Unfavorable Prognostic Indicator Research Articles

BCAR3 and BCAR3-related competing endogenous RNA expression in hepatocellular carcinoma and their prognostic value.

Hepatocellular carcinoma (HCC) is a malignant tumor that has a high incidence and mortality worldwide. Despite extensive studies, the detailed molecular mechanism of HCC development remains unclear. Studies have shown that the occurrence and development of HCC are closely related to abnormal gene expression. BCAR3 has been shown to be overexpressed in a variety of malignant tumors. However, the role of BCAR3 in HCC remains unclear. To investigate the expression of BCAR3 and BCAR3-related competing endogenous RNAs (ceRNAs) in HCC and their clinical significance, in order to provide new ideas for the diagnosis and treatment of HCC. The data of HCC were obtained from the Cancer Genome Atlas database and The Genotype Tissue Expression, including transcriptome data and clinical information. Multiple common databases, including UALCAN, Timer 2.0, cBioPortal, LinkedOmics, starBase, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes, were used to analyse the expression of BCAR3, prognostic value, genetic alteration, co-expressed genes, differentially expressed genes, BCAR3 gene-related ceRNAs and functional enrichment analysis in HCC patients. Kaplan-Meier analysis, univariate and multivariate Cox regression analysis were used to analyze survival prognosis and the Spearman test was used to measure correlations between BCAR3 and immune functions. And R language package was used to analyze the correlation between BCAR3 and immune invasion of HCC. Our study indicated that BCAR3 was differentially expressed in various tumor tissues. The over-expression of BCAR3 gene was an unfavorable prognostic indicator for HCC patients, and associated with unfavorable cytogenetic risk and gene mutations. Moreover, most immune cells were positively correlated with BCAR3 (P < 0.05). According to the results of functional enrichment analysis, BCAR3 was involved in the positive regulation of epidermal growth factor receptor signaling pathway and ERBB signaling pathway, and was related to DNA replication and GTPase regulator activity. Finally, our study found that based on RAB30-DT and miR-19b-3p pathways, targeting BCAR3 might promote the occurrence and development of HCC. Collectively, this study indicated that the BCAR3 gene was involved in the occurrence and development of HCC, and it might be a new biomarker and therapeutic target for HCC, but the specific mechanism remains to be further verified.

Sesamolin serves as an MYH14 inhibitor to sensitize endometrial cancer to chemotherapy and endocrine therapy via suppressing MYH9/GSK3β/β-catenin signaling

BackgroundEndometrial cancer (EC) is one of the most common gynecological cancers. Herein, we aimed to define the role of specific myosin family members in EC because this protein family is involved in the progression of various cancers.MethodsBioinformatics analyses were performed to reveal EC patients’ prognosis-associated genes in patients with EC. Furthermore, colony formation, immunofluorescence, cell counting kit 8, wound healing, and transwell assays as well as coimmunoprecipitation, cycloheximide chase, luciferase reporter, and cellular thermal shift assays were performed to functionally and mechanistically analyze human EC samples, cell lines, and a mouse model, respectively.ResultsMachine learning techniques identified MYH14, a member of the myosin family, as the prognosis-associated gene in patients with EC. Furthermore, bioinformatics analyses based on public databases showed that MYH14 was associated with EC chemoresistance. Moreover, immunohistochemistry validated MYH14 upregulation in EC cases compared with that in normal controls and confirmed that MYH14 was an independent and unfavorable prognostic indicator of EC. MYH14 impaired cell sensitivity to carboplatin, paclitaxel, and progesterone, and increased cell proliferation and metastasis in EC. The mechanistic study showed that MYH14 interacted with MYH9 and impaired GSK3β-mediated β-catenin ubiquitination and degradation, thus facilitating the Wnt/β-catenin signaling pathway and epithelial–mesenchymal transition. Sesamolin, a natural compound extracted from Sesamum indicum (L.), directly targeted MYH14 and attenuated EC progression. Additionally, the compound disrupted the interplay between MYH14 and MYH9 and repressed MYH9-regulated Wnt/β-catenin signaling. The in vivo study further verified sesamolin as a therapeutic drug without side effects.ConclusionsHerein, we identified that EC prognosis-associated MYH14 was independently responsible for poor overall survival time of patients, and it augmented EC progression by activating Wnt/β-catenin signaling. Targeting MYH14 by sesamolin, a cytotoxicity-based approach, can be applied synergistically with chemotherapy and endocrine therapy to eventually mitigate EC development. This study emphasizes MYH14 as a potential target and sesamolin as a valuable natural drug for EC therapy.Graphical

P4HA2 involved in SLUG-associated EMT predicts poor prognosis of patients with KRAS-positive colorectal cancer.

