Sequential Test Research Articles

Effects of exercise or metformin on myokine concentrations in patients with breast and colorectal cancer: A phase II multi-centre factorial randomized trial.

Physical activity and metformin pharmacotherapy are associated with improved clinical outcomes in breast and colorectal cancer survivors. Myokines are cytokines secreted from skeletal muscle that may mediate these associations. This hypothesis-generating analysis used biospecimens collected from a multi-centre 2×2 factorial randomized design of 116 patients with stage I-III breast and colorectal cancer who were randomized to 12weeks of (1) aerobic exercise (moderate intensity titrated to 220min/week); (2) metformin (850mg daily for 2weeks and then titrated to 850mg twice per day); (3) aerobic exercise and metformin; or (4) control. Fourteen myokines were quantified using a multiplex panel. Myokine concentrations were log-transformed, and main effects analyses were conducted using linear mixed-effects regression models. The type I error rate was controlled with the Holm sequential testing procedure. Randomization to exercise increased leukaemia inhibitory factor (1.26pg/mL, 95% confidence interval [CI]: 0.69, 1.84; adjusted P=0.001) and interleukin-15 (2.23pg/mL, 95% CI: 0.87, 3.60; adjusted P=0.013) compared with randomization to no exercise. Randomization to metformin decreased apelin (-2.69pg/mL, 95% CI: -4.31, -1.07; adjusted P=0.014) and interleukin-15 (-1.74pg/mL, 95% CI: -2.79, -0.69; adjusted P=0.013) compared with randomization to no metformin. Metformin decreased myostatin, irisin, oncostatin M, fibroblast growth factor 21 and osteocrin; however, these changes were not statistically significant after correction for multiple comparisons. This pilot study demonstrates that randomization to exercise and metformin elicit unique effects on myokine concentrations in cancer patients. This hypothesis-generating observation warrants further basic, translational and clinical investigation and replication.

The Usefulness of the Breast Density Assessment Application Used by Breast Radiologists.

Breast density determined by breast radiologists and also automatically estimated by applications has been widely investigated. However, no study has yet clarified whether the use of these applications by breast radiologists improves reading efficacy. Therefore, this study aimed to assess the usefulness of applications when used by breast radiologists. A Breast Density Assessmentapplication (App) developed by Konica Minolta, Inc. (Tokyo, Japan) was used. Independent and sequential tests were conducted to assess the usefulness of the concurrent- and second-look modes. Fifty and 100 cases were evaluated using sequential and independent tests, respectively. Each dataset was configured based on the evaluation by an expert breast radiologist who developed the Japanese guidelines for breast density. Nine breast radiologists evaluated the mammary gland content ratio and breast density; the inter-observer and expert-to-observer variability were calculated. The time required to complete the experiments was also recorded. The inter-observer variability was significant with the App, as revealed by the independent test. The use of the App significantly improved the agreement between the responses of the observers for the mammary gland content ratio and those of the expert by 6.6% and led to a reduction of 186.9 seconds in the average time required by the observers to evaluate 100 cases. However, the results of the sequential test did not suggest the effectiveness of the App. These findings suggest that the concurrent use of the App improves reading efficiency.

