Six-long non-coding RNA signature predicts recurrence-free survival in hepatocellular carcinoma

BACKGROUND Recent evidence shows that long non-coding RNAs(lncRNAs) are closely related to hepatogenesis and a few aggressive features of hepatocellular carcinoma(HCC). Increasing studies demonstrate that lncRNAs are potential prognostic factors for HCC. Moreover, several studies reported the combination of lncRNAs for predicting the overall survival(OS) of HCC, but the results varied. Thus,more effort including more accurate statistical approaches is needed for exploring the prognostic value of lncRNAs in HCC.AIM To develop a robust lncRNA signature associated with HCC recurrence to improve prognosis prediction of HCC.METHODS Univariate COX regression analysis was performed to screen the lncRNAs significantly associated with recurrence-free survival(RFS) of HCC in GSE76427 for the least absolute shrinkage and selection operator(LASSO) modelling. The established lncRNA signature was validated and developed in The Cancer Genome Atlas(TCGA) series using Kaplan-Meier curves. The expression values of the identified lncRNAs were compared between the tumor and non-tumor tissues. Pathway enrichment of these lncRNAs was conducted based on the significantly co-expressed genes. A prognostic nomogram combining the lncRNA signature and clinical characteristics was constructed.RESULTS The lncRNA signature consisted of six lncRNAs: MSC-AS1, POLR2 J4, EIF3 J-AS1,SERHL, RMST, and PVT1. This risk model was significantly associated with the RFS of HCC in the TCGA cohort with a hazard ratio(HR) being 1.807(95%CI[confidence interval]: 1.329-2.457) and log-rank P-value being less than 0.001. The best candidates of the six-lncRNA signature were younger male patients with HBV infection in relatively early tumor-stage and better physical condition but with higher preoperative alpha-fetoprotein. All the lncRNAs were significantly upregulated in tumor samples compared to non-tumor samples(P < 0.05). The most significantly enriched pathways of the lncRNAs were TGF-β signaling pathway, cellular apoptosis-associated pathways, etc. The nomogram showed great utility of the lncRNA signature in HCC recurrence risk stratification.CONCLUSION We have constructed a six-lncRNA signature for prognosis prediction of HCC.This risk model provides new clinical evidence for the accurate diagnosis and targeted treatment of HCC.

Lymph node ratio and preoperative CA 19-9 levels predict overall survival and recurrence-free survival in patients with resected pancreatic adenocarcinoma

AIM:Clinicopathologic factors predicting overall survival (OS) would help identify a subset to benefit from adjuvant therapy. METHODS: One hundred and sixty-nine patients patients from 1984 to 2009 with curative resections for pancreatic adenocarcinoma were included. Tumors were staged by American Joint Committee on Cancer 7th edition criteria. Univariate and multivariable analyses were performed using Kaplan-Meier methodology or Cox proportional hazard models. Log-rank tests were performed. Statistical inferences were assessed by two-sided 5% significance level. RESULTS: Median age was 67.1 (57.2-73.0) years with equal gender distribution. Tumors were in the head (89.3%) or body/tail (10.7%). On univariate analysis, adjuvant therapy, lymph node (LN) ratio, histologic grade, negative margin status, absence of peripancreatic extension, and T stage were associated with improved OS. Adjuvant therapy, LN ratio, histologic grade, number of nodes examined, negative LN status, and absence of peripancreatic extension were associated with improved recurrence-free survival (RFS). On multivariable analysis, LN ratio and carbohydrate antigen (CA) 19-9 levels were associated with OS. LN ratio was associated with RFS. CONCLUSION: The LN ratio and CA 19-9 levels are independent prognostic factors following curative resections of pancreatic cancer.

Do Tumor Characteristics and Pre-Transplant Locoregional Therapy Predict Survival after OLT in Patients with Hepatocellular Carcinoma?

HCC prognosis after OLT is associated with criteria related to the number and size. However, the degree of differentiation and efficacy of locoregional therapies may also influence outcome. Aim: Characterize patients with and without HCC and compare outcomes according to tumor characteristics. Methods: Retrospective query of an electronic medical record of 328 patients transplanted at California Pacific Medical Center (CPMC) in 2001-2007. HCC was defined by pre-OLT listing data as well as the finding of a tumor consistent with HCC at liver explant. Milan and UCSF criteria were applied to the lesions as described by pathology upon explant examination. Results: 328 patients were evaluated, with 109 liver malignancies, 103 females (26 (25%) HCC) and 225 males (83 (37%) HCC p = 0.04). HCC patients were older (56 ± 7.2 yr) than non HCC patients (51 ± 9.2, p 0.001). The age of the donor and cold ischemia time was not different in the 2 groups. Survival was shorter in HCC (mean 984 ± 599 days) vs. non HCC (1103 ± 642) but not statistically significant (p = 0.10). Kaplan Meier survivals were superposable when comparing patients with or without malignancy and when patients with low (≤22) vs. high MELD (>22) were compared. Survival curves in patients that fulfilled Milan vs. UCSF criteria were identical. However, more patients outside Milan died of metastatic disease (5/6, 83%) vs. within Milan (6/14, 43%, p = 0.01). Cox proportional hazards regression showed that MELD, but not malignancy, differentiation or necrosis, was associated with mortality;HR = 6% (95% C.I. 1%-10%) per additional MELD point (p = 0.02). 69 pts had TACE pre-OLT, 17 had RFA ± any other modality. There was no difference in survivals in pts who received any locoregional therapy vs. those who did not (p

