bluuebunny/crossref_metadata_2025 huggingface dataset:
Isoniazid preventive therapy completion in children under 5 years old who are contacts of tuberculosis cases in Lima, Peru: study protocol for an open-label, cluster-randomized superiority trial
Authors: Otero L. , Zetola N. , Campos M. , Zunt J. , Bayer A. , Curisinche M. , Ochoa T. , Reyes M. , Vega V. , Van der Stuyft P. , Sterling TR.
Published: January 2023

Background

Children < 5 years old in contact with TB cases are at high risk for developing severe and fatal forms of TB. Contact investigation, BCG vaccination, and isoniazid preventive therapy (IPT) are the most effective strategies to prevent TB among children. However, the implementation of IPT faces challenges at several stages of the cascade of care of TB infection among children, particularly those less than 5 years old. In Peru, a large proportion of children do not complete IPT, which highlights the need to design effective interventions that enhance preventive therapy adherence and completion. Although the body of evidence for such interventions has grown, interventions in medium TB incidence settings are lacking. This study aims to test the effectiveness, acceptability, and feasibility of an intervention package to increase information and motivation to complete IPT among children < 5 who have been prescribed IPT.

Methods

An open-label, cluster-randomized superiority trial will be conducted in two districts in South Lima, Peru. Thirty health facilities will be randomized as clusters, 10 to the intervention and 20 to control (standard of care). We aim to recruit 10 children from different households in each cluster. Participants will be caretakers of children aged < 5 years old who initiated IPT. The intervention consists of educational material, and short message services (SMS) reminders and motivators. The primary outcomes will be the proportion of children who picked up > 90% of the 24 weeks of IPT (22 pick-ups) and the proportion of children who picked up the 24 weeks of IPT. The standard of care is a weekly pick-up with monthly check-ups in a health facility. Feasibility and acceptability of the intervention will be assessed through an interview with the caretaker.

Discussion

Unfavorable outcomes of TB in young children, high effectiveness of IPT, and low rates of IPT completion highlight the need to enhance adherence and completion of IPT among children < 5 years old. Testing of a context-adapted intervention is needed to improve IPT completion rates and therefore TB prevention in young children.

Trial registration

ClinicalTrials.gov NCT03881228. Registered on March 19, 2019.
Temporal transcriptomic changes in microRNAs involved in the host immune response and metabolism during Neospora caninum infection
Authors: Chen Jin-Ming , Zhao Shan-Shan , Tao De-Liang , Li Jing-Yu , Yang Xin , Fan Ying-Ying , Song Jun-Ke , Liu Qun , Zhao Guang-Hui
Published: January 2023

Background

Neospora caninuminfection is a major cause of abortion in cattle, which results in serious economic losses to the cattle industry. However, there are no effective drugs or vaccines for the control ofN. caninuminfections. There is increasing evidence that microRNAs (miRNAs) are involved in many physiological and pathological processes, and dysregulated expression of host miRNAs and the biological implications of this have been reported for infections by various protozoan parasites. However, to our knowledge, there is presently no published information on host miRNA expression duringN. caninuminfection.

Methods

The expression profiles of miRNAs were investigated by RNA sequencing (RNA-seq) in caprine endometrial epithelial cells (EECs) infected withN. caninumat 24 h post infection (pi) and 48 hpi, and the functions of differentially expressed (DE) miRNAs were predicted by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses. The transcriptome data were validated by using quantitative real-time polymerase chain reaction. One of the upregulated DEmiRNAs, namely chi-miR-146a, was selected to study the effect of DEmiRNAs on the propagation ofN. caninumtachyzoites in caprine EECs.

Results

RNA-seq showed 18 (17 up- and one downregulated) and 79 (54 up- and 25 downregulated) DEmiRNAs at 24 hpi and 48 hpi, respectively. Quantitative real-time polymerase chain reaction analysis of 13 randomly selected DEmiRNAs (10 up- and three downregulated miRNAs) confirmed the validity of the RNA-seq data. A total of 7835 messenger RNAs were predicted to be potential targets for 66 DEmiRNAs, and GO and KEGG enrichment analysis of these predicted targets revealed that DEmiRNAs altered byN. caninuminfection may be involved in host immune responses (e.g. Fc gamma R-mediated phagocytosis, Toll-like receptor signaling pathway, tumor necrosis factor signaling pathway, transforming growth factor-β signaling pathway, mitogen-activated protein kinase signaling pathway) and metabolic pathways (e.g. lysine degradation, insulin signaling pathway, AMP-activated protein kinase signaling pathway, Rap1 signaling pathway, calcium signaling pathway). Upregulated chi-miR-146a was found to promoteN. caninumpropagation in caprine EECs.

Conclusions

This is, to our knowledge, the first report on the expression profiles of host miRNAs during infection withN. caninum, and shows that chi-miR-146a may promoteN. caninumpropagation in host cells. The novel findings of the present study should help to elucidate the interactions between host cells andN. caninum.

Graphical Abstract
Phthalates impact on the epigenetic factors contributed specifically by the father at fertilization
Authors: Swanson G. M. , Nassan F. L. , Ford J. B. , Hauser R. , Pilsner J. R. , Krawetz S. A.
Published: January 2023

Background

Preconception exposure to phthalates such as the anti-androgenic dibutyl-phthalate (DBP) impacts both male and female reproduction, yet how this occurs largely remains unknown. Previously we defined a series of RNAs expressly provided by sperm at fertilization and separately, and in parallel, those that responded to high DBP exposure. Utilizing both populations of RNAs, we now begin to unravel the impact of high-DBP exposure on those RNAs specifically delivered by the father.

