bluuebunny/crossref_metadata_2025 huggingface dataset:
Paxillin participates in the sphingosylphosphorylcholine-induced abnormal contraction of vascular smooth muscle by regulating Rho-kinase activation
Authors: Zhang Ying , Li Nan , Kobayashi Sei
Published: January 2024

Background

The Ca2+-independent contraction of vascular smooth muscle is a leading cause of cardiovascular and cerebrovascular spasms. In the previous study, we demonstrated the involvement of Src family protein tyrosine kinase Fyn and Rho-kinase in the sphingosylphosphorylcholine (SPC)-induced abnormal and Ca2+-independent contraction of vascular smooth muscle, but the specific mechanism has not been completely clarified.

Methods

Paxillin knockdown human coronary artery smooth muscle cells (CASMCs) and smooth muscle-specific paxillin knockout mice were generated by using paxillin shRNA and the tamoxifen-inducible Cre-LoxP system, respectively. CASMCs contraction was observed by time-lapse recording. The vessel contractility was measured by using a myography assay. Fyn, Rho-kinase, and myosin light chain activation were assessed by immunoprecipitation and western blotting. The paxillin expression and actin stress fibers were visualized by histological analysis and immunofluorescent staining.

Results

The SPC-induced abnormal contraction was inhibited in paxillin knockdown CASMCs and arteries of paxillin knockout mice, indicating that paxillin is involved in this abnormal contraction. Further study showed that paxillin knockdown inhibited the SPC-induced Rho-kinase activation without affecting Fyn activation. In addition, paxillin knockdown significantly inhibited the SPC-induced actin stress fiber formation and myosin light chain phosphorylation. These results suggest that paxillin, as an upstream molecule of Rho-kinase, is involved in the SPC-induced abnormal contraction of vascular smooth muscle.

Conclusions

The present study demonstrated that paxillin participates in the SPC-induced abnormal vascular smooth muscle contraction by regulating Rho-kinase activation.
ALA-RDT in GBM: protocol of the phase I/II dose escalation trial of radiodynamic therapy with 5-Aminolevulinic acid in patients with recurrent glioblastoma
Authors: Pepper Niklas Benedikt , Eich Hans Theodor , Müther Michael , Oertel Michael , Rehn Stephan , Spille Dorothee Cäcilia , Stummer Walter
Published: January 2024

Background

Despite improvements in surgical as well as adjuvant therapies over the last decades, the prognosis for patients with glioblastoma remains poor. Five-Aminolevulinic acid (5-ALA) induced porphyrins are already used for fluorescence-guided resection and as photosensitizer for photodynamic therapy. New findings reveal their potential use as sensitizing agents in combination with ionizing radiation.

Methods

We initiated a phase I/II dose escalation study, treating patients with recurrence of glioblastoma with oral 5-ALA concurrent to radiotherapy (RT). This prospective single-center study based in the University Hospital Münster aims to recruit 30 patients over 18 years of age with histologically verified recurrence of supratentorial glioblastoma in good performance status (KPS ≥ 60). Following a 3 + 3 dose-escalation design, patients having undergone re-resection will receive a 36 Gy RT including radiodynamic therapy fractions (RDT). RDT constitutes of oral administration of 5-ALA before the irradiation session. Two cohorts will additionally receive two fractions of neoadjuvant treatment three and two days before surgery. To determine the maximum tolerated dose of repeated 5-ALA-administration, the number of RDT-fractions will increase, starting with one to a maximum of eight fractions, while closely monitoring for safety and toxicity. Follow-up will be performed at two and five months after treatment. Primary endpoint will be the maximum tolerated dose (MTD) of repeated ALA-administration, secondary endpoints are event-free-, progression-free-, and overall-survival. Additionally, 5-ALA metabolites and radiobiological markers will be analysed throughout the course of therapy and tissue effects after neoadjuvant treatment will be determined in resected tissue. This protocol is in accordance with the SPIRIT guidelines for clinical trial protocols.

Discussion

This is the protocol of the ALA-RDT in GBM-study, the first-in-man evaluation of repeated administration of 5-ALA as a radiosensitizer for treatment of recurrent glioblastoma.

Trial registration

This study was approved by the local ethics committee of the Medical Association of Westphalia-Lippe and the University of Münster on 12.10.2022, the German federal institute for Drugs and medical devices on 13.10.2022 and the federal office for radiation protection on 29.08.2022. This trial was registered on the public European EudraCT database (EudraCT-No.: 2021-004631-92) and is registered under www.cliniclatrials.gov (Identifier: NCT05590689).
An analysis of the prevalence and risk factors of deep vein thrombosis in non-fracture patients awaiting total hip arthroplasty: a retrospective study of 1244 cases
Authors: Yao Yao , Chai Senlin , Qiao Liang , Jiang Qing , Xu Rong
Published: January 2024

Background

Deep vein thrombosis (DVT) has been one of the most dangerous complications in total hip arthroplasty (THA). If a patient’s pre-surgical DVT is overlooked, it can easily be mistaken for a post-operative thrombus and lead to an increased risk of DVT during and after surgery. This retrospective study was to explore the incidence and associated risk factors of deep vein thrombosis (DVT) in non-fracture patients before total hip arthroplasty (THA).

Methods

From September 2015 to September 2020, 1242 patients admitted for THA were enrolled with 1120 patients (90.2%) for primary THA and 122 patients (9.8%) for revision THA. An experienced sonographer performed a bedside ultrasound to detect DVT in bilateral lower limbs preoperatively. Univariate and logistic regression analysis was performed to identify the independent risk factors.

