High Risk Of Metastasis Research Articles

Surgical treatment of pilomatrix carcinoma: a systematic review.

Pilomatrix carcinoma (PMC), also known as pilomatrical carcinoma, is a rare, malignant tumor of the hair follicle that may arise from a benign pilomatricoma or de novo and carries a high risk of recurrence and metastasis. This study sought to investigate and compare surgical modalities for PMC, including reported outcomes and recurrence rates. In July 2024, a systematic review of PubMed, Embase, and Web of Science databases on surgical modalities and PMC was conducted. Randomized controlled trials and observational studies were included. The search yielded 257 articles; after the application of inclusion and exclusion criteria, 50 articles were included: four case series and 46 case reports with a total of 101 cases. There were 17 cases treated with Mohs micrographic surgery (MMS) with no recurrences. There were 84 cases treated with surgical excision with an overall recurrence rate of 34.5%. The mean follow-up time was 7.5 months for MMS and 7.6 months for surgical excision. MMS showed excellent outcomes for PMC with no recurrences compared with a recurrence rate of 34.5% for surgical excision (P < 0.0025). No recurrences or metastases were found on follow-up reported in all 17 cases treated with MMS in the literature, compared with a recurrence rate of 34.5% for the 84 cases of surgical excision. Due to the importance of early surgical intervention and attaining true negative margins to prevent recurrence and metastasis, MMS should be considered for the treatment of PMC, especially where tissue sparing is essential.

METTL3/YTHDF1 stabilizes CORO6 expression promoting osteosarcoma progression through glycolysis

This study investigates the role of CORO6 (Coronin 6) in the development of osteosarcoma. Osteosarcoma is a common malignant bone tumor in children and adolescents, characterized by rapid and irregular bone growth and a high risk of distant lung metastasis. CORO6 is a member of the Coronin family, known for its conserved WD40 repeat domain. This structure allows CORO6 to inhibit actin dynamics through interactions with F-actin and Arp2/3, thereby affecting the organization of the cytoskeleton. Our research found that in osteosarcoma patients, the levels of CORO6 are significantly elevated. Experimental observations showed that reducing the expression of CORO6 significantly inhibits the growth, migration, and invasion abilities of osteosarcoma cells. Moreover, in vivo experiments demonstrated that the absence of CORO6 effectively inhibits the growth of osteosarcoma in animal models. We also discovered that CORO6 promotes the proliferation, migration and invasion capabilities of osteosarcoma cells by activating the Wnt/β-catenin signaling pathway. Moreover, CORO6 play a critical important role in glycosis of osteosarcoma cells. Mechanically, we found that METTL3/YTHDF1 induced m6A modification of CORO6 mRNA promoted the expression of CORO6 by enhancing its stability. These findings offer new directions for the treatment of osteosarcoma, suggesting that CORO6 could be a novel prognostic biomarker and an effective therapeutic target for patients.In summary, CORO6, as an oncogene, plays a key role in the development of osteosarcoma, providing a crucial theoretical basis for the development of new osteosarcoma treatment strategies.

High Fracture Risk of Femoral Bone Metastasis Treated with Palliative Radiotherapy in Recent Years

High Fracture Risk of Femoral Bone Metastasis Treated with Palliative Radiotherapy in Recent Years

In a prospective, multicenter study, the 31-GEP identified patients at increased risk of tumor recurrence and added significant prognostic value to AJCC staging

