bluuebunny/crossref_metadata_2025 huggingface dataset:
Double vision: 2D and 3D mosquito trajectories can be as valuable for behaviour analysis via machine learning
Authors: Qureshi Yasser Mehmood , Voloshin Vitaly , Towers Catherine Elizabeth , Covington James Anthony , Towers David Peter
Published: July 2024

Background

Mosquitoes are carriers of tropical diseases, thus demanding a comprehensive understanding of their behaviour to devise effective disease control strategies. In this article we show that machine learning can provide a performance assessment of 2D and 3D machine vision techniques and thereby guide entomologists towards appropriate experimental approaches for behaviour assessment. Behaviours are best characterised via tracking—giving a full time series of information. However, tracking systems vary in complexity. Single-camera imaging yields two-component position data which generally are a function of all three orthogonal components due to perspective; however, a telecentric imaging setup gives constant magnification with respect to depth and thereby measures two orthogonal position components. Multi-camera or holographic techniques quantify all three components.

Methods

In this study a 3D mosquito mating swarm dataset was used to generate equivalent 2D data via telecentric imaging and a single camera at various imaging distances. The performance of the tracking systems was assessed through an established machine learning classifier that differentiates male and non-male mosquito tracks. SHAPs analysis has been used to explore the trajectory feature values for each model.

Results

The results reveal that both telecentric and single-camera models, when placed at large distances from the flying mosquitoes, can produce equivalent accuracy from a classifier as well as preserve characteristic features without resorting to more complex 3D tracking techniques.

Conclusions

Caution should be exercised when employing a single camera at short distances as classifier balanced accuracy is reduced compared to that from 3D or telecentric imaging; the trajectory features also deviate compared to those from the other datasets. It is postulated that measurement of two orthogonal motion components is necessary to optimise the accuracy of machine learning classifiers based on trajectory data. The study increases the evidence base for using machine learning to determine behaviours from insect trajectory data.

Graphical Abstract
Twenty-year evolution of Leishmania infantum infection in dogs in Valdeorras (Galicia, Northwestern Spain): implication of climatic factors and preventive measures
Authors: Olmeda Patricia , Díaz-Regañón David , Villaescusa Alejandra , Amusategui Inmaculada , García Adolfo , Herrero Francisco , Tesouro Miguel A. , Rodríguez-Franco Fernando , García-Sancho Mercedes , Martín-Fraile Daniel , Sainz Ángel
Published: July 2024

Background

Abiotic factors play a significant role in the evolution of Leishmania infantum infection due to its vectorial nature. This study aims to assess the evolution in the detection of new L. infantum infection cases in Valdeorras (Ourense, Northwestern Spain) over a 20-year period and how different climatic variables and preventive measures may have affected it.

Methods

Indirect immunofluorescence antibody tests (IFAT) were performed on serum samples collected from dogs attending the ‘Servicios Veterinarios de Sil’ veterinary clinic (Valdeorras, Northwestern Spain) between May 2003 and April 2023 to detect L. infantum exposure. The percentage of new cases of L. infantum infection was calculated from May of one year to April of the following year. Climatic conditions in the region, global sales of ectoparasiticides and the number of vaccines against L. infantum delivered in the veterinary clinic from 2003 to 2022 were recorded. Statistical analyses were conducted to determine the associations between these factors and the percentage of new cases of L. infantum infection.

Results

A total of 2909 dogs were assessed, and 3785 IFAT tests were performed between May 2003 and April 2023. The mean percentage of new seropositive cases over the 20-year period studied was 21.65 ± 10.8%, with a decline from the beginning to the end of the period studied. The percentage was significantly higher between May 2003 and April 2008 compared with the other periods (May 2008 to April 2013, May 2013 to April 2018 and May 2018 to April 2023). There was a positive correlation between the percentage of new cases of L. infantum infection and the maximum relative humidity in winter. Conversely, there was a negative correlation between the percentage of new cases and sales of ectoparasiticides and vaccination against L. infantum.

Conclusions

This study is one of the longest evaluations of the evolution of L. infantum infection in a fixed location and its association with external factors including climatic conditions and preventive measures. The results confirm that Valdeorras is a high-risk area for L. infantum infection. The use of ectoparasiticides and vaccines against L. infantum has been shown to play a significant role in preventing L. infantum infection, highlighting the crucial role of veterinarians in the fight against this disease.

Graphical Abstract
Acceleration of bone repairation by BMSCs overexpressing NGF combined with NSA and allograft bone scaffolds
Authors: Ji Ying , Mao Yongkang , Lin Honghu , Wang Ye , Zhao Peishuai , Guo Yong , Gu Lantao , Fu Can , Chen Ximiao , Lv Zheng , Wang Ning , Li Qiang , Bei Chaoyong
Published: July 2024

Background

Repairation of bone defects remains a major clinical problem. Constructing bone tissue engineering containing growth factors, stem cells, and material scaffolds to repair bone defects has recently become a hot research topic. Nerve growth factor (NGF) can promote osteogenesis of bone marrow mesenchymal stem cells (BMSCs), but the low survival rate of the BMSCs during transplantation remains an unresolved issue. In this study, we investigated the therapeutic effect of BMSCs overexpression of NGF on bone defect by inhibiting pyroptosis.

Methods

The relationship between the low survival rate and pyroptosis of BMSCs overexpressing NGF in localized inflammation of fractures was explored by detecting pyroptosis protein levels. Then, the NGF+/BMSCs-NSA-Sca bone tissue engineering was constructed by seeding BMSCs overexpressing NGF on the allograft bone scaffold and adding the pyroptosis inhibitor necrosulfonamide(NSA). The femoral condylar defect model in the Sprague–Dawley (SD) rat was studied by micro-CT, histological, WB and PCR analyses in vitro and in vivo to evaluate the regenerative effect of bone repair.

