bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comprehensive genomic and transcriptomic profiling analysis of the recurrent gastrointestinal stromal tumor (GIST).
Authors: Sun Lu , Wang Xiaohui , Wu Xin , Zhu Fengwei , Hong Liu , Chen Wen , Piao Yingshi , Luo Hong , Zhang Yiqun , Liu Ling , Zang Yuehua , Li Wenjing , Pei Zhihua , Wang Dongliang , Zhou Qiming , Shi Huaiyin 
Published: June 2023

e23506 Background: The gastrointestinal stromal tumor (GIST) is a potentially malignant mesenchymal tumor (sarcoma), whose management has been transformed by approvals of TKIs. However, recurrence or metastasis is a formidable challenge in managing high-risk GIST. Comprehensive investigation of the transcriptome and genome in GIST is helpful to determine the therapy strategy for patients. This study aims to explore the molecular features of high-risk recurrence GIST. Methods: The tumor tissue samples of 42 patients with primary GIST were collected, in which all patients were divided into low-risk (n = 12), intermediate-risk (n = 11), and high-risk (n = 19) groups according to the NIH 2017th, in which 8 developed recurrence within three years and 11 without recurrence over three years in the high-risk group. Tumor-normal whole-exome and tumor mRNA sequencing was performed on baseline tissue DNA isolated from all patients. Results: Consistent with prior knowledge, KIT was the predominant mutation. The top mutated genes in GISTs were KIT (82%), PHLDA1 (39%), MUC6 (22%), ARID1B(20%), SURF2(20%), MGA(16%), MUC17(16%), MPRIP(16%) and PDGFRA(16%), which MUC6 was a significantly different mutation gene (DMG) associated with disease progression in terms of either high-risk(p = 0.04), recurrence(p = 0.02) or progression(p = 0.05). Interestingly, PDGFRA mutation co-occurs with CTNND2(p < 0.01) and its correlated genes. Additionally, we further explored the somatic copy number variations (CNVs). amp_RAD51B(49%), amp_MLH3(41%), amp_CHEK2(37%), and amp_RB1(12%) seemed to be more frequent in the recurrence group, while these observations were not significant (p > 0.05). Notably, del_NCOR1 or amp_NCOR1 was uniquely observed in the recurrence group. Compared with non-recurrence GIST, gene expression profiles revealed that mast cell activate (MCA)，M1-macrophages infiltration were higher in recurrence group, and mRNA was significantly upregulated in Systemic lupus erythematosus、Neutrophil extracellular trap formation、Viral carcinogenesis、Endocytosis. These pathways were indentified as being associated with recurrence and progression in other cancer studies. For example, the endocytosis pathway expression is positively associated with oncogenic pathway signaling in CRC, and neutrophil extracellular trap on cancer cells promotes liver metastasis in the tumor microenvironment. In the other, NCOR1 is a crucial regulator of T cell and B cell development. Conclusions: Here, we demonstrated the DNA/RNA profiles of GISTs. We observed higher CNVs in high-risk GIST. Especially, the high-risk recurred tumor presented different CNVs frequency and microenvironment. These results may contribute to understanding the mechanism of recurrence and improving recurrence detection.
Clinical characteristics of gastrointestinal stromal tumors with lymph node metastasis: A retrospective single-centre case-controlled study.
Authors: Zhang Xinhua , Guo Xiaodan , Huang Shaoqing , Xia Yanzhe , Zhou Xuefu 
Published: June 2023

e23509 Background: Lymph node metastasis of gastrointestinal stromal tumors (GISTs) rarely occurs, and lymphadenectomy is not routinely performed in GIST resection. To date, the relevant characteristics and prognosis of GIST patients with lymph node metastasis are not well known. Methods: From January 2010 to December 2021, GIST patients who underwent lymph node resection were enrolled in this study from a GIST referral centre. All patients were divided into either the LN- group (GISTs without lymph node metastasis) or the LN+ group (GISTs with lymph node metastasis). The clinicopathological features and follow-up data were analysed, and propensity score matching (PSM) was conducted to reduce bias caused by confounders. Results: Out of 1024 surgical patients, 198 patients (age, 52.23±13.54 years; 56.6% males) underwent GIST resection with lymph node dissection for lymphadenopathy, and 17 patients had lymph node metastases (17/1024, 1.66%; 17/198, 8.59%). The LN+ group had a higher mitotic count (P = 0.012) and a higher proportion of distant metastasis (P < 0.001) than the LN- group. After PSM, 28 patients were included (18 in the LN- group and 10 in the LN+ group). The LN- group had both longer postoperative progression-free survival (PFS, not reached vs. 15.0 months, P = 0.002) and overall survival (OS) than the LN+ group, but the difference in OS was not statistically significant (not reached vs. 35.0 months, P = 0.069). Conclusions: The rate of lymph node metastasis in GISTs is low. Lymph node metastasis may be a less common form of distant metastasis. Moreover, GIST with lymph node metastasis has an unfavourable prognosis. Further studies are warranted to identify GISTs with lymph node involvement and the potential involved mechanism. [Table: see text]
Sex differences in localized gastrointestinal stromal tumor.
