WHO Subtypes Research Articles

Dual-energy CT for predicting serosal invasion in gastric cancer and subtype analysis.

To predict the serosal invasion of gastric cancer (GC) using dual-energy CT (DECT)-based parameters and analyze the diagnostic performance according to different subtypes. The patients were divided into the T1-3 group and T4a group. The irregular region of interest (ROI) was manually delineated on the largest cross-section of the lesion. The ROI area, iodine concentration (IC), normalized iodine concentration (nIC), fat fraction, CT value mean, and standard deviation were measured in the late arterial (LAP) and venous phase (VP). The Mann-Whitney U test was used to assess differences between different T-stage groups and histopathological subtypes of GC. A model was established based on DECT parameters, and the receiver operating characteristic (ROC) curve was used to evaluate the diagnostic performance. Preliminary analysis showed that there were significant differences in ROI area, IC, nIC and CT value mean in VP and ROI area in LAP between T1-3 and T4a GC (all p < 0.05). The AUC of the comprehensive model composed of ROI and nIC in VP was 0.805. For different subtypes, multiple DECT parameters of poorly cohesive carcinoma (PCC) showed significant differences. ROI area in LAP and VP, IC, nIC, and CT value mean in VP have significant differences in distinguishing between T1-3 and T4a GC. Iodine-related parameters in VP differed significantly between T1-3 and T4a in PCCs, rather than TACs. Considering the heterogeneity of different WHO subtypes, DECT iodine-related parameters in VP are more predictive of the serosal invasion status of GC compared to LAP.

Identification and validation of miRNA-target genes network in pediatric brain tumors

Alterations in miRNA levels have been observed in various types of cancer, impacting numerous cellular processes and increasing their potential usefulness in combination therapies also in brain tumors. Recent advances in understanding the genetics and epigenetics of brain tumours point to new aberrations and associations, making it essential to continually update knowledge and classification. Here we conducted molecular analysis of 123 samples of childhood brain tumors (pilocytic astrocytoma, medulloblastoma, ependymoma), focusing on identification of genes that could potentially be regulated by crucial representatives of OncomiR-1: miR-17-5p and miR-20a-5p. On the basis of microarray gene expression analysis and qRTPCR profiling, we selected six (WEE1, CCND1, VEGFA, PTPRO, TP53INP1, BCL2L11) the most promising target genes for further experiments. The WEE1, CCND1, PTPRO, TP53INP1 genes showed increased expression levels in all tested entities with the lowest increase in the pilocytic astrocytoma compared to the ependymoma and medulloblastoma. The obtained results indicate a correlation between gene expression and the WHO grade and subtype. Furthermore, our analysis showed that the integration between genomic and epigenetic pathways should now point the way to further molecular research.

The remarkable antitumor efficacy of corticosteroid treatment in patients with refractory thymomas

BackgroundSome case reports have found that corticosteroid treatments shrunk thymoma lesions remarkably after the failure of chemotherapy or surgery. However, few studies have comprehensibly evaluated the antitumor effects of corticosteroids in patients with invasive thymomas. MethodsWe reviewed the medical records of 13 consecutively enrolled patients with locally advanced or metastatic thymomas treated via corticosteroid monotherapies from January 2010 to March 2021 in our institute. A Cox's proportional hazard model and the Kaplan-Meier method were used to identify factors associated with survival. ResultsThe median follow-up time was 26 months (range, 13–115 months). The median initial dose of corticosteroid was 0.90 mg/kg/day prednisolone equivalent (range, 0.4–1.1 mg/kg/day). Of the 13 cases, 7 (53.8%, 95% CI: 0.25–0.81) exhibited a partial response and 5 (38.5%, 95% CI: 0.14–0.68) stable disease. The median progression-free survival was 5.7 months [95% confidence interval (CI): 1.5–9.6 months]. The median overall survival was 25.3 months (95% CI: 7.1–not attained). The median duration of corticosteroid use was 3 months (range, 1–64 months). Patients with WHO subtype B thymomas exhibited a better overall response rate to corticosteroids than did patients with other disease subtypes (75%, 95% CI: 0.19–0.99). Adverse events of Grade 3 or more were not observed. ConclusionsCorticosteroids are clinically valuable for patients with thymomas.

Surgical interpretation of the WHO subclassification of intrahepatic cholangiocarcinoma: a narrative review.

