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Contrast-enhanced mammography (CEM) is an emerging functional breast imaging technique that entails the acquisition of dual-energy digital mammographic images after IV administration of iodine-based contrast material. CEM-guided biopsy technology was introduced in 2019 and approved by the FDA in 2020. This technology's availability enables direct sampling of suspicious enhancement seen only on, or predominantly on, recombined CEM images and addresses a major obstacle to the clinical implementation of CEM technology. Scarce literature has described clinical indications and procedural techniques of CEM-guided biopsy. This article describes our initial experience in performing challenging CEM-guided biopsies and proposes a step-by-step procedural algorithm designed to proactively address anticipated technical difficulties and thereby increase the likelihood of achieving successful targeting.

Breast angiosarcoma is a rare malignancy of endothelial origin that can be categorized as primary angiosarcoma (PAS) or secondary angiosarcoma (SAS) based on etiology. Primary angiosarcoma typically affects younger women with no known risk factors, whereas SAS of the breast typically develops in older women who have undergone breast cancer treatment. There are two types of SAS, one that develops in the setting of chronic lymphedema and one that develops as a radiation-associated neoplasm after breast-conserving therapy (BCT). Clinically, PAS often presents as a palpable mass that may be rapidly growing, whereas SAS presents with skin changes such as erythematous plaques or nodules or with areas of skin discoloration. Mammographically, the appearance of PAS can be nonspecific and may be obscured by the dense tissue that is characteristic of the young patient population it typically affects. Cases of mammographically occult PAS have been visible at US and MRI. Mammography and US have been found to be less sensitive than MRI for the diagnosis of secondary radiation-associated angiosarcoma. Angiosarcomas, both PAS and SAS, are graded, depending on degree of differentiation, as low, intermediate, or high grade. Endothelial markers such as ERG and CD31 immunohistochemical stains are used to support the diagnosis of angiosarcomas. In this article, we review the clinical presentation, imaging findings, associated histopathology, and treatment of primary and secondary breast angiosarcoma.

This study aimed to investigate mid-treatment breast tumor ultrasound characteristics that may predict eventual pathologic complete response (pCR) in triple-negative breast cancer; specifically, we examined associations between pCR and two parameters: tumor response pattern and tumor appearance. Ultrasound was performed at mid-treatment, defined as the completion of four cycles of anthracycline-based chemotherapy and before receiving taxane-based chemotherapy. Consensus imaging review was performed while blinded to pathology results (i.e., pCR/non-pCR) from surgery. Tumor response pattern was described as "complete," "concentric," "fragmented," "stable" or "progression." Tumor appearance was designated as "mass," "architectural distortion," "flat tumor bed" or "clip only." Univariate and multivariate regression analyses of 144 participants showed significant associations between mid-treatment response pattern and pCR (p = 0.0348 and p = 0.0173, respectively), with complete and concentric response patterns more likely to achieve pCR than other patterns. Univariate and multivariate regression analyses further showed significant associations between mid-treatment tumor appearance and pCR (p0.0001 for both), with persistent appearance of mass less likely than other appearances to achieve pCR. To conclude, our study demonstrated strong associations between pCR and both tumor response pattern and tumor appearance, thereby suggesting that these parameters have potential as qualitative imaging biomarkers of pCR in triple-negative breast cancer.

Patient-derived xenograft (PDX) models of breast cancer are an effective discovery platform and tool for preclinical pharmacologic testing and biomarker identification. We established orthotopic PDX models of triple negative breast cancer (TNBC) from the primary breast tumors of patients prior to and following neoadjuvant chemotherapy (NACT) while they were enrolled in the ARTEMIS trial (NCT02276443). Serial biopsies were obtained from patients prior to treatment (pre-NACT), from poorly responsive disease after four cycles of Adriamycin and cyclophosphamide (AC, mid-NACT), and in cases of AC-resistance, after a 3-month course of different experimental therapies and/or additional chemotherapy (post-NACT). Our study cohort includes a total of 269 fine needle aspirates (FNAs) from 217 women, generating a total of 62 PDX models (overall success-rate = 23%). Success of PDX engraftment was generally higher from those cancers that proved to be treatment-resistant, whether poorly responsive to AC as determined by ultrasound measurements mid-NACT (p = 0.063), RCB II/III status after NACT (p = 0.046), or metastatic relapse within 2 years of surgery (p = 0.008). TNBC molecular subtype determined from gene expression microarrays of pre-NACT tumors revealed no significant association with PDX engraftment rate (p = 0.877). Finally, we developed a statistical model predictive of PDX engraftment using percent Ki67 positive cells in the patient’s diagnostic biopsy, positive lymph node status at diagnosis, and low volumetric reduction of the patient’s tumor following AC treatment. This novel bank of 62 PDX models of TNBC provides a valuable resource for biomarker discovery and preclinical therapeutic trials aimed at improving neoadjuvant response rates for patients with TNBC.

Widely-used Streptomyces-derived antibacterial aminoglycosides have encountered challenges because of antibiotic resistance and toxicity. Today, they are largely relegated to medicinal topical applications. However, chemical modification to amphiphilic aminoglycosides can revive their efficacy against bacterial pathogens and expand their targets to other pathogenic microbes and disorders associated with hyperactive connexin hemichannels. For example, amphiphilic versions of neomycin and neamine are not subject to resistance and have expanded antibacterial spectra, and amphiphilic kanamycins are effective antifungals and have promising therapeutic uses as connexin hemichannel inhibitors. With further research and discoveries aimed at improved formulations and delivery, amphiphilic aminoglycosides may achieve new horizons in pharmacopeia and agriculture for Streptomyces aminoglycosides beyond just serving as topical antibacterials.

Neoadjuvant systemic therapy (NST) for triple-negative breast cancer and HER2-positive breast cancer yields a pathological complete response in approximately 60% of patients. A pathological complete response to NST predicts an excellent prognosis and can be accurately determined by percutaneous image-guided vacuum-assisted core biopsy (VACB). We evaluated radiotherapy alone, without breast surgery, in patients with early-stage triple-negative breast cancer or HER2-positive breast cancer treated with NST who had an image-guided VACB-determined pathological complete response.This multicentre, single-arm, phase 2 trial was done in seven centres in the USA. Women aged 40 years or older who were not pregnant with unicentric cT1-2N0-1M0 triple-negative breast cancer or HER2-positive breast cancer and a residual breast lesion less than 2 cm on imaging after clinically standard NST were eligible for inclusion. Patients had one biopsy (minimum of 12 cores) obtained by 9G image-guided VACB of the tumour bed. If no invasive or in-situ disease was identified, breast surgery was omitted, and patients underwent standard whole-breast radiotherapy (40 Gy in 15 fractions or 50 Gy in 25 fractions) plus a boost (14 Gy in seven fractions). The primary outcome was the biopsy-confirmed ipsilateral breast tumour recurrence rate determined using the Kaplan-Meier method assessed in the per-protocol population. Safety was assessed in all patients who received VACB. This study has completed accrual and is registered with ClinicalTrials.gov, NCT02945579.Between March 6, 2017, and Nov 9, 2021, 58 patients consented to participate; however, four (7%) did not meet final inclusion criteria and four (7%) withdrew consent. 50 patients were enrolled and underwent VACB following NST. The median age of the enrolled patients was 62 years (IQR 55-77); 21 (42%) patients had triple-negative breast cancer and 29 (58%) had HER2-positive breast cancer. VACB identified a pathological complete response in 31 patients (62% [95% CI 47·2-75·4). At a median follow-up of 26·4 months (IQR 15·2-39·6), no ipsilateral breast tumour recurrences occurred in these 31 patients. No serious biopsy-related adverse events or treatment-related deaths occurred.Eliminating breast surgery in highly selected patients with an image-guided VACB-determined pathological complete response following NST is feasible with promising early results; however, additional prospective clinical trials evaluating this approach are needed.US National Cancer Institute (National Institutes of Health).

