Citations

Abstract Lessons learned Intravenous paricalcitol did not improve the efficacy of pembrolizumab, likely related to the short half-life. Background Immunotherapy has limited benefit in the treatment of advanced pancreatic cancer with the tumor microenvironment playing a key role in immune resistance. In preclinical studies, vitamin D receptor (VDR) agonists have been shown to sensitize pancreatic tumors to PD-1 blockade. Methods This was a randomized, double-blinded, placebo-controlled, phase II trial to evaluate pembrolizumab with or without paricalcitol as maintenance therapy for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). Participants were ≥18 years; histologically or cytologically confirmed metastatic PDAC showing no disease progression after frontline systemic therapy, and achieving maximal cytoreduction (eg, with no further antitumor effect), Eastern Cooperative Oncology Group (ECOG) status of 0 or 1; adequate organ function. Study treatment included: pembrolizumab 200 mg IV every 3 weeks and either paricalcitol 25 mcg IV 3 times per week or placebo. The primary objective was to evaluate 6-month progression free survival (PFS). Secondary objectives include evaluating the toxicity of the combination and overall survival (OS). Results There was no significant difference in 6-month PFS, median PFS, median OS, nor treatment-related AEs between the 2 arms. Conclusions and relevance Paricalcitol did not improve the efficacy of pembrolizumab likely related to its short half-life of only 5-7 hours. Microbiome analysis revealed significant difference between long-term (>12 weeks) and short-term (<12 weeks) survival groups across treatment arms. Modulation of the tumor microenvironment will likely require more sustained VDR activity. Trial Registration Clinicaltrials.gov, ID: NCT03331562.

Abstract As patients with relapsed/refractory multiple myeloma (RRMM) continue to live longer, they might get exposed to most available drugs and drug classes during the disease course. For such late line RRMM or among patients without access to novel therapies, retreatment with a drug that the disease had previously been refractory to might be one option. In this retrospective study, we describe 315 patients with RRMM at our institution who were retreated with a drug that the disease had been previously refractory to. We found an overall response rate of 56.2% and a median progression-free survival (PFS) of 11 months with retreatment. Patients with a longer time on initial therapy with the index drug (>28.4 months) had a superior PFS with retreatment (median PFS, 16.9 vs 8.1 months; P < .001). Similarly, patients with a longer time gap between the initial line of therapy with index drug and retreatment with index drug (>46.1 months) had better PFS with retreatment (28.2 vs 8.9 months; P = .016). In conclusion, retreatment with a previously refractory drug is a viable therapeutic option for RRMM, with the most significant benefit derived in disease demonstrating sensitivity to initial drug exposure and among those with a longer gap between initial drug exposure and retreatment.

