tbuckley/cabot-search huggingface dataset:
Analyzing the effect of treatment modalities on survival in synovial sarcoma.
Authors: Maya Mary Samuel, Prachi Saldhi, Peter T. Silberstein, Jasleen Kaur Chaddha
Journal: Journal of Clinical Oncology (2024)

11570 Background: Synovial sarcoma (SS) is a rare, slow growing, and aggressive soft tissue sarcoma that commonly affects young adults, with a diagnosis at an average age of 30 years. It usually originates near the joints of the extremities and presents as a painless lump. Metastasis to the regional lymph nodes and lungs is common. SS is proposed to be a result of a chromosomal translocation leading to the fusion of SYT and SSX genes. Standard treatment is tumor resection followed by adjuvant therapy. No study has compared the effects of different surgery and adjuvant therapy types on overall survival. This study will compare the effects of various therapeutic modalities on overall survival for patients with SS. Methods: The National Cancer Database (NCDB) was used to identify patients diagnosed with SS from 2004 to 2020 using histology code 9040 as assigned by the Commission on Cancer Accreditation program. Kaplan-Meier, ANOVA Chi-Square, and Logistic Regression tests were performed, and data were analyzed using SPSS version 29. Statistical significance was set at α = 0.05. Results: The sample retrieved from NCDB consisted of 2566 patients with SS. Of these 2566 patients, 1962 patients (76.5%) received surgery at the primary site. The receipt of surgery was associated with a marked increase in survival (132.2 months vs. 48.6 months, p&lt;0.001). Out of the surgical patients, 883 patients (45.0%) received a lobectomy, 696 patients (35.5%) received a wedge segmental resection, 21 patients (1.07%) received an extended lobectomy and 1 patient (0.05%) received a hepatectomy. Patients who underwent lobectomy and wedge/segmental resections had improved outcomes compared to patients who received other types of surgery (p&lt;0.001). In addition, 898 patients (45.8%) received adjuvant chemotherapy, 38 patients received adjuvant chemoradiation (1.94%), and 22 patients received adjuvant radiation (1.12%). The receipt of adjuvant chemotherapy was associated with better outcomes than receiving no adjuvant therapy (121.9 months vs. 108.4 months, p&lt;0.001). The receipt of adjuvant chemoradiation was also associated with better outcomes than receiving no adjuvant therapy (132.2 months vs. 108.4 months, p=0.023). The receipt of adjuvant chemotherapy versus adjuvant chemoradiation is not significantly different in regard to overall survival. Conclusions: This study confirms that receiving surgery for SS is associated with markedly increased overall survival. Furthermore, wedge/segmental resections and lobectomies are associated with improved outcomes compared to other types of surgery. Receiving adjuvant therapy is associated with improved outcomes as compared to the receipt of surgery alone. Adjuvant chemotherapy and adjuvant chemoradiation are associated with better outcomes than adjuvant radiation alone. Further studies are needed to understand the factors involved in choosing specific treatment modalities for SS.
PD-L1 promotes oncolytic virus infection via a metabolic shift that inhibits the type I IFN pathway
Authors: Jonathan J. Hodgins, John Abou-Hamad, Colin Edward O’Dwyer, Ash Hagerman, Edward Yakubovich, Christiano Tanese de Souza, Marie Marotel, Ariel Buchler, Saleh Fadel, Maria M. Park, Claire Fong-McMaster, Mathieu F. Crupi, Olivia Joan Makinson, Reem Kurdieh, Reza Rezaei, Harkirat Singh Dhillon, Carolina S. Ilkow, John C. Bell, Mary-Ellen Harper, Benjamin H. Rotstein, Rebecca C. Auer, Barbara C. Vanderhyden, Luc A. Sabourin, Marie-Claude Bourgeois-Daigneault, David P. Cook, Michele Ardolino
Journal: The Journal of Experimental Medicine (2024)

While conventional wisdom initially postulated that PD-L1 serves as the inert ligand for PD-1, an emerging body of literature suggests that PD-L1 has cell-intrinsic functions in immune and cancer cells. In line with these studies, here we show that engagement of PD-L1 via cellular ligands or agonistic antibodies, including those used in the clinic, potently inhibits the type I interferon pathway in cancer cells. Hampered type I interferon responses in PD-L1–expressing cancer cells resulted in enhanced efficacy of oncolytic viruses in vitro and in vivo. Consistently, PD-L1 expression marked tumor explants from cancer patients that were best infected by oncolytic viruses. Mechanistically, PD-L1 promoted a metabolic shift characterized by enhanced glycolysis rate that resulted in increased lactate production. In turn, lactate inhibited type I IFN responses. In addition to adding mechanistic insight into PD-L1 intrinsic function, our results will also help guide the numerous ongoing efforts to combine PD-L1 antibodies with oncolytic virotherapy in clinical trials.
