bluuebunny/crossref_metadata_2025_split huggingface dataset:
Validation of a chemotherapy toxicity prediction model in older adults with cancer in Taiwan.
Authors: Chang Chieh-Ying , Hung Yu-Shin , Kuo Ming-Chung , Hsu Chih-Chung , Chen Jen-Shi , Chou Wen-Chi 
Published: August 2024

223 Background: The Cancer and Aging Research Group (CARG) model is established for predicting chemotherapy-related toxicities in older patients; however, its applicability has not been validated in Taiwanese or non-solid tumor populations. Due to biopsychosocial distinctions in the Taiwanese demographic and inherent disparities between lymphoma and solid tumors, a modified CARG (mCARG) was assessed for its toxicity prediction capabilities. Methods: In this study, 337 consecutive patients aged ≥65 years with solid tumors (N=258) or lymphoma (N=79), slated for first-line chemotherapy, were recruited from a single medical center in Taiwan between 2018 and 2021, with follow-up until December 31, 2021. Patients were categorized into low-, medium-, and high-risk groups based on mCARG, excluding the cancer-type parameter from the original CARG variables. Validation of mCARG involved receiver operating characteristic (ROC) curves, and individual mCARG variables were analyzed using univariate analysis for their impact on chemotherapy toxicities and overall survival. Results: This study included 337 patients (mean age, 70 years; 160 female [47%]; 177 male [53%]) classified as low-(N=112, 33.2%), medium-(N=106, 31.5%), and high-(N=119, 35.3%) risk. Toxicities of grades ≥3 were 41.1%, 50.0%, and 71.4% ( P<0.001), respectively. ROC was 0.665 (95% CI: 0.608–0.722), indicating satisfactory discrimination. However, the lymphoma subgroup exhibited no significant differences in toxicity risk levels (70.0%, 74.1%, and 81.0%; P=0.39). Among mCARG variables, age ≥72 years ( P=0.008), polychemotherapy ( P=0.009), decreased hemoglobin ( P<0.001), falls ( P=0.008), and inability to walk one block ( P=0.01) were associated with toxicities. One-year overall survival rates were 80.6%, 69.4%, and 57.2%, respectively, in ascending-risk groups, with high-risk groups showing decreased survival ( P=0.001). Conclusions: This prognostic study validated the mCARG model in a heterogeneous cancer cohort in Taiwan but failed to do so in the lymphoma subgroup. Although unable to predict all toxicities, mCARG could offer insights into patient survival among older individuals with cancer.
Osteosarcoma patient-derived orthotopic xenograft (PDOX) models for identification of novel and effective therapeutics.
Authors: Higuchi Takashi , Hoffman Robert M. , Tsuchiya Hiroyuki , Yamamoto Norio , Hayashi Katsuhiro , Miwa Shinji , Igarashi Kentaro 
Published: August 2024

228 Background: Osteosarcoma is the most common malignant primary tumor of bone and mainly occurs in young generations. Due to the heterogeneity, rarity, poor response rate to systemic therapy, and metastatic potential of osteosarcoma, individualized precision medicine and novel drug discovery are greatly needed. Toward this goal, we have established the patient-derived orthotopic xenograft (PDOX) mouse model with surgical orthotopic implantation for all major cancers. The PDOX models recapitulate human tumors better than subcutaneous-transplanted xenografts including patient-derived xenograft (PDX). Metastasis is observed to a greater extent in PDOX models due to the intact histology and correct-organ tumor micro-environment of the orthotopically implanted tissue. Therefore, the PDOX model is highly predictive of drug efficacy and useful for identifying effective drugs for tumors in which new drugs are difficult to develop. Methods: We have reported 18 osteosarcoma PDOX studies evaluating approved and experimental drugs since 2017. The present report reviews our research group’s experience with the osteosarcoma-PDOX model, and the power of the PDOX models to identify effective therapeutics. Results: Effective treatment for drug-resistant osteosarcoma includes regorafenib, as monotherapy, and temozolomide-irinotecan, trabectedin-irinotecan, sorafenib-everolimus, sorafenib-palbociclib, and olaratumab-doxorubicin-cisplatin, as combinations. Experimental therapy with recombinant methioninase, tumor-targeting S. typhimurium A1-R, or combinations of these agents and other drugs have shown surprising efficacy in the recalcitrant-osteosarcoma PDOX models. Conclusions: Owing to the high concordance of drug efficacy between patients and their corresponding PDOX models, these models provide improved and personalized treatment options for patients with osteosarcoma. The patient does not need to suffer from the potential drug toxicity and morbidity of ineffective chemotherapies. In an era of growing promise of new treatment and precision medicine, PDOX models can offer a unique opportunity to provide specific and individualized therapy and novel therapeutic options for osteosarcoma patients.
An exploratory investigator-initiated trial via intrathecal or intracerebroventricular delivery of B7H3-specific allogeneic universal CAR-T cells in patients with recurrent high-grade gliomas.
Authors: Shang Xiaoyun , Li Xuetao , Zhang Xuewen , Huang Yulun 
Published: August 2024

