bluuebunny/crossref_metadata_2025 huggingface dataset:
Poly-3-hydroxybutyrate-co-3-hydroxyvalerate(PHBV)-Polyethylene glycol 20k(PEG20k) as a promising delivery system for PT2399 in the treatment of disc degeneration
Authors: Li Zhencong , Zhang Weilin , Huang Shengbang , Dai Zhiwen , Liang Jinguo , Qiu Qiulan , Chen Siyuan , Guo Weixiong , Wang Zhongwei , Wei Jinsong
Published: January 2024

Disc degeneration often leads to a highly prevalent symptom known as low back pain. Healthy nucleus pulposus tissue exhibited a hypoxic environment devoid of blood vessels, while degenerated nucleus pulposus experienced hypoxic deterioration and the formation of new blood vessels. In this study, the expression of important genes like HIF-2α was found to vary between normal and degenerated nucleus pulposus cells when compared to the hypoxic surroundings. The aim of this study was to examine how HIF-2α is controlled in nucleus pulposus cells under hypoxic conditions and its role in angiogenic mechanisms. To assess the impact of gradual inhibition of HIF-2α on disc degeneration, we utilized PHBV-based synthetic materials loaded with inhibitors of HIF-2α. Specifically, we employed LPS and PT2399 loaded PHBV-PEG20k (PP20) to intervene with human nucleus pulposus cells. Additionally, we treated APD rat models with PT2399 loaded PP20 to evaluate its effects. The expression levels of target markers in nucleus pulposus cells were detected using PCR, WB, and immunofluorescence. Additionally, the effect of drugs on disc degeneration was identified through HE staining. The findings indicated that HIF-2α, CAIX, PPP1R15A, VEGFA, and EGLN3 could potentially serve as new indicators of disc degeneration. Additionally, HIF-2α might contribute to the progression of disc degeneration through involvement in angiogenesis and the regulation of hypoxia. Furthermore, the utilization of PT2399 loaded PHBV-PEG20k (PP20) could potentially offer a fresh alternative for treating disc degeneration.
Risk factors for tick attachment in companion animals in Great Britain: a spatiotemporal analysis covering 2014–2021
Authors: Arsevska Elena , Hengl Tomislav , Singleton David A. , Noble Peter-John M. , Caminade Cyril , Eneanya Obiora A. , Jones Philip H. , Medlock Jolyon M. , Hansford Kayleigh M. , Bonannella Carmelo , Radford Alan D.
Published: January 2024

Background

Ticks are an important driver of veterinary health care, causing irritation and sometimes infection to their hosts. We explored epidemiological and geo-referenced data from > 7 million electronic health records (EHRs) from cats and dogs collected by the Small Animal Veterinary Surveillance Network (SAVSNET) in Great Britain (GB) between 2014 and 2021 to assess the factors affecting tick attachment in an individual and at a spatiotemporal level.

Methods

EHRs in which ticks were mentioned were identified by text mining; domain experts confirmed those with ticks on the animal. Tick presence/absence records were overlaid with a spatiotemporal series of climate, environment, anthropogenic and host distribution factors to produce a spatiotemporal regression matrix. An ensemble machine learning spatiotemporal model was used to fine-tune hyperparameters for Random Forest, Gradient-boosted Trees and Generalized Linear Model regression algorithms, which were then used to produce a final ensemble meta-learner to predict the probability of tick attachment across GB at a monthly interval and averaged long-term through 2014–2021 at a spatial resolution of 1 km. Individual host factors associated with tick attachment were also assessed by conditional logistic regression on a matched case–control dataset.

Results

In total, 11,741 consultations were identified in which a tick was recorded. The frequency of tick records was low (0.16% EHRs), suggesting an underestimation of risk. That said, increased odds for tick attachment in cats and dogs were associated with younger adult ages, longer coat length, crossbreeds and unclassified breeds. In cats, males and entire animals had significantly increased odds of recorded tick attachment. The key variables controlling the spatiotemporal risk for tick attachment were climatic (precipitation and temperature) and vegetation type (Enhanced Vegetation Index). Suitable areas for tick attachment were predicted across GB, especially in forests and grassland areas, mainly during summer, particularly in June.

Conclusions

Our results can inform targeted health messages to owners and veterinary practitioners, identifying those animals, seasons and areas of higher risk for tick attachment and allowing for more tailored prophylaxis to reduce tick burden, inappropriate parasiticide treatment and potentially TBDs in companion animals and humans. Sentinel networks like SAVSNET represent a novel complementary data source to improve our understanding of tick attachment risk for companion animals and as a proxy of risk to humans.

Graphical Abstract
Response of rhizosphere soil physicochemical properties and microbial community structure to continuous cultivation of tobacco
Authors: Gong Bo , He Yi , Luo Zhenbao , Peng Huawei , Cai Heqing , Zhu Yuening , Bin Jun , Ding Mengjiao
Published: January 2024

Purpose

The health of rhizosphere soil microorganisms is an important indicator to evaluate soil quality. Therefore, understanding the response of rhizosphere soil microorganisms to tobacco crop succession is crucial for promoting the sustainable development of agriculture.

Methods

The microbial diversity and community structure of rhizosphere soil in continuous cropping and non-cropped tobacco for 7 years were analyzed by the Illumina platform.

Result

(1) Continuous cropping tobacco cause rhizosphere soil acidification and reduction in alkaline nitrogen (AN) and soil organic matter (SOM). (2) Continuous cropping tobacco reduces the diversity of rhizosphere soil microbial communities, increasing harmful functional microorganisms and declining beneficial ones. (3) The abundance of bacteria that perform nitrification and saprophytic fungi in the rhizosphere soil of continuous cropping areas decreases, inhibiting carbon and nitrogen cycling processes. (4) The composition and diversity of the soil rhizosphere microbial community are affected by the imbalance in the physicochemical property of the rhizosphere.