Colombian consensus for the molecular diagnosis of endometrial cancer

Objective: The Cancer Genome Atlas research program (TCGA) developed the molecular classification for endometrial cancer with prognostic and therapeutic utility, which was replaced by the ProMisE (Proactive Molecular Risk Classifier for Endometrial Cancer) classification by consensus and international guidelines due to its high cost. This article aims to present national recommendations from an expert consensus that allows unification and implementation of the molecular classification for women with endometrial cancer nationwide, with a rational use of resources and technology. Methods: Consensus of 36 experts in clinical oncology, oncological gynecology, pathology, and genetics, with clinical practice in the national territory. The leader group performed a literature review and structuring of questions rated 1 to 9 points. A modified nominal group technique was used. There was a face-to-face meeting with master presentations, deliberative dialogue, and Google Forms (Google LLC, Mountain View, CA, USA) questionnaire voting with analysis and discussion of responses. The non-consensual responses led to a second round of voting. The final manuscript was finally prepared and revised. Results: Seven recommendations were formulated integrating the panelist responses based on evidence, but adjusted to the Colombian context and reality. Recommendation 1. The molecular classification is recommended in all the endometrial cancers using the immunohistochemistry markers as subrogated results from the molecular profile initially proposed in the TCGA classification. Recommendation 2. The sequential test strategy is recommended, starting with the immunohistochemistry markers (p53, MLH1, MSH 2, MSH6, PMS2) simultaneously in all the patients, defining to request POLE (DNA polymerase epsilon) (if available) according to the risk classification based on the surgical piece. Recommendation 3. It is recommended, that the gynecologist oncologist should be the one to request the POLE (if available) according to the final pathology report. This test must be requested for all endometrial cancers stage I-II, except in low risk (stage IA low grade endometrioid histology without linfovascular invasion normal p53) and, stages III-IV without residual disease, without affecting the request of subrogated immunohistochemistry molecular markers upon histology. The consensus proposes that the POLE is requested after the immunohistochemistry and according to the categories in the risk classification established by the 2020 ESGO/ESTRO/ESP guidelines. Recommendation 4. It is recommended to perform immunohistochemistry for hormonal receptors for all women with endometrial cancer and the HER2 in patients with p53abn, simultaneously with the others immunohistochemistry markers. Recommendation 5. It is recommended to perform the immunohistochemistry markers (p53, MLH1, MSH2, MSH6 y PMS2) in an initial endometrial biopsy or curettage when the specimen is adequate and available. In case the initial immunohistochemistry is inconclusive, or there are histological discrepancies between the initial and definitive pathology, it is recommended to repeat the molecular profile in the surgical pathology. The immunohistochemistry markers must be reported in the pathology report according to the CAP (College of American Pathologists) recommendations, independently of the type of sample. Recommendation 6. It is recommended to perform MLH1 promoter methylation testing in patients who exhibit loss of expression of MLH1 in immunohistochemistry whether it is accompanied or not with loss of expression of PMS2. All the patients with deficient MMR (mismatch repair), should be sent for genetic counseling to rule out Lynch syndrome. Recommendation 7. It is recommended to consider the molecular classification in addition to the classical histopathological criteria when making adjuvant judgments, as incorporated by the classification of prognostic groups of the 2020 ESGO/ESTRO/ESP guidelines. Conclusions: It is necessary to implement the molecular classification of endometrial cancer in clinical practice in accordance to the Colombian context, due to its prognostic and probably predictive value. This will enable the characterization of the Colombian population in order to offer individualized guided treatments. This is an academic and nonregulatory document.

Disease characterization in cloned foals in Colombia, the effect of placental pathologies on the success and survival of cloned foalsfrom two different cell lines

Cloned foals born in the different cloning programs in the USA, Argentina, and recently in Colombia have experienced several pathological entities during their pregnancy and neonatal period. These entities include abortions, stillbirths, hypoxic-ischemic encephalopathy, large umbilical remanent, and angular deformity on the fore limb. The objectives of this study were to determine whether cloned foals suffer similar diseases and have the same mortality rate as noncloned ones and the differences between cloned foals from two different cell lines (fibroblastic and bone marrow cells) and, to establish whether mares carrying cloned foals from different cell lines have ultrasonographic, paraclinical, and hormonal profile parameters equal to traditional pregnancies and to determine whether there are differences between the cloned foals from the two different cell lines. In the analysis of the continuous variables, significant mean differences were established in the three groups of mares in PCV, hemoglobin, erythrocyte count, MCV, MCH, serum proteins and globulins, and in lymphocyte counts p<0.05. A risk analysis was made for morbidity and mortality associated with the cell origin of the clone and its pregnancy using chi-square sequential tests and logistic regression, and it was considered statistically significant at p< 0.05. A principal component analysis of the paraclinical findings of the mares with the outcome of the foal and the paraclinical parameters of the foals divided by the origin of gestation was performed to evaluate the components of the response variable and their dynamics. Thirty-four pregnancies of clones of fibroblastic origin, 26 of clones of bone marrow origin, and 32 of non-clones were studied. The presentation of placental diseases compatible with placentitis was significantly more frequent (p= 0.026) in mares with cloned foals from fibroblastic cell lines. Neonatal sepsis was determined to be the most frequent disease and was diagnosed more commonly in foals of fibroblastic cell origin—an increase in the risk (OR 37) (p=0.0006). The risk of death was positive and significant with the fibroblast cell line foals (OR: 9.1. P<0.01) compared to the cloned foals of marrow cell origin and non-cloned foals. The risk of death can be predicted in the neonatal period, and some indicators found in this study, such as signs related to placentitis, are associated with increased neonatal mortality and are more frequent in foals of fibroblastic cell origin.

