Number Of Cycles Research Articles

Structural forming of soil composites using as a pavement subgrade strengthening

The article substantiates the possibility of obtaining composite materials with improved functional properties to strengthen the subgrade, containing technogenic soil stabilized by an additive based on a gelling polymer. The introduction of technogenic soils into composites will not only reduce the consumption of expensive materials, but also solve a complex of acute environmental problems. Composite materials can be used in the construction of structural layers of road pavements, foundations of buildings and structures, sites for various purposes, for the prevention and elimination of defects in the foundations of engineering structures during their construction, reconstruction and repair, including in permafrost areas. Stabilized technogenic soils are more durable, frost-resistant and waterproof, which makes them applicable for creating impervious curtains in hydraulic structures and sealing storage facilities for hazardous substances. The cryogenic effect on a composite material allows one to vary its properties within a wide range and modify its macroporous structure. Studying the process of structure formation of the resulting organic-inorganic materials, consisting of macromolecules of high-molecular substances and inorganic inclusions that have undergone cryogenic treatment, will make it possible to specifically regulate their performance characteristics. The best values of strength characteristics were obtained for samples with a stabilizing additive concentration of 100g/l. The resulting composite materials are hydrophobic, frost-resistant, characterized by a compressive strength of 2.3-6.5MPa and a thermal conductivity of 0.19-0.20W/(m·K). Data from differential scanning calorimetry and thermogravimetry and IR spectroscopy revealed that the binding of mineral particles by a stabilizing additive occurs due to the formation of organomineral complexes with the participation of clay minerals and the restructuring of hydration shells. SEM data indicate that crystallinity zones formed due to hydrogen bonds of hydroxyl groups of neighboring polymer chains can participate in the formation of the composite structure. An increase in the number of cryogenic treatment cycles promotes additional structuring and strengthening of the polymer phase due to the formation of additional nodes of the supramolecular network, ordering of crystallinity zones and the appearance of compacted areas in the structure. Computed X-ray tomography revealed an increase in the density of the composite upon drying, which helps to increase its strength characteristics. The structure of the sample is characterized by heterogeneity of the pore space, which is characterized by the presence of both fine-porous and large-porous regions, which determines its thermophysical properties.

A modified perturbation method for global dynamic analysis of generalized mixed Rayleigh–Liénard oscillator with cubic and quintic nonlinearities

Deriving analytical relationship between the system parameters and amplitude of the limit cycle is a meaningful and challenging task. Currently, numerous existing analytical approximate methods struggle to achieve this goal when expressions of restoring force or nonlinear damping is complicated. To overcome this shortcoming, this study proposes a modified generalized harmonic function perturbation method. Using the proposed method, a generalized mixed RayleighLiénard oscillator with cubic and quintic nonlinearities was investigated. The analytical relationships between the system parameters and amplitude of the limit cycle, as well as the expression of its characteristic quantity, were derived. By employing these analytical relationships, the existence, stability, number, position, and amplitude of each limit cycle are quantitatively analysed. The homoclinic and heteroclinic bifurcations were also predicted using the above analytical relationships. Additionally, analytical approximate solutions for this oscillator were calculated using the proposed method. All results obtained in this study were subsequently confirmed numerically to demonstrate their feasibility and validity. Consequently, the proposed method can be considered an effective supplement to perturbation-based methods. This also implies that the work presented in this paper has a certain theoretical significance and application value in the research area of quantitative analysis methods for strongly nonlinear oscillators.

Oil-soluble contrast medium bathing attenuated endometrial inflammation and improved endometrial receptivity in women with recurrent implantation failure: a descriptive study

BackgroundThe oil-soluble contrast medium used in hysterosalpingography has been shown to have a fertility-enhancing effect, but the underlying mechanism is unclear, especially regarding the role of window of implantation (WOI). This study aimed to assess the endometrial immunological impact of the WOI before and after bathing with the oil-soluble contrast medium in women with recurrent implantation failure (RIF).MethodsThis descriptive study involved two medical centers between December 18, 2019, and December 30, 2020. We included infertile women who underwent three or more transfer cycles, cumulative transplantation of at least four high-quality cleavage-stage embryos or three high-quality blastocysts without clinical pregnancy, and high-quality frozen embryos that were still available for implantation. Patients received 5 ml of ethiodized poppyseed oil bathing, endometrial biopsy around bathing, and frozen-thawed embryo transfer (FET) within four menstrual cycles after bathing. Patients were excluded if failure to complete anyone. Data on the baseline characteristics and clinical data of the FET cycles were collected, and endometrial biopsy specimens were collected in the luteal phase before and after bathing and subjected to immunohistochemistry. The number of CD56 and CD138 positive cells and H-score of expression of ανβ-3 and HOXA10 in endometrium were collected.ResultsThirty-four patients were initially enrolled in the study; ultimately, twelve patients with a median age of 32.5 years (range 27–40 years) completed the research. The median number of embryo transfer cycles was three (range 3–8). A total of 4 of 12 women (33.33%) were diagnosed with chronic endometritis before oil-soluble contrast bathing. After bathing, the median numbers of CD138-positive cells in endometrium decreased from 0.75 (range 0–13.5) to 0.65 (range 0–6), P = 0.035; additionally, the H-score of expression of ανβ-3 in endometrium increased from 148.50 ± 31.63 to 175.58 ± 31.83, P < 0.001. The thickness of the endometrium also significantly increased (8.90 ± 1.45 mm vs.10.11 ± 1.98 mm, P = 0.005). However, no consistent changes were found in the expression of CD56 and HOXA10 in the endometrium. Five patients experienced biochemical pregnancies (41.67%), four had clinical pregnancies (33.33%), and three achieved live births following oil-soluble contrast bathing (25%).ConclusionsThese results suggest that oil-soluble contrast medium bathing decreased CD138-positive cells and upregulated expression of ανβ-3 during WOI in patients with RIF. This histological impact of endometrium may result in enhanced fertility during FET cycles. Investigating the ability of intrauterine bathing with lower-dosage oil-soluble contrast to improve pregnancy in the RIF population is warranted.

