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Introduction: The immunomodulatory impact of corticosteroids and concurrent chemotherapy is poorly understood within triple-negative breast cancer (TNBC). On a biochemical level, steroids have been linked to the signaling of chemotherapy-resistant pathways. However, on a clinical level, steroids play an essential role in chemotherapy tolerance through the prevention of chemotherapy-induced nausea and vomiting (CINV) and hypersensitivity reactions. Given these conflicting roles, we wanted to evaluate this interplay more rigorously in the context of early-stage TNBC. Methods: We performed a retrospective analysis of patients with operable TNBC who received neoadjuvant chemotherapy (NAC) between January 2012 and November 2018, with the primary goal of examining the dose-dependent relationship between pathological complete response (pCR) rates and corticosteroid use. Secondary endpoints included the impact of steroid dosing on overall survival (OS) and recurrence-free survival (RFS), along with a breakdown in pCR rates based on steroid doses provided during each chemotherapy phase. Further adjusted analyses were performed based on patient age, diabetic status, and anatomical stage. Finally, we explored the relationship between tumor-infiltrating lymphocytes (TILs) seen on tissue samples at baseline and dexamethasone doses in terms of pCR rates. Results: In total, of the 174 patients screened within this study period, 116 met full eligibility criteria. Of these eligible patients, all were female, with a median age of 51.5 years (27.0 to 74.0) and a mean body mass index (BMI) of 29.7 [standard deviation (SD) 7.04]. The majority were nondiabetic (80.2%). For cancer stage, 69.8% (n = 81) had stage 2 breast cancer. We found no statistically significant association between pCR rates and dexamethasone use, both in terms of the total dose (p = 0.55) and mean dose per NAC cycle (p = 0.74). Similarly, no difference was noted when adjusting for diabetic status, metformin use, or age at diagnosis, regardless of the total steroid dose provided (p = 0.72) or mean dose per cycle (p = 0.49). No meaningful changes to pCR rate were seen with higher mean or higher total steroid doses during the paclitaxel (T) phase (adjusted p = 0.16 and p = 0.76, respectively) or doxorubicin and cyclophosphamide (AC) phase (adjusted p = 0.83 and p = 0.77, respectively). Furthermore, we found no clinically significant association between dexamethasone dose and either RFS (p = 0.45) or OS (p = 0.89). Of the 56 patients who had available pre-treatment biopsy tissue samples, 27 achieved pCR, with higher TILs at baseline being associated with higher pCR rates, regardless of the mean dexamethasone dose used. Conclusion: Our findings demonstrate that dexamethasone has no clinically significant impact on pCR, RFS, or OS when given concurrently with NAC in patients with curative TNBC, regardless of diabetic status. [ABSTRACT FROM AUTHOR]

Background: Mutations in genes involved in DNA damage repair (DDR), a hallmark of cancer, are associated with increased cancer cell sensitivity to certain therapies. This study sought to evaluate the association of DDR pathogenic variants with treatment efficacy in patients with advanced non‐small cell lung cancer (NSCLC). Methods: A retrospective cohort of consecutive patients with advanced NSCLC attending a tertiary medical center who underwent next‐generation sequencing in 01/2015‐8/2020 were clustered according to DDR gene status and compared for overall response rate (ORR), progression‐free survival (PFS) (patients receiving systemic therapy), local PFS (patients receiving definitive radiotherapy), and overall survival (OS) using log‐rank and Cox regression analyses. Results: Of 225 patients with a clear tumor status, 42 had a pathogenic/likely pathogenic DDR variant (pDDR), and 183 had no DDR variant (wtDDR). Overall survival was similar in the two groups (24.2 vs. 23.1 months, p = 0.63). The pDDR group had a higher median local PFS after radiotherapy (median 45 months vs. 9.9 months, respectively; p = 0.044), a higher ORR (88.9% vs. 36.2%, p = 0.04), and a longer median PFS (not reached vs. 6.0 months, p = 0.01) in patients treated with immune checkpoint blockade. There was no difference in ORR, median PFS, and median OS in patients treated with platinum‐based chemotherapy. Conclusion: Our retrospective data suggest that in patients with stage 4 NSCLC, pathogenic variants in DDR pathway genes may be associated with higher efficacy of radiotherapy and immune checkpoint inhibitors (ICIs). This should be further explored prospectively. [ABSTRACT FROM AUTHOR]