Updated efficacy results of olverembatinib (HQP1351) in patients with tyrosine kinase inhibitor (TKI)-resistant succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GIST) and paraganglioma.
Authors: Haibo Qiu, Zhi-wei Zhou, Ye Zhou, Jie Chen, Xiangbin Wan, Ning Li, Kaixiong Tao, Yong Li, Xin Wu, Zi Chen, Lihui Liu, Chen Yang, Lichuang Men, Hengbang Wang, Eric Liang, Cunlin Wang, Lixin Jiang, Dajun Yang, Yifan Zhai, Rui-Hua Xu
Journal: Journal of Clinical Oncology (2024)

11502 Background: SDH-deficient GIST is a rare type of GIST, mainly observed in the stomach of children and adolescents or young adults &lt; 30 years of age. No active targeted therapies have been identified in this subset of GIST. Olverembatinib, approved in China for treatment of patients with chronic myeloid leukemia, has shown promising clinical efficacy in SDH-deficient GIST. We report here updated efficacy data in SDH-deficient GIST and preliminary efficacy data in paraganglioma, which is an SDH-deficient–related tumor. Methods: The aim of this study was to evaluate the safety and efficacy (per RECIST v1.1) of olverembatinib in patients with TKI-resistant SDH-deficient GIST and other solid tumors. Olverembatinib was administered orally once every other day (QOD) in 28-day cycles. Results: As of December 27, 2023, 26 patients with SDH-deficient GIST (confirmed by IHC) had received ≥ 1 dose of olverembatinib (median [range] age, 30 [13-56] years), and 25 had received 1 to 4 TKIs (42.3% of patients, ≥ 3; Table 1). Olverembatinib was administered QOD in doses ranging from 30 to 50 mg (30 mg [n = 6]; 40 mg [n = 14]; 50 mg [n = 6]). The median (range) treatment duration was 15.6 (1.8-42.3) months. A total of 6 of 26patients experienced partial response (PR) as the best response. A further 18 patients had stable disease (SD) lasting &gt; 4 cycles. The clinical benefit rate (CBR; complete response [CR] + PR + SD &gt; 4 cycles) was hence 92.3% (24/26) and the longest treatment duration was 40 months. After a median follow-up of 17.0 (4.1-57.5) months, the median progression-free survival (PFS) was 25.7 months (12.1-not reached [NR]). Among the 6 patients with paraganglioma enrolled in this study, best responses were observed in 5, with SD lasting &gt; 4 cycles (CBR, 83.3%), and the median PFS was 8.25 (1.87-NR) months. The adverse event profile was the same as previously reported (Qiu H et al, J Clin Oncol 41:11540), with no newly emergent safety issues observed. Conclusions: Olverembatinib was well tolerated. The CBR exceeded 90%, and the estimated median PFS was significantly prolonged, indicating potential benefit of this treatment and providing a benchmark for future studies in this rare subtype of GIST. Clinical trial registration: NCT03594422; internal study identifier: SJ-0003. Clinical trial information: NCT03594422 .[Table: see text]
Final results of a randomized phase II/III study comparing perioperative adriamycin plus ifosfamide and gemcitabine plus docetaxel for high-grade soft tissue sarcomas: Japan Clinical Oncology Group study JCOG1306.