Results

38 patients (3.1%) were detected with preoperative DVT. Univariate analysis showed that age (P < 0.001), D-dimer level (P = 0.002), female patients (P = 0.016), revision THA (P < 0.001), Barthel Index score (P = 0.010) were significantly associated with preoperative DVT. In subgroup comparison, the incidence of DVT increased with age significantly (P < 0.001) and D-dimer level (P < 0.001). In logistic regression analysis, age ≥ 75 years old (odds ratio [OR] 3.678, 95% CI [2.197–18.721], P < 0.001), gender (OR 2.709, 95% CI [1.244–5.896], P = 0.012), higher D-dimer ≥ 0.5 mg/l (OR 6.841, 95% CI [2.197–18.721], P < 0.001) and revision THA (OR 2.240, 95% CI [1.143–5.372], P = 0.05) were confirmed as the independent risk factors.

Conclusions

The incidence of preoperative DVT in non-fracture patients was 3.1%, with 2.4% in primary THA and 9.0% in revision THA. Age ≥ 75 years old, female, D-dimer ≥ 0.5 mg/l, and revision THA were independent risk factors. When evaluating the risk factors associated with thrombus formation preoperatively, it is important to take these into account before surgery.
HRCTCov19-a high-resolution chest CT scan image dataset for COVID-19 diagnosis and differentiation
Authors: Abedi Iraj , Vali Mahsa , Otroshi Bentolhoda , Zamanian Maryam , Bolhasani Hamidreza
Published: January 2024

Introduction

Computed tomography (CT) was a widely used diagnostic technique for COVID-19 during the pandemic. High-Resolution Computed Tomography (HRCT), is a type of computed tomography that enhances image resolution through the utilization of advanced methods. Due to privacy concerns, publicly available COVID-19 CT image datasets are incredibly tough to come by, leading to it being challenging to research and create AI-powered COVID-19 diagnostic algorithms based on CT images.

Data description

To address this issue, we created HRCTCov19, a new COVID-19 high-resolution chest CT scan image collection that includes not only COVID-19 cases of Ground Glass Opacity (GGO), Crazy Paving, and Air Space Consolidation but also CT images of cases with negative COVID-19. The HRCTCov19 dataset, which includes slice-level and patient-level labeling, has the potential to assist in COVID-19 research, in particular for diagnosis and a distinction using AI algorithms, machine learning, and deep learning methods. This dataset, which can be accessed through the web at http://databiox.com, includes 181,106 chest HRCT images from 395 patients labeled as GGO, Crazy Paving, Air Space Consolidation, and Negative.
Multiple electrolytes imbalances in a patient with inflammatory bowel disease associated with vitamin D deficiency: a case report
Authors: Nakamura Yumiko , Kawai Yuichiro , Nagoshi Sumiko , Ogawa Tomonari , Hasegawa Hajime
Published: January 2024

Background

Inflammatory bowel disease involves chronic inflammation and ulceration, primarily Crohn’s disease and ulcerative colitis. The prevalence of inflammatory bowel disease is rising in industrialized countries. We describe the case of a patient with inflammatory bowel disease and multiple electrolyte disturbances that emphasize the link between a vitamin D deficiency and electrolyte imbalances.

Case

An 86‐year‐old Japanese man with severe hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia was referred to the gastroenterology and hepatology department our university hospital for severe diarrhea and abdominal pain. Based on clinical symptoms and biochemical and endoscopic findings, Crohn’s disease, intestinal Behçet’s disease, and intestinal tuberculosis were considered as differential diagnoses, but a final diagnosis was not reached. Prednisolone, azathioprine, and metronidazole were administered, and no apparent electrolyte abnormality was observed at the patient’s admission to our hospital. On the 80th hospital day, marked hypocalcemia, hypophosphatemia, hypokalemia, and hypomagnesemia were noted and prolonged, despite daily supplementation with Ca and inorganic P. At his consultation with our department, we observed decreased fractional excretion of Ca, tubular reabsorption of phosphate, fractional excretion of K, and fractional excretion of Mg, suggesting the depletion of vitamin D and extrarenal wasting of K and Mg. The patient’s serum Ca and inorganic P were quickly elevated in response to treatment with an active form of vitamin D, and his serum levels of K and Mg were restored to the normal range by an intravenous administration of K and Mg. A vitamin D deficiency is not rare in inflammatory bowel disease and is caused primarily by the decreased intestinal absorption of vitamin D. In the management of electrolyte imbalances in patients with inflammatory bowel disease, clinicians must consider the possible development of vitamin D deficiency-related disorders.

Conclusion

Vitamin D deficiency in entero-Behçet’s disease leads to severe hypocalcemia and hypophosphatemia, highlighting the importance of awareness in management.
Assessing risk of bias in the meta-analysis of round 1 of the Health Care Innovation Awards
Authors: Smith Kevin W. , Freeman Nikki L. B. , Bir Anupa
Published: January 2024

Background

Systematic reviews of observational studies can be affected by biases that lead to under- or over-estimates of true intervention effects. Several tools have been reported in the literature that attempt to characterize potential bias. Our objective in this study was to determine the extent to which study-specific bias may have influenced intervention impacts on total costs of care (TCOC) in round 1 of the Health Care Innovation Awards.

Methods

We reviewed 82 statistical evaluations of innovation impacts on Medicare TCOC. We developed five risk-of-bias measures and assessed their influence on TCOC impacts using meta-regression.

