Metastatic Carcinoma Research Articles

Corrigendum] Jak3 is involved in CCR7‑dependent migration and invasion in metastatic squamous cell carcinoma of the head and neck

Corrigendum] Jak3 is involved in CCR7‑dependent migration and invasion in metastatic squamous cell carcinoma of the head and neck

Supraclavicular lymph node metastasis should not be defined as regional lymph node metastasis in cervical and upper thoracic esophageal squamous cell carcinoma.

The importance of supraclavicular lymph node (SCLN) metastasis in cervical and upper thoracic esophageal squamous cell carcinoma (ESCC) has not been determined. The aim of the present study was to provide a detailed definition of the range of SCLN regions and to explore whether SCLNs should be considered as a regional lymph nodes for patients with cervical and upper thoracic ESCC. A retrospective analysis was performed on 230 patients with locally advanced cervical or upper thoracic ESCC who underwent radical radiotherapy and chemotherapy. The range of SCLN regions was defined in detail on contrast enhanced computed tomography images of the neck. According to whether the patient had lymph node metastasis in the supraclavicular region, the included patients were divided into two groups, and the survival differences and reasons for treatment failure between the two groups were analyzed. Of the 230 patients with ESCC, 71 (30.87%) exhibited lymph node metastases in the supraclavicular region. The median overall survival time of ESCC patients with and without SCLN metastasis was 17 and 30 months, respectively (P<0.001). After propensity score matching (PSM), the median overall survival time of ESCC patients with and without SCLN metastasis was 17 and 28 months, respectively (P<0.001). During the follow-up period, there were a total of 101 cases of failure of treatment in the irradiation field, 6 cases had esophageal metastasis in the non-irradiated field and 27 cases had regional lymph node metastasis in the non-irradiated field. In addition, there were 33 cases of metastasis to the distant lymph nodes or organs. There was no significant difference in the local treatment failure rate between the groups with or without SCLN metastasis in both the irradiation field and the non-irradiation field, but the probability of distant metastasis in the SCLN metastasis group was significantly higher than that in the group without SCLN metastasis (P=0.025). In conclusion, patients with cervical and upper thoracic ESCC with SCLN metastasis have a poor prognosis and the median overall survival time is closer to that of metastatic ESCC than ESCC with regional lymph node metastasis; therefore, SCLNs should not be defined as regional lymph nodes in patients with cervical and upper thoracic ESCC.

Characteristics of lymph node metastasis and short-term outcome of esophageal squamous-cell carcinoma undergoing minimally invasive esophagectomy: a prospective cross-sectional study (with video)

Introduction: Surgery for esophageal squamous-cell carcinoma (ESCC) presents many potential challenges owing to malignant lymph node metastasis, complex procedures and severe postoperative complications. The appropriate lymphadenectomy for ESCC remains controversial. This study aims to evaluate the characteristics of lymph node metastasis and postoperative complications in patients with ESCC undergoing minimally invasive esophagectomy and extended two-field lymph node dissection. Patients and methods: This prospective, single-center, cross-sectional study was conducted from October 2022 to May 2024. All patients with ESCC who underwent minimally invasive esophagectomy and extended two-field lymph node dissection were selected for this study. Postoperative lymph nodes were divided into upper thoracic, middle thoracic, lower thoracic and abdominal lymph node groups. Results: Seventy-four patients with ESCC, including 49 patients who underwent upfront surgery and 25 patients who received preoperative chemoradiotherapy, were selected. The rate of lymph node metastasis in all patients was 39.2%, with 13.6% of patients having upper thoracic metastasis. The factors affecting the rate of lymph node metastasis included preoperative chemoradiotherapy, tumor stage, poor differentiation, lymphovascular/perineural invasion, and tumor size greater than 2 cm, all of which were significantly different (P&lt;0.05). Common postoperative complications included pneumonia (25.7%), recurrent laryngeal nerve (RLN) palsy (10.8%) and anastomotic leak (4.1%). There were no cases required conversion to open surgery, nor any deaths within 90 days postoperatively. Conclusion: Lymph node metastasis in esophageal squamous-cell carcinoma has a high incidence, occurs in the early stages, and is widely distributed in all regions of the mediastinum and abdomen. Minimally invasive esophagectomy and extended two-field lymph node dissection are feasible and safe, with low complication rates.

