Targeting the TCA cycle through cuproptosis confers synthetic lethality on ARID1A-deficient hepatocellular carcinoma.

ARID1A is among the most commonly mutated tumor suppressor genes in hepatocellular carcinoma (HCC). In this study, we conduct a CRISPR-Cas9 synthetic lethality screen using ARID1A-deficient HCC cells to identify approaches to treat HCC patients harboring ARID1A deficiency. This strategy reveals that the survival of these ARID1A-deficient HCC cells is highly dependent on genes related to the tricarboxylic acid (TCA) cycle. Mechanistically, ARID1A loss represses expression of key glycolysis-related gene PKM, shifting cellular glucose metabolism from aerobic glycolysis to dependence on the TCA cycle and oxidative phosphorylation. Cuproptosis is a recently defined form of copper-induced cell death reported to directly target the TCA cycle. Here, we find that ARID1A-deficient HCC cells and xenograft tumors are highly sensitive to copper treatment. Together, these results offer evidence of the synthetic lethality between ARID1A deficiency and mitochondrial respiration impairment, suggesting that copper treatment constitutes a promising therapeutic strategy for selectively targeting ARID1A-deficient HCC.

The accuracy of ultrasound-guided fine-needle aspiration and core needle biopsy in diagnosing axillary lymph nodes in women with breast cancer: a systematic review and meta-analysis.

Background: This study evaluates the diagnostic accuracy of ultrasound-guided fine needle aspiration (US-FNA) and core needle biopsy (US-CNB) for detecting axillary lymph nodes in women with breast cancer. Methods: Eligible studies and pertinent literature resources were identified in Cochrane, PubMed, Embase, CNKI, VIP, and Wanfang databases using subject-specific keywords. Study outcomes were tested for heterogeneity, and meta-analyses were performed to estimate sensitivity, specificity, and diagnostic odds ratios (DORs). The summary receiver operating characteristic (SROC) curve analysis was also performed. Results: A total of 22 studies involving 3,548 patients were included to evaluate the diagnostic accuracy of US-FNA and 11 studies involving 758 patients were included to evaluate the diagnostic accuracy of US-CNB in identifying axillary lymph nodes in women with breast cancer. The accuracy of US-FNA in identifying suspicious axillary lymph nodes was as follows: overall sensitivity, 79% (95% CI: 73%-84%); global specificity, 96% (95% CI: 92%-98%); overall positive likelihood ratio, 18.55 (95% CI: 10.53-32.69); overall negative likelihood ratio, 0.22 (95% CI: 0.17-0.28); DOR, 71.68 (95% CI: 37.19-138.12); and the area under the SROC curve, 0.94 (95% CI: 0.92-0.96). The accuracy of US-CNB in identifying suspicious axillary lymph nodes was as follows: overall sensitivity, 85% (95% CI: 81%-89%); global specificity, 93% (95% CI: 87%-96%); overall positive likelihood ratio, 11.88 (95% CI: 6.56-21.50); overall negative likelihood ratio, 0.16 (95% CI: 0.12-0.21); overall DOR, 66.83 (95% CI: 33.28-134.21), and the area under SROC curve 0.96 (95% CI: 0.94-0.97). Conclusions: The results indicate that both US-FNA and US-CNB have high accuracy for suspicious axillary lymph nodes.

The Role of Endophilin A1 in Lipopolysaccharide-Induced Parkinson's Disease Model Mice.