Results

Enrichment of RNAs altered by DBP exposure within the Molecular Signature Database highlighted cellular stress, cell cycle, apoptosis, DNA damage response, and gene regulation pathways. Overlap within each of these five pathways identified those RNAs that were specifically (≥ fivefold enriched) or primarily (≥ twofold enriched) provided as part of the paternal contribution compared to the oocyte at fertilization. Key RNAs consistently altered by DBP, including CAMTA2 and PSME4, were delivered by sperm reflective of these pathways. The majority (64/103) of overlapping enriched gene sets were related to gene regulation. Many of these RNAs (45 RNAs) corresponded to key interconnected CRREWs (Chromatin remodeler cofactors, RNA interactors, Readers, Erasers, and Writers). Modeling suggests that CUL2, PHF10, and SMARCC1 may coordinate and mechanistically modulate the phthalate response.

Conclusions

Mediated through a CRREW regulatory network, the cell responded to exposure presenting stressed-induced changes in the cell cycle—DNA damage—apoptosis. Interestingly, the majority of these DBP-responsive epigenetic mediators’ direct acetylation or deacetylation, impacting the sperm's cargo delivered at fertilization and that of the embryo.
Early visual alterations in individuals at-risk of Alzheimer’s disease: a multidisciplinary approach
Authors: López-Cuenca Inés , Nebreda Alberto , García-Colomo Alejandra , Salobrar-García Elena , de Frutos-Lucas Jaisalmer , Bruña Ricardo , Ramírez Ana I. , Ramirez-Toraño Federico , Salazar Juan J. , Barabash Ana , Gil Pedro , Maestú Fernando , Ramírez José M. , de Hoz Rosa
Published: January 2023

Background

The earliest pathological features of Alzheimer’s disease (AD) appear decades before the clinical symptoms. The pathology affects the brain and the eye, leading to retinal structural changes and functional visual alterations. Healthy individuals at high risk of developing AD present alterations in these ophthalmological measures, as well as in resting-state electrophysiological activity. However, it is unknown whether the ophthalmological alterations are related to the visual-related electrophysiological activity. Elucidating this relationship is paramount to understand the mechanisms underlying the early deterioration of the system and an important step in assessing the suitability of these measures as early biomarkers of disease.

Methods

In total, 144 healthy subjects: 105 with family history of AD and 39 without, underwent ophthalmologic analysis, magnetoencephalography recording, and genotyping. A subdivision was made to compare groups with less demographic and more risk differences: 28 high-risk subjects (relatives/APOEɛ4 +) and 16 low-risk (non-relatives/APOEɛ4 −).

Differences in visual acuity, contrast sensitivity, and macular thickness were evaluated. Correlations between each variable and visual-related electrophysiological measures (M100 latency and time–frequency power) were calculated for each group.

Results

High-risk groups showed increased visual acuity. Visual acuity was also related to a lower M100 latency and a greater power time–frequency cluster in the high-risk group. Low-risk groups did not show this relationship. High-risk groups presented trends towards a greater contrast sensitivity that did not remain significant after correction for multiple comparisons. The highest-risk group showed trends towards the thinning of the inner plexiform and inner nuclear layers that did not remain significant after correction. The correlation between contrast sensitivity and macular thickness, and the electrophysiological measures were not significant after correction. The difference between the high- and low- risk groups correlations was no significant.

Conclusions

To our knowledge, this paper is the first of its kind, assessing the relationship between ophthalmological and electrophysiological measures in healthy subjects at distinct levels of risk of AD. The results are novel and unexpected, showing an increase in visual acuity among high-risk subjects, who also exhibit a relationship between this measure and visual-related electrophysiological activity. These results have not been previously explored and could constitute a useful object of research as biomarkers for early detection and the evaluation of potential interventions’ effectiveness.
CT and MR imaging features of mixed neuroendocrine–non-neuroendocrine neoplasm of the pancreas compared with pancreatic ductal adenocarcinoma and neuroendocrine tumor
Authors: Zhong Yanqi , Zhang Heng , Wang Xian , Sun Zongqiong , Ge Yuxi , Dou Weiqiang , Hu Shudong
Published: January 2023

Objective

This study aimed to assess the computed tomography (CT) and magnetic resonance imaging (MRI) features of pancreatic mixed neuroendocrine–non-neuroendocrine neoplasm (MiNEN) and compare them with those of pancreatic ductal adenocarcinoma (PDAC) and neuroendocrine tumor (NET).

Methods

Twelve patients with pancreatic MiNEN, 24 patients with PDAC, and 24 patients with NET, who underwent both contrast-enhanced CT and MRI, were included. Clinical data and the key imaging features were retrospectively evaluated by two independent readers and compared between MiNEN and PDAC or NET. Univariate and multivariable logistic regression analyses were performed to obtain predictors for pancreatic MiNEN.

Results

Patients with pancreatic MiNEN more frequently presented with large size and heterogeneous and cystic components compared with PDAC (p < 0.031) and ill-defined irregular margins, progressive enhancement, and adjacent organ involvement compared with NET (p < 0.036). However, vascular invasion was less commonly seen in MiNEN than PDAC (p = 0.010). Moderate enhancement was observed more frequently in MiNEN than in PDAC or NET (p < 0.001). Multivariate logistic analyses demonstrated that moderate enhancement and ill-defined irregular margin were the most valuable features for the prediction of pancreatic MiNEN (p ≤ 0.044). The combination of the two features resulted in a specificity of 93.8%, sensitivity of 83.3%, and accuracy of 91.7%.

Conclusions

We have mainly described the radiological findings of pancreatic MiNEN with ill-defined irregular margin and moderate enhancement compared with PDAC and NET. The combination of imaging features could improve diagnostic efficiency and help in the selection of the correct treatment method.
Predictive biomarkers for the responsiveness of recurrent glioblastomas to activated killer cell immunotherapy
Authors: Hwang Sohyun , Lim Jaejoon , Kang Haeyoun , Jeong Ju-Yeon , Joung Je-Gun , Heo Jinhyung , Jung Daun , Cho Kyunggi , An Hee Jung
Published: January 2023

Background

Recurrent glioblastoma multiforme (GBM) is a highly aggressive primary malignant brain tumor that is resistant to existing treatments. Recently, we reported that activated autologous natural killer (NK) cell therapeutics induced a marked increase in survival of some patients with recurrent GBM.