Cutaneous melanoma (CM) guidelines base management decisions on a patient’s American Joint Committee on Cancer (AJCC) tumor stage. However, limitations in staging accuracy suggest additional tools could improve risk-aligned patient management decisions. The 31-gene expression profile (GEP) test identifies patients with CM with low (Class 1A), intermediate (Class 1B/2A), or high (Class 2B) risk for sentinel lymph node (SLN) positivity, recurrence, metastasis, and death. In this multicenter, prospective study, we validated the 31-GEP for risk of recurrence and demonstrated the added value of 31-GEP to AJCC staging. Patients were included in the prospective CONNECTION study if they were tested with the 31-GEP from 2018 to the present (n=876). Survival was estimated using Kaplan-Meier analysis and 31-GEP stratification tested with the log-rank test. Cox regression was performed to identify predictors of recurrence. ANOVA was used to compare Cox models for the most accurate recurrence prediction. Patients with a Class 1A result had significantly higher 3-year recurrence-free survival than those with a Class 1B/2A or Class 2B result (98.5% vs. 80.8% vs. 63.0%, p&lt;0.001). The 31-GEP had higher sensitivity (75.0% vs. 37.5%) and negative predictive value (98.6% vs. 96.9%) than AJCC staging. Multivariable analysis demonstrated that Class 1B/2A (hazard ratio, HR=3.12, p=0.037) and Class 2B (HR=5.91, p=0.002) were significant predictors of recurrence in addition to stage IB (HR=4.02, p=0.02), IIA (HR=6.06, p=0.006), IIC (HR=17.14, p&lt;0.001), and III (HR=8.84, p&lt;0.001). Stage IIB (HR=4.63, p=0.057) was not significant. Comparing a staging-only model to a 31-GEP+staging model showed that adding 31-GEP to staging significantly improved prediction accuracy over staging alone (ANOVA: c2=10.58, p=0.005). In this prospective study, the 31-GEP stratified risk of recurrence, was a significant predictor of recurrence, and added significant predictive value to AJCC staging. The 31-GEP identifies patients at high risk of recurrence who should be managed more intensely, and adding 31-GEP to staging allows better risk-aligned care decisions, which can lead to improved patient outcomes.

Abstract A034: Single cell RNA sequencing of triple negative breast cancer patient-derived xenograft model identifies CRABP1 of cancer-associated fibroblast as a key regulator of breast cancer metastasis

Abstract Triple-negative breast cancer (TNBC) is associated with a high risk of distant metastasis, particularly to the lung and liver. Both intrinsic characteristics of cancer cells and the tumor microenvironment (TME) influence TNBC growth and metastasis. The TME, comprising stromal, immune, and endothelial cells, exhibits heterogeneity both between and within cell types. Identifying the molecular characteristics of TME cells that affect cancer progression is crucial. We aim to investigate this using single-cell RNA sequencing of patient-derived xenograft (PDX) models to explore TME cells and genes involved in TNBC metastasis. We established PDX models by transplanting tumor tissues from 26 TNBC patients into immunodeficient mice. These models were categorized based on their metastatic potential and patient outcomes: non-metastatic (n=5) and metastatic (n=4). Single-cell RNA sequencing of nine PDX tumors revealed significant differences in gene expression of murine stromal cells between metastatic and non-metastatic models. We identified ten genes (Serpinb2, Spp1, Tnc, Thbs1, Timp1, Il11, Mt2, Crabp1, Cck, Mt1) that were highly expressed in the stromal cells of metastatic PDX models. To test if TNBC cells influence these fibroblast genes, we exposed NIH3T3 fibroblasts to conditioned media from the 4T1 TNBC cell line. In three independent experiments, only Crabp1 expression in NIH3T3 cells was consistently increased by 4T1- conditioned media. CRABP1, a retinoic acid-binding protein, is known for its role in differentiation and proliferation by regulating MAPK signaling. Although Crabp1-positive cancer-associated fibroblasts have been noted, its role in TNBC metastasis was previously unexplored. We investigated CRABP1 function using a CRABP1 knockdown NIH3T3 cell line. CRABP1 knockdown led to reduced invasion and migration of 4T1 cells in trans-well assays and decreased invasiveness of 4T1 spheroids in a collagen matrix. Additionally, CRABP1 knockdown NIH3T3 cells showed reduced proliferation in vitro and fewer alpha-SMA positive cancer-associated fibroblasts in co-injected 4T1 tumors in BALB/C mice. In summary, CRABP1, identified through single-cell RNA sequencing of stromal cells in TNBC PDX models, is a potential regulator of TNBC metastasis, affecting cancer cell migration, invasion, and fibroblast proliferation. Citation Format: Woohang Heo, Yujeong Her, Sieun Yang, Dakyung Lee, Rokhyun Kim, Jong-Il Kim, Hyeong-Gon Moon. Single cell RNA sequencing of triple negative breast cancer patient-derived xenograft model identifies CRABP1 of cancer-associated fibroblast as a key regulator of breast cancer metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr A034.