Evaluating tumor inflammation and PD-L1 expression in sequential biopsies of real-world primary and metastatic breast cancer.

e13035 Background: Biomarkers for measuring immunogenicity of tumors such as PD-L1 immunohistochemistry (IHC), tumor mutational burden (TMB), and immune gene expression have been studied in many cancers including breast cancer. How these biomarkers change over time and how their detection differs with sequential testing in the real-world clinical setting has been studied to a lesser extent but is an important consideration for optimal patient care. Methods: We performed an analysis of 30 patients with primary and metastatic breast cancer sequentially tested by comprehensive genomic and immune profiling (CGIP) at two time points during routine clinical care to observe temporal changes in immunotherapy markers and immune gene expression. Genomic variants and TMB were assessed with DNA-seq, while immune gene expression was assessed with RNA-seq. PD-L1 expression was determined using IHC. Immune gene expression signatures characterizing the tumor microenvironment (TME) were calculated, including tumor inflammation (TIGS), cell proliferation (CP), and cancer testis antigen burden (CTAB). Differences between sequential tests were tested for using linear mixed effect models. Results: Time between biopsies for sequential tests ranged from the same day to 4.5 years, with 40% of specimens being collected within 30 days of the first. Sequential specimens were collected from breast (27%), non-breast (40%), or a mix of breast and non-breast (33%) tissue. Non-breast tissue types included sites from lymph node (18%), GI tract (15%), skin (10%), thorax (7%), and musculoskeletal sites (7%). Overall, TMB, PD-L1 IHC, and gene expression signatures were relatively stable between sequential tests (P > 0.05); however, trends were noted for second tests detecting lower tumor inflammation (TIGS score) and PD-L1 IHC (P = 0.1). Further, second tests detected significantly lower levels of tumor inflammation when both were performed on non-breast tissue (P = 0.04), but not when performed on all breast (P = 0.7) or a mix of breast and non-breast (P = 0.6) tissues. An opposite trend was noted for PD-L1 where second tests detected lower levels of PD-L1 IHC when both tests were performed on breast tissue (P = 0.1), but not when performed on all non-breast (P = 0.4) or a mix of breast and non-breast (P = 0.5) tissue. Tissue-dependent trends were still present even when excluding lymph node specimens (P = 0.1). Conclusions: Changes in immunotherapy markers and immune gene expression signatures, on average, remained relatively stable over time, except for tumor inflammation and PD-L1 IHC when sequentially testing all non-breast or breast tissue, respectively. These observations highlight the utility of clinical CGIP testing in revealing temporal changes of the TME, which may help inform clinical trial or treatment strategies occurring over time for primary and metastatic breast cancer.

Spectrum of Resistance Mechanisms to ALK TKIs in NSCLC: Largest Single-Center Experience from India

Abstract Introduction Anaplastic lymphoma kinase (ALK) rearranged non-small cell lung carcinoma (NSCLC) has emerged as a distinct entity with growing number of potent ALK tyrosine kinase inhibitors (TKIs). Despite showing durable responses and promising survival rates, resistance to these ensue. This is the largest series of repeat biopsies from patients of ALK-positive NSCLC progressing on ALK-directed therapy from this part of the world. Using a combinatorial approach of genomics and histology, we describe the spectrum of various resistance mechanisms encountered. Methods This is a cross-sectional study recruiting ALK-positive NSCLC cases who have progressed on any line ALK TKI and have undergone repeated biopsies followed by genomic sequencing by next-generation sequencing (NGS). Results Thirty-two ALK-positive NSCLC patients progressed on TKI were enrolled. Median age was 53 years (range: 36–75 years) with a male predilection (male:female 1.3:1). Twenty-seven (84.4%) cases harbored an additional resistance mechanism. Eighteen of these harbored an on-target ALK alteration, with L1196M gatekeeper mutation being the most common, in 11 cases, and G1202 alteration in 3 cases. In 9 cases an off-target alteration was detected, the most frequent being TP53 mutation in 8 cases, KRAS mutation in 4 cases and MET amplification in 3 cases. Four patients underwent sequential NGS testing and allele frequency changes in ALK fusion and resistance mechanisms were demonstrated. Sixteen patients have been offered lorlatinib therapy, the median progression-free survival of which has not yet been reached. Conclusion This is the largest series depicting ALK resistance mechanisms from a single center to date. The SPACEWALK study which demonstrated ALK TKI resistance mechanisms using plasma-based genotyping was a multicentric study. The spectrum encountered in this study is distinct from the rest of the world, thus highlighting heterogeneity within ALK-rearranged tumors. Comprehensive clinical evaluation at disease progression coupled with NGS-based genotyping will pave the way for lucid understanding of disease biology, thus aiding in the institution of optimal therapy.

