Massachusetts General Hospital Research Articles

Educational attainment, severity and short-term prognosis of intracerebral haemorrhage

BackgroundEducational attainment is a critical social determinant of health that impacts the risk and severity of incident ischaemic stroke, but less is known of its impact on intracerebral haemorrhage (ICH)....

Chondrosarcoma of the Mobile Spine: An Update on Patients Treated at a Single Institution.

Retrospective study. The objective is to report the clinical data for patients treated with mobile spine chondrosarcoma. Chondrosarcoma of the mobile spine is a rare and challenging entity. A handful of case series have been published that report the clinical results of treatment, largely influenced by chondrosarcoma of the appendicular skeleton and pelvis. The clinical results of patients treated for chondrosarcoma of the mobile spine from our institution were published over ten years ago and this represents and update since that publication. Inclusion criteria were adults patients treated for chondrosarcoma of the mobile spine at Massachusetts General Hospital between 2007-2020. Patients with large sacral tumors extending into the lumbar spine were excluded. Further, we excluded patients with metastatic chondrosarcoma undergoing palliative decompressions for neurologic instability or instrumented procedures for biomechanical instability. Therefore, only patients undergoing definitive surgery at the primary site of disease in the mobile spine were included. Twenty-four patients were included for review in this series. Seventeen of the 24 patients had their tumors excised with negative (R0) margins. Three of these 17 patients (18%) were dead of disease at final follow-up. There were two patients with R1 resections and five patients with R2 resections. Three of the 7 patients (43%) with positive margins were dead of disease at final follow-up. A Cox proportional hazard analysis indicated total radiation dose was a significant covariate (HR 1.18, 95% CI 1.01 - 1.39, P=0.03). We found higher percentages of overall survival with R0 tumor resection and lower histologic grade whereas development of metastatic disease was closely associated with local recurrence and poor survival. Despite the improvements in treatment paradigms, it is sobering that our findings largely mirror those of previous work considering patients treated between 1984 and 2006.

Clinical study on improving the function of female bladder in controlling urine by acupuncture Zhibian (BL54) under ultrasound guidance

ObjectiveTo observe the effect of acupuncture Zhibian (BL54) on the function of the bladder in controlling urine in women under ultrasound.Method74 healthy subjects were randomly divided into deep acupuncture group of 37 cases and shallow acupuncture group of 37 cases. Under the guidance of ultrasound, the two groups of subjects were acupunctured at bilateral BL54. The deep acupuncture group was acupunctured to the pudendal nerve, and the shallow acupuncture group was acupunctured to the superficial fascia. Ultrasound was used to observe the peak systolic velocity (PSV), time average maximum velocity (TAMX), end diastolic velocity (EDV), pulsation index (PI), resistance index (RI) of the pudendal arteries, and bladder volume of two groups of subjects before and after acupuncture. The anatomical hierarchical structure of bilateral BL54 and score of Chinese version of the Massachusetts General Hospital Acupuncture Sensation Scale (C-MASS) of all subjects was measured.ResultAfter acupuncture, the PSV, TMAX of the pudendal artery, bladder volume, and the Score of C-MASS Scale in the deep acupuncture group were higher than in the shallow acupuncture group (P < 0.05). The RI of the pudendal arteries in the shallow acupuncture group decreased compared to before acupuncture (P < 0.05).ConclusionAcupuncture at the BL54 can increase the blood flow velocity of the pudendal artery, improve the function of the bladder in controlling urine in women, and different depths of acupuncture will have different therapeutic effects.

Sex differences in histopathological markers of cerebral amyloid angiopathy and related hemorrhage.

Men with cerebral amyloid angiopathy (CAA) may have an earlier onset of intracerebral hemorrhage, and a more hemorrhagic disease course compared to women. In this cohort study we investigated sex differences in histopathological markers associated with amyloid-β burden and hemorrhage in cognitively impaired individuals and patients with CAA, using neuropathological data from two autopsy databases. First, we investigated presence of parenchymal (Thal score) and vascular amyloid-β (CAA severity score) in cognitively impaired individuals from the National Alzheimer's Coordinating Center (NACC) neuropathology database. Next, we examined sex differences in hemorrhagic ex vivo MRI-markers and local cortical iron burden, and the interaction of sex on factors associated with cortical iron burden (CAA percentage area and vessel remodelling) in patients with pathologically confirmed clinical CAA from the Massachusetts General Hospital (MGH) CAA neuropathology database. In 6120 individuals from the NACC database (45% women, mean age 80y), the presence of parenchymal amyloid-β (OR [95%CI]=0.68 [0.53-0.88]) but not vascular amyloid-β was less in men compared to women. In 19 patients with definite CAA from the MGH CAA database (35% women, mean age 75y), a lower microbleed count (p<0.001), but a higher proportion of cortical superficial siderosis and a higher local cortical iron burden was found in men (p<0.001) compared to women. CAA percentage area was comparable in men and women (p=0.732). Exploratory analyses demonstrated a possible stronger negative relation between cortical CAA percentage area and cortical iron density in men compared to women (p=0.03). Previously observed sex differences in hemorrhage onset and progression in CAA patients are likely not due to differences in global CAA severity between men and women. Other factors, such as vascular remodelling, may contribute, but future studies are necessary to replicate our findings in larger datasets and to further investigate the underlying mechanisms behind these complex sex differences.

A Retrospective Study of Adult Patients with Parry Romberg Syndrome.

