Low-risk Subtypes Research Articles

Prognostic effects of clinical parameters, genetic abnormalities, and subtypes in primary gastric diffuse large B-cell lymphoma: a cohort analysis of 146 patients

This study included 146 primary gastric diffuse large B-cell lymphoma patients. Next-generation RNA sequencing and fluorescent in situ hybridization were performed on tumors from 27 and 38 patients, respectively. Five-year and 10-year overall survival (OS) rates were 77% and 57%, respectively. Lugano and TNM clinical stage were independent survival factors. Tier I mutation was found in 21 patients. The genetic subtypes were A53 (n = 3), MCD (n = 5), BN2 (n = 5), N1 (n = 5), EZB (n = 1), and NOS (n = 8). OS was significantly shorter in high-risk genetic subtypes (A53, MCD, and N1) than low-risk subtypes (BN2, EZB, and NOS). Frequencies of high-risk genetic subtypes were higher in patients with Lugano stage II/IV and TNM clinical stage III + IV than in those with Lugano stage I and TNM clinical stage I + II. Although genetic testing was performed in only a small number of cases, the results suggested that high-risk genetic subtypes were associated with advanced clinical stages and shorter survival.

The Prognostic Role of Cuproptosis in Head and Neck Squamous Cell Carcinoma Patients: A Comprehensive Analysis.

Purpose Head and neck squamous cell carcinoma (HNSCC) exhibits a high mortality and morbidity rate, and its treatment is facing clinical challenges. Cuproptosis, a copper-dependent cell death process, can help derive new forms of cancer therapies. However, the potential of cuproptosis-related genes (CRGs) as novel biomarkers for risk prediction, screening, and prognosis remains to be further explained in HNSCC. Methods We built a prognostic multigene signature with CRGs, which is associated with the tumor immune microenvironment (TME) by gene set enrichment analysis (GSEA), in the TCGA cohort. Furthermore, we systematically correlated risk signature with immunological characteristics in TME including tumor-infiltrating immune cells (TIICs), immune checkpoints, T cell inflamed score, and cancer immunity cycles. We also thoroughly investigated the biological functions of cuproptosis-associated lncRNAs and its immunological characteristics. Results CRGs-related prognostic model showed good prediction performance. A higher risk score was associated with a poorer overall survival (OS) than those with low-risk scores, according to the results of the survival analysis (p < 0.0001). The risk score was significantly related to the variable clinicopathological factors. Samples with high-risk scores had lower levels of CD8+ T cells infiltration. Immune therapy might be effective for the low-risk subtype of HNSCC patients (p < 0.05). Moreover, 11 differentially expressed lncRNAs as the independent prognostic factor could also predict TME in an accurate manner. Conclusion Our study identified and validated novel cuproptosis-related biomarkers for HNSCC prognosis and screening, which offer better insights into developing accurate, reliable, and novel cancer therapies in the era of precision medicine.

Nodular and Micronodular Basal Cell Carcinoma Subtypes Are Different Tumors Based on Their Morphological Architecture and Their Interaction with the Surrounding Stroma.

Basal cell carcinoma (BCC) is the most frequent cancer of the skin and comprises low-risk and high-risk subtypes. We selected a low-risk subtype, namely, nodular (N), and a high-risk subtype, namely, micronodular (MN), with the aim to identify differences between them using a classical morphometric approach through a gray-level co-occurrence matrix and histogram analysis, as well as an approach based on deep learning semantic segmentation. From whole-slide images, pathologists selected 216 N and 201 MN BCC images. The two groups were then manually segmented and compared based on four morphological areas: center of the BCC islands (tumor, T), peripheral palisading of the BCC islands (touching tumor, TT), peritumoral cleft (PC) and surrounding stroma (S). We found that the TT pattern varied the least, while the PC pattern varied the most between the two subtypes. The combination of two distinct analysis approaches yielded fresh insights into the characterization of BCC, and thus, we were able to describe two different morphological patterns for the T component of the two subtypes.

Abstract 5128: Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment

Abstract Accurate risk stratification for patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) is crucial for treatment decisions and prognosis. Here, we introduce a circRNA-based classifier that could improve the prognostic stratification of LA-NPC patients. The circRNAs are identified by microarray profiling, followed by qRT-PCR validation and selection using a machine learning method in the training cohort (n = 170). Based on the proposed classifier, two prognostic-distinctive NPC subtypes are identified, namely the high-risk subtype (subtype H) and low-risk subtype (subtype L), which have significantly different disease-free survival (HR 2.99, 95% CI 1.58-5.67, P &amp;lt; 0.001). Validation in the internal cohort (n = 170) and external cohort (n = 150) yield similar results and the circRNA-based classifier is an independent risk factor of posttreatment relapse. Meanwhile, multiple interdependent features of different subtypes are observed, including relatively higher immune cell infiltration and immune-related pathways activation in subtype L; and predominant stromal, immunosuppressive and tumor-promoting components with moderate immune activation in subtype H. With a less aggressive and more immune-active tumor microenvironment, patients of subtype L could benefit from the addition of induction chemotherapy. In contrast, patients of subtype H, who are vulnerable to chemoresistance, display a strong tendency to benefit from additional immunotherapy. Overall, we define two NPC prognostic subtypes based on a circRNA classifier across multiple cohorts, which exhibit distinct biological ecosystems and suggest opportunities for the personalization of therapeutic regimens. Citation Format: Yelin Liang, Yuheng Zhao, Qian Li, Wei Jiang, Jun Ma, Na Liu, Yingqin Li. Identification and characterization of nasopharyngeal carcinoma prognostic subtypes based on a circRNA classifier: Implications of stratified treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5128.