Identifying pleiotropic genes via the composite test amidst the complexity of polygenic traits.

Identifying the causal relationship between genotype and phenotype is essential to expanding our understanding of the gene regulatory network spanning the molecular level to perceptible traits. A pleiotropic gene can act as a central hub in the network, influencing multiple outcomes. Identifying such a gene involves testing under a composite null hypothesis where the gene is associated with, at most, one trait. Traditional methods such as meta-analyses of top-hit $P$-values and sequential testing of multiple traits have been proposed, but these methods fail to consider the background of genome-wide signals. Since Huang's composite test produces uniformly distributed $P$-values for genome-wide variants under the composite null, we propose a gene-level pleiotropy test that entails combining the aforementioned method with the aggregated Cauchy association test. A polygenic trait involves multiple genes with different functions to co-regulate mechanisms. We show that polygenicity should be considered when identifying pleiotropic genes; otherwise, the associations polygenic traits initiate will give rise to false positives. In this study, we constructed gene-trait functional modules using the results of the proposed pleiotropy tests. Our analysis suite was implemented as an R package PGCtest. We demonstrated the proposed method with an application study of the Taiwan Biobank database and identified functional modules comprising specific genes and their co-regulated traits.

A method for detecting faults in integrated navigation system based on improved SPRT adaptive filtering

GNSS measurement noise faults can easily cause a drop or even divergence in the filter accuracy of integrated navigation system. Therefore, real-time fault detection and processing are necessary. With the aim of the defects of residual Chi-square test and sequential probability ratio test (SPRT) in detecting measurement noise faults, an adaptive filtering algorithm based on improved SPRT detection is proposed. On the one hand, the influence of the current time innovation on the statistics is strengthened by the method of fading weighting. On the other hand, the measurement update equation of the adaptive filter is constructed by calculating the weight factor of the statistics in real-time, which improves the accuracy and robustness of the state estimation. Simulation experiments show that the proposed algorithm is more sensitive and non-missing compared to the residual Chi-square test in the case of large value abrupt faults in the measurement noise. The proposed algorithm reduces the fault detection delay time by about 65.5% compared to SPRT in the case of slow change faults in measurement noise. In the case of slow change faults with small values, the proposed algorithm reduces the missing detection rate by 40% compared to the residual Chi-square test. In addition, the proposed algorithm is compared with the robust Kalman filter based on the residual Chi-square and Sage-Husa adaptive filtering. The results show that the proposed algorithm has higher navigation accuracy when the system has slow change faults.

GH provocative tests stimulate the growth in children with idiopathic short stature

ContextGrowth hormone (GH) deficiency in a child with short stature is diagnosed by GH secretion provocative tests. When the test response is considered adequate, the short stature is considered idiopathic (ISS).ObjectiveTo determine the effect of GH provocative tests on the growth rate in children with idiopathic short stature.DesignChildren with short stature with a normal response to at least one GH provocative test were enrolled. Height and growth velocity were measured prior to and after stimulus tests during the follow-up.MethodsHeight, mid-parental height, body weight, and body mass index were measured. The height and growth rate were converted to percentiles and Standard Deviation Scores (SDS) using reference ranges standardized by age and sex. GH provocative tests employed arginine or clonidine as secretagogues.ResultsFourty-six children of both genders were enrolled. In thirty-six children, height was measured at the time of testing and on an average time prior to and after the tests of 210 days and 180 days respectively. After testing the children displayed a 3.4-fold increase in their estimated 90-day growth rate. The median (inter-quartile range, IQR) 90 days growth of children pre-and post-tests were 0.7 (0.2–1.0) cm and 2.4 (1.7–3.1) cm respectively with a mean 3,4-fold increase (p < 0.0001). The median (IQR) 90 days growth of children pre- and post-tests calculated as standard deviation scores (SDS) were −4.0 (−5.4–−2.1) SDS and 0.1 (−1.9–1.4) SDS respectively (p < 0.0001). Ten children with ISS were observed for about 5 months before the GH provocative tests. A small increase in the growth rate was seen only in 2 out of 10 children before testing while it increased in all of them after the tests. The difference in the median growth rate at the first and the second observation was not significant (p = 0.219).ConclusionsTwo sequential somatotropic axis provocative tests increase the growth rate in children with idiopathic short stature. The duration of this effect is yet to be determined.