Intrahepatic cholangiocarcinoma (iCCA) has been subclassified by its gross morphology into the mass-forming (MF), periductal-infiltrating (PI), and intraductal growth (IG) types and their combinations. This classification correlates well with clinical features; for example, MF-iCCA has less lymph-node metastasis and a better prognosis than PI-iCCA. According to the recently accumulated evidence from histological investigations, the WHO classification endorsed a subclassification scheme in which iCCA cases are classified into small- and large-duct types. Small-duct iCCA is considered to originate from septal or smaller bile ducts and is characterized by less frequent lymph-node metastasis, a favorable prognosis, and an MF appearance. Large-duct iCCA arises around the second branch of the biliary tree and has more aggressive biology and distinct genetic abnormalities. According to the practice guidelines for iCCA from the Liver Cancer Study Group of Japan and the National Comprehensive Cancer Network, upfront surgery is recommended for iCCA without distant metastasis regardless of the morphological subtype, based on clinical experience. In consideration of the biological heterogeneity of iCCA, the treatment strategy for iCCA needs to be reconsidered based on the WHO subtypes.

Allogeneic haematopoietic cell transplantation for advanced systemic mastocytosis: Best practice recommendations on behalf of the EBMT Practice Harmonisation and Guidelines Committee.

Systemic Mastocytosis (SM) is a multifaceted clinically heterogeneous disease. Advanced SM (AdvSM) comprises three entities: aggressive SM (ASM), mast cell leukaemia (MCL) and SM with an associated hematologic neoplasm (SM-AHN), the latter accounting for 60-70% of all AdvSM cases. Detection of a disease-triggering mutation in the KIT gene (esp. KIT D816V) in >90% of the patients with ASM or SM-AHN has led to a significant improvement in therapeutic options by the implementation of two KIT-targeting kinase inhibitors: midostaurin and avapritinib. Although complete remissions have been reported, neither of these targeted agents is 'curative' in all patients and the duration of responses varies. The median overall survival, depending on the WHO subtype and scoring result, is approximately 1 to 4 years. Although the European Competence Network on Mastocytosis (ECNM) and American Initiative in Mast Cell Diseases (AIM) consensus groups recommend allogeneic haematopoietic cell transplantation (allo-HCT) in drug-resistant and other high-risk patients, there is a relative lack of information to guide clinicians on which patients with AdvSM should be considered for transplant, and how KIT inhibitors may fit into the transplant algorithm, including their use pre- and post-transplant to optimise outcomes. Following the generation of an expert panel with a specialist interest in allo-HCT and mastocytosis, these best practice recommendations were generated according to the European Society for Blood and Marrow Transplantation (EBMT) Practice Harmonisation and guidelines and ECNM methodology. We aim to provide a practical, clinically relevant and up-to-date framework to guide allo-HCT in AdvsM in 2024 and beyond.

Use of deep learning for the classification of hyperplastic lymph node and common subtypes of canine lymphomas: a preliminary study.

Artificial Intelligence has observed significant growth in its ability to classify different types of tumors in humans due to advancements in digital pathology technology. Among these tumors, lymphomas are quite common in dogs, despite studies on the application of AI in domestic species are scarce. This research aims to employ deep learning (DL) through convolutional neural networks (CNNs) to distinguish between normal lymph nodes and 3 WHO common subtypes of canine lymphomas. To train and validate the CNN, 1,530 high-resolution microscopic images derived from whole slide scans (WSIs) were used, including those of background areas, hyperplastic lymph nodes (n = 4), and three different lymphoma subtypes: diffuse large B cell lymphoma (DLBCL; n = 5), lymphoblastic (LBL; n = 5), and marginal zone lymphoma (MZL; n = 3). The CNN was able to correctly identify 456 images of the possible 457 test sets, achieving a maximum accuracy of 99.34%. The results of this study have demonstrated the feasibility of using deep learning to differentiate between hyperplastic lymph nodes and lymphomas, as well as to classify common WHO subtypes. Further research is required to explore the implications of these findings and validate the ability of the network to classify a broader range of lymphomas.

Communication That Enables Shared Decision-Making in Myelodysplastic Syndrome Is Suboptimal: Early Results from the Cancer Experience Registry

