Chemogenetics refers to experimental methods that use novel recombinant proteins that can be dynamically and uniquely regulated by specific biochemicals. Chemogenetic approaches allow the precise manipulation of cellular signaling to delineate the molecular pathways involved in both physiological and pathological disease states. Approaches utilizing yeast d-amino acid oxidase (DAAO) enable manipulation of intracellular redox metabolism through generation of hydrogen peroxide in the presence of d-amino acids and have led to the development of new and informative animal models to characterize the impact of oxidative stress in heart failure and neurodegeneration. These chemogenetic models, in which DAAO expression is regulated by different tissue-specific promoters, have led to a range of cardiac phenotypes. This review discusses chemogenetic approaches to manipulate oxidative stress in models of heart failure. These approaches provide new insights into the relationships between redox metabolism and normal and pathologic states in the heart, as well as in other diseases characterized by oxidative stress.

Purpose To compare quantitative measures of tumor metabolism and perfusion using fluorine 18 (18F) fluorodeoxyglucose (FDG) dedicated breast PET (dbPET) and breast dynamic contrast-enhanced (DCE) MRI during early treatment with neoadjuvant chemotherapy (NAC). Materials and Methods Prospectively collected DCE MRI and 18F-FDG dbPET examinations were analyzed at baseline (T0) and after 3 weeks (T1) of NAC in 20 participants with 22 invasive breast cancers. FDG dbPET-derived standardized uptake value (SUV), metabolic tumor volume, and total lesion glycolysis (TLG) and MRI-derived percent enhancement (PE), signal enhancement ratio (SER), and functional tumor volume (FTV) were calculated at both time points. Differences between FDG dbPET and MRI parameters were evaluated after stratifying by receptor status, Ki-67 index, and residual cancer burden. Parameters were compared using Wilcoxon signed rank and Mann-Whitney U tests. Results High Ki-67 tumors had higher baseline SUVmean (difference, 5.1; P = .01) and SUVpeak (difference, 5.5; P = .04). At T1, decreases were observed in FDG dbPET measures (pseudo-median difference T0 minus T1 value [95% CI]) of SUVmax (-6.2 [-10.2, -2.6]; P < .001), SUVmean (-2.6 [-4.9, -1.3]; P < .001), SUVpeak (-4.2 [-6.9, -2.3]; P < .001), and TLG (-29.1 mL3 [-71.4, -6.8]; P = .005) and MRI measures of SERpeak (-1.0 [-1.3, -0.2]; P = .02) and FTV (-11.6 mL3 [-22.2, -1.7]; P = .009). Relative to nonresponsive tumors, responsive tumors showed a difference (95% CI) in percent change in SUVmax of -34.3% (-55.9%, 1.5%; P = .06) and in PEpeak of -42.4% (95% CI: -110.5%, 8.5%; P = .08). Conclusion 18F-FDG dbPET was sensitive to early changes during NAC and provided complementary information to DCE MRI that may be useful for treatment response evaluation. Keywords: Breast, PET, Dynamic Contrast-enhanced MRI Clinical trial registration no. NCT01042379 Supplemental material is available for this article. © RSNA, 2024.

Hypertrophic cardiomyopathy (HCM) is frequently caused by pathogenic variants in genes encoding sarcomere proteins and is characterized by left ventricular (LV) hypertrophy, hypercontractility, and—in many cases—left ventricular outflow tract (LVOT) obstruction. Despite standard management, obstructive HCM (oHCM) can still cause substantial morbidity, highlighting the critical need for more effective disease-specific therapeutic approaches. Over the past decade, improved understanding of the molecular pathobiology of HCM has culminated in development of cardiac myosin inhibitors (CMIs), a novel drug class that in recent randomized clinical trials has been shown to decrease LVOT obstruction, improve exercise capacity, and ameliorate symptom burden in patients with oHCM. Although promising, areas of uncertainty remain, including the long-term safety and efficacy of CMIs and whether they have the potential to modify progression of disease. Herein, we review key milestones in the clinical development of CMIs, contextualize CMIs with established oHCM therapies, and discuss future challenges and opportunities for the use of CMIs across the HCM spectrum.

