Here we demonstrate a novel application of 'surface enhanced resonance Raman scattering nanoparticles' (SERRS NPs) for imaging breast cancer lung metastases with much higher precision than currently ...feasible. A breast cancer lung metastasis mouse model was established by intravenous injection of LM2 cells. These mice were intravenously administered SERRS NPs conjugated with ALT-836, an anti-tissue factor (TF) monoclonal antibody, and subjected to Raman imaging to visualize the expression of TF both
in vivo
and
ex vivo
. Raman imaging indicated marked uptake of αTF-SERRS-NPs by the lung metastases compared to isotype and blocking controls. Conversely, little uptake of αTF-SERRS-NPs was observed in the lungs of healthy mice. Successful detection and delineation of pulmonary micrometastatic lesions as small as 200 μm, corroborated by histology, immunohistochemistry, and bioluminescence imaging confirmed the suitability of both TF as a target and αTF-SERRS-NPs as an effective contrast agent for imaging breast cancer lung metastases. Further advancements of this technique in the form of Raman endoscopes coupled with ultrabright SERRS NPs developed in this work could lead to minimally invasive detection and resection of lung metastases.
Ultra-sensitive tissue-factor targeted SERRS-nanostars for Raman-based detection and delineation of microscopic pulmonary metastases.
Abstract only
e12536
Background: Ovarian ablation is increasingly used to complement endocrine therapy in select premenopausal women with hormone-receptor positive (HR+) breast cancer (BC). It can be ...achieved by either medical ovarian suppression (OS) or therapeutic bilateral salpingo-oophorectomy (BSO). We sought to investigate trends of therapeutic BSO in premenopausal patients at our institution. Methods: Premenopausal women with HR+ primary BC diagnosed from 2010-2014 were identified in our prospectively maintained BC database. Patients with confirmed BRCA1/2 mutations were excluded. Distribution of patient and disease characteristics between treatment groups were assessed using univariate logistic regression analyses. Surgical details and complications were extracted from our surgical database. Results: We identified 2,854 eligible patients; 2,113 (74%) received endocrine therapy without ovarian ablation, 246 (9%) received endocrine therapy plus medical OS, 180 (6%) underwent additional BSO, and 315 (11%) did not receive endocrine therapy at the time of analysis. Independent predictors for undergoing ovarian ablation were younger age (OR 0.98; 95%CI, 0.96-0.99; p < 0.001), higher grade (grade 3 vs 1: OR 3.17; 95%CI, 1.70-5.90; grade 2 vs 1: OR 3.13; 95%CI, 1.64-5.95; p < 0.001), lymph node involvement (OR 1.46; 95%CI, 1.19-1.80; p < 0.001), and higher AJCC stage as well as de novo metastatic BC (II vs I: OR = 1.35; 95%CI, 1.03-1.76; III vs I: OR 2.57; 95%CI, 1.86-3.55; IV vs I: OR 19.69; 95%CI, 12.76-30.39; p < 0.001). Among patients who underwent ovarian ablation, patients of younger age (1.04; 95%CI, 1.01-1.07; p = 0.009) and with metastatic BC (stage IV vs I: OR 0.36; 95%CI, 0.20-0.68; p = 0.007) were less likely to undergo BSO than OS. In 180 patients undergoing BSO, five adverse events were noted: two grade 1, two grade 2, and one grade 3 complication. Conclusions: Premenopausal women with HR+ BC with high-risk features or metastatic disease were more likely to undergo ovarian ablation at our institution. Surgical ovarian ablation is a safe alternative, with low complication rates. Understanding patient preferences, side effects, and quality of life implications will help guide personalized treatment decisions.
Visualizing the presence and distribution of multiple specific molecular markers within a tumor can reveal the composition of its microenvironment, inform diagnosis, stratify patients, and guide ...treatment. Raman imaging with multiple molecularly-targeted surface enhanced Raman scattering (SERS) nanoprobes could help investigate emerging cancer treatments preclinically or enable personalized treatment assessment. Here, we report a comprehensive strategy for multiplexed imaging using SERS nanoprobes and machine learning (ML) to monitor the early effects of immune checkpoint blockade (ICB) in tumor-bearing mice. We used antibody-functionalized SERS nanoprobes to visualize 7 + 1 immunotherapy-related targets simultaneously. The multiplexed images were spectrally resolved and then spatially segmented into superpixels based on the unmixed signals. The superpixels were used to train ML models, leading to the successful classification of mice into treated and untreated groups, and identifying tumor regions with variable responses to treatment. This method may help predict treatment efficacy in tumors and identify areas of tumor variability and therapy resistance.
Multiplexed imaging of 8 molecular targets with SERS nanoprobes in mice reveals spatially heterogeneous tumor responses to immunotherapy. Multichannel image segmentation enables classification of the tumor regions into responders and naïve.
