N-Benzylhydroxylamine as a novel synthetic block in "C1N1" embedding reaction via α-C(sp3)-H activation strategy.

A novel process using N-benzylhydroxylamine hydrochloride as a "C1N1 synthon" in [2+2+1] cyclization for the construction of 1,2,5-trisubstituted imidazoles has been described for the first time. The key to realizing this process lies in capturing arylamines by in situ generated novel acyl ketonitrone intermediates. Subsequent tautomerization activates the α-C(sp3)-H of N-benzylhydroxylamines, and thus breaks through its inherent reaction mode and achieves N, α-C site-selective cyclization. Furthermore, this method enables scale-up synthesis and late-stage modification of complex molecules.

Value of adjuvant chemotherapy for patients with pT2N0M0 non-small cell lung cancer receiving radical resection.

BACKGROUND: Associations between adjuvant chemotherapy (ACT) and the improvement in survival for patients with pT2N0M0 non-small cell lung cancer (NSCLC) who received R0 resection remain controversial. This study aimed to evaluate the value of ACT for patients with pT2N0M0 NSCLCs, and to identify the subgroups who could benefit from ACT. METHODS: Multivariable Cox proportional hazards regression models were used to estimate independent prognostic factors. High-risk factor (HRF) included visceral pleural invasion (VPI), lymphovascular invasion (LVI) and poor differentiation/undifferentiated tumors. RESULTS: Of the 899 patients, 277 (30.8%) patients received ACT. More younger patients (p < 0.001) and male patients (p = 0.007) received ACT. With the increase of pathological tumor size (p < 0.001) and the number of HRFs (p < 0.001), there was a significant rise in the proportion of patients receiving ACT. For all patients, ACT could not improve recurrence-free survival (RFS) (p = 0.672) and overall survival (OS) (p = 0.306). For patients with pathological stage IIA or radiological pure-solid tumors, ACT could significantly improve the OS (p = 0.011 and p = 0.037, respectively), and multivariate analysis revealed that ACT was an independent prognostic factor for patients with pathological stage IIA (p = 0.005). ACT could improve the OS significantly in patients with pathological stage IB pure-solid lung adenocarcinoma (LUAD) (p = 0.043). CONCLUSION: ACT was valuable for patients with pathological stage IIA (pT2bN0M0) and patients with radiological pure-solid LUAD of pathological stage IB. A combination of radiological features and pathological subtypes could be helpful when selecting patients with pT2N0M0 NSCLCs for ACT.

Radiologic Identification of Pathologic Tumor Invasion in Patients With Lung Adenocarcinoma.

Importance: It is currently unclear whether high-resolution computed tomography can preoperatively identify pathologic tumor invasion for ground-glass opacity lung adenocarcinoma. Objectives: To evaluate the diagnostic value of high-resolution computed tomography for identifying pathologic tumor invasion for ground-glass opacity featured lung tumors. Design, Setting, and Participants: This prospective, multicenter diagnostic study enrolled patients with suspicious malignant ground-glass opacity nodules less than or equal to 30 mm from November 2019 to July 2021. Thoracic high-resolution computed tomography was performed, and pathologic tumor invasion (invasive adenocarcinoma vs adenocarcinoma in situ or minimally invasive adenocarcinoma) was estimated before surgery. Pathologic nonadenocarcinoma, benign diseases, or those without surgery were excluded from analyses; 673 patients were recruited, and 620 patients were included in the analysis. Statistical analysis was performed from October 2021 to January 2022. Exposure: Patients were grouped according to pathologic tumor invasion. Main Outcomes and Measures: Primary end point was diagnostic yield for pathologic tumor invasion. Secondary end point was diagnostic value of radiologic parameters. Results: Among 620 patients (442 [71.3%] female; mean [SD] age, 53.5 [12.0] years) with 622 nodules, 287 (46.1%) pure ground-glass opacity nodules and 335 (53.9%) part-solid nodules were analyzed. The median (range) size of nodules was 12.1 (3.8-30.0) mm; 47 adenocarcinomas in situ, 342 minimally invasive adenocarcinomas, and 233 invasive adenocarcinomas were confirmed. Overall, diagnostic accuracy was 83.0% (516 of 622; 95% CI, 79.8%-85.8%), diagnostic sensitivity was 82.4% (192 of 233; 95% CI, 76.9%-87.1%), and diagnostic specificity was 83.3% (324 of 389; 95% CI, 79.2%-86.9%). For tumors less than or equal to 10 mm, 3.6% (8 of 224) were diagnosed as invasive adenocarcinomas. The diagnostic accuracy was 96.0% (215 of 224; 95% CI, 92.5%-98.1%), diagnostic specificity was 97.2% (210 of 216; 95% CI, 94.1%-99.0%); for tumors greater than 20 mm, 6.9% (6 of 87) were diagnosed as adenocarcinomas in situ or minimally invasive adenocarcinomas. The diagnostic accuracy was 93.1% (81 of 87; 95% CI, 85.6%-97.4%) and diagnostic sensitivity was 97.5% (79 of 81; 95% CI, 91.4%-99.7%). For tumors between 10 to 20 mm, the diagnostic accuracy was 70.7% (220 of 311; 95% CI, 65.3%-75.7%), diagnostic sensitivity was 75.0% (108 of 144; 95% CI, 67.1%-81.8%), and diagnostic specificity was 67.1% (112 of 167; 95% CI, 59.4%-74.1%). Tumor size (odds ratio, 1.28; 95% CI, 1.18-1.39) and solid component size (odds ratio, 1.31; 95% CI, 1.22-1.42) could each independently serve as identifiers of pathologic invasive adenocarcinoma. When the cutoff value of solid component size was 6 mm, the diagnostic sensitivity was 84.6% (95% CI, 78.8%-89.4%) and specificity was 82.9% (95% CI, 75.6%-88.7%). Conclusions and relevance: In this diagnostic study, radiologic analysis showed good performance in identifying pathologic tumor invasion for ground-glass opacity-featured lung adenocarcinoma, especially for tumors less than or equal to 10 mm and greater than 20 mm; these results suggest that a solid component size of 6 mm could be clinically applied to distinguish pathologic tumor invasion.