BACKGROUND Heterogeneity exists in the response of triple-negative breast cancer (TNBC) to standard anthracycline (AC)/taxane-based neoadjuvant systemic therapy (NAST), with 40% to 50% of patients having a pathologic complete response (pCR) to therapy. Early assessment of the imaging response during NAST may identify a subset of TNBCs that are likely to have a pCR upon completion of treatment. The authors aimed to evaluate the performance of early ultrasound (US) after 2 cycles of neoadjuvant NAST in identifying excellent responders to NAST among patients with TNBC. METHODS Two hundred fifteen patients with TNBC were enrolled in the ongoing ARTEMIS (A Robust TNBC Evaluation Framework to Improve Survival) clinical trial. The patients were divided into a discovery cohort (n = 107) and a validation cohort (n = 108). A receiver operating characteristic analysis with 95% confidence intervals (CIs) and a multivariate logistic regression analysis were performed to model the probability of a pCR on the basis of the tumor volume reduction (TVR) percentage by US from the baseline to after 2 cycles of AC. RESULTS Overall, 39.3% of the patients (42 of 107) achieved a pCR. A positive predictive value (PPV) analysis identified a cutoff point of 80% TVR after 2 cycles; the pCR rate was 77% (17 of 22) in patients with a TVR ≥ 80%, and the area under the curve (AUC) was 0.84 (95% CI, 0.77-0.92; P < .0001). In the validation cohort, the pCR rate was 44%. The PPV for pCR with a TVR ≥ 80% after 2 cycles was 76% (95% CI, 55%-91%), and the AUC was 0.79 (95% CI, 0.70-0.87; P < .0001). CONCLUSIONS The TVR percentage by US evaluation after 2 cycles of NAST may be a cost-effective early imaging biomarker for a pCR to AC/taxane-based NAST.

Introduction: BI-RADS category 4 is associated with a wide variability in probability of malignancy, ranging from 2 to 95% while biopsy-derived positive predictive value (PPV3) for this category’s lesions remains low at 21.1% in the US. A major fallout of these facts is that we have way very high false positive rate leading to too many unnecessary biopsies and their associated costs and emotional burden. We improved our in-house intelligent-augmented Breast cancer RISK calculator (iBRISK), an integrated deep learning (DL) based decision support app and assessed its performance in a multicenter IRB-approved study. Methods: We improved iBRISK by retraining the DL model with an expanded dataset of 9,700 patient records of clinical risk-factors and mammographic descriptors from Houston Methodist Hospital (HMH) and validated using another 1,078 patient records. These patients were all seen between March 2006 and December 2016. We assessed the model using blinded, independent retrospective BI-RADS 4 patients who had biopsies subsequently after mammography and seen January 2015 - June 2019 at three major healthcare institutions in Texas, USA: MD Anderson Cancer Center, the University of Texas Health Sciences Center at San Antonio, and HMH. We dichotomized and trichotomized the data to evaluate precision of risk stratification and probability of malignancy (POM) estimation translated into biopsy decision augmentation. The iBRISK score as a continuous predictor of malignancy and possible cost savings was also analyzed. Results: The multicenter validation dataset had 4,209 women, median age (interquartile) was 56 (45, 65) years. The use of iBRISK score as a continuous predictor of malignancy yielded an AUC of 0.97. Among “low” and “moderate” POM patients, only two out of 1,228 patients (0.16%) and 118 out of 1788 (6.6%) were malignant respectively. This translates to an even better precision when compared to newly introduced BI-RADS 4 subcategories 4A and 4B, with associated PPV3s of 7.6% and 22%, respectively. The “high” POM group had a malignancy rate of 85.9% (1,025/1,193). Estimated potential cost savings in the US was over $260 million. Conclusion: The iBRISK app demonstrated high sensitivity in malignancy prediction and can potentially be used to safely obviate biopsies in up to 50% of patients in low/moderate POM-groups. This would result in significant healthcare quality improvement, cost savings, and help reduce patient anxiety. Citation Format: Chika F. Ezeana, Tiancheng He, Tejal A. Patel, Virginia Kaklamani, Maryam Elmi, Erica Ibarra, Pamela M. Otto, Kenneth A. Kist, Heather Speck, Lin Wang, Joe Ensor, Ya-Chen T. Shih, Bumyang Kim, I-Wen Pan, David Spak, Wei T. Yang, Jenny C. Chang, Stephen T. Wong. A multicenter study validated an integrated deep learning model for precision malignancy risk assessment and reducing unnecessary biopsies in BI-RADS 4 cases. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5698.

This study examined trait mindfulness, spiritual well-being, and distress tolerance as moderators of the effect of a brief mindfulness intervention on anxiety reported during stereotactic breast biopsy (SBB). This is a secondary analysis of an RCT examining guided meditation (GM; n = 30), focused breathing (FB; n = 30), or standard care (SC; n = 16) on anxiety for women undergoing SBB. Women in GM and FB were guided through their respective interventions for 10 min before and during biopsy. Anxiety (0–10 visual analogue scale), trait mindfulness (FFMQ), spiritual well-being (FACIT-SP), and discomfort intolerance (DI) were assessed at baseline, and anxiety was assessed every 4 min during SBB. Multilevel modeling examined moderator-by-group-by-time interactions. Significant 3-way interactions were decomposed using a median split. FFMQ observing, FFMQ describing, FACIT-SP meaning/peace, and DI moderated the group-by-time effects on anxiety during biopsy (p’s

Objective The A6702 multisite trial confirmed that apparent diffusion coefficient (ADC) measures can improve breast MRI accuracy and reduce unnecessary biopsies, but also found that technical issues rendered many lesions non-evaluable on diffusion-weighted imaging (DWI). This secondary analysis investigated factors affecting lesion evaluability and impact on diagnostic performance. Methods The A6702 protocol was IRB-approved at 10 institutions; participants provided informed consent. In total, 103 women with 142 MRI-detected breast lesions (BI-RADS assessment category 3, 4, or 5) completed the study. DWI was acquired at 1.5T and 3T using a four b-value, echo-planar imaging sequence. Scans were reviewed for multiple quality factors (artifacts, signal-to-noise, misregistration, and fat suppression); lesions were considered non-evaluable if there was low confidence in ADC measurement. Associations of lesion evaluability with imaging and lesion characteristics were determined. Areas under the receiver operating characteristic curves (AUCs) were compared using bootstrapping. Results Thirty percent (42/142) of lesions were non-evaluable on DWI; 23% (32/142) with image quality issues, 7% (10/142) with conspicuity and/or localization issues. Misregistration was the only factor associated with non-evaluability (P = 0.001). Smaller (≤10 mm) lesions were more commonly non-evaluable than larger lesions (p Conclusion Image quality remains a technical challenge in breast DWI, particularly for smaller lesions. Protocol optimization and advanced acquisition and post-processing techniques would help to improve clinical utility.

Heme oxygenase-1 (HO-1) expression promotes osteogenesis, but the mechanisms remain unclear and therapeutic strategies using it to target bone disorders such as osteoporosis have not progressed. Mesobiliverdin IXα is a naturally occurring bilin analog of HO-1 catalytic product biliverdin IXα. Inclusion of mesobiliverdin IXα in the feed diet of ovariectomized osteoporotic mice was observed to increase femur bone volume, trabecular thickness and osteogenesis serum markers osteoprotegrin and osteocalcin and to decrease bone resorption serum markers cross-linked N-teleopeptide and tartrate-resistant acid phosphatase 5b. Moreover, in vitro exposure of human bone marrow mesenchymal stem cells to mesobiliverdin IXα enhanced osteogenic differentiation efficiency by two-fold over non-exposed controls. Our results imply that mesobiliverdin IXα promotes osteogenesis in ways that reflect the potential therapeutic effects of induced HO-1 expression in alleviating osteoporosis.

Pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC) is a strong predictor of patient survival. Edema in the peritumoral region (PTR) has been reported to be a negative prognostic factor in TNBC.To determine whether quantitative apparent diffusion coefficient (ADC) features from PTRs on reduced field-of-view (rFOV) diffusion-weighted imaging (DWI) predict the response to NAST in TNBC.Prospective.A total of 108 patients with biopsy-proven TNBC who underwent NAST and definitive surgery during 2015-2020.A 3.0 T/rFOV single-shot diffusion-weighted echo-planar imaging sequence (DWI).Three scans were acquired longitudinally (pretreatment, after two cycles of NAST, and after four cycles of NAST). For each scan, 11 ADC histogram features (minimum, maximum, mean, median, standard deviation, kurtosis, skewness and 10th, 25th, 75th, and 90th percentiles) were extracted from tumors and from PTRs of 5 mm, 10 mm, 15 mm, and 20 mm in thickness with inclusion and exclusion of fat-dominant pixels.ADC features were tested for prediction of pCR, both individually using Mann-Whitney U test and area under the receiver operating characteristic curve (AUC), and in combination in multivariable models with k-fold cross-validation. A P value 0.05 was considered statistically significant.Fifty-one patients (47%) had pCR. Maximum ADC from PTR, measured after two and four cycles of NAST, was significantly higher in pCR patients (2.8 ± 0.69 vs 3.5 ± 0.94 mmQuantitative ADC features from PTRs may serve as early predictors of the response to NAST in TNBC.1 TECHNICAL EFFICACY: Stage 4.

