bluuebunny/crossref_metadata_2025 huggingface dataset:
Precision medicine-based platform to guide the treatment of EML4-ALK fusion lung cancers and other non-small cell lung cancers.
Authors: Merrill Nathan , Udager Aaron M. , Qin Angel , Lagisetty Kiran , Aikins Marisa , Bao Liwei , Cheng Xu , Goo Laura , Kathawate Varun , Vandenburg Bryce , Ulintz Peter , Qin Zhaoping , Liu Albert , Serhan Habib , Nagrath Sunitha , Hsu Peggy , Soellner Matthew , Merajver Sofia
Published: August 2023

146

Background: Lung cancer remains the number one cause of cancer-associated mortality worldwide, with a 10-year survival rate of only 5%. While most lung cancers are smoking related, 25% of non-small cell lung cancer (NSCLC) are diagnosed in patients with little or no smoking history. Fusions involving anaplastic lymphoma kinase (ALK) are the oncogenic driver in ~3–7% of NSCLC. While inhibitors targeting the kinase domain of ALK have proven extremely effective in the treatment of ALK-positive NSCLC, inevitably, resistance develops with limited effective treatment options. Methods: We developed a precision medicine-based platform to screen patient-derived material (PDM) directly from the operating room with curated panels of approved and IND drugs. PDM collected during clinically indicated procedures is dissociated into single cells, plated in culture to generate patient-derived organoids (PDOs), and screened with drugs that are curated to each tumor based on treatment history and clinically relevant sequencing. PDOs are screened at therapeutically relevant levels, drawing from pharmacokinetic data for each drug, when available. We have optimized an assay to rapidly screen for EML4-ALK fusions and can perform next-generation DNA and RNA sequencing in real time (~7 days) to integrate with drug screening results. Results: To date, we have screened 51NSCLC cases, including 7 ALK-positive NSCLC. Screening in highly progressed EML4-ALK patients demonstrates sensitivity to earlier generation ALK TKIs, a known phenomenon in the literature. Our screening results recapitulate known clinical resistance/progression in samples previously exposed to therapy, demonstrating a strong negative predictive value. Longitudinal assessment will be required to robustly assess the positive predictive value (PPV). In one EML4-ALK NSCLC (JTI026) we were able to collect PDM from two distinct regions (pleural effusion and thoracentesis) and screen them with the same panel of drugs, with identical results. These data highlight the reproducibility of our assay. Conclusions: Our precision medicine-based platform captures robust and reproducible results that are consistent with known clinical pathogenesis. Moving forward, we are collecting longitudinal data from enrolled patients in parallel with clinical trials to demonstrate PPV of our platform. We additionally strive to demonstrate reproducibility to obtain Clinical Laboratory Improvement Amendments (CLIA) approval and to deliver results to patients and physicians to help guide clinical care. [Table: see text]
A panel of seven protein tumour markers for effective and affordable multi-cancer early detection by artificial intelligence.
Authors: Mao Mao , Luan Yi , Zhong Guolin , Li Shiyong , Wu Wei , Liu Xiaoqiang , Zhu Dandan , Tu Shichun , Feng Yumin , Zhang Yixia , Duan Chaohui
Published: August 2023