23 Background: The MT027, developed by T-Maximum, is a B7-H3 (CD276)-directed genetically modified allogeneic T cell, targeting CD276-overexpressed tumor cells. Here, we reported a first-in-human, single-center, open-label investigator-initiated trial (IIT) via intrathecal or Intracerebroventricular delivery targeting recurrent high-grade glioma (ChiCTR2100047968). Methods: As of March 7, 2024, a total of 50 adult patients with recurrent high-grade glioma, B7H3+ expression, and KPS ≥40 were enrolled and administered at least one dose of MT027 (FAS), of whom, 32 received at least 3 doses (PPS1), 15 subjects with ≥3 doses and at least 1 efficacy visit (PPS2). 4 dose levels of 1.0, 1.5, 2.0, 2.5×107 cells per injection were administered once every 4 weeks. Results: The overall results demonstrated the favorable tolerability, safety, PK/PD characteristics, and preliminary efficacy. In FAS, the most common AE were fever and headache, without any CRS, ICANS, GvHD, or drug-related death. There were 4 cases (8%) of grade 3 AE or greater and 3 cases (6%) of SAEs. The copies of CAR in all groups reached 10000-100000 copy/ug, and persisted for > 60 days after a single dose. After multiple doses, the MT027 CAR-T cell numbers maintained at a high level (median 8850 copies /μg (range: 200-385900)) and for a long time. The levels of IL6, TNF-α and IFN-γ in CSF increased significantly and maintained for a long time. The mOS was 13.54 m (95% CI: 7.45; 19.63) and 20.73 m (95% CI: 16.12; 25.34) in PPS1 and PPS2, respectively. The 12-month OS rate was 53.30% (95%CI: 37.5%-75.7%) and 84.60% (95%CI: 67.1%-100%) in PPS1 and PPS2, respectively (historical data: 14%). The objective response rate (ORR) was 33% and the disease control rate (DCR) was 80% in PPS2. Conclusions: In patients with relapsed high-grade glioma, the intrathecal or ICV administration of MT027 cell therapy was found to be safe and well-tolerated. The toxicity of grade 3 or above was 1/5 of similar products. The pharmacokinetics and pharmacodynamics of single-dose and multiple-dose treatments were stable. MT027 exhibited longer persistence in the body of the patients, and the cell numbers and cytokine responses induced in vivo were 1-2 orders of magnitude higher than those of similar products. MT027 cell therapy demonstrated the excellent efficacy in treating relapsed high-grade glioma, with significantly prolonged overall survival and higher objective response rate compared to the historical data and similar product data. Currently, we are preparing for the IND filing in US (expected in 2024) with the recurrent glioblastoma as the first indication. Clinical trial information: ChiCTR2100047968 .
Anti-tumor effect of zartoprofen, a non-steroidal anti-inflammatory drug, targeting PPARγ (peroxisome proliferator-activated receptor gamma) on chondrosarcoma.
Authors: Higuchi Takashi , Takeuchi Akihiko , Miwa Shinji , Hayashi Katsuhiro , Yamamoto Norio , Tsuchiya Hiroyuki 
Published: August 2024