BACKGROUND: Endophilin A1 (EPA1) is encoded by the SH3GL2 gene, and SH3GL2 was designated as a Parkinson's disease (PD) risk locus by genome-wide association analysis, suggesting that EPA1 may be involved in the occurrence and development of PD. OBJECTIVE: To investigate the role of EPA1 in lipopolysaccharide (LPS)-induced PD model mice. METHODS: The mice PD model was prepared by injecting LPS into the substantia nigra (SN), and the changes in the behavioral data of mice in each group were observed. The damage of dopaminergic neurons, activation of microglia, and reactive oxygen species (ROS) generation were detected by immunofluorescence method; calcium ion concentration was detected by calcium content detection kit; EPA1 and inflammation and its related indicators were detected by western blot method. EPA1 knockdown was performed by an adeno-associated virus vector containing EPA1-shRNA-eGFP infusion. RESULTS: LPS-induced PD model mice developed behavioral dysfunction, SN dopaminergic nerve damage, significantly increased calcium ion, calpain 1, and ROS production, activated NLRP1 inflammasome and promoted pro-inflammatory cell release, and SN EPA1 knockdown improves behavioral disorders, alleviates dopaminergic neuron damage, reduces calcium, calpain 1, ROS generation, and blocks NLRP1 inflammasome-driven inflammatory responses. CONCLUSION: The expression of EPA1 in the SN of LPS-induced PD model mice was increased, and it played a role in promoting the occurrence and development of PD. EPA1 knockdown inhibited the NLRP1 inflammasome activation, decreased the release of inflammatory factors and ROS generation, and alleviated dopaminergic neuron damage. This indicated that EPA1 may participating in the occurrence and development of PD.

A better overall survival (OS) for total (ipsilateral) retroperitoneal lipectomy than standard complete resection in patients with retroperitoneal liposarcoma: a comparative multi-institutional study.

Background: Complete resection (CR) serves as the standard of surgical treatment for retroperitoneal liposarcoma (RPLS). Unfortunately, even at referral centers, recurrence rates are high, and CR may not address multifocal diseases, which are a common phenomenon in RPLS. We sought to retrospectively compare the clinical outcomes of RPLS patients treated with total (ipsilateral) retroperitoneal lipectomy (TRL) and CR. Because TRL remove potentially multifocal tumors in the fat, patients may have a better prognosis than CR. Methods: Patients with primary/first-recurrent RPLS who had been treated at 5 referral centers were recruited from December 2014 to June 2018. Multivariable Cox regression analyses were conducted to determine the effects of demographic, operative, and clinicopathological variables on the following primary endpoints: local recurrence (LR), local recurrence-free survival (LRFS), and overall survival (OS). Results: A total of 134 patients were enrolled in this retrospective study, 53 of whom underwent TRL, and 81 of whom underwent CR. The 2 groups were comparable in terms of age, gender, presentation (primary vs. first-recurrent RPLS), number of tumors (unifocal vs. multifocal) at presentation, and Fédération Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grade. The TRL group had higher levels of preoperative hemoglobin (Hb) (13 vs. 12.5 g/dL; P=0.008) and a lower amount of intraoperative blood loss (400 vs. 500 mL; P=0.034), but there were no significant differences in the length of hospital stay (23 vs. 22 d; P=0.47) or complications (32 vs. 30; P=0.82) between the 2 groups. In a subset of patients with multifocal tumors at initial presentation, OS was more prolonged in those treated with TRL than those treated with CR (P=0.0272). Based on the multivariable analysis, primary liposarcoma and a low FNCLCC grade were associated with decreased LR and improved OS. Conclusions: TRL is a safe procedure that positively affects the OS of patients with multifocal RPLS. This novel strategy deserves further investigation in prospective studies.

Comparison study of clinicopathological features of cellular schwannoma between retroperitoneum and other sites.

