bluuebunny/crossref_metadata_2025_split huggingface dataset:
The prognostic factor of severe COVID-19 in cancer patients and outcomes.
Authors: Neesanun Sunee 
Published: August 2023

162 Background: Cancer is a high risk for worse COVID-19 outcomes. However, the data on factors of severe COVID-19 cancer patients in Thailand are underrepresented. This study aims to evaluate the factors of severe COVID-19 in cancer patients. Methods: From October 2020 - April 2022, cancer patients with SARS-CoV-2 infection confirmed by a positive RT–PCR test or COVID antigen test at Sawanpracharak Hospital were retrospectively analyzed. Severe COVID-19 is defined as requiring a high-flow nasal cannula, or mechanical ventilator. Demographic and risk factors data were collected from the electronic medical record. Univariate and multivariate logistic regression analyses were performed to identify risk factors for severe COVID-19. Results: Among 213 patients, 20 (9.4%) developed severe COVID-19 and the mortality rate was 6.5%. There was a significantly higher rate of discontinued cancer treatment and disease progression in severe than non-severe COVID-19 (73.7% vs 9.9%, P<0.001 and 82.4% vs 25.3%, P=0.001). Univariate analysis revealed that diarrhea (OR 6.042, 95% CI 1.541-23.629, P=0.010), oxygen saturation < 92% (OR 9.625 95% CI 2.968-31.208, P<0.001), ECOG ≥ 2 (OR 4.215 95% CI (1.598-11.114, P=0.004), Best supportive care (OR 4.190, 95% CI 1.328-13.223, P=0.015), diabetic mellitus (OR 5.123, 95% CI 1.866-14.065, P=0.002), hypertension (OR 4.758 (95% CI 1.772-12.775, P=0.002), liver disease (OR 4.362, 95% CI 1.371-13.897, P=0.013), polypharmacy (OR 4.991, 95% CI 1.805-13.799, P=0.002), < 2 vaccines (OR 3.558, 95%CI 1.342-10.188, P=0.018), Neutrophil/Lymphocyte Ratio (NLR) ≥ 12 (8.479, 95% CI 2.833-25.247, P<0.001), CRP≥ 65(OR 3.580, 95% CI 1.111-11.542, P< 0.001), hospital-acquired pneumonia (HAP) (OR 18.920, 95%CI 6.112-58.574, P<0.001) are associated with severe COVID-19. Multivariate analysis found that high NLR (OR 46.787, 95%CI 2.063-1061.227, P=0.012), Liver disease (OR 26.885, 95%CI 1.666-433.785, P=0.020), and hypertension (OR 44.095, 95% CI 1.082-1797.017, P=0.045) were significant factors of severe COVID-19. Conclusions: High baseline NLR, liver disease, and hypertension were independent factors for severe COVID-19 in cancer patients. Therefore, patients with these risk factors should be more carefully monitored.
Development of INER-PP-F11N as the radionuclide theragnostics agent against cholecystokinin B receptor-overexpressed tumors.
Authors: Chiang Ping Fang 
Published: August 2023

164 Background: We aimed to evaluate an albumin affinity structure-containing radiopharmaceutical agents INER-PP-F11N-1 and INER-PP-F11N-2 for diagnostic/therapeutic the CCK2R-overexpressed cancers. Methods: We developed the radionuclide labeled In-111/Lu-177-INER-PP-F11N radiopharmaceuticals in comparison with the current PP-F11N to investigate the radiochemical purity, SPECT/CT imaging, bio-distribution, and therapeutic responses in CCK2R-expressing tumor xenograft mice. Results: The radiochemical purity of In-111/Lu-177-INER-PP-F11N radiopharmaceuticals reached more than 90% after 144 hours of labeling. Both INER-PP-F11N increased cellular uptake and internalization 27% and 11% in compared with PP-F11N, respectively. In-vivo SPECT-CT imaging confirmed INER-PP-F11N could accumulate in the tumor site of mice in 24 hours after receiving those two radiopharmaceutical agents. Bio-distribution analysis revealed a significantly greater tumor uptake and reduced accumulation of INER-PP-F11N in kidney in compared with PP-F11N. Furthermore, INER-PP-F11N could significantly inhibit growth of the CCK2R-overexpressing tumors in mice. Conclusions: The INER-PP-F11N radiopharmaceuticals was superior to the current PP-F11N as a theragnostic agent. Our study suggested INER-PP-F11N could be an innovative radiopharmaceutical agent for CCK2R-overexpressing cancer patients.