Results

The majority of evaluations used propensity score matching to create their comparison groups. One third of the non-randomized interventions were judged to have some risk of biased effects due largely to the way they recruited their treatment groups, and 35% had some degree of covariate imbalance remaining after propensity score adjustments. However, in the multivariable analysis of TCOC effects, none of the bias threats we examined (comparison group construction method, risk of bias, or degree of covariate imbalance) had a major impact on the magnitude of HCIA1 innovation effects. Evaluations using propensity score weighting produced larger but imprecise savings effects compared to propensity score matching.

Discussion

Our results suggest that it is unlikely that HCIA1 TCOC effect sizes were systematically affected by the types of bias we considered. Assessing the risk of bias based on specific study design features is likely to be more useful for identifying problematic characteristics than the subjective quality ratings used by existing risk tools.
Accuracy of procalcitonin for diagnosing sepsis in adult patients admitted to the emergency department: a systematic review and meta-analysis
Authors: Zaki Hany A. , Bensliman Soumaya , Bashir Khalid , Iftikhar Haris , Fayed Mohamed H. , Salem Waleed , Elmoheen Amr , Yigit Yavuz
Published: January 2024

Background

Differentiating sepsis from non-infectious systemic inflammatory response syndrome (SIRS) is challenging. Biomarkers like procalcitonin (PCT) aid early risk assessment and guide antibiotic use. This study aims to ascertain PCT's accuracy as a sepsis biomarker among adult emergency department admissions.

Method

The PRISMA guidelines were followed to search for relevant articles in five electronic databases between April 14th and August 4th, 2023: PubMed, Cochrane Library, ProQuest, EMBASEs, and ScienceDirect. Studies had to be published in English to avoid directly translating scientific terms. Besides, the inclusion criteria were based on the diagnosis of sepsis in adult patients admitted to an emergency department. QUADAS-2 tool provided by the Review Manager version 5.4.1 was utilized to assess the risk of bias in included studies. STATA (v. 16) software was used to perform the meta-analysis.

Results

Ten of 2457 studies were included. We sampled 2980 adult sepsis patients for the under-investigated role of PCT in ED sepsis diagnosis. PCT emerged as the primary early diagnostic biomarker with high levels (29.3 ± 85.3 ng/mL) in sepsis patients. Heterogeneity in outcomes, possibly due to bias in cohort and observational studies, was observed.

Conclusion

PCT tests offer moderate accuracy in diagnosing sepsis and stand out for rapidly and precisely distinguishing between viral and bacterial inflammations.
Blockchain-enabled supervised secure data sharing and delegation scheme in Web3.0
Authors: Gao Hongmin , Duan Pengfei , Pan Xiaofeng , Zhang Xiaojing , Ye Keke , Zhong Ziyuan
Published: January 2024

Web3.0 represents the ongoing evolution of blockchain technology, placing a strong emphasis on establishing a decentralized and user-controlled Internet. Current data delegation solutions for Web3.0 predominantly rely on attribute-based encryption algorithms (ABE) but lack the essential capabilities for processing ciphertext. Additionally, the attribute-based ciphertext transformation algorithm (ABCT) falls short when it comes to verifying the transformed ciphertext provided by data proxies. The primary objective of this article is to design a fine-grained and supervised attribute-based data delegating solution tailored specifically for Web3.0. This scheme aims to enhance the ciphertext processing capabilities of existing data delegation solutions based on blockchain and ABE. Additionally, it addresses the current limitations of ABCT technology. This includes its inability to verify re-encrypted ciphertext and ensure non-repudiation of transformation results. We leverage smart contracts to ensure the automatic execution of the data delegation process and to store permanent records on the blockchain for auditing and traceability. This approach guarantees a fair distribution of interests among all stakeholders. Furthermore, we employ a commitment mechanism and digital signature to enhance the regulatory compliance of existing ABCT technology. We present a secure access control and supervised data delegation scheme for Web3.0 with blockchain along with its instantiation, emphasizing its fine-grained nature and verifiability. Finally, the evaluation results demonstrate its practicality and effectiveness.
Taxonomic dependency and spatial heterogeneity in assembly mechanisms of bacteria across complex coastal waters
Authors: Yan Huizhen , Lin Dandan , Gu Gaoke , Huang Yujie , Hu Xuya , Yu Zhenhao , Hou Dandi , Zhang Demin , Campbell Barbara J. , Wang Kai
Published: January 2024

Background

Understanding community assembly mechanisms across taxa and space is fundamental for microbial ecology. However, the variability and determinants of assembly processes over taxa and space remain unclear. Here, we investigated taxonomic dependency and spatial heterogeneity in bacterial assembly mechanisms across coastal waters in the East China Sea using neutral and null models with customized visualization strategies.

Results

Overall, bacterial assembly mechanisms varied across broad taxonomic groups (phyla and proteobacterial classes) and space at the regional scale. A determinism–stochasticity balanced mechanism governed total bacterial assembly, while taxonomic dependency existed in assembly mechanisms and ecological processes. Among community ecological features, niche breadth and negative-to-positive cohesion ratio were strongly associated with the determinism-to-stochasticity ratio of bacterial groups. Bacterial assembly mechanisms commonly exhibited spatial heterogeneity, the extent and determinants of which varied across taxonomic groups. Spatial assembly of total bacteria was directly driven by many environmental factors and potential interactions between taxa, but not directly by geographic factors. Overall, the bacterial groups with higher spatial heterogeneity in assembly mechanisms were more related to environmental and/or geographic factors (except Bacteroidetes), while those with lower heterogeneity were more related to ecological features.

