Full Approval Research Articles

HER2-Positive Serous Endometrial Cancer Treatment: Current Clinical Practice and Future Directions

The most common histological subtypes of endometrial cancer consist of endometrioid and uterine serous carcinoma, with the latter being more aggressive and accompanied by poor prognosis. Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor associated with cell proliferation, differentiation, and survival. HER2 positivity can be diagnosed in many solid tumors. It has been found that approximately one-third of the patients diagnosed with serous carcinoma may overexpress HER2/neu protein and/or show the amplification of the c-erBb2 gene. The prognostic and predictive value of HER2 biomarker is nowadays highlighted and the updates of HER2-directed treatment offer new opportunities for improved efficacy and survival. A number of HER2-targeted therapies have become available in recent years and have had promising results, prompting full drug approvals and additional investigation in many cancer types, among which is endometrial cancer. Data from clinical trials combining classical chemotherapy with anti-HER2 agents, mainly trastuzumab, alone or in combination with pertuzumab, do exist and have been incorporated into international guidelines. Moreover, further research with antibody–drug conjugates and tyrosine kinase inhibitors is being conducted. Acquired resistance remains an important problem, and its underlying mechanisms in endometrial cancer are mostly unknown. Studies exploring earlier use of Her2-directed therapy are also on the way. The purpose of this literature review is to describe the available therapies in the current clinical practice and the most prominent research data regarding the future. In any case, a number of unmet medical needs do exist for HER2-positive serous endometrial cancer, and additional research and studies are warranted to provide further understanding and improved outcomes for this tumor type.

Assessing the characteristics of suicidal ideation and self-harm in a national older adult population attending emergency departments across Ireland: cohort study protocol

IntroductionOlder people (people aged 65 years and older) have high rates of death by suicide, and self-harm is a major risk factor for suicide. While rates of self-harm decrease with...

The Utilization of the Accelerated Approval Pathway in Oncology: A Case Study of Pembrolizumab.

The accelerated approval (AA) pathway was established by the United States Food and Drug Administration (FDA) to provide earlier access to therapies for patients with serious medical conditions and unmet medical needs. Since its inception, the AA pathway has been used for novel treatments across different therapeutic areas, but most prominently in oncology, including the immune checkpoint inhibitor class. This review article describes the history of regulatory approvals for pembrolizumab, an immunotherapy agent targeting programmed death receptor-1 (PD-1), and use of the AA pathway and the corresponding regulatory decisions made by the FDA. From its first AA in September 2014 to February 2024, pembrolizumab has used the accelerated pathway for roughly 40% of the approved indications listed in the US Prescribing Information and was the first oncology therapy to receive an AA for an alternate dosing regimen and a tissue-agnostic indication. As of February 2024, 14 of the 18 indication-specific AAs and 1 post-marketing requirement (PMR) for the alternate dosing regimen AA were converted to traditional approvals. Accelerated approvals for two indications were withdrawn, and the remaining ongoing PMRs are not due until later in 2024 or 2025. The median conversion time from AA to traditional approval was 2.6 years, which is roughly 6 months earlier than the median time reported for oncology AAs. While FDA was the first agency to establish an expedited approval pathway, regulators from other countries have established similar pathways. For pembrolizumab, approximately half of the datasets that supported US AAs also supported expedited approval, or sometimes full approval, in Canada, EU, Australia or Japan. Ultimately, the AA pathway balances the provision of earlier access to therapies with overcoming uncertainty about potential effectiveness, and therefore it is important to confirm treatment benefit and withdraw indications that do not confirm benefit in a timely manner. The regulatory strategy and use of this expedited program for pembrolizumab highlights the importance of the AA pathway in providing oncology patients with earlier access to life-saving medications.

The case for regulatory approval of amyloid-lowering immunotherapies in Alzheimer's disease based on clearcut biomarker evidence.