Abstract STUDY QUESTION How should premature/primary ovarian insufficiency (POI) be diagnosed and managed based on the best available evidence from published literature? SUMMARY ANSWER The current guideline provides 145 recommendations on symptoms, diagnosis, causation, sequelae, and treatment of POI. WHAT IS KNOWN ALREADY Premature ovarian insufficiency (POI) presents a significant challenge to women’s health, with far-reaching implications, both physically and emotionally. The potential implications include adverse effects on quality of life; fertility; and bone, cardiovascular, and cognitive health. Although hormone therapy (HT) can mitigate some of these effects, many questions still remain regarding the optimal management of POI. STUDY DESIGN, SIZE, DURATION The guideline was developed according to the structured methodology for development of ESHRE guidelines. Key questions were determined by a group of experts and informed by a scoping survey of women and health care professionals. Literature searches and assessments were then performed. Papers published up to 30 January 2024 and written in English were included in the guideline. An integrity review was conducted for the randomized controlled trials (RCTs) on POI included in the guideline. PARTICIPANTS/MATERIALS, SETTING, METHODS Based on the collected evidence, recommendations were formulated and discussed within the guideline development group until consensus was reached. Women with lived experience of POI informed the recommendations in general, and particularly on those on provision of care. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline development group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE New data indicate a higher prevalence of POI, 3.5%, than was previously thought. This guideline aims to help health care professionals to apply best practice care for women with POI. The recent update of the POI guideline covers 40 clinical questions on diagnosis of the condition, the different sequelae, including bone, cardiovascular, neurological and sexual function, fertility and general well-being, and treatment options, including HT. The list of clinical questions was expanded from the previous iteration of the guideline (2015) based on the scoping survey and appreciation of emerging knowledge of POI. Questions were added on the role of anti-Müllerian hormone (AMH) in the diagnosis of POI, fertility preservation, muscle health, and specific considerations for HT in iatrogenic POI. Additionally, the topic on complementary treatments was extended with specific focus on non-hormonal treatments and lifestyle management options. Significant changes from the previous 2015 guideline include the recommendations that only one elevated FSH >25 IU is required for diagnosis of POI, and guidance that AMH testing, repeat FSH measurement, and/or AMH may be required where there is diagnostic uncertainty. Recommendations were also updated regarding genetic testing, estrogen doses and regimens, use of the combined oral contraceptive and testosterone therapy. Women with lived experience of POI informed the recommendations on provision of care. LIMITATIONS, REASONS FOR CAUTION The guideline describes different management options, but it must be acknowledged that for most of these options, supporting evidence is limited for POI. WIDER IMPLICATIONS OF THE FINDINGS The guideline provides health care professionals with clear advice on best practice in POI care, based on the best evidence currently available. In addition, a list of research recommendations is provided to guide further studies in POI. STUDY FUNDING/COMPETING INTEREST(S) The guideline was developed and funded by ESHRE, American Society for Reproductive Medicine (ASRM), Centre for Research Excellence in Women's Health in Reproduction Life (CRE-WHiRL), and International Menopause Society (IMS), covering expenses associated with the guideline meetings, literature searches, and dissemination of the guideline. The guideline group members did not receive payments. N.P. declared grants from Bayer Pharma (research and consultancy) and NIHR—research POISE; consulting fees from Abbott, Astellas, Bayer, Besins, Lawley, Mithra, Theramex, Viatris; honoraria from Astellas, Bayer, Besins, Gedeon Richter, Theramex, Viatris; support for attending meetings and/or travel from Astellas, Bayer, Theramex, Viatris; President, International Menopause Society, Medical Advisory Committee member, British Menopause Society, Patron Daisy Network. A.J.V. declared grants from Amgen Australia, Australian NHMRC, and Australian MRFF; consulting fees from IQ Fertility; honoraria from the Australasian Menopause Society; participation on a Data Safety Monitoring Board or Advisory Board of Astellas; Board Member of the International Menopause Society (2020 to current) and Past president of the Australasian Menopause Society (2017–2019); R.A.A. declared grants from Roche (Research support, to institution), and participation on a Data Safety Monitoring Board of Bayer. M.C. declared grants from NHI; payments or honoraria from Up-to-Date (as editor/reviewer); Board Member of American Society of Reproductive Medicine, and of American Gynecological and Obstetrical Society. M.D. declared (NIHR—HTA Reference Number: NIHR133461; NIHR—HTA Reference Number: NIHR128757; Action Medical Research and Borne: GN2818) consulting fees from a small personal medical practice, support for attending meetings and/or travel from ESHRE, Bayer and UCLH special Trustees; Participation on the Advisory Board of the British Menopause Society, UKSTORE project, the Progress Educational Trust, and the Turner Syndrome Support Society UK; Leadership or fiduciary roles in the British Fertility Society (Trustee), Elizabeth Garrett Anderson Hospital Charity (chair of Trustees), and the Essex Wynter charitable trust (Trustee). C.E. declared being Chair of a SIG from the Royal Australian College of General Practitioners Integrative Medicine Specific Interest Group and Program Lead for Next Practice Western Sydney Integrative Health. C.H.G. declared grants from Novo Nordisk Foundation (Nos. NNF15OC0016474 and NNF20OC0060610), sygesikringen danmark (No 2022-0189), and the Independent Research Fund Denmark (Nos. 0134-00406 and 0134-00130B); consulting fees from Novo Nordisk, Merck, and Astra Zeneca. S.K. declared grants from Roche diagnostics. A.K. declared grants from NIH R01 5R01HD101475; consulting fees as Medical Reviewer for Flo and for Healthline; honoraria as Medical Consultant for Summus; support for attending meetings from the Reproductive Scientist Development Program; Society for Reproductive Investigation Council Member and Society for Assisted Reproduction Registry/Validation Chair; R.E.N. declared consulting fees from Astellas, Bayer Pharma, Besins Healthcare, Fidia, Theramex; honoraria from Abbott, Astellas, Exeltis, Fidia, Gedeon Richter, Merck & Co, Novo Nordisk, Shionogi Limited, Theramex, Viatris; payment for expert testimony from Vichy Laboratories; Participation in Data Safety Monitoring Board of Advisory board from Astellas and Bayer Healthcare; President elect of the International Menopause Society (IMS). H.T. declared a grant from NHMRC Centre for Research Excellence for women’s health in reproductive life. A.B. declared being chair of the Daisy Network Charity. The other authors have no conflicts of interest to declare. DISCLAIMER This guideline represents the views of ESHRE, ASRM, CRE-WHiRL, and IMS, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant stakeholders has been obtained. Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgement to each individual presentation, nor variations based on locality and facility type. The collaborating societies make no warranty, expressed or implied, regarding the clinical practice guidelines and specifically exclude any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.)