Conclusions

Our results confirm the pervasiveness of taxonomic dependency and spatial heterogeneity in bacterial assembly, providing a finer understanding about regulation across complex coastal waters.
Determinants of employees’ creativity: modeling the mediating role of organizational motivation to innovate
Authors: Yesuf Yohannes Mekonnen , Getahun Demis Alamirew , Debas Asemamaw Tilahun
Published: January 2024

The study aims to empirically investigate the effects of the work environment and family–work resource spillover on employees’ creativity in agricultural research institutes. Additionally, this research proposes to examine the mediating role of organizational motivation to innovate in the relationships between the work environment and family–work resource spillover on employees’ creativity. Using a sample of 302 researchers from agricultural research institutes in Ethiopia, the hypothesized relationships were tested through the partial least squares structural equation modeling (PLS-SEM) technique. The results reveal significantly positive direct effects of work group support and family–work resource spillover on employees’ creativity. However, the results did not confirm the direct relationships of factors such as sufficient resources, reliable workload pressure, freedom, challenging work, managerial encouragement, and employees’ creativity. The findings of the study contribute to our understanding of work contexts in agricultural research institutes and suggest ways in which administrators can create a conducive working environment to enhance employees’ creativity.
Cellular automata-based simulators for the design of prescribed fire plans: the case study of Liguria, Italy
Authors: Perello Nicoló , Trucchia Andrea , Baghino Francesco , Asif Bushra Sanira , Palmieri Lola , Rebora Nicola , Fiorucci Paolo
Published: January 2024

Background

Socio-economic changes in recent decades have resulted in an accumulation of fuel within Mediterranean forests, creating conditions conducive to potential catastrophic wildfires intensified by climate change. Consequently, several wildfire management systems have integrated prescribed fires as a proactive strategy for land management and wildfire risk reduction. The preparation of prescribed fires involves meticulous planning, entailing the identification of specific objectives, verification of prescriptions, and the definition of various scenarios. During the planning phase, simulation models offer a valuable decision-support tool for the qualitative and quantitative assessment of different scenarios. In this study, we harnessed the capabilities of the well-established wildfire simulation tool , to identify areas where prescribed fires can be performed, optimizing the wildfire risk mitigation and the costs. We selected a case study in the Liguria region, Italy, where the model is utilized operationally by the regional wildfire risk management system in emergency situations.

Results

Initially, we employed the propagation model to simulate a historical wildfire event, showcasing its potential as an emergency response tool. We focused on the most significant fire incident that occurred in the Liguria region in 2022. Subsequently, we employed to identify optimal areas for prescribed fires with the dual objectives of maximizing the mitigation of wildfire risk and minimizing treatment costs. The delineation of potential areas for prescribed fires has been established in accordance with regional regulations and expert-based insights. The methodology put forth in this study is capable of discerning the most suitable areas for the implementation of prescribed burns from a preselected set. A Monte Carlo simulation framework was employed to evaluate the efficacy of prescribed burns in mitigating the spread of wildfires. This assessment accounted for a variety of conditions, including fuel loads, ignition points, and meteorological patterns. The model was utilized to simulate the progression of wildfire spread.

Conclusions

This study underscores the utility of in offering both quantitative and qualitative insights that can inform prescribed fire planning. Our methodology has been designed to involve active engagement with subject matter experts throughout the process, to develop scenarios grounded in their expert opinions. The ability to assess diverse scenarios and acquire quantitative information empowers decision-makers to make informed choices, thereby advancing safer and more efficient fire management practices.
The role of BIM as a lean tool in design phase
Authors: Aziz Rania Mohsen , Nasreldin Tark Ibrahim , Hashem Omnia Mamdouh
Published: January 2024

In the architectural, engineering, and construction industry, poor visualization of construction processes and lack of information exchange between different work teams can lead to poor performance. To address these challenges, lean construction methodologies aim to reduce and eliminate waste in construction processes, while BIM technology aims to enhance collaboration between project team members. In general, these technologies can be used together to improve project management and cost reduction. This can be achieved through improving workflow and coordination, enhancing interaction among project members, and using available tools to analyze and improve work. Many aspects of the integration between LC and BIM have been studied, and researchers have come up with some findings and recommendations. Most studies previously demonstrated theoretically that cost reductions using BIM techniques are significant compared to the traditional approach of project management. This is what this study proved practically by applying BIM in the design of a building which is quite successful in construction as it identifies the main causes of construction waste such as reducing waiting time and reducing non-value-added work by using Dynamo to develop these designs. So, the research problem comes, which is how to keep up with development in the field of construction by applying different BIM programs, which results in reducing the time and cost used in design. BIM is a technology that aims to enhance project management and cut costs. A digital representation of the project that contains all the data required for planning, managing, and carrying out the project is created using BIM.
Prospective observational study investigating the impact of treatment sequence using regorafenib and FTD/TPI for metastatic colorectal cancer on overall survival (OSERO study).
Authors: Chida Akihiko , Kawakami Takeshi , Hamano Tetsutaro , Masuishi Toshiki , Mitani Seiichiro , Yasui Hisateru , Ishiguro Atsushi , Ando Takayuki , Sawada Kentaro , Harada Kazuaki , Takahashi Naoki , Boku Shogen , Kashiwada Tomomi , Esaki Taito , Yagisawa Masataka , Sugiyama Keiji , Yamamoto Kouji , Yuki Satoshi , Yamazaki Kentaro , Oki Eiji
Published: January 2024

