Failure Of Trials Research Articles

An interpretable framework to identify responsive subgroups from clinical trials regarding treatment effects: Application to treatment of intracerebral hemorrhage.

Randomized Clinical trials (RCT) suffer from a high failure rate which could be caused by heterogeneous responses to treatment. Despite many models being developed to estimate heterogeneous treatment effects (HTE), there remains a lack of interpretable methods to identify responsive subgroups. This work aims to develop a framework to identify subgroups based on treatment effects that prioritize model interpretability. The proposed framework leverages an ensemble uplift tree method to generate descriptive decision rules that separate samples given estimated responses to the treatment. Subsequently, we select a complementary set of these decision rules and rank them using a sparse linear model. To address the trial's limited sample size problem, we proposed a data augmentation strategy by borrowing control patients from external studies and generating synthetic data. We apply the proposed framework to a failed randomized clinical trial for investigating an intracerebral hemorrhage therapy plan. The Qini-scores show that the proposed data augmentation strategy plan can boost the model's performance and the framework achieves greater interpretability by selecting complementary descriptive rules without compromising estimation quality. Our model derives clinically meaningful subgroups. Specifically, we find those patients with Diastolic Blood Pressure≥70 mm hg and Systolic Blood Pressure<215 mm hg benefit more from intensive blood pressure reduction therapy. The proposed interpretable HTE analysis framework offers a promising potential for extracting meaningful insight from RCTs with neutral treatment effects. By identifying responsive subgroups, our framework can contribute to developing personalized treatment strategies for patients more efficiently.

A promising breakthrough in pancreatic cancer research: The potential of spheroids as 3D models

Pancreatic ductal adenocarcinoma (PDAC) stands as the fourth leading cause of cancer-related deaths, primarily attributable to its resistance to chemotherapy, resulting in a nearly universal fatality rate. Despite the promise exhibited by numerous drugs in preclinical studies, their subsequent failure in clinical trials underscores the inherent limitations of conventional two-dimensional cell culture models commonly employed in early drug screening endeavors. The inadequacies of two-dimensional (2D) models prompted the exploration of three-dimensional (3D) culture systems, which more faithfully recapitulate the native tumor microenvironment. These 3D systems have distinct advantages over 2D models in morphology, proliferation, drug response, and protein expression. Among these 3D platforms, tumor organoids and spheroids, generated through different methodologies, have emerged as next-generation models that closely mirror aspects of pancreatic tumor biology. This comprehensive review scrutinizes pancreatic cancer spheroids' techniques, tissue sources, and applications, offering a nuanced analysis of their advantages and limitations. By comparing these distinct 3D culture systems, researchers gain valuable insights to inform the selection of optimal model designs aligned with their specific experimental objectives. The utilization of these advanced models holds significant promise for enhancing the clinical relevance of both in vitro and in vivo cancer research, thereby contributing to the development of improved therapeutics against pancreatic cancer.

Need of orthogonal approaches in neurological disease modeling in mouse.

Over the years, advancements in modeling neurological diseases have revealed innovative strategies aimed at gaining deeper insights and developing more effective treatments for these complex conditions. However, these progresses have recently been overshadowed by an increasing number of failures in clinical trials, raising doubts about the reliability and translatability of this type of disease modeling. This mini-review does not aim to provide a comprehensive overview of the current state-of-the-art in disease mouse modeling. Instead, it offers a brief excursus over some recent approaches in modeling neurological diseases to pinpoint a few intriguing strategies applied in the field that may serve as sources of inspiration for improving currently available animal models. In particular, we aim to guide the reader toward the potential success of adopting a more orthogonal approach in the study of human diseases.