Authors: Boye Kjetil , Hompland Ivar , Berner Jeanne-Marie , Meza-Zepeda Leonardo A. , Hølmebakk Toto 
Published: June 2023

e23511 Background: Sex plays an important role in the incidence and prognosis of several cancer types. Male patients with gastrointestinal stromal tumors (GISTs) have inferior outcomes compared to women, but the reasons behind the sex differences are not well understood. This study aimed to investigate whether sex was a prognostic factor in localized GIST and to explore the relationship between sex and established clinical, molecular and histopathological characteristics. Methods: The study cohort is population-based and consisted of patients who underwent surgical resection of primary, non-metastatic GIST at Oslo University Hospital, Norway between January 2000 and September 2017. Recurrence-free survival (RFS) was the primary endpoint. Mutation analysis was performed by Sanger sequencing or by the AmpliSeq for Illumina Cancer Hotspot Panel version 2. Results: The study cohort comprised 409 patients, 202 women and 207 men. There were 275 gastric tumors (67.2%) and 134 non-gastric tumors (32.8%). Disease recurrence was recorded in 87 patients (21%) after a median follow-up of 64 months. Men with gastric tumors had inferior RFS compared to women (HR 2.18; 95% CI 1.07-4.45; P= 0.029), while there was no difference for non-gastric tumors (HR 0.77; 95% CI 0.44-1.33; P= 0.341). There was a substantial sex variation in the type of primary KIT mutation related to tumor location. Men with gastric tumors had a deletion or insertion-deletion that involved codons 557 and 558 (del557/558) more than twice as frequently as women (34% versus 16%; P= 0.008). Men also had slightly larger tumors (mean 6.6 cm versus 5.5 cm; P= 0.035) and more often tumors located in the upper third of the stomach, but there was no difference in mitotic count (23% versus 22% with > 5 mitoses per 5 mm2). There was no difference in adjuvant imatinib treatment between men and women. No sex differences in primary mutation, tumor size or mitotic count were observed for non-gastric tumors. When KIT del557/558 mutation was included in the Cox regression analysis for gastric tumors, sex was not significantly associated with RFS (HR 1.49; 95% CI 0.70-3.18; P= 0.303), while del557/558 mutation was a strong prognostic factor (HR 6.40; 95% CI 3.17-12.94; P< 0.001). Del557/558 mutation was not associated with RFS in non-gastric tumors (HR 0.67; 95% CI 0.33-1.35; P= 0.262). Conclusions: Women with localized, gastric GISTs had a lower risk of recurrence compared to men. There was no sex difference in outcome or baseline characteristics for non-gastric tumors. Men with gastric tumors more often had KIT del557/558 primary mutations, which may explain their inferior outcome. The observed sex difference in primary mutations in GISTs is unexplained and should be further explored.
Predicting the immunotherapy response based on molecular subtypes of pan-immune signatures in gastrointestinal stromal tumor.