Timed up and go demonstrates strong interrater agreement and criterion validity as a functional test in geriatric dogs.

To measure interobserver agreement for 4 functional tasks and their summed geriatric functional score (GFS) and correlate tasks and GFS with client-specific outcome measurements (CSOMs): Canine Brief Pain Inventory (CBPI) pain severity, CBPI pain interference, and Liverpool Osteoarthritis in Dogs. 89 geriatric dogs were recruited between April and September 2023 from staff, friends, and clients of the Cornell University College of Veterinary Medicine with a median age of 11.0 years and weight of 26.4 kg. Dogs underwent 4 sequential functional tests: timed up and go (TUG), cavallettis, figure 8s, and down to stands. Two observers independently scored each dog. The GFS was calculated based on the summed scores of the individual tests. Additional information collected included signalment, weight, measurements reflecting the comorbidities of aging (body condition score and muscle condition score), and CSOMs. Strong interrater agreement was found for all functional tests. The TUG in seconds (sTUG) and figure 8s demonstrated significant (P < .05) moderate to strong correlations to all CSOMs. The GFS showed similar significant correlations with all CSOMs except CBPI pain severity; however, when correlating individual tests to CSOMs, only figure 8s and TUG were significantly contributing to GFS results. Receiver operating characteristic curve analysis defined highly functional dogs as those completing the sTUG in under 3.83 seconds. The sTUG represented the best test for geriatric function given it was objective, reliable, correlated well to CSOMs, and could help identify highly functioning dogs. The sTUG appears to be the first practical and reliable functional test of canine geriatric mobility.

A rank-based sequential test of independence

Summary We consider the problem of independence testing for two univariate random variables in a sequential setting. By leveraging recent developments on safe, anytime-valid inference, we propose a test with time-uniform Type-I error control and derive explicit bounds on the finite-sample performance of the test. We demonstrate the empirical performance of the procedure in comparison to existing sequential and nonsequential independence tests. Furthermore, since the proposed test is distribution-free under the null hypothesis, we empirically simulate the gap due to Ville’s inequality, the supermartingale analogue of Markov’s inequality, that is commonly applied to control Type-I error in anytime-valid inference, and apply this to construct a truncated sequential test.

Detection of Emergent Anomalous Structure in Functional Data

Motivated by an example arising from digital networks, we propose a novel approach for detecting the emergence of anomalies in functional data. In contrast to classical functional data approaches, which detect anomalies in completely observed curves, the proposed approach seeks to identify anomalies sequentially as each point on the curve is received. The new method, the Functional Anomaly Sequential Test (FAST), captures the common profile of the curves using Principal Differential Analysis and uses a form of CUSUM test to monitor a new functional observation as it emerges. Various theoretical properties of the procedure are derived. The performance of FAST is then assessed on both simulated and telecommunications data.

Magnetite particles accelerate methanogenic degradation of highly concentrated acetic acid in anaerobic digestion process

