Genomic profiling, prognosis, and potential interventional targets in young and old patients with cholangiocarcinoma.

Molecular mechanisms behind potentially inferior prognosis of old cholangiocarcinoma (CCA) patients are unclear. Prevalence of interventional targets and the difference between young and old CCA patients are valuable for promising precision medicine. A total of 188 CCA patients with baseline tumor tissue samples were subgrouped into the young (≤45 years) and old (>45 years) sub-cohorts. Somatic and germline mutation profiles, differentially enriched genetic alterations, and actionable genetic alterations were compared. An external dataset was used for the validation of molecular features and the comparison of overall survival (OS). Compared to young patients, KRAS alterations were more common in old patients (P = .04), while FGFR2 fusions were less frequent (P = .05). TERT promoter mutations were exclusively detected in old patients. The external dataset (N = 392) revealed no significant difference in OS between young and old patients; however, old patient-enriched KRAS (hazard ratio [HR]: 1.96, 95% confidence interval [CI]: 1.37-2.80) and TERT alterations (HR: 2.03, 95% CI: 1.22-3.38) were associated with inferior OS. Approximately 38.3% of patients were identified of actionable oncogenic mutations indicative of a potential response to targeted therapy or immunotherapy. Actionable FGFR2 fusions (P = .01) and BRAFV600E (P = .04) mutations were more frequent in young females than old patients. The enrichment of KRAS/TERT alterations in CCA patients over 45 years resulted in inferior OS. Approximately one-third of CCA patients were eligible for targeted therapy or immunotherapy given the actionable mutations carried, especially young females.

Analgesic effectiveness of preoperative ultrasound-guided erector spinae plane block versus paravertebral nerve block for breast surgery: A systematic review and meta-analysis of four randomized controlled trials.

OBJECTIVE: Our meta-analysis aimed to compare the analgesic effectiveness of ultrasound-guided preoperative erector spinae plane block (ESPB) versus paravertebral nerve block (PVB) in breast surgery. METHODS: PubMed, EMBASE, and the Cochrane Library were searched for randomized controlled trials (RCTs) between January 1, 1980 and April 31, 2021. The primary endpoints were perioperative pain score, analgesic consumption, and assessment of the block procedure. The secondary endpoints were intraoperative hemodynamic response, duration of surgery, postoperative antiemetic consumption, and adverse effects. RESULTS: Four RCTs comprised a total of 310 patients were included in our meta-analysis. No significant differences in the perioperative pain score and analgesic consumption were observed between ESPB and PVB in the operating room, post-anesthesia care unit (PACU), and ward (at 1, 16, 12, and 24 h), and the morning of postoperative day 1 (POD1) (all p > 0.05). Similarly, no significant differences in the duration of block, time to first analgesic, hemodynamic response, duration of surgery, postoperative antiemetic consumption, and adverse effects were observed (all p > 0.05). However, our meta-analysis revealed that ultrasound-guided preoperative ESPB significantly reduced the duration of procedure time and frequency of guidance interventions, as well as increased the block success rate among residents (all p < 0.05). CONCLUSIONS: Both ultrasound-guided preoperative ESPB and PVB showed comparable analgesic effects in patients undergoing breast surgery. However, with a significantly shorter procedure time and higher block success rate, our findings suggest that ESPB may be a simple alternative to PVB in breast surgery.

Raltitrexed versus 5-fluorouracil with cisplatin and concurrent radiotherapy for locally advanced nasopharyngeal carcinoma: An open labeled, randomized, controlled, and multicenter clinical trial.

BACKGROUND: This study aimed to compare the efficacy and toxicity of raltitrexed (Saiweijian® ) plus cisplatin (SP regimen) and 5-fluorouracil plus cisplatin (FP regimen) as concurrent chemoradiotherapy (CCRT) in patients with locally advanced nasopharyngeal carcinoma (LA-NPC). METHODS: Eligible patients (N = 135) were allocated randomly in a ratio of 1:1 to receive CCRT with either SP or FP. At least 2 cycles of chemotherapy was administrated during radiotherapy. Progression free survival (PFS) was primary endpoint. Secondary endpoints included overall survival (OS), loco-regional relapse free survival (LRRFS), distant metastasis free survival (DMFS) and toxicity. RESULTS: In this study, 68 patients received SP as CCRT, and 67 received FP. Objective responses were noted in 97.1% of the patients in the SP group and in 97.0% of the patients in the FP group (P = 1.00). At the end of a median 36 months follow-up period, the estimated 3-year PFS rates were 70.1% for SP and 66.6% for FP, respectively. The 3-year LRRFS, DMFS and OS rates were 88.9%, 74.7% and 84.0%, respectively, for the SP group, and 92.3%, 71.0% and 73.7%, respectively, for the FP group. Overall, there was no difference between treatment groups with regard to response or survival. The most frequent acute toxicities monitored in both groups were bone marrow suppression, gastrointestinal side effects and oral mucositis (OM). The overall incidence of grade 3-4 OM in the FP group (47.8%) was higher than in the SP group (11.8%). However, the incidence of other adverse effects observed in both groups was similar (P > .05). CONCLUSIONS: These data indicate that SP and FP therapies have similar efficacy in treating LA-NPC. The SP regimen showed a tolerable safety profile along with a lower frequency of severe OM and therefore, an improved life quality. In conclusion, SP was a well tolerated, effective, regimen for LA-NPC treatment.

