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.

Characteristics and prognosis of isolated aortic valve infective endocarditis in patients with bicuspid aortic valves: a propensity matched study.

Introduction: Bicuspid aortic valve (BAV) is the most common congenital heart disease with an increased risk of infective endocarditis (IE). Few data are available on isolated native BAV-IE. The aim of this study was to compare patients with tricuspid aortic valve (TAV) IE and BAV-IE in terms of characteristics, management and prognosis. Material and methods: We included 728 consecutive patients with IE on isolated native aortic valve in 3 centres: Amiens and Marseille Hospitals in France and Salerno Hospital in Italy. We studied in hospital and long-term mortality before and after matching for age, sex and comorbidity index. Median follow-up was 67.2 [IQR: 19-120] months. Results: Of the 728 patients, 123 (16.9%) had BAV. Compared with patients with TAV-IE, patients with BAV-IE were younger, had fewer co-morbidities and were more likely to be male. They presented more major neurological events and perivalvular complications (both p < 0.05). Early surgery (<30 days) was performed in 52% of BAV-IE cases vs. 42.8% for TAV-IE (p = 0.061). The 10-year survival rate was 74 ± 5% in BAV-IE patients compared with 66 ± 2% in TAV-IE patients (p = 0.047). After propensity score matching (for age, gender and comorbidities), there was no difference in mortality between the two groups, with an estimated 10-year survival of 73 ± 5% vs. 76 ± 4% respectively (p = 0.91). Conclusion: BAV is a frequent finding in patients with isolated aortic valve IE and is associated with more perivalvular complications and neurological events. The differences in survival with TAV-IE are probably related to the age and comorbidity differences between these two populations.

Tumor-Reactive CD8+ T Cells Enter a TCF1+PD-1- Dysfunctional State.

T cells recognize several types of antigens in tumors, including aberrantly expressed, nonmutated proteins, which are therefore shared with normal tissue and referred to as self/shared-antigens (SSA), and mutated proteins or oncogenic viral proteins, which are referred to as tumor-specific antigens (TSA). Immunotherapies such as immune checkpoint blockade (ICB) can activate T-cell responses against TSA, leading to tumor control, and also against SSA, causing immune-related adverse events (irAE). To improve anti-TSA immunity while limiting anti-SSA autoreactivity, we need to understand how tumor-specific CD8+ T cells (TST) and SSA-specific CD8+ T (SST) cells differentiate in response to cognate antigens during tumorigenesis. Therefore, we developed a genetic cancer mouse model in which we can track TST and SST differentiation longitudinally as liver cancers develop. We found that both TST and SST lost effector function over time, but while TST persisted long term and had a dysfunctional/exhausted phenotype (including expression of PD1, CD39, and TOX), SST exited cell cycle prematurely and disappeared from liver lesions. However, SST persisted in spleens in a dysfunctional TCF1+PD-1- state: unable to produce effector cytokines or proliferate in response to ICB targeting PD-1 or PD-L1. Thus, our studies identify a dysfunctional T-cell state occupied by T cells reactive to SSA: a TCF1+PD-1- state lacking in effector function, demonstrating that the type/specificity of tumor antigen may determine tumor-reactive T-cell differentiation.

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.

Multimodality imaging in marantic endocarditis associated with cancer: a multicentric cohort study.

AIMS: We aimed to assess the role of multimodality imaging (MMI) in the diagnosis of marantic endocarditis (ME) associated with cancers and to describe the clinical characteristics, management, and outcome of these patients. METHODS AND RESULTS: In a retrospective multicentric study including four tertiary centres for the treatment of endocarditis in France and Belgium, patients with a diagnosis of ME were included. Demographic, MMI [echocardiography, computed tomography (CT), and 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT)], and management data were collected. Long-term mortality was analysed. Between November 2011 and August 2021, 47 patients with a diagnosis of ME were included. Mean age was 65 ± 11 years. ME occurred in 43 cases (91%) on native valves. Vegetations were detected by echocardiography in all cases and in 12 cases (26%) by CT. No patient had an increased cardiac 18F-FDG valve uptake. The most common cardiac valve involved was aortic (34 cases, 73%). Twenty-two patients (46%) had a known cancer before ME, and 25 cases (54%) were diagnosed thanks to multimodality imaging. 18FDG PET/CT was performed in 30 patients (64%) and allowed a new diagnosis of cancer in 14 patients (30%). Systemic embolism was frequent (40 patients, 85% of cases). Forty-one patients (87%) were treated medically with anticoagulation therapy. One-year mortality was 55% (26 patients). CONCLUSION: ME remains associated with a high risk of complications and death.

