Tissue sampling of biliary tract carcinomas (BTCs) for molecular characterization is challenging. The aim of this study was to investigate the possibility of identifying individual actionable ...mutations derived from bile cell‑free DNA (cfDNA) using targeted deep sequencing. Ten BTC patients, four with gallbladder carcinomas and six with cholangiocarcinomas, were enrolled in the present study. Using targeted deep sequencing with a panel of 150 tumor‑related genes, paired bile cfDNA and tumor DNA were analyzed for mutational variants individually and then compared. The present study, to the best of our knowledge, is the first to reveal that bile cfDNA is predominantly comprised of long DNA fragments, which is not the case for plasma cfDNA. Herein, paired bile cfDNA and tumors from ten BTC patients were examined using targeted deep sequencing. When comparing bile cfDNA and tumor DNA for single nucleotide variation (SNV)/insertion and deletion (Indel), the results using targeted deep sequencing revealed high sensitivity (94.7%) and specificity (99.9%). Additionally, the sensitivity of detecting a copy number variation (CNV) was 75.0%, with a specificity of 98.9%. When comparing two bile extraction methods, including percutaneous transhepatic cholangial drainage and operation, no significant difference in SNV/Indel or CNV detection sensitivity was noted. Moreover, when examining the tumor stage and incidence site, AJCC stage II and the distal bile duct both had significantly decreased CNV detection sensitivities. The present study revealed that targeted deep sequencing can reliably detect mutational variants within bile cfDNA obtained from BTC patients. These preliminary results may shed light on bile cfDNA as a promising liquid biopsy for BTC patients.
We aimed to evaluate the prognosis and adjuvant chemotherapy (ACT) in intrahepatic cholangiocarcinoma (ICC) patients with different etiology after radical resection.
A total of 448 patients with ICC ...who underwent radical resection between 2010 and 2018 at ten Chinese tertiary hospitals were analyzed in the study. These patients were divided into conventional ICC (Con-ICC, n = 261, 58.2%), hepatitis B virus ICC (HBV-ICC, n = 102, 22.8%) and hepatolithiasis (Stone-ICC, n = 85,19.0%) subtypes according to different etiology. Propensity score matching (PSM) was conducted to mitigate the baseline differences between Con-ICC and HBV-ICC, Con-ICC and Stone-ICC, HBV-ICC and Stone-ICC subtypes.
Univariate and multivariate analysis showed that different etiology was a prognostic factor for overall survival and relapse-free survival, and different etiology was an independent risk factor for overall survival in ICC patients, respectively (P < 0.05). In addition, there was a statistical difference for overall survival in early recurrence patients among the three etiological subtypes (P < 0.05). After PSM, the overall survival of patients with Stone-ICC was worse than those of Con-ICC and HBV-ICC subtypes (P < 0.05), while the relapse-free survival of patients with Stone-ICC was equivalent to patients with Con-ICC and HBV-ICC (P > 0.05). In Stone-ICC patients, the median overall survival was 16.0 months and 29.7 months, and the median relapse-free survival was 9.0 months and 20.0 months for non-ACT and ACT patients, respectively (P < 0.05).
The prognosis of Stone-ICC patients was significantly worse than those of Con-ICC and HBV-ICC patients. Interestingly, postoperative adjuvant chemotherapy can improve the prognosis of Stone-ICC patients effectively.
Index cholecystectomy is insufficient for curing T3 incidental gallbladder cancer (IGC), and once residual cancer (RC) is found, the prognosis is often poor. The purpose of this study was to ...investigate the effect of RC on the prognosis and the optimal choice of adjuvant therapy for R0 reresection patients with T3 IGC.
We retrospectively reviewed data from patients with T3 IGC who underwent radical reresection from January 2013 to December 2018. RC was defined as histologically proven cancer at reresection. Demographics and tumour treatment-related variables were analysed in correlation with RC and survival. Adjuvant (Adj) chemoradiotherapy (CRT) was correlated with overall survival (OS) and disease-free survival (DFS).
Of the 167 patients with IGC who underwent surgery, 102 underwent radical extended resection. Thirty-two (31.4%) RCs were found. Hepatic side tumours (T3h) and both side tumours (T3h + T3p) were associated with the presence of RC. In multivariate analysis, RC and lymph node metastasis were independent prognostic factors for DFS and OS (P < 0.05). RC was associated with a significantly shorter median OS (20 vs. 53 months; P < 0.01) and DFS (11 vs. 40 months; P < 0.001) despite R0 resection. For R0 reresection patients with RC and/or lymph node metastasis, Adj CRT significantly improved OS (P = 0.024).