Atezolizumab, a humanized monoclonal antibody against programmed cell death ligand 1 (PD‐L1), was initially approved in 2016, around the same time that the sponsor published the minimum serum concentration to maintain the saturation of receptor occupancy (6 μg/mL). The initially approved dose regimen of 1200 mg every 3 weeks (q3w) was subsequently modified to 840 mg q2w or 1680 mg q4w through pharmacokinetic simulations. Yet, each standard regimen yields steady‐state trough concentrations (CMIN,SS) far exceeding (≈ 40‐fold) the stated target concentration. Additionally, the steady‐state area under the plasma drug concentration–time curve (AUCSS) at 1200 mg q3w was significantly (P =.027) correlated with the probability of adverse events of special interest (AESIs) in patients with non‐small cell lung cancer (NSCLC) and, coupled with excess exposure, this provides incentive to explore alternative dose regimens to lower the exposure burden while maintaining an effective CMIN,SS. In this study, we first identified 840 mg q6w as an extended‐interval regimen that could robustly maintain a serum concentration of 6 μg/mL (≥99% of virtual patients simulated, n = 1000), then applied this regimen to an approach that administers 2 "loading doses" of standard‐interval regimens for a future clinical trial aiming to personalize dose regimens. Each standard dose was simulated for 2 loading doses, then 840 mg q6w thereafter; all yielded cycle‐7 CMIN,SS values of >6 μg/mL in >99% of virtual patients. Further, the AUCSS from 840 mg q6w resulted in a flattening (P =.63) of the exposure–response relationship with adverse events of special interest (AESIs). We next aim to verify this in a clinical trial seeking to validate extended‐interval dosing in a personalized approach using therapeutic drug monitoring. [ABSTRACT FROM AUTHOR]

Importance: Although durable left ventricular assist device (LVAD) therapy has emerged as an important treatment option for patients with advanced heart failure refractory to pharmacological support, outcomes, including survival, beyond 2 years remain poorly characterized.Objective: To report the composite end point of survival to transplant, recovery, or LVAD support free of debilitating stroke (Modified Rankin Scale score >3) or reoperation to replace the pump 5 years after the implant in participants who received the fully magnetically levitated centrifugal-flow HeartMate 3 or axial-flow HeartMate II LVAD in the MOMENTUM 3 randomized trial and were still receiving LVAD therapy at the 2-year follow-up.Design, Setting, and Participants: This observational study was a 5-year follow-up of the MOMENTUM 3 trial, conducted in 69 US centers, that demonstrated superiority of the centrifugal-flow LVAD to the axial-flow pump with respect to survival to transplant, recovery, or LVAD support free of debilitating stroke or reoperation to replace the pump at 2 years. A total of 295 patients were enrolled between June 2019 to April 2021 in the extended-phase study, with 5-year follow-up completed in September 2021.Exposures: Of 1020 patients in the investigational device exemption per-protocol population, 536 were still receiving LVAD support at 2 years, of whom 289 received the centrifugal-flow pump and 247 received the axial-flow pump.Main Outcomes and Measures: There were 10 end points evaluated at 5 years in the per-protocol population, including a composite of survival to transplant, recovery, or LVAD support free of debilitating stroke or reoperation to replace the pump between the centrifugal-flow and axial-flow pump groups and overall survival between the 2 groups.Results: A total of 477 patients (295 enrolled and 182 provided limited data) of 536 patients still receiving LVAD support at 2 years contributed to the extended-phase analysis (median age, 62 y; 86 [18%] women). The 5-year Kaplan-Meier estimate of survival to transplant, recovery, or LVAD support free of debilitating stroke or reoperation to replace the pump in the centrifugal-flow vs axial-flow group was 54.0% vs 29.7% (hazard ratio, 0.55 [95% CI, 0.45-0.67]; P < .001). Overall Kaplan-Meier survival was 58.4% in the centrifugal-flow group vs 43.7% in the axial-flow group (hazard ratio, 0.72 [95% CI, 0.58-0.89]; P = .003). Serious adverse events of stroke, bleeding, and pump thrombosis were less frequent in the centrifugal-flow pump group.Conclusions and Relevance: In this observational follow-up study of patients from the MOMENTUM 3 randomized trial, per-protocol analyses found that receipt of a fully magnetically levitated centrifugal-flow LVAD vs axial-flow LVAD was associated with a better composite outcome and higher likelihood of overall survival at 5 years. These findings support the use of the fully magnetically levitated LVAD.Trial Registration: ClinicalTrials.gov Identifier: NCT02224755 and NCT03982979. [ABSTRACT FROM AUTHOR]