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.

Impact of cardiac surgery on left-sided infective endocarditis with intermediate-length vegetations.

OBJECTIVE: The best strategy to manage patients with left-sided infective endocarditis (IE) and intermediate-length vegetations (10-15 mm) remains uncertain. We aimed to evaluate the role of surgery in patients with intermediate-length vegetations and no other European Society of Cardiology guidelines-approved surgical indication. METHODS: We retrospectively enrolled 638 consecutive patients admitted to three academic centres (Amiens, Marseille and Florence University Hospitals) between 2012 and 2022 for left-sided definite IE (native or prosthetic) with intermediate-length vegetations (10-15 mm). We compared four clinical groups: medically (n=50) or surgically (n=345) treated complicated IE, medically (n=194) or surgically (n=49) treated uncomplicated IE. RESULTS: Mean age was 67±14 years. Women were 182 (28.6%). The rate of embolic events on admission was 40% in medically treated and 61% in surgically treated complicated IE, 31% in medically treated and 26% in surgically treated uncomplicated IE. The analysis of all-cause mortality showed the lowest 5-year survival rate for medically treated complicated IE (53.7%). We found a similar 5-year survival rate for surgically treated complicated IE (71.4%) and medically treated uncomplicated IE (68.4%). The highest 5-year survival rate was observed in surgically treated uncomplicated IE group (82.4%, log-rank p<0.001). The analysis of the propensity score-matched cohort estimated an HR of 0.23 for uncomplicated IE treated surgically compared with medical therapy (p=0.005, 95% CI: 0.079 to 0.656). CONCLUSIONS: Our results suggest that surgery is associated with lower all-cause mortality than medical therapy in patients with uncomplicated left-sided IE with intermediate-length vegetations even in the absence of other guideline-based indications.

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.

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.

Influence of the healthcare pathway on the outcome of patients with infective endocarditis.

AIMS: To determine the prognosis of patients treated for infective endocarditis (IE) according to their healthcare pathway. To assess how the ESC guidelines are implemented concerning the performance of transoesophageal echocardiography, the use of antibiotic therapy, and the performance of valve surgery; and to compare the epidemiological profile of IE according to the type of centres in which the patients are hospitalized. METHODS AND RESULTS: In a prospective multicentric study including 22 hospitals in the South-East of France, 342 patients were classified into three groups according to their healthcare pathway: 119 patients diagnosed and taken care entirely in a reference centre or hospital with cardiac surgery [Referral Center (RC) group], 111 patients diagnosed and initially taken care in a non-RC (NRC), then referred in a centre including cardiac surgery [transferred to the Referral Center (TRC) group] and 112 patients totally taken care in the NRC (NRC group). One-year mortality was 26% (88 deaths) and was not significantly different between Groups 1 and 2 (20 vs. 21%, P = 0.83). Patients in the NRC group had a higher mortality (37%) compared with patients in the RC and TRC groups (P < 0.001). ESC guidelines were not implemented similarly depending on the healthcare pathway (P = 0.04). Patients in the NRC group were significantly older (P < 0.001) and had more comorbidities (P < 0.001) than patients treated in referral centres. CONCLUSION: Prognosis of patients with IE is influenced by their healthcare pathway. Patients treated exclusively in NRC have a worse prognosis than patients treated in referral or surgical centres.

Socioeconomic variations determine the clinical presentation, aetiology, and outcome of infective endocarditis: a prospective cohort study from the ESC-EORP EURO-ENDO (European Infective Endocarditis) registry.