Utilization of Traditional Chinese Medicine in the management of cutaneous ulceration induced by cervical lymph node metastasis in tonsillar carcinoma: a case report

Utilization of Traditional Chinese Medicine in the management of cutaneous ulceration induced by cervical lymph node metastasis in tonsillar carcinoma: a case report

Britannin inhibits hepatocellular carcinoma development and metastasis through the GSK-3β/β-catenin signaling pathway

BackgroundHepatocellular carcinoma (HCC) stands out as a significant contributor of cancer-related death. Traditional Chinese Medicine (TCM) presents numerous advantages in the treatment of HCC. Britannin, a pivotal compound found in Inulae Flos, demonstrates pharmacological effects against various cancers, yet research on its specific impact on anti-hepatocellular carcinoma remains limited. PurposeThis study aims to explore both the anti-hepatocellular carcinoma effects of britannin and its underlying mechanism of action. MethodsMTT assay, clone formation assay and flow cytometry were utilized to detect the cell activity, proliferation ability and apoptosis of britannin against HCC cell lines. Cell migration and invasion abilities of britannin on HCC cell lines were evaluated by wound-healing assay and transwell migration and invasion assay. H22 xenografted tumor mouse model was constructed and britannin treatment was performed to observe the effect of britannin on HCC tumor. The expression levels of liver cancer biomarkers AFP, AFP-L3, APT and TGF-β were detected by Elisa, and the histopathology was observed by HE staining. Network pharmacology and molecular docking were used to predict the possible signaling pathway of anti- hepatocellular carcinoma effect of britannin. The surface plasmon resonance (SPR) experiments was used to verify the interaction between britannin and proteins. The cell kinase activity function experiment was employed to detect the effect of britannin on enzyme activity. RT-qPCR and Western-Blot were used to verify the effect of britannin on the mRNA expressions of key genes and protein levels related to GSK-3β/β-catenin pathway in hepatocellular carcinoma cells and tumor tissues in mice. ResultsIn vitro experiments showed that britannin could inhibit the activity, proliferation, migration and invasion abilities of HCC cells, while promoting their apoptosis. In vivo experiments revealed that britannin exerted inhibitory effects on the growth of transplanted liver cancer tumors, reducing the inflammatory infiltration and the expression levels of AFP, AFP-L3, APT and TGF-β of liver cancer markers in transplanted mice. Network pharmacology and molecular docking predicted that cell adhesion factors and GSK-3β/β-catenin pathway might be the related signaling pathway and had potential docking activity with key proteins. The SPR experiments elucidated the molecular interaction between britannin and GSK-3β. Enzyme activity assays indicated that britannin could modulate the functional activity of GSK-3β kinase. RT-qPCR suggested britannin could regulate the mRNA expressions of β-catenin, GSK-3β, E-cadherin and N-Cadherin. Western-Blot further verified that britannin could significantly up-regulate the expression of GSK-3β and down-regulate the expression of p-GSK-3β and β-catenin. At the same time, the expression of E-cadherin increased and N-Cadherin decreased, thereby reducing the occurrence of EMT and inhibiting the metastasis of hepatocellular carcinoma. ConclusionIn conclusion, britannin could inhibit the growth, development and metastasis of HCC, and its mechanism may be related to the regulation of GSK-3β/β-catenin signaling pathway to inhibit epithelial-mesenchymal transition of HCC.