Parry Romberg Syndrome (PRS), also known as progressive hemifacial atrophy, is characterized by atrophy of skin and subcutaneous tissue, which can include muscle, bone, and cartilage. PRS is a clinical diagnosis, although supportive imaging and/or histology may be obtained. We present a case series of 10 adult patients with a diagnosis of PRS seen at Massachusetts General Hospital and Brigham and Women’s Hospital from 2000 to 2021. Nine out of 10 patients were female, with an average age of onset of 27.3 years and an average of 12.4 years between onset and diagnosis. Of the 10 patients, 4 had biopsies with supportive histopathology findings, and 7 had positive imaging findings. Patients typically received both medical and surgical treatments.

Abstract PO4-19-06: Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer with a somatic BRCA1/2 mutation present in cell-free DNA or tumor tissue genotyping

Abstract Background: PARP inhibitors improve both progression free survival (PFS) and patient quality of life in germline BRCA1/2 mutant metastatic breast cancer (MBC), which accounts for 5-10% of breast cancer, leading to their approval in this setting. We have previously shown that a subset of patients with MBC who are not germline BRCA1/2 carriers may harbor pathogenic somatic BRCA1/2 mutations that are identified by cell-free DNA and/or tumor tissue genotyping. In our prior work, we developed a circulating tumor cell culture from a patient with MBC harboring a pathogenic somatic BRCA1 mutation, and demonstrated that a PARP inhibitor induced cell growth inhibition similar to germline BRCA1/2 mutant cultures. Thus, we hypothesize that a PARP inhibitor may be effective in treating somatic BRCA1/2 mutant MBC. In this clinical trial, we are studying the efficacy of a PARP inhibitor in somatic BRCA1/2 mutant MBC. Our work may help expand the clinical application of PARP inhibitors in MBC. Trial Design: This phase II investigator-initiated clinical trial is enrolling 30 patients with MBC who have a pathogenic somatic BRCA1/2 mutation identified by a CLIA certified cell-free DNA and/or tumor tissue genotyping assay. Patients are treated with the PARP inhibitor talazoparib 1 mg/day until progression of disease. Imaging (CT chest, abdomen and pelvis, and bone scan) occurs for disease assessment at baseline and every 3 months. Cell-free DNA is collected at baseline and then monthly to evaluate changes in the genomic environment. Patients also undergo the Cancer Risk B (CR-B) assay, a novel flow variant assay to identify double-strand break repair mutations in circulating blood cells, at baseline. Eligibility Criteria: Patients must have MBC with a pathogenic somatic BRCA1/2 mutation identified in a cell-free DNA and/or tumor tissue genotyping assay, with pathogenicity confirmed by a genetics counselor using validated genomic databases such as ClinVar. Patients may have triple-negative (receipt of at least 1 prior chemotherapy) or hormone receptor positive/HER2- MBC (receipt of at least 1 prior hormone therapy). Patients must not be known germline BRCA1/2 carriers. Any number of prior therapies including a prior platinum (in absence of progressive disease on a platinum) are allowed, but patients should not have received a prior PARP inhibitor. Patients must have adequate organ function and performance status. Specific Aims: The primary aim is to determine PFS (RECIST 1.1). Secondary aims include determining the objective response rate and toxicity (NCI CTCAE v 5.0). Exploratory aims include evaluating serial changes in BRCA1/2 mutant allelic frequency in cell-free DNA, understanding the impact of BRCA1/2 reversion mutations in cell-free DNA, comparing pre- and post-treatment cell-free DNA results to understand changes in the genomic environment, studying the CR-B assay positivity rate, and correlating these biomarker analyses with treatment response. Statistical Methods: This study has 81% power to demonstrate that the 12-week PFS is 53% or higher. In contrast, there is a 4% (alpha) probability of concluding that the 12-week PFS is ≥ 53% if the true 12-week PFS is 30% or lower. If 14 or more of 30 total patients achieve PFS &amp;gt; 12 weeks, the null hypothesis (12-week PFS ≤ 30%) will be rejected. Present accrual and target accrual: This study (NCT03990896) is open at Massachusetts General Hospital, MD Anderson, University of California San Francisco, Emory, Northwestern, and Vanderbilt. As of 7/2023, 14/30 patients are enrolled. Funding: This study is funded by a Pfizer ASPIRE award and Conquer Cancer Foundation of ASCO–Breast Cancer Research Foundation- Career Development Award. Contact information: Neelima Vidula, MD, Massachusetts General Hospital, nvidula@mgh.harvard.edu. Citation Format: Neelima Vidula, Senthil Damodaran, Manali Bhave, Hope Rugo, Ami N. Shah, Erica Blouch, Nathan Royce Ruffle-Deignan, Ogadinma Ogbenna, Lisa E. Flaum, Massimo Cristofanilli, Joseph Sparano, Harry Ostrer, Vandana Abramson, Nora Horick, Aditya Bardia. Phase II study of a PARP inhibitor, talazoparib, in HER2- metastatic breast cancer with a somatic BRCA1/2 mutation present in cell-free DNA or tumor tissue genotyping [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-19-06.

Abstract PO5-01-11: Breast Cancer Index and comparative analysis of late distant recurrence risk with results from the TEAM trial