On the influence of the shearing rate on the monotonic and cyclic response of Malaysian kaolin

This article experimentally evaluates the influence of shearing rate on the monotonic and cyclic response of isotropically-consolidated samples of Malaysian kaolin. On the one hand, a series of undrained monotonic triaxial tests were performed with varying shearing displacement rate. On the other hand, undrained cyclic triaxial tests were conducted considering different deviatoric stress amplitudes and loading frequencies. The well-known soil rate-dependency under monotonic loading was confirmed up to a displacement rate threshold. The experimental results under cyclic loading suggest that for the given loading frequency, the variation of the deviatoric stress amplitude remarkably influences the strains and pore water pressure accumulation rates. In addition, the results suggest that depending on the loading frequency different shapes of mobilized effective stress loops are obtained. Larger loading frequencies lead to banana-shaped effective stress loops, while smaller frequencies reproduce eight-shaped effective stress loops. Furthermore, higher loading frequencies result in a larger number of cycles required to reach failure conditions. The reasons for the observed differences in the behavior are thoroughly analyzed and discussed.

Antegrade anterior column acetabulum fracture fixation with cannulated compression headless screws-A biomechanical study on standardized osteoporotic artificial bone.

Due to the increase in life expectancy and high-energy traumas, anterior column acetabular fractures (ACFs) are also increasing. While open reduction and internal fixation (ORIF) is still the standard surgical procedure, minimally invasive, percutaneous fixation of osteoporotic acetabulum fractures (AF) are growing in popularity. The aim of this biomechanical study was to evaluate the biomechanical competence following antegrade fixation with a standard screw versus a cannulated compression headless screw. Eight anatomical osteoporotic composite pelvises were given an anterior column fracture. Two groups of eight specimens each (n = 8) for fixation with either a 6.5 mm cannulated compression headless screw in group Anterior Acetabulum Canulated Compression Headless Screw (AACCH), or with a 6.5 mm partially threaded cannulated screw in group Anterior Acetabulum Standard Screw (AASS) where compared. Each specimen was biomechanically loaded cyclically at a rate of 2 Hz with monotonically increasing compressive load until failure. Motions were assessed by means of optical motion tracking. Initial construct stiffness trended higher in group AACCH at 152.4 ± 23.1 N/mm compared to group AASS at 118.5 ± 34.3 N/mm, p = 0.051. Numbers of cycles and corresponding peak load at failure, were significantly higher in group AACCH at 6734 ± 1669 cycles and 873.4 ± 166.9 N versus group AASS at 4440 ± 2063 cycles and 644.0 ± 206.3 N, p = 0.041. Failure modes were breakout of the screws around the proximal entry point. From a biomechanical perspective, group AACCH was associated with superior biomechanical competence compared to standard partially threaded cannulated screws and could therefore be considered as valid alternative for fixation of anterior acetabulum fractures.

Effect of Torsional Load on Electrical and Mechanical Properties/Behaviour of Stretchable GNP-Ag Conductive Ink

Stretchable conductive inks (SCIs) have gained significant attention in recent years due to their potential applications in flexible and wearable electronics. Graphene nanoplatelet (GNP) hybridization conductive ink is a promising material for stretchable electronics due to its high electrical conductivity and excellent mechanical properties. However, the resistivity of GNP ink on flexible substrates can be affected by various factors, such as the torsion of the substrate. This paper aims to investigate the effect of torsional load in terms of the electrical and mechanical behaviour of hybridization conductive ink between GNP and Ag. The research was carried out on the formulation and performance of GNP hybrids using GNP and silver flakes (Ag). The GNP hybrid ink was printed on a copper substrate using a mesh stencil method and cured at 250 °C for an hour. The resistivity was evaluated at room temperature before and after the torsional tests in terms of electrical characteristics. The finding exposed that the resistivity values for each of the three samples of torsional tests significantly changed after 1000 cycles. Eventually, the resistance value at cycle 5000 rose due to the damaging impact of increasing the number of torsional cycles on the sample. In future work, it is recommended that the evaluation is made under temperature dependence and supported by SEM images.