KRT14 as a potential prognostic marker for metastasis in metaplastic breast carcinoma

Metaplastic breast cancer (MBC) is an aggressive breast cancer subtype with poor prognosis. To elucidate underlying genomic aberrations driving MBC, we conducted integrated transcriptomic analyses of MBC tumors and basal breast cancer cell lines with various transitioning phases (xE = epithelial phase clone, xM = mesenchymal phase clone and xEM = Epithelial-mesenchymal clone). Differential gene expression analysis between MBC vs non-MBC samples as well as between epithelial-mesenchymal (xEM) transitioning cells vs parental cells revealed 12 commonly dysregulated genes intersected from both the datasets meditates pathways governing EMT, migration, proliferation and metastasis. Further investigation onto those genes based on multi-omics approaches that include survival analysis, correlated expression patterns and interactomics indicated KRT14 had a key role in promoting MBC aggression through Epithelial mesenchymal transition leading to metastasis. Moreover, NPR3 was found to be a possible link between KRT14 and EMT in metastasis. To our knowledge, this is the first evident gene expression study to investigate the potential association between the expression of KRT14 and NPR3 and metastasis in MBC, and their potential involvement in the epithelial-mesenchymal transition (EMT) process.. These mechanistic and prognostic insights gained can lead to targeted therapeutics against this rare, refractory disease. Overall, this work highlights the effectiveness of integrated multi-omics in revealing gene expression pattern and predictive biomarkers for metaplastic breast cancer subtypes with poor prognosis.

GPR56 facilitates hepatocellular carcinoma metastasis by promoting the TGF-β signaling pathway

The metastasis of hepatocellular carcinoma (HCC) poses a significant threat to the survival of patients. G protein-coupled receptor 56 (GPR56) has garnered extensive attention within malignant tumor research and plays a crucial role in cellular surface signal transmission. Nonetheless, its precise function in HCC remains ambiguous. Our investigation reveals a notable rise in GPR56 expression levels in human HCC cases, with heightened GPR56 levels correlating with unfavorable prognoses. GPR56 regulates TGF-β pathway by interacting with TGFBR1, thereby promoting HCC metastasis. At the same time, GPR56 is subject to regulation by the canonical cascade of TGF-β signaling, thereby establishing a positive feedback loop. Furthermore, the combination application of TGFBR1 inhibitor galunisertib (GAL) and GPR56 inhibitor Dihydromunduletone (DHM), significantly inhibits HCC metastasis. Interventions towards this signaling pathway could offer a promising therapeutic approach to effectively impede the metastasis of GPR56-mediated HCC.

Upregulation of LY6K induced by FTO-mediated demethylation promotes the tumorigenesis and metastasis of oral squamous cell carcinoma via CAV-1-mediated ERK1/2 signaling activation.

Lymphocyte antigen 6 complex locus K (LY6K) has been demonstrated to play a significant role in cancers and identified as a therapeutic biomarker for head and neck squamous cell carcinoma. However, the role of LY6K in oral squamous cell carcinoma (OSCC) has not been explored. The current study discovered that LY6K was aberrantly upregulated in OSCC cell lines and tissues and that high LY6K expression significantly correlated with poorer survival of OSCC patients. Through stable knockdown of LY6K, we found that the growth, colony formation, migration, and invasion of OSCC cells were substantially suppressed. In addition, tumor growth and lung metastasis in vivo were effectively inhibited by LY6K depletion. Mechanically, LY6K binds with CAV-1 and activates CAV-1-mediated MAPK/ERK signaling to exert its oncogenic effects on OSCC. In addition, LY6K expression in OSCC was discovered to be regulated by FTO-mediated RNA N6-methyladenosine (m6A) modification in an IGF2BP1-dependent manner. Generally, LY6K expression was upregulated by FTO-mediated demethylation in OSCC, which promoted the tumorigenesis and metastasis of OSCC via activating the CAV-1-mediated ERK1/2 signaling pathway.