e18555 Background: Disparities in cancer screening have been well documented during the Covid-19 pandemic. However, there are limited patient-reported data describing the prevalence and drivers of patient hesitancy towards cancer screening and willingness to resume screening. As health systems continue to experience pandemic-related capacity strain, there is an urgent need for innovative models of re-engaging patients in preventive screening. To address this issue, we developed a medical student-led, high-touch outreach model to re-engage primary care patients at Brookside Community Health Center in cancer screening. Methods: We iteratively optimized semi-structured call scripts and surveys in English and Spanish to contact patients overdue for mammography screening. Student callers included medical and pre-medical students with native Spanish fluency. Using the call script, students identified patient-reported barriers and facilitated mammogram scheduling for consenting patients. For consenting patients, student callers placed a telephone encounter with a pended screening mammogram order in the electronic medical record. PCP confirmation of the order triggered outreach by the radiology department for mammogram scheduling. Patients also received reminder calls from students the week of their appointment. Primary outcomes include screening consent rates, mammogram scheduling and completion rates, and screening results. Patient survey responses were securely recorded using the REDCap survey platform. Results: 198 patients were eligible for the intervention. 60% are primarily Spanish-speaking and 81% are insured by Medicaid. 145 patients (73%) have successfully been contacted, of which 129 (89%) consented for mammogram screening. 74 (57%) of the consenting patients have scheduled their mammogram and 38 (29%) have completed their mammogram. 36% of consenting Spanish-speaking patients with active mammogram orders did not have a mammogram scheduled, compared to 9% of consenting English-speaking. To date, 6 patients had abnormal mammograms requiring subsequent diagnostic imaging, and 1 patient was diagnosed with ductal carcinoma in situ requiring oncologic care. Qualitative analysis of patient surveys found that primary barriers to screening included factors associated with the Covid-19 pandemic (32.9% of contacted patients), lack of awareness of overdue status (25.9%) and patient unavailability (e.g. outside of country) (20%). Conclusions: In this single-center quality improvement study, we found that patients had a high willingness to engage in cancer screening during the pandemic and that trainees can play a vital role in re-engaging patients in preventative care. The disparity between Spanish and English-speaking patients’ ability to schedule a mammogram after the consent process suggests that patients with limited English proficiency face additional challenges in accessing screenings.

Background Patient-reported outcomes (PROs) are used increasingly in routine clinical care and inform policies, reimbursements, and quality improvement. Less is known regarding PRO implementation in routine clinical care for diverse and underrepresented patient populations. Objective This review aims to identify studies of PRO implementation in diverse and underrepresented patient populations, elucidate representation of clinical specialties, assess implementation outcomes, and synthesize patient needs, concerns, and preferences. Methods MEDLINE, Embase, Web of Science, CINAHL, and PsycINFO were searched September 2021 for studies aiming to study PRO implementation in diverse and underrepresented patient populations within the United States. Studies were screened and data extracted by three independent reviewers. Implementation outcomes were assessed according to Proctor et al. taxonomy. A descriptive analysis of data was conducted. Results The search yielded 8,687 records, and 28 studies met inclusion criteria. The majority were observational cohort studies (n = 21, 75%) and conducted in primary care (n = 10, 36%). Most studies included majority female (n = 19, 68%) and non-White populations (n = 15, 54%), while fewer reported socioeconomic (n = 11, 39%) or insurance status (n = 9, 32.1%). Most studies assessed implementation outcomes of feasibility (n = 27, 96%) and acceptability (n = 19, 68%); costs (n = 3, 11%), penetration (n = 1, 4%), and sustainability (n = 1, 4%) were infrequently assessed. Conclusion PRO implementation in routine clinical care for diverse and underrepresented patient populations is generally feasible and acceptable. Research is lacking in key clinical specialties. Further work is needed to understand how health disparities drive PRO implementation outcomes.