Abstract
Preclinical and clinical studies have shown that intratumoral oncolytic viruses (OVs) can potentiate host anti-tumor immunity and overcome resistance to immune checkpoint blockade, although ...clinical responses to OVs have been modest to date. While T cell infiltration of tumors is frequently cited as a measure of OV immunogenicity, this measure is non-specific as OVs elicit a strong virus-directed T cell response, and it remains unknown what proportion of T cells expanded by OV therapy are virus-specific vs. tumor-specific or how these T cells distribute across virus-treated and distant tumors. We employed oncolytic Newcastle disease virus (NDV) in a bilateral flank melanoma mouse model to identify and phenotypically characterize anti-viral and anti-tumor T cells using single cell (sc) RNA and T cell receptor (TCR) sequencing. Intratumoral NDV therapy to a single flank tumor resulted in increased infiltration of CD4+ and CD8+ T cells in the injected (enestic) and distant (non-enestic) tumors and increased the breadth of the TCR repertoire at both sites with preferential expansion of several dominant clonotypes. There was substantial expansion of the proportion of T cell clonotypes shared between enestic and nonenestic tumors as well as the spleen, indicative of inter-tumor TCR repertoire normalization. In both treated and distant tumors, we observed a significant increase in the frequency of convergent TCR clonotypes, i.e. TCRs encoded by different nucleotide sequences that converge on the same amino acid sequence, implying that the presence of these TCRs in tumors is non-random. Using scRNA and paired TCR sequencing, we demonstrate that NDV therapy leads to expansion of unique clusters of terminally differentiated and activated CD4+ and CD8+ T cells associated with distinct TCR-based clonotypes. Notably, the predominant phenotypic clusters were distinct between the enestic and non-enestic tumors. Enestic tumors were dominated by CD8+ T cells exhibiting a signature associated with terminal dysfunction (PDCD1, LAG3, TOX), while the predominant expanded CD8+ T cells in non-enestic tumors exhibited an activation signature associated with high expression of cytolytic markers. While phenotypic states were conserved for the dominant TCR clones shared across the enestic and non-enestic tumors, TCRs unique to the non-enestic tumor were predominantly associated with an activated T cell state. Taken together, these studies highlight that T cells expanded by OV therapy exhibit unique functional states and TCRs in treated and distant tumors and imply that virus- and tumor-specific T cells may be identified by distinct TCR repertoires and phenotypes. Understanding the balance between virus- and tumor-directed T cells elicited by OV therapy will be key to engineering OVs and designing combination strategies that drive stronger tumor-directed T cell response.
Citation Format: Bharat Burman, Nicholas Ceglia, Daniel Hirschhorn, Sadna Budhu, Levi Mangarin, Anton Oseledchyk, Yonina Bykov, Andrew McPherson, Sohrab Shah, Jedd Wolchok, Taha Merghoub, Dmitriy Zamarin. Defining the balance of anti-viral and anti-tumor T cell responses to oncolytic virus therapy using single cell approaches abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5217.
Ovarian suppression is recommended to complement endocrine therapy in premenopausal women with breast cancer and high-risk features. It can be achieved by either medical ovarian suppression or ...therapeutic bilateral salpingo-oophorectomy. Our objective was to evaluate characteristics of patients with stage I-III hormone receptor positive primary breast cancer who underwent bilateral salpingo-oophorectomy at our institution.
Premenopausal women with stage I-III hormone receptor positive primary breast cancer diagnosed between January 2010 and December 2014 were identified from a database. Patients with confirmed
mutations were excluded. Distribution of characteristics between treatment groups was assessed using χ
test and univariate logistic regression. A multivariate model was based on factors significant on univariate analysis.
Of 2740 women identified, 2018 (74%) received endocrine treatment without ovarian ablation, 516 (19%) received endocrine treatment plus ovarian ablation, and 206 (7.5%) did not receive endocrine treatment. Among patients undergoing ovarian ablation 282/516 (55%) received medical ovarian suppression, while 234 (45%) underwent bilateral salpingo-oophorectomy. By univariate logistic analyses, predictors for ovarian ablation were younger age (OR 0.97), histology (other vs ductal: OR 0.23), lymph node involvement (OR 1.89), higher International Federation of Gynecology and Obstetrics (FIGO) stage (stage II vs I: OR 1.48; stage III vs I: OR 2.86), higher grade (grade 3 vs 1: OR 3.41; grade 2 vs 1: OR 2.99), chemotherapy (OR 1.52), and more recent year of diagnosis (2014 vs 2010; OR 1.713). Only year of diagnosis, stage, and human epidermal growth factor receptor 2 (HER-2) treatment remained significant in the multivariate model. Within the cohort undergoing ovarian ablation, older age (OR 1.05) was associated with therapeutic bilateral salpingo-oophorectomy. Of 234 undergoing bilateral salpingo-oophorectomy, 12 (5%) mild to moderate adverse surgical events were recorded.