Energy-based surgery generated carbonized particles promote the development of ovarian cancer

Cancer patients face a high risk of tumor recurrence and metastasis after surgery. Surgical stress has been reported to be an important trigger for cancer recurrence and metastasis. Energy-based surgical devices have become the most commonly used surgical tool in recent years. However, there is a lack of studies investigating whether using energy-based surgical devices promotes the development of residual tumors. This study aimed to examine the impact of energy-based surgery on tumor growth in comparison to conventional surgery. Results indicated that energy-based surgery is more likely to promote tumor growth than conventional surgery. Further investigation revealed that the carbonized particles produced by energy-based surgical devices during tissue combustion are robust inducers, strongly inducing the polarization of M2-like macrophages in vivo and in vitro. Additionally, carbonized particles induced an immunosuppressive tumor microenvironment in vivo, promoting tumor growth similarly to energy-based surgery. These findings suggested that the production of carbonized particles during energy-based surgery contributed to the development of residual tumor cells. Therefore, it is advisable to implement measures to either eliminate or prevent the production of carbonized particles during energy-based surgery procedures.

Characteristics of multiple esophageal squamous cell carcinomas detected in the surveillance after endoscopic resection.

Endoscopic resection (ER) of esophageal squamous cell carcinoma (ESCC) is an organ-preserving treatment; however, heterochronic carcinomas are often encountered. Most patients are treated using ER; however, for some, this is inadequate and requires additional treatment. We sought to identify the characteristics and frequency of lesions at high risk of metastasis during surveillance based on Lugol-voiding lesion (LVL) grading and esophagogastroduodenoscopy (EGD) intervals. Of the 1301 patients who underwent ER, 956 underwent surveillance EGD at our hospital for at least 1year (median, 59months). We analyzed identified multiple ESCCs to reveal the characteristic of high-metastasis-risk lesions, which was defined ESCC with submucosal or lymphovascular invasion. In the 956 patients, 444 multiple ESCCs were identified in 216 patients and the cumulative incidence of multiple ESCCs was 15.4% and 22.9% at 3 and 5years, respectively, while for high-risk lesions, it was 1.0% and 1.8%. The risk factors for high-metastasis-risk lesions were being female (odds ratio (OR):5.58, 95% confidence interval (CI):1.96-15.9), lesions located in the cervical/upper thoracic esophagus (OR: 4.81, 95% CI:1.80-12.8), and the presence of submucosal tumor (SMT)-like marginal elevation (OR:65.4, 95% CI:11.0-390). No significant differences in the frequency of high-risk lesions were found based on LVL grade at any EGD intervals. During endoscopic surveillance, attention should be given to the cervical/upper thoracic esophagus and lesions with SMT-like marginal elevation. The frequency of high-metastasis-risk lesions was not different by LVL grade or EGD intervals.

Revealing the structural microenvironment of high metastatic risk uveal melanomas following decellularisation

Uveal melanoma (UM) is a rare aggressive intraocular tumour that spreads most commonly to the liver in tumours with loss of one copy of chromosome 3 (HR-M3); current treatments for metastatic disease remain largely ineffective. Pre-clinical research is increasingly using three-dimensional models that better recapitulate the tumour microenvironment (TME). One aspect of the TME is the acellular extracellular matrix (ECM) that influences cell proliferation, migration and response to therapy. Although commercial matrices are used in culture, the composition and biochemical properties may not be representative of the tumour ECM in vivo. This study identifies UM metastatic risk specific ECM proteins by developing methodology for decellularisation of low- and high- metastatic risk tissue samples (LR-D3 vs. HR-M3). Proteomic analysis revealed a matrisome signature of 34 core ECM and ECM-associated proteins upregulated in HR-M3 UM. Combining additional UM secretome and whole cell iTRAQ proteomic datasets revealed enriched GO and KEGG pathways including ‘regulating ECM binding’ and ‘PI3K/Akt signalling’. Structural analyses of decellularised matrices revealed microarchitecture of differing fibre density and expression differences in collagen 4, collagen 6A1 and nidogen 1, between metastatic risk groups. This approach is a powerful tool for the generation of ECM matrices relevant to high metastatic risk UM.

