Time Trend Analysis of Splenectomy for Splenic Marginal Zone Lymphoma: Declining Surgery, Promising Survival.

BACKGROUND: The purpose of current study was to examine the incidence, characteristics, treatment, and survival of splenic marginal zone lymphoma (SMZL). METHODS: Using SEER-18 database, patients diagnosed with SMZL between 2000 and 2018 were included. Effect of splenectomy on survival was evaluated after balancing the confounding factors by propensity score matching. Rates of splenectomy and 1-year relative survival were calculated for each year. A logistic regression model identified factors related to splenectomy, and a Cox regression model assessed factors linked to overall survival (OS). RESULTS: A total of 2790 patients with SMZL were analyzed. The majority were older than 60 years, female, and white. The age-adjusted incidence of SMZL was 0.17/100,000 person-years, with higher incidence in males. Incidence increased by 0.68%/year and peaked at 80-84 years for both genders. The SMZL-specific survival rates at 3 and 5 years were 89.6% and 85.3%, respectively. Meanwhile, the relative survival rates for the same periods were 88.6% and 85.9%, respectively. Splenectomy patients were more likely to be younger, male, and diagnosed with early-stage disease. Despite the decreasing utilization rate of splenectomy from 59.4% in 2000 to 16.2% in 2018, the 1-year relative survival rate remained relatively stable with minor fluctuations over time. Whether or not the patient underwent splenectomy was not found to be a significant prognostic indicator for OS. CONCLUSIONS: Our study demonstrated a decreasing use of splenectomy but a relatively stable survival in patients with SMZL, highlighting the urgency to better understand the role of splenectomy and its associated outcomes.

A novel prognostic signature for hepatocellular carcinoma based on SUMOylation-related genes.

SUMOylation (SUMO modification) has been confirmed to play an essential role in the progression of various malignancies. As the value of SUMOylation-related genes (SRGs) in prognosis prediction of hepatocellular carcinoma (HCC) has not been explored, we aim to construct an HCC SRGs signature. RNA sequencing was utilized to identify differentially expressed SRGs. The 87 identified genes were used in Univariate Cox regression analysis and the Least Absolute Shrinkage and Selection Operator (LASSO) analysis to build a signature. The accuracy of the model was validated by the ICGC and GEO datasets. The GSEA revealed that the risk score was associated with common cancer-related pathways. The ssGSEA showed that NK cells in the high-risk group were significantly reduced. The sensitivities of anti-cancer drugs confirmed the sensitivity of the high-risk group to sorafenib was lower. Further, our cohort showed that risk scores were correlated with advanced grade and vascular invasion (VI). Finally, the results of H&E staining and immunohistochemistry of Ki67 showed that higher-risk patients are more malignant.

Development and verification of prognostic nomogram for ampullary carcinoma based on the SEER database.

Background: Ampullary carcinoma (AC) is a rare cancer of the digestive system that occurs in the ampulla at the junction of the bile duct and pancreatic duct. However, there is a lack of predictive models for overall survival (OS) and disease -specific survival (DSS) in AC. This study aimed to develop a prognostic nomogram for patients with AC using data from the Surveillance, Epidemiology, and End Results Program (SEER) database. Methods: Data from 891 patients between 2004 and 2019 were downloaded and extracted from the SEER database. They were randomly divided into the development group (70%) and the verification group (30%), and then univariate and multivariate Cox proportional hazards regression, respectively, was used to explore the possible risk factors of AC. The factors significantly related to OS and DSS were used to establish the nomogram, which was assessed via the concordance index (C-index), and calibration curve. An internal validation was conducted to test the accuracy and effectiveness of the nomogram. Kaplan-Meier calculation was used to predict the further OS and DSS status of these patients. Results: On multivariate Cox proportional hazards regression, the independent prognostic risk factors associated with OS were age, surgery, chemotherapy, regional node positive (RNP),extension range and distant metastasis with a moderate C-index of 0.731 (95% confidence interval (CI): 0.719-0.744) and 0.766 (95% CI: 0.747-0.785) in the development and verification groups, respectively. While, marital status, surgery, chemotherapy, regional node positive (RNP),extension range and distant metastasis were significantly linked to AC patients' DSS, which have a better C-index of 0.756 (95% confidence interval (CI): 0.741-0.770) and 0.781 (95% CI: 0.757-0.805) in the development and verification groups. Both the survival calibration curves of 3- and 5-year OS and DSS brought out a high consistency. Conclusion: Our study yielded a satisfactory nomogram showing the survival of AC patients, which may help clinicians to assess the situation of AC patients and implement further treatment.

