Absence Of Therapy Research Articles

Therapeutic inertia in achieving lipid targets in secondary cardiovascular prevention: a multicentre study from the itacare-p network

Abstract Introduction The 2019 ESC/EAS guidelines recommend stringent low-density lipoprotein cholesterol (LDL-C) targets of ≤55 mg/dL for very high-risk patients and ≤40 mg/dL for those with multiple events within two years. Despite the availability of potent lipid-lowering therapies (LLT), therapeutic inertia—a failure to intensify treatment in patients not achieving targets—remains a major barrier to achieving these goals. Objective This study assessed the proportion of secondary cardiovascular prevention patients meeting LDL-C targets and evaluated the adequacy of proposed LLT modifications for those not at target. The role of percentage distance from LDL-C targets as a predictor of therapeutic inertia was also analyzed. Methods A multicenter, cross-sectional observational study was conducted, retrospectively analyzing medical records of 1909 ambulatory outpatients evaluated in 9 Italian cardiac rehabilitation/secondary cardiovascular prevention clinics from January 2023 to June 2024. Inclusion criteria included a prior history of atherosclerotic cardiovascular disease (ASCVD) and recent LDL cholesterol levels. Data collected included demographics, ASCVD presentation, lipid profiles, and LLT. Patients were considered at very high cardiovascular risk, with LDL cholesterol targets of ≤55 mg/dL, or ≤40 mg/dL for those with recurrent events within two years. For patients not at target, the clinician’s approach to LLT modification was recorded. The efficacy of LLT changes was estimated using established reduction percentages for different therapies. Results Among 1909 patients, 41.3% achieved the LDL cholesterol target. Multivariate analysis identified male gender, cardiac rehabilitation participation, recent acute coronary syndrome, diabetes mellitus, and triple therapy (statin + ezetimibe + PCSK9 inhibitors) as predictors of achieving LDL targets. Conversely, a target level of ≤40 mg/dL, absence of therapy, and monotherapy were negative predictors. Among 1074 patients not at target, only 48.6% had LLT modifications proposed. Positive independent predictors for LLT modification included recent ASCVD events, participation in cardiac rehabilitation, and a greater percentage distance from the LDL target, while advanced age and an LDL target of ≤40 mg/dL were negative predictors. Despite therapy modifications, only 42.3% were predicted to be appropriate and to achieve their LDL targets. Conclusion Despite the diffusion of 2019 ESC/EAS guidelines, a significant proportion of high-risk patients still did not achieve LDL cholesterol targets, and proposed LLT modifications were often insufficient to reach the desired levels. More aggressive or optimized therapy adjustments are necessary to improve outcomes in this population.

Варианты медикаментозного воздействия на процессы фибротизации слезоотводящих путей

Relevance One of the key problems of dacryology is the disruption of lacrimation caused by dacryostenosis, which develops as a result of a chronic inflammatory process in the lacrimal ducts [1]. Currently, the option for resolving dacryostenosis is dacryocystorhinostomy, but the relapse rate reaches 18%, which determines the need to develop algorithms for drug action on fibrogenesis in the lacrimal drainage system [2]. We analyzed the effectiveness of drug action of different groups of drugs on the processes of fibrotization of the lacrimal ducts. The use of the antitumor drug Mitomycin C (MMC), which inhibits RNA synthesis in fibroblasts and reduces collagen formation, was carried out after endoscopic endonasal and external dacryocystorhinostomy, as well as after balloon dacryoplasty in the form of washing the lacrimal ducts with MMC, applications of turunda with MMC lasting from 2 to 30 minutes, as well as injections into the dacryostomy area intraoperatively and in the late period [3, 4]. Observations have shown that the success of surgical treatment in combination with drug prophylaxis is 10% higher than in the absence of therapy. Glucocorticosteroids (GCS) reduce the activity of fibroblasts, preventing fibrotization. The use of triamcinolone and dexamethasone in the form of turunda applications, hemostatic sponges and intraoperative injections into the dacryostomy area also led to a better functional result compared to the control group by 5-10%. The use of hyaluronic acid-based drugs (Merogel, Antiadgesin) by tamponade of the nasal cavity with hemostatic sponges, as well as by intraoperative rinsing of the lacrimal ducts made it possible to achieve a 10% reduction in the relapse rate after 6 months. The use of the biological drug chitosan in the composition of biodegradable xerogel sponges resulted in 100% success in postoperative patency of the lacrimal ducts. Low-molecular drugs pirfenidone, which reduces the synthesis of fibroblast collagenase, and dihydroartemisinin, which inhibits the activation of fibroblasts at the RNA and protein level, were effective in vitro on a cell culture of periorbital connective tissue and require further study [5]. Nanoparticles are a new pharmacological direction that has shown effectiveness in preventing conjunctival scarring, symblepharon and fibrosis after glaucoma filtration surgery. Genetically engineered drugs, namely small RNA molecules, can affect organ fibrosis, but their use in dacryology has not yet been described. Conclusion The presented data indicate that drug prevention of dacryostomy scarring in the postoperative period is certainly effective and should be carried out with the studied drugs. In addition, there is an obvious need to study the clinical effects of such groups of drugs as low-molecular, genetically engineered drugs and nanoparticles that have shown effectiveness in laboratory studies. Key words: dacryocystorhinostomy; dacryostenosis; prevention of fibrosis