Alternating load failure analysis under the high-temperatures vibration of thermal barrier coatings

During thermal barrier coatings (TBCs) service, high-temperature and vibration are environmental factors that cannot be ignored. The vibration fatigue damage mode of TBCs under operating conditions that couple vibrations with high temperatures is unclear. In this paper, a high-temperature vibration coupled environment simulator was developed to investigate the evolution of high-temperature vibration fatigue damage modes of LaZrCeO/7-YSZ(LZC/YSZ) TBCs under alternating loads by employing acoustic emission detection. The results show that in the initial fatigue stage, the damage appears as discrete micro-cracks formed by the initial defects in the TBCs. With the increase in the number of cycles, the initiation of transverse microcracks began to occur inside the LZC layer and at the LZC/YSZ interface. When the transverse microcracks accumulate to the critical value, the applied alternating loads accelerate the propagation of opening interfacial cracks. Finally, the columnar crystal structures of the ceramic layers fracture at different heights under cyclic loading by high-temperature vibrations.

Trastuzumab-induced cardiotoxicity in patients with metastatic HER2-positive breast cancer treated at a reference hospital in Mexico.

e13032 Background: In Mexico, breast cancer represents the leading cause of cancer-related death in women, and up to 52% is diagnosed at a metastatic stage. Up to 20-25% of women with breast cancer have overexpression of the human epidermal growth factor receptor 2 (HER2) which is associated with an aggressive behavior. The most relevant adverse effect associated with therapy targeting this receptor is an increase of up to 4 times in the rate of myocardial dysfunction. There is limited research in the Mexican population, especially in the metastatic context. This review is intended to be conducted in the national population, including patients with HER2-positive metastatic breast cancer who have received trastuzumab treatment, to determine the main characteristics of such myocardial dysfunction using the definition of cardiac dysfunction proposed by the International Cardio-Oncology Society (ICOS) in 2021, as well as its current prevalence. Methods: Observational, descriptive, cross-sectional, retrospective study. Medical records of patients diagnosed with metastatic HER2-positive breast cancer between January 2017 and December 2022, who received trastuzumab and had a determination of left ventricular ejection fraction (LVEF) before treatment and at least two LVEF determinations during treatment to determine the presence or absence of cardiotoxicity. LVEF could have been determined by MUGA (Multigated Acquisition Scan) or by echocardiogram. Results: A total of 103 patients were included, with a mean age of 55 years. The found prevalence of cardiotoxicity was 30.09%. Among the most frequent clinical characteristics of these patients were obesity in 32.2% [n= 10], smoking habit in 12.9% [n= 4], and type 2 diabetes in 9.7% [n= 3]. The diagnosis of de novo metastatic disease was 48.4% [n= 15]. A history of ischemic heart disease was present in 3.2% [n= 1], and a frequency of 12.9% [n= 4] of patients with borderline LVEF (50-54%) was reported at baseline, with only 3.2% [n= 1] documented with a baseline LVEF &lt; 50%. The median number of trastuzumab cycles administered during follow-up was 14 cycles, anthracycline therapy was documented in most patients, and previous exposure to thoracic and/or mediastinal radiotherapy with a dose exceeding 30 Gy was found in 35.5% [n= 11]. Referral to cardiology and/or cardio-oncology service was 51.6% [n= 16]. Discontinuation of anti-HER2 treatment was carried out in 3 patients (2.9%). Conclusions: We demonstrated a prevalence of cardiotoxicity from anti-HER2 agents in our population similar to that reported in the international literature. Multicenter studies are necessary to define the prevalence more accurately in the Mexican population, as well as prospective studies to demonstrate the association between cardiovascular risk factors and clinical characteristics with the development of cancer therapy-related cardiac dysfunction.

First-line pembrolizumab for lung cancer in a Spanish real-world study.