Residual cancer and lymphatic metastasis are important factors for the poor prognosis of T3 IGC despite R0 resection, and these patients should actively receive adjuvant therapy.
The aim of this study was to explore the clinical value of lymph node dissection (LND) for intrahepatic cholangiocarcinoma (ICC).
Clinical and pathological data were collected from 147 ICC patients ...who attended two tertiary centers over the past 5 years. The patients were classified into two groups: the LND group (group A) and the no-performance LND (NLND) group (group B). Clinical and pathological parameters were compared between the two groups to analyze the impact of LND on the long-term survival time of ICC patients.
Of the 147 patients, 54.4% (80) received LND and 42.5% (34/80) of these were found to have lymph node metastasis (LNM). LND did not increase postoperative complications (27.5%, P = 0.354), but postoperative hospital stays were longer (12.2 ± 6.3 d, P = 0.005) in group A compared with group B (20.9%, 9.5 ± 3.5 d). The 5-year survival rates of groups A and B are almost similar (21% vs 29%, P = 0.905). The overall survival rate of cN0 (diagnosis obtained by imaging) is better than pN1 (diagnosis obtained by histopathology), but lower than pN0 (all P < 0.05). Compared with NLND, the median survival time of LND patients with T1 has not significantly improved (29.3 vs 35.1 months, P = 0.762), but the patients with T2-4 has been significantly increased (29.0 vs 17.1 months, P = 0.040). Elevated CA19-9 level (HR = 1.764, 95% CI: 1.113–2.795, P = 0.016), vascular invasion (HR = 2.697, 95% CI: 1.103–6.599, P = 0.030), and T category (HR = 1.848, 95% CI: 1.059–3.224, P = 0.031) were independent risk factors for poor long-term survival time of the ICC patients (all P values < 0.05).
ICC patients with cN0 may have LNM, and the long-term survival time of LNM patients is usually poor. We suggest that patients with ICC may require routine LND, especially those with T2-4 category.
Background
The influence of different postoperative recurrence times on the efficacy of adjuvant chemotherapy (ACT) for intrahepatic cholangiocarcinoma (ICC) remains unclear. This study aimed to ...investigate the independent risk factors and establish a nomogram prediction model of early recurrence (recurrence within 1 year) to screen patients with ICC for ACT.
Methods
Data from 310 ICC patients who underwent radical resection between 2010 and 2018 at eight Chinese tertiary hospitals were used to analyze the risk factors and establish a nomogram model to predict early recurrence. External validation was conducted on 134 patients at the other two Chinese tertiary hospitals. Overall survival (OS) and relapse-free survival (RFS) were estimated by the Kaplan–Meier method. Multivariate analysis was conducted to identify independent risk factors for prognosis. A logistic regression model was used to screen independent risk variables for early recurrence. A nomogram model was established based on the above independent risk variables to predict early recurrence.
Results
ACT was a prognostic factor and an independent affecting factor for OS and RFS of patients with ICC after radical resection (
p
< 0.01). The median OS of ICC patients with non-ACT and ACT was 14.0 and 15.0 months, and the median RFS was 6.0 and 8.0 months for the early recurrence group, respectively (
p
> 0.05). While the median OS of ICC patients with non-ACT and ACT was 41.0 and 84.0 months, the median RFS was 20.0 and 45.0 months for the late recurrence group, respectively (
p
< 0.01). CA19-9, tumor size, major vascular invasion, microvascular invasion, and N stage were the independent risk factors of early recurrence for ICC patients after radical resection. The C-index of the nomogram was 0.777 (95% CI: 0.713~0.841) and 0.716 (95%CI: 0.604~0.828) in the training and testing sets, respectively.
Conclusion
The nomogram model established based on the independent risk variables of early recurrence for curatively resected ICC patients has a good prediction ability and can be used to screen patients who benefited from ACT.
The preoperative nutritional status and the immunological status have been reported to be independent prognostic factors of patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to ...investigate whether prognostic nutritional index (PNI) + albumin-bilirubin (ALBI) could be a better predictor than PNI and ALBI alone in patients with ICC after radical resection.