Screen Failures in Clinical Trials in Retina

PurposeDisparities in clinical trials are a major problem due to significant underrepresentation of certain gender, racial and ethnic groups. Several factors including stringent eligibility criteria and recruitment strategies hinder our understanding of retinal disease. Thus, we aimed to study the various reasons of screen failures and specific patient and study characteristics among screen failures. DesignThis is a cross-sectional retrospective study MethodsScreening data of 87 trials from 6 centers were analyzed. Study characteristics (disease studied, phase of trial, route of drug administration) and patient demographics (age, gender, race, ethnicity, and employment status) were compared among different causes of screen failures. Screen failures were broadly classified into six categories: exclusion due to vision-based criteria, exclusion due to imaging findings, exclusion due to other factors, patient-related criteria, physician related criteria and miscellaneous. Descriptive statistics, Pearson Chi-square test and ANOVA were used for statistical analysis. Main outcome measuresDetermine the prevalence of various reasons for screen failures in multiple trials and its trend among different study and patient characteristics. ResultsAmong 87 trials and 962 patients, 465(48.2%) patients were successfully randomized and 497(51.8%) patients were classified as screen failures. The trials were conducted for various retinal diseases. Mean age was 76.50 ±10.45 years and 59.4% were females. Predominantly whites(93.4%) and unemployed/retired patients(66.6%) were screened. Of the 497 screen failures, most were due to patients not meeting inclusion criteria of imaging findings (n=221[44.5%]) followed by inclusion of vision-based criteria (n=73 [14.7%]), exclusion due to other factors (n=75[15.1%]), patient-related (n=34[6.8%]), physician-related (n=28[5.6%]) and miscellaneous reasons (n= 39[17.8%]). Reason for screen failure was not available for 27(5.4%) patients. A higher proportion of patients screened for surgical trials (15%) declined to participate in the study compared to non-invasive trials involving topical drugs and photobiomodulation (0%).(p=0.02) ConclusionPatients not meeting the imaging and vision-cased criteria were the most common reasons for screen failures. Whites and unemployed patients predominantly participated in clinical trials. Patients are more inclined to continue participation in non-invasive clinical trials compared to surgical trials. Better recruitment strategies and careful consideration of study criteria can aid in decreasing the rate of screen failures.

Assessing patient risk, benefit, and outcomes in drug development: A decade of ramucirumab clinical trials.

This study aims to evaluate published clinical trials of ramucirumab to assess the risk/benefit profile and burden over time for patients. The burden of oncologic drug development on patients paired with increasing clinical trial failure rates emphasizes the need for reform of drug development. Identifying and addressing patterns of excess burden can guide policy, ensure evidence-based protections for trial participants, and improve medical decision-making. On May 25, 2023 a literature search was performed on Pubmed/MEDLINE, Embase, Cochrane CENTRAL, and ClinicalTrials.gov for clinical trials using ramucirumab as monotherapy or in combination with other interventions for cancer treatment. Authors screened titles and abstracts for potential inclusion in a masked, duplicate fashion. Following data screening, data was extracted in a masked, duplicate fashion. Trials were classified as positive when meeting their primary endpoint and safety, negative or indeterminate. Ramucirumab was initially approved for gastric cancer but has since been tested in 20 cancers outside of its FDA approved indications. In our analysis of ramucirumab trials, there were a total of 10,936 participants and 10,303 adverse events reported. Gains in overall survival and progression-free survival for patients were 1.5 and 1.2 months, respectively. FDA-approved indications have reported more positive outcomes in comparison to off-label indications. We found that FDA-approved indications for ramucirumab had better efficacy outcomes than non-approved indications. However, a concerning number of adverse events were observed across all trials assessed. Participants in ramucirumab randomized controlled trials saw meager gains in overall survival when evaluated against a comparison group. Clinicians should carefully weigh the risks associated with ramucirumab therapy given its toxicity burden and poor survival gains.

Definition of Implanted Neurological Device Abandonment: A Systematic Review and Consensus Statement.

Establishing a formal definition for neurological device abandonment has the potential to reduce or to prevent the occurrence of this abandonment. To perform a systematic review of the literature and develop an expert consensus definition for neurological device abandonment. After a Royal Society Summit on Neural Interfaces (September 13-14, 2023), a systematic English language review using PubMed was undertaken to investigate extant definitions of neurological device abandonment. Articles were reviewed for relevance to neurological device abandonment in the setting of deep brain, vagal nerve, and spinal cord stimulation. This review was followed by the convening of an expert consensus group of physicians, scientists, ethicists, and stakeholders. The group summarized findings, added subject matter experience, and applied relevant ethics concepts to propose a current operational definition of neurological device abandonment. Data collection, study, and consensus development were done between September 13, 2023, and February 1, 2024. The PubMed search revealed 734 total articles, and after review, 7 articles were found to address neurological device abandonment. The expert consensus group addressed findings as germane to neurological device abandonment and added personal experience and additional relevant peer-reviewed articles, addressed stakeholders' respective responsibilities, and operationally defined abandonment in the context of implantable neurotechnological devices. The group further addressed whether clinical trial failure or shelving of devices would constitute or be associated with abandonment as defined. Referential to these domains and dimensions, the group proposed a standardized definition for abandonment of active implantable neurotechnological devices. This study's consensus statement suggests that the definition for neurological device abandonment should entail failure to provide fundamental aspects of patient consent; fulfill reasonable responsibility for medical, technical, or financial support prior to the end of the device's labeled lifetime; and address any or all immediate needs that may result in safety concerns or device ineffectiveness and that the definition of abandonment associated with the failure of a research trial should be contingent on specific circumstances.