Distribution and failure patterns of primary central nervous system lymphoma related to the hippocampus: Implications for hippocampal sparing irradiation.
Authors: Lee Jooho , Ryu Hye Jo 
Published: August 2023

20 Background: Hippocampus (HC) injury by conventional whole brain radiotherapy (C-WBRT) contributes to the neurocognitive decline in primary central nervous system lymphoma (PCNSL). Hippocampal avoidance (HA–WBRT) could minimize neurocognitive impairment by reducing the radiation dose to HC. However, its feasibility in PCNSL has not been examined regarding the incidence of HC involvement and failures. In this retrospective study, we assessed the risk of hippocampal area involvement at diagnosis and after treatments in PCNSL patients. Methods: We identified 278 immunocompetent PCNSL patients diagnosed between 2000 and 2020. After high dose methotrexate-based induction chemotherapy followed by observation or consolidation including RT, cytarabine alone, or autologous stem cell transplantation (ASCT). HC was contoured on T1 MRI image and expanded with a 5mm margin, generating hippocampal avoidance region (HAR). The extent of initial and recurrent lesions was evaluated using pre-induction and post-consolidation T1 contrast-enhanced MRI images. HC failure was defined as recurrence or progression at HAR and those who progressed after induction were excluded. The median follow up was 38.7 months (3.1-239.4). Results: Of 278 patients diagnosed with PCNSL, 39.9% of them had initial lesions at HAR. After induction therapy, 212 evaluable patients received consolidation as follows: RT (n=145, 68.4%) consisting of C-WBRT (n=114), HA-WBRT (n=23), and focal RT (n=8), observation (n=38, 17.9%), cytarabine only (24, 11.3%), and ASCT (n=5, 2.4%). Intracranial failures occurred in 47.6% (n=101) of patients, with 33.7% (n=34) of them in HAR. The multivariate analysis identified multifocal disease (HR 3.86, 95% CI 1.15-9.73, p=0.004) as the only factor associated with the risk of HC failure. Those with unifocal lesion outside HAR showed the lowest HC failure rate, 7.0%, while the highest HC failure rate, 25.4% was observed in the subgroup with multifocal disease within HAR at diagnosis. In the lowest risk group (unifocal lesion outside HAR, n=66), C-WBRT was not significantly associated with HC failure (HR 0.57, CI 0.09-3.33, P=.572) or intracranial failure (HR 0.88, CI 0.40-1.91, P=.748). Conclusions: Our data suggest the HA-WBRT could be explored in patients whose lesion is unifocal and located outside HAR. WBRT, including the hippocampus, did not significantly change HC failure for patients without initial HAR involvement. Further prospective study will be warranted to assess the feasibility of HA-WBRT in the subgroup with low risk of HC failure.
Phase 1A, first-in-human study of ARB202, bispecific antibody to CDH17 and CD3, in advanced gastrointestinal malignancies expressing CDH17.
Authors: Leung Roland Ching-Yu , Yau Thomas , Wong Dennis A , Luk John Moon , de Souza Paul L. 