Causes of death among patients with hepatocellular carcinoma in United States from 2000 to 2018.

BACKGROUND: The gains in survival outcomes of US patients with hepatocellular carcinoma (HCC) have come at the expense of developing non-cancer-related morbidities, such as cardiovascular diseases (CVDs) and infections. However, population-based data on causes of death (CODs) in patients with HCC are scarce. METHODS: A cancer registry database in the United States was used to analyze the CODs among patients with HCC. Death cause distribution and standardized mortality ratios were calculated to quantify the disease-specific death burden. RESULTS: A total of 40,094 patients with a histological diagnosis of HCC were identified from the SEER-18 database between 2000 and 2018, of which 30,796 (76.8%) died during the follow-up period. The majority of these deaths (25,153, 81.7%) occurred within 2 years after diagnosis, 13.2% (4075) occurred within 2-5 years, and 5.1% (1568) occurred after 5 years. All age groups had a lower burden of female deaths than of male deaths during the study period. With respect to CODs, 23,824 (77.4%), 2289 (7.4%), and 4683 (15.2%) were due to HCC, other cancers, and non-cancer causes, respectively. Non-cancer-related deaths were more common among older patients and those with longer latency periods since diagnosis. The major causes of non-cancer-related deaths are other infectious and parasitic diseases, including HIV and CVDs. CONCLUSIONS: CODs during HCC survivorship varied, and a growing number of survivors tended to die from causes other than HCC, with an increasing latency period since diagnosis. Comprehensive analyses of mortality patterns and temporal trends could underpin strategies to reduce these risks.

Risk of second primary malignancies in survivors of pancreatic neuroendocrine neoplasms from 2000 to 2018.

BACKGROUND AND AIM: As a result of improved survival, cancer survivors continue to remain at risk of developing second primary malignancies (SPMs). However, the association between first primary pancreatic neuroendocrine neoplasms (PanNENs) and SPMs has not been thoroughly investigated. METHODS: Using the Surveillance, Epidemiology, and End Results-18 database, patients histologically diagnosed with PanNENs as their first malignancy between 2000 and 2018 were identified. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) and excess absolute risks per 10 000 person-years of SPMs were calculated to estimate the risk of being diagnosed with subsequent cancers compared with the general population. RESULTS: A total of 489 (5.7%) PanNENs survivors developed an SPM during the follow up, with a median latency between first and second cancer diagnoses of 32.0 months. The overall SIR of SPMs was 1.30 (95% CI: 1.19, 1.42) and the excess absolute risk was 35.67 cases per 10 000 person-years in comparison with the general population. Age 25-64 years at PanNENs diagnosis was associated with statistically higher risks for SPMs of all cancers combined. Latency stratification was significant for elevated SPMs risk between 2-23 and 84+ months after diagnosis. White patients were found to have a significantly increased incidence of SPMs (SIR: 1.23, 95% CI: 1.11, 1.35), mainly owing to the higher risk of stomach, small intestine, pancreas, kidney and renal pelvis, and thyroid cancers. CONCLUSION: Pancreatic neuroendocrine neoplasms survivors experience a significant increase in the burden of SPMs compared with the reference population. The heightened relative risk calls for careful long-term scrutiny as part of survivorship care plans.