Results

The pyroptosis that occurs in BMSCs overexpressing NGF is associated with the nerve growth factor receptor (P75NTR) during osteogenic differentiation. Furthermore, NSA can block pyroptosis in BMSCs overexpression NGF. Notably, the analyses using the critical-size femoral condylar defect model indicated that the NGF+/BMSCs-NSA-Sca group inhibited pyroptosis significantly and had higher osteogenesis in defects.

Conclusion

NGF+/BMSCs-NSA had strong osteogenic properties in repairing bone defects. Moreover, NGF+/BMSCs-NSA-Sca mixture developed in this study opens new horizons for developing novel tissue engineering constructs.
Mesenteric lymph nodes: a critical site for the up-regulatory effect of hUC-MSCs on Treg cells by producing TGF-β1 in colitis treatment
Authors: Zhang Qixiang , Zeng Zhu , Wei Ning , Su Yueyan , Wang Jing , Ni Qi , Wang Yukai , Yang Jingwen , Liu Xiaoyan , Xu Huanke , Wang Guangji , Shan Yunlong , Zhou Fang
Published: July 2024

Background

Mesenchymal stem cells (MSCs) demonstrate a wide range of therapeutic capabilities in the treatment of inflammatory bowel disease (IBD). The intraperitoneal injection of MSCs has exhibited superior therapeutic efficacy on IBD than intravenous injection. Nevertheless, the precise in vivo distribution of MSCs and their biological consequences following intraperitoneal injection remain inadequately understood. Additional studies are required to explore the correlation between MSCs distribution and their biological effects.

Methods

First, the distribution of human umbilical cord MSCs (hUC-MSCs) and the numbers of Treg and Th17 cells in mesenteric lymph nodes (MLNs) were analyzed after intraperitoneal injection of hUC-MSCs. Subsequently, the investigation focused on the levels of transforming growth factor beta1 (TGF-β1), a key cytokine to the biology of both Treg and Th17 cells, in tissues of mice with colitis, particularly in MLNs. The study also delved into the impact of hUC-MSCs therapy on Treg cell counts in MLNs, as well as the consequence of TGFB1 knockdown hUC-MSCs on the differentiation of Treg cells and the treatment of IBD.

Results

The therapeutic effectiveness of intraperitoneally administered hUC-MSCs in the treatment of colitis was found to be significant, which was closely related to their quick migration to MLNs and secretion of TGF-β1. The abundance of hUC-MSCs in MLNs of colitis mice is much higher than that in other organs even the inflamed sites of colon. Intraperitoneal injection of hUC-MSCs led to a significant increase in the number of Treg cells and a decrease in Th17 cells especially in MLNs. Furthermore, the concentration of TGF-β1, the key cytokine for Treg differentiation, were also found to be significantly elevated in MLNs after hUC-MSCs treatment. Knockdown of TGFB1 in hUC-MSCs resulted in a noticeable reduction of Treg cells in MLNs and the eventually failure of hUC-MSCs therapy in colitis.

Conclusions

MLNs may be a critical site for the regulatory effect of hUC-MSCs on Treg/Th17 cells and the therapeutic effect on colitis. TGF-β1 derived from hUC-MSCs promotes local Treg differentiation in MLNs. This study will provide new ideas for the development of MSC-based therapeutic strategies in IBD patients.
An inertial self-adaptive algorithm for solving split feasibility problems and fixed point problems in the class of demicontractive mappings
Authors: Berinde Vasile
Published: July 2024

We propose a hybrid inertial self-adaptive algorithm for solving the split feasibility problem and fixed point problem in the class of demicontractive mappings. Our results are very general and extend several related results existing in the literature from the class of nonexpansive or quasi-nonexpansive mappings to the larger class of demicontractive mappings. Examples to illustrate numerically the effectiveness of the new analytical results are presented.
Angle-dependent image-domain least-squares migration through analytical point spread functions
Authors: Zhang Wei , Guo Xuebao , Ravasi Matteo , Gao Jinghuai , Sun Wenbo
Published: July 2024

Image-domain least-squares migration (IDLSM) is an established approach to recover high-fidelity seismic images of subsurface reflectors; this is achieved by removing the blurring effects of the Hessian operator in the standard migration approach with the help of so-called point spread functions (PSFs). However, most of the existing IDLSM approaches recover an angle-independent image of the subsurface reflectors, which is not suitable for subsequent amplitude-variation-with-angle (AVA) analysis. To overcome this limitation, we have developed an angle-dependent IDLSM approach, denoted as AD-IDLSM, which can recover a high-fidelity and high-resolution angle-dependent reflectivity image of subsurface reflectors. The problem is formulated here as an angle-dependent image-domain inversion with PSFs computed by means of full-wave Green’s function. More specifically, we derive an analytical expression to compute angle-dependent PSFs by means of a wave-equation-based Kirchhoff migration (WEBKM) engine, where a localization assumption is made in both spatial directions to decrease the computational cost and memory overhead. The amplitude and traveltime of the Green’s functions involved in the WEBKM approach are estimated by the excitation amplitude and excitation time of the full-wave wavefield. The scattering angle is then approximately estimated from the Poynting vector of the excitation-time field. To stabilize the solution of AD-IDLSM, we use a regularization scheme that applies a second derivative along the direction of the reflection angle of angle-domain common-image gathers (ADCIGs) to ensure continuity in the amplitude variations versus angle and suppress migration artifacts. We demonstrate the effectiveness of the AD-IDLSM approach through two synthetic and one field marine data set; the presented results confirm that AD-IDLSM can create ADCIGs with higher spatial resolution, better amplitude fidelity, and fewer migration artifacts compared with those obtained by its migration counterpart. Moreover, AD-IDLSM amplitude variations with angle are shown to closely resemble the theoretical AVA curve of the reflectors.
Circulating tumor cells and tumor DNA in patients with resectable colorectal liver metastases: The MIRACLE.
Authors: Wullaert Lissa , Jansen Maurice P. H. M. , Kraan Jaco , Beaufort Corine M. , Van Ngoc M. , Belt Eric J. Th. , Vermaas Maarten , Gobardhan Paul D. , Sleijfer Stefan , Verheul Henk M.W. , Wilting Saskia M , Grunhagen Dirk J. , Martens John W.M. , Verhoef Cornelis
Published: July 2024