155

Background: Cancer early detection aims at reducing cancer deaths. Unfortunately, many established cancer screening technologies are not suitable for use in low- and middle-income countries (LMICs) due to cost, complexity, and dependency on extensive medical infrastructure. Methods: Nearly 10,000 participants [1959 cancer cases (containing more than nine common cancer types) and 7423 non-cancer cases] were divided into one training and two independent validation cohorts. One tube of peripheral blood samples was collected from each participant and quantified using a panel of seven selected protein tumour markers (PTMs) by a common clinical electrochemiluminescence immunoassay analyser. An algorithm named OncoSeek was established using artificial intelligence (AI) to distinguish cancer from non-cancer cases by calculating the probability of cancer (POC) index based on the quantification results of the seven PTMs and clinical information including sex and age of the subjects, and to predict the possible affected tissue of origin (TOO) for those who have been detected with cancer signal. Results: The conventional clinical method relied only on a single threshold for each PTM which would make a big problem when combining the results of those markers, the false positive rate would accumulate as the number of markers increased. Nevertheless, OncoSeek was empowered by AI technology to significantly reduce the false positive rate, increasing the specificity from 56·9% [95% confidence interval (CI): 55·8% to 58·0%] to 92·9% (95% CI: 92·3% to 93·5%). In all cancer types, the overall sensitivity of the OncoSeek test was 51·7% (95% CI: 49·4% to 53·9%). And the performance was generally consistent in the training and the two validation cohorts. The sensitivities ranged from 37·1% to 77·6% for the detection of the nine common cancer types (breast, colorectum, liver, lung, lymphoma, oesophagus, ovary, pancreas, and stomach), which account for ~59·2% of global cancer deaths annually. Furthermore, it has shown excellent sensitivity in several high-mortality cancer types for which there are lacking routine screening tests in the clinic, such as the sensitivity of pancreatic cancer was 77·6% (95% CI: 69·3% to 84·6%). The overall accuracy of TOO prediction in the true positives was 66·8%, which could assist the clinical diagnostic workup. Conclusions: OncoSeek significantly outperforms the conventional clinical method, representing a novel blood-based test for multi-cancer early detection (MCED) which is a non-invasive, easy, efficient, and robust approach. Moreover, the accuracy of TOO facilitates the follow-up diagnostic workup and this method is affordable (less than $25) and accessible requiring nothing more than a blood draw at the screening sites, which makes it acceptable and sustainable in LMICs.
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).
DNA damage response (DDR) variants and effects on the tumor transcriptome and microenvironment in east Asian (EA) prostate cancers (PCa).
Authors: Hong Boon Hao , Hakansson Alexander K. , Ong Enya , Chow Wen Min , Tay Kae-Jack , Tuan Jeffrey K.L. , Wang Michael L.C. , Lee Lui Shiong , Kanesvaran Ravindran , Liu Yang , Davicioni Elai , Khor Li Yan , Chua Melvin Lee Kiang
Published: August 2023

75

Background: Aberrations of the DDR pathway have been shown to be prognostic of survival and predictive of PARP inhibition in PCa. We have previously reported on the prevalence of germline DDR mutations based on a 32-gene set in localized PCa in EA men, and observed comparable rates with that of White men. Here, we performed additional analyses investigating for associations between DDR variants to the somatic transcriptome of localized PCa. Methods: We utilized a prospectively recruited cohort of 172 EA patients, with centrally assessed Gleason’s score (GS) by an expert pathologist. Germline profiling was performed by whole exome sequencing (100X) using the Illumina Novaseq (CA). Joint genotyping was performed to annotate variants that were deemed to be pathogenic (P)/likely pathogenic (LP)/conflict of interest pathogenic (CIP) based on the CADD and REVEL scores. Tumor transcriptome was profiled using the Decipher Genomic Classifier (GC, Veracyte, CA) based on the Affymetrix ST array (ThermoFisher, CA). Results: Among the subset of 172 EA men, we observed DDR variants in 26 (15%) patients, which was comparable to the larger cohort of 890 men from the same institution. Among the DDR mutations, 2 (7.7%) were classified as P/LP, while 24 (92.3%) were CIP. Decipher GC scores were comparable between patients with and without DDR mutations (median GC score 0.87 vs 0.53, Mann-Whitney U P=0.10). For luminal-basal subtyping by either the PAM50 and Prostate specific subtyping models, we did not observe a difference for the basal (P=0.48) and luminal subtypes (P=0.21). Interestingly, DNA repair gene-set expression were comparable between patients with DDR mutations versus those without (median score -0.2 vs -0.17). However, we observed microenvironment differences for immune-related genes, where patients harboring DDR mutations manifested a less immune-suppressive environment versus those without (PDL2: -0.15 vs 0.2; Treg: 0.09 vs 0.13; MDSC: 0.03 vs 0.07, respectively). Conclusions: Herein, we report an extension of our previous work (Lua, et al. ASCO GU, 2023), where we show potential linkages between the germline DDR variant status and the tumor transcriptome. Our findings suggest the influence of germline DDR variants that extends beyond tumorigenesis.
Outcomes using enfortumab vedotin for metastatic urothelial carcinoma stratified by prior response to immunotherapy: A single institution experience.
Authors: Wee Christopher Eing , Nizam Amanda , Ornstein Moshe Chaim , Gilligan Timothy D. , Chen Yanwen , Maroli Kimberly , Martin Allison , Bonham Amanda , Lynn David , Vyas Neil , Gupta Shilpa
Published: August 2023