AIMS: Infective endocarditis (IE) is a life-threatening disease associated with high mortality and morbidity worldwide. We sought to determine how socioeconomic factors might influence its epidemiology, clinical presentation, investigation and management, and outcome, in a large international multicentre registry. METHODS AND RESULTS: The EurObservational Programme (EORP) of the European Society of Cardiology EURO-ENDO (European Infective Endocarditis) registry comprises a prospective cohort of 3113 adult patients admitted for IE in 156 hospitals in 40 countries between January 2016 and March 2018. Patients were separated in three groups, according to World Bank economic stratification [group 1: high income (75.6%); group 2: upper-middle income (15.4%); group 3: lower-middle income (9.1%)]. Group 3 patients were younger [median age (interquartile range, IQR): group 1, 66 (53-75) years; group 2, 57 (41-68) years; group 3, 33 (26-43) years; P < 0.001] with a higher frequency of smokers, intravenous drug use, and human immunodeficiency virus infection (all P < 0.001) and presented later [median (IQR) days since symptom onset: group 1, 12 (3-35); group 2, 19 (6-54); group 3, 31 (12-62); P < 0.001] with a higher likelihood of developing congestive heart failure (13.6%, 11.1%, and 22.6%, respectively; P < 0.001) and persistent fever (9.8%, 14.2%, and 27.9%, respectively; P < 0.001). Among 2157 (69.3%) patients with theoretical indication for cardiac surgery, surgery was performed less frequently in group 3 patients (75.5%, 76.8%, and 51.3%, respectively; P < 0.001), who also demonstrated the highest mortality (15.0%, 23.0%, and 23.7%, respectively; P < 0.001). CONCLUSION: Socioeconomic factors influence the clinical profile of patients presenting with IE across the world. Despite younger age, patients from the poorest countries presented with more frequent complications and higher mortality associated with delayed diagnosis and lower use of surgery.

Mitral valve repair is better than mitral valve replacement in native mitral valve endocarditis: Results from a prospective matched cohort.

BACKGROUND: In native mitral valve infective endocarditis (NMIE), the respective values of mitral valve repair (MVRep) and replacement (MVR) are still debated. AIM: To compare MVRep and MVR in a large prospective matched cohort. METHODS: Between 2010 and 2017, all consecutive patients operated on for NMIE in our centre were included prospectively. Clinical and outcome features were compared between the two groups. Primary endpoint was event-free survival, including death, reoperation and relapse. Univariate and multivariable survival analyses and a propensity score analysis were performed. RESULTS: Among 152 patients, 115 (75.7%) underwent MVRep, and 37 (24.3%) MVR. Median follow-up was 28±22months. Surgery was performed during the active phase in 75.0% of patients (25.7% on an urgent basis). Compared with the MVRep group, patients in the MVR group were more frequently intravenous drug abusers (10.8% vs. 0.9%; P=0.016), had a more frequent history of rheumatic fever (13.5% vs. 0%; P=0.001), more aortic abscesses (16.7% vs. 3.5%; P=0.018), larger vegetations (16.6±8.1mm vs. 12.6±9.9mm; P=0.042) and poorer New York Heart Association status (P=0.006). Overall mortality was lower in the MVRep group than in MVR group (11.3% vs. 29.3%; P=0.018). Event-free survival was better in the MVRep group than in the MVR group in univariate analysis (hazard ratio: 2.72, 95% confidence interval: 1.34-5.52; P=0.004). Survival analysis in the propensity-matched cohort showed that MVRep was safer than MVR (log rank test: P=0.018). Multivariable analysis using the Cox proportional hazard model confirmed this finding (hazard ratio: 3.48, 95% confidence interval: 1.15-10.61; P=0.03). CONCLUSIONS: MVRep is feasible in most cases of NMIE and, when technically possible, should be preferred, even in urgent surgery.

Viral and cellular oncogenes promote immune evasion.

Thirteen percent of cancers worldwide are associated with viral infections. While many human oncogenic viruses are widely endemic, very few infected individuals develop cancer. This raises the question why oncogenic viruses encode viral oncogenes if they can replicate and spread between human hosts without causing cancer. Interestingly, viral infection triggers innate immune signaling pathways that in turn activate tumor suppressors such as p53, suggesting that tumor suppressors may have evolved not primarily to prevent cancer, but to thwart viral infection. Here, we summarize and compare several major immune evasion strategies used by viral and non-viral cancers, with a focus on oncogenes that play dual roles in promoting tumorigenicity and immune evasion. By highlighting important and illustrative examples of how oncogenic viruses evade the immune system, we aim to shed light on how non-viral cancers avoid immune detection. Further study and understanding of how viral and non-viral oncogenes impact immune function could lead to improved strategies to combine molecular therapies targeting oncoproteins in combination with immunomodulators.

TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion.

