Hallmarks of CD8+ T cell dysfunction are established within hours of tumor antigen encounter before cell division.

Tumor-specific CD8+ T cells (TST) in patients with cancer are dysfunctional and unable to halt cancer progression. TST dysfunction, also known as exhaustion, is thought to be driven by chronic T cell antigen receptor (TCR) stimulation over days to weeks. However, we know little about the interplay between CD8+ T cell function, cell division and epigenetic remodeling within hours of activation. Here, we assessed early CD8+ T cell differentiation, cell division, chromatin accessibility and transcription in tumor-bearing mice and acutely infected mice. Surprisingly, despite robust activation and proliferation, TST had near complete effector function impairment even before undergoing cell division and had acquired hallmark chromatin accessibility features previously associated with later dysfunction/exhaustion. Moreover, continued tumor/antigen exposure drove progressive epigenetic remodeling, 'imprinting' the dysfunctional state. Our study reveals the rapid divergence of T cell fate choice before cell division in the context of tumors versus infection.

CD226 Throttles up CD8+ T Cell Antitumor Activity.

In this issue of Immunity, Weulersse et al. and Braun et al. explain how CD226 expression loss on CD8+ T cells impairs TCR-driven activation, and thereby anti-tumor effector responses, tantamount to taking the CD8+ T cell's foot off the gas pedal.

Tumor-Specific T Cell Dysfunction Is a Dynamic Antigen-Driven Differentiation Program Initiated Early during Tumorigenesis.

CD8(+) T cells recognizing tumor-specific antigens are detected in cancer patients but are dysfunctional. Here we developed a tamoxifen-inducible liver cancer mouse model with a defined oncogenic driver antigen (SV40 large T-antigen) to follow the activation and differentiation of naive tumor-specific CD8(+) T (TST) cells after tumor initiation. Early during the pre-malignant phase of tumorigenesis, TST cells became dysfunctional, exhibiting phenotypic, functional, and transcriptional features similar to dysfunctional T cells isolated from late-stage human tumors. Thus, T cell dysfunction seen in advanced human cancers may already be established early during tumorigenesis. Although the TST cell dysfunctional state was initially therapeutically reversible, it ultimately evolved into a fixed state. Persistent antigen exposure rather than factors associated with the tumor microenvironment drove dysfunction. Moreover, the TST cell differentiation and dysfunction program exhibited features distinct from T cell exhaustion in chronic infections. Strategies to overcome this antigen-driven, cell-intrinsic dysfunction may be required to improve cancer immunotherapy.

Differential Effects of Glutamine Inhibition Strategies on Antitumor CD8 T Cells.

Activated T cells undergo metabolic reprogramming to meet anabolic, differentiation, and functional demands. Glutamine supports many processes in activated T cells, and inhibition of glutamine metabolism alters T cell function in autoimmune disease and cancer. Multiple glutamine-targeting molecules are under investigation, yet the precise mechanisms of glutamine-dependent CD8 T cell differentiation remain unclear. We show that distinct strategies of glutamine inhibition by glutaminase-specific inhibition with small molecule CB-839, pan-glutamine inhibition with 6-diazo-5-oxo-l-norleucine (DON), or by glutamine-depleted conditions (No Q) produce distinct metabolic differentiation trajectories in murine CD8 T cells. T cell activation with CB-839 treatment had a milder effect than did DON or No Q treatment. A key difference was that CB-839-treated cells compensated with increased glycolytic metabolism, whereas DON and No Q-treated cells increased oxidative metabolism. However, all glutamine treatment strategies elevated CD8 T cell dependence on glucose metabolism, and No Q treatment caused adaptation toward reduced glutamine dependence. DON treatment reduced histone modifications and numbers of persisting cells in adoptive transfer studies, but those T cells that remained could expand normally upon secondary Ag encounter. In contrast, No Q-treated cells persisted well yet demonstrated decreased secondary expansion. Consistent with reduced persistence, CD8 T cells activated in the presence of DON had reduced ability to control tumor growth and reduced tumor infiltration in adoptive cell therapy. Overall, each approach to inhibit glutamine metabolism confers distinct effects on CD8 T cells and highlights that targeting the same pathway in different ways can elicit opposing metabolic and functional outcomes.