Methods

To identify biomarkers that predict responsiveness to NK cell therapeutics, we examined immune profiles in tumor tissues using NanoString nCounter analysis and compared the profiles between 5 responders and 7 non-responders. Through a three-step data analysis, we identified three candidate biomarkers (TNFRSF18, TNFSF4, and IL12RB2) and performed validation with qRT-PCR. We also performed immunohistochemistry and a NK cell migration assay to assess the function of these genes.

Results

Responders had higher expression of many immune-signaling genes compared with non-responders, which suggests an immune-active tumor microenvironment in responders. The random forest model that identified TNFRSF18, TNFSF4, and IL12RB2 showed a 100% accuracy (95% CI 73.5–100%) for predicting the response to NK cell therapeutics. The expression levels of these three genes by qRT-PCR were highly correlated with the NanoString levels, with high Pearson’s correlation coefficients (0.419 (TNFRSF18), 0.700 (TNFSF4), and 0.502 (IL12RB2)); their prediction performance also showed 100% accuracy (95% CI 73.54–100%) by logistic regression modeling. We also demonstrated that these genes were related to cytotoxic T cell infiltration and NK cell migration in the tumor microenvironment.

Conclusion

We identified TNFRSF18, TNFSF4, and IL12RB2 as biomarkers that predict response to NK cell therapeutics in recurrent GBM, which might provide a new treatment strategy for this highly aggressive tumor.
Personality traits among major depressive disorder in southern Thailand: a hospital-based case–control study
Authors: Pitanupong Jarurin , Sa-i Adchara
Published: January 2023

Background

Residual depression can cause functional impairment. This study aimed to assess personality traits among individuals with depression, to compare the results with personality traits found in outpatients without psychiatric disorders recruited from general practitioner settings, and to study the association between personality traits and the age-onset of depression, duration of treatment, and the presence of depressive residual symptoms.

Methods

A case–control study surveyed Thai individuals with depression and outpatients without psychiatric disorders recruited from general practitioner settings at an outpatient clinic of Songklanagarind hospital, in 2022. The questionnaires were: (1) demographic data, (2) the PHQ-9 Thai version, and (3) the International Personality Item Pool-NEO (IPIP-NEO) Thai version. The difference between personality traits and the assigned clinical group were analyzed using the Student’s t-test and the Wilcoxon rank sum test. A generalized linear model was performed to examine differences of personality traits between the assigned clinical group (case–control), and the presence of depressive residual symptoms. The association between personality traits and treatment profiles was assessed by using an analysis of the variance test and the Kruskal–Wallis test.

Results

In regards to 73 individuals with depression in the case group, and 73 gender-and age-matched outpatients without psychiatric disorders recruited from general practitioner settings in the control group; 78.1% of cases and 82.2% of controls were female. Thirty-eight (52.1%) cases had depressive residual symptoms. Regarding the IPIP-NEO Thai version, there was a statistically significant difference in Neuroticism, Extraversion, and Conscientiousness domains between the case and the control groups. In comparison to the control group, the case group scored higher on the Neuroticism domain, and lower on the Extraversion and Conscientiousness domains. Every 0.18-point reduction in the Neuroticism score and every 0.09-point increment in regards to the Openness score were associated with a 1-year increment of age-onset of depression. This study found an association between a higher score of Neuroticism and a lower score of Conscientiousness with the presence of depressive residual symptoms.

Conclusion

Different personality profiles were found between individuals with depression and outpatients without psychiatric disorders recruited from general practitioner settings. Individuals with depressive residual symptoms featured a higher score of Neuroticism and a lower score of Conscientiousness. A higher score of Neuroticism and a lower score of Openness were associated with age-onset of depression, but no personality traits were associated with treatment duration.
Radiogenomic association of deep MR imaging features with genomic profiles and clinical characteristics in breast cancer
Authors: Liu Qian , Hu Pingzhao
Published: January 2023

Background

It has been believed that traditional handcrafted radiomic features extracted from magnetic resonance imaging (MRI) of tumors are normally shallow and low-ordered. Recent advancement in deep learning technology shows that the high-order deep radiomic features extracted automatically from tumor images can capture tumor heterogeneity in a more efficient way. We hypothesize that MRI-based deep radiomic phenotypes have significant associations with molecular profiles of breast cancer tumors. We aim to identify deep radiomic features (DRFs) from MRI, evaluate their significance in predicting breast cancer (BC) clinical characteristics and explore their associations with multi-level genomic factors.

Methods

A denoising autoencoder was built to retrospectively extract 4,096 DRFs from 110 BC patients’ MRI. Visualization and clustering were applied to these DRFs. Linear Mixed Effect models were used to test their associations with multi-level genomic features (GFs) (risk genes, gene signatures, and biological pathway activities) extracted from the same patients’ mRNA expression profile. A Least Absolute Shrinkage and Selection Operator model was used to identify the most predictive DRFs for each clinical characteristic (tumor size (T), lymph node metastasis (N), estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status).

Results

Thirty-six conventional radiomic features (CRFs) for 87 of the 110 BC patients provided by a previous study were used for comparison. More than 1,000 DRFs were associated with the risk genes, gene signatures, and biological pathways activities (adjustedP-value < 0.05). DRFs produced better performance in predicting T, N, ER, PR, and HER2 status (AUC > 0.9) using DRFs. These DRFs showed significant powers of stratifying patients, linking to relevant biological and clinical characteristics. As a contrast, only eight risk genes were associated with CRFs. The RFs performed worse in predicting clinical characteristics than DRFs.