A novel molecular subtype of hepatocellular carcinoma based on the tumor purity and tumor microenvironment-related polygenic risk scores.

e15040 Background: The molecular classification of hepatocellular carcinoma (HCC) plays a vital role in the management of precision therapy. Several molecular classification systems, mainly focusing on the tumor cells, were developed according to distinct omics features of HCC. Heterogeneous tumor microenvironment (TME) in HCC is recognized as a crucial part of inter-tumor heterogeneity. Few molecular classifications of HCC have so far taken into account both the related molecules of tumor cells and TME. Methods: Wefirstly identified the tumor purity (TP)-related and TME-related genes in the differentially expressed genes in HCC using GSE14520 data set, and separately constructed the TP-related and TME-related polygenic risk score (PRS). Secondly, according to the TP-related and TME-related PRSs, we proposed the TP-TME risk classification which was validated in two external data sets from The Cancer Genome Atlas Program and International Cancer Genome Consortium database. We also performed functional enrichment and drug repositioning analysis to reveal the potential biological heterogeneity among different subtypes. Results: The three TP-TME risk subtypes of HCC had significantly different prognosis and biological characteristics. The TP-TME low risk subtype had the best prognosis and was characterized by well-differentiated, the TP-TME high risk subtype had the worst prognosis and was characterized by aberrant activation of TGFβ and WNT pathways, and the TP-TME high risk subtype had the moderate prognosis and was characterized by exhibited activated MYC targets and proliferation-related gene sets. We also found that these three TP-TME risk subtypes may respond differently to immunotherapy (e.g., immune checkpoint inhibitors and chimeric antigen receptor-modified T cells) or other drug therapies. Conclusions: By combining separately constructed TP-related PRS and TME-related PRS, we proposed and validated a novel molecular classification system, the TP-TME risk subtyping system, to divide patients with HCC into three subtypes with distinct biological characteristics and prognosis. These findings highlight the significant clinical implications of the TP-TME risk subtyping system and provide potential personalized immunotherapy strategies for patients with HCC.

The Aging-Related Prognostic Signature Reveals the Landscape of the Tumor Immune Microenvironment in Head and Neck Squamous Cell Carcinoma.

BackgroundNumerous studies have shown that the aging microenvironment played a huge impact on tumor progression. However, the clinical prognostic value of aging-related risk signatures and their effects on the tumor immune microenvironment (TIME) in head and neck squamous cell carcinoma (HNSCC) remains largely unclear. This study aimed to identify novel prognostic signatures based on aging-related genes (AGs) and reveal the landscape of the TIME in HNSCC.MethodsDifferentially expressed AGs were identified using the gene set enrichment analysis (GSEA). The prognostic risk model of AGs was established by univariate and multivariate Cox regression and least absolute shrinkage and selection operator (LASSO) regression analyses. The independent prognostic value of the risk model and the correlations of the prognostic signature with immune score, tumor immune cell infiltration, and immune checkpoints were systematically analyzed.ResultsA prognostic risk model of four AGs (BAK1, DKK1, CDKN2A, and MIF) was constructed and validated in the training and testing datasets. Kaplan–Meier curves and time-dependent receiver operating characteristic (ROC) curve analysis confirmed that the four-AG risk signature possessed an accurate predictive value for the prognosis of patients with HNSCC. Correlation analysis revealed that the risk score was negatively associated with immune score and immune cell infiltration level while positively correlated with immune checkpoint blockade (ICB) response score. Patients of the high-risk subtype contained higher infiltration levels of resting natural killer (NK) cells, M0 macrophages, M2 macrophages, and resting mast cells while having lower infiltration levels of memory B cells, CD8+ T cells, follicular helper T cells, regulatory T cells (Tregs), and activated mast cells than did those of the low-risk subtype. The expressions of CTLA4, PDCD1, and TIGIT were downregulated while the PDCD1LG2 expression was upregulated in the high-risk subtype compared to those in the low-risk subtype. Furthermore, the four selected AGs in the risk model were demonstrated to possess important functions in immune cell infiltration and ICB response of HNSCC.ConclusionsThe aging-related risk signature is a reliable prognostic model for predicting the survival of HNSCC patients and provides potential targets for improving outcomes of immunotherapy.

