Implementation Of New Therapies Research Articles

Hereditary angioedema due to C1-inhibitor deficiency: current therapeutic approaches.

For decades, treatment options for hereditary angioedema (HAE) were limited by major adverse effects, insufficient efficacy, and difficult routes of administration. However, the growing body of knowledge regarding HAE pathophysiology has led to the development of innovative drugs for self-administered, on-demand therapy and for short- and long-term prophylaxis. This review provides a comprehensive overview of the approved drugs and the development of HAE treatments. The implementation of new therapies will improve the application of individualized action plans based on the key goals of minimizing the number of attacks and meeting the complex needs of patients. HAE is a rare genetic disease with a high impact on patients' quality of life due to the unpredictability and variable severity of attacks. Advances in HAE research have allowed optimization of attack management and individualization of therapeutic approaches.

Perioperative platform for muscle-invasive bladder cancer trials: designs and endpoints.

This review explores the design and endpoints of perioperative platforms in clinical trials for muscle-invasive bladder cancer (MIBC). The choice of clinical trial design in perioperative platforms for MIBC must align with specific research objectives to ensure robust and meaningful outcomes. Novel designs in perioperative platforms for MIBC integrate bladder-sparing approaches. Primary endpoints such as pathological complete response and disease-free survival are highlighted for their role in expediting trial results in perioperative setting. Incorporating patient-reported outcomes is important to inform healthcare decision makers about the outcomes most meaningful to patients. Given the growing body of evidence, potential biomarkers, predictive and prognostic tools should be considered and implemented when designing trials in perioperative platforms for MIBC. Effective perioperative platforms for MIBC trials are critical in enhancing patient outcomes. The careful selection and standardization of study designs and endpoints in the perioperative platform are essential for the successful implementation of new therapies and the advancement of personalized treatment approaches in MIBC.

Contemporary Treatment Patterns and Oncological Outcomes of Metastatic Hormone-sensitive Prostate Cancer and First- to Sixth- line Metastatic Castration-resistant Prostate Cancer Patients

Background and objectiveWith approval of novel systemic therapies within the past decade for metastatic hormone-sensitive (mHSPC) and castration-resistant (mCRPC) prostate cancer, patients may receive several therapy lines. However, the use of these treatments is under an ongoing change. We investigated contemporary treatment trends and progression-free (PFS) and overall (OS) survival of different therapy lines. MethodsRelying on our institutional tertiary-care database, we identified mHSPC and mCRPC patients. The main outcome consisted of treatment changes (estimated annual percentage change [EAPC]) within the past decade, as well as PFS and OS for different mHSPC and mCRPC treatment lines. Key findings and limitationsIn 1098 metastatic patients, the median age was 70 yr with a median of two systemic therapy lines. For first-line mCRPC between 2013 and 2023, androgen deprivation monotherapy (ADT) monotherapy usage decreased significantly from 31% to 0% (EAPC −38.3%, p < 0.001), while the administration of chemotherapy increased from 16.7% to 33.3% (EAPC: +10.1%, p < 0.001). The PFS/OS rates of mHSPC patients was 21/67 mo, and those for first-, second-, third-, fourth-, fifth-, and sixth-line mCRPC patients were 11/47, eight of 30, seven of 24, six of 19, seven of 17, and seven of 13 mo, respectively. With an increased number of new combination therapy lines received, the median OS in mCRPC improved from 26 mo (one systemic treatment) to 52 mo (two or more lines of systemic treatment). Conclusions and clinical implicationsSignificant changes in treatment patterns could be observed for mHSPC and mCRPC patients within the past decade, and usage of ADT monotherapy has decreased rapidly in real-world practice. Moreover, PFS decreases significantly with every therapy line, and OS increases with the implementation of new therapies. Patient summaryImprovements in the real-world setting regarding the usage of combination therapies for metastatic hormone-sensitive and castration-resistant prostate cancer were made, which is reflected in contemporary survival outcomes.

BPI24-017: Optimizing the Implementation of New Therapies in Multiple Myeloma.

BPI24-017: Optimizing the Implementation of New Therapies in Multiple Myeloma.

