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Hodgkin lymphoma (HL) is composed of neoplastic Hodgkin and Reed‐Sternberg cells in an inflammatory background. The neoplastic cells are derived from germinal center B cells that, in most cases, are infected by Epstein‐Barr virus (EBV), which may play a role in tumorigenesis. Given that EBV‐latent membrane protein 1 (LMP1) regulates autophagy in B cells, we explored the role of autophagy mediated by EBV or LMP1 in HL. We found that EBV‐LMP1 transfection in HL cells induced a modest increase in autophagy signals, attenuated starvation‐induced autophagic stress, and alleviated autophagy inhibition‐ or doxorubicin‐induced cell death. LMP1 knockdown leads to decreased autophagy LC3 signals. A xenograft mouse model further showed that EBV infection significantly increased expression of the autophagy marker LC3 in HL cells. Clinically, LC3 was expressed in 15% (19/127) of HL samples, but was absent in all cases of nodular lymphocyte‐predominant and lymphocyte‐rich classic HL cases. Although expression of LC3 was not correlated with EBV status or clinical outcome, autophagic blockade effectively eradicated LMP1‐positive HL xenografts with better efficacy than LMP1‐negative HL xenografts. Collectively, these results suggest that EBV‐LMP1 enhances autophagy and promotes the viability of HL cells. Autophagic inhibition may be a potential therapeutic strategy for treating patients with HL, especially EBV‐positive cases. EBV‐LMP1 enhances autophagy and promotes viability of Hodgkin lymphoma cells. Autophagic inhibition may be a potential therapeutic strategy for treating patients with Hodgkin lymphoma, especially EBV‐positive cases.

Osteosarcoma (OS) was a malignant tumor occurring with unknown etiology that made prevention and early diagnosis difficult. Mesenchymal stem cells (MSCs), which were found in bone marrow, were claimed to be a possible origin of OS but with little direct evidence. We aimed to characterize OS cells transformed from human MSCs (hMSCs) and identify their association with human primary OS cells and patient survival. Genetic modification with p53 or retinoblastoma (Rb) knockdown and c‐Myc or Ras overexpression was applied for hMSC transformation. Transformed cells were assayed for proliferation, differentiation, tumorigenecity, and gene expression profile. Only the combination of Rb knockdown and c‐Myc overexpression successfully transformed hMSCs derived from four individual donors, with increasing cell proliferation, decreasing cell senescence rate, and increasing ability to form colonies and spheres in serum‐free medium. These transformed cells lost the expression of certain surface markers, increased in osteogenic potential, and decreased in adipogenic potential. After injection in immunodeficient mice, these cells formed OS‐like tumors, as evidenced by radiographic analyses and immunohistochemistry of various OS markers. Microarray with cluster analysis revealed that these transformed cells have gene profiles more similar to patient‐derived primary OS cells than their normal MSC counterparts. Most importantly, comparison of OS patient tumor samples revealed that a combination of Rb loss and c‐Myc overexpression correlated with a decrease in patient survival. This study successfully transformed human MSCs to OS‐like cells by Rb knockdown and c‐Myc overexpression that may be a useful platform for further investigation of preventive and target therapy for human OS. Stem Cells Translational Medicine 2017;6:512–526

Background The advent of novel therapeutic agents has advanced biomarker characterization in non-small-cell lung cancer (NSCLC), driving increased adoption of next-generation sequencing (NGS) technologies for molecular testing. However, comprehensive data addressing the clinical utility of different NGS platforms for NSCLC remains limited. Methods This retrospective study analyzed real-world data from 478 Taiwanese NSCLC patients over five years, using the Oncomine Focus Assay (OFA) to assess genetic alterations. The evaluation focused on assay accuracy, limit of detection (LoD), sequencing performance, and the genetic landscape of NSCLC. Results The OFA achieved an NGS success rate of 80.5% (385/478), with tumor cell percentage, specimen source and FFPE block age identified as key factors affecting success. Quality metrics demonstrated robust sequencing performance, including 97.0 ± 9.6% on-target alignment, 94.7 ± 6.4% uniformity, and ≥ 500 × coverage for 98.0 ± 6.6% of amplicons. Among the 385 patients analyzed, 86.8% (334/385) were found to harbor pathogenic or likely pathogenic variants, of which 78.4% (262/334) were SNVs/Indels, 41.6% (139/334) were CNVs, 2.7% (9/334) were exon skipping alterations, and 10.2% (34/334) were gene fusions. Actionable driver mutations included EGFR mutations (46.2%, 178/385), KRAS mutations (9.4%, 36/385), ERBB2 mutations (6.8%, 26/385), ALK fusions (4.4%, 17/385), MET exon 14 skipping (2.3%, 9/385), BRAF mutations (2.3%, 9/385), ROS1 and RET fusions (1.8%, 7/385 each), and NTRK1 fusions (0.5%, 2/385). Notably, KRAS G12 C mutation was detected in 2.8% (11/385) of cases. Conclusions This study demonstrates the robust performance of the OFA in identifying clinically relevant genetic alterations in NSCLC. The findings support its clinical utility in precision oncology and provide valuable insights into the genetic landscape of Asian NSCLC, enhancing personalized treatment strategies for lung cancer patients.