Profile of p53 Protein Expression in Basal Cell Carcinoma Low-Risk and High-Risk Subtype

Background: Basal cell carcinoma is one of the most common cancers in the world, and its incidence is increasing over time. It is estimated that it accounts for three-quarters of all non-melanoma skin cancers, and the incidence increases exponentially in predominantly white areas. The p53 gene is the gene that most undergoes mutations due to sun exposure and is the cause of skin cancer, especially basal cell carcinoma. This finding explains that p53 expression can be used as marker analysis in cases of basal cell carcinoma.&#x0D; Methods: Observational analytic design was carried out with a cross-sectional. The population and samples were paraffin blocks which histopathologically diagnosed Basal Cell Carcinoma in the anatomical pathology laboratory, Dr. Kariadi General Hospital Semarang. Samples were processed by the p53 immunohistochemical staining method. The p53 expression was given a quantitative score to be 0 = negative, 1-2 = low, 3-4 = high. The expression of p53 was considered positive when it was colored in the cell nucleus. The correlation between variables was analyzed by Spearman and Mann Whitney correlation test.&#x0D; Results: There is no correlation between p53 expression and the age of p53 patients with p = 0.390 (p &gt; 0.05). There is no correlation between p53 expression and lesion location with p = 0.817 (p &gt; 0.05) There is no difference significant, between p53 expression and gender with p = 0.576 (p &gt; 0.05).&#x0D; Conclusion: There is no correlation between high and low-risk Basal Cell Carcinoma subtype associated with age, gender, and lesion location.

Variation in Molecularly Defined Prostate Tumor Subtypes by Self-identified Race

BackgroundSocioeconomic and health care utilization factors are major drivers of prostate cancer (PC) mortality disparities in the USA; however, tumor molecular heterogeneity may also contribute to the higher mortality among Black men. ObjectiveTo compare differences in PC subtype frequency and genomic aggressiveness by self-identified race. Design, setting, and participantsFive molecular subtype classifiers were applied for 426 Black and 762 White PC patients in the Decipher Genomics Resource Information Database (GRID). Outcome measurements and statistical analysisDifferences in subtype frequency and tumor genomic risk (Decipher score >0.6) by race were evaluated using χ2 tests and multivariable-adjusted logistic regression models. Results and limitationsSubtype frequencies differed by race for four classifiers. Subtypes characterized by the presence of SPOP mutations, SPINK1 overexpression, and neuroendocrine differentiation were more common among Black men. ERG and ETS fusion-positive subtypes were more frequent among White men, with no clear differences for subtypes reflecting luminal versus basal lineage. The hypothesized low-risk Kamoun S2 subtype was associated with a lower Decipher score among White men only (p = 0.01 for heterogeneity), while the aggressive You PCS1 subtype was associated with a higher Decipher score among White men only (p = 0.001 for heterogeneity). The Tomlins ERG+ subtype was associated with a higher Decipher score relative to all other subtypes among Black men, with no association among White men (p = 0.007 for heterogeneity). ConclusionsThe frequency of PC molecular subtypes differed by self-identified race. Additional studies are required to evaluate whether our observations suggest differences in the tumor genomic risk of progression by self-identified race. Patient summaryWe studied five classifiers that identify subtypes of prostate tumors and found that subtypes differed in frequency between Black and White patients. Further research is warranted to evaluate how differences in tumor subtypes may contribute to disparities in prostate cancer mortality.

Reclassifying the International Association for the Study of Lung Cancer Residual Tumor Classification According to the Extent of Nodal Dissection for NSCLC: One Size Does Not Fit All

IntroductionThe extent of nodal assessment may require risk-based adjustments in NSCLC. We reclassified the International Association for the Study of Lung Cancer Residual tumor classification according to the extent of nodal dissection and evaluated its long-term prognosis by tumor stage and histologic subtype. MethodsWe reclassified 5117 patients who underwent resection for clinical stages I to III NSCLC and had complete or uncertain resection by International Association for the Study of Lung Cancer classification into the following 3 groups according to compliance with three components (N1, N2, and subcarinal node) of systematic nodal dissection criteria: fully compliant group (FCG), partially compliant group (PCG), and noncompliant group (NCG). Recurrence-free survival (RFS) and overall survival (OS) were compared. ResultsOf the 5117 patients, 2806 (55%), 1959 (38%), and 359 (7%) were FCG, PCG, and NCG, respectively. PCG and NCG were more likely to be of lower clinical stage and adenocarcinoma with lepidic component than FCG. The 5-year RFS and OS were significantly better in NCG than in FCG or PCG (RFS, 86% versus 70% or 74%, p < 0.001; OS, 90% versus 80% or 83%, p < 0.001). In particular, NCG had better RFS and OS than FCG or PCG in clinical stage I and in lepidic-type adenocarcinoma. ConclusionsIn early stage NSCLC with low-risk histologic subtype, a less rigorous nodal assessment was not associated with a worse prognosis. Although surgeons should continue to aim for complete resection and thorough nodal assessment, a uniform approach to the extent and invasiveness of nodal assessment may need to be reconsidered.