P106 Higher preoperative maximum Standardized Uptake Values (SUVmax) are associated with a higher risk of metastases following robot-assisted radical prostatectomy for patients undergoing 68Ga-PSMA-11 and 18F-DCFPyL PET/CT

P106 Higher preoperative maximum Standardized Uptake Values (SUVmax) are associated with a higher risk of metastases following robot-assisted radical prostatectomy for patients undergoing 68Ga-PSMA-11 and 18F-DCFPyL PET/CT

Brain metastasis burden and management in patients with small cell lung cancer in Canada: a retrospective, population-based cohort study

Patients with small cell lung cancer (SCLC) have historically been characterised by poor overall survival (OS) and high risk for brain metastasis (BM), but large-scale real-world evidence on clinical presentation and treatment in this population is lacking. Our aim was to describe the clinical characteristics and outcomes of patients with SCLC and BM in Ontario, Canada. This population-based, retrospective cohort study included all patients in Ontario, Canada, who were diagnosed with SCLC between April 1, 2010, and March 31, 2018. Data were analysed between June 2, 2022, and December 20, 2023. Patients with second cancer diagnosis were excluded. Patients were identified and data retrieved from the Institute for Clinical Evaluative Sciences (ICES) databases. Kaplan-Meier and multivariable Cox regression analyses were performed to compare OS between patient cohorts stratified by disease stage, BM diagnosis, and intracranial treatment modality. Propensity score-matching based on age, disease stage, time to BM, and receipt of chemotherapy was performed to compare OS between intracranial treatment modalities. 8705 patients were included (male: 4433, female: 4272). Median age at diagnosis was 68 years (interquartile range, IQR, 61-75). Median OS of all patients was 7.46 months (95% confidence interval, CI, 7.23-7.69). 32% (n=2686) of patients developed BM (synchronous, 43.7%; asynchronous, 56.3%) with median OS of 9.76 months (95% CI, 9.36-10.22). 102 (4%), 1654 (62%), and 930 (35%) patients received stereotactic radiosurgery (SRS), whole brain radiation therapy (WBRT), or no treatment, respectively, for their BM in the first-line setting or after prophylactic cranial irradiation (PCI). In propensity score-matched analyses, OS from time of BM diagnosis was non-inferior between SRS- and WBRT-treated cohorts among patients who did not receive PCI (hazard ratio, HR, 0.68, 95% CI, 0.44-1.06, p=0.091, n=86) and in favour of SRS for those who received PCI prior to BM development (HR, 0.47, 95% CI, 0.31-0.72, p=0.0042, n=112). OS for patients with SCLC remains poor, and many patients present with BM. With careful selection, patients with SCLC and BM may benefit from SRS treatment. Future research should incorporate information on burden of intracranial disease and novel immunotherapies. None.

Pyrotinib induces cell death in HER2-positive breast cancer via triggering HSP90-dependent HER2 degradation and ROS/HSF-1-dependent oxidative DNA damage.

HER2-positive breast cancer (HER2+ BC) is distinguished by its poor prognosis, propensity for early onset, and high risk of recurrence and metastasis. Consequently, anti-HER2-targeted therapy has emerged as a principal strategy in the treatment of this form of breast cancer. Pyrotinib, a novel irreversible pan-HER2 tyrosine kinase inhibitor, has brought fresh hope to patients with advanced HER2+ breast cancer. In this study, we conducted a comprehensive exploration of pyrotinib's anti-tumor mechanism. The in vitro results showed that pyrotinib significantly inhibited SKBR3 cells viability and induced apoptosis by promoting HER2 endocytosis and ubiquitylation, leading to HER2 degradation through the displacement of HSP90 from HER2. Beyond targeting the HER2 signaling pathway, pyrotinib also induced DNA damage, which was mediated by the activation of the ROS/HSF-1 signaling pathway and the downregulation of PCNA expression. Furthermore, the in vivo results demonstrated a pronounced anticancer effect of pyrotinib in the SKBR3 xenograft mouse model, concomitant with a reduction in HER2 expression. In summary, our findings provide novel insights into the mechanism of pyrotinib in the treatment of HER2+ BC.