Decades of research have provided evidence that Alzheimer's disease (AD) is caused in part by cerebral accumulation of amyloid beta-protein (Aβ). In 2023, the US Food and Drug Administration gave full regulatory approval to a disease-modifying Aβ antibody for early AD. Secondary prevention trials with Aβ antibodies are underway. We summarize peer-reviewed evidence for targeting Aβ and argue that regulators should consider approving new agents working by similar mechanisms (Aβantibodies and vaccines) based on robust amyloid lowering and reasonable safety. The urgent need to provide treatments to millions of mildly symptomatic patients suggests that AD should join other diseases for which standard approval is based on significant changes in mechanistically meaningful biomarkers coupled with safety. Robust amyloid lowering in secondary prevention trials of people who have amyloid plaques but are asymptomatic could also provide evidence of a change in the pathophysiological progression of AD as a basis for regulatory approval. HIGHLIGHTS: Thirteen key findings support amyloid beta as a cause of Alzheimer's disease (AD). Three immunotherapies lower amyloid and slow decline, allowing regulatory approval. New such agents could be considered for approval due to amyloid lowering and safety. Urgency suggests AD may join diseases with approval due to a key biomarker + safety.

DDDR-36. LOOKING AROUND THE CORNER: PREDICTING SYNERGY OR FUTILITY TO COMBINATION OF ARSENIC TRIOXIDE PLUS MNK1 INHIBITORS IN GLIOBLASTOMA

Abstract Glioblastoma (GBM) is the most prevalent type of malignant tumor within the central nervous system. The five-year survival rate of 6.8% highlights the challenges inherent to exceptionally heterogeneous tumors that grow behind the blood brain barrier. The protracted dearth in new agents approved for GBM begs innovative strategies by which to approach clinical trials. Arsenic trioxide (ATO) is the standard of care for myelodysplasia and relapsed or refractory acute promyelocytic leukemia. ATO has an idiopathic mechanism of action, but has shown beneficial effects in other solid tumors. Across six GBM PDX models a 10-fold difference in sensitivity manifests, indicative of underlying innate sensitivity or resistance to ATO. This resistance has been previously shown to correlate with MNK1 expression. In order to sensitize PDX models innately resistant to ATO we utilized combination therapy with the MNK1 inhibitor AUM001 (AUM Biosciences, Singapore; NCT05462236). In high MNK1 expressing PDX models the combination of ATO + AUM001 induces cytotoxic synergy. Additionally, when narrowly measuring effects on the glioma stem cell population (ELDA), strong synergy was observed in models, including those failing to show such using bulk cell population viability assay. GSEA analysis revealed differential high enrichment in gene sets related to oxidative phosphorylation in the models failing to show synergy. Such criteria could act as exclusionary criteria (futility) for clinical trials by excluding such putative non-responder patients from the treatment population. Synergistic models showed enrichment in gene sets related to epithelial/mesenchymal transition, skeletal and sensory organ development, and regionalization. These signatures could serve to prioritize patient inclusion in clinical trials of ATO in combination with AUM001, enriching the fraction of responsive glioma patients. Such molecular signatures may bring precision medicine in early-stage clinical trials to advance promising new agents and combinations of agents to full FDA approval.

Do Caregivers Value the New Antiamyloid Treatments for Alzheimer's Disease More Than Home-Based Care?

ObjectiveThe new antiamyloid medications Lecanemab (Leqembi) and donanemab (Kisunla) are the first disease-modifying treatments for Alzheimer's disease (AD) to receive full FDA approval. However, some commentators question whether the drugs’ benefits outweigh their risks, burdens, and costs to patients. This study assessed the perceived value of these medications by asking caregivers of persons with AD to compare them to a widely used intervention in AD management: home-based care. DesignOnline survey (March 27th–April 17th, 2024) of 392 AD caregivers recruited via CloudResearch Prime Panels to match the U.S. public in education, household income, race, and ethnicity. The survey used vignettes describing antiamyloid medication and 25 hours/week of home-based care (estimated to be of similar monetary value). After rating the desirability of medication and home-based care, respondents indicated their preference for which intervention they wanted their loved one's insurance to cover. ResultsRespondents expressed a desire for their loved ones to receive both the medication and home-based care. Over half (56.9%) favored home-based care coverage. Those preferring medication coverage were more likely to believe its benefits outweigh its risks and burdens. Preference for medication coverage was also associated with being male, Hispanic, less educated, and correctly answering fewer comprehension questions. ConclusionsOur findings show most caregivers perceive modest clinical value in the novel antiamyloid therapies, and the decision to use these drugs will be preference-sensitive, pointing to the need for thorough informed consent discussions.

