Citations

AimsDue to its rarity and non‐specific clinical and pathological features, low‐grade adenosquamous carcinoma (LGASC) of the breast continues to pose diagnostic challenges. Unlike other triple‐negative breast carcinomas, LGASC tends to have an indolent clinical behaviour. It is essential to recognise this lesion for accurate diagnosis and appropriate management.Methods and resultsTwenty‐five cases of LGASC were identified in our archives and collaborating institutes. Cases of LGASC with dominant coexisting other type carcinomas were excluded. We studied the clinical presentation, morphological features, patterns of the commonly used immunohistochemical stains and follow‐up. In our cohort, LGASC was commonly located at the outer aspect of the breast and associated with intraductal papilloma. The morphology of LGASC is characterised by infiltrating small glands and nests with variable squamous differentiation. We also found cuffing desmoplastic (fibrolamellar) stromal change in 75% of patients and peripheral lymphocytic aggregates in 87.5% of patients. P63 and smooth muscle myosin (SMM) were the most common myoepithelial markers used to assist in diagnosis. P63 often stained peripheral tumour cells surrounding invasive glands (circumferential staining in 80% of the cases), mimicking myoepithelial cells. It also stained the small nests with squamous differentiation. However, SMM was negative in 63% of the cases. The vast majority of our cases were triple‐negative; only a few had focal and weak expressions of ER and PR. One patient who did not have excision developed lymph node metastasis. Most patients underwent excision or mastectomy with negative margins as surgical treatment; there were no recurrences or metastases in these patients with clinical follow‐ups up to 108 months.ConclusionsLGASC has some unique, although not entirely specific, morphological features and immunohistochemical staining patterns. Fibrolamellar stromal change, peripheral lymphocytic aggregates and variable staining of p63 and SMM are valuable features to facilitate the diagnosis.

Abstract Background Surgery is the mainstay of treatment for meningioma, the most common primary intracranial tumor, but improvements in meningioma risk stratification are needed and current indications for postoperative radiotherapy are controversial. Recent studies have proposed prognostic meningioma classification systems using DNA methylation profiling, copy number variants, DNA sequencing, RNA sequencing, histology, or integrated models based on multiple combined features. Targeted gene expression profiling has generated robust biomarkers integrating multiple molecular features for other cancers, but is understudied for meningiomas. Methods Targeted gene expression profiling was performed on 173 meningiomas and an optimized gene expression biomarker (34 genes) and risk score (0 to 1) was developed to predict clinical outcomes. Clinical and analytical validation was performed on independent meningiomas from 12 institutions across 3 continents (N = 1856), including 103 meningiomas from a prospective clinical trial. Gene expression biomarker performance was compared to 9 other classification systems. Results The gene expression biomarker improved discrimination of postoperative meningioma outcomes compared to all other classification systems tested in the independent clinical validation cohort for local recurrence (5-year area under the curve [AUC] 0.81) and overall survival (5-year AUC 0.80). The increase in area under the curve compared to the current standard of care, World Health Organization 2021 grade, was 0.11 for local recurrence (95% confidence interval [CI] 0.07–0.17, P < 0.001). The gene expression biomarker identified meningiomas benefiting from postoperative radiotherapy (hazard ratio 0.54, 95% CI 0.37–0.78, P = 0.0001) and re-classified up to 52.0% meningiomas compared to conventional clinical criteria, suggesting postoperative management could be refined for 29.8% of patients. Conclusions A targeted gene expression biomarker improves discrimination of meningioma outcomes compared to recent classification systems and predicts postoperative radiotherapy responses.