Published: August 2023

25 Background: Cadherin-17 (CDH17) is a highly specific therapeutic cancer target, of which aberrant expression has been reported in 50-95% in GI tumor samples (including stomach, pancreas, liver/bile duct, rectum, and colon). Normal CDH17 expression is primarily in the water-tight junction between mucosal epithelial cells which is potentially “masked” from the immune system (Feng, Z., et al., Nat Cancer, 2022). A bispecific T-cell engager ARB202 using CD3 to aid the formation of an immunological synapse CDH17 tumor cells and T-cells is being studied. Methods: In an ongoing dose-escalation phase IA part of a continuous study, patients with advanced CD17+ solid tumors are being given up to 3 doses of ARB202 bispecific. In part 1, 28 pts can be treated at dose levels from 0.0003 mg/kg to 10 mg/kg; Based on clinical response intra-dosing of tolerated (higher) doses can occur in for the 2nd and 3rd doses. Second and 3 doses are planned at the 4th cohort starting at a dose of 0.010 mg/kg when tissue levels are likely physiologically active. Minimum anticipated biological effect level (MABEL) dosing which is based on the most sensitive in vitro assay is being used to set the initial 3 doses to ensure safety of any T-cell engagement at low levels in circulation. Data cutoff 10.04.23. Results: Colorectal, gastric, pancreatic and cholangiocarcinoma patients have screened positive for CDH17 by semi-automated tissue immunostaining. Seven patients have completed dosing in the first 3 cohorts and have shown tolerability to 0.0003 to 0.003 mg/kg single IV doses. The Cmax measured within 1 hour of dosing has confirmed the circulating PK range of 10-20 ng/ml for the 2nd cohort and 40-50 ng/ml in the 3rd cohort consistent with the expected PK of antibody-like volume of distribution. The safety review committee has approved the dose escalation to proceed to the 4th cohort Identifier: NCT05411133. Conclusions: ARB202 a bispecific T-cell engager has shown tolerability up to 40ng/ml Cmax in circulation suggesting no clinically significant CD3 only binding cell activation at these levels. These data allow for higher dosing to achieve tissue ARB202 concentrations where anti-CDH17/CD3 aided synapse formation between tissue tumor cells and T-cells can lead to clinical evidence of bispecific target engagement and their expected effects. Clinical trial information: NCT05411133 .
Gastric cancer: Neural networks, complex system analysis, statistics and computer modeling for best management.
Authors: Kshivets Oleg 
Published: August 2023

37 Background: We examined factors of alive supersystems – gastric cancer (GC) patients (GCP) and cell ratio factors (CRF) significantly affecting GCP survival. CRF - ratio between cancer cells (CC) and blood cells subpopulations. Methods: We analyzed data of 799 consecutive GCP (T1-4N0-2M0) (age=57.1±9.4 years; tumor size=5.4±3.1 cm) radically operated (R0) and monitored in 1975-2023 (m=558, f=241; total gastrectomies (G)=173, distal G=461; proximal G=165; combined G=247 with resection of esophagus, pancreas, liver, duodenum, diaphragm, colon transversum, splenectomy, etc; only surgery-S=624, adjuvant chemoimmunotherapy-AT=175 (5-FU + thymalin/taktivin); T1=238, T2=220, T3=184, T4=157; N0=437, N1=109, N2=253, M0=799. Variables selected for prognosis study were input levels of 45 blood parameters, sex, age, TNMG, cell type, tumor size. Survival curves were estimated by the Kaplan-Meier method. Differences in curves between groups of GCP were evaluated using a log-rank test. Multivariate Cox modeling, discriminant analysis, clustering, SEPATH, Monte Carlo, bootstrap and neural networks computing were used to determine any significant dependence. Results: Overall life span (LS) was 2128.9±2300.3 days and cumulative 5-year survival (5YS) reached 58.4%, 10 years – 51.9%, 20 years – 39%, 30 years – 27.2%. 318 GCP lived more than 5 years (LS=4304.5±2290.6 days), 169 GCP – more than 10 years (LS=5919.5±2020 days). 290 GCP died because of GC (LS=651±347.2 days). Cox modeling displayed that GCP survival significantly depended on CRF: healthy cells/CC, erythrocytes/CC, monocytes/CC, phase transition (PT) in terms of synergetics early—invasive cancer; PT N0--N12, age, G1-3, hemorrhage time, ESS, sex, AT, prothrombin index, residual nitrogen. Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early—invasive cancer (rank=1); PT N0--N12 (2); healthy cells/CC (3), erythrocytes/CC (4), thrombocytes/CC (5), monocytes/CC (6), segmented neutrophils/CC (7), leucocytes/CC (8), lymphocytes/CC (9), stick neutrophils/CC (10), eosinophils/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0). Conclusions: 5-year survival of GCP after radical procedures significantly depended on: PT “early-invasive cancer”; PT N0--N12; CRF; blood cell circuit; biochemical factors; hemostasis system; AT; GC characteristics; GC cell dynamics; tumor localization; anthropometric data; surgery type. Best diagnosis and treatment strategies for GC are: 1) screening and early detection of GC; 2) availability of experienced abdominal surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunotherapy for GCP with unfavorable prognosis.
