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Quadruple-negative breast cancer (QNBC) is a triple-negative breast cancer (TNBC) subtype that lacks expression of the androgen (AR) receptor. Few studies have focused on this highly aggressive breast cancer, portending worse survival rates. We aimed to determine the following: (1) QNBC’s molecular and clinical characteristics and compare them with other subtypes and (2) QNBC’s association with clinicopathological factors and prognostic markers. We performed immunohistochemical evaluations of ARs on tissue tumor microarrays from FFPE tumor blocks of invasive ductal breast carcinomas in 202 African American women. Univariate analysis was performed using the chi-square test, with survival rates calculated using Kaplan–Meier curves. Overall, 75.8% of TNBCs were AR-negative. Compared to the luminal subtypes, TNBC and QNBC tumors were likely to be a higher grade (p < 0.001); HER2+/AR- and QNBCs were also larger than the other subtypes (p < 0.001). They also expressed increasing mean levels of proteins involved in invasion, such as CD44, fascin, and vimentin, as well as decreasing the expression of proteins involved in mammary differentiation, such as GATA3 and mammaglobin. We found no association between QNBC and stage, recurrence-free survival, or overall survival rates. The high prevalence of TNBC AR-negativity in these women could explain observed worse outcomes, supporting the existence of the unique QNBC subtype.

Abstract Cytomegalovirus (CMV) infection and disease are important causes of morbidity and mortality in transplant recipients. For the purpose of developing consistent reporting of CMV outcomes in clinical trials, definitions of CMV infection and disease were developed and most recently published in 2017. Since then, there have been major developments, including registration of new antiviral agents. Therefore, the Transplant Associated Virus Infections Forum, which consists of scientists, clinicians, regulators, and industry representatives, has produced an updated version of these definitions that incorporates recent knowledge with the aim of supporting clinical research and drug development. This also includes an update regarding the definition of resistant and refractory CMV infections previously published in 2019. As the field evolves, the need for updates of these definitions is clear, and collaborative efforts among clinicians, scientists, regulators, and industry representatives can provide a platform for this work.

AbstractBackgroundVasomotor symptoms (VMS), such as hot flashes and night sweats, are highly prevalent and burdensome for women experiencing menopausal transition. Fezolinetant, a selective neurokinin 3 receptor (NK3R) antagonist, is a potential therapeutic option for mitigating VMS.ObjectivesOur aim is to assess the efficacy and evaluate the safety profile of fezolinetant compared with placebo in post‐menopausal women suffering from VMS, by pooling all the relevant data and reflecting the most current evidence.Search Strategy/Selection CriteriaAn extensive literature search was performed in the PubMed, Medline and Cochrane Library databases from inception until June 2023 to identify relevant trials.Data Collection and AnalysisMean differences (MDs) and 95% confidence intervals (CIs) were calculated for continuous outcomes. Risk ratios (RRs) were calculated for dichotomous outcomes. All statistical analyses were performed using R Statistical Software.Main ResultsA total of six randomized controlled trials were added. For the frequency of daily VMS, the combined pooled result favored the fezolinetant group over placebo (MD –2.38, 95% CI –2.64 to −2.12; P < 0.001, I2 = 0%). For the severity of daily VMS, fezolinetant was again found to be superior to the placebo group (MD –0.40, 95% CI –0.51 to −0.29; P < 0.001, I2 = 70%). Fezolinetant (120 mg) consistently demonstrated a significant reduction in the severity of daily moderate/severe VMS compared with other doses at both 4 and 12 weeks. Patient‐reported outcomes (PROs) of Greene Climacteric Scale (GCS), PROMIS the Sleep Disturbance Short Form 8b and Menopause‐Specific Quality of Life (MENQoL) scores indicated significant improvement with fezolinetant. No significant difference in efficacy of fezolinetant at 4 and 12 weeks were observed in any outcome. As for safety, no significant differences in the treatment emergent adverse events at 12 weeks were found between fezolinetant and placebo.ConclusionsOur study significantly favors fezolinetant over placebo regarding the primary efficacy outcomes of daily moderate to severe VMS frequency and severity, including PROs, while both the groups are comparable in terms of treatment emergent adverse events. Further studies are needed to confirm these findings.

