Dual and triple gene combinations of KRT5, KRT17, and S100A2 identify basal-like subtype of pancreatic ductal adenocarcinoma and correlate with survival outcome.

There is a significant difference in prognosis and response to chemotherapy between basal and classical subtypes of pancreatic ductal adenocarcinoma (PDAC). Further biomarkers are required to identify subtypes of PDAC. We selected candidate biomarkers via review articles. Correlations between these candidate markers and the PDAC molecular subtype gene sets were analyzed using bioinformatics, confirming the biomarkers for identifying classical and basal subtypes. Subsequently, 298 PDAC patients were included, and their tumor tissues were immunohistochemically stratified using these biomarkers. Survival data underwent analysis, including Cox proportional hazards modeling. Our results indicate that the pairwise and triple combinations of KRT5/KRT17/S100A2 exhibit a higher correlation coefficient with the basal-like subtype gene set, whereas the corresponding combinations of GATA6/HNF4A/TFF1 show a higher correlation with the classical subtype gene set. Whether analyzing unmatched or propensity-matched data, the overall survival time was significantly shorter for the basal subtype compared with the classical subtype (p < .001), with basal subtype patients also facing a higher risk of mortality (HR = 4.017, 95% CI 2.675-6.032, p < .001). In conclusion, the combined expression of KRT5, KRT17, and S100A2, in both pairwise and triple combinations, independently predicts shorter overall survival in PDAC patients and likely identifies the basal subtype. Similarly, the combined expression of GATA6, HNF4A, and TFF1, in the same manner, may indicate the classical subtype. In our study, the combined application of established biomarkers offers valuable insights for the prognostic evaluation of PDAC patients.

Unexpected submucosal lesion with malignant potential.

The inverted hyperplastic polyp (IHP) is known as hyperplastic gastric mucosa growth into submucosa and endoscopically presented as sessile or pedunculated submucosa lesion. It occurs in between 3.1% to 20.1% of cases, while its malignant transformation rate is just 0.02%. A male underwent esophagogastroduodenoscopy (EGD) and discovered a submucosal lesion with a pinhole-like orifice in the fundus. And endoscopic ultrasound (EUS) showed it was a heterogenous hypoechoic lesion located in the submucosa. After endoscopic resection, the pathological findings and immunohistochemical staining revealed it was inverted hyperplastic polyp (IHP) with adenocarcinoma. The measurement of the cancerous IHP depth of invasion is controversial. Thus, how to define the depth of lesion invasion in this patient needs to be seriously considered. To manage IHP with adenocarcinoma better, the depth of lesion invasion cancerous IHP needs to be seriously considered.

Evaluation of clinical efficacy, adverse reactions, and safety of PD-1 inhibitors combined with chemotherapy when treating advanced gastric cancer.

OBJECTIVE: This paper aimed to assess the clinical efficacy, adverse reactions, and safety of employing PD-1 inhibitors in conjunction with chemotherapy as a treatment strategy for advanced gastric cancer (GC). METHODS: Ninety patients with advanced GC from January 2020 to December 2021 were divided into the research group (n = 45) and the control group (n = 45). The control group was treated with apatinib and tigio. The study group was treated with PD-1 inhibitor combined with apatinib and tigio. The remission rate (RR), disease control rate (DCR), overall survival (OS), Eastern Oncology Collaborative Group Physical Status Assessment (ECOG-PS) score, EORTCQLQ-C30 (v3.0) score, and incidence of adverse reactions were compared between the two groups. RESULTS: The research group exhibited improved outcomes in several key metrics relative to the control group. Specifically, the RR, DCR, and OS were notably higher in the research group. Additionally, the ECOG-PS score was significantly reduced, indicating better performance. At a median follow-up of 8.7 months, the research group's functional and total health scores on the EORTC QLQ-C30 (v3.0) scale had seen significant improvement compared to their initial scores and were also superior to the control group's scores. Importantly, both groups demonstrated comparable incidence rates for adverse reactions, with no significant difference observed (P > 0.05). CONCLUSION: PD-1 inhibitor combined with chemotherapy was more effective when treating patients with advanced GC. It was more beneficial to enhance the patient's condition, promote survival time, and improve physical status and life quality. In addition, the adverse reactions could be controlled.