Abstract Background: Individualized risk assessment of distant recurrence (DR) is critical for early-stage HR+ breast cancer patients, as prolonged risk of recurrence continues even after completing 5 years of adjuvant endocrine therapy. The Breast Cancer Index (BCI) is a guideline-endorsed, validated gene expression assay that provides an individualized risk of overall (0-10y) and late (5-10y) DR and predicts the likelihood of benefit from extended endocrine therapy. The current BCI assay reports prognostic risk estimates based on tamoxifen-treated patients from the Stockholm (STO-3) cohort for node-negative (N0) patients, enrolled between 1976 through 1990 and a retrospective cohort from Massachusetts General Hospital (MGH) for patients with 1 to 3 positive nodes (N1), diagnosed between 1993 and 2007, of which approximately 50% were tamoxifen-treated. More recently, additional validation was completed in the Tamoxifen and Exemestane Adjuvant Multinational (TEAM) trial, in which patients were enrolled between 2001 and 2006. Here, individualized DR risk estimates from the TEAM trial were compared with those from Stockholm and MGH cohorts. Methods: For the TEAM translational study, BCI testing was performed blinded to clinical outcome and BCI and BCIN+ risk scores were calculated as previously described. A total of 2910 postmenopausal patients with HR+ breast cancer, including 1285 N0 and 1625 N1 patients, who remained DR-free for five years were analyzed to determine the risk of late DR. Cox proportional hazard models using Breslow estimates were used to calculate the risk of late DR as a function of continuous BCI risk scores. Results: Late DR risk estimates from both the TEAM trial and the Stockholm/MGH cohorts are summarized in the table below. In N0 patients, comparison of 5-10y risk estimates of late DR observed in TEAM patients were higher than those in the Stockholm cohort for BCI scores less than 8.0, but reduced for BCI scores greater than 8.0. Risk estimates differed by 1.5% for a BCI score of 0 and -4.3% for a BCI score of 10. A similar pattern was observed for N1 patients between the TEAM and MGH cohorts, with risk estimates from TEAM trial being higher for BCI scores less than 8.0 but reduced for BCI scores greater than 8.0 compared to those from the MGH cohort. Conclusions: BCI prognostic validation in the TEAM trial enabled the characterization of DR risk that is more compatible with the current standard of care in the US, as postmenopausal patients were all treated with at least 2-3 years or 5 years of primary adjuvant endocrine therapy with an aromatase inhibitor. Results from the TEAM study provide a more representative assessment of late DR risk to guide individualized treatment decision-making for HR+ early-stage breast cancer patients. Table. Citation Format: John MS Bartlett, Yi Zhang, Gregory Pond, Jenna Wong, Keying Xu, Melanie Spears, Elizabeth Mallon, Karen Taylor, Annette Hasenburg, Christos Markopoulos, Luc Dirix, Caroline Seynaeve, Cornelis J.H. van de Velde, Daniel Rea, Adam Brufsky, Olle Stål, Dennis Sgroi, Catherine Schnabel, Kai Treuner, Jane Bayani. Breast Cancer Index and comparative analysis of late distant recurrence risk with results from the TEAM trial [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-11.

Abstract PS06-03: Differences in ctDNA genomic profiles and outcomes of Black and White patients with metastatic breast cancer: results from a large multicenter consortium

Abstract Background: Black breast cancer patients have a well-documented survival disparity when compared to White patients. It is imperative to explore the reasons for this disparity from both a socioeconomic and biological perspective. Prior studies evaluating somatic genetic differences have primarily focused on tumor tissue analysis, which could be limited by inter- and intra-tumor heterogeneity. Circulating tumor DNA (ctDNA) testing allows for non-invasive detection of these heterogenous somatic mutations in the peripheral blood. We hypothesized that there could be differences in cancer-specific genetic profiles across Black and White patients with metastatic breast cancer (MBC), and that these differences may impact treatment response and clinical outcomes. Methods: This retrospective cohort study included a total of 1327 patients with MBC who were treated at Washington University in St. Louis (N=474 patients), Massachusetts General Hospital (N=412), and Northwestern University (N=441). All patients underwent ctDNA profiling using the commercially available Guardant360 assay. Race information was patient-reported, and ancestry data were not available. Descriptive analysis of clinical variables and pathway variants was performed. Univariate and multivariate analyses were done to evaluate single gene mutations and genetic pathways in both the entire cohort and the hormone-receptor positive (HR+), HER2-negative population (HR+/HER2-). The potential prognostic impact of these somatic mutations was assessed through multivariate analysis in both White and Black patient populations. Results: The cohort of 1327 patients included 1057 White patients (79.6%) and 140 Black patients (10.5%). The remaining patients (9.9%) were not included in the analysis due to low numbers. Black patients had significantly higher rates of GATA3 single nucleotide variants (snv) (OR 2.13, 95% CI 1.07-4.25, P=0.03), PTPN11 snv (OR 7.90, CI 1.10-56.56, P=0.04), and CCND2 copy number variants (cnv) (OR 3.78, CI 1.51-9.45, P=0.004). These alterations were also significantly more common in Black patients in the HR+/HER2- population (N = 812) for GATA3 snv (OR 2.28, CI 1.09-4.76, P=0.028), PTPN11 snv (OR 16.60, CI 1.49-184.93, p=0.022), and CCND2 cnv (OR 4.17, CI 1.02-16.97, P=0.046). Multivariate analysis confirmed that GATA3 snv (OR 2.23, CI 1.12-4.45, P=0.023) and CCND2 cnv (OR 3.97, CI 1.59-9.94, P=0.003) were significantly more common in Black patients in both the full cohort and HR+/HER2- subset. Mutations in the PI3K pathway were more prevalent in White patients, but this difference was not statistically significant in univariate or multivariate analysis. Overall survival (OS) from time of ctDNA collection was significantly worse in Black patients compared to White patients when corrected for lines of therapy and sites of metastasis (median 22 vs. 29 months, log-rank test, P=0.03). Among HR+/HER2- patients specifically, worse prognosis in White patients was associated with TP53 snv (HR 1.55, CI 1.19-2.01, P=0.001), NF1 snv (HR 1.99, CI 1.11-3.56, P=0.021), MYC cnv (HR 1.76, CI 1.09-2.87, P=0.02), PIK3CA cnv pathway (HR 1.69, CI 1.07-2.66, P=0.024), and MYC cnv pathway (HR 1.85, CI 1.15-2.97, P=0.011). No significant gene mutation or pathway association was found in Black patients. Prognostic differences in the cohort based on clinical, pathological, and treatment history were also explored and will be presented. Discussion: To our knowledge, this is the largest clinical genomic dataset examining ctDNA differences across Black and White patients. Our findings revealed that Black patients had higher frequencies of GATA3 snv and CCND2 cnv. The shorter OS observed in Black patients in our study aligns with previous studies and is likely multifactorial, especially given the early separation of the survival curves. Future research should focus on both socioeconomic and genetic factors to explain this disparity. Citation Format: Emily Podany, Lorenzo Foffano, Lorenzo Gerratana, Arielle Medford, Katherine Clifton, Whitney Hensing, Renee Morecroft, Marko Velimirovic, Ami Shah, Carolina REDUZZI, Laura Munoz Arcos, Charles S. Dai, Jennifer Keenan, Elyssa Denault, Foluso Ademuyiwa, Fabio Puglisi, Cynthia Ma, Aditya Bardia, Massimo Cristofanilli, Andrew Davis. Differences in ctDNA genomic profiles and outcomes of Black and White patients with metastatic breast cancer: results from a large multicenter consortium [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PS06-03.