Abstract 641: Identification of anti-tumoral neutrophil phenotypes induced by immunotherapies in head and neck cancer

Abstract Only ∼20% of recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) patients respond to immune-checkpoint blockade (ICB) therapy. A major roadblock is the immunosuppressive nature of the tumor microenvironment. Increased infiltration of neutrophils in blood and tumors of HNSCC patients is associated with worse prognosis and ICB therapy resistance. Depleting neutrophils, however, with or without ICB treatment, has not inhibited tumor growth in mice bearing syngeneic MOC2 tumors, which are phenotypically analogous to immunologically “cold”, aggressive HNSCC tumors. We hypothesize that this is due to the heterogeneity of tumor-infiltrated neutrophils with both pro- and anti-tumoral phenotypes. This study uses multi-omics single-cell profiling, combining RNA and protein, to identify pro- and anti-tumoral neutrophil states in MOC2 tumors treated with recently reported neutrophil-related therapies. Specifically, we tested anti-CD40 agonist, TNF-alpha, and both in combination with cetuximab, an anti-tumor antibody (designated Neutrophil Activating Therapy, NAT) that has been recently reported in other cancers. Cetuximab (an anti-EGFR mAb) was used for MOC2-huEGFR (M2h), an HNSCC cancer model transduced with human-EGFR. We found this treatment induced new neutrophil subsets, defined by scRNA-Seq bioinformatics analysis. One subset has recently reported interferon-stimulated phenotypes, which we found in the anti-CD40 alone, and NAT combinatorial treatment groups; these two groups also showed the best anti-tumor efficacy. Gene signature of this subset is also found in scRNA-Seq of infiltrating neutrophils in our previous K17-KO MOC2 model, which shows spontaneous tumor regression in the absence of therapy. In addition, we identified a neutrophil subset associated with migration-related transcription factors only in NAT and TNFa treatment groups, which might explain why NAT is superior to anti-CD40 alone. Our findings thus far demonstrate the presence of neutrophil heterogeneity, with some phenotypes associated with anti-tumor responses, including a potentially new phenotype, in a murine head and neck cancer model induced by a combination of immunotherapies. Ongoing and future work includes identifying specific synergistic mechanisms of the anti-tumoral neutrophil subpopulations induced by anti-CD40 and TNF-alpha treatment and if these phenotypes are also seen in ICB-treated HNSCC patients who respond to their therapy. We anticipate our characterization of anti-tumoral neutrophil phenotypes induced by NAT in M2h tumors may provide insights into how more effective immunotherapy regimens beyond ICB can be designed to confer tumor clearance and prolonged survival in patients with head and neck cancer. Citation Format: Anqi Gao, Amy Erbe-Gurel, Natalie B. Winn, Joel Matthews, Kaia N. Heimstreet, Wei Wang, Paul F. Lambert, Paul M. Sondel, Huy Q. Dinh. Identification of anti-tumoral neutrophil phenotypes induced by immunotherapies in head and neck cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 641.

The prognostic value of <i>FLT3</i>-ITD in different cytogenetic and molecular genetic subgroups of pediatric acute myeloid leukemia

