Postoperative subphenotypes modified the hepatoma arterial-embolization prognostic score: A novel smHAP-II nomogram.

Background: Three subphenotypes were identified for unresectable hepatocellular carcinoma (uHCC) after frontline transarterial chemoembolization (TACE). This study aimed to develop an individual smHAP-Ⅱ nomogram for uHCC patients after TACE. Methods: Between January 2007 to December 2016, 1517 uHCC patients undergoing TACE were included from four hospitals in China (derivation cohort: 597 cases; validation cohort: 920 cases). Multivariable Cox proportion regression analysis was used to develop a nomogram, incorporating postoperative subphenotypes (Phenotype 1, 2, 3) and HAP score (Score 0 to 4). The model was validated by a 1000-time bootstrap resampling procedure. The performance of the model was compared with existing ones by Harrell's C-index and Area Under Curve (AUC). Results: Postoperative subphenotypes modified the HAP score (smHAP-Ⅱ nomogram) was developed and validated, with the Harrell's C-index of the nomogram was 0.679 (SD: 0.029) for the derivation cohort and 0.727(SD:0.029) for the external cohort. The area under curves of the nomogram for 1-, 3-, and 5-year OS were 0.750, 0.710, and 0.732 for the derivation cohort, respectively (0.789, 0.762, and 0.715 for the external cohort). In the calibration curves stratified by treatment after TACE, the lines for re-TACE and stop-TACE cross at 0.23, indicating that patients with a 3-year predicted survival >23% would not benefit from TACE. Conclusions: The addition of postoperative subphenotypes significantly improved the prognostic performance. The smHAP-Ⅱ nomogram can be used for accurate prognostication and selection of optimal candidates for TACE, with the value to guide sequential treatment strategy.

Development and Validation of Deep Learning Model for Intermediate-Stage Hepatocellular Carcinoma Survival with Transarterial Chemoembolization (MC-hccAI 002): a Retrospective, Multicenter, Cohort Study.

Background: There are few effective prediction models for intermediate-stage hepatocellular carcinoma (IM-HCC) patients treated with transarterial chemoembolization (TACE) to predict overall survival (OS) is available. The learning survival neural network (DeepSurv) was developed to showed a better performance than cox proportional hazards model in prediction of OS. This study aimed to develop a deep learning-based prediction model to predict individual OS. Methods: This multicenter, retrospective, cohort study examined data from the electronic medical record system of four hospitals in China between January 1, 2007, to December 31, 2016. Patients were divided into a training set(n=1075) and a test set(n=269) at a ratio of 8:2 to develop a deep learning-based algorithm (deepHAP IV). The deepHAP IV model was externally validated on an independent cohort(n=414) from the other three centers. The concordance index, the area under the receiver operator characteristic curves, and the calibration curve were used to assess the performance of the models. Results: The deepHAP IV model had a c-index of 0.74, whereas AUROC for predicting survival outcomes of 1-, 3-, and 5-year reached 0.80, 0.76, and 0.74 in the training set. Calibration graphs showed good consistency between the actual and predicted OS in the training set and the validation cohort. Compared to the other five Cox proportional-hazards models, the model this study conducted had a better performance. Patients were finally classified into three groups by X-tile plots with predicted 3-year OS rate (low: ≤ 0.11; middle: > 0.11 and ≤ 0.35; high: >0.35). Conclusion: The deepHAP IV model can effectively predict the OS of patients with IM-HCC, showing a better performance than previous Cox proportional hazards models.

Development and validation of serological dynamic risk score to predict outcome in gastric cancer with adjuvant chemotherapy: a multicentre, longitudinal, cohort study.