Background: Cellular schwannoma (CS) is a relatively rare neural tumor with few reports. This study aimed to compare the clinicopathological characteristics of CS in the retroperitoneum and other sites by analyzing the hematoxylin-eosin (HE) staining and immunohistochemical (IHC) staining results, to provide some help for pathological diagnosis. Methods: A total of 79 CS cases from the Department of Pathology, Peking University International Hospital were collected, and the diagnosis was based on the 5th WHO classification of soft tissue tumors. The staining results of HE and IHC were judged and analyzed according to the instructions. The t-tests, Chi-square test and Fisher's exact probability test were used for statistical analysis. Results: Compared with other sites, the volume of retroperitoneal CS tumors were larger (t=4.265, P=0.001) and more likely to recur (χ2=4.223, P=0.04). Nerve sheath structures were rare around the tumors (χ2=60.096, P=0.000). Immunohistochemically, there was a difference in the expression of glial fibrillary acidic protein (GFAP), Cytokeratin (CK), and myelin basic protein (MBP) between the two groups (χ2=54.290, P=0.000; χ2=4.879, P=0.027; χ2=31.792, P=0.000). But there was no difference in expression between the two groups in the other indexes. Conclusions: It founded that Retroperitoneal CS was often positive for GFAP and CK, suggesting it originated from unmyelinated Schwann cells. CS in other sites, the expression of GFAP and CK was often negative, indicating they derived from myelinated Schwann cells. The expression of MBP in the peripheral nerve sheath structure of CS can be used to determine whether the tumor originates from myelinated or unmyelinated Schwann cells. These findings may provide a reference for revealing pathogenesis, diagnosis and evaluating prognosis of CS.

41-year-old male with a pituitary mass.

Cranial coronal T1-weighted magnetic resonance imaging with contrast enhancement showed a sellar irregular lesion (Figure A). Hematoxylin and eosin staining showed two different morphologies. The majority of tumor cells had medium-sized to large cells with a high nucleus to cytoplasm ratio, vesicular nuclei with prominent nucleoli, and poor adhesion (Figure B), which revealed positive expression of CD20 by Immunohistochemistry (Figure C). The other component showed abundant cytoplasm, spindle-like to ovoid nucleus and rare mitotic figures (Figure D). These tumor cells were positive for Pit-1 (Figure E) and perinuclear punctated structures immunopositive for CK18 (Figure F).

Pyloric gland adenoma with low-grade intraepithelial neoplasia: A case report and literature review.

RATIONALE: Pyloric gland adenoma (PGA) is often associated with pyloric gland metaplasia. It has high malignant potential but a low clinical diagnosis rate. Therefore, we reported a case of PGA and reviewed the literature to summarize the clinicopathological features of pyloric adenoma. PATIENT CONCERNS: A 62-year-old female underwent gastroscopy due to intermittent acid regurgitation and heartburn, which revealed a 4×6 mm flat, elevated lesion in the greater curvature of the upper gastric body, with depression in the central region and blood scab attachment. DIAGNOSIS AND INTERVENTION: Biopsy revealed gastric adenoma with low-grade intraepithelial neoplasia. The patient was treated with ESD, and pathology showed gastric pyloric gland adenoma with low-grade dysplasia. The cells were positive for MUC6 and MUC5AC immunohistochemically. OUTCOMES: The patient received proton pump inhibitors and gastric mucosal protective agents for one month after ESD. She occasionally presented acid regurgitation and heartburn, with no abdominal pain, abdominal distension, melena, or hematochezia. Follow-up gastroscopy will be reexamined 1 year later. LESSONS: PGA has nonspecific performance under endoscopy, and its diagnosis mainly depends on pathology. Clinicians need to increase their ability to recognize such lesions and treat them in time to improve the prognosis.

Gastric adenocarcinoma of the fundic gland type: A case report.