Classifying cancer genetic variants based on clinical actionability is crucial yet challenging in precision oncology. Large language models (LLMs) offer potential solutions, but their performance remains underexplored. This study evaluates GPT-4o, Llama 3.1, and Qwen 2.5 in classifying genetic variants from the OncoKB and CIViC databases, as well as a real-world dataset derived from FoundationOne CDx reports. GPT-4o achieved the highest accuracy (0.7318) in distinguishing clinically relevant variants from variants of unknown clinical significance (VUS), outperforming Qwen 2.5 (0.5731) and Llama 3.1 (0.4976). LLMs demonstrated better concordance with expert annotations for variants with strong clinical evidence but exhibited greater inconsistencies for those with weaker evidence. All three models showed a tendency to assign variants to higher evidence levels, suggesting a propensity for overclassification. Prompt engineering significantly improved accuracy, while retrieval-augmented generation (RAG) further enhanced performance. Stability analysis across 100 iterations revealed greater consistency with the CIViC system than with OncoKB. These findings highlight the promise of LLMs in cancer genetic variant classification while underscoring the need for further optimization to improve accuracy, consistency, and clinical applicability.

Epstein–Barr virus (EBV) infection is a risk factor for Hodgkin lymphoma (HL). To test whether the frequency of HL subtypes and their association with EBV has shifted with rising socioeconomic status in Taiwan, we compared the pathological features and EBV status, detected by in situ hybridization, of HL diagnosed between 1996 and 2007 (99 cases) and 1982 and 1995 (74 cases). The male‐to‐female ratio was 121:52 (2.3:1) and the mean age at presentation was 41.5 years. The overall EBV positivity rate was 50% (86/173 cases). Comparing the distribution of HL cases diagnosed at two different time periods, we found an increased frequency of the nodular sclerosis (NS) subtype (53 vs 68%, P = 0.045), a decreased frequency of the mixed cellularity subtype (35 vs 13%, P < 0.001), a reduced male‐to‐female ratio (2.9:1 compared to 1.4:1) and mean age (42.4 vs 36.6 years) in the NS subtype, and a significant decrease in EBV positivity rates among the NS and lymphocyte‐depletion subtypes (61 vs 39%, P = 0.03). These data indicate shifts in the frequency of histological subtype and EBV association for HL in Taiwan over the last decade, with a trend closer to that seen in Western countries and Japan. (Cancer Sci 2008; 99: 345–349)

•Totally, 11,393 soft tissue sarcoma cases were included.•Gastrointestinal stromal tumor was the most common subtype (29.2%).•Angiosarcoma incidence was higher in Taiwan than in the United States and Europe.•Leiomyosarcoma and Kaposi sarcoma incidence was low in Taiwan. Asian studies on soft tissue sarcoma (STS) incidence, irrespective of the primary site, are scant. STS data were acquired from the population-based 2007–2013 Taiwan Cancer Registry of the Health and Welfare Data Science Center, Taiwan. Histological subtype-, site-, sex-, and age-specific STS incidence rates were analyzed according to the 2013 classification of the World Health Organization. In total, 11,393 patients with an age-standardized incidence rate (ASIR) of 5.62 (95% confidence interval, 5.51–5.73) per 100,000 person-years were identified. Overall, a male predominance (sex-standardized incidence rate ratio, 1.2) was noted, and the rate increased with age, peaking at >75 years. Approximately 30% of STSs occurred in connective, subcutaneous, and other soft tissues and 70% in other sites. In addition to connective, subcutaneous, and other soft tissues, the three most common primary sites were the stomach (15.9%), skin (14.3%), and small intestines (10.5%). Gastrointestinal stromal tumor was the most common subtype (29.2%; ASIR, 1.55/100,000 person-years), followed by liposarcoma (11.5%; ASIR, 0.63/100,000 person-years) and leiomyosarcoma (9.7%; ASIR, 0.53/100,000 person-years). Compared with relevant data from Western countries, the incidence rate of angiosarcomas was higher than that in other regions, whereas the incidence rates of leiomyosarcoma and Kaposi sarcoma were lower than those in other regions. STS incidence varied by histological subtype, sex, age, and primary site in an Asian population. Our results suggested regional and racial discrepancies in the incidence rates of certain STS subtypes.