Authors: Kazuhiro Tanaka, Ryunosuke Machida, Makoto Endo, Akira Kawai, Robert Nakayama, Satoshi Tsukushi, Kunihiro Asanuma, Hiroaki Hiraga, Koji Hiraoka, Shinichiro Yoshida, Tsukasa Yonemoto, Jungo Imanishi, Hirohisa Katagiri, Yoshihiro Nishida, Akihito Nagano, Yuta Sekino, Haruhiko Fukuda, Toshifumi Ozaki, Yukihide Iwamoto
Journal: Journal of Clinical Oncology (2024)

11503 Background: We have previously reported long-term follow-up results of the favorable efficacy of perioperative chemotherapy with adriamycin plus ifosfamide (AI) for high-grade soft tissue sarcomas (STS) (JCOG0304). We have also reported the results of the second interim analysis of a phase II/III trial to confirm the non-inferiority of perioperative gemcitabine plus docetaxel (GD) to AI for high-grade STS (JCOG1306) in 2020 ASCO Annual Meeting. This study was terminated at the preplanned second interim analysis based on the point estimate of hazard ratio (HR) being above the pre-specified allowable HR of 1.61. The estimated 2-year overall survival (OS) was 94.3% (95% confidence interval (CI) 83.4–98.1%) in AI and 91.6% (80.9–96.4%) in GD (HR 2.55, 95% CI 0.80–8.14) in the analysis. We herein report the final results of JCOG1306 at 5-year follow-up. Methods: Patients with operable, FNCLCC grade 2/3 STS primary tumor (T2bN0M0 or anyTN1M0, AJCC 7th edition) or first local recurrent tumor in the extremities or trunk were randomized to AI or GD. Chemotherapy consisted of adriamycin 60 mg/m 2 plus ifosfamide 10 g/m 2 for AI or gemcitabine 1,800 mg/m 2 plus docetaxel 70 mg/m 2 for GD. The treatments were repeated for 3 courses preoperatively and 2 courses postoperatively in a 3-week interval. The primary endpoint in phase III part was OS. Planned sample size was 140 with a one-sided alpha of 0.1, power of 0.7 and a non-inferiority margin of 8% at 3-year OS (HR of 1.61), assuming 3-year OS of AI to be 85% and that of GD as 87%. Results: A total of 143 patients were enrolled between February 2014 and September 2018, and 5-year follow-up has finished in September 2023. Seventy and 73 patients were assigned to AI and GD, respectively, and included in the efficacy analysis. At the final analysis with a median follow-up of 6.0 years, the estimated 5-year OS was 90.0% (95% CI 80.1–95.1%) in AI and 76.1% (64.5–84.4%) in GD (HR 2.67, 95% CI 1.23–5.80). The estimated 5-year progression-free survival was 65.2% (95% CI: 52.7–75.2%) in AI and 57.4% (45.2–67.8%) in GD (HR: 1.33, 95% CI 0.81–2.18). At the 5-year follow-up analysis, there were no treatment-related deaths in both arms. Conclusions: The results of the second interim analysis were confirmed in the final analysis after five-year follow-up, i.e., non-inferiority of GD to AI in terms of OS could not be confirmed. In the perioperative chemotherapy for high-grade STS in the extremities and trunk, AI remains the standard regimen. Clinical trial information: jRCTs031180003 .
Impact of ATRX loss on survival and immune microenvironment in multiple sarcoma subtypes.