The germline/somatic DNA damage repair gene mutations modulate the therapeutic response in Chinese patients with advanced pancreatic ductal adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with molecular heterogeneity, inducing differences in biological behavior, and therapeutic strategy. NGS profiles of pathogenic alterations in the Chinese PDAC population are limited. We conducted a retrospective study to investigate the predictive role of DNA damage repair (DDR) mutations in precision medicine. METHODS: The NGS profiles were performed on resected tissues from 195 Chinese PDAC patients. Baseline clinical or genetic characteristics and survival status were collected. The Kaplan-Meier survival analyses were performed by the R version 3.6.1. RESULTS: The main driver genes were KRAS, TP53, CDKN2A, and SMAD4. Advanced patients with KRAS mutation showed a worse OS than KRAS wild-type (p = 0.048). DDR pathogenic deficiency was identified in 30 (15.38%) of overall patients, mainly involving BRCA2 (n = 9, 4.62%), ATM (n = 8, 4.10%) and RAD50 genes (n = 3, 1.54%). No significance of OS between patients with or without DDR mutations (p = 0.88). But DDR mutation was an independent prognostic factor for survival analysis of advanced PDAC patients (p = 0.032). For DDR mutant patients, treatment with platinum-based chemotherapy (p = 0.0096) or olaparib (p = 0.018) respectively improved the overall survival. No statistical difference between tumor mutation burden (TMB) and DDR mutations was identified. Treatment of PD-1 blockades did not bring significantly improved OS to DDR-mutated patients than the naive DDR group (p = 0.14). CONCLUSIONS: In this retrospective study, we showed the role of germline and somatic DDR mutation in predicting the efficacy of olaparib and platinum-based chemotherapy in Chinese patients. However, the value of DDR mutation in the prediction of hypermutation status and the sensitivity to the PD-1 blockade needed further investigation.

Early response to upfront neoadjuvant chemotherapy (CAPOX) alone in low- and intermediate-risk rectal cancer: a single-arm phase II trial.

BACKGROUND: With local recurrence of rectal cancer continuing to decrease, distant recurrence is becoming a major concern, especially for patients with low- and intermediate-risk stage II/III rectal cancer. Therefore, a new treatment strategy is warranted for these patients. This single-arm phase II trial aimed to assess the effect of neoadjuvant chemotherapy (NCT) in low- and intermediate-risk stage II/III rectal cancer and explore candidate radiological and clinical parameters for early prediction of tumour response after two cycles of CAPOX. METHODS: Patients with mid-low stage II/III rectal cancer with low and intermediate risk were examined. The primary outcome was defined as a clinicopathological response by integrating tumour longitudinal length reduction (TLLR) on MRI into pathological tumour regression grade (TRG). After completing NCT, patients with TRG0-2 and TRG3 with a TLLR rate greater than 30 per cent were considered to be responders. Secondary outcomes included pathological complete response (pCR), adverse events and local and distant recurrence. RESULTS: This study enrolled 61 eligible patients. No patient was converted to neoadjuvant chemoradiotherapy owing to tumour progression. The clinicopathological response and pCR rates were 78.7 and 21.3 per cent respectively. After two cycles of CAPOX, TLLR, TRG on MRI, and mucosal lesion regression grade on endoscopy had potential discriminative ability (area under the curve greater than 0.7) for predicting both clinicopathological and pathological response. CONCLUSION: NCT alone achieves good tumour response rates in patients with low- and intermediate-risk stage II/III rectal cancer, and predicting tumour response to NCT is feasible at an early treatment phase. REGISTRATION NUMBER: NCT03666442 (http://www.clinicaltrials.gov).

The effect of pericolic lymph nodes metastasis beyond 10 cm proximal to the tumor on patients with rectal cancer.

