An integrative pan-cancer analysis of the molecular characteristics of dietary restriction in tumour microenvironment.

BACKGROUND: Dietary restriction (DR), a general term for dieting, has been demonstrated as an effective intervention in reducing the occurrence of cancers. Molecular activities associated with DR are crucial in mediating its anti-cancer effects, yet a comprehensive exploration of the landscape of these activities at the pan-cancer level is still lacking. METHODS: We proposed a computational approach for quantifying DR-related molecular activities and delineating the landscape of these activities across 33 cancer types and 30 normal tissues within 27,320 samples. We thoroughly examined the associations between DR-related molecular activities and various factors, including the tumour microenvironment, immunological phenotypes, genomic features, and clinical prognosis. Meanwhile, we identified two DR genes that show potential as prognostic predictors in hepatocellular carcinoma and verified them by immunohistochemical assays in 90 patients. FINDINGS: We found that DR-related molecular activities showed a close association with tumour immunity and hold potential for predicting immunotherapy responses in various cancers. Importantly, a higher level of DR-related molecular activities is associated with improved overall survival and cancer-specific survival. FZD1 and G6PD are two DR genes that serve as biomarkers for predicting the prognosis of patients with hepatocellular carcinoma. INTERPRETATION: This study presents a robust link between DR-related molecular activities and tumour immunity across multiple cancer types. Our research could open the path for further investigation of DR-related molecular processes in cancer treatment. FUNDING: National Natural Science Foundation of China (Grant No. 82000628) and the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine Foundation of Guangdong Province (Grant No. 2023LSYS001).

Metagenomic analysis reveals gut plasmids as diagnosis markers for colorectal cancer.

Background: Colorectal cancer (CRC) is linked to distinct gut microbiome patterns. The efficacy of gut bacteria as diagnostic biomarkers for CRC has been confirmed. Despite the potential to influence microbiome physiology and evolution, the set of plasmids in the gut microbiome remains understudied. Methods: We investigated the essential features of gut plasmid using metagenomic data of 1,242 samples from eight distinct geographic cohorts. We identified 198 plasmid-related sequences that differed in abundance between CRC patients and controls and screened 21 markers for the CRC diagnosis model. We utilize these plasmid markers combined with bacteria to construct a random forest classifier model to diagnose CRC. Results: The plasmid markers were able to distinguish between the CRC patients and controls [mean area under the receiver operating characteristic curve (AUC = 0.70)] and maintained accuracy in two independent cohorts. In comparison to the bacteria-only model, the performance of the composite panel created by combining plasmid and bacteria features was significantly improved in all training cohorts (mean AUCcomposite = 0.804 and mean AUCbacteria = 0.787) and maintained high accuracy in all independent cohorts (mean AUCcomposite = 0.839 and mean AUCbacteria = 0.821). In comparison to controls, we found that the bacteria-plasmid correlation strength was weaker in CRC patients. Additionally, the KEGG orthology (KO) genes in plasmids that are independent of bacteria or plasmids significantly correlated with CRC. Conclusion: We identified plasmid features associated with CRC and showed how plasmid and bacterial markers could be combined to further enhance CRC diagnosis accuracy.

Comparative Recurrence Analysis of Pancreatic Adenocarcinoma after Resection.

PURPOSE: The relation between tumor sites of pancreatic ductal adenocarcinoma (PDAC) and recurrence was not fully investigated before. We aimed to describe the differences of recurrent patterns in PDAC of head and body/tail after curative surgery. METHODS: The recurrent patterns of PDAC were compared and the associations with clinical characteristics were analyzed in these patients. Prognostic factors of overall survival (OS) and progression-free survival (PFS) were analyzed and validated. Predictive systems were constructed and measured by the area under the AUC curve and concordance index (C-index). RESULTS: A total of 302 PDAC patients were included in this study, including 247 patients with PDAC of head and another 55 patients with PDAC of body/tail. Patients who developed tumor recurrence within 24 months after resection had significantly shorter OS in both groups. Liver metastasis occupied most of the tumor progressions and diminished while local recurrence increased gradually over time. The variation trends were similar for patients in both groups while these changes were more pronounced for patients in the head group. Local recurrence and liver-only metastasis seemed to indicate a better OS. Furthermore, predictive systems for OS and PFS prediction based on independent risk factors were established and showed significant higher values of AUC and C-indexes compared with the TNM stage system. CONCLUSIONS: Different characteristics of progressions for PDAC of head and body/tail suggested biological heterogeneity. The exploration of these variations helps to provide personalized management of recurrence in PDAC.

