bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association between activating GNAS mutations and outcomes with chemotherapy in metastatic appendiceal adenocarcinoma.
Authors: Gujarathi Rushabh , Rodman Christopher , Bansal Varun Vivek , Belmont Erika , Setia Namrata , Alpert Lindsay , Hart John , Moller Mecker , Eng Oliver S. , Lee Grace , Chin Janet , Amin Manik A. , Polite Blase N. , Liao Chih-Yi , Turaga Kiran , Shergill Ardaman 
Published: June 2024

4179 Background: Data regarding predictive biomarkers in Appendiceal Adenocarcinoma (AA) is scarce. GNAS mutations, frequent in mucinous AA, have been linked with poor objective response (OR) to chemotherapy. We hypothesize that activating GNAS mutations are associated with differential outcomes for metastatic AA treated with chemotherapy. Methods: We reviewed the records of AA patients (pts) seen between 2013 and 2023. Pts who received 5-Flurouracil/Capecitabine (5-FU/Cape) based chemotherapy for at least 3 months (m) in the metastatic/recurrent setting (no chemotherapy for localized AA in prior 12 m) and had data available for GNAS mutations were included. The primary outcome was disease event-free survival (dEFS): the time from first dose of 5-FU/Cape given for metastatic/recurrent AA to the earliest disease event: death, radiographic recurrence in pts with complete cytoreduction (CC0), or clinical/radiographic progression. The secondary outcome was overall survival (OS). Associations between GNAS status, clinicopathologic features, and study outcomes were assessed using univariable and multivariable (for variables with p values < 0.2) Cox proportional hazards regression analysis. Results: 48 pts were eligible. GNAS activating mutations (excluding variants of uncertain significance) were seen in 18/48 (37.5%), all at the R201 hotspot ( R201H = 15, R201C= 3). Clinicopathologic characteristics between activating GNAS mutated ( GNASmt) and GNAS wild-type ( GNASwt) groups are compared in Table 1. Over a median follow-up of 29.83 m, GNASmt pts had worse dEFS (adjusted HR [aHR], 5.62; 95% CI, 1.65 – 19.12; p = 0.006), after adjusting for CC0 reduction, histology (mucinous vs. non-mucinous), and synchronous metastases (vs. metachronous). CC0 reduction (aHR, 0.43; 95% CI, 0.21 – 0.88; p = 0.02) and synchronous metastases (aHR, 0.30; 95% CI, 0.12 – 0.74; p = 0.009) were also associated with improved dEFS. There was no significant difference in OS between GNASmt vs. GNASwt pts (HR, 0.82; 95% CI, 0.39 – 1.73; p = 0.61). Conclusions: GNAS mutated metastatic AAs show worse disease event free survival with chemotherapy which aligns with historic OR data. A previously reported survival benefit of GNAS mutations in AA, likely due to favorable disease at baseline (see table), is negated in the setting of metastatic disease treated with chemotherapy. Evaluating GNAS status as a predictive biomarker for AA is warranted. [Table: see text]
Disparities in diagnosis and access to care in patients with young-onset rectal cancers in northeast Ohio.
Authors: Patel Rohan , Price Alex , Steinhagen-Golbig Emily , Conces Madison , Dorth Jennifer Anne , Miller-Ocuin Jennifer , Selfridge J. Eva , Mohamed Amr , Chakrabarti Sakti , Mahipal Amit , Bajor David L , Henke Lauren E. , Lumish Melissa Amy 
Published: June 2024