Computed Tomography Imaging-Based Radiogenomics Analysis Reveals Hypoxia Patterns and Immunological Characteristics in Ovarian Cancer.

PurposeThe hypoxic microenvironment is involved in the tumorigenesis of ovarian cancer (OC). Therefore, we aim to develop a non-invasive radiogenomics approach to identify a hypoxia pattern with potential application in patient prognostication.MethodsSpecific hypoxia-related genes (sHRGs) were identified based on RNA-seq of OC cell lines cultured with different oxygen conditions. Meanwhile, multiple hypoxia-related subtypes were identified by unsupervised consensus analysis and LASSO–Cox regression analysis. Subsequently, diversified bioinformatics algorithms were used to explore the immune microenvironment, prognosis, biological pathway alteration, and drug sensitivity among different subtypes. Finally, optimal radiogenomics biomarkers for predicting the risk status of patients were developed by machine learning algorithms.ResultsOne hundred forty sHRGs and three types of hypoxia-related subtypes were identified. Among them, hypoxia-cluster-B, gene-cluster-B, and high-risk subtypes had poor survival outcomes. The subtypes were closely related to each other, and hypoxia-cluster-B and gene-cluster-B had higher hypoxia risk scores. Notably, the low-risk subtype had an active immune microenvironment and may benefit from immunotherapy. Finally, a four-feature radiogenomics model was constructed to reveal hypoxia risk status, and the model achieved area under the curve (AUC) values of 0.900 and 0.703 for the training and testing cohorts, respectively.ConclusionAs a non-invasive approach, computed tomography-based radiogenomics biomarkers may enable the pretreatment prediction of the hypoxia pattern, prognosis, therapeutic effect, and immune microenvironment in patients with OC.

Abstract PD2-04: Molecular plasticity of luminal breast cancer and response to CDK 4/6 inhibition - The biomarker program of the PENELOPE-B trial investigating post-neoadjuvant palbociclib

Abstract Background: Molecular plasticity of breast cancer is crucial for the development of therapy-resistant disease. In this investigation, we studied changes in molecular signatures between pretherapeutic (pre-Tx) and post-therapeutic (post-NACT) tumor samples from patients included in the PENELOPE-B (NCT01864746) trial. The phase III PENELOPE-B study did not show a significant benefit from palbociclib in women with centrally confirmed HR+, HER2- primary breast cancer without a pathological complete response after taxane-containing neoadjuvant chemotherapy (NACT) and at high-risk of relapse (CPS-EG score ≥3 or 2 and ypN+) (Loibl et al. JCO 2021). However, first translational investigations showed that a small number of patients with a luminal-B tumor subtype, based on absolute intrinsic molecular subtyping (AIMS, Paquet &amp; Hallet, JNCI 2014) subtyping after NACT, had a numerical benefit from post-NACT palbociclib. We have therefore extended the analysis and included a cohort of paired pre-Tx and post-NACT samples. Methods: We investigated gene expression in pre-Tx (n=259) tumor tissue samples using the HTG EdgeSeq Oncology Biomarker Panel including 2549 genes (HTG Molecular Diagnostics Inc.); for the same patients the same panel on post-NACT residual tumor samples were available. The paired samples were selected based on a case-cohort approach. Based on 91 genes of this panel, the AIMS subtype was calculated. In addition, we performed exploratory biomarker analyses to identify genes and gene signatures with prognostic and predictive relevance. After completion of NACT, PENELOPE-B patients were randomized to palbociclib versus placebo in addition to standard endocrine therapy. Results: The prevalence of AIMS subtypes, in particular LumA vs LumB, changed in pre-Tx and post-NACT tumors. In the pre-Tx samples, 115 (44%) and 123 (47%) of tumors had LumA and LumB subtypes, respectively, as expected from a high-risk cohort. However, in the post-NACT samples, LumA tumors were predominant (n=183, 71%) over LumB (n=30; 12%). 78 (30%) and 6 (2%) tumors switched their subtype from LumB to LumA and LumA to LumB, respectively. For further analyses, we compared the groups of low proliferating (LumA and NormL) and high proliferating subtypes (LumB, BasalL and HER2E). In bivariable Cox regression analysis, the grouped pre-Tx and post-NACT AIMS subtypes were independent prognostic factors for iDFS: HR=1.85 (1.16-2.98, p=0.011) for pre-Tx LumB/BasalL/HER2E vs LumA/NormL and HR=2.18 (1.24-3.84, p=0.007) for post-NACT. Similar results were found when adjusted for prognostic clinical factors and for DDFS and OS endpoints although the pre-Tx subtype did not reach significance. These and further Cox models investigating interaction effects show that patients with tumors developing from high (pre-Tx) to low proliferation (post-NACT) had a higher iDFS risk compared to stable low proliferating tumors but a lower iDFS risk compared to stable high proliferating tumors. Neither in the pre-Tx LumB/BasalL/HER2E nor in the pre-Tx LumA/NormL subgroup a benefit from palbociclib was observed. Based on the results of the AIMS subtyping, we extended the exploratory analysis to identify genes that might be involved in the prognostic and predictive effects as well as genes driving the subtype switch. The analysis is ongoing and the relevant genes will be presented at the conference. Conclusions: Our findings show that the switch from high-risk molecular subtypes (in particular LumB) to low-risk subtypes (in particular LumA) is common in neoadjuvant therapy of luminal tumors. The adaptation of luminal high-risk tumors to therapy-induced stress is crucial for the clinical outcome and the results suggest that molecular defined tumor subtypes might not be as stable as originally thought. Citation Format: Carsten Denkert, Frederik Marmé, Miguel Martin, Michael Untch, Hervé Bonnefoi, Sung-Bae Kim, Harry Bear, Agnieszka Witkiewicz, Seock-Ah Im, Angela DeMichele, Laura Van’t Veer, Nicole McCarthy, Thorsten Stiewe, Karen A. Gelmon, José A. García-Sáenz, Catherine M. Kelly, Toralf Reimer, Erik Knudsen, Nicholas Turner, Federico Rojo, Peter A. Fasching, Julia Teply-Szymanski, Yuan Liu, Masakazu Toi, Hope S. Rugo, Michael Gnant, Andreas Makris, Bärbel Felder, Karsten Weber, Sibylle Loibl. Molecular plasticity of luminal breast cancer and response to CDK 4/6 inhibition - The biomarker program of the PENELOPE-B trial investigating post-neoadjuvant palbociclib [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD2-04.