Development of preoperative prognostic models including radiological features for survival of singular nodular HCC patients

Background:Early singular nodular hepatocellular carcinoma(HCC)is an ideal surgical indication in clinical practice.However,almost half of the patients have tumor recurrence,and there is no reliable prognostic prediction tool.Besides,it is unclear whether preoperative neoadjuvant therapy is necessary for patients with early singular nodular HCC and which patient needs it.It is critical to identify the patients with high risk of recurrence and to treat these patients preoperatively with neoadjuvant therapy and thus,to improve the outcomes of these patients.The present study aimed to develop two prognostic models to preoperatively predict the recurrence-free survival(RFS)and overall survival(OS)in patients with singular nodular HCC by integrating the clinical data and radiological features.Methods:We retrospective recruited 211 patients with singular nodular HCC from December 2009 to January 2019 at Eastern Hepatobiliary Surgery Hospital(EHBH).They all met the surgical indications and underwent radical resection.We randomly divided the patients into the training cohort(n=132)and the validation cohort(n=79).We established and validated multivariate Cox proportional hazard models by the preoperative clinicopathologic factors and radiological features for association with RFS and OS.By analyzing the receiver operating characteristic(ROC)curve,the discrimination accuracy of the models was compared with that of the traditional predictive models.Results:Our RFS model was based on HBV-DNA score,cirrhosis,tumor diameter and tumor capsule in imaging.RFS nomogram had fine calibration and discrimination capabilities,with a C-index of 0.74(95%CI:0.68-0.80).The OS nomogram,based on cirrhosis,tumor diameter and tumor capsule in imaging,had fine calibration and discrimination capabilities,with a C-index of 0.81(95%CI:0.74-0.87).The area under the receiver operating characteristic curve(AUC)of our model was larger than that of traditional liver cancer staging system,Korea model and Nomograms in Hepatectomy Patients with Hepatitis B VirusRelated Hepatocellular Carcinoma,indicating better discrimination capability.According to the models,we fitted the linear prediction equations.These results were validated in the validation cohort.Conclusions:Compared with previous radiography model,the new-developed predictive model was concise and applicable to predict the postoperative survival of patients with singular nodular HCC.Our models may preoperatively identify patients with high risk of recurrence.These patients may benefit from neoadjuvant therapy which may improve the patients’outcomes.

Intertwined leukocyte balances in tumours and peripheral blood as robust predictors of right and left colorectal cancer survival

BACKGROUND Colorectal cancer(CRC)accounts for 9.4%of overall cancer deaths,ranking second after lung cancer.Despite the large number of factors tested to predict their outcome,most patients with similar variables show big differences in survival.Moreover,right-sided CRC(RCRC)and left-sided CRC(LCRC)patients exhibit large differences in outcome after surgical intervention as assessed by preoperative blood leukocyte status.We hypothesised that stronger indexes than circulating(blood)leukocyte ratios to predict RCRC and LCRC patient outcomes will result from combining both circulating and infiltrated(tumour/peritumour fixed tissues)concentrations of leukocytes.AIM To seek variables involving leukocyte balances in peripheral blood and tumour tissues and to predict the outcome of CRC patients.METHODS Sixty-five patients diagnosed with colon adenocarcinoma by the Digestive Surgery Service of the La Paz University Hospital(Madrid,Spain)were enrolled in this study:43 with RCRC and 22 with LCRC.Patients were followed-up from January 2017 to March 2021 to record overall survival(OS)and recurrence-free survival(RFS)after surgical interventions.Leukocyte concentrations in peripheral blood were determined by routine laboratory protocols.Paraffin-fixed samples of tumour and peritumoural tissues were assessed for leukocyte concentrations by immunohistochemical detection of CD4,CD8,and CD14 marker expression.Ratios of leukocyte concentration in blood and tissues were calculated and evaluated for their predictor values for OS and RFS with Spearman correlations and Cox univariate and multivariate proportional hazards regression,followed by the calculation of the receiver-operating characteristic and area under the curve(AUC)and the determination of Youden’s optimal cutoff values for those variables that significantly correlated with either RCRC or LCRC patient outcomes.RCRC patients from the cohort were randomly assigned to modelling and validation sets,and clinician-friendly nomograms were developed to predict OS and RFS from the respective significant indexes.The accuracy of the model was evaluated using calibration and validation plots.RESULTS The relationship of leukocyte ratios in blood and peritumour resulted in six robust predictors of worse OS in RCRC:CD8+lymphocyte content in peritumour(CD8pt,AUC=0.585,cutoff<8.250,P=0.0077);total lymphocyte content in peritumour(CD4CD8pt,AUC=0.550,cutoff<10.160,P=0.0188);lymphocyte-to-monocyte ratio in peritumour(LMRpt,AUC=0.807,cutoff<3.185,P=0.0028);CD8+LMR in peritumour(CD8MRpt,AUC=0.757,cutoff<1.650,P=0.0007);the ratio of blood LMR to LMR in peritumour(LMRb/LMRpt,AUC=0.672,cutoff>0.985,P=0.0244);and the ratio of blood LMR to CD8+LMR in peritumour(LMRb/CD8MRpt,AUC=0.601,cutoff>1.485,P=0.0101).In addition,three robust predictors of worse RFS in RCRC were found:LMRpt(AUC=0.737,cutoff<3.185,P=0.0046);LMRb/LMRpt(AUC=0.678,cutoff>0.985,P=0.0155)and LMRb/CD8MRpt(AUC=0.615,cutoff>1.485,P=0.0141).Furthermore,the ratio of blood LMR to CD4+LMR in peritumour(LMRb/CD4MRpt,AUC=0.786,cutoff>10.570,P=0.0416)was found to robustly predict poorer OS in LCRC patients.The nomograms showed moderate accuracy in predicting OS and RFS in RCRC patients,with concordance index of 0.600 and 0.605,respectively.CONCLUSION Easily obtainable variables at preoperative consultation,defining the status of leukocyte balances between peripheral blood and peritumoural tissues,are robust predictors for OS and RFS of both RCRC and LCRC patients.

