bluuebunny/crossref_metadata_2025 huggingface dataset:
Supporting emergency service workers to cope with critical incidents that can lead to psychological burden at work - developing skills in the Post Critical Incident Seminar: a qualitative interview study
Authors: Korpela Sanna , Nordquist Hilla
Published: January 2024

Background

Emergency service workers face critical incidents causing psychological burden. This qualitative study investigates how attending a Post Critical Incident Seminar could affect the skills of emergency service workers to overcome incidents that can cause psychological burden at work and their consequences with the following research questions: (1) How did attending the Post Critical Incident Seminar impact the skills to overcome work incidents that can lead to psychological burden? and (2) How have these skills been manifested since attending the Post Critical Incident Seminar?

Methods

The data consists of individual interviews with fifteen emergency services workers who attended a Post Critical Incident Seminar in April 2021 in Finland. The interviews were conducted six months after the Post Critical Incident Seminar and analysed using inductive content analysis.

Results

The results of the first research question formed two main categories: improved performance abilities and improved self-regulation abilities. From the results of the second research question two main categories were created: new kind(s) of well-being and readiness to help. Several upper categories and sub-categories were discovered.

Conclusions

Based on the results, attending a Post Critical Incident Seminar may be effective in developing skills to overcome critical incidents that can lead to psychological burden. Further follow-up studies should investigate how acquired skills from the Post Critical Incident Seminar practically affect emergency service workers and their well-being in the longer term.
Effect of lignin in cellulose nanofibers on biodegradation and seed germination
Authors: Stocker Craig W. , Wong Vanessa N. L. , Patti Antonio F. , Garnier Gil
Published: January 2024

Pure cellulose nanofibers (CNFs) rapidly degrade in soil, limiting their prospective applications in agriculture. We incorporated lignin into CNFs as an antimicrobial and crosslinking agent to control the biodegradation rate. CNFs with different lignin concentrations were prepared by mechanochemical treatment in the presence of choline chloride-urea deep eutectic solvent. These were characterized using conductometric titration, scanning electron microscopy, and FT-IR. The fibers were applied to soil to determine the effect of lignin on soil respiration and nanocellulose degradation, and were used as a substrate for radish and cress seed germination. Modifying the lignin content of the fibers successfully modulated the biodegradation rate in soil. Fibers containing 35% lignin degraded 5.7% in 14 days, while fibers with 20% lignin degraded 20.8% in 14 days. Nanofiber suspensions showed low chemical inhibition for the germination of radish and cress seeds but higher lignin contents reduced the imbibition rate as a seed coating. This study presents the first use of lignin to control the biodegradation rate of cellulose nanofibers in a one-pot, scalable and sustainable system, allowing the advancement of lignocellulose nanofibers for applications such as seed coatings, mulches, and controlled release fertilizers.

Graphical Abstract
Detoxification and enhancement of in vitro rumen digestibility of exhausted olive pomace wastes through alkaline hydrogen peroxide treatment
Authors: Masmoudi Rahma , Ben Yahmed Nesrine , Moujahed Nizar , Darej Cyrine , Smaali Issam
Published: January 2024

Background

Due to the sharp rise in animal feed costs, funding alternatives to substitute high-cost raw materials used in animal feed is a persistent need. This study investigated the effect of alkaline hydrogen peroxide pretreatment as straightforward non-toxic technology to enhance the in vitro rumen digestibility of exhausted olive pomace (EOP), an abundant agricultural waste, to be suitable as animal feedstock. It examined the efficiency to eliminate the toxic phenolic content and minimize lipid oxidation of EOP.

Results

The pretreatment was first optimized using a central composite experimental design. Under the optimized conditions (1.6% H2O2, 5% NaOH), the measured phenolic content was 1.51 ± 0.03 mg/100 g dry weight (DW) for treated olive pomace (TOP) versus 4.91 ± 0.06 mg/100 g for the untreated one. The pretreatment showed that approximately 25% of the lignin was removed. Crude proteins, neutral detergent fibers, and acid detergent fibers yields of TOP were, respectively, 3.320 ± 0.05, 75.24 ± 0.23, and 54.05 ± 0.35 g/100 g of DW, significantly more important than those of untreated EOP. The enzymatic hydrolysis with a cellulase-based cocktail (Celluclast15 FPU/gDW), recorded a 48% of reducing sugar yield for TOP against 33% for EOP. When the in vitro organic matter digestibility (IVOMD) was assayed, the potential gas production of TOP (41.371 ml/g DM) was significantly higher than EOP (25.771 ml/g DM). The metabolizable energy of TOP (9.28 kcal/kg DM) was higher than that of EOP (7.78 kcal/kg DM).

Conclusions

The present study revealed that alkaline hydrogen peroxide (AHP) could be an efficient treatment for the detoxification and enhancement of in vitro rumen digestibility of olive pomace. This straightforward approach demonstrated that treated olive pomace waste may be well valorized as suitable animal feedstock.