Comparisons of successful and failed Phase III trials of drugs and biologicals tested for mitigation of oral mucositis in patients being treated with radiotherapy with or without concomitant chemotherapy for cancers of the head and neck.

Oral mucositis (OM) remains a significant toxicity among patients being treated with radiotherapy (RT) alone or with concomitant chemotherapy (CRT) for cancers of the head and neck (HNC). Given its clinical significance as an unmet need and its potential commercial viability, the pharmaceutical industry has been actively pursuing an effective intervention. Despite this interest and activity, only a few agents have been studied in Phase III trials (n = 6). The objective of this study was to identify common features that differentiate successful and failed Phase III OM trials. We used the United States Patent and Trademark Office Patent Public Search database to search patents with "oral mucositis" in the claims. We then searched ClinicalTrials.gov and PubMed to determine if Phase III or Phase II trial data for identified biologics/drugs had been published. We assessed each Phase III and Phase II trial for characteristics that may be associated with trial success or failure. We considered a study as a "success" if the primary endpoint reached statistical significance, and we considered a study as "failure" if the primary endpoint did not reach statistical significance. Of the three successful Phase III trials, one investigated avasopasem manganese (Galera Therapeutics) and two examined palifermin (Amgen). The three failed trials included those evaluating dusquetide (Soligenix), iseganan hydrochloride (IntraBiotics Pharmaceuticals), and clonidine (Monopar Therapeutics). We found that differences in the level of sponsor funding, patient inclusion criteria including radiation source and concomitant chemotherapy regimen, and concordance of primary efficacy outcomes between Phase II and Phase III trials influenced outcomes. To properly design clinical trials for OM in HNC patients, it is important that researchers and sponsors take note of specific study characteristics associated with success or failure, particularly with Phase III trials where the risks and costs are the highest.

Frozen shoulder release: Ten-step technique

Frozen shoulder is a condition associated with painful restriction of shoulder joint movement. This condition has a prevalence of 2–5% in the general population, seen most often in females and the diabetic population. It is essentially a self-limiting condition passing through stages of freezing, frozen, and thawing. It has been reported that up to 90% of patients recover with conservative measures. Patients with more severe initial symptoms, younger age at the time of onset, and reduction in motion despite four months of compliance with therapy are most likely to require surgery. The author presents ten-step techniques for frozen shoulder release in cases of failed conservative trials in the management of frozen shoulder.

Nitroxyl donating and visualization with a coumarin-based fluorescence probe

Nitroxyl (HNO), the single-electron reduction product of nitric oxide (NO), has attracted great interest in the treatment of congestive heart failure in clinical trials. In this paper, we describe the first coumarin-based compound N-hydroxy-2-oxo-2H-chromene-6-sulfonamide (CD1) as a dualfunctional HNO donor, which can release both an HNO signaling molecule and a fluorescent reporter. Under physiological conditions (pH 7.4 and 37 °C), the CD1 HNO donor can readily decompose with a half-life of ∼90 min. The corresponding stoichiometry HNO from the CD1 donor was confirmed using both Vitamin B12 and phosphine compound traps. In addition to HNO releasing, specifically, the degradation product 2-oxo-2H-chromene-6-sulfinate (CS1) was generated as a fluorescent marker during the decomposition. Therefore, the HNO amount released in situ can be accurately monitored through fluorescence generation. As compared to the CD1 donor, the fluorescence intensity increased by about 4.9-fold. The concentration limit of detection of HNO releasing was determined to be ∼0.13 μM according to the fluorescence generation of CS1 at physiological conditions. Moreover, the bioimaging of the CD1 donor was demonstrated in the cell culture of HeLa cells, where the intracellular fluorescence signals were observed, inferring the site of HNO release. Finally, we anticipate that this novel coumarin-based CD1 donor opens a new platform for exploring the biology of HNO.