Background: Myelodysplastic Syndromes (MDS) are a heterogeneous group of marrow failure diseases whose prognosis and treatments are guided by marrow morphology, degrees of cytopenias, and genetic changes. Due to the complexity of the disorder, combined with the advanced age and frailty of most patients, conveying crucial information for shared decision-making poses challenges. Despite efforts designed to enhance communication, there is limited understanding of these initiatives' effectiveness. Methods: The Cancer Experience Registry® is an ongoing online research study conducted by the Cancer Support Community that seeks to uncover the emotional, physical, practical, and financial impact of cancer from the patient's perspective. In association with the MDS Foundation, this observational, cross-sectional study enrolls patients with MDS who provide socio-economic and clinical history, supplemented with information related to their MDS diagnosis. Frequencies and descriptive statistics are presented. Results: Between December 2021 and February 2023, 140 MDS patients joined the registry. By self-report, the study population was 51% female and 91% non-Hispanic white with a median age 61 (range 34-93). Like other cancer disease cohorts in the online registry, the MDS population was highly educated (81% attending college and 31% obtaining advanced degrees). 18% reported gross annual incomes less than $40,000 but 29% reported incomes above $80,000 (with 25% not responding). 70% were retired, 15% were still employed and 11% considered themselves unemployed due to disability. 41% of the patients were newly diagnosed (disease duration less than 1 year) and an additional 19% had MDS for less than 2 years. Interestingly, 24% carried a diagnosis of MDS for more than 6 years (including 11% reporting &amp;gt;10 years duration). 51% were in active treatment, 18% were between therapies, and 26% had never received any MDS-directed therapy. 76% self-reported a primary MDS diagnosis and 7% secondary MDS, with the remainder unsure. 33% of the respondents did not know their WHO morphologic subtype with 13% stating that they were never informed and 16% unsure if they were told this information. Similarly, although the IPSS-R is a critical determinant of prognosis and informs treatment decisions, 23% could not recall this score with 11% stating that they were not told their IPSS-R and 9% not sure if they were informed. Among 118 respondents, only 18% could remember their genetic testing results. 120 participants answered questions regarding whether they received additional assistance with MDS-related information and when this was provided. By patient recall, general information about MDS was provided to 78% at the time of diagnosis and an additional 5% after starting treatment. Help in understanding the WHO subtype and IPSS-R was remembered by 41% and 52%, respectively, at the time of diagnosis, and 8% and 9% after starting treatment. A third could not recall being informed about genetic mutational testing. Information about the possibility of MDS transforming into AML was not recalled by 21%. Information about transfusion support was remembered by 46% at the time of diagnosis and 17% after starting treatment (with 29% stating that they had not received information about transfusions and 8% unable to recall). A discussion about transplant options was remembered by 67%. Although a quarter of patients have never received therapy, 32% stated that they had never had a discussion of treatment options and an additional 6% were unsure if a discussion had occurred. A discussion about specific MDS medications was remembered by 51% at the time of diagnosis and 19% only after the start of therapy, with 30% not recalling any assistance in understanding medication options. Conclusions: Based on the early results of the Cancer Experience Registry® derived from a cohort of highly educated and motivated MDS patients, it appears that effective communication about MDS and treatment options is suboptimal. A significant proportion of respondents were unable to recall information about their diagnosis critical to informed shared decision-making. Given the complexities of an MDS diagnosis, additional efforts to educate patients are necessary. Patient support organizations, such as the Cancer Support Community and the MDS Foundation, can serve as valuable educational resources.

Mast Cell Leukemia: An Update with a Practical Review.

Mast cell leukemia (MCL) is the leukemic form of SM with at least 20% mostly immature mast cells on bone marrow aspirate. MCL may develop de novo, in the absence of a prior SM, or it may represent a progression from a previous SM. MCL may be sub-divided into the more frequent, aggressive acute form with signs of organ damage (C-findings) and the chronic form lacking C-findings and presenting a more stable course, although over time, progression to acute MCL is common. The 2022 WHO subtype of MCL with an associated hematological neoplasm was renamed MCL with an associated myeloid neoplasm in the 2022 International Consensus Classification (ICC). The relevance of the distinction between the leukemic and aleukemic forms based on the percentage of circulating mast cells is a matter of debate. The current knowledge on MCL is restricted mainly to single reports or case series with a limited number of larger studies. Our aim is to provide a comprehensive overview of this rare disease in terms of clinical manifestations, morphology, phenotype, molecular characteristics, differential diagnosis, outcome and treatment. A general overview on mastocytosis is also included.

Integrated genetic profiling of archival pediatric high-grade glial tumors and reassessment with 2021 WHO classification of paediatric CNS tumours

Though rare, pediatric high-grade gliomas (pHGG) are a leading cause of cancer-related mortality in children. We wanted to determine whether our currently available clinical laboratory methods could better define diagnosis for pHGG that had been archived at our institution for the past 20 years (1998 to 2017). We investigated 33 formalin-fixed paraffin-embedded pHGG using ThermoFisher Oncoscan SNP microarray with somatic mutation analysis, Sanger sequencing, and whole genome sequencing. These data were correlated with historical histopathological, chromosomal, clinical, and radiological data. Tumors were subsequently classified according to the 2021 WHO Classification of Paediatric CNS Tumours. All 33 tumors were found to have genetic aberrations that placed them within a 2021 WHO subtype and/or provided prognostic information; 6 tumors were upgraded from WHO CNS grade 3 to grade 4. New pHGG genetic features were found including two small cell glioblastomas with H3 G34 mutations not previously described; one tumor with STRN-NTRK2 fusion; and a congenital diffuse leptomeningeal glioneuronal tumor without a chromosomal 1p deletion but with KIAA1549-BRAF fusion. Overall, the combination of laboratory methods yielded key information for tumor classification. Thus, even small studies of these uncommon tumor types may yield new genetic features and possible new subtypes that warrant future investigations.