e23268 Background: KEYNOTE (KN) 024 trial showed that pembrolizumab significantly improves progression free survival (PFS) and overall survival (OS) in patients with previously untreated advanced non-small cell lung cancer (NSCLC) with a PD-L1 expression ≥ 50% without EGFR/ALK alterations. The main aim of this study is to report the outcomes (PFS and OS) of pembrolizumab in a real life setting. Methods: Multicenter retrospective study in 42 Spanish hospitals. Inclusion period: 01/2016 – 07/2020; cut-off date: 31/12/2021. Demographic, clinical and treatment-related data were retrospectively obtained from patients’ medical files. Statistical analysis was carried out using descriptive metrics and survival analysis techniques (Kaplan-Meier, log-rank test, Cox regression). Results: In our cohort of 1005 patients, 74.5% were males, mean age was 66.4 ± 9.7 and mean BMI 25.6 ± 4.6. The majority were current (35.6%) or former smokers (56.6%), with 11 % of patients with ECOG ≥ 2. Patients with a non squamous histology were 79.5% and 95.2% were classified as IV stage (30.3% had hepatic and/or brain metastases, 49.3% had ≥ 2 metastatic sites). Pembrolizumab dose was mainly fixed (83.1% of patients), while the number of treatment cycles was highly variable. 31.8% received concurrent radiotherapy, while previous corticoid (PCE), antibiotic and proton pump inhibitors (PPI) exposure were 18.2%, 7.7% and 40.7% respectively. With a median follow-up of 6.3 months, median OS and PFSwere 19 (95%CI: 16.2 – 21.3) and 8.7 (95%CI: 7.2 – 10.1) months. Several variables were associated with PFS and OS after univariate survival analysis. Age and previous antibiotic exposure were associated to worse OS but not to PFS. Multivariate analysis showed that ECOG ≥2 (HR 2.7 95%CI 2-3.5) and previous PPI exposure (HR 1.3 95%CI 1.1-1.6) were predictors of poor outcome. Conclusions: In our cohort, pembrolizumab showed lower OS and similar PFS than KN 024. Our results confirm that poor PS (ECOG) is a negative predictive factor for effectiveness. [Table: see text]

A mechanistic approach to determine the relationship between film structure, electronic properties, and photocatalytic activity of ALD ZnO thin films on glass gibers

Atomic layer deposition (ALD), a high-conformality thin-film deposition technique, offers the opportunity to immobilize photocatalytic materials on high surface area substrates. Textile substrates are inexpensive, easily accessible materials with a fibrous nature, making them high surface area scaffolds for photocatalytic applications. This study applied ZnO thin-film coatings to fabric structures with different numbers of ALD cycles. The effect of coating thickness on the surface and electronic properties of the films and their photocatalytic properties were investigated. SEM, XRD, PL, and UV–Vis were used to examine the surface morphology, crystal structure, defects, and optical properties of the ZnO thin films. As the film thickness increased, the crystal sizes and the number of defects in the structure increased. Contact angle and Hall Effect measurements revealed that these structural defects are present on the surface of the films. Optimum wettability, mobility, and photocatalytic efficiency values were observed in the 15-nm coated samples, resulting in the highest photocatalytic activity and a turning point.

Real-world safety and healthcare resource utilization (HCRU) of lurbinectedin (lurbi) in patients (pts) with small cell lung cancer (SCLC): Jazz EMERGE 402 updated analysis.

e23266 Background: Lurbi monotherapy received approval in multiple countries, including accelerated US FDA approval and conditional Health Canada approval for adults with metastatic (US) or stage III/metastatic (Canada) SCLC with disease progression on or after platinum-based chemotherapy, based on a phase 2, open-label, single-arm trial (Trigo et al, Lancet Oncol 2020). Jazz EMERGE 402 (NCT04894591) is a phase 4 observational study assessing the effectiveness, safety profile, and HCRU of lurbi in pts with extensive-stage SCLC treated in real-world clinical settings. Here, we report updated safety data and HCRU. Methods: This study is enrolling pts with extensive-stage SCLC treated with lurbi according to the local approved label in the US and Canada. Results: Enrollment is ongoing with a target of 300 pts. Between 28JUN2021 and 27DEC2022, 105 pts were enrolled and followed for ≥6 months after the first dose of lurbi (data cutoff: 27JUN2023). The median (range) age was 67 (44-87) years; 72 (69%) pts had prior immunotherapy; 22 (21%) had an Eastern Cooperative Oncology Group performance status of ≥2; and 25 (24%) had central nervous system involvement. All pts received ≥1 cycle of lurbi; 56 (53%) as second-line (2L) and 37 (35%) as third-line (3L) therapy. The median (range) number of lurbi cycles was 4 (1-31) and the median (range) duration of exposure was 97 (21-694) days. Dose modifications occurred in 27 (26%) pts, with 17 (16%) requiring dose reductions. Granulocyte colony-stimulating factor was administered in 43 (41%) pts (34 [79%] as primary and 7 [16%] as secondary prophylaxis; 2 [5%] were unknown). At the time of data extraction, lurbi treatment was ongoing in 11 (10%) pts and 23 (22%) pts received subsequent anticancer therapy after lurbi. Treatment-related adverse events (TRAEs) were reported in 40 (38%) pts and treatment-related serious adverse events (SAEs) in 13 (12%) pts. The most common TRAEs were anemia (n = 13, 12%), neutropenia (n = 10, 10%), nausea (n = 8, 8%), and fatigue (n = 7, 7%). Thirty-six pts were hospitalized for a median (interquartile range [IQR]) duration of 10 (4, 18) days (Table). No pts were hospitalized on the first day of treatment; 4 pts were hospitalized during the first 21-day cycle. The most common reasons for hospitalization were pneumonia (n = 10, 28%) and sepsis (n = 6, 17%; one was an SAE). Conclusions: In this phase 4 study, lurbi was well tolerated, with low rates of HCRU and a safety profile generally consistent with that reported in the phase 2 trial. Clinical trial information: NCT04894591 . [Table: see text]

Simultaneous Determination of 23 Pyrrolizidine and Tropane Alkaloids in Infusions from Dry Edible Flowers Using Optimized μSPEed® Microextraction Prior to Their Analysis by UHPLC-IT-MS/MS.