Background: Baseline serological biomarkers have the potential to predict the benefits of adjuvant chemotherapy in patients with gastric cancer. However, the fluctuating nature of postoperative recurrence risk makes precise treatment challenging. We aimed to develop a risk score in real-time predicting outcomes for postoperative GC patients using blood chemistry tests. Materials and methods: This was a retrospective, multicentre, longitudinal cohort study from three cancer centres in China, with a total of 2737 GC patients in the pTNM stage Ib to III. Among them, 1651 patients with at least two serological records were assigned to the training cohort. Model validation was carried out using separate testing data with area under curve (AUC). The least absolute shrinkage and selection operator (LASSO) and random forest-recursive feature elimination (RF-RFE) algorithm were used to select the parameters. Results: The Cox regression model derived six risk factors to construct a composite score (low-risk: 0-2 score; high risk: 3-6 score), including CEA, CA125, CA199, haemoglobin, albumin, and neutrophil to lymphocyte ratio. The risk score accurately predicted mortality in 1000-time bootstrap (AUROCs:0.658; 95% CI: 0.645, 0.670), with the highest AUROC (0.767; 95% CI: 0.743, 0.791) after 1 year since the gastrectomy. In validation dataset, the risk score had an AUROC of 0.586 (95% CI 0.544, 0.628). Furthermore, patients with high risk at 1 month derived significant clinical benefits from adjuvant chemotherapy (P for interaction <0.0001). Compared with the low-low-low risk group, the low-low-high risk group of the long-term state chain (risk state at baseline, 6 months, 1 year) had the worse OS (HR, 6.91; 95%CI: 4.27, 11.19) and DFS (HR, 7.27; 95%CI: 4.55, 11.63). Conclusion: The dynamic risk score is an accurate and user-friendly serological risk assessment tool for predicting outcomes and assisting clinical decisions after gastrectomy.

Association of survival with adjuvant chemotherapy in patients with stage IB gastric cancer: a multicentre, observational, cohort study.

Background: Recurrence following radical resection in patients with stage IB gastric cancer (GC) is not uncommon. However, whether postoperative adjuvant chemotherapy could reduce the risk of recurrence in stage IB GC remains contentious. Methods: We collected data on 2110 consecutive patients with pathologic stage IB (T1N1M0 or T2N0M0) GC who were admitted to 8 hospitals in China from 2009 to 2018. The survival of patients who received adjuvant chemotherapy was compared with that of postoperative observation patients using propensity score matching (PSM). Two survival prediction models were constructed to estimate the predicted net survival gain attributable to adjuvant chemotherapy. Findings: Of the 2110 patients, 1344 received adjuvant chemotherapy and 766 received postoperative observation. Following the 1-to-1 matching, PSM yielded 637 matched pairs. Among matched pairs, adjuvant chemotherapy was not associated with improved survival compared with postoperative observation (OS: hazard ratio [HR], 0.72; 95% CI, 0.52-1.00; DFS: HR, 0.91; 95% CI, 0.64-1.29). Interestingly, in the subgroup analysis, reduced mortality after adjuvant chemotherapy was observed in the subgroups with elevated serum CA19-9 (HR, 0.22; 95% CI, 0.08-0.57; P = 0.001 for multiplicative interaction), positive lymphovascular invasion (HR, 0.32; 95% CI, 0.17-0.62; P < 0.001 for multiplicative interaction), or positive lymph nodes (HR, 0.17; 95% CI, 0.07-0.38; P < 0.001 for multiplicative interaction). The survival prediction models mainly based on variables associated with chemotherapy benefits in the subgroup analysis demonstrated good calibration and discrimination, with relatively high C-indexes. The C-indexes for OS were 0.74 for patients treated with adjuvant chemotherapy and 0.70 for patients treated with postoperative observation. Two nomograms were built from the models that can calculate individualized estimates of expected net survival gain attributable to adjuvant chemotherapy. Interpretation: In this cohort study, pathologic stage IB alone was not associated with survival benefits from adjuvant chemotherapy compared with postoperative observation in patients with early-stage GC. High-risk clinicopathologic features should be considered simultaneously when evaluating patients with stage IB GC for adjuvant chemotherapy. Funding: National Natural Science Foundation of China; the National Key R&D Program of China.

A Longitudinal Study of AFP Trajectories and Clinical Outcomes in Intermediate-Stage Hepatocellular Carcinoma After Hepatectomy.

Background: Previous studies have shown that the alpha-fetoprotein (AFP) response has been a key tumour marker in hepatocellular carcinoma (HCC), but its definition remains controversial. Recently, a new study has explored and defined the AFP serological response and used it to explain the subclass of intermediate-stage hepatocellular carcinoma (IM-HCC) with "sharp-falling" AFP change after transarterial chemoembolization (TACE). It may be a new and simple tool for assessing the prognosis of patients. This study aims to explore a simplified AFP trajectory and its impact on overall survival (OS) and disease-free survival (DFS) for IM-HCC after hepatectomy. Patients and Methods: Between January 2007 and May 2012, data from the Sun Yat-sen University Cancer Center was examined in this longitudinal, retrospective cohort study. A generalized additive model was applied to distinguish potential AFP dynamic trajectories. The Kaplan-Meier method was applied to analyze OS and DFS, and multivariate Cox models were used to calculate adjusted hazard ratios (aHRs) and 95% CIs for overall survival. Results: 144 patients who had IM-HCC with at least three AFP repeat measurements were included in the study. Three similar trajectories are displayed using the generalized additive model: low-stable (35.4%; n = 51), high-rising (36.1%; n = 52), and sharp-falling (28.5%; n = 41). Compared with the low-stable class, the aHRs for death were 2.84 (1.50, 5.41) and 0.59 (0.25, 1.40) for the high-rising and sharp-falling classes, adjusted by age and log AFP. Simplified AFP trajectory had higher relative importance than sex, intrahepatic tumor number, Child-Pugh class, and baseline AFP. Conclusion: The simplified AFP trajectory is a promising biomarker for IM-HCC patients undergoing hepatectomy. In the future, it should be verified by a larger population containing various stages of HCC.