Graphical Abstract
Simulation study of atmosphere–ionosphere variations driven by the eruption of Hunga Tonga-Hunga Ha’apai on 15 January 2022
Authors: Shinagawa Hiroyuki , Miyoshi Yasunobu
Published: January 2024

The volcano of Hunga Tonga-Hunga Ha’apai in Tonga erupted on 15 January 2022, generating severe disturbances in the atmosphere and the ionosphere. This event provided us with large amount of data of the atmosphere and the ionosphere, and various kinds of observational studies have been made. Recently several simulation studies have also been made to reproduce and understand the atmosphere–ionosphere variations driven by the volcanic eruption. Although the simulation studies have reproduced the global variations of the atmosphere and the ionosphere successfully, phenomena related with acoustic waves have not been fully investigated. We employed an axisymmetric three-dimensional nonhydrostatic atmospheric model and the whole atmosphere–ionosphere coupled model GAIA. We found that the simulation can produce various kinds of atmospheric waves generated by the eruption, such as acoustic waves, gravity waves, Lamb waves, Pekeris waves, and TIDs concentrically propagating from the eruption site, and atmospheric oscillations with a period of a few minutes. In addition, the results indicate that the eruption generates supersonic shock waves in the volcanic region, leading to the extremely large vertical oscillations in the thermosphere and ionosphere above the volcanic eruption region.

Graphical Abstract
Bathymetric effect on geoid modeling over the Great Lakes area
Authors: Li Xiaopeng , Lin Miao , Krcmaric Jordan , Carignan Kelly
Published: January 2024

Bathymetry data over lake areas are not included in the current and previous NGS (National Geodetic Survey) geoid models. Lake surfaces are simply treated as land surfaces during the modeling regardless of the apparent density difference between water and rock, resulting in artificial masses that distort the model from the actual gravity field and the corresponding geoid surface. In this study, compiled high-resolution bathymetry data provided by National Centers for Environmental Information are used to identify the real volume of water bodies. Under the mass conservation principle, two strategies are deployed to properly account the water body bounded by the mean lake surface and the bathymetry indicated lake floor into the current NGS geoid modeling scheme, where the residual terrain modeling method is used to account for topographic effects. The first strategy condenses water bodies into equivalent rock masses, with the cost of changing the geometrical shape of the water body. The second one keeps the shape of the water body unchanged but replaces the water and rock densities inside each topographical column bounded by the geoid surface and the mean lake surface by an averaged density. Both strategies show up to 1-cm geoid changes when compared with the previous geoid model that does not consider bathymetric information. All three geoid models are evaluated by local GNSS/Leveling benchmarks and multi-year-multi-mission altimetry indicated mean lake surface heights. The results show that both strategies can improve the geoid model precision. And the second strategy yields more realistic results.

Graphical Abstract
Comparison of different classification systems for pulmonary nodules: a multicenter retrospective study in China
Authors: Song Feipeng , Yang Qian , Gong Tong , Sun Kai , Zhang Wenjia , Liu Mengxi , Lv Fajin
Published: January 2024

Background

To compare the diagnostic performance of Lung-RADS (lung imaging-reporting and data system) 2022 and PNI-GARS (pulmonary node imaging-grading and reporting system).

Methods

Pulmonary nodules (PNs) were selected at four centers, namely, CQ Center (January 1, 2018-December 31, 2021), HB Center (January 1, 2021–June 30, 2022), SC Center (September 1, 2021–December 31, 2021), and SX Center (January 1, 2021–December 31, 2021). PNs were divided into solid nodules (SNs), partial solid nodules (PSNs) and ground-glass nodules (GGNs), and they were then classified by the Lung-RADS and PNI-GARS. The sensitivity, specificity and agreement rate were compared between the two systems by the χ2 test.

Results

For SN and PSN, the sensitivity of PNI-GARS and Lung-RADS was close (SN 99.8% vs. 99.4%, P < 0.001; PSN 99.9% vs. 98.4%, P = 0.015), but the specificity (SN 51.2% > 35.1%, PSN 13.3% > 5.7%, all P < 0.001) and agreement rate (SN 81.1% > 74.5%, P < 0.001, PSN 94.6% > 92.7%, all P < 0.05) of PNI-GARS were superior to those of Lung-RADS. For GGN, the sensitivity (96.5%) and agreement rate (88.6%) of PNI-GARS were better than those of Lung-RADS (0, 18.5%, P < 0.001). For the whole sample, the sensitivity (98.5%) and agreement rate (87.0%) of PNI-GARS were better than Lung-RADS (57.5%, 56.5%, all P < 0.001), whereas the specificity was slightly lower (49.8% < 53.4%, P = 0.003).

Conclusion

PNI-GARS was superior to Lung-RADS in diagnostic performance, especially for GGN.
Radiomics signature based on robust features derived from diffusion data for differentiation between benign and malignant solitary pulmonary lesions
Authors: Zhou Jiaxuan , Wen Yu , Ding Ruolin , Liu Jieqiong , Fang Hanzhen , Li Xinchun , Zhao Kangyan , Wan Qi
Published: January 2024

Background

Classifying and characterizing pulmonary lesions are critical for clinical decision-making process to identify optimal therapeutic strategies. The purpose of this study was to develop and validate a radiomics nomogram for distinguishing between benign and malignant pulmonary lesions based on robust features derived from diffusion images.

Material and methods

The study was conducted in two phases. In the first phase, we prospectively collected 30 patients with pulmonary nodule/mass who underwent twice EPI-DWI scans. The robustness of features between the two scans was evaluated using the concordance correlation coefficient (CCC) and dynamic range (DR). In the second phase, 139 patients who underwent pulmonary DWI were randomly divided into training and test sets in a 7:3 ratio. Maximum relevance minimum redundancy, least absolute shrinkage and selection operator, and logistic regression were used for feature selection and construction of radiomics signatures. Nomograms were established incorporating clinical features, radiomics signatures, and ADC(0, 800). The diagnostic efficiency of different models was evaluated using the area under the curve (AUC) and decision curve analysis.

