Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study.

Background: Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods: A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results: Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion: Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

Connecting Transcriptomics with Computational Modeling to Reveal Developmental Adaptations in the Human Pediatric Myocardium.

Background: Nearly 1% or 1.3 million babies are born with congenital heart disease (CHD) globally each year - many of whom will require palliative or corrective heart surgery within the first few years of life. A detailed understanding of cardiac maturation can help to expand our knowledge on cardiac diseases that develop during gestation, identify age-appropriate cardiovascular drug therapies, and inform clinical care decisions related to surgical repair, myocardial preservation, or postoperative management. Yet, to date, our knowledge of the temporal changes that cardiomyocytes undergo during postnatal development is largely limited to animal models. Methods: Right atrial tissue samples were collected from n=117 neonatal, infant, and pediatric patients undergoing correct surgery due to (acyanotic) CHD. Patients were stratified into five age groups: neonate (0-30 days), infant (31-364 days), toddler to preschool (1-5 years), school age (6-11 years), and adolescent to young adults (12-32 years). We measured age-dependent adaptations in cardiac gene expression, and used computational modeling to simulate action potential and calcium transients. Results: Enrichment of differentially expressed genes (DEG) was explored, revealing age-dependent changes in several key biological processes (cell cycle, cell division, mitosis), cardiac ion channels, and calcium handling genes. Gene-associated changes in ionic currents exhibited both linear trends and sudden shifts across developmental stages, with changes in calcium handling ( I NCX ) and repolarization ( I K1 ) most strongly associated with an age-dependent decrease in the action potential plateau potential and increase in triangulation, respectively. We also note a shift in repolarization reserve, with lower I Kr expression in younger patients, a finding likely tied to the increased amplitude of I Ks triggered by elevated sympathetic activation in pediatric patients. Conclusion: This study provides valuable insights into age-dependent changes in human cardiac gene expression and electrophysiology among patients with CHD, shedding light on molecular mechanisms underlying cardiac development and function across different developmental stages.

Comparison of Real-Time PCR and Digital PCR for Detection of Plasma Epstein-Barr Virus DNA in Nasopharyngeal Carcinoma.

Plasma Epstein-Barr virus (EBV) DNA is an established biomarker for endemic nasopharyngeal carcinoma. However, existing real-time quantitative PCR (qPCR) assays are limited by poor interlaboratory reproducibility. This is a barrier to biomarker integration into staging systems and management. It was hypothesized that EBV digital PCR (dPCR) would have similar sensitivity but improved precision relative to qPCR. Using the World Health Organization EBV standard and patient specimens, the NRG-HN001 BamHI-W qPCR, two commercial EBNA-1 qPCR assays, and two laboratory-developed dPCR assays amplifying the BamHI-W, EBNA-1, and EBER targets were compared. Testing was conducted in the North American reference laboratory for the NRG-HN001 randomized trial. The EBV dPCR assays achieved similar performance compared with qPCR. Although dPCR does not require quantitation standards, different dPCR thresholding algorithms yielded significant qualitative and quantitative variation. This was most evident with low levels of EBV DNA. No-template control-informed thresholding (ddpcRquant) mitigated false-positive/false-negative findings. The NRG-HN001 BamHI-W qPCR and laboratory-developed BamHI-W droplet dPCR offered higher sensitivity, lower limit of blank, higher precision at low plasma EBV DNA levels (≤1500 IU/mL), and higher overall agreement with clinical specimens versus single-copy qPCR/dPCR targets (EBNA-1/EBER). These data confirm the rationale for using the BamHI-W target to define prognostic thresholds and indicate that both qPCR and dPCR methods harmonized to the World Health Organization standard can provide the necessary analytical performance.

Recommendations for Epstein-Barr virus-based screening for nasopharyngeal cancer in high- and intermediate-risk regions.

A meeting of experts was held in November 2021 to review and discuss available data on performance of Epstein-Barr virus (EBV)-based approaches to screen for early stage nasopharyngeal carcinoma (NPC) and methods for the investigation and management of screen-positive individuals. Serum EBV antibody and plasma EBV DNA testing methods were considered. Both approaches were found to have favorable performance characteristics and to be cost-effective in high-risk populations. In addition to endoscopy, use of magnetic resonance imaging (MRI) to investigate screen-positive individuals was found to increase the sensitivity of NPC detection with minimal impact on cost-effectiveness of the screening program.