Ten year evolution of clinical characteristics and short-term outcome of patients admitted with heart failure

Abstract Background/Introduction Heart failure (HF) continues to be a leading cause of morbidity, decreased quality of life (QoL) and mortality worldwide. Contributing to decreased QoL is the high rehospitalization rate, which is often related to non-cardiac causes, highlighting the important multimorbidity of the HF population. Detailed clinical and outcome data for HF admissions in Belgium over time are only scarcely available. Purpose We aimed to evaluate and compare two groups of patients admitted with HF ten years apart, regarding clinical characteristics, comorbidities, use of HF medication and devices, as well as rehospitalization rate and all-cause mortality three months post-discharge. Methods This is a monocentric retrospective observational cohort study conducted in Belgium. Two groups of patients admitted for acute decompensated HF who were discharged alive were included and compared: 340 patients during 2011-2012 and 319 patients during 2021-2022. Results The two cohorts did not differ significantly regarding age (77.3 vs. 78.4 years), gender (47.4 vs. 44.5% women), number of patients with HF with reduced ejection fraction (47.4 vs. 48.6%) and NT-proBNP on admission (8514 vs. 7398 pg/mL). Similarly, comorbidities including diabetes, chronic obstructive pulmonary disease, peripheral artery disease, stroke and renal failure were comparable in both groups. Concerning medical therapy at discharge, mineralocorticoid receptor antagonists (MRA) were used significantly more frequently in the latest cohort. However, there was no change in administration of beta-blockers or renin angiotensin aldosterone system antagonists. As part of the implementation of new therapies for heart failure with reduced ejection fraction, 29% of patients were prescribed sodium-glucose cotransporter-2 (SGLT-2) inhibitors, while sacubitril/valsartan was given in 13% of the cases. The use of internal defibrillators (ICD) and resynchronization devices (CRT) doubled from 2011-2012 to 2021-2022 (3.9 vs. 9.6%, p = 0.002). In-hospital length of stay decreased significantly over a ten-year period across all ejection fraction subgroups from 7 to 5 days (figure 1). The combined outcome of rehospitalization for HF and all-cause mortality three months post-discharge remained constant at approximately 20% (figure 2). Conclusion Clinical characteristics and comorbidities of patients admitted with acute decompensated HF did not change significantly between 2011 and 2022. Uptake of evidence-based medicine for HF increased, especially for MRA, SGLT-2 inhibitors and sacubitril/valsartan, as did the use of ICD and CRT, but still with considerable potential for improvement. Although in-hospital length of stay decreased significantly over time, rehospitalization rates for HF and all-cause mortality within 90 days post-discharge remained high and did not improve. These sobering results illustrate the need for continuing efforts to improve the care and outcome of HF patients.

Towards better antivenoms: navigating the road to new types of snakebite envenoming therapies.

Snakebite envenoming is a significant global health challenge, and for over a century, traditional plasma-derived antivenoms from hyperimmunized animals have been the primary treatment against this infliction. However, these antivenoms have several inherent limitations, including the risk of causing adverse reactions when administered to patients, batch-to-batch variation, and high production costs. To address these issues and improve treatment outcomes, the development of new types of antivenoms is crucial. During this development, key aspects such as improved clinical efficacy, enhanced safety profiles, and greater affordability should be in focus. To achieve these goals, modern biotechnological methods can be applied to the discovery and development of therapeutic agents that can neutralize medically important toxins from multiple snake species. This review highlights some of these agents, including monoclonal antibodies, nanobodies, and selected small molecules, that can achieve broad toxin neutralization, have favorable safety profiles, and can be produced on a large scale with standardized manufacturing processes. Considering the inherent strengths and limitations related to the pharmacokinetics of these different agents, a combination of them might be beneficial in the development of new types of antivenom products with improved therapeutic properties. While the implementation of new therapies requires time, it is foreseeable that the application of biotechnological advancements represents a promising trajectory toward the development of improved therapies for snakebite envenoming. As research and development continue to advance, these new products could emerge as the mainstay treatment in the future.