Internal tandem duplications in the FLT3 gene (FLT3-ITD) are common in acute myeloid leukemia (AML) in adults (25–35%) and less common in children (15–17%) and, in the absence of therapy with specific inhibitors, are predictors of a poor prognosis. However, this unfavorable impact has been demonstrated mainly in AML with a normal karyotype in the absence of mutations in the NPM1 gene, or in the presence of a combination of mutations in the NPM1 gene and FLT3-ITD with a high allele ratio ( 0.5). Our study shows a high genetic heterogeneity in the patients with FLT3-ITD and its unfavorable prognostic impact in all the AML subgroups. The presence of FLT3-ITD worsens disease outcomes in the group of patients with a normal karyotype (the 2-year event-free survival (EFS) – 32%, overall survival (OS) – 55%), irrespective of the ratio of mutated to wild-type allele and the presence of mutations in the NPM1 gene. In the group of patients with markers of a favorable prognosis, the presence of FLT3ITD was associated with reduced rates of the 2-year EFS (45%; 95% CI 26–78%) and OS (43%; 95%CI 22–83%), as well as with the resistance to FLT3 inhibitors during relapse therapy. In the groups of patients with intermediate and unfavorable risk markers, the presence of FLT3-ITD was associated with a high resistance to induction therapy (57.9% and 55%, respectively). However, the addition of FLT3 kinase inhibitors to salvage therapy and a high rate of first-line hematopoietic stem cell transplantation in combination with FLT3 inhibitors as maintenance therapy in these groups significantly improved the 2-year OS rate (68% vs 62%, respectively). The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation.

"Psychiatric oblivion": considerations on the hypothesis of a law.

The introduction of a law on psychiatric oblivion, similar to the recent one for oncological oblivion, presents numerous complexities due to the differences between the two areas of illness, especially in terms of recovery and clinical stability. While a definitive cure is often achievable in oncological diseases, in severe mental disorders, such as schizophrenia or bipolar disorder, complete remission in the absence of therapies is rare. Even in cases of effective treatment response, patients may exhibit subclinical symptoms or cognitive and functional deficits, making the concept of psychiatric oblivion particularly problematic. Some diagnostic categories, such as brief psychotic disorder or postpartum depression, could theoretically benefit from oblivion legislation, given the potentially limited course and frequent absence of relapses. However, for the majority of psychiatric conditions the requirement of a long period of remission without therapy appears difficult to achieve. An alternative could be the introduction of criteria based on the stabilization of maintenance therapy, but this would require a more complex and less easily standardized clinical judgment. Other limitations are the residual vulnerability to relapses, the difficulty in determining a precise medical history and the influence of persistent social stigmatization, which could undermine the effects of oblivion. Therefore, the creation of a law on psychiatric oblivion would require a restrictive and selective approach, focused on specific diagnoses and long-term clinical remission criteria, tailored to the clinical and adaptive peculiarities of mental illness.

Clinical Implications of Breast Cancer Intrinsic Subtypes.

Estrogen receptor-positive (ER+) and estrogen receptor-negative (ER-) breast cancers have different genomic architecture and show large-scale gene expression differences consistent with different cellular origins, which is reflected in the luminal (i.e., ER+) versus basal-like (i.e., ER-) molecular class nomenclature. These two major molecular subtypes have distinct epidemiological risk factors and different clinical behaviors. Luminal cancers can be subdivided further based on proliferative activity and ER signaling. Those with a high expression of proliferation-related genes and a low expression of ER-associated genes, called luminal B, have a high risk of early recurrence (i.e., within 5years), derive significant benefit from adjuvant chemotherapy, and may benefit from adding immunotherapy to chemotherapy. This subset of luminal cancers is identified as the genomic high-risk ER+ cancers by the MammaPrint, Oncotype DX Recurrence Score, EndoPredict, Prosigna, and several other molecular prognostic assays. Luminal A cancers are characterized by low proliferation and high ER-related gene expression. They tend to have excellent prognosis with adjuvant endocrine therapy. Adjuvant chemotherapy may not improve their outcome further. These cancers correspond to the genomic low-risk categories. However, these cancers remain at risk for distant recurrence for extended periods of time, and over 50% of distant recurrences occur after 5years. Basal-like cancers are uniformly highly proliferative and tend to recur within 3-5years of diagnosis. In the absence of therapy, basal-like breast cancers have the worst survival, but these also include many highly chemotherapy-sensitive cancers. Basal-like cancers are often treated with preoperative chemotherapy combined with an immune checkpoint inhibitor which results in 60-65% pathologic complete response rates that herald excellent long-term survival. Patients with residual cancer after neoadjuvant therapy can receive additional postoperative chemotherapy that improves their survival. Currently, there is no clinically actionable molecular subclassification for basal-like cancers, although cancers with high androgen receptor (AR)-related gene expression and those with high levels of immune infiltration have better prognosis, but currently their treatment is not different from basal-like cancers in general. A clinically important, minor subset of breast cancers are characterized by frequent HER2 gene amplification and high expression of a few dozen genes, many residing on the HER2 amplicon. This is an important subset because of the highly effective HER2 targeted therapies which are synergistic with endocrine therapy and chemotherapy. The clinical behavior of HER2-enriched cancers is dominated by the underlying ER subtype. ER+/HER2-enriched cancers tend to have more indolent course and lesser chemotherapy sensitivity than their ER counterparts.