TOX is a critical regulator of tumour-specific T cell differentiation.

Tumour-specific CD8 T cell dysfunction is a differentiation state that is distinct from the functional effector or memory T cell states1-6. Here we identify the nuclear factor TOX as a crucial regulator of the differentiation of tumour-specific T (TST) cells. We show that TOX is highly expressed in dysfunctional TST cells from tumours and in exhausted T cells during chronic viral infection. Expression of TOX is driven by chronic T cell receptor stimulation and NFAT activation. Ectopic expression of TOX in effector T cells in vitro induced a transcriptional program associated with T cell exhaustion. Conversely, deletion of Tox in TST cells in tumours abrogated the exhaustion program: Tox-deleted TST cells did not upregulate genes for inhibitory receptors (such as Pdcd1, Entpd1, Havcr2, Cd244 and Tigit), the chromatin of which remained largely inaccessible, and retained high expression of transcription factors such as TCF-1. Despite their normal, 'non-exhausted' immunophenotype, Tox-deleted TST cells remained dysfunctional, which suggests that the regulation of expression of inhibitory receptors is uncoupled from the loss of effector function. Notably, although Tox-deleted CD8 T cells differentiated normally to effector and memory states in response to acute infection, Tox-deleted TST cells failed to persist in tumours. We hypothesize that the TOX-induced exhaustion program serves to prevent the overstimulation of T cells and activation-induced cell death in settings of chronic antigen stimulation such as cancer.

Regional brain glucose metabolism is differentially affected by ketogenic diet: a human semiquantitative positron emission tomography.

PURPOSE: Ketogenic diet (KD) is recommended to avoid intense [18F]FDG myocardial physiologic uptake in PET imaging. Neuroprotective and anti-seizure effects of KD have been suggested, but their mechanisms remain to be elucidated. This [18F]FDG PET study aims to evaluate the effect of KD on glucose brain metabolism. METHOD: Subjects who underwent KD prior to whole-body and brain [18F]FDG PET between January 2019 and December 2020 in our department for suspected endocarditis were retrospectively included. Myocardial glucose suppression (MGS) on whole-body PET was analyzed. Patients with brain abnormalities were excluded. Thirty-four subjects with MGS (mean age: 61.8 ± 17.2 years) were included in the KD population, and 14 subjects without MGS were considered for a partial KD group (mean age: 62.3 ± 15.1 years). Brain SUVmax was first compared between these two KD groups to determine possible global uptake difference. Semiquantitative voxel-based intergroup analyses were secondarily performed to determine possible inter-regional differences by comparing KD groups with and without MGS, separately, to 27 healthy subjects fasting for at least 6 h (mean age of 62.4 ± 10.9 years), and KD groups between them (p-voxel < 0.001, and p-cluster < 0.05, FWE-corrected). RESULTS: A 20% lower brain SUVmax was found in subjects under KD with MGS in comparison to those without MGS (Student's t-test, p = 0.02). Whole-brain voxel-based intergroup analysis revealed that patients under KD with and without MGS had relative hypermetabolism of limbic regions including medial temporal cortices and cerebellum lobes and relative hypometabolism of bilateral posterior regions (occipital), without significant difference between them. CONCLUSION: KD globally reduces brain glucose metabolism but with regional differences, requiring special attention to clinical interpretation. On a pathophysiological perspective, these findings could help understand underlying neurological effects of KD through possible decrease of oxidative stress in posterior regions and functional compensation in the limbic regions.

Chromatin states define tumour-specific T cell dysfunction and reprogramming.