Analgesic Effectiveness of Perioperative Ultrasound-Guided Serratus Anterior Plane Block Combined with General Anesthesia in Patients Undergoing Video-Assisted Thoracoscopic Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: To investigate whether perioperative ultrasound-guided serratus anterior plane block (SAPB) combined with general anesthesia is more effective and safer than current analgesic techniques for postoperative analgesia after video-assisted thoracoscopic surgery (VATS). METHODS: PubMed, the Cochrane Library, and EMBASE were searched for clinical trials published up to July 31, 2019. Outcomes, including operative duration, postoperative pain scores, postoperative analgesia use, patient satisfaction with analgesia, time to chest tube removal, length of stay, and adverse effects were analyzed. RESULTS: Four clinical trials, including 262 patients, met inclusion criteria. Ultrasound-guided SAPB reduced pain scores at zero, 15, 30, 45, and 60 minutes in the postoperative anesthesia care unit (all P < 0.05) and at one, two, six, 12, and 24 hours in the ward (all P < 0.001). Additionally, postoperatively, morphine consumption at 15 and 30 minutes, overall morphine consumption, and total consumption (morphine plus tramadol) were significantly lower in the SAPB cohort (P < 0.05). Similarly, postoperative tramadol consumption at one, two, six, 12, and 24 hours was also lower in this cohort (all P < 0.05). The postoperative consumption of fentanyl, tramadol, and total morphine in patient-controlled analgesia (PCA) at 24 hours was significantly reduced (P < 0.05). Moreover, SAPB provided better patient satisfaction with analgesia (P = 0.0038). However, no statistically significant difference was found in duration of operation, time to chest tube removal, length of stay, or side effects (all P > 0.05). CONCLUSIONS: Perioperative ultrasound-guided SAPB combined with general anesthesia provided more effective postoperative analgesia after VATS. However, no significant advantage was found regarding side effects.

Genome-wide study of salivary microRNAs as potential noninvasive biomarkers for detection of nasopharyngeal carcinoma.

BACKGROUND: Recent studies reported that blood-based microRNAs (miRNAs) could detect cancers and predict prognosis have opened a new field of utilizing circulating miRNAs as cancer biomarkers. In this pilot study, we conducted for the first time, to our knowledge, the evaluation of the applicability of salivary miRNAs as novel biomarkers for nasopharyngeal carcinoma (NPC) detection. METHODS: Microarray miRNA expression profiling was performed on saliva samples from 22 newly diagnosed NPC patients and 25 healthy controls, and 12 significantly down-regulated miRNAs were selected for quantitative real-time-PCR (qRT-PCR) validation and further analysis. Their target genes enriched by gene ontology and pathway analysis were used to construct regulatory and interaction networks. The receiver operating characteristic analyses (ROC) and logistic regression were calculated to assess discriminatory accuracy. RESULTS: Twelve dysregulated miRNAs screened by microarray that showed the same expression patterns with qRT-PCR analysis. Through bioinformatics analysis, the most prominent hub gene probably regulated by the 12 down-regulated miRNAs is found to be TP53. The ROC including the 12 miRNAs separated NPC patients from healthy controls with very high accuracy (areas under the receiver operating characteristic curve [AUC] = 0.999, sensitivity = 100.00%, specificity = 96.00%). Furthermore, if only six significantly dysregulated miRNAs were selected for the ROC analysis, the accuracy is still impressive (AUC = 0.941, sensitivity = 95.45%, specificity = 80.00%). CONCLUSIONS: This study highlights the potential for salivary miRNAs as biomarkers for the detection of NPC. Meanwhile, differentially expressed miRNAs in saliva might play critical roles in NPC by regulating their target genes, which associated with some significant pathways, such as p53 signaling pathway.