Results

Among the features extracted from DWI and ADC images, 42.7% and 37.4% were stable (both CCC and DR ≥ 0.85). The AUCs for distinguishing pulmonary lesions in the test set for clinical model, ADC, ADC radiomics signatures, and DWI radiomics signatures were 0.694, 0.802, 0.885, and 0.767, respectively. The nomogram exhibited the best differentiation performance (AUC = 0.923). The decision curve showed that the nomogram consistently outperformed ADC value and clinical model in lesion differentiation.

Conclusion

Our study demonstrates the robustness of radiomics features derived from lung DWI. The ADC radiomics nomogram shows superior clinical net benefits compared to conventional clinical models or ADC values alone in distinguishing solitary pulmonary lesions, offering a promising tool for noninvasive, precision diagnosis in lung cancer.
An ampullary adenoma presenting with jaundice caused by duodenal intussusception: a case report
Authors: Nojima Hiroyuki , Shimizu Hiroaki , Hirota Mihono , Murakami Takashi , Yamazaki Masato , Yamazaki Kazuto , Shuto Kiyohiko , Kosugi Chihiro , Mori Mikihito , Usui Akihiro , Sazuka Tetsutaro , Koda Keiji
Published: January 2024

Background

Ampullary adenomas are premalignant lesions. However, biliary obstruction causing jaundice is rare. Duodenal intussusception secondary to an ampullary adenoma rarely occurs because of the fixed position of the duodenum in the retroperitoneum. Herein, we have described a rare case of ampullary adenoma with jaundice caused by duodenal intussusception.

Case presentation

A 40-year-old woman presenting with vomiting and yellowish discoloration of the skin was admitted to another hospital. The patient had experienced recurrent epigastric pain and vomiting for the past 18 months. Blood test results showed elevated levels of bilirubin (3.9 mg/dL), and abdominal computed tomography (CT) showed a 60-mm hypovascular mass in the third part of the duodenum and a left lateral shift of the dilated common bile duct. The patient was referred to our hospital for further evaluation. She recovered from hyperbilirubinemia spontaneously (levels of bilirubin, 1.0 mg/dL), and the CT showed a tumor shift from the third part of the duodenum to the second part and improvement of the dilated common bile duct. Hypotonic duodenography revealed a tumor that moved easily from the second to the third portion of the patient's position. Upper gastrointestinal endoscopy revealed a large papillary tumor occupying the second part of the duodenum, which was diagnosed as an adenoma through biopsy. The possibility of malignancy could not be negated owing to the presence of jaundice and an elevated carbohydrate antigen 19-9 level (76.0 U/mL). Pancreaticoduodenectomy was performed. The resected specimen showed a 60 × 40 × 40-mm pedunculated ampullary mass with submucosal elongation. The pathological examination indicated that the ampullary tumor was a high-grade intestinal adenoma. The postoperative course was uneventful, and the patient was discharged 26 days postoperatively.

Conclusions

This report describes a rare case of a patient with an ampullary adenoma presenting with jaundice resulting from duodenal intussusception. Owing to the possibility of a postoperative cancer diagnosis which may have caused the biliary obstruction and the difficulty in making an accurate preoperative diagnosis, it is imperative to choose the appropriate surgical procedure such as a pancreaticoduodenectomy.
Physiologically based radiopharmacokinetic (PBRPK) modeling to simulate and analyze radiopharmaceutical therapies: studies of non-linearities, multi-bolus injections, and albumin binding
Authors: Fele-Paranj Ali , Saboury Babak , Uribe Carlos , Rahmim Arman
Published: January 2024

Background

We aimed to develop a publicly shared computational physiologically based pharmacokinetic (PBPK) model to reliably simulate and analyze radiopharmaceutical therapies (RPTs), including probing of hot-cold ligand competitions as well as alternative injection scenarios and drug designs, towards optimal therapies.

Results

To handle the complexity of PBPK models (over 150 differential equations), a scalable modeling notation called the “reaction graph” is introduced, enabling easy inclusion of various interactions. We refer to this as physiologically based radiopharmacokinetic (PBRPK) modeling, fine-tuned specifically for radiopharmaceuticals. As three important applications, we used our PBRPK model to (1) study the effect of competition between hot and cold species on delivered doses to tumors and organs at risk. In addition, (2) we evaluated an alternative paradigm of utilizing multi-bolus injections in RPTs instead of prevalent single injections. Finally, (3) we used PBRPK modeling to study the impact of varying albumin-binding affinities by ligands, and the implications for RPTs. We found that competition between labeled and unlabeled ligands can lead to non-linear relations between injected activity and the delivered dose to a particular organ, in the sense that doubling the injected activity does not necessarily result in a doubled dose delivered to a particular organ (a false intuition from external beam radiotherapy). In addition, we observed that fractionating injections can lead to a higher payload of dose delivery to organs, though not a differential dose delivery to the tumor. By contrast, we found out that increased albumin-binding affinities of the injected ligands can lead to such a differential effect in delivering more doses to tumors, and this can be attributed to several factors that PBRPK modeling allows us to probe.