Effectiveness of an mHealth App as an add-on for Smoking Cessation in One year: A multicenter and randomized Trial (The MASCOT study)

Introduction: Smoking accounts for 480,000 deaths per year in the United States. Traditional pharmacotherapeutic interventions for smoking cessation continue to fail, urging the implementation of new therapies to prevent further harm. Mobile Health apps have appeared to support smoking cessation; their low cost, wide availability, absence of side effects, and drug-to-drug interaction make them useful adjuncts in some populations. Despite promising results, only a small number of smoking cessation apps have been formally researched as an add-on therapy. Therefore, we hypothesize that using a mobile health app (PIVOT) as an add-on to the current standard therapy (varenicline plus cognitive-behavioral therapy) could increase the smoking cessation rate. Methods: We propose a Phase III, multicenter, randomized, parallel-group, open-label, superiority trial. The control group will receive varenicline 1mg/daily for 3 months plus 10 sessions of cognitive-behavioral therapies. The intervention group will receive the same treatment plus the addition of the PIVOT® app for one year. Participants will be 21 to 60 years old who meet the Tobacco Use Disorder criteria. The primary outcome will be smoking abstinence at 1 year of follow-up. Secondary outcomes will be lapses and relapses, cotinine hair drug testing at the end of follow-up, and the impact on Quality of Life measured through the WHO Quality of Life Scale-Brief questionnaire.&nbsp; Discussion: mobile Health Apps are widely available and extensively used by smokers to aid smoking cessation; however, their effectiveness as an add-on is unproven. This study will provide evidence on this matter to advise future clinical practice guidelines and decrease the morbidity and mortality attributable to tobacco use.

Identification and Prioritization of Research Questions on Paraplegia Caused by Traumatic Spinal Cord Injury with Those Affected, Their Relatives and Health Care Professionals

Objective With expertise based on experience, paraplegics, their relatives and health care professionals can contribute to the development of research questions relevant for those affected and those in health care practice. For this purpose, the James Lind Alliance (JLA) has provided a methodological approach. The aim of this study was to develop a research agenda for paraplegia resulting from traumatic spinal cord injury with an adapted JLA approach. Four consecutive online surveys of people with paraplegia caused by traumatic spinal cord injury, their relatives and caregivers were conducted. In the first survey, the respondents freely formulated research questions unanswered from their point of view. These were synthesized and checked to see if they can already be answered by available evidence. The unresolved questions were prioritized stepwise in the subsequent surveys. In the second survey, the relevance of questions was rated on a five-point rating scale (1-5). Questions with a mean value of 4 or higher were taken up in the third survey, in which the 10 most relevant questions were determined. These were ranked in the fourth survey as a top-10 list. Based on the first survey (n=52), 38 unresolved research questions were identified. Of these, 26 questions were rated as important (2nd survey; n=53), from which 10 questions were selected (3rd survey; n=17) and ranked (4th survey; n=12) as a top-10 list. Four prioritized questions related to treatment of spinal cord injury or associated health issues, three to aspects of the health care system with regard to assistive devices and the implementation of new therapies, two to possibilities of those affected to improve their own situation, and one to research on the course of disease. Nine priorities focus on research that could help improve the life and health care situation of paraplegic patients and one on curative treatment. The prioritized questions should be taken up by researchers and research funders for the benefit of patients and to help health care providers. For some priorities, a need for research was consistently identified in present guidelines or systematic reviews.

Exploring barriers and facilitators for mental health professionals delivering behavioural activation to young people with depression: qualitative study using the Theoretical Domains Framework.

Depression prevalence among young people is increasing, with growing pressures on specialist mental health services. Manualised behavioural activation therapy may be effective for young people, and can be delivered by a range of mental health professionals (MHPs). This study explored clinician perspectives of barriers and facilitators to implementing behavioural activation with young people in routine practice. We conducted a qualitative study with individual semi-structured interviews with MHPs, as part of a wider feasibility study. Participants were mental health professionals (therapists and supervisors) from two UK NHS sites delivering manualised behavioural activation for young people. Data were analysed with an inductive followed by deductive approach, applying the Theoretical Domains Framework (TDF) to understand key influences on practice change. Identified domains were mapped onto possible behaviour change techniques (BCTs) to support implementation, using the Theory and Techniques Tool (TTT). Nine MHPs were interviewed. Thirteen of fourteen TDF domains were relevant, including perceived professional identity, beliefs about own capabilities and perceived positive or negative consequences of using manualised behavioural activation, social influences, memory and attention, and environmental resources. Fourteen theory-linked BCTs were identified as possible strategies to help clinicians overcome barriers (e.g. integrating behavioural practice/rehearsal, prompts and persuasive communications within training, and supervision). Behavioural science approaches (TDF, TTT) helped conceptualise key barriers and facilitators for MHPs delivering manualised behavioural activation with young people. Interventions using BCTs to address identified barriers could help the implementation of new therapies into routine practice, working to bridge the research-practice gap in clinical psychology.