Effectiveness of Cetuximab in Combination with Concurrent Chemoradiotherapy in Locoregionally Advanced Nasopharyngeal Carcinoma: A 1:2 Propensity Score-matched Analysis.

Background: This study aimed to compare concurrent chemoradiotherapy (CCRT) plus cetuximab (C) with CCRT alone in locoregionally advanced nasopharyngeal carcinoma(NPC). Methods: A total of 682 locoregionally advanced NPC patients who had undergone chemoradiotherapy with or without cetuximab were included. Propensity score-matching method was used to match patients. Progression-free survival (PFS), overall survival (OS), locoregional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS) were compared between the two treatment arms. Results: After matching, 225 patients were identified for the analysis. Compared to CCRT, CCRT plus C was associated with significantly improved 3-year PFS (83.7% vs 71.9%, P = 0.036), LRFS (98.6% vs 90.2%, P = 0.034) but not OS (91.4% vs 85.4%, P = 0.117). Among patients with T4 and/or N3 category, CCRT plus C significantly prolonged 3-year PFS (81.0% vs 61.4%, P = 0.022) and increased 3-year OS (88.0% vs 77.9%, P = 0.086). No significant differences were observed between CCRT plus C and CCRT alone groups with regard to 3-year PFS, OS, LRFS and DMFS rates in stage III patients. Acute oral and oropharyngeal mucositis during radiotherapy were more common in the CCRT plus C than that in CCRT, but late toxicities were comparable. Conclusions: This study reveals that patients with locoregionally advanced NPC could benefit from the addition of cetuximab to CCRT, and this therapeutic gain mainly originated from T4 and/or N3 subgroup although suffering more acute moderate to severe toxicities.

Comparing the efficacy of induction-concurrent with concurrent-adjuvant chemotherapy in locoregionally advanced nasopharyngeal carcinoma: a propensity score matching analysis.

PURPOSE: This study aimed to compare the efficacy of induction-concurrent (IC-CCRT) with concurrent-adjuvant (CCRT-AC) chemotherapy in patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) treated by intensity-modulated radiotherapy (IMRT). MATERIALS AND METHODS: Data on 834 patients with newly diagnosed, non-metastatic stage III-IVA (except T3N0) NPC receiving either IC-CCRT or CCRT-AC between July, 2004 and December, 2014 were retrospectively reviewed. Propensity score matching (PSM) method was adopted to balance prognostic factors and match patients. Survival outcomes of matched patients between IC-CCRT and CCRT-AC were compared. RESULTS: The median follow-up duration is 45.2 months (range, 1.07-145.4 months). Overall, 309 pairs were selected by PSM. Univariate analysis revealed the CCRT-AC group achieved significantly higher 3-year DFS (83.9% vs. 78.7 %; P = 0.014) and OS (87.6% vs. 87.0%; P = 0.031). Multivariate analysis also identified treatment group (IC-CCRT vs. CCRT-AC) as an independent prognostic factor for 3-year DFS (HR, 1.546; 95% CI, 1.113-2.149; P = 0.009) and OS (HR, 1.487; 95% CI, 1.035-2.136; P = 0.032). Subgroup analysis revealed IC-CCRT was a protective factor for DMFS (HR, 0.145; 95% CI, 0.043-0.488; P = 0.002) in stage III disease; however, it could adversely affected DFS (HR, 2.009; 95% CI, 1.316-3.065; P = 0.001), OS (HR, 1.671; 95% CI, 1.060-2.636; P = 0.027) and DMFS (HR, 1.986; 95% CI, 1.155-3.416; P = 0.013) in stage IVA disease. CONCLUSIONS: CCRT-AC may be a more effective treatment modality in patients with stage IVA NPC disease, while IC-CCRT was superior in stage III disease.

lncRNA-PVT1 Facilitates Invasion Through Upregulation of MMP9 in Nonsmall Cell Lung Cancer Cell.

Lung cancer is the most common solid tumor around the world. It has been reported that upregulation of long noncoding RNA (lncRNA) plasmacytoma variant translocation 1 (lncRNA-PVT1) is closely associated with tumor metastasis. However, the function and underlying molecular mechanism of lncRNA-PVT1 in nonsmall cell lung cancer (NSCLC) invasion remain unknown. In this study, we found that overexpression of lncRNA-PVT1 promoted the invasive ability of NSCLC cells, whereas silence of lncRNA-PVT1 suppressed cell invasion. Furthermore, we found that lncRNA-PVT1 upregulated MMP9 expression in a post-transcriptional manner. Specifically, lncRNA-PVT1 directly interacted with miR-200a and miR-200b, which suppressed MMP9 expression. Taken together, lncRNA-PVT1 functions as a competitive endogenous RNA to regulate MMP9 expression through competitively binding the common microRNAs, miR-200a and miR-200b. These findings suggest that lncRNA-PVT1 could predispose NSCLC patients to metastases and may serve as a promising target for antimetastatic therapies.