This study aimed to examine the immunohistochemical expression of epithelial-mesenchymal transition biomarkers: P4HA2 and SLUG in colorectal carcinoma (CRC) specimens, then to assess their relation to clinicopathological features including KRAS mutations and patients' survival, and finally to study the correlation between them in CRC. The result of this study showed that SLUG and P4HA2 were significantly higher in association with adverse prognostic factors: presence of lympho-vascular invasion, perineural invasion, higher tumor budding, tumor stage, presence of lymph node metastasis, and presence of distant metastasis. CRC specimens with KRAS mutation were associated with significant higher SLUG and P4HA2 expression. High expression of both SLUG and P4HA2 was significantly unfavorable prognostic indicator as regards overall survival (OS) and disease-free survival (DFS). In KRAS mutated cases, high P4HA2 expression was the only significant poor prognostic indicator as regarding DFS. In conclusions, our data highlight that both SLUG and P4HA2 expression may serve as potentially important poor prognostic biomarkers in CRC and targeting these molecules may be providing a novel therapeutic strategy. In KRAS mutation group, high P4HA2 expression is the only independent prognostic factor for tumor recurrence, so it can be suggested to be a novel target for therapy.

Angiographic demonstration of a cutoff sign as an unfavorable prognostic indicator for patients with acute ischemic stroke undergoing mechanical thrombectomy

ObjectivesThe aim was to investigate whether the angiographic demonstration of a cutoff sign on the initial angiogram could predict recanalization and prognosis in acute ischemic stroke patients treated by endovascular thrombectomy. MethodsThe angiographic and clinical data of patients who underwent endovascular treatment from October 2018 to April 2023 were retrospectively reviewed. The pretreatment angiographic appearance of the thrombus's proximal part was assessed and classified as either the cutoff sign (+) or (-). Patients’ baseline characteristics and angiographic and clinical outcomes between the two groups were analyzed using propensity score matching. Then, the two commonly used techniques, stent retrieval and contact aspiration, were compared in terms of successful reperfusion and clinical outcome in patients with the cutoff sign. ResultsThe cutoff sign was observed in 77 (36.2%) of 213 patients. Patients with the cutoff sign were younger and were less likely to have involvement of the anterior circulation. Compared with the cutoff sign (-) group, the cutoff sign (+) group had a significantly longer procedure time (103 versus 80 min, P =0.002) and a lower percentage of 3-month good functional outcomes (18.2% versus 36%, P =0.006). After propensity score matching, the procedure time (100 versus 75 min, P =0.002) and the 3-month good outcome (19.2% versus 41.4%, P =0.004) remained significantly different. No significant differences were observed in the radiological (OR 0.758, 95% CI 0.157 to 3.658; P =0.730) and clinical (OR 0.747, 95% CI 0.147 to 3.787; P =0.725) outcomes between the two techniques. ConclusionsThe cutoff sign might be an unfavorable prognostic indicator in patients undergoing mechanical thrombectomy, and the efficacy of mechanical thrombectomy techniques does not differ in patients positive for the cutoff sign.

Identification of SPP1 as a Prognostic Biomarker and Immune Cells Modulator in Urothelial Bladder Cancer: A Bioinformatics Analysis

Secreted phosphoprotein-1 (SPP1) expression is differentially altered in many malignancies and could serve as a potential prognostic biomarker. Recent findings indicated that SPP1 possesses a broader role in bladder cancer (BC) pathogenesis than previously envisioned; however, the underlying mechanisms governing its expression, cellular localization, prognostic value and immune-related role in bladder cancer remain poorly understood. The expression and the prognosis value of SPP1 were assessed using immunohistochemistry (IHC) staining on a tissue microarray. SPP1 expression was correlated with the clinicopathological parameters, and survival analysis was calculated using a Kaplan–Meier plotter. Bioinformatics analysis of TCGA data was queried using UALCAN, CIBERSORT and TIMER datasets to decipher the biological processes enrichment pattern, protein–protein interactions and characterize tumor-infiltrating immune cells, respectively. IHC revealed that SPP1 expression is significantly associated with tumor type, stage, grade and smoking status. The Kaplan–Meier survival curve showed that low SPP1 expression is an unfavorable prognostic indicator in bladder cancer patients (p = 0.02, log-rank). The significant increased expression of the SPP1 level is associated with evident hypomethylation of the gene promoter in cancer compared to normal tissues in the TCGA-bladder dataset. Missense mutation is the most frequent genetic alteration of the SPP1 gene. Protein–protein interactions demonstrated that SPP1 shares the same network with many important genes and is involved in many signaling pathways and biological processes. TIMER reported a significant correlation between SPP1 expression and multiple immune cells infiltration. Furthermore, the expression of SPP1 was found to be positively correlated with a number of immune checkpoint genes such as PD-1 and CTLA4. The current investigation indicates that the SPP1 protein could serve as a prognostic biomarker and merit further investigation to validate its clinical usefulness in patients with bladder cancer.

Clinical Utility of Spectral-Domain Optical Coherence Tomography Marker Disorganization of Retinal Inner Layers in Diabetic Retinopathy.