Tumour-specific CD8 T cells in solid tumours are dysfunctional, allowing tumours to progress. The epigenetic regulation of T cell dysfunction and therapeutic reprogrammability (for example, to immune checkpoint blockade) is not well understood. Here we show that T cells in mouse tumours differentiate through two discrete chromatin states: a plastic dysfunctional state from which T cells can be rescued, and a fixed dysfunctional state in which the cells are resistant to reprogramming. We identified surface markers associated with each chromatin state that distinguished reprogrammable from non-reprogrammable PD1hi dysfunctional T cells within heterogeneous T cell populations from tumours in mice; these surface markers were also expressed on human PD1hi tumour-infiltrating CD8 T cells. Our study has important implications for cancer immunotherapy as we define key transcription factors and epigenetic programs underlying T cell dysfunction and surface markers that predict therapeutic reprogrammability.

Presentation and characteristics of breast cancer in young women under age 40.

PURPOSE: Although uncommon, breast cancer is the leading cause of cancer death in young women. There are limited studies on the presentation and characteristics of breast cancer in women under age 40. METHODS: This is a retrospective study investigating patient demographics, clinical presentations, imaging findings, and cancer characteristics of a cohort of 145 women under age 40 with breast cancer. RESULTS: Our cohort had more aggressive cancer subtypes than reported in older women; 33.1% triple negative, 80% high Ki-67, and 21.3% with stage 3+ disease. Most were referred from primary care or obstetrician/gynecologist, though 5.5% initially presented from the emergency department and another 2.1% were incidental findings. 16.6% of patients presented while pregnant or breastfeeding. Most patients presented with breast related symptoms. Of the 9.1% of patients diagnosed through our high-risk screening program, 84.6% of the cancers were identified on mammography or simultaneously with mammography and MRI. Most breast cancers presented with typically worrisome imaging (82.6%), though several cancers presented with findings that were typically benign. CONCLUSIONS: We recommend prompt breast imaging for young women presenting with breast-related symptoms or an incidental breast finding, as younger patients have more aggressive cancer subtypes and are of a higher grade at presentation compared to older women. We also recommend vigilance when distinguishing suspicious symptoms from pregnancy-related breast changes to minimize delays in diagnosis. Additionally, it is important to identify patients who qualify for high risk screening, since cancers in screening patients were found at a lower grade than those presenting with symptoms.

Tomosynthesis-Guided Vacuum-Assisted Breast Biopsy of Architectural Distortion Without a Sonographic Correlate: A Retrospective Review.

BACKGROUND. Digital breast tomosynthesis-guided vacuum-assisted breast biopsy (DBT VAB) allows biopsy of findings seen better or exclusively on digital breast tomosynthesis (DBT), including architectural distortion. Although architectural distortion with an associated sonographic mass correlate has a high risk of malignancy, limited data describe the radiologic-pathologic correlation of tomosynthesis-detected architectural distortion without a sonographic correlate. OBJECTIVE. This study evaluates the malignancy rate of architectural distortions without a sonographic correlate that undergo DBT VAB and provides radiologic-pathologic correlation for benign, high-risk, and malignant entities that are associated with architectural distortion. METHODS. We retrospectively reviewed imaging, as well as pathology slides and/or reports, for DBT VABs performed for architectural distortion without a sonographic correlate at a single institution between June 1, 2017, and January 15, 2020. According to the correlative histopathology, cases were categorized as benign, high risk, or malignant, and specific histopathologic diagnoses were summarized. RESULTS. During the study period, 142 patients (mean age, 59 years) underwent DBT VAB for 151 unique architectural distortions without a sonographic correlate. DBT VAB revealed a malignant diagnosis in 27 (18%), a high-risk lesion in 50 (33%), and a benign diagnosis in 74 (49%). Two cases of atypical ductal hyperplasia were upgraded to malignancy, resulting in a final malignancy rate of 19% (n = 29/151). Most malignant lesions were invasive carcinomas (83%, n = 24/29); most invasive carcinomas were of lobular subtype (54%, n = 13/24). Most high-risk lesions were radial scars/complex sclerosing lesions (62%, n = 31/50). Most benign results represented fibrocystic change (66%, n = 49/74). A subset (11%, n = 8/74) of benign results were considered discordant and subsequently excised, with none representing malignancy. CONCLUSION. The final malignancy rate of 19% in architectural distortion without a sonographic correlate justifies a recommendation for biopsy using DBT VAB. CLINICAL IMPACT. Our results highlight the utility of DBT VAB in the era of DBT. The detailed radiologic-pathologic correlations will assist radiologists in assessing concordance when performing DBT VAB for architectural distortions and provide a reference for future patient management.