The activation of the Notch signaling pathway by UBE2C promotes the proliferation and metastasis of hepatocellular carcinoma

UBE2C, a ubiquitin-conjugating enzyme, functions as an oncogene in different types of human cancers. Nonetheless, the exact influence of UBE2C on the development of HCC via regulation of ubiquitination remains uncertain. Here, we found that UBE2C displayed elevated levels of expression in HCC and was associated with an unfavorable prognosis, as evidenced by the analysis of the TCGA database and the examination of clinical specimens. The role of UBE2C in HCC revealed its ability to promote the growth and metastasis of HCC. Mechanistically, UBE2C activated Notch signaling, as evidenced by the upregulation of N1ICD and Hes1, crucial components of the Notch pathway, and activation of the RBP-JK luciferase reporter by UBE2C. Finally, rescue experiments demonstrated that the oncogenic role of UBE2C was eliminated through treatment with the Notch inhibitor DAPT, while overexpression of N1ICD alleviated the anticarcinogenic impact of knockdown of UBE2C. Altogether, the results of our study indicate that UBE2C plays a role in the activation of Notch signaling and could potentially serve as a viable target for therapeutic interventions in HCC.

Multi-instance learning for identifying high-risk subregions associated with synchronous distant metastasis in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is one of the most common histological subtypes of renal tumors. To identify high-risk subregions associated with synchronous distant metastasis. This study enrolled a total of 277 patients with ccRCC. Voxel intensity and local entropy values were compiled within the region of interest for all patients. Unsupervised k-means clustering yielded three subregions per tumor. Radiomic features were extracted, and random forest-based feature selection was conducted. The selected features were used in a multi-instance support vector machine (mi-SVM) model for training, and predictions were made on the validation cohort. Model performance was evaluated using five-fold cross-validation. The subregion with the highest score for patients with synchronous distant metastasis was identified across all cohorts. The mi-SVM model yielded an average area under the curve (AUC) of 0.812 in the training cohort and 0.805 in the validation cohort. In the entire cohort of patients with synchronous distant metastasis, subregion 2, characterized by tumor periphery and intratumoral transitional components, accounted for the highest proportion (48.57%, 30.6/63) among all subregions. It represents a high-risk subregion for synchronous distant metastasis of clear cell renal cell carcinoma. The peripheral and intratumoral transition zones of clear cell renal cell carcinoma are high-risk subregions associated with synchronous distant metastasis.

Growth differentiation factor 7 alleviates the proliferation and metastasis of hepatocellular carcinoma

Background and aimInflammatory factors play significant roles in the development and occurrence of hepatocellular carcinoma (HCC). However, the tumor-protective functions of growth differentiation factors (GDFs) in HCC are yet to be clarified. In this study, we aimed to evaluate the expression levels of 10 GDFs in tumor and paratumor tissues from patients with HCC and perform in vitro and in vivo experiments to elucidate the role of GDF7 in regulating the proliferation and metastasis of HCC. MethodsThe gene expression of 10 GDFs was compared between HCC and paratumors using The Cancer Genome Atlas dataset and patient-derived tissues. A tumor microarray containing 108 HCC tissue samples was used to explore the prognostic value of GDF7 expression. Loss-of-function experiments were also performed in vitro and in vivo to investigate the role of GDF7 in HCC. ResultsThe mRNA and protein levels of GDF7 were significantly lower in HCC tumors than in paratumors (P < 0.001). Kaplan–Meier analysis showed that decreased GDF7 expression in HCC was associated with worse overall survival (5-year rate: 61.8% vs. 27.5%, P < 0.001) and increased recurrence risk (P < 0.001). Multivariate Cox regression analysis demonstrated that low GDF7 expression, the presence of microvascular invasion, and elevated alpha-fetoprotein (AFP) levels were independent risk factors for tumor recurrence and poor survival. Downregulation of GDF7 also increased the tumor growth in HCC cells and in an HCC xenograft model. GDF7 knockdown promoted migration and invasion via epithelial–mesenchymal transition. Meanwhile, a negative correlation between JunB proto-oncogene (JUNB) and GDF7 was observed in HCC tissues. Modulating JUNB levels altered GDF7 protein expression. ConclusionGDF7 is a potential biomarker for predicting superior outcomes in patients with HCC. GDF7 amplification is a potential therapeutic option for HCC.