Abstract PO1-10-01: Racial/Ethnic Disparities in Rates of Pathological Complete Response and Survival in Patients with Inflammatory Breast Cancer

Abstract Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis Rayan Bensenane1 MD, Arnaud Beddok1,2,3 MD, Nadine Andrieu4 PhD, Fabienne Lesueur4 PhD, Eve Cavaciuti 4 MSc, Dorothee Le Gal4 MSc, Eon-Marchais Severine4 PhD, Dominique Stoppa Lyonnet 5MD PhD, Youlia Kirova1 MD 1. Institut Curie, PSL Research University, Radiation Oncology Department, Paris/Saint-Cloud/Orsay, France. 2. Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St., Boston, MA, 02114, USA 3. Institut Curie, PSL Research University, University Paris Saclay, Inserm LITO U1288 Orsay, France 4. Inserm, U900, Institut Curie, PSL Research University, Mines ParisTech, Paris, France 5.Department of Genetics, Institut Curie; Inserm U830, Institut Curie; Paris-Cité University Abstract (characters: 2952; max 3400 characters, not include spaces) Background: The Ataxia-Telangiectasia Mutated (ATM) gene, involved in the repair of DNA double-strand breaks, can contribute to radiosensitivity when a bi-allelic variant is present and lead to Ataxia-Telangiectasia syndrome. Moreover, monoallelic ATM pathologic variant (PV) carriers, especially women, has an estimated occurrence rate of 0.5-1% globally and face a 2 to 3-fold increased risk of developing breast cancer. Despite evidence of in vitro radiosensitivity in cells derived from monoallelic variant carriers, there is a dearth of patient studies examining the risk of radiation-induced toxicity. This study aims to explore radiation therapy (RT) toxicities in non-metastatic breast cancer women carrying a germline monoallelic ATM variant, compared to non-carriers. Methods: A retrospective study was conducted on patients treated at Institut Curie, Paris from 1999 to 2014 and participating to CoF-AT (a French national study) and GENESIS database. ATM variant screenings encompassed both PV and non-PV, with toxicities evaluated using CTCAE v.5. Variants were classified as pathogenic, variant of unknown significance (VUS), or benign. Follow-up started from age/date at breast cancer to acute, late toxicities, disease recurrence or last news. Survival and toxicity comparisons were made using Kaplan-Meier survival analysis and Chi-square tests, respectively, with a significance level of α set at 0.05. Results: Among 50 patients, nine were ATM variant carriers (3 PV/5 VUS/1 benign), and 41 were non-carriers. Most patients had no smoking history (68%), and invasive ductal carcinoma was the predominant diagnosis (82%). The majority underwent breast-conservative surgery (80%), and the dominant RT techniques were 3D-Conformational Radiation Therapy (70%) and Isocentric Lateral Decubitus (30%). The median RT dose was 50 Gy over an average period of 36.5 days. With a median follow-up of 12 years post-diagnosis, no significant difference in acute dermatitis, esophagitis, lymphedema, cutaneous fibrosis, telangiectasia, or heart disease was observed between the groups. Analysis of overall survival (OS) showed a 5-year OS of 98%, decreasing to 89% at 10 years. For ATM variant carriers, the OS at 5, 10, and 15 years was 100%, 89%, and 89%, respectively, similar to non-carriers. Kaplan-Meier analysis revealed no significant differences in 5, 10, and 15-year overall survival, progression-free survival, local failure-specific survival, and contralateral breast cancer rates between the groups. Conclusion: In non-metastatic breast cancer patients, monoallelic ATM variant carrier status does not significantly influence acute or late RT toxicities and survival outcomes. These findings, derived from a small cohort, highlight the need for prospective studies for further validation. Table: Acute and Late Toxicities Post-Radiation Therapy in Monoallelic ATM Variant Carriers vs Non-Carriers Citation Format: Rebecca Zasloff, Samantha Thomas, Kendra Parrish, Astrid Botty van de Bruele, Gayle DiLalla, Maggie DiNome, Laura Rosenberger, Hannah Woriax, E Shelley Hwang, Jennifer Plichta, Akiko Chiba. Racial/Ethnic Disparities in Rates of Pathological Complete Response and Survival in Patients with Inflammatory Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-10-01.