Tislelizumab versus sorafenib in first-line treatment of unresectable hepatocellular carcinoma: Impact on health-related quality of life in RATIONALE-301 population.
Authors: Finn Richard S. , Qin Shukui , Kudo Masatoshi , Meyer Tim , Boisserie Frederic , Li Songzi , Chen Yaxi , Barnes Gisoo , Abdrashitov Ramil , Zhu Andrew X. , Vogel Arndt 
Published: August 2023

43 Background: RATIONALE-301 (NCT03412773), a global Phase 3 study, comparing tislelizumab (TIS) to sorafenib (SOR) as 1L treatment in adult patients (pts) with unresectable HCC (uHCC), met its primary endpoint of OS non-inferiority. This analysis examined the HRQoL outcomes in pts in both arms. Methods: Systemic therapy-naïve adults with histologically confirmed uHCC were randomized 1:1 to receive TIS (200 mg IV Q3W, n=342) or SOR (400 mg PO BID, n=332). HRQoL was assessed using EORTC QLQ-C30, QLQ-HCC18 and EQ5D-5L. A mixed model for repeated measures using key pre-specified PRO endpoints of global health status/quality of life (GHS/QoL), physical functioning and fatigue scales of the QLQ-C30, and HCC18 index score, fatigue and pain scores at the key pre-specified clinical cycles 4 and 6 were performed. Time to deterioration was examined with the Kaplan-Meier method using the PRO endpoints. Results: At both cycles, TIS had better HRQoL outcomes than SOR, as indicated by LS mean differences in GHS/QoL, physical functioning, fatigue and HCC symptom index, but not for pain. TIS had a lower risk for deterioration of QLQ-C30 GHS/QoL (hazard ratio [HR] 0.68 [95% CI, 0.49-0.94]), physical functioning (0.53 [0.39-0.73]) and fatigue (0.48 [0.37, 0.63]) as well as for deterioration in the HCC18 index (0.53 [0.34-0.81]) and fatigue (0.60 [0.46-0.80]). Both arms had a similar risk for deterioration in pain (HR 0.78 [0.56-1.09]). TIS maintained while SOR declined EQ-5D-5L VAS (general health status) scores at cycle 4 (mean change from baseline =-0.4 [SD = 14.52] vs -4.3 [12.92]) and cycle 6 (-0.2 [17.03] vs -5.4 [13.09]). Conclusions: Pts with HCC treated with 1L TIS had better HRQoL outcomes compared with pts treated with SOR, particularly in terms of fatigue and physical functioning. These results, along with effects on overall survival, response rate, and a favorable safety profile, support the benefit of TIS as a potential 1L treatment option for uHCC. Clinical trial information: NCT03412773 . [Table: see text]
Clinical profiles and outcomes of patients enrolled in the department of health: Breast cancer medicines access program in the philippines—A single center experience.