Early-onset pancreatic neuroendocrine neoplasms: A distinct disease with improved survival compared with old individuals.

Background: The incidence, clinicopathologic characteristics, treatment patterns, and survival of early-onset pancreatic neuroendocrine neoplasms (EOPanNENs) have not been well explored. Methods: Patients diagnosed with PanNENs were identified from the SEER database between 2000 and 2018. EOPanNENs were defined as diagnosis in patients aged less than 50 years, while the remaining were defined as later-onset pancreatic neuroendocrine neoplasms (LOPanNENs). Incidence, clinical features, management, and prognosis were analyzed in our study. Multivariable analyses were performed to identify factors associated with overall survival (OS) in EOPanNENs and LOPanNENs, respectively. Results: A total of 5172 patients with PanNENs were included: 1267 (24.5%) in the EOPanNENs cohort and 3905 (75.5%) in the LOPanNENs cohort. The age-adjusted incidence rate significantly increased among later-onset cases, while it remained relatively stable in early-onset cases. EOPanNENs were more frequently to be female, unmarried, and with better tumor differentiation compared with LOPanNENs. Of note, early-onset patients presented with a higher rate of lymph node involvement, and they were more likely to receive surgical treatment. For local-regional disease at presentation, surgery alone was the most frequently used regimen over the last two decades. With regard to distant stage, a combination of surgery and chemotherapy was more often utilized. Risk factors for PanNENs survival were more correlated with LOPanNENs compared with EOPanNENs. The OS and cancer-specific survival (CSS) were significantly better in the EOPanNENs group. Further analyses showed that EOPanNENs ≤ 2cm were associated with more favorable survival outcomes than EOPanNENs>2cm. Conclusion: EOPanNENs are a clinically rare and distinct entity from LOPanNENs. The advantages in survival for the EOPanNENs cohort over time were largely driven by the indolent clinical courses including better tumor differentiation and intensified surgical treatment. Further investigations are warranted to better understand the characteristics of this disease subgroup.

Effects of preoperative oral enzyme-hydrolyzed rice flour solution on gastric emptying and insulin resistance in patients undergoing laparoscopic cholecystectomy: a prospective randomized controlled trial.

BACKGROUND: The effect of preoperative oral carbohydrates (POC) on insulin resistance (IR) of laparoscopic cholecystectomy (LC) remains debatable. Enzyme-hydrolyzed rice flour (EHR) is a kind of water-soluble micromolecular carbohydrates. This study aimed to investigate the impact of preoperative oral EHR solution on gastric emptying and IR in patients undergoing LC. METHODS: Patients (n = 100) undergoing LC were divided into oral-water group (group C) or oral-EHR solution (group E) randomly (n = 50 each), and the patients drank 300 ml water or EHR solution 2-3 h before surgery respectively. Gastric emptying which was quantized by gastric volume (GV) from antrum ultrasonography, IR indicators, subjective comfort indicators, handgrip strength, postoperative recovery indexes, and complications were recorded. RESULTS: There were no differences in GV between the two groups before oral administration (V0), immediately after oral administration (V1) and before anesthesia induction(V2). The GV at V2 (GV2) reduced to the level of V0 (GV0) in the two groups. Fasting glucose (FG), fasting insulin (FINS) and Homa-IR in the two groups increased at postoperative day 1 (Pos 1d) compared with those at preoperative day 1(Pre 1d). Homa-IS and Homa-ß in the two groups decreased at Pos 1d compared with those at Pre 1d. FG, FINS and Homa-IR in group E were lower than those in group C at Pos 1d, and Homa-IS and Homa-ß were higher in group E than those in group C at Pos 1d. Subjective comfort indictors (hunger, fatigue and anxiety) in group E were lower than those in group C at preoperative 15 min (Pre 15 min) and postoperative 1 h (Pos 1 h). Handgrip strength in group E was raised compared with that in group C at Pre 15 min, Pos 1 h and Pos 1d. There was a lower incidence of nausea and earlier exhaust time in group E. CONCLUSION: Oral 300 ml EHR solution 2-3 h before LC surgery did not increase the occurrence of reflux and aspiration during anesthesia induction with a normal gastric emptying, ameliorated postoperative IR, improved subjective comfort, and promoted postoperative gastrointestinal function recovery. TRIAL REGISTRATION: Prospectively registered at the China Clinical Trial Registry, registration number: ChiCTR2000039939, date of registration:14/11/2020.