Bilateral salpingo-oophorectomy is used frequently as an endocrine ablation strategy. Older age was associated with bilateral salpingo-oophorectomy. Perioperative morbidity was acceptable. Evaluation of long-term effects and quality of life associated with endocrine ablation will help guide patient/provider decision-making.
Adjuvant chemotherapy is recommended for patients with resected high‐risk adult granulosa cell tumors (GCT), although strong data to support this are lacking. The objective of this study was to ...assess the outcomes of GCT patients, with the specific focus on patients that received adjuvant chemotherapy with curative intent (stage I‐III), reported in a large national cancer registry. Data from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2013 were used for analysis. Patient and disease characteristics were extracted and analyzed for association with administration of chemotherapy. Impact on disease‐specific survival (DSS) was analyzed using log‐rank test. A total of 739 patients with surgically treated adult GCT were identified. Median age was 51 years. 570 (77%) patients were stage I, 87 (12%) were stage II, and 82 (11%) were stage III. Adjuvant chemotherapy was administered to 176 (24%) patients. Young age, higher stage, and hysterectomy were associated with chemotherapy administration. Higher disease stage was associated with decreased five‐year DSS (IA/B 98.5%, IC 95.1%, II 86.1%, III 83.5%, P < 0.01). Notably, administration of adjuvant chemotherapy was not associated with improved five‐year DSS (P = 0.45) regardless of disease stage (stage IA/B: 96% with chemotherapy vs. 99% without chemotherapy; P = 0.64), (stage IC: 97% with chemotherapy vs. 94% without chemotherapy; P = 0.49), (stage II: 89% with chemotherapy vs. 83% without chemotherapy; P = 0.56), (stage III: 73% with chemotherapy vs. 93% without chemotherapy; P = 0.18). In this analysis, chemotherapy was not found to be associated with improved DSS of patients with operable disease regardless of stage, questioning the role for adjuvant chemotherapy in GCT.
Data supporting the rationale for adjuvant chemotherapy in resectable granulosa cell tumors of the ovary are very limited. Here, we used the SEER database to assess the outcomes of patients with operable (stage I–III) granulosa cell tumors of the ovary in the context of adjuvant chemotherapy. Our findings show that adjuvant chemotherapy was not associated with improved overall or disease‐specific survival in patients with operable granulosa cell tumors.
Extensive surgical efforts to achieve an optimal debulking (no residual tumor) in primary surgery of ovarian cancer are today's criterion standard in gyneco-oncologic surgery. However, it is ...controversial whether extensive surgery, including resections of metastases in the upper abdomen and bowel resections, is justifiable in patients with not completely operable lesions.
All patients who had undergone surgery for ovarian cancer in the years 2002 to 2013 at our institution were viewed (n = 472). We retrospectively identified 278 operations for primary ovarian cancer. Ninety-six (35%) of the 278 patients showed postoperative tumor residuals and were included in this study.
Fifty-five (57%) of 96 patients underwent bowel resection, showing significantly higher complication rates (64% vs 39% minor complications, P = 0.017; 31% vs 9.8% severe complications, P = 0.013) compared with patients without bowel resections as well as no improvement in progression-free or overall survival (median overall survival, 19.5 vs 32.9; P = 0.382). Multiple anastomoses (≥2) were associated with higher rates for anastomotic leakage (16.7% vs 2.6%, P = 0.02) and a higher mortality (16.7% vs 0%, P = 0.04) compared with patients with only 1 anastomosis. Extensive surgery of the upper abdomen was not associated with a significant increase in complication rates.
Because of the increased morbidity of bowel resections without any evidence for improvement of survival, we suggest to restrain from further resection of intestines if an optimal debulking seems not feasible after removal of the major tumor bulk.
The purpose of this analysis was to evaluate the impact of preoperative magnetic resonance imaging (MRI) on management in patients with locoregional recurrent breast cancer.
Forty-three patients who ...underwent treatment for locoregional relapse of breast cancer from 2008 through 2012 were analyzed. All patients underwent both conventional surveillance by mammography, ultrasound, and clinical examination and subsequent bilateral breast MRI.
Preoperative MRI detected additional tumor foci in 15 of 43 patients (34.9%). In two cases (4.7%), the diagnosis of occult sites had no influence on the subsequent treatment. Two patients (4.7%) had an unfavorable change of surgical management with unnecessary additional resection of benign foci. Eleven patients benefited from the MRI scan detecting malignant occult lesions (25.6%) resulting in either additional surgical resection or radiotherapy. Patient and tumor characteristics in primary disease did not differ significantly between patients with a favorable impact on surgical management and patients who experienced either no benefit or even disadvantage from MRI scan.
Preoperative breast MRI has a strong impact on the management of locoregional recurrent breast cancer. This study demonstrates that breast MRI is a powerful supplement to conventional diagnostic work-up, both during follow-up or preoperative treatment planning in recurrent disease.
PDF