Authors: Liu Ling , Wang Xiaohui , Dai Chan , Pei Zhihua , Zhou Qiming , Wang Dongliang 
Published: June 2023

e23512 Background: Gastrointestinal stromal tumor (GIST) is the most common sarcoma, often originate in the stomach or the small intestine. Although the application of imatinib has brought a breakthrough in the clinical treatment of GIST, not all GIST patients are effective, and most GIST patients who receive imatinib sensitivity will develop drug resistance and eventually malignant progression. The tumor microenvironment (TME) is a key mediator of cancer progression and treatment outcome, and plays an important role in predicting cancer prognosis and treatment response. This study aims to investigate the role of TME in the treatment of GIST and the response to immunotherapy. Methods: Raw microarray data of 199 GIST patients were downloaded from GEO, including 159 KIT-mutant, 21 PDGFRA-mutant and 19 WT. All affymetrix datasets were re-normalized using the gcRMA package with default parameters. We integrated 275 TME and malignant signaling pathways related signatures from different database and previous researches, including CIBERSORT, MCP-counter, TIMER, and others. Fisher exact test's was used to identify signatures that differential between KIT-mutant, PDGFRA-mutant, and WT (p < 0.05), and 85 signatures were finally obtained. To classify the molecular profiles, the expression patterns were assessed in all 199 GIST patients using unsupervised clustering based on their ssGSEA scores, and can be clustered into three distinct microenvironments. Results: Using GSEA with all TME signatures genes ranked by the log2(fold change) between the threee clustes, we found that gene sets were considered immune favorable in cluster A, including gene sets related to activated CD8+ T cells (p = 0.0003)and activated CD4 T cell signaling pathway (p = 0.009). Cluster B enriched to the epithelial mesenchymal transformation pathway (p = 0.04) and TGFb signaling pathway (p = 0.003), cluster C enriched into DNA-repair pathway (p = 0.02). In an independent skin cutaneous melanoma cohorts (n = 86) treated with anti-PD-1 therapy, patients were classified into three molecular clusters, which significantly corrleated with response to ipilimumab (p = 0.007). The percentage of responders to anti-PD-1 therapy in cluster A was 75% in contrast to only 10% in cluster B. The three molecular clusters discern a potential responder versus non-responder (AUC = 0.87; p = 0.0015), with essentially a 80% chance of correctly predicting the response, which supporting the utilization of the classification method. Conclusions: In this study, the immuno-infiltrating landscape was characterized based on pan-immune signatures using transcriptomic profile in GIST. The molecular subtypes derived from pan-immune signatures have the potential to predict the efficacy of immunotherapy.
National overview of gastrointestinal stromal tumors: Experience from middle income setting.
Authors: Mkhitaryan Benik , Zohrabyan Davit , Safaryan Liana , Bardakhchyan Samvel , Arzumanyan Armen , Harutyunyan Martin , Mkhitaryan Armen , Sargsyan Amalya , Rushanyan Marine , Mkrtchyan Gohar , Mailyan Mariam , Karapetyan Nune 
Published: June 2023

e23515 Background: Gastrointestinal stromal tumors (GISTs) are mesenchymal malignancies representing 1-2% of all gastrointestinal cancers. There is a general shortage of reported data on GISTs from the Republic of Armenia (RA). This paper aims to conduct a national assessment of the epidemiological, diagnostic, and treatment approaches of the GISTs in RA. Methods: The study utilizes a cross-sectional design. Five-year retrospective data on patients with the moderate and high-risk group has been analyzed (from August 31, 2016, up to February 01, 2023). Data has been obtained through medical records. It was feasible to apply census sampling since each GIST patient receives Imatinib in the Hematology Center after prof. Yeolyan free of charge and all the medical records are centered in this facility. Descriptive analysis has been done to demonstrate patients’ demographic characteristics, the spread of the disease, pathological and genetic features of the tumor, and performed treatment. Results: In total 69 moderate and high-risk patients have been targeted. That counts for about 1% of all GI tumors diagnosed in Armenia in 2021. The mortality rate was 10%. The male-to-female ratio was 1.56:1. Age range was 30-81 years (median 58). Advanced disease was observed in 31.9% of cases. The primary site of the tumor (gastric vs non-gastric) was not significantly associated with the disease stage (p-value: 0.192). Expression of CD34, CD117, and DOG1 was positive in 97.3%, 100%, and 96.7% of cases respectively. However, it is worth mentioning that data on immunohistochemical (IHC) features are lacking due to the incompleteness of medical records and the absence of a joint e-health system in Armenia. Furthermore, significant under-testing of the tumor genetic profile was observed. Only 3 patients were tested for KiT mutation (positive in all cases) and no one for PDGFRA mutation. Under-testing is caused by the high cost of genetic profiling which is covered out-of-pocket in RA. All patients received first-line tyrosine kinase inhibitors (TKI). Adjuvant or palliative radiation therapy (RT) was not applied. The majority of patients (95%) underwent tumor resection for curative or palliative purposes. Conclusions: Demographic and epidemiological profile of GISTs in RA is similar to the reported international data. In contrast, the rate of advanced diseases is higher in RA, possibly due to diagnosis delays. [Table: see text]
Treatment response prediction with circulating tumor cell-derived organoids for soft tissue sarcoma.