The Breast JournalVolume 27, Issue 4 p. 406-408 COMMENTARY Accuracy of sentinel lymph node biopsy in invasive lobular carcinoma of the breast: Factors associated with false negatives Rita A. Mukhtar MD, Corresponding Author Rita A. Mukhtar MD rita.mukhtar@ucsf.edu orcid.org/0000-0001-8079-7846 Department of Surgery, University of California, San Francisco, CA, USA Correspondence Rita Mukhtar, 1825 4th Street, 3rd Floor, Box 1710, San Francisco, CA 94143. Email: rita.mukhtar@ucsf.eduSearch for more papers by this authorCase E. Brabham AB, Case E. Brabham AB Harvard Medical School, Harvard University, Boston, MA, USASearch for more papers by this authorRuby Guo AB, Ruby Guo AB Harvard Medical School, Harvard University, Boston, MA, USASearch for more papers by this authorMary Kathryn Abel AB, Mary Kathryn Abel AB Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorJasmine Wong MD, Jasmine Wong MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorCheryl Ewing MD, Cheryl Ewing MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorLaura J. Esserman MD, MBA, MD, Laura J. Esserman MD, MBA, MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorMichael Alvarado MD, Michael Alvarado MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this author Rita A. Mukhtar MD, Corresponding Author Rita A. Mukhtar MD rita.mukhtar@ucsf.edu orcid.org/0000-0001-8079-7846 Department of Surgery, University of California, San Francisco, CA, USA Correspondence Rita Mukhtar, 1825 4th Street, 3rd Floor, Box 1710, San Francisco, CA 94143. Email: rita.mukhtar@ucsf.eduSearch for more papers by this authorCase E. Brabham AB, Case E. Brabham AB Harvard Medical School, Harvard University, Boston, MA, USASearch for more papers by this authorRuby Guo AB, Ruby Guo AB Harvard Medical School, Harvard University, Boston, MA, USASearch for more papers by this authorMary Kathryn Abel AB, Mary Kathryn Abel AB Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorJasmine Wong MD, Jasmine Wong MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorCheryl Ewing MD, Cheryl Ewing MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorLaura J. Esserman MD, MBA, MD, Laura J. Esserman MD, MBA, MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this authorMichael Alvarado MD, Michael Alvarado MD Department of Surgery, University of California, San Francisco, CA, USASearch for more papers by this author First published: 24 January 2021 https://doi.org/10.1111/tbj.14161Citations: 1Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat No abstract is available for this article.Citing Literature Volume27, Issue4April 2021Pages 406-408 RelatedInformation

Neoadjuvant therapy in breast cancer can downstage axillary lymph nodes and reduce extent of axillary surgery. As such, accurate determination of nodal status after neoadjuvant therapy and before surgery impacts surgical management. There are scarce data on the diagnostic accuracy of breast magnetic resonance imaging (MRI) for nodal evaluation after neoadjuvant therapy in patients with invasive lobular carcinoma (ILC), a diffusely growing tumor type. We retrospectively analyzed patients with stage 1–3 ILC who underwent pre-operative breast MRI after either neoadjuvant chemotherapy or endocrine therapy at our institution between 2006 and 2019. Two breast radiologists reviewed MRIs and evaluated axillary nodes for suspicious features. All patients underwent either sentinel node biopsy or axillary dissection. We evaluated sensitivity, specificity, negative and positive predictive values, and overall accuracy of the post-treatment breast MRI in predicting pathologic nodal status. Of 79 patients, 58.2% received neoadjuvant chemotherapy and 41.8% neoadjuvant endocrine therapy. The sensitivity and negative predictive value of MRI were significantly higher in the neoadjuvant endocrine therapy cohort than in the neoadjuvant chemotherapy cohort (66.7 vs. 37.9%, p = 0.012 and 70.6 vs. 40%, p = 0.007, respectively), while overall accuracy was similar. Upstaging from clinically node negative to pathologically node positive occurred in 28.0 and 41.7%, respectively. In clinically node positive patients, those with an abnormal post-treatment MRI had a significantly higher proportion of patients with ≥4 positive nodes on pathology compared to those with a normal MRI (61.1 versus 16.7%, p = 0.034). Overall, accuracy of breast MRI for predicting nodal status after neoadjuvant therapy in ILC was low in both chemotherapy and endocrine therapy cohorts. However, post-treatment breast MRI may help identify patients with a high burden of nodal disease (≥4 positive nodes), which could impact pre-operative systemic therapy decisions. Further studies are needed to assess other imaging modalities to evaluate for nodal disease following neoadjuvant therapy and to improve clinical staging in patients with ILC.