Machine Learning Models to Predict Bone Metastasis Risk in Patients With Lung Cancer.

The aim of this study was to find the most appropriate variables to input into machine learning algorithms to identify those patients with primary lung malignancy with high risk for metastasis to the bone. Patients with either histological or radiological diagnoses of lung cancer were included in this study. The patient cohort comprised 1864 patients diagnosed from 2016 to 2021. A total of 25 variables were considered as potential risk factors. These variables have been identified in previous studies as independent risk factors for bone metastasis. Treatment methods for lung cancer were taken into account during model development. The outcome variable was binary, (presence or absence of bone metastasis) with follow-up until death or 12-month survival, whichever is the sooner. Results showed that American Joint Committee on Cancer staging, the use of EGFR inhibitor, age, T-staging, and lymphovascular invasion were the five input features contributing the most to the model algorithm. High AJCC staging (OR 1.98; p < 0.05), the use of EGFR inhibitor (OR 6.14; p < 0.05), high T-staging (OR 1.47; p < 0.05), and the presence of lymphovascular invasion (OR 4.92; p < 0.05) increase predicted risk of bone metastasis. Conversely, older age reduces predicted bone metastasis risk (OR 0.98; p < 0.05). The machine learning model developed in this study can be easily incorporated into the hospital's Clinical Management System so that input variables can be immediately utilized to give an accurate prediction of bone metastatic risk, therefore informing clinicians on the best treatment strategy for that individual patient.

MammaPrint Genomic Assay Providing Prognostic Information in Early Breast Cancer: 10-Year Follow-Up From a Retrospective German Breast Cancer Registry Analysis

Introduction: Gene expression assays, such as the MammaPrint® (Agendia, Amsterdam, the Netherlands) 70-gene signature, are increasingly used by oncologists to understand breast cancer biology and improve treatment planning. This study assesses the utility of MammaPrint genomic risk in predicting treatment outcomes for women with breast cancer in a retrospective German cohort with a 10-year follow-up, treated based on clinicopathological features alone. Methods: The sample set of 117 tumours from the ‘Patients Tumour Bank of Hope’ (PATH) biobank with 10-year follow-up were classified using MammaPrint into high or low risk of distant metastasis. Patients were previously treated according to St. Gallen and Adjuvant! Online high- or low-risk criteria. Statistical analyses compared overall survival (OS) and treatment outcomes between clinical and genomic risk groups. Results: Among the 78 patients with clinically high-risk tumours, 50% (39) were reclassified as MammaPrint low risk. In total, 57.3% (67/117) patients with MammaPrint low-risk tumours demonstrated a significantly higher 10-year OS of 93.4%, irrespective of nodal status, compared to patients with MammaPrint high-risk tumours (71.2%; p=0.001). Chemotherapy improved OS in patients with MammaPrint high-risk tumours by 29.4%, but not for patients with MammaPrint low-risk tumours (p=0.016). Discussion: The findings confirm the prognostic utility of MammaPrint for identifying genomically low-risk patients who may safely omit chemotherapy while suggesting genomically high-risk cases may benefit from chemotherapy. By providing a more precise assessment of cancer risk than traditional clinicopathological methods alone, MammaPrint may help reduce unnecessary treatments and improve long-term quality of life for patients diagnosed with early-stage breast cancer.

Metallic-based phthalocyanine nanoemulsions for photodynamic purging of ovarian tissue in leukemia patients

For cancer patients with a high risk of ovarian tissue metastasis, ovarian autotransplantation is not advised due to the potential spread of malignant cells. Ex vivo purging of ovarian fragments may offer a more suitable alternative for fertility restoration. Eradicating malignant cells should be done selectively without affecting follicles or ovarian stromal cells (SCs). As a clinically licensed method, photodynamic therapy (PDT) is a minimally invasive treatment to destroy cancer cells. This study evaluates the effectiveness of nanoemulsions (NE) containing two phthalocyanine photosensitizers; aluminum (III) phthalocyanine (AlPc) and zinc (II) phthalocyanine (ZnPc) in eliminating cancer cells. Human leukemic malignant (HL-60) and ovarian stromal cells (SCs) were treated with AlPc/ZnPc loaded NEs with or without diode laser irradiation. HL-60 leukemia cells in 2D culture were eliminated by treatment with 10 nM AlPc-NE or 0.1 µM ZnPc-NE, while no toxicity was observed in SCs. In 3D culture models, although the cells showed more resistance to the NEs as a result of limited oxygen and photosensitizer penetration, the treatment remained selective for cancer cells. These approaches have the potential to eliminate malignant cells from ovarian tissue fragments.