First-Line Respiratory Support for Children With Hematologic Malignancy and Acute Respiratory Failure.

To characterize trends in noninvasive ventilation (NIV) and invasive mechanical ventilation (IMV) use over time in children with hematologic malignancy admitted to the PICU with acute respiratory failure (ARF), and to identify risk factors associated with NIV failure requiring transition to IMV. Retrospective cohort analysis using the Virtual Pediatric Systems (VPS, LLC) between January 1, 2010 and December 31, 2019. One hundred thirteen North American PICUs participating in VPS. Two thousand four hundred eighty children 0-21 years old with hematologic malignancy admitted to participating PICUs for ARF requiring respiratory support. None. There were 3013 total encounters, of which 868 (28.8%) received first-line NIV alone (NIV only), 1544 (51.2%) received first-line IMV (IMV only), and 601 (19.9%) required IMV after a failed NIV trial (NIV failure). From 2010 to 2019, the NIV only group increased from 9.6% to 43.1% and the IMV only group decreased from 80.1% to 34.2% (p < 0.001). The NIV failure group had the highest mortality compared with NIV only and IMV only (36.6% vs. 8.1%, vs. 30.5%, p < 0.001). However, risk-of-mortality (ROM) was highest in the IMV only group compared with NIV only and NIV failure (median Pediatric Risk of Mortality III ROM 8.1% vs. 2.8% vs. 5.5%, p < 0.001). NIV failure patients also had the longest median PICU length of stay compared with the other two study groups (15.2 d vs. 6.1 and 9.0 d, p < 0.001). Higher age was associated with significantly decreased odds of NIV failure, and diagnosis of non-Hodgkin lymphoma was associated with significantly increased odds of NIV failure compared with acute lymphoid leukemia. For children with hematologic malignancy admitted to the PICU with ARF, NIV has replaced IMV as the most common initial therapy. NIV failure rate remains high with high-observed mortality despite lower PICU admission ROM.

EFFECTS OF LEVOSIMENDAN ON DIAPHRAGMATIC DYSFUNCTION IN PATIENTS WITH SEPSIS.

Objective: In this study, our aim was to examine the effects of levosimendan on diaphragmatic dysfunction in patients with sepsis, as well as assess its impact on respiratory muscle contractility and the outcome of weaning. Methods: This was a single-blind, randomized, controlled trial. Patients with diaphragmatic dysfunction and failure of spontaneous breathing trials (SBTs) were randomly and equally assigned to the experimental and control groups. The experimental group received levosimendan at a loading dose of 6 μg/kg for 10 min, followed by a continuous infusion at 0.2 μg/kg/min. The control group received an equivalent dose of a placebo. The preadministration and postadministration respiratory mechanics parameters of the patients were recorded. Evaluation of the effect of levosimendan on patients with sepsis-induced diaphragm dysfunction comprised arterial blood gas analysis as well as ultrasound measurements of diaphragm excursion (DE), diaphragm thickness (DT), diaphragm thickening fraction (TFdi), and diaphragm-rapid shallow breathing index (D-RSBI). Results: Forty-four patients were enrolled in the study. We found that postadministration of levosimendan, the patients' tidal volume (GCSMV) increased, whereas the D-RSBI decreased, and the partial pressure of carbon dioxide (PACO 2 ) decreased when compared to the preadministration levels. Additionally, following levosimendan administration, patients showed increased DE and pressure support (PS) when compared to before administration (1.14 ± 0.177 vs. 1.22 ± 0.170 cm and 0.248 ± 0.03 vs. 0.284 ± 0.06, respectively) and decreased D-RSBI (22.76 ± 6.14 vs. 20.06 ± 6.04, respectively), all of which were statistically significant ( P < 0.05). In contrast, in the control group of patients, there were no statistically significant differences in the postadministration levels of DE, TFdi, and D-RSBI as compared to the preadministration period ( P > 0.05). Furthermore, in terms of weaning outcomes, we did not find any statistically significant difference in the number of patients in the two groups who eventually underwent weaning ( P = 0.545). Conclusion: In this study, we found that levosimendan enhanced diaphragm contractile function. However, further investigations are required to explore its effect on weaning outcomes in patients undergoing mechanical ventilation.