77

Background: Enfortumab vedotin (EV) is a preferred systemic therapy for patients with metastatic urothelial carcinoma (mUC) who have already been treated with checkpoint inhibitor immunotherapy (IO) +/- cytotoxic chemotherapy. We examined our institution’s experience using EV to treat mUC to determine whether prior-line IO response could predict subsequent clinical outcomes on EV. Methods: Patients treated with EV for mUC at our institution were reviewed. Patient characteristics were noted, including age, sex, primary site of disease, and prior lines of treatment for mUC. Clinical responses to IO and EV were defined by best response to that line of therapy; patients were deemed to have “initial benefit” to a line of therapy if their best response was complete response (CR), partial response (PR), or stable disease (SD). Patients were deemed to have “initial resistance” to a line of therapy if their best response was progression of disease (PD). Progression free survival (OS) and overall survival (OS) were calculated from time of EV start to progression/death or death, respectively. Results: Thirty-six patients treated with EV were identified, of whom 30 had received prior IO and were included in the final analysis. The median age at time of EV start was 69.5 years, 21/30 patients were male, and 19/30 had a primary site of bladder for their (mUC). Eighteen patients (60%) had initial resistance as their best response to IO, while only 12 (40%) had initial benefit as their best response to IO (before eventually being treated with EV in a subsequent line). There were no statistical differences in OS or PFS for patients treated with EV when stratifying by prior IO response (Table). Half (15/30) of the patients had initial benefit as best response to EV, while 9/30 patients had initial resistance, and 6/30 patients were not evaluable. There was no statistically significant association between response to EV (initial benefit vs initial resistance) and response to IO as assessed by Fisher’s exact test (p=0.4). Conclusions: Patients have similar clinical outcomes on EV regardless of their responses to prior-line IO therapy. [Table: see text]
Clinicopathological characteristics and oncological outcomes of three subtypes of neuroendocrine carcinoma of the cervix: A multicenter retrospective study of 288 patients in China.
Authors: Gu Yu , Xiang Yang
Published: August 2023

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Background: Neuroendocrine carcinoma of the cervix (NECC) is a rare pathological classification of cervical cancer, and is divided into small cell neuroendocrine carcinoma (SCNEC), large cell neuroendocrine carcinoma (LCNEC) and mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). Present literature on NECC mainly focus on SCNEC, and the clinical features of LCNEC, especially MiNEN, are not well understood. Methods: A multicenter, retrospective study enrolled 288 patients. The primary outcomes were progression-free survival (PFS) and overall survival (OS). The Kaplan-Meier method and Cox proportional hazard analysis were performed to determine risk factors of PFS and OS. Results: With a median follow up of 25 months, the 5-year PFS of NECC, SCNEC, LCNEC and MiNEN was 40.2%, 40.4%, 30.3%, and 41.6%, respectively; and the 5-year OS was 45.4%, 44.0%, 32.3%, and 50.3%. In the whole cohort, it showed that LVSI (HR=1.996, 95%CI:1.275~3.126, p=0.003) and >2/3 stromal invasion (HR=2.009, 95%CI:1.222~3.303, p=0.006) were independent risk factors of PFS; age>45 (HR=1.956, 95%CI: 1.170~3.272, p=0.011), LVSI (HR=1.722, 95%CI: 1.016~2.918, p=0.043) and >2/3 stromal invasion (HR=1.778, 95%CI: 1.024~3.087, p=0.041) were independent risk factors for OS. In patients undertaking surgery, it revealed that LVSI (HR=1.996, 95%CI:1.275~3.126, p=0.003) and NACT (HR=1.691, 95%CI: 1.040~2.748, p=0.034) were independent risk factors, and that adjuvant chemoradiotherapy was an independent protective factor of PFS (HR=0.201, 95%CI: 0.103~0.428, p<0.001); age>42 (HR=2.377, 95%CI: 1.417~3.986, p=0.001) and LVSI (HR=2.450, 95%CI: 1.388~4.324, p=0.002) were independent risk factors of OS, and that adjuvant chemoradiotherapy was an independent protective factor of OS (HR=0.175, 95%CI: 0.079~0.388, p<0.001). Conclusions: This multicenter retrospective study first focused on three pathological subtypes of NECC including SCNEC, LCNEC and MiNEN. Patients with MiNEN did not have better prognosis, compared to patients with SCNEC and LCNEC at the same stage. LVSI and >2/3 stromal invasion and adjuvant chemoradiotherapy are prognostic factors for PFS; age, LVSI, and >2/3 stromal invasion and adjuvant chemoradiotherapy are prognostic factors for OS in patients with NECC. [Table: see text]
Precocious Puberty Diagnoses Spike, COVID-19 Pandemic, and Body Mass Index: Findings From a 4-year Study
Authors: Fava Daniela , Pepino Carlotta , Tosto Valentina , Gastaldi Roberto , Pepe Alessia , Paoloni Dalila , Strati Marina Francesca , Angelelli Alessia , Calandrino Andrea , Tedesco Caterina , Camia Tiziana , Allegri Anna Elsa Maria , Patti Giuseppa , Casalini Emilio , Bassi Marta , Calevo Maria Grazia , Napoli Flavia , Maghnie Mohamad
Published: August 2023

Context

Since the COVID-19 outbreak, the number of girls with suspected precocious puberty has increased.