PURPOSE: To determine if tumor necrosis by pretreatment breast MRI and its quantitative imaging characteristics are associated with response to NAST in TNBC. METHODS: This retrospective study included 85 TNBC patients (mean age 51.8 ± 13 years) with MRI before NAST and definitive surgery during 2010–2018. Each MRI included T2-weighted, diffusion-weighted (DWI), and dynamic contrast-enhanced (DCE) imaging. For each index carcinoma, total tumor volume including necrosis (TTV), excluding necrosis (TV), and the necrosis-only volume (NV) were segmented on early-phase DCE subtractions and DWI images. NV and %NV were calculated. Percent enhancement on early and late phases of DCE and apparent diffusion coefficient were extracted from TTV, TV, and NV. Association between necrosis with pathological complete response (pCR) was assessed using odds ratio (OR). Multivariable analysis was used to evaluate the prognostic value of necrosis with T stage and nodal status at staging. Mann–Whitney U tests and area under the curve (AUC) were used to assess performance of imaging metrics for discriminating pCR vs non-pCR. RESULTS: Of 39 patients (46%) with necrosis, 17 had pCR and 22 did not. Necrosis was not associated with pCR (OR, 0.995; 95% confidence interval [CI] 0.4–2.3) and was not an independent prognostic factor when combined with T stage and nodal status at staging (P = 0.46). None of the imaging metrics differed significantly between pCR and non-pCR in patients with necrosis (AUC < 0.6 and P > 0.40). CONCLUSION: No significant association was found between necrosis by pretreatment MRI or the quantitative imaging characteristics of tumor necrosis and response to NAST in TNBC.

Establishing preclinical models of Alzheimer’s disease that predict clinical outcomes remains a critically important, yet to date not fully realized, goal. Models derived from human cells offer considerable advantages over non-human models, including the potential to reflect some of the inter-individual differences that are apparent in patients. Here we report an approach using induced pluripotent stem cell-derived cortical neurons from people with early symptomatic Alzheimer’s disease where we sought a match between individual disease characteristics in the cells with analogous characteristics in the people from whom they were derived. We show that the response to amyloid-β burden in life, as measured by cognitive decline and brain activity levels, varies between individuals and this vulnerability rating correlates with the individual cellular vulnerability to extrinsic amyloid-β in vitro as measured by synapse loss and function. Our findings indicate that patient-induced pluripotent stem cell-derived cortical neurons not only present key aspects of Alzheimer’s disease pathology but also reflect key aspects of the clinical phenotypes of the same patients. Cellular models that reflect an individual’s in-life clinical vulnerability thus represent a tractable method of Alzheimer’s disease modelling using clinical data in combination with cellular phenotypes.

Background: Connexins (Cxs) are proteins that help cells to communicate with the extracellular media and with the cytoplasm of neighboring cells. Despite their importance in several human physiological and pathological conditions, their pharmacology is very poor. In the last decade, some molecules derived from aminoglycosides have been developed as inhibitors of Cxs hemichannels. However, these studies have been performed in E. coli, which is a very simple model. Therefore, our main goal is to test whether these molecules have similar effects in mammalian cells. Methods: We transfected HeLa cells with the human Cx46tGFP and characterized the effect of a kanamycin-derived molecule (KI04) on Cx46 hemichannel activity by time-lapse recordings, changes in phosphorylation by Western blot, localization by epifluorescence, and possible binding sites by molecular dynamics (MD). Results: We observed that kanamycin and KI04 were the most potent inhibitors of Cx46 hemichannels among several aminoglycosides, presenting an IC50 close to 10 μM. The inhibitory effect was not associated with changes in Cx46 electrophoretic mobility or its intracellular localization. Interestingly, 5 mM DTT did not reverse KI04 inhibition, but the KI04 effect completely disappeared after washing out KI04 from the recording media. MD analysis revealed two putative binding sites of KI04 in the Cx46 hemichannel. Results: These results demonstrate that KI04 could be used as a Cx46 inhibitor and could help to develop future selective Cx46 inhibitors.

Sjögren’s syndrome is a chronic and insidious autoimmune disease characterized by lymphocyte infiltration of exocrine glands. Patients typically present with dry eye, dry mouth, and other systemic manifestations. Currently, the available molecules and drug-delivery systems for the treatment of Sjögren’s syndrome dry eye (SSDE) have limited efficacy since they are not specific to SSDE but to dry eye disease (DED) in general. The current treatment modalities are based on a trial-and-error approach using primarily topical agents. However, this approach gives time for the vicious cycle of DED to develop which eventually causes permanent damage to the lacrimal functional unit. Thus, there is a need for more individualized, specific, and effective treatment modalities for SSDE. The purpose of this article is to describe the current conventional SSDE treatment modalities and to expose new advances in ocular drug delivery for treating SSDE. A literature review of the pre-clinical and clinical studies published between 2016 and 2022 was conducted. Our current understanding of SSDE pathophysiology combined with advances in ocular drug delivery and novel therapeutics will allow the translation of innovative molecular therapeutics from the bench to the bedside.

We aimed to develop a predictive model based on pretreatment MRI radiomic features (MRIRF) and tumor-infiltrating lymphocyte (TIL) levels, an established prognostic marker, to improve the accuracy of predicting pathologic complete response (pCR) to neoadjuvant systemic therapy (NAST) in triple-negative breast cancer (TNBC) patients.This Institutional Review Board (IRB) approved retrospective study included a preliminary set of 80 women with biopsy-proven TNBC who underwent NAST, pretreatment dynamic contrast enhanced MRI, and biopsy-based pathologic assessment of TIL. A threshold of ≥ 20% was used to define high TIL. Patients were classified into pCR and non-pCR based on pathologic evaluation of post-NAST surgical specimens. pCR was defined as the absence of invasive carcinoma in the surgical specimen. Segmentation and MRIRF extraction were done using a Food and Drug Administration (FDA) approved software QuantX. The top five features were combined into a single MRIRF signature value.Of 145 extracted MRIRF, 38 were significantly correlated with pCR. Five nonredundant imaging features were identified: volume, uniformity, peak timepoint variance, homogeneity, and variance. The accuracy of the MRIRF model, P = .001, 72.7% positive predictive value (PPV), 72.0% negative predictive value (NPV), was similar to the TIL model (P = .038, 65.5% PPV, 72.6% NPV). When MRIRF and TIL models were combined, we observed improved prognostic accuracy (P .001, 90.9% PPV, 81.4% NPV). The models area under the receiver operating characteristic curve (AUC) was 0.632 (TIL), 0.712 (MRIRF) and 0.752 (TIL + MRIRF).A predictive model combining pretreatment MRI radiomic features with TIL level on pretreatment core biopsy improved accuracy in predicting pCR to NAST in TNBC patients.

During a landslide, the multi-phase nature of landslide debris defines its mobility. Eventually, frictional forces cause the slide energy to dissipate, and contact forces transmit the energy into nearby material. To analyze the dynamic characteristics of high-velocity long-runout landslides, we conducted flume model tests to empirically determine the mobility characteristics of flow-like landslides with various slide materials. Our conclusions are as follows: (1) Liquid-phase flow-like landslides are highly mobility and have long runout; solid-phase flow-like landslides are highly destructive because of their higher kinetic energy; and two-phase flow-like landslides are both highly mobility. (2) During a two-phase flow-like landslide, the mobility ability of the liquid-phase material is stronger than that of the solid-phase material; when the liquid slide volume fraction is sufficiently large, the liquid phase exerts a drag force on the solid phase. (3) Various liquids exert different drag effects on the solid; the solid-liquid velocity difference and the liquid viscosity determine the drag intensity and the mobility and depositional characteristics of the landslide.