BACKGROUND: This study aims to determine the real incidence of pericolic lymph nodes metastasis beyond 10 cm proximal to the tumor (pPCN) and its prognostic significance in rectal cancer patients. METHODS: Consecutive patients with rectal cancer underwent curative resection between 2015 and 2017 were included. Margin distance was marked and measured in vivo and lymph nodes were harvested on fresh specimens. Clinicopathological characteristics and oncological outcomes (3-year overall survival (OS) and disease-free survival (DFS)) were analyzed between patients with pPCN and patients without pPCN (nPCN). RESULTS: There were 298 patients in the nPCN group and 14 patients (4.5%) in pPCN group. Baseline characteristics were balanced except more patients received preoperative or postoperative chemoradiotherapy in pPCN group. Preoperative more advanced cTNM stage (log-rank p = 0.005) and intraoperative more pericolic lymph nodes beyond 10 cm proximal to the tumor (PCNs) (log-rank p = 0.002) were independent risk factors for pPCN. The maximum short-axis diameter of mesenteric lymph nodes ≥8 mm was also contributed to predicting the pPCN. pPCN was an independent prognostic indicator and associated with worse 3-year OS (66% vs 91%, Cox p = 0.033) and DFS (58% vs 92%, Cox p = 0.012). CONCLUSION: The incidence of pPCN was higher than expected. Patients with high-risk factors (cTNM stage III or more PCNs) might get benefits from an extended proximal bowel resection to avoid residual positive PCNs.

Whole exome and target sequencing identifies MAP2K5 as novel susceptibility gene for familial non-medullary thyroid carcinoma.

Although the genotype-phenotype for familial medullary thyroid carcinoma (FMTC) is well studied, only few low susceptibility risk loci were identified for familial non-medullary thyroid carcinoma (FNMTC). The aim of this study is to screen and identify high-penetrate genes for FNMTC. A total of 34 families with more than two first-degree relatives diagnosed as papillary thyroid cancer without other familial syndrome were recruited. Whole exome and target gene sequencing were performed for candidate variants. These variants were screened and analyzed with ESP6500, ExAC, 1000 genomes project, and the Cancer Genome Atlas (TCGA) with SIFT score and Polyphen2 prediction. Finally, we identified recurrent genetic mutation of MAP2K5 variants c.G961A and c.T1100C (p. A321T and p.M367 T) as susceptibility loci for FNMTC. The frequencies of MAP2K5 c.G961A and c.T1100C were found, 0.0385 and 0.0259 in FNMTC and 0 and 0.00022523 in healthy Chinese controls (n = 2200, P < 0.001), respectively. Both variants were located in the protein kinase domain. The functional study showed that MAP2K5 A321T or M367 T could consistently phosphorylate downstream protein ERK5 on site Ser731 + Thr733 or Ser496, promoting nuclear translocation and subsequently altering target gene expressions. Our data revealed that MAP2K5 variants A321T or M367 T can activate MAP2K5-ERK5 pathway, alter downstream gene expression, and subsequently induce thyroid epithelial cell malignant transformation. While classic MAP2K1/2(MEK1/2)-ERK1/2 signaling is well known for driving sporadic NMTC, our research indicated that MAP2K5 (MEK5) is a susceptibility gene for FNMTC. These findings highlight the potential application of MAP2K5 for molecular diagnosis as well as early prevention.

Dose-response relation between serum total cholesterol levels and overall cancer risk: evidence from 12 prospective studies involving 1,926,275 participants.

This study aimed to clarify the association between serum total cholesterol (TC) levels and overall cancer risk. Study-specific relative risks (RR) and 95% confidence intervals (CI) were pooled using a random-effects model, and dose-response relation was also evaluated. Twelve prospective studies were identified with a total of 1,926,275 participants and 13,1676 cases. High levels of serum TC showed an inverse association with overall cancer risk (RR for the highest versus the lowest category: 0.87, 95% CI: 0.83 ∼ 0.90; I2 = 52.5%). A linear dose-response relation between serum TC levels and overall cancer risk was found (p = .004 for Wald test; I2 = 49.6%), and the pooled RR was 0.92 (95% CI: 0.89 ∼ 0.94) for 3 mmol/L, 0.86 (95% CI: 0.81 ∼ 0.90) for 5 mmol/L, 0.80 (95% CI: 0.74 ∼ 0.87) for 7 mmol/L. Our dose-response meta-analysis of 12 prospective studies indicated that higher serum TC levels were significantly associated with reduced cancer risk.