Abstract Objectives To capture patients' perspectives on migraine‐related cognitive symptoms during pre‐headache, headache, post‐headache, and interictal periods. Background Migraine‐related cognitive symptoms are reported by people with migraine both during and between attacks. Associated with disability, they are increasingly viewed as a priority target for treatment. The Migraine Clinical Outcome Assessment System (MiCOAS) project is focused on developing a patient‐centered core set of outcome measures for the evaluation of migraine treatments. The project focuses on incorporating the experience of people living with migraine and the outcomes most meaningful to them. This includes an examination of the presence and functional impact of migraine‐related cognitive symptoms and their perceived impact on quality of life and disability. Methods Forty individuals with self‐reported medically diagnosed migraine were recruited via iterative purposeful sampling for semi‐structured qualitative interviews conducted using audio‐only web conferencing. Thematic content analysis was performed to identify key concepts around migraine‐related cognitive symptoms. Recruitment continued until concept saturation was achieved. Results Participants described symptoms consistent with migraine‐related deficits in language/speech, sustained attention, executive function, and memory that manifest during pre‐headache (36/40 [90%] reported ≥1 cognitive feature), headache (35/40 [88%] reported ≥1 cognitive feature), post‐headache (27/40 [68%] reported ≥1 cognitive feature), and interictal periods (13/40 [33%] reported ≥1 cognitive feature). Among participants reporting cognitive symptoms during pre‐headache, 32/40 (81%) endorsed 2–5 cognitive symptoms. Findings were similar during the headache phase. Participants reported language/speech problems consistent with, for example, impairments in receptive language, expressive language, and articulation. Issues with sustained attention included fogginess, confusion/disorientation, and trouble with concentration/focus. Deficits in executive function included difficulty processing information and reduced capacity for planning and decision‐making. Memory issues were reported across all phases of the migraine attack. Conclusions This patient‐level qualitative study suggests that cognitive symptoms are common for persons with migraine, particularly in the pre‐headache and headache phases. These findings highlight the importance of assessing and ameliorating these cognitive problems.

AbstractObjectiveImprove data‐driven research to inform clinical decision‐making with pediatric epilepsy surgery patients by expanding the Pediatric Epilepsy Research Consortium Epilepsy Surgery (PERC‐Surgery) Workgroup to include neuropsychological data. This article reports on the process and initial success of this effort and characterizes the cognitive functioning of the largest multi‐site pediatric epilepsy surgery cohort in the United States.MethodsPediatric neuropsychologists from 18 institutions completed surveys regarding neuropsychological practice and the impact of involvement in the collaborative. Neuropsychological data were entered through an online database. Descriptive analyses examined the survey responses and cognitive functioning of the cohort. Statistical analyses examined which patients were evaluated and if composite scores differed by domain, demographics, measures used, or epilepsy characteristics.ResultsPositive impact of participation was evident by attendance, survey responses, and the neuropsychological data entry of 534 presurgical epilepsy patients. This cohort, ages 6 months to 21 years, were majority White and non‐Hispanic, and more likely to have private insurance. Mean intelligence quotient (IQ) scores were below to low average, with weaknesses in working memory and processing speed. Full‐scale IQ (FSIQ) was lowest for patients with younger age at seizure onset, daily seizures, and magnetic resonance imaging (MRI) abnormalities.SignificanceWe established a collaborative network and fundamental infrastructure to address questions outlined by the Epilepsy Research Benchmarks. There is a wide range in the age and IQ of patients considered for pediatric epilepsy surgery, yet it appears that social determinants of health impact access to care. Consistent with other national cohorts, this US cohort has a downward shift in IQ associated with seizure severity.

OBJECTIVE The rates of women and underrepresented racial and ethnic minority (UREM) students successfully matching into neurosurgical residency are extremely low and do not reflect the makeup of the general population. As of 2019, only 17.5% of neurosurgical residents in the United States were women, 4.95% were Black or African American, and 7.2% were Hispanic or Latinx. Earlier recruitment of UREM students will help to diversify the neurosurgical workforce. Therefore, the authors developed a virtual educational event for undergraduate students entitled "Future Leaders in Neurosurgery Symposium for Underrepresented Students’’ (FLNSUS). The primary objectives of the FLNSUS were to expose attendees to 1) neurosurgeons from diverse gender, racial, and ethnic backgrounds; 2) neurosurgical research; 3) opportunities for neurosurgical mentorship; and 4) information about life as a neurosurgeon. The authors hypothesized that the FLNSUS would increase student self-confidence, provide exposure to the specialty, and reduce perceived barriers to a neurosurgical career. METHODS To measure the change in participant perceptions of neurosurgery, pre- and postsymposium surveys were administered to attendees. Of the 269 participants who completed the presymposium survey, 250 participated in the virtual event and 124 completed the postsymposium survey. Paired pre- and postsurvey responses were used for analysis, yielding a response rate of 46%. To assess the impact of participant perceptions of neurosurgery as a field, pre- and postsurvey responses to questions were compared. The change in response was analyzed, and a nonparametric sign test was performed to check for significant differences. RESULTS According to the sign test, applicants showed increased familiarity with the field (p < 0.001), increased confidence in their abilities to become neurosurgeons (p = 0.014), and increased exposure to neurosurgeons from diverse gender, racial, and ethnic backgrounds (p < 0.001 for all categories). CONCLUSIONS These results reflect a significant improvement in student perceptions of neurosurgery and suggest that symposiums like the FLNSUS may promote further diversification of the field. The authors anticipate that events promoting diversity in neurosurgery will lead to a more equitable workforce that will ultimately translate to enhanced research productivity, cultural humility, and patient-centered care in neurosurgery.