Readjustment of nodal staging by integrating tumor deposits and positive lymph nodes in patients with stage III colon cancer: a population-based analysis.

Whether tumor deposits (TDs) should be classified as lymph node metastasis or distant metastasis remains controversial. To address this predicament, we conducted this study to identify the predictive value of TDs on the survival of patients diagnosed with stage III colon cancer (CC). 12,904 eligible patients diagnosed with stage III CC between 2010 and 2015 were extracted from the Surveillance, Epidemiology, and End Results (SEER) database. The best cutoff point of TD quantity was determined based on the difference in survival. Cox proportional hazards model was employed to perform univariate and multivariate analyses. The Kaplan-Meier method and log-rank test were performed to calculate the differences between overall survival (OS). Our results showed that the number of TDs was a significant prognostic factor in patients with stage III CC (P < 0.0001). We added the number of TDs to the pN stage and devised a new pN stage, there were no significant differences in the survival of npN, except npN2a (P > 0.05). Upon re-staging to the same npN stage, the difference in survival between TDs+ and TDs- disappeared (P > 0.05). The median survival times for N2aTDs > 4 and N2bTDs > 4 were 33 and 37 months, respectively, which were significantly shorter than that of N2TDs- (65 months) and represented the worst survival rates among all groups. In conclusion, the number of TDs indicated a poor prognosis for patients with stage III CC. Incorporating TDs into the pN is feasible to predict prognosis.

Prognosis of Patients with Hepatocellular Carcinoma Treated with Transarterial Chemoembolization(MC-hccAI 001): Development and Validation of the ALFP Score.

Background: Transarterial chemoembolization (TACE) is the recommended first-line treatment for intermediate-stage Hepatocellular carcinoma (HCC) patients. However, predicting the survival of HCC patients receiving TACE remains challenging. Methods: In this retrospective study, we analyzed a total of 1805 HCC patients who received TACE. The patients were randomly divided into a training set (n = 1264) and a validation set (n = 541). We examined various prognostic factors within the training set and developed a simple ALFP (ALBI grade, AFP, and Prothrombin time) score, which was subsequently validated using the independent validation set. Results: Our multivariate analysis revealed that baseline ALBI grade 2 or 3, AFP ≥ 100 ng/mL, and PT > 13.1 s were independent unfavorable prognostic factors for HCC patients receiving TACE (p < 0.05). Based on these findings, we constructed the ALFP score, which assigns 1 point each for ALBI grade 2 or 3, AFP ≥ 100 ng/mL, and PT > 13.1 s. The score has a range of 0 to 3, and higher scores are associated with poorer outcomes. The median overall survival (OS) varied significantly among different ALFP score groups, both in the training set and the validation set (p < 0.001). We further examined the ALFP score in subgroups based on tumor diameter and the number of intrahepatic lesions. In each subgroup, higher ALFP scores were consistently associated with lower OS (p < 0.05). Conclusion: Our study confirms the prognostic value of the ALFP score in predicting the survival of HCC patients undergoing TACE. The score incorporates easily obtainable baseline parameters and provides a simple and practical tool for risk stratification and treatment decision-making in HCC patients.

Trajectories of α-fetoprotein and unresectable hepatocellular carcinoma outcomes receiving atezolizumab plus bevacizumab: a secondary analysis of IMbrave150 study.