INTRODUCTION: Gastric adenocarcinoma of the fundic gland type (GA-FG) is a newly described entity that is characterized by well-differentiated neoplasm with unclear etiopathogenesis. PATIENT CONCERNS: A 60-year-old Chinese man was referred to our hospital for abdominal distension. DIAGNOSIS: Esophagogastroduodenoscopy (EGD) showed a depressed lesion found using in the greater curvature of the stomach. The pathological diagnosis of the biopsy specimens indicated that the tumor was GA-FG (chief cell predominant type, GA-FG-CCP). INTERVENTIONS: Endoscopic submucosal dissection (ESD) was performed. The histopathological examination of the ESD specimen revealed gastric hyperplasia of the fundic gland type around the adenocarcinoma cells. OUTCOMES: The surgical outcomes were good. The EGD showed a scar with no recurrence, and no symptoms were observed 1 year postoperatively during the follow-up. CONCLUSION: We present a rare case of a depressed lesion with a pathogenic expression suggesting gastric hyperplasia of the fundic gland type around the adenocarcinoma cells. Considering the origin of oxyntic mucosa, we consider that it may develop into GA-FG. To understand this issue better, similar cases should be monitored in the future.

Clinical and pathological analysis of 116 cases of adult adrenal cortical adenoma and literature review.

BACKGROUND: The aim of this study is to investigate origin, gross features, microscopic features, immunohistochemical properties, and differential diagnosis of adrenal cortical adenoma (ACA) in patients ≥20 years old. METHODS: The clinicopathological features of 116 cases of ACA and the immunohistochemical features of 50 cases of ACA were evaluated, and the relevant literature was reviewed. RESULTS: In our cohort, 76.72% (89/116) of the cases were functional, and 27 cases had non-functional, benign adrenal adenomas. ACA presented as an island tumor with an envelope, and the mean tumor size was 3.6 cm (range 1-5 cm), with a mean tumor weight of 9.28 g (range 5-113 g). The shape of the tumor cells was consistent, and mitosis was rarely observed. Forty of the 46 patients with cortisol-secreting ACA had tumors containing granule cells. Primary aldosteronism was observed in 43 cases. Thirty-eight cases had endoscopically visible tumors, with clear cells and lipid-rich cytoplasm arranged in irregular patches or strips. Cortisol-producing ACAs were associated with atrophy of the non-tumorous cortex. Adrenocortical adenomas displayed positive immunohistochemical staining for MELAN-A, Syn (46 of 50 cases of ACA), NSE (44 of 50 cases of ACA), Vim (42 of 50 cases of ACA) and Ki-67 <5% (24 of 50 cases of ACA; the remaining 26 cases were negative for Ki-67). CONCLUSION: Prediction of endocrine syndrome in functional ACA was possible based on its structure and morphologic features, which could prevent an unanticipated postoperative crisis. However, a clinical study is needed to validate these findings.

ERG rearrangement is associated with prostate cancer-related death in Chinese prostate cancer patients.

Recently, ETS-related gene (ERG) gene rearrangements, phosphatase tensin homologue (PTEN) deletions and EGFR family aberrations were characterized as potential biomarkers for prostate cancer (PCa) patient management. Although ERG gene rearrangement has been identified in approximately 50% of localized prostate cancers in western countries, the prognostic significance of this critical molecular event remains unknown in Chinese patients. Using fluorescence in situ hybridization (FISH) and immunohistochemistry, we evaluated ERG, PTEN and EGFR family aberrations in a cohort of 224 Chinese prostate cancer patients diagnosed in transurethral resection of the prostate (TUR-P). Overall, ERG rearrangement was detected in 23.2% (44/190) cases, of which 54.5% (24/44) showed deletion of the 5'end of ERG. PTEN deletion was identified in 10.8% (19/176) cases. Amplification of EGFR and HER2 genes was present in 1.1% (2/178) and 5.8% (10/173) of cases, respectively. Significant correlation between ERG rearrangement and PTEN deletion was identified in this cohort. EGFR and HER2 aberrations occurred more frequently in PCas without ERG rearrangement than in those with ERG rearrangement, although this did not reach statistical significance. Overall, ERG rearrangement was associated with pre-operative PSA values (P = 0.038) and cancer-related death (P = 0.02), but not with the age, clinical T stage, Gleason score, or Ki-67 labeling index (LI). Notably, multivariate analysis including known prognostic markers revealed ERG rearrangement was an independent prognostic factor (P = 0.022). Additionally, ERG rearrangement status was helpful to identify patients with poor prognosis from PCa group with low Ki-67 LI. In summary, we reported that ERG rearrangement was associated with cancer-related death in Chinese PCa patients. Determination of ERG rearrangement status allows stratification of PCa patients into different survival categories.