Patients with epidermal growth factor receptor 2-positive (HER2+) breast cancer and pathologic complete response (pCR) after neoadjuvant systemic therapy (NST) may be candidates for nonoperative clinical trials if residual invasive and in situ disease are eradicated. This study analyzed 280 patients with clinical T1-2N0-1 HER2+ breast cancer who underwent NST followed by surgical resection to determine key characteristics of patients with pCR in the breast and lymph nodes compared with those with residual disease. Of the 280 patients, 102 (36.4%) had pCR in the breast and lymph nodes after NST, and 50 patients (17.9%) had residual ductal carcinoma in situ (DCIS) in the breast only. For 129 patients (46.1%), DCIS was present on the pretreatment biopsy, and NST failed to eradicate the DCIS component in 64.3%. Patients with residual disease were more likely to have hormone receptor-positive (HR+) tumors than those with negative tumors (73.4% vs. 50.8%; p

OBJECTIVE: To determine the relationship between negative margin width and locoregional recurrence (LRR) in a contemporary cohort of ductal carcinoma in situ (DCIS) patients. BACKGROUND: Recent national consensus guidelines recommend an optimal margin width of 2 mm or greater for the management of DCIS; however, controversy regarding re-excision remains when managing negative margins < 2 mm. METHODS: One thousand four hundred ninety-one patients with DCIS who underwent breast-conserving surgery from 1996 to 2010 were identified from a prospectively managed cancer center database and analyzed using univariate and multivariate Cox proportional hazard models to determine the relationship between negative margin width and LRR with or without adjuvant radiation therapy (RT). RESULTS: A univariate analysis revealed that age

Background: Despite there being a well-established connection between the gut microbiome and metabolic disease in humans, intra-tumor microbes and the mechanisms by which they regulate cell signaling, inflammation, and adipocyte growth to exacerbate disease severity in cancer patients also suffering from obesity remains largely unclear. In this study, we identified microbes to be distinctly abundant in cancer patients who are obese and correlated microbe abundance to patient survival, clinical variables, and immunological genes and pathways, in order to mechanistically explain how differential microbe abundance may influence clinical outcome. Methods: Microbial reads were aligned and extracted from raw whole-transcriptome RNA-sequencing data of cancer patient samples using Pathoscope 2.0 software. The Kruskal-Wallis test was used to correlate body mass index (BMI)-associated microbes to clinical variables. Reactome FIViz and Gene Set Enrichment Analysis were used to calculate pathway enrichment. Results: We identified specific microbes, including Pseudomonas fluorescens SBW25 and Enterobacter cloacae, and chemokine and interleukin-related genes to be potential determining factors of disease severity among cancer patients in BMI-associated groups. Gene set enrichment analysis revealed that microbes abundant in cancer tissue in obese patient samples, including Pseudomonas baetica in liver cancer patients, were significantly associated with the upregulation oncogenic, cell migration-related signaling pathways. Intra-tumor microbes from obese patient samples were also found to correlate with chemokine signaling and TFR2/NFkB-related genes, both of which have well-established roles in inflammatory activity. Conclusions: Our study significantly advances the understanding of the microbiome composition of the tumor microenvironment in patients who are obese and microbes’ relationship with clinical and immunologic variables, particularly inflammatory-related genes and pathways. We uncovered unknown mechanisms of the microbiome-immune interaction and obtained definitive data on microbiome dysbiosis in patients with obesity as a key determinant of severity of cancer, including microbe regulation of inflammasome activity. While deeper sequencing, more rigorous contamination correction, and in vitro and in vivo experiments are necessary to fully elucidate how microbe species can effectively act as therapeutic agents in probiotic and prebiotic therapies to reduce insulin resistance, inflammation, and glucose levels, our results are essential for guiding this future research. Citation Format: Aditi Gnanasekar, Neil Shende, Jaideep Chakladar, Wei T. Li, Lindsay M. Wong, Michael Karin, Weg M. Ongkeko. Influence of obesity-associated intra-tumor microbes on exacerbating cancer severity [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 3528.

Optoacoustic imaging, based on the differences in optical contrast of blood hemoglobin and oxyhemoglobin, is uniquely suited for the detection of breast vasculature and tumor microvasculature with the inherent capability to differentiate hypoxic from the normally oxygenated tissue. We describe technological details of the clinical ultrasound (US) system with optoacoustic (OA) imaging capabilities developed specifically for diagnostic imaging of breast cancer. The combined OA/US system provides co-registered and fused images of breast morphology based upon gray scale US with the functional parameters of total hemoglobin and blood oxygen saturation in the tumor angiogenesis related microvasculature based upon OA images. The system component that enabled clinical utility of functional OA imaging is the hand-held probe that utilizes a linear array of ultrasonic transducers sensitive within an ultrawide-band of acoustic frequencies from 0.1 MHz to 12 MHz when loaded to the high-impedance input of the low-noise analog preamplifier. The fiberoptic light delivery system integrated into a dual modality probe through a patented design allowed acquisition of OA images while minimizing typical artefacts associated with pulsed laser illumination of skin and the probe components in the US detection path. We report technical advances of the OA/US imaging system that enabled its demonstrated clinical viability. The prototype system performance was validated in well-defined tissue phantoms. Then a commercial prototype system named Imagio™ was produced and tested in a multicenter clinical trial termed PIONEER. We present examples of clinical images which demonstrate that the spatio-temporal co-registration of functional and anatomical images permit radiological assessment of the vascular pattern around tumors, microvascular density of tumors as well as the relative values of the total hemoglobin [tHb] and blood oxygen saturation [sO2] in tumors relative to adjacent normal breast tissues. The co-registration technology enables increased accuracy of radiologist assessment of malignancy by confirming, upgrading and/or downgrading US categorization of breast tumors according to Breast Imaging Reporting And Data System (BI-RADS). Microscopic histologic examinations on the biopsied tissue of the imaged tumors served as a gold standard in verifying the functional and anatomic interpretations of the OA/US image feature analysis. Keywords: Optoacoustic, Photoacoustic, Ultrasound, Functional-anatomical imaging, Breast cancer, Diagnostics, Dual modality

BACKGROUND Dynamic contrast-enhanced (DCE) MRI is useful for diagnosis and assessment of treatment response in breast cancer. Fast DCE MRI offers a higher sampling rate of contrast enhancement curves in comparison to conventional DCE MRI, potentially characterizing tumor perfusion kinetics more accurately for measurement of functional tumor volume (FTV) as a predictor of treatment response. PURPOSE To investigate FTV by fast DCE MRI as a predictor of neoadjuvant systemic therapy (NAST) response in triple-negative breast cancer (TNBC). STUDY TYPE Prospective. POPULATION/SUBJECTS Sixty patients with biopsy-confirmed TNBC between December 2016 and September 2020. FIELD STRENGTH/SEQUENCE A 3.0 T/3D fast spoiled gradient echo-based DCE MRI ASSESSMENT: Patients underwent MRI at baseline and after four cycles (C4) of NAST, followed by definitive surgery. DCE subtraction images were analyzed in consensus by two breast radiologists with 5 (A.H.A.) and 2 (H.S.M.) years of experience. Tumor volumes (TV) were measured on early and late subtractions. Tumors were segmented on 1 and 2.5-minute early phases subtractions and FTV was determined using optimized signal enhancement thresholds. Interpolated enhancement curves from segmented voxels were used to determine optimal early phase timing. STATISTICAL TESTS Tumor volumes were compared between patients who had a pathologic complete response (pCR) and those who did not using the area under the receiver operating curve (AUC) and Mann-Whitney U test. RESULTS About 26 of 60 patients (43%) had pCR. FTV at 1 minute after injection at C4 provided the best discrimination between pCR and non-pCR, with AUC (95% confidence interval [CI]) = 0.85 (0.74,0.95) (P

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

Dynamic contrast-enhanced (DCE) MRI provides both morphological and functional information regarding breast tumor response to neoadjuvant chemotherapy (NAC). The purpose of this retrospective study is to test if prediction models combining multiple MRI features outperform models with single features. Four features were quantitatively calculated in each MRI exam: functional tumor volume, longest diameter, sphericity, and contralateral background parenchymal enhancement. Logistic regression analysis was used to study the relationship between MRI variables and pathologic complete response (pCR). Predictive performance was estimated using the area under the receiver operating characteristic curve (AUC). The full cohort was stratified by hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status (positive or negative). A total of 384 patients (median age: 49 y/o) were included. Results showed analysis with combined features achieved higher AUCs than analysis with any feature alone. AUCs estimated for the combined versus highest AUCs among single features were 0.81 (95% confidence interval [CI]: 0.76, 0.86) versus 0.79 (95% CI: 0.73, 0.85) in the full cohort, 0.83 (95% CI: 0.77, 0.92) versus 0.73 (95% CI: 0.61, 0.84) in HR-positive/HER2-negative, 0.88 (95% CI: 0.79, 0.97) versus 0.78 (95% CI: 0.63, 0.89) in HR-positive/HER2-positive, 0.83 (95% CI not available) versus 0.75 (95% CI: 0.46, 0.81) in HR-negative/HER2-positive, and 0.82 (95% CI: 0.74, 0.91) versus 0.75 (95% CI: 0.64, 0.83) in triple negatives. Multi-feature MRI analysis improved pCR prediction over analysis of any individual feature that we examined. Additionally, the improvements in prediction were more notable when analysis was conducted according to cancer subtype.