3011

Background: Recurrence risk after curative surgery for colorectal liver metastases (CRLM) remains high, underlining the need for prognostic markers to detect minimal residual disease after local treatment. The aim of this study was to determine the association between recurrence-free survival (RFS) and detection of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) before and after surgical treatment of resectable CRLM. Methods: The MIRACLE isa prospective, observational biomarker study in patients with isolated, resectable CRLM without (neo)adjuvant chemotherapy, recruited between October 2015 and December 2021. The study was powered to detect at least a 20% difference in one-year recurrence rate between detectable and undetectable circulating tumor load after surgery. Blood samples were collected one day before surgery (T0) and three weeks (T3) after surgery. CTCs were enumerated using the FDA-approved CellSearch system. ctDNA before surgery was measured by next generation sequencing (NGS) using a targeted panel (Oncomine Colon cfDNA assay) and postoperatively by digital PCR (dPCR). Results: CTC enumeration resulted in positivity for 43 out of 192 patients (22%) at baseline and 14 out of 161 patients (9%) at T3. ctDNA was detected in 125 out of 191 patients (65%) at baseline, of which 25 (20%) still had detectable ctDNA at T3. Patients with postoperative undetectable CTC had a significantly improved RFS (1-year RFS: 15% vs. 51%, log-rank test p=0.009). Also, patients with postoperative undetectable ctDNA had a significantly improved RFS (1-year RFS: 20% vs. 54%, log-rank test p<0.001). In multivariable analysis, at baseline no association was found between RFS and CTCs (HR 1.01; p=0.97) or ctDNA (HR 1.29; p=0.29). In contrast, after surgery a significantly shorter RFS was observed in patients with detectable CTCs (HR 3.09; p=0.002) and ctDNA (HR 3.53; p<0.001). Postoperative ctDNA status was a stronger predictor of recurrence compared to known clinical risk factors. Conclusions: This is the first study conducted in patients with resectable CRLM without (neo)adjuvant chemotherapy, which demonstrates the impact of detectable circulating tumor load after surgery on RFS. Postoperative ctDNA and CTC detection are a strong predictor for a shorter RFS after local treatment, as opposed to preoperative ctDNA or CTC detection. [Table: see text]
Dose optimization and exposure-response analyses to support optimal dose of ABBV-400, a novel C-met–targeting antibody drug conjugate, in patients with metastatic colorectal cancer (mCRC).
Authors: Biesdorf de Almeida Carla , Engelhardt Benjamin , Babel Heiko , Badillo Jesus D , Sharma Manish , Powderly John D. , Neagu Aristide Martha Raluca , Freise Kevin Jay , Mensing Sven , Parikh Apurvasena
Published: July 2024

3030

Background: ABBV-400 is an antibody drug conjugate (ADC) consisting of a c-Met targeting antibody conjugated to a potent inhibitor of topoisomerase 1 (Top1) payload. ABBV-400 has shown encouraging activity and demonstrated tolerability of dosages up to 3.0 mg/kg Q3W as monotherapy in patients with advanced solid tumors in an ongoing phase 1 study (1). Dosage optimization is a critical aspect of oncology drug development and FDA Project Optimus has focused on reformulating the dosage selection paradigm for oncology products. The phase 1 study included a dose optimization phase in mCRC patients in which 3 doses were evaluated (1.6, 2.4 and 3.0 mg/kg Q3W) to determine the optimal dose for further development. Herein, exposure-response analyses are reported to determine optimal monotherapy dose in mCRC patients. Methods: Data across a range of doses (1.6 – 6.0 mg/kg Q3W) from the phase 1 study (NCT05029882) were used. Population pharmacokinetics (PK) and exposure-response (E-R) analyses were conducted to characterize ABBV-400 conjugate and unconjugated payload PK and the relationship between exposures and efficacy (objective response rate [ORR]) and safety (Grade (Gr) ≥ 3 neutropenia, anemia and thrombocytopenia) endpoints. Relative dose intensity (RDI) analysis was performed. Results: ABBV-400 conjugate and payload PK were adequately described by a combined multi-analyte population PK model with first order kinetics (n=204). ABBV-400 conjugate average concentration was a better predictor of response and showed that higher exposure correlated with higher probability of response (n=122 CRC, ORR, p < 0.05) and safety events (n=204, Gr ≥ 3 neutropenia, anemia and thrombocytopenia, p < 0.001). Dose intensity analyses showed greater number of dose reductions for 3 mg/kg Q3W with effective (actual) dose received of 2.6 mg/kg Q3W in mCRC patients. E-R analyses for safety and efficacy and dose intensity analyses in mCRC 3L+ patients indicate that both 2.4 and 3.0 mg/kg doses provided meaningful efficacy (ORR); while the 3.0 mg/kg dose may provide higher response rates, the 2.4 mg/kg Q3W dosing regimen provides an optimal balance of safety and efficacy compared to 3.0 mg/kg Q3W. Conclusions: Population PK, E-R for efficacy and safety and RDI analyses and totality of clinical data supported the selection of 2.4 mg/kg Q3W as optimal ABBV-400 monotherapy dose for further study in mCRC patients. 1. Sharma M, et al. ASCO 2023. Abstract 3015. Clinical trial information: NCT05029882 .
(CDK) 4/6 inhibitors: An effective treatment for homologous recombination deficient (HRD) luminal breast cancers (BC)?
Authors: Gouvêa Lucas , Santos Elizabeth , Cesca Marcelle , Lopes Mario Machado , Soldi Nathalia , Primo Basilio De Souza Viviane , Braga Fabricio , Silva Eduardda B. , Ferreira Izabella , Bertoli Victor , Fernandes Thaissa , Carneiro Amanda , Chinelato Juliana Rosa , Novello Roberto
Published: July 2024