Abstract PO4-15-04: Differential genomic profiling of progesterone receptor (PR) negative, estrogen receptor (ER) positive HER2-negative metastatic breast cancer (MBC) through circulating tumor DNA

Abstract Background: MBC is usually classified based on ER and HER2 status. Although the absence of PR expression is commonly associated with a poorer response to endocrine therapy (ET) and an unfavorable prognosis, data regarding the underlining molecular features that occur in this subgroup are still unclear. The aim of this study was to investigate genomic differences between ER/PRpos HER2neg (PRpos) and ERpos PR/HER2neg (PRneg) MBC through circulating tumor DNA (ctDNA) profiling in a large multicenter consortium. Methods: This retrospective study analyzed a cohort of 1089 patients at Weill Cornell Medicine, Northwestern University, Massachusetts General Hospital, and Washington University in St. Louis with HER2neg MBC and ctDNA testing by Guardant360. Oncogenic pathway status (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, and PI3K) was defined based on previous research (Sanchez-Vega et al. Cell, 2018). Associations across single nucleotide variations (SNVs), copy number variations (CNVs), pathway classification, and ER/PR status were tested by multinomial logistic regression and corrected for significant clinical characteristics (i.e., lines of treatment, metastatic sites). Prognosis was analyzed through Cox regression for overall survival (OS) defined from time of ctDNA collection. Results: Among the 1089 analyzed patients, PRpos was the most represented subtype (N:580, 53%), followed by PRneg (N:300, 28%) and Triple Negative (TNBC) (N:209, 19%). In the hormone receptor positive subgroup, bone (N:663, 75%), liver (N:323, 37%) and lymph nodes (N:314, 36%) were the main sites of distant involvement. The TNBC group was exposed to significantly fewer lines of therapy (RRR:0.37, P= 0.005 for ≥5 lines). As compared to PRneg, TNBC had less frequent and PRpos had more frequent bone involvement (RRR:0.44, P&amp;lt; 0.001 and RRR:1.80, P&amp;lt; 0.001, respectively) and less frequent liver involvement (RRR:0.64, P=0.019 and RRR:0.71, P=0.020, respectively for TNBC and PRpos). After multivariable analysis, a significant difference with respect to PRneg was observed in SNVs for the PI3K and P53 pathways for TNBC (RRR 0.49 P = 0.013 and RRR 4.06 P &amp;lt; 0.001, respectively) but not for PRpos. On a single gene level, a lower incidence in CDH1 SNVs (RRR 0.09 P = 0.036) and a higher incidence of ESR1 SNVs (RRR 0.09 P = 0.036) was present in PRpos compared to PRneg. TNBC, on the other hand, was characterized by a lower prevalence of KRAS SNVs (RRR 0.09 P = 0.036) and PIK3CA SNVs (RRR 0.25 P &amp;lt; 0.001) and a higher prevalence of TP53 SNVs (RRR 0.09 P &amp;lt; 0.001). No ESR1mutations were detected in TNBC. Median OS was 15 months (mo) for TNBC, 21 mo for PRneg and 31 mo for PRpos (P &amp;lt; 0.001). The differential prognostic impact of ctDNA features on OS was then analyzed across the PRpos and PRneg subpopulations. ESR1 SNVs was prognostic for both subgroups in univariable analysis (HR 2.19 P &amp;lt; 0.001 and HR 1.96 P = 0.001 for PRpos and PRneg, respectively). In multivariable analysis corrected for lines of therapy, ESR1 SNVs retained its significance only in the PRpos subgroup (HR 1.41 P = 0.021) together with NF1 SNVs (HR 2.04 P = 0.034). On the other hand, TP53 SNVs had a significant impact on OS in the PRneg subgroup (HR 2.02 P = 0.014). Conclusions: Our study confirmed the prognostic impact of PR status in ER positive, HER2 negative MBC. Moreover, it suggested a differential profile in terms of ctDNA-detectable genomic features and their impact on survival, including well-established markers such as ESR1 SNVs, with a potential relevance for disease subtyping and future algorithms for drug development trials. Citation Format: Lorenzo Gerratana, Andrew Davis, Arielle Medford, Carolina Reduzzi, Katherine Clifton, Emily Podany, Whitney Hensing, Marko Velimirovic, Ami N. Shah, Lorenzo Foffano, Laura Munoz Arcos, Eleonora Nicolò, Charles S. Dai, Jennifer Keenan, Amir Behdad, Seth Wander, William Gradishar, Cynthia Ma, Fabio Puglisi, Aditya Bardia, Massimo Cristofanilli. Differential genomic profiling of progesterone receptor (PR) negative, estrogen receptor (ER) positive HER2-negative metastatic breast cancer (MBC) through circulating tumor DNA [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-15-04.