Conclusion

Continuous cropping tobacco cause rhizosphere soil acidification and nutrient imbalance, and the carbon and nitrogen cycles involved in microorganisms were damaged. Furthermore, the decreased diversity of rhizosphere soil microorganisms and the increased abundance of pathogenic fungi contribute to the continuous cropping obstacles of tobacco.
Comparative analysis of classical and Caputo models for COVID-19 spread: vaccination and stability assessment
Authors: Tassaddiq Asifa , Qureshi Sania , Soomro Amanullah , Arqub Omar Abu , Senol Mehmet
Published: January 2024

Several epidemiological models use the Caputo fractional-order differential operator without establishing its significance. This study verifies a Caputo operator-based fractional-order epidemiological model of the SAIVR type. COVID-19 kills. Infection weakens the immune system. The fractional Caputo operator describes COVID-19 immunization. Fundamental system characteristics are determined using fractional calculus. Our analysis included the fractional system’s Hyers–Ulam–Rassias stability and stable states. The uniqueness and existence of fractional Caputo system solutions are explored. The least-squares approach determines system parameters. The Caputo fractional-orderαvalue is optimized to$6.757\text{e}{-}01$6.757e−01, indicating that the system best fits real-life medical data for infection. Caputo and classical systems were compared for absolute mean errors. The Box-Whisker chart case summaries show the Caputo operator superiority. When$\alpha \rightarrow 1$α→1, the memory traces and hereditary traits are also observed. Finally, the Caputo fractional framework simulates COVID-19 using strong numerical methods.
Food miles on the shelves: the share of local food products in the Hungarian retail sector
Authors: Kasza Gyula , Oláh Judit , Popp József , Lakner Zoltán , Fekete László , Pósa Enikő , Nugraha Widya Satya , Szakos Dávid
Published: January 2024

Share of national food products in retail is a frequent subject of policy debates. Local food is often associated with national security, sustainability, and support of local economy, contributing to value-added production, employment, rural development, and preservation of local food culture. Despite its importance, relevant academic literature about the proportion of national food in retail is basically non-existent. This paper presents a unique study that fills this gap and gives an account of the proportion of the main national food products in the Hungarian retail sector. The study presents a comprehensive picture of the food supply situation of the 10 largest retail chains in Hungary in the second half of 2020 for 16 key product categories (representing 67% of total food sales in value in the country), based on the experience of research that covered the physical examination of nearly 40 thousand individual food products. The study found that 70.85% of the analysed food products were supplied by domestic companies. Proportion of national products was higher for fresh food (meat, milk, perishable meat and milk products, eggs, fruits, and vegetables) and honey, while imports were dominant in higher value-added categories. Domestic chains had 15.37% points more local products in stock than international ones. The exact results can be used for benchmarking between companies and sectors, indicating comparative advantages and disadvantages, and provide solid basis for economic development plans.
Neurophysiological and psychophysical effects of dry versus sham needling of the infraspinatus muscle in patients with chronic shoulder pain: a randomized feasibility study
Authors: Laramée Antoine , Léonard Guillaume , Morin Mélanie , Roch Mélanie , Gaudreault Nathaly
Published: January 2024

Background: Dry needling (DN) is increasingly used for treating myofascial trigger points (MTrPs) and has shown significant effects on pain and function. This study aimed to assess feasibility of conducting a randomized shamcontrolled trial and to collect preliminary data on the effects of infraspinatus DN on corticospinal excitability and mechanical pain sensitivity. Method: This randomized feasibility study included adults with chronic non-traumatic shoulder pain and a infraspinatus MTrP. Participants were randomized to receive real DN or sham DN in the infraspinatus MTrP. Feasibility outcomes included data pertaining to recruitment, retention of participants, completeness and safety of assessment procedures. Neurophysiological and psychophysical outcomes included corticospinal excitability and mechanical pain sensitivity measured by active motor threshold (aMT) and pressure pain threshold (PPT), respectively. They were assessed at baseline, immediately after and 24 h post-intervention. Results: Twenty-one participants were recruited over a 6-month period. Nineteen participants completed the treatment and follow-up assessment. Motor evoked potential responses were discernible in all but 1 participant. Only 1 minor adverse event related to transcranial magnetic stimulation (mild headache) affected the measurements. No DN adverse effects were recorded in both groups. An overall completeness rate of 81% was reached, with 70% completeness in the DN group and 91% in the sham group. Data analysis revealed that real DN increased corticospinal excitability (reduced aMT) 24 h post-intervention (Mdn = − 5.96% MSO, IQR = 5.17, p = 0.04) and that sham DN triggered similar responses immediately after the intervention (Mdn = − 1.93% MSO, IQR = 1.11, p = 0.03). Increased mechanical pain sensitivity (reduced PPT) was significant only in the sham group, both immediately (Mdn = − 0.44 kg/cm2, IQR = 0.49, p = 0.01) and 24 h post-intervention (Mdn = − 0.52 kg/cm2, IQR = 1.02, p = 0.02). Changes in corticospinal excitability was positively correlated with changes in mechanical pain sensitivity in the DN group, both immediately (r = 0.77, p = 0.02) and 24 h post-intervention (r = 0.75, p = 0.05). Conclusion: The present study demonstrates the feasibility of quantifying the neurophysiological and psychophysical effects of DN, and provides recommendations and guidelines for future studies. Moreover, it provides preliminary evidence that DN may increase corticospinal excitability of the infraspinatus muscle in patients with chronic shoulder pain and that the relationship of neurophysiological and psychophysical effects is promising to better understand its mechanisms of action.
ESTSS—energy system time series suite: a declustered, application-independent, semi-artificial load profile benchmark set
Authors: Günther Sebastian , Brandt Jonathan , Bensmann Astrid , Hanke-Rauschenbach Richard
Published: January 2024