Aim: The aim of this analysis was to assess the cost–effectiveness of the EmboTrap ® Revascularization Device compared with the Solitaire™ Revascularization Device and Trevo ® Retriever for the treatment of acute ischemic stroke (AIS) from the perspective of the Chinese healthcare system. Methods: According to MASTRO I, a recent living systematic literature review and meta-analysis, mechanical thrombectomy (MT) with EmboTrap in the treatment of AIS resulted in better functional outcomes compared with the use of Solitaire or Trevo. Based on the proportion of patients that achieved 90-day modified Rankin Scale (mRS) scores of 0–2, 3–5 and 6 reported in MASTRO I, a combined 90-day short-term decision tree and Markov model with a 10-year time horizon was used to compare the cost–effectiveness of the three devices. The primary outcome was the incremental cost–effectiveness ratio (ICER), representing the incremental cost (in 2022 Chinese Yuan [CNY]) per incremental quality-adjusted life-year (QALY). The ICERs were compared against willingness-to-pay (WTP) thresholds of 1, 1.5 and 3-times the 2022 national gross domestic product (GDP) per capita in China. Results: Treatment with EmboTrap resulted in total QALYs of 3.28 and total costs of 110,058 CNY per patient. Treatment with Trevo resulted in total QALYs of 3.05 and total costs of 116,941 CNY per patient. Treatment with Solitaire resulted in total QALYs of 2.81 and total costs of 99,090 CNY per patient. Trevo was dominated by EmboTrap as it was a more costly and less effective intervention. As such, Trevo was not cost-effective at any WTP threshold. Compared with Solitaire, EmboTrap was more effective and more costly, with an ICER of 23,615 CNY per QALY. This result suggests that EmboTrap is cost-effective when compared with Solitaire since the ICER was lower than all WTP thresholds assessed. Conclusion: EmboTrap dominated Trevo and is cost-effective for the treatment of patients with AIS compared with Solitaire when assessed from the perspective of the Chinese healthcare system and based on the device-level meta-analysis MASTRO I. Selecting a stent retriever (SR) that optimizes 90-day mRS score is an important consideration from both a clinical and healthcare payer perspective in China as it is associated with reduced long-term costs and increased quality of life.