NATURAL HISTORY OF ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION WITH TOTAL OCCLUSION OF INFARCT-RELATED ARTERY DURING SIX-MONTH FOLLOW-UP WITH OPTIMUM MEDICAL THERAPY

Objectives- Fate of STEMI patients on optimum medical therapy who remains asymptomatic following MI within 24 hours ,electrically and haemodynamically stable regarding their clinical status , LV function, with totally occluded infarct related artery. Methods-100 patients whose angiography performed 3 to 28 days after ST segment elevation myocardial infarction, showed total occlusion of the infarct-related artery with poor or absent ante grade flow,were put on optimum medical therapy in absence of contraindication and follwed up for 6 months. Results- At 1st month among 100 patients 46 ( 46% ) patients were asymptomatic.43 (43%)patients were presented with shortness of breath on exertion (SOBE) and rest 11(11%)had both chest pain and shortness of breath. In subsequent visit at 6 months 46 % patients were asymptomatic and rest presented with SOBE, none of them presented with significant chest pain Conclusion- In spite of optimum medical therapy patients with total occlusion of IRA and non viable myocardium developed progressive remodeling. Collateral flow is not adequate to prevent remodeling.Remodeling causes gradually progressive HF symptoms.If the patient has not developed new coronary lesion patients usually didn’t present with chest pain, shortness of breath was predominant symptoms in follow up in this group of patients.

Outcomes of Patients with Chronic Lymphocytic Leukemia Discontinuing Bruton Tyrosine Kinase Inhibitors Due to Adverse Effects

Outcomes of Patients with Chronic Lymphocytic Leukemia Discontinuing Bruton Tyrosine Kinase Inhibitors Due to Adverse Effects

The Prospect and Challenges of Repurposing Established Drugs in Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a progressive disorder caused by the narrowing of small blood vessels in the lungs, which, in the absence of therapies, leads to right heart failure and premature death. No cure for this devastating disorder is known. Current management therapies aim to improve symptoms, and hence, there is a need to identify novel therapeutic interventions. The major objectives of this review are to critically evaluate current treatment strategies and highlight the challenges and prospects of established drugs and natural products for the resolution of PAH.

(116) SUBJECTIVE AND GENITAL SEXUAL RESPONSE IN FEMALE BREAST CANCER SURVIVORS: RESULTS FROM A PSYCHOPHYSIOLOGY STUDY

Abstract Introduction Sexual dysfunction is a prevalent concern affecting more than 70% of female breast cancer survivors, casting a substantial shadow on their quality of life. Beyond the physical impact of cancer and its treatments, the emotional and psychological toll of sexual dysfunction introduces additional challenges, amplifying stress levels and undermining overall well-being. Acknowledging the profound implications of sexual dysfunction in this group and the absence of therapies, there is an urgent need to delve deeper into the intricacies of its manifestations. Objective This study aimed to gather preliminary data on psychophysiological aspects of sexual function in premenopausal breast cancer patients undergoing antihormonal therapy and compare them with a healthy control group. Exploring sexual arousal in breast cancer patients may unveil potential targets for innovative treatment strategies to address sexual dysfunction in this population. Methods Participants were prescreened during a telephone interview. We included 40 premenopausal breast cancer survivors with an age range of 29 to 57 years (M = 43.5, SD = 6.36) on current hormonal treatment and 20 healthy controls with an age range of 22 to 35 (M = 27.55, SD = 3.19). Physiological measures (VPA and HRV), subjective sexual arousal (SSA) and self-reported orgasm were assessed in response to audiovisual stimuli and vibrotactile clitoral stimulation sexual stimuli in breast cancer survivors and healthy controls. Self-reported measures like the Female Sexual Function Index (FSFI), the Sexual Self-Esteem Inventory (SSEI) und the PROMIS29 were incorporated. Data were analyzed using 2-level mixed effect models. Results No significant differences in VPA scores were observed between healthy controls and breast cancer survivors. Both groups exhibited a greater genital response to clitoral vibrator use than to visual stimuli. Group differences emerged in SSA and HRV, with higher SSA and lower HRV being detected. Breast cancer survivors climaxed less frequently than healthy controls and had significantly lower self-reported sexual function. Conclusions Physiological measures of arousal in breast cancer survivors were comparable to healthy controls and only subjective arousal differed. This finding indicates that subjective arousal should be further explored as the focus of intervention and treatment methods for breast cancer patients experiencing sexual dysfunction. Our findings underscore the importance of tailored strategies that resonate with individual narratives, acknowledging the emotional intricacies of post-cancer sexual well-being. This study not only contributes to scientific knowledge but also calls for a compassionate and personalized treatment paradigm, enriching the landscape of survivorship care. Disclosure Yes, this is sponsored by industry/sponsor: WOW Tech GmbH Clarification: No industry support in study design or execution.