HPV infection in esophageal squamous cell carcinoma and its relationship to the prognosis of patients in northern China.

PURPOSE: Human papillomavirus (HPV) as a risk factor for esophageal squamous cell carcinoma (ESCC) has previously been studied, but importance of HPV status in ESCC for prognosis is less clear. METHODS: A total of 105 specimens with ESCC were tested by in situ hybridization for HPV 16/18 and immunohistochemistry for p16 expression. The 5-year overall survival (OS) and progression-free survival were calculated in relation to these markers and the Cox proportional hazards model was used to determine the hazard ratio (HR) of variables in univariate and multivariate analysis. RESULTS: HPV was detected in 27.6% (29) of the 105 patients with ESCC, and all positive cases were HPV-16. Twenty-five (86.2%) of the 29 HPV-positive tumors were stained positive for p16. HPV infected patients had better 5-year rates of OS (65.9% versus 43.4% among patients with HPV-negative tumors; P = 0.002 by the log-rank test) and had a 63% reduction in the risk of death (adjusted HR = 0.37, 95% CI = 0.16 to 0.82, and P = 0.01). CONCLUSIONS: HPV infection may be one of many factors contributing to the development of ESCC and tumor HPV status is an independent prognostic factor for survival among patients with ESCC.

High GOLPH3 expression is associated with a more aggressive behavior of epithelial ovarian carcinoma.

Overexpression of GOLPH3 (Golgi phosphoprotein 3, 34 kDa) is associated with the progression of many solid tumor types leading to an unfavorable clinical outcome. The present study examined the association between GOLPH3 expression and tumor development, clinicopathological factors, and prognosis of epithelial ovarian carcinoma. GOLPH3 expression was examined by immunohistochemistry in 18 normal ovarian samples, 28 benign tumors, 55 serous borderline ovarian tumors, and 135 epithelial ovarian carcinomas. The association of GOLPH3 expression with clinical characteristics, response to chemotherapy, and overall survival of epithelial ovarian carcinoma patients was analyzed on fresh tissue samples. GOLPH3 mRNA and protein expression in ovarian cancer and normal ovarian tissues were detected by real-time quantitative RT-PCR and Western blotting, respectively. The results are the following: (1) GOLPH3 immunostaining localized to the cytoplasm in two patterns, condensed into large granules with perinuclear distribution, and dispersed in the cytoplasm as fine granules. (2) GOLPH3 expression was higher in epithelial ovarian carcinoma than in normal ovarian tissues at the mRNA and protein level. The frequency of high-level expression of GOLPH3 increased progressively from benign (cystadenoma) to borderline neoplasms to malignant lesions. (3) Dispersed cytoplasmic GOLPH3 expression in epithelial ovarian carcinoma patients was highly correlated with FIGO stage (p < 0.001), tumor histological grade (p = 0.003), lymph node involvement (p = 0.001), and chemotherapy response (p = 0.034). (4) A dispersed pattern of GOLPH3 expression was an independent prognostic factor for poor overall survival. Patients with low dispersed cytoplasmic GOLPH3 expression had significantly longer overall survival than patients with high dispersed cytoplasmic expression. In contrast, GOLPH3 condensed expression was not correlated with clinicopathological features, chemotherapy response, or prognosis. GOLPH3 gene expression might play a role in tumorigenesis in epithelial ovarian carcinoma as upregulation of GOLPH3 expression is associated with a more aggressive tumor phenotype. GOLPH3 immunohistochemistry may be of value to predict the outcome of ovarian carcinoma patients.