A miniaturized solid-phase extraction of two tropane alkaloids (TAs) and twenty-one pyrrolizidine alkaloids (PAs) from infusions of dry edible flowers using optimized µSPEed® technique was developed. The optimization of the µSPEed® methodology involved testing different cartridges and comparing various volumes and numbers of loading cycles. The final conditions allowed for a rapid extraction, taking only 3.5 min. This was achieved using a C18-ODS cartridge, conditioning with 100 µL of methanol (two cycles), loading 100 µL of the infusion sample (seven cycles), and eluting the analytes with 100 µL of methanol (two cycles). Prior to their analysis by UHPLC-IT-MS/MS, the extracts were evaporated and reconstituted in 100 µL of water (0.2% formic acid)/methanol (0.2% ammonia) 95:5 (v/v), allowing for a preconcentration factor of seven times. The methodology was successfully validated obtaining recoveries ranging between 87 and 97%, RSD of less than 12%, and MQL between 0.09 and 0.2 µg/L. The validated methodology was applied to twenty samples of edible flower infusions to evaluate the safety of these products. Two infusion samples obtained from Acmella oleracea and Viola tricolor were contaminated with 0.16 and 0.2 µg/L of scopolamine (TA), respectively, while the infusion of Citrus aurantium was contaminated with intermedine and lycopsamine (PAs) below the MQL.

Safety and efficacy of B7-H3 targeting CAR-T cell therapy for patients with recurrent GBM.

2062 Background: Glioblastoma Multiforme (GBM) is one of the most deadly cancers, and nearly all patients experience recurrence upon the current standard of care for newly diagnosed GBM. The recurrent GBM (rGBM) exhibits a median survival of less than 8 months with limited therapeutic options. We have previously cloned the B7-H3 gene, characterized its function, demonstrated altered B7-H3 expression in human solid tumors, and identified B7-H3 as a promising therapeutic target. We present herein the preliminary findings of an investigator-initiated trial (NCT05241392), where patients with rGBM were treated with autologous chimeric antigen receptor-T (CAR-T) cells targeting B7-H3 (TX103). Methods: This is an open, single-arm, "3+3" dose-escalation and multiple-dose study. The primary objective was to evaluate the safety and the maximal-tolerated dose. Secondary objectives included survival outcomes, tumor responses, immunological responses, and pharmacokinetic parameters. Patients aged 18 to 75 were enrolled with confirmed recurrence by image scan and B7-H3 expression &gt;= 30% by immunohistochemistry analysis. TX103 was administered intracavity and/or intraventricularly to patients via an Ommaya reservoir. TX103 was given biweekly to patients each cycle at dose levels 1, 2, and 3 (20, 60, 150 million cells, respectively), with four cycles as one course. Results: Between March 2022 and January 2024, 13 patients received at least one intracranial infusion of TX103, with 3, 4, and 6 patients in dose levels 1, 2, and 3, respectively. The median number of infusion cycles was 4 (Min, Max 1,9). All patients were included in the safety analysis, revealing no dose-limiting toxicity or CAR-T treatment-related death. All patients experienced at least one adverse event (AE), and the treatment-related AEs (TRAEs) included cytokine release syndrome, increased intracranial pressure (ICP), headache, epilepsy, decreased level of consciousness, vomiting, and pyrexia. Most TRAEs were grade 1-2, while three grade-3 TRAEs were observed: one case of increased ICP in dose level 2, one case of epilepsy, and another case of decreased level of consciousness in dose level 3. As of January 2024, six patients from dose levels 1 and 2 were eligible for a 12-month survival assessment; the 12-month overall survival (OS) rate was 83.3% (95% CI: 58.3%~100%), and the median OS was 20.3 mo (95% CI: 20.3~not reach). Two of the three patients from dose level 2 achieved partial and complete responses, respectively. Following CAR-T administration, significant increases in cytokines, including IL-6 and IFN-γ, and elevated copy numbers of the CAR gene were observed in the cerebrospinal fluid, while only minimal elevations were noted in the peripheral blood. Conclusions: In this trial, treating rGBM with TX103 is deemed safe and tolerated. These interim results support further study using TX103 to enhance the survival outcomes in patients with rGBM.