Breast MRI biopsy cancellation due to lesion nonvisualization.

It is a clinical dilemma when a finding reported as suspicious on a breast MRI is not visualized at the time of a scheduled MRI-guided breast biopsy. We retrospectively reviewed all canceled MRI-guided biopsies at our institution between 6/1/2009 and 9/20/2019 and found a cancellation rate of 6.9% (72/1051). In one case, a mastectomy was performed after the canceled biopsy revealing a focus of DCIS in the same quadrant as the original finding (malignancy rate 2.1%). Our results support the current practice of 6-month follow-up MRI recommendation after a canceled MRI-guided biopsy for lesion nonvisualization.

Bendamustine with rituximab, etoposide and carboplatin (T(R)EC) in relapsed or refractory aggressive lymphoma: a prospective multicentre phase 1/2 clinical trial.

We sought to develop a safe and effective outpatient salvage regimen by replacing ifosfamide within the (R)ICE (rituximab, ifosfomide, carboplatin, etoposide) regimen with bendamustine (T(R)EC) via a multicentre phase I/II study for patients with relapsed or refractory diffuse large B cell lymphoma (DLBCL) and classic Hodgkin lymphoma (HL). Therapy consisted of 60-120 mg/m2 per day bendamustine on days 1 and 2 in combination with carboplatin, etoposide and rituximab (only for CD20+ lymphoma) used in the (R)ICE regimen for up to 2 cycles. The objectives were to define a maximally tolerated dose (MTD) of bendamustine, determine safety and toxicity, assess efficacy, and evaluate impact on stem cell collection. Forty-eight patients were treated of which 71% had refractory disease. No dose-limiting toxicities were observed. The recommended phase II dose of bendamustine was 120 mg/m2 per day on days 1 and 2. Response rates were 85% (70% complete response, CR) in HL, and 65% (40% CR) in DLBCL. Stem cell collection was successful in 30 of 32 patients. The most common non-haematological toxicities ≥grade 3 were febrile neutropenia (8%) and dehydration (8%). The T(R)EC regimen safely yields high response rates, successfully mobilizes peripheral blood stem cells and compares favourably to RICE, offering an effective outpatient treatment option for patients with relapsed or refractory DLBCL and HL.

Beyond Genomics: Multidimensional Analysis of Cancer Therapy Resistance.

Cancer resistance to therapy occurs through a selection process generally thought to be driven by mutations. In a recent study, Hugo et al. use multidimensional analysis of the dynamic genetic, transcriptional, epigenetic, and immune landscape alterations in baseline and MAPK inhibitor-resistant melanoma tumors, demonstrating a role for 'non-genomic' drivers in cancer evolution.

Heme exporter FLVCR is required for T cell development and peripheral survival.