The role of anti-IgE therapy in achieving remission of bronchial asthma

Bronchial asthma is one of the most common respiratory diseases, and follows a severe clinical course in 10% of patients. 70–80% of patients with severe asthma have signs of type 2 (T2) inflammation, which is clinically defined as an increase in blood and airways eosinophil counts. The emergence of genetically engineered biological drugs has made it possible to review the purpose of asthma therapy, that is, achieving remission instead of disease control, which includes managing the symptoms, absence of exacerbations, stabilization of functional parameters and normalization of biomarkers in the absence of therapy with systemic glucocorticoids. Clinical studies have shown that therapy with genetically engineered biological drugs can reduce the frequency of asthma exacerbations, decrease the need for maintenance therapy with systemic glucocorticoids, relieve symptoms, improve quality of life, which results in achieving a disease remission in 19.6–31.6% of patients. Predictors of suboptimal response to biological therapy were a high body mass index, admission to the intensive care unit and a history of severe asthma exacerbations, as well as initially more severe clinical manifestations of the disease. The most pronounced effect of omalizumab therapy was observed in patients with atopic severe asthma showing symptoms and exacerbations that are clinically associated with allergic sensitization confirmed by positive results of skin prick testing and (or) identification of serological allergen-specific IgE, elevated levels of T2 biomarkers. This publication presents the latest data on asthma remission: the concept, basic criteria, as well as the role of genetically engineered biological drugs in achieving a remission.

Assessing the impact of autologous neutralizing antibodies on rebound dynamics in postnatally SHIV-infected ART-treated infant rhesus macaques

The presence of antibodies against HIV in infected children is associated with a greater capacity to control viremia in the absence of therapy. While the benefits of early antiretroviral treatment (ART) in infants are well documented, early ART may interfere with the development of antibody responses. In contrast to adults, early treated children lack detectable HIV-specific antibodies, suggesting a fundamental difference in HIV pathogenesis. Despite this potential adverse effect, early ART may decrease the size of the latent reservoir established early in infection in infants, which can be beneficial in viral control. Understanding the virologic and immunologic aspects of pediatric HIV is crucial to inform innovative targeted strategies for treating children living with HIV. In this study, we investigate how ART initiation time sets the stage for trade-offs in the latent reservoir establishment and the development of humoral immunity and how these, in turn, affect posttreatment dynamics. We also elucidate the biological function of antibodies in pediatric HIV. We employ mathematical modeling coupled with experimental data from an infant nonhuman primate Simian/Human Immunodeficiency Virus (SHIV) infection model. Infant Rhesus macaques (RMs) were orally challenged with SHIV.C.CH505 375H dCT four weeks after birth and started treatment at different times after infection. In addition to viral load measurements, antibody responses and latent reservoir sizes were measured. We estimate model parameters by fitting viral load measurements to the standard HIV viral dynamics model within a nonlinear fixed effects framework. This approach allows us to capture differences between rhesus macaques (RMs) that develop antibody responses or exhibit high latent reservoir sizes compared to those that do not. We find that neutralizing antibody responses are associated with increased viral clearance and decreased viral infectivity but decreased death rate of infected cells. In addition, the presence of detectable latent reservoir is associated with less robust immune responses. These results demonstrate that both immune response and latent reservoir dynamics are needed to understand post-rebound dynamics and point to the necessity of a comprehensive approach in tailoring personalized medical interventions.

Прогностические критерии преждевременных родов у беременных, перенесших COVID-19 в третьем триместре: исследование случай–контроль