1239 Trends in Geospatial Availability of Neuro-oncology Clinical Trials in the United States Over Two Decades

INTRODUCTION: Advances in brain tumors treatments rely on successful neuro-oncology (NO) clinical trials. To date, data on NO trials completion in the US is scarce. Understanding these factors could help improve access to and the design of future clinical trials. METHODS: NO clinical trials registered in the US were analyzed (2000-2019). Univariate and multivariate analysis were used to compare success rates among trials. Geospatial analysis was performed to determine the trial density and failure rates across different states. Trial density was estimated by the number of trials/state population. RESULTS: A total of 2,610 neuro-oncology clinical trials were registered in the US during the study period, of which 1,257 met a primary endpoint – completion or trial failure. North Dakota had the highest trial density (6.03 trials/100,000 residents), followed by South Dakota (5.83) and several Northeastern states (3.90-5.60). The change in trial failure rates did not correlate with trial density by state (p = 0.777). The states with the greatest increase in trial failure rates were Nevada (23.1%), West Virginia, Alaska, and Idaho (all three at 20.0%). Florida showed a trend towards a statistically significant increase in failure rates to 10.9% (p = 0.09). CONCLUSIONS: The results of this study highlight the variations in success rates and geographic distribution of neuro-oncology clinical trials in the United States. Factors beyond trial density may be critical to trial success. The significant geographic variations in trial density and failure rates across states emphasize the need for targeted efforts to improve access participation to trials in certain regions. Further studies aimed at identifying the factors contributing to the increase in trial failure rates are needed to develop strategies to improve trial enrollment.

Tumor vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA): Suppresses macrophage capping protein beyond STING activation

The vascular disrupting agent (VDA) 5,6-dimethylxanthenone-4-acetic acid (DMXAA) induces apoptosis in vascular endothelial cells and leads to tumor hemorrhagic necrosis. While DMXAA has been proven to be a potent agonist of murine stimulator of interferon genes (mSTING), it has little effect on human-STING (hSTING). This species selectivity of DMXAA may explain its effectiveness against solid tumors in mice and its failure in clinical trials. However, DMXAA did reduce tumor volume in some patients during clinical trials. These paradoxical results have prompted us to investigate the anti-tumor mechanism of DMXAA beyond STING in the destruction of tumor vasculature in humans. In this study, we demonstrated that DMXAA binds to both human and mouse macrophage capping protein (CapG), with a KD of 5.839 μM for hCapG and a KD of 2.867 μM for mCapG, as determined by surface plasmon resonance (SPR) analysis. Homology modeling and molecular docking analysis of hCapG indicated that the critical residues involved in the hydrogen bond interaction of DMXAA with hCapG were Arg153, Thr151, and GLN141, Asn234. In addition, electrostatic pi-cation interaction occurred between DMXAA and hCapG. Further functional studies revealed that CapG protein plays a crucial role in the effects of DMXAA on human umbilical endothelial vein cell (HUEVC) angiogenesis and migration, as well as the expression of cytoskeletal proteins actin and tubulin, and the invasion of A549 lung adenocarcinoma cells. Our study has originally uncovered a novel cross-species pathway underlying the antitumor vascular disruption of DMXAA extends beyond STING activation. This finding deepens our understanding of the multifaceted actions of flavonoid VDAs in animal models and in clinical settings, and may provide insights for the precise therapy of DMXAA based on the biomarker CapG protein.

Optimal timing for repeat in-office voiding trial after failed post-operative voiding trial

Optimal timing for repeat in-office voiding trial after failed post-operative voiding trial

10 kHz stimulation as rescue therapy for spinal cord stimulation trial failure or loss of efficacy: A retrospective study.