Disorganization of retinal inner layers (DRIL) is a potential spectral-domain optical coherence tomography (SD-OCT) imaging biomarker with clinical utility in diabetic retinopathy (DR). A cross-sectional study was conducted at a large academic center. The cohort was composed of 1,175 patients with type 2 diabetes with and without retinopathy on initial examination between September 2009 and January 2019 (n = 2,083 eyes). DR risk and progression factors were obtained from the medical record. Trained graders masked to patients' clinical histories evaluated SD-OCT scans for DRIL. Of 2,083 eyes, 28.1% (n = 585) demonstrated presence of DRIL with high interrater reliability (K = 0.88, 95% CI 0.86-0.90). DRIL was associated with worse visual acuity (VA) (P < 0.001) and DR severity (P < 0.0001). Insulin users had more severe DR (P < 0.0001). DR-related factors, race (Black, White) and sex (male) were significantly associated with DRIL (P < 0.05). DRIL was strongly associated with DR severity and worse VA, supporting its utility as an unfavorable prognostic indicator. [Ophthalmic Surg Lasers Imaging Retina 2023;54:692-700.].

Her-2 promoting tumor progression and cisplatin resistance as a novel therapeutic target in penile squamous cell carcinoma.

67 Background: Cisplatin-based chemotherapy has been the first choice for advanced penile squamous cell carcinoma (PSCC) in the last decade, but remains challenging owing the unsatisfied response rates, frustrating systemic toxicity and chemoresistance leading to poor prognosis. There is no standard second-line therapy for advanced PSCC. Antibody-drug conjugates (ADC) were novel targeted and low-toxicity agents, of which Her-2 targeted ADCs widely used and have greatly improved clinical outcomes in breast, gastric and bladder cancers. We aimed to explore the expression pattern, clinical significance, oncogenic roles of Her-2 and the therapeutic potentiality of Her-2 target ADCs in PSCC. Methods: The immunohistochemical expression of Her-2 was detected in the largest single center cohort of 367 PSCC patients up to date. PSCC cell lines, cisplatin-resistant cell lines and animal models were established to investigated the biological roles of Her-2 in PSCC progression and cisplatin chemoresistance. Disitamab vedotin (RC48), an Her-2 targeted ADC drug, was used to evaluate the efficiency in PSCC. Results: Her-2 was an unfavourable prognostic indicator with around 47.7% immunohistochemical expression rate (1+, 23.2%; 2+, 18.0%; 3+, 6.5%) in PSCC. Her-2 positive immunohistochemical expression (2+/3+) was associated with advanced pT, pN stages, metastasis and poor overall survival (positive vs. negative, HR (95%Cl): 3.133 (2.120-4.631), p=0.000). Cellular and animal experiments confirmed that Her-2 promoted tumor progression, inhibited cisplatin-induced cell apoptosis via Akt pathways and increased cisplatin resistance in PSCC. Meanwhile, cisplatin-resistant PSCC cells up-regulated Her-2 expression. More importantly, Her-2 targeted ADCs Disitamab Vedotin displayed remarkable anti-tumor activities both in Her2-positive and cisplatin-resistant PSCC tumors. Conclusions: Our study suggested that Her-2 was an available therapeutic biomarker in PSCC. Targeting Her-2 ADCs might be a prospective option to improve clinical outcomes in high-risk Her-2 positive advanced PSCC patients and provided precious opportunity for cisplatin-based chemoresistance patients.

Positive regulatory loop of platelet-derived growth factor DD-induced STAT3 activation is associated with poor prognosis in advanced urothelial carcinoma

Immune checkpoint inhibitor (ICI) therapy has been established for patients with advanced urothelial cancer (UC). The necessity of overcoming resistance to ICIs and identifying a predictive factor for the same has been highlighted, such as the assessment of combination therapy with other targeted drugs and the characterization of molecular signatures in the tumor microenvironment. Recently, we reported that low hemoglobin (Hb) levels and a high platelet-to-lymphocyte ratio (PLR) were significantly associated with overall survival in patients with UC who did not benefit from pembrolizumab treatment. In the present study, we identified a possible link between these unfavorable prognostic indicators and PDGF-DD-induced STAT3 activation in UC. Overlapping patients between the high STAT3- or phosphorylated STAT3-positive score group (as assessed by immunohistochemistry) and low Hb levels or high PLR group (as assessed by blood tests) showed significantly worse outcomes after pembrolizumab treatment. Additionally, using the bladder cancer JMSU1 cell line, we demonstrated a possible positive regulatory loop between autocrine/paracrine PDGF-DD and STAT3 signaling. Therefore, we suggest that STAT3 inhibition and PDGF-DD detection in the tumor microenvironment might represent a potential therapeutic strategy to overcome resistance to pembrolizumab. Moreover, this can help identify patients with UC who could benefit from combination treatment.