All aerobic cells and organisms must synthesize heme from the amino acid glycine and the tricarboxylic acid cycle intermediate succinyl CoA for incorporation into hemoproteins, such as the cytochromes needed for oxidative phosphorylation. Most studies on heme regulation have been done in erythroid cells or hepatocytes; however, much less is known about heme metabolism in other cell types. The feline leukemia virus subgroup C receptor (FLVCR) is a 12-transmembrane domain surface protein that exports heme from cells, and it was shown to be required for erythroid development. In this article, we show that deletion of Flvcr in murine hematopoietic precursors caused a complete block in αß T cell development at the CD4(+)CD8(+) double-positive stage, although other lymphoid lineages were not affected. Moreover, FLVCR was required for the proliferation and survival of peripheral CD4(+) and CD8(+) T cells. These studies identify a novel and unexpected role for FLVCR, a major facilitator superfamily metabolite transporter, in T cell development and suggest that heme metabolism is particularly important in the T lineage.

Pretransplantation Minimal Residual Disease Predicts Survival in Patients with Mantle Cell Lymphoma Undergoing Autologous Stem Cell Transplantation in Complete Remission.

Autologous stem cell transplantation (ASCT) is standard therapy for mantle cell lymphoma (MCL) in remission after induction chemotherapy, with the best results for patients in complete remission (CR). We hypothesized that evaluation of minimal residual disease (MRD) before ASCT could further stratify outcomes for these patients. Patients with MCL who underwent ASCT in clinical CR between 1996 and 2011 with pretransplantation MRD testing were eligible. Presence of a clonal IgH rearrangement, t(11; 14) by PCR or positive flow cytometry from blood or bone marrow, was considered positive. An adjusted proportional hazards model for associations with progression-free (PFS) and overall survival (OS) was performed. Of 75 MCL patients in CR, 8 (11%) were MRD positive. MRD positivity was associated with shorter OS and PFS. The median OS for MRD-negative patients was not reached, with 82% survival at 5 years, whereas for the MRD-positive patients, median OS was 3.01 years (hazard ratio [HR], 4.04; P = .009), with a median follow-up of 5.1 years. The median PFS for MRD-negative patients was not reached with 75% PFS at 5 years, whereas for MRD-positive patients, it was 2.38 years (HR, 3.69; P = .002). MRD positivity is independently associated with poor outcomes after ASCT for MCL patients in CR.

High-dose CD20-targeted radioimmunotherapy-based autologous transplantation improves outcomes for persistent mantle cell lymphoma.

Autologous stem cell transplant (ASCT) can improve outcomes for mantle cell lymphoma (MCL) patients, yet relapses are frequent. We hypothesized that high-dose anti-CD20 radioimmunotherapy (RIT)-based conditioning could improve results in this setting. We thus assessed 162 consecutive patients with MCL at our centre undergoing ASCT following high-dose RIT-based (n = 61) or standard (n = 101) conditioning. RIT patients were less likely to be in first remission (48% vs. 72%; P = 0·002), be in complete remission (CR) (26% vs. 61%; P < 0·001) and have chemosensitive disease (84% vs. 96%; P = 0·006). RIT-based conditioning was associated with a reduced risk of treatment failure [hazard ratio (HR) 0·40; P = 0·001] and mortality (HR 0·49; P = 0·01) after adjusting for these imbalances. This difference increased as disease status worsened (from CR to partial remission to stable/progressive disease), with respective HRs of 1·14, 0·53 and 0·04 for mortality, and 0·66, 0·36 and 0·14 for treatment failure. RIT-based conditioning appears to improve outcome following ASCT for MCL patients unable to achieve CR after controlling for imbalances in important risk factors. These data support the further study of RIT and radiation-based strategies in a risk-adapted approach to ASCT for persistent MCL.

Brentuximab vedotin administered to platinum-refractory, transplant-naïve Hodgkin lymphoma patients can increase the proportion achieving FDG PET negative status.