Authors: Liu Yang-Wei , Burnouf Thierry , Chang Chia-Yau , Chen Shu-Huey , Chen Yin-Ju , Chen Yi-Hsuan , Ho Wan-Ling , Liao Yu-Mei , Lin Pei-Chin , Liu Yen-Lin , Miser James S. , Wang Jinn-Li , Wang Peng Yuan , Wang Shih-Chung , Wong Tai-Tong , Wu Shih-Pei , Wu Yuan-Hung , Chiou Jeng-Fong , Lu Long-Sheng 
Published: June 2023

e23521 Background: Pharmacologic treatment for soft tissue sarcoma (STS) remains challenging. There is a lack to predict treatment responses to chemotherapy or targeted therapy to oncologic drivers. We hypothesize that circulating tumor cells may enrich cancer initiating cells and represent a window to probe personalized drug treatment response. In this study, we test if drug sensitivity profile of short-term culture of tumor organoids derived from circulating tumor cells (CTCs) correlates to clinical treatment response. Methods: From April 2019 to December 2020, 50 patients with biopsy-confirmed STS, who had either recurrent or metastatic tumors, were enrolled in a prospective observational study in Taipei Medical University Hospital. The median age of the patients was 47, and the top 3 diagnoses were leiomyosarcoma, aggressive fibromatosis and rhabdomyosarcoma. 74% of patients had metastatic diseases at the time of blood collection. Fifty-five blood samples were collected and processed for CTC organoid culture and drug sensitivity analysis (EVASelect, CancerFree Biotech, Taipei, Taiwan), which involves culturing nucleated blood cells on a binary colloid crystal-coated surface. Clinical response was evaluated using RECIST criteria 3 months after blood collection. The relationship between CTC viability and clinical response was analyzed using a contingency table and Chi-square analysis. Results: The success rate of CTC expansion was 87.2% (48/55), as defined by ATP abundance higher than 3000 U2OS cells after 18 days of culture. Clinical information from 32 of the 50 cases was eligible for analysis, and the results showed that CTC viability at a 70% cutoff correlated with clinical disease control at 3 months after blood collection. The odds ratio, sensitivity, specificity, and diagnostic accuracy were 12 (p = 0.036), 92.3%, 50%, and 79%, respectively. A demonstration of the interaction between this research and the Molecular Tumor Board (MTB) in the Taipei Medical University Healthcare System is presented through a case study of metastatic angiosarcoma and its correlation. Conclusions: The study highlights the potential of using CTC drug sensitivity as a biomarker for precision medicine in STS, despite limitations such as small sample size, short follow-up, and disease and treatment heterogeneity. Advancements in gene-based precision medicine have been made in the past decade, but only a small number of STS patients have seen benefits from it. This emphasizes the need for further research to thoroughly evaluate the potential of CTC drug sensitivity as a predictive biomarker in clinical practice. Key words: soft tissue sarcoma; circulating tumor cells; liquid biopsy; predictive biomarker; precision medicine.
Methylation classifier array and classification of solitary fibrous tumors.