Background: RCTs studying the effect of sodium-glucose co-transporter 2 inhibitors (SGLT2i) on cardiovascular (CV) risk factors and outcomes have been underpowered to assess patients with overweight or obesity, thus presenting the need for a meta-analysis. Methods: Electronic databases were queried up till February 2022 for RCTs comparing SGLT2i with placebo in patients with overweight (BMI ≥25 kg/m2) or obesity (BMI ≥30 kg/m2) - irrespective of diabetes status - with a follow-up of ≥24 weeks. Meta-analyses were performed using the generic inverse variance technique and a random-effects model. Results are presented as weighted mean differences (WMD) for continuous outcomes, and hazard ratios (HR) for dichotomous outcomes. Outcomes studied were: (i) weight; (ii) systolic BP; (iii) diastolic BP; (iv) heart rate; (v) HDL-C; (vi) LDL-C; (vii) major adverse cardiac events (MACE), i.e., composite of CV death, non-fatal myocardial infarction (MI) and non-fatal stroke; (viii) composite of heart failure hospitalization and CV death (HFH/CV death); (ix) mortality; (x) MI; and (xi) stroke. Results: Seventeen RCTs (47,649 patients) were included. Compared with placebo, SGLT2i significantly reduced weight (WMD: -2.32 kg [-2.77, -1.88]), HbA1c (WMD: -0.79 % [-0.98, - 0.61]) and systolic BP (WMD: -2.15 mm Hg [-3.08, - 1.22]). SGLT2i did not have a significant effect on diastolic BP (WMD: -0.55 mmHg [-1.51, 0.41]), heart rate (WMD: 0.08 bpm. [-0.21, 0.37]), HDL-C (WMD: 1.62 mmol l -1 [-0.21, 3.45]) or LDL-C (WMD: 0.53 mmol l -1 [-0.88, 1.94]). Amongst CV outcomes, SGLT2i reduced the risk of MACE (HR: 0.90 [0.81, 0.99]), HFH/CV death (HR: 0.82 [0.75, 0.90]), and mortality (HR: 0.85 [0.77, 0.94]). No effect was noted on stroke (HR: 0.99 [0.85, 1.26]) or MI (HR: 0.89 [0.77, 1.02]). Conclusions: In patients with overweight or obesity, SGLT2i produce a modest but significant reduction in weight, systolic BP and HbA1c. SGLT2i may also reduce the risk of MACE, HFH/CV death, and mortality.

AbstractCOVID-19 is also manifested with hypercoagulability, pulmonary intravascular coagulation, microangiopathy, and venous thromboembolism (VTE) or arterial thrombosis. Predisposing risk factors to severe COVID-19 are male sex, underlying cardiovascular disease, or cardiovascular risk factors including noncontrolled diabetes mellitus or arterial hypertension, obesity, and advanced age. The VAS-European Independent Foundation in Angiology/Vascular Medicine draws attention to patients with vascular disease (VD) and presents an integral strategy for the management of patients with VD or cardiovascular risk factors (VD-CVR) and COVID-19. VAS recommends (1) a COVID-19-oriented primary health care network for patients with VD-CVR for identification of patients with VD-CVR in the community and patients' education for disease symptoms, use of eHealth technology, adherence to the antithrombotic and vascular regulating treatments, and (2) close medical follow-up for efficacious control of VD progression and prompt application of physical and social distancing measures in case of new epidemic waves. For patients with VD-CVR who receive home treatment for COVID-19, VAS recommends assessment for (1) disease worsening risk and prioritized hospitalization of those at high risk and (2) VTE risk assessment and thromboprophylaxis with rivaroxaban, betrixaban, or low-molecular-weight heparin (LMWH) for those at high risk. For hospitalized patients with VD-CVR and COVID-19, VAS recommends (1) routine thromboprophylaxis with weight-adjusted intermediate doses of LMWH (unless contraindication); (2) LMWH as the drug of choice over unfractionated heparin or direct oral anticoagulants for the treatment of VTE or hypercoagulability; (3) careful evaluation of the risk for disease worsening and prompt application of targeted antiviral or convalescence treatments; (4) monitoring of D-dimer for optimization of the antithrombotic treatment; and (5) evaluation of the risk of VTE before hospital discharge using the IMPROVE-D-dimer score and prolonged post-discharge thromboprophylaxis with rivaroxaban, betrixaban, or LMWH.