BACKGROUND: α-fetoprotein (AFP) response has been demonstrated as a biomarker for unresectable hepatocellular carcinoma (uHCC) patients receiving immunotherapy, but its definition is still unclear. This exploratory study investigated the AFP trajectory and clinical outcomes of receiving atezolizumab plus bevacizumab (Atez/Bev) therapy. METHODS: This secondary analysis used the Atez/Bev arm data of phase III IMbrave150 study to distinguish potential AFP changing rate trajectories through latent class trajectory models. The multivariable Cox models were applied to calculate adjusted hazard ratios (HRs) and 95% CIs for clinical outcomes. RESULTS: Three distinct trajectories were identified among the uHCC patients with 7 times (range, 3 to 28) of AFP measurements: low-stable (50.0%, n = 132), sharp-falling (13.3%, n = 35), and high-rising (36.7%, n = 97). Compared with the high-rising class, HRs of disease progression were 0.52 (95% CI: 0.39, 0.70) and 0.26 (95% CI: 0.16, 0.43) for the low-stable class and sharp-falling class, respectively. In contrast, HRs of death were 0.59 (95% CI: 0.40, 0.81) and 0.30 (95% CI: 0.16, 0.57) for the two groups after propensity score adjustment. Besides, AFP trajectories had the highest relative importance of each covariate to survival. DISCUSSION: There are three distinct AFP trajectories in uHCC patients receiving Atez/Bev, and it is an independent biomarker for clinical outcomes.

The aMAP Score is an Independent Risk Factor for Intermediate-stage Hepatocellular Carcinoma: A Large Retrospective Cohort Study.

Background: A less effective nomogram for patients with intermediate-stage hepatocellular carcinoma (HCC) to predict overall survival (OS) is available. This study aimed to investigate the role of age-male-albumin-bilirubin-platelet (aMAP) scores in the prognosis of patients with intermediate-stage HCC and develop an aMAP score-based nomogram to predict OS. Methods: Data on newly diagnosed intermediate-stage patients with HCC at Sun Yat-sen University Cancer Center between January 2007 and May 2012 were retrospectively collected. Independent risk factors affecting prognosis were selected by multivariate analyses. The optimal cut-off value for the aMAP score was determined using X-tile. The survival prognostic models were presented by the nomogram. Results: For the 875 patients with intermediate-stage HCC included, the median OS was 22.2 months (95% CI 19.6-25.1). Patients were classified into three groups by X-tile plots (aMAP score < 49.42; 49.42 ≤ aMAP score < 56; aMAP score ≥ 56). Alpha-fetoprotein, lactate dehydrogenase, aMAP score, diameter of main tumor, number of intrahepatic lesions, and treatment regimen were independent risk factors for prognosis. A predicted model was constructed with a C-index of 0.70 (95% CI: 0.68-0.72) in the training goup, and its 1-, 3-, and 5-year area under the receiver operating curve were: 0.75, 0.73, and 0.72. The validation group of the C-index is 0.82. Calibration graphs showed good consistency between the actual and predicted survival rates. The decision curve analysis suggested the clinical utility of the model, which may help clinicians guide clinical decision-making. Conclusion: The aMAP score was an independent risk factor for intermediate-stage HCC. The aMAP score-based nomogram has good discrimination, calibration, and clinical utility.

Age is a significant biomarker for the selection of neoadjuvant chemotherapy plus radiotherapy versus concurrent chemoradiotherapy in patients with advanced nasopharyngeal carcinoma.

BACKGROUND: The optimal timing of combined chemotherapy with radiotherapy for locally advanced nasopharyngeal carcinoma (LA-NPC) is undetermined. OBJECTIVE: This study aimed to compare the therapeutic efficacy of neoadjuvant chemotherapy (NACT) followed by radiotherapy (RT) and concurrent chemoradiotherapy (CCRT). METHODS: Five hundred and thirty-eight patients diagnosed with LA-NPC and treated with NACT + RT or CCRT alone were enrolled in the study. Restricted cubic spline regression (RCS) was used to determine the relationship between age and the hazard Ratio of death. A Kaplan-Meier analysis was performed to evaluate overall survival (OS) related to NACT + RT or CCRT alone. Cox proportional hazards models were used to adjust for potential confounding factors. RESULTS: Compared with the CCRT alone regimen, the NACT + RT regimen showed a significantly better OS rate with a 62% decreased risk of death in a subgroup of patients aged ⩾ 45 years (hazard ratio, HR: 0.38; 95% confidence interval, CI: 0.24-0.61). In patients aged < 45 years, the risk of death was significantly increased when NACT + RT was chosen compared with CCRT (HR: 4.10; 95% CI: 2.09-8.07). CONCLUSIONS: Age is a significant biomarker when selecting NACT + RT or CCRT alone in patients with locally advanced NPC.

Clinical models to predict lymph nodes metastasis and distant metastasis in newly diagnosed early esophageal cancer patients: A population-based study.