[Pathological Analysis of Endoscopic Submucosal Dissection Specimen of Esophageal Superficial Infiltrating Squamous Cell Carcinoma].

OBJECTIVE: To analyze the pathological characteristics of superficial infiltrating squamous cell carcinoma of endoscopic submucosal dissection (ESD). METHODS: 187 cases of invasive squamous cell carcinoma after ESD operation were collected from 2016 Jan 31 to 2017 Dec 31. The tumor differentiation, invasion depth, infiltrative growth pattern (INF), tumor budding, angiovascular lymphatic invasion and margin were determined. The pathological diagnosis of endoscopic biopsy and surgical operation after ESD were searched. RESULTS: The patients were aged from 42 to 83 years old, including 147 males and 40 females. 9.1% patients had carcinoma/intraepithelial neoplasia in other sites, among which gastric adenocarcinoma was the most common one. Well, moderately and poorly differentiated squamous cell carcinoma accounted for 0.5%, 41.7% and 15.0%, respectively, while the remaining 42.8% cases were microinvasion and were difficult to be graded. Mucosa lamina propria, muscularis mucosa and submucosa invasion accounted for 39.6%, 32.6% and 27.8%, respectively. Submucosa infiltration <200 µm (SM1) accounted for 9.1% and submucosa infiltration ≥200 µm (SM2) accounted for 18.7%. Lymphatic vessel invasion was related to the depth of tumor invasion, tumor budding, INF. The invasion rate of lymphatic vessels increased with the increase of infiltration depth and the grade of tumor budding. The lymphatic invasion rate in INFb/c group was higher than that in INFa group. There was no statistical difference in the incidence of lymphatic vessel invasion between well/moderately differentiated squamous cell carcinoma and poorly differentiated squamous cell carcinoma. Multivariate analysis showed that tumor budding was an independent risk factor for lymphatic vessel invasion. The complete resection occupied 69.5% (130 cases), while most of incomplete resection cases (57 cases) were involved by low-grade intraepithelial neoplasia. 69 cases had biopsy after ESD, among which there were 46 cases (66.67%) with no recurrence, 19 cases (27.54%) with recurrence, and 4 cases (5.80%) occurring in other sites. There was no statistical difference in recurrent rate between the complete resection (28.3%, 13/46) and the incomplete resection (31.6%, 6/19, P>0.05). CONCLUSIONS: Tumor invasion depth, INF, tumor budding andlymphatic vessel invasion should all be disclosed for the ESD specimen pathological report. Tumor budding was an independent risk factor for lymphatic vessel invasion.

Stiffness Value and Serum Biomarkers in Liver Fibrosis Staging: Study in Large Surgical Specimens in Patients with Chronic Hepatitis B.