e13100

Background: Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) with endocrine therapy (ET) still represents the best 1st-line choice for hormone receptor (HR) positive(+)/HER2 negative(-) metastatic breast cancer (MBC) patients (pts). Approximately 8% of pts with HR+ BC harbors germline BRCA mutation (g BRCAmt). The interaction between Cyclin/CDK pathway, endocrine receptor (ER) and Breast Cancer gene 1/2 (BRCA1/2) is complex and evidence reported so far, await confirmation in the context of future randomized clinical trials. So far, limited data exist about treatment effectiveness of CDK4/6i in homologous recombination deficiency (HRD) Luminal BC. A current frequent question in clinical practice is which additional adjuvant therapy to prioritize for luminal BRCA tumors (tu), considering the approval of both CDK4/6i andpoly ADP ribose polymerase (PARP) inhibitors in this scenario. Considering potential impacts of genetic instability in tu biology, such as potential loss of Rb protein related to Loss of Heterozygosity (LOH) of BRCA2 as a primary resistance mechanism in CDK4/6i, we sought to analyze the clinical results of that drug in tu with genetic instability. Methods: We retrospectively analyzed real-world outcomes of CDK4/6i performance in HR+/HER2- MBC treated in a single institution, with focus in clinical outcomes of HRD BC. germline HR genes status and somatic phosphatidylinositol 3-kinase (PIK3CA) status were also analyzed. Results: A total of 384 consecutive MBC pts treated with CDK4/6i were included in this study. The most used CDK4/6i was palbociclib (40,6%), followed by ribociclib (29,8%) and abemaciclib (29,2%). Considering the whole cohort PFSm 30months (95%IC 26-34) and OSm were 56 months (95%IC 52-60) No differences in PFS or OS was observed among the 3 CDK4/6i. Median age of the cohort was 60 years old. 38.5% were premenopause Pts and 59.9% were postmenopause. A total of 149 (39%) pts performed germline screening. Between 19 pts with gHR mt, 12 were BRCA1/2 mt (just one BRCA1). The other were: 2 PALB2, 2 CHEK2, 1 ATM, 1 RAD51D, 1 RAD51C mt. So far, no differences in PFS ou OS was observed in the presence of BRCA 1/2 or other gHR mt. Nevertheless, PIK3CA mt was tested in 142 pts, 51 were positives. That mt was a predictor of worse OS (55m; 95%IC 45-65) x 63m (95%IC 56-69), p 0,019. Conclusions: The results of this real-world study suggest that treatment outcomes with CDK4/6i may be worse in pts with HRD tu due to potential differences in tu biology. Future exploration in larger samples of patients who have had biomarker testing is ongoing. Patients with Pik3CA mt treated with CDK4/6i presented worse clinical outcomes.
Real-world data of efficacy and safety of denosumab on patients with breast cancer with bone metastasis: Results from Chinese clinical experience.
Authors: Liang Xu , Zhang Ruyan , Zhu Anjie , Gui Xin-Yu , Li Huiping , Song Guohong
Published: July 2024

e13103

Background: Bone is the most common metastasis site in advanced metastatic breast cancer disease. Denosumab is advocated by various guidelines with high-quality of evidence for the treatment of breast cancer patients with bone metastases (BM) to delay or reduce the occurrence of skeletal related events (SRE). Data for bone lesion repair after treatment on image is still needed in real world. This retrospective study aims to evaluate the efficacy of denosumab on breast cancer with BM by MD Anderson (MDA) criteria which is specific to BM and its safety in real world. Methods: Data of patients age ≥18 years diagnosed with advanced breast cancer with BM and treated with denosumab from June 1st 2020 to Dec 31st 2022 were retrospectively analyzed. The primary endpoint was the objective response rate (ORR) for bone lesions by MDA criteria in evaluable patients. Secondary endpoints include disease control rate (DCR) for bone lesions, risk of SRE occurrence and safety in total population. Subgroup analysis investigated the impact of the time of denosumab treatment initiation post-diagnosis of BM as well as the duration of treatment with denosumab on efficacy. Comparative analysis was performed using Chi-squared test and a p value of <0.05 was considered statistically significant. Results: Atotal of 185 patients were enrolled with median age of 52.45 (SD: 12.02) years. The median follow-up time was 25.2 months. 49 out of the 130 evaluable patients achieved partial response, resulting in an ORR of 37.69% (95% CI: 0.29-0.47), and a DCR of 90% (95% CI: 0.84-0.95). 16 out of 185 (8.65%) patients developed SRE after denosumab treatment with the median time to the first occurrence of SRE not reached. The ORR and DCR for bone lesions of starting denosumab after diagnosis of BM in ≤3 months vs. >3 months were 31.54% vs. 6.15% (p<0.001) and 68.46% vs. 21.54% (p<0.001), respectively. The ORR and DCR for bone lesions of the duration of denosumab treatment <6 months vs. ≥6 months were 4.62% vs. 33.08% (p<0.001) and 37.69% vs. 76.92% (p<0.001), respectively. Renal function impairment decreased from 33 patients before treatment to 8 patients post-treatment, while hypocalcemia increased from 1.62% to 11.35%. Osteonecrosis of the jaw occurred in one patient (1/185,0.54%) post-treatment. Conclusions: Denosumab was found to be effective and safe for breast cancer patients with BM in this large retrospective study. Early initiation and longer duration of denosumab treatment may generate better clinical outcomes for bone lesions by MDA criteria.
Safety profile of sacituzumab govitecan in patients with breast cancer: A systematic review and meta-analysis.
Authors: Dacoregio Maria Inez , Michelon Isabella , Castro Caio , Moraes Francisco Cezar A. , Ravani Lis Victoria , Rossato de Almeida Guilherme , Vilbert Maysa , Costa Ricardo L.
Published: July 2024