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.

Posttreatment FDG-PET/CT Hopkins criteria predict locoregional recurrence after definitive radiotherapy for oropharyngeal squamous cell carcinoma.

BACKGROUND: Metabolic response assessment for oropharyngeal squamous cell carcinoma (OPSCC) aids in identifying locoregional persistence/recurrence (LRR). The Hopkins Criteria are a standardized qualitative response assessment system using posttreatment FDG-PET/CT. METHODS: We conducted a retrospective cohort study of patients with node-positive OPSCC treated with definitive (chemo)radiotherapy. We assessed Hopkins Criteria performance for LRR, then developed and validated a competing-risks model. RESULTS: Between 2004 and 2018, 259 patients were included with median follow-up of 43 months. The Hopkins Criteria sensitivity, specificity, negative predictive value, and accuracy were 68%, 88%, 95%, and 85%. The 36-month cumulative incidence of LRR was greater with positive scores (45% vs. 5%, HR 12.60, p < 0.001). PET/CTs performed ≤10 weeks after radiotherapy were associated with a four-fold increase in pathologically negative biopsies/surgeries (36% vs. 9%, p = 0.03). The AUC for LRR was 0.89 using a model integrating the Hopkins score. CONCLUSIONS: The Hopkins Criteria predict LRR with high accuracy for OPSCC response assessment.

Multiplex Epstein-Barr virus BALF2 genotyping detects high-risk variants in plasma for population screening of nasopharyngeal carcinoma.

BACKGROUND: Epstein-Barr Virus (EBV)-associated nasopharyngeal carcinoma (NPC) exhibits unusual geographic restriction despite ubiquitous lifelong infection. Screening programs can detect most NPC cases at an early stage, but existing EBV diagnostics are limited by false positives and low positive predictive value (PPV), leading to excess screening endoscopies, MRIs, and repeated testing. Recent EBV genome-wide association studies (GWAS) suggest that EBV BALF2 variants account for more than 80% of attributable NPC risk. We therefore hypothesized that high-risk BALF2 variants could be readily detected in plasma for once-lifetime screening triage. METHODS: We designed and validated a multiplex genotyping assay to detect EBV BALF2 polymorphisms in human plasma. Targeted next-generation sequencing was used to validate this assay, conduct association studies with clinical phenotype, and longitudinally genotype plasma to assess within-host haplotype stability. We examined the association between NPC and BALF2 haplotypes in a large non-endemic population and three prior EBV GWAS. Finally, we estimated NPC mortality reduction, resource utilization, and cost-effectiveness of BALF2 variant-informed screening using a previously-validated cohort model. RESULTS: Following analytical validation, the BALF2 genotyping assay had 99.3% concordance with sequencing in a cohort of 24 NPC cases and 155 non-NPC controls. BALF2 haplotype was highly associated with NPC in this non-endemic population (I613V: odds ratio [OR] 7.9; V317M: OR 178.8). No other candidate BALF2 polymorphisms were significantly associated with NPC or hematologic disorders. Longitudinal genotyping revealed 97.8% within-host haplotype concordance, indicative of lifelong latent infection. In a meta-analysis of 755 NPC cases and 981 non-NPC controls, BALF2 I613V and V317M were significantly associated with NPC in both endemic and non-endemic populations. Modeled variant-informed screening strategies achieved a 46% relative increase in PPV with 7% decrease in effective screening sensitivity, thereby averting nearly half of screening endoscopies/MRIs among endemic populations in east/southeast Asia. CONCLUSIONS: EBV BALF2 haplotypes are temporally stable within hosts and can be readily detected in plasma via an inexpensive multiplex genotyping assay that offers near-perfect sequencing concordance. In endemic and non-endemic populations, I613V and V317M were highly associated with NPC and could be leveraged to develop variant-informed screening programs that mitigate false positives with small reductions in screening sensitivity.

The economic impact of circulating tumor-tissue modified HPV DNA for the post-treatment surveillance of HPV-driven oropharyngeal cancer: A simulation.