Aim: The MOMENTUM 3 pivotal trial established superiority of the HeartMate 3 (HM3) left ventricular assist device (LVAD), a fully magnetically levitated centrifugal-flow pump, over the HeartMate II axial-flow pump. We now evaluate HM3 LVAD outcomes in a single-arm prospective continuous access protocol (CAP) post-pivotal trial study.Methods and Results: We enrolled 2200 HM3 implanted patients (515 pivotal trial and 1685 CAP patients) and compared outcomes including survival free of disabling stroke or reoperation to replace or remove a malfunctioning device (primary composite endpoint), overall survival and major adverse events at 2 years. The 2-year primary endpoint [76.7% vs. 74.8%; adjusted hazard ratio (HR) 0.87, 95% confidence interval (CI) 0.71-1.08, P = 0.21] and overall survival (81.2% vs. 79.0%) were similar among CAP and pivotal cohorts despite sicker patients (more intra-aortic balloon pump use and INTERMACS profile 1) in CAP who were more often intended for destination therapy. Survival was similar between the CAP and pivotal trial in transplant ineligible patients (79.1% vs. 76.7%; adjusted HR 0.89, 95% CI 0.68-1.16, P = 0.38). In a pooled analysis, the 2-year primary endpoint was similar between INTERMACS profiles 1-2 ('unstable' advanced heart failure), profile 3 ('stable' on inotropic therapy), and profiles 4-7 ('stable' ambulatory advanced heart failure) (75.7% vs. 77.6% vs. 72.9%, respectively). The net burden of adverse events was lower in CAP (adjusted rate ratio 0.93, 95% CI 0.88-0.98, P = 0.006), with consequent decrease in hospitalization.Conclusions: The primary results of accumulating HM3 LVAD experience suggest a lower adverse event burden and similar survival compared to the pivotal MOMENTUM 3 trial. [ABSTRACT FROM AUTHOR]

Cardiac recovery after left ventricular assist device (LVAD) implantation is rare. Recurrent heart failure after device explantation is also rare. We describe a patient who is the recipient of a third-generation LVAD due to recurrent heart failure nearly one decade after successfully being bridged to recovery after implantation of a first-generation LVAD. [ABSTRACT FROM AUTHOR]

Background: Breast cancer is the second most common cancer worldwide, the most common among women, and the most frequent cause of death among women in less developed regions. Trastuzumab is a humanized monoclonal antibody that downregulates the extracellular domain of the HER2 protein. Using trastuzumab to treat women with localized HER2-positive breast cancer has been shown to improve survival. The objective of this study is to explore the cost-effectiveness of adjuvant trastuzumab, from a societal perspective, in 11 African countries. In addition, we aimed to establish value-based prices for trastuzumab based on the gross domestic product per capita in each country. Methods: We developed a Markov model in order to assess the costs and benefits associated with trastuzumab treatment over a lifetime horizon. A probabilistic sensitivity analysis was performed in order to estimate the impact of uncertainty of parameter-values on the results. Efficacy inputs were derived using clinical trial data from non-African countries. Results: In the base case analysis, trastuzumab yielded a gain ranging from 0.92 LYs in Nigeria to 1.07 LYs in South Africa, and 0.9 QALYs in Nigeria to 1.02 QALYs in South Africa. The incremental cost ranged from 19,561 USD in Nigeria to 19,997 USD in Congo, and an incremental cost-effectiveness ratio ranging from 19,534 USD/QALY in South Africa to 21,697 USD/QALY in Nigeria. Using willingness to pay estimates based on World Health Organization recommendations, trastuzumab appear to not be cost-effective in all countries analyzed. Cost-effectiveness estimates were most sensitive to the discount rate, trastuzumab cost, and the hazard ratio. Conclusions: Trastuzumab does not appear to be cost effective in the African countries analyzed. In order for trastuzumab to be cost-effective, the costs of treatment would require significant discounts. [ABSTRACT FROM AUTHOR]