The clinical significance of thyroid antibodies in non-thyroid diseases

Background: Epidemiological studies showed that the population has a high immune disease prevalence, and thyroid immune diseases are among the top autoimmune disorders seen in clinical practice. Investigators noticed an association between some non-thyroidal conditions with thyroid autoantibodies, and some of the outcomes of these non–thyroid diseases may be affected by the presence of these thyroid antibodies. Objective: To investigate the association of thyroid autoantibodies with non-thyroidal diseases and their clinical significance, such as the positive or negative impact on the disease outcome. Methods: A systematic literature review was done using selection criteria with the help of search questions. Multiple search engines were searched for eligible articles. Articles were filtered based on the inclusion and exclusion criteria. Data were extracted and analysed for clinical or statistical significance between case and control groups in selected studies. Results: Eighteen (18) articles fulfilled the inclusion and exclusion criteria; 44.4% were analytical cross-section studies, 5% were prospective studies, 5.5% were meta-analysis studies, 5.5% were case-control studies, and 16.7% were retrospective studies. The included studies aimed to find an association between TPO-Ab, TG-Ab, and some non-thyroidal diseases such as Vitamin D deficiency, Allergic diseases, mood disorders, women’s reproductive system diseases, abortion, systemic lupus erythematosus, rheumatoid disease, Celiac disease, Type 1 diabetes, and breast cancer. The ORs in the included studies were &gt; 1, and the confidence intervals did not cross 1, which means both clinical (favour positivity in case groups) and statistical (existing difference between case and control groups) significance. The “I^2 value”, which is an indicator for heterogeneity of the studies included in the meta-analysis, was high in the included research (&gt;50%), which indicates heterogeneity of the included study. TPO-Ab was a favourable prognostic indicator in cases of breast cancer. Relative risk (RR) was used to assess the disease-free survival rate in subjects with breast carcinoma. The survival rate between patients with TPO-Ab &gt; 0.3u/ml and &lt;0.3u/ml was statistically significant (P value 0.016), and relative risk = 3.46. Conclusion: Thyroid autoantibodies are not exclusively markers of thyroid autoimmune diseases but can also be markers and indicators of non-thyroidal illnesses. Their presence could be either a favourable prognostic indicator, as with breast carcinoma cases or unfavourable prognostic indicator, as with abortion. Further studies are recommended to explore more associations. Key words: Thyroid, thyroid autoantibodies, thyroid diseases, non-thyroidal diseases.

Clinical and magnetic resonance imaging features, and pathological findings of spinal lymphoma in 27 cats.

This multicentric retrospective study describes the clinical and MRI features and pathological studies of spinal lymphoma in 27 cats. MRI characteristics and their possible correlations with histopathological findings were studied. The most frequent neurological signs were rapidly progressive paraparesis (62.9%) or paraplegia (22.2%). Bimodal age distribution was found with 40.7% of cats aged ≤2.5 years (63.6% of them FeLV positive), and 44.4% of cats aged ≥8 years (16.7% of them FeLV positive). Spinal lymphoma was generally presented on MRI as an ill-defined epidural focal lesion with moderate to severe spinal cord compression, expanding more than one vertebral body. MRI lesions were typically localized in the lumbar vertebral segment (p = 0.01), circumferential to the spinal cord (p = 0.04), hyperintense on T2-weighted sequences (p = 4.3e-06), and isointense on T1-weighted sequences (p = 8.9e-07). The degree and pattern of contrast enhancement were variable. Other morphological patterns included paravertebral masses with extension into the vertebral canal and lesions centered in the spinal nerve roots. Involvement of vertebrae and adjacent spinal soft tissues was present in 74% of cases when present vertebral involvement was characterized by cortical sparing. When follow-up MRI studies (n = 4) were performed after treatment new lesions of similar nature but different localizations and extension were observed. Confirmation of spinal lymphoma was performed by CSF analysis in 4/27 (14.8%) of cases, by FNA in 6/27 (22.2%) of cases, by surgical biopsy in 10/27 (37%) of cases, by FNA and surgical biopsy in 1/27 (3.7%) of cases, by CSF, FNA, surgical biopsy and postmorten examination in 1/27 (3.7%) of cases, and postmorten studies in 5/27 (18.5%) of cases. Antemortem diagnosis was achieved in 22/27 (81.5%) cats. The presence of necrosis in histopathological studies as an unfavorable prognostic indicator of survival was significantly more probable when lesions were not hyperintense on T2-weighted sequences (p = 0.017). Spinal lymphoma in cats is a complex entity with heterogeneous imaging and histopathological appearance. However, certain MRI features may support a tentative diagnosis, which in a group of cases can be confirmed when combined with the CSF findings. For the rest of the cases, tissue sampling assisted by imaging findings remains necessary for definitive diagnosis.

BDNF is a prognostic biomarker involved in immune infiltration of lung adenocarcinoma and is associated with brain metastasis.

Non-small cell lung cancer (NSCLC) is one of the leading causes of death worldwide. Brain metastases are a common complication of a wide range of human malignancies, particularly lung adenocarcinoma (LUAD). Brain-derived neurotrophic factor (BDNF), a member of the neurotrophin family, has been linked to several human malignancies and has been shown to promote LUAD tumorigenesis. However, its function in the tumour immune microenvironment (TIME) remains largely unexplored, especially in complex brain tissue environments. In this study, BDNF was found to be particularly increased in patients with advanced tumour stage, lymphatic metastasis, and distant metastasis, indicating a correlation with LUAD progression. We characterized the prognostic value of BDNF and defined BDNF as an unfavourable prognostic indicator through a common driver gene-independent mechanism in LUAD. Furthermore, patients with increased BDNF levels in primary LUAD might have a higher risk of developing brain metastasis (BM), and central nervous system (CNS) metastasis showed an elevated expression of BDNF compared to their matched primary lesions. Additionally, we investigated the interaction between BDNF and infiltrating immune cells in both primary lesions and paired BM using multiplex immunostaining. The results showed that BDNF might drive an immunosuppressive tumour microenvironment (TME) by re-education of tumour-associated macrophages (TAMs) toward a pro-tumorigenic M2 phenotype, particularly in BM. Our findings demonstrate that BDNF serves as an independent potential prognostic marker and correlates with BM in LUAD. As it is closely related to TAM polarization, BDNF may be a promising immune-related biomarker and molecular target in patients with LUAD.