Clinicopathologic Analysis of Sinonasal Inverted Papilloma, with Focus on Human Papillomavirus Infection Status.

Sinonasal inverted papilloma (SNIP) can recur; however, the factors related to tumor recurrence remain unclear. This study aimed to analyze risk factors, including human papillomavirus (HPV) infection, as well as other factors associated with SNIP recurrence. Thirty-two patients who were diagnosed with SNIP and underwent surgery between 2010 and 2019 were enrolled: 24 men and 8 women, with a mean age of 59.2 years. The mean follow-up was 57.3 months. Demographics and information about history of smoking, diabetes mellitus (DM), hypertension, allergic rhinitis, alcohol consumption, tumor stage, surgical approach, and recurrence were reviewed retrospectively. Specimens were investigated using polymerase chain reaction to detect HPV DNA (high-risk subtypes: 16, 18, 31, 33, 35, 52b, and 58; low-risk subtypes: 6 and 11). Seven patients (21.9%) experienced recurrence. HPV DNA was detected in five (15.6%) patients (high-risk subtypes, n = 2; low-risk subtypes, n = 3). Patients with recurrence of SNIP had a higher proportion of young adults and displayed higher rates of HPV infection, DM, and advanced tumor stage than those without recurrence. HPV infection, young adulthood, DM, and advanced tumor stage could be associated with a high recurrence rate, which suggests that patients with these risk factors could require close follow-up after surgery.

Human papillomavirus E6E7 mRNA and TERC lncRNA in situ detection in cervical scraped cells and cervical disease progression assessment

BackgroundHuman papillomavirus screen in female cervical cells has demonstrated values in clinical diagnosis of precancerous lesions and cervical cancers. Human papillomavirus tests of cervical cells by utilizing Polymerase Chain Reaction (PCR) method provides human papillomavirus infection status however no further virus in situ information. Although it is well known that the tests of human papillomavirus E6/E7 RNA location in infected cervical cells and cell internal malignancy molecular will provide clues for gynecologists to evaluate disease progression, there are technique difficulties to preserve RNAs in cervical scraped cells for in situ hybridization.MethodsIn current study, after developing a cervical cell collection and preparation method for RNA in situ hybridization, we captured the chance to screen 98 patient cervical cell samples and detected human papillomavirus E6/E7 mRNAs of high-risk subtypes, low-risk subtypes and long non-coding RNA (lncRNA) TERC in the cells.ResultsThere were 69 samples exhibited consistence between human papillomavirus PCR and human papillomavirus RNA in situ hybridization results in cervical collected cells. Among them, 23 were both positive and 46 were both negative. In the rest 29 samples, 8 were HPV RNAscope positive, either high risk or low risk subtypes, however HPV PCR negative. Another 9 samples were HPV PCR results positive whereas RNAscope negative. The last 12 samples were HPV positive detected by both RNAscope and PCR methods, however inconsistent between high-risk and low-risk subtypes. In RNAscope positive samples, viral E6/E7 mRNAs were observed to distribute in cervical scraped cell nucleus and cytoplasm. Moreover, HPV viral RNA gathered clusters were observed outside of cells through human papillomavirus RNA in situ hybridization detection. Varied numbers of human papillomavirus infective cells were detected by RNAscope assay in different patients even though they were all human papillomavirus high-risk subtype positive discovered by human papillomavirus PCR results. A cell malignancy related long non-coding RNA, TERC, has been detected in seven patient samples. The patient follow-up information was further analyzed with RNAscope results which indicated a combination of RNAscope positive signals of TERC and human papillomavirus high risk signals in more than 10 cells (cytoplasm or nucleus) may connect with cervical lesion fast progression which deserves further studies in the future.CConclusionsTaken together, current study has provided an observable clue for gynecologists to evaluate human papillomavirus infection stage and cell malignancy status which may contribute for assessment of cervical disease progression.