Abstract The radiologically isolated syndrome (RIS) was defined in 2009 as the presence of asymptomatic, incidentally identified demyelinating-appearing white matter lesions in the CNS within individuals lacking symptoms typical of multiple sclerosis (MS). The RIS criteria have been validated and predict the transition to symptomatic MS reliably. The performance of RIS criteria that require fewer MRI lesions is unknown. 2009-RIS subjects, by definition, fulfil three to four of four criteria for 2005 dissemination in space (DIS) and subjects fulfilling only one or two lesions in at least one 2017 DIS location were identified within 37 prospective databases. Univariate and multivariate Cox regression models were used to identify predictors of a first clinical event. Performances of different groups were calculated. Seven hundred and forty-seven subjects (72.2% female, mean age 37.7 ± 12.3 years at the index MRI) were included. The mean clinical follow-up time was 46.8 ± 45.4 months. All subjects had focal T2 hyperintensities suggestive of inflammatory demyelination on MRI; 251 (33.6%) fulfilled one or two 2017 DIS criteria (designated as Groups 1 and 2, respectively), and 496 (66.4%) fulfilled three or four 2005 DIS criteria representing 2009-RIS subjects. Group 1 and 2 subjects were younger than the 2009-RIS group and were more likely to develop new T2 lesions over time (P &lt; 0.001). Groups 1 and 2 were similar regarding survival distribution and risk factors for transition to MS. At 5 years, the cumulative probability for a clinical event was 29.0% for Groups 1 and 2 compared to 38.7% for 2009-RIS (P = 0.0241). The presence of spinal cord lesions on the index scan and CSF-restricted oligoclonal bands in Groups 1–2 increased the risk of symptomatic MS evolution at 5 years to 38%, comparable to the risk of development in the 2009-RIS group. The presence of new T2 or gadolinium-enhancing lesions on follow-up scans independently increased the risk of presenting with a clinical event (P &lt; 0.001). The 2009-RIS subjects or Groups 1 and 2 with at least two of the risk factors for a clinical event demonstrated better sensitivity (86.0%), negative predictive value (73.1%), accuracy (59.8%) and area under the curve (60.7%) compared to other criteria studied. This large prospective cohort brings Class I evidence that subjects with fewer lesions than required in the 2009 RIS criteria evolve directly to a first clinical event at a similar rate when additional risk factors are present. Our results provide a rationale for revisions to existing RIS diagnostic criteria.