Conclusions

Advanced computational PBRPK modeling enables simulation and analysis of a variety of intervention and drug design scenarios, towards more optimal delivery of RPTs.
Highlights on the link between vitamin D and lipid panel in Egyptian multiple sclerosis patients
Authors: Swelam Mahmoud S. , Abdel Nasser Azza , Masoud Janet , Mamdouh Rasha , Said Shima , Abdel Hafeez Mohamed
Published: January 2024

Background

Diversity of risk factors, namely, vitamin D and lipid panel abnormalities, are connected to multiple sclerosis (MS) etiology and may possess an influential role on disease course. In a cross-sectional study, we correlated the demographic, clinical and radiological characteristics of 111 relapsing–remitting MS (RRMS) patients with their serum levels of vitamin D and lipid profile to evaluate the consequences of their abnormalities on disease activity and/or its progression.

Results

In the study group, the mean serum level of vitamin D was 18.93 ± 9.85 ng/mL, over 80% had insufficient level ( < 30 ng/mL) and significantly lower in females (P = 0.011). Insufficient vitamin D significantly associated with high relapse frequency (P = 0.005). Measurement the direction of this association showed that each 1 ng/mL increase in vitamin D was correlated with both decrease in annualized relapse rate (ARR) of 0.02 relapse/year (P = 0.017) and with decrease in number of relapses during last 2 years of 0.02 relapse (P = 0.045). Analysis of serum lipid panel showed a direct link between higher levels of TC and LDL to increased total number of relapses (P < 0.001 and 0.003, respectively) and EDSS (P = 0.001 and 0.022), also between higher TG and EDSS (P = 0.001). This link became indirect between HDL and both total number of relapse and EDSS (P = 0.001 and 0.001). Radiologically, positively linked confluent brain lesion to elevated TC and TG levels (P = 0.001 and 0.002, respectively) and cord lesions to elevated TC (P = 0.007). Longer disease duration positively associated with all lipids-related variables. As a direct effect on lipid metabolism, each 1 ng/mL increase in vitamin D was associated with reduction in serum TC of 1.48 mg/dL (P = 0.002) and rise in HDL of 0.35 mg/dL (P = 0.028).

Conclusions

Management of vitamin D insufficiency may decrease risk of higher ARR and the same for dyslipidemia in reduction of disability and confluent brain T2 lesion. Increasing vitamin D was positively correlated with HDL but negatively with TC.
Oxidative stress and inflammation: elucidating mechanisms of smoking-attributable pathology for therapeutic targeting
Authors: Addissouky Tamer A. , El Sayed Ibrahim El Tantawy , Ali Majeed M. A. , Wang Yuliang , El Baz Ayman , Elarabany Naglaa , Khalil Ahmed A.
Published: January 2024

Background

Tobacco smoking remains a major preventable cause of disease and death worldwide. Combustible cigarettes release thousands of chemicals that can initiate inflammatory pathways leading to smoking-related illness. This review aims to synthesize current scientific knowledge on mechanisms of smoking-induced disease, epidemiological trends, and clinical strategies from recent literature.

Main body of the abstract

At the cellular level, cigarette smoke triggers oxidative stress through reactive oxygen species (ROS), causing DNA damage. This provokes inflammatory signaling cascades mediated by damage-associated molecular patterns (DAMPs), receptors like RAGE and TLRs, and downstream cytokines. Smoking also disrupts apoptosis and autophagy. In the lungs, oxidative stress and inflammation from smoking play central roles in COPD pathogenesis. Smoking-induced oxidative DNA damage, chronic inflammation, and impaired immunity combine to promote lung carcinogenesis. For cardiovascular disease, smoking triggers endothelial dysfunction, platelet activation, and atherogenesis through oxidized LDL and effects on nitric oxide and adhesion molecules.

Short conclusion

Given the unequivocal evidence of health risks, smoking cessation is critical to reducing preventable death and disability. Both counseling and pharmacotherapy have proven efficacy for quitting, but efficacy remains limited long-term. Emerging nicotine products like e-cigarettes have unknown impacts on cessation and population health. Comprehensive efforts encompassing prevention, screening, treatment innovation, harm reduction, and policy reform focused on curbing smoking-attributable morbidity and mortality are warranted.
Value of S-Detect combined with multimodal ultrasound in differentiating malignant from benign breast masses
Authors: Li Na , Liu Wanling , Zhan Yunyun , Bi Yu , Wu Xiabi , Peng Mei
Published: January 2024

Background

Ultrasonography (US) still has some limitations in the differentiation of benign and malignant breast masses. Therefore, we introduced new technologies such as S-Detect, microvascular flow imaging (MVFI), and strain elastography (SE) into the examination and compared the multimodal method with Breast Imaging Reporting and Data System (BI-RADS).

Objectives

This prospective study aimed to evaluate the value of multimodal diagnostic methods that add S-Detect, MFI, and SR to US in differentiating benign from malignant breast masses.

Methods

We recruited 186 patients with 189 masses between July 2021 and March 2022. The masses were examined using US, S-Detect, SR, and MFI before biopsy, and the benign and malignant differentiation value of each and their combination were assessed compared with surgical pathology results using the area under the receiver operating characteristic curve (AUC), accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). Subgroup analysis by lesion size was also performed.

Results

The respective optimal cutoff values of SR and MFI for differentiating benign from malignant masses were 3.15 and 2.45, respectively, and the sensitivity and specificity were 79.3% and 85.6% and 94.6% and 69.1%, respectively. The multimodal AUC (0.907), sensitivity (97.8%), accuracy (90.5%), PPV (84.9%), and NPV (97.6%) were larger than those of each modality (p < 0.05), regardless of the mass size.