Proteogenomics of diffuse gliomas reveal molecular subtypes associated with specific therapeutic targets and immune-evasion mechanisms

Diffuse gliomas are devastating brain tumors. Here, we perform a proteogenomic profiling of 213 retrospectively collected glioma tumors. Proteogenomic analysis reveals the downstream biological events leading by EGFR-, IDH1-, TP53-mutations. The comparative analysis illustrates the distinctive features of GBMs and LGGs, indicating CDK2 inhibitor might serve as a promising drug target for GBMs. Further proteogenomic integrative analysis combined with functional experiments highlight the cis-effect of EGFR alterations might lead to glioma tumor cell proliferation through ERK5 medicates nucleotide synthesis process. Proteome-based stratification of gliomas defines 3 proteomic subgroups (S-Ne, S-Pf, S-Im), which could serve as a complement to WHO subtypes, and would provide the essential framework for the utilization of specific targeted therapies for particular glioma subtypes. Immune clustering identifies three immune subtypes with distinctive immune cell types. Further analysis reveals higher EGFR alteration frequencies accounts for elevation of immune check point protein: PD-L1 and CD70 in T-cell infiltrated tumors.

Comparison of Cytomorphology and Histopathology in Myelodysplastic Syndromes (MDS)

Introduction: Bone marrow cytomorphology, cytogenetics and molecular analyses are essential tools for diagnosing a myelodysplastic syndrome. MDS are characterized by dysplastic features of hematopoietic cells and may also show an increased blast cell count. Histopathology can provide additional information on bone marrow fibrosis and cellularity. We analysed correlations and differences between cytomorphological and histopathological findings at diagnosis. Patients and methods: In the Duesseldorf MDS registry, we identified 127 patients with detailed information available on bone marrow cytomorphology, blast count, blood cell counts and clinical features, who also had a bone marrow core biopsy taken at the time of diagnosis. From their formalin-fixed, paraffin-embedded histopathology specimens new sections and stains were made and evaluated by one reviewing pathologist (SB) who assessed a predefined set of features. The pathologist had no knowledge of the cytomorphological findings, except for the information that the specimen was from a "patient with myelodysplastic syndrome". Statistical analyses were performed by SPSS. Procedures were in accordance with the current version of the Helsinki Declaration. Informed consent was obtained from all patients included in the study. Results: The estimation of the percentage of CD34-positive cells by histopathology differed significantly from the cytomorphologically assessed medullary blast count, with a trend towards histopathological underestimation of blast cells (figure 1). Assessment of dysmegakaryopoiesis by histopathology identified 44 cases with dysplastic features, which were deemed inconspicious by cytomorphology. Histopathology yielded a significant positive correlation (p=0.002) between cellularity and degree of dysmegakaryopoiesis, and these two features were also correlated with higher-risk WHO subtypes. Fibrosis and dysmegakaryopoiesis were negatively correlated. Bone marrow cellularity seemed to be overestimated by cytomorphology compared with histopathology. The percentage of erythropoietic cells did not correlate well between cytomorphological and histopathological review. Neither WHO subtype nor medullary blast count showed an association with the proportion of erythropoiesis, regardless of the mode of evaluation. All patients with expanded erythropoiesis also showed signs of dysmegakaryopoiesis. There was no case of cytomorphologically diagnosed MDS that was not confirmed by histopathology, and 48% of MDS diagnoses were identical as to their WHO subtype. However, in 66 cases (52%), the WHO type diagnosed by histopathology differed from the WHO type diagnosed by cytomorphology. The discrepancy was mainly due to differing estimates of medullary blast counts. In our cohort, the degree of fibrosis positively correlated with bone marrow cellularity, a finding that appeared counterintuitive to clinical experience. Increased cellularity also correlated with higher-risk MDS subgroups. Prognosis in terms of overall survival was influenced by the following parameters: Cytomorphologically assessed medullary blast count, bone marrow cellularity, fibrosis, and percentage of erythropoiesis, the latter assessed by histopathology. Patients with of grade 2 or 3 fibrosis had an inferior outcome (figure 2). Conclusions: In our study, histopathology was fully congruent with bone marrow cytology as far as making a diagnosis of MDS is concerned. Histopathology, though, often underestimated the blast count and showed difficulty in identifying the correct MDS type according to the WHO classification. Histopathology is also at a disadvantage regarding evaluation of single cell morphology, with the exception of assessing certain aspects of dysmegakaryopoiesis. A clear advantage of histopathology is its exclusive capability of gauging bone marrow fibrosis and cellularity, both of which are relevant for the diagnosis and prognosis of MDS. We conclude that cytomorphology and histopathology should both be harnessed to optimize the characterization of a patient's myelodysplastic syndrome. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