Real-Time Surveillance of New Anticancer Therapies in the National Veterans Affairs System

<h3>Purpose/Objective(s)</h3> The Veterans Affairs (VA) system is the largest integrated health system in the US, with one of the world's longest-running electronic medical record (EMR) systems. We describe the potential of VA EMR data for real-time surveillance of efficacy, toxicity, and uptake of new therapies in oncology. As a case study, we describe the implementation of durvalumab for adjuvant treatment of stage III non-small-cell lung cancer (NSCLC) treated with concurrent chemoradiation (CRT) after publication of the landmark PACIFIC trial in 2017. <h3>Materials/Methods</h3> We used the Veterans Affairs Informatics and Computing Infrastructure (VINCI) to identify all intravenous administrations of durvalumab from November 2017 to January 2021 among patients with at least one inpatient or outpatient lung cancer ICD-10 diagnosis code. Cancer stage and tumor histology were algorithmically extracted from physician notes and reviewed for accuracy. Radiation therapy dates and concurrent chemotherapy delivery were ascertained through outpatient CPT codes for radiation delivery and intravenous chemotherapy infusion records. Overall survival (OS) was obtained from the VA Vital Status File (updated on a quarterly basis) and from the VA Master Patient Index (updated on a daily basis). Date of radiographic progression were obtained through physician review of extracted CT and PET scan reports. Demographic, staging, and treatment information were supplemented with VA Central Cancer Registry information where available. Statistics were performed with statistical analysis software. <h3>Results</h3> We identified 1106 patients with stage III NSCLC (60% stage IIIA, 35% IIIB, and 3% IIIC) treated with upfront CRT who received at least one adjuvant durvalumab infusion, of whom only 135 (12%) were represented in cancer registry data. The median age was 69 years and 95% were male. Eighty-six percent reported current or former tobacco use, and the cohort was evenly split between adenocarcinoma (48%) and squamous cell histology (48%). Patients received a median of 6 durvalumab infusions (IQR 3 to 15) over a median of 154 days (IQR 35 to 308 days). Compared to patients enrolled in the PACIFIC trial, veterans received a lower number of durvalumab infusions (6 vs. 14) and had a higher rate of systemic steroid initiation for possible immune-related toxicity (43% vs 20%). Three-year progression-free survival was 32.5% (95% CI 25% to 40%). Three-year OS was 51% (95% CI 46% to 56%) compared to 57% in PACIFIC. <h3>Conclusion</h3> Veterans received fewer adjuvant durvalumab infusions than in the PACIFIC trial but maintained comparable survival. National VA administrative data, which are largely updated on a daily or weekly basis, are a unique resource to study real-time implementation of new therapies in large national cohorts. Improved case-finding algorithms are necessary to capture patients not included in the VA Central Cancer Registry.

A Call to Action for New Global Approaches to Cardiovascular Disease Drug Solutions.

While we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic "buckets." Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased "omic" approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.

A call to action for new global approaches to cardiovascular disease drug solutions.

Whilst we continue to wrestle with the immense challenge of implementing equitable access to established evidence-based treatments, substantial gaps remain in our pharmacotherapy armament for common forms of cardiovascular disease including coronary and peripheral arterial disease, heart failure, hypertension, and arrhythmia. We need to continue to invest in the development of new approaches for the discovery, rigorous assessment, and implementation of new therapies. Currently, the time and cost to progress from lead compound/product identification to the clinic, and the success rate in getting there reduces the incentive for industry to invest, despite the enormous burden of disease and potential size of market. There are tremendous opportunities with improved phenotyping of patients currently batched together in syndromic 'buckets'. Use of advanced imaging and molecular markers may allow stratification of patients in a manner more aligned to biological mechanisms that can, in turn, be targeted by specific approaches developed using high-throughput molecular technologies. Unbiased 'omic' approaches enhance the possibility of discovering completely new mechanisms in such groups. Furthermore, advances in drug discovery platforms, and models to study efficacy and toxicity more relevant to the human disease, are valuable. Re-imagining the relationships among discovery, translation, evaluation, and implementation will help reverse the trend away from investment in the cardiovascular space, establishing innovative platforms and approaches across the full spectrum of therapeutic development.