e15521 Background: The rising incidence of young-onset colorectal cancers (YO-CRC) in individuals < 50 years old is alarming. Despite the updated USPSTF recommended age for CRC screening ( < 45) in 2021, disparities in receiving proper care for YO-CRC remained largely under addressed. We sought to identify modifiable disparities to be addressed with future interventions for patients with YO-rectal cancer (YO-RC). Methods: We analyzed a cohort of patients with newly diagnosed YO-RC from 2001 to 2023 at a large academic center in Northeast Ohio. Demographic data included sex, race, age, smoking status, and poverty index. A retrospective chart review was completed to assess diagnosis date and time from symptom onset to diagnosis. Access to guideline-concordant care was assessed via clinic visits with specialty providers in medical oncology, radiation oncology, colorectal surgery, genetics, and onco-fertility. Chi-square testing and Cox regression modeling was used for statistical analyses. Results: We identified 83 patients with YO-RC, 52% female (n = 43) and 48% male (n = 40), of which 76% were White (n = 63), 21% Black (n = 17), 2% Hispanic (n = 2), and 1% Asian (n = 1). Median age at diagnosis was 44 years (IQR[39-49]). Non-White (NW) patients had a greater delay from symptom onset to diagnosis compared to White (W) patients, with an average time of 6.9mo vs 1.3mo (p < 0.00001). Colonoscopy completion rates after symptom onset for NW and W patients at 2-months was 11% vs 81% and 33% vs 98% at 4-months (p < 0.0001, respectively). Rate of access to specialty care once diagnosed was not statistically significant for either groups, but there is a lower percentage of all YO-RC patients who accessed onco-fertility (13%, n = 11) or genetics services (46%, n = 38). The median 1-year overall survival was 50% for NW patients vs 85.7% for W patients, which was statically significant on univariate analysis (p = 0.04), but not on multivariate analysis. Conclusions: We found significant disparities for YO-RC from symptom onset to diagnosis with longer delays noted in NW patients. Such delays in diagnosis may lead to higher staging upon presentation and impact survival. Once a diagnosis was made, access to specialty oncology care rates was similar across groups. This study encourages further evaluation and consideration of socioeconomic factors and care access patterns to address disparities in diagnosis, access, and treatment of YO-CRC. [Table: see text]
Cost-effectiveness of targeted vs. multi-cancer blood tests for colorectal cancer.
Authors: Meester Reinier G.S. , Piscitello Andrew J. , Baldo Lance , Griffin Noelle , Grady William 
Published: June 2024

e15526 Background: Recent research suggested that current blood tests are not cost-effective for colorectal cancer (CRC) screening in patients declining other options, i.e., compared to not screening those patients.(1) The findings were from a new decision-analytic model evaluating a multi-cancer detection (MCD) test. Relative to this MCD test, emerging “targeted” CRC blood tests have higher suggested sensitivity for CRC precursors and lower specificity for subjects without any adenomas or CRC. We examine the cost-effectiveness of these emerging tests. Methods: An established CISNET model was replicated, validated, and then used to evaluate blood testing from age 45 to age 75 years, at 1, 2 or 3-year intervals. An MCD test (Galleri®) with 99.5% specificity, 0.5% advanced adenoma (AA) sensitivity, and 82.0% CRC sensitivity (99.5%, 0.5%, 82%) was compared to two hypothetical targeted CRC tests: a low-sensitivity blood test (lsBT) just meeting U.S. national coverage criteria (90%, 10%, 74%), and a high-sensitivity blood test (hsBT) with performance assumptions based on published data (90%, 20%, 90%). Galleri costs $949 per test; lsBT and hsBT costs were varied ($100-$1500). Outcomes included the estimated mortality reduction, and the discounted quality-adjusted life-years (QALY) gained, costs of screening, follow-up colonoscopy and treatment, and costs/QALY gained vs. no screening. Results: Estimated lifetime CRC incidence and mortality without screening were 85.9 and 32.9 per 1000, respectively. Triennial screening with Galleri reduced estimated CRC mortality by 15.6%, yielded 26.9 QALYs gained per 1000, and cost $191,135/QALY gained. Annual screening increased benefit to 28.9% mortality reduction and 46.6 QALYs gained, at $300,254/QALY gained. In contrast, at $1000 per test, lsBT every 1-3 years reduced mortality by 50.2-76.4%, yielded 71.0-109.5 QALYs gained, and cost $51,330-$67,420/QALY gained. hsBT testing further improved outcomes to 60.8-80.9% mortality reduction, 88.1-119.6 QALY gained, and $35,519-$58,125/QALY gained. Costs per QALY gained were lower for lsBT and hsBT vs. Galleri irrespective of the assumed unit costs, and never exceeded $82,902 for triennial testing. Conclusions: Emerging targeted blood tests for CRC can be cost-effective for screening and could be important in reaching underserved populations, once available. Targeted tests and MCD tests differ meaningfully in their accuracy, clinical interpretation, and use, and should not be treated as a similar type of screening test.
Liquid biopsy multiomics enable clinical triage for early colorectal cancer diagnosis.
Authors: Sha Michael , Tanaka Hiromi , Chuang Rachel , Shen Shuo , Pastor Larry , Scimia Mauro , Bianco Maria Antonia , Troncone Giancarlo , Scimia Simone , Malapelle Umberto , Pepe Francesco , Russo Gianluca , Fu Andrew Y. , Li Di , Zhang Aiguo 
Published: June 2024