The anaerobic digestion (AD) process has become significant for its capability to convert organic wastewater into biogas, a valuable energy source. Excessive acetic acid accumulation in the anaerobic digester can inhibit methanogens, ultimately leading to the deterioration of process performance. Herein, the effect of magnetite particles (MP) as an enhancer on the methanogenic degradation of highly-concentrated acetate (6 g COD/L) was examined through long-term sequential AD batch tests. Bioreactors with (AM) and without (AO) MP were compared. AO experienced inhibition and its methane production rate (qm) converged to 0.45 L CH4/g VSS/d after 10 sequential batches (AO10, the 10th batch in a series of the sequential batch tests conducted using bioreactors without MP addition). In contrast, AM achieved 3–425% higher qm through the sequential batches, indicating that MP could counteract the inhibition caused by the highly-concentrated acetate. MP addition to inhibited bioreactors (AO10) successfully restored them, achieving qm of 1.53 L CH4/g VSS/d, 3.4 times increase from AO10 after 8 days lag time, validating its potential as a recovery strategy for inhibited digesters with acetate accumulation. AM exhibited higher microbial populations (1.8–3.8 times) and intracellular activity (9.3 times) compared to AO. MP enriched Methanosaeta, Peptoclostridium, Paraclostridium, OPB41, and genes related to direct interspecies electron transfer and acetate oxidation, potentially driving the improvement of qm through MP-mediated methanogenesis. These findings demonstrated the potential of MP supplementation as an effective strategy to accelerate acetate-utilizing methanogenesis and restore an inhibited anaerobic digester with high acetate accumulation.

Economic modelling and optimisation of SPRT-based quality control schemes for individual observations

In many industrial processes, it may not be practical to obtain sample sizes larger than one due to various reasons. As a result, practitioners must rely on control charts based on individual observations for statistical process monitoring and control. The sequential probability ratio test (SPRT) chart is an appropriate solution for such situations. Existing literature predominantly delves into the statistical aspects of designing or optimising an SPRT chart, neglecting the economic and associated design aspects. However, past experience suggests that statistical design may not always be optimal from an economic perspective. This paper aims to bridge this research gap by proposing a two-stage Markov chain approach to develop an economic model for the optimal design of the SPRT chart with individual observations. Following the principles of economic-statistical designs, optimal parameters are determined by solving a mixed-integer non-linear programming problem that minimises the long-run cost per item while ensuring compliance with practical constraints. Through an extensive study, we find that the economic performance of the SPRT chart surpasses that of competing individual control charts in many cases. This indicates that the economic-statistical design of the SPRT chart can yield significant economic benefits while maintaining desirable statistical properties. Moreover, enhancements have been introduced to refine the optimal design of the SPRT chart, retaining excellent overall performance across a wide range of shifts. Finally, we provide two industrial examples to illustrate the effectiveness of the proposed SPRT chart.

Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India

BackgroundCurrent clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India.Results903 smMIPs were designed to target exon and exon–intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood.ConclusionWe developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.

Adaptive two-stage seamless sequential design for clinical trials

ABSTRACT We propose an adaptive sequential testing procedure for the selection and testing of multiple treatment options, such as dose/regimen, different drugs, sub-populations, endpoints, or a mixture of them in a seamlessly combined phase II/III trial. The selection is to be made at the end of phase 2 stage. Unlike in many of the published literature, the selection rule is not required to be to “select the best”, and does not need to be pre-specified, which provides flexibility and allows the trial investigators to use any efficacy and safety information/criteria, or surrogate or intermediate endpoint to make the selection. Sample size and power calculations are provided. The calculations have been confirmed to be accurate by simulations. Interim analysis can be performed after the selection, sample size can be modified if the observed efficacy deviates from the assumed. Inference after the trial, including p-value, median unbiased point estimate and confidence intervals, are provided. By applying a dominance theorem, the procedure can be applied to normal, binary, Poisson, negative binomial distributed endpoints and time-to-event endpoints, and a mixture of these distributions (in trials involving endpoint selection).

Sequential fusion‐based defense strategy against sophisticated Byzantine attacks in cognitive IoT networks

Sequential fusion‐based defense strategy against sophisticated Byzantine attacks in cognitive <scp>IoT</scp> networks

Abstract PO4-14-10: Circulating Tumor DNA as a Biomarker for ADCs in Metastatic Breast Cancer