Doxorubicin-induced upregulation of follistatin-like 3 (FSTL3): a new therapeutic target

Abstract Introduction Doxorubicin (DOX) is among the most used anticancer drugs with associated cardiotoxicity. Follistatin-like 3 (FSTL3), a secreted member of the follistatins family that can selectively bind to members of the TGF-β superfamily, is involved in regulation of cardiac hypertrophy and heart failure. FSTL3 is also upregulated in breast and colorectal cancer tumours, is also an unfavourable prognostic indicator for various cancers. Purpose We aim to determine the dual role of FSTL3 in prevention of DOX-induced cardiotoxicity and synergistic anti-cancer effects. Methods Human cardiomyocytes (HCMs) were treated with DOX at 1uM (EC50) for 72 hours. Cell viability was assessed via CellTiter-Glo®. Secreted FSTL3 levels, as measured by ELISA (R&amp;D systems). FSTL3 and TGF-β mRNA levels were measured by qPCR. Co-treatment of DOX with human anti-FSTL3 antibodies (Aviva Systems Biology) at 10ug/mL were introduced for 72hrs treatment. Results Secreted FSTL3 levels were significantly increased in DOX-treated HCMs at 72hrs compared to control (n=5, p&amp;lt;0.001). Consistently, FSTL3 and TGF-β mRNA levels, in collected HCMs were significantly increased in DOX-treated cells. Co-treatment of DOX with human anti-FSTL3 antibodies at 10ug/mL significantly improved HCM viability compared to IgG control group. Conversely, anti-FSTL3 antibodies provided synergistic anti-cancer effects with DOX: MCF-7 breast cancer cells were significantly reduced when co-treated with DOX and anti-FSTL3 antibody vs. IgG controls. Conclusion We show, for the first time, that: 1) FSTL3 is secreted directly from HCMs; 2) FSTL3 levels (both circulating and mRNA) is markedly elevated with DOX treatment; 3) neutralisation of FSTL3 in DOX-treated HCMs, restored HCM viability; and 4) exhibit synergistic anti-cancer effects with DOX. Taken together, FSTL3 is a potential target for dual anti-cancer and cardioprotective effects. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Heart Foundation of Australia Future Leader FellowshipsNSW Ministry of Health EMC FellowshipNSW Ministry of Health Translational Research Grant

Dirty necrosis in renal cell carcinoma is associated with NETosis and systemic inflammation.

Dirty necrosis (DN) in renal cell carcinoma (RCC) is morphologically characterized by abundant neutrophil infiltration and has significant potential as an unfavorable prognostic indicator. This study aimed to analyze the pathological and biological features of DN. A total of 81 RCC tumors, including 33 cases of DN and 48 cases of tumor necrosis without DN features (ghost necrosis [GN]), were enrolled in this study. We compared the number of neutrophils; the activation of cell death pathways, including ferroptosis, NETosis, and apoptosis; the rate of epithelial-mesenchymal transition (EMT); and proliferation status using immunohistochemistry. We further assessed the effect of the necrosis type on systemic inflammation. DN tumors had a significantly higher number of neutrophils in both areas around the necrotic foci and far from the necrotic foci. Ferroptosis status did not differ between DN and GN; however, DN tumors had significantly larger areas exhibiting cell detritus with neutrophil extracellular traps (NETs) detected by citrullinated histone H3 (citH3) than GN tumors. DN tumors also had more apoptotic cells within areas around the necrotic foci. There was no significant difference between the EMT and proliferation status between DN and GN groups. Systemic inflammation markers including C-reactive protein (CRP), CRP-to-albumin ratio (CRP/Alb), platelet-to-lymphocyte ratio (PLR), and hemoglobin were significantly higher in patients with DN. In addition, some of these inflammation markers (CRP/Alb and PLR) significantly decreased after surgery. DN in RCC is characterized by NETs production and systemic inflammation.

The analysis of prognostic factors of primary small intestinal gastrointestinal stromal tumors with R0 resection: A single-center retrospective study.