e15599 Background: Colorectal cancer (CRC) is the second most common cause of cancer death in the United State. Despite advancements in screening, diagnosis, and treatment, the disease remains a formidable public health issue. In 2023, approximately 153020 individuals were diagnosed with CRC and 52550 will die from the disease. In order to meet early diagnostic, we developed this multiomics assay to enable clinical triage for liquid biopsy screening. Methods: Xenonucleic acid (XNAs) are artificial genetic polymers that retain the Watson-Crick base-pairing capability and exhibit high chemical and biological stability. They can be employed as molecular clamps in RT-qPCR due to the stronger hybridizing/binding capability seen in XNA/DNA duplexes than DNA/DNA duplexes. We are developing an XNA-based multiplex RT-qPCR assay for APC, BRAF, CTNNB1, KRAS, NRAS, PIK3CA, SMAD4 and TP53 gene mutation panel and CRC 9 genes methylation panel combined with multiplex protein panel, called ColoscapeTM Plus. We enrolled in FIT positive subjects of both genders, aged 50-74, attending the CRC screening program, we tested 152 plasma samples, 75 health, 50 AA and 27 early CRC with this multiomics assay. Results: The assay results showed that its sensitivity was about 44% (95% CI: 0.302- 0.587) and specificity about 80% (95%CI: 0.689- 0.880) for advanced adenoma (AA). For CRC stage I and II, its sensitivity is about 63% and 78% with 80% specificity separately. Conclusions: The primary data has shown that this low cost and rapid turnaround time multiomics assay has a comparable sensitivity for early colorectal cancer diagnostic.
A phase I/II, first-in-human study of VLS-1488, an oral KIF18A inhibitor, in patients with advanced cancer.
Authors: Gaillard Stephanie , Starodub Alexander , O'Neil Bert , Mathews Cara Amanda , Dumbrava Ecaterina Elena , Friedman Claire Frances , Swiecicki Paul , Oh Cindy , Andreu Celia , Lee Linda , Campbell Jacqueline , Bowler Timothy Geoffrey , Drutman Scott , LoRusso Patricia 
Published: June 2024

TPS3181 Background: Chromosomal instability (CIN) is a hallmark of cancer characterized by high rates of chromosomal segregation errors during mitosis. This creates structural and numerical changes to chromosomes, driving genetic heterogeneity and cancer evolution. KIF18A is a mitotic kinesin protein shown to be important for successful division of cancer cells with CIN but not required for mitosis in normal diploid cells. Pre-clinical studies demonstrated that treatment of chromosomally unstable cancer cells in vitro and in xenograft models (HCC15 and OVCAR-3) with a KIF18A inhibitor resulted in failure of chromosomal congression, mitotic arrest, cell death and dose-dependent inhibition of tumor growth. VLS-1488 is an oral small molecule inhibitor of KIF18A that is being examined in an open-label, phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics (PK) and preliminary anti-tumor activity in advanced solid tumors with high prevalence of CIN. Methods: Key eligibility criteria include specific histologically confirmed metastatic or advanced tumor types with at least one site of measurable disease per RECIST 1.1, adequate organ function, and mismatch repair proficient/microsatellite stable.Eligible tumor types include high grade serous ovarian/fallopian tube/primary peritoneal cancer, squamous non-small cell lung cancer, triple negative breast cancer, gastric adenocarcinoma, gastroesophageal cancer, esophageal cancer, colorectal adenocarcinoma, transitional cell carcinoma of bladder, head and neck squamous cell carcinoma, ovarian or uterine carcinosarcoma, and uterine serous carcinoma. Subjects will receive VLS-1488 monotherapy continuously for 28-day cycles once daily. The study consists of two parts, Dose Escalation and Dose Expansion. Utilizing a Bayesian Optimal Interval (BOIN) design, Dose Escalation will examine the safety and tolerability of VLS-1488 at various dose levels (DLs) to identify the Maximum Tolerated Dose (MTD) and to select DLs for Dose Expansion. Dose Expansion may commence after the MTD or DLs of interest are identified. Dose Expansion will examine the safety, tolerability, preliminary efficacy and preliminary drug-drug interaction (DDI) and food effect risk of VLS-1488 in selected tumor types. Subjects enrolled to specific tumor type cohorts may be randomized to DLs of interest. Enrollment to Dose Escalation began in September 2023 and is ongoing. Clinical trial information: NCT05902988 .
Phase I/II study of pegylated arginine deiminase (ADI-PEG 20) in combination with gemcitabine and docetaxel in non-small cell and small cell lung cancers.
Authors: Auberle Christine , Cohen Jared , Waqar Saiama Naheed , Morgensztern Daniel , Fischer Kaitlyn , Cole Tamara , Gordon Allison , Porzel Jessica , Fogal Cynthia , Kraft Katlyn , Liu Jingxia , Haarberg Sasha , Bomalaski John S. , Govindan Ramaswamy , Van Tine Brian Andrew 
Published: June 2024