BACKGROUND: Patients with early esophageal cancer (EC) receive individualized therapy based on their lymph node metastasis (LNM) and distant metastasis (DM) status; however, deficiencies in current clinical staging techniques and the issue of cost-effectiveness mean LNM and DM often go undetected preoperatively. We aimed to develop three clinical models to predict the likelihood of LNM, DM, and prognosis in patients with early EC. METHOD: The Surveillance, Epidemiology, and End Results database was queried for T1 EC patients from 2004 to 2015. Multivariable logistic regression and Cox proportional hazards models were used to recognize the risk factors of LNM and DM, predict overall survival (OS), and develop relevant nomograms. Receiver operating characteristic (ROC)/concordance index and calibration curves were used to evaluate the discrimination and accuracy of the three nomograms. Decision curve analyses (DCAs), clinical impact curves, and subgroups based on model scores were used to determine clinical practicability. RESULTS: The area under the curve of the LNM and DM nomograms were 0.668 and 0.807, respectively. The corresponding C-index of OS nomogram was 0.752. Calibration curves and DCA showed an effective predictive accuracy and clinical applicability. In patients with T1N0M0 EC, surgery alone (p < 0.01) proved a survival advantage. Chemotherapy and radiotherapy indicated a better prognosis in the subgroup analysis for T1 EC patients with LNM or DM. CONCLUSIONS: We created three nomograms to predict the likelihood of LNM, DM, and OS probability in patients with early EC using a generalizable dataset. These useful visual tools could help clinical physicians deliver appropriate perioperative care.

DNA damage response-related immune activation signature predicts the response to immune checkpoint inhibitors: from gastrointestinal cancer analysis to pan-cancer validation.

OBJECTIVE: DNA damage response (DDR) deficiency has emerged as a prominent determinant of tumor immunogenicity. This study aimed to construct a DDR-related immune activation (DRIA) signature and evaluate the predictive accuracy of the DRIA signature for response to immune checkpoint inhibitor (ICI) therapy in gastrointestinal (GI) cancer. METHODS: A DRIA signature was established based on two previously reported DNA damage immune response assays. Clinical and gene expression data from two published GI cancer cohorts were used to assess and validate the association between the DRIA score and response to ICI therapy. The predictive accuracy of the DRIA score was validated based on one ICI-treated melanoma and three pan-cancer published cohorts. RESULTS: The DRIA signature includes three genes (CXCL10, IDO1, and IFI44L). In the discovery cancer cohort, DRIA-high patients with gastric cancer achieved a higher response rate to ICI therapy than DRIA-low patients (81.8% vs. 8.8%; P < 0.001), and the predictive accuracy of the DRIA score [area under the receiver operating characteristic curve (AUC) = 0.845] was superior to the predictive accuracy of PD-L1 expression, tumor mutational burden, microsatellite instability, and Epstein-Barr virus status. The validation cohort demonstrated that the DRIA score identified responders with microsatellite-stable colorectal and pancreatic adenocarcinoma who received dual PD-1 and CTLA-4 blockade with radiation therapy. Furthermore, the predictive performance of the DRIA score was shown to be robust through an extended validation in melanoma, urothelial cancer, and pan-cancer. CONCLUSIONS: The DRIA signature has superior and robust predictive accuracy for the efficacy of ICI therapy in GI cancer and pan-cancer, indicating that the DRIA signature may serve as a powerful biomarker for guiding ICI therapy decisions.

Decision curve analysis to identify optimal candidates of liver resection for intermediate-stage hepatocellular carcinoma with hepatitis B cirrhosis: A cohort study.

The selection criterion for liver resection (LR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) is still controversial. This study aims to compare LR and transarterial chemoembolization (TACE) in the range of predicted death risk The multivariable Cox regression model (MVR) was estimated to predict mortality at 5 year. The cutoff values were determined by a 2-piece-wise linear regression model, decision curve analysis with MVR model, and hazard ratio curve for treatment plotted against the predicted mortality. 825 IM-hepatocellular carcinoma (IM-HCC) with hepatitis B cirrhosis were included for analysis (TACE, n = 622; LR, n = 203). The 5-year overall survival (OS) rate of LR patients was higher than the TACE group (52.8% vs 20.8%; P < .0001). The line of LR and TACE were crossing with predicted death risk at 100% (P for interaction = .008). The benefit of LR versus TACE decreased progressively as predicted death risk > 0.55 (95%CI: 0.45, 0.62). When predicted death risk over 0.7, decision curve analysis suggested that LR and TACE did not increase net benefit. Patients were then divided into 4 subgroups by the cutoff values (<0.45, 0.45≥/<0.62, 0.62≥/<0.7, ≥0.7). The stratified analysis of treatment in different subgroups, hazard ratios were 0.39 (95%CI: 0.27, 0.56), 0.36 (95%CI: 0.23, 0.56), 0.51 (95%CI: 0.27, 0.98), and 0.46 (95%CI: 0.27, 0.80), respectively. LR reached the maximal relative utility in the interval of 0.45 to 0.62, and both LR and TACE did not increase net benefit at the 5-year death risk over 0.7.