232 Background: Peroxisome proliferator-activated receptor gamma (PPARγ) plays a central role in the differentiation of adipocytes. Anti-tumor effects by activating PPARγ have been reported on chondrosarcoma. We revealed that zaltoprofen, a non-steroidal anti-inflammatory drug (NSAID), could activate and induce PPARγ in chondrosarcoma cells. We report antitumor effects of zaltoprofen targeting PPARγ on chondrosarcoma. Methods: PPARγ activation by zaltoprofen was assessed with luciferase assay. Human chondrosarcoma cells and PPARγ-silencing cells established with shRNA were subjected to the anti-tumor analyses, western blotting, RT-PCR, and zymography. For in vivo study, chondrosarcoma cells were subcutaneously inoculated into nude mice. Zaltoprofen was administered to mice (30 mg/kg/day). Tumors were pathologically assessed. We obtained tumor tissue specimens from a patient who underwent several surgeries for recurrent spinal chondrosarcoma. The patient was administered zaltoprofen as a therapeutic agent for algia the tumor remained stable for more than 2 years. Pathological analyses were performed on the specimen before and after administration of zaltoprofen). Results: Zaltoprofen significantly increased PPARg activation (EC50 47.3 uM). Treatment with 200–400 uM zaltoprofen significantly inhibited cell viability and induced PPARγ protein and mRNA expression in chondrosarcoma cells. Zaltoprofen (400 uM) significantly decreased the cell proliferation, migration, invasion, and MMP2 expression in control cells, whereas these were significantly increased in PPARγ-silencing cells. Also, zaltoprofen (400 uM) induced p21, p27, and p53 expression in control cells, whereas these effects were canceled in PPARg-silencing cells. Upregulation of KROX20 followed by CEBP-α and –β, all of which were reported to induce PPARγ in normal adipose tissue, were detected after zaltoprofen administration. Tumor growth was significantly inhibited in mice administered zaltoprofen. Apoptotic indices in the TUNEL-labeled area were significantly larger and Ki-67 positive cells were significantly lower in tumor specimens from mice administered zaltoprofen. Patient’s specimens revealed that PPARγ expression was stronger and MMP2 expression was weaker in post-administration specimens. Conclusions: Zaltoprofen suppressed tumor progression by inhibiting cell proliferation, migration, and invasion with induction of PPARγ expression in chondrosarcoma cells. The suppressing effect on tumor progression by zaltoprofen was also observed in vivo. Zaltoprofen induced PPARγ expression and MMP2 downregulation in clinical specimens with expected antitumor effects. This is the first study demonstrating that one of the NSAIDs, zaltoprofen, may act as an antitumor agent by targeting PPARγ for chondrosarcoma.
Potential for boron neutron capture therapy (BNCT) with ASCT2-targeted boron agents.
Authors: Eza Kenichiro , Tsujino Kohei , Kawabata Shinji , Fujikawa Yoshiki , Kashiwagi Hideki , Hutamura Gen , Hiramastu Ryo , Miyatake Sinichi , Tanaka Hiroki , Suzuki Minoru , Wanibuchi Masahiko , Nakamura Hiroyuki , Araki Tomoyuki , Morita Taiki 
Published: August 2024

233 Background: Boron Neutron Capture Therapy (BNCT) is a cutting-edge particle irradiation technique that utilizes the nuclear reaction triggered by the irradiation of non-radioactive boron-10 with thermal neutrons, selectively annihilating tumor cells that have incorporated boron. In the clinical arena, Boronophenylalanine (BPA), a phenylalanine compound targeting amino acid receptors, has been the cornerstone of BNCT. While BNCT has been effective against malignant gliomas, its dependency on BPA uptake has illuminated the existence of inherent resistance within specific cells, tissues, and cancer types. This study pivots towards the Alanine-serine-cysteine transporter 2 (ASCT2)—a transporter distinct from LAT1—investigating its potential as a gateway for the development of innovative boron carriers, with the aim of expanding the clinical applicability and effectiveness of BNCT. Methods: This research embarked on in vitro investigations to evaluate boron accumulation in F98 and C6 rat glioma cells, and 9L rat gliosarcoma, following 24 hours of exposure to BPA and GluB-2 (10 μg B/ml each). Complementary in vivo studies involved the intravenous administration of these compounds to an F98 rat brain tumor model, with the subsequent measurement of boron distribution at 2.5, 6, and 24 hours post-administration. The efficacy of these treatments was then ascertained through neutron irradiation experiments, gauging therapeutic outcomes via the survival periods of the subjects. Results: In vitro findings highlighted that GluB-2 facilitated a significantly higher intracellular boron concentration compared to BPA in F98 cells (p=0.02, Student's t-test). In vivo results indicated that the apex of boron biodistribution in tumors was achieved at 2.5 hours post-BPA treatment and at 6 hours post-GluB-2 treatment, with GluB-2 securing a superior maximum intratumor boron concentration. Survival analysis revealed a mean survival of 28.0±2.5 days for the neutron alone group, 37.7±5.0 days for the group receiving BPA IV + BNCT at 2.5 hours, 55.1±19.9 days for the group treated with GluB-2 IV + BNCT at 6 hours, and 25.3±1.4 days for the untreated group. Remarkably, the group treated with GluB-2 demonstrated significantly prolonged survival compared to the BPA-treated group (p<0.001, log-rank test). Conclusions: Combining BNCT with GluB-2 showed superior efficacy over BPA. Further research is needed to optimize boron concentration timing and ASCT2 expression levels, yet GluB-2 presents a promising advancement in BNCT, potentially transforming malignant brain tumor treatment.
Exploratory study of PD-1 inhibitors for recurrent meningioma.
Authors: Wang Yali , Chen Feng , Wu Zhen , Li Wenbin 
Published: August 2024