Objective:We aim to assess factors that affect overall survival in patients with primary small intestinal gastrointestinal stromal tumors (GISTs) who had undergone R0 resection.Method:A retrospective analysis reviewed the data of 82 consecutive confirmed GIST patients at a single medical center in China from January 2012 to June 2020. The survival curve was estimated using the Kaplan–Meier method, and independent prognostic factors were confirmed using the Cox regression model.Results:A total of 82 patients were included in the study: 42 men and 40 women, the mean age was 59 years old (23–83 years old). Tumors were commonly found in the jejunum (46.3%), ileum (20.7%), and duodenum (32.9%). The median tumor size was 6.0 cm (range: 1.0–15.0 cm). The number of mitoses per one 50 high-power field was used to define the mitotic rates. In our present study, 56 patients presented a mitotic rate ≤5 (68.3%) and 26 patients showed a rate >5 (31.7%) at the time of diagnosis. All patients accepted tumor resection without lymph node resection. The positivity rate was 97.6% for CD117, 96.3% for delay of germination 1, 65.9% for CD34, 6.1% for S-100, and 59.8% for smooth muscle actin using immunohistochemistry. Tumor size, tumor rupture, Ki67 index, mitotic index, and postoperative imatinib were independent prognostic factors for small intestinal GISTs.Conclusions:In this study, larger tumor size, high Ki67 index, high mitotic index, the occurrence of tumor rupture, and use of imatinib were independent unfavorable prognostic indicators.

Heparanase 1 Upregulation Promotes Tumor Progression and Is a Predictor of Low Survival for Oral Cancer.

Background: Oral cavity cancer is still an important public health problem throughout the world. Oral squamous cell carcinomas (OSCCs) can be quite aggressive and metastatic, with a low survival rate and poor prognosis. However, this is usually related to the clinical stage and histological grade, and molecular prognostic markers for clinical practice are yet to be defined. Heparanase (HPSE1) is an endoglycosidase associated with extracellular matrix remodeling, and although involved in several malignancies, the clinical implications of HPSE1 expression in OSCCs are still unknown. Methods: We sought to investigate HPSE1 expression in a series of primary OSCCs and further explore whether its overexpression plays a relevant role in OSCC tumorigenesis. mRNA and protein expression analyses were performed in OSCC tissue samples and cell lines. A loss-of-function strategy using shRNA and a gain-of-function strategy using an ORF vector targeting HPSE1 were employed to investigate the endogenous modulation of HPSE1 and its effects on proliferation, apoptosis, adhesion, epithelial-mesenchymal transition (EMT), angiogenesis, migration, and invasion of oral cancer in vitro. Results: We demonstrated that HPSE1 is frequently upregulated in OSCC samples and cell lines and is an unfavorable prognostic indicator of disease-specific survival when combined with advanced pT stages. Moreover, abrogation of HPSE1 in OSCC cells significantly promoted apoptosis and inhibited proliferation, migration, invasion, and epithelial-mesenchymal transition by significantly decreasing the expression of N-cadherin and vimentin. Furthermore, a conditioned medium of HPSE1-downregulated cells resulted in reduced vascular endothelial growth. Conclusion: Our results confirm the overexpression of HPSE1 in OSCCs, suggest that HPSE1 expression correlates with disease progression as it is associated with several important biological processes for oral tumorigenesis, and can be managed as a prognostic marker for patients with OSCC.

Abstract 2689: FGF19 is a novel serum colorectal cancer biomarker that exerts endocrine paraneoplastic effects on hepatic tissue

Abstract Despite having excellent prognosis when detected early, colorectal cancer (CRC) remains a leading cause of cancer-related deaths globally. Barriers to screening reduces compliance and negatively impacts patient outcomes, necessitating alternatives. A blood-based approach provides a more convenient and accessible modality, but serum markers are lacking. Using a meta-transcriptomics approach, we identified Fibroblast Growth Factor 19 (FGF19), an enteroendocrine FGF responsible for bile acid (BA) homeostasis, as an attractive CRC marker. However, whether FGF19 is aberrantly secreted into blood by colorectal tumors or induces endocrine-like paraneoplastic effects is unknown. To assess the strength of FGF19 as a CRC biomarker, expression data from the Genotype-Tissue Expression consortium (GTEx), The Cancer Genome Atlas (TCGA-COADREAD), and our curated Meta-dataset (E-MTAB-10089) were downloaded and analyzed for associations with prognostic indicators. Next, in silico FGF19 expression profiles were validated in vitro using a panel of five CRC cell lines via western blot with secretion quantitated by sandwich ELISA. To determine whether colorectal tumors contribute FGF19 to circulation, subcutaneous xenografts of HCT116 and Colo201 cells were established in four male and female NOD Scid gamma (NSG) mice. Tumor volume, as well as serum and urine FGF19 were assessed weekly over a 36-day period. Following euthanasia, murine liver and ileal tissue were processed for downstream mRNA and bile acid quantification. To determine if malignant FGF19 exerts paraneoplastic effects RNA sequencing was performed on hepatic mRNA using the Illumina NovaSeq 6000 system. Reads were processed, aligned, mapped, and analyzed for differential expression and functional enrichment using an integrated informatics pipeline implemented in R. Meta-transcriptomics revealed that ectopic overexpression of FGF19 was highly indicative of CRC and associated with unfavorable prognostic indicators including disease progression, treatment failure, and poor survival. In vitro testing recapitulated in silico findings, showing that that four out of five CRC cell lines constitutively express and secrete FGF19. We also readily detected FGF19 in serum and urine of mice harboring xenografts derived from Colo201, but not HCT116, cells. Moreover, circulating FGF19 levels increased with tumor size and exerted paraneoplastic effects on liver tissue such as suppression of BA synthesis, dysregulation of cholesterol metabolism, and induction of pre-neoplasia. In summary, we describe FGF19 as a putative serum CRC biomarker that exerts novel endocrine-like paraneoplastic effects on the liver. Study limitations included the lack of FGF19 quantification in CRC patient blood, in vivo experimentation using two different cell lines, and gender-related batch effects identified by RNA sequencing. Citation Format: Michael Walter Rohr, Jordan Beardsley, Sai Preethi Nakkina, Dexter Hadley, Deborah Altomare. FGF19 is a novel serum colorectal cancer biomarker that exerts endocrine paraneoplastic effects on hepatic tissue [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 2689.