Utilizing a surgical sabermetrics framework to assess the impact of trainer behavior on trainee cognitive load during vascular surgery simulation

Abstract Surgical training programs lack data-driven, objective feedback of resident surgeon technical performance, non-technical skill and intraoperative cognitive load (CogL). Cognitive load is the working memory resource required to perform a task. When capacity is exceeded, cognitive overload occurs, which can negatively affect fine motor and communication skills. Surgical sabermetrics is an emerging field, which focuses on advanced analytics of data derived from audiovisual recordings of operations and non-invasive physiological sensors measuring surgeon CogL. Incivility is prevalent across surgical specialties and has been shown to negatively influence morale, teamwork and performance. Little is known about the impact of CogL on trainee surgeon development, and a gap in knowledge is the impact of intraoperative trainer teaching style and behavior on trainee CogL. Simulation models provide an opportunity to instigate a sabermetrics framework to assess whether trainer behavior objectively impacts trainee CogL and surgical performance, with no risk to patient safety. In this randomized trial, vascular surgery residents will be allocated to one of two groups: supportive trainer or critical trainer. All participants will be tasked with completing a standardized, simulated vascular anastomosis using a femoral artery model, during which they will be exposed to one of these trainer behaviors. A sabermetrics framework will be utilized to collate objective data about participant technical performance, non-technical skills and CogL. Full ethical approval has been obtained for this study. Dissemination of the results will be through conferences and publications in peer reviewed journals.

Public and health care provider attitudes, understanding, and behaviors regarding emergency use authorizations: a scoping literature review

BackgroundUnder Sect. 564 of the Federal Food, Drug, and Cosmetic Act, when the US Department of Health and Human Services Secretary issues a declaration based on one of four types of determinations, FDA may authorize an unapproved product or unapproved uses of an approved product for emergency use. It is unclear how much the public and health care providers understand about emergency use authorizations and how that understanding influences perceptions or behavioral intentions. The current study aimed to explore consumer and health care provider perceptions of emergency use authorizations and how promotion of emergency use authorizations has been investigated in the literature.MethodsWe conducted a scoping review via PubMed, Embase, Web of Science, and CINAHL for original research published in English from January 1, 2012, through November 10, 2022. We conducted surveillance of the literature through March 2023.ResultsWe identified 13 studies reported in 14 publications that addressed public and health care provider attitudes, understanding, and behaviors with regard to products authorized under an emergency use authorization. We did not identify any articles describing research regarding the promotion of emergency use authorization products. Findings suggest gaps in understanding of emergency use authorizations, both for the public and health care providers. Findings also suggest the public and health care providers have concerns about safety or the lack of full FDA approval that may contribute to decreased willingness to receive treatments and vaccines under an emergency use authorization.ConclusionsFuture research should explore how emergency use authorizations have been promoted and how that promotion impacts public and health care provider perceptions.

Establishing the Foundations of Emotional Intelligence in Care Companion Robots to Mitigate Agitation Among High-Risk Patients With Dementia: Protocol for an Empathetic Patient-Robot Interaction Study.

An estimated 6.7 million persons are living with dementia in the United States, a number expected to double by 2060. Persons experiencing moderate to severe dementia are 4 to 5 times more likely to fall than those without dementia, due to agitation and unsteady gait. Socially assistive robots fail to address the changing emotional states associated with agitation, and it is unclear how emotional states change, how they impact agitation and gait over time, and how social robots can best respond by showing empathy. This study aims to design and validate a foundational model of emotional intelligence for empathetic patient-robot interaction that mitigates agitation among those at the highest risk: persons experiencing moderate to severe dementia. A design science approach will be adopted to (1) collect and store granular, personal, and chronological data using Personicle (an open-source software platform developed to automatically collect data from phones and other devices), incorporating real-time visual, audio, and physiological sensing technologies in a simulation laboratory and at board and care facilities; (2) develop statistical models to understand and forecast the emotional state, agitation level, and gait pattern of persons experiencing moderate to severe dementia in real time using machine learning and artificial intelligence and Personicle; (3) design and test an empathy-focused conversation model, focused on storytelling; and (4) test and evaluate this model for a care companion robot (CCR) in the community. The study was funded in October 2023. For aim 1, architecture development for Personicle data collection began with a search for existing open-source data in January 2024. A community advisory board was formed and met in December 2023 to provide feedback on the use of CCRs and provide personal stories. Full institutional review board approval was received in March 2024 to place cameras and CCRs at the sites. In March 2024, atomic marker development was begun. For aim 2, after a review of open-source data on patients with dementia, the development of an emotional classifier was begun. Data labeling was started in April 2024 and completed in June 2024 with ongoing validation. Moreover, the team established a baseline multimodal model trained and validated on healthy-person data sets, using transformer architecture in a semisupervised manner, and later retrained on the labeled data set of patients experiencing moderate to severe dementia. In April 2024, empathy alignment of large language models was initiated using prompt engineering and reinforcement learning. This innovative caregiving approach is designed to recognize the signs of agitation and, upon recognition, intervene with empathetic verbal communication. This proposal has the potential to have a significant impact on an emerging field of computational dementia science by reducing unnecessary agitation and falls of persons experiencing moderate to severe dementia, while reducing caregiver burden. PRR1-10.2196/55761.