Abstract Background: Breast cancer is a complex disease characterized by heterogeneity, and the analysis of circulating tumor DNA (ctDNA) holds promise for capturing this heterogeneity. Recently, ctDNA testing has been employed in clinical practice to guide targeted therapies for metastatic breast cancer, particularly in cases of hormone receptor-positive disease with mutations in PIK3CA and ESR1. This approach becomes necessary when traditional tumor biopsies are inadequate for next-generation sequencing (NGS) testing or fail to capture the full extent of the cancer's heterogeneity. Moreover, the utilization of antibody-drug conjugates (ADC) in addressing tumor heterogeneity continues to expand. However, there has been no biomarker, outside of HER2 protein expression, to predict ADC response. In this project, we test the hypothesis that ctDNA can be utilized as a biomarker to predict response to novel therapies such as ADCs. Methods: We analyzed a subset of patients from the Dallas Metastatic Breast Cancer Study comprised of patients with metastatic breast cancer (n= 109) who underwent ctDNA testing using the Tempus xF liquid biopsy ctDNA sequencing panel. This panel detects 105-genes that are known oncogenic drivers and resistance mutations. The data was collected from a single academic medical center between the initial year of ctDNA collection in 2019 and 2023. Results: Among these patients, 85 (77.9%) had hormone receptor-positive disease, 13 (11.9%) had triple-negative breast cancer, and 11 (10.0%) had HER2-positive disease (including 3 (2.75%) patients with triple-positive disease). Only 22 of these patients had tissue biopsies that underwent NGS testing. Analysis of all patients revealed that the most common gene alteration was PIK3CA, which was identified in 70 patients. Specifically, the most frequently observed alteration was PIK3CA p.545K, found in 25 patients. Table 1 further details the frequency of each gene in this subset of patients. Among the patients, 34 out of 109 (31%) received an ADC, while only 8 out of 109 (7%) received immunotherapy. Patients with CDKN2A achieved the longest progression-free survival (PFS) on an ADC, with a median PFS of 7 months, whereas patients carrying mutations in TP53, PIK3R1, PIK3CA, PTEN, NF1, BRAF, RHOA, FGFR4, KRAS, TERT, GATA3, HNF1A, FB1, STOP had median PFSs of 2 months or less. Table 2 provides additional information on the response of patients with specific mutations to ADCs. Notably, only one patient received sequential ctDNA testing, and in that case, there was a gain of TP53 p.N239S following sacituzumab govitecan administration compared to the baseline ctDNA test, followed by a gain of PIK3CA p.P449_L455del after trastuzumab deruxtecan administration. Conclusions: As we observe changes in subtypes following treatment progression, researchers are actively seeking biomarkers to better characterize real-time changes in tumor biology that can predict response and resistance to treatments. Further studies are needed to identify additional genes present in ctDNA that can provide mechanistic insights into why certain patients respond favorably to ADCs while others do not. We are currently enrolling patients for a prospective study that aims to assess baseline ctDNA levels and monitor changes in variant allele frequency following treatment with ADCs and immunotherapy. Table 2 Median PFS on ADC by Gene Citation Format: Hannah Chang, Isabela Anawate, Alyssa Low, Shao-Po Huang, Julia Maues, Christine Hodgdon, Isaac Chan. Circulating Tumor DNA as a Biomarker for ADCs in Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-10.

Abstract PO2-06-04: Prospective study on eribulin efficacy in advanced and metastatic breast cancer: changes in TGF-β compared to other standard chemotherapy agents (KBCSG-TR 2018, POTENTIAL)