Survival Comparisons of Hepatic Arterial Infusion Chemotherapy With mFOLFOX and Transarterial Chemoembolization in Patients With Unresectable Intrahepatic Cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis and 40%-60% of patients present with advanced disease at the time of diagnosis. Transarterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have recently been used in unresectable ICC. The aim of this study was to compare the survival differences of unresectable ICC patients after TACE and HAIC treatment. METHODS: Between March 2011 and October 2019, a total of 126 patients with unresectable ICC, as evident from biopsies and imaging, and who had received TACE or HAIC were enrolled in this study. Baseline characteristics and survival differences were compared between the TACE and HAIC treatment groups. RESULTS: ICC Patients had significantly higher survival rates after the HAIC treatment, compared with those after TACE treatment [1-year overall survival (OS) rates: 60.2% vs. 42.9%, 2-year OS rates: 38.7% vs. 29.4%, P=0.028; 1-year progression-free survival (PFS) rates: 15.0% vs. 20.0%, 2-year PFS rates: 0% vs. 0%, P=0.641; 1-year only intrahepatic PFS (OIPFS) rates: 35.0% vs. 24.4%, 2-year OIPFS rates: 13.1% vs. 14.6%, P = 0.026]. Multivariate Cox regression analysis showed that HAIC was a significant and independent factor for OS and OIPFS in the study cohort. CONCLUSIONS: HAIC is superior to TACE for treatment of unresectable ICC. A new tumor response evaluation procedure for HAIC treatment in unresectable ICC patients is needed to provide better therapeutic strategies. A randomized clinical trial comparing the survival benefits of HAIC and TACE is therefore being considered.

Comparison of combination therapies in the management of locally advanced pancreatic cancer: Induction chemotherapy followed by irreversible electroporation vs radiofrequency ablation.

BACKGROUND: Locally advanced pancreatic cancer (LAPC) remains a challenge for current treatments. Local destructive therapies, such as irreversible electroporation (IRE) and radiofrequency ablation (RFA), were used more and more frequently in the treatment of LAPC. OBJECTIVE: This study aimed to compare the efficacy of IRE with RFA in patients with LAPC. METHODS: From August 2015 to August 2017, 58 LAPC patients after IRE or RFA therapy, which was performed through open approach, were retrospectively reviewed. The survival outcomes after IRE (36 patients) and RFA (18 patients) were compared after propensity score matching (PSM) analysis. RESULTS: Before PSM analysis, IRE after the induction chemotherapy resulted in significant higher overall survival (OS) rates and progression-free survival (PFS) rates to RFA (2-year OS, 53.5% vs 30.8%, P = .013; 2-year PFS, 28.4% vs 12.1%, P = .043). After PSM analysis, compared with RFA, the survival benefit of IRE was even more obvious, (2-year OS, 53.5% vs 27.0%, P = .010; 2-year PFS, 28.4% vs 6.4%, P = .018). For patients with tumor larger than 4 cm, IRE resulted in comparable OS and PFS between RFA and IRE while IRE also achieved better long-term OS to RFA for those with tumor smaller than 4 cm. Multivariate analysis illustrated that IRE was a favorable prognostic factor in terms of OS and PFS in patients with LAPC. CONCLUSIONS: IRE after induction chemotherapy is superior to RFA after induction chemotherapy for treating LAPC patients while these two therapies have comparable efficacy for tumors which were larger than 4 cm.