Огюст Конт и режим Второй империи

The article analyzes the doctrine of the late Comte in his attitude to the Bona­partist regime. Although Comte experienced a short-term fascination with Napoleon’s personality in his youth, from the Restoration period he spoke of the empire in a negative way. At the same time, the coming to power of Louis Bonaparte seemed to him a favorable omen for the fate of positivism. Through public lectures on the philosophy of human history allowed by the new regime, he set the task of influencing public opinion. The Bonapartist coup met the full approval from the founder of positivism, and he did not renounce this kind of as­sessment even later. The transformation of republican power seemed inevitable to him: from parliamentarism to dictatorship. In this regard the dictatorship was conceived as a transitional stage to a true positivist regime. The idea of centra­lizing power impressed Comte, so he interpreted the coup as a logical conse­quence of the entire previous history of France. This was more than an episode. But then the philosopher became disappointed with Bonapartist politics. The presi­dent proclaimed an empire, which, in the opinion of the philosopher, acted only as a metamorphosis of an obsolete monarchical principle. But Comte did not refuse to adhere to the “republican dictatorship”, he spoke of the need for a posi­tivist triumvirate to come to power, personally outlined by him. He assigned himself the role of a spiritual mentor of secular power, the high priest of the new, scientific religion of Mankind. Both the philosopher and the emperor saw their mission as helping to end the era of revolutions. But the ways of its implementa­tion were thought so differently that there was no way to synchronize the two political positions

Alzheimer's Disease Anti-Amyloid Immunotherapies: Imaging Recommendations and Practice Considerations for ARIA Monitoring.

With the full FDA approval and centers for Medicare & Medicaid services (CMS) coverage of lecanemab and donanemab, a growing number of practices are offering anti-amyloid immunotherapy to appropriate patients with cognitive impairment (MCI) or mild dementia due to amyloid-positive Alzheimer's disease (AD). The goal of this paper is to provide updated practical considerations for radiologists, including implementation of MR imaging protocols, workflows and reporting and communication practices relevant to anti-amyloid immunotherapy and monitoring for amyloid-related imaging abnormalities (ARIA). Based on consensus discussion within an expanded ASNR Alzheimer's, ARIA, and Dementia study group, we will: (1) summarize the FDA guidelines for evaluation of radiographic ARIA; (2) review the three key MRI sequences for ARIA monitoring and standardized imaging protocols based on ASNR-industry collaborations; (3) provide imaging recommendations for three key patient scenarios; (4) highlight the role of the radiologist in the care team for this population; (5) discuss implementation of MRI protocols to detect ARIA in diverse practice settings; and (6) present results of the 2023 ASNR international neuroradiologist practice survey on dementia and ARIA imaging.ABBREVIATIONS: AD = Alzheimer's disease; ARIA = amyloid-related imaging abnormalities; APOE = apolipoprotein-E; CMS = centers for Medicare & Medicaid services; MCI = mild cognitive impairment.

Factors Affecting Resilience and Prevention of Alzheimer's Disease and Related Dementias.