Purpose To investigate the capabilities of stiffness value and serum biomarkers in the staging of liver fibrosis in patients with chronic hepatitis B (CHB), with pathologic findings in large surgical specimens serving as the reference standard. Materials and Methods This study was approved by the institutional review board, and informed consent was obtained from all patients. Liver stiffness (determined by means of ultrasonography-based elastography point quantification), aspartate aminotransferase-platelet ratio index (APRI), and fibrosis index (based on the four-factor Fibrosis-4 [FIB-4] calculation) were obtained in 386 patients with CHB. With pathologic fibrosis stages in large surgical specimens as the reference standard, capabilities and cutoffs of stiffness and serum biomarkers were first investigated in a cohort of 284 patients and then validated in an independent cohort of 102 patients by means of area under the receiver operating characteristic curve (AUC) analysis. Results Liver stiffness demonstrated significantly stronger correlation with fibrosis stages than did APRI and FIB-4 (r = 0.738 vs r = 0.477 vs r = 0.427, respectively; P < .05 for all). In the development cohort, liver stiffness had significantly higher AUCs in identifying fibrosis of stage 1 or higher, stage 2 or higher, stage 3 or higher, and stage 4 or higher (0.97, 0.96, 0.91, and 0.87, respectively) than APRI (0.89, 0.84, 0.73, and 0.74, respectively) and FIB-4 (0.82, 0.79, 0.70, and 0.72, respectively). In the validation cohort, liver stiffness was validated as showing significantly higher AUCs in identifying fibrosis of stage 1 or higher, stage 2 or higher, stage 3 or higher, and stage 4 or higher (0.99, 0.95, 0.89, and 0.88, respectively) than APRI (0.83, 0.76, 0.78, and 0.68, respectively) and FIB-4 (0.76, 0.69, 0.75, and 0.67, respectively). Conclusion Liver stiffness demonstrated considerable capability in identifying each stage of liver fibrosis in patients with CHB, whereas serum biomarkers showed limited capabilities. (©) RSNA, 2016 Online supplemental material is available for this article.

TRIM26 functions as a novel tumor suppressor of hepatocellular carcinoma and its downregulation contributes to worse prognosis.

Hepatocellular carcinoma (HCC) is the one of the most common malignancies worldwide and its prognosis is extremely poor. Tripartite motif (TRIM) proteins play crucial roles in cancer cell biology but the function of tripartite motif 26 (TRIM26) has not been investigated. We demonstrated that low expression level of TRIM26 in tumor samples was significantly correlated with worse prognosis in HCC patients. We also demonstrated its expression level was associated with several clinicopathologic features such as AFP level and T stage of HCC patients. Furthermore, we validated that TRIM26 was significantly downregulated in HCC tissue compared with normal liver tissue. To further clarify the functional role of TRIM26 in HCC, We confirmed that TRIM26 silencing can promote cancer cell proliferation, colony forming, migration and invasion in vitro with HCC cell lines HepG2 and Bel-7402. Then we utilized bioinformatic tool to predict gene influenced by TRIM26, showing TRIM26 could modulate gene sets about cancer cell metabolism. In conclusion, we proved that TRIM26 is a novel tumor suppressor modulating multiple metabolism-related pathways in HCC. To our best knowledge, this is the first study to investigate the function of TRIM26 in cancer biology. Our findings provide useful insight into the mechanism of HCC origin and progression. Moreover, TRIM26 may represent a novel therapeutic target for HCC.

Hepatocellular carcinoma: stiffness value and ratio to discriminate malignant from benign focal liver lesions.

PURPOSE: To investigate the use of stiffness value and stiffness ratio (ratio of lesion to background liver parenchyma values) to discriminate malignant from benign focal liver lesions by using histologic results as the reference standard. MATERIALS AND METHODS: This study was approved by the institutional review board, and written informed consent was obtained. Three hundred seventy-three patients with focal liver lesions proven at histologic examination underwent measurement of liver stiffness with elastography point quantification. First, stiffness values in two regions of the background liver parenchyma (at 0.5-2 cm and >2 cm from the lesion periphery) near 163 hepatocellular carcinomas were analyzed to determine a reference background liver for calculating the stiffness ratio. Second, the use of the lesion stiffness value and the stiffness ratio for prediction of liver malignancy was investigated in a cohort of patients with 58 benign and 201 malignant lesions. Results were validated in another independent cohort of patients with 25 benign and 89 malignant lesions by using analysis of the area under the receiver operating characteristic (AUC) curve. RESULTS: The coefficient of variation for the background liver at 0.5-2 cm from the lesion was higher (196%) than that at greater than 2 cm from the lesion (66%). In the development phase, diagnostic accuracy with use of the stiffness value was significantly higher than that with use of the stiffness ratio for discrimination of malignant from benign lesions (AUC, 0.86 vs 0.66, respectively; P < .001). Diagnostic performance with the stiffness value was lower than that with the stiffness ratio (AUC, 0.53 vs 0.86, respectively; P < .001) for discrimination of cirrhotic nodules from other benign lesions. Diagnostic performance with the stiffness value was significantly lower than that with the stiffness ratio (AUC, 0.58 vs 0.71 respectively; P = .007) for discrimination of metastasis from primary liver cancers. In the validation phase, similar findings were revealed for the discrimination of malignant from benign lesions (AUC, 0.87 vs 0.67; P < .001) and discrimination between metastasis and primary liver cancers (AUC, 0.49 vs 0.73; P < .001). CONCLUSION: Use of stiffness values measured in the liver parenchyma at more than 2 cm from the lesion allowed better diagnostic performance than did values measured in a region closer to the tumor. Stiffness value was more accurate than stiffness ratio for differentiation of malignant from benign focal liver lesions, but the stiffness ratio might be useful for subclassification of benign and malignant lesions. Online supplemental material is available for this article.