The impact of a telemedicine intervention on home non-invasive ventilation in a rural population with advanced COPD.

Rural regions have unique challenges with the implementation of new therapies upon discharge from the hospital due to multiple barriers. We investigated the effect of home non-invasive ventilation (NIV) plus the implementation of a call center following hospitalization for acute exacerbations of COPD (chronic obstructive lung disease) on NIV usage and readmissions. In this prospective pilot study, consecutive patients were screened at our institution for diagnosis of hypercarbic respiratory failure or COPD exacerbation from 2018 to 2019. Patients with more than two admissions in the last year were reviewed for eligibility. Of the 82 patients screened, 22 were eligible. There were 10 participants randomized to the intervention (NIV and call center) arm and 10 to NIV alone. A total of 20 patients were randomized (mean age of 64, 45% males, BMI of 32). At three months, average usage was 32.1 days out of 90, 35%. When comparing the call center group to the standard group, there was a statistically significant difference in total days of device usage 48.7 compared to 15.5 (significant U-value of 16, critical value of U at p<.05 of 27) and cumulative use in hours 284 versus 87.7 (significant U-value of 20). Participants in the call center group were readmitted on average 4.2 times compared to 2.4 in the control group which was not statistically different (non-significant U-value of 42). In the follow-up period, 9/20 (45%) of the participants died. This pilot study highlights the challenges in implementing care for advanced COPD in a rural population. Our data suggest that telemedicine may favorably address therapy adherence.

Adult Patients Affected by Cystic Fibrosis in Therapy with Cystic Fibrosis Transmembrane Regulator Modulators and Lung Transplant: Renal Function, Metabolic and Nutritional Status

Background. Cystic fibrosis (CF) is one of the most frequent genetic diseases. The discovery and implementation of new therapies prolonged the survival of CF patients in the last years. Evaluation of long-term complications could be useful to improve the outcome of these patients. Aim of the Study. To evaluate renal function, metabolic, nutritional, and inflammatory status in CF patients on cystic fibrosis transmembrane regulator (CFTR) modulators therapy as well as lung transplant recipients (LRs) and patients on conservative therapy (control group). Materials and Methods. We performed a prospective, longitudinal study on 69 CF patients. Clinical and laboratory parameters (metabolic and nutritional indices and inflammatory markers) were evaluated in all patients before starting CFTR therapy or transplant (T0) and after 3 years (T1). Results. We enrolled 69 CF patients (42 males). Patients were distributed into three groups. The average age was 35.01 ± 10.57 years for the control group (group 0), 32.47 ± 9.40 years for patients on CFTR modulators therapy (group 1), and 38.93 ± 7.14 years for LRs (group 2). At T1, we showed a significant difference among the three groups in terms of renal function indices: creatinine, eGFR, serum nitrogen as well as serum uric acid, sodium, and potassium ( p &lt; 0.001 , p &lt; 0.001 , p &lt; 0.001 , p &lt; 0.001 , p &lt; 0.001 , and p &lt; 0.001 , respectively), particularly in LRs patients. Significant differences were found in nutritional status parameters among the three groups: total protein, serum albumin, serum fibrinogen, serum transferrin, and white blood cell counts ( p &lt; 0.001 , p = 0.037 , p = 0.04 , p = 0.003 , and p = 0.007 , respectively), particularly in LRs compared with other groups. Moreover, we found significant differences in metabolic profile (HbA1c, p = 0.026 ) and inflammatory status, with a significant difference in C-reactive protein values, neutrophil counts, and neutrophil-lymphocyte ratio (NLR) among the three groups ( p &lt; 0.001 , p = 0.005 , and p = 0.026 , respectively). Conclusions. Our study showed a reduced renal function and poor nutritional status in LRs, along with worse metabolic control. Moreover, we showed a lower inflammatory status in patients on CFTR modulators therapy. Therefore, we suggest early and careful monitoring of renal function, metabolic, and nutritional parameters in CF patients, whether they are on conservative therapy, CFTR modulators therapy, and LRs patients.