This paper introduces an univariate application-independent set of load profiles or time series derived from real-world energy system data. The generation involved a two-step process: manifolding the initial dataset through signal processors to increase diversity and heterogeneity, followed by a declustering process that removes data redundancy. The study employed common feature engineering and machine learning techniques: the time series are transformed into a normalized feature space, followed by a dimensionality reduction via hierarchical clustering, and optimization. The resulting dataset is uniformly distributed across multiple feature space dimensions while retaining typical time and frequency domain characteristics inherent in energy system time series. This data serves various purposes, including algorithm testing, uncovering functional relationships between time series features and system performance, and training machine learning models. Two case studies demonstrate the claims: one focused on the suitability of hybrid energy storage systems and the other on quantifying the onsite hydrogen supply cost in green hydrogen production sites. The declustering algorithm, although a bys study, shows promise for further scientific exploration. The data and source code are openly accessible, providing a robust platform for future comparative studies. This work also offers smaller subsets for computationally intensive research. Data and source code can be found at https://github.com/s-guenther/estss and https://zenodo.org/records/10213145.
Integral imaging near-eye 3D display using a nanoimprint metalens array
Authors: Fan Zhi-Bin , Cheng Yun-Fan , Chen Ze-Ming , Liu Xia , Lu Wen-Long , Li Shi-Hao , Jiang Shao-Ji , Qin Zong , Dong Jian-Wen
Published: January 2024

Integral imaging (II) display, one of the most critical true-3D display technologies, has received increasing research recently. Significantly, an achromatic metalens array has realized a broadband metalens-array-based II (meta-II). However, the past micro-scale metalens arrays were incompatible with commercial micro-displays; furthermore, the elemental image array (EIA) rendering is always slow. The two hinders in device and algorithm prevent meta-II from being used for practical video-rate near-eye displays (NEDs). This research demonstrates a meta-II NED combining a commercial micro-display and a metalens array. The large-area nanoimprint technology fabricates the metalens array, and a novel real-time rendering algorithm is proposed to generate the EIA. The hardware and software efforts solve the bottlenecks of video-rate meta-II displays. We also build a see-through prototype based on our meta-II NED, demonstrating the feasibility of augmented reality. Our work explores the potential of video-rate meta-II displays, which we expect can be valuable for future virtual and augmented reality.
Neoadjuvant botensilimab plus balstilimab in resectable mismatch repair proficient and deficient colorectal cancer: NEST-1 clinical trial.
Authors: Kasi Pashtoon Murtaza , Jafari Mehraneh D. , Yeo Heather , Lowenfeld Lea , Khan Uqba , Nguyen Alana , Siolas Despina , Swed Brandon , Khan Sahrish , Wood Madeleine , Ocean Allyson J. , Popa Elizabeta C. , Garrett Kelly A. , Golden Encouse , Guniganti Preethi , Zhou Xi K. , Pigazzi Alessio , Shah Manish A. , Hissong Erika , Hidalgo Manuel
Published: January 2024

117

Background: There is an unmet need to have an effective systemic immunotherapeutic option for patients with mismatch repair proficient/microsatellite stable (pMMR/MSS) colorectal cancer. The neoadjuvant platform presents an ideal setting as a window of opportunity to evaluate new drugs. The NEST-1 trial explored the safety and efficacy of neoadjuvant botensilimab (BOT), an Fc-enhanced next-generation anti–CTLA–4 antibody, alongside balstilimab (BAL; an anti-PD-1 antibody) in patients with colon and rectal cancer who were candidates for surgery. Methods: NEST-1, was a single-arm trial testing the feasibility, safety, and efficacy of the BOT/BAL regimen in neoadjuvant settings for patients with colorectal cancer before resection. All patients received 1 fixed dose of 75 mg of BOT and 2 fixed doses of 240 mg of BAL 2 weeks apart. Patients could proceed to surgery 1 week after completion of the 2nd dose of BAL. Less than 25% of patients were allowed to be mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H). Other inclusion and exclusion criteria were in accordance with ongoing immunotherapy-based clinical trials. Results: The study met its primary endpoints. A total of 12 patients with colon and rectal cancers were safely treated with the BOT/BAL combination without delaying surgery or increasing the risk of any severe adverse events. Significant regression of tumors was noted (Table). Spatial biology analyses on pre-treatment biopsy and post-treatment surgical samples using RareCyte Inc. revealed novel mechanisms of action and patterns of response/regression; most of the viable tumor if present was superficially oriented near the luminal surface. ctDNA reductions correlated with pathological responses. Conclusions: BOT/BAL appears to be a safe and active regimen both in pMMR/MSS and dMMR/MSI-H colon as well as rectal cancers. The downstaging observed may spare surgery and/or adjuvant chemotherapy. Given the findings, the study has now expanded to two additional cohorts that are now enrolling to study further the dosing, and timing and/or need for surgery in these patients. Clinical trial information: NCT05571293 . [Table: see text]
BOLD-100-001 (TRIO039): A phase 2 study of BOLD-100 in combination with FOLFOX in patients with advanced mCRC previously treated with FOLFOX/CAPOX—Efficacy and safety analysis.
Authors: Spratlin Jennifer L. , O'Kane Grainne M. , Oh Do-Youn , Rha Sun Young , McWhirter Elaine , Elimova Elena , Kavan Petr , Choi Moon Ki , Kim Dae Won , Goodwin Rachel Anne , Hecht J. Randolph , Kim Seung Tae , Koo Dong-Hoe , Halani Khalif , McAllister E. Russell , Jones Michelle , Snow Malcolm , Lemmerick Yasmin , Spera Gonzalo , Pankovich Jim
Published: January 2024