Radiomics in Gastric Cancer: First Clinical Investigation to Predict Lymph Vascular Invasion and Survival Outcome Using 18F-FDG PET/CT Images.

BackgroundLymph vascular invasion (LVI) is an unfavorable prognostic indicator in gastric cancer (GC). However, there are no reliable clinical techniques for preoperative predictions of LVI. The aim of this study was to develop and validate PET/CT-based radiomics signatures for predicting LVI of GC preoperatively. Radiomics nomograms were also established to predict patient survival outcomes.MethodsThis retrospective study registered 148 GC patients with histopathological confirmation for LVI status, who underwent pre-operative PET/CT scans (Discovery VCT 64 PET/CT system) from December 2014 to June 2019. Clinic-pathological factors (age, gender, and tumor grade, etc.) and metabolic PET data (maximum and mean standardized uptake value, total lesion glycolysis and metabolic tumor volume) were analyzed to identify independent LVI predictors. The dataset was randomly assigned to either the training set or test set in a 7:3 ratios. Three-dimensional (3D) radiomics features were extracted from each PET- and CT-volume of interests (VOI) singularly, and then a radiomics signature (RS) associated with LVI status is built by feature selection. Four models with different modalities (PET-RS: only PET radiomics features; CT-RS: only CT radiomics features; PET/CT-RS: both PET and CT radiomics features; PET/CT-RS plus clinical data) were developed to predict LVI. Patients were postoperatively followed up with PET/CT every 6-12 months for the first two years and then annually up to five years after surgery. The PET/CT radiomics score (Rad-scores) was calculated to assess survival outcome, and corresponding nomograms with radiomics (NWR) or without radiomics (NWOR) were established.ResultsTumor grade and maximum standardized uptake value (SUVmax) were the independent LVI predictor. 1037 CT and PET 3D radiomics features were extracted separately and reduced to 4 and 5 features to build CT-RS and PET-RS, respectively. PET/CT-RS and PET/CT-RS plus clinical data (tumor grade and SUVmax) were also developed. The ROC analysis demonstrated clinical usefulness of PET/CT-RS plus clinical data (AUC values for training and validation, respectively 0.936 and 0.914) and PET/CT-RS (AUC values for training and validation, respectively 0.881 and 0.854), which both are superior to CT-RS (0.838 and 0.824) and PET-RS (0.821 and 0.812). SUVmax and LVI were independent prognostic indicators of both OS and PFS. Decision curve analysis (DCA) demonstrated NWR outperformed NWOR and was established to assess survival outcomes. For estimation of OS and PFS, the C-indexes of the NWR were 0. 88 and 0.88 in the training set, respectively, while the C-indexes of the NWOR were 0. 82 and 0.85 in the training set, respectively.ConclusionsThe PET/CT-based radiomics analysis might serve as a non-invasive approach to predict LVI status in GC patients and provide effective predictors of patient survival outcomes.

DOK2 Has Prognostic and Immunologic Significance in Adults With Acute Myeloid Leukemia: A Novel Immune-Related Therapeutic Target.

BackgroundThe role of downstream tyrosine kinase 2 (DOK2), a major member of the DOK family, remains poorly defined in acute myeloid leukemia (AML). Herein, we investigated the expression levels, clinical outcomes, and biological functions of DOK2 in patients with AML.MethodsDatasets were obtained from the Cancer Genome Atlas (TCGA) database for transcriptomic and clinical information. Nomogram construction and assessment were conducted using Cox regression analysis, receiver operating characteristic (ROC) curves, and calibration plots. Public databases, including the Gene Expression Omnibus, Cancer Cell Line Encyclopedia, LinkedOmics, GeneMANIA, TISIDB, and Gene Set Cancer Analysis, were employed for relevant bioinformatic studies. Moreover, we utilized the CIBERSORT algorithm to evaluate the level of infiltration of immune cells into the bone marrow microenvironment.ResultsWe observed that DOK2 transcription levels were markedly upregulated in AML samples (P < 0.001), and its high expression was associated with inferior overall survival (OS) (HR = 2.17, P < 0.001) and disease-free survival (DFS) (HR = 2.50, P < 0.001). ROC curve analysis also showed the reliable diagnostic efficiency of DOK2 in AML. For treatment regimens, patients with high DOK2 expression could significantly prolong OS by receiving hematopoietic stem cell transplantation (HSCT) (P < 0.001), whereas those with low DOK2 expression were more likely to improve DFS by chemotherapy alone rather than HSCT. Nomograms constructed for predicting OS and DFS exhibited satisfactory discrimination and accuracy. Functional enrichment analysis identified that DOK2 was involved in important pathways associated with immune-related activities. Furthermore, CIBERSORT scores reflected negative correlations of DOK2 with activated mast cells and resting CD4+ memory T cells, which indicated its adverse immunomodulatory potential.ConclusionWe suggest that elevated DOK2 expression could be an unfavorable prognostic indicator of survival in patients with AML. Our findings provide new insights into the role of DOK2 in AML, with promising clinical implications.