26 Background: Meningiomas are the most common primary intracranial tumor. Some patients still have poorly controlled conditions after multiple surgeries and radiotherapies. More effective treatment methods are urgently needed. Previous studies have suggested that meningioma may shape an inhibitory tumor immune microenvironment and achieve immune escape by expressing programmed cell death ligand 1 (PD-L1) and other factors. Immune checkpoint inhibitors (ICIs) such as PD-1 inhibitors have shown promising efficacy in cases, but large-sample studies are needed to confirm these findings. Methods: Recurrent meningioma patients were included and treated with PD-1 inhibitors until tumor progression or intolerance occurred. The efficacy evaluation of enrolled patients used the Response Assessment in Neuro-Oncology (RANO) criteria. The primary endpoint was progression-free survival at 6 months (PFS-6), and secondary endpoints were progression-free survival at 12 months (PFS-12) and overall survival (OS). Adverse events were also recorded. Regular imaging follow-ups were conducted, and clinical characteristics were collected for survival analysis. Peripheral blood lymphocyte subsets and cytokines were detected before and after treatment, and tumor paraffin sections were used for immunohistochemical detection of relevant molecular markers. Results: A total of 35 recurrent meningioma patients (10 grade I, 14 grade II, 11 grade III) were included. Among all grades of patients, the median PFS was 9 months, PFS-6 was 63.6%, and PFS-12 was 47.6%. In grade I patients, the median PFS was 14 months, PFS-6 was 83%, and PFS-12 was 67%. In grade II/III patients, the median PFS was 9 months, PFS-6 was 58.9%, and PFS-12 was 42%. Among all grades of meningioma patients, PFS was significantly correlated with Ki-67 index (P = 0.021) and tumor progression times (P = 0.019). In grade II/III meningioma patients, PFS was only correlated with tumor progression times (P = 0.012). Twenty-five patients had stable disease, and seven patients had disease progression, with no patient achieving partial or complete remission. There was no significant correlation between tumor mutation burden (TMB) and PFS. Further immunohistochemical analysis of tumor tissues in three recurrent high-grade patients revealed varying degrees of increase in local CD3+, CD4+, CD8+ and PD-1+ T lymphocytes after treatment compared to baseline. Conclusions: Our study suggests that PD-1 inhibitors may prolong PFS in recurrent meningioma patients (especially high-grade) with good drug safety, warranting further exploration. Recurrent meningiomas have an immunosuppressive tumor microenvironment, and PD-1 inhibitors may improve the immune status of tumor microenvironments. Clinical trial information: NCT04728568 .
In-hospital outcome of central nervous system malignancy with COVID-19 infection: Analysis from National Inpatient Sample (NIS).
Authors: Suenghataiphorn Thanathip , Wattanachayakul Phuuwadith , Srikulmontri Thitiphan , Saowapa Sakditad , Buasri Kochakorn , Kulthamrongsri Narathorn 
Published: August 2024