Abstract Introduction: Atrial fibrillation (AF) represents a cardiovascular syndrome which can lead to embolic stroke. Several AF clinical trials have shown a decrease risk of stroke with anticoagulation using warfarin. Currently, there are two approaches for anticoagulation in AF patients. For outpatients, warfarin is used with an INR goal 2.0–3.0. For inpatients requiring cardioversion, unfractionated heparin (UFH, IV) is used as a bridge to therapeutic warfarin. More recently, anticoagulation with a low molecular weight heparin, enoxaparin, has been reported to give a more predictable anticoagulant response than UFH in TEEguided cardioversion. The present study compares the markers of inflammation and thrombin generation in patients included in the ACUTE II study. Methods: This was a randomized multicenter trial of 155 patients from 17 clinical sites, the anticoagulant activity of LMWH (enoxaparin, 1 mg/kg sc bid, Sanofi-Aventis, n=76) was compared to that of UFH (APTT 1.5 – 2.5 x control, n=79). Blood samples were drawn at enrollment (baseline), day 2 (peri cardioversion) and day 4 in both groups. Day 2 and day 4 samples were taken 3–4 hours after the injection of LMWH in patients in the LMWH group. Blood samples were evaluated for inflammation: C-reactive protein (CRP), CD 40 ligand (CD 40L), monocyte chemotactic protein 1 (MCP-1) and anticoagulant effect: thrombin antithrombin complex (TAT) and prothrombin fragment (F 1.2). Results: The APTT and anti-Xa levels indicated therapeutic anticoagulation was achieved (previously reported). In addition, both TAT and F1.2 levels were increased at baseline and were significantly decreased with LMWH (p&lt;0.01) in comparison to UFH. The CRP, CD40L, MCP-1 were decreased after treatment in both groups of patients. These results suggest that AF patients treated with LMWH demonstrate a stronger anticoagulant effect as measured by a significant reduction in the markers of thrombin generation. Furthermore, anticoagulation with either UFH of LMWH results in a decrease in inflammation which was not different between groups. Conclusion: In the ACUTE II trial, anticoagulation with LMWH in AF patients may be a better alternate than UFH during TEE-guided cardioversion due to a a stronger anticoagulant.

Background: Thromboembolism (TE) is one of major causes of morbidity and mortality in patients with malignancy. Pathophysiological connection between TE and inflammation has been established and it is being thoroughly studied recently. The neutrophil to lymphocyte ratio (NLR) and the platelet to lymphocyte ratio (PLR) are biomarkers for systemic inflammation and might represent a yet unrecognized risk factor for development of venous thromboembolism in lymphoma patients having in mind chronic inflammatory milieu specific for lymphomas. Aims: We aimed to investigate the association between NLR, PLR and future risk of TE, in a prospective cohort of lymphoma patients receiving chemotherapy. Methods: We prospectively included 630 patients with B cell non Hodgkin lymphoma /indolent and agressive/, T cell non Hodgkin lymphoma and Hodgkin lymphoma who were diagnosed and treated (period 2014-2019.) at the Clinic for Hematology, Clinical Center of Serbia. Data for newly diagnosed patients, who had completed a minimum of one chemotherapy cycle, were collected for venous TE events from time of diagnosis to 3 months after the last cycle of therapy. NLR and PLR were calculated according to the CBC with differential count. TE complications were diagnosed based on clinical examination, laboratory evaluation and radiographic studies (duplex venous ultrasound, contrast-enhanced computed tomography scan, magnetic resonance imaging (MRI)). Response to therapy was assessed according to Cheson criteria. Logistic regression analysis and ROC curve were performed to assess the association of NLR and PLR with TE and therapy response. Cox regression and Kaplan Meier analysis were used to assess overall survival. Results: The mean age in our group of patients was 53 years (range, 18-89 years) while 52.8% were males. Most patients had advanced stage disease: clinical stage III 20.6% and stage IV, 41.5%. A total of 327 patients (51.9%) had aggressive NHL; 175 (27.8%) had indolent NHL; 102 (16.2%) had HL; 26 (4.1%) had T cell NHL. 51 (8.2%) patients developed thromboembolic events. NLR and PLR were significantly higher in TE patients compared to patients without TE (p=0.001 and p=0.002, respectively). The NLR was positively associated with PLR (p&lt;0.001). A positive NLR was considered 3 or higher, while a positive PLR was a ratio of 10 or more. The ROC curve analysis demonstrated acceptable specificity and sensitivity of NLR and PLR in predicting TE. NLR and PLR were found to be prognostic factors for the TE (relative risk [RR] = 2.9, 95% confidence interval [CI] = 1.6-5.3, p=0.001 and RR=2.7, 95% CI =1.4-5.1, p=0.002, respectively) as well as for overall response to therapy (RR=2.7, 95%CI=1.7-5.7, p&lt;0.001 and RR=2.0, 95%CI=1.1-3.4, p=0.015, respectively). Regarding the overall survival, in univariate analysis there was an association of the development of TE and decreased survival, while in multivariate model NLR was found to be an independent risk factor for overall survival in lymphoma patients (HR=1.8, 95%CI=1.1-2.9, p=0.024) (Figure 1). Summary/Conclusion: NLR could represent useful clinical predictor of TE complications in patients with lymphoma without additional costs to the national health systems. Our research showed that NLR is also predictive for response to therapy and overall survival of lymphoma patients. Simplicity, cost effectiveness, and rapid turn around qualify this new tool for routine prognostic assessment in lymphoma patients. Figure 1 Disclosures No relevant conflicts of interest to declare.