KS04.5.A Development of a somatostatin receptor type 2 (SSTR2)-targeted probe for near infrared fluorescence guided meningioma surgery

Abstract Background Meningioma mostly recur at the primary resection bed requiring improvement in the intraoperative tumor visualization and surgical technique. This study aims to develop a highly specific and sensitive optical probe for intraoperative meningioma imaging to guide the tumor resection. Fluorescent dyes in the near infrared (NIR I, 700-1000nm) and shortwave infrared (NIR II, 1000-2000nm) allow detection by suitable cameras up to few millimeters in depth in real time. Our objective is to invent a fluorescent NIR I and II probe specifically targeting the somatostatin receptor type 2 (SSTR2) reliably overexpressed in meningioma independently of WHO grade and subtype. Material and Methods By linking a somatostatin analogue (TATE, Tyr(3)Thr(8)-Octreotid) to a new developed dye (sNIR), we synthesized a SSTR2 specific probe. Its optical properties are comparable to indocyanine green and stability as well as bleaching kinetic were observed in vitro. The probe was intravenously injected in native mice to evaluate pharmacokinetics and biodistribution and detected by a custom-built camera setup focusing on physiologically highly expressing SSTR2 tissues validated by immunohistochemistry (IHC). As proof-of-principle fluorescence guided tumor resection was performed in an ectopic and orthotopic meningioma IOMM-Lee mouse model. Results The SSTR2-sNIR probe is stable in aqueous solution up to 12h with favorable optical properties regarding kinetics, biodistribution and photostability compared to its IRDye800 analogue. In vivo, we observed a highly specific physiological signal uptake in the gastric epithelium, the pancreas and pituitary (they are highly expressing SSTR2 on IHC) compared to autofluorescence and negative controls (unlabeled dye and scrambled version). Given the moderate SSTR2 expression in the preclinical meningioma model we could still detect a mean tumor-to-brain ratio of 6.12 (n = 5; SD 1.8) in the orthotopic meningioma mouse model, allowing the fluorescence guidance to be feasible. Conclusion Our preclinical results demonstrate that the innovative SSTR2-targeted fluorescent probe is stable in various biological media over time and capable of specifically targeting the SSTR2 in vitro and in vivo potentially enabling sensitive and specific meningioma fluorescent guided surgery in the future.

Clinical features and independent predictors of Behçet's disease associated with myelodysplastic syndrome.

To investigate the correlation of Behçet's disease (BD) with myelodysplastic syndrome (MDS) and identify the predictive risk factors in Chinese patients. A retrospective study of BD associated with MDS (BD-MDS) patients from the First Affiliated Hospital of Zhengzhou University was conducted. Among 15 BD-MDS patients, 10 were females and 5 males. While 13 (86.7%) patients had abnormal karyotype, 11 patients with trisomy 8. 10 (66.7%) had gastrointestinal (GI) involvement. Compared with 60 general BD patients without MDS, the BD-MDS patients were significantly older. In addition, fever and GI involvement were more common in BD-MDS patients, whereas these patients had lower levels of leukocyte count, haemoglobin, and platelet count (p<0.05). Logistic regression analysis showed that GI involvement, low haemoglobin, and high ESR level were independently associated with the development of MDS in BD patients. BD-MDS patients with GI involvement (IBD-MDS) were usually much older and have more fever than IBD patients without MDS, as well as lower leukocyte count, haemoglobin level, platelet count, and higher erythrocyte sedimentation rate (ESR) and C-reactive protein levels (p<0.05). By comparison with 60 primary MDS patients without BD, the BD-MDS patients had more abnormal karyotypes and more trisomy 8 (p<0.05), while the distribution of 2016 WHO subtypes of MDS and IPSS-R categories were similar. Our findings suggest that cytogenetic abnormalities, especially trisomy 8, may play a role in the association of GI involvement, BD, and MDS. GI involvement, low haemoglobin, and high ESR level were independent predictors for MDS development in BD patients.