Downregulation of TRIM21 contributes to hepatocellular carcinoma carcinogenesis and indicates poor prognosis of cancers.

The aim of our work is to clarify the clinical implication and functional role of tripartite motif 21 (TRIM21) in hepatocellular carcinoma (HCC). We validated that TRIM21 was downregulated in liver cancer samples by immunohistochemical (IHC) staining. We also demonstrated that its downregulation was associated with several clinicopathologic features such as tumor numbers, T stage, Barcelona Clinic Liver Cancer (BCLC) stage, and Cancer of the Liver Italian Program (CLIP) stage of HCC patients. Importantly, the expression of TRIM21 in tumor samples is significantly correlated with the prognosis of the patients. We further silenced TRIM21 in HCC cell HepG2 and LM3 and confirmed that TRIM21 silencing will promote cancer cell proliferation (CCK-8 assay), colony forming (plate colony-forming assay), migration (transwell assay), and the ability of antiapoptosis (annexin V-FITC/PI staining) in vitro. Then, we predicted gene sets influenced by TRIM21 by using bioinformatic tools. For the first time, we prove that TRIM21 is a potential tumor suppressor in HCC and its low expression indicates poor prognosis. Our findings provide useful insight into the mechanism of HCC origin and progression and offer clues to novel HCC therapies.

[Superficial Esophageal Carcinoma and Esophageal Intraepithelial Neoplasia: a Pathological Study of 130 Cases].

OBJECTIVE: To identify the pathological features of superficial esophageal carcinoma and esophageal intraepithelial neoplasia resected through endoscopic submucosal dissection (ESD). METHODS: The clinical and pathologic profiles of 130 cases were reviewed, including gross type, histology type, infiltration depth, infiltrative growth pattern, presence of tumor budding, lymphatic and vascular invasion, and margin status. RESULTS: The patients had a median age of 62 years old. The predominant gross type was mixed type (78/130, 60.0%), followed by Type 0-II (49/130, 37.7%). The longest diameter of lesionshad a median of 13.8 mm. Morphologically, there were 3 cases (2.3%) of undetermined dysplasia, 25 cases (19.2%) of low grade intraepithelial neoplasia, 56 cases (43.1%) of high grade of intraepithelial neoplasia, and 46 cases (35.4%) of invasive carcinoma. No correlation was found between histological type and gross type. Intramucosal and submucosal invasive carcinoma accounted for 87.0% (40/46) and 13.0% (6/46) of the cases, respectively; sm1 and sm2 accounted for 4.3% (2/46) and 8.7% (4/46) of the cases, respectively. Infiltrative growth pattern was identified as infiltrative growth pattern (INF) a (23/46, 50.0%), INFbeta (17/46, 37.0%) and INFc (6/46, 13.0%). Tumor budding was found in 3 cases and lymphatic and vascular invasion was found in 2 cases. Margin was positive in 30 cases (23.1%). Invasive carcinomahad a higher margin positive rate (24/46, 52.1%) than low grade intraepithelial neoplasia (1/25, 4.0%) and high grade intraepithelial neoplasia (5/56, 89%) (P<0.001). No association between margin positivity and invasive pattern was found (P=0.208). Fifteen cases (11.5%) recurred, with invasive carcinoma being more likely to recur (17.4%, 8/46) than low grade intraepithelial neoplasia (8.0%, 2/25) and high grade intraepithelial neoplasia (8.9%, 5/56) (P<0.05). No association between margin positivity and recurrence rate was found (P= 0.590). CONCLUSION: The superficial esophageal carcinoma and esophageal intraepithelial neoplasia resected by ESD are predominantly mixed type under endoscope, with histological features of high grade intraepithelial neoplasia and invasive carcinoma. Invasive carcinomas are more likely to recur and present with a positive margin.