Fibronectin type III domain-containing protein 5 promotes autophagy via the AMPK/mTOR signaling pathway in hepatocellular carcinoma cells, contributing to nab-paclitaxel chemoresistance.

Chemotherapy resistance is a huge challenge in the treatment of hepatocellular carcinoma because resistance to nab-paclitaxel largely affects the efficacy of chemotherapy. An increased expression of fibronectin type III domain-containing protein 5 (FNDC5) in hepatocellular carcinoma cells can predict post-hepatectomy complications in patients with hepatocellular carcinoma and also stimulate proliferation and invasion of hepatocellular carcinoma cells; however, its role in the chemotherapy of hepatocellular carcinoma cells has never been evaluated. Thus, this study aimed to explore whether FNDC5 regulates chemoresistance in hepatocellular carcinoma. We identified by immunohistochemistry that hepatocellular carcinoma tissues had a higher FNDC5 expression than normal tissues adjacent to the cancer cells. Subsequently, knockdown of FNDC5 in hepatocellular carcinoma cells resulted in their diminished resistance to cell death after chemotherapy with nab-paclitaxel. By contrast, overexpression of FNDC5 in hepatocellular carcinoma cells increased the resistance of hepatocellular carcinoma cells to treatment. Moreover, FNDC5 mechanistically promoted autophagy via the AMPK/mTOR signaling pathway, thereby reducing cell death induced by nab-paclitaxel. Finally, we tested our hypothesis by conducting animal experiments. In conclusion, FNDC5 could be used as a biomarker for predicting chemotherapeutic efficacy in hepatocellular carcinoma treated with nab-paclitaxel chemotherapy, and as a therapeutic target to overcome resistance to nab-paclitaxel in hepatocellular carcinoma chemotherapy.

Integrative multiomics evaluation reveals the importance of pseudouridine synthases in hepatocellular carcinoma.

Background: The pseudouridine synthases (PUSs) have been reported to be associated with cancers. However, their involvement in hepatocellular carcinoma (HCC) has not been well documented. Here, we assess the roles of PUSs in HCC. Methods: RNA sequencing data of TCGA-LIHC and LIRI-JP were downloaded from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), respectively. GSE36376 gene expression microarray was downloaded from the Gene Expression Omnibus (GEO). Proteomics data for an HBV-related HCC cohort was obtained from the CPTAC Data Portal. The RT-qPCR assay was performed to measure the relative mRNA expression of genes in clinical tissues and cell lines. Diagnostic efficiency was evaluated by the ROC curve. Prognostic value was assessed using the Kaplan-Meier curve, Cox regression model, and time-dependent ROC curve. Copy number variation (CNV) was analyzed using the GSCA database. Functional analysis was carried out with GSEA, GSVA, and clusterProfiler package. The tumor microenvironment (TME) related analysis was performed using ssGSEA and the ESTIMATE algorithm. Results: We identified 7 PUSs that were significantly upregulated in HCC, and 5 of them (DKC1, PUS1, PUS7, PUSL1, and RPUSD3) were independent risk factors for patients' OS. Meanwhile, the protein expression of DKC1, PUS1, and PUS7 was also upregulated and related to poor survival. Both mRNA and protein of these PUSs were highly diagnostic of HCC. Moreover, the CNV of PUS1, PUS7, PUS7L, and RPUSD2 was also associated with prognosis. Further functional analysis revealed that PUSs were mainly involved in pathways such as genetic information processing, substance metabolism, cell cycle, and immune regulation. Conclusion: PUSs may play crucial roles in HCC and could be used as potential biomarkers for the diagnosis and prognosis of patients.