Comparison of Survival Between Irreversible Electroporation Followed by Chemotherapy and Chemotherapy Alone for Locally Advanced Pancreatic Cancer.

Locally advanced pancreatic cancer (LAPC) has a dismal prognosis even after standard chemotherapy, and local progression contributes to nearly one-third of the deaths of these patients. As a local destructive method, irreversible electroporation (IRE) can feasibly treat LAPC. The aim of this study was to evaluate IRE combined with chemotherapy as a new treatment and compare its efficacy with that of chemotherapy alone in patients with LAPC. The data of LAPC patients who received chemotherapy with or without IRE were extracted from Surveillance, Epidemiology, and End Results (SEER) database and medical records of Sun Yat-sen University Cancer Center (SYSUCC). The efficacy of these two treatments was compared using propensity score matching (PSM) analysis. LAPC patients treated with the combination therapy had better overall survival (OS). Significantly higher cancer-specific survival (CSS) and progression-free survival (PFS) rates were also observed in patients after IRE combined with chemotherapy, compared with chemotherapy alone. IRE combined with chemotherapy was established as a favorable factor for OS, CSS, and PFS in LAPC patients. This combination method may be a more suitable treatment for patients with LAPC.

A tumor-microenvironment-responsive nanomaterial for cancer chemo-photothermal therapy.

Taxol (TAX) is a typical anticancer drug that is widely used in clinical treatment of cancer, while gold nanorods (AuNRs) are a kind of well-known material applied for photothermal therapy (PTT). The therapeutic outcome of TAX in chemotherapy is however limited by drug resistance, while AuNRs often show poor accuracy in PTT. To optimize the functions of TAX and AuNRs, we developed a hydrogen peroxide (H2O2)-triggered nanomaterial (LV-TAX/Au@Ag) for combined chemo-photothermal therapy. In normal tissues, TAX is protected in the lipid bilayer and isolated from the surrounding normal cells, while AuNRs are coated with silver shells and show low photothermal capacity. However, after reaching the tumor tissues, the silver shells can be etched by endogenous H2O2 in the tumor microenvironment, and the photothermal properties of AuNRs are then recovered. Meanwhile, the generated oxygen destabilizes the LV, which makes the 100 nm sized nanosystems disassemble into the smaller sized TAX and AuNRs, leading to the deep penetration and direct interaction with tumor tissues. The related in vitro experiments proved the validity of this "turn off/on" effect. Extensive necrosis and apoptosis were observed in the tumor tissues and the proliferation of solid tumor was greatly suppressed due to this combined chemo-photothermal therapy. In addition, no significant damage was found in normal tissues after the treatment of LV-TAX/Au@Ag. Therefore, the strategy to achieve environmental response by modifying the photothermal agents enhanced the efficiency and safety of nanomedicine, which may help improve cancer treatment.

A Quantitative Clinicopathological Signature for Predicting Recurrence Risk of Pancreatic Ductal Adenocarcinoma After Radical Resection.

Recurrence and distant metastases were main reasons of unfavorable outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) after surgery. The aim of this study was to describe the patterns, timing, and predictors of recurrence or metastasis in PDAC patients after curative surgery. Patients with PDAC who underwent radical pancreatectomy were included. Associations between clinicopathological and radiological characteristics and specific pattern of progression were investigated. Least absolute shrinkage and selection operator (LASSO) and Cox regression were applied to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). A total of 302 patients were included into present study, and 173 patients were documented as recurrence after a median survival of 24.7 months. More than half of patients recurred after 12 months after surgery, and the liver was the most common metastatic site. Decreased time interval to progression, elevated carbohydrate antigen 19-9 (CA19-9) level, and lymph node (LN)16 metastasis were independent predictors for reduced OS. Independent prognostic factors for PFS included elevated carcinoembryonic antigen (CEA) level, local progression, liver or lung-only metastasis, local + distant progression, multiple metastases, LN16 metastasis, imaging tumor size, chemotherapy, and tumor-node-metastasis (TNM) stage. The predictive system showed valuable prediction performance with values of concordance indexes (C-indexes) and the area under the receiver operating characteristic curve (AUC) over 0.80. Different survival curves and predictive factors for specific patterns of disease progression suggested the biological heterogeneity, providing new versions into personal management of recurrence in PDAC patients after surgery.