Authors: Ryan Austin Denu, Rossana Lazcano Segura, Ahsan Saleem Farooqi, Davis Ingram, Khalida M. Wani, Yiming Cai, Keila E Torres, Emily Zhi-Yun Keung, Christina Lynn Roland, Neeta Somaiah, Haoqiang Ying, Jason T. Huse, Kunal Rai, Anthony Paul Conley, Shreyaskumar Patel, Wei-Lien Wang, Alexander J. Lazar, Elise F Nassif Haddad
Journal: Journal of Clinical Oncology (2024)

11511 Background: Sarcomas are heterogeneous mesenchymal malignancies often with few treatment options and poor outcomes. ATRX is commonly altered in sarcoma, with loss-of-function (LOF) mutations observed in up to 35% of cases. ATRX plays roles in DNA damage response, telomere maintenance, and epigenetic regulation. However, the impact of ATRX loss on sarcoma biology and the potential of ATRX mutation to serve as a prognostic biomarker in sarcoma are under investigation. Methods: The predominant alteration seen in ATRX in sarcoma is LOF mutation, thus tumor specimens were scored for presence or absence of ATRX staining by immunohistochemistry (IHC) in clinically-annotated tissue microarrays (TMAs) including 95 patients with uterine leiomyosarcoma (ULMS), 127 with soft tissue leiomyosarcoma (STLMS), 82 with undifferentiated pleomorphic sarcoma (UPS), and 84 with well-differentiated/dedifferentiated liposarcoma (WD/DDLPS). We also performed IHC staining using a panel of immune cell markers and checkpoints on the ULMS TMA, including CD8, CD20, CD68, PDL1, CTLA4, CD47, and CD163, among others. Kaplan-Meier analysis with log rank tests were used to assess the impact of ATRX loss on overall survival (OS), disease-specific survival (DSS), and progression free survival (PFS). Cox proportional hazards modeling was used to determine whether ATRX loss is an independent predictor of survival. T tests, ANOVA, and Chi squared tests were used to test for association between ATRX loss and immune markers in the ULMS TMA. Results: ATRX loss was seen in 14.1% of STLMS (n = 18), 52.6% of ULMS (n = 50), 36.6% of UPS (n = 30), and 8.3% of WD/DDLPS (n = 7). In univariate analysis, ATRX loss was associated with significantly worse OS (HR 0.50, 95% CI 0.31-0.80, p = 0.004) and PFS (HR 0.51, 95% CI 0.33-0.81, p = 0.004) in ULMS, worse DSS in UPS (HR 0.46, 95% CI 0.23-0.95, p = 0.03), and worse PFS in WD/DDLPS (HR 0.13, 95% CI 0.02-0.73, p = 0.02). In multivariate analyses, ATRX loss was also associated with worse OS and PFS in ULMS and worse DSS in UPS. In ULMS, ATRX loss was associated with increased density of CD8+ T cells (p = 0.01), PDL1 expression (p = 0.03), CTLA4 expression (p = 0.049), IDO-positive tumor cells (p = 0.01), and CD163-positive cells (p = 0.003). Conclusions: ATRX loss is associated with worse outcomes in ULMS, UPS, and WD/DDLPS. ATRX loss is also associated with a distinct immune microenvironment in ULMS characterized by T cell exhaustion and immunosuppressive M2 macrophages. Future work will focus on understanding the molecular underpinnings of these associations and potential ways to exploit these findings therapeutically.
Sintilimab, doxorubicin and ifosfamide (AI) as first-line treatment in patients with advanced undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), myxoid liposarcoma (MLPS) and de-differentiated liposarcoma (DDLPS): A single-arm phase 2 trial.