Reappraisal of a 2-cm Cutoff Size for the Management of Nonfunctional Pancreatic Neuroendocrine Tumors: A Population-Based Study.

Background: Expectant observation and aggressive surgery are both recommended for small nonfunctional pancreatic neuroendocrine tumors (NF-PanNETs). However, the optimal management of small NF-PanNETs remains disputable due to the heterogeneous clinical behavior. Methods: Patients who were diagnosed with pancreatic neuroendocrine neoplasms (PanNENs) between 2000 and 2018 were identified from the surveillance, epidemiology, and end results (SEER) database and reviewed retrospectively. Tumor aggressiveness was defined as poor differentiation, lymph node involvement, liver involvement, and advanced stage. The best cutoff of tumor size associated with tumor aggressiveness was determined through the receiver operating characteristic (ROC) curve analysis. Univariate and multivariate analyses were used to identify prognostic factors in patients with tumors of ≤2 cm. Results: A total of 5,172 patients with PanNENs were enrolled, including 1,760 (34.0%) tumors ≤2 cm and 3,412 (66.0%) tumors >2 cm. A 2.5-cm cutoff size was found to be associated with a satisfactory ability in predicting tumor aggressiveness. On multivariate analysis, age, gender, ethnicity, tumor grade, tumor number, and stage were independent prognostic factors for overall survival (OS) in patients with tumors less than or equal to 2 cm in size. A total of 1,621 patients were diagnosed with NF-PanNETs according to the WHO classification, of whom 1,350 underwent surgery, 271 performed active observation. The OS was significantly better in the surgery group compared to the observation group regardless of propensity score analysis. Additionally, a total of 407 patients were selected based on the multivariate Cox regression analysis, of whom 46 underwent observation, 361 underwent surgery, and the OS was comparable. Conclusion: Expectant observation may be a reasonable alternative to aggressive surgical resection in highly selected small NF-PanNET patients. Also, the decision to observe versus surgery should not only be based on tumor size alone but also take into account other important clinicopathological factors.

Comparison of clinicopathologic characteristics and survival outcomes between invasive IPMN and invasive MCN: A population-based analysis.

Background: Intraductal papillary mucinous neoplasm (IPMN) and mucinous cystic neoplasm (MCN) are two main histological subtypes of pancreatic cystic neoplasms with rapidly increasing incidence recently. The natural histories, treatment patterns, and survival outcomes of invasive IPMN and invasive MCN have not been well explored. Methods: Patients with a diagnosis of invasive IPMN and invasive MCN in the SEER database from 2000 through 2018 were retrospectively identified. Multivariable Cox regression analysis was conducted to determine the independent risk factors associated with overall survival (OS). Subgroup analyses of survival outcomes for invasive IPMN and invasive MCN were conducted. The OS for invasive IPMN was compared between patients who underwent surgery alone and those who received surgery plus chemotherapy by propensity score matching (PSM). Results: A total of 2,505 patients were included, of whom 2,300 were diagnosed with invasive IPMN and 205 were diagnosed with invasive MCN. Half of the invasive IPMN (48.4%) and three-quarters of the invasive MCN (76.1%) patients were female. Of all patients, both the OS and cancer-specific survival were significantly better in the invasive MCN cohort compared to the invasive IPMN cohort. In subgroup analyses, while invasive MCN experienced better OS compared to invasive IPMN in the subgroups of patients with local-regional disease, the survival advantages disappeared in patients at a distant stage. In addition, surgery plus chemotherapy in invasive IPMN patients was associated with significantly better survival compared to surgery alone after PSM. Conclusion: We examined the demographic and clinical characteristics between invasive IPMN and invasive MCN patients using a large-population-based analysis. Although the OS is significantly better for invasive MCN versus invasive IPMN, the difference disappeared in patients with distant disease. A combination of surgery and chemotherapy in selected invasive IPMN patients could confer survival benefits compared to surgery alone.