Effect of prior cancer on survival outcomes for patients with pancreatic adenocarcinoma: a propensity score analysis.

BACKGROUND: With the increase in cancer survivors, more pancreatic ductal adenocarcinomas (PDACs) are developing as second primary cancers. Whether a prior cancer has an inferior impact on survival outcomes in patients with PDAC remains unknown, and the validity of criteria used to exclude patients with prior cancers in clinical trials needs to be determined. The aim of this study was to evaluate the prognostic factors and assess the survival impact of a prior cancer in patients with second primary PDAC. METHODS: Patients with PDAC were retrospectively selected from the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer-specific mortality rates were compared between patients with and those without prior cancer. RESULTS: The data of 9235 patients with PDAC from 2004 to 2015 were retrieved from the SEER database, consisting of 438 (4.74%) patients with a prior cancer and 8797 (95.26%) patients without a prior cancer, the patients were then pair-matched using propensity score matching (PSM) analysis. The median OS rates were 7 months for both groups of patients with PDAC with and without prior cancer. These two groups of patients had similar survival rates and cancer-specific mortalities before and after the PSM analysis. In the multivariate analysis, a history of prior cancer was not a significant prognostic factor of OS in patients with PDAC. CONCLUSIONS: Patients with PDAC who had a prior cancer had similar OS and cancer-specific mortality rates as those of patients without a prior cancer. The inclusion of patients with a prior cancer in the clinical trials of PDAC should be considered.

Development and validation of a nomogram to predict liver metastasis in patients with pancreatic ductal adenocarcinoma: a large cohort study.

Background: Few studies have explored the relationship between clinicopathological factors of patients with pancreatic ductal adenocarcinoma (PDAC) and liver metastasis. The aim of this study was to develop and validate a nomogram to predict liver metastasis in patients with PDAC. Patients and methods: Patients diagnosed with PDAC between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. The nomogram was established based on a logistic regression model. The precision of the nomogram was evaluated and compared using concordance index (C-index), and the area under receiver operating characteristic curve (AUC). The clinical use of nomogram was evaluated by making use of a decision curve analysis (DCA). Results: A total of 12,644 eligible patients, which were randomly divided into training (n=9,483) and validation cohorts (n=3,161), were included in this study. The nomograms, which were established on the basis of independent predictors, were well calibrated, and demonstrated good discriminative ability, with C-indexes of 0.784 for the training cohort and 0.790 for validation cohort. The values of AUC for training and validation cohort were 0.792 and 0.800, respectively. When other sites of distant metastases were included into this predictive system, the new predictive model demonstrated a better discriminative ability and greater net benefit in predicting liver metastasis in patients with PDAC in both the training and validation cohorts. Conclusion: Nomograms were constructed to predict liver metastasis in patients with PDAC. Validation revealed excellent discrimination and calibration of the nomograms, suggesting that the nomograms were well calibrated and could serve to improve the prediction of the risks of liver metastasis which can be used to guide the management of patients with PDAC.

Competing risk analyses of overall survival and cancer-specific survival in patients with combined hepatocellular cholangiocarcinoma after surgery.