Relative Expression of mRNA BARF1 Epstein-Barr Virus from Tumor Tissue Biopsy in Formalin-Fixed Paraffin-Embedded in Nasopharyngeal Carcinoma

Nasopharyngeal carcinoma (NPC) is a malignant tumor originating from nasopharyngeal epithelial cells. NPC is endemic in some regions, especially in Southeast Asia countries. NPC is also a multifactorial disease involving environmental factors, genetic factors, and infection from Epstein-Barr virus (EBV). According to WHO classification, Undifferentiated NPC is histopathologically associated with EBV infection and categorized into WHO subtype 3. EBV has two phases in its infection cycle: the lytic and latent phases. The BARF1 gene is a mediator of the transition from the latent phase to the lytic phase. Previous studies suggest measurement of EBV mRNA activity at the primary tumor site in the nasopharyngeal reflects the pathogenesis of NPC rather than measuring circulating EBV DNA or serological diagnosis. This study aimed to determine the relative expression potential of BARF1 mRNA at different tumor stages in NPC patients as a predictor of NPC pathogenesis. This research design was a descriptive research method in the form of a cross-sectional study. The samples used were 22 patients diagnosed as NPC WHO class III at the Anatomical Pathology Section of Prof. Dr. Margono Soekarjo, Purwokerto, who met the inclusion criteria. The relative expression of BARF1 mRNA was carried out using the one-step real-time RT-PCR technique and then calculated using a formula of 2-ΔCt. The T-test was used to compare the relative expression of early and late-stage BARF1 mRNA. The relative expression of BARF1 mRNA in the late-stage advanced stage (n = 6; 0.708292-0.840177; med = 0.7164655) was increased compared to the early stage (n = 2; 0.708841-0.712423; med = 0. 710632).

PB1847: ACUTE MYELOID LEUKEMIA – IS IT MORE BESIDES GENETIC ABNORMALITIES?

Background: Acute myeloid leukaemia (AML) still carries a poor prognosis, despite novel aproaches. Age and previous myelodysplastic syndrome (MDS) are important risk factors. Environmental factors: professional benzene exposure, residential background and exposure to chemotherapy (CT)/radiotherapy (RT) have also been implicated. Aims: To evaluate environmental factors of AML patients, its genetic characteristics and overall survival (OS), in a tertiary centre. Methods: We retrospectively revised newly diagnosed AML in our centre between 2018 - 2020. Clinical and laboratory data were obtained by clinical files review Results: We included 235 patients, 47.2% (n=111) male. Median age 69 (19-97) years. (67 [28.5%]≤60 years old. – YOUNG and 168 [71.5%] with >60 years old - OLD). The most common WHO 2016 category was AML with myelodysplasia-related changes (MRC) (37.0%; n=87), followed by AML NOS (21.3%; n=50); 15 (6.4%) patients had acute promyelocytic leukaemia with PML―RARA, 21 (8.9%) therapy-related myeloid neoplasm and 17 (7.2%) post-myeloproliferative neoplasm (post-NMP) AML. The main category within YOUNG patients was AML with mutated NPM1 (19.4%) and in the OLD group was AML-MRC (45.2%). Genomic classification (GC) (Papaemmanuil, 2016) was available for 117 cases (49.8%): AML with no detected driver mutations (n=28; 23.9%); AML with mutated chromatin, RNA-splicing genes, or both (n=26; 22.2%). Considering YOUNG vs OLD patients, the main category was AML with mutated NPM1 (25%) vs AML with no detected driver mutations (32.3%). Regarding ELN risk stratification: 20.0% were low-risk, 27.1% intermediate risk and 52.9% high-risk category. OS for total cohort was 4.2 months, with 177 events (75.3% of included patients). The YOUNG patients had a median OS of 18,7 months while the OLD had median OS of 2,6 months, with P<0,001 (HR 2,31). Ninety nine (42.1%) patients lived in industrial regions. We found no correlation between living place and dysplasia, even after adjusting for age, ELN risk or GC. We found an apparent association of WHO subtype with living place (p=0.013), as post-MPN AML was more common in non-industrial (10.3 vs 3.0%) and AML with mutated NPM1 in industrial areas (11.1 vs 7.3%), but they were lost after adjusting for age. There was no OS difference between industrial and non-industrial places even after adjusting for age. Regarding professional exposure (available for 85 patients), 7.1% were exposed to benzene, 2.4% to agricultural activities and 31.8% to other chemicals, 58.8% with no significant exposure, with no differences in WHO classification, GC nor age. Smoking appeared associated with longer OS (6.6 vs 34.9%; p=0.026; HR 0.53), but this effect is lost after adjusting for age, as smoking was more common in YOUNG (65.7 vs 25.0%). There was no correlation with AML subtype or risk. Concerning other risk factors like alcohol consumption, obesity, family history of cancer, previous solid neoplasm, previous chemotherapy or previous radiotherapy none of them had impact in AML subtype, ELN risk or OS (p=NS). Summary/Conclusion: In our cohort, the majority of patients were over 60 years old and presented with AML-MRC, as described in the literature. Concerning GC, the dominant category was AML with no detected driver mutations. Looking at environmental factors, in our cohort only residential background correlated with AML subtype, despite non-significance impact in prognosis.