143

Background: BOLD-100 is a first-in-class metallotherapeutic with a unique multimodal mechanism of action currently in phase 2 clinical development for the treatment of advanced gastrointestinal cancers. Standard treatment options for patients (pts) with metastatic colorectal cancer (mCRC) include FOLFOX or CAPOX in first or second line therapy. This study explored the benefit of BOLD-100 + FOLFOX in previously treated mCRC patients. Methods: This prospective, phase 2 study evaluates BOLD-100 + FOLFOX in pts with mCRC. All pts received prior standard treatment, including FOLFOX or CAPOX. Pts received 625 mg/m2 of BOLD-100 + FOLFOX on day 1 of each 14-day cycle and treated until progressive disease or unacceptable toxicity. The primary objective is to evaluate PFS, OS, and ORR in treated patients. Disease Control Rate (DCR) was also determined. Results: As of 31Aug2023, 36 pts with advanced mCRC were treated. Median age was 62 years (range 40-78), 56% were women, all pts were ECOG 0 (25%) or 1 (75%). Enrolled pts had a median of 4 prior systemic therapies, including FOLFOX/CAPOX. All but one patient had stage IV disease. On study, pts received a median of 6 cycles of BOLD-100 + FOLFOX [range 1-17]. Five pts remain on treatment with 19 in follow-up. Median PFS was 3.9 [2.7, 5.7] months, median OS 9.6 [6.0, 17] months, ORR 7% [1,20] and DCR 76% [58, 88] in the 29 evaluable pts. Two pts achieved a partial response, and 2 pts had target tumor lesion decreases between 20-29%. Study treatment was well tolerated. Of the 36 treated pts, 33 had 1 or more treatment-emergent adverse events (AEs), most common neutropenia (n=17, 47%), nausea (n=15, 42%), vomiting (n=8, 22%), fatigue (n=7, 19%), infusion related reaction (n=7, 19%), and pruritus (n=6, 17%). Most related AEs were grade (G) 1-2. 15 pts (42%) had G3/4 neutropenia. Despite previous oxaliplatin treatment, fewer than 6% of pts reported peripheral neuropathy or peripheral sensory neuropathy and all were G1/2. Conclusions: BOLD-100 + FOLFOX is an active and well-tolerated treatment in this heavily pre-treated Stage IV mCRC study population. There were no new safety signals. The mPFS, mOS, ORR and DCR data demonstrate significant clinical benefit and improvement over the currently available therapies, with minimal treatment emergent neuropathy or significant toxicities. This promising treatment combination should be further studied. Clinical trial information: NCT04421820 .
Metachronous remnant gastric cancer after proximal gastrectomy.
Authors: Ishizu Kenichi , Yoshikawa Takaki , Ogawa Rei , Nishino Masahi , Sakon Ryota , Wada Takeyuki , Hayashi Tsutomu , Yamagata Yukinori
Published: January 2024

260

Background: Proximal gastrectomy is frequently selected for early gastric cancer located at the upper third of the stomach. Annual postoperative endoscopy is considered to be useful for the early detection of metachronous remnant gastric cancer (MRGC). Despite that, we sometimes have also encountered cases that are not suitable for endoscopic resection (ER). The aim of this study is to identify the risk factors for the patients who developed MRGC after proximal gastrectomy, received annual endoscopy, but are not eligible for ER (non-ER). Methods: We retrospectively analyzed 191 patients who had received annual endoscopic surveillance after undergoing PG for cT1 gastric cancer at NCCH between 2006-2015. MRGCs were categorized into two groups: ER group and non-ER group. The remnant stomach was defined as three locations: pseudo-fornix (PF), corpus and antrum. Results: The median observation period was 73 (range 12-168) months. MRGC was observed in 29 cases with 32 lesions. ER was eligible for 20 lesions (ER group, 62.5%), but 12 were not (non-ER group, 37.5%). We compared the characteristics between of ER group and non-ER group in terms of sex, age (>65 years), interval from the initial surgery (>60months), the location (PF vs non-PF), and cross-sectional circumference (posterior wall vs. others). In both univariate and multivariate logistic regression analysis, only the location at PF was identified as a risk factor for non-ER group (OR 25.0, 95% CI: 1.8–339, p = 0.015). Among 12 lesions of the non-ER group, the location of PF was found in 6 (50%) lesions. As compared with MRGC at the non-PF, that at the PF (n = 6) was characterized by younger patients (57.5 (range 37-69) years vs. 69 (56-77) years), larger size (36 (7-57) mm vs. 9 (9-24) mm), deeper depth (MP or deeper; 5/6 vs. 0/6), more frequent undifferentiated-type histology (4/6 vs. 0/6) and frequent nodal metastasis (3/6 vs. 0/6). The interval to detect MRGC appears to be longer in the PF (78 (31-96) months than that of the non-PF (60 (31-96) months), but the difference was not statistically significant (p = 0.86). Then, we examined the visibility and the mucosal normality of the area developing MRGC in the annual follow-up endoscopy one year before the detection of MRGC (n =32). In 25 lesions at the non-PF, the visibility and the mucosal normality was secured in 21 (84%). while 5 PF lesions were difficult to observe (71.4%, p = 0.01) due to food residues in 4 (57%, p = 0.047) and insufficient expansion of the gastric mucosa in 4 (57%, p = 0.001). Conclusions: Detection of the MRGC at the PF at an early stage is crucial and challenging. With annual follow-up endoscopy, complete clearance and adequately extending the gastric mucosa could lead to the early detection of MRGC at the PF.
Safety and short-term efficacy of adjuvant nivolumab after neoadjuvant docetaxel, cisplatin, and fluorouracil for locally advanced esophageal squamous cell carcinoma.
Authors: Okunaka Mashiro , Kotani Daisuke , Sato Kazuma , Fujiwara Naoto , Mishima Saori , Shitara Kohei , Fujita Takeo , Kojima Takashi
Published: January 2024