Myofibroblastic Sarcoma of the Maxillary Sinus: Very Rare Entity

Introduction: The Myofibroblastic Sarcoma is a recently discovered malignant tumor that mainly affects the face and neck region, but it occurs most often in the tongue and oral cavity. However, involvement of the maxillary sinus has only been reported a few times in the literature. It is a slowly growing neoplasm with a high recurrence and metastasis risk.  Case Presentation: 18 years old female patient, admitted for a painless mass of the left hemi palate increasing progressively in volume evolving since 5 months, associated to a left nasal obstruction and purulent rhinorrhea. Once in our department, she underwent a facial CT scan, followed by a facial MRI, which showed a tissue process centered primarily on the left maxillary sinus, causing lysis of the inferior wall and bulging of the hard palate on the left side . The surgical decision involved combining an endoscopic and external approach, and was supplemented by radiation therapy. The follow up demonstrated a successful outcome. the patient did not present any recurrence or distant metastasis.  Conclusion: The key lessons are the essential role of imaging in diagnosing and treating LGMS , as well as the crucial role of postoperative radiotherapy in preventing recurrence even though this subject is still controversial.

Single-Nuclei Transcriptome Profiling Reveals Intra-Tumoral Heterogeneity and Characterizes Tumor Microenvironment Architecture in a Murine Melanoma Model

Malignant melanoma is an aggressive cancer, with a high risk of metastasis and mortality rates, characterized by cancer cell heterogeneity and complex tumor microenvironment (TME). Single cell biology is an ideal and powerful tool to address these features at a molecular level. However, this approach requires enzymatic cell dissociation that can influence cellular coverage. By contrast, single nucleus RNA sequencing (snRNA-seq) has substantial advantages including compatibility with frozen samples and the elimination of a dissociation-induced, transcriptional stress response. To better profile and understand the functional diversity of different cellular components in melanoma progression, we performed snRNA-seq of 16,839 nuclei obtained from tumor samples along the growth of murine syngeneic melanoma model carrying a BRAFV600E mutation and collected 9 days or 23 days after subcutaneous cell injection. We defined 11 different subtypes of functional cell clusters among malignant cells and 5 different subsets of myeloid cells that display distinct global transcriptional program and different enrichment in early or advanced stage of tumor growth, confirming that this approach was useful to accurately identify intratumor heterogeneity and dynamics during tumor evolution. The current study offers a deep insight into the biology of melanoma highlighting TME reprogramming through tumor initiation and progression, underlying further discovery of new TME biomarkers which may be potentially druggable.

Medical imaging for the diagnosis, recurrence and metastasis evaluation of clear cell sarcoma

Clear cell sarcoma (CCS) of soft tissue is extremely rare, accounting for approximately 1% of all soft tissue tumours. It is very difficult to diagnose CCS based on clinical manifestations. Magnetic resonance imaging (MRI) provides high-resolution images of soft tissues and pathological features such as mucus, necrosis, bleeding, and fat through high and low signals on T1 weighted image (T1WI) and T2 weighted image (T2WI). On the other hand, the paramagnetism of melanin in CCS shortens the relaxation time of T1 and T2, and high signal intensity on T1WI and low signal intensity on T2WI can be found. This is different from most other soft tissue sarcomas. At present, the treatment method for CCS is surgical resection. MRI can effectively display the tumour edge, extent of surrounding oedema, and extent of fat involvement, which is highly important for guiding surgical resection and predicting postoperative recurrence. As an invasive sarcoma, CCS has a high risk of metastasis. Regardless of the pathological condition of the resected tumour, MRI or computed tomography (CT) should be performed every 1-2 years to assess recurrence at the primary site and to screen for metastasis in the lungs, liver, and bones. If necessary, PET-CT can be performed to evaluate the overall condition of the patient.