P762: NONLINIEAR IMPACT OF CLINICAL FEATURES ON THE SURVIVAL OUTCOME OF MYELODYSPLASTIC SYNDROMES PATIENTS

Background: Myelodysplastic syndromes (MDS) are a group of hematopoietic stem-cell disorders with heterogenous prognosis. The revised international prognostic scoring system (IPSS-R) (Greenberg et al., Blood, 2012) is the most widely used score for prognostication. However, the allocation of IPSS-R risk categories remains imprecise for some patients leading to unsatisfactory therapy decisions. Newer molecular prognostic models (Nazha et al., JCO, 2021 and Bernard et al., ASH, 2021) have added mutation data to improve survival predictions for MDS patients. Aims: Our aims were to investigate the nonlinear association of normalized clinical data in combination with molecular and cytogenetic data and to improve the prognostication potential of IPSS-R for patients with MDS. Methods: A multivariable fractional polynomials (MFP) algorithm was applied on clinical data of 943 MDS patients and nonlinear associations between continuous covariates and survival outcomes were efficiently modeled within Cox regression. Selected transformed variables were picked and the potential overfit was avoided by a closed test procedure for function selection (Royston et al., John Wiley & Sons, 2008). The performance of the model was evaluated in an independent set of 436 MDS patients and the accuracy was assessed using a concordance (c)index and the area under the Receiver Operating Characteristic curve (AUC) at each time point. Mutation data was obtained in a subset of 695 patients using next-generation sequencing, evaluating a panel of 81 genes at the time of diagnosis. Results: An MFP-model consisting of cytogenetics per IPSS-R and WHO subtypes, continuous forms of age and hemoglobin, and non-linear transformations of platelets and bone marrow blast percentage yielded a c-index performance of 0.82 vs 0.78 for IPSS-R and a significant AUC upgrade at all time points in the training set (Figure a). In comparison with the IPSS-R, absolute neutrophil count was not identified as an independent prognostic covariate and common features were treated in a non-linear fashion. Validation of the model in an independent set of 438 patients yielded a higher c-index (0.72 vs 0.68) with an improved AUC over time compared to the IPSS-R (Figure b). Based on MFP risk score, patients were then clustered into 5 different risk categories and compared with IPSS-R classifications. Our data showed no significant difference in time to death between IPSS-R groups for very low risk and low risk or between low risk and intermediate risk (Figure c); however, MFP classification showed 5 significantly different subgroups in predicting time to death for MDS patients (Figure d). We further investigated the effect of molecular data on disease prognostics in a subset of 695 patients sequenced using an 81 gene panel. In addition to the selected clinical covariates, occurrence of TP53, SRSF2, and ZRSR2 mutations were independently associated with lower survival, while the presence of TET2 mutation showed a depression effect on TP53 mutation towards a better outcome. As SF3B1 was not selected in the final model, we further evaluated its potential interactions and identified its correlation with cytogenetics and platelets, which predominated in the MFP model. This might be due to heterogeneity within the data set (e.g., 25% co-occurrence of SF3B1 with TP53 mutation) and needs to be investigated in larger cohorts. Image:Summary/Conclusion: We have established a nonlinear model that yields improved risk assessment compared to IPSS-R criteria.

CD47 expression patterns in thymic epithelial tumors.

8586 Background: Blockade of CD47, an immunoglobulin overexpressed on solid tumor cells that inhibits macrophage phagocytosis, is a promising anti-cancer immunotherapy which has not yet been explored in thymic epithelial tumors (TETs). TETs, including thymomas and thymic carcinomas, are rare tumors with limited immunotherapy treatment options due to the high rates of immune-related adverse effects observed with PD-1/PD-L1 checkpoint inhibitors. This study aimed to examine CD47 protein expression in TETs. Methods: A clinically annotated tissue microarray of 67 TETs consisting of 64 thymomas and 3 thymic carcinomas, as well as 14 thymic controls were included. Each sample with an average of 3 cores was stained for CD47 epithelial expression (rabbit monoclonal antibody SP279, Abcam, USA). Samples were scored for intensity as follows: 0 = none, 1 = weak, 2 = moderate, and 3 = strong. An H-score, defined as intensity x percentage of tumor involved, was also assigned and ranged from 0 to 300. Samples with an intensity score of &lt; 2 or an H-score of &lt; 150 were categorized as CD47low, while the rest as CD47high. Multivariate linear regression analysis accounted for WHO subtype, stage, resection status and presence of paraneoplastic syndrome (Prism 9, Graphpad). Results: Compared to normal thymic tissue, TETs were more frequently CD47 positive and had significantly higher levels of CD47 expression. CD47 was present in 91% of TETs, compared to 64.3% of normal thymus. Importantly, the level of expression was significantly higher in TETs by 16-fold (mean H-score 75.0 vs 4.6, p = 0.003). Among tumors, univariate analyses showed that higher CD47 expression was correlated with a lower stage (p = 0.032) and more complete resection (p = 0.058). A multivariate analysis accounting for these factors showed that CD47 expression by both H-score and intensity were each highly correlated with WHO histology subtype (p = 0.0005; p = 0.0017 respectively) with lower grade subtypes more frequently found in CD47high tumors. The most frequent subtype in CD47high, when compared to CD47low tumors, was AB (61.5% vs 13.7%) and the least frequent was B2 (0% vs 37.3%). Tumors with the highest grade (subtype C, thymic carcinomas) were exclusively CD47low. CD47high tumors were associated with an increased incidence of paraneoplastic syndromes (52.4% vs 12.0%, p = 0.0014). Conclusions: CD47 expression was found in the vast majority of TETs, and in significantly higher levels than normal thymic tissue. Among tumors, those with higher CD47 expression tended to have lower grade and stage, as well as higher frequency of paraneoplastic syndromes. This study is the first to examine CD47 expression in TETs. Given the prevalent expression of CD47 found in TETs and current available CD47 targeted agents, this study lends support for further investigation of this novel therapeutic approach.