Timing of US Food and Drug Administration (FDA) cancer drug approvals relative to publication of clinical trial results.

2071 Background: Publication of clinical trial results in peer reviewed literature is essential to inform clinicians regarding the use of new anti-cancer treatments, which often have a low therapeutic ratio and require careful assessment of risks and benefits. Publication of registration trials should precede FDA approval to facilitate evaluation and implementation of new therapies. The timing of trial publication relative to FDA drug approvals has not been systematically investigated. Methods: We collected all FDA drug approvals for a cancer indication between 2000-19. Trials were identified using FDA labels as well as drugs and publications indexed on HemOnc.org. Approvals for generics/biosimilars, non-oncology indications and label revisions without supportive evidence were excluded. Dates of approval, the approval pathway, approval type (new vs expansion), and the first full publication related to the registration were recorded. Trials and approvals were matched using available metadata. We calculated the proportion of drugs approved prior to publication overall and for those receiving accelerated approval (AA). We used logistic regression to compare rates of pre-publication approval by approval pathway and by new vs expanded approval. Results: Among a total of 378 drug approvals, 139 (37%) had pre-publication approval. Of these, the median overall time from approval to publication was 140 days (IQR 64-281 days). For those with approval after publication, median time from publication to approval was 157 days (IQR 72-359 days). The number of drugs approved pre-publication rose by 27% between the first and last quarters of the study period, though, the proportion decreased as more anti-cancer drugs have been approved in recent years (Table). More drugs were approved pre-publication through AA than regular approval (46% vs 34%, OR 1.66 [95% CI 1.03-2.70], p=0.04) and as new approvals vs. expanded approvals (45% vs 32%, OR 1.76 [95% CI 1.15-2.70], p=0.01). Conclusions: A substantial minority of FDA approvals occur before trial results are published, with the odds being higher for drugs receiving AA and for new approvals. Since clinicians rely upon published results to inform risk/benefit decisions, efforts are needed to ensure trial results are published by the time of FDA approval of new cancer drugs and indications. [Table: see text]

Knowledge Translation in Heart Failure

The treatment of heart failure has expanded over the past three decades with large numbers of new medications and healthcare innovations available for these patients. At the same time, the prevalence of heart failure continues to increase across Canada and these patients are managed by a variety of clinicians from differing backgrounds in both primary care and hospital settings. Despite national recommendations advocating uptake of these new therapies, their utilization remains limited and inconsistent across the country. This review discusses the importance of knowledge translation in heart failure and examines the barriers to implementation of new therapies and models of care, providing a range of solutions to facilitate the delivery of guideline-directed care for heart failure patients.

Reply to the letter to the editor "Are we compromising on value versus performance: time to consider the Portico valve as a third major market player?". Rapid implementation of new therapies, new devices, new procedures... fast but under control: be vigilant!

Reply to the letter to the editor "Are we compromising on value versus performance: time to consider the Portico valve as a third major market player?". Rapid implementation of new therapies, new devices, new procedures... fast but under control: be vigilant!

Sequential treatment with pazopanib (PAZO) followed by nivolumab (NIVO) in patients with advanced or metastatic renal cell carcinoma (mRCC): Third interim results of the non-interventional study PAZOREAL.