Abstract Introduction Eribulin (E) has been demonstrated to improve overall survival (OS) compared to standard chemotherapies in pivotal phase III clinical trials (studies 301 and 305), although there was no difference in progression-free survival. These findings suggest that E might have a mechanism for OS improvement different from the common anti-tumor effect. Several studies reported that E inhibits epithelial-mesenchymal transition and the suppression of TGF-β plays a central role. Data on the relationship between the E-induced serial change in TGF-β and the improvement in OS remains insufficient. Therefore, we conducted this prospective observational study of patients treated with E while undergoing sequential TGF-β testing. This study also enrolled patients who received chemotherapy other than E as a control. Methods Patients with HER2-negative recurrent/metastatic breast cancer (MBC) were prospectively enrolled from 23 breast cancer centers in Japan, if they had not previously used E, had received two or fewer prior chemotherapy regimens, and were scheduled to start either E, capecitabine, S-1 or paclitaxel (± bevacizumab) between September 2020 and February 2022. The target sample sizes were 150 and 50 patients scheduled to receive E (Cohort E) and other drugs (Cohort Others), respectively. We collected blood samples for TGF-β testing at baseline, at two or three weeks (week 2/3), and at four or five weeks (week 4/5) from the beginning. The observation period was until February 2023. The primary endpoint was to evaluate the relationship between changes in TGF-β and clinical response, including OS and time to treatment failure (TTF). Results A total of 202 of the 203 enrolled patients were included in the analysis (1 patient declined consent). The median age was 60.0 (interquartile range, 52.0-69.0) years and ECOG performance status was 0 or 1 in all patients. Among 152 patients in Cohort E and 50 patients in Cohort Others, 37 patients (24.3%) and 12 patients (24.0%) had hormonal receptor-negative breast cancer, and 29 patients (19.1%) and 30 patients (60.0%) had no prior chemotherapy for MBC, respectively. Visceral metastasis totaled 115 (75.7%) in Cohort E and 46 (92.0%) in Cohort Others. In OS analysis of 199 patients, the median OS was 24.5 months (95% CI, 17.3-NA) for no prior chemotherapy, and 17.7 months for one or two prior chemotherapy (median follow-up 14.5 months). In Cohort E and Cohort Others, 139 and 45 patients, respectively, had paired samples for TGF-β testing at baseline and week 2/3. The proportion of patients with a percent change at week 2/3 from baseline in TGF-β (ΔTGF-β) of less than zero (decreased TGF-β) was 46.8% in Cohort E and 33.3% in Cohort Others, indicating a 13.4% (-2.6% – 29.5%) higher trend in Cohort E. Based on the time-dependent receiver operating characteristic (ROC) curves at 6 months for TTF, the threshold of ΔTGF-β was determined to be 27%. For the low ΔTGF-β group (&amp;lt; 27%) and the high ΔTGF-β group (≥27%), OS rates at median follow-up (14.5 months) were 70.6% and 54.3% (p=0.085) in Cohort E and 68.9% and 58.2% (p=0.585) in Cohort Others, respectively, suggesting a relationship between low ΔTGF-β and a favorable prognosis only in Cohort E. Conclusions The current study showed the trend in the higher frequency of decreased TGF-β, as well as the important relationship between decreased TGF-β and a favorable prognosis in patients treated with E compared with those receiving other chemotherapies. As the next step, further biomarker analyses including cytokines and chemokines, and immunological analyses are planned. Citation Format: Takahiro Nakayama, Tersuhiro Yoshinami, Fumie Fujisawa, Minako Nishio, Takashi Yamanaka, Toshinari Yamashita, Chiya Oshiro, Ayaka Izui, Nobumoto Tomioka, Hideki Maeda, Masafumi Shimoda, Kenzo Shimazu, Michiko Tsuneizumi, Ryoichi Matsunuma, Hiroko Bando, Aya Ueda, Hiroyuki Yasojima, Kumiko Okada, Kenichi Inoue, Yuichiro Kai, Katsuhide Yoshidome, Hidetoshi Kawaguchi, Masayuki Nagahashi, Kazuteru Oshima, Shinichiro Kashiwagi, Tsutomu Iwasa, Kanae Taruno, Shigeru Tsuyuki, Fumine Tsukamoto, Takashi Morimoto, Nobuyoshi Kittaka, Toru Higuchi, Yoichi Naito, Ryotaro Saita, Hiroyoshi Nishikawa, Daisuke Sugiyama, Yasuo Miyoshi, Yohei Uchida, Tomomi Yamada, Norikazu Masuda. Prospective study on eribulin efficacy in advanced and metastatic breast cancer: changes in TGF-β compared to other standard chemotherapy agents (KBCSG-TR 2018, POTENTIAL) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-04.

Trend Behavior of Malaysia Consumer Price Index: Evidence from National Database (2003–2022)

The Consumer Price Index (CPI) is a general indicator used to measure price changes over time. The Malaysia CPI is published using a base year of 2010. This study aimed to identify the significant trend behavior in the Malaysia CPI series for the period 2003–2022. The main question of the paper is whether there exists any difference in trends between the main and overall CPI variables? If so, is the difference significant? If so, how strong or weak is the magnitude of its trend? This is analyzed empirically through five statistical analysis methods involving the serial correlation analysis, Mann–Kendall test, Mann–Kendall sequential test, Sen’s-T test, and Sen’s estimator. Overall, we conclude that there is a significant upward trend for 11 of the 13 variables, while two variables, which are Transportation and Communication, showed no significant monotonic trend. The results of this study provide insight into a better understanding of the behavioral trends of the CPI in Malaysia. This study can help policymakers to understand the importance of increasing expenditure into certain sectors in order to have better production and with this implementation, the trend of inflation rate can be better understood.