Targeted axillary dissection (TAD) involves locating and removing both clipped nodes and sentinel nodes for assessment of the axillary response to neoadjuvant chemotherapy (NAC) by clinically node-positive breast cancer patients. Initial reports described radioactive seeds used for localization, which makes the technique difficult to implement in some settings. This trial was performed to determine whether magnetic seeds can be used to locate clipped axillary lymph nodes for removal.This prospective registry trial enrolled patients who had biopsy-proven node-positive disease with a clip placed in the node and treatment with NAC. A magnetic seed was placed under ultrasound guidance in the clipped node after NAC. All the patients underwent TAD.Magnetic seeds were placed in 50 patients by 17 breast radiologists. All the patients had successful seed placement at the first attempt (mean time for localization was 6.1 min; range 1-30 min). The final position of the magnetic seed was within the node (n = 44, 88%), in the cortex (n = 3, 6%), less than 3 mm from the node (n = 2, 4%), or by the clip when the node could not be adequately visualized (n = 1, 2%). The magnetic seed was retrieved at surgery from all the patients. In 49 (98%) of the 50 cases, the clip and magnetic seed were retrieved from the same node. Surgeons rated the transcutaneous and intraoperative localization as easy for 43 (86%) of the 50 cases. No device-related adverse events occurred.Localization and selective removal of clipped nodes can be accomplished safely and effectively using magnetic seeds.

Background: to develop and validate a serum lipid and inflammatory marker model based on the nomogram for the prediction of stroke risk in rheumatoid arthritis patients.Methods: This study was conducted among 313 rheumatoid arthritis with stroke patients and 1827 rheumatoid arthritis patients divided into develop and validation cohorts from the First Affiliated Hospital of China Medical University during January 2011 to December 2018. Logistic regression analysis was used to create a nomogram of predictive model of stroke risk in rheumatoid arthritis patients, after comparing with other machine algorithms. The performance of the nomogram was evaluated by discrimination, calibration and decision curve analysis, also compared with the Framingham Risk Score in predicting stroke in rheumatoid arthritis patients.Results: the nomogram was performed by logistic regression algorithm, and predictors of which included the stratifications of sex, age, systolic blood pressure, C-reactive protein, erythrocyte sedimentation rate, total cholesterol, low density lipoprotein cholesterol and the distribution of being accompanied with hy-med, diabetes, atrial fibrillation and coronary heart disease history, which exhibited a well goodness fit and a good agreement. The analysis with area under the curve, the net reclassification index, the integrated discrimination improvement and clinical use, suggested that this is an easy-to-use nomogram compared with the Framingham Risk Score.Conclusion: This study presents a risk nomogram that incorporates the traditional risk factors, serum lipids and inflammatory markers which can be used to predict stroke in rheumatoid arthritis patients.

Spectroscopy is a well-established nonintrusive tool that has played an important role in identifying substances and quantifying their compositions, from quantum descriptions to chemical and biomedical diagnostics. Challenges exist in accurate measurements in dynamic environments, especially for understanding chemical reactions in arbitrary free-space. We develop a distributed free-space spectroscopy realized by a comb-referenced frequency-scanning single-photon lidar, providing multidimensional (time-range-spectrum) remote sensing. A continuous field experiment over 72 hours is deployed to obtain the spectra of multiple molecules (CO2 and HDO) in free-space over 6 km, with a range resolution of 60 m and a time resolution of 10 min over a spectrum span of 30 GHz. The CO2 and HDO concentrations are retrieved from the spectra acquired. This distributed free-space spectroscopy holds much promise for increasing knowledge of atmospheric environments and chemistry research, especially for complex molecular spectra evolution in any location over large areas., Comment: 5 pages, 5 figures

BACKGROUND: Increasing use of neoadjuvant systemic therapy (NAT) for early and locally advanced breast cancer led to critical need for development of tools capable of early treatment response assessment after NAT. Tc-99m sestamibi Molecular breast Imaging (MBI) as a functional imaging modality has a promise to detect changes in the tumor prior to anatomical changes detected by mammogram or ultrasound. PURPOSE: To evaluate the ability of quantitative MBI parameters to predict pathologic complete response (pCR) after completion of NAT in breast cancer patients. MATERIALS AND METHODS: Patients with invasive breast cancer (T1-T4, N0-N3, M0) planned for NAT followed by surgery were enrolled in a prospective IRB approved trial. MBI was performed at baseline and after two cycles of NAT. Patient demographic and tumor biology information (Ki-67, HER2, ER/PR) was collected. MBI images were quantified using a novel approach with corrections for scatter and attenuation and regions of interest (ROI) were drawn over tumors to compute three quantitative MBI uptake metrics for correlation with pathologic response: MBI-specific standardized uptake value (SUV), tumor to background ratio (TBR), and tumor volume. Pathologic complete response was determined based on final histopathology report at the time of surgery as absence of the invasive disease in the breast and axillary lymph nodes. MBI metrics at baseline, after 2 cycles of NAT and interval change were correlated with pCR and tumor biology using the Wilcoxon Rank Sum test, Kruskal-Wallis test or Fisher’s exact test. Statistical analysis was carried out using R (version 3.6.3, R Development Core Team). RESULTS: A total of 70 patients with median age 47.5 years (range 30-77) were included in the analysis. Breast cancer subtypes were: HER2 negative (ER/PR+) 35.7% (25/70), HER2 positive (ER/PR +/-) 35.7% (25/70), and triple negative (HER2-, ER/PR-) 28.6% (20/70). Change in SUV after 2 cycles of NAT was higher in patients with pCR compared to those who did not achieve pCR (mean decrease in SUV of 15.57 and 4.83 respectively, p Citation Format: Miral M Patel, Beatriz E Adrada, Benjamin Lopez, Rosalind P Candelaria, Jia Sun, Medine Boge, Rania M Mohamed, Nabil Elshafeey, Gary Whitman, MD, Huong T Le-Petross, Lumarie Santiago, Marion E Scoggins, Deanna Lane, Tanya Moseley, Galit Zylberman, Jerica Saddler, Jessica WT Leung, Wei T Yang, Vincente Valero, S Cheenu Kappadath, Gaiane M Rauch. Quantitative molecular breast imaging for early prediction of neoadjuvant systemic therapy response in locally advanced breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-03.

Background: Triple negative breast cancer (TNBC) has a poor prognosis. In particular, TNBC patients who have significant residual disease at the time of surgery following completion of neoadjuvant systemic therapy (NST) have an especially poor prognosis. In an effort to identify patients who are unlikely to achieve pathologic complete response (pCR), we investigated if pre-treatment breast MRI morphological characteristics and imaging response patterns during NST can predict pCR in TNBC patients. Materials and Methods: As part of a prospective IRB-approved clinical trial (ARTEMIS, NCT02276443), 199 patients with biopsy-proven stage I-III TNBC received NST and were classified as pCR or non-pCR based on histopathology at surgery. Patients underwent breast MRI at baseline (BL), after 2 cycles (C2), and 4 cycles (C4) of Adriamycin-based chemotherapy (AC). Subsequently, patients received either taxane-based NST or targeted therapy guided by mid-treatment imaging response. MRI studies were reviewed by two fellowship-trained breast radiologists who were blinded to the pathology results. ACR MRI BIRADS lexicon (5th Ed) was used to describe BL tumor morphology. Imaging response pattern at C2 and C4 MRI was classified as follows: type 0 (complete), type 1 (concentric shrinkage), type 2 (crumble), type 3 (diffuse enhancement), type 4 (stable), or type 5 (progression). Morphological baseline features and response patterns were summarized and compared to the pCR status on surgical pathology using Fisher’s exact test. P values less than 0.05 were considered statistically significant. Results: Median age was 53 years, range 24-79. Of 199 patients, 95 (48%) had pCR and 104 (52%) had non-pCR. At BL MRI, an irregularly-shaped mass and homogenous or clumped non-mass enhancement were associated with pCR (p=0.026 and p=0.013, respectively). Multifocality, peritumoral edema, and intratumoral necrosis were independent of pCR. Following NST, the most common MRI response pattern was type 1, seen with equal frequency in pCR and non-pCR at C2 (58% and 42%, respectively) and C4 (47% and 53%, respectively). The following response pattern associations were found: type 0 was associated with pCR at both C2 and C4 timepoints (p Citation Format: Mary S Guirguis, Beatriz E Adrada, Rosalind P Candelaria, Jia Sun, Gary J Whitman, Wei T Yang, Medine Boge, Rania M Mohamed, Nabil A Elshafeey, Deanna L Lane, Huong Le-Petross, Jessica WT Leung, Lumarie Santiago, Marion E Scoggins, David A Spak, Miral Patel, Frances Perez, Peng Wei, Debu Tripathy, Jason White, Elizabeth Ravenberg, Lei Huo, Jennifer Litton, Banu Arun, Vincente Valero, Alastair Thompson, Stacy Moulder, Clinton Yam, Gaiane M Rauch. Prediction of response to neoadjuvant systemic therapy in triple negative breast cancer using baseline tumor MRI characteristics and imaging patterns of response [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-03-06.