103

Background: Regorafenib (REG) and trifluridine/tipiracil (FTD/TPI) with or without bevacizumab (BEV) are widely used as a later-line treatment for patients (pts) with metastatic colorectal cancer (mCRC). It is still unclear which is the preferable treatment strategy to start with, either REG, FTD/TPI, or FTD/TPI + BEV in clinical practice. Methods: We conducted a non–intervention, prospective, observational study in pts with mCRC at 41 sites. The key eligibility criteria were ECOG performance status (PS) 0 or 1, pts refractory to or intolerant of fluoropyrimidine, oxaliplatin, irinotecan, anti–angiogenesis, and anti–EGFR therapy if RAS status were wild type, and pts who plan to receive sequential treatment with REG and FTD/TPI BEV. Pts who starts with REG are enrolled in cohort A, FTD/TPI in cohort B, or FTD/TPI plus BEV in cohort C. The primary endpoint is overall survival (OS) of each group. Results: Between September 2020 and December 2022, a total of 501 pts were enrolled and 455 were identified as full analysis set. Pts’ characteristics of cohort A (149 pts) / B (80 pts) /C (226 pts) were as follows: median age 64.0 / 65.5 / 67.0 years, male 53.0 / 52.5 / 55.3%, ECOG PS 0 52.3 / 31.3 / 48.7%, tumor location right–sided 33.6 / 27.5 / 20.4%, RAS wild type 35.6 / 41.3 / 43.4%, and BRAF V600E mutant type 6.7 / 7.5 / 4.0 %. Pts who received subsequent with FTD/TPI BEV in cohort A / REG in cohort B / REG in cohort C were 62.4 / 37.5 / 62.8%. The median OS of cohort A / B / C was 11.8 / 7.1 / 10.2 months. Cox hazard model revealed hazard ratio (HR) 1.40 (95% confidence interval [CI] 1.01–1.94; p = 0.043) for cohort B, and HR 1.04 (95% CI 0.80–1.34; p = 0.784) for cohort C compared with cohort A. After adjusting age, ECOG PS, tumor location, the number of metastatic sites, the adjusted HR were 1.29 (95% confidence interval [CI] 0.87–1.91; p = 0.213) for cohort B, and 1.00 (95% CI 0.75–1.34; p = 0.998) for cohort C compared with cohort A. Conclusions: This study demonstrates that the OS are comparable regardless of whether REG, FTD/TPI, or FTD/TPI + BEV is administered first. Clinical trial information: UMIN000040586 .
DKN-01 plus bevacizumab and chemotherapy as second-line (2L) investigational therapy in advanced microsatellite stable (MSS) colorectal adenocarcinoma (CRC): DeFianCe trial.
Authors: Pelster Meredith , Strickler John H , Sirard Cynthia A. , Baum Jason , Haas Mike , Devoe Craig E. , Bustamante Liliana , Bubis Jeffrey Alan , Womack Mark Sanders , Chung Ki Y. , Raff Joshua P. , Wainberg Zev A.
Published: January 2024

104

Background: CRC is characterized by hyperactivation of the Wnt pathway where DKK1 plays a critical regulatory role. DKN-01 is an IgG4 monoclonal antibody that potently neutralizes DKK1. DKN-01 has immunomodulatory activity and stimulates a pro-inflammatory tumor microenvironment. Elevated DKK1 expression has been shown to correlate with fluorouracil (5FU) resistance in CRC tumors. 5FU-based combination therapies have demonstrated promising clinical activity in combination with DKN-01 in gastric cancer. In pre-clinical models of 5FU-resistant CRC, DKN-01 showed potent anti-tumor effects. Methods: DeFianCe (NCT05480306) is a Phase 2 randomized, open-label, two-part, multicenter study to evaluate efficacy and safety of DKN-01 plus FOLFIRI/FOLFOX and bevacizumab versus standard of care (SOC) [FOLFIRI/FOLFOX and bevacizumab] as 2L treatment of advanced MSS CRC patients (pts). The primary endpoint of the single arm Part A (DKN-01 + SOC) was safety and tolerability with secondary endpoints including overall response rate (ORR), progression-free survival (PFS) and overall survival. Retrospective analysis of tumoral DKK1 mRNA expression was measured centrally by in situ hybridization. Results: Thirty-three pts enrolled in Part A between Sept 2022-April 2023. As of 21 Aug 2023, median age 56 years (35, 84); 20 males. 29 pts had tumors with evaluable baseline DKK1 expression; 55% were DKK1-expressing (≥1% tumor cells). All patients had received prior 5FU-based therapies, 30 pts (91%) with oxaliplatin in combination and 17 pts (52%) had prior bevacizumab. 24 pts (73%) had RAS mutations (22 KRAS, 2 NRAS) and 23 pts (70%) had liver metastasis. 30 pts (91%) received DKN-01 + bevacizumab + FOLFIRI. 17 pts (52%) had ≥grade 3 treatment related adverse events (TRAE) with neutrophil count decreased, anemia and fatigue representing the most common. No pt discontinued DKN-01 due to a TRAE. Of the 27 response evaluable pts the ORR was 30% and the DCR was 93%: 8 PR, 17 SD and 2 PD. The median PFS has not been reached. Conclusions: DKN-01 in combination with SOC was well tolerated with promising preliminary activity (ORR 30% and DCR 93%) in the single arm Part A. PFS has not been reached and survival follow up is ongoing. Part B randomized expansion phase has begun and is enrolling an additional 130 pts. Tumoral DKK1 expression and correlation with clinical outcomes will be evaluated as an exploratory efficacy endpoint. Clinical trial information: NCT05480306 .
Anlotinib plus chemotherapy as first-line therapy for patients with gastrointestinal tumor with unresectable liver metastasis: Updated results from multi-cohort, multi-center phase II trial ALTER-G-001-cohort A.
Authors: Wu Junwei , Zhu Lingjun , Zhou Chenfei , Shi Min , Chen Jun , Zhao Liqin , Han Zhengxiang , Wang Chunbing , Jiang Jinling , Yan Jun , Wang Chun , Wei Xiaowei , Mao Yong , Cui Donghai , Yang Xiuli , Qin Zhiquan , Tang Xinyu , Zhang Jun
Published: January 2024