Identification of targetable epigenetic vulnerabilities in uveal melanoma.

Uveal melanoma (UM) is the most prevalent primary intraocular malignancy in adults, which preferentially metastasizes to the liver in approximately half of all cases. Metastatic UM is notoriously resistant to therapy and is almost uniformly fatal. UM metastasis is most strongly associated with mutational inactivation of the BAP1 tumor suppressor gene. Given the role of BAP1 in epigenetic regulation as the ubiquitin hydrolase subunit of the polycomb repressive deubiquitinase (PR-DUB) complex, we conducted high-throughput drug screening using a well-characterized epigenetic compound library to identify new therapeutic vulnerabilities. We identified several promising new lead compounds, in particular the extra-terminal domain protein (BET) inhibitor mivebresib (ABBV-075). Mivebresib significantly improved survival rates in a metastatic uveal melanoma xenograft mouse model and entirely prevented detectable metastases to the bones, spinal cord, and brain. RNA sequencing revealed a notable overlap between the genes and pathways affected by HDAC and BET inhibition, including the reversal of gene signatures linked to high metastatic risk and upregulation of genes associated with a neuronal phenotype. Together, we found that UM cells are particularly vulnerable to class I HDAC and BET inhibition, and highlight the BET inhibitor mivebresib as a promising candidate for further clinical evaluation.

Recent Advances in Bacterium-Based Therapeutic Modalities for Melanoma Treatment.

Melanoma is one of the most severe skin cancer indications with rapid progression and a high risk of metastasis. However, despite the accumulated advances in melanoma treatment including adjuvant radiation, chemotherapy, and immunotherapy, the overall melanoma treatment efficacy in the clinics is still not satisfactory. Interestingly, bacterial therapeutics have demonstrated unique properties for tumor-related therapeutic applications, such as tumor-targeted motility, tailorable cytotoxicity, and immunomodulatory capacity of the tumor microenvironment, which have emerged as a promising platform for melanoma therapy. Indeed, the recent advances in genetic engineering and nanotechnologies have boosted the application potential of bacterium-based therapeutics for treating melanoma by further enhancing their tumor-homing, cell-killing, drug delivery, and immunostimulatory capacities. This review provides a comprehensive summary of the state-of-the-art bacterium-based anti-melanoma modalities, which are categorized according to their unique functional merits, including tumor-specific cytotoxins, tumor-targeted drug delivery platforms, and immune-stimulatory agents. Furthermore, a perspective is provided discussing the potential challenges and breakthroughs in this area. The insights in this review may facilitate the development of more advanced bacterium-based therapeutic modalities for improved melanoma treatment efficacy.

AXILLARY LYMPH NODE METASTASIS IN SONOLOGICALLY NODE-NEGATIVE BREAST CARCINOMA

Objectives: This study describes the risk factors for axillary metastasis in patients with sonologically node-negative breast carcinoma and also develops a predictive model to evaluate the risk of axillary metastasis in these patients. Methods: Patients admitted to the Department of General Surgery with carcinoma breast qualifying the inclusion and exclusion criteria were included in the study for a period of 1 year. Study was conducted to determine the risk factors of Carcinoma breast by evaluating some clinical and pathological parameters of carcinoma breast patients. Results: Out of 102 patients, 41 had axillary metastasis, factors found significant with p&lt;0.05 were T stage, grade of tumor, estrogen receptor (ER), progesterone receptor (PR) &lt; human epidermal growth factor receptor 2 (HER 2) neu status, histology, and lymphovascular invasion. Mathematical model was developed by binary logistic regression analysis and the probability of axillary metastasis is obtained. Conclusion: The present study demonstrated that T stage, grade of tumor, ER, PR, HER 2 neu status, histology, and lymphovascular invasion are associated with a high risk of axillary metastasis and the newly generated tool shows a sensitivity of 87.8% and specificity of 93.44% for an optimum cut off of &gt;0.2708.