Conclusions

The deep learning-based auto MRI features perform better in predicting BC clinical characteristics, which are more significantly associated with GFs than traditional semi-auto MRI features. Our radiogenomic approach for identifying MRI-based imaging signatures may pave potential pathways for the discovery of genetic mechanisms regulating specific tumor phenotypes and may enable a more rapid innovation of novel imaging modalities, hence accelerating their translation to personalized medicine.
Artificial intelligence for differentiating COVID-19 from other viral pneumonias on CT: comparative analysis of different models based on quantitative and radiomic approaches
Authors: Zorzi Giulia , Berta Luca , Rizzetto Francesco , De Mattia Cristina , Felisi Marco Maria Jacopo , Carrazza Stefano , Nerini Molteni Silvia , Vismara Chiara , Scaglione Francesco , Vanzulli Angelo , Torresin Alberto , Colombo Paola Enrica
Published: January 2023

Background

To develop a pipeline for automatic extraction of quantitative metrics and radiomic features from lung computed tomography (CT) and develop artificial intelligence (AI) models supporting differential diagnosis between coronavirus disease 2019 (COVID-19) and other viral pneumonia (non-COVID-19).

Methods

Chest CT of 1,031 patients (811 for model building; 220 as independent validation set (IVS) with positive swab for severe acute respiratory syndrome coronavirus-2 (647 COVID-19) or other respiratory viruses (384 non-COVID-19) were segmented automatically. A Gaussian model, based on the HU histogram distribution describing well-aerated and ill portions, was optimised to calculate quantitative metrics (QM, n = 20) in both lungs (2L) and four geometrical subdivisions (GS) (upper front, lower front, upper dorsal, lower dorsal; n = 80). Radiomic features (RF) of first (RF1, n = 18) and second (RF2, n = 120) order were extracted from 2L using PyRadiomics tool. Extracted metrics were used to develop four multilayer-perceptron classifiers, built with different combinations of QM and RF: Model1 (RF1-2L); Model2 (QM-2L, QM-GS); Model3 (RF1-2L, RF2-2L); Model4 (RF1-2L, QM-2L, GS-2L, RF2-2L).

Results

The classifiers showed accuracy from 0.71 to 0.80 and area under the receiving operating characteristic curve (AUC) from 0.77 to 0.87 in differentiating COVID-19 versus non-COVID-19 pneumonia. Best results were associated with Model3 (AUC 0.867 ± 0.008) and Model4 (AUC 0.870 ± 0.011. For the IVS, the AUC values were 0.834 ± 0.008 for Model3 and 0.828 ± 0.011 for Model4.

Conclusions

Four AI-based models for classifying patients as COVID-19 or non-COVID-19 viral pneumonia showed good diagnostic performances that could support clinical decisions.
Pseudoaneurysm of the left ventricular free wall occurring after cardiac surgery of endocarditis affecting mitral and aortic valves: a case report
Authors: El Hadj Sidi Chighaly , Isselmou Varha , Mohamed Ahmed Mohamed Feissal , Diop El Hadj Abdelaziz , Argueina Taleb Ekhyar , Mady Haimouda , Boye Khaled
Published: January 2023

Background

Infective endocarditis remains a serious condition. Left ventricular pseudoaneurysm may complicate the clinical course of infective endocarditis or occur postoperatively.

Case presentation

We describe a case of a pseudoaneurysm of the left ventricular lateral wall which developed one month following cardiac surgery of active endocarditis affecting aortic and mitral valves. The diagnosis was established by transthoracic echocardiography and computed tomography angiography of the chest. Urgent cardiac surgery is performed with excision of the pseudoaneurysm and direct closure of the defect. The patient had a complete recovery and was discharged on the twelfth postoperative day.

Conclusions

Left ventricular pseudoaneurysms are rare but potentially fatal. The symptoms revealing such complications are very diverse. Surgical treatment can be offered to younger patients.
Emerging steel frames with Fe-SMA U-shaped dampers for enhancing seismic resilience
Authors: Zhang Zhe-Xi , Zhang Jie , Fang Cheng , Zhang Yuelin , Li Yuanmu
Published: January 2023

Post-earthquake financial loss of structures induced by residual inter-story deformation (RID) has been recently noticed and various strategies have been proposed. A newly-emerged energy-dissipation material, namely, iron-based shape-memory-alloy (Fe-SMA), has gain favor in civil engineering community due to its extraordinary low-cycle fatigue resistance property. Besides, Fe-SMA is believed to help improve structure’s post-earthquake residual inter-story deformation control capacity due to its moderate strain hardening behavior and pseudo-elasticity. This study explores the performance of emerging steel frame systems equipped with energy-dissipation devices fabricated with Fe-SMA. In particular, a brace with built-in Fe-SMA-based U-shaped strips (USSs) is employed serving as the energy-dissipation devices in the proposed system. In this paper, the basic mechanical properties of Fe-SMA are discussed firstly, followed by a description of the working principle of the USSs. The hysteresis behavior of two types of USSs, fabricated with Fe-SMA and conventional mild steel (Q235), were investigated experimentally. Based on the test results, numerical models for the prototype braces equipped with USSs are established using ABAQUS and OpenSEES, and the necessary key material parameters are calibrated. Subsequently, system-level analysis is performed on 5-story prototype steel buildings. Specially, two types of steel frames, i.e., frames with high-strength-steel columns and frames with conventional structural steel-based columns, are established. Concurrently, braces with Fe-SMA-based USSs as well as mild steel-based USSs are considered. The results demonstrated that the Fe-SMA-based energy-dissipation devices along with the steel frames with high-strength-steel columns can provide the most satisfied RID control effectiveness compared with the other yielding structural systems investigated in this paper.
Visualizing the ultra-structure of microorganisms using table-top extreme ultraviolet imaging
Authors: Liu Chang , Eschen Wilhelm , Loetgering Lars , Penagos Molina Daniel S. , Klas Robert , Iliou Alexander , Steinert Michael , Herkersdorf Sebastian , Kirsche Alexander , Pertsch Thomas , Hillmann Falk , Limpert Jens , Rothhardt Jan
Published: January 2023