Case report: Long response to PD-1 blockade after failure of trastuzumab plus chemotherapy in advanced Epstein-Barr virus-associated gastric cancer.

Background: Trastuzumab-containing chemotherapy is the first-line treatment for advanced gastric cancer (GC) with HER2 positive. Although PD-1 inhibitors significantly improved the outcome of GC patient's refractory to previous chemotherapy regimens, few studies explore the role of anti-PD-1 therapy overcomes resistance to trastuzumab plus chemotherapy in advanced Epstein-Barr Virus-associated gastric cancer (EBVaGC) with PD-L1 and HER2 positive. Case Presentation: We report a case of advanced EBVaGC in a 45-year-old man presenting with fatigue, dysphagia, and weight loss for several months. Initial endoscopy revealed a large tumor at the gastroesophageal junction. Computed tomography revealed GC accompanied by multiple lymph nodes and hepatic and pulmonary metastases. The immunohistochemistry indicated that HER-2 and PD-L1 were overexpressed, and tumor cells were positive for EBV-encoded small RNA (EBER) by in situ hybridization. Trastuzumab plus DCS was started as first-line chemotherapy with a PFS of 4 months and shifted to trastuzumab plus FOLFIRI or gemcitabine as second-/third-line therapy. After five-cycle nivolumab monotherapy, the patient received partial response and was treated with total radical gastrectomy plus sequential radiotherapy. He continued the postoperative immunotherapy over 30 cycles with a PFS of 28 months. Due to a new abdominal lymph node metastasis confirmed by PET-CT, he received toripalimab as the next-line treatment and achieved complete remission as the best objective response. Summary: We presented an advanced HER2-positive EBVaGC patient with PD-L1 high expression, refractory to trastuzumab plus chemotherapy, and had a durable clinical benefit sequence with a single dose of the PD-1 inhibitor.

Latent Class Analysis of Subphenotypes in Intermediate-Stage Hepatocellular Carcinoma after Transarterial Chemoembolization.

Background: Transarterial chemoembolization (TACE) is the standard first-line therapy for intermediate-stage hepatocellular carcinoma (HCC). However, no latent-classing indices, concerning repeat conventional TACE or switching to another treatment, have been incorporated into the guidelines. Methods: The unsupervised latent class modeling was applied to identify subphenotypes using the clinical and medical imaging data of 1517 HCC patients after the first TACE from four hospitals (derivation cohort: 597 cases; validation cohort: 920 cases); modeling was conducted independently in each cohort. We then explored the relationship of subphenotypes with clinical outcomes in both cohorts and response to treatment strategies after the first TACE in the derivation cohort. Results: Independent latent class models suggested that a three-class model was optimal for both cohorts. In both cohorts, we identified a TACE-refractory subphenotype (Phenotype 1: PS score 1, stage progress, more intrahepatic lesions, and new intrahepatic lesions), TACE-responsive subphenotype (Phenotype 3: PS score 0, No intrahepatic lesions and new intrahepatic lesions), compared to TACE-intermediate subphenotype (Phenotype 2). Compared to Phenotype 1 or 2, patients in Phenotype 3 had significantly lower 3-month or 3-year mortality (all P<0.001). In the derivation cohort, the effects of treatment strategy (surgery/ablation vs. repeat TACE vs. stop TACE) differed significantly in phenotype 2 but not in phenotype 3 (P=0.721 for interaction). Conclusions: Latent class models identified three subphenotypes for HCC after the first TACE treatment. Differences were significant in clinical outcome and response to treatment strategy after the first TACE among three subphenotypes.

Trajectories of serum α-fetoprotein and intermediate-stage hepatocellular carcinoma outcomes after transarterial chemoembolization: A longitudinal, retrospective, multicentre, cohort study.

