality was associated with increased +LN count. LRR and DM risk both increased in parallel up to 5 +LNs, but only DM continued to increase for further +LN increases. These differing recurrence patterns can help inform design of future treatments.

Quantitative Nodal Burden and Mortality Across Solid Cancers.

BACKGROUND: Nodal staging systems vary substantially across solid tumors, implying heterogeneity in the behavior of nodal variables in various contexts. We hypothesized, in contradiction to this, that metastatic lymph node (LN) number is a universal and dominant predictor of outcome across solid tumors. METHODS: We performed a retrospective cohort analysis of 1 304 498 patients in the National Cancer Database undergoing surgery between 2004 and 2015 across 16 solid cancer sites. Multivariable Cox regression analyses were constructed using restricted cubic splines to model the association between nodal number and mortality. Recursive partitioning analysis (RPA) was used to derive nodal classification systems for each solid cancer based on metastatic LN count. The reproducibility of these findings was assessed in 1 969 727 patients from the Surveillance, Epidemiology, and End Results registry. Two-sided tests were used for all statistical analyses. RESULTS: Consistently across disease sites, mortality risk increased continuously with increasing number of metastatic LNs (P < .001 for all spline segments). Each RPA-derived nodal classification system produced multiple prognostic groups spanning a wide spectrum of mortality risk (P < .001). Multivariable models using these RPA-derived nodal classifications demonstrated improved concordance with mortality compared with models using American Joint Committee on Cancer staging in sites where nodal classification is not based on metastatic LN count. Each RPA-derived nodal classification system was reproducible in a large validation cohort for all-cause and cause-specific mortality (P < .001). High quantitative nodal burden was the single strongest tumor-intrinsic variable associated with mortality in 12 of 16 disease sites. CONCLUSIONS: Quantitative metastatic LN burden is a fundamental driver of mortality across solid cancers and should serve as a foundation for pathologic nodal staging across solid tumors.

Advances in Combining Radiation and Immunotherapy in Breast Cancer.

Breast irradiation has long been utilized in the adjuvant or metastatic setting to eliminate microscopic disease or to palliate existing disease, respectively. However, preclinical data have demonstrated that radiation can also alter the tumor microenvironment and induce antitumor immune responses. As a result, multiple clinical studies have been undertaken and have reported synergy between radiation and immune checkpoint blockade across various cancer types. Given recent clinical successes with immune checkpoint blockade in both early-stage and metastatic breast cancer, there has been substantial interest in combining radiation and immunotherapy to enhance local and systemic immune responses. Herein, we review the preclinical rationale for combining radiotherapy and immunotherapy, the early clinical trials that have adopted this strategy in breast cancer, and the landscape of ongoing relevant clinical trials. Finally, we propose future directions based on promising preclinical studies that integrate radiation, checkpoint blockade, and novel agents for the treatment of breast cancer.

Development and Validation of a Modified Pathologic Nodal Classification System for Cutaneous Melanoma.

Importance: Given the evolving patterns of lymph node evaluation for cutaneous melanoma, it is unclear whether the current nodal classification system will continue to accurately reflect prognosis in the modern era. Existing nodal staging for cutaneous melanoma was developed primarily for patients undergoing completion lymph node dissection (CLND) for node-positive disease and does not produce groups with continuously increasing mortality. Objective: To develop and validate a modified nodal classification system for cutaneous melanoma. Design, Setting, and Participants: This retrospective cohort analysis included 105 785 patients with cutaneous melanoma undergoing surgery and nodal evaluation from January 1, 2004, to December 31, 2015, in the National Cancer Database. Extent of lymph node dissection was available for patients diagnosed in 2012 and onward. Multivariable models were generated with number of positive lymph nodes modeled using restricted cubic splines. A modified nodal classification system was derived using recursive partitioning analysis (RPA). The proposed lymph node classification system was validated in 85 499 patients from the Surveillance, Epidemiology, and End Results (SEER-18) database. Data were analyzed from April 9, 2020, to May 28, 2021. Main Outcomes and Measures: Overall survival. Results: Among the 105 785 patients included in the analysis (62 496 men [59.1%]; mean [SD] age, 59.9 [15.5] years), number of positive lymph nodes (hazard ratio [HR] per lymph node for 0 to 2 positive lymph nodes, 2.48 [95% CI, 2.37-2-61; P < .001]; HR per lymph node for ≥3 positive lymph nodes, 1.10 [95% CI 1.07-1.13; P < .001]), clinically detected metastases (HR, 1.35; 95% CI, 1.27-1.42; P < .001), and in-transit metastases (HR, 1.48; 95% CI, 1.34-1.65; P < .001) were independently associated with mortality. An RPA-derived system using these variables demonstrated continuously increasing mortality for each proposed lymph node classification group, with HRs of 1.83 (95% CI, 1.76-1.91) for N1a, 2.72 (95% CI, 2.58-2.86) for N1b, 3.79 (95% CI, 3.51-4.08) for N2a, 4.56 (95% CI, 4.22-4.92) for N2b, 6.15 (95% CI, 5.59-6.76) for N3a, and 8.25 (95% CI, 7.64-8.91) for N3b in the proposed system (P < .001). By contrast, the current American Joint Committee on Cancer (AJCC) nodal classification system produced a more haphazard mortality profile, with HRs of 1.83 (95% CI, 1.76-1.91) for N1a, 3.81 (95% CI, 3.53-4.12) for N1b, 2.59 (95% CI, 2.30-2.93) for N1c, 2.71 (95% CI, 2.56-2.87) for N2a, 4.51 (95% CI, 4.17-4.87) for N2b, 3.44 (95% CI, 2.60-4.55) for N2c, 6.06 (95% CI, 5.51-6.67) for N3a, 8.15 (95% CI, 7.54-8.81) for N3b, and 6.90 (95% CI, 5.60-8.49) for N3c. As a sensitivity analysis, the proposed system continued to accurately stratify patients when excluding those undergoing CLND for microscopic lymph node metastases. This system was validated for overall survival and cause-specific mortality in SEER-18. Last, a new overall staging system for node-positive patients was developed by RPA and demonstrated improved concordance vs the AJCC, 8th edition system (C statistic, 0.690 [95% CI, 0.689-0.691] vs 0.666 [95% CI, 0.666-0.668]). Conclusions and Relevance: The findings of this cohort study suggest that a modified nodal classification system can accurately stratify mortality risk in cutaneous melanoma in an era of increasing use of sentinel lymph node biopsy without CLND and should be considered for future staging systems.