Table-top extreme ultraviolet (EUV) microscopy offers unique opportunities for label-free investigation of biological samples. Here, we demonstrate ptychographic EUV imaging of two dried, unstained model specimens: germlings of a fungus (Aspergillus nidulans), and bacteria (Escherichia coli) cells at 13.5 nm wavelength. We find that the EUV spectral region, which to date has not received much attention for biological imaging, offers sufficient penetration depths for the identification of intracellular features. By implementing a position-correlated ptychography approach, we demonstrate a millimeter-squared field of view enabled by infrared illumination combined with sub-60 nm spatial resolution achieved with EUV illumination on selected regions of interest. The strong element contrast at 13.5 nm wavelength enables the identification of the nanoscale material composition inside the specimens. Our work will advance and facilitate EUV imaging applications and enable further possibilities in life science.
Using the hearing in noise test (HINT) in the assessment of the performance of directional microphone
Authors: Kamal Wafaa Ahmed , Essawy Wessam Mostafa , Emara Afaf Ahmad , El-Gharib Amani Mohamed
Published: January 2023

Objectives

Hearing in noise test (HINT) is used to evaluate and compare the performance of different hearing aid. This research was designed to compare the performance of a fixed directional microphone (FDM) and an automatic adaptive directional microphone (AADM) with different noise directions using aided Arabic HINT.

Methods

Control group (CG): 20 normal peripheral hearing adults. Study group (SG): 40 adults with bilateral symmetrical sensorineural hearing loss. Arabic HINT was performed in three noise situations at 0°, 90°, and 270° azimuths for both groups. For SG, test was done in 4 conditions: condition (I), without hearing aid; condition (II), aided response with omnidirectional microphone; condition (III), aided response with FDM; and condition (IV), aided response with AADM.

Results

For all azimuths, there was a statistically considerable difference between CG and SG in all conditions. Also, there was a statistically significant difference between SG conditions I and II and II and III. But no statistically significant difference was observed between conditions III and IV when the noise was at 90° and 270° azimuths.

Conclusion

AADM is the best choice of selection in hearing aid fitting, and it performs better in noise, especially when the noise and speech are in front of the patient.
Prospective cohort study of patients with stage III colorectal cancer aged ≥ 80 years who underwent curative resection: The HiSCO-04 study.
Authors: Shimomura Manabu , Ikeda Satoshi , Nakahara Masahiro , Adachi Tomohiro , Saitoh Yasufumi , Shimizu Yosuke , Toyota Kazuhiro , Ishizaki Yasuyo , Yoshimitsu Masanori , Takakura Yuji , Shimizu Wataru , Sumitani Daisuke , Kodama Shinya , Fujimori Masahiko , Oeda Mamoru , Kobayashi Hironori , Ohdan Hideki
Published: January 2023

102

Background: There was no consensus about the safety and effectiveness of adjuvant chemotherapy for patients with stage III colorectal cancer (CRC) aged ≥80 years who underwent curative resection. We conducted a prospective cohort study of patients with stage III CRC aged ≥80 years who underwent curative resection together with a phase II feasibility study on uracil-tegafur and leucovorin (UFT/LV) as adjuvant chemotherapy. Methods: This multi-institutional prospective cohort study involved 17 institutions in Hiroshima, Japan. Patients with stage III CRC aged ≥80 years who underwent curative resection were enrolled. We prospectively collected the clinicopathological data including the status of the administration of adjuvant chemotherapy, follow-up, and oncological outcomes. The primary endpoint was three-year disease-free survival (DFS) and secondary endpoints were three-year overall survival (OS) and relapse-free survival (RFS). Results: From December 2013 to June 2021, 214 patients were examined. There were 99 men and 115 women with the median age of 84 years (range, 80–101). There were stage IIIA diseases in 27 cases, IIIB in 158 cases, and IIIC in 29 cases (TNM eighth edition). Median follow-up time was 42.5 months (range, 0.16–84.04 months). Thirty-six patients died due to CRC and 30 patients died due to other causes. There was recurrence in 58 cases (27.1%), and any treatment was administrated in 29 patients. Secondary cancers were observed in 17 cases in the follow-up period. The three-year DFS was 63.6%, 3-year OS was 76.9%, and 3-year RFS was 63.1%. Adjuvant chemotherapy was administrated in 64 cases and the completion rate was 53%. Adjuvant chemotherapy tends not to be given in older age, poor performance status, high Charlson comorbidity index, and low preoperative prognostic nutritional index. In a study of 80 patients adjusted for background factors using propensity score matching, it was shown that patients who completed planned treatment have improved DFS. Conclusions: Completion of adjuvant chemotherapy may improve prognosis in CRC patients over 80 years of age, but the number of patients who would benefit was limited. Appropriate dose adjustment and supportive care for postoperative adjuvant chemotherapy are important, as well as the need to identify patient groups who will not tolerate chemotherapy.
A phase Ia/b first-in-human, open-label, multicenter study of BI 905711, a bispecific TRAILR2 agonist, in patients with advanced gastrointestinal cancers.
Authors: Harding James J. , Hofheinz Ralf-Dieter , Elez Elena , Kuboki Yasutoshi , Rasco Drew W. , Cecchini Michael , Shen Lin , He Min , Archuadze Shorena , Chhaya Niraj , Pant Shubham
Published: January 2023