A meta-analysis GWAS of taxane-induced peripheral neuropathy in patients with breast cancer.

12089 Background: Taxane-induced peripheral neuropathy (TIPN) is a common dose-limiting toxicity in the medical management of breast cancer patients. Despite the clinical efficacy of taxane treatment, there is significant heterogeneity in the development of neuropathy and its severity, and no clear genetic etiologies have yet been identified. We sought to discover genetic risk variants in two large electronic health record linked DNA biobanks. Methods: A meta-analysis genome wide association study (GWAS) was performed with participants in the All of Us Research Program and BioVU biobanks. All participants of the study population were of female sex at birth and had a breast cancer diagnosis. Cases were defined as taxane-exposed participants who received their first neuropathy diagnosis code within one year after first taxane exposure. Controls were defined as taxane-exposed participants without a neuropathy diagnosis code and without gabapentin initiation after taxane exposure. GWAS was performed with PLINK version 2.0 using age at taxane initiation, number of taxane cycles received, and the first 10 principal components as covariates. Expression quantitative trait loci (eQTL) analysis was performed with the GTEx 8.0 and EyeGEx databases. Results: The All of Us cohort had 196 cases and 254 controls. The BioVU cohort had 244 cases and 528 controls. In our meta-analysis GWAS, rs3065465 (chr11:69138693; closest gene by distance is LOC338694) was associated with TIPN (OR=2.14, P= 8.27E-09) and was similar across different genetic ancestries (Table). The eQTL analysis of rs3065465 shows significant association with mRNA expression of TPCN2(P= 6.44E-06), a cation channel involved in neuronal differentiation and intracellular calcium homeostasis. Conclusions: rs3065465 represents a potential novel genetic marker for TIPN risk in breast cancer patients.[Table: see text]

On the Number of Maintenance Cycles in Systems With Critical and Noncritical Components

On the Number of Maintenance Cycles in Systems With Critical and Noncritical Components

Alliance A071401: Phase II trial of abemaciclib in patients with grade 2/3 meningiomas harboring somatic NF2 or CDK pathway alterations.

2001 Background: Systemic treatments are limited for patients with meningiomas that have progressed after surgery and/or radiation. Loss of NF2and CDKN2A/Bare common in higher grade meningiomas and promote meningioma progression in preclinical models. We evaluated the efficacy of abemaciclib, a cyclin-dependent kinase (CDK) 4/6 inhibitor, as part of Alliance umbrella trial A071401, a genomically driven phase II study in recurrent or progressive meningiomas. Methods: Eligible patients (pts) with grade 2/3 tumors and NF2 mutations or CDK pathway alterations were treated with abemaciclib 200 mg orally twice daily until progressive disease. Two co-primary endpoints were used: progression-free survival at 6 months (PFS6) and response rate (RR) by Macdonald criteria; the trial would be declared positive if either endpoint was met. Twenty-four evaluable pts provided &gt;85% power to detect a PFS6 &gt;41.5% (vs. null 15%; alpha =0.02). The threshold for promising results for PFS6 was 8+/24 pts. For RR, 24 evaluable pts provided &gt;89% power to detect RR &gt;20% (vs. null 2.5%; alpha = 0.021). The threshold for promising results for RR was 3+/24 pts. Results: Of 83 pts screened while the abemaciclib arm was open between September 15, 2021 and October 3, 2022, 36 eligible pts received treatment. The mean number of treatment cycles administered was 7 and median follow-up since start of treatment was 11 months. The first 24 pts that met eligibility criteria and began treatment were considered evaluable for the primary endpoint analysis. Of the 24 pts evaluated, 58% were female and the median age was 62 years. The observed PFS6 rate was 54% (13/24 pts, 95% confidence interval 33-75%), thus the study met PFS6 endpoint. No objective responses were observed. Of the 36 pts who started treatment, eight had a grade 3 and two had a grade 4 adverse event at least possibly related to treatment. Grade 3 toxicities included anemia (2), neutropenia (2), leukopenia (1), blurry vision (1), diarrhea (2), fatigue (2), ALT elevation (1), dehydration (1), hyperkalemia (1), hyponatremia (1), dizziness (1), acute kidney injury (1), and thromboembolic event (1). Grade 4 toxicities included ALT elevation (1), AST elevation (1) and vomiting (1). Conclusions: Abemaciclib was well tolerated and resulted in an improved PFS6. The overall trial endpoint was met. Abemaciclib warrants further investigation for the treatment of patients with progressive grade 2/3 meningiomas. Support: U10CA180821, U10CA180882; UG1CA189867 (NRG Oncology); Eli Lilly; https://acknowledgments.alliancefound.org . Clinical trial information: NCT02523014 .