e13106

Background: Sacituzumab govitecan (SG), a first-in-class TROP-2-directed antibody conjugated to a topoisomerase inhibitor, has shown antitumor activity across various breast cancer (BC) subtypes. Following SG approval for metastatic triple negative breast cancer (TNBC) and its broad use, understanding SG’ safety profile is crucial. Hence, we conducted a systematic review and meta-analysis to evaluate the safety and tolerability of SG in patients with BC. Methods: We comprehensively searched PubMed, Embase, and Cochrane databases, and ASCO and ESMO websites for clinical trials assessing the safety of SG in BC patients. Outcomes of interest included treatment-related adverse events (TRAEs) of any grade, grade 3/4, adverse events (AEs) leading to death, and AEs leading to SG dose reduction or discontinuation. All analyses were performed in R software (v.4.2.2) using random effects models. Heterogeneity was assessed using I2 test. Results: A total of 1,325 patients from six studies – three randomized clinical trials (RCTs) and three non-RCTs – were included. Median age of population ranged from 47 to 56 years. Most had metastatic disease (86%, n=1187), and triple-negative BC (48.6%, n=670). Regarding therapies, 798 patients received SG and 527 had treatment of physician's choice (TPC). In the pooled analysis of 748 patients on SG, the overall risk of AEs was 100% (95% CI 99-100%). The estimated risk of the most common all grade AEs were neutropenia (66%), anemia (44%), nausea (56%), vomiting (30%), fatigue (46%), constipation (17%), diarrhea (45%), and alopecia (46%), as described (Table). The risk of grade 3/4 AEs among 748 patients on SG was 55% (95% CI 36-74%). Neutropenia was the most important grade ≥3 AE, with a estimated frequency of 47%; followed by anemia and diarrhea, with an incidence of at 9% and 7%, respectively. The incidence of all other grade 3/4 AEs (e.g. anemia, vomiting, leukopenia, fatigue, constipation, and diarrhea) was below 10%. Dose reduction and discontinuation were observed in 14.4% and 2.9% of patients, respectively. Toxicity-related deaths occurred in six patients (0.4%). In a comparative sensitivity analysis of RCTs only, SG had significantly higher toxicity than TCPs, all grade AEs (OR 12.30 95%CI 1.68-89.87, p=0.01), and grade >3 AEs (OR 1.69 95%CI 1.25-2.28, p=0.0006). Conclusions: In this systematic review and meta-analysis, SG was associated with a high incidence of AEs. Neutropenia is a notable and potentially serious adverse event. Toxicity associated with SG may be addressed through close monitoring and early management. [Table: see text]
Prognostic factors for patients with breast cancer brain metastasis after stereotactic radiotherapy.
Authors: Xiong Jie , Chen Qiuchi , Zhao Yanxia
Published: July 2024

e13109

Background: Breast cancer (BC) is the most common cancer in females and BC brain metastasis (BCBM) is considered as the second most frequent brain metastasis. Numerous prognostic factors are associated with survival for patients with BCBMs. Here we investigated the clinical factors associated with overall survival (OS) and distant intracranial control (DIC) after stereotactic radiotherapy (SRT) for BCBM. Methods: The records of BCBM patients treated with SRT were collected from electronic database in Cancer Center, Union Hospital, Tongji medical college, Huazhong University of Science and Technology Hospital. Based on the univariate and multivariate Cox regression analysis, the prognostic significance of available variables was assessed. The nomogram was created from Cox models and internally validated by use of bootstrap and cross-validation. Model discrimination was measured by calibration plots and the concordance index, and the clinical benefits were evaluated through clinical decision curve analysis (DCA). Results: 101 BCBM patients receiving SRT were analyzed in this study, and 5 patients were excluded with other primary malignancies or missing data. Median observation time was 15.0 months, and median OS was 22.0 months. OS rate was 71.5% in 1 year, 45.8% in 2 years, and 32.8% in 3 years. DIC was 49.8% in 1 year, 26.6% in 2 years, and 18.3% in 3 years. Multivariable analysis identified prognostic factors for OS including number of the brain metastasis, molecular subtypes type, brain metastasis as the first metastasis site, Karnofsky performance status (KPS), and receiving systemic therapy after SRT. KPS<80, triple-negative subtype, the existence of extracranial metastases, the existence of lung metastases were associated with decreased DIC. Selected by the Akaike information criterion (AIC), the nomogram model contains age, KPS, histological subtype, number of brain metastases, brain metastasis as first metastasis site, PTV size, liver metastases, albumin and neutrophils. The calibration curve for probability of survival showed high consistencies between prediction by nomogram and actual observation. The C-index of the nomogram for predicting survival was 0.823, and the bias-corrected C-index generated by bootstrap validation with 1,000 resamples was 0.772, which was statistically higher than the C-index values of the other systems: Recursive partitioning analysis (RPA) (0.627), Graded prognostic assessment (GPA) (0.637), Breast-specific Graded Prognostic Assessment (breast-GPA) (0.699). BCBM patients receiving SRT were divided into four risk groups: I group (risk score < 150), II group (150≤risk score< 220), III group (220≤risk score<290) and IV group (risk score≥290). The Kaplan‐Meier OS curves showed great discrimination among the four risk groups. Conclusions: The proposed nomogram resulted in a more-accurate prognostic prediction for BCBM patients receiving SRT.
Investigating the outcome of vascular emboli in patients with breast cancer.
Authors: Hassan Abdelilah Tafenzi , Choulli Farah , Essadi Ismail , Belbaraka Rhizlane
Published: July 2024