Abstract Introduction: Dedicated breast positron emission tomography (dbPET) is an emerging imaging technique with the spatial resolution needed to assess functionality and intra-tumor heterogeneity in primary breast lesions. Breast cancer patients may benefit from dbPET imaging combined with molecularly targeted agents to non-invasively assess and predict response to targeted therapy in the neoadjuvant treatment setting. We have previously observed that [18F]-fluorodeoxyglucose (FDG) PET provides tumor metabolic information complementary to the angiogenic properties reflected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for characterizing triple-negative breast cancers (TNBC) (1). In this study, we examined the relationship between FDG-dbPET and MRI features in a cohort of breast cancer patients receiving neoadjuvant chemotherapy (NAC). Methods: With institutional review board approval, patients with biopsy-proven locally-advanced breast cancer were imaged with breast MRI and dbPET before (T0) and after three weeks (T1) of NAC. Standard DCE-MRI was obtained using a dedicated breast coil. Patients also underwent dbPET with 5 mCi of FDG at 45 minutes post-injection. Functional tumor volumes (FTV) were calculated from DCE-MRI by summing all voxels with an early percent enhancement (PE) exceeding 70% within a manually defined volume of interest (VOI). Maximum and mean PE (PEMax, PEMean) values within the VOI were also computed for analyses. Tumors were segmented in dbPET images using semi-automated threshold-driven methods. Body weight-corrected maximum and mean standardized uptake values (SUVMax, SUVMean), total lesion glycolysis (TLG), and metabolic tumor volume (MTV) were calculated for FDG-dbPET. Percent change relative to T0 (Δ = 100*(T1 - T0)/T0) was calculated for each feature. Spearman’s correlation coefficient was used to evaluate the relationship between MRI and dbPET features. Results: Of the 16 patients enrolled in this study, 13 patients (N = 15 unique tumors) with MRI and dbPET at T0 and T1 were included in the analysis. 46% (6/13) of the patients had TNBC. Our initial findings indicated that ΔPEMax and ΔSUVMax had the highest correlation (ρ = 0.59, p = 0.022). FTV and TLG at T1 were also correlated (ρ = 0.56, p = 0.032). Among all imaging features, ΔMTV showed the largest post-treatment difference between TNBC (-54.5%) and non-TNBC (-6.06%) groups. Among MRI features, ΔFTV exhibited the largest difference between the groups: -70.4% in TNBC and -43.1% in non-TNBC. ΔSUVMax and ΔTLG were additional dbPET features with large differences between TNBC and non-TNBC patients (Table 1). Conclusion: This exploratory study suggests that post-treatment ΔSUVMax and TLG provide complementary metabolic information to angiogenic properties (ΔPEMax and FTV, respectively) reflected by MRI. Other dbPET features may provide independent information adjunct to MRI for describing primary breast tumors. Patients with TNBC exhibited larger reductions in FDG uptake values and metabolic volume than non-TNBC patients. These observed reductions may improve early treatment response in patients with TNBC, enabling more precise treatment guidance. Further studies in larger cohorts are needed to validate these initial observations. 1. Bolouri MS, et al. Triple-Negative and Non-Triple-Negative Invasive Breast Cancer: Association between MR and Fluorine 18 Fluorodeoxyglucose PET Imaging. Radiology 2013;269:354-61 Comparison of ΔMRI and ΔFDG-dbPET in TNBC vs non-TNBC patientsAll Tumors (N = 15 tumors) Median(IQR)TNBC (N = 6 tumors) Median(IQR)non-TNBC (N = 9 tumors) Median(IQR)DCE-MRIΔFTV (%)-66.1 (-77.6, -19.1)-70.4 (-79.0, -62.1)-43.1 (-72.5, -2.95)ΔPEMax (%)-9.91 (-31.5, 19.5)-10.3 (-26.3, 24.2)-9.91 (-31.8, 8.42)ΔPEMean (%)-10.7 (-22.4, 2.77)-9.57 (-12.8, 0.29)-17.0 (-26.0, 2.33)FDG-dbPETΔSUVMax (%)-31.6 (-53.9, -20.6)-47.3 (-55.7, -41.1)-23.1 (-31.6, 1.13)ΔSUVMean (%)-34.1 (-65.4, -14.2)-48.5 (-74.6, -9.74)-34.1 (-44.5, -14.8)ΔMTV (%)-6.18 (-57.0, 38.5)-54.5 (-75.4, 15.3)-6.06 (-47.2, 38.9)ΔTLG (%)-64.9 (-75.2, 23.3)-75.2 (-84.0, -60.0)-47.9 (-65.2, 31.1) Citation Format: Deep K Hathi, Ella F Jones, Wen Li, David C Newitt, Ruby Guo, Youngho Seo, Robert R Flavell, Bonnie N Joe, Diane Heditsian, Susie Brain, ISPY-2 Imaging Working Group, ISPY-2 Consortium, Laura J Esserman, Nola M Hylton. Relationship of dedicated breast PET and MRI features in breast cancer patients receiving neoadjuvant chemotherapy [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 PS13-50.