Authors: Xin Liu, Yanjing Guo, Wangjun Yan, Yong Chen, Yu Xu, Chun-Meng Wang, Weiqiang Yao, Jian Wang, Lin Yu, Shiyu Jiang, Xiaowei Zhang, Zhiguo Luo
Journal: Journal of Clinical Oncology (2024)

11505 Background: Anti-PD-1 antibody had showed encouraging activity as salvage treatment in patients with certain subtypes of advanced soft tissue sarcoma. However, its role in first-line setting is uncertain. We assessed the safety and activity of sintilimab, an anti-PD-1 antibody, combined with doxorubicin (ADM) and ifosfamide (IFO) in patients with advanced undifferentiated pleomorphic sarcoma (UPS), synovial sarcoma (SS), myxoid liposarcoma (MLPS) and de-differentiated liposarcoma (DDLPS). Methods: This is a single-arm, phase 2 study. Systemic treatment naïve patients with metastatic or unresectable locally advanced UPS, SS, MLPS and DDLPS were treated with sintilimab (200mg, d1), ADM (60mg/m 2 , d1) and IFO (1.8 g/m 2 /d, d1-5) every 3 weeks for up to 6 cycles, followed by sintilimab maintenance until disease progression, unacceptable toxicities or up to 2 years. The primary endpoint was objective response rate (ORR, per RECIST 1.1), and secondary endpoints included progression free survival (PFS), overall survival (OS) and safety. Results: Between June 2020 and June 2023, 46 eligible patients were enrolled. 31 were male, and the median age was 47 years old. Of the 41 evaluable pts, ORR was 68.3% (28/41), including 7/8 (87.5%) UPS, 13/20 (65.0%) SS, 3/3 (100%) MLPS and 5/10 (50%) DDLPS patients. At a median follow-up time of 28.0 months (95% CI: 9.4-46.7 months), the median PFS and OS were 9.0 months (95% CI: 6.5-11.5 months) and 19.9 months (95% CI: 14.9-24.9 months), respectively. 1 DLT was observed in the first six patients during the DLT observation window. The most frequent ≥ grade 3 adverse events were leucopenia (50.0%), neutropenia (45.7%), thrombocytopenia (21.7%), anemia (21.7%), and febrile neutropenia (21.7%). Conclusions: The primary endpoint of ORR was met. This study indicated promising efficacy and safety of sintilimab combined with AI in the first-line treatment of UPS, SS, MLPS and DDLPS. Clinical trial information: NCT04356872 .
The Legacy of Redlining: Increasing Childhood Asthma Disparities Through Neighborhood Poverty
Authors: Patrick H Ryan, Antonella Zanobetti, Brent A. Coull, Howard Andrews, Leonard B Bacharier, Dakota Bailey, Paloma I. Beamer, Jeff Blossom, Cole Brokamp, Soma Datta, Tina Hartert, Gurjit K. Khurana Hershey, Daniel J Jackson, Christine C Johnson, Christine Joseph, Jorja Kahn, Nathan Lothrop, Margee Louisias, Heike Luttmann-Gibson, Fernando D. Martinez, Eneida Mendonça, Rachel L. Miller, Dennis Ownby, Sima Ramratnam, Christine M Seroogy, Cynthia M Visness, Anne L Wright, Edward M. Zoratti, James E. Gern, Diane R. Gold
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Identifying the root causes of racial disparities in childhood asthma is critical for health equity.
Perlin noise generation of physiologically realistic cardiac fibrosis
Authors: Brodie A.J. Lawson, Christopher Drovandi, Pamela Burrage, Alfonso Bueno-Orovio, Rodrigo Weber dos Santos, Blanca Rodriguez, Kerrie Mengersen, Kevin Burrage
Journal: Medical Image Analysis (2024)

Fibrosis, a pathological increase in extracellular matrix proteins, is a significant health issue that hinders the function of many organs in the body, in some cases fatally. In the heart, fibrosis impacts on electrical propagation in a complex and poorly predictable fashion, potentially serving as a substrate for dangerous arrhythmias. Individual risk depends on the spatial manifestation of fibrotic tissue, and learning the spatial arrangement on the fine scale in order to predict these impacts still relies upon invasive ex vivo procedures. As a result, the effects of spatial variability on the symptomatic impact of cardiac fibrosis remain poorly understood. In this work, we address the issue of availability of such imaging data via a computational methodology for generating new realisations of cardiac fibrosis microstructure. Using the Perlin noise technique from computer graphics, together with an automated calibration process that requires only a single training image, we demonstrate successful capture of collagen texturing in four types of fibrosis microstructure observed in histological sections. We then use this generator to quantitatively analyse the conductive properties of these different types of cardiac fibrosis, as well as produce three-dimensional realisations of histologically-observed patterning. Owing to the generator's flexibility and automated calibration process, we also anticipate that it might be useful in producing additional realisations of other physiological structures.