271

Background: Efficacy and safety of adjuvant nivolumab has been demonstrated in patients with locally advanced esophageal cancer who received neoadjuvant chemoradiotherapy followed by surgery and had residual pathological disease in the CheckMate-577 trial. Although neoadjuvant docetaxel, cisplatin, and fluorouracil (DCF) is the standard neoadjuvant therapy for patients with locally advanced esophageal squamous cell carcinoma (ESCC) in Japan based on the JCOG1109 study, the safety and efficacy of adjuvant nivolumab in this population remains unclear. Here, we report the short-term safety and efficacy of adjuvant nivolumab after neoadjuvant DCF in patients with locally advanced ESCC. Methods: We retrospectively reviewed medical records of patients who received adjuvant nivolumab after neoadjuvant DCF and surgery for locally advanced ESCC from Nov 2021 to Jun 2023 at National Cancer Center Hospital East. Pathological stage was classified by UICC-TNM 8th edition. Adverse events were assessed according to CTCAE v5.0. Disease-free survival (DFS) was calculated by Kaplan-Meier method. Results: The study included a total of 33 patients with a median age of 67 years (range, 56-77), of which 29 patients were male. All patients had residual pathological disease, with ypStage I/II/III/IV of 5/1/16/11 patients. Median time from surgery to the initiation of adjuvant nivolumab was 10.6 weeks (range, 7.1-16.4 weeks). Treatment-related adverse events (TRAEs) occurred in 27 patients (82%), with pruritus (n = 13, 39%), rash (n = 7, 21%), hypothyroidism (n=7, 21%), xerosis (n = 6, 18%), diarrhea (n = 5, 15%), hypopituitarism (n = 5, 15%), pneumonitis (n = 1, 3%), and hepatic dysfunction (n = 1, 3%). Among these TRAEs, one patient developed grade 3 of hepatic dysfunction, which resolved with corticosteroid. TRAEs which led to discontinuation of nivolumab were hepatic dysfunction (n = 1, 3%), diarrhea (n = 1, 3%), and pneumonitis (n = 1, 3%). No treatment-related death was observed. With a median follow-up of 10.3 months, 1-year DFS rate was 63.3% (95% CI, 39.8-79.7%). Among 9 patients who experienced recurrence (locoregional; n = 3, distant; n = 6), 8 patients received subsequent therapy, including systemic chemotherapy (n = 5) and salvage chemoradiotherapy (n = 3). Conclusions: The safety and short-term efficacy of adjuvant nivolumab after neoadjuvant DCF and surgery was comparable to the results of the CheckMate-577 trial. Our study suggests that adjuvant nivolumab might be a possible treatment option in patients with locally advanced ESCC patients with residual pathological disease after neoadjuvant DCF followed by surgery.
Tumor regression grade after neoadjuvant chemotherapy in patients with locally advanced gastric cancer treated with modern chemotherapy (FLOT): Experience in patients in Guatemala.
Authors: Ramirez Rixci , Rosales-Lopez Daniel Estuardo , Dominguez Jennifer , Camey Carolina , Ovalle Julia
Published: January 2024

287

Background: Perioperative chemotherapy is the standard of care for locally advanced gastric cancers in Western populations. At this moment perioperative chemotherapy with FLOT (Fluorouracil, leucovorin, oxaliplatin and docetaxel) regimen is recommended in patients who are medically fit with benefit in progression-free survival (PFS) and overall survival (OS). However, the impact of response to this treatment is not well established. The objective of this study is to find the pathological response to FLOT chemotherapy measured by the degree of tumor regression (TRG), the benefit on disease-free survival (DFS) and OS, in patients with gastric cancer locally advanced treated with FLOT chemotherapy. Methods: Patients from the Instituto Guatemalteco de Seguridad Social (IGSS) from Guatemala City, who underwent radical gastrectomy for non-metastatic invasive gastric adenocarcinoma after perioperative chemotherapy (T1-4/N0/N+cM0) from 2019 to 2023 were included. Demographic data, clinical staging, histologic phenotype, surgical factors, tumor regression grade after gastrectomy and survival outcomes were included. The association between ORR and OS were evaluated. OS and DFS were estimated using the Kaplan Meier method with adjustment for covariates using Cox regression. Results: Thirty-eight patients with locally advanced cancer gastric were identified. The median age was 58 years (29-79), most of the patients were men (23, 61%), 35 (92%) patients have primary gastric tumor, 26 (68%) has cT3/T4 tumors and 22 (58%) has intestinal gastric cancer, all patients underwent to surgery. Two patients (6%) had TRG of 1 (complete and almost complete), 8 patients (21%) had an TGR of 2, and 28 patients (74%) had an TGR of 3; 13 patients (38%) developed recurrence, median DFS was 5.2 months (95% CI: 1.0–28). The median OS was 15.3 months (95% CI: 3.0-45). Lack of tumor regression (TRG 3) was significantly associated with lower survival HR 1.42 (1.05-2.24) p= 0.008. Clinical T4 tumors and diffuse histology were associated with poor prognostic (cT4 HR 3.04, p = 0.038, diffuse histology HR 2.08 (p = 0.001) (Table). Conclusions: Since cT4 tumors are an independent risk factor associated with poor prognostic HR 3.04, p = 0.038, it is important to make an adequate clinical staging before deciding to use three-drug treatment regimens of chemotherapy. Other factors in addition to clinical ones should be investigated, such as molecular factors that may be related to this poor response and survival in patients with cT4. This study of molecular factors is currently underway at our institution. [Table: see text]
HLX22 plus HLX02 and XELOX for first-line treatment of HER2-positive locally advanced or metastatic gastric/gastroesophageal junction cancer: A randomized, double-blind, multicenter phase 2 study.
Authors: Li Jin , Gao Yong , Li Ning , Qiu Meng , Zhang Yan-Qiao , Yang Mudan , Lu Linzhi , Li Wei , Ma Yuntao , Hou Xiaoming , Sun Guoping , Cai Mingquan , Wang Jingran , Lu Jianwei , Zhong Diansheng , Yang Futang , Li Jing , Wang Qingyu , Zhu Jun ,   HLX22-GC Investigators
Published: January 2024