Spinal cord stimulation (SCS) is currently used for the management of pain of different origin, and since its inception, many waveforms have been developed. Some patients experience no pain relief already during SCS trial, while other patients go through a loss of efficacy due to habituation after a variable period of satisfying pain control. Our retrospective study represents the first report exploring the potential role of 10 kHz stimulation as rescue therapy for patients who did not benefit not only from conventional stimulation but even from other waveforms during SCS trial or follow-up. This study was conducted in Germany; we retrospectively enrolled patients with no pain relief during SCS trial or with loss of efficacy of other waveforms over time; and we recorded visual analogic scale (VAS), Oswestry Disability Index (ODI), and daily opioid consumption expressed as morphine milligram equivalents (MME), right before and 12 months after the switching to 10 kHz simulation. The rate of successful switching to 10 kHz stimulation was comparable in patients enrolled during the SCS trial and during the follow-up (43% vs. 40%, respectively); notably, the highest rate of failed rescue was recorded in case of persistent spinal pain syndrome (PSPS) II. Patients who responded to the switching showed a significant improvement in VAS and ODI after 12 months of treatment compared to baseline (3.6 ± 1.0 vs. 8.2 ± 0.9, p < 0.00001 and 34.0 ± 7.8 vs. 64.3 ± 8.7, p < 0.0001, respectively), whereas there was no reduction in the consumption of opioids in terms of MME (3 (0-16) vs. 5 (0-8.75), p = 0.1003). Rescue therapy with 10 kHz stimulation could be an important strategy to avoid SCS explant in both patients non-responsive during trial or experiencing a loss of efficacy during the years with other waveforms.

Tumor microenvironment responsive multifunctional smart living materials based on engineered bacteria for inducing macrophage polarization to enhance tumor immunotherapy

The utilization of bacteria as a drug delivery system represents a promising strategy for tumor therapy, owing to their inherent ability to selectively colonize and induce apoptosis of tumor cells at the solid tumor. However, the occurrence of dose-dependent toxicity has led to the failure of clinical trials. Unfortunately, the implementation of a singular bacterial treatment strategy for tumor therapy is inherently limited. In this study, we developed a living drug delivery material named DOX@TA@ECN (D@T@E) by utilizing Fe3+ and tannin acid (TA) as a cross-linking network to encapsulate doxorubicin (DOX) and form a protective coating on the surface of Escherichia coli Nissle 1917 (ECN). In an acidic tumor microenvironment, D@T@E disintegrated the coating to release DOX through the highly expressed H2O2. To enhance biosafety, the D@T@E was equipped with a hypoxic lytic circuit (Pvhb-Lysis) to regulate the number of ECN in vivo (D@T@E-PL). The hypoxic promotor of Vitreoscilla hemoglobin protein (Pvhb) were activied to induce expression of lysis protein (PhiX174E) in the tumor hypoxic microenvironment (3 %), resulting in ECN lysis and subsequent elimination by the immune system. Additionally, D@T@E-PL pass lysis to release relevant antigens (DNA and flagellin). This antigen promotes the polarization of M2-type tumor-promoting macrophages towards M1-type anti-tumor macrophages at the tumor microenvironment by activating Toll-like receptor 4 (TLR4), eliciting immune-mediated anti-tumor responses. The in vivo findings demonstrated that D@T@E-PL intelligent material demonstrated enhanced biosecurity through the lytic circuit and effectively suppressed tumor growth, thereby achieving a dual therapeutic approach combining chemotherapy and immunotherapy for tumor inhibition.

Birth after Caesarean Section: A Retrospective Audit of 10 Years of State-Wide Data