Robotic-assisted surgery (RAS) with its advantages continues to gain popularity among surgeons. This study analyzed the increased costs of RAS in common surgical procedures using the National Inpatient Sample. Retrospective analysis of the 2012–2014 Healthcare Cost and Utilization Project-NIS was performed for the following laparoscopic/robotic procedures: cholecystectomy, ventral hernia repair, right and left hemicolectomy, sigmoidectomy, abdominoperineal resection, and total abdominal hysterectomy (TAH). Patients with additional concurrent procedures were excluded. Costs were compared between the laparoscopic procedures and their RAS counterparts. Total costs and charges for cholecystectomy (the most common procedure in the dataset) were compared based on the payer and characteristics of hospital (region, rural/urban, bed size, and ownership). A total of 91,630 surgeries (87,965 laparoscopic, 3665 robotic) were analyzed. The average cost for the laparoscopic group was $10,227 ± $4986 versus $12,340 ± $5880 for the robotic cases (p

Diabetic retinopathy (DR) is the leading cause of blindness in patients with diabetes. However, biomarkers for early detection of DR are still lacking. MicroRNAs (miRNAs) regulate multiple biological functions and are often deregulated in DR. We aimed to investigate whether circulating miRNAs can be used as biomarkers of early-stage DR. We used RNA-seq and qRT-PCR to identify differential serum miRNAs in patients with type 2 diabetes mellitus with DR (T2DM-DR), T2DM without DR (T2DM-no-DR), and healthy controls. We validated differential circulating miRNAs in two phases using qRT-PCR assays. RNA-seq analysis identified 7 differential circulating miRNAs between T2DM-DR and T2DM-no-DR and 47 differential miRNAs between T2DM-DR and healthy subjects. Two-stage analysis verified that a profile of five serum miRNAs (hsa-let-7a-5p, hsa-miR-novel-chr5_15976, hsa-miR-28-3p, has-miR-151a-5p, has-miR-148a-3p) was significantly associated with T2DM-DR. Receiver-operator-characteristic analyses showed that a panel of three miRNAs (hsa-let-7a-5p, hsa-miR-novel-chr5_15976, and hsa-miR-28-3p) presented 0.92 sensitivity and 0.94 specificity for distinguishing T2DM-DR from T2DM-no-DR, and 0.93 sensitivity and 0.86 specificity for differentiating early-stage T2DM-DR (NPDR) from late-stage DR (PDR). Lentivirus-mediated overexpression of hsa-let-7a-5p in human retinal microvascular endothelial cells (HRMECs) significantly promoted proliferation rates of HRMECs. In conclusion, the three-miRNA signature from serum may serve as a noninvasive diagnostic biomarker for DR. Furthermore, we showed that DR-associated miRNAs may be involved in the pathogenesis of DR, at least in part, through modifying proliferation of HRMECs.

OBJECTIVE. The objective of this study is to analyze the incidence of women with breast pain who present to an imaging center and assess the imaging findings, outcomes, and workup costs at breast i...

Significant advances in the genetic and molecular characterization of cancer have led to the development of effective immunotherapies. These therapeutics help the host immune system recognize cancer as foreign, promote the immune system, and relieve the inhibition that allows growth and spread of tumors. Experience with various immunotherapies, particularly the immunomodulatory monoclonal antibody ipilimumab, has demonstrated that unique patterns of response may be encountered that cannot be adequately captured by traditional response criteria, such as the World Health Organization (WHO) criteria and Response Evaluation Criteria in Solid Tumors (RECIST), which have been used primarily with cytotoxic chemotherapies. In response to these observations, several novel response criteria have been developed to evaluate patients who receive immunotherapy, including immune-related response criteria (irRC), immune-related RECIST (irRECIST), and immune RECIST (iRECIST). These criteria are typically used in conjunction with RECIST version 1.1 in the clinical trial setting, because approval of new therapeutics by the US Food and Drug Administration relies on the responses derived from RECIST version 1.1. Finally, a wide variety of immune-related adverse events may affect patients who receive immunotherapy, many of which can be identified on imaging studies such as computed tomography, magnetic resonance imaging, and 2-deoxy-2-(fluorine-18)fluoro-D-glucose-positron emission tomography/computed tomography. In this review, the authors present the role of imaging in the evaluation of patients treated with immunotherapy, including the background and application of irRC, irRECIST, and iRECIST; the imaging of immune-related adverse events; and future directions in advanced imaging of immunotherapy. Cancer 2018;124:2906-22. © 2018 American Cancer Society.

This study was designed to present the secondary imaging endpoints of the trial for evaluating mammogram (MMG), ultrasound (US) and image guided biopsy (IGBx) assessment of pathologic complete response (pCR) in breast cancer (BC) patients undergoing neoadjuvant chemotherapy (NAC). Patients with T1–3, N0–3, M0 triple-negative or HER2-positive BC who received NAC were enrolled in an Institutional Review Board-approved prospective, clinical trial. Patients underwent US and MMG at baseline and after NAC. Images were evaluated for residual abnormality and to determine modality for IGBx [US-guided (USG) or stereotactic guided (SG)]. Fine-needle aspiration and 9-G, vacuum-assisted core biopsy (VACBx) of tumor bed was performed after NAC and was compared with histopathology at surgery. Forty patients were enrolled. Median age was 50.5 (range 26–76) years; median baseline tumor size was 2.4 cm (range 0.8–6.3) and 1 cm (range 0–5.5) after NAC. Nineteen patients had pCR: 6 (32%) had residual Ca2+ presurgery, 5 (26%) residual mass, 1 (5%) mass with calcifications, and 7 (37%) no residual imaging abnormality. Sensitivity, specificity, and accuracy of US, MMG, and IGBx for pCR were 47/95/73%, 53/90/73%, and 100/95/98%, respectively. Twenty-five (63%) patients had SGBx and 15 (37%) had US-guided biopsy (USGBx). Median number of cores was higher with SGBx (12, range 6–14) than with USGBx (8, range 4–12), p

Background and Purpose:There is currently a lack of recognized imaging criteria for prediction of treatment response to NAST in breast cancer patients with recent reports showing that breast MRI is the most accurate modality for evaluation of NAST response. DCE-MRI evaluates tumor perfusion that influences tumor enhancement at the post-contrast subtraction images and allows for more accurate measurement of changes in tumor volume during NAST. In this study, we evaluated the ability of tumor volumetric changes after 2 and 4 cycles of NAST by longitudinal ultrafast DCE-MRI to predict pathologic complete response (pCR) in TNBC undergoing NAST. Materials and Methods: Stage I-III TNBC patients enrolled in an IRB approved prospective clinical trial (ARTEMIS, NCT02276433) who had ultrafast DCE-MRI at baseline (BL, N=103), post 2 cycles (C2, N=59), and post 4 cycles (C4, N=103) of anthracycline-based NAST,and had surgery, were included in this analysis. Tumor volume was calculated using 3D measurements of the index lesion at BL, C2, and C4. Percent change of tumor volume (%TV) between BL, C2, and C4 was calculated at early (9-12 sec) and delayed (360-480 sec) phases of DCE-MRI. The largest lesion was used for analysis in patients with multicentric or multifocal disease. Demographic, clinical, and pathologic data and treatment response at surgery (pCR versus non-pCR) were documented. Receiver operating characteristics curve (ROC) analysis was performed for prediction of pCR status. Positive predictive value (PPV), negative predictive value (NPV) and Youden Index were used to select %TV cut-off thresholds for pCR prediction.Results: 103 patients (median age, 53 years; range, 24-79 years) were included, 48 (47%) had pCR, and 55 (53%) had non-pCR at surgical pathology. The %TV reduction at C2 DCE-MRI was predictive of pCR on both early phase DCE MRI (AUC, 0.873; CI:0.779-0.968, p < .0001) and delayed phase DCE MRI (AUC, 0.844; CI:0.742-0.947, p < .0001). Optimal thresholds were as follows: 70% TV reduction on early phase DCE MRI with Youden’s index of 1.58 was able to predict pCR correctly for 79% of patients with PPV of 81%; 75% TV reduction on delayed phase with Youden’s Index of 1.44 was able to predict pCR correctly for 71% of patients with PPV of 85%.%TV reduction was also predictive of pCR at the C4 time point on both early phase DCE MRI (AUC, 0.761; CI:0.665-0.856, p < .0001) and delayed phase DCE MRI (AUC, 0.737; CI:0.641-0.833, p < .0001). Optimal thresholds were as follows: 90% TV reduction on early phase DCE MRI with Youden’s index of 1.43 was able to correctly predict pCR in 72% of patients with PPV of 70%; and 90% TV reduction on delayed phase with Youden’s Index of 1.34 was able to predict pCR correctly in 68% of patients with PPV of 71%.Conclusion: Our data shows that percent tumor volume reduction by DCE-MRI after 2 and 4 cycles of NAST was able to predict pCR in TNBC with high accuracy and can be used as an early imaging biomarker of NAST response prediction. Volumetric changes by longitudinal DCE-MRI can be used to differentiate chemoresistant and chemosensitive TNBC patients as early as after 2 cycles of NAST, and can help to triage patients for treatment de-escalation or targeted therapy. Citation Format: Gaiane Margishvili Rauch, Adrada E Beatriz, Rosalind P Candelaria, Nabil Elshafeey, Abeer H Abdelhafez, Benjamin C Musall, Jia Sun, Medina Boge, Rania M.M Mohamed, Jong Bum Son, Shu Zhang, Jessica Leung, Deanna Lane, Marion Scoggins, David Spak, Elsa Arribas, Lumarie Santiago, Gary J Whitman, Huong T. Le-Petross, Tanya W Moseley, Jason B. White, Elizabeth Ravenberg, Ken-Pin Hwang, Peng Wei, Lei Huo, Jennifer K Litton, Vicente Valero, Debu Tripathy, Alastair M Thompson, Mark D Pagel, Jingfei Ma, Wei T Yang, Stacy Moulder. Volumetric changes on longitudinal dynamic contrast enhanced MR imaging (DCE-MRI) as an early treatment response predictor to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-07.