354

Background: Gastric/gastroesophageal junction (G/GEJ) cancer represents a global healthcare challenge. With more than 1 million new cases estimated in 2020, it ranked fifth among all cancers. HER2 amplification or overexpression were reported in around 20% of advanced G/GEJ cancer cases. Despite the improved overall survival with trastuzumab plus chemotherapy, the prognosis remains unsatisfactory, and thus more effective treatments are needed. This study aimed to evaluate the combination of HLX22 (a novel anti-HER2 monoclonal antibody), HLX02 (a trastuzumab biosimilar), and chemotherapy for patients with G/GEJ cancer in the first-line setting. Methods: The study was unblinded 3 months after the last patient was enrolled. Patients with locally advanced or metastatic HER2-positive G/GEJ cancer and had not received prior systemic antitumor therapy were enrolled. The study consisted of 2 parts; current report will focus on part 1. In part 1, patients were randomized 1:1:1 to receive HLX22 25 mg/kg + HLX02 + XELOX (group A), HLX22 15 mg/kg + HLX02 + XELOX (group B), or placebo + HLX02 + XELOX (group C) in 3-week cycles. Primary endpoints were PFS and ORR assessed by IRRC per RECIST v1.1. Secondary endpoints included other efficacy measures and safety. Results: As of July 30, 2023 (data cutoff), 53 patients were randomized to group A (n=18), B (n=17), and C (n=18), and were followed up for a median of 14.3 months. 44 (83.0%) patients were male. Main efficacy results are presented in Table. Tumor assessments reported in Table were performed by IRRC. Treatment-related adverse events (TRAEs) occurred in 18 (100.0%), 16 (94.1%), and 17 (94.4%) patients in the respective groups. Serious TRAEs were observed in 5 (27.8%) patients in group A, 1 (5.9%) in group B, and 1 (5.6%) in group C. Only 1 (5.6%) patient in group C had a grade 5 TRAE. Conclusions: Adding HLX22 to HLX02 + XELOX improved survival and antitumor response in patients with HER2-positive G/GEJ cancer in the first-line setting, with a manageable safety profile. Clinical trial information: NCT04908813 . [Table: see text]
Real-world clinical efficacy of epidermal growth factor receptor inhibitors (EGFRi) in patients with early-onset (eo), metastatic colorectal cancer (mCRC).
Authors: Bando Hideaki , Misumi Toshihiro , Pittell Harlan , Ng Dionne , Tajima Eri , Royce Trevor Joseph , Altomare Ivy , Paliwal Prashni , Aoyagi Yoshihiro , Mizuguchi Kazuya , Suzuki Motoko , Takeda Yuriko , Yoshino Takayuki , Ohtsu Atsushi
Published: January 2024

36

Background: The incidence of eo CRC (age of onset: <50 years) is rising globally, although specific reasons remain unknown. In a prior study using the ARCAD database, the addition of EGFRi to chemotherapy (chemo) significantly improved progression-free survival (PFS) in late-onset (lo) KRAS wild-type (wt) left-sided mCRC patients (pts); however, no such effect was observed in eo mCRC pts (Jin Z et al., 2022). Methods: This retrospective study used the nationwide Flatiron Health electronic health record-derived de-identified database of adult patients diagnosed with mCRC on/after January 1, 2013 with data cut-off on June 30, 2023. The cohort included pts with RAS/BRAF wt and left-sided primary tumors who were treated with first-line (1L) chemo+EGFRi, chemo+bevacizumab (bev), or chemo alone. Associations of disease onset and 1L therapy with real-world overall survival and time to next treatment (rwOS, rwTTNT) were assessed using Kaplan-Meier methods and hazard models adjusted for clinical confounders including year of metastatic diagnosis, group stage at initial diagnosis, site of disease, gender, race/ethnicity, and ECOG performance status. Results: Among 895 left-sided RAS/BRAF wt mCRC pts, 216 and 679 pts had eo and lo mCRC, respectively. In pts treated with chemo+EGFRi vs chemo alone, the adjusted hazard ratio (HR) (95% CI) of rwTTNT was 0.93 (0.56-1.53) and 0.77 (0.58-1.02) for eo and lo pts, respectively; the adjusted HR (95% CI) of rwOS was 0.96 (0.51-1.83) and 0.78 (0.57-1.07) in eo and lo pts, respectively. In pts treated with chemo+bev vs chemo alone, the adjusted HR (95% CI) of rwTTNT was 1.00 (0.62-1.60) and 0.75 (0.58-0.97) for eo and lo pts, respectively; the adjusted HR (95% CI) of rwOS was 0.97 (0.54-1.75) and 0.78 (0.58-1.03) in eo and lo pts, respectively. Conclusions: Adding EGFRi to chemotherapy suggested potential improvements in rwTTNT and rwOS in lo pts but not in eo pts, similar to findings from the prior ARCAD database study. Such differences in outcomes, similarly observed in pts treated with chemo+bev, underscore the need for tailored therapeutic strategies. Given the wide confidence intervals in this study, future research with larger patient cohorts or longer follow-up may yield more precise estimates of these differences. [Table: see text]
Management of nausea and vomiting (N/V) following first-line (1L) zolbetuximab + chemotherapy treatment in claudin-18.2 (CLDN18.2)+, HER2−, locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: Analysis from the phase 3 SPOTLIGHT and GLOW studies.
Authors: Shitara Kohei , Pophale Rupesh , Matsangou Maria , Park Jung Wook , Oh Mok , Bhattacharya Pranob P. , Ranganath Radhika
Published: January 2024