Rates of Caesarean Section (CS) have been increasing worldwide with varying rates of [5] percent in Sub-Saharan Africa to 43 percent in Latin America and the Caribbean [1]. In Australia too rates have increased from 32 percent in 2011 to 38 percent in 20212. Attempts have been made to seek ways at slowing the rise in rates of CS but with little success [3]. Women who have had a previous CS may elect to have a Elective Repeat CS (ERCS) or have an attempt at a Vaginal Birth (VBAC) in their subsequent pregnancy. A planned VBAC, considering the woman’s individual history and needs, is viewed as a safe option for many women with a single previous lower segment caesarean section [4]. Studies have shown that a Trial of Labour (TOL) ending in a VBAC is most favourable for the mother, newborn, and the health service [5,6]. Likelihood of success rates are reported to be between 60 and 80 percent [7]. A recent meta-analysis [8] noted successful vaginal birth rates of 74.3 percent if labour was spontaneous and 60.7 percent if induced. Achieving successful VBAC has also been reported to be less expensive and more effective than undergoing an ERCS [9,10]. There has recently been an international multi-centre trial that aims to increase the proportion of women having VBAC by increasing woman-centred care and facilitating women’s empowerment in their choice of birth in three countries – Germany, Ireland and Italy [1]. An attempt at vaginal birth is also supported by various colleges across countries [4,7,12]. One of the reasons for the preference of ERCS may be a concern of a failed trial at vaginal birth resulting in an emergency CS. In one study of 29 352 women who attempted a vaginal birth after CS compared to 169 377 women without previous CS, Odds Ratio (OR) for emergency CS was 3.65 (CI: 3.26-4.08) higher when compared to women without previous CS [13]. The scibasejournals.org aim of this retrospective study however was to use a large dataset with a specific objective to report on the success and failure rate and to identify any specific predictors of a successful or an unsuccessful vaginal birth in women who are pregnant after one previous CS.

A case report of unsuccessful VBAC in primary care: highlighting the lesson learned

Purpose: To delve into the patient’s attempt at vaginal birth after cesarean section (VBAC) in the primary care center and to highlight the importance of the primary care center for women opting for VBAC. Methods: This case report describes a woman with unsuccessful VBAC in primary care. Informed consent was obtained before the study. Results: A woman in her mid-thirties with a history of a prior cesarean section and a failed trial of labor was referred to the hospital at 40 weeks gestational age due to prolonged labor. The patient was referred to the hospital after 14.5 hours of trial labor in primary care. After delivery, the patient had urinary retention caused by pelvic nerve injury. The newborn baby had an APGAR Score of 3/5 and was treated in the Neonatal Intensive Care Unit (NICU) with respiratory distress syndrome and meconium aspiration syndrome. Conclusion: Vaginal birth after cesarean can be done by considering its indications and contraindications. However, it is recommended to perform VBAC in hospitals equipped with emergency cesarean facilities, in which the cesarean section can be done within 30 minutes after the decision has been made. Primary care centers have a role in educating patients, providing guidance, and selecting patients for referral. This case also highlights the importance of a holistic approach to social obstetrics, addressing medical, social, economic, and systemic factors. By doing so, healthcare systems can ensure equitable access to timely and appropriate care, ultimately enhancing the well-being of pregnant women and improving VBAC success rates.

Efficacy and safety of tofacitinib for chronic plaque psoriasis and psoriatic arthritis: a systematic review and meta-analysis of randomized controlled trials.

To summarize and analyze the results of published randomized controlled trials of tofacitinib for the treatment of chronic plaque psoriasis and psoriatic arthritis(PsA) and discuss its efficacy and safety. An exhaustive systematic search encompassing PubMed, Cochrane, Embase, and Web of Science databases was conducted up to July 2023. Studies eligible for inclusion were analyzed, organized using Review Manager version 5.4.1 (Cochrane Collaboration, Oxford, UK) and STATA 15.0 version (Stata Corp, College Station, TX, USA) software. A total of six articles, covering 1393 patients (844 treated with tofacitinib and 549 with placebo), were included. The foundational characteristics of tofacitinib and placebo group showed similarity, except for age and Dermatology Life Quality Index (DLQI) score, especially in the context of chronic plaque psoriasis. It is noteworthy that we discovered tofacitinib exhibited a significant impact on Psoriasis Area and Severity Index 75 (PASI75) response, Physician's Global Assessment (PGA) response, and adverse events (AEs) in cases of chronic plaque psoriasis. Similarly, tofacitinib demonstrated substantial influence on American College of Rheumatology 20/50 (ACR20/50) response, PASI75 response, as well as alterations in Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Score, Health Assessment Questionnaire-Disability Index (HAQ-DI) Score, Dactylitis Severity Score (DSS), and Leeds Enthesitis Index (LEI) Score in the context of psoriatic arthritis (PsA). Nevertheless, there was no statistically significant impact of tofacitinib on serious adverse events (SAEs) in chronic plaque psoriasis, as well as on both adverse events (AEs) and SAEs in psoriatic arthritis (PsA). A comprehensive analysis revealed that tofacitinib has a positive effect on addressing skin and joint symptoms, as well as improving the quality of life for patients with chronic plaque psoriasis and psoriatic arthritis (PsA). However, the safety of the drug's long-term usage even requires further validation. Key Points • In 6 analyses involving a total of 1393 patients, tofacitinib exhibits positive effect on the treatment of both chronic plaque psoriasis and psoriatic arthritis (PsA). • Although dose-based subgroup analyses have demonstrated effectiveness. Some studies indicate that the 5-mg dose (twice daily) may not show an effect due to the failure of non-inferiority trials comparing tofacitinib with placebo. Therefore, caution is required when interpreting its effectiveness. On the other hand, the 10-mg dose (BID) has been associated with an increase in adverse events and serious adverse events,and is recommended to be used with caution in patients with cardiovascular or uveitis risk factors. • Tofacitinib has efficacy in comorbid psychiatric disorders (depression, anxiety, or Alzheimer's disease) and inflammatory bowel disease (ulcerative colitis), but patients with comorbid renal insufficiency, hepatic dysfunction, osteoporosis, cardiovascular disease, or uveitis may need to be moderated or avoided with tofacitinib.