e12604 Background: The safety of the sentinel lymph node biopsy procedure (SLNB) in the surgical management of breast cancer relies upon a false negative rate (FNR) being less than 10%. The accuracy of SLNB in invasive lobular carcinoma (ILC), the second most common type of breast cancer, has not been evaluated. Because of high rates of false negative imaging and the diffuse growth pattern in ILC, less accurate pre-operative staging and a potentially unreliable lymphatic drainage pattern may impact the accuracy of SLNB in this tumor type. We therefore sought to characterize the accuracy of SLNB in a cohort of patients with ILC. Methods: We queried an institutional database of 707 patients with ILC and identified 196 patients who underwent SLN mapping with excision of both sentinel and non-sentinel nodes. A false negative was defined as having negative sentinel lymph nodes and a positive non-sentinel node. We calculated the FNR and sensitivity of SLNB and evaluated clinicopathologic variables. Results: Of 196 cases, 183 were clinically node-negative, 9 were clinically node-positive, and 4 had unknown clinical node status. Of the 183 clinically node-negative patients, 69 (37.7%) patients had node-positive disease at surgery. Overall, 7 of 196 cases had false negative SLNB, yielding an FNR of 8.97%. The sensitivity of SLNB was 91%. Patients with a false negative SLNB were significantly older than patients without (mean age 63 versus 54.7 years, p = 0.041). Significantly fewer sentinel and non-sentinel nodes were removed in women aged 50 years or older compared to those under 50 (1.9 vs. 2.5 sentinel nodes, p = 0.0158; 4.7 vs. 7.9 non-sentinel nodes, p = 0.0077). There were no differences in tumor receptor subtype, grade, stage, presence of lymphovascular invasion, or receipt of neoadjuvant therapy in those with a false negative SLNB compared to those without. Conclusions: The high rate of nodal positivity in clinically node negative patients highlights the challenges of clinical nodal assessment in ILC. Despite this, the SLNB procedure had a FNR that fell within the acceptable range, supporting its use in ILC. The relationship between number of sentinel nodes removed and FNR deserves further study, particularly in older women where extent of nodal surgery continues to decline.

BackgroundThe safety of breast conservation therapy (BCT) has not been demonstrated in large ILC tumors, potentially contributing to the higher mastectomy rates seen in ILC.MethodsWe queried a prospectively maintained database to identify patients with ILC measuring ≥4 cm and evaluated difference in recurrence free survival (RFS) between those treated with BCT versus mastectomy using a multivariate model.ResultsOf 180 patients, 30 (16.7%) underwent BCT and 150 (83.3%) underwent mastectomy. Patients undergoing mastectomy were younger (56.6 vs. 64.3 years, p = 0.003) and had larger tumors (7.2 vs. 5.4 cm, p < 0.001). While tumor size, nodal stage, receptor subtype, and margin status were significantly associated with RFS, there was no difference in RFS at 5 (p = 0.88) or 10 (p = 0.65) years for individuals undergoing BCT versus mastectomy.ConclusionsFor patients with ILC ≥4 cm, BCT provides similar tumor control as mastectomy, provided that negative margins are achieved.

Purpose Invasive ductal carcinoma (IDC) and invasive lobular carcinoma (ILC) are the first and second most common histological subtype of invasive breast carcinoma, with the prevalence of approximately 85% and 10–20% of diagnoses, respectively. ILC is composed of loosely cohesive cells that are individually dispersed or arranged in lines, infiltrating the healthy tissue with diffuse or multifocal/multicentric growth pattern. This makes it difficult to detect in the early stages and to determine the optimal surgical margin. Breast MRI has potential to yield not only morphological information but also functional information (e.g. change in dynamic contrast enhancement [DCE] kinetics). In previous reports using visual assessment, ILC showed relatively slow contrast enhancement compared to IDC and wash-out in the late phase was less common. To better understand the difference between IDC and ILC, we aimed to quantitatively investigate whole-tumor DCE kinetics.