372

Background: The phase 3 SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) studies showed clinically meaningful, statistically significant improvement in PFS and OS using 1L zolbetuximab + chemotherapy vs placebo (PBO) + chemotherapy in patients (pts) with CLDN18.2+, HER2−, LA unresectable or mG/GEJ adenocarcinoma. N/V were the most common treatment-emergent adverse events (TEAEs) reported in the zolbetuximab arm of these studies. We report an analysis of the incidence and management of N/V in SPOTLIGHT and GLOW. Methods: In SPOTLIGHT, pts (N = 565) were randomized 1:1 to zolbetuximab + mFOLFOX6 vs PBO + mFOLFOX6. In GLOW, pts (N = 507) were randomized 1:1 to zolbetuximab + CAPOX vs PBO + CAPOX. In both studies, neurokinin-1 receptor blockers (NK-1), selective serotonin receptor blockers (5-HT3), and other prophylactic antiemetic regimens were recommended to prevent and mitigate N/V per institutional care and guidelines. Results: A total of 279 pts in SPOTLIGHT and 253 pts in GLOW received zolbetuximab + chemotherapy. In SPOTLIGHT and GLOW combined, nausea occurred in 58% vs 18% of pts, and vomiting occurred in 43% vs 15% of pts in the first vs second zolbetuximab infusions, respectively; lower incidences of N/V were observed thereafter. During the first zolbetuximab infusion, the first episode of N/V occurred within 1 hour (median time, 48.0 min in SPOTLIGHT and 56.5 min in GLOW). Antiemetic usage and associated N/V rates are presented in the Table. The 96 pts in SPOTLIGHT and 52 pts in GLOW who had infusion modifications in cycle 1 due to TEAEs had numerically higher infusion rates than pts without infusion modifications; 85% of these modifications in SPOTLIGHT and 79% in GLOW were due to N/V. Zolbetuximab was discontinued within the first 9 weeks in 11 and 7 pts in SPOTLIGHT and 6 and 4 pts in GLOW due to nausea or vomiting, respectively. Conclusions: In SPOTLIGHT and GLOW, slower infusion rate and use of antiemetic combinations may have helped to mitigate N/V. These strategies will be important to support continued treatment and allow pts to achieve maximum clinical benefit with zolbetuximab + chemotherapy. Clinical trial information: NCT03504397 and NCT03653507 . [Table: see text]
Genomic characterization of unresectable/recurrent early-onset gastric cancer by comprehensive genomic profiling tests.
Authors: Matsuguma Kunihito , Hirano Hidekazu , Fujii Hiroyuki , Shiraishi Kouya , Shoji Hirokazu , Hirose Toshiharu , Okita Natsuko Tsuda , Takashima Atsuo , Koyama Takafumi , Kato Ken ,   Division of Genome Biology, National Cancer Center Research Institute
Published: January 2024

393

Background: The incidence of early-onset gastric cancer (EOGC: age ≤45 years) is showing an increasing trend. Although EOGC has unique clinicopathological features compared with late-onset gastric cancer (LOGC: age>45 years), disparities in genetic alterations (GAs) between EOGC and LOGC are not fully understood in patients with unresectable/recurrent GC. We aim to investigate to elucidate unique GAs in unresectable/recurrent EOGC. Methods: We retrospectively reviewed data on patients with unresectable/recurrent GC who underwent comprehensive genomic profiling (CGP) tests and were registered as “Stomach adenocarcinoma (STAD)” cases in the Center for Cancer Genomics and Advanced Therapeutics (C-CAT) in Japan from June 2019 to April 2023. CGP tests were conducted by NCC Oncopanel System (NOP) or FoundationOne CDx (F1). We examined somatic GAs, microsatellite instability (MSI) status, and tumor mutation burden (TMB) of GC. TMB-high was defined as ≥10 mutations/Mb. Actionable GAs were counted if they were classified as “pathogenic/oncogenic” or “likely pathogenic/likely oncogenic variants”. Druggable GAs are actionable GAs that can be treated with drugs approved for GC or other types of cancer or have shown efficacy in clinical trials for either GC or different types of cancer. Results: In total,112 patients with EOGC and 810 patients with LOGC were identified. In EOGC group, most common actionable GAs included TP53 (59.8%), ARID1A (17.0%), KRAS (15.2%), CDKN2A (11.6%), FGFR2 (11.6%), and CDH1 (9.8%). Compared to the LOGC group, the EOGC group exhibited a significantly higher frequency of actionable GAs in FGFR2(11.6% vs. 4.6%, P=0.0059), CDH1 (9.8% vs. 4.1%, P=0.015) and BAP1 (3.6% vs. 0.6%, P=0.016). On the other hand, the EOGC group showed a significantly lower frequency of actionable GAs in ERBB2(7.1% vs. 20.1%, P=0.0004), CCNE1 (4.5% vs. 19.0%, P=0.0001), and AURKA (0% vs. 7.9%, P=0.0003) compared with the LOGC group. In the EOGC group compared to the LOGC group, the proportions of MSI-high were 0.9% vs. 2.6% (P=0.345), and those of TMB-high were 4.5% vs. 11.6% (P=0.011). Excluding ERBB2 amplification, druggable GAs in the ECOG group included FGFR2 amplification (9.8%), MET amplification (4.5%), EGFR amplification (1.8%), KRAS G12C mutation (1.8%), and MDM2 amplification (0.9%). Conclusions: Among unresectable/recurrent GC population, EOCG has displayed distinct genetic profiles of GAs compared to LOGC. CGP tests may be useful in expanding treatment opportunities for patients with unresectable/recurrent EOGC.
Atezolizumab plus bevacizumab (A+B) in patients with unresectable hepatocellular carcinoma (uHCC): Real-world experience from a US community oncology network.
Authors: Cosgrove David , Tan Amie , Osterland Andrew , Hernandez Sairy , Ogale Sarika , Mahrus Sami , Murphy John , Wilson Thomas W , Patton Gregory A. , Loaiza-Bonilla Arturo , Singal Amit G.
Published: January 2024