Real-world efficacy and adverse events of neoadjuvant immunotherapy in patients with early-stage triple-negative breast cancer: A multi-center experience.

e23293 Background: Pembrolizumab (pembro) combined with neoadjuvant chemotherapy (NAC) consisting of carboplatin- paclitaxel and doxorubicin-cyclophosphamide is the current standard of care in early-stage triple negative breast cancer (TNBC) based on KEYNOTE 522, which demonstrated improvements in pathologic complete response (pCR) to 65% but associated with high incidence of immune related adverse events (irAEs). We investigated real-world clinical outcomes and toxicity of this regimen. Methods: We conducted a retrospective, multi-center observational study among TNBC patients (pts) treated with NAC and pembro at 4 academic institutions from July 2021-December 2023. Data on clinicodemographic variables, irAEs, and clinical outcomes were collected. Multivariable logistic regressions were used to evaluate the association between demographic/clinical characteristics and pathological response while controlling for confounders. Analyses were performed in R (v4.2.3) at a significance level of ≤ 0.05. Results: 145 pts were analyzed, all females, with median age 53.5 years (IQR 43.4-62.7), 66% White and 23.4 % Black, median body mass index 28.3 kg/m2 (IQR 23-32), 55.6% stage II and 34% stage III disease. Median follow up was 12.3 months from the date of diagnosis. 94 pts (64.8%) attained pathological complete response (pCR). The median number of Pembro cycles prior to surgery was 7. Receipt of &lt; 8 pembro cycles was associated with lower pCR rate compared to ≥ 8 cycles (37.2% vs 62.8%, p = 0.03). Pts in pCR group were younger than in non-pCR group (50.8 vs. 58.5 years, p = 0.002). The non-pCR group received lower relative dose intensity (RDI) of carboplatin (91.7% vs 96.6%, p = 0.001), paclitaxel (90% vs 92%, p = 0.03), cyclophosphamide (91% vs 96%, p = 0.04)compared to the pCR group. Median absolute eosinophil count (AEC) was higher in pCR group compared to non-pCR group (140/μl vs 110/μl). Higher baseline AEC was associated with higher pCR rate on multivariate analysis (OR 4.54, CI 2.08 - 50.0, p = 0.02) after adjusting for confounders such as age, number of pembro cycles, RDI, race and comorbidities. No other variables were predictive of pCR in multivariate analyses. 48.3% pts experienced irAE of any grade and 38% grade 3+ irAE. The most common irAEs were hypothyroidism (21.3%), transaminitis (20%), rash (17.5%), colitis (12.5%), adrenal insufficiency (10%), pneumonitis (8.8%), and infusion reactions (8.8%). No significant difference in pCR rate (57% vs 62%) and incidence of irAEs (42% vs 50%) were noted between Black and White pts respectively. Conclusions: The pCR rate in our study (64.8%) was comparable to KEYNOTE 522 but there was higher incidence of irAEs (48.3%). Higher AEC at baseline was associated with improved pathologic response to chemoimmunotherapy. More real world studies are needed to confirm the high incidence of irAEs that was observed in our study.

Investigation of cardiotoxicity with concomitant use of anthracyclines and checkpoint inhibitors.

e24022 Background: Immune checkpoint inhibitors (ICI) have revolutionized cancer treatment and currently are the standard of care for early stage triple negative breast cancer in combination with anthracyclines (AC). It is known that both ICI and AC carry risk of cardiotoxicity. Studies have also shown that there is increased risk of cardiotoxicity with dual ICI. However no studies have evaluated the risk with concomitant use of ICI and AC. Here we investigated if there is increased cardiotoxicity risk with this combination regimen in a retrospective study. Methods: We did a retrospective analysis of patients with stage II and stage III triple negative breast cancer treated with combined AC and ICI at University of South Alabama Mitchell Cancer Institute Mobile, AL from January 2020 until June 2023. Data included demographics, cardiovascular (CV) risk factors and treatment. CV risk factors were detailed from 2022 ASCO guidelines. Echocardiograms were used to evaluate left ventricular ejection (LVEF). Therapy related cardiovascular toxicity was defined by ESC guidelines 2022 as any new decrease in LVEF to &lt; 40% or any decrease in LVEF &lt; 50% and 10 percentage points decrease from baseline. Adverse events (AE) and risk analysis were calculated. Results: Of the total 49 patients, all were female with a mean age of 53 years old (30-82). 55% of patients had less than 2 CV risk factors (n = 27) and 45% had more than 2 (n = 22). 84% completed all 4 cycles of neoadjuvant AC course without dose adjustment. The median number of cycles of Pembrolizumab was 12 with a range of 7 to 17 cycles including adjuvant Pembrolizumab. All patients had a baseline echo with LVEF &gt; 55%. Two patients (0.04%) developed cardiotoxicity. One patient had LVEF that decreased to EF 45-50% while on surveillance. Another patient developed myocarditis during treatment with EF 25-30% and died from cardiogenic shock. Both patients had 2 CV risk factors and were African American. Only 24% (n = 12) had surveillance echocardiograms completed one year post treatment. Conclusions: Our study results showed that cardiotoxicity risk was lower compared to that in the Keynote-522 trial. The outcomes are limited as a majority (76%) of the patients did not have surveillance echos completed. While the risk of cardiotoxicity with ICI and AC have been studied independently, there have been mouse models that showed that AC therapy may make heart vulnerable to toxicity from ICI therapy. To our knowledge, this is the first study to evaluate cardiotoxicity in patients who received concomitant AC and ICI treatment. Our study highlights the importance of prospective studies and long term follow up to monitor cardiotoxicity in these patients as early detection is key to prevent future morbidity. [Table: see text]

Phase I trial of chidamide, an oral HDAC inhibitor, in combination with oral etoposide in patients with refractory/recurrent neuroblastoma.