BACKGROUND: Our objective was to identify risk factors affecting overall survival (OS) and cancer-specific survival (CSS) and build nomograms to predict survival based on a large population-based cohort. METHODS: Two hundred and thirty patients diagnosed with CHCC between 2004 and 2015 were retrospectively extracted from the Surveillance, Epidemiology, and End Results (SEER) database as a training cohort. In addition, Ninety-nine patients diagnosed with CHCC between 2000 and 2017 were retrospectively extracted from Sun Yat-Sen University Cancer Center (SYSUCC) as an external validation. Nomograms for predicting probability of OS and CSS were established. Performance of the nomograms was measured by concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC). RESULTS: In training cohort, the 1-, 2 and 3-year OS were 67.7, 46.8 and 37.9%, and the 1-, 2 and 3-year CSS were 73.1, 52.0 and 43.0%, respectively. The established nomograms were well calibrated in both training and validation cohort, with concordance indexes (C-index) of 0.652 and 0.659, respectively for OS prediction; 0.706 and 0.763, respectively for CSS prediction. Nomograms also displayed better discriminatory compared with 8th edition tumor-node-metastasis (TNM) stage system for predicting OS and CSS. CONCLUSION: We constructed nomograms to predict OS and CSS based on a relatively large cohort. The established nomograms were well validated and could serve to improve predictions of survival risks and guide management of patients with CHCC after surgery.

The prognostic and predictive value of the combination of the neutrophil-to-lymphocyte ratio and the platelet-to-lymphocyte ratio in patients with hepatocellular carcinoma who receive transarterial chemoembolization therapy.

PURPOSE: This study was designed to evaluate the prognostic value of the combination of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) (neutrophil/platelet-to-lymphocyte ratio [NLR-PLR]) in patients with hepatocellular carcinoma (HCC) who receive transarterial chemoembolization (TACE) therapy. PATIENTS AND METHODS: Data from 216 patients who were diagnosed with HCC after TACE therapy were retrospectively collected. R software was used to analyze the time-dependent receiver operating characteristic (ROC) curves and to compare the area under the ROC curves (AUROCs). RESULTS: The long-term survival rates were significantly higher for patients with lower values than those with higher values of NLR, PLR, and NLR-PLR. The mean overall survival decreased gradually with increases in the NLR-PLR score (P<0.0001). The AUROC values of the NLR-PLR score were consistently higher than those of NLR and PLR. CONCLUSION: This study showed that the NLR-PLR score might be a useful predictor for patients with HCC who receive TACE therapy.

The impact of surgery in metastatic pancreatic neuroendocrine tumors: a competing risk analysis.

Aim The role of surgery in the treatment of metastatic pancreatic neuroendocrine tumors (PNETs) was controversial. The objectives of this study were to illustrate the impact of surgery in improving the prognosis of patients with metastatic PNETs and build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) based on a large population-based cohort. Methods Patients diagnosed with metastatic PNETs between 2004 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database were retrospectively collected. Nomograms for estimating OS and CSS were established based on Cox regression model and Fine and Grey's model. The precision of the nomograms was evaluated and compared using concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC). Results The study cohort included 1966 patients with metastatic PNETs. It was shown that the surgery provided survival benefit for all groups of patients with metastatic PNETs. In the whole study cohort, 1-, 2- and 3-year OS and CSS were 51.5, 37.1 and 29.4% and 53.0, 38.9 and 31.1%, respectively. The established nomograms were well calibrated, and had good discriminative ability, with C-indexes of 0.773 for OS prediction and 0.774 for CSS prediction. Conclusions Patients with metastatic PNETs could benefit from surgery when the surgery tolerance was acceptable. The established nomograms could stratify patients who were categorized as tumor-node-metastasis (TNM) IV stage into groups with diverse prognoses, showing better discrimination and calibration of the established nomograms, compared with 8th TNM stage system in predicting OS and CSS for patients with metastatic PNETs.

Prognostic Model to Predict Cancer-Specific Survival for Patients With Gallbladder Carcinoma After Surgery: A Population-Based Analysis.