Objective

To compare the incidence of idiopathic central precocious puberty (ICPP) during COVID-19 with that of the previous 4 years.

Methods

Anthropometric, biochemical, and radiological parameters were collected between January 2016 and June 2021 from 133 girls who met the Rapidly Progressive ICPP criteria (RP-ICPP).

Results

We found a higher incidence of RP-ICPP between March 2020 and June 2021 (group 2) compared with January 2016 through March 2020 (group 1) (53.5% vs 41.1%); 2021 showed the highest annual incidence (P < .05). Group 1 and group 2 differed in age at diagnosis (7.96 ± 0.71 vs 7.61 ± 0.94; P < .05), mean Tanner stage (2.86 ± 0.51 vs 2.64 ± 0; P < .05), and in the time between the appearance of thelarche and diagnosis (0.93 ± 0.75 vs 0.71 ± 0.62 years, P < .05). There was an increase in the number of girls aged <8 years in group 2 and a significantly higher number of girls aged >8 years was found in group 1 (42 in group 1 vs 20 in group 2, P < 0.05). Overall body mass index SD score showed higher values ​​in group 2 (1.01 ± 1.23 vs 0.69 ± 1.15; P = .18), which spent an average of 1.94 ± 1.81 hours per day using electronic devices; 88.5% of this group stopped any physical activity.

Conclusions

A spike in new diagnoses of idiopathic (1.79-fold higher) and RP-CPP coincided with the COVID-19 pandemic. The incidence of RP-ICPP was 1.3-fold higher during COVID-19 with a trend toward an increase in body mass index SD score. The expanding use of digital devices and the reduction of daily physical activity represent possible risk factors.
On some Technical Applications of the Spectrum. Microscope
Authors: Sorby H. C.
Published: August 2023

My object in publishing the following paper is to show that the spectrum microscope may be applied with advantage in several departments of technical inquiry, and more especially to describe the methods useful in such investigations. Since these will be much more readily understood by means of practical illustrations, I shall not make many general introductory remarks, but reserve an account of each particular process until I come to those practical questions which require its adoption.
Exploring Novel Synthetic Concepts and Strategies Using Mechanochemistry
Authors: Kubota Koji
Published: August 2023

In the field of organic synthesis, a ball-milling synthetic technique has garnered significant attention in recent years as an eco-friendly and sustainable alternative to traditional solution-based methods. In addition to its environmental benefits, solid-state organic synthesis using mechanochemical protocols enables access to novel areas of chemical space that are unavailable by conventional solution-based reactions. In this context, we are interested in designing and developing new organic transformations based on the unique solid-state reaction environment and the use of mechanical forces in a ball mill. In this Account, we highlight our latest findings concerning the creation of novel synthetic concepts and strategies. These approaches harness the distinctive reaction environment of mechanochemistry, rather than merely transferring well-established reactions from solution-based protocols to mechanochemical conditions.
Sodium Bicarbonate Ingestion in a Fasted State Improves 16.1-km Cycling Time-Trial Performance
Authors: LEACH NICHOLAS K. , HILTON NATHAN P. , TINNION DANIEL , DOBSON BEN , MCNAUGHTON LARS R. , SPARKS S. ANDY
Published: August 2023

Purpose

The use of sodium bicarbonate (SB) as a preexercise ergogenic aid has been extensively studied in short-duration high-intensity exercise. Very few studies have considered the effects of SB ingestion before prolonged high-intensity exercise. The aim of the present study was to determine the effects of a 0.3 g·kg−1 body mass dose of SB ingested before the start of a 16.1-km cycling time trial in cyclists.

Method

Ten trained male cyclists (age, 31.1 ± 9 yr; height, 1.84 ± 0.05 m; body mass, 82.8 ± 8.5 kg; and V̇O2peak, 60.4 ± 3.1 mL·kg−1·min−1) completed this study. Participants ingested 0.3 g·kg−1 in gelatine (SB-G) and enteric capsules (SB-E) 1 wk apart to determine individualized time-to-peak alkalosis for each ingestion form. Using a randomized crossover design, participants then performed simulated 16.1-km time trials after ingestion of SB-G, SB-E, or a placebo.