Identification and Characterization of a Glucometabolic Prognostic Gene Signature in Neuroblastoma based on N6-methyladenosine Eraser ALKBH5.

Background: Neuroblastoma (NB) is a pediatric cancer occurring in the peripheral nervous system. A demethylase, alkylation repair homolog protein 5 (ALKBH5), is one type of N6-methyladenosine (m6A) eraser that plays a tumor-suppressive role in a variety of cancers. The significance of carbohydrate metabolism in cancer has been intensively investigated over the years, but the correlation between ALKBH5 and glucose metabolism in NB remains to be elucidated.Methods: Based on the overlapped genes (DE-GRGs) of ALKBH5-related differentially expressed genes (ALKBH5-DEGs) in GSE62564 (n=498) and genes related to glucose metabolism (GRGs), a LASSO regression model was constructed. External validations with datasets (EGAS00001001308, n=139 & GSE16476, n=88) and the NB samples from Shanghai Children's Hospital (SCH) were performed. Meanwhile, biological and clinical utility, immune cell subtypes and drug sensitivity were assessed.Results: ALKBH5 was significantly correlated with better overall survival (OS) in NB patients, and gene set enrichment analysis (GSEA) showed its enrichment in GO/ KEGG terms regarding glucose metabolism. 27 of the 31 DE-GRGs were included in the LASSO screen after the univariate analysis. A prognostic glucometabolic model including AHCY, NCAN, FBP2, GALNT3 and AKR1C2 was established with the internal and external validation with biological experiments: the high-risk subtype compared to the low-risk subtype showed oncogenic and MYCN-related malignancy, glucometabolic dysregulation, poor prognosis and immunosuppression. TGX-221 was predicted to be a potential therapeutic drug and validated to suppress NB oncogenes including MYCN, AHCY and NCAN and immunosuppressive DNMT1 in NB cells.Conclusion: ALKBH5 was closely related to glucometabolic processes, and our prognostic model had high application value in predicting & assessing the OS of NB patients, and even served potential drug targets.

Position paper on a simplified histopathological classification of basal cell carcinoma: results of the European Consensus Project.

Histopathological classification of basal cell carcinoma (BCC) has important prognostic and therapeutic implications, but reproducibility of BCC subtyping among dermatopathologists is poor. To obtain a consensus paper on BCC classification and subtype definitions. A panel of 12 recognized dermatopathologists (G12) from nine European countries used a modified Delphi method and evaluated 100 BCC cases uploaded to a website. The strategy involved five steps: (I) agreement on definitions for WHO 2018 BCC subtypes; (II) classification of 100 BCCs using the agreed definitions; (III) discussion on the weak points of the WHO classification and proposal of a new classification with clinical insights; (IV) re-evaluation of the 100 BCCs using the new classification; and (V) external independent evaluation by 10 experienced dermatopathologists (G10). A simplified classification unifying infiltrating, sclerosing, and micronodular BCCs into a single "infiltrative BCC" subtype improved reproducibility and was practical from a clinical standpoint. Fleiss' κ values increased for all subtypes, and the level of agreement improved from fair to moderate for the nodular and the unified infiltrative BCC groups, respectively. The agreement for basosquamous cell carcinoma remained fair, but κ values increased from 0.276 to 0.342. The results were similar for the G10 group. Delphi consensus was not achieved for the concept of trichoblastic carcinoma. In histopathological reports of BCC displaying multiple subtypes, only the most aggressive subtype should be mentioned, except superficial BCC involving margins. The three BCC subtypes with infiltrative growth pattern, characteristically associated with higher risk of deep involvement (infiltrating, sclerosing, and micronodular), should be unified in a single group. The concise and encompassing term "infiltrative BCCs" can be used for these tumors. A binary classification of BCC into low-risk and high-risk subtypes on histopathological grounds alone is questionable; correlation with clinical factors is necessary to determine BCC risk and therapeutic approach.

Prognostic Nomograms Based on Ground Glass Opacity and Subtype of Lung Adenocarcinoma for Patients with Pathological Stage IA Lung Adenocarcinoma.