RAB20 Promotes Proliferation via G2/M Phase through the Chk1/cdc25c/cdc2-cyclinB1 Pathway in Penile Squamous Cell Carcinoma.

Simple SummaryThere is no available biomarker that could be used to predict the prognosis or progression of penile squamous cell carcinoma (PSCC) currently. Here, we conducted comprehensive genomic sequencing on eight pairs of PSCC tissues and found that RAB20 was upregulated in tumors, especially in metastatic lymph nodes. We then detected the expression of RAB20 in a large cohort of 259 PSCC cases using IHC assay and analyzed the association between the RAB20 expression and clinical features. We found that high RAB20 expression predicted poor prognosis and advanced clinicopathological features. Further in vitro and in vivo tumorigenesis assays revealed that RAB20 regulates cell proliferation at the G2/M cell cycle phase through the Chk1/cdc25c/cdc2-cyclinB1 pathway. Our results indicated that RAB20 could be a promising prognostic biomarker of advanced PSCC with poor survival and could be a potential therapeutic target.RAB20, a member of the RAS GTPase oncogene family, is overexpressed in several cancers with poor outcomes, promoting tumorigenesis and inducing genomic instability. Here, we performed comprehensive genomic sequencing on eight penile squamous cell carcinoma (PSCC) and normal tissue pairs and found that RAB20 was upregulated in tumors, especially in metastatic lymph nodes. RAB20 overexpression in tumors was further verified by qPCR, Western blotting, and immunohistochemistry of our newly established PSCC cell lines and paired tissues. The clinical significance of RAB20 was validated in 259 PSCC patients, the largest cohort to date, and high RAB20 expression positively correlated with the T, N, M status, extranodal extension, and clinical stage (all p < 0.01). RAB20 was an unfavorable independent prognostic indicator in the survival analysis (p = 0.011, HR = 2.090; 95% Cl: 1.183–4.692), and PSCC patients with high RAB20 expression experienced shorter 5-year cancer-specific survival times (p < 0.001). Furthermore, tumorigenesis assays demonstrated that RAB20 knockdown inhibited cell proliferation, migration, and colony formation in vitro and tumor growth in vivo. RAB20 depletion also induced PSCC cell cycle arrest at G2/M by increasing Chk1 expression and promoting cdc25c phosphorylation to reduce cdc2-cyclinB1 complex formation. Our study revealed an oncogenic role for RAB20 in promoting PSCC cell proliferation at the G2/M phase via the Chk1/cdc25c/cdc2-cyclinB1 pathway. Thus, RAB20 could be a promising prognostic biomarker of advanced PSCC with poor patient survival outcomes and could be a potential therapeutic target.

Peritoneal metastases from colorectal cancer in the absence of lymph node metastases show a high survival rate despite unfavorable prognostic indicators

BackgroundPatients with colorectal cancer die as a result of metastases to liver, lymph nodes or the peritoneal surfaces. The primary is almost always controlled by colon or rectal cancer resection. MethodsConsecutive patients with isolated metastases to peritoneal surfaces (no lymph node, liver or systemic metastases) were referred to the Washington Cancer Institute from all over the United States and abroad. The study of this particular group of patients was to determine the impact of clinical and histologic features on overall survival. These variables were collected from the primary colorectal cancer resection performed at the referring institute and from the cytoreductive surgery (CRS) performed at the Washington Hospital Center. The data was prospectively accumulated and retrospectively analyzed. ResultsThirty-one consecutive patients had a complete cytoreduction. This restricted cohort of patients was studied in an attempt to eliminate confounding variables. The median age was 47 years (range 19–80). There were 14 (45%) males. The median overall survival following CRS was 67.9 months with a 5-year and 10-year survival of 51.9% and 43.6%, respectively. None of the clinical or histologic features, including peritoneal cancer index (PCI) and presence of signet ring cells, significantly predicted survival except for carbohydrate antigen 19-9 (CA19-9) (p = 0.0033). None of the involved abdominopelvic regions predicted a guarded outcome. ConclusionsIn this restricted group of lymph node negative colorectal PM patients with a complete cytoreduction, a high PCI or the presence of signet ring cells should not exclude patients from CRS and perioperative chemotherapy.