Background: Papillary thyroid carcinoma (PTC) is characterized by varied prognosis between gender and cancer subtype, but the cause for gender and subtype-based dissimilarities is unclear. Women are more frequently diagnosed with PTC, while men suffer more advanced-staged PTC. Additionally, tall cell and poorly differentiated variants are more aggressive than classical and follicular variants of PTC. While the intratumor microbiome has become increasingly implicated in cancer development, the microbial landscape of PTC is essentially uninvestigated. Past studies have shown how microbes within tumor tissue can contribute to or inhibit tumor growth by regulating gene expression and immune and cancer pathways. For example, a study published by Bahmani S. et. al. found that the absence of folate-producing Bifidobacterium and Lactobacillus was correlated with hypomethylation at regions of the p53 gene in colorectal cancer. We hypothesized that intratumor microbiome composition distinctly alters the immune landscape by preventing or inducing methylation of critical genes and may therefore predict cancer progression between PTC subtypes and between patient genders. Methods: Raw whole-transcriptome RNA-sequencing data for PTC and adjacent normal tissue was downloaded from The Cancer Genome Atlas, and microbial reads were extracted using Pathoscope 2.0 software. The Kruskal-Wallis test was performed to identify differentially abundant microbes between tumor and normal samples. Level 3 normalized DNA methylation 450k sequencing was downloaded from the GDC portal. We converted B-values to M-values and then performed the probe-wise differential methylation analysis on the matrix of M-values in limma to obtain t-statistics and p-values for each CpG site. The Kruskal-Wallis test was used to correlate microbe abundance to extent of methylation. R Results: Overall, PTC tumor tissue significantly lacked microbes that are populated in adjacent normal tissue. Tissue from different genders and subtypes was characterized by dysbiosis of specific microbe species, and microbes distinctly abundant in tall cell and male patient cohorts were correlated with greater methylation of tumor suppressors. The most significantly methylated sites occurred on chromosomes 1 and 17 and specifically at cell cycle related genes. Lower microbe abundance (Anabaena sp. K119, Trueperella pyogenes, Frankia sp.) in tumor tissue was predominantly correlated with greater extent of methylation at known tumor suppressor genes including NEURL1B, POLE, and SRCIN1. Conclusions: We identified microbes that are uniquely abundant in specific PTC types and are predominantly negatively correlated with methylation of tumor suppressors and cell cycle-related genes. Our results may provide a basis for developing specialized prebiotic and probiotic treatments for varied PTC tumors. Citation Format: Aditi Gnanasekar, Grant Castaneda, Anjali Iyangar, Shruti Magesh, Jaideep Chakladar, Wei T. Li, Lindsay M. Wong, Weg M. Ongkeko. Absence of intratumor microbes induces methylation of tumor suppressors and cell cycle-related genes in papillary thyroid carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1784.

The internal thoracic (IT) nodal basin is a first-echelon drainage pathway in the breast, accounting for up to a quarter of its lymphatic drainage, primarily from the deep structures of the breast. The presence of internal thoracic node (ITN) metastases upstages the breast cancer (BC) patient to a minimum of clinical stage III disease. Medial tumors, deep tumors, young age, axillary nodal metastases, tumors of a high nuclear grade, lymphovascular invasion, and triple-negative hormone receptor status are predisposing factors for ITN metastases from primary BC. It has been observed that medial tumors carry a worse prognosis than lateral tumors when all other factors are equal, indicating that understaging of ITN has a significant impact on patient outcomes. Despite the established prognostic significance of IT adenopathy in BC, this nodal basin is not routinely staged due to the difficulty in accessing it and due to the controversy regarding its management. Since the initial ITN studies in the 1960s, improvement in imaging techniques and the availability of minimally invasive biopsy techniques have fueled renewed interest in ITNs and their clinical significance in BC. Radiologists who image and diagnose BC can offer more accurate staging assessments by consistently evaluating the IT nodal chain in the BC patient. In this article, the authors discuss current knowledge of the ITNs in BC and review ITN anatomy. The imaging appearance of pathologic ITNs using various modalities, potential mimics of IT adenopathy, and image-guided sampling techniques are described. A succinct discussion of the clinical management of ITN-positive BC and its challenges is also included. © RSNA, 2017.

Recent published guidelines suggest that adequate margins for DCIS should be ≥ 2 mm after breast conserving surgery followed by radiotherapy (RT). Many groups now use this guideline as an absolute indication for additional surgery. This article describes detailed multidisciplinary practices including extensive preoperative/intraoperative pathologic/histologic image-guided assessment of margins, offering some patients with small low/intermediate grade DCIS no RT, the use/magnitude of radiation boost tailoring to margin width, and endocrine therapy for ER-positive DCIS. Use of these protocols over the past 20-years has resulted in 10-year local recurrence rates below 5% for patients with negative margins < 2 mm who received RT. Patients with margins < 2 mm who do not receive RT experience significantly higher local failure rates. Thus, there is not an absolute need to achieve wider negative surgical margins when < 2 mm for patients treated with RT and this should be determined by the multidisciplinary team. Utilization of these multidisciplinary treatment protocols and techniques may not be exportable and extrapolated to all hospitals, breast programs and systems as they can be complex and resource intensive.

OBJECTIVE. This review provides historical and current data to support the role of imaging-based axillary lymph node staging and sentinel lymph node biopsy as the standard of care for axillary management in women with a diagnosis of breast cancer, before and after neoadjuvant systemic therapy. CONCLUSION. The implications of surgical trials (American College of Surgeons Oncology Group [ACOSOG] Z011 and ACOSOG Z1071) on imaging protocols for the axilla are reviewed, in conjunction with the American Joint Committee on Cancer nodal staging guidelines.

The general goal of this thesis was to implement a new, catalytic, enantioselective isocyanoacetate ketone aldol reaction into a challenging total synthesis plan, in order to achieve a catalyst controlled stereoselective total synthesis of a specific subset of quinazolinone alkaloids - tryptoquivalines and chaetominine. Chapter 1 firstly introduces the panorama of quinazolinone alkaloids and pioneering synthetic achievements on tryptoquivalines and chaetominines. Subsequently, previous crucial development of isocyanoacetate ester aldol/Mannich reactions were concisely reviewed. Chapter 2 demonstrates our first-generation catalytic divergent synthetic approach towards both tryptoquivaline F and chaetominine. Chapter 3 mainly illustrates the second-generation total synthetic approach towards tryptoquivaline F. Chapter 4 shows our total synthesis work on a naturally occurring pentacyclic quinazolinone natural product and core of tryptoquivalines, followed with homologations towards tryptoquivaline F.