Background: α-fetoprotein (AFP) response has been proven a key tumor marker for hepatocellular carcinoma (HCC), but its definition remains controversial. This study aims to characterize AFP trajectories after transarterial chemoembolization (TACE) and examine its impact on clinical outcomes. Methods: This longitudinal, multicenter, retrospective, cohort study examined data from the electronic medical record system of four hospitals in China between January 1, 2007 to December 31, 2016. A latent class growth mixed model was applied to distinguish potential AFP dynamic changing trajectories. The multivariable Cox models were used to calculate adjusted hazard ratios (aHRs) and 95% CIs for overall survival. Inverse-probability-of-treatment weighted analyses were performed to eliminate unmeasured confounders through marginal structural models. Findings: A total of 881 patients, who had intermediate-stage HCC with AFP repeatedly measured 3 to 10 times, were included in the study. Three distinct trajectories were identified using the latent class growth mixture model: high-rising (25.7%; n = 226), low-stable (58.7%; n = 517), and sharp-falling (AFP serological response, 15.6%; n = 138). Compared with the low-stable class, the aHRs for death were 5.13 (3.71, 7.10) and 0.52 (0.33, 0.81) for the high-rising and sharp-falling class, adjusted by gender, baseline major tumor size, intrahepatic lesions number, and logAFP(smooth). Furthermore, high-rising class had a significantly higher HR in the subgroup of female patients (10.60, 95%CI: 6.29, 17.86), age<55 (6.78, 95%CI: 4.79, 9.59) and Child-Pugh class B (23.01, 95%CI:8.07, 65.63) (P = 0.014, 0.046 and 0.033 for interaction, respectively). Trajectories of AFP had the highest relative importance of each parameter to survival, including largest tumor size, intrahepatic lesions number, Child-Pugh class, and baseline AFP. Interpretation: AFP trajectories were associated with overall survival for intermediate-stage HCC after TACE. Funding: The Natural Science Foundation of Fujian Province (Nos. 2018J01352, 2016J01576 and 2016J01586); the Science and Technology Innovation Joint Foundation of Fujian Province (Nos. 2017Y9125).

Impact of prior cancer on the overall survival of patients with nasopharyngeal carcinoma.

PURPOSE: Prior cancer history is an important exclusion criterion from clinical trials and may decrease their generalizability. This study aimed to investigate the impact of prior cancer on the prognosis of patients with nasopharyngeal carcinoma and to describe their characteristics. MATERIALS AND METHODS: Data of patients with nasopharyngeal carcinoma diagnosed between 2010 and 2015 were collected from the Surveillance, Epidemiology, and End Results database. The discrepancy in baseline characteristics was adjusted by propensity score matching. Kaplan-Meier and Cox regression analyses were performed to assess the impact of prior cancer on overall survival. RESULTS: A total of 3412 individuals were identified, of which 418 (12.25%) had prior cancer. Prostate cancer was the most frequently detected type of prior cancer (18.42%). Nearly 45% of the prior cancers were diagnosed within 5 years before the nasopharyngeal carcinoma. Patients with prior cancer had an inferior survival compared to those without prior cancer (p < 0.001). Notably, patients with prior prostate, breast, hematological, and nasopharyngeal cancers had a non-inferior overall survival. Prior cancer history was an independent factor of poor overall survival (hazard ratio = 1.329, p = 0.003). CONCLUSIONS: This is the first study to provide the comprehensive insight that patients with nasopharyngeal carcinoma and prior cancer have lower overall survival. Different prior cancer types had a different impact on the clinical outcome, suggesting that the exclusion criteria should be individually defined by unique cancer types.

Neoadjuvant chemotherapy plus intensity-modulated radiotherapy versus neoadjuvant chemotherapy plus concurrent chemoradiotherapy for ascending or descending types of nasopharyngeal carcinoma: A retrospective study.