29 Background: Previous research highlights central nervous system (CNS) malignancy as significant contributors to disability-adjusted life-years. However, there's a lack of information on the impact of COVID-19 infection in hospitalized CNS malignancy patients. Methods: Using the 2020 U.S. National Inpatient Sample (NIS), we investigated the impact of COVID-19 infection affected patients primarily hospitalized for CNS malignancy. We calculated adjusted odds ratios (aORs) for specific outcomes using multivariable logistic and linear regression analyses. The primary outcome was inpatient mortality, with secondary outcomes including system-based complications. Results: We identified 37,385 patients diagnosed with CNS malignancy, averaging 53.6 years old, with 57.76% being female. Among them, 0.84% (315/37,385) were also diagnosed with COVID-19. After adjusting for patient and hospital factors, COVID-19 infection was linked to higher in-hospital mortality (aOR 4.12, 95% CI: 1.55, 10.89, p = 0.004), longer stays (Beta-coefficient 6.06, 95% CI: 2.97, 9.14, p < 0.001), increased total hospital costs (Beta-coefficient 11,855, 95% CI: 1,410, 22,301, p = 0.026), elevated risks of shock (aOR 3.96, 95% CI 1.03, 15.10, p = 0.018), acute respiratory failure (aOR 4.33, 95% CI: 1.83, 10.22, p = 0.001), and sepsis (aOR 3.96, 95% CI: 1.03, 15.10, p = 0.044). Conclusions: Our study reveals that COVID-19 infection is associated with higher in-hospital mortality and multiple adverse outcomes in patients hospitalized for CNS malignancy. Further longitudinal studies are necessary to thoroughly investigate the causality of these clinical outcomes in this population.
An artificial intelligence system for early prediction of breast cancer regression pattern during neoadjuvant chemotherapy.
Authors: Huang Yuhong , Zhu Teng , Wang Kun 
Published: August 2024

3 Background: Breast cancer exhibits diverse tumor regression patterns (TRP) following neoadjuvant chemotherapy (NAC). We aims to develop an artificial intelligence (AI) system utilizing longitudinal magnetic resonance imaging (MRI) for precise TRP prediction. Methods: This retrospective study involved 2249 breast cancer patients from 12 institutions. The dataset comprised a training cohort (n=1006) from institutions I and II, and an external validation cohort (n=1243) from institutions III-XII. We utilized a 3D U-Net model for automated tumor delineation, incorporating spatial habitat analysis and 3D ResNet-50 model for extracting imaging featur, to develop an AI system. Results: The 3D U-Net model showed significant accuracy, with Dice coefficients of 0.875 in the validation cohort. The AI system achieved areas under the curve of 0.912. It demonstrated robust performance across diverse molecular subtypes (accuracies: 80·68% to 87·87%) and tumor stages (accuracies: 80·16% to 84·98%) in the validation cohorts. Conclusions: Our study provides a noninvasive AI system for early TRP prediction in breast cancer, potentially assisting clinicians in adjusting NAC regimens and planning breast-conserving surgery.
Reduced cardiovascular disease risk after gastrectomy for gastric cancer: Unexpected treatment benefits.
Authors: Kwon Yeongkeun , Kim Dohyang 
Published: August 2024

51 Background: The relationship between gastrectomy for gastric cancer and subsequent cardiovascular risk modifications has been noted, yet the direct consequences of such surgeries on cardiovascular incidences are not fully established. This study evaluated cardiovascular event rates among patients who received gastrectomy versus a matched general cohort. Methods: In a nationwide retrospective cohort analysis, we examined individuals diagnosed with gastric cancer who underwent gastrectomy (n=18,698), and a control group matched for demographics (n=81,787) from 2004 to 2008. Criteria for inclusion were patients devoid of any previous cancer diagnosis (except gastric cancer), myocardial infarction, or ischemic stroke. The primary outcome was the incidence of major adverse cardiovascular events (MACE) such as acute myocardial infarction (MI) or acute ischemic stroke, in patients with gastric cancer. Results: Within a seven-year observational window, 2.7% of the gastrectomy group (or 4.29 events per 1000 person-years) experienced new MAC). The gastrectomy group showed a significantly lower incidence rate of MACE compared to the matched control subjects (hazard ratio [HR] 0.65; 95% confidence interval [CI] 0.63–0.71; P<0.001), MI (HR, 0.68; 95% CI, 0.60–0.78; P < 0.001), and stroke (HR, 0.73; 95% CI, 0.66–0.79; P<0.001). In the subgroup analyses, no significant interactions were identified between the study groups and baseline variables. Conclusions: The study indicates a decreased risk of developing cardiovascular diseases post-gastrectomy for gastric cancer, as opposed to the general population. Beyond their significance for public health strategies aimed at cardiovascular risk management in gastric cancer patients, these findings empower both patients and healthcare providers with enhanced knowledge for making decisions about gastric cancer surgical options. Furthermore, this study lays the groundwork for future investigations into the metabolic effects of gastric cancer surgeries, notably their potential in lowering cardiovascular risk.