The aim was to determine whether sonographic features of metastatic axillary lymph nodes predict pathologic nodal status post-neoadjuvant chemotherapy (NCT) and help to tailor less invasive surgical management of the axilla. Patients with biopsy-proven cN1 primary breast malignancy who received NCT between January 2011 and December 2014 and had performed ultrasound were included in this study. Sonographic features of biopsy-proven clipped metastatic axillary nodes pre- and post-NCT were retrospectively reviewed by two independent readers. Changes in lymph node shape, fatty hilum status, cortical thickness, and cortical echogenicity were compared in patients with and without nodal pathologic complete response (pCR) using univariate and multivariate logistic regression models. Inter-reader variation was analyzed to determine the reproducibility of data. Of the 195 patients included in the study, 75 (45%) showed nodal pCR and 90 (55%) persistent metastatic disease post-NCT. pCR was significantly more likely in lymph nodes with isoechoic or hypoechoic cortical echogenicity post-NCT, (P = .02), conversion to normal cortical thickness (P = .0001), and oval shape (odds ratio = 0.17, P = .004), compared to lymph nodes with anechoic cortical echogenicity, persistent or diffuse cortical thickening, and irregular shape, respectively. The overall accuracy of sonographic nodal features in the prediction of pCR was 65% (95% CI: 58%-72%). The overall accuracy of sonographic features of biopsy-proven metastatic axillary lymph nodes post-NCT is not sufficiently high to predict pCR of axillary nodal status and thereby should not be solely used in guiding less invasive surgical approaches to the axilla.

Background and Purpose:Image-based tumor phenotypes by using computer extraction techniques have been studied for evaluation of breast cancer invasiveness, stage, lymph node involvement, molecular subtypes and genomics. In this project we aimed to investigate ability of computer-extracted breast MR imaging radiomic phenotypes to predict nodal and distant metastasis in breast cancer patients. MATERIALS AND METHODS:This retrospective IRB approved study included 416 biopsy proven breast cancer patients who had pretreatment DCE MRI in a single institution between 2014 and 2018. Patient’s demographic, clinical data, pathology at diagnosis and surgery, nodal and distant metastasis (M1) at follow up were documented. Using QuantX imaging software, the tumor volume of interest was automatically-segmented using the multiple dynamic phases of DCE MRI. A total of 33 radiomic features describing tumor phenotype were extracted from each tumor site. A linear discriminant analysis (LDA) as a classifier with nested feature selection 10-fold cross validation was used to build the radiomic signature for prediction of nodal and distant metastasis occurrence. Receiver operating characteristic (ROC) and precision-recall analyses were used to evaluate performance, with 95% confidence intervals from 1000 bootstraps, and Kaplan-Meier was used to calculate the progression-free survival estimates and associated hazard ratio at the median cutpoint of the probability of metastasis calculated by the LDA in the 10-fold cross-validation. RESULTS:The quantitative DCE MRI radiomic model was able to differentiate between breast cancer patients with and without distant metastatic disease at follow up with area under the ROC of 0.75 (95% CI 0.65; 0.82) and precision-recall curves 0.46 (0.33;0.69), hazard ratio at median cut point is 3.76 (2.27; 6.24), p The DCE radiomic model was able predict presence of ipsilateral nodal disease (≥1 positive lymph nodes) at surgery with AUC 0.66 (95% CI: 0.60; 0.71), ≥4 positive lymph nodes at surgery with AUC 0.67 (95% CI: 0.60; 0.74), and N2/N3 disease with AUC 0.64 (95% CI: 0.56; 0.72). Effective radius was most important feature for nodal disease prediction. CONCLUSIONS:Our results show that DCE MRI based radiomic phenotypes were able to predict nodal involvement and distant metastasis in breast cancer patients. Quantitative breast DCE MRI radiomics shows promise for noninvasive image based phenotyping for prediction of nodal and distant metastatic disease in breast cancer patients. Citation Format: Gaiane Margishvili Rauch, Karen Drukker, Nabil Elshafeey, Rania M.m. Mohamed, Medina Boge, Beatriz E. Adrada, Rosalind P Candelaria, Mo Salama, Irene Shkatova, Maryellen Giger, Wei T Yang. Quantitative dynamic contrast-enhanced (DCE) MRI radiomic phenotypes for prediction of nodal and distal metastasis in breast cancer patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS3-01.

Background and Purpose:Early and accurate assessment ofbreast cancer response to NAST is important for patient management. In this study, we investigated the value of radiomic phenotypes derived from semi-quantitative and quantitative DCE-MRI parametric maps for early prediction of NASTresponse in TNBC patients. MATERIALS AND METHODS:This IRB approved study included 74 patients with stage I-III TNBC who were enrolled in the prospective ARTEMIS trial (NCT02276443). Pathologic complete response (pCR) and non-pCR were assessed by surgical histopathology after NAST (pCR=34; non-pCR=40).MRI scans were obtained at 3 time points during the NAST treatment with every 2-week anthracycline-based chemotherapy (AC): at baseline (BSL=74), post-2 cycles of AC (C2= 27) and post-4 cycles of AC (C4= 27). Patients went on to receive taxane-based chemotherapy prior to surgery. Tumor regions of interest (ROIs) were segmented by a breast radiologist at the early-phase subtractions of DCE-MRI scans using in-house developed software, followed by co-registration of the ROIs with quantitative (Ktrans, Veand Kep), and semi-quantitative DCE parametric maps (Maximum Slope Increase (MSI), Positive Enhancement Integral (PEI) and Peak Signal Enhancement Ratio (SER)).A total of 93 first order radiomic features were extracted from the tumor ROIs of each time point semi-quantitative DCE parametric map, while a total of 390 extracted radiomic features (first order-histogram features and second order grey-level-co-occurrence matrix) were extracted from each quantitative DCE parametric map using an in-house developed Matlab software.Radiomic features at each time point and changes between the 3 time points were compared between pCR and non-pCR using Wilcoxon Rank Sum test and Fisher’s exact test. Area under the receiver operating characteristics curve (AUC) was used to determine which features predicted pCR.Logistic regression was performed for feature selection, and used to build the radiomic phenotype model. The model performance was assessed by leave-one-out cross validation and 3-fold cross validation. RESULTS:Thirty-three radiomic features from PEI map were significantly different between pCR and non-pCR. The PEI most significant features were changesbetween BSL and C4 in skewness, mean and median (AUC=0.87, 0.85 and 0.87, p= Citation Format: Nabil Elshafeey, Beatriz E Adrada, Rosalind P Candelaria, Abeer H Abdelhafez, Benjamin C Musall, Jia Sun, Medine Boge, Rania M.M Mohamed, Hagar S Mahmoud, Jong Bum Son, Aikaterini Kotrosou, Shu Zhang, Jessica Leung, Deanna Lane, Marion Scoggins, David Spak, Elsa Arribas, Lumarie Santiago, Gary J. Whitman, Huong T Le-Petross, Tanya W Moseley, Jason B White, Elizabeth Ravenberg, Ken-Pin Hwang, Peng Wei, Jennifer K Litton, Lei Huo, Debu Tripathy, Vicente Valero, Alastair M Thompson, Stacy Moulder, Wei T Yang, Mark D Pagel, Jingfei Ma, Gaiane M Rauch. Radiomic phenotypes from dynamic contrast-enhanced MRI (DCE-MRI) parametric maps for early prediction of response to neoadjuvant systemic therapy (NAST) in triple negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD6-06.

Patients with advanced cancers are treated with combined radiotherapy and chemotherapy, however curability is poor and treatment side effects severe. Drugs sensitizing tumors to radiotherapy have been developed to improve cell kill, but tumor specificity remains challenging. To achieve tumor selectivity of small molecule radiosensitizers, we tested as a strategy active tumor targeting using peptide-based drug conjugates. We attached an inhibitor of the DNA damage response to antibody or cell penetrating peptides. Antibody drug conjugates honed in on tumor overexpressed cell surface receptors with high specificity but lacked efficacy when conjugated to the DNA damage checkpoint kinase inhibitor AZD7762. As an alternative approach, we synthesized activatable cell penetrating peptide scaffolds that accumulated within tumors based on matrix metalloproteinase cleavage. While matrix metalloproteinases are integral to tumor progression, they have proven therapeutically elusive. We harnessed these pro-tumorigenic extracellular proteases to spatially guide radiosensitizer drug delivery using cleavable activatable cell penetrating peptides. Here, we tested the potential of these two drug delivery platforms targeting distinct tumor compartments in combination with radiotherapy and demonstrate the advantages of protease triggered cell penetrating peptide scaffolds over antibody drug conjugates to deliver small molecule amine radiosensitizers.