Conclusions

The diagnostic method of S-Detect combined with multimodal ultrasound can effectively improve the diagnostic efficiency of breast masses and is expected to become a routine examination for breast in future for better evaluation the benign and malignancy of breast masses.
Reconfigurable flexible metasurfaces: from fundamentals towards biomedical applications
Authors: Tian Jiangtao , Cao Wenhan
Published: January 2024

Metamaterials and metasurfaces of artificial micro-/nano- structures functioning from microwave, terahertz, to infrared regime have enabled numerous applications from bioimaging, cancer detection and immunoassay to on-body health monitoring systems in the past few decades. Recently, the trend of turning metasurface devices flexible and stretchable has arisen in that the flexibility and stretchability not only makes the device more biocompatible and wearable, but also provides unique control and manipulation of the structural and geometrical reconfiguration of the metasurface in a creative manner, resulting in an extraordinary tunability for biomedical sensing and detection purposes. In this Review, we summarize recent advances in the design and fabrication techniques of stretchable reconfigurable metasurfaces and their applications to date thereof, and put forward a perspective for future development of stretchable reconfigurable metamaterials and metasurfaces.
Talazoparib (Tala) in patients (pts) with colorectal cancer (CRC) with BRCA1/2 mutations (mut): Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.
Authors: Yost Kathleen J , Rothe Michael , Mangat Pam K. , Garrett-Mayer Elizabeth , Duvivier Herbert Leon , Ahn Eugene R. , Cannon Timothy Lewis , Chiu Vi Kien , Khalil Maged F. , Kim Brian , Prinz Allison Marie , Grantham Gina N. , Gregory Abby , Hinshaw Dominique C. , Halabi Susan , Schilsky Richard L.
Published: January 2024

106

Background: TAPUR is a phase II basket study evaluating antitumor activity of commercially available targeted agents in pts with advanced cancers with specific genomic alterations. Results in a cohort of pts with CRC with BRCA1/2 mut treated with Tala are reported. Methods: Eligible pts had measurable disease, ECOG performance status (PS) 0-2, adequate organ function, and no standard treatment (tx) options. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received 1 mg of Tala orally daily until disease progression. Primary endpoint was disease control (DC) per investigator defined as complete or partial response or stable disease of at least 16 weeks (wks) duration (SD16+) per RECIST v 1.1. Simon 2-stage design tested the null DC rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled; otherwise, the cohort is closed. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints were objective response (OR), progression-free survival (PFS), overall survival (OS), and safety. Results: 10 pts with advanced CRC and BRCA1 mut (n=3), BRCA2 mut (n=5), or both (n=2) were enrolled from February 2020 to June 2021. Germline or somatic status was not reported in 7 of 10 pts, 2 pts had somatic BRCA2 muts and 1 pt had a germline BRCA2 mut. 2 pts had left sided tumors, 2 had right sided, 3 had rectal tumors, and 3 pts had tumors that were site undetermined. All pts were evaluable for efficacy and toxicity. Table summarizes pt demographics and outcomes. No pts experienced DC, median PFS was 8 wks (95% CI, 6 to 8) and median OS was 24 wks (95% CI, 7 to 43). Co-alterations were observed in the following genes: KRAS (3 pts) and BRAF (2 pts). 2 pts had 3 separate grade 3 adverse events of anemia or fatigue at least possibly related to Tala. Conclusions: Monotherapy Tala did not demonstrate sufficient clinical activity in pts with advanced CRC with BRCA1/2 mut. Other tx should be considered for these pts, including tx offered in clinical trials. Clinical trial information: NCT02693535 . [Table: see text]
An ARCAD database nomogram for prognostic prediction of treatment refractory metastatic colorectal cancer.
Authors: Oki Eiji , Bando Hideaki , Yamazaki Kentaro , Misumi Toshihiro , Takeda Yuriko , Suzuki Motoko , Wakabayashi Masashi , Wakabayashi Masashi , Grothey Axel , Mayer Robert J. , Li Jin , Andre Thierry , Shi Qian , De Gramont Aimery , Yoshino Takayuki
Published: January 2024

107

Background: The "No Placebo Initiative" demonstrated that the survivals of patients (pts) receiving placebo in a salvage-line setting, exhibited no significant difference across trials (CORRECT, RECOURSE, CONCUR and TERRA). Therefore, we believe that a nomogram can be generated using the ARCAD database to predict survival of pts who completed standard therapy. Methods: Of 40,889 Individual patient data (IPD) from 59 studies, 723 pts received placebo from 4 randomized studies were pooled. The potential prognostic factors considered include BMI and Age. Imputed datasets were constructed by a multiple imputation method since the original dataset contains some missing values. Overall survival (OS) was defined as the time from randomization to death from any cause. Multivariate Cox proportional hazards models for OS were estimated based on the variables showing clinically and statistically significant by univariate analysis. Prediction performance of the final model was evaluated using the concordance index for survival data and calibration plots. Results: From univariate and multivariate analysis, ECOG performance status, Royal Marsden Hospital score (calculated by albumin level, LDH level, and number of metastatic site), primary site location, liver meta, peritoneal meta were selected as variables. We successfully developed a highly accurate nomogram to predict post-standard treatment prognosis for pts with mCRC. Concordance index for OS was 0.66. Conclusions: Although further validation in other cohorts is needed, this nomogram could be very useful to estimate the survival for clinical practice and enrolling in clinical trials. [Table: see text]
Short course immunotherapy as curative-intent treatment in stage I-III dMMR rectal cancer.
Authors: Pfeiffer Per , Andersen Per Vadgaard , Salomon Søren , Øgaard Nadia , Demuth Christina , Andersen Claus Lindbjerg , Gögenur Ismail , Justesen Tobias Freyberg , de Lima Vinicius Araujo , Tarpgaard Line Schmidt
Published: January 2024