e13116

Background: Vascular emboli (VE) represent a critical event in breast cancer pathophysiology. Despite their clinical relevance, their relative impact on breast cancer outcomes remains underexplored. In this study, we delve into comparing the survival outcomes and recurrence rates of patients with and without VE in patients with breast cancer (BC) and adjust for other patient-related variables. Methods: This study was designed based on a retrospective cohort of pathologically confirmed de novo, local, or metastatic recurrence BC female patients diagnosed between 2020 and 2022 and aged > 18 years. Kaplan-Meier curves and Cox proportional hazards models were used to estimate the effect of vascular emboli on survival and recurrence while controlling other reviewed demographic, clinic, pathologic, and therapeutic features following a course of adjuvant or neo-adjuvant treatments. Results: A total of 501 patients were eligible for this study (216 patients without VE vs. 285 patients with VE). The median follow-up was 274 (IQR: 195–523) days. In the group of patients with positive VE, the median age at diagnosis was 49 years, and the median progression-free survival (mPFS) was 881 (95% CI: 856, 1555) days; Patients with bilateral BC have a poorer mPFS of 515 (95% CI: 411, Not Estimable [NE]), while right BC was associated with a better outcome of 1,035 (95% CI: 869, NE) days (p = 0.001). Moreover, patients with positive hormonal receptors (HR >=10%) who benefited from endocrine therapies have a better PFS of 974 (95% CI: 872, NE) days compared to those with negative HR (<10%) of 656 (95% CI: 586, NE) days (p = 0.02). In addition to the molecular profile, TNBC was associated with poorer survival 579 (95% CI: 553, NE), compared to RH-/HER2+ 675 (95% CI: 635, NE), RH+/HER2- 935 (95% CI: 777, NE), and RH+/HER2+ 1,133 (95% CI: 856, NE) days (p < 0.001). Surgery was associated with better mPFS (935 (95% CI: 869, NE) days compared to neo-adjuvant or palliative patients 856 (95% CI: 635, NE) (p = 0.002). In the group of patients with negative VE, the median age was 48 years. The mPFS was 852 (95% CI: 789–996) days. Patients presented with positive lymph (N2) have a worse PFS of 611 (95% CI: 505, NE) days; in addition, patients with HER2=0 have a worse PFS of 775 (95% CI: 595, 1,320) days compared to HER2 1+ or non-amplified HER2 2+ 928 (95% CI: 840, NE) days, while no statistically significant differences between patients who received different treatment options (HER2 TKI, chemotherapy, radiotherapy, and endocrine therapy) were found. Conclusions: These findings emphasize the importance of considering VE status and hormonal receptor expression in tailoring treatment strategies for BC patients. Identifying high-risk individuals who may benefit from aggressive or novel therapies remains crucial for improving outcomes. Further research is warranted to validate these results and guide clinical decision-making.
CNS efficacy of trastuzumab deruxtecan in metastatic breast cancer: A single-institution, real-world analysis.
Authors: Zhang XiaojiE , Yeung Kay T.
Published: July 2024

e13117

Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate that revolutionized the management of patients with HER2+ (HER2 FISH+, IHC 3+) and HER2low (HER2 FISH-, IHC 1+/2+) metastatic breast cancer (MBC). Studies have shown that T-DXd may induce antitumor activity in HER2+ MBC with brain metastases (BM). However, data is limited on the central nervous system (CNS) efficacy of T-DXd in HER2low disease. The only report thus far is from the HER2low cohorts in the DEBBRAH study with 12 patients showing an intracranial overall response rate (ORR-IC) of 50% and progression free survival (PFS) of 5.7 months. Here, we provide a real-world, retrospective analysis of the CNS efficacy of T-DXd in HER2+, HER2low, and HER2null MBC with BM. Methods: This is a single institution, retrospective analysis of patients with MBC with BM who received T-DXd between January 2020 and November 2023. Patients with HER2+, HER2low, or HER2null MBC and BM, treated or untreated at the time of T-DXd initiation, were included. All patients had baseline brain magnetic resonance imaging before T-DXd initiation. Efficacy analyses were performed using the RECIST 1.1 criteria to CNS target lesions by investigator assessment. ORR-IC and intracranial clinical benefit rate (CBR-IC) were reported. CNS PFS, defined as time until CNS progression or death of any cause, and overall survival (OS) were also evaluated. Results: 29 patients were included in the study: 10 (35%) had HER2+, 16 (55%) had HER2low, and 3 (10%) had HER2null disease. The patients had ECOG performance status ranging from 0 to 3, and received a median of 3 prior lines of therapy (range 1-8). At baseline, 3 patients (10%) had untreated BM, 6 (21%) had prior surgery, and 23 (79%) had prior radiation. 28 (97%) had concurrent extra-cranial metastases. Best CNS response and duration of response are listed in the table below. ORR-IC was 10% overall and 6% in HER2low group. CBR-IC was 58% overall and 50% in HER2low group. Median OS in all patients was 65 weeks. Median CNS PFS was not statistically different in the overall group (24 weeks) compared to the HER2low group (21 weeks) with p=0.4661 via log rank test. Conclusions: This is the first real-world study reporting the CNS efficacy of T-DXd in patients with MBC across HER2 expression levels. The CNS efficacy of T-DXd in our institutional experience was similar in HER2+ and HER2low MBC, and was much lower than previously reported in prospective clinical trials. Performance status, extent of prior treatment, and systemic disease burden likely contributed to this difference. Larger cohort and prospective studies on patients with HER2low MBC with BM are warranted. [Table: see text]
A single-arm, open-label phase II clinical trial of SHR-1210 (camrelizumab) in combination with nimotuzumab in the second-line treatment of advanced esophageal squamous cell carcinoma.
Authors: Wang Feng , Xia Jin , Meng Xiangrui , Ji Yinghua , Yang Xiuli , Hong Yong-Gui , Wang Junsheng , Cui Donghai , Luo Zhiquan
Published: July 2024