Survival Benefit of Surgical Resection for Pancreatic Neuroendocrine Tumors With Oligometastatic Liver Metastasis: A Retrospective and Propensity Score-Matching Analysis.

Background: Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of pancreatic malignancies. Surgical resection is the only curative treatment option for patients with localized PanNETs, yet the role of cancer-directed surgery (CDS) in the setting of oligometastatic liver metastasis remains a controversy. Methods: All patients diagnosed with PanNETs and liver-only metastasis from 2010 to 2018 were identified from the SEER database. The biases of baseline characteristics between CDS and no-CDS cohorts were reduced by the propensity score-matching (PSM) method, and the prognostic role of CDS was estimated using the Kaplan-Meier method and Cox regression models. Logistic regression analysis was utilized to identify factors associated with patients who underwent CDS. Results: A total of 1,270 PanNET patients with oligometastatic liver metastasis were included and analyzed. Of these patients, 283 (22.3%) patients underwent CDS of the primary tumor, while the remaining 987 (77.7%) did not. The OS and CSS were significantly better in the CDS cohort regardless of the propensity score analysis. Multivariate analysis revealed that age, tumor differentiation, tumor location, and lymph node status were significantly associated with patients who were more likely to receive CDS. Conclusion: Our study demonstrated that CDS was associated with survival benefits in selected patients with PanNETs and liver-only metastasis based on a large population database.

Comparative outcomes of pancreatic neuroendocrine neoplasms: A population-based analysis of the SEER database.

BACKGROUND: A paucity of data exists regarding the natural history and survival outcomes of pancreatic neuroendocrine neoplasms (PanNENs), a rare histological subtype which can be classified as functional (F-PanNENs) and non-functional (NF-PanNENs). The purpose of this study is to characterize their clinicopathological features and survival outcomes in a large cohort of patients from United States. METHODS: All patients diagnosed with F-PanNENs or NF-PanNENs between 1998 and 2018 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. Patient demographic, clinicopathological features and survival outcomes were analyzed. Logistic regression analysis was used to identify factors associated with NF-PanNENs diagnosis over F-PanNENs. Cox regression analysis was utilized to determine the prognostic variables for overall survival (OS) in all PanNENs patients. RESULTS: A total of 2347 patients were identified: 1181 in the F-PanNENs group and 1206 in the NF-PanNENs group. NF-PanNENs were larger in size, poorly differentiated, more commonly found in a head pancreas location, and had increased lymph node positivity and liver involvement compared to F-PanNENs. Patients with F-PanNENs were associated better survival outcomes than those with NF-PanNENs. Diagnosis at early year, poorer differentiation, and larger tumor size were independently correlated with NF-PanNENs diagnosis. In addition, multivariable analysis determined that age, gender, year of diagnosis, marital status, tumor grade, size, stage, number, and surgical treatment were independent prognostic factors for OS of all PanNENs patients. CONCLUSION: The clinicopathological characteristics and survival outcomes were significantly different between NF-PanNENs and F-PanNENs. Furthermore, we identified the clinical features correlated with NF-PanNENs diagnosis over F-PanNENs.

A Panel of E2F Target Gene Signature Predicting the Prognosis of Hepatocellular Carcinoma.