Previous studies suggest a possible sex-specific response to bevacizumab in metastatic colorectal carcinoma (mCRC), showing a benefit in males, while the effect in females is less significant. Data from 3369 patients with mCRC enrolled on four first-line randomised trials testing chemotherapy with or without bevacizumab (2000–2007) were pooled. Association between sex and progression-free survival and overall survival (OS) was evaluated by stratified Cox regression model, adjusted for potential confounders. Predictive value was evaluated by interaction effect between sex and treatment. In a pre-planned secondary analysis, analyses were stratified using an age cut point of 60 years to evaluate the possible role of menopausal-related effects. Bevacizumab was associated with an improved median OS in males and females, with a 2.3- and 0.6-months benefit, respectively. Stratified by age, bevacizumab resulted in improved OS in males at both age categories. In females at or above the age of 60 (n = 731), bevacizumab resulted in improved OS. However, in females below the age of 60 (n = 634), OS benefit did not reach statistical significance (adjusted hazard ratio = 0.94, 95% confidence interval 0.74–1.20). Our results confirmed the OS benefit from the addition of bevacizumab to first-line chemotherapy in mCRC in both sexes. Among females, the benefit was less than 1 month. For females under the age of 60, there was no survival benefit. These findings could be used to relieve financial toxicity or be redistributed within healthcare systems for other health-related purposes. • Bevacizumab was associated with an improved median overall survival (OS) of 1.8 months. • For females, median OS benefit from bevacizumab was <1 month. • For females under the age of 60, there was no OS benefit. • Sex- and age-specific reporting is essential in future trials testing bevacizumab. [ABSTRACT FROM AUTHOR]

Aspirin (ASA) anti-platelet therapy is mandated with left ventricular assist devices (LVADs) to prevent hemocompatibility-related adverse events (HRAEs). However, the optimal dose of ASA with HeartMate 3 (HM3) LVAD is unknown. In an exploratory analysis of HM3-supported patients in the MOMENTUM 3 study (NCT02224755), 2 groups were analyzed: usual-dose (325 mg) and low-dose (81 mg) ASA with anti-coagulation targeted to an international normalized ratio of 2.0 to 3.0. Exclusion criteria included patients not receiving either ASA 81 mg or 325 mg, those with HRAEs ≤7 days after device implantation, and those receiving >1 anti-platelet agent. The primary end-point was survival free from HRAEs (non-surgical bleeding, pump thrombosis, stroke, and peripheral arterial thromboembolic events) at 2 years. Overall, 321 HM3 patients (usual-dose: n = 141, low-dose: n = 180) were included in this analysis. Usual-dose group patients were younger (57 ± 13 vs 60 ± 12 years, p = 0.035) and less often assigned destination therapy (55% vs 67%, p = 0.029) than low-dose ASA. At 2 years, a similar proportion of patients in the usual- and low-dose groups (43.4% vs 45.3%, p = 0.94) met the primary end-point. There were no differences in survival free from hemorrhagic (usual-dose: 54.4% vs low-dose: 51.7%, p = 0.42) or thrombotic (usual-dose: 76.8% vs low-dose: 75.7%, p = 0.92) events. Usual- and low-dose ASA revealed similar rates of bleeding and thrombotic events in HM3 LVAD-supported patients within the MOMENTUM 3 trial. Whether ASA therapy provides any meaningful therapeutic effect in patients treated by the HM3 LVAD remains to be determined. [ABSTRACT FROM AUTHOR]