T cell receptor (TCR) signal strength is a key determinant of T cell responses. We developed a cancer mouse model in which tumor-specific CD8 T cells (TST cells) encounter tumor antigens with varying TCR signal strength. High-signal-strength interactions caused TST cells to up-regulate inhibitory receptors (IRs), lose effector function, and establish a dysfunction-associated molecular program. TST cells undergoing low-signal-strength interactions also up-regulated IRs, including PD1, but retained a cell-intrinsic functional state. Surprisingly, neither high- nor low-signal-strength interactions led to tumor control in vivo, revealing two distinct mechanisms by which PD1hi TST cells permit tumor escape; high signal strength drives dysfunction, while low signal strength results in functional inertness, where the signal strength is too low to mediate effective cancer cell killing by functional TST cells. CRISPR-Cas9-mediated fine-tuning of signal strength to an intermediate range improved anti-tumor activity in vivo. Our study defines the role of TCR signal strength in TST cell function, with important implications for T cell-based cancer immunotherapies.

CD8+ T cell differentiation and dysfunction in cancer.

CD8+ T cells specific for cancer cells are detected within tumours. However, despite their presence, tumours progress. The clinical success of immune checkpoint blockade and adoptive T cell therapy demonstrates the potential of CD8+ T cells to mediate antitumour responses; however, most patients with cancer fail to achieve long-term responses to immunotherapy. Here we review CD8+ T cell differentiation to dysfunctional states during tumorigenesis. We highlight similarities and differences between T cell dysfunction and other hyporesponsive T cell states and discuss the spatio-temporal factors contributing to T cell state heterogeneity in tumours. An important challenge is predicting which patients will respond to immunotherapeutic interventions and understanding which T cell subsets mediate the clinical response. We explore our current understanding of what determines T cell responsiveness and resistance to immunotherapy and point out the outstanding research questions.

Dose-dense brentuximab vedotin plus ifosfamide, carboplatin, and etoposide for second-line treatment of relapsed or refractory classical Hodgkin lymphoma: a single centre, phase 1/2 study.

BACKGROUND: Relapsed or refractory classical Hodgkin lymphoma could be treated with multiagent salvage chemotherapy followed by autologous haematopoietic stem-cell transplantation. The aim of this study is to establish the safety and activity of dose-dense brentuximab vedotin combined with ifosfamide, carboplatin, and etoposide (BV-ICE) chemotherapy in second-line treatment of classical Hodgkin lymphoma. METHODS: We conducted a single-arm, open-label, phase 1/2 study of dose-dense BV-ICE at the Seattle Cancer Care Alliance, University of Washington (Seattle, WA, USA). Eligibility criteria were age 18 years or older; diagnosis of first relapse, primary refractory classical Hodgkin lymphoma after one previous line of therapy; measurable disease of at least 1 cm in the longest axis, CT of chest, abdomen, and pelvis with PET within the past 28 days; Eastern Cooperative Oncology Group performance status of 0-1; and adequate organ function. A 3 + 3 dose escalation study was done for the phase 1 part of the trial to establish the maximum tolerated dose to be used for the phase 2 study. Brentuximab vedotin was delivered on days 1 and 8 at either 1·2 mg/kg (dose level 1) or 1·5 mg/kg (dose level 2) intravenously (capped at 150 mg) with standard dosing of ICE on days 1-3 (ifosfamide 5 g/m2 plus mesna 5 g/m2 intravenously over 24 h on day 2, carboplatin area under the curve 5 on day 2 in one intravenous injection, and etoposide 100 mg/m2 on days 1-3 in one intravenous injection per day) for two 21-day cycles. The primary endpoint was to establish the recommended phase 2 dose (phase 1 part) and complete response rate after two cycles, with a prespecified target of 78% (phase 2 part). Safety analysis was done in all enrolled participants and the primary activity analysis was done in all patients with evaluable response data. This study is registered with ClinicalTrials.gov (NCT02227199); enrolment and study treatment are complete. FINDINGS: Between Oct 16, 2014, and Feb 10, 2020, we enrolled 45 patients with a median age of 31 years (IQR 28-45). The recommended phase 2 dose of brentuximab vedotin was established to be 1·5 mg/kg. After a median follow-up of 3·1 years (IQR 1·7-4·1), 32 (74%; 95% CI 58·8-86·5) of 43 evaluable patients had complete responses after two cycles of treatment. Grade 3-4 haematological toxic effects were common, including neutropenia (33 [73%]), anaemia (six [13%]), and thrombocytopenia (36 [80%]). The most common grade 3-4 non-haematological toxic effects were febrile neutropenia (four [9%]), sepsis (six [13%]), increased alanine aminotransferase (five [11%]), hyperglycaemia (three [7%]), pulmonary embolism (two [4%]), and increased aspartate aminotransferase (two [4%]). There was one (2%) on-treatment death due to multisystem organ failure that was considered treatment related. Serious adverse events occurred in 13 (29%) patients. INTERPRETATION: Our data suggest that dose-dense BV-ICE is a rapidly administered and active salvage regimen for patients with relapsed or refractory classical Hodgkin lymphoma despite a complete response in this trial lower than the prespecified phase 2 target. Although cross-trial comparisons should be made with caution, activity results seem to be similar to previously presented brentuximab vedotin chemotherapy salvage combinations delivered over much longer durations and can be considered in young (<60 years), transplantation-eligible patients for second-line therapy. FUNDING: Seagen, Lymphoma Research Foundation, National Institutes of Health/National Cancer Institute, and generous philanthropic donations to the University of Washington from numerous individuals and families in support of lymphoma research.