Normalization of fluorodeoxyglucose positron emission tomography (FDG PET) imaging prior to high-dose therapy and autologous stem cell transplantation (ASCT) improves outcomes in relapsed and refractory (RR) Hodgkin lymphoma (HL), but many patients refractory to platinum-based salvage regimens are unable to achieve this goal. We therefore investigated whether brentuximab vedotin (BV) could normalize FDG PET in platinum-refractory HL prior to ASCT. Fifteen consecutive patients with RR HL and FDG PET positive disease after platinum-based salvage therapy were treated with a median of 4 cycles of BV. Normalization of FDG PET (Deauville ≤2) occurred in 8/15 (53%) patients but was only observed in patients that had achieved partial remission or stable disease after platinum-based salvage therapy. All patients eventually proceeded to ASCT, regardless of FDG PET status. Our data suggest that BV can normalize FDG PET in a subset of patients with platinum-refractory HL prior to ASCT.

Atrioventricular conduction disorders in aortic valve infective endocarditis.

BACKGROUND: Aortic valve infective endocarditis may be complicated by high-degree atrioventricular block in up to 10-20% of cases. AIM: To assess high-degree atrioventricular block occurrence, contributing factors, prognosis and evolution in patients referred for aortic infective endocarditis. METHODS: Two hundred and five patients referred for aortic valve infective endocarditis between January 2018 and March 2021 were included in this study. A comprehensive assessment of clinical, electrocardiographic, biological, microbiological and imaging data was conducted, with a follow-up carried out over 1 year. RESULTS: High-degree atrioventricular block occurred in 22 (11%) patients. In univariate analysis, high-degree atrioventricular block was associated with first-degree heart block at admission (odds ratio 3.1; P=0.015), periannular complication on echocardiography (odds ratio 6.9; P<0.001) and severe biological inflammatory syndrome, notably C-reactive protein (127 vs 90mg/L; P=0.011). In-hospital mortality (12.7%) was higher in patients with high-degree atrioventricular block (odds ratio 4.0; P=0.011) in univariate analysis. Of the 16 patients implanted with a permanent pacemaker for high-degree atrioventricular block and interrogated, only four (25%) were dependent on the pacing function at 1-year follow-up. CONCLUSIONS: High-degree atrioventricular block is associated with high inflammation markers and periannular complications, especially if first-degree heart block is identified at admission. High-degree atrioventricular block is a marker of infectious severity, and tends to raise the in-hospital mortality rate. Systematic assessment of patients admitted for infective endocarditis suspicion, considering these contributing factors, could indicate intensive care unit monitoring or even temporary pacemaker implantation in those at highest risk.

Vaccination generates functional progenitor tumor-specific CD8 T cells and long-term tumor control.

Background: Immune checkpoint blockade (ICB) therapies are an important treatment for patients with advanced cancers; however only a subset of patients with certain types of cancer achieves durable remissions. Cancer vaccines are an attractive strategy to boost patient immune responses, but less is known about whether and how immunization can induce long-term tumor immune reprogramming and arrest cancer progression. We developed a clinically-relevant genetic cancer mouse model in which hepatocytes sporadically undergo oncogenic transformation. We compared how tumor-specific CD8 T cells (TST) differentiate in mice with early sporadic lesions as compared to late lesions and tested how immunotherapeutic strategies, including vaccination and ICB, reprogram TST and impact liver cancer progression. Methods: Mice with a germline floxed allele of the SV40 large T antigen (TAG) undergo spontaneous recombination and activation of the TAG oncogene, leading to rare early pre-cancerous lesions that inevitably progress to established liver cancer. We assessed the immunophenotype and function of TAG-specific CD8 T cells in mice with early and late liver lesions. We vaccinated mice, either alone or in combination with ICB, to test whether these immunotherapeutic interventions could stop liver cancer progression. Results: In mice with early lesions, a subset of TST were PD1 + TCF1 + TOX - and could produce IFNγ, while TST present in mice with late liver cancers were PD1 + TCF1 lo/- TOX + and unable to make effector cytokines. Strikingly, vaccination with attenuated TAG epitope-expressing Listeria monocytogenes (LM TAG ) blocked liver cancer development and led to a population of TST that were TCF1 + TOX - TST and polyfunctional cytokine producers. In contrast, ICB administration did not slow cancer progression or improve LM TAG vaccine efficacy. Conclusion: Vaccination, but not ICB, generated a population of progenitor TST and halted cancer progression in a clinically relevant model of sporadic liver cancer. In patients with early cancers or at high-risk of cancer recurrence, immunization may be the most effective strategy. What is already known on this topic: Immunotherapy, including immune checkpoint blockade and cancer vaccines, fails to induce long-term remissions in most patients with cancer. What this study adds: Hosts with early lesions but not hosts with advanced cancer retain a progenitor TCF1+ TST population. This population can be reprogrammed and therapeutically exploited by vaccination, but not ICB, to block tumor progression. How this study might affect research practice or policy: For people at high-risk of cancer progression, vaccination administered when a responsive progenitor TST population is present may be the optimal immunotherapy to induce long-lasting progression-free survival.