Alzheimer's disease (AD) is a devastating, age-associated neurodegenerative disorder and the most common cause of dementia. The clinical continuum of AD spans from preclinical disease to subjective cognitive decline, mild cognitive impairment, and dementia stages (mild, moderate, and severe). Neuropathologically, AD is defined by the accumulation of amyloid β (Aβ) into extracellular plaques in the brain parenchyma and in the cerebral vasculature, and by abnormally phosphorylated tau that accumulates intraneuronally forming neurofibrillary tangles (NFTs). Development of treatment approaches that prevent or even reduce the cognitive decline because of AD has been slow compared to other major causes of death. Recently, the United States Food and Drug Administration gave full approval to 2 different Aβ-targeting monoclonal antibodies. However, this breakthrough disease modifying approach only applies to a limited subset of patients in the AD continuum and there are stringent eligibility criteria. Furthermore, these approaches do not prevent progression of disease, because other AD-related pathologies, such as NFTs, are not directly targeted. A non-mutually exclusive alternative is to address lifestyle interventions that can help reduce the risk of AD and AD-related dementias (ADRD). It is estimated that addressing such modifiable risk factors could potentially delay up to 40% of AD/ADRD cases. In this review, we discuss some of the many modifiable risk factors that may be associated with prevention of AD/ADRD and/or increasing brain resilience, as well as other factors that may interact with these modifiable risk factors to influence AD/ADRD progression. [Color figure can be viewed at www.annalsofneurology.org] ANN NEUROL 2024;96:633-649.

Impact of the Korea Early Childhood Home-visiting Intervention (KECHI) on child health and development and maternal health: a randomised controlled trial protocol

IntroductionRandomised controlled trials (RCTs) of early childhood home-visiting interventions led by nurses have been conducted mainly in Western countries, whereas such trials have been limited in non-Western cultures, including Asia....

Utilizing Leadless Pacemakers in Extremely Elderly Patients With a Conventional Pacemaker System: A Two-Year Follow-Up Case Series Without Generator Extraction in High-Risk Scenarios.

Background and objectives Leadless pacemakers, known for their safer clinical profile, offer significant advantages for elderly patients at a higher risk of complications associated with transvenous pacemaker procedures, particularly those susceptible to high-risk bleeding and infections related to cardiac implantable electronic device interventions. This study explores an alternative use of leadless pacemakers without removing existing transvenous systems, deviating from conventional generator replacement and lead re-interventions. Methods This study was conducted with full approval from the Institutional Review Board, Medical Ethical Committee, Centro Hospitalar Conde São Januário, Macau. Between January 2018 and December 2021, we conducted a retrospective case series involving extremely elderly individuals (aged 85 years or older) at a high risk of complications, necessitating either generator replacement or lead re-implantation. The study considered implanting a leadless pacemaker (Micra; Medtronic,Minneapolis, MN, USA) without removing the transvenous generator. For the primary endpoints, we evaluated procedure-related complications and clinical outcomes during hospitalization. Secondary endpoints included the stability of parameters and any unexpected interference or interactions between the two systems during the two-year follow-up. Results Eleven patients (aged 86-101) were enrolled, most receiving antiplatelet or anticoagulation therapy. Leadless pacemaker implantation proceeded without major complications or adverse clinical outcomes during hospitalization. Regular follow-up was conducted every three to six months for adjusting pacemaker parameters and interrogating each patient. Over two years, three patients died from non-cardiac causes: two from infection and one from spontaneous intracranial hemorrhage, while eight completed regular follow-ups. We didn't detect any episodes of ventricular arrhythmias or intracardiac capture from the transvenous pacemaker system. We observed the stability in both the longevity and the voltage of the conventional generator battery, maintaining similar parameters without significant depletion (mean voltage decline: -0.07V/year). Parameters of the leadless pacemaker remained consistently normal without interference with existing pacing systems. Conclusion Implanting leadless pacemakers without removing transvenous pacemaker generators appears safe and effective for extremely elderly patients who are at high risk of complications. Comprehensive two-year follow-up supports the safety and viability of this approach. Opting for this approach instead of conventional generator replacement, with or without additional lead implantation, may be reasonable in this population. However, further research within this patient cohort, such as exploring long-term outcomes beyond two years or comparing clinical outcomes with conventional strategies, may be necessary.