10034 Background: Chidamide, an oral subtype-selective histone deacetylase (HDAC) inhibitor, has been shown to be effective in adult patients with hematological tumors. However, there is no data on its safety and efficacy in pediatric cancer patients. Combination of HDAC inhibitors and etoposide have shown synergistic anti-tumor effects in preclinical studies of neuroblastoma. We conducted a phase I trial in pediatric patients with recurrent or refractory neuroblastoma to determine the maximum tolerable dose (MTD) of chidamide combined with oral etoposide treatment. Methods: Daily oral etoposide 35 mg/m2/dose was administered on days 1–21 in combination with escalating doses of chidamide (14 and 17 mg/m2/d) twice weekly in each 28-day cycle using the standard 3 + 3 design. Patients with response or stable disease after two cycles would maintain treatment until disease progression or unacceptable toxicity occurred. Chidamide pharmacokinetic testing was performed. Results: 31 patients were enrolled in this study. The median age was 7 years (range 3 – 18). 14 patients were included in the dose escalation phase (Ia), 17 patients in the expansion cohort (Ib). The MTD of chidamide was 14 mg/m2/d, with dose limiting neutropenia and thrombocytopenia observed at 17 mg/m2/d. Median number of cycles completed was 2.5 (range 1–11). A total of 19 patients (61.3%) experienced treatment-related grade 3/4 hematologic toxicity, and no grade 3/4 non-hematological toxicity was observed. No objective responses were seen. Conclusions: In children with refractory/recurrent neuroblastoma, chidamide is well-tolerated at 14 mg/m2/d twice weekly when combining with oral etoposide 35 mg/m2/d daily. Prolonged disease stability achieved in patients with minimal residual diseases deserves further investigation. Clinical trial information: NCT05338541 .

Adverse events of patients treated with antibody-drug conjugates in phase 1 clinical trials at the Royal Marsden Drug Development Unit from 2014 to 2024.

e15020 Background: Antibody-drug conjugates (ADCs) are designed to improve therapeutic indices of cytotoxic agents. Nevertheless, they may induce unexpected toxicities not observed with parent payloads. This study aimed to characterize the adverse events (AEs) seen in patients treated with ADCs in Phase 1 trials at The Royal Marsden Drug Development Unit (DDU). Methods: This is a retrospective cohort analysis of consecutive patients who received at least one dose of an ADC in a phase I trial from January 2014 to January 2024 at The Royal Marsden DDU. Descriptive statistics of patient characteristics, ADCs, and treatment-related AEs were performed. Univariate and multivariate logistic regression will be utilized to assess correlations among patient and ADC characteristics and adverse events. P values of &lt; 0.05 will be considered significant. Results: A total of 131 patients who participated in twelve ADC trials were included. The median age of participants was 63 years (range: 31-84) and 61% were females. Patients received a median of three prior lines of systemic treatment. The most common type of ADC target, antibody, linker and payload were receptor tyrosine kinase (51%), humanized IgG monoclonal antibody (69%), valine-citrulline (VC) cleavable linker (85%), and a tubulin-binding payload (59%), respectively. Most patients received an ADC dose of 1-3 mg/kg (76%) with each cycle given once every 3 weeks (64%). The median number of cycles was 3 with an average treatment duration of 63 days. Within the cohort, 89% of patients developed any grade AE and 17% experienced grade 3 or higher AEs. The major treatment-related AEs were fatigue (48%), nausea/vomiting (27%), ocular toxicity (26%), neuropathy (26%), skin rash (20%) and pneumonitis (8%). The median time to first onset of treatment-related adverse events were 37 days for ocular toxicity, 46 days for pneumonitis, and 54 days for neuropathy. ADC-related AEs led to treatment interruptions (51%), dose reductions (13%), and treatment discontinuations (28%). Two treatment-related grade 5 events occurred. The objective response rate was 18%, with 1 complete response and 22 partial responses. Conclusions: Despite being designed to minimize side effects, ADCs were associated with significant toxicities, including unexpected adverse events unrelated to target, antibodies or the payloads, limiting their therapeutic indices. Further analysis of the relationship between different components of the wide range of ADCs and AEs are warranted to better understand the potential mechanisms of ADC toxicity.