121

Background: Neoadjuvant chemo-radiation followed by resection is standard treatment for patients with locally advanced rectal cancer (RC). A subset of RC are mismatch repair deficient (dMMR). Check-point inhibitors (CPI) are the standard of care in dMMR colorectal cancer (CRC) in the metastatic setting, and recent trials have demonstrated impressive efficacy in early CRC, even with a limited number of cycles. In the NICHE-II trial (Chalabi et al, ESMO 2022) 72 of 107 patients (67%) with colon cancer obtained pathological complete response (pCR) after short course CPI. In patients with RC, Cercek et al (NEJM 2022) showed that 12 patients (100%) obtained pCR after 6 months of dostarlimab. The efficacy of CPI in dMMR RC has only been evaluated in few studies. Here we report data from a Danish trial with early dMMR RC. EU CT number 2022-500646-14-00. Methods: The purpose was to evaluate the efficacy and tolerability of 1 cycle of nivolumab (3 mg/kg days 1 and 15 - nivo) and ipilimumab (1 mg/kg day 1 - ipi) in patients with early stage dMMR RC. The primary endpoint was number of patients with clinical complete response (cCR - no visible or palpable tumor) evaluated 4 weeks after nivo-ipi. Patients achieving a clinical, radiological, pathological (representative biopsy without viable tumor cells), and molecular complete response was offered a thorough watchful waiting strategy without surgery. Results: 5 patients were treated, 4 patients received a single cycle of nivo-ipi and 1 patient received 2 cycles of nivo-ipi, as the tumor was still visible at the first endoscopy (Table). All 5 patients were evaluated 4 weeks after completing nivo-ipi and all 5 patients (100%) achieved cCR. All 5 patients were ctDNA positive (Jensen et al, Clin Chem 2020) at diagnosis, 4 patients turned negative after therapy (1 pending). No patient needed radiotherapy and all patients agreed to non-surgical watchful waiting. No patient has had progression or recurrence (1-42 months follow-up). Conclusions: Short-course nivo-ipi is very effective in locally advanced dMMR rectal cancer and may become an alternative to resection. Clinical trial information: 2022-500646-14-00 . [Table: see text]
A phase 1b study of sotorasib combined with panitumumab as second-line treatment of KRAS G12C-mutated colorectal cancer.
Authors: Yaeger Rona , Langer Corey J. , Ruffinelli Jose Carlos , Fakih Marwan , Furqan Muhammad , Machiels Jean-Pascal H. , Saportas Yaneth , Nolte-Hippenmeyer Jane , Chan Emily , Xia Caihong , Masuishi Toshiki
Published: January 2024

128

Background: In the CodeBreaK 101 phase 1b study, sotorasib, a KRASG12C inhibitor, plus panitumumab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, showed acceptable safety and promising efficacy for patients with chemorefractory KRAS G12C–mutated metastatic colorectal cancer: an objective response rate (ORR) of 30% and median progression-free survival (PFS) of 5.7 months were observed. Here, we evaluated sotorasib plus panitumumab in the second-line (2L) setting. Methods: CodeBreaK 101 (NCT04185883) subprotocol H includes dose exploration and expansion in multiple cohorts. Patients eligible for the 2L sotorasib plus panitumumab dose-expansion cohort were KRASG12C inhibitor–naïve and had received no more than one prior regimen for metastatic disease. Patients received oral sotorasib at 960 mg daily and IV panitumumab 6 mg/kg every 2 weeks. The primary endpoint was safety. Secondary endpoints included efficacy endpoints. Results: As of May 23, 2023, this cohort was fully enrolled; all 20 patients (50% female, median age 60.0 years) were included in this analysis. All patients received fluoropyrimidine-based treatment and 17 (85%) patients received oxaliplatin-based treatment as first-line therapy. Any-grade treatment-related adverse events (TRAEs) occurred in 19 (95%) patients. The most common any-grade TRAEs were dermatitis acneiform (60%), dry skin (55%), pruritus (45%), and hypomagnesemia (30%). Grade ≥3 TRAEs occurred in 4 (20%) patients and included fatigue, hypomagnesemia, decreased appetite, and rash (5% each). No TRAEs were grade ≥4 or resulted in treatment discontinuation or deaths. Confirmed ORR was 30% (95% CI: 11.9, 54.3). The disease control rate was 90% (95% CI: 68.3, 98.8). At a median follow-up of 11.3 months (95% CI: 5.6, not estimable), median PFS was 8.3 months (95% CI: 4.3, 14.1). Conclusions: This is the first report of safety and efficacy from a 2L cohort evaluating a KRASG12C inhibitor plus an anti-EGFR antibody in KRAS G12C-mutated metastatic colorectal cancer. The toxicities of sotorasib plus panitumumab were consistent with the expected safety profile of the individual agents and with that reported previously for this combination; the ORR was similar to that previously observed for this combination in a more chemorefractory population. The ORR and PFS of sotorasib plus panitumumab compare favorably to current standard approaches in the 2L treatment of metastatic colorectal cancer. Clinical trial information: NCT04185883 .
Amivantamab monotherapy in relapsed/refractory metastatic colorectal cancer: OrigAMI-1, an open-label, phase 1b/2 study.
Authors: Oberstein Paul Eliezer , Moreno Victor , Raghav Kanwal Pratap Singh , Hong Yong Sang , Han Sae-Won , Su Yu-Li , Yuan Ying , Pietrantonio Filippo , Van Cutsem Eric , Eng Cathy , Curtin Joshua C , Chowdhury Sanjib , Bhattacharya Rianka , Maul Raymond Scott , Iwasawa Ryota , Schnepp Robert W. , Knoblauch Roland Elmar , Thayu Meena , Ho Gwo Fuang , Kim Han Sang
Published: January 2024