Abstract PO1-22-05: Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis

Abstract Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis Rayan Bensenane1 MD, Arnaud Beddok1,2,3 MD, Nadine Andrieu4 PhD, Fabienne Lesueur4 PhD, Eve Cavaciuti 4 MSc, Dorothee Le Gal4 MSc, Eon-Marchais Severine4 PhD, Dominique Stoppa Lyonnet 5MD PhD, Youlia Kirova1 MD 1. Institut Curie, PSL Research University, Radiation Oncology Department, Paris/Saint-Cloud/Orsay, France. 2. Gordon Center for Medical Imaging, Massachusetts General Hospital, Harvard Medical School, 125 Nashua St., Boston, MA, 02114, USA 3. Institut Curie, PSL Research University, University Paris Saclay, Inserm LITO U1288 Orsay, France 4. Inserm, U900, Institut Curie, PSL Research University, Mines ParisTech, Paris, France Abstract (characters: 2952; max 3400 characters, not include spaces) Background: The Ataxia-Telangiectasia Mutated (ATM) gene, involved in the repair of DNA double-strand breaks, can contribute to radiosensitivity when a bi-allelic variant is present and lead to Ataxia-Telangiectasia syndrome. Moreover, monoallelic ATM pathologic variant (PV) carriers, especially women, has an estimated occurrence rate of 0.5-1% globally and face a 2 to 3-fold increased risk of developing breast cancer. Despite evidence of in vitro radiosensitivity in cells derived from monoallelic variant carriers, there is a dearth of patient studies examining the risk of radiation-induced toxicity. This study aims to explore radiation therapy (RT) toxicities in non-metastatic breast cancer women carrying a germline monoallelic ATM variant, compared to non-carriers. Methods: A retrospective study was conducted on patients treated at Institut Curie, Paris from 1999 to 2014 and participating to CoF-AT (a French national study) and GENESIS database. ATM variant screenings encompassed both PV and non-PV, with toxicities evaluated using CTCAE v.5. Variants were classified as pathogenic, variant of unknown significance (VUS), or benign. Follow-up started from age/date at breast cancer to acute, late toxicities, disease recurrence or last news. Survival and toxicity comparisons were made using Kaplan-Meier survival analysis and Chi-square tests, respectively, with a significance level of α set at 0.05. Results: Among 50 patients, nine were ATM variant carriers (3 PV/5 VUS/1 benign), and 41 were non-carriers. Most patients had no smoking history (68%), and invasive ductal carcinoma was the predominant diagnosis (82%). The majority underwent breast-conservative surgery (80%), and the dominant RT techniques were 3D-Conformational Radiation Therapy (70%) and Isocentric Lateral Decubitus (30%). The median RT dose was 50 Gy over an average period of 36.5 days. With a median follow-up of 12 years post-diagnosis, no significant difference in acute dermatitis, esophagitis, lymphedema, cutaneous fibrosis, telangiectasia, or heart disease was observed between the groups. Analysis of overall survival (OS) showed a 5-year OS of 98%, decreasing to 89% at 10 years. For ATM variant carriers, the OS at 5, 10, and 15 years was 100%, 89%, and 89%, respectively, similar to non-carriers. Kaplan-Meier analysis revealed no significant differences in 5, 10, and 15-year overall survival, progression-free survival, local failure-specific survival, and contralateral breast cancer rates between the groups. Conclusion: In non-metastatic breast cancer patients, monoallelic ATM variant carrier status does not significantly influence acute or late RT toxicities and survival outcomes. These findings, derived from a small cohort, highlight the need for prospective studies for further validation. Table: Acute and Late Toxicities Post-Radiation Therapy in Monoallelic ATM Variant Carriers vs Non-Carriers * Pearson/Chi2 test ; NS: non significant at α=0.05; ATM +/+: wild type for ATM; ATM +/- : ATM monoallelic germline variant carrier Citation Format: Rayan BENSENANE, Youlia Kirova, Arnaud BEDDOK, Andine ANDRIEU, Fabienne Lesueur, Eve CAVACIUTI, Dorothée Le GAL, Severine EON-MARCHAIS, Dominique STOPPA LYONNET. Radiation Therapy Toxicities and Survival Outcomes in Monoallelic ATM Variant Carriers with Non-Metastatic Breast Cancer: A Retrospective Analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-22-05.

Sleep and circadian biomarkers of postoperative delirium (SLEEP-POD): protocol for a prospective and observational cohort study

IntroductionSurgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. This...

Interleukin-6 drives endothelial glycocalyx damage in COVID-19 and bacterial sepsis.

Damage of the endothelial glycocalyx (eGC) plays a central role in the development of vascular hyperpermeability and organ damage during systemic inflammation. However, the specific signalling pathways for eGC damage remain poorly defined. Aim of this study was to combine sublingual video-microscopy, plasma proteomics and live cell imaging to uncover further pathways of eGC damage in patients with coronavirus disease 2019 (COVID-19) or bacterial sepsis. This secondary analysis of the prospective multicenter MICROCODE study included 22 patients with COVID-19 and 43 patients with bacterial sepsis admitted to intermediate or intensive care units and 10 healthy controls. Interleukin-6 (IL-6) was strongly associated with damaged eGC and correlated both with eGC dimensions (rs=0.36, p = 0.0015) and circulating eGC biomarkers. In vitro, IL-6 reduced eGC height and coverage, which was inhibited by blocking IL-6 signalling with the anti-IL-6 receptor antibody tocilizumab or the Janus kinase inhibitor tofacitinib. Exposure of endothelial cells to 5% serum from COVID-19 or sepsis patients resulted in a significant decrease in eGC height, which was attenuated by co-incubation with tocilizumab. In an external COVID-19 cohort of 219 patients from Massachusetts General Hospital, a previously identified proteomic eGC signature correlated with IL-6 (rs=-0.58, p < 0.0001) and predicted the combined endpoint of 28-day mortality and/or intubation (ROC-AUC: 0.86 [95% CI: 0.81-0.91], p < 0.001). The data suggest that IL-6 may significantly drive eGC damage in COVID-19 and bacterial sepsis. Our findings provide valuable insights into pathomechanisms of vascular dysfunction during systemic inflammation and highlight the need for further in vivo studies.