PURPOSE: Following treatment of HPV-driven oropharynx cancer, surveillance nasopharyngoscopy and imaging are often performed but are expensive and frequently ineffective. A novel plasma circulating tumor-tissue modified viral HPV DNA (TTMV-HPV-DNA) assay accurately detects recurrences. We modeled the cost of the new assay. METHODS: We designed and validated a partitioned survival model which replicated the results of the RTOG 1016 study and calculated cumulative surveillance costs from the payer's perspective. Two strategies were considered: a standard of routine endoscopy with imaging as needed and an alternative strategy which omitted scopes and imaging but obtained serial TTMV-HPV-DNA samples. No difference in effectiveness (QALY or LY) was assumed in the base case. A 5-year horizon was used, costs were reported in 2020 U.S. dollars discounted by 3%. Seven scenarios tested model assumptions and practice variation. Deterministic and probabilistic sensitivity analyses assessed parameter uncertainty. RESULTS: In the base case, at the list TTMV-HPV-DNA price, the cumulative cost of surveillance was $11,674 for the standard strategy and $20,756 for the TTMV-HPV-DNA strategy (+$9082 over 5 years). Probabilistic sensitivity analysis demonstrated the cost difference ranged from $4917-$12,047. The TTMV-HPV-DNA strategy was most likely to be either cost saving or cost-effective if future data demonstrate small improvements in quality or quantity of life (approximately 33 quality-adjusted life-days), if the assay reduces utilization of imaging, and if the periodicity of TTMV-HPV-DNA draws could be reduced from that on clinical trials. CONCLUSIONS: This data informs providers seeking to design more accurate, accessible, and economical post-treatment surveillance strategies.

Pancreatic Stereotactic Body Radiation Therapy With or Without Hypofractionated Elective Nodal Irradiation.

PURPOSE: Pancreatic stereotactic body radiation therapy (SBRT) is limited to gross tumor without elective coverage for subclinical disease. Given a better understanding of recurrence patterns, we hypothesized that the addition of elective nodal irradiation (ENI) to pancreatic SBRT would be tolerable and would decrease locoregional progression. METHODS AND MATERIALS: We conducted a retrospective 1:2 propensity-matched cohort study to compare toxicity and locoregional progression among patients treated with pancreatic SBRT with or without ENI. In the SBRT + ENI cohort, an elective target volume was delineated per Radiation Therapy Oncology Group guidelines and treated to 25 Gy in 5 fractions alongside 40 Gy in 5 fractions to gross disease. The primary outcome was the cumulative incidence of locoregional progression, with death as a competing risk. RESULTS: Among 135 candidate controls treated with SBRT alone, 100 were propensity-matched to 50 patients treated with SBRT + ENI. All patients completed SBRT. Median potential radiographic follow-up was 28 months. The incidence of late and serious acute toxicity was similar between matched cohorts. However, SBRT + ENI was associated with a statistically significant increase in acute grade 1 to 2 nausea (60% vs 20%, P < .001). The 24-month cumulative incidences of locoregional progression with and without ENI were 22.6% (95% confidence interval [CI], 10.0%-35.1%) versus 44.6% (95% CI, 34.8%-54.4%; multivariable-adjusted hazard ratio, 0.39; 95% CI, 0.18-0.87; P = .021). This was stable in sensitivity analyses of uniform prescription dose, multiagent chemotherapy, and resectability. There were fewer peripancreatic (0% vs 7%), porta hepatis (2% vs 7%), and peri-aortic/aortocaval (5% vs 12%) recurrences after SBRT + ENI, but no difference in survival. CONCLUSIONS: Pancreatic SBRT + ENI was tolerable and did not increase late or serious acute toxicity relative to a matched cohort undergoing SBRT alone, but did increase acute grade 1 to 2 nausea. The addition of ENI to SBRT was associated with decreased locoregional progression but not improved survival. Further studies are warranted to determine whether ENI offers meaningful benefit.

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.

Cost-Effectiveness of Nasopharyngeal Carcinoma Screening With Epstein-Barr Virus Polymerase Chain Reaction or Serology in High-Incidence Populations Worldwide.