Objective. To determine the prognostic criteria for preterm birth due to SARS-CoV-2 infection. Patients and methods. A retrospective case-control study was conducted. Data on 1041 pregnant women infected with COVID-19 in the third trimester between April 2020 and December 2022 were analyzed. The Chi-square test was used to compare qualitative variables. The binary logistic regression model was used to identify factors associated with preterm birth in women infected with COVID-19. The ROC curve analysis for logistic regression was performed to assess the prognostic significance of the combination of the identified risk factors for preterm birth in women with COVID-19. Results. Regression analysis showed a positive correlation between pre-eclampsia (OR = 2.927, 95% CI: 1.328–6.452, p = 0.008), chronic infections (OR = 3.751, 95% CI: 1.931–7.287, p < 0. 0001), absence of therapy with low-molecular-weight heparin (OR = 2.481, 95% CI: 1.302–4.729, p = 0.006) and acetylsalicylic acid (OR = 1.945, 95% CI: 1.051–3.597, p = 0.034) and preterm birth. The ROC curve analysis for separate factors such as the absence of therapy with low-molecular-weight heparin and acetylsalicylic acid, age, aggravated obstetric history, pre-eclampsia and chronic infections did not show a high predictive value. The area under the curve (AUC) was less than 0.6 (0.395; 0.445; 0.589; 0.557; 0.558; 0.575, respectively). At the same time, the combination of absent anticoagulant therapy and each factor separately had a significantly higher prognostic value (AUC above 0.6 in all cases). Conclusion. The risk of preterm birth in pre-eclampsia and the presence of chronic infections in pregnant women infected with COVID-19 in the third trimester is significantly higher in the absence of anticoagulant therapy. Key words: COVID-19, pregnancy, preterm birth, anticoagulants, prognostic criteria

A calibration and uncertainty quantification analysis of classical, fractional and multiscale logistic models of tumour growth

A calibration and uncertainty quantification analysis of classical, fractional and multiscale logistic models of tumour growth

Cassandra speaks: a case series of unanticipated subcutaneous ICD premature battery depletion in a single-centre experience

Abstract Background Subcutaneous ICDs (S-ICD) are a valuable option in sudden cardiac death prevention. The main advantage over conventional transvenous ICDs is the absence of intravascular hardware for patients without the need for cardiac stimulation, resynchronization therapy or anti-tachycardia pacing. The claim of reduced lead-related complications has on the contrary been challenged by recent warnings of unexpected lead fracture. Moreover, concerns related to premature battery depletion (PBD) leading to unanticipated device replacement are increasing. Purpose To evaluate retrospectively the incidence of unanticipated S-ICD premature battery depletion in a single-centre experience. Method 168 consecutive patients implanted with S-ICD from February 2015 to November 2022 in our tertiary cardiology centre were included in this study. 4 patients moved to other sites and were thus lost to follow-up, leaving a total of 164 patients. PBD was defined as the occurrence of battery depletion requiring generator replacement earlier than 60 months post-implantation in the absence of therapy being delivered, or as a result of manufacturer recommendations. Results Most patients were implanted for primary prevention (101 patients, 60%). The main aetiology was hypertrophic cardiomyopathy (47 patients, 28%), followed by arrhythmogenic (35, 21%) and dilated idiopathic cardiomyopathy (24, 14%). Mean age and left ventricular ejection fraction at baseline were 46±18yrs and 51±16%, respectively. Over a total follow up period of 44±25 months, at 58±17 months following implantation 19 (11,6%) patients needed early replacement due to PBD, while 2 (1.2%) patients had lead fracture after respectively 41 and 26 months, for a total of 12,8% of patients with system-related complications. In addition to those patients requiring early replacement due to PBD or lead fracture, two underwent S-ICD extraction due to infection. Analysis of freedom from unanticipated PBD per year of implantation showed higher rates in years 2016 and 2017, with 67% and 27% of all implanted patients, respectively (Figure 1). Conclusions In this study, the incidence of PBDs appear to be higher than reported in literature though confined to a limited device series. However, if on the contrary the trend should remain remarkably high, that would not only endanger patients health due to repeated replacements, but also pose a huge economic burden to health systems.

Use of real-world evidence to benchmark clinical trial results: A case study in von Hippel-Lindau (VHL) disease.