Diagnosis and treatment of biliary mucinous cystic neoplasms: A single-center experience

Background: Biliary mucinous cystic neoplasms(BMCNs) are rare hepatobiliary cystic tumors, which can be divided into noninvasive and invasive types. This study aimed to investigate the diagnosis, treatment, and prognosis of BMCNs in a large single center. Methods: We analyzed 49 patients with BMCNs confirmed by postoperative pathology at the First Afflliated Hospital, Zhejiang University School of Medicine between January 2007 and December 2021. Results: Among the 49 patients, 37 were female(75.5%), and the average age was 57.04 years. Common symptoms included abdominal discomfort, jaundice and fever, while 22 patients(44.9%) had no symptoms. Serum carbohydrate antigen(CA) 19-9 and CA125 concentrations were elevated in 34.8% and 19.6% of patients, respectively. Forty-eight patients had tumors in the intrahepatic bile ducts and only one had a tumor in the extrahepatic bile duct. Forty-eight patients with noninvasive intrahepatic BMCNs were further analyzed in terms of pathological features: 34(70.8%) had low-grade intraepithelial neoplasms(LGINs), and 14(29.2%) had high-grade intraepithelial neoplasms(HGINs). The potential immunohistochemical markers of BMCNs were cytokeratin(CK) 19, CK7, estrogen receptor and progesterone receptor. Follow-up data for 37 patients with intrahepatic BMCNs were obtained. The median overall survival(OS) of BMCNs was not reached. The longest survival time was 137 months.The 5-and 10-year OS rates were 100% and 85.4%, respectively. The 5-and 10-year recurrence-free survival(RFS) rates were 93.9% and 80.2%, respectively. Conclusions: BMCNs are rare cystic neoplasms that commonly occur in middle-aged females. BMCNs can only be diagnosed and classified by postoperative pathology, as there are no specific clinical presentations, serological indicators or imaging modalities for preoperative diagnosis. Complete surgical resection is necessary for BMCNs, and the postoperative prognosis is favorable.

Assessing recent recurrence after hepatectomy for hepatitis Brelated hepatocellular carcinoma by a predictive model based on sarcopenia

BACKGROUND Sarcopenia may be associated with hepatocellular carcinoma(HCC)following hepatectomy.But traditional single clinical variables are still insufficient to predict recurrence.We still lack effective prediction models for recent recurrence(time to recurrence<2 years)after hepatectomy for HCC.AIM To establish an interventable prediction model to estimate recurrence-free survival(RFS)after hepatectomy for HCC based on sarcopenia.METHODS We retrospectively analyzed 283 hepatitis B-related HCC patients who underwent curative hepatectomy for the first time,and the skeletal muscle index at the third lumbar spine was measured by preoperative computed tomography.94 of these patients were enrolled for external validation.Cox multivariate analysis was per-formed to identify the risk factors of postoperative recurrence in training cohort.A nomogram model was developed to predict the RFS of HCC patients,and its predictive performance was validated.The predictive efficacy of this model was evaluated using the receiver operating characteristic curve.RESULTS Multivariate analysis showed that sarcopenia[Hazard ratio(HR)=1.767,95%CI:1.166-2.678,P<0.05],alpha-fetoprotein≥40 ng/mL(HR=1.984,95%CI:1.307-3.011,P<0.05),the maximum diameter of tumor>5 cm(HR=2.222,95%CI:1.285-3.842,P<0.05),and hepatitis B virus DNA level≥2000 IU/mL(HR=2.1,95%CI:1.407-3.135,P<0.05)were independent risk factors associated with postoperative recurrence of HCC.Based on the sarcopenia to assess the RFS model of hepatectomy with hepatitis B-related liver cancer disease(SAMD)was established combined with other the above risk factors.The area under the curve of the SAMD model was 0.782(95%CI:0.705-0.858)in the training cohort(sensitivity 81%,specificity 63%)and 0.773(95%CI:0.707-0.838)in the validation cohort.Besides,a SAMD score≥110 was better to distinguish the high-risk group of postoperative recurrence of HCC.CONCLUSION Sarcopenia is associated with recent recurrence after hepatectomy for hepatitis B-related HCC.A nutritional status-based prediction model is first established for postoperative recurrence of hepatitis B-related HCC,which is superior to other models and contributes to prognosis prediction.