Predicting the prognosis of gallbladder carcinoma (GBC) has always been important for improving survival. The objective of this study was to determine the risk factors of survival for patients with GBC after surgery and to develop predictive nomograms for overall survival (OS) and cancer-specific survival (CSS) using a large population-based cohort. We identified 2,762 patients with primary resectable GBC in the Surveillance, Epidemiology, and End Results (SEER) database for the period of 2004 to 2014 and another 152 patients with GBC after surgery from Sun Yat-sen University Cancer Center (SYSUCC) for the period of 1997 to 2017. The 1-, 2-, and 3-year cancer-specific mortalities were 37.2, 52.9, and 59.9%, while the competing mortalities were 5.8, 7.8, and 9.0%, respectively. Nomograms were developed to estimate OS and CSS, and these were validated by concordance indexes (C-indexes) and evaluated using receiver operating characteristic (ROC) curves. The C-indexes of the nomograms for OS and CSS prediction were 0.704 and 0.732, respectively. In addition, compared with the 8th Tumor-Node-Metastasis staging system, the newly established nomograms displayed higher areas under the ROC curves for OS and PFS prediction. The nomograms are well-validated and could thus aid individual clinical practice.

Nomogram to Predict Cancer-Specific Survival in Patients with Pancreatic Acinar Cell Carcinoma: A Competing Risk Analysis.

Background: The objective of this study was to evaluate the probability of cancer-specific death of patients with acinar cell carcinoma (ACC) and build nomograms to predict overall survival (OS) and cancer-specific survival (CSS) of these patients. Methods: Data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. Patients diagnosed with ACC between 2004 and 2014 were retrospectively collected. Cancer-specific mortality and competing risk mortality were evaluated. Nomograms for estimating 1-, 2- and 3-year OS and CSS were established based on Cox regression model and Fine and Grey's model. The precision of the 1-, 2- and 3-year survival of the nomograms was evaluated and compared using the area under receiver operating characteristic (ROC) curve (AUC). Results: The study cohort included 227 patients with ACC. The established nomograms were well calibrated, and had good discriminative ability, with a concordance index (C-index) of 0.742 for OS prediction and 0.766 for CSS prediction. The nomograms displayed better discrimination power than 7th or 8th edition Tumor-Node-Metastasis (TNM) stage systems in training set and validation set for predicting both OS and CSS. The AUC values of the nomogram predicting 1-, 2-, and 3-year OS rates were 0.784, 0.797 and 0.805, respectively, which were higher than those of 7th or 8th edition TNM stage systems. Regard to the prediction of CSS rates, the AUC values of the nomogram were also higher than those of 7th or 8th edition TNM stage systems. Conclusion: We evaluated the 1-, 2- and 3-year OS and CSS in patients with ACC for the first time. Our nomograms showed relatively good performance and could be considered as convenient individualized predictive tools for prognosis.

Overall survival and cancer-specific survival in patients with surgically resected pancreatic head adenocarcinoma: A competing risk nomogram analysis.

Background: The objective of this study was to estimate probabilities of overall survival (OS) and cancer-specific survival (CSS) in patients with pancreatic head adenocarcinoma after surgery. In addition, we attempted to build nomograms to predict prognosis of these patients. Methods: Patients diagnosed with surgically resected pancreatic head adenocarcinoma between 2004 and 2014 were selected for the study from the Surveillance, Epidemiology, and End Results (SEER) database. Nomograms were established for estimating 1-, 2- and 3-year OS and CSS based on Cox regression model and Fine and Grey's model. The performance of the nomogram was measured by concordance index (C-index) and the area under receiver operating characteristic (ROC) curve (AUC). Results: A total of 2374 patients were retrospectively collected from the SEER database. The discrimination of nomogram for OS prediction was superior to that of the Tumor-Node-Metastasis (TNM) 7th or 8th edition stage systems (C-index = 0.640, 95% CI, 0.618 - 0.662 vs 0.573, 95% CI, 0.554 - 0.593, P < 0.001; 0.640, 95% CI, 0.618 - 0.662 vs 0.596, 95% CI, 0.586 - 0.607, P < 0.001, respectively). The comparisons of values of AUC showed that the established nomograms displayed better discrimination power than TNM 7th or 8th stage systems for predicting both OS and CSS. Conclusions: The nomograms which could predict 1-, 2- and 3-year OS and CSS were established in this study. Our nomograms showed a relatively good performance and could be served as an effective tool for prognostic evaluation of patients with pancreatic head adenocarcinoma after surgery.