115

Background: BI 905711 is a tetravalent bispecific antibody that cross-links TRAILR2 with CDH17. This cross-linking drives CDH17-dependent TRAILR2 oligomerization, leading to caspase activation and eventual apoptosis, inhibiting tumor growth in preclinical models of GI cancer. Methods: This Phase Ia/b study of BI 905711 in patients (pts) with advanced GI cancers (NCT04137289) aimed to determine the maximum tolerated dose (MTD) based on the proportion of pts with dose-limiting toxicities (DLT) and explore preliminary antitumor activity. In Phase Ia, pts received BI 905711 every 14 days. One pt with colorectal cancer (CRC) was enrolled at each of the 2 lowest dose levels (0.02/0.06 mg/kg) and 4 pts with CRC were enrolled at each subsequent level (0.2/0.6/1.2/2.4/3.6/4.8 mg/kg). Up to 4 pts with non-CRC GI cancers were included at the dose level below the CRC cohort. Dose escalation was guided by a Bayesian logistic regression model. Results: As of 01 August 2022, 48 pts (CRC: n = 26; non-CRC: n = 22, including 13 with pancreatic ductal adenocarcinoma [PDAC]) had received BI 905711 (dose range 0.02–4.8 mg/kg); pts had a median age of 61 years (range 27–78) and had received a median of 3 (range 1–11) prior lines of treatment. No DLTs were observed and the MTD was not reached. 41 pts had AEs (grade [G] 3–5: 14 pts; serious: 13 pts). 17 pts had treatment-related AEs (TRAEs); 4 TRAEs were G3: AST increased (2 pts), fatigue and ALT increased (1 pt each). 1 pt had serious TRAEs: G2 decreased appetite and G3 fatigue. 2 pts had G1/2 infusion-related reactions that resolved and did not prevent resumption of treatment. PD biomarker modulation on the level of plasma caspase-3/7 activity was most common at 0.6 mg/kg (4/7 pts) or 1.2 mg/kg (2/6 pts). 13 pts achieved stable disease (SD) and 8 pts were progression-free for ≥4 months (PFS4). In pts with CRC, 6 pts achieved SD and 3 had PFS4. Among non-CRC pts, 7 pts achieved SD (PDAC: n = 6) and 5 had PFS4 (PDAC: n = 4). Median duration of treatment was 30.5 days (range 15–246) overall and 71 days (range 15–211) in the 0.6 mg/kg group (n = 8, predicted therapeutic dose; of whom 3 pts had PFS4: CRC: n = 1/4 [all CDH17+]; non-CRC: n = 2/4). Conclusions: In heavily pretreated pts, BI 905711 was associated with a tolerable safety profile and early signs of disease control. BI 905711 will be further assessed in Phase Ib in 4 dose groups: 0.6/1.2/2.4 mg/kg every 14 days, and 0.6 mg/kg weekly. Clinical trial information: NCT04137289 .
Phase II evaluation of combination immunotherapy with CV301, N-803, bintrafusp alfa, and M9241 in patients with advanced small bowel and colorectal cancers.
Authors: Pastor Danielle M. , Redman Jason M. , Floudas Charalampos S. , Lamping Elizabeth , Francis Deneise C. , Cordes Lisa M. , Marte Jennifer L. , Schlom Jeffrey , Gulley James L. , Strauss Julius
Published: January 2023

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Background: Although immune checkpoint inhibitors (CPI) are inactive as monotherapy for microsatellite stable (MSS) mCRC, preclinical modeling suggests that addition of other immune-oncology agents can produce antitumor activity. CV301 is a poxviral vaccine against CEA and MUC1. N-803 is an IL-15 superagonist. M9241 is tumor-targeted IL-12. Bintrafusp alfa (BA) is a bifunctional anti-PD-L1/TGF-βRII fusion protein. Methods: Patients with advanced MSS or proficient mismatch repair (pMMR) small bowel or CRC were eligible (NCT04491955). Patients enrolling to Arm 1 received triple therapy with BA 1200 mg IV every 2 weeks, N-803 15 mcg/kg SC every 4 weeks, and CV301 SC on D1, D15, D29, and monthly, thereafter. Patients enrolling to Arm 2 received quadruple therapy, with M9241 (8 mcg/kg or 16.8 mcg/kg SC every 4 weeks) plus BA (300 mg or 1200 mg IV), N-803 (10 mcg/kg SC) and CV301 SC, depending on dose escalation schedule. Results: Thirty patients (2 small intestinal, 17 colon, 11 rectal) were treated. All patients had received prior 5-fluorouracil-based treatment, with 29/30 (96.7%) having received ≥ 2 lines of systemic therapy. Twelve patients received triple therapy; 18 received quadruple therapy. Grade 3 treatment-related AEs (TRAEs) occurred in 8 patients (26.7%); anemia occurred most commonly (n = 5), with grade 3 gastrointestinal hemorrhages occurring in 2 patients (on quadruple therapy). Other grade 3 TRAEs included elevated cardiac troponin, AST, and alkaline phosphatase (n = 1 each; all with triple therapy), and adrenal insufficiency (n = 1; quadruple therapy). No grade 4 or 5 TRAEs occurred. Triple therapy resulted in disease reduction in 2 patients (7.5%, 25.6%); quadruple therapy resulted in disease reduction in 2 patients (26.7%, 70.6%). Median overall survival (OS) for triple and quadruple therapy have not been reached, with 12 month survival being 66.7% (95% CI: 33.7-86.0%) for triple therapy and 77.2% (95% CI: 43.3-92.3%) for quadruple therapy. Conclusions: Combination therapies with CV301, N-803, bintrafusp alfa, and M9241 had manageable safety profiles. Preliminary clinical activity was observed in patients with advanced MSS/pMMR small bowel or CRC. Median OS was promising as compared to historical median survivals of 6-7 months following receipt of multiple lines of therapy. Clinical trial information: NCT04491955 .
BREAKWATER safety lead-in (SLI): Encorafenib (E) + cetuximab (C) + chemotherapy for BRAFV600E metastatic colorectal cancer (mCRC).
Authors: Kopetz Scott , Yoshino Takayuki , Kim Tae Won , Yaeger Rona , Desai Jayesh , Wasan Harpreet Singh , Van Cutsem Eric , Ciardiello Fortunato , Maughan Tim , Eng Cathy , Tie Jeanne , Elez Elena , Lonardi Sara , Zhang Xiaosong , Chung Chin-Hee , Usari Tiziana , Nicholz Tim , Murphy Danielle A. , Tabernero Josep
Published: January 2023