Chylous ascites has a higher incidence after robotic surgery and is associated with poor recurrence-free survival after rectal cancer surgery

Background:Postoperative chylous ascites is an infrequent condition after colorectal surgery and is easily treatable.However,its effect on the long-term oncological prognosis is not well established.This study aimed to investigate the short-term and long-term impact of chylous ascites treated with neoadjuvant therapy followed by rectal cancer surgery and to evaluate the incidence of chylous ascites after different surgical approaches.Methods:A total of 898 locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery between January 2010 and December 2018 were included.The clinicopathological data and outcomes of the patients with chylous ascites were compared with those of the patients without chylous ascites.The primary endpoint was recurrence-free survival(RFS).To balance baseline confounders between groups,propensity score matching(PSM)was performed for each patient with a logistic regression model.Results:Chylous ascites was detected in 3.8%(34/898)of the patients.The incidence of chylous ascites was highest after robotic surgery(6.9%,6/86),followed by laparoscopic surgery(4.2%,26/618)and open surgery(1.0%,2/192,P=0.021).The patients with chylous ascites had a significantly higher number of lymph nodes harvested(15.6 vs.12.8,P=0.009)and a 3-day longer postoperative hospital stay(P=0.017).The 5-year RFS rate was 64.5%in the chylous ascites group,which was significantly lower than the rate in the no chylous ascites group(79.9%;P=0.007).The results remained unchanged after PSM was performed.The chylous ascites group showed a nonsignificant trend towards a higher peritoneal metastasis risk(5.9%vs.1.6%,P=0.120).Univariate analysis and multivariate analysis confirmed chylous ascites(hazard ratio=3.038,P<0.001)as an independent negative prognostic factor for RFS.Conclusions:Considering the higher incidence of chylous ascites after laparoscopic and robotic surgery and its adverse prognosis,we recommend sufficient coagulation of the lymphatic tissue near the vessel origins,especially during minimally invasive surgery.

Shorter recurrence-free survival time, higher risk of multiple recurrences： a retrospective study of non-muscle invasive bladder cancer after transurethral resection

Background Multiple recurrences are common in non-muscle invasive bladder cancer, but the-risk of multiple recurrences has not been fully described. Identifying patients at high risk of multiple recurrences will help to select an optimal therapeutic strategy and to improve prognosis. This study was conducted to identify the risk factors for multiple recurrences of non-muscle invasive bladder cancer. Methods We reviewed the clinical data of all patients with non-muscle invasive bladder cancer in our hospital between January 2003 and February 2010. Patients with at least one recurrence were included. Multivariate analysis was performed for theorized risk factors （age, gender, tumor stage, grade, size, location, number of lesions, adjuvant intra-vesical chemotherapy after transurethral resection, and recurrence-free survival after each resection） to clarify risk factors for multiple recurrences of non-muscle invasive bladder cancer. Results Of the 278 patients with non-muscle invasive bladder cancer, 84 were with at least one recurrence and a total of 222 recurrences among them were followed up for 6-70 months （mean, 36.1 months）. Recurrence-free survival after initial resection predicted the overall frequency of bladder cancer recurrence （risk ratio （RR） = 37.83, 95% confidence interval （C/）=3.45-396.13, P=0.001） and second recurrence （RR=6.15, 95% C/=1.28-29.57, P=0.023）. Similarly, recurrence-free survival after a second resection was the only significant risk factor for third recurrence （RR=31.08, 95% C1=2.53-381.47, P=0.007）. Moreover, recurrence-free survival after initial resection was the only significant factor to predict later progression to muscle invasive bladder cancer （RR=8.62, 95% C1=1.47-58.34, P=0.001）. Conclusions Recurrence-free survival after resection is an independent predictor of multiple recurrences of non-muscle invasive bladder cancer. The shorter the period between resection and recurrence is, the higher the risk of multiple recurrences.