Object The utilization of endovascular treatment for ruptured intracranial aneurysms is expected to change since the publication of the International Subarachnoid Aneurysm Trial (ISAT) in 2002. The authors performed this analysis to determine the impact of ISAT results on treatment selection for ruptured intracranial aneurysms and associated in-hospital outcomes using nationally representative data. Methods We determined the national estimates of treatments used for ruptured intracranial aneurysms and associated in-hospital outcomes, length of stay, mortality, and cost incurred using the Nationwide Inpatient Survey (NIS) data. The NIS is the largest all-payer inpatient care database in the US and contains data from 986 hospitals approximating a 20% stratified sample of US hospitals. All the variables pertaining to hospitalization were compared between 2000–2002 and 2004–2006, and in-hospital outcomes were analyzed using multivariate analysis. Results In the 3-year periods prior to and after the ISAT, there were 70,637 and 77,352 admissions for ruptured intracranial aneurysms, respectively. There was a significant increase in endovascular treatment after publication of the ISAT (trend test, p < 0.0001) The in-hospital mortality for ruptured intracranial aneurysm admissions decreased from 27% to 24% (odds ratio [OR] 0.89, 95% CI 0.83–0.96, p = 0.003) after the publication of the ISAT. The cost of hospitalization after adjusting for procedures practices was not significantly higher after the publication of the ISAT ($21,437 vs $22,817, p < 0.89), but cost of hospitalization was higher in the post-ISAT period for patients undergoing endovascular procedure. Conclusions The results of the ISAT have been associated with a prominent change in practice patterns related to the treatment of ruptured aneurysms. The cost of hospitalization has increased and the mortality has decreased, presumably due to a larger proportion of patients receiving any treatment and endovascular treatment.

Object The results of the International Subarachnoid Aneurysm Trial (ISAT) demonstrated lower rates of death and disability with endovascular treatment (coiling) than with open surgery (clipping) to secure the ruptured intracranial aneurysm. However, cost-effectiveness may not be favorable because of the greater need for follow-up cerebral angiograms and additional follow-up treatment with endovascular methods. In this study, the authors' goal was to compare the cost-effectiveness of endovascular and neurosurgical treatments in patients with ruptured intracranial aneurysms who were eligible to undergo either type of treatment. Methods Clinical data (age, sex, frequency of retreatment, and rebleeding) and quality of life values were obtained from the ISAT. Total cost included those associated with disability, hospitalization, retreatment, and rebleeding. Cost estimates were derived from the Premier Perspective Comparative Database, data from long-term care in stroke patients, and relevant literature. Incremental cost-effectiveness ratios (ICERs) were estimated during a 1-year period. Parametric bootstrapping was used to determine the uncertainty of the estimates. Results The median estimated costs of endovascular and neurosurgical treatments (in US dollars) were $45,493 (95th percentile range $44,693–$46,365) and $41,769 (95th percentile range $41,094–$42,518), respectively. The overall quality-adjusted life years (QALY) in the endovascular group was 0.69, and for the neurosurgical group it was 0.64. The cost per QALY in the endovascular group was $65,424 (95th percentile range $64,178–$66,772), and in the neurosurgical group it was $64,824 (95th percentile range $63,679–$66,086). The median estimated ICER at 1 year for endovascular treatment versus neurosurgical treatment was $72,872 (95th percentile range $50,344–$98,335) per QALY gained. Given that most postprocedure angiograms and additional treatments occurred in the 1st year and the 1-year disability status is unlikely to change in the future, ICER for endovascular treatment will progressively decrease over time. Conclusions Using outcome and economic data obtained in the US at 1 year after the procedure, endovascular treatment is more costly but is associated with better outcomes than the neurosurgical alternative among patients with ruptured intracranial aneurysms who are eligible to undergo either procedure. With accrual of additional years with a better outcome status, the ICER for endovascular coiling would be expected to progressively decrease and eventually reverse.