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Background: Based on the phase 3 BEACON study (NCT02928224), BRAF inhibitor (i) encorafenib (E) + EGFRi cetuximab (C) was approved for the treatment (tx) of previously treated patients (pts) with BRAFV600E mCRC, with mPFS of 4.3 months (mo) and ORR of 19.5%. In the phase 2 ANCHOR study (NCT03693170), mPFS was 5.8 mo and ORR was 48% for 1L EC + binimetinib in BRAFV600E mCRC. To further assess 1L approaches, the ongoing phase 3 BREAKWATER study (NCT04607421) is evaluating EC ± chemotherapy vs standard-of-care chemotherapy in BRAFV600E mCRC. Here, we present updated safety and antitumor activity data as well as biomarker data from the BREAKWATER SLI. Methods: Inclusion criteria for the SLI were BRAFV600E mCRC (blood or tumor tissue), ≤1 prior systemic tx for mCRC, and ECOG PS 0/1. Pts previously treated with BRAFi/EGFRi or both oxaliplatin and irinotecan were excluded. Pts received E 300 mg daily + C 500 mg/m2 every 2 weeks (Q2W) + either mFOLFOX6 Q2W (n=27) or FOLFIRI Q2W (n=30) in 28-day cycles until disease progression or unacceptable toxicity. The primary endpoint was frequency of dose-limiting toxicities. Secondary endpoints included safety, pharmacokinetics, and antitumor activity. Exploratory endpoints included evaluation of plasma (circulating tumor DNA [ctDNA] genomic profiling) and tumor tissue (molecular profiling) biomarkers. Updated results from the BREAKWATER SLI will be presented, including overall safety and tolerability and antitumor activity. Biomarker data, including changes from baseline in BRAFV600E ctDNA following treatment (Cycle 1 Day 15, Cycle 2 Day 15 and Cycle 7 Day 1) and MSI status of pts, will also be presented. Expected conclusions will be included in the final abstract. Clinical trial information: NCT04607421 .
Phase II trial of rosuvastatin combined with chemoradiation therapy (CRT) in the treatment of high-risk locally advanced rectal cancer (STARC trial).
Authors: Monzon Jose Gerard , Joseph Kurian , Chen Eric Xueyu , Tang Patricia A. , Sinha Rishi , Dennis Kristopher , Goodwin Rachel Anne , Severin Diane , Dimitroulakos Jim , Vickers Michael M.
Published: January 2023

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Background: Pre-clinical evidence suggest that statins have antiproliferative, proapoptotic, and anti-invasive properties. Also, statins can sensitize cancer tissues and protect normal tissues to the effects of radiation. A standard treatment of locally advanced rectal cancer (LARC) involves neoadjuvant CRT followed by surgery and adjuvant chemotherapy. Retrospective analyses of statin use in rectal cancer patients receiving CRT suggest a higher pathological complete response rate (pCRr). Methods: Patients with clinical stage II-III rectal adenocarcinoma, within 5 cm of the anal verge (AV) or less than 12cm from the AV with threatened circumferential resection margin were treated with rosuvastatin 40 mg daily starting 2 weeks prior to the start and until 4 weeks after the end of CRT. The primary objective of the study was pCRr. Secondary objectives included, near-CRr, Ro resection rate (RR), sphincter preservation, 3-year relapse free survival (RFS), 3-year overall survival (OS), toxicity and safety. A Simon’s minimax two-stage design was used to determine significance. A pCRr of ≥25% was required to reject the null hypothesis. RFS and OS rates were calculated using the Kaplan-Meier product-limit method. Results: Forty-five patients were enrolled from 2016 to 2021. Sixty-seven percent were male with a median age of 54 (IQR 37- 61), 97.8% (44/45) had ECOG PS of 0-1, 15.6% (7/45) were cT4, 73.3% (33/45) were cN+. Of the 38 evaluable patients, 9 had a pCR (23.7%), an additional 9 had a near-pCR (23.7%). With a median follow-up of 3.26 years, the 3-year OS rate was 96.3% (95% CI (0.765, 0.995)) and the 3-year DFS rate was 77.9% (95% CI (0.604, 0.883)) in the evaluable patients. One patient elected for non-operative management and has an on-going clinical CR for the last 15 months. Surgery was sphincter sparing in 17 patients (43.6%) and an 87.2% Ro RR was observed. Toxicities attributable to rosuvastatin included: two patients with elevations in liver enzymes, grade 3. Remaining toxicities were grade 2 or less, with the most common toxicities being fatigue (n = 5) and pain (n = 3). Only 2 patients experienced CPK elevations, both grade 2. Conclusions: The addition of rosuvastatin to nCRT resulted in a considerable complete and near-complete response rate with an acceptable toxicity profile. Rosuvastatin treatment should be studied further in the total neoadjuvant and non-operative management settings for locally advanced rectal cancer. Clinical trial information: NCT02569645 .
Updated results of ALTER-C002: Anlotinib combined with CAPEOX as first-line treatment in RAS/BRAF wild-type unresectable metastatic colorectal cancer.
Authors: Ding Ke-Feng , Liu Yue , Xiao Qian , He Jinjie , Hu Hanguang , Du Jinlin , Zhu Yuping , Chen Jiaqi , Liu Zhuo , Wang Jianping , Sun Lifeng , Xu Dong , Li Jun , Liao Xiujun , Wang Jianwei , Cai Yibo , Cai Cheng , Jin Zhekang , Yuan Ying
Published: January 2023