447

Background: A+B is the standard first-line (1L) treatment for uHCC based on the IMbrave150 trial, which demonstrated superior efficacy over sorafenib with longer median overall survival (19.2 vs 13.4 months) and progression-free survival (6.8 vs 4.3 months) among patients with Child Pugh (CP) A cirrhosis. Evidence about A+B use and outcomes in routine clinical practice, including in patients with impaired liver function, remains limited. Methods: This retrospective observational study included adult patients who initiated 1L A+B for uHCC within The US Oncology Network between 1/1/2019 and 8/31/2022 (followed through 11/30/2022) using structured and unstructured electronic health records (EHR) based data. CP classes were reported by physicians or derived from risk factors. Kaplan-Meier methods were used to assess real-world overall survival (rwOS) and progression-free survival (rwPFS) from initiation of A+B. Exploratory subgroup analyses were conducted by CP class, albumin-bilirubin (ALBI) grade, liver disease etiology, and race/ethnicity. Results: We identified 374 patients with uHCC who initiated 1L A+B during the study period. Compared with patients enrolled in IMbrave150 (n=336), those treated with A+B in clinical practice were older (median age: 69 vs 64 years), had worse liver function (CP A: 61% vs 100%; ALBI Grade >1: 66% vs 43%), and had poorer performance status (ECOG PS>1: 18% vs 0%). At a median follow-up of 5.6 months, 78% (n=293) had discontinued treatment. Among them, 57% discontinued was progression and 4% discontinued due to toxicity alone. Median rwOS was 13.2 months (95%CI: 9.5–15.9) and median rwPFS was 6.4 months (95%CI: 5.1–7.7). Subgroup results are shown (Table). Conclusions: In community oncology settings, 1L A+B demonstrates effectiveness in diverse patient cohorts, including those with impaired liver function, non-viral liver disease, and racial/ethnic minorities. Predictive biomarkers can help identify subgroups who may most benefit from 1L A+B. [Table: see text]
Second-line regorafenib in patients (pts) with unresectable hepatocellular carcinoma (uHCC) after progression on first-line atezolizumab plus bevacizumab (Atezo-Bev): Phase 2 REGONEXT trial.
Authors: Yoo Changhoon , Cheon Jaekyung , Ryoo Baek-Yeol , Ryu Min-Hee , Kim Hyung-Don , Kim Kyu-Pyo , Kang Beodeul , Chon Hong Jae , Finn Richard S.
Published: January 2024

477

Background: Atezo-Bev is the standard first-line therapy against uHCC. However, there is no globally established subsequent treatment after failure on first-line Atezo-Bev. We aimed to evaluate the efficacy and safety of second-line regorafenib in uHCC pts who progressed on first-line Atezo-Bev. Methods: This is a phase II investigator-initiated trial involving 2 academic centers in Korea. Key eligibility criteria include confirmed diagnosis of HCC; prior treatment with Atezo-Bev at least ≥ 2 cycles; Child-Pugh A; ECOG performance status 0-1. Eligible patients received regorafenib 160 mg once daily 3 weeks on/1 week off until progressive disease or intolerable toxicity. The primary endpoint is progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), disease control rate (DCR) according to the RECIST v1.1, overall survival (OS) and treatment-related adverse event (TRAE). Results: Total 40 pts were recruited from Dec 2021 to May 2023. Pts characteristics were as follows: median age of 56 (range, 36-81); hepatitis B (77.5%), hepatitis C (10.0%), non-viral (12.5%); BCLC C stage (97.5%); and AFP ≥ 400 ng/ml (40.0%). As of the date of data cut-off (15 Aug 2023), the median follow-up duration was 6.6 mo (95% CI, 5.0-8.2). The median PFS was 3.5 mo (95% CI, 3.0-4.0). ORR and DCR were 10.0% and 82.5%. The median OS was 9.7 mo (95% CI, 8.3-11.1) and 6-month OS rate was 55.0%. The median OS since the start of prior Atezo-Bev was 16.6 mo (95% CI, 11.9-21.3). When stratified according to the duration of prior Atezo-Bev (<4 cycles [n=10] vs. ≥4 cycles [n=30]), pts with ≥4 cycles of prior Atezo-Bev showed better median OS (not reached vs 3.6 mo; p=0.001) and ORR (13.3% vs 0%; p=0.009), while there was a trend for better median PFS (3.8 mo vs 2.5 mo; p=0.107). The most common grade 3-4 TRAEs were thrombocytopenia (5.0%), palmar-plantar erythrodysesthesia (2.5%), and fatigue (2.5%). Conclusions: Regorafenib was effective as second-line therapy in uHCC pts who progressed on first-line Atezo-Bev. Efficacy and safety outcomes from our study were consistent with those observed in the pivotal phase 3 RESORCE trial which included sorafenib-tolerated/progressed pts. Clinical trial information: NCT05134532 .