Importance Since 2018, a movement has emerged to define Alzheimer disease (AD) as a purely biological entity based on biomarker findings. The recent revision of the Alzheimer’s Association (AA) criteria for AD furthers this direction. However, concerns about a purely biological definition of AD being applied clinically, the understanding of AD by society at large, and the translation of blood-based biomarkers into clinical practice prompt these International Working Group (IWG) updated recommendations. Objective To consider the revised AA criteria and to offer an alternative definitional view of AD as a clinical-biological construct for clinical use. The recommendations of the 2021 IWG diagnostic criteria are updated for further elaborating at-risk and presymptomatic states. Evidence Review PubMed was searched for articles published between July 1, 2020, and March 1, 2024, using the terms “biomarker” OR “amyloid” OR “tau” OR “neurodegeneration” OR “preclinical” OR “CSF” OR “PET” OR “plasma” AND “Alzheimer’s disease.” The references of relevant articles were also searched. Findings In the new AA diagnostic criteria, AD can be defined clinically as encompassing cognitively normal people having a core 1 AD biomarker. However, recent literature shows that the majority of biomarker-positive cognitively normal individuals will not become symptomatic along a proximate timeline. In the clinical setting, disclosing a diagnosis of AD to cognitively normal people with only core 1 AD biomarkers represents the most problematic implication of a purely biological definition of the disease. Conclusions and Relevance The ultimate aim of the field was to foster effective AD treatments, including preventing symptoms and dementia. The approach of diagnosing AD without a clinical and biological construct would be unwarranted and potentially concerning without a clear knowledge of when or whether symptoms will ever develop. It is recommended that those who are amyloid-positive only and, more generally, most biomarker-positive cognitively normal individuals, should not be labeled as having AD. Rather, they should be considered as being at risk for AD. The expansion of presymptomatic AD is viewed as a better diagnostic construct for those with a specific pattern of biomarkers, indicating that they are proximate to the expression of symptoms in the near future.

ABSTRACT Over the past two decades, there has been increasing interest in the diagnosis and management of schwannomas of the inner ear including hearing rehabilitation with cochlear implants. However, tumor nomenclature and classification within the literature have been variable and oftentimes cumbersome. The term “intralabyrinthine schwannoma” is in common use when describing these tumors but is a potential source of confusion given that people often use the term “labyrinth” or “labyrinthine” to refer to the vestibular component of the inner ear only (i.e., labyrinthectomy or the translabyrinthine approach). During the Ninth Quadrennial Conference on Vestibular Schwannoma and Other Cerebellopontine Angle Lesions in Bergen, Norway, in May 2023, a multidisciplinary group of conference participants met and discussed issues pertaining to current terminology and classifications to enhance clarity and to reflect recent advances in tumor management and hearing rehabilitation. Although a variety of terms have been previously used to describe inner ear schwannomas, consensus was achieved on the term “inner ear schwannoma (IES)” to describe eighth nerve schwannomas of the cochlea, vestibule, or semicircular canals. Subgroups under this term comprise intravestibular, intracochlear, or intravestibulocochlear inner ear schwannomas (low complexity tumors), inner ear schwannomas with transfundal extension into the internal auditory canal but without modiolar involvement (intermediate complexity tumors), and inner ear schwannomas with transfundal extension with modiolar involvement (high complexity tumors). The details of the recommendations for an updated and simplified tumor nomenclature centered around tumor control and hearing rehabilitation with cochlear implantation are presented.

Asthma is a heterogeneous chronic lung disease that affects nearly 340 million people globally. Airway hyperresponsiveness, remodeling (thickening and fibrosis), and mucus hypersecretion are some hallmarks of asthma. With several current treatments having serious side effects from long-term use and a proportion of patients with uncontrolled asthma, there is an urgent need for new therapies. With an increasing understanding of asthma pathophysiology, there is a recognized need to target therapies to specific cell types of the airway, which necessitates the identification of delivery systems that can overcome increased mucus and thickened airways. Nanoparticles (NPs) that are highly customizable (material, size, charge, and surface modification) are a potential solution for delivery systems of a wide variety of cargoes (nucleic acids, proteins, and/or small molecules), as well as sole therapeutics for asthma. However, there is a need to consider the safety of the NPs in terms of potential for inflammation, toxicity, nonspecific targets, and accumulation in organs. Ongoing clinical trials using NPs, some FDA-approved for therapeutics in other diseases, provide confidence regarding the potential safety and efficacy of NPs in asthma treatment. This review highlights the current state of the use of NPs in asthma, identifying opportunities for further improvements in NP design and utilization for targeting this chronic lung disease.