TPS3189 Background: Arginine is essential to neoplastic growth and development, yet many cancer cells do not express argininosuccinate synthetase (ASS1), an enzyme necessary to produce arginine. ADI-PEG 20 is a microbial enzyme that degrades arginine causing arginine auxotrophy in cancer cells that are ASS1 negative. Preclinical data suggests that ADI-PEG 20 in combination with docetaxel (D), resulted in increased expression of hENT, the transporter for gemcitabine (G) as well upregulation of dCK to trap G inside of cancer cells. A phase II trial of ADI-PEG 20, G and D was shown to be a safe and efficacious combination in soft tissue sarcoma (STS). We are conducting a phase I/II trial examining the safety, tolerability, to determine the recommended phase II dose (R2PD) and evaluate the efficacy of this combination in patients with previously treated metastatic non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC) with an alternative dosing regimen than that used in STS based on the mechanism of action. Methods: Eligible pts include previously treated metastatic NSCLC and SCLC with performance status 0-1 with adequate organ function. Pts are excluded if previously treated with G; however, prior use of docetaxel is permitted. Up to 12 patients will be enrolled in an open-label phase I trial with a 3 + 3 dose escalation design with ADI-PEG 20 in combination with G and D. Primary objectives of the phase I portion are to determine the safety, tolerability and recommend phase II dose (RP2D) of combination ADI-PEG 20, G and D. Pts will be treated with ADI-PEG 20 intramuscularly at 36mg/m2 on day -7 of cycle 1 and then on days 1, 8, and 15 of each subsequent cycle with dose-escalated G (600, 750, 900 mg/m2) on day 2 and D (60, 75, 75 mg/m2) on day 1 of each 21-day cycle for up to 8 cycles then will continue with combination therapy at provider discretion for up to 34 cycles. The phase II will consist of two cohorts (NSCLC and SCLC) receiving the triplet treatments at the RP2D determined during phase I. Primary objective of the phase II portion is to determine the objective response rate (ORR) in each cohort. Phase II uses a Simon optimal two-stage design per cohort for ORR with a minimum of 12 patients and a maximum of 36 patients per cohort. In the phase I, patient accrual at the maximum tolerated dose level is nearing completion and ADI-PEG in combination with G and D will be further evaluated in the phase II with separate cohorts for NSCLC and SCLC. Clinical trial information: NCT05616624 .
Modeling Extraordinary Response Through Targeting Secondary Alterations in Fusion-Associated Sarcoma
Authors: Vanoli Fabio , Song Evan , Dermawan Josephine K. , Fishinevich Eve , Sung Patricia , Min Soe S. , Xie Ziyu , de Traux de Wardin Henry , Hwang Sinchun , Maki Robert G. , Antonescu Cristina R. 
Published: June 2024