Osteosarcoma (OS) patients who suffer manipulation therapy (MT) prior to diagnosis resulted in poor prognosis with increasing metastasis or recurrence rate. The aim of the study is to establish an in vivo model to identify the effects of MT on OS. The enrolled 235 OS patients were followed up in this study. In vivo nude mice model with tibia injection of GFP-labeled human OS cells were randomly allocated into MT(+) that with repeated massage on tumor site twice a week and no treatment as MT(-) group. The five-year survival, metastasis and recurrence rates were recorded in clinical subjects. X-ray plainfilm, micro-PET/CT scan, histopathology, serum metalloproteinase 2 (MMP2), metalloproteinase 9 (MMP9) level and human kinase domain insert receptor (KDR) pattern were assayed in mice model. The results showed that patient with MT decreased 5-year survival and higher recurrence or metastasis rate. Compatible with clinical findings, the decreased body weight (30.5 ± 0.65 g) and an increased tumor volume (8.3 ± 1.18 mm3) in MT(+) mice were observed. The increasing signal intensity over lymph node region of hind limb by micro-PET/CT and the tumor cells were detected in lung and bilateral lymph nodes only in MT(+) group. MMP2 (214 ± 9.8 ng/ml) and MMP9 (25.5 ± 1.81 ng/ml) were higher in MT(+) group than in MT(-) group (165 ± 7.8 ng/ml and 16.9 ± 1.40 ng/ml, individually) as well as KDR expression. Taking clinical observations and in vivo evidence together, MT treatment leads to poor prognosis of primary osteosarcoma; physicians should pay more attention on patients who seek MT before diagnosis.

Background Adult soft tissue sarcomas (STS) of extremities are prone to recurrence despite apparently complete resection. This study aimed to explore the impact of clinicopathological factors on outcome and to define an “oncological safe margin” in these patients. Methods A total of 181 patients with extremity STS were enrolled in a retrospective study. The prognostic influence of margin status and other clinicopathological characteristics on local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-specific survival (DSS), were examined by univariate and multivariate analyses. The influence of surgical margins on postrecurrence survival (PRS) of patients undergoing reoperation for relapsed lesions during follow-up was analyzed by the Kaplan–Meier method. Results Surgical margin width <10 mm and deep tumor depth at primary operation were consistently statistically significant independent adverse factors for LRFS, DMFS, and DSS. Patients with liposarcoma or low grade tumors had significantly higher chances of achieving adequate margins. Of 83 patients who experienced recurrence or metastasis, 53 (63.9%) received reoperation for their relapsed lesions. Patients who achieved microscopically negative margins (R0) at reoperation had significantly better PRS than those who did not ( P  < 0.007). Overall, patients with no recurrences had the best DSS, while relapsed patients receiving R0 reoperation had better DSS than those receiving either non-R0 reoperation or no reoperation at all. Conclusion Surgical margins prognostically influence survival in both patients undergoing primary surgery and those undergoing reoperation for relapse of extremity STS. In primary surgery, the chance of achieving adequate margin may reflect the underlying aggressiveness of tumors.

Purpose The cancerous inhibitor of protein phosphatase 2A (CIP2A) oncoprotein is overexpressed in colon cancer tissue compared to normal colon mucosa. We investigated the impact of CIP2A on colon cancer. Methods A tissue microarray consisting of 167 colon cancer specimens was investigated. The association between CIP2A and clinicopathological parameters was analyzed using the χ 2 test. Survival was analyzed using the Kaplan–Meier method. The impact of CIP2A on proliferation and drug resistance was evaluated using the 3-(4, 5-dimethylthiazolyl-2)-2, 5-diphenyltetrazolium bromide test. An anchorage-independent colony formation assay was also performed. Results CIP2A was an independent prognostic factor in colon cancer after controlling for other clinical confounding factors, such as stage and lymphovascular invasion, particularly in stages III and IV (hazard ratio = 2.974, P  < 0.001). The knockdown of CIP2A reduced the proliferation and anchorage-independent colony formation of colon cancer cells. Knockdown of CIP2A decreased the resistance of the cells to 5-fluorouracil, oxaliplatin, and SN38 (an active metabolite of irinotecan). Treatment with 5-fluorouracil, oxaliplatin, and SN38 decreased CIP2A expression. Conclusions CIP2A is a prognostic factor in colon cancer. The knockdown of CIP2A reduced proliferation and anchorage-independent colony formation and increased 5-fluorouracil, oxaliplatin, and SN38 efficacy in colon cancer cell lines.

Parosteal osteosarcoma is a rare malignant bone tumor arising from the bone cortical surface. It most commonly occurs in young women over the metaphyseal region, especially the long bones near the knee joint. Patients usually report a slow-growing mass for years. The tumor is characterized by its bland microscopic morphology, prone to be misdiagnosed as other benign tumors. In the absence of dedifferentiation, the prognosis is generally better than that of conventional osteosarcoma. Recent studies demonstrated distinctive cytogenetic abnormality resulting in amplification of the CDK4 and MDM2 genes, which may serve as markers for molecular diagnosis. In this article, we review the clinical, radiologic, and pathologic features of parosteal osteosarcoma and identify some diagnostic pitfalls, discuss the prognostic variables, and update recent molecular advances and their application in the diagnosis.