112

Background: Advanced gastrointestinal (GI) tumors, such as colorectal, gastric and pancreatic cancers (CRC, GC, and PC), and esophageal squamous cell carcinoma (ESCC), 20%-50% with liver metastases (LMs). The prognosis of CRC with unresectable LMs is poor, with a 5-year survival rate of less than 5%. Previous trials showed that anlotinib plus chemotherapy has promising clinical activity and a tolerable safety profile for advanced CRC and ESCC, especially with LMs. In this phase II trial, we assessed the efficacy and safety of anlotinib plus chemotherapy as first-line treatment for LMs GI tumors. Methods: Patients with unresectable LMs GI tumors and without previous systemic treatment would be divided into cohort A (CRC), cohort B (ESCC), and cohort C (other GI tumors, such as PC, GC, etc.). In cohort A, CRC patients received induction therapy (6 cycles, q3w): anlotinib (12 mg, PO, QD, days 1-14), oxaliplatin (130 mg/m2, IV, day 1), capecitabine (850 mg/m2, PO, BID, days 1-14). Patients without PD and radical resection received anlotinib and metronomic capecitabine (500 mg, PO, BID, days 1-21, q3w) maintenance until PD or unacceptable toxicity. The primary endpoint was ORR (RECIST 1.1). Secondary endpoints were DoR, PFS, OS, DCR, radical resection rate for LMs, and safety. Results: As of September 14, 2023, 45 patients were enrolled in cohort A, the median age was 67 years (35-75), 66.7% male, 91.1% ECOG-PS 1 and 60% had LMs only. After induction therapy, 8 patients received surgical resection. Currently, 13 patients are receiving induction therapy and 10 are undergoing maintenance therapy, with a maximum duration of treatment (DOT) of 13.7 months. Of 39 evaluable patients in cohort A, ORR and DCR were 48.7% and 97.4% (PR, n=19; SD, n=19, 16 SD had reduced tumor size). The median PFS was not reached. 36 patients had TEAEs and ≥ grade 3 TEAEs (33.3%) mainly included neutropenia (11.1%), hypertension (6.7%), and white blood cell decreased (6.7%). Conclusions: Anlotinib plus chemotherapy as first-line treatment has shown promising efficacy and acceptable safety and maybe a favorable option for advanced LMs CRC tumors. Clinical trial information: NCT05262335 .
HGCSG1801: A multicenter, prospective, phase II trial of second-line FOLFIRI plus aflibercept in patients with metastatic colorectal cancer (mCRC) refractory to anti-EGFR antibodies.
Authors: Ishiguro Atsushi , Nakatsumi Hiroshi , Harada Kazuaki , Yuki Satoshi , Sawada Kentaro , Sogabe Susumu , Ando Takayuki , Sasaki Yusuke , Yoshikawa Ayumu , Nakamura Michio , Dazai Masayoshi , Tateyama Miki , Muto Osamu , Kotaka Masahito , Sagawa Tamotsu , Hatanaka Kazuteru , Takagi Ryo , Sakata Yuh , Komatsu Yoshito
Published: January 2024

113

Background: Aflibercept (AFL) combined with FOLFIRI prolongs overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC) who failed a prior oxaliplatin-based regimen. However, there is limited evidence on the efficacy and safety of AFL plus FOLFIRI in RAS / BRAF wild type pts previously treated with anti-epidermal growth factor receptor (EGFR) agents. Therefore, we conducted a phase II trial evaluating the efficacy and safety of AFL plus FOLFIRI in Japanese pts with mCRC failing a prior oxaliplatin-based chemotherapy combined with an anti-EGFR agent. Methods: This was a prospective open-label phase II trial. AFL (4 mg/kg iv) followed by FOLFIRI (irinotecan 180 mg/m2, leucovorin 200 mg/m2 iv, bolus 5-FU 400 mg/m2 and infusional 5-FU 2400 mg/m2/46 h) was given every 2 weeks until progression or unacceptable toxicities. The primary endpoint was progression-free survival (PFS) rate at 6 months; secondary endpoints included OS, PFS, overall response rate (ORR), disease control rate (DCR), adverse events, and relative dose intensity (RDI) for each drug. Given a PFS rate threshold at 6 months of 38.9% and an expected PFS rate of 58.4% with AFL plus FOLFIRI, a sample size of 41 pts was required (two-sided alpha, 0.1; beta, 0.2). Analyses were conducted in the full analysis set (FAS) of pts satisfying eligibility criteria. Results: Forty-three patients were enrolled between November 2019 and October 2022, and 43 were analyzed (median age 68 years (range 27-80); male, 69.8%; ECOG PS 0/1, 72.1%/27.9%; left sided primary tumor, 90.7%). The primary endpoint was met: 6-month PFS rate was 58.7% (90%CI, 45.5%-71.9%). Median PFS and OS were 7.3 months (95%CI, 5.5-11.0 months) and 18.8 months (95%CI, 12.9-26.6 months), respectively. The ORR was 23.3 % (95%CI, 11.8-38.6%) and DCR was 88.4% (95%CI, 74.9- 96.1%). Mean RDI of AFL, irinotecan, bolus 5-FU and infusional 5-FU were 75.3% (SD, 26.2), 50.6% (SD, 12.5), 31.6% (SD, 26.6), and 58.7% (SD, 7.21), respectively. The main grade ≥3 adverse events included hypertension (62.8%), neutropenia (55.8%), leukopenia (25.6%), febrile neutropenia (11.6%), fatigue (9.3%), anorexia (9.3%), proteinuria (9.3%) and diarrhea (7.0%). No deaths and no new safety signals with a causal relation to the study treatment were observed. Conclusions: Results of this prospective phase II study suggest that AFL plus FOLFIRI shows a high response rate and a manageable safety profile in Japanese pts with mCRC who failed a first-line oxaliplatin-based plus anti-EGFR regimen. Clinical trial information: jRCTs011190006 .
Prognostic factors of patients (pts) with salvage-line metastatic colorectal cancer (mCRC).
Authors: Bando Hideaki , Oki Eiji , Takeda Yuriko , Misumi Toshihiro , Suzuki Motoko , Wakabayashi Masashi , Yamazaki Kentaro , Grothey Axel , Mayer Robert J. , Li Jin , Andre Thierry , Shi Qian , De Gramont Aimery , Yoshino Takayuki
Published: January 2024