Pure Squamous Cell Carcinoma of the Prostate With a Complete Remission to Gemcitabine-Cisplatin: Case Presentation and Literature Review

Abstract Squamous cell carcinoma of prostate is a very rare condition and little is known regarding the appropriate managment. Here we reported our patient with pure squamous cell carcinoma of prostate who had complete remission with gemcitabine and cisplatin treatment which last 5 months. Based on his genomic study of prostate cancer, he enrolled to our clinical trial and now receiveing mTOR pathway inhibtor. We also briefly reviewed previous cases of metastatic squamous cell carcinoma of prostate and their managment.

Enfortumab Vedotin Following Platinum Chemotherapy and Avelumab Maintenance in Patients with Metastatic Urothelial Carcinoma: A Retrospective Data from the ARON-2EV Study.

Enfortumab vedotin (EV) has been approved for the treatment of patients with locally advanced/metastatic urothelial carcinoma (la/mUC) who previously received platinum-based chemotherapy followed by immune checkpoint inhibitors. However, the pivotal clinical trials did not include patients previously treated with avelumab maintenance therapy. The aim of the present retrospective analysis was to assess the effectiveness of EV following avelumab in patients with mUC enrolled in the ARON-2EV study. The study included 182 patients with mUC treated with EV following avelumab maintenance. The primary objective was to assess clinical outcomes, including progression-free survival (PFS), overall survival (OS), overall response rate (ORR), and duration of response (DoR). Statistical analysis involved Fisher exact test, Kaplan-Meier method, log-rank test, and univariate/multivariate Cox proportional hazard regression models. Median OS and PFS were 12.7 (95% CI 10.2-14.1) and 7.9 (95% CI 6.4-9.9) months, respectively. Complete response (CR) was achieved in 5% and partial response (PR) in 34% of patients, with an ORR of 39%. The DoR in patients who achieved CR/PR was 10.9 months (95% CI 8.1-11.4). The incidence of grade ≥ 3 peripheral neuropathy and skin rash was 9%, followed by 8% of grade ≥ 3 diarrhea and 4% of grade ≥ 3 hyperglycemia. The results of our large international retrospective study confirm the effectiveness of EV and endorse its use in the population of patients with mUC treated with EV following the frontline platinum-based chemotherapy and subsequent maintenance treatment with avelumab.

7396 IGF-2 Induced Hypoglycemia Associated with Metastatic Hepatocellular Carcinoma

7396 IGF-2 Induced Hypoglycemia Associated with Metastatic Hepatocellular Carcinoma

The impact of neighborhood socioeconomic deprivation on clinical outcomes for locally advanced and metastatic hepatocellular carcinoma: An incidence-based retrospective cohort study.

108 Background: Prior studies show that socioeconomic status impacts hepatocellular carcinoma (HCC) outcomes. However, these have used larger geographic areas such as zip codes or counties for assessment. Using a statewide cancer registry the Area Deprivation Index (ADI), a granular measure of socioeconomic deprivation (SED), was used to assess receipt of treatment and overall survival (OS) for locally advanced and metastatic HCC. Methods: The incidence-based Florida Cancer Data System was used to identify stage III/IV HCC patients diagnosed from 2007-2015. The ADI was used to measure SED and is a validated dataset that ranks neighborhoods (census block groups) from 1-100 (higher scores = higher deprivation) based on income, education, housing, and other socioeconomic factors. Demographic, tumor, and treatment variables were assessed using descriptive statistics, regression plots, and survival analysis. Chemotherapeutic treatment (CT) included receipt of chemotherapy and/or chemoembolization. Results: The study identified 2,534 eligible patients. Males comprised 80.6% of the cohort. The median age was 63 years. By SED quartile, there were significant differences by age, race, insurance, and receipt of chemotherapy (p&lt;0.05) but no difference by gender, ethnicity, stage, or survival. Overall, 39.1% received chemotherapeutic treatment. However, 41.0% of the lowest-deprivation patients received CT compared to 32.1% in the highest-deprivation cohort (p&lt;0.01). After adjustment for potential confounders, the lowest deprivation quartile had increased odds of CT compared to the highest deprivation quartile (OR 1.47; 95% CI,1.15-1.87). The median OS for the cohort was 4.0 months and was 4.6 and 3.3 months, respectively, for the lowest and highest deprivation quartiles (p&lt;0.01). For patients who received and did not receive CT, the median OS was 8.0 and 2.2 months, respectively (p&lt;0.01). However, there was no difference in median OS by SED for those who received CT (p=0.14). Conclusions: In an incidence-based, statewide cancer registry, the median OS for locally advanced and metastatic HCC remains poor and most patients do not receive CT. While there were differences in receipt of CT by SED, when patients did receive CT, median OS was similar across SED quartiles. These data suggest that SED may impact receipt of treatment and efforts are needed to understand and address treatment disparities. Lowest Deprivation Low Deprivation High Deprivation Highest Deprivation p-Value N=624 N=650 N=589 N=629 Chemotherapeutic treatment 0.001 No 347 (55.6%) 345 (53.1%) 339 (57.6%) 411 (65.3%) Yes 256 (41.0%) 283 (43.5%) 235 (39.9%) 202 (32.1%) Unknown 21 (3.4%) 22 (3.4%) 15 (2.5%) 15 (2.6%) Vital Status 0.93 Alive 41 (5.7%) 44 (5.9%) 43 (6.0%) 44 (6.5%) Dead 682 (94.3%) 695 (94.1%) 673 (94.0%) 632 (93.5%)