The value of lung adenocarcinoma (LUAD) subtypes and ground glass opacity (GGO) in pathological stage IA invasive adenocarcinoma (IAC) has been poorly understood, and reports of their association with each other have been limited. In the current study, we retrospectively reviewed 484 patients with pathological stage IA invasive adenocarcinoma (IAC) at Sun Yat-sen University Cancer Center from March 2011 to August 2018. Patients with at least 5% solid or micropapillary presence were categorized as high-risk subtypes. Independent indicators for disease-free survival (DFS) and overall survival (OS) were identified by multivariate Cox regression analysis. Based on these indicators, we developed prognostic nomograms of OS and DFS. The predictive performance of the two nomograms were assessed by calibration plots. A total of 412 patients were recognized as having the low-risk subtype, and 359 patients had a GGO. Patients with the low-risk subtype had a high rate of GGO nodules (p < 0.001). Multivariate Cox regression analysis showed that the high-risk subtype and GGO components were independent prognostic factors for OS (LUAD subtype: p = 0.002; HR 3.624; 95% CI 1.263–10.397; GGO component: p = 0.001; HR 3.186; 95% CI 1.155–8.792) and DFS (LUAD subtype: p = 0.001; HR 2.284; 95% CI 1.448–5.509; GGO component: p = 0.003; HR 1.877; 95% CI 1.013–3.476). The C-indices of the nomogram based on the LUAD subtype and GGO components to predict OS and DFS were 0.866 (95% CI 0.841–0.891) and 0.667 (95% CI 0.586–0.748), respectively. Therefore, the high-risk subtype and GGO components were potential prognostic biomarkers for patients with stage IA IAC, and prognostic models based on these indicators showed good predictive performance and satisfactory agreement between observational and predicted survival.

Accuracy Of the Gynecology Imaging Reporting And Data System Based Upon Ultrasound Evaluation Of Adnexal Lesions

Background: Globally as growing occurrence ratio of ovarian cancer as well as efficacy of Gynecologic-Imaging Reporting-and-Data-System GI-RADS to diagnose pathologies like ovaries cancer, we designed for evaluating the presentation of diagnosis of this system to differentiate among the adnexal benign and malignant lesions. For routine gynecologic examinations, pelvic ultrasound is generally used, consequential in analysis of adnexal lesions, main stream of which are benign or functional. Though, because of probable difficulties including benign adnexal cyst (i.e. pelvic pain and adnexal torsion) as well as ultimate significance of initial analysis as well as cure of ovarian cancer, precise ultrasound analysis of adnexal lesions is important in clinical run through Methods: We searched google scholar and pubmed form 2000 to December 2019. Selection criteria reporting on the accuracy of GI-R-A-D-S system in ultrasound. Results: In this study, we evaluated 197 women with suspected appendicitis. The proportions of GI-RADS II, III, IV and V were 34.5 (69 cases), 38.0 (76 cases), 19.5 (39 cases) and 6.5 (13 cases). For the high-risk and low-risk GI-RADS subtypes, 72.5% were classified as GI-RADS II and III, and 26 were classified as GI-RADS IV and V, respectively. Conclusive histopathologic analysis was testified for 158 cases. Histopathologic assessment designated that 12(7.6%) of were malignant masses as well as 146(92.6%) were benign. Associating by histopathologic analysis, the GIRADS system specificity, sensitivity, negative predictive value and positive predictive value, as well as negative LR were 91.6, 80.82, 28.2, 99.1, 4.77, and 0.10, correspondingly. The accurateness of the scoring system was 81.64%. Conclusion: This systemic review concluded that by Gynecologic-Imaging-Reporting-Data System, we could measure the possibility of malignant stage through such an organized along with modest recording system thus that system could be valuable in clinician to perform a suitable clinical organization Keywords: Adnexal Diseases, Ovarian Neoplasms, Ultrasonography.

The Prevalence of High- and Low-Risk Types of HPV in Patients with Squamous Cell Carcinoma of the Head and Neck, Patients with Chronic Tonsillitis, and Healthy Individuals Living in Poland.

Human papillomavirus (HPV) is a virus with the potential to infect human epithelial cells and an etiological agent of many types of cancer, including head and neck cancer. The aim of the study was to determine the prevalence of HPV infection in patients with head and neck squamous cell carcinoma (HNSCC), patients with chronic tonsillitis, and healthy individuals, and to establish high- and low-risk HPV genotypes in these groups. The objectives also comprised the delineation of the relationship between the infection with high- or low-risk HPV subtypes and clinicopathological and demographic characteristics of the study groups. This study was composed of 76 patients diagnosed with HNSCC, 71 patients with chronic tonsillitis, and 168 cases without either of these conditions (the control group). HPV detection and identification of subtypes were performed on isolated DNA using a test which allowed detection of 33 common high-risk and low-risk HPV subtypes. The prevalence of HPV infection was 42.1%, 25.4%, and 37.5% in HNSCC, chronic tonsillitis, and control groups, respectively. HPV 16 was the most prevalent genotype in all groups and the non-oncogenic HPV 43/44 was frequent in HNSCC patients. This analysis provides insight into the prevalence of oral oncogenic and non-oncogenic HPVs in patients with head and neck cancer, patients with chronic tonsillitis and healthy individuals, and leads to the conclusion that further investigations are warranted to examine a larger cohort of patients focusing on high- and low-risk HPV genotypes. Efforts should be focused on screening and prevention strategies, and therefore, it is important to introduce tools for effective detection of HPV genotypes. Furthermore, given the role of vaccines against oral HPV infection, our observations lead to the suggestion that HPV vaccination should be of considerable importance in public health strategies.