e16007

Background: The prognosis of advanced esophageal cancer is bleak, and the current first-line regimen based on paclitaxel, cisplatin and fluorouracil (TPF) with an effective rate is about 30%. The second-line treatment regimen based on anti-PD-1/PD-L1 monoclonal antibodies obtained median overall survival (mOS) 10.8 months in phase I-II clinical trials, but a large proportion of patients (pts) still do not respond to this therapy. Additionally, nimotuzumab in the previous Cuba phase 2 study had a good disease control rate (DCR) combined with PF regimen. So, we conducted the study to evaluate the new combination modality efficacy and treatment-related adverse events (safety). The primary endpoints was ORR, and the secondary endpoints included overall survival (OS), DCR, progression-free survival (PFS), duration of response (DoR), time to response (TTR), 9-month and 12-month survival rate, as well as safety. Methods: According to the relevant literature, the second-line treatment for ORR is about 15%, and the efficacy of camrelizumab combined with nimotuzumab is expected to be 35%, alpha=0.05. A total of 38 cases were enrolled in the two-stage Simon method, with a bilateral α value of 5% and a test efficiency of 90%. In the first phase, 23 pts were enrolled 15 pts in the second stage. If 9 or more pts reached CR/PR. The trial is considered successful. The dropout rate of 10% was calculated, and a total of 42 pts were enrolled. Results: In this phase 2 study, a total of 41 pts were administered. One case was lost to follow-up. The mean age was 45 years (range, 42-77). The results of the intention-to-treat analysis showed that the ORR was 36% (15/42). The mOS was 12.62 months with median follow-up 8.28 months. The 9-month and 12-month survival rates were 84% and 51%, respectively. The DCR was 81% (34/42). Median PFS was 9.89 months with median follow-up 9.17 months. In terms of safety, the incidence of TEAEs was 60% (25/42), of which 71% (30/42) had adverse events below grade 3 and 26% (11/42) had adverse events above grade 3 including 0 case related to nimotuzumab and 4 cases related to camrelizumab. The overall incidence of adverse drug reactions grade 3 or above was 10% (4/42), of which 0 case related to nimotuzumab and 4 cases related to camralizumab. Conclusions: The combination of camrelizumab and nimotuzumab in the second-line treatment of advanced esophageal squamous cell carcinoma showed a trend benefit for ORR and OS with a controllable toxicity.
Impact of positive tumor-informed margin and TP53 mutations on surgical outcomes in esophageal squamous cell carcinoma.
Authors: Lu Di , Tong Yu , Liu Jingwen , Chen Zhiming , Wang Zhizhi , He Chunhong , Li Shaobin , Mai Shijie , Rao Xuguang , Cai Kaican
Published: July 2024

e16024

Background: The complete removal of esophageal squamous cell carcinoma (ESCC) with clear margins (R0 resection) is pivotal for patient prognosis. However, it is limited by the potential inaccuracies of conventional histopathology. Next-generation sequencing (NGS) for minimal residual disease (MRD) detection might improve the prediction of postoperative outcomes. Methods: The study cohort included a total of 48 operable ESCC patients, from whom resected esophageal tumors, resection margins, and normal tissues were collected and profiled by a 425-gene panel. Comparisons of mutational features were conducted across various tissue types, and their associations with disease-free survival (DFS) were explored. Results: Mutations were detected in 81.8% (27/33) of normal tissues, 95.8% (46/48) of tumors, and 50.0% (24/48) of resection margins. In general, genetic alterations in resection margins closely resembled those in tumor tissues, but were distinct from normal tissues. Both tumor and margin samples showed higher variant allele frequencies (VAFs) and fewer mutations per patient than normal samples ( p < 0.0001). Moreover, eight patients exhibited identical mutations in paired margin and tumor samples. Notably, one patient out of eight with the same TP53 p.T175H mutation across all sample types exhibited the shortest DFS of only two months. Mutations in TP53 and NOTCH1 were the most common, displaying unique mutational patterns among different sample types. While NOTCH1 mutations were detected more frequently in normal tissues ( p = 0.001), TP53 mutations were enriched in tumors ( p = 0.04). Furthermore, normal tissues exhibited a distinct pattern of mutation sites for TP53 and NOTCH1 compared to those observed in tumor or margin tissues. We characterized tumor-informed margin (TiM) by the presence of identical mutations in both tumor and adjacent margins. The positive TiM status was associated with a shorter DFS, particularly when considering TP53 mutations alone ( p = 0.022) or excluding NOTCH1 mutations ( p = 0.031). Conclusions: A positive TiM status with TP53 mutations is a promising biomarker indicating poor surgical outcomes in ESCC. Mutations within NOTCH1 are common but showed no association with DFS. These findings provide novel insights into the feasibility of genetic profiling of resection margins to facilitate optimizing postoperative therapeutic regimens for ESCC.
A single-arm, multicenter, phase II study of utidelone in advanced solid tumors: Efficacy data from screening and the expansion cohort assessing utidelone plus sintilimab and oxaliplatin for advanced gastric cancer.
Authors: Sun Meili , Yao Herui , Zhou Ying , Chen Hua , Fan Qingxia , Jiang Hua , Wang Shubin , Wu Yumei , Zhao Rui , Tang Li , Li Jin
Published: July 2024