Abstract PURPOSE: Treatment options for patients (pts) with HER2+ BCBM remain limited. We previously reported that neratinib monotherapy is associated with a volumetric central nervous system objective response rate (CNS ORR) of 8%, whereas the combination of neratinib and capecitabine resulted in a volumetric CNS ORR of 49% (in lapatinib-naïve pts). Preclinical data suggest that neratinib may overcome resistance to trastuzumab-emtansine (T-DM1) and that the combination has potential CNS efficacy. Here, we report results of neratinib plus T-DM1 in pts with HER2+ BCBM. PATIENTS AND METHODS: In this prospective, multicenter, phase II study, pts with measurable HER2+ BCBM received neratinib 160 mg orally once daily plus T-DM1 3.6 mg/kg IV every 21 days in three parallel-enrolling cohorts. Cohort 4A enrolled pts with previously untreated brain metastases. Cohort 4B enrolled pts with BCBM progressing after prior local CNS-directed therapy without prior exposure to T-DM1. Cohort 4C enrolled pts with BCBM progressing after prior local CNS-directed therapy who had previous exposure to T-DM1. Diarrhea prophylaxis with colestipol and loperamide was required during cycle 1. Cohorts 4A and 4B were single-stage with a planned enrollment of 20 patients; cohort 4C had a two-stage design, with a requirement for at least 1 of the first 9 pts to achieve a response in order to enroll a total of 24 patients. The primary endpoint was Response Assessment in Neuro-Oncology-Brain Metastases (RANO BM) in each cohort separately. Correlative studies included patient-reported outcomes (PROs) for gastrointestinal toxicity. RESULTS: We enrolled 6, 17, and 21 patients to cohorts 4A, 4B, and 4C, during 11/07/2018 – 11/01/2021. Enrollment was stopped prematurely due to slow accrual. Across Cohorts 4A-4C, the median number of prior lines of chemotherapy prior to enrollment was 2 (range 1-10); 25% received prior lapatinib and no patients received prior tucatinib. In cohorts 4B and 4C (prior CNS-treated cohorts), 33% had prior CNS surgery and &gt;94% had prior CNS radiation. Among evaluable patients, CNS ORR in cohorts 4A (n=6), 4B (n=16), and 4C (n=21) was 50.0% (95% CI 18.8- 81.2%), 25.0% (95% CI 8.3-52.6%), and 38.1% (95% CI 19.0-61.3%), respectively. Median (range) number of cycles completed for 4A, 4B, and 4C was 4.5 (1-15), 4 (range 0-49+), and 6 (0-23); three patients on Cohort 4B remain on protocol therapy (cycles 14, 45, and 49). The overall survival at 12-months for cohorts 4A, 4B, and 4C was 83.3% (95% CI, 58.3-100%), 86.2% (95% CI 70-100%), and 83.3% (95% CI 67.6-100%). Diarrhea was the most common grade 3 toxicity (19.0–33.3% across cohorts); one grade 4 liver function event occurred in cohort 4B. Updated efficacy results will be reported at the meeting; PRO analyses are ongoing. CONCLUSION: Intracranial activity was observed for the combination of neratinib plus T-DM1 across all three enrolled cohorts, including those with prior T-DM1 exposure, suggesting synergistic effects of this treatment combination. Our data provide additional evidence for consideration of neratinib-based combinations in pts with HER2+ BCBM. Citation Format: Rachel Freedman, Siyang Ren, Nabihah Tayob, Rebecca Gelman, Karen L. Smith, Raechel Davis, Alyssa Pereslete, Victoria Attaya, Christine Cotter, Wendy Y. Chen, Cesar Augusto Santa-Maria, Catherine Van Poznak, Beverly Moy, Adam M. Brufsky, Michelle Melisko, Ciara C. O’Sullivan, Nadia Ashai, Yasmeen Rauf, Julie Nangia, Dario Trapani, Jennifer Savoie, Robyn Burns, Antonio C. Wolff, Eric Winer, Mothaffar Rimawi, Ian Krop, Nancy U. Lin. Translational Breast Cancer Research Consortium Trial 022: Neratinib and Trastuzumab-Emtansine for HER2+ Breast Cancer Brain Metastases (BCBM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD7-03.

Abstract Purpose: We previously demonstrated that high levels of circulating methylated DNA are associated with subsequent disease progression in women with metastatic breast cancer (MBC). In this study, we validated the clinical utility of a Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) prototype assay using the GeneXpert® cartridge system for early assessment of disease progression in MBC. Study Design: The 9-marker, LBx-BCM prototype assay was evaluated in TBCRC-005, a prospective biomarker study, using plasma collected at baseline, week 4 and week 8 from 144 MBC patients. Results: At week 4 MBC patients with high cumulative methylation (CM) had a significantly shorter median PFS (2.88 months v 6.60 months, p = 0.001) and OS (14.52 months v 22.44 months, p=0.005) compared to those with low CM. In a multivariable model, high versus low CM was also associated with shorter PFS (HR = 1.90, 95%CI 1.20-3.01; p =0.006). Change in CM from baseline to week 4 (OR = 4.60, 95%CI 1.77, 11.93; p = 0.002) and high levels of CM at week 4 (OR = 2.78, 95%CI 1.29, 5.99; p = 0.009) were associated with progressive disease at the time of first restaging. A robust risk model (AUC = 0.733) based on week 4 circulating CM levels was developed to predict disease progression as early as 3 months after initiating a new treatment. Conclusion: The easy to perform and automated LBx-BCM prototype assay is a promising clinical tool for detecting disease progression early after initiating treatment in women with MBC. Further validation in larger clinical datasets is needed. Citation Format: Kala Visvanathan, Leslie Cope, Mary Jo Fackler, Michael Considine, Lisa Carey, Andres Forero-Torres, James N. Ingle, Nancy U. Lin, Rita Nanda, Anna Maria Storniolo, Suzana Tulac, Natalie C. Wu, Sudhakar Marla, Neesha R. Venkatesan, Antonio C. Wolff, Saraswati Sukumar. Evaluation of the Automated Liquid Biopsy-Breast Cancer Methylation (LBx-BCM) Cartridge Assay for Predicting Early Disease Progression and Survival: TBCRC-005 Prospective Trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-09.