Specific features identify patients with relapsed or refractory mantle cell lymphoma benefitting from autologous hematopoietic cell transplantation.

Outcomes with autologous hematopoietic cell transplantation (auto HCT) for relapsed and/or refractory mantle cell lymphoma (MCL) are typically poor. We hypothesized that certain factors could predict which patients experience a favorable outcome with this approach. We thus developed a predictive score from a cohort of 67 such patients using 3 factors independently associated with progression-free survival (PFS): (1) simplified Mantle Cell Lymphoma International Prognostic Index score before auto HCT (hazard ratio [HR], 2.9; P = .002); (2) B symptoms at diagnosis (HR, 2.7; P = .005); and (3) remission quotient, calculated by dividing the time, in months, from diagnosis to auto HCT by the number of prior treatments (HR, 1.4; P = .02). The estimated 5-year PFS for favorable-risk patients (n = 23) and unfavorable-risk patients (n = 44) were 58% (95% confidence interval [CI], 34% to 75%) and 15% (95% CI, 6% to 28%), respectively. These factors also independently predicted overall survival. In summary, we have defined 3 simple factors that can identify patients with relapsed/refractory MCL who derive a durable benefit from salvage auto HCT.

Solitary Dilated Ducts Revisited: Malignancy Rate and Implications for Management.

RATIONALE AND OBJECTIVES: A solitary dilated duct (SDD) is a single asymmetrically dilated breast duct with diameter more than 2 mm. The Breast Imaging Reporting and Data System (BI-RADS) fifth edition recommends additional imaging and biopsy for SDDs without demonstrated benign etiology, however management of this rare entity remains controversial. This study describes practice patterns, malignancy rate, and features associated with high-risk/malignant SDDs to better stratify patients requiring biopsy versus follow-up. MATERIALS AND METHODS: This IRB-approved retrospective study identified mammographic, sonographic and MRI exams utilizing the term "solitary dilated duct" at a multisite academic institution between 1/1/2010 and 12/31/2020. Clinical and imaging features, BI-RADS assessments, and outcomes were analyzed. Univariate and multivariate analyses identified predictors of high-risk/malignant histology. RESULTS: SDDs identified in 49 women (mean age 56.1 years) were assessed as BI-RADS 4/5 (31/49, 63%), BI-RADS 3 (9/49, 18%), or BI-RADS 2 (9/49, 18%). Most sampled lesions were benign (16/31, 52%) and the remaining were high-risk (15/31, 48%, all papillary lesions). The only papilloma with atypia on core biopsy upgraded to grade 2 DCIS on excision (malignancy rate 1/49, 2%). All anechoic SDDs were benign (n=13), and all benign SDDs lacked internal vascularity. SDDs with associated masses were associated with malignant/high-risk outcomes on multivariate analysis (p < .001). CONCLUSION: The BI-RADS fifth edition recommends biopsy for SDDs without demonstrated benign etiology. In our 11-year study period, practice patterns were variable with a low malignancy rate of 2%. Our findings suggest that anechoic SDDs may be followed, and SDDs with associated masses or internal vascularity require biopsy.