Case report: A rare case of coexistence of low-grade appendiceal mucinous neoplasia and goblet cell adenocarcinoma in the appendix.

Background: Primary appendiceal tumors are rare. Low-grade appendiceal mucinous neoplasia (LAMN) and goblet cell adenocarcinoma (GCA) account for 20% and 14% of primary appendiceal tumors, respectively. The coexistence of LAMN and GCA is an extremely rare event. This report presents a case of an elderly male patient with an appendiceal tumor composed of LAMN and GCA in the same appendix. Case presentation: A 72-year-old male patient was admitted to our institution presenting with a history of abdominal pain localized to the right lower quadrant for two months. Abdominal computed tomography (CT) showed a large dilated thickened cystic mass in the appendix, along with a small duodenal diverticulum. Laboratory tests indicated elevated levels of serum carcinoembryonic antigen (CEA) and cancer antigen 199 (CA19-9) markers. The patient underwent a laparoscopic right hemicolectomy and exploration of the duodenal diverticulum, and there was no finding of perforation of the duodenal diverticulum. Focal positivity for chromogranin A (CgA) and synaptophysin (Syn) was observed in the tumor cells of GCA. The final pathological diagnosis revealed the coexistence of LAMN staged pT4a and grade 1 GCA staged pT3 in the appendix. Unfortunately, the patient died due to severe septic shock and circulatory failure secondary to a perforated duodenal diverticulum. Conclusions: The coexistence of LAMN and GCA are extremely rare in the appendix and may result from the proliferation of two independent cellular lines. The coexistence of distinct neoplasms poses diagnostic and management challenges. Multidisciplinary team discussion may be essential in the effective management of these patients.

WITHDRAWN: Metformin mitigates cisplatin-induced ovarian damage through inhibiting the pyroptosis of granulosa cells via ROS/TXNIP/NLRP3 signaling pathway.

This paper was originally published in Aging Advance Online Publications on March 14, 2024. In compliance with Aging's withdrawal policy, the paper was withdrawn in its entirety. It will not appear in Aging internal or any external indexes or archives.

Chromothripsis is a novel biomarker for prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms.

This study aimed to identify the role of chromothripsis as a novel biomarker in the prognosis and differentiation diagnosis of pancreatic neuroendocrine neoplasms (pNENs). We conducted next-generation gene sequencing in a cohort of 30 patients with high-grade (G3) pNENs. As a reference, a similar analysis was also performed on 25 patients with low-grade (G1/G2) pancreatic neuroendocrine tumors (pNETs). Chromothripsis and its relationship with clinicopathological features and prognosis were investigated. The results showed that DNA damage response and repair gene alteration and TP53 mutation were found in 29 and 11 patients, respectively. A total of 14 out of 55 patients had chromothripsis involving different chromosomes. Chromothripsis had a close relationship with TP53 alteration and higher grade. In the entire cohort, chromothripsis was associated with a higher risk of distant metastasis; both chromothripsis and metastasis (ENETS Stage IV) suggested a significantly shorter overall survival (OS). Importantly, in the high-grade pNENs group, chromothripsis was the only independent prognostic indicator significantly associated with a shorter OS, other than TP53 alteration or pathological pancreatic neuroendocrine carcinomas (pNECs) diagnosis. Chromothripsis can guide worse prognosis in pNENs, and help differentiate pNECs from high-grade (G3) pNETs.