4531 Background: Data from a natural history study can be used to benchmark results from single arm trials with comparable ascertainment of exposures and outcomes. Despite limitations of externally controlled trials, natural history study data can provide important information, especially when clinical trial results provide compelling evidence of change in the established progression of disease. Such results could include partial or complete response for patients receiving drug in a disease where spontaneous regression is not observed. The aim was to conduct a natural history study to benchmark results of a Phase 2 single-arm trial (LITESPARK [LS]-004) for a new HIF-2a inhibitor (belzutifan) using comparable RECIST-based study endpoints. After a median follow-up of 37.8 months, the objective response rate (ORR) for patients with renal cell carcinoma (RCC) in LS-004 was 64.0% (95% CI: 50.6 to 75.8). Methods: A study of existing electronic medical records was conducted for VHL patients with disease-associated RCC undergoing active surveillance at the US National Cancer Institute. VHL patients with ≥1 cm solid RCC, confirmed by independent review, were followed until death or last encounter. Additional LS-004 exclusion criteria were applied to define the natural history study cohort: ≥3.0 cm tumor and procedure performed within 60 days, prior systemic oncologic therapy, and metastasis prior the index date. The index date was the date of the earliest radiology report with measurable disease during the study window (July 2004 - June 2020). An analysis of radiographic outcomes was performed according to RECIST V1.1 for patients with ≥3 scans prior to last encounter, death, or renal therapy using an imaging charter similar to LS-004. Adjudication of best overall response (BOR) was performed if there was discordance between assessments by the two independent radiologists. Results: The natural history study population included 244 VHL patients (100% genetic confirmation; 55% male; median age: 41 years, median follow-up: 10 years). The median size of largest RCC tumor diameter at baseline was 2.5 cm (IQR: 1.9, 3.1), and 76% of patients had ≥1 surgery after the index date. Among patients with ≥3 scans (n=178/244), the confirmed real-world ORR within 5 years of follow-up was 1.8% (95% CI: 0.4%, 5.2%), all with partial response. The real-world BOR was progressive disease and stable disease for 22% and 74% of patients, respectively. Within 5 years, 80% of patients had disease progression. Conclusions: Using similar trial endpoints, this natural history study demonstrates that spontaneous regression of RCC solid tumors is unlikely for patients with VHL undergoing active surveillance in the absence of therapy, and most patients experience disease progression. These findings help contextualize the antitumor activity and efficacy of belzutifan in the treatment of patients with VHL disease-associated RCC.

Prospective classification of Alzheimer’s disease conversion from mild cognitive impairment

Prospective classification of Alzheimer’s disease conversion from mild cognitive impairment

Effective preconception preparation for women with iron deficiency

Introduction. Latent iron deficiency, which has a high prevalence among women of childbearing age, most often, in the absence of therapy, progresses in pregnant women into manifest iron deficiency, manifested by clinical symptoms of anemia and associated with a complicated course of pregnancy, childbirth, the postpartum period, unfavorable outcomes of newborns. The above justifies the need for correction of iron deficiency at the preconception period.Aim. To evaluate the effectiveness of therapy latent iron deficiency at the stage of preconception period.Materials and methods. The study included 32 women at the stage of pregnancy planning with latent iron deficiency. All women taking the drug Ferretab 1 pill per day for 1 month. The level of blood parameters was assessed at 3 months before the intended conception, in the I, II and III trimesters of pregnancy, in the 3rd day after delivery. In newborns, the indicators of a clinical blood test were evaluated on the 2nd day after birth. We evaluated such indicators as the level of hemoglobin, erythrocytes, hematocrit, the average content of hemoglobin in erythrocytes, serum ferritin, serum iron, transferrin.Results. Evaluation of laboratory data in the course of the study confirmed the effectiveness of the use the complex drug Ferretab. Patients already at the first visit to the doctor during pregnancy had a positive trend and a significant increase in the level of hematological parameters.Conclusions. Oral administration of the complex drug Ferretab showed high efficiency in the treatment of latent iron deficiency at the stage of preconception period, significantly increasing the levels of hematological parameters, good tolerance and a small number of side effects, contribute to the high adherence of patients to therapy, which allows achieving significant clinical results.

Abstract 552: Stromal facilitated multifactorial resistance to tumor cells against targeted therapies in ALK+ NSCLC