Background: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired, life-threatening disease characterized by complement-mediated hemolysis. OPERA is the first US longitudinal real-world study on C3 inhibitor therapy, known as pegcetacoplan. Methods: OPERA enrolled US patients with PNH, age ≥18, who were prescribed pegcetacoplan, and data were collected from routine care. Hemoglobin was reported by patients during regular follow-up (censored from transfusions). The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue (0–52 score) and Patient-Reported Outcomes Measurement Information System scale for Cognitive Function Abilities (PROMIS-CF; 23.27–67.09 t-score) were completed electronically (low score = negative outcome). Patients self-reported incidence of healthcare resource utilization (HCRU). Results: By January 2024, 70 patients (mean age 44.6 years; 57.1% female) reported up to 9 months of pegcetacoplan treatment, with a median [IQR] follow-up of 6.6 [3.8] months. The latest reported hemoglobin levels improved by a mean (SD) of 2.6 (1.9) g/dL from baseline. At 3, 6 and 9 months, patients reported clinically meaningful improvements (≥5 points) in FACIT-F (53.3–69.0%) and (≥2 points) PROMIS-CF (46.7–55.2%). Patients reported a <10% incidence rate per person month of all HCRU events. Conclusions: This first longitudinal real-world US study indicates a positive trend in Hb, fatigue, and cognition with limited HCRU during pegcetacoplan treatment in adults with PNH.

Background Acute ischemic stroke arising from medium vessel occlusions (MeVO) poses substantial challenges in treatment and management. This study aims to elucidate the outcomes and factors contributing to achieving excellent recanalization (modified Thrombolysis in Cerebral Infarction [mTICI] 2c–3) versus successful recanalization (mTICI 2b) in patients with MeVO stroke undergoing mechanical thrombectomy (MT). Methods We conducted a multinational study analyzing data from the MAD‐MT (Multicenter Analysis of Distal Medium Vessel Occlusions: Effect of Mechanical Thrombectomy) registry, encompassing 37 centers across North America, Asia, and Europe, collected between September 2017 and July 2023. The study included acute ischemic stroke patients with MeVO treated with MT, with or without intravenous thrombolysis, who achieved mTICI 2b–3 post‐MT. Results Among 1463 patients with successful recanalization (mTICI 2b–3), 523 achieved mTICI 2b recanalization, and 940 achieved mTICI 2c–3. Distal occlusions exhibited higher odds of excellent recanalization compared with proximal MeVO vessel occlusions (odds ratio, 1.58; 95% CI, 1.17–2.15; P = 0.003). Cardioembolic stroke pathogenesis was associated with a higher likelihood of excellent recanalization (1.67; 95% CI, 1.07–2.59; P = 0.018). Patients achieving mTICI 2c–3 recanalization demonstrated lower initial National Institutes of Health Stroke Scale scores, significant improvements in postprocedural National Institutes of Health Stroke Scale shift, and a higher percentage of favorable 90‐day outcomes compared with those with mTICI 2b. However, no significant difference in 90‐day mortality rates was observed. Conclusion This study underscores that among patients with MeVO stroke with successful recanalization (mTICI 2b–3) there is higher likelihood of achieving excellent recanalization (mTICI 2c–3) in distal occlusions and cardioembolic pathogenesis. mTICI 2c–3 scores post‐MT correlate with improved clinical outcomes compared with mTICI 2b, affirming the superiority of excellent recanalization over successful recanalization in patients with MeVO stroke. Further prospective studies and randomized controlled trials are warranted for validation.