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Background: Anlotinib is an oral multi-target tyrosine kinase inhibitor, mainly targeting VEGFR1-3, FGFR 1-4, PDGFR a/b and c-kit. Previous trial had demonstrated that anlotinib monotherapy was effective and safe in advanced colorectal cancer. ALTER-C002 trial is an open-label, single-arm, phase II study, aimed to evaluate the efficacy and safety of anlotinib plus CAPEOX as first-line therapy in patients with RAS/ BRAF wild-type unresectable metastatic colorectal cancer (mCRC). Preliminary results demonstrated significant antitumor activity and manageable toxicity. Here we reported the updated results at the data cutoff of August 19, 2022. Methods: RAS/BRAF wild-type unresectable mCRC patients with no prior systemic treatment received anlotinib (12 mg p.o. qd, d1-d14, q3w), capecitabine (850 mg/m2 p.o., bid, d1-d14, q3w) and oxaliplatin (130 mg/m2 i.v., d1, q3w) for 6 cycles followed by anlotinib and capecitabine as maintenance therapy until disease progression. Tumor response was assessed every 6 weeks according to RECIST v1.1 by investigator. The primary endpoint was ORR, and secondary endpoints included safety, DCR, DOR and PFS. Results: From Nov 2019 to February 2021, 30 eligible patients were enrolled, of whom, median age was 60y (range, 32-72y), 26 (86.7%) had left colon or rectal cancer, and 25 (83.3%) had liver metastases. The ORR was 76.7% (95% CI, 57.7-90.1%) with 2 patient achieved a complete response (CR); DCR was 93.3% (95% CI, 77.9-99.2%). At the data cutoff date, the median DOR was 7.9 months (95% CI, 4.3–11.4) and the median DOT was 8.38 months (95%CI, 5.9-10.9). The median OS has not reached yet, the 24-month OS rate was 72.8% (95%CI, 50.7-86.3%) and the 30-month OS rate was 58.3% (95%CI:25.5-80.8%). Grade 3-4 treatment-emergent adverse events (TEAEs) occurred in 25 (83.3%) patients; the most common grade 3 or 4 TEAEs ( > 10%) were hypertension (50%, 15/30 pts), neutropenia (26.7%, 8/30 pts) and diarrhea (13.3%, 4/30 pts). No grade 5 treatment-related events occurred. Conclusions: Anlotinib combined with CAPEOX exhibited promising ORR in the first-line treatment of mCRC compared to those of previous treatment. A longer follow-up is needed for a more complete assessment, and we launched a phase III, multicenter, open-label trial to assess the efficacy of this regimen comprehensively. Clinical trial information: NCT04080843 .
Association of transanal minimally invasive surgical approach with oncologic outcomes over conventional transanal excision for early-stage rectal cancer: An analysis of the US Rectal Cancer Consortium.
Authors: Warren Emilie , Gamboa Adriana C. , Medin Caroline , Hendren Samantha , Regenbogen Scott E. , Holder-Murray Jennifer , Kalady Matthew , Ejaz Aslam , Hawkins Alexander , Wise Paul , Silviera Matthew , Maithel Shishir K. , Balch Glen C.
Published: January 2023

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Background: For early-stage rectal cancer, minimally invasive surgical (MIS) approaches such as transanal endoscopic microsurgery (TEM) and transanal minimally invasive surgery (TAMIS) have not been widely adopted over conventional transanal excision (TAE). Direct comparisons are lacking. Our aim was to compare oncologic and perioperative outcomes between the two approaches. Methods: We identified patients with Tis or T1 tumors who underwent TAE or MIS (TEM or TAMIS) between 2007-2017 from the US Rectal Cancer Consortium database. Patients who received neoadjuvant therapy were excluded. Primary outcomes were rate of recurrence and recurrence-free survival (RFS). Results: Of 1881 patients, 89 met inclusion criteria: 44 TAE and 45 MIS (20 TEM, 25 TAMIS). Median age was similar between groups (63.5 years TAE vs 61 years MIS; p=0.582). Patients in each group had similar functional status and tumor size (1.86 cm TAE vs 1.79 cm MIS, p=0.837). The majority of patients had tumors ≤ 6 cm from the anal verge (75.7% TAE vs 65.5% MIS, p=0.544). The TAE group had a 10.3% margin positive rate versus 0% in the MIS group (p=0.049). There was a lower incidence of recurrence in the MIS group (4.5%) compared to TAE (26%, p=0.01); all recurred locally except for one in the TAE group. Median follow-up time was 23.7 months. On Kaplan-Meier analysis, MIS approach was associated with improved 5-year RFS (86.4%, p=0.005) and local RFS (86.4%, p=0.01), versus TAE (46.9% and 50.5%, respectively). On univariate cox regression analysis, lymphovascular invasion was associated with worse RFS (HR 4.23, p=0.033) and local RFS (HR 5.26, p=0.02), while MIS approach was associated with improved RFS (HR 0.15, p=0.015) and local RFS (HR 0.17, p=0.023). On multivariable cox regression, only MIS approach remained associated with improved RFS (HR 0.09, p=0.028) and local RFS (HR 0.11, p=0.045). Perioperative complication and readmission rates were equal between the two groups. Conclusions: In patients with Tis and T1 rectal cancers who undergo local excision, an MIS approach (TEM or TAMIS) is associated with a decreased rate of recurrence and improved RFS and local RFS compared to TAE, with no significant difference in perioperative complication rate. The MIS approach should be more frequently incorporated into standard practice. [Table: see text]