Sirolimus improves the prognosis of liver recipients with hepatocellular carcinoma:A single-center experience

Background:Tumor recurrence after liver transplantation(LT)for selective patients diagnosed with hepatocellular carcinoma(HCC)in the setting of cirrhosis is the greatest challenge effecting the prognosis of these patients.The aim of this study was to evaluate the efficacy of sirolimus on the prognosis for these recipients.Methods:The data from 193 consecutive HCC patients who had undergone LT from January 2015 to December 2019 were retrospectively analyzed.These patients were divided into the sirolimus group[patients took sirolimus combined with calcineurin inhibitors(CNIs)(n=125)]and non-sirolimus group[patients took CNI-based therapy without sirolimus(n=68)].Recurrence-free survival(RFS)and overall survival(OS)were compared between the two groups.The prognostic factors and independent risk factors for RFS and OS were further evaluated.Results:Non-sirolimus was an independent risk factor for RFS(HR=2.990;95%CI:1.050-8.470;P=0.040)and OS(HR=3.100;95%CI:1.190-8.000;P=0.020).A higher proportion of patients beyond Hangzhou criteria was divided into the sirolimus group(69.6%vs.80.9%,P=0.030).Compared with the non-sirolimus group,the sirolimus group had significantly better RFS(P<0.001)and OS(P<0.001).Further subgroup analysis showed similar results.Conclusions:This study demonstrated that sirolimus significantly decreased HCC recurrence and prolonged RFS and OS in LT patients with different stage of HCC.

Derivation and validation of a preoperative prognostic model for resectable pancreatic ductal adenocarcinoma

Background: The prognosis of patients with pancreatic ductal adenocarcinoma(PDAC) remains poor even after radical pancreaticoduodenectomy(PD). The study aimed to develop and validate a novel preoperative prognostic model to accurately predict the long-term survival of patients with PDAC.Methods: Patients with PDAC of pancreatic head from Chinese PLA General Hospital were included. The preoperative PDAC model with contour plots was developed using a non-linear model in the training cohort and then tested in the validation cohort.Results: Of 421 patients who met the inclusion criteria, 280 were in the training cohort and 141 in the validation cohort. Contour plots for preoperative PDAC model were established to visually predict the survival probabilities of these patients, based on preoperative carbohydrate antigen 19-9, preoperative fibrinogen to albumin ratio and pain symptoms. This model stratified patients into low-and high-risk groups with distinctly different long-term survival in the training cohort [median overall survival(OS)32.1 vs. 17.5 months;median recurrence-free survival(RFS) 19.3 vs. 10.0 months, both P < 0.001] and the validation cohort(median OS 28.3 vs. 19.0 months;median RFS 17.5 vs. 11.2 months, both P < 0.001).Time-dependent receiver operating characteristic and decision curve analyses revealed that the model provided higher diagnostic accuracy and superior net benefit compared to other staging systems.Conclusions: This study constructed and validated a novel preoperative prognostic model that can accurately and conveniently predict the long-term survival of patients with resectable PDAC of pancreatic head. Besides, the model can screen high-risk patients with poor prognosis, which may provide references for personal treatment strategies in the future.

Any role for transarterial radioembolization in unresectable intrahepatic cholangiocarcinoma in the era of advanced systemic therapies?

Intrahepatic cholangiocarcinoma(iCCA)is recognized as the second most frequently diagnosed liver malignancy,following closely after hepatocellular carcinoma.Its incidence has seen a global upsurge in the past several years.Unfortunately,due to the lack of well-defined risk factors and limited diagnostic tools,iCCA is often diagnosed at an advanced stage,resulting in a poor prognosis.While surgery is the only potentially curative option,it is rarely feasible.Currently,there are ongoing investigations into various treatment approaches for unresectable iCCA,including conventional chemotherapies,targeted therapies,immunotherapies,and locoregional treatments.This study aims to explore the role of transarterial radioembolization(TARE)in the treatment of unresectable iCCA and provide a comprehensive review.The findings suggest that TARE is a safe and effective treatment option for unresectable iCCA,with a median overall survival(OS)of 14.9 months in the study cohort.Studies on TARE for unresectable iCCA,both as a first-line treatment(as a neo-adjuvant down-staging strategy)and as adjuvant therapy,have reported varying median response rates(ranging from 34%to 86%)and median OS(12-16 mo).These differences can be attributed to the heterogeneity of the patient population and the limited number of participants in the studies.Most studies have identified tumor burden,portal vein involvement,and the patient’s performance status as key prognostic factors.Furthermore,a phase 2 trial evaluated the combination of TARE and chemotherapy(cisplatin-gemcitabine)as a first-line therapy for locally advanced unresectable iCCA.The results showed promising outcomes,including a median OS of 22 mo and a 22%achievement in down-staging the tumor.In conclusion,TARE represents a viable treatment option for unresectable iCCA,and its combination with systemic chemotherapy has shown promising results.However,it is important to consider treatment-independent factors that can influence prognosis.Further research is necessary to identify optimal treatment combinations and predictive factors for a favorable response in iCCA patients.