Multidisciplinary lifestyle interventions for neurological disorders during the Silent phase (MINDS) study: a multi-omics randomized controlled trial protocol

IntroductionGiven the prevalence and staggering cost of neurological disorders, there is dire need for effective early detection and intervention tools. Emerging evidence suggests that multidisciplinary lifestyle interventions (MLI) may mitigate the risk and progression of neurological disorders. The objectives of this protocol are (1) to test the impact of MLI on the progression of neurological disorders and (2) to identify multi-omic biomarkers for early stages of neurological disease and the impact of MLIs on these biomarkers.Methods and analysisWe present the Multidisciplinary lifestyle Interventions for Neurological Disorders during the Silent phase (MINDS) protocol, a randomized controlled trial of MLI in neurologically healthy older adults (≥ 50 years old) exhibiting elevated risk for common neurological disorders: stroke, epilepsy, Parkinson’s Disease, or Alzheimer’s disease and related dementias. Participants will be randomly assigned to intervention (n = 100) or control (n = 100) groups. The intervention group will receive 3 months of weekly 2-hour sessions on diet education, yoga, music therapy, and cognitive skills training. The participants’ neurological health and engagement in relevant lifestyle practices will be assessed at regular intervals for 12 months. Neuroimaging and samples for multi-omic analyses will be collected at baseline, and at 3 months and 12 months after enrollment. Primary outcomes will be signs of progression of the neurological disorder risk that qualified them for study enrollment or a clinical diagnosis of the disorder. Secondary and exploratory outcomes will be based on self-reported health and multi-omic data. Data analysis will include between-group and longitudinal within-group analyses.PerspectivesThe MINDS protocol and trial aims to clarify the impact of MLI on the progression of neurological disorder risk or diagnosis in older adults and to identify biomarkers that can be used to confirm MLI efficacy. The ability to validate the impact of MLI on neurological disorder progression based on biomarker data allows the identification of individuals most likely to benefit from such therapies in the early stages of neurological disease.Trial registrationThe trial is registered on the National Institutes of Health (NIH) ClinicalTrials.gov (NCT05984056) site. It was registered on August 2nd, 2023. The trial has full approval of the Cleveland Clinic Internal Review Board.

Analysis of cancer drugs receiving FDA’s Accelerated Approval between 1992 and 2021

Abstract Objectives This cross-sectional study examines the Food and Drug Administration (FDA)’s Accelerated Approval (AA) pathway for cancer drugs from 1992 to 2021, which expedites the development and approval of new drugs, including biologics, for severe or life-threatening conditions such as cancers. Methods Based on the ‘CDER Drug and Biologic AAs Based on a Surrogate Endpoint’ report, the number of indications where anticancer agents received AA and the conversion rates to Full Approval (FA) were analysed. Outcome measures used in phase II and phase III trials for these drugs were obtained from US National Library of Medicine for comparison. Key findings Of the 278 AA-granted indications, 67% were for anticancer agents. Lymphoma, leukemia, and lung cancer had the highest number of AA indications among all cancer types. The conversion rates to FA varied among periods: Early (1995–2003), Middle (2004–2012), and Late (2013–2021). The conversion rates for drugs were 82%, 79%, and 31%, while biologics exhibited rates of 100%, 78%, and 27%, respectively. The overall response rate was often the primary outcome measure in phase II trials, whereas overall survival and progression-free survival were the common outcome measures in phase III trials. Secondary outcome measures included disease control rate and duration of response. Conclusions This study provides valuable insights for stakeholders seeking to understand the approval criteria and processes for cancer drugs via the AA pathway. However, limitations in data availability, phase-specific variations in drug doses and combinations, and the inability to manage uncertain data should be acknowledged. Research on the AA program to non-cancer drugs is also required.

PI3K Inhibitors in Hematology: When One Door Closes….