Hepatocellular carcinoma is one of the most malignant tumors, and the therapeutic effects of traditional treatments are poor. It is urgent to explore and identify new biomarkers and therapeutic targets to develop novel treatments which are individualized and effective. Three hallmarks, including E2F targets, G2M checkpoint and DNA repair, were collected by GSEA analysis. The panel of E2F-related gene signature consisted of five genes: HN1, KIF4A, CDCA3, CDCA8 and SSRP1. They had various mutation rates ranging from 0.8 to 5% in hepatocellular carcinoma, and patients with gene mutation had poorer prognosis. Among these genes, HN1 has the greatest mutation rate, and SSRP1 has the greatest impact on the model with a B (COX) value of 0.8842. Patients with higher expression of these genes had poorer prognosis. Kaplan-Meier curves in stratified survival analysis confirmed that patients with high risk scores had poor prognosis (p < 0.05). The results of univariate and multivariate COX survival analysis showed that risk score was closely related to the overall survival of patients with hepatocellular carcinoma. For clinical validation, we found that all the genes in the model were upregulated in hepatocellular carcinoma tissues compared to normal liver tissues, which was consistent with the previous results we obtained. Our study demonstrated that a panel of E2F target genes signature including five genes could predict the prognosis of hepatocellular carcinoma. This panel gene signature can facilitate the development of individualized and effective treatment for hepatocellular carcinoma.

FNDC5 Causes Resistance to Sorafenib by Activating the PI3K/Akt/Nrf2 Pathway in Hepatocellular Carcinoma Cells.

In this study, we aimed to reveal the resistance mechanism of hepatocellular carcinoma (HCC) cells to sorafenib by exploring the effect of FNDC5 on sorafenib-induced ferroptosis in HCC cells. We compared the expression level of FNDC5 between sorafenib-resistant and sorafenib-sensitive HCC cell lines and the level of ferroptosis between the groups after treatment with sorafenib. We knocked down FNDC5 in drug-resistant cell lines and overexpressed it in sorafenib-sensitive HCC cell lines to further demonstrate the role of FNDC5 in sorafenib-induced ferroptosis. Using PI3K inhibitors, we revealed the specific mechanism by which FNDC5 functions. In addition, we verified our findings obtained in in vitro experiments using a subcutaneous tumorigenic nude mouse model. The findings revealed that FNDC5 inhibits sorafenib-induced ferroptosis in HCC cells. In addition, FNDC5 activated the PI3K/Akt pathway, which in turn promoted the nuclear translocation of Nrf2 and increased the intracellular antioxidant response, thereby conferring resistance to ferroptosis. Our study provides novel insights for improving the efficacy of sorafenib.

Comprehensive Analysis of HOX Family Members as Novel Diagnostic and Prognostic Markers for Hepatocellular Carcinoma.

BACKGROUND: The homeobox (HOX) gene family has been found to be involved in human cancers. However, its involvement in hepatocellular carcinoma (HCC) has not been well documented. Here, we comprehensively evaluated the role of HOXs in HCC. METHODS: RNA sequencing profile of TCGA-LIHC and LIRI-JP were obtained from the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), respectively. Data of TCGA-LIHC methylation were downloaded from UCSC Xena. Genetic alteration data for the TCGA samples was obtained from cBioPortal and GSCA. The diagnostic efficiency was assessed using ROC curves. The prognostic significance was evaluated by the Kaplan-Meier method and Cox regression analysis. Subsequent functional analysis was performed through the clusterProfiler package. ssGSEA, ESTIMATE, and TIDE algorithms were employed to explore the relationship between HOXs and the HCC microenvironment. Finally, pRRophetic package and NCI-60 cancerous cell lines were applied to estimate anticancer drug sensitivity. RESULTS: The mRNA levels of HOXs in HCC tissues were higher than those of noncancerous tissues and were correlated with poor overall survival (OS). HOXA6, C6, D9, D10, and D13 could serve as independent risk factors for OS. Further functional analysis revealed that these five HOXs regulate the cell proliferation, cell cycle, immune response, and microenvironment composition of HCC. In addition, the aberrant expression and methylation of HOXs is of great value in the diagnosis of HCC. CONCLUSION: HOXs play crucial roles in HCC and could serve as potential markers for HCC diagnosis and prognosis.