Abstract Despite inducing strong and durable remissions, inhibitors of mutant ALK (ALKi) are not curative for advanced ALK+ lung cancers, as residual tumors eventually develop resistance and relapse. Apart from tumor cells’ intrinsic ability to escape from therapy, there is a growing body of evidence suggesting the contribution of extrinsic factors, produced by cancer-associated fibroblasts (CAFs). Despite the multitude of studies that demonstrated the ability of multiple CAF-produced factors to reduce the sensitivity of tumor cells to ALKi, the contribution of these effects toward responses in vivo remains unresolved. To study the impact of stroma on the ability of tumor cells to survive and develop resistance to ALKi, we derived multiple isolates of fibroblasts from clinical samples. Consistent with previous reports, we found that co-culture with CAFs or CAF-conditioned media protects tumor cells against ALKi. We observed that the degree of protection varies between different CAF isolates. This variability in the extent of protection could be attributed to variability in the levels of secreted hepatocyte growth factor (HGF) a known paracrine mediator of environmental resistance. Moreover, exogenous HGF phenocopied the effect of CAFs while blocking HGF-cMET signaling with neutralizing antibodies or pharmacologically abrogated the protective effect. To test the relevance of these findings in vivo, we took advantage of the inability of murine HGF to activate human cMET by comparing the response of ALK+ xenograft tumors to front-line ALKi alectinib between NSG mice and NSG-derivative strain with humanized HGF. In contrast to the in vitro data, HGF status had only a minimal impact on the remission-relapse dynamics of xenograft tumors. This lack of differences reflected a strong HGF-independent sheltering effect of the stromal niche. Our histological analyses of samples at different points of remission-relapse response revealed that while alectinib potently suppressed tumor cell proliferation, proximity to stroma reduced this cytostatic effect, without impacting cell proliferation in the absence of therapy. To gain insights into the mechanistic underpinning of this HGF-independent effect, we used spatial transcriptomics, comparing stroma-proximal and stroma-distant tumor regions. These analyses, as well as functional validation studies, indicate that stroma-sheltering effects are mediated by multiple mechanisms, acting in an additive fashion. In summary, our studies indicate that therapy resistance of tumor cells reflects the combined action of both intrinsic and microenvironmental factors. Our findings indicate that focusing on a single resistance mechanism at a time is unlikely to induce strong, durable responses. Instead, tackling the issue of therapy resistance necessitates the consideration of multiple resistance mechanisms as well as the moving target nature of tumors under therapy. Citation Format: Bina Desai, Tatiana Miti, Daria Miroshnychenko, Viktoriya Marusyk, Chandler Gatenbee, Menkara Henry, Uwe Rix, Alexander Anderson, Eric Haura, David Basanta, Andriy Marusyk. Stromal facilitated multifactorial resistance to tumor cells against targeted therapies in ALK+ NSCLC [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 552.

Abstract 1052: Background variability in plasma ctDNA levels in patients with advanced lung cancer in the absence of treatment

Abstract Introduction: Molecular response (MR) is defined as a reduction in circulating tumor DNA (ctDNA) levels between baseline and early on-treatment timepoint(s). MR is predictive of long-term outcomes in several advanced cancers treated with different therapeutic modalities. Common MR thresholds include reductions in ≥50%, or 100% (clearance) in ctDNA levels. A better understanding of the background variability in measured plasma ctDNA levels in the absence of therapy is required to enable improved interpretation of MR, especially as its use increases in drug development and clinical management. Methods: In the largest study of double baseline pre-treatment ctDNA samples reported to date, paired screening and pre-treatment cycle 1 day 1 (C1D1) samples (IQR: 8-24, median 17 days apart) from 360 patients with advanced EGFRm non-small cell lung cancer (NSCLC) from the FLAURA (1L, N=132) and AURA3 (2L, N=228) trials were compared to characterize background variability in ctDNA. ctDNA was quantified using NGS (Guardant Health G360 and OMNI) and ddPCR (Biodesix) assays. Various potential drivers of background variability, such as ctDNA quantification platforms, coverage, and number of variants at baseline were evaluated to better understand any underlying confounding effects. Results: Pre-treatment background variability was consistently observed in both AURA3 and FLAURA cohorts. Most of the variability reflected any increase in pre-treatment ctDNA in 28% (64/228) of cases in AURA3, and 13% (17/132) of cases in FLAURA. Variability reflecting a ≥50% decrease in pre-treatment ctDNA was observed in 8% (18/228) of cases in AURA3 and 9% (12/132) of cases in FLAURA, with only 2% of cases showing ctDNA clearance in AURA3 and 0% in FLAURA. Testing technical replicates sequenced a year apart and comparing ctDNA levels quantified with NGS v. ddPCR for potential sources of technical variability did not show large variability. Moreover, sources like cell-free DNA input, allele frequency levels, and days in between screening and C1D1 were tested but could not fully account for the variability observed. Conclusion: Although pre-treatment increases in ctDNA levels were expected in patients with advanced cancer, background variability also included reductions in ctDNA that may be confounded as MR. Understanding the impact of factors on the transient nature of ctDNA is key, but as momentum mounts to use ctDNA as a biomarker of therapeutic response, it is crucial to test and account for background variability rates to improve MR interpretability. Additional work is warranted to elucidate the background variability rate in other cancer types and settings. Citation Format: Diana M. Vega, Aleksandra Markovets, Christopher Abbosh, Katie Quinn, Kyle Chang, Sara Wienke, Ryan Hartmaier, Matthew Hellmann, J Carl Barrett, Darren Hodgson. Background variability in plasma ctDNA levels in patients with advanced lung cancer in the absence of treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1052.