BACKGROUND: The incidence of endemic Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) varies considerably worldwide. In high-incidence regions, screening trials have been conducted. We estimated the mortality reduction and cost-effectiveness of EBV-based NPC screening in populations worldwide. METHODS: We identified 380 populations in 132 countries with incident NPC and developed a decision-analytic model to compare 10 unique onetime screening strategies with no screening for men and women aged 50 years. Screening performance and the stage distribution of undiagnosed NPC were derived from a systematic review of prospective screening trials. RESULTS: Screening was cost-effective in up to 14.5% of populations, depending on the screening strategy. These populations were limited to East Asia, Southeast Asia, and North Africa or were Asian, Pacific Islander, or Inuit populations in North America. A combination of serology and nasopharyngeal polymerase chain reaction was most cost-effective, but other combinations of serologic and/or plasma polymerase chain reaction screening were also cost-effective. The estimated reduction in NPC mortality was similar across screening strategies. For a hypothetical cohort of patients in China, the 10-year survival improved from 71.0% (95% confidence interval = 68.8% to 73.0%) without screening to a median of 86.3% (range = 83.5%-88.2%) with screening. This corresponded to a median 10-year reduction in NPC mortality of 52.9% (range = 43.1%-59.3%). Screening interval affected absolute mortality reduction and cost-effectiveness. CONCLUSIONS: We observed decreased NPC mortality with EBV-based screening. Screening was cost-effective in many high-incidence populations and could be extended to men and women as early as age 40 years in select regions. These findings may be useful when choosing among local public health initiatives.

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.

Cost-Effectiveness and Quality-Adjusted Survival of Watch and Wait After Complete Response to Chemoradiotherapy for Rectal Cancer.

BACKGROUND: Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision (TME) is the standard treatment for locally advanced rectal cancer. There is interest in deescalating local therapy after a clinical complete response to CRT. We hypothesized that a watch-and-wait (WW) strategy offers comparable cancer-specific survival, superior quality-adjusted survival, and reduced cost compared with upfront TME. METHODS: We developed a decision-analytic model to compare WW, low anterior resection, and abdominoperineal resection for patients achieving a clinical complete response to CRT. Rates of local regrowth, pelvic recurrence, and distant metastasis were derived from series comparing WW with TME after pathologic complete response. Lifetime incremental costs and quality-adjusted life-years (QALY) were calculated between strategies, and sensitivity analyses were performed to study model uncertainty. RESULTS: The base case 5-year cancer-specific survival was 93.5% (95% confidence interval [CI] = 91.5% to 94.9%) on a WW program compared with 95.9% (95% CI = 93.6% to 97.4%) after upfront TME. WW was dominant relative to low anterior resection, with cost savings of $28 500 (95% CI = $22 200 to $39 000) and incremental QALY of 0.527 (95% CI = 0.138 to 1.125). WW was also dominant relative to abdominoperineal resection, with a cost savings of $32 100 (95% CI = $21 800 to $49 200) and incremental QALY of 0.601 (95% CI = 0.213 to 1.208). WW remained dominant in sensitivity analysis unless the rate of surgical salvage fell to 73.0%. CONCLUSIONS: Using current multi-institutional recurrence estimates, we observed comparable cancer-specific survival, superior quality-adjusted survival, and decreased costs with WW compared with upfront TME. Upfront TME was preferred when surgical salvage rates were low.

Quality of Life and Cost Implications of Pseudarthrosis After Anterior Cervical Discectomy and Fusion and its Subsequent Revision Surgery.

BACKGROUND: More than 120,000 anterior cervical discectomy and fusions (ACDFs) are performed annually. Pseudarthrosis is a potential delayed adverse event that affects up to 33% of patients. The degree to which this adverse event affects both patient quality-of-life (QOL) outcomes and health care costs is poorly understood. METHODS: Patients who underwent revision surgery for pseudarthrosis between 2007 and 2012 were identified and matched to controls not experiencing pseudarthrosis in a 1:2 fashion (case/control). Cases and controls were compared regarding total health care costs incurred in the year after the index ACDF and QOL outcomes on the following metrics: EuroQol Five-Dimensions Questionnaire, Patient Health Questionnaire-9, and Pain Disability Questionnaire. RESULTS: Of 738 patients who underwent ACDF, 11 underwent surgery for pseudarthrosis. No differences were noted between cases and controls regarding any of the matched variables. Patients in the pseudarthrosis cohort had poorer postoperative scores on the EuroQol Five-Dimensions Questionnaire mobility, usual activities, pain/discomfort, and quality-adjusted life-year dimensions. In addition, 64% of patients with pseudarthrosis had worsened quality-adjusted life-year scores compared with only 9% of controls (P < 0.01). Patients with pseudarthrosis also had poorer mental health (P < 0.01) and pain disability outcomes (P < 0.01) than did controls. Pseudarthrosis was associated with significant increases in direct costs, direct postoperative costs, and total costs (all P < 0.01). CONCLUSIONS: This is the first study to characterize the effect of surgical revision for pseudarthrosis on both QOL outcomes and care costs after ACDF. Patients requiring revision experienced significantly poorer QOL outcomes and higher care costs relative to controls.