4574 Background: Randomized clinical trials for the implementation of new therapies include only a selection of patients that are later treated with these new options. Thus, real-world evidence is urgently needed not only to monitor the translation of treatment approaches into routine practice but also to improve cancer treatment and survivorship care on a broader scale. Methods: PAZOREAL is a prospective, multicenter, non-interventional study to evaluate effectiveness [primary time on drug (TD)], tolerability, safety, and quality of life (QoL) in patients (pts) with mRCC, treated with 1st L PAZO followed by 2nd L NIVO or everolimus (EVE). Results: Between Dec. 2015 and Sep. 2017, 421 pts were enrolled and 402 pts started 1st L PAZO treatment (Tx), 127 and 5 pts received NIVO and EVE as 2nd L Tx, resp., 56 entered follow-up. At time of data-cut (08 Nov 2018) median TD was 6.6 months (95%CI 6.0-7.9) for 1st L PAZO and 4.1 months (95%CI 3.2-5.8) for 2nd L NIVO (all pts), 8.1 months (95% CI 6.6-9.5) for PAZO and 3.2 (2.7-6.5) for NIVO Tx for trial eligible pts (39.1% of 402 pts). Median TD for pts with or without prior nephrectomy was 7.6 vs 4.5 months, resp. The clinical benefit rate of 1st L PAZO was 58.2 % (95% CI 53.3-62.9) based on investigator assessment. Median OS of PAZO was 29.5 months (95%CI 23.6-NA) for all pts, 28.2 months (95% CI 22.2-NA) for NIVO in 2nd L. The most commonly reported AEs for PAZO Tx were diarrhea (35%), nausea (20.3%) and fatigue (17.5%). Most common PAZO-related grade 3/4 adverse events were hypertension (5%), hypertensive crisis (2.3%) and GGT increase (1.8%). QoL evaluated by EQ-5D-5L remained stable over different Tx lines. Conclusions: The interim results of the PAZOREAL study confirm a favorable overall survival in pts with mRCC treated with 1st L PAZO in a real-world setting, good benefit-risk profile of PAZO and sustained QoL monitored over several treatment lines. In Germany NIVO as 2nd L Tx is commonly applied after 1st L Tx with PAZO.

Link between Endometriosis, Atherosclerotic Cardiovascular Disease, and the Health of Women Midlife

Endometriosis and atherosclerotic cardiovascular disease (ASCVD) are both essentially diseases of inflammation. It is well established that inflammation is the leading mechanism in the initiation and maintenance of vascular injury and in the development and progression of atherosclerosis. Thus, if women with endometriosis do indeed have increased general inflammation, they are at increased risk of developing microvascular dysfunction and atherosclerosis. Currently available evidence suggests that young female patients with proven endometriosis may be at a higher lifetime risk of developing cardiovascular disease; this may be unrecognized due to the relatively young age of women found to have endometriosis. Other mechanisms proposed to explain the link between endometriosis and ASCVD include similarities in the genetic underpinnings of each condition, including microRNA dysfunction and the association between endometriosis and early menopause, a risk for developing ASCVD. Although physicians today primarily focus on traditional risk factors when evaluating an individual female patient's risk of developing ASCVD, we believe that a history of endometriosis should be included as a possible risk factor and needs further exploration. A better understanding of the mechanisms linking endometriosis with ASCVD will hopefully guide the implementation of new therapies to mitigate the increased cardiovascular disease burden that patients with endometriosis might face.

E. coli High Throughput Assay Identifies Regulators of Endothelial Barriers

Regulation of endothelial barrier function is critical for vascular homeostasis, as dynamic and local control of vascular permeability permits macromolecular transport, immune surveillance, and deposition of a fibrin barrier to contain infection at sites of inflammation. Many of the signaling pathways promoting useful vascular permeability, however, are also triggered during disease, resulting in prolonged or uncontrolled vascular leak. Hyper-permeability triggered by inflammation or ischemia in the heart, brain, or lung promotes edema, exacerbates disease progression, and impairs recovery. Currently there is no clinical solution for the regulation of the endothelial barriers. A main reason for the lack of translational solutions is the technical difficulties (e.g. low throughput, and lengthy assays) to explore libraries of small compounds to begin drug development. Regulating endothelial barriers is crucial in the prevention of disease, disease progression, and the discovery and implementation of new therapies. Claudins, and occludin, are Tight Junction membrane proteins (TJ-MP) that seal the paracellular space creating the endothelial barriers. Our laboratory has devised a strategy to express TJ-MPs in the outer membrane of E. coli. TJ-MP expression drives cell-cell interactions above the unicellular behavior of E. coli. TJ-MPs force this aggregation in a manner that correlates with their strength in the native endothelial barriers. The aggregation of E. coli can be quantified using flow cytometry. Our preliminary results suggest that our assay has sensitivity to detect hyper-permeability (barrier opening) as well as hypo-permeability (barrier closing or strengthening).