Omega-3 world map: 2024 update
Authors: Jan Philipp Schuchardt, Philine Beinhorn, Xue Feng Hu, Hing Man Chan, Kaitlin Roke, Aldo Bernasconi, Andreas Hahn, Aleix Sala-Vila, Ken D. Stark, William S. Harris
Journal: Progress in Lipid Research (2024)

In 2016, the first worldwide n3 PUFA status map was published using the Omega-3 Index (O3I) as standard biomarker. The O3I is defined as the percentage of EPA + DHA in red blood cell (RBC) membrane FAs. The purpose of the present study was to update the 2016 map with new data. In order to be included, studies had to report O3I and/or blood EPA + DHA levels in metrics convertible into an estimated O3I, in samples drawn after 1999. To convert the non-RBC-based EPA + DHA metrics into RBC we used newly developed equations. Baseline data from clinical trials and observational studies were acceptable. A literature search identified 328 studies meeting inclusion criteria encompassing 342,864 subjects from 48 countries/regions. Weighted mean country O3I levels were categorized into very low ≤4%, low >4-6%, moderate >6-8%, and desirable >8%. We found that the O3I in most countries was low to very low. Notable differences between the current and 2016 map were 1) USA, Canada, Italy, Turkey, UK, Ireland and Greece (moving from the very low to low category); 2) France, Spain and New Zealand (low to moderate); and 3) Finland and Iceland (moderate to desirable). Countries such as Iran, Egypt, and India exhibited particularly poor O3I levels.
CpG island turnover events predict evolutionary changes in enhancer activity
Authors: Acadia A. Kocher, Emily V. Dutrow, Severin Uebbing, Kristina M. Yim, María F. Rosales Larios, Marybeth Baumgartner, Timothy Nottoli, James P. Noonan
Journal: Genome biology (2024)

Abstract Background Genetic changes that modify the function of transcriptional enhancers have been linked to the evolution of biological diversity across species. Multiple studies have focused on the role of nucleotide substitutions, transposition, and insertions and deletions in altering enhancer function. CpG islands (CGIs) have recently been shown to influence enhancer activity, and here we test how their turnover across species contributes to enhancer evolution. Results We integrate maps of CGIs and enhancer activity-associated histone modifications obtained from multiple tissues in nine mammalian species and find that CGI content in enhancers is strongly associated with increased histone modification levels. CGIs show widespread turnover across species and species-specific CGIs are strongly enriched for enhancers exhibiting species-specific activity across all tissues and species. Genes associated with enhancers with species-specific CGIs show concordant biases in their expression, supporting that CGI turnover contributes to gene regulatory innovation. Our results also implicate CGI turnover in the evolution of Human Gain Enhancers (HGEs), which show increased activity in human embryonic development and may have contributed to the evolution of uniquely human traits. Using a humanized mouse model, we show that a highly conserved HGE with a large CGI absent from the mouse ortholog shows increased activity at the human CGI in the humanized mouse diencephalon. Conclusions Collectively, our results point to CGI turnover as a mechanism driving gene regulatory changes potentially underlying trait evolution in mammals.
COATi: statistical pairwise alignment of protein-coding sequences
Authors: Juan José García Mesa, Ziqi Zhu, Reed A Cartwright
Journal: Molecular Biology and Evolution (2024)

Abstract Sequence alignment is an essential method in bioinformatics and the basis of many analyses, including phylogenetic inference, ancestral sequence reconstruction, and gene annotation. Sequencing artifacts and errors made during genome assembly, such as abiological frameshifts and incorrect early stop codons, can impact downstream analyses leading to erroneous conclusions in comparative and functional genomic studies. More significantly, while indels can occur both within and between codons in natural sequences, most amino-acid- and codon-based aligners assume that indels only occur between codons. This mismatch between biology and alignment algorithms produces suboptimal alignments and errors in downstream analyses. To address these issues, we present COATi, a statistical, codon-aware pairwise aligner that supports complex insertion–deletion models and can handle artifacts present in genomic data. COATi allows users to reduce the amount of discarded data while generating more accurate sequence alignments. COATi can infer indels both within and between codons, leading to improved sequence alignments. We applied COATi to a dataset containing orthologous protein-coding sequences from humans and gorillas and conclude that 41% of indels occurred between codons, agreeing with previous work in other species. We also applied COATi to semiempirical benchmark alignments and find that it outperforms several popular alignment programs on several measures of alignment quality and accuracy.