Increase in Functional Tic Presentations in Sexual Orientation and Gender Identity Minority Youth During Coronavirus Disease 2019

BackgroundFunctional tic disorders are among the least common functional movement disorders, but their prevalence rose during the coronavirus disease 2019 (COVID-19) pandemic. Although female adolescents develop functional neurological disorders at higher rates than males, investigations into sexual orientation and gender identity (SOGI) status of these patients are limited. MethodsWe completed a retrospective, cross-sectional time series examining the incidence of new-onset functional tic disorders in youth presenting to the Massachusetts General Hospital Movement Disorder clinics before and during the COVID-19 pandemic. Data were collected by searching for relevant International Classification of Diseases (ICD)-10 diagnostic codes in youth aged nine to 26 years using a hospital-wide data repository. Individual cases were reviewed for inclusion based on clinical criteria and expert consensus. ResultsThe prevalence of functional tic presentations in youth rose 8.6-fold from pre- to postpandemic levels (Fisher exact test P < 0.001), whereas the prevalence of developmental tic presentations pre- and postpandemic remained stable (114 vs 112). SOGI minority youth comprised 37% of those with functional tics (total n = 19). Ninety five percent of patients with functional tics identified as female, with 10% of these identifying as transgender. ConclusionsOur data confirm previously demonstrated dramatic rises in functional tic presentations during the COVID-19 pandemic and, more notably, reveal a strong association with SOGI minority status. We highlight the potential link between functional tic disorders and SOGI minority status. Providing a safe and supportive clinical environment and addressing stress linked to SOGI minority status may help to improve patient prognosis.

A bibliometric analysis of the research landscape on vascular normalization in cancer

Tumor vascular normalization profoundly affects the advancement of cancer therapy. Currently, with the rapid increase in research on tumor vascular normalization, few analytical and descriptive studies have investigated the trends in its development, key research power, present research hotspots, and future outlooks. In this study, articles and reviews published between January 1, 2003, and October 29, 2022 were retrieved from Web of Science database. Subsequently, published research trends, countries/regions, institutions, authors, journals, references, and keywords were analyzed based on traditional bibliometric laws (such as Price's exponential growth, Bradford's, Lotka's, and Zipf's). Our results showed that the last two decades have seen an increase in tumor vascular normalization research. USA emerged as the preeminent contributor to the field, boasting the highest H-index and accruing the greatest quantity of publications and citations. Among institutions, Massachusetts General Hospital and Harvard University made significant contributions, and Professor RK Jain was identified as a key leader in this field. Out of 583 academic journals, Cancer Research and Clinical Cancer Research published the most articles on vascular normalization. The research focal points in the field primarily include immunotherapy, tumor microenvironments, nanomedicine, and emerging frontier themes such as metabolism and mechanomedicine. Concurrently, the challenges of vascular normalization in cancer are discussed as well. In conclusion, the study presented a thorough analysis of the literature covering the past 20 years on vascular normalization in cancer, highlighting leading countries, institutions, authors, journals, and the emerging research focal points in this field. Future studies will advance the ongoing efforts in the field of tumor vascular normalization, aiming to enhance our ability to effectively manage and treat cancer.

Patch testing outcomes in children at the Massachusetts General Hospital

Patch testing outcomes in children at the Massachusetts General Hospital

399 Source Localization of Burst Suppression in Post-Cardiac Arrest Patients

OBJECTIVES/GOALS: Burst suppression is a neurophysiological marker associated with severe hypoxic-ischemic injury following cardiac arrest. The goal of this study is to identify the anatomical regions of the brain associated with burst suppression post-cardiac arrest. METHODS/STUDY POPULATION: 86 comatose patients post-cardiac arrest admitted to the neurological-ICU from Massachusetts General Hospital and Brigham and Women’s Hospital were included in this study. EEG data after return of spontaneous circulation were preprocessed and artifact was rejected. Burst segments were extracted for source localization analysis from epochs with burst suppression. Four bursts for each patients were manually selected. The source of the bursts were obtained using the Champagne algorithm and mapped on the Desikan-Killiany atlas. The source for each burst was defined as any region of interest (ROI) with power &gt; = 75th percentile relative to all ROIs. The power of the bursts at each source was correlated with the burden of brain injury measured using apparent diffusion coefficient (ADC) per ROI. RESULTS/ANTICIPATED RESULTS: 48 (56%) patients had burst suppression. 5 (10.4%) of patients with burst suppression were independent at the time of hospital discharge. Preliminary analyses was performed on 6 patients (24 bursts in total). ROI’s determined to be sources in a majority of the burst (&gt;=13) were bilateral superior frontal, rostral middle frontal, parstriangularis precentral, superior parietal, inferior parietal, right post central, superior temporal, lateral occipital, and left middle temporal ROI. A lower mean ADC intensity was associated with a higher EEG power in the bilateral superior frontal (r = -0.80, p &lt; 0.0001; r = -0.677, p &lt; 0.001, respectively), left superior parietal (r = -0.53, p = 0.009), left middle temporal (r = -0.43, p = 0.042) ROI. DISCUSSION/SIGNIFICANCE: The source of bursts in patients post-cardiac arrest experiencing burst suppression is not well defined. This study will improve our understanding of how burst suppression is a measure of cortical injury, how it may relate to the burden of injury found on ADC imaging, and patient outcomes.

297 Impact of Navigated Intraoperative Ultrasound on Brain Shift and Gross Tumor Resection

INTRODUCTION: Intraoperative imaging and neuronavigation aid in achieving maximum tumor resection. However, tissue removal during surgery can cause brain shift, which alters the relative anatomy and “de-calibrates” the standard approaches. While intraoperative MRI (iMRI) is the gold-standard to correct for brain shift, it is expensive, time-consuming, and logistically difficult. As an alternative, we investigated an approach which combines intraoperative ultrasound (ioUS) technology with preoperative imaging to allow for real-time compensation of brain shift and assessment of extent of resection (EOR). METHODS: We prospectively enrolled patients undergoing neurosurgical tumor resection at Massachusetts General Hospital beginning April 2023. Patients were registered with Brainlab Ultrasound Navigation prior to surgery. ioUS sweeps were acquired before cortex incision, mid-resection, and post-resection with bkActiv and fused to preoperative MRIs. Four points around the tumor were longitudinally tracked to assess brain shift. Data included sweep duration, image processing speed, extent of brain shift as determined by intraoperative markers, and EOR assessed from the ioUS compared with postoperative MRIs. RESULTS: Seven patients were enrolled (average age 62 ± 15, 75% male) with frontal (n = 5), temporal (n = 1), and occipital (n = 1) gliomas (n = 4) and metastases (n = 3). All patients exhibiting total resection as determined by ioUS also demonstrated total resection on post-operative MRI, evaluated independently by a neuroradiologist. The average time of scan and image processing (n = 19) was 5.7 ± 1.9 and 27.8 ± 6.5 seconds respectively. CONCLUSIONS: Navigated ioUS offers accurate and efficient assessment of EOR during surgery for tumor resections. Furthermore, when brain shift is detected, navigated ioUS can allow for compensation and continued utilization of navigation via the acquisition of a brand new, navigable, intraoperatively acquired dataset.