115

Background: Randomized clinical trials provide the best evidence for the effects of a new treatment. However, the use of a placebo control arm may present practical and ethical concerns for enrolled patients and treating providers. The CRC ARCAD global database includes a total of 1,673 individual patient data (IPD) treated with placebo plus best supportive care in a salvage-line setting for refractory mCRC. By using placebo IPD, we have proposed to construct a synthetic control arm for clinical trials (Yoshino T. et al., Nature Medicine 2023). Methods: From 40,889 IPD from 59 studies in ARCAD mCRC database, 723 placebo pts were selected from 4 placebo-controlled randomized studies in a salvage-line setting (CORRECT, RECOURSE, CONCUR and TERRA). We analyzed the impact of baseline patient characteristics and various prognostic factors on outcome in the placebo control. Results: The adjusted hazard ratios (HRs) (95% confidence interval [CI]) were 0.52 (0.40-0.67) for the number of metastatic sites (1 vs 2+), 0.71 (0.59-0.84) for ECOG performance status (PS) (0 vs 1), 0.54 (0.45-0.66) for liver metastases (No vs Yes), 0.54 (0.40-0.71) for peritoneal metastases (No vs Yes), and 0.51 (0.38-0.70) for Royal Marsden Hospital (RMH) Score (consisting of albumin level, number of metastatic sites, and LDH level) (0-1 vs 2-3). Conclusions: Number of metastatic sites, ECOG PS, liver metastasis, peritoneal metastasis and RMH Score were significant prognostic factors in patients with mCRC receiving placebo in a salvage-line setting. Further prognostic factors should be investigated to increase the accuracy of the proposed synthetic control arm. [Table: see text]
Quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis of fruquintinib + best supportive care (BSC) compared with placebo + BSC in metastatic colorectal cancer (mCRC): Results from the FRESCO-2 trial.
Authors: Stintzing Sebastian , Tabernero Josep , Satoh Taroh , Dasari Arvind , Lonardi Sara , Eng Cathy , Garcia-Carbonero Rocio , Elez Elena , Yoshino Takayuki , Sobrero Alberto F. , Yao James C. , Kasper Stefan , Arnold Dirk , Basic Edin , Granold Matthias , Petschulies Marco , Wu Liwen , Chen Lucy , Yang Zhao , Van Cutsem Eric
Published: January 2024

116

Background: As mCRC and its treatment can adversely impact quality of life (QoL), maintaining QoL is an important treatment goal in addition to improving survival outcomes, particularly as patients progress through lines of therapy. In the global, randomized, double-blind, phase 3 FRESCO-2 trial (NCT04322539), fruquintinib (F) + BSC vs placebo (P) + BSC demonstrated significantly improved overall survival (OS) (median 7.4 months vs 4.8 months; HR 0.66, 95% confidence interval [CI] 0.55–0.80) and progression-free survival, with a manageable safety profile and without deterioration of QoL in heavily pretreated patients with refractory mCRC. The objective of this post-hoc Q-TWiST analysis was to assess the quality-adjusted survival benefit of F + BSC in the context of the FRESCO-2 trial. Methods: The Q-TWiST analysis was applied to all 691 randomized patients from FRESCO-2 (F + BSC n=461 vs P + BSC n=230). Survival time of each patient was partitioned into 3 health states: time spent with treatment-emergent adverse events of CTCAE grade 3 or 4 before disease progression (TOX), time before disease progression without toxicity (TWiST), and time between disease progression and death or censoring (REL). Assuming utility coefficients of 1 for TWIST and 0.5 for TOX and REL, Q-TWiST was calculated as the utility-weighted sum of the time spent in each health state. The mean time spent in each of the 3 health states was calculated for each treatment group using Kaplan-Meier analysis, and a 95% CI for the difference between treatment was calculated using the nonparametric bootstrap method. Results: Q-TWiST was 6.25 months for F + BSC and 4.21 months for P + BSC, a difference of 2.04 (95% CI 1.51–2.57) months longer with F + BSC vs P + BSC. This difference in Q-TWiST was mainly driven by the difference in the TWiST component (2.14 months [95% CI 1.78–2.49]; F + BSC 4.06 months vs P + BSC 1.92 months). The relative Q-TWiST gain, calculated as the difference in Q-TWiST divided by the mean OS time of the P + BSC group, was 31.4% in favor of F + BSC. Conclusions: In the FRESCO-2 trial, F + BSC demonstrated a clinically meaningful quality-adjusted survival benefit compared with P + BSC in heavily pretreated patients with refractory mCRC. Clinical trial information: NCT04322539 .
Subgroup analyses of the phase 3 CAIRO3 trial: Association of number and total volume of metastases on survival in patients with metastatic colorectal cancer based on a deep-learning automatic segmentation model.
Authors: Zwart Koen , Zeeuw Michiel J. , Stehouwer Bertine L. , Al-Toma Dania , Kurk Sophie , Braat Manon N.G.J.A. , de Jong Pim A. , Lagendijk Jan J.W. , May Anne M. , Koopman Miriam , Punt Cornelis J. A. , Kazemier Geert , Bol Guus
Published: January 2024