PURPOSE: This study aimed to compare the efficacy between neoadjuvant chemotherapy (NACT) plus intensity-modulated radiotherapy (IMRT) and NACT plus concurrent chemoradiotherapy (CCRT) in patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: Data from 603 patients with ascending (T4 and N0-1) or descending (T1-2&N3) NPC who were treated at Sun Yat-sen University Cancer Center between October 2009 and February 2012 were retrospectively analyzed. These patients were divided into two groups: NACT+IMRT (n = 302) and NACT+CCRT (n = 301). The primary endpoint was overall survival (OS), which was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards model, and landmark analysis. RESULTS: In univariate analysis, there was no significant difference in 5-year OS between the NACT+IMRT and NACT+CCRT groups (hazard ration [HR]: 0.69; 95% confidence interval [CI]: 0.47-1.01; P = 0.057). However, after adjustment for age (<45 years, ≥45 years), gender, histological stage (I/II, III), T stage (1/2, 3, 4), and N stage (0/1, 2/3), NACT+IMRT was more effective in improving OS, with a 33% decrease in the risk of death than NACT+CCRT (HR: 0.67; 95%CI: 0.45-0.99). Furthermore, landmark analysis indicated that patients in the NACT+IMRT group had higher OS rates within 24 months (HR: 1.83; 95%CI: 1.00-3.34), whereas those treated with NACT+CCRT had higher OS rates after 24 months (HR, 0.47; 95% CI, 0.29-0.77). We also found significant survival benefits of NACT+IMRT regimen in patients younger than 45 years old (HR: 0.27; 95%CI: 0.14-0.49), and in those at stage T3 (HR: 0.50; 95%CI: 0.27-0.93) and stage N2/3 (HR: 0.52; 95%CI: 0.32-0.83). CONCLUSION: Patients with ascending or descending NPC who are treated with NACT+IMRT may have better long-term survival outcomes than those treated with NACT+CCRT, especially the patients younger than 45 years old or in stage T3/N2/N3. Additionally, NACT+IMRT may be a better option than NACT+CCRT in patients within the first 24 months.

Gut Microbiota and Sunitinib-Induced Diarrhea in Metastatic Renal Cell Carcinoma: A Pilot Study.

INTRODUCTION: Sunitinib-induced diarrhea seriously affects the prognosis of patients with metastatic renal cell carcinoma (mRCC) and reduces their quality of life. We aim to explore and find the relationship between sunitinib-induced diarrhea and gut microbiota. METHODS: Feces were collected from 31 mRCC patients receiving sunitinib treatment. To characterize the feces gut microbiome profiles of patients, the V3-V4 region of 16S rRNA sequencing was carried out in this study. RESULTS: Gut microbial diversity was decreased both in the severe diarrhea group and in the sunitinib-post group. The microbial composition with higher abundance of Bacteroides (mucus degrading bacteria) and lower abundance of Faecalibacterium, Oscillospira, Ruminococcaceae, Eubacterium and Coriobacteriaceae (butyrate-producing bacteria) were found in patients with diarrhea. Interestingly, the abundance of Actinobacteria was decreased in patients receiving sunitinib with severe diarrhea. CONCLUSION: This study reported an association between gut microbiota and sunitinib-induced diarrhea. Defects of the butyrate-producing bacteria and the increase in Bacteroides may be the physiological basis of sunitinib-induced diarrhea.

Hepatic Resection Versus Transarterial Chemoembolization for Intermediate-Stage Hepatocellular Carcinoma: A Cohort Study.

BACKGROUND: The selection criteria for hepatic resection (HR) in intermediate-stage (IM) hepatocellular carcinoma (HCC) are still controversial. We used real-world data to evaluate the overall survival (OS) in treatment with HR or transarterial chemoembolization (TACE). METHODS: In total, 942 patients with IM-HCC were categorized into the HR group and the TACE group. OS was analyzed using the Kaplan-Meier method, log-rank test, Cox proportional hazards models, and propensity score-matched (PSM) analysis. Curve smoothing was performed through the generalized additive model. The interaction test was performed to evaluate the impact of HR on OS concerning risk factors. Also, we used multiple imputation to deal with missing data. RESULTS: In total, 23.0% (n = 225) of patients received HR. At a median OS of 23.7 months, HR was associated with improved OS in the multivariate analysis [hazard ratio (HzR) = 0.45, 95%CI = 0.35-0.58; after PSM: HzR = 0.56, 95%CI = 0.41-0.77]. Landmark analyses limited to long-term survivors of ≥6 months, ≥1 year, and ≥2 years demonstrated better OS with HR in all subsets (all p < 0.05). After PSM analysis, however, HR increased the risk of death by 20% (HzR = 1.20, 95%CI = 0.67-2.15) in the subgroup of patients with lactate dehydrogenase (LDH) ≤192 U/L (p for interaction = 0.037). Furthermore, the significant interaction was robust between the LDH and HR with respect to the 1-, 3-, and 5-year observed survival rates (all p < 0.05). CONCLUSION: HR was superior to TACE for intermediate-stage HCC in patients with LDH levels >192 U/L. Moreover, TACE might be suitable for patients with LDH levels ≤192 U/L.