Real-world (rw) treatment (tx) patterns and clinical outcomes among patients (pts) with metastatic urothelial carcinoma (mUC) receiving first-line (1L) systemic tx and avelumab 1L maintenance (1LM): Results from the IMPACT UC-III study.

390 Background: Avelumab 1LM is a standard of care for pts with mUC that has not progressed after 1L platinum-based chemotherapy (PBC). Immuno-oncology (IO) monotherapy is considered in pts with mUC who are ineligible to receive PBC. Recently approved 1L tx options include enfortumab vedotin + pembrolizumab and nivolumab + gemcitabine/cisplatin. This US retrospective study examined pt characteristics, tx patterns, and clinical outcomes among pts with mUC receiving 1L tx, including avelumab 1LM. Methods: Pts with mUC (bladder cancer; stage IIIB or IV, or ≥2 claims with ICD-10 diagnoses for metastatic cancer) aged ≥18 years, who initiated 1L tx (index date) from Jan 1, 2020 to Jul 31, 2023, were identified from the Healthcare Integrated Research Database (HIRD®; claims and clinical data from the health plan’s Cancer Care Quality Program). Clinical outcomes, including time to next tx (TTNT; time from 1L tx initiation to second-line tx) and overall survival (OS), were evaluated post index date. Pt characteristics and tx patterns were summarized using descriptive statistics. Avelumab 1LM use was identified on/after June 30, 2020 and ≤90 d after 1L PBC discontinuation. OS from the start of 1L tx or 1LM was analyzed using Kaplan-Meier methodology. Results: Of 2,820 pts with mUC, 1L tx was PBC in 37.0% (n=1,044), IO monotherapy in 39.0% (n=1,099), and other tx in 24.0% (n=677; antibody-drug conjugates and non-PBC). Among pts who received 1L PBC, 15.0% (n=157) initiated avelumab 1LM within 90 days of completing 1L PBC. Avelumab uptake in 2020-2023 by year was 10.8% (Jun-Dec 2020), 29.9%, 34.4%, and 24.8% (Jan-Aug 2023), respectively; 38.9% of pts were still receiving avelumab at the end of the study period. In the 1L PBC and IO cohorts, mean age (SD) was 65.5 (11.1) and 74.6 (10.7) years, respectively. 60% of pts were male. In the 1L PBC and 1L IO monotherapy cohorts, respectively, median follow-up (IQR) was 11.2 (5.6-20.3) and 8.6 (4.0-17.7) months (mo); median TTNT (IQR) was 4.8 (2.8-8.3) and 5.5 (2.8-11.0) mo; and median OS (95% CI) was 29.7 (25.1-37.2) and 20.0 (17.1-25.6) mo. In pts who received avelumab 1LM, median follow-up (IQR) from start of 1L PBC was 14.6 (9.2-21.3) mo; median TTNT (IQR) was 7.6 (6.2-12.3) mo; median time on avelumab tx was 5.0 (1.8-10.2) mo; and 1- and 2-year OS rates, respectively, from start of avelumab 1LM were 78% and 65%, and from start of 1L PBC were 84% and 68% (median OS was not estimable because &gt;50% of pts remained alive at the end of the study period). Conclusions: Despite advances in 1L tx for mUC, IO monotherapy remains a prevailing option for older, commercially insured patients in the US. In this descriptive rw study, pts treated with 1L PBC had longer OS than pts treated with 1L IO monotherapy. Future studies with longer follow-up are needed to further evaluate pt outcomes.