Concurrent chemoradiotherapy with weekly docetaxel versus cisplatin in the treatment of locoregionally advanced nasopharyngeal carcinoma:a propensity score-matched analysis

Background:Promising efficacy and manageable toxicity of docetaxel-based concurrent chemoradiotherapy(CCRT)were reported in head and neck cancer.In addition,the effect of CCRT in combination with cisplatin and/or 5-fluorouracil on both locoregionally advanced and metastatic/recurrent nasopharyngeal carcinoma(NPC)was verified.However,CCRT with docetaxel for locoregionally advanced NPC are not well studied.This study aimed to compare effectiveness and toxicities of CCRT with weekly docetaxel versus tri-weekly cisplatin for locoregionally advanced NPC.Methods:Clinical data of patients with locoregionally advanced NPC newly diagnosed between January 2010 and December 2014 receiving CCRT with either weekly docetaxel(15 mg/m2)or tri-weekly cisplatin(80-100 mg/m2)were reviewed.Propensity score matching at a 1:1 ratio was performed to balance baseline characteristics.Adverse events and survival were compared between the two groups.Results:A total of 962 patients were included as the whole cohort,and 448 patients were matched and were regarded as the matched cohort.The median follow-up duration was 48 months for the whole cohort.The 3-year nodal recurrence-free survival rate was significantly increased for patients treated with docetaxel in both the whole(hazard ratio[HR]=0.37,95%confidence interval[CI]0.19-0.72,P=0.030)and matched cohorts(HR=0.33,95%CI 0.14-0.79,P=0.023).However,no significant differences were observed in overall survival,local recurrence-free survival,and distant metastasis-free survival between the two groups in both cohorts.Significantly higher rates of grade 3 radiodermatitis(6.7%vs.1.8%,P=0.001),mucositis(74.5%vs.37.9%,P<0.001),and leucopenia(2.2%vs.11.6%,P<0.001)were observed in the docetaxel group,but any grade of renal injury(1.8%vs.15.1%,P<0.001),vomiting(18.8%vs.88.3%,P<0.001),and ALT elevation(19.2%vs.31.3%,P=0.027)were more common in the cisplatin group.Conclusions:CCRT with weekly low-dose docetaxel is an effective and tolerable therapeutic regimen for locally advanced NPC.It provides a survival benefit mainly by improving the control of regional lymph node metastases,especially for patients with low pretreatment EBV DNA levels.

Role of adjuvant chemoradiotherapy and chemotherapy in patients with resected gallbladder carcinoma: a multiinstitutional analysis (KROG 19-04)

Objective:The effectiveness of adjuvant treatments for resected gallbladder carcinoma(GBC)has remained unclear due to lack of randomized controlled trials;thus,the aim of present study was to evaluate the role of adjuvant treatments,including chemoradiotherapy(CRT)and/or chemotherapy(CTx),in patients with resected GBC.Methods:A total of 733 GBC patients who received curative-intent surgical resection were identified in a multi-institutional database.Of 733 patients,372(50.8%)did not receive adjuvant treatment,whereas 215(29.3%)and 146(19.9%)received adjuvant CTx and CRT,respectively.The locoregional recurrence-free survival(LRFS),recurrence-free survival(RFS),and overall survival(OS)of the adjuvant treatment groups were compared according to tumor stage(stage II vs.stage III–IV).Results:In stage II disease(n=381),the 5-year LRFS,RFS,and OS were not significantly different among the no-adjuvant therapy,CTx,and CRT groups,and positive resection margin,presence of perineural invasion,and Nx classification were consistently associated with worse LRFS,RFS,and OS in the multivariate analysis(P<0.05).For stage III–IV(n=352),the CRT group had significantly higher 5-year LRFS,RFS,and OS than the no-adjuvant therapy and CTx groups(67.8%,45.2%,and 56.9%;37.9%,28.8%,and 35.4%;and 45.0%,30.0%,and 45.7%,respectively)(P<0.05).Conclusions:CRT has value as adjuvant treatment for resected GBC with stage III–IV disease.Further study is needed for stage II disease with high-risk features.

Downstaging disease in patients with hepatocellular carcinoma outside up-to-seven criteria: Strategies using degradable starch microspheres transcatheter arterial chemo-embolization

AIM: To evaluate the downstaging rates in hepatitis C virus-patients with hepatocellular carcinoma(HCC), treated with degradable starch microspheres transcatheter arterial chemoembolization(DSM-TACE), to reach new-Milan-criteria(nM C) for transplantation. METHODS: This study was approved by the Ethics Committee of our institution. From September 2013 to March 2014 eight patients(5 men and 3 women) with liver cirrhosis and multinodular HCC, that did not meet n MC at baseline, were enrolled in this study. Patients who received any other type of treatment such as termal ablation or percutaneous ethanol injection were excluded. DSM-TACE was performed in all patients using Embo Cept? S and doxorubicin. Baseline and follow-up computed tomography or magnetic resonance imaging was assessed measuring the longest enhancing axial dimension of each tumor according to the modified Response Evaluation Criteria In Solid Tumors measure-ments, and medical records were reviewed.RESULTS: DSM-TACE was successfully performed in all patients without major complication. We treated 35 lesions(mean 4.3 per patient). Six of eight patients(75%) had their HCC downstaged to meet nM C. Every patient whose disease was downstaged eventually underwent transplantation. The six patients who received transplant were still living at the time of this writing, without recurrence of HCC. Baseline age(P = 0.25), Model for End-stage Liver Disease score(P = 0. 77), and α-fetoprotein level(P = 1.00) were similar between patients with and without downstaged HCC. CONCLUSION: DSM-TACE represents a safely and effective treatment option with similar safety and efficacy of conventional chemoembolization and could be successfully performed also for downstaging disease in patients without n MC, allowing them to reach liver transplantation.