PURPOSE Targeted therapy in translocation-associated sarcomas has been limited to oncogenic activation of tyrosine kinases or ligands while gene fusions resulting in aberrant expression of transcription factors have been notoriously difficult to target. Moreover, secondary genetic alterations in sarcomas driven by translocations are uncommon, comprising mostly alterations in tumor suppressor genes ( TP53, CDKN2A/ B). Our study was triggered by an index patient showing a dramatic clinical response by targeting the secondary BRAF V600E mutation in a metastatic angiomatoid fibrous histiocytoma (AFH) harboring the typical EWSR1::CREB1 fusion. MATERIALS AND METHODS The patient, a 28-year-old female, was diagnosed with an AFH of the thigh and followed a highly aggressive clinical course, with rapid multifocal local recurrence within a year and widespread distant metastases (adrenal, bone, liver, lung). The tumor showed characteristic morphologic features, with histiocytoid cells intermixed with hemorrhagic cystic spaces and lymphoid aggregates. In addition to the pathognomonic EWSR1::CREB1 fusion, targeted DNA sequencing revealed in both primary and adrenal metastatic sites a hot spot BRAF V600E mutation and a CDKN2A/ B deletion. Accordingly, the patient was treated with a BRAF-MEK inhibitor combination (encorafenib/binimetinib) showing an excellent but short-lived response. RESULTS Using a CRISPR-Cas9 approach, we introduced the BRAF c.1799 T>A point mutation in human embryonic stem (hES) cells harboring a conditional EWSR1 (exon7):: CREB1 (exon7) translocation and further differentiated to mesenchymal progenitors (hES-MP) before fusion expression. The cells maintained the fusion transcript expression and the AFH core gene signature while responding to treatment with encorafenib and binimetinib. CONCLUSION These results highlight that additional targeted DNA NGS in chemotherapy-resistant translocation-associated sarcomas may reveal actionable oncogenic drivers occurring as secondary genetic events during disease progression.
Xu Bing's The Character of Characters and the Possibilities of Calligraphic Animation
Authors: Yang Panpan 
Published: June 2024

Abstract
This article examines contemporary Chinese artist Xu Bing's (b. 1955) 2012 animation video, The Character of Characters, which remediates Zhao Mengfu's (1254–1322) calligraphy and painting. The video, in which Chinese written words become the true protagonists, was originally a commissioned installation presented at the Asian Art Museum of San Francisco from October 2012 to January 2013. The article aims to model a form of extremely close analysis of new media art, which borrows vocabulary and methodologies from both art history and media studies. While making a timely contribution to Xu Bing scholarship by focusing on an understudied work in his oeuvre, it also adds new lines of inquiry: first, with regard to text-image reciprocity, which continues to be a focal point in studies of contemporary Chinese art; and second, with regard to animation-calligraphy reciprocity, which begs more critical attention. The Character of Characters, I argue, invokes a double vision that sees words on screen simultaneously as linguistic texts and pictorial shapes, a vision through which and because of which the activities of looking and reading are combined into one.
To Fill “a Gap in Indian History”
Authors: Shaffer Holly , Sharma Yuthika 
Published: June 2024

Abstract
This essay examines the category of “Company” painting, shorthand for painting associated with the East India Company, which dominates the art historiography of eighteenth- and nineteenth-century South Asia. Using the archive of Mildred Archer (1911–2005), the British Library curator who formalized this approach in Western scholarship in tandem with scholarly commentaries by art enthusiasts P. C. Manuk (1873–1946) and Rai Krishnadas (1892–1980), we highlight the complexities of Company painting as both modality and practice. Providing insight into the little-recognized role of Ishwari Prasad (1870–1949), whom Archer and Manuk lauded as the last living artist of the Mughal tradition, we examine his vanguard formulation of a Kampani qalam (“Company style”), where he reframed Mughal art in the era of Company mercantilism and thriving exchange between European and Indian artists at Patna. Further, Prasad emerges as a key interlocutor between the critic and educator E. B. Havell (1861–1934) and the artist Abanindranath Tagore (1871–1951), integrating Mughal and Company lineages within the growing pan-Asian sensibility at the Calcutta School of Art. Foregrounding Prasad's obscured history illuminates how ideas of Mughal, Company, and Modern art belonged to a common intellectual ferment; yet these approaches took separate paths in post-independence India. In tracing the genealogy of Archer's Company painting, we recover multiple voices and strands of artistry informing its gestation in addition to its colonial legacy, complicating Archer's focus on it as an artistic inheritance of the British Empire.
The Rumors Are True
Authors: Baer Nicholas 
Published: June 2024

Abstract
This essay examines the role of rumors in F. W. Murnau’s films as well as in later writings about his life and career. While Murnau perpetuates long-standing figurations of gossip as a frivolous or even malicious activity, he also grants unverified information a truth value. Where Heidegger claimed that Gerede (idle talk) is based on “groundlessness” and “indifferent intelligibility,” this essay shows that rumors in Murnau’s films are often well-founded and also essential to a nuanced understanding of his work. Bringing together film analyses, archival materials, and philosophical texts, the essay sheds light on an underexamined aspect of Murnau’s oeuvre and addresses broader questions about the status of speculative, uncertain, or contested knowledge. A study of Gerede does not entail a concealment of authentic discourse but illuminates Murnau’s philosophy of rumors as part of a dialectic of destabilized knowledge.