Loss of Lipocalin2 confers cisplatin vulnerability through modulating NF-ĸB mediated ferroptosis via ferroportin.

Cisplatin is a widely used anti-cancer drug. Unfortunately, many cancers often develop resistance, which contributes to tumor recurrence and poorly prognosis. Growing knowledge has suggested the therapeutic potential of ferroptosis in cancer. Lipocalin2 (LCN2) is demonstrated to be a critical iron metabolic factor and implies in ferroptosis. Here, we aim to explore its role in chemotherapy resistance. The influence of LCN2 on colorectal cancer (CRC) cell chemoresistance and ferroptosis were evaluated by in vitro and in vivo approaches. The interaction between LCN2, NF-ĸB and ferroportin (FPN) was assessed by western blots, immunohistochemistry and dual luciferase reporter assays. Results showed that LCN2 was highly expressed in tumor regression grade 1 (TRG1) cases than that in TRG3 specimens. Loss of LCN2 contributed to resistance to cisplatin-induced ferroptosis. Mechanistically, loss of LCN2 inhibited cisplatin sensitivity and cisplatin-induced ferroptosis through elevating FPN expression which was regulated by NF-ĸB, subsequently reducing Fe2+ mediated Fenton reaction. Furthermore, FPN expression rate was much lower in TRG1 cases, and negative correlation between LCN2 and FPN expression was observed in clinical specimens. Collectively, low LCN2 expression enhances insensitivity of cisplatin to CRC cells via Fenton reaction mediated ferroptosis. LCN2/NF-ĸB/FPN pathway might be potentially utilized for chemoresistance strategy. LCN2 and FPN expression might be a promising biomarker of chemotherapy effect for CRC patients.

Diagnosis and treatment of biliary mucinous cystic neoplasms: A single-center experience.

BACKGROUND: Biliary mucinous cystic neoplasms (BMCNs) are rare hepatobiliary cystic tumors, which can be divided into noninvasive and invasive types. This study aimed to investigate the diagnosis, treatment, and prognosis of BMCNs in a large single center. METHODS: We analyzed 49 patients with BMCNs confirmed by postoperative pathology at the First Affiliated Hospital, Zhejiang University School of Medicine between January 2007 and December 2021. RESULTS: Among the 49 patients, 37 were female (75.5%), and the average age was 57.04 years. Common symptoms included abdominal discomfort, jaundice and fever, while 22 patients (44.9%) had no symptoms. Serum carbohydrate antigen (CA) 19-9 and CA125 concentrations were elevated in 34.8% and 19.6% of patients, respectively. Forty-eight patients had tumors in the intrahepatic bile ducts and only one had a tumor in the extrahepatic bile duct. Forty-eight patients with noninvasive intrahepatic BMCNs were further analyzed in terms of pathological features: 34 (70.8%) had low-grade intraepithelial neoplasms (LGINs), and 14 (29.2%) had high-grade intraepithelial neoplasms (HGINs). The potential immunohistochemical markers of BMCNs were cytokeratin (CK) 19, CK7, estrogen receptor and progesterone receptor. Follow-up data for 37 patients with intrahepatic BMCNs were obtained. The median overall survival (OS) of BMCNs was not reached. The longest survival time was 137 months.The 5- and 10-year OS rates were 100% and 85.4%, respectively. The 5- and 10-year recurrence-free survival (RFS) rates were 93.9% and 80.2%, respectively. CONCLUSIONS: BMCNs are rare cystic neoplasms that commonly occur in middle-aged females. BMCNs can only be diagnosed and classified by postoperative pathology, as there are no specific clinical presentations, serological indicators or imaging modalities for preoperative diagnosis. Complete surgical resection is necessary for BMCNs, and the postoperative prognosis is favorable.

Non-iatrogenic implantation of cutaneous metastasis from hepatocellular carcinoma.

PURPOSE: Cutaneous metastases as an extrahepatic metastasis from hepatomas (HCC) is extremely rare and always carry a poor prognosis and less survival time. Previously, there has been a limited number of literature that reported skin metastasis in a large number of cases, which has rarely been discussed in the empirical treatment and therapy of cutaneous metastasis, especially for non-iatrogenic implantation. It is necessary to discuss this kind of metastasis. PATIENTS AND METHODS: We summarize cases from our medical center from 2013 to 2021, there are 12 patients diagnosed with non-iatrogenic implantation of cutaneous metastasis after HCC. We conducted the investigation of the clinical prognosis, pathological characteristics, and treatment of those patients. RESULTS: All patients were male, the age ranged from 21 to 71 years old, the average size of primary HCC was over 5 cm, there was four patient's cutaneous metastasis from the skin of head (including scalp and occipital region), followed by right abdominal (2 patients), right chest wall (2 patients), back (2 patients), umbilical (1 patient), gluteal region (1 patient). The cutaneous metastases presented as solitary or multiple nodules, papules, and erythema without ulcers with sizes between 0.5 cm and 5 cm. 7 patients died after being diagnosed with cutaneous metastasis within 2-19 months. CONCLUSIONS: The rate of non-iatrogenic implantation cutaneous metastasis is low, but the prognosis is poor, combining with histopathological analysis and history of diseases can be helpful in diagnosis. For large HCC (> 5 cm), systematic treatment is recommended to prevent the occurrence of cutaneous metastasis and improve the prognosis after hepatectomy.