De Novo myelodysplastic syndromes in patients 20–50 years old are enriched for adverse risk features

Data concerning the treatment approach and clinical outcomes in younger patients with myelodysplastic syndromes (MDS) are lacking. Furthermore, published results from genomic profiling in the young adult MDS population are few. We identified patients aged 20–50 at diagnosis evaluated for de novo MDS at our institution over a 32-year period. Clinical information and results from sequencing panels were extracted for analysis. 68 eligible patients were found, including 32% with multilineage dysplasia and 29% with excess blasts-2 WHO subtypes. Revised International Prognostic Scoring System for MDS (IPSS-R) categorization had 47% high/very high-risk, and this classification held prognostic significance. The median overall survival was 59 months, and most patients (75%) underwent allogeneic hematopoietic cell transplantation (alloHCT). Thirty-four patients had mutational profiling; the most commonly mutated gene was TP53 and most commonly altered gene category was epigenetic regulators. Younger patients with de novo MDS represented a unique subset with high-risk disease features (adverse cytogenetics, higher R-IPSS) frequently observed along with alterations in TP53 and genes related to epigenetic and transcription pathways.

Trends in Incidence and Survival of Patients With Thymic Epithelial Tumor in a High-Incidence Asian Country: Analysis of the Korean Central Cancer Registry 1999 to 2017

IntroductionTo report the trends in incidence and survival associated with thymic epithelial tumors (TETs) in Korea. MethodsData from 1999 to 2017 were obtained from the Korean Central Cancer Registry. Age-standardized incidence rates and average annual percentage changes (AAPCs) were calculated. Net survival (NS) was estimated by the Pohar-Perme method. ResultsAmong 5812 patients diagnosed with having TETs, 58.9%, 38.1%, and 3.0% were diagnosed with having thymoma, thymic carcinoma, and thymic neuroendocrine tumor (NET), respectively. Age-standardized incidence rates were 0.50, 0.30, 0.18, and 0.02 per 100,000 for all TETs and the respective subtypes. There was an increase in incidence of all TETs (AAPC = 6.1%) and subtypes: thymoma (AAPC = 5.6%), thymic carcinoma (AAPC = 7.0%), and thymic NET (AAPC = 3.4%). Proportions of patients with thymoma, thymic carcinoma, and thymic NET were 58.9%, 38.1%, and 3.0%, respectively. For thymoma, the relative proportion of distant stage decreased (19.4% in 2005 to 8.8% in 2017) and low-grade WHO subtype (A, AB, B1) increased faster than high-grade WHO type (B2, B3) (AAPC = 19.8% versus 9.6%). For thymoma, the 5-year NS was 82.3%. This increased from 64.3% in 1999 to 2002 to 90.6% in 2013 to 2017. For thymic carcinoma, the 5-year NS was 46.2% and only slightly increased from 39.4% in 1999 to 2002 to 47.9% in 2013 to 2017. ConclusionsThis study indicates a high incidence of TET and its continuous increase in Korea. The proportion of thymic carcinoma was relatively higher than in the United States or Europe. Survival for thymoma improved during the study period, whereas this was not evident for thymic carcinoma or thymic NET.

Reduced Plasmacytoid Dendritic Cell Output Is Associated With High Risk in Low-grade Myelodysplastic Syndrome.

Reduced Plasmacytoid Dendritic Cell Output Is Associated With High Risk in Low-grade Myelodysplastic Syndrome.