The prognostic prediction evaluation of the PNI, ALBI, and the PNI+ALBI grade was performed in 373 patients with ICC who underwent radical resection between 2010 and 2018 at six Chinese tertiary hospitals, and external validation was conducted in 162 patients at four other Chinese tertiary hospitals. Overall survival (OS) and relapse-free survival (RFS) were estimated using the Kaplan-Meier method. Multivariate analysis was conducted to identify independent prognostic factors. A time-dependent receiver operating characteristic (ROC) curve and a nomogram prediction model were further constructed to assess the predictive ability of PNI, ALBI, and the PNI+ALBI grade. The C-index and a calibration plot were used to assess the performance of the nomogram models.
Univariate analysis showed that PNI, ALBI, and the PNI+ALBI grade were prognostic factors for the OS and RFS of patients with ICC after radical resection in the training and testing sets (
< 0.001). Multivariate analysis showed that the PNI+ALBI grade was an independent risk factor for OS and RFS in the training and testing sets (
< 0.001). Analysis of the relationship between the PNI+ALBI grade and clinicopathological characteristics showed that the PNI+ALBI grade correlated with obstructive jaundice, alpha-fetoprotein (AFP), cancer antigen 19-9 (CA19-9), cancer antigen 125 (CA125), PNI, ALBI, Child-Pugh grade, type of resection, tumor size, major vascular invasion, microvascular invasion, T stage, and N stage (
< 0.05). The time-dependent ROC curves showed that the PNI+ALBI grade had better prognostic predictive ability than the PNI, ALBI, and the Child-Pugh grade in the training and testing sets.
Preoperative PNI+ALBI grade is an effective and practical predictor for the OS and RFS of patients with ICC after radical resection.
Many factors regulate cancer cell apoptosis, among which Survivin has a strong anti-apoptotic effect and PHLPP is a tumor suppressor gene that can induce significant apoptosis. However, the ...relationship between PHLPP and Survivin in gallbladder carcinoma (GBC) has not been reported. This study found that PHLPP expression is decreased and Survivin expression is increased in GBC tissues and cell lines. Their expression levels showed an inverse relationship and were associated with poor prognosis of GBC patients. Loss of PHLPP can increase the level of phosphorylated Survivin and induce the nuclear export of Survivin, which thus inhibit cell apoptosis and promote cell proliferation in GBC cells. The process that PHLPP regulates Survivin phosphorylation and intracellular localization is involved in AKT activity. Re-overexpression of PHLPP in GBC cells can decrease AKT phosphorylation level. Reduced expression of PHLPP in GBC is associated with high expression of miR-495. Increasing PHLPP expression or inhibiting miR-495 expression can induce apoptosis and suppress tumor growth in GBC xenograft model in nude mice. The results revealed the role and mechanism of PHLPP and Survivin in GBC cells and proposed strategies for gene therapies targeting the miR-495 / PHLPP / AKT / Survivin regulatory pathway.
This study aimed to evaluate the prognostic value of lymph node dissection (LND) in node-negative intrahepatic cholangiocarcinoma (ICC) and identify the appropriately total number of lymph nodes ...examined (TNLE).
Data from node-negative ICC patients who underwent curative intent resection in ten Chinese hepatobiliary centers from January 2010 to December 2018 were collected. Overall survival (OS), relapse-free survival (RFS) and postoperative complications were analyzed. Propensity score matching (PSM) was performed to reduce the bias due to confounding variables in LND group and non-lymph node dissection (NLND) group. The optimal TNLE was determined by survival analysis performed by the X-tile program using the enumeration method.
A total of 637 clinically node-negative ICC patients were included in this study, 74 cases were found lymph node (LN) positive after operation. Among the remaining 563 node-negative ICC patients, LND was associated with longer OS but not RFS before PSM (OS: 35.4 vs 26.0 months, p = 0.047; RFS: 15.0 vs 15.4 months, p = 0.992). After PSM, patients in LND group had better prognosis on both OS and RFS (OS: 38.0 vs 23.0 months, p < 0.001; RFS: 15.0 vs 13.0 months, p = 0.029). There were no statistically differences in postoperative complications. When TNLE was greater than 8, OS (48.5 vs 31.1 months, p = 0.025) and RFS (21.0 vs 13.0 months, p = 0.043) were longer in the group with more dissected LNs.
Routinely LND for node-negative ICC patients is recommended for it helps accurate tumor staging and associates with better prognosis. The optimal TNLE is more than 8.
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