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Background: Amivantamab (ami), an EGFR-MET bispecific antibody with immune cell-directing activity, has shown preclinical activity in colorectal cancer (CRC) models. MET amplification is implicated in driving resistance to anti-EGFR therapies in metastatic CRC (mCRC). We hypothesize that dual, co-inhibition of EGFR and MET with ami could improve outcomes in relapsed/refractory mCRC. Methods: OrigAMI-1 (NCT05379595) is assessing the safety and efficacy of ami as monotherapy in patients (pts) with refractory mCRC in 3 separate cohorts (Table). Eligible pts were wild-type for KRAS, NRAS, BRAF, and EGFR ectodomain by ctDNA testing, without ERBB2/ HER2 amplification. Cohorts A and B included pts with left-sided mCRC without/with prior exposure to anti-EGFR monoclonal antibodies, respectively, and cohort C included pts with right-sided mCRC. Safety population included all pts receiving the recommended phase 2 dose (RP2D; 1050 mg [1400 mg, ≥80kg]). Investigator-assessed response per RECIST v1.1 is reported for evaluable pts with post-baseline disease assessment(s) or who discontinued for any reason. Ami plus FOLFOX or FOLFIRI is being explored in additional cohorts. Results: As of September 4, 2023, 93 pts were treated at RP2D; 89 were response evaluable (median follow-up: 4.4 mo). Median age was 60 years, 66% were male, and median prior lines of therapy were 2, with 94% receiving prior bevacizumab and 69% prior anti-EGFR therapy. Best timepoint responses were: Cohort A: 7/17, 41.2%; Cohort B: 13/54, 24.1%; Cohort C: 1/18, 5.6%. Disease control rates (DCR) were 88.2%, 72.2%, and 77.8% for Cohorts A, B, and C, respectively. Median duration of response (mDoR) for confirmed responders was 7.5 and 7.4 mo for Cohorts A and B, respectively. Treatment is ongoing for the responder in Cohort C. 10/13 responders (77%) remain on treatment. Preliminary biomarker data suggest ami may be active in alterations associated with anti-EGFR antibody resistance (eg, EML4-ALK fusion, PTEN). The most frequent treatment-emergent adverse events were rash (84%) and infusion-related reactions (53%). No new safety signals were observed. Updated results will be presented at the meeting. Conclusions: Ami monotherapy demonstrated promising, durable antitumor activity in refractory mCRC, including pts treated with prior anti-EGFR therapy and pts with right-sided disease. The safety profile of ami in mCRC is manageable and consistent with prior NSCLC experience. Clinical trial information: NCT05379595 . [Table: see text]
Validation of a novel web-based application for hepatic arterial infusion floxuridine dosing.
Authors: Ellis Carleton Scott , Nutalapati Snigdha , Moss Jessica Jane , Barry-Hundeyin Mautin S. , Pandalai Prakash , Kim Joseph , Patel Reema Anil , Cavnar Michael J.
Published: January 2024

15

Background: Hepatic arterial infusion (HAI) floxuridine (FUDR) dosing is a complex, multifactorial process with weight-based dosing dependent on the fold change of aspartate aminotransferase, alkaline phosphatase, and total bilirubin relative to reference values from preceding cycles and compounded over time. Given the complexity of dosing calculations and lack of experience with this treatment in community centers, HAI is typically administered only at tertiary oncology centers with limited access for rural disadvantaged patients. We developed an online tool to automate the dosing of FUDR to broaden safe and effective administration of HAI. Methods: The FUDR dosing algorithm developed at Memorial Sloan Kettering Cancer Center was digitalized as eDoseHAI, a novel multi-layer architecture web application tool featuring JavaScript (front-end), C# RESTful API (back-end) and Azure SQL server (data storage with Splunk data lake event registration). To validate this tool, manual dosing from patients who received ≥1 dose of HAI FUDR at our institution 6/2020-8/2023 was retrospectively compared to app-based dosing. Mismatch between app-based dosing and historical manual dosing was designated as dosing errors, excluding intentional adjustments based on physician discretion. Results: Internal validity was tested by entering records into eDoseHAI from 54 patients who received a total of 370 FUDR cycles (median 6; range 1-19). Ten patients (18.5%) were found to have unintentional dosing errors (e.g., delayed dose reductions) during treatment, impacting 52 cycles (14.1%). The median cycle at first error was 3 (range 2-6), impacting a median of 5 cycles (range 3-12). Dosing errors occurred in only 11.1% of the 45 patients supervised by a senior HAI physician, compared to 55.6% of the 9 patients supervised by three less experienced HAI physicians. Dosing accuracy improved over time; among the 14 patients on active HAI therapy, only 1 had an identified dosing error. eDoseHAI was able to reliably and accurately calculate dosing for all patients. Conclusions: HAI FUDR dosing is nuanced and complex, such that dosing errors occurred even with senior HAI oncologists. eDoseHAI is a web-based application tool designed to improve accuracy and thus safety of HAI dosing. We plan to further validate eDoseHAI using external data from an international HAI consortium, and to conduct a phase II clinical trial in which our team supervises FUDR dosing by community oncologists using eDoseHAI's supervisory mode with a goal to disseminate HAI therapy to disadvantaged rural patients who lack access.
Genomic alteration in sporadic adolescent and young adult-onset colorectal adenocarcinoma.
Authors: Korphaisarn Krittiya , Sakornsakolpat Phuwanat , Pongpaibul Ananya , Roothumnong Ekkapong , Thongnoppakhun Wanna , Akewanlop Charuwan , Pithukpakorn Manop
Published: January 2024