CCN6 Suppresses Metaplastic Breast Carcinoma by Antagonizing Wnt/β-Catenin Signaling to Inhibit EZH2-Driven EMT.

Metaplastic breast carcinomas (mBrCA) are a highly aggressive subtype of triple-negative breast cancer with histologic evidence of epithelial-to-mesenchymal transition and aberrant differentiation. Inactivation of the tumor suppressor gene cellular communication network factor 6 (CCN6; also known as Wnt1-induced secreted protein 3) is a feature of mBrCAs, and mice with conditional inactivation of Ccn6 in mammary epithelium (Ccn6-KO) develop spindle mBrCAs with epithelial-to-mesenchymal transition. Elucidation of the precise mechanistic details of how CCN6 acts as a tumor suppressor in mBrCA could help identify improved treatment strategies. In this study, we showed that CCN6 interacts with the Wnt receptor FZD8 and coreceptor LRP6 on mBrCA cells to antagonize Wnt-induced activation of β-catenin/TCF-mediated transcription. The histone methyltransferase EZH2 was identified as a β-catenin/TCF transcriptional target in Ccn6-KO mBrCA cells. Inhibiting Wnt/β-catenin/TCF signaling in Ccn6-KO mBrCA cells led to reduced EZH2 expression, decreased histone H3 lysine 27 trimethylation, and deregulation of specific target genes. Pharmacologic inhibition of EZH2 reduced growth and metastasis of Ccn6-KO mBrCA mammary tumors in vivo. Low CCN6 is significantly associated with activated β-catenin and high EZH2 in human spindle mBrCAs compared with other subtypes. Collectively, these findings establish CCN6 as a key negative regulator of a β-catenin/TCF/EZH2 axis and highlight the inhibition of β-catenin or EZH2 as a potential therapeutic approach for patients with spindle mBrCAs. Significance: CCN6 deficiency drives metaplastic breast carcinoma growth and metastasis by increasing Wnt/β-catenin activation to upregulate EZH2, identifying EZH2 inhibition as a mechanistically guided treatment strategy for this deadly form of breast cancer.

Value of miR-31 and miR-150-3p as diagnostic and prognostic biomarkers for breast cancer.

The most prevalent malignancy among women is breast cancer (BC). MicroRNAs (miRNAs) play a role in the initiation and progression of BC by influencing breast cancer stem cells (BCSCs) but the diagnostic and prognostic roles of those miRNAs on BC patients are still unknown. It was aimed to investigate expression profiles, diagnostic and prognostic potentials of BCSC-related miRNAs in different subtypes (Luminal A and B, HER2 + and TNBC) of BC patients. Expression analysis of 15 BCSC-related miRNAs was performed in 50 breast tumor tissues and 20 adjacent non-tumor tissues obtained from BC patients using the qRT-PCR method. The expression levels of miR-31 and miR-150-3p were significantly upregulated in the tumor tissues compared to the adjacent non-tumor tissues (p < 0.05). miR-31 expression upregulated in the Luminal A and Luminal B group compared to non-tumor tissue (p < 0.05). miR-31 expression was determined to be significantly higher in the Luminal group (Luminal A and B) compared to the aggressive group (HER2 + and TNBC) (p < 0.05). According to the ROC analysis, the area under the curve (AUC) of miR-31 and miR-150-3p were 0.66 with a sensitivity of 68% and a specificity of 70%. A significant inverse correlation was observed between miR-31 expression with metastatic carcinoma status, in situ component, and Ki67 value in tumors, and high miR-150-3p expression was correlated with p63 expression (p < 0.05). miR-31 and miR-150-3p have the potential to serve as biomarkers for guiding diagnosis, evaluating prognosis, and metastatic process in patients with BC.