Infective endocarditis with neurological complications: Delaying cardiac surgery is associated with worse outcome.

BACKGROUND: Infective endocarditis (IE) is associated with a high mortality rate, related in part to neurological complications. Studies suggest that valvular surgery should be performed early when indicated, but is often delayed by the presence of neurological complications. AIM: To assess the effect of delaying surgery in patients with IE and neurological complications and to identify factors predictive of death. METHODS: In a prospective, single-centre study in a referral centre for IE, all patients with IE underwent systematic screening for neurological complications. The primary outcome was 6-month death. In patients presenting with neurological complications, the prognosis according to surgical status was analysed and a Cox regression model used to identify variables predictive of death. RESULTS: Between April 2014 and January 2018, 351 patients with a definite diagnosis of left-sided IE were included. Ninety-four patients (26.8%) presented with at least one neurological complication. Fifty-nine patients (17.7%) died during 6-month follow-up. Six-month mortality rates did not differ significantly between patients with and without neurological complications (P=0.60). Forty patients had a temporary surgical contraindication because of neurological complications. During the period of surgical contraindication, seven of these patients (17.5%) died, six (15.0%) presented a new embolic event, and 12 (30.0%) presented cardiac or septic deterioration. In multivariable analysis, predictive factors of death in patients presenting with neurological complications were temporary surgical contraindication (hazard ratio 7.36, 95% confidence interval 1.61-33.67; P=0.010) and presence of a mechanical prosthetic valve (hazard ratio 16.40, 95% confidence interval 2.22-121.17; P=0.006). CONCLUSIONS: Patients with a temporary surgical contraindication due to neurological complications had a higher risk of death and frequent major complications while waiting for surgery. When indicated, the decision to postpone surgery in the early phase should be weighed against the risk of infectious or cardiac deterioration.

18F-fluorodeoxyglucose positron emission tomography/computed tomography for the diagnosis of native valve infective endocarditis: A prospective study.

BACKGROUND: 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (18F-FDG PET/CT) has recently been added as a major criterion in the European Society of Cardiology (ESC) 2015 infective endocarditis guidelines. PET/CT is currently used in patients with suspected prosthetic valve and cardiac device-related endocarditis. However, the value of the ESC classification and the clinical impact of PET findings are unknown in patients with native valve endocarditis (NVE). AIMS: Our aims were: to assess the value of the ESC criteria (including PET/CT) in NVE; to determine the usefulness of PET/CT concerning embolic detection; and to describe a new PET/CT feature (diffuse splenic uptake). METHODS: Between 2012 and 2017, 75 patients with suspected NVE were included prospectively, after exclusion of patients with uninterpretable or unfeasible PET/CT. Using gold standard expert consensus, 63 cases of infective endocarditis were confirmed and 12 were rejected. RESULTS: Significant valvular uptake was observed in 11 of 63 patients with definite NVE and in no patients who had the diagnosis of infective endocarditis rejected (sensitivity 17.5%, specificity 100%). Among the 63 patients with NVE, a peripheral embolism or mycotic aneurysm was observed in 20 (31.7%) cases. Application of the ESC criteria increased Duke criteria sensitivity from 63.5% to 69.8% (P<0.001), without a change in specificity. Diffuse splenic uptake was observed in 39 (52.0%) patients, including 37 (58.7%) with a final diagnosis of NVE (specificity 83.3%). CONCLUSIONS: 18F-FDG PET/CT has poor sensitivity but high specificity in the diagnosis of NVE. The usefulness of 18F-FDG PET/CT is high for embolic detection. Diffuse splenic uptake represents a possible new diagnostic criterion for NVE.

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.