Abstract 2697: Simultaneous activation of innate immune suppressive components impairs antitumor efficacy of immunotherapy against the innate immune system

Abstract Cancer immunotherapy has shown noticeable clinical efficacy in many cancer types, while clinical benefits are only observed in 20-40% of treated patients. Therefore, combination cancer immunotherapy targeting multiple factors that limit antitumor immunity has been tested in the clinic. Accumulating evidence reveals that cancers that harbor limited immune cell infiltration (so-called immunologically cold tumors) respond poorly to current immunotherapy. Preclinical studies using animal models have shown that activation of innate immunity by TLR agonists or STING agonists can successfully remodel the TME to effectively induce antitumor immunity in those immunologically cold tumors. However, unexpectedly, all TLR agonists and STING agonists tested have not shown clinical efficacy in combination with immune checkpoint blockade therapy, including PD-1/PD-L1 blockade therapy. Hence, we addressed the mechanism(s) why stimulators of innate immunity failed to elicit effective antitumor immunity in cancer patients. We then employed OK-432, which reportedly stimulates TLR-2, TLR-4, and/or TLR-9, as OK-432 is widely used in Japan in the clinic. In vitro OK-432 treatment accelerated the maturation DCs, and efficiently induced CD8+ T cells in humans. However, the combination treatment with anti-PD-1 mAb and OK-432 failed to augment antitumor immunity in animal models using anti-PD-1 mAb monotherapy-resistant tumors; the data mirrors the failure of clinical trials of combination therapy with immune checkpoint blockade and TLR agonists or STING agonists in humans. Therefore, using the animal models, we explored the acquired resistance mechanism developed after combination treatment. While OK-432 treatment effectively stimulated DCs, innate immune suppressive cells, such as MDSCs, were concurrently accumulated in the TME. The accumulation of PMN-MDSCs after OK-432 treatment was induced in a CXCL1-CXCR2-dependent fashion. Accordingly, triple combination treatment with a PMN-MDSC inhibitor along with OK-432 and anti-PD-1 mAb attenuated the accumulation of PMN-MDSCs in the TME and improved the antitumor effect of the combination treatment. Taken together, we propose that successful combination treatment stimulating innate immunity against immunogenically cold cancers requires controlling the unwanted co-activation of innate immune suppressive cells. This study clearly demonstrates the mechanism of acquired resistance after administration of reagents that activate innate immunity, such as TLR agonists or STING agonists, and provides the basis for future successful combination therapy. Citation Format: Hitomi Nishinakamura, Sayoko Shinya, Takuma Irie, Shugo Sakihama, Tadaaki Ioroi, Takeo Naito, Keisuke Watanabe, Daisuke Sugiyama, Motohiro Tamiya, Tatsuya Yoshida, Tetsunari Hase, Takao Yoshida, Kennosuke Karube, Yuka Maeda, Shohei Koyama, Hiroyoshi Nishikawa. Simultaneous activation of innate immune suppressive components impairs antitumor efficacy of immunotherapy against the innate immune system [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2697.