Systemic Inflammation Indexes and Risk of Immune-related Adverse Events in Patients With Metastatic Urothelial Carcinoma Treated With Immunotherapy.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of metastatic urothelial carcinoma (mUC). However, they could be associated with immune-related adverse events (irAEs), which may be clinically significant. Identifying clinical characteristics that may be associated with a higher risk of irAEs is of great importance. We retrospectively collected data from all patients who received anti-PD1 or anti-PD-L1 for metastatic UC at our Institution from January 2017 to December 2022. Patients were dichotomized according to baseline neutrophil-to-lymphocyte ratio (NLR), systemic immune-inflammation index (SII), and platelet-to-lymphocyte ratio (PLR) values. We performed univariate and multivariate logistic regression to determine the association between baseline characteristics and the development of irAEs. A total of 119 patients were identified. At a median follow-up of 29.6 months, 96 patients progressed and 82 died. Forty-five patients developed irAEs of any grade, 8 patients developed grade 3 toxicities. In the univariate analysis PS of 0 (p<0.01), baseline NLR <3.52, baseline PLR <194 (p=0.04) and baseline SII <906 (p=0.01) were significantly associated with a higher risk of developing irAEs, whereas in the multivariate analysis only PS=0 (p<0.01) and NLR <3.52 (p=0.03) maintained their correlation. Median progression-free survival (mPFS) and overall survival (mOS) were significantly longer in patients with NLR <3 (mPFS 3.8 vs. 2.6 months, p=0.01; mOS 15.3 vs. 5.6 months, p=0.002) and PS=0 (mPFS 4.8 vs. 2.1 months, p<0.001; mOS 15.3 vs. 3.8 months, p<0.001). Low baseline NLR, PLR, and SII and good PS are associated with a higher risk of developing irAEs in patients treated with ICIs for mUC.

MALEXNET-EUNET: MULTI-CLASS LIVER CANCER CLASSIFICATION AND SEGMENTATION USING A HYBRID DEEP LEARNING SYSTEM

Background and objective: One of the most prevalent and significant causes of cancer-related mortality worldwide is considered to be liver cancer. Techniques for automatically segmenting and classifying liver tumors are crucial for supporting medical professionals during the tumor diagnostic process. Classifying liver tumors is challenging due to noise, nonhomogeneity, and the significant appearance diversity observed in tumor tissue. Also, in recent years, most of the research has performed binary classification, but there is still a lack of research on multi-class liver cancer classification. Therefore, we perform a multi-class liver cancer classification and segmentation in this research. Methods: We propose a hybrid deep learning-based multi-class liver cancer classification and segmentation system in this research. The collected CT images are pre-processed in four stages: contrast enhancement, noise filtering, smoothing and sharpening, and liver region segmentation. Next, the binary, texture, histogram, and rotational, scalability, and translational (RST) features are extracted from the pre-processed images. Then, the average correlation (AC) and probability of error (POE) approaches are applied to selecting relevant features and excluding less significant features. After feature selection, a modified AlexNet (MAlexNet) model is used to classify the multi-class classification of liver tumors. Finally, the identified liver tumor regions are segmented using the enhanced U-Net (EUNet) model. Results: Identified liver tumors are accurately classified into three different categories using the proposed classification model: hemangioma (HEM), hepatocellular carcinoma (HCC), and metastatic carcinoma (MET), with an average accuracy of 99.19%. We have collected the multi-class liver cancer CT images from real time patients. The results of the experiments show that proposed hybrid system provides adequate overall accuracy, is less noise-sensitive, and outperforms other state-of-the-art techniques such as SVM, Faster RCNN, Mask RCNN, and SAR-U-Net on a wide range of CT images. Conclusion: Radiologists and doctors can identify liver tumors more accurately using the suggested innovative framework.