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Background: Maintenance treatment with capecitabine and bevacizumab after capecitabine, oxaliplatin, and bevacizumab therapy in metastatic colorectal cancer (mCRC) is shown to be effective with observation as an acceptable alternative. Metastatic burden might aid in shared decision-making and the aim of this exploratory analysis is to assess the prognostic and predictive value of number and total volume of metastases in mCRC patients included in the CAIRO3 study. Methods: Patients in the CAIRO3 study with liver and/or lung metastases were included. Every individual liver and lung metastasis was counted and volumes were assessed using deep-learning automatic segmentation software (SAS analytical platform and Philips IntelliSpace). Lymph node metastases were counted manually. Each scan was supervised by a dedicated radiologist. Kaplan-Meier analyses were used to estimate progression-free survival (PFS) and overall survival (OS) using log-rank testing for statistical comparison. Hazard ratios (HR) were estimated using Cox regression models. Results: A total of 156 patients were included with 154 OS events, in which 8198 metastases were identified: 5179 were liver metastases, 2835 lung metastases, and 184 lymph node metastases. Patients had a mean age of 63 years and 67% were male. At randomization, the median number of metastases was 9 and mean total metastatic volume was 116 cm3. Median OS for patients with ≤10 versus >10 metastases was 22.0 months (95%CI: 19.3-29.3) and 14.3 months (95% CI: 11.6-20.9, p-value <0.01), with similar differences for low/high tumor volume. In multivariable analysis number and total volume were independent prognostic markers for PFS and OS, respectively, after adjustment for age, sex, WHO performance score, treatment arm, serum lactate dehydrogenase (LDH) level, site of primary tumor, time to metastases, and treatment response. Benefit of maintenance therapy was most pronounced in patients with ≤10 compared to >10 metastases with a PFS HR of 0.24 (0.12-0.46) compared to 0.52 (0.28-0.96) and OS HR of 0.75 (0.42-1.34) compared to 1.17 (0.66-2.08), demonstrating potential predictive value. Conclusions: Metastatic burden is associated with a poor prognosis in patients with mCRC. Furthermore, patients with limited metastatic disease (1-10 metastases) benefit most from maintenance treatment and this could potentially be a predictive biomarker. [Table: see text]
Patterns of presentation and delivery of care of appendiceal neoplasms in the largest municipal health care delivery system in the United States.
Authors: Ahmed Armaan , Whittington Jennifer , Shafaee Zahra
Published: January 2024

14

Background: Appendiceal neoplasms (AN) are rare tumors with a broad spectrum of referral and treatment patterns. NYC Health+Hospital (HHC) is the largest municipal health care system in the United States. Here, we study patterns of presentation and management of AN in this safety-net setting. Methods: We identified 92 patients in HHC with AN between 01/01/2017 to 07/01/2023. Statistical analyses were performed in Python. Results: There were 38 (41.3%) mucinous neoplasms, 24 (26.1%) adenocarcinomas, 23 (25.0%) neuroendocrine, and 7 (7.6%) ex-goblet cell adenocarcinomas. 16 cases of pseudomyxoma peritonei were identified. The median age at diagnosis was 55 (IQR: 45-65). 49% were Hispanic, and African Americans were the largest racial block (28%). 50% of cases presented as appendicitis. Appendectomy and a second surgical intervention were more common in this group (p<0.001 and p=0.044, respectively). Other surgical interventions included colon resections and cytoreduction ± Hyperthermic intraperitoneal chemotherapy. Among the patients with mucinous neoplasm or adenocarcinoma, 35 had multidisciplinary tumor board discussion (15 mucinous neoplasm and 20 adenocarcinomas). The median follow-up period was 22.0 months (95% CI: 11.5-30.7 months). Surveillance modalities included CT (75%), CEA (74%), and colonoscopy (35%). 85% remained within HHC during treatment. 16 patients were planned to have chemotherapy, including 9 pseudomyxoma peritonei cases. 5 patients did not follow through, and the other cases had a median of 10 cycles. The following adjuvant chemotherapy regimens were employed: 50% FOLFOX, 20% FOLFIRI, 20% XELODA, and 10% CapeOX and FOLFIRI. There were 2 cancer-related deaths (pseudomyxomas). Excluding pseudomyxomas, none had evidence of disease at the last follow-up. Conclusions: Minorities and immigrants constitute the majority of the population of HHC. 50% of AN presented as appendicitis emphasizing the need for a robust system to identify these cases. Despite challenges encountered in providing long-term oncological care, HHC has treated and provided vigorous follow-up for this underserved population. [Table: see text]