Integrative Analysis of Primary SF3B1 mt Ring Sideroblasts Provides Fundamental Insights into MDS-RS Pathogenesis and Dyserythropoiesis

Myelodysplastic syndromes (MDS) constitute a heterogeneous group of clonal hematopoietic stem cell (HSC) disorders characterized by aberrant HSC differentiation, cytopenia, and an increased risk of progression to leukemia. The low-risk subtype MDS with ring sideroblasts (MDS-RS) is specifically characterized by expanded and ineffective erythropoiesis, with more than 80% of patients displaying mutations in the core spliceosome component SF3B1 (SF3B1 mt).A hallmark of the MDS-RS bone marrow (BM) is the progressive accumulation of ring sideroblasts (RS), erythroblasts displaying perinuclear mitochondria loaded with aberrant ferritin-iron complexes. Whilst several in vitro and in vivo model systems exist for studying the impact of SF3B1 mt on erythropoiesis and RS development, primary SF3B1 mt erythroid biology remains largely unexplored due to the inability to purify live SF3B1 mt cells or fully replicate BM conditions in vitro.To address this issue, we developed an innovative two-step method to isolate live ring sideroblasts from SF3B1 mt MDS-RS BM aspiration material with extremely high purity (as determined through droplet digital PCR-based genotyping [Fig. 1A] and morphology-based detection through Prussian blue staining [Fig. 1B,C]). Unexpectedly, evaluation of matching peripheral blood samples showed that circulating ring sideroblasts are strikingly common in MDS-RS (Fig. 1D), with their abundance being significantly positively associated with clinically-determined BM RS frequencies and serum erythropoietin levels, as well as negatively associated with hemoglobin levels.Through high-throughput Chromium 3'-based single-cell RNA sequencing (scRNAseq) analysis of purified RS, we then showed that these cells comprise a heterogeneous population encompassing all stages of the erythroid differentiation continuum, from early progenitors to orthochromatic erythroblasts (Fig. 1E). The RS transcriptome was shown to be dynamically regulated towards the maintenance of cell survival during late terminal erythroid differentiation (exemplified through parkin 1 [PINK1] expression), with SF3B1 K700E erythroblasts employing multiple strategies to preserve homeostasis despite undergoing extreme oxidative stress. These observations were confirmed through a parallel whole-transcript RNAseq investigation comprising CD34 + and GPA +-enriched samples obtained from normal bone marrow (NBM) donors and SF3B1 K700E MDS-RS patients, as well as purified RS samples. This bulk RNAseq experiment validated the RS transcriptomic signature observed in scRNAseq (Fig. 1F) and allowed for a detailed investigation of RNA splicing. SF3B1 K700E-associated alternative splicing in CD34 + and RS was consistent with previous literature, but also highly context-dependent and with substantial changes in scope and magnitude throughout erythroid differentiation (Fig. 1G-I).Finally, we substantiated these RNAseq results through Tandem Mass Tag-based semi-quantitative proteomic analysis of purified RS and GPA-enriched cells from NBM donors and MDS-RS patients. We confirmed that ring sideroblast survival is heavily dependent on redox balance modulation and suppression of ER stress via an increased dependence on glutamine, mirroring the molecular mechanisms observed in malignancy. Additionally, our data strongly indicate that the RS population is a major modulator of the MDS-RS BM microenvironment due to expression of stress factors (with particular emphasis on GDF15, erythroferrone and IL-18). In conclusion, our integrative analysis of primary RS constitutes a unique platform for the study of MDS-RS, with special interest for the investigation of potential drivers of disease severity or treatment avenues. [Display omitted] DisclosuresKretzschmar: Vanadis Diagnostics, a PerkinElmer company.: Current Employment.

A Multi-Center Validated Subtyping Model of Esophageal Cancer Based on Three Metabolism-Related Genes.

Metabolic reprogramming is a hallmark of malignancy. Understanding the characteristics of metabolic reprogramming in esophageal squamous cell carcinoma (ESCC) helps uncover novel targets for cancer progression. In this study, 880 metabolism-related genes were identified from microarray data and then filtered to divide patients into two subgroups using consensus clustering, which exhibits significantly different overall survival. After a differential analysis between two subtypes, 3 genes were screened out to construct a two subtypes decision model on the training cohort (GSE53624), defined as high-risk and low-risk subtypes. These risk models were then verified in two public databases (GSE53622 and TCGA-ESCC), an independent cohort of 49 ESCC patients by RT-qPCR and an external cohort of 95 ESCC patients by immunohistochemistry analysis (IHC). Furthermore, the immune cell infiltration of regulatory T cells (Tregs) and plasma cells showed a significant difference between the high and low-risk subtypes in the IHC experiment with 119 ESCC patients. In conclusion, our study indicated that three metabolism-related prognostic genes could stratify patients into subgroups and were associated with immune infiltration, clinical features and clinical outcomes.