The PI3K signaling pathway regulates key cellular processes and is one of the most aberrantly activated pathways in cancer. The class I PI3K catalytic subunits p110γ and p110δ are highly enriched in leukocytes, providing an additional rationale for targeting these PI3Ks in hematologic malignancies. In 2014, the PI3Kδ inhibitor idelalisib was the first of four PI3K inhibitors (PI3Ki) to receive regulatory approval for relapsed B-cell malignancies. This was followed by approvals of the pan-class I inhibitor copanlisib (2017), the dual PI3Kγ/δ inhibitor duvelisib (2018), and the PI3Kδ and casein kinase 1ε inhibitor umbralisib (2021). Copanlisib and umbralisib received accelerated approvals, whereas idelalisib and duvelisib received initial accelerated approvals followed by full approvals. The accelerated approvals were based on overall response rates; however, follow-up studies showed increased risk of death and serious side effects. Furthermore, the confirmatory trial with copanlisib failed to show an improvement in progression-free survival when compared with chemoimmunotherapy. These developments led to black box warnings for idelalisib and duvelisib and withdrawal of copanlisib and umbralisib from the market by their manufacturers. Given the uncertain future of this drug class, additional manufacturers terminated ongoing phase III trials with novel PI3Kis. In this study, we review the development and current status of PI3Kis in hematology, limitations to their use, and our perspective on whether there is a future for PI3Kis in hematology.

Insights on Nefecon®, a Targeted-Release Formulation of Budesonide and Its Selective Immunomodulatory Effects in Patients with IgA Nephropathy.

Immunoglobulin A nephropathy (IgAN) is a chronic, immune-mediated kidney disease characterized by the deposition of galactose-deficient immunoglobulin A1 (Gd-IgA1) in the kidneys. Excess Gd-IgA1 production in patients with IgAN is located within the mucosa-associated lymphoid tissue, particularly within the lamina propria in the distal ileum. Nefecon® is a targeted-release formulation of the corticosteroid budesonide, which became the first treatment approved by the US Food and Drug Administration (FDA; brand name, TARPEYO®) and European Medicines Agency (EMA; KINPEYGO®) for patients with primary IgAN at risk of rapid disease progression, after demonstrating clinically significant reduction of proteinuria in an interim analysis of the Phase III NefIgArd trial. After showing a significant reduction in estimated glomerular filtration rate decline in the full 2-year analysis of the trial, Nefecon was granted full approval by the FDA to reduce the loss of kidney function. Nefecon was specifically designed to deliver budesonide to the distal ileum, selectively targeting excess Gd-IgA1 production in the gut-associated lymphoid tissue. In this review, we describe the properties of Nefecon and the evidence to date that confirms its localized treatment effect. We also present unpublished evidence from Phase I trials investigating the pharmacokinetics and cortisol suppression effects of Nefecon in healthy participants. These studies demonstrated that Nefecon has a distinct pharmacokinetic profile from other budesonide products, allowing for targeted, localized action in the distal ileum. When considered alongside existing clinical trial data showing the effect of Nefecon on gut-associated biomarkers, available evidence indicates that Nefecon has a selective immunomodulatory mechanism of action and a direct disease-modifying effect in patients with IgAN, while having low systemic exposure and adverse effects.

Brak rzetelnej sądowej kontroli aresztu tymczasowego po wydaniu ściganego jako bezwzględna przeszkoda do ekstradycji

The article is a research and scientific study prepared using the dogmatic method. It addresses the most sensitive issues that the Polish Supreme Court has dealt with in recent years in the area of interpretation of obstacles to extradition, i.e. the problem of the lack of prompt and ex officio judicial review of non-judicial pre-trial detention at the stage of preparatory proceedings in the State requesting the extradition of a prosecuted person. In one of its rulings, which is crucial in this matter, the Supreme Court took the position that this deficiency was not a sufficient basis for finding a legal obstacle to extradite the prosecuted. The argumentation of the Court does not deserve full approval. It is a manifestation of failure to notice the requirement, under Article 5 (3) of the European Convention on Human Rights and Article 9 (3) of the International Covenant on Civil and Political Rights, to bring each detained person promptly ex officio before a judge in the context of their personal security. It should be assumed that the lack of prompt and ex officio review of pre-trial detention at the stage of the preparatory proceedings, including bringing the detained person before a judge, after the defendant has been transferred to the authorities of the requesting state, may constitute grounds for assuming that there is a well-founded concern about violation of the defendant’s personal security for this reason. Such an assessment should be made a casu ad casum as necessary, after supplementing the information from the requesting party.

Tisotumab Vedotin (Tivdak) for Cervical Cancer

Tisotumab vedotin-tftv (Tivdak – Seagen/Genmab), a tissue factor-directed antibody and microtubule inhibitor conjugate, has received full approval from the FDA for treatment of recurrent or metastatic cervical cancer that progressed on or after chemotherapy.