Doxorubicin-eluting bead vs conventional transcatheter arterial chemoembolization for hepatocellular carcinoma before liver transplantation

AIM:To assess the possible effect of two different types of preoperative transcatheter arterial chemoembolization(TACE)on recurrence-free survival after liver transplantation(LT)in patients with hepatocellular carcinoma(HCC)and to analyze the effects of TACE on tumor histology.METHODS:We retrospectively analyzed the histological features of 130 HCC nodules in 63 native livers removed at transplantation.Patients who received any other type of treatment such as radiofrequency tumor ablation,percutaneous ethanol ablation or who were not treated at all were excluded.All patients in the present study were within the Milan Criteria at the last imaging findings before transplantation.Doxorubicineluting bead TACE(DEB-TACE)was performed in 22patients(38 nodules),and conventional TACE(c-TACE)in 16(25 nodules).Patients’and tumors’characteristics were retrospectively reviewed.We performed a pernodule analysis of the explanted livers to establish the mean percentage of necrosis of any nodule treated by TACE(conventional or DEB)and a per-patient analysis to establish the percentage of necrosis in the cumulative tumor area,including 21 nodules not reached by TACE.Inflammatory and fibrotic changes in the tissue surrounding the tumor nodule were analyzed and categorized as poor/absent,moderate and enhanced reaction.Uni-and multivariate analysis of risk factors for HCC-recurrence were performed.RESULTS:The number and diameter of the nodules,the time spent on the waiting list and the number of treatments were similar in the two groups.A trend towards higher appropriate response rates(necrosis≥90%)was observed in the DEB-TACE group(44.7%vs32.0%,P=0.2834).The mean percentage of necrosis in the cumulative tumor area was 58.8%±36.6%in the DEB-TACE group and 50.2%±38.1%in the c-TACE group(P=0.4856).Fibrotic and inflammatory reactions surrounding the tumor nodule were markedly more common in the DEB-TACE group(P<0.0001,for both the parameters).The three-year recurrence-free survival was higher in DEB-TACE-treated patients than in conventionally treated patients(87.4%vs 61.5%,P=0.0493).Other factors affecting recurrence-free survival included viable tumor beyond Milan Criteria on histopathological examination,the percentage of necrosis on CTA≤50%and a pre-transplant serum-fetoprotein level greater than 70 ng/mL.On multivariate analysis,the lack of treatment with DEB-TACE,high levels of-fetoprotein and viable tumor beyond Milan Criteria at histology examination were identified as independent predictors of tumor recurrence.CONCLUSION:DEB-TACE can effectively promote tumor necrosis and improves recurrence-free survival after LT in HCC.

Hepatocellular carcinoma: Advances in diagnosis, management, and long term outcome

Hepatocellular carcinoma(HCC) remains a common and lethal malignancy worldwide and arises in the setting of a host of diseases. The incidence continues to increase despite multiple vaccines and therapies for viruses such as the hepatitis B and C viruses. In addition, due to the growing incidence of obesity in Western society, there is anticipation that there will be a growing population with HCC due to non-alcoholic fatty liver disease. Due to the growing frequency of this disease, screening is recommended using ultrasound with further imaging using magnetic resonance imaging and multi-detector computed tomography used for further characterization of masses. Great advances have been made to help with the early diagnosis of small lesions leading to potential curative resection or transplantation. Resection and transplantation maybe used in a variety of patients that are carefully selected based on underlying liver disease. Using certain guidelines and clinical acumen patients may have good outcomes with either resection or transplantation however many patients are inoperable at time of presentation. Fortunately, the use of new locoregional therapies has made down staging patients a potential option making them potential surgical candidates. Despite a growing population with HCC, new advances in viral therapies, chemotherapeutics, and an expanding population of surgical and transplant candidates might all contribute to improved long-term survival of these patients.

Efficacy of postoperative adjuvant transcatheter arterial chemoembolization in hepatocellular carcinoma patients with microvascular invasion