Results

There were significant differences in performance between the SB and placebo ingestion strategies (f = 5.50, P = 0.014, pη
2 = 0.38). Performance time was significantly improved by SB ingestion (mean improvement: 34.4 ± 42.6 s (P = 0.031) and 40.4 ± 45.5 s (P = 0.020) for SB-G and SB-E, respectively) compared with the placebo. Gastrointestinal symptoms were lower after SB-E compared with SB-G (36.3 ± 4.5 vs 5.6 ± 3.1 AU, P < 0.001, g = 7.09).

Conclusions

This study demonstrates that increased buffering capacity after acute preexercise SB ingestion can improve endurance cycling time-trial performances. The use of SB could be considered for use in 16.1-km cycling time trials, but further work is required to establish these effects after a preexercise meal.
Carbon Border Adjustments, Climate Clubs, and Subsidy Races When Climate Policies Vary
Authors: Clausing Kimberly A. , Wolfram Catherine
Published: August 2023

Jurisdictions adopt climate policies that vary in terms of both ambition and policy approach, with some pricing carbon and others subsidizing clean production. We distinguish two types of policy spillovers from these diverse approaches. First, when countries have different levels of climate ambition, free-riders benefit at the expense of more committed countries. Second, when countries pursue different approaches, carbon-intensive producers within cost-imposing jurisdictions are at a relative competitive disadvantage compared with producers in subsidizing jurisdictions. Carbon border adjustments and climate clubs respond to these spillovers, but when countries have divergent approaches, one policy alone cannot address both spillovers. We also consider the policy dynamics arising from carbon border adjustments and climate clubs; both have the potential to encourage upward harmonization of climate policy, but come with risks. Further, the pressures of international competition may result in subsidy races, with attendant risks and benefits.
Direct dsRNA preparation by promoter-free RCT and RNase H cleavage using one circular dsDNA template with a mismatched bubble
Authors: Chen Hui , Gu Zhenzhu , Yang Liu , Liu Feng , An Ran , Ge Yinlin , Liang Xingguo
Published: August 2023

Double-stranded RNA (dsRNA) has aroused widespread interest due to its effects on immunity and applications based on RNAi. However, the in vitro preparation of dsRNA is costly and laborious. In this study, we have developed a novel and interesting method designated as pfRCT (promoter-free rolling-circle transcription) for direct, facile, and efficient dsRNA preparation. This method generates equal amounts of sense and antisense strands simultaneously from a single circular dsDNA template. To initiate transcription by T7 RNA polymerase without directional preference, a 9–15-bp bubble (mismatched duplex with strong sequence symmetry) is introduced into the template. During RCT, all the necessary reagents, including the template, NTPs, RNA polymerase, RNase H, and Helpers, are present in one pot; and the just-transcribed RNA is immediately truncated by RNase H to monomers with the desired size. The ends of the dsRNA product can also be simply sealed by T4 RNA ligase 1 after pfRCT. This new approach is expected to promote the applications of dsRNA.
Via Egnatia in the province of Macedonia
Authors: Γκιόγκη Αναστασία
Published: August 2023

Τα ενδιαφέροντα ερωτήματα που προκύπτουν σχετικά με την παρουσία ενός σημαντικού οδικού άξονα, όπως η Via Egnatia, και της εξέλιξης που παρατηρείται στο αστικό οδικό δίκτυο των συνδεδεμένων πόλεων, οδήγησαν σε μια προσέγγιση μέσω της συγκριτικής μελέτης δεδομένων που ορίζονται από συγκεκριμένες παραμέτρους. Η επιλεγμένη περιοχή ενδιαφέροντος αντιστοιχεί στα γεωγραφικά όρια της επαρχίας Μακεδονίας. Οι τρεις σημαντικότερες πόλεις επιλέχθηκαν για να εξεταστούν ως μελέτες περίπτωσης, δηλαδή οι πόλεις της Έδεσσας, της Θεσσαλονίκης και των Φιλίππων, με βάση την αντίστοιχη θέση και σύνδεσή τους μέσω της Εγνατίας Οδού, όπως και την ιστορική τους σημασία και εξέλιξη, γεγονός που, κατά συνέπεια, παρήγαγε πληθώρα αρχαιολογικών δεδομένων τόσο σε σχέση με αρχιτεκτονικά κατάλοιπα όσο και με στοιχεία του αστικού οδικού συστήματος. Εφαρμόστηκε μια προσέγγιση μέσω προγράμματος Gis, με βάση την υποβολή κατάλληλων ερωτημάτων σε μια προσπάθεια για την κατανόηση του κατά πόσον η καθιερωμένη διαδρομή της Via Egnatia υπακούει πράγματι σε γεωγραφικούς περιορισμούς και παραχωρήσεις ή ακολουθεί διαφορετικούς κανόνες που ορίζονται από κοινωνικές ή πολιτικές επιλογές.