The effects of microRNA-98 inhibits cell proliferation and invasion by targeting STAT3 in nasopharyngeal carcinoma.

MicroRNA-98 (miR-98) is downregulated in many tumors, and is closely related to tumor progression. In addition, it shows anticarcinogenic functions in various tumor. However, few study show that the biological function and regulatory mechanisms of miR-98 in nasopharyngeal carcinoma (NPC) progression. The identification and its target genes which regulate by dysregulated miRNAs may strengthen our understanding of the molecular mechanisms of NPC. In this study, we observe that miR-98 is not only significantly reduced in NPC tissues, but also decreased markedly in NPC cell lines. Moreover, silencing miR-98 expression studies not only show miR-98 induced cell proliferation, migration and invasion in vitro, but also it promoted xenograft tumor growth in vivo in NPC. Furthermore, western blot assay was used to detected the level of STAT3 protein and we demonstrate that miR-98 regulate cells poliferation, migration and invasion through directly modulating functional target STAT3 by directly binding its 3'-UTR. These findings illustrate miR-98 as a anticarcinogenic functions through targeting STAT3, the miR-98/STAT3 pathway gives new clues for understanding NPC carcinogenesis and provides novel therapeutic targetsfor NPC.

Ten-year survival outcomes for patients with nasopharyngeal carcinoma receiving intensity-modulated radiotherapy: An analysis of 614 patients from a single center.

OBJECTIVES: Intensity-modulated radiotherapy (IMRT) has been applied in nasopharyngeal carcinoma (NPC) for nearly twenty years, while little is known about the ten-year survival outcomes. This study aimed at evaluating the 10-year survival outcomes for patients with NPC receiving IMRT. MATERIALS AND METHODS: Data on 614 patients with newly diagnosed, non-disseminated NPC treated by IMRT between 2004 and 2008 were retrospectively reviewed. Survival outcomes stratified by tumor stage were compared. RESULTS: The median follow-up duration was 112.7months (range, 7.6-156.8months) for the entire cohort. The 10-year local relapse-free survival rates for T1, T2 and T3 were 94.2%, 92.5% and 91.4% (P>0.05), respectively, and significantly higher than that of T4 disease (79.3%, P<0.05 for all rates). As N category increased from N0 to N3, the 10-year distant metastasis-free survival rates significantly decreased accordingly (P<0.01 for all rates). Furthermore, the 10-year overall survival rates were 100%, 87.1%, 75.5% and 55.6% for stage I, II, III and IV, respectively (P<0.05 except stage I and II). Multivariate analysis established tumor stage and age as independent prognostic factors. Late toxicities were assessable for 495 (80.6%) patients and most were Grade I/II damages. Xerostomia (387 of 489, 79.1%) and hearing impairment (212 of 495, 42.8%) remained the most troublesome. CONCLUSION: IMRT could achieve satisfactory survival outcomes for NPC patients with acceptable late toxicities. However, distant control still remains poor, especially for patients with N3 disease.

Recombinant protein transduction domain-Cu/Zn superoxide dismutase alleviates bone cancer pain via peroxiredoxin 4 modulation and antioxidation.

Bone cancer pain (BCP) is a serious chronic clinical condition and reactive oxygen species (ROS) were considered to be involved in its development and persistency. Normally, superoxide dismutase (SOD) converts superoxide anions to hydrogen peroxide (H2O2) and H2O2 is then naturalized to be water by peroxiredoxin 4. We reported previously that recombinant protein transduction domain (PTD)-Cu/Zn SOD effectively scavenged excessive ROS and prevented cardiomyocytes from hypoxia-reoxygenation damage. However, whether PTD-Cu/Zn SOD would prevent BCP development is unknown. In the current study, we found that an implanted carcinoma in the rat tibia induced remarkable hyperalgesia, increased H2O2 levels and decreased SOD and peroxiredoxin 4 levels. After administration of recombinant PTD-Cu/Zn SOD to these tumor-burden rats, their hyperalgesia was significantly attenuated and peroxiredoxin 4 expression was significantly increased. In addition, an increased expression of N-methyl-d-aspartic acid (NMDA) receptors and a decreased expression of γ-aminobutyric acid (GABA) receptors in this cancer pain were prevented by PTD-Cu/Zn SOD administration or peroxiredoxin 4 overexpression. Our data suggested that reactive oxygen species, at least in part, play a role in cancer metastatic pain development and persistency which can be attenuated by the adminstration of recombinant PTD-Cu/Zn SOD via the peroxiredoxin 4 modulation from oxidative stress.