Development and Validation of Nomograms to Predict Overall Survival and Cancer-Specific Survival in Patients With Pancreatic Adenosquamous Carcinoma.

Background: Pancreatic adenosquamous carcinoma (PASC) is a heterogeneous group of primary pancreatic cancers characterized by the coexistence of both glandular and squamous differentiation. The aim of this study was to develop nomograms to predict survival outcomes in patients with PASC. Methods: In this retrospective study, data on PASC, including clinicopathological characteristics, treatments, and survival outcomes, were collected from the SEER database between 2000 and 2018. The primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The eligible patients were randomly divided into development cohort and validation cohort in a 7:3 ratio. The nomograms for prediction of OS and CSS were constructed by the development cohort using a LASSO-Cox regression model, respectively. Besides the model performance was internally and externally validated by examining the discrimination, calibration, and clinical utility. Results: A total of 632 consecutive patients who had been diagnosed with PASC were identified and randomly divided into development (n = 444) and validation (n = 188) cohorts. In the development cohort, the estimated median OS was 7.0 months (95% CI: 6.19-7.82) and the median CSS was 7.0 months (95% CI: 6.15-7.85). In the validation cohort, the estimated median OS was 6.0 months (95% CI: 4.46-7.54) and the median CSS was 7.0 months (95% CI: 6.25-7.75). LASSO-penalized COX regression analysis identified 8 independent predictors in the OS prediction model and 9 independent risk factors in the CSS prediction model: age at diagnosis, gender, year of diagnosis, tumor location, grade, stage, size, lymph node metastasis, combined metastasis, surgery, radiation, and chemotherapy. The Harrell C index and time-dependent AUCs manifested satisfactory discriminative capabilities of the models. Calibration plots showed that both models were well calibrated. Furthermore, decision curves indicated good utility of the nomograms for decision-making. Conclusion: Nomogram-based models to evaluate personalized OS and CSS in patients with PASC were developed and well validated. These easy-to-use tools will be useful methods to calculate individualized estimate of survival, assist in risk stratification, and aid clinical decision-making.

Survival outcomes of combined hepatocellular-cholangiocarcinoma compared with intrahepatic cholangiocarcinoma: A SEER population-based cohort study.

BACKGROUND: Combined hepatocellular-cholangiocarcinoma (CHC) is a heterogeneous group of primary liver cancers characterized by the coexistence of both hepatic and biliary cellular contents. The aim of this study was to compare CHC and intrahepatic cholangiocarcinoma (ICC) and investigate the treatment and survival of patients with CHC. METHODS: Data on CHC and ICC, including clinicopathological characteristics, treatments, and survival outcomes were extracted from the SEER database between 2004 and 2016. Univariate and multivariate analyses of all data were performed to identify the risk factors associated with survival outcomes. The overall survival (OS) rates of CHC patients who underwent hepatic resection (HR) or liver transplantation (LT) were also assessed before and after propensity score matching. RESULTS: A total of 1066 consecutive patients who had been diagnosed with CHC (n = 286) or ICC (n = 780) were identified. The mean age of the CHC cohort was 60.8±10.7 years old. Among the CHC group, a large proportion of the patients were men and of White ethnicity (73.1% and 71.3%, respectively). The majority of tumors were poorly differentiated (37.8%), while the most common AJCC stage at presentation was stage I (31.4%). Multivariable analysis of all CHC patients revealed that only tumor size, M1  stage, AJCC stage IIIC, AJCC stage IV, surgery, and chemotherapy were significantly associated with OS. The OS was comparable with the ICC in the initial 36 months and better in the subsequent follow-up after treatment. Surgery was associated with better survival outcomes, whether in the early or advanced stages. Regarding the specific types of surgery, the OS rates were similar in selected patients following HR or LT. CONCLUSION: In patients with CHC, surgical intervention resulted in better long-term survival outcomes than nonsurgical treatments. The OS rate of CHC patients compared with that of ICC patients was discriminated before and after a 3-year follow-up.