Role of hemolysis on pulmonary arterial compliance and right ventricular systolic function after cardiopulmonary bypass

BackgroundCardiopulmonary bypass (CPB) is associated with intravascular hemolysis which depletes endogenous nitric oxide (NO). The impact of hemolysis on pulmonary arterial compliance (PAC) and right ventricular systolic function has not been explored yet. We hypothesized that decreased NO availability is associated with worse PAC and right ventricular systolic function after CPB. MethodsThis is a secondary analysis of an observational cohort study in patients undergoing cardiac surgery with CPB at Massachusetts General Hospital, USA (2014–2015). We assessed PAC (stroke volume/pulmonary artery pulse pressure ratio), and right ventricular function index (RVFI) (systolic pulmonary arterial pressure/cardiac output), as well as NO consumption at 15 min, 4 h and 12 h after CPB. Patients were stratified by CPB duration. Further, we assessed the association between changes in NO consumption with PAC and RVFI between 15min and 4 h after CPB. ResultsPAC was lowest at 15min after CPB and improved over time (n = 50). RVFI was highest -worse right ventricular function- at CPB end and gradually decreased. Changes in hemolysis, PAC and RVFI differed over time by CPB duration. PAC inversely correlated with total pulmonary resistance (TPR). TPR and PAC positively and negatively correlated with RVFI, respectively. NO consumption between 15min and 4 h after CPB correlated with changes in PAC (−0.28 ml/mmHg, 95%CI −0.49 to −0.01, p = 0.012) and RVFI (0.14 mmHg*L−1*min, 95%CI 0.10 to 0.18, p < 0.001) after multivariable adjustments. ConclusionPAC and RVFI are worse at CPB end and improve over time. Depletion of endogenous NO may contribute to explain changes in PAC and RVFI after CPB.

Abstract 3888: TOP1 mutations mediate cross resistance to ADCs in metastatic breast cancer

Abstract Background: Antibody-drug conjugates (ADCs) have improved survival for patients with metastatic breast cancer (MBC). In patients with HER2 negative MBC, two ADCs have FDA approval: sacituzumab govitecan (SG) and trastuzumab deruxtecan (T-DXd), both with topoisomerase-I (topo-I) inhibitor payloads. Given the many other ADCs in development, there is great interest in using ADC after ADC to maximize treatment benefit for patients. However, there is limited understanding regarding resistance mechanisms to ADCs and impact on ADC sequencing. We conducted a translational study to address this, and here we report the incidence of TOP1 mutations and clinical impact on ADC sequencing. Methods: All patients with MBC treated with ADCs at a large academic medical institution (Massachusetts General Hospital) who had comprehensive plasma-based genotyping (500 gene GuardantOMNI panel) were included. Since both SG and T-DXd have topo-I inhibitor-based payloads, we particularly focused on TOP1 mutations, variant allele frequency (VAF), and germline/somatic characterization. Incidence of TOP1 mutations in the ADC cohort was compared to The Cancer Genome Atlas (TCGA). Clinical “cross-resistance” was defined as progressive disease (PD) as best response to second ADC (ADC2) or treatment time on ADC2 of less than 60 days. Results: Based on comprehensive plasma-based genotyping we identified 4 distinct TOP1 mutations: S57C, R364H, W401C, G359E, at a frequency of 6.0% (4/67) at the time of disease progression on ADC compared to a frequency of 0.5% described in primary breast cancer in TCGA. Two of the amino acids found to be mutated are known to form direct interactions with the DNA backbone (G359) or the topoisomerase inhibitor itself (R364). For clinical resistance, one patient was briefly on ADC2 but stopped after 1 dose for toxicity; among the other 3 patients, two had cross-resistance to ADC after ADC, with both ADCs containing topo-I inhibitor payloads. Median duration on first ADC was 455 days compared to a median of 52 days for ADC2. Finally, one patient treated sequentially with 3 ADCs (all with topo-I inhibitor payloads) was found to have rising TOP1 VAF with progressive ADC treatments. Conclusion: This is the first report describing emergence of TOP1 mutations under selective pressure from ADCs and the impact on mediating cross-resistance to ADC after ADC with topo-I inhibitor payloads. Novel ADCs with alternative payloads may potentially be more effective when used sequentially after an ADC with a topo-I inhibitor. Further biomarker research is needed to optimize ADC sequencing for patients with TOP1 mutant MBC. Citation Format: Rachel Occhiogrosso Abelman, Haley Barnes, Arielle J. Medford, Annika Putur, Bogang Wu, Caroline Weipert, Geoffrey Fell, Laura M. Spring, Seth A. Wander, Beverly Moy, Andreas Varkaris, Dejan Juric, Leif Ellisen, Ryan Corcoran, Aditya Bardia. TOP1 mutations mediate cross resistance to ADCs in metastatic breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3888.