Background: The MOMENTUM 3 study (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3) has demonstrated that the HeartMate 3 (HM3) pump is associated with reduced strokes compared with the HeartMate II (HMII) device. We now perform a comprehensive analysis of stroke events to evaluate their longitudinal occurrence, clinical correlates, patterns, and impact on outcome across the 2-year duration of support.Methods: MOMENTUM 3 is a randomized controlled trial of the HM3 centrifugal-flow pump versus the HMII axial-flow pump in patients with advanced heart failure, regardless of the intended goal of support (bridge to transplantation or destination therapy). Baseline and postimplantation clinical correlates of stroke events were assessed with multivariable analyses. Longitudinal patterns, including device association, type of stroke (hemorrhagic versus ischemic), changing severity of impairment assessed with the modified Rankin Scale (disabling [modified Rankin Scale score >3] versus nondisabling [modified Rankin Scale score ≤3]) over time, and association with outcome, were determined.Results: In 361 patients with the intended implant (189 HM3 and 172 HMII), 65 strokes (40 ischemic strokes and 25 hemorrhagic strokes) occurred in 52 patients at a median of 131 (range, 1-733) days. No difference in stroke rate was noted between 0 and 180 days of follow-up between devices. However, stroke incidence in the long-term period (181-730 days after left ventricular assist device) was 3.3 times lower for the HM3 group (HM3: 0.04 versus HMII: 0.13 events per patient-year; odds ratio, 0.23; 95% CI, 0.08-0.63; P=0.01). Treatment with the HM3 pump was the only independent predictor of lower stroke events. We found no direct association of blood pressure or antithrombotic regimens with observed stroke rates. A stroke event significantly lowered 2-year postimplantation survival regardless of subtype or initial severity of neurological impairment compared with patients without a stroke (43±12% for hemorrhagic stroke, 57±9% for ischemic stroke, 51±11% for disabling, and 51±11% for nondisabling compared with 85±2% 2-year survival for patients without stroke).Conclusions: The HM3 pump is associated with a marked reduction in stroke rates compared with the HMII device, with benefits observed in the long-term period (>6 months). The occurrence of stroke of any type (hemorrhagic and ischemic) or of any functional severity (disabling and nondisabling) is predictive of a poor 2-year clinical outcome.Clinical Trial Registration: URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT02224755. [ABSTRACT FROM AUTHOR]

Background: The HeartMate 3 (HM3) Left Ventricular Assist System (LVAS) (Abbott) is a centrifugal, fully magnetically levitated, continuous-flow blood pump engineered to enhance hemocompatibility and reduce shear stress on blood components. The MOMENTUM 3 trial (Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy With HeartMate 3) compares the HM3 LVAS with the HeartMate II (HMII) LVAS (Abbott) in advanced heart failure refractory to medical management, irrespective of therapeutic intention (bridge to transplant versus destination therapy). This investigation reported its primary outcome in the short-term cohort (n=294; 6-month follow-up), demonstrating superiority of the HM3 for the trial primary end point (survival free of a disabling stroke or reoperation to replace the pump for malfunction), driven by a reduced need for reoperations. The aim of this analysis was to evaluate the aggregate of hemocompatibility-related clinical adverse events (HRAEs) between the 2 LVAS.Methods: We conducted a secondary end point evaluation of HRAE (survival free of any nonsurgical bleeding, thromboembolic event, pump thrombosis, or neurological event) in the short-term cohort (as-treated cohort n=289) at 6 months. The net burden of HRAE was also assessed by using a previously described hemocompatibility score, which uses 4 escalating tiers of hierarchal severity to derive a total score for events encountered during the entire follow-up experience for each patient.Results: In 289 patients in the as-treated group (151 the HM3 and 138 the HMII), survival free of any HRAE was achieved in 69% of the HM3 group and in 55% of the HMII group (hazard ratio, 0.62; confidence interval, 0.42-0.91; P=0.012). Using the hemocompatibility score, the HM3 group demonstrated less pump thrombosis requiring reoperation (0 versus 36 points, P<0.001) or medically managed pump thrombosis (0 versus 5 points, P=0.02), and fewer nondisabling strokes (6 versus 24 points, P=0.026) than the control HMII LVAS. The net hemocompatibility score in the HM3 in comparison with the HMII patients was 101 (0.67±1.50 points/patient) versus 137 (0.99±1.79 points/patient) (odds ratio, 0.64; confidence interval, 0.39-1.03; P=0.065).Conclusions: In this secondary analysis of the MOMENTUM 3 trial, the HM3 LVAS demonstrated greater freedom from HRAEs in comparison with the HMII LVAS at 6 months.Clinical Trial Registration: URL: http://clinicaltrials.gov. Unique identifier: NCT02224755. [ABSTRACT FROM AUTHOR]