Body of Evidence: Do Autopsy Findings Impact Medical Malpractice Claim Outcomes?

OBJECTIVE: Clinicians may hesitate to advocate for autopsies out of concern for increased malpractice risk if the pathological findings at time of death differ from the clinical findings. We aimed to understand the impact of autopsy findings on malpractice claim outcomes. METHODS: Closed malpractice claims with loss dates between 1995 and 2015 involving death related to inpatient care at 3 Harvard Medical School hospitals were extracted from a captive malpractice insurer's database. These claims were linked to patients' electronic health records and their autopsy reports. Using the Goldman classification system, 2 physician reviewers blinded to claim outcome determined whether there was major, minor, or no discordance between the final clinical diagnoses and pathologic diagnoses. Claims were compared depending on whether an autopsy was performed and whether there was major versus minor/no clinical-pathologic discordance. Primary outcomes included percentage of claims paid through settlement or plaintiff verdict and the amount of indemnity paid, inflation adjusted. RESULTS: Of 293 malpractice claims related to an inpatient death that could be linked to patients' electronic health records, 89 claims (30%) had an autopsy performed by either the hospital or medical examiner. The most common claim allegation was an issue with clinician diagnosis, which was statistically less common in the autopsy group (18% versus 38%, P = 0.001). There was no difference in percentage of claims paid whether an autopsy was performed or not (42% versus 41%, P = 0.90) and no difference in median indemnity of paid claims after adjusting for number of defendants ($1,180,537 versus $906,518, P = 0.15). Thirty-one percent of claims with hospital autopsies performed demonstrated major discordance between autopsy and clinical findings. Claims with major clinical-pathologic discordance also did not have a statistically significant difference in percentage paid (44% versus 41%, P > 0.99) or amount paid ($895,954 versus $1,494,120, P = 0.10) compared with claims with minor or no discordance. CONCLUSIONS: Although multiple factors determine malpractice claim outcome, in this cohort, claims in which an autopsy was performed did not result in more paid outcomes, even when there was major discordance between clinical and pathologic diagnoses.

The role of concomitant chemoradiotherapy in AJCC 7th edition T1-2N1 oropharyngeal carcinoma in the human papillomavirus era.

BACKGROUND: Radiotherapy (RT) without chemotherapy is considered a standard of care for the management of American Joint Committee on Cancer (AJCC) 7th edition (7E) T1-2N1 oropharyngeal squamous cell carcinoma (OPSCC). Recent data suggests concurrent chemoradiation (CCRT) may benefit these patients but did not include human papillomavirus (HPV) status. Given the radiosensitivity differences between HPV-positive versus HPV-negative OPSCC, the effect of chemotherapy may differ in these patients. METHODS: We analyzed patients in the National Cancer Database diagnosed between 2010 and 2015 with AJCC 7E stage cT1-2N1M0 OPSCC and known HPV status undergoing definitive RT or CCRT. RESULTS: Overall, 1964 patients were included, including 1297 (66%) HPV-positive and 667 (34%) HPV-negative patients. 66% received CCRT and 34% received RT alone. In multivariate analysis, CCRT was associated with improved survival compared with RT alone (hazard ratio [HR], 0.70; 95% confidence interval [CI], 0.57-0.87; P = 0.001). In propensity score-matched cohorts, 4-year overall survival was 87.4% vs 78.4% in HPV-positive patients receiving CCRT and RT alone, respectively (P = 0.002), and 65.5% vs 58.9% in HPV-negative patients, respectively (P = 0.2). There was no evidence that HPV-positivity diminished the association between CCRT and longer survival (HR, 0.57; 95% CI, 0.42-0.81) versus what was observed in HPV-negative patients (HR, 0.86; 95% CI, 0.64-1.16) (interaction P = 0.06). CONCLUSIONS: CCRT is associated with improved survival in AJCC 7E T1-2N1 OPSCC. Despite the radiosensitivity of HPV-positive OPSCC, the association of CCRT with improved survival for T1-2N1 HPV-positive OPSCC was at least as strong, if not stronger, than what was observed in HPV-negative patients.