GPR30 disrupts the balance of GABAergic and glutamatergic transmission in the spinal cord driving to the development of bone cancer pain.

Cancer induced bone pain is a very complicated clinical pain states that has proven difficult to be treated effectively due to poorly understand of underlying mechanism, but bone cancer pain (BCP) seems to be enhanced by a state of spinal sensitization. In the present study, we showed that carcinoma tibia implantation induced notable pain sensitization and up-regulation of G-protein-coupled estrogen receptor (GPR30) in the spinal cord of rats which was reversed by GPR30 knockdown. Further studies indicated that upregulation of GPR30 induced by cancer implantation resulted in a select loss of γ-aminobutyric acid-ergic (GABAergic) neurons and functionally diminished the inhibitory transmission due to reduce expression of the vesicular GABA transporter (VGAT). GPR30 contributed to spinal cord disinhibition by diminishing the inhibitory transmission via upregulation of α1 subunit and downregulation of γ2 subunits. GPR30 also facilitated excitatory transmission by promoting functional up-regulation of the calcium/calmodulin-dependent protein kinase II α (CaMKII α) in glutamatergic neurons and increasing the clustering of the glutamate receptor subunit 1 (GluR1) subunit to excitatory synapse.Taken together, GPR30 contributed to the development of BCP by both facilitating excitatory transmission and inhibiting inhibitory transmission in the spinal cord. Our findings provide the new spinal disinhibition and sensitivity mechanisms underlying the development of bone cancer pain.

Circulating tumor cells in the blood of poorly differentiated nasal squamous cell carcinoma patients: correlation with treatment response.

CONCLUSION: The results implied that CTCs were common even in early TNM stages and might become a potential parameter in evaluating therapeutic effects of radio and chemotherapies. BACKGROUND: Nasopharyngeal carcinoma (NPC) is a head and neck malignancy with an extraordinary high incidence in Southern China and a high metastasis rate. Analysis of circulating tumor cells (CTCs) in peripheral blood is a relatively new prognostic marker for cancer patients. PATIENTS AND METHODS: This retrospective study included data from 38 nasopharyngeal patients with poorly differentiated squamous cell carcinoma in TNM stage I (n = 2), TNM stage II (n = 12), TNM stage III (n = 8), and TNM stage IV (n = 16). CTCs in peripheral blood of all patients were counted before and 1 week as well as 1 months after radiotherapy. RESULTS: The data showed that in 52.6% of the patients CTCs could be detected in peripheral blood and the numbers were significantly decreased 1 month after radiotherapy treatment (p < 0.001). There was no correlation between CTC number or positivity and TNM stages or other clinical parameters.

Altered distribution of beta-catenin and prognostic roles in colorectal carcinogenesis.

OBJECTIVE: Although beta-catenin cytoplasmic stabilization and nuclear translocation play a key role in initiation of colorectal cancer (CRC), the mechanisms are far from clear. The aim of this study was to investigate the relation of expressions of cyclooxygenase (COX)-2 and E-cadherin, and the beta-catenin gene exon 3 mutation to the altered distribution of beta-catenin, and their roles in CRC progression and prognosis. MATERIAL AND METHODS: Expressions of beta-catenin, COX-2 and E-cadherin in 96 tissue specimens were detected by immunohistochemistry, and mutation of beta-catenin gene exon 3 was screened by polymerase chain reaction (PCR) and denaturing high-performance liquid chromatography (DHPLC). RESULTS: Cytoplasmic/nuclear expression of beta-catenin and reduced membranous expression of E-cadherin were associated, respectively, with the earlier and later stages of sequential colorectal carcinogenesis (p<0.05). The altered distribution of beta-catenin was significantly associated with both high Dukes' stages and poor differentiation of CRC (p<0.05). It also had a parallel relationship with COX-2 overexpression (p<0.05, Spearman's rank analysis), but not with reduced E-cadherin expression. Kaplan-Meier analysis showed a significantly worse survival rate for CRC patients with altered expression of beta-catenin (p<0.05, log-rank test). Nevertheless, we failed to find any exon 3 mutation of beta-catenin gene in all 60 cases of CRC. CONCLUSIONS: Altered distribution of beta-catenin occurs in the early stage of colorectal carcinogenesis and has a parallel relationship with COX-2 overexpression. It may serve as a potential marker for the progression and prognosis of CRC. The exon 3 mutation did not appear contributive to the abnormal expression of beta-catenin in CRCs in a Chinese population.