Authors: Talao Jason King Dalusung , Juat Necy Saguisag , Luna Herdee Gloriane Cristal , Mendoza Marvin Jonne Limbo , Tejada Kristine Geraneo , Cardenas Lyrene Cataquiz , Medina Sharon Reyes 
Published: August 2023

6 Background: The magnitude of breast cancer as a major public health problem throughout the world has always been emphasized. In the Philippines, the incidence of breast cancer is 17.7% in 2020, which makes it the most common malignancy among women. According to the American Cancer Society, when breast cancer is detected early, the 5-year relative survival rate is 99% as compared to a patient with distant metastasis, which decreased to 29%. Therefore, enhanced screening techniques for early disease detection and prompt treatment are necessary to improve cure and survival rates. The Breast Cancer Medicines Access Program (BCMAP) aimed to provide ready access to free medicines for the adjuvant chemotherapy treatment of Stage I-IIIb breast cancer patients to alleviate financial toxicity associated with the costly cancer treatment. This study aims to assess the impact of the BCMAP, and determine the clinical profiles and outcomes of patients enrolled in the program at National Kidney and Transplant Institute. Specifically, this study aims to identify factors causing delay of treatment, to evaluate the program and to provide recommendations for implementation improvement. Methods: This is a retrospective cohort study which included all enrolled patients at the BCMAP from October 2020 to December 2021. The patients were followed up until July 2022 to determine survival rates. Results: There were 52 eligible breast cancer patients enrolled. More than two-thirds completed systemic treatment as per physician’s discretion. The results showed that the overall survival rate is at 95.9% and the disease-free survival rate is at 88.7%. Less than 10% had progressed, and there were two mortalities reported. COVID-19 infection (p=0.0001) and unavailability of trastuzumab (p=0.0216) were identified to be significant factors for treatment delay. Conclusions: There was a trend towards a favorable overall survival and disease-free survival for patients with early breast cancer enrolled to DOH-BCMAP at 21 months follow-up. COVID-19 infection and unavailability of Trastuzumab were significant factors for treatment delay.
Multi-omics characterization of cholangiocarcinoma and association with prognostic and therapeutic molecular subtypes.
Authors: Chen Lu , Song Tianqiang 
Published: August 2023

60 Background: Cholangiocarcinoma (CCA) is a highly heterogeneous cancer with a poor prognosis. Previous multiplex proﬁling have been partly identified molecular features of CCA but the underpinnings of CCA’s development, tumor microenvironment (TME) and therapeutic resistance remain largely unknown. Our objective was to characterise genomic/transcriptomic/epigenetic landscapes of CCA aiming to establish therapeutic associated molecular classification. Methods: We profiled 450 untreated CCA with various anatomical subtypes from multiple centers with whole-genome sequencing (WGS), whole-exome sequencing (WES), RNA sequencing, whole-genome bisulfite sequencing (WGBS) and protein immunohistochemistry and performed an integrated analysis as well as clinical-pathological characteristics to identify the molecular determinants, developing a classifier for clinical-molecular prognostic classiﬁcation and predicting responsiveness of immune checkpoint blockade therapy. Results: Integrative clustering deﬁned 4 CCA subtypes (C1-C4) with distinct clinical-pathological features, TME characteristics, putative therapeutics and prognoses. Then, a 160-gene classifier was created, and this classifier was able to classify the vast majority of CCA cases into the C1-C4 subtypes and was verified to be valuable for guiding clinical treatment. Patients with C3 characteristics had the best prognosis and exhibited higher responsiveness to immune checkpoint blockade therapy than others (75% vs 15%). Moreover, we demonstrated that the CpG island methylator phenotype (CIMP) could serve as an indicator of immunocyte infiltration in the TME of CCA. SOS1 and ATP2B1 were identified as potential new driver genes and signiﬁcant prognostic biomarkers of CCA. Conclusions: Our studies yield insights into the heterogeneity and clinical-molecular classiﬁcation of CCA and could aid in the establishment of diagnostic and individualized therapeutic strategies.
Multimodal analysis of methylomics and fragmentomics in plasma cell-free DNA for multi-cancer early detection and localization.