Single-center Experience in the Diagnosis and Treatment of Hepatic Perivascular Epithelioid Cell Neoplasm.

BACKGROUND AND AIMS: Perivascular epithelioid cell neoplasms (PEComas) are a rare type of mesenchymal neoplasm and their preoperative diagnosis is challenging. In this study, we summarized the experience from a single medical center to study the examinations, clinical presentations, and pathological and histological characteristics of PEComas in the liver in order to optimize overall understanding of the diagnosis and treatment of these neoplasms. METHODS: We conducted a retrospective analysis to investigate the clinical and pathological characteristics as well as imaging presentations of 75 patients diagnosed with hepatic PEComa in The First Affiliated Hospital of Zhejiang University between April 2010 and April 2020. RESULTS: Among the 75 patients, 52 were women, and the median age was 48 years. Most patients had no specific symptoms, and two were admitted to the hospital for a second time owing to relapse. All patients underwent surgical resection. Histologically, 38 patients had classical angiomyolipoma (AML) and 37 had epithelioid AML. The PEComas were accompanied by positive immunohistochemical expression of HMB45, Melan-A, and smooth muscle actin. Follow-up data were obtained from 47 of the total 75 patients, through October 2020. Two patients had metastasis after surgery. CONCLUSIONS: AML is the most common type of hepatic PEComa. There are no specific symptoms of hepatic PEComa, and serological examinations and imaging modalities for accurate preoperative diagnosis are lacking. Epithelioid AML should be considered a tumor of uncertain malignant potential; however, the prognosis of PEComa after resection is promising.

CT Radiomics for the Preoperative Prediction of Ki67 Index in Gastrointestinal Stromal Tumors: A Multi-Center Study.

PURPOSE: This study established and verified a radiomics model for the preoperative prediction of the Ki67 index of gastrointestinal stromal tumors (GISTs). MATERIALS AND METHODS: A total of 344 patients with GISTs from three hospitals were divided into a training set and an external validation set. The tumor region of interest was delineated based on enhanced computed-tomography (CT) images to extract radiomic features. The Boruta algorithm was used for dimensionality reduction of the features, and the random forest algorithm was used to construct the model for radiomics prediction of the Ki67 index. The receiver operating characteristic (ROC) curve was used to evaluate the model's performance and generalization ability. RESULTS: After dimensionality reduction, a feature subset having 21 radiomics features was generated. The generated radiomics model had an the area under curve (AUC) value of 0.835 (95% confidence interval(CI): 0.761-0.908) in the training set and 0.784 (95% CI: 0.691-0.874) in the external validation cohort. CONCLUSION: The radiomics model of this study had the potential to predict the Ki67 index of GISTs preoperatively.

Primary Prostatic Extra-Gastrointestinal Stromal Tumor Treated with Imatinib Mesylate as Neoadjuvant and Adjuvant Therapy: A Case Report and Literature Review.

The current study presents a case of primary prostatic extra-gastrointestinal stromal tumor (EGIST) in a 43-year-old man who suffered acute urinary retention. The serum level of prostate-specific antigen was normal. Imaging examinations demonstrated a diffusely enlarged prostate compressing the rectum without evidence of metastasis. After excluding the possibility of secondary involvement by a rectal GIST, the pathologic diagnosis of primary prostatic EGIST was established based on microscopic study, immunohistochemistry, and molecular analysis. This patient is the first case with primary EGISTs of prostate received imatinib mesylate as neoadjuvant and adjuvant therapy reported in the literature to date. We hope this case could provide the experience of diagnosis and treatment of primary prostatic EGISTs.

Lipocalin2 suppresses metastasis of colorectal cancer by attenuating NF-κB-dependent activation of snail and epithelial mesenchymal transition.

BACKGROUND: Lipocalin2 (LCN2) is a secretory protein that is aberrantly expressed in several types of cancer and has been involved in metastatic progression. However, neither mechanisms nor the role that LCN2 plays in the metastasis of colorectal cancer are clear. METHODS: LCN2 expression in colorectal cancer was detected by immunohistochemistry in 400 tissue specimens and Kaplan-Meier survival analysis was performed. In vitro, real-time PCR, western blot, colony formation assay, immunofluorescence assay, wound healing assay, migration and invasion experiment were performed to investigate the effects of LCN2 in epithelial mesenchymal transition (EMT), migration and invasion, respectively. In vivo mouse xenograft and metastasis models were utilized to determine tumorigenicity and metastasis ability, and immunohistochemistry, real-time PCR, western blot were used to evaluate the related protein expression. Luciferase reporter assay was used to explore the role of LCN2 on NF-ĸB promoter. RESULTS: LCN2 was highly expressed in 66.5% of the specimens, and significantly correlated with positive E-cadherin in the membrane and negative nuclear ß-catenin. Higher expression of LCN2 together with negative NF-κB expression was negatively related to nuclear accumulation of snail and predicted favorable prognosis. LCN2 blocked cell proliferation, migration and invasion in vitro and in vivo, and inhibited translocation of NF-κB into nucleus. NF-κB could reverse the effect of LCN2 on EMT and promote snail expression. Rescued snail expression had similar effect without influencing NF-κB activity. CONCLUSION: LCN2 may be an important negative regulator in EMT, invasion and metastasis of CRC via acting as upstream of NF-κB/snail signaling pathway. Thereby combinative manipulation of LCN2 and NF-κB/snail pathway may represent a novel and promising therapeutic approach for the patients with CRC.