Predictors of favorable quality of life outcome following kyphoplasty and vertebroplasty.

OBJECTIVE: In 2009, 2 randomized controlled trials demonstrated no improvement in pain following vertebral augmentation compared with sham surgery. However, a recent randomized trial demonstrated significant pain relief in patients following vertebroplasty compared to controls treated with conservative medical management. This study is a retrospective review of prospectively collected patient-reported quality of life (QOL) outcomes. The authors hypothesized that vertebral augmentation procedures offer a QOL benefit, but that this benefit would be diminished in patients with a history of depression and/or in patients undergoing vertebral augmentation at more than 1 level. METHODS: Multivariable linear regression was used to identify predictors of postoperative pain assessed using the Pain Disability Questionnaire (PDQ), Patient Health Questionnaire 9 (PHQ-9), and EQ-5D scores. Eleven candidate predictors were selected a priori: age, sex, smoking history, coronary artery disease, depression, diabetes, procedure location (thoracic, lumbar), BMI, prior spine surgery, procedure indication (metastases, osteoporosis/osteopenia, other), and number of levels (1, 2, 3, or more). RESULTS: A total of 143 patients were included in the study. For each 10-year increase in age, postoperative PDQ scores decreased (improved) by 9.7 points (p < 0.001). Patients with osteoporosis/osteopenia had significantly higher (worse) postoperative PDQ scores (+17.97, p = 0.028) than patients with metastatic lesions. Male sex was associated with higher (worse) postoperative PHQ-9 scores (+2.48, p = 0.010). Compared to single-level augmentation, operations at 2 levels were associated with significantly higher PHQ-9 scores (+2.58, p = 0.017). Current smokers had significantly lower PHQ-9 scores (-1.98, p = 0.023) than never smokers. No predictors were associated with significantly different EQ-5D score. CONCLUSIONS: Variables associated with worse postoperative PDQ scores included younger age and osteoporosis/osteopenia. Variables associated with decreased (better) postoperative PHQ-9 scores included female sex, single operative vertebral level, and positive smoking status (i.e., current smoker). These clinically relevant predictors may permit identification of patients who may benefit from vertebral augmentation.

Stereotactic radiosurgery with concurrent lapatinib is associated with improved local control for HER2-positive breast cancer brain metastases.