Abstract Purpose: To determine the rate of rib fracture in a cohort of patients with breast cancer treated with proton therapy and enrolled on a prospective registry. In series investigating photon therapy for breast cancer, the rib fracture rate ranges from 0.3-13% Methods: From a prospective database, we identified patients treated with proton therapy for breast cancer at our institution between January 1, 2012 and December 31, 2020. Clinical and dosimetric data was extracted from the electronic medical record. The cumulative incidence method assessed rib fracture rate; the Fine-Gray test statistic assessed prognostic significance select variables. Results: 225 patients were identified, 223 women and 2 men. Median age at the time of radiation was 57.8 years (range, 25 – 87). 26% of patients were black, 69% white and 5% were other races or race not disclosed. 5% were Hispanic. 74% of patients had left-sided breast cancer, 5% bilateral, and 21% right-sided. DEXA scan was normal in 20%, showed osteopenia in 34%, osteoporosis in 6%, and not performed in 40%. 57% of patients received antiendocrine therapy with an aromatase inhibitor. For 16% of patients, the breast +/- internal mammary nodes (IMN) were treated, while 32% underwent proton therapy to treat the breast and comprehensive regional lymphatics. 1% of patients had chest wall +/- IMN treated, while 51% underwent proton therapy to treat the chest wall and comprehensive regional lymphatics. 41% of patients were treated with passive scatter proton therapy (n=92); 52% of these had mastectomy. 58% of patients received treatment with pencil beam scanning (PBS) proton therapy (n=131); 53% of these had mastectomy. A combination of passive scatter and PBS was used for 2 patients (1%). 85% of patients received a boost. Median follow-up was 3.1 years (range, 0.2 – 9.1). 97% of patients had &gt; 12 months of follow-up. The 3 year cumulative incidence of in-field rib fracture was 3.7% (95%CI: 1.6%-7.1%). In total, 8 patients developed in-field rib fractures, one symptomatic and 7 identified incidentally on surveillance imaging, for a 0.4% rate of symptomatic rib fracture. Median time from completion of radiation to identification of rib fracture was 1.8 years (range, 0.4-7.4 years). Rib fractures occurred within 2.2 years from radiotherapy completion for seven of the eight patients who experienced this side effect. Three patients developed rib fractures outside of the radiation field, for a cumulative incidence of out-of-field rib fracture of 0.9% (95%CI: 0.2-3.0%). No variables were associated with rib fracture on univariate analysis. Of those with in-field rib fractures, 3 had low and 3 had normal bone density while 2 had not undergone testing; of those with out-of-field rib fractures, 2 had osteopenia and 1 did not have testing. Conclusions: Although a proton beam has higher biological dose deposition at end-of-range than the assumed constant RBE=1.1, the 3 year rate of any in-field rib fractures in our series remains low at 3.7%, with a 0.4% rate of symptomatic rib fracture. Contouring ribs as an OAR and establishing a dose constraint warrants further investigation as a means to maintaining a low rate of rib fracture with proton therapy. Citation Format: Julie Bradley, Xiaoying Liang, Raymond Mailhot Vega, Chunbo Liu, Eric Brooks, Teena Burchianti, Emma Viviers, Roi Dagan, Oluwadamilola Oladeru, Christopher Morris, Nancy Mendenhall. Incidence of rib fracture following treatment with proton therapy for breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-10-08.