Authors: Tran Le Son , Nguyen Van Thien Chi , Nguyen Hoai-Nghia , Giang Hoa , Phan Minh-Duy 
Published: August 2023

62 Background: In an era marked by a global rise in cancer-related morbidity and mortality, the development of liquid biopsy screening tests that can detect and localize cancer at an early stage holds tremendous potential to revolutionize cancer diagnosis and therapy. However, challenges in test performance and cost must still be overcome, due mostly to the limited abundance of circulating tumor DNA and its inherent variability. To address these challenges, published liquid biopsy assays to date demanded a very high-depth sequencing or a combination of protein and genetic biomarkers, resulting in an elevated price of test. Methods: Herein, we developed a multimodal assay called SPOT-MAS (Screening for the Presence Of Tumor by Methylation And Size) to simultaneously profile methylomics, fragmentomics, copy number, and end motifs in a single workflow using targeted and shallow genome-wide sequencing (with a depth coverage of ~0.55X) of cell-free DNA. We applied SPOT-MAS to 738 nonmetastatic patients with breast, colorectal, gastric, lung and liver cancer, and 1,550 healthy controls to extract multiple discriminative signatures for detecting and locating cancer. Results: SPOT-MAS detected the five cancer types with an overall sensitivity of 72.4% (range: 49.3% to 91.1%) at a specificity of 97.0%. The sensitivities for detecting early-stage cancers including stage I and II were 62.3% and 73.9%, respectively, increasing to 88.3% for nonmetastatic cancers (stage IIIA). For tumor-of-origin, a graph convolutional neural network was adopted and could achieve an accuracy of 70%. Conclusions: Our study demonstrates comparable performance to other early cancer detection assays while requiring significantly lower sequencing depth, making it economically feasible for population-wide screening in low-income countries.
Mechanism of action (MOA) for TGF-ß2 driven survival.
Authors: Trieu Vuong N. 
Published: August 2023

70 Background: Tumor Growth Factor β (TGF-β) plays an important role in cancer development. There are three TGF-β isoforms in human: β1, β2, β3. OT-101- an antisense against TGF-β2 – has been shown to be active against glioblastoma and pancreatic cancer and melanoma in various phase 2 clinical trials (NCT00431561, NCT00844064, NCT04862767). In the glioblastoma phase 2 trial, OT-101 single agent was as active as temozolomide (TMZ) (NCT00431561). Methods: To understand the MOA of OT-101, we analyzed the tumor microenvironment including TGF-β and IL-2 through CBioPortal and Km plotter portals to access more than 10,000 pts across multiple clinical trials (Cerami E et al., Cancer Discov (2012) 2: 401; Gao J et al., Sci-Signal. (2013) 6:269; Lanczky A et al., (2012) J Med Internet Res 26:e27633). Results: Surprisingly, only low TGF-β2 was predictive of OS and not TGF-β1 nor TGF-β3. Analysis was performed using quartiles for mRNA level and significance was declared only if the trend was consistent across all quartiles. As OT-101 is the only TGF-β2 specific therapeutic, this would explain the failure of other TGF-β clinical programs. Tumor microenvironment has significant impact on TGF-β2 driven survival including mutation load, regulatory T cell, CD8, Th2 regulatory T-cell, B-cell, macrophage, and MSC. The combination of these factors resulted in improved separation between the low TGF-β2 and the high TGF-β2. In pancreatic cancer (PDAC), macrophage and mutation burden/neoantigen burden were the most important factors. Combined, they drove median survival from 15 to 73 mos (p=7.6e-05). Low TGF-β2 enhanced survival across multiple therapeutics including FOFIRNOX for PDAC; TMZ, Radiation, and Bevacizumab for GBM, and PD-1 for melanoma. For radiation therapy in GBM, there was a steady increase in median survival across the quartiles (25, 73, 93, 95 mos, p=7.68e-08); for TMZ therapy there was a similar trend across the quartiles (25, 50, 114, 95 mos, p=5.25e-10). For PD-1 in melanoma, the ratio of IL-2/TGF-β2 was the most potent, driving upper quartile survival of patients treated with PD-1 from 6.7 to 15 mos (p=5.4e-06) with more than double the long-term survivors normally seen with PD-1 therapy. Conclusions: These findings are supportive of a significant role of TGF-β2, but not TGF-β1 nor TGF-β3, in cellular immunity against the tumor and support the development of OT-101 as an immunotherapeutic agent. There are currently multiple combination trials with OT-101 including IL-2, PD-1, and FOFIRINOX with the pivotal phase 3 trials being planned for PDAC and diffuse midline glioblastoma (DMG).