Association between AKT/mTOR signalling pathway and malignancy grade of human gliomas.

The mammalian target of rapamycin (mTOR) signaling pathway has emerged as a major effector of cell growth and proliferation, and is an attractive target for cancer therapy. However, the association between mTOR pathway and the malignancy grade of human gliomas has not been thoroughly investigated. Tumor tissues from 87 Chinese patients (49 males, average age of 51.7 ± 13.0 years, range 15-78) with glioma were prospectively collected. The expression of three key proteins of the mTOR pathway, pAKT, pmTOR and p-p70S6 kinase (p-p70S6K) was measured by semi-quantitative immunohistochemical techniques. Grade I-II, III and IV glioma was pathologically identified in 27 (31.0%), 24 (27.6%) and 36 (41.4%) patients, respectively. Of the 87 patients, pAKT, pmTOR and p-p70S6K were found in 63 (72.4%), 65 (74.7%), and 63 (72.4%) patients, respectively. The expression of all three pAKT, pmTOR and p-p70S6K proteins was found in 42 (48.3%) patients, while only one or two of the three proteins were found in the remaining patients (51.7%). The percentage of patients with very strong expression of pAKT, pmTOR and p-p70S6K in grade IV glioma was 13 (36.1%), 16 (44.4%) and 15 (41.7%), respectively, which was greater than in grade I or II tumors (0-3.7%, P < 0.01). In conclusion, expression of mTOR pathway proteins pAKT, pmTOR and p-p70S6K can be found in human glioma of all malignancy grades. However, higher levels of these proteins were associated with advanced malignancy grades of the tumor.

[Changing trends in the clinicopathological characteristics of patients with gastric carcinoma undergoing surgery between 1979 and 2008 in Liaocheng Shandong province].

OBJECTIVE: To evaluate the changing trends in clinicopathological characteristics of patients with gastric carcinoma undergoing surgery between 1979 and 2008. METHODS: Two thousand seven hundred and fifteen patients with gastric cancer who received operation in Liaocheng People's hospital between 1979 and 2008 were analyzed retrospectively, and were compared to 168 patients between 1974 and 1978. Categorical data were evaluated with Chi-squared or Fisher's exact test. Quantitative data were analyzed with nonparametric test. Time series analysis was used to evaluate the changing trend of data. RESULTS: The male to female ratio during 1979-2008 was 3.393, which was higher than that (1.897) during 1974-1978 (χ2=12.193, P<0.01). The median age (59 years) during 1979-2008 was higher than that (53.5 years) during 1974-1978 (z=-6.294 P<0.01). Comparing the tumor distribution of gastric cancer during 1979-2008 with that during 1974-1978, proportion of gastric cardia and fundus cancer was higher (45.7% vs. 13.0%, χ2=56.596, P<0.01), while the proportion of gastric antrum cancer was lower (44.9% vs. 73.2%, χ2=53.980, P<0.01). There was no significant difference in gastric body cancer (13.8% vs. 9.4%, χ2=2.026, P=0.155). Compared to 1994-1998, there were more poorly differentiated adenocarcinomas during 2004-2008 (62.1% vs. 51.7%, χ2=12.267, P<0.01), and there were less tubular adenocarcinomas during 2004-2008 (23.9% vs. 31.8%, χ2=8.78, P<0.01). Time series analysis showed the patient age during 1979 to 2008 increased (Root mean square error=1.275, R-square=0.702), gastric cardia and fundus cancer was increasing and antrum cancer was decreasing (Root mean square error=0.055, R-square=0.798). CONCLUSIONS: In the past 30 years from 1979 to 2008, the male to female ratio and the median age of surgical patients with gastric cancer increased with time. The gastric cardia and fundus cancer increased over time, however antrum cancer decreased with time. In the past 15 years from 1994 to 2008, the proportion of poorly differentiated adenocarcinoma increased, and that of tubular adenocarcinoma declined.