Authors: Chelsky Zachary L , Obeidin Farres , Alexiev Borislav A. , Santana-Santos Lucas , Duckett Drew , Parker Stephanie , Baczkowski Joseph , Pollack Seth , Vormittag-Nocito Erica , Jennings Lawrence J 
Published: June 2023

e23522 Background: Solitary fibrous tumors (SFTs) are fibroblastic tumors which carry a characteristic NAB2::STAT6 gene rearrangement. SFTs represent a heterogenous group that may arise in multiple locations and have variable risk of progression. Despite a consistent oncogenic driver, there is little biological data explaining this variability. Recently, the German Cancer Research Network (DKFZ) have modified their brain tumor methylation classifier for use in sarcomas. We subjected solitary fibrous tumors diagnosed at our institution to a validated, in-house sarcoma methylation array classifier modeled after that of the DKFZ in order to assess for differences in methylation patterns that may account for biological or clinical variances. Methods: Twenty-eight primary site SFTs from 2011-2021 were subjected to the sarcoma methylation classifier. Histologic diagnosis was confirmed by STAT6 immunohistochemistry or by the presence of the NAB2::STAT6 fusion. The methylation classifier was run on the Illumina iScan platform and the resulting IDAT files were analyzed via a custom bioinformatics pipeline. The sarcoma classifier was trained using the same samples and normalization strategies used by the DKFZ group and validated using the same publicly available samples. Results: Methylation data for each tumor was collected, given a classification score, and visualized by t-distributed stochastic neighbor embedding (t-SNE). We noted three distinct groups of SFTs on the t-SNE plot. Group 1 was comprised of all eight intracranial SFTs and were correctly classified as SFT (classifier score ≥0.9). Group 2 contained nine pleural-based tumors and one SFT each from the mediastinum and bladder wall. Classification was successful in only seven of eleven tumors. Group 3 SFTs predominantly arose in the soft tissues or bone (two pelvis, four extremity, and one mediastinum) and all failed accurate classification. Finally, two orbital SFTs stratified separately from all groups on t-SNE plot but did achieve an appropriate classification. There were no significant differences in grade or risk stratification among the three groups. Conclusions: Our preliminary data show differential clustering based on tumor location, suggesting biological differences between intracranial, pleural/visceral, and connective tissue locations. These results highlight the heterogeneity of these tumors and the inadequacy of the current methylation classification scheme for SFT. Future directions will include analysis of additional cases, gene expression patterns, and outcome data.
Pegylated liposomal doxorubicin combined with ifosfamide for advanced soft tissue sarcomas: A phase I dose-escalation study.
Authors: Ye Ting , Fan Li , Cao Rubo , Peng Ling , Chen Jing 
Published: June 2023

e23525 Background: Doxorubicin combined with ifosfamide (IFO) is one of the preferred treatment options for non-specific soft tissue sarcomas (STS), but is limited by cumulative cardiotoxicity and severe myelosuppression. Pegylated liposomal doxorubicin (PLD) provides an effective alternative to conventional anthracyclines with reduced toxicity. However, there is no standard dose recommendation for PLD combined with IFO for STS. The present study aimed to investigate the maximum tolerated dose (MTD) of PLD combined with IFO in advanced STS patients. Methods: This was a phase I, open-label, single-center, dose-escalation study. Patients with locally advanced or metastatic STS were enrolled, except for gastrointestinal stromal tumors, Ewing's sarcomas, embryonal rhabdomyosarcomas, and alveolar rhabdomyosarcomas. We used a standard 3 + 3 dose-escalation design with progressively increasing PLD and IFO (3 g/m2 per day for 3 days, q3w) for one cycle, with a dose escalation ranged from 30 to 70 mg/m2 (5mg/m2 increment per step). The primary endpoint was determination of the MTD, and the secondary endpoint was the incidence/severity of adverse events (AEs). Results: From January 2020 to September 2022, 23 patients were enrolled in this study, including 3 patients at doses 30-45 mg/m2, 6 patients at dose 50 mg/m2, and 5 patients at 55 mg/m2. The median age was 49 years (ranges from 30 to 68 years), the male/female ratio was 12/11, and 22 (95.65%) patients had stage IV disease (AJCC staging system). Initially, no DLT was observed at doses of 30-50 mg/m2, with 3 patients in each dose phase. Two patients developed DLTs at the 55 mg/m2 dose, resulting in the 50 mg/m2 dose extending to a total of 6 patients who completed treatment without DLT. The DLTs at dose 55 mg/m2 of the first patient were grade 4 neutropenia lasting ≥ 5 days and grade 3 thrombocytopenia with hemorrhage tendency; the second patient had grade 4 neutropenia lasting ≥ 5 days, grade 4 thrombocytopenia relapsed after platelet transfusion, and grade 3 increased alanine aminotransferase. Therefore, the MTD of PLD was 50 mg/m2. The most common (≥ 10%) grade 3-4 AEs in all patients were lymphopenia (56.52%), neutropenia (82.61%), leukopenia (86.96%), and thrombocytopenia (13.04%). Conclusions: For patients with locally advanced or metastatic STS, single cycle PLD combined with IFO had a tolerable AE profile, with an MTD of 50 mg/m2 for PLD. Further researches are needed to confirm the multi-cycle recommendation. Clinical trial information: ChiCTR1900028270 .