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Background: Colorectal cancer (CRC) incidence is increasing in adults younger than 50 years. This study evaluated genomic alteration in adolescent and young adult (AYA)-onset sporadic CRC patients who aged between 15 and 39 years. Methods: DNA from 90 archived formalin-fixed, paraffin-embedded (FFPE) tissue samples that histologically confirmed adenocarcinoma with proficient mismatch repair tumors at Siriraj Hospital (Bangkok, Thailand) were extracted. Patients who clinically suspected familial adenomatous polyposis were excluded. Gene mutational analysis was performed by next-generation sequencing (NGS) using an Oncomine Comprehensive Assay Plus kit (Thermo Fisher Scientific, Inc., Waltham, MA, USA) and compared with previous reported molecular data in adult-onset CRC from our group. Results: The top 5 mutations frequency observed were TP53, KRAS, FBXW7, PIK3CA, and SMAD4 mutations which were comparable to what reported in adult-onset CRC. However, FBXW7, PIK3CA, NOTCH1, FGFR3, ERBB2, and PTEN were reported more frequent in AYA group. No difference in number of KRAS, NRAS, and BRAF mutations among 2 groups. Table below shows key cancer genes mutation frequencies. Conclusions: This study is the comprehensive report hotspot mutations using NGS in sporadic AYA-onset sporadic CRC patients. The most commonly identified gene mutation frequencies among AYA-onset were similar to those reported in adult-onset, except for FBXW7, PIK3CA, NOTCH1, FGFR3, ERBB2, and PTEN mutations that had a slightly higher frequency. Further studies on larger sample set for genetic and epigenetic landscape are required. [Table: see text]
Comparison of colorectal cancer (CRC) characteristics across genetic ancestries: Implications for early cancer detection (ECD).
Authors: Myer Parvathi , Srinivasan Preethi , Bristow Sara L. , Krinshpun Shifra , Solari Omid , Aushev Vasily N. , Jurdi Adham A , Liu Minetta C. , Mitchell Breeana L. , Aleshin Alexey , Reiter Johannes G. , Weitzel Jeffrey N. , Nakamura Yoshiaki , Yoshino Takayuki , Wall Jeffrey , Ioannidis Alexander , Bustamante Carlos
Published: January 2024

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Background: Blood-based ECD has the potential to reduce mortality rates by improving strategies for, adoption of, and adherence to screening. A deeper understanding of the cancer genomic landscape across genetic ancestries will aid comparable detection performance across a broad population. We evaluated the mutational landscape in patients with CRC across genetic ancestries. Methods: 16,080 de-identified patients with stage I-IV CRC who had personalized, tumor-informed commercial ctDNA testing (Signatera) based on whole exome sequencing (WES) were included. Genetic ancestry determined via supervised local ancestry inference (pmid36042219) included African (AFR), East Asian (EAS), European (EUR), Latino (LAT), and South Asian (SAS). Patients assigned to a single ancestry were included (except SAS due to small cohort size). Somatic single nucleotide variants called from WES were used for mutational signature inference. EUR was the reference group for standard statistical tests with corrections for multiple hypothesis testing. Results: A single genomic ancestry was assigned for 16,257 (99.2%) patients (AFR n=1697, 10%; EAS n=2247, 14%; EUR n=10,526, 64%; LAT n=1291, 1%; SAS n=184, 1%). Across AFR, EAS, EUR, and LAT, approximately half of patients were male (range, 47-54%) and most were aged >50 years. Microsatellite instability (MSI) rates were significantly higher in EUR (14.5%) v AFR (11%, p<0.001), EAS (8%, p<0.001), and LAT (11%, p=0.002). Compared to EUR (range 0.027-875.1 mut/Mb), the distribution of TMB was significantly higher in EAS (0.304-906.2 mut/Mb, p<0.001) and lower in LAT (0.053-476.7 mut/Mb, p<0.001). The POLE hyper-mutator signature was seen in 1.2% of all patients and in 7.6% of all hyper-mutated cases. Patients with the POLE signature were less common in EUR (1.1%) v AFR (2%, p=0.001). There were significant differences in the frequency of driver mutations in APC, BRAF, KRAS, TP53, and PIK3CA between EUR and the other ancestry groups in both MSI and MSS tumors (Table). Median exposure levels to alkylation were higher in EAS v EUR. Conclusions: These data confirm previous results in AFR populations, and reveal novel differences in the EAS and LAT populations. Findings from this study may provide information for developing risk stratification and prevention strategies for the early detection of cancer and provide rationale for precision treatment based on ancestry. [Table: see text]