AIM To investigate the efficacy and safety of postoperative adjuvant transcatheter arterial chemoembolization(PA-TACE) in preventing tumor recurrence and improving survival in Barcelona Clinic Liver Cancer(BCLC) early(A) and intermediate(B) stage hepatocellular carcinoma(HCC) patients with microvascular invasion(MVI).METHODS A total of 519 BCLC A or B HCC patients treated by liver resection alone or followed by PA-TACE between January 2012 and December 2015 were studied retrospectively. Univariate and multivariate analyses were performed to investigate the risk factors for recurrence-free survival(RFS) and overall survival(OS). Multiple logistic regression was used to identify the clinicopathological characteristics associated with MVI. The rates of RFS and OS were compared among patients with or without MVI treated with liver resection alone or followed by PA-TACE. RESULTS Univariate and multivariate analyses demonstrated that serum AFP level > 400 ng/m L, tumor size > 5 cm, tumor capsule invasion, MVI, and major hepatectomy were risk factors for poor OS. Tumor capsule invasion, MVI, tumor size > 5 cm, HBV-DNA copies > 1 x 104 IU/m L, and multinodularity were risk factors for poor RFS. Multiple logistic regression identified serum AFP level > 400 ng/m L, tumor size > 5 cm, and tumor capsule invasion as independent predictors of MVI. Both OS and DFS were significantly improved in patients with MVI who received PA-TACE as compared to those who underwent liver resection alone. Patients without MVI did not show a significant difference in OS and RFS between those treated by liver resection alone or followed by PA-TACE.CONCLUSION PA-TACE is a safe adjuvant intervention and can efficiently prevent tumor recurrence and improve the survival of BCLC early-and intermediate-stage HCC patients with MVI.

Radiological response and inflammation scores predict tumour recurrence in patients treated with transarterial chemoembolization before liver transplantation

To investigate the prognostic value of the radiological response after transarterial chemoembolization (TACE) and inflammatory markers in patients affected by hepatocellular carcinoma (HCC) awaiting liver transplantation (LT).METHODSWe retrospectively evaluated the preoperative predictors of HCC recurrence in 70 patients treated with conventional (n = 16) or doxorubicin-eluting bead TACE (n = 54) before LT. The patient and tumour characteristics, including the static and dynamic alpha-fetoprotein, neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio (PLR) measurements, were recorded. Treatment response was classified according to the modified Response Evaluation Criteria in Solid Tumours (mRECIST) and the European Association for the Study of the Liver (EASL) criteria as complete response (CR), partial response (PR), stable disease or progressive disease. After examination of the explanted livers, histological necrosis was classified as complete (100% of the cumulative tumour area), partial (50%-99%) or minimal (< 50%) and was correlated with the preoperative radiological findings.RESULTSAccording to the pre-TACE radiological evaluation, 22/70 (31.4%) and 12/70 (17.1%) patients were beyond Milan and University of San Francisco (UCSF) criteria, respectively. After TACE procedures, the objective response (CR + PR) rates were 71.4% and 70.0% according to mRECIST and EASL criteria, respectively. The agreement between the two guidelines in defining the radiological response was rated as very good both for the overall and target lesion response (weighted k-value: 0.98 and 0.93, respectively). Complete and partial histological necrosis were achieved in 14/70 (20.0%) and 28/70 (40.0%) patients, respectively. Using histopathology as the reference standard, mRECIST criteria correctly classified necrosis in 72.9% (51/70) of patients and EASL criteria in 68.6% (48/70) of cases. The mRECIST non-response to TACE [Exp(b) = 9.2, p = 0.012], exceeding UCSF criteria before TACE [Exp(b) = 4.7, p = 0.033] and a preoperative PLR > 150 [Exp(b) = 5.9, p = 0.046] were independent predictors of tumour recurrence.CONCLUSIONThe radiological response and inflammatory markers are predictive of tumour recurrence and allow the proper selection of TACE-treated candidates for LT.

The clinical association of programmed cell death protein 4(PDCD4) with solid tumors and its prognostic significance:a meta-analysis

Background: Programmed cell death protein 4(PDCD4) is a novel tumor suppressor protein involved in pro?grammed cell death. Its association with cancer progression has been observed in multiple tumor models, but evidence supporting its association with solid tumors in humans remains controversial. This study aimed to determine the clinical signiicance and prognostic value of PDCD4 in solid tumors.Methods: A systematic literature review was performed to retrieve publications with available clinical informa?tion and survival data. The eligibility of the selected articles was based on the criteria of the Dutch Cochrane Centre proposed by the Meta?analysis Of Observational Studies in Epidemiology group. Pooled odds ratios(ORs), hazard ratios(HRs), and 95% conidence intervals(CIs) for survival analysis were calculated. Publication bias was examined by Begg's and Egger's tests.Results: Clinical data of 2227 cancer patients with solid tumors from 23 studies were evaluated. PDCD4 expression was signiicantly associated with the diferentiation status of head and neck cancer(OR 4.25, 95% CI 1.87–9.66) and digestive system cancer(OR 2.87, 95% CI 1.84–4.48). Down?regulation of PDCD4 was signiicantly associated with short overall survival of patients with head and neck(HR: 3.44, 95% CI 2.38–4.98), breast(HR: 1.86, 95% CI 1.36–2.54), digestive system(HR: 2.12, 95% CI 1.75–2.56), and urinary system cancers(HR: 3.16, 95% CI 1.06–9.41).Conclusions: The current evidence suggests that PDCD4 down?regulation is involved in the progression of several types of solid tumor and is a potential marker for solid tumor prognoses. Its clinical usefulness should be conirmed by large?scale prospective studies.