e16055

Background: Treatment regimens for many advanced solid tumors are limited and alternative options are needed.Utidelone is approved for the treatment of advanced breast cancer in China. NCT04911907 is a single-arm, multicenter, phase II study to assess the efficacy and safety of utidelone in advanced cancer. Stage I of the trial, completed in October 2023, included patients (pts) with pretreated advanced solid tumors. Based on the stage I data, a stage II expansion cohort (USO-G) investigated utidelone plus sintilimab and oxaliplatin as first-line therapy for advanced gastric cancer (GC). Here, we report efficacy and safety data from stage I and stage II for interim analysis. Methods: Eligible pts aged 18–70 years with pretreated advanced solid tumors were enrolled in stage I and received utidelone monotherapy (35 mg/m2/day iv on days 1–5 every 21 days). In stage II, eligible pts with metastatic and/or unresectable HER2 negative GC received utidelone (30mg/m2/day iv on days 1–5 every 21 days) plus sintilimab (200 mg iv Q3W) and oxaliplatin (130 mg/m2/day Q3W for up to 6 cycles), until disease progression or unacceptable toxicity. Results: From March 18th 2021 to October 13th 2022, 79 pts were enrolled into 7 tumor cohorts and 54 pts were evaluable for efficacy. The best overall responses were 1 CR, 3 PRs and 3 SDs in 10 esophageal cancer pts, 3 PRs and 5 SDs in 15 GC pts, 1 PR and 3 SDs in 10 ovarian cancer pts, SD for all 4 cholangiocarcinoma pts, 3 SDs in 4 cervical cancer pts, 2 SDs in 3 pancreatic cancer pts and a PR in 1 neuroectodermal tumor patient. Grade 3/4 TRAEs occurred in 27.8% of pts in stage I, and included anemia (13.9%), peripheral neuropathy (11.4%) and neutropenia (7.6%). No treatment-related deaths occurred. Gastric cancer was chosen as the expansion cohort indication. As of February 1st 2024, 14 eligible pts with GC with a median age of 57 years (range, 41–69) were enrolled. The median follow-up was 5.5 months (range, 1.0–9.7) and the longest duration of response was 8.0 months. A total of 8 PRs and 3 SDs were achieved in the 11 pts evaluable for efficacy, and 6 pts including the 3 with SD were still receiving treatment. Grade 3/4 TRAEs occurred in 28.6% of pts including diarrhea (14.3%), fatigue (14.3%), neutropenia (14.3%), and vomiting (7.1%). Other AEs were all Grade 1 or 2, with no treatment-related deaths. Conclusions: Utidelone monotherapy showed antitumor activity and manageable toxicity in pts with advanced solid tumors. Utidelone plus sintilimab and oxaliplatin demonstrated promising efficacy and an acceptable safety profile as first-line treatment for pts with GC. Stage II of the USO-G study is still actively enrolling; further data will be provided at the time of presentation. Clinical trial information: NCT04911907 .
Analysis of the value of chromosomal instability test for evaluating early efficacy assessment in advanced gastric cancer.
Authors: Luo Xinpei , Yuan Min , Liu Zhuqing , Xie Rongjia , Xu Qing
Published: July 2024

e16060

Background: Gastric Cancer is featured by frequent somatic copy number alterations (SCNA) and high chromosomal instability (CIN). Circulating tumor DNA (ctDNA) is a minimally invasive approach, effective for the real-time follow-up of cancer. However, the clinical significance in gastric cancer is not yet determined.We performed this study to to evaluate whether ctDNA-based CIN analysis can predict treatment efficacy in advanced gastric cancer (AGC). Methods: The patients with surgery or cytopathology confirmed AGC and who received chemotherapy were enrolled. The blood sample (10ml) for ctDNA sequencing were obtained at baseline (BL) (before first-line chemotherapy) and at the time of efficacy assessment, respectively.The ctDNA of gastric cancer patients was isolated from plasma using QIAseq ctDNA extraction kit (Qiagen), and then repaired and amplified. The whole genome data were analyzed for DNA copy number abnormality, which was expressed as TFx value, and TFx ≥ 0.06% was taken as the positive value of chromosomal instability.Clinical responses (by RECIST 1.1 criteria) were estimated at the time points after 2 cycles of treatment. Results: A total of 18 patients were registered.There were 12 males and 6 females with a median age of 64 years (range 43-72 years).According to the RECIST1.1 criteria, there were 7cases of PR, 9 cases of SD, and 1 case of PD after treatment,1 case was under observation. Patients with CR+PR+SD were defined as the treatment-effective group, and with PD were defined as the treatment-ineffective group.The treatment-effective group mean value of CIN TFx value before treatment was 3.47±7.69, after treatment was 0.59±1.46(P<0.05),14 (82.35%) of these patients experienced a decrease in TFx values after treatment.Patients in the treatment-naïve group showed elevated TFx values.We divided the patients into group A and group B,group A was defined as the TFx value did not fall into the normal range after treatment, and group B was defined as the TFx value fell into the normal range and was called the rapid clearance group.Comparing the efficacy to the CIN group, 71.4% of patients with PR showed rapid clearance of ctDNA, while no clearance of ctDNA was observed in patients with PD,50.0% of patients with SD showed rapid clearance of ctDNA. Rapid clearance of ctDNA was also associated with longer survival, with a median OS of 7.2 months in group A and 17.85 months in group B, with HR of 0.55 (95% CI: 0.081-3.775 P > 0.05) However, there was no significant difference, probably due to too little data.In terms of PFS, Group B did not demonstrate benefit, with a median PFS of 5.9 months in Group A compared to only 3.9 months in Group B (P = 0.647). Conclusions: Dynamic ctDNA-based CIN assay can be used as a biomarker for efficacy assessment in metastatic gastric cancer. Rapid clearance of ctDNA is associated with longer survival, but this still needs to be validated with extensive data.