OBJECTIVE: With increasing survival for patients with human epidermal growth factor receptor 2-positive (HER2+) breast cancer in the trastuzumab era, there is an increased risk of brain metastasis. Therefore, there is interest in optimizing intracranial disease control. Lapatinib is a small-molecule dual HER2/epidermal growth factor receptor inhibitor that has demonstrated intracranial activity against HER2+ breast cancer brain metastases. The objective of this study was to investigate the impact of lapatinib combined with stereotactic radiosurgery (SRS) on local control of brain metastases. METHODS: Patients with HER2+ breast cancer brain metastases who underwent SRS from 1997-2015 were included. The primary outcome was the cumulative incidence of local failure following SRS. Secondary outcomes included the cumulative incidence of radiation necrosis and overall survival. RESULTS: One hundred twenty-six patients with HER2+ breast cancer who underwent SRS to 479 brain metastases (median 5 lesions per patient) were included. Among these, 75 patients had luminal B subtype (hormone receptor-positive, HER2+) and 51 patients had HER2-enriched histology (hormone receptor-negative, HER2+). Forty-seven patients received lapatinib during the course of their disease, of whom 24 received concurrent lapatinib with SRS. The median radiographic follow-up among all patients was 17.1 months. Concurrent lapatinib was associated with reduction in local failure at 12 months (5.7% vs 15.1%, p < 0.01). For lesions in the ≤ 75th percentile by volume, concurrent lapatinib significantly decreased local failure. However, for lesions in the > 75th percentile (> 1.10 cm3), concurrent lapatinib did not significantly improve local failure. Any use of lapatinib after development of brain metastasis improved median survival compared to SRS without lapatinib (27.3 vs 19.5 months, p = 0.03). The 12-month risk of radiation necrosis was consistently lower in the lapatinib cohort compared to the SRS-alone cohort (1.3% vs 6.3%, p < 0.01), despite extended survival. CONCLUSIONS: For patients with HER2+ breast cancer brain metastases, the use of lapatinib concurrently with SRS improved local control of brain metastases, without an increased rate of radiation necrosis. Concurrent lapatinib best augments the efficacy of SRS for lesions ≤ 1.10 cm3 in volume. In patients who underwent SRS for HER2+ breast cancer brain metastases, the use of lapatinib at any time point in the therapy course was associated with a survival benefit. The use of lapatinib combined with radiosurgery warrants further prospective evaluation.

Cxcr3-expressing leukocytes are necessary for neurofibroma formation in mice.

Plexiform neurofibroma is a major contributor to morbidity in patients with neurofibromatosis type I (NF1). Macrophages and mast cells infiltrate neurofibroma, and data from mouse models implicate these leukocytes in neurofibroma development. Antiinflammatory therapy targeting these cell populations has been suggested as a means to prevent neurofibroma development. Here, we compare gene expression in Nf1-mutant nerves, which invariably form neurofibroma, and show disruption of neuron-glial cell interactions and immune cell infiltration to mouse models, which rarely progresses to neurofibroma with or without disruption of neuron-glial cell interactions. We find that the chemokine Cxcl10 is uniquely upregulated in NF1 mice that invariably develop neurofibroma. Global deletion of the CXCL10 receptor Cxcr3 prevented neurofibroma development in these neurofibroma-prone mice, and an anti-Cxcr3 antibody somewhat reduced tumor numbers. Cxcr3 expression localized to T cells and DCs in both inflamed nerves and neurofibromas, and Cxcr3 expression was necessary to sustain elevated macrophage numbers in Nf1-mutant nerves. To our knowledge, these data support a heretofore-unappreciated role for T cells and DCs in neurofibroma initiation.

Stereotactic radiosurgery with concurrent HER2-directed therapy is associated with improved objective response for breast cancer brain metastasis.

BACKGROUND: Patients with breast cancer positive for human epidermal growth factor receptor 2 (HER2) remain at high risk of intracranial relapse following treatment and experience increased rates of intracranial failure after stereotactic radiosurgery (SRS). We hypothesized that the addition of concurrent lapatinib to SRS would improve intracranial complete response rates. METHODS: Patients with newly diagnosed HER2-amplified breast cancer brain metastases from 2005-2014 who underwent SRS were included and divided into 2 cohorts based on timing of treatment with lapatinib. Outcome variables included the proportion of patients who achieved an intracranial complete response or progressive disease according to the RECIST 1.1 criteria, as well as individual lesion response rates, distant intracranial failure, and radiation necrosis. RESULTS: Eighty-four patients with 487 brain metastases met inclusion criteria during the study period. Over 138 treatment sessions, 132 lesions (27%) were treated with SRS and concurrent lapatinib, while 355 (73%) were treated with SRS without lapatinib. Compared with patients treated with SRS alone, patients treated with concurrent lapatinib had higher rates of complete response (35% vs 11%, P = 0.008). On a per-lesion basis, best objective response was superior in the concurrent lapatinib group (median 100% vs 70% reduction, P < 0.001). Concurrent lapatinib was not associated with an increased risk of grade 2+ radiation necrosis (1.0% with concurrent lapatinib vs 3.5% without, P = 0.27). Lapatinib had no protective effect on distant intracranial failure rates (48% vs 49%, P = 0.91). CONCLUSION: The addition of concurrent lapatinib to SRS was associated with improved complete response rates among patients with HER2-positive brain metastases.