Epidemiological landscape of esophageal cancer in Asia: Results from GLOBOCAN 2020.

BACKGROUND: Esophageal cancer (EC) is a global health problem. Asia represents a huge burden of EC globally, and incidence and mortality vary considerably across different Asian regions. METHODS: Data on incidence, mortality, and preference were extracted from GLOBOCAN 2020. Age-standardized incidence and mortality rates were calculated overall by sex, age, country, region, and continent. The predicted burden of incidence and mortality in 2040 was calculated based on global demographic projections. RESULTS: It was estimated there were 481 552 new cases of and 434 363 deaths from EC in Asia in 2020, accounting for 79.7% and 79.8% of world EC cases and deaths, respectively. EC incidence and mortality in Asia ranked the highest among all continents. Eastern Asia represents the highest age-standardized world incidence rate (ASWIR) of 12.3 per 100 000 for all Asian regions. Western Asia represents the lowest ASWIR of 1.7 per 100 000, accounting for 0.7% of the globe. There exist obvious differences in epidemiological features in Asian countries, including incidence, mortality, prevalence, and mortality incidence ratio. There is forecast to be up to 781 000 new cases of EC in Asia by 2040, with increasing rates of 63% for incidence and 72% for mortality from 2020. CONCLUSIONS: Asia has an increasing number of EC cases and deaths. Strategies for targeting in high-incidence areas, the elderly, and survival should be prioritized to reduce the global EC burden, especially in low- and middle-income countries in Asia.

Selective Mediastinal Lymph Node Dissection Strategy for Clinical T1N0 Invasive Lung Cancer: A Prospective, Multicenter, Clinical Trial.

INTRODUCTION: We aimed to prospectively evaluate our previously proposed selective mediastinal lymph node (LN) dissection strategy for peripheral clinical T1N0 invasive NSCLC. METHODS: This is a multicenter, prospective clinical trial in China. We set six criteria for predicting negative LN stations and finally guiding selective LN dissection. Consolidation tumor ratio less than or equal to 0.5, segment location, lepidic-predominant adenocarcinoma (LPA), negative hilar nodes (stations 10-12), and negative visceral pleural invasion (VPI) were used separately or in combination as predictors of negative LN status in the whole, superior, or inferior mediastinal zone. LPA, hilar node involvement, and VPI were diagnosed intraoperatively. All patients actually underwent systematic mediastinal LN dissection. The primary end point was the accuracy of the strategy in predicting LN involvement. If LN metastasis occurred in certain mediastinal zone that was predicted to be negative, it was considered as an "inaccurate" case. RESULTS: A total of 720 patients were enrolled. The median number of LN dissected was 15 (interquartile range: 11-20). All negative node status in certain mediastinal zone was correctly predicted by the strategy. Compared with final pathologic findings, the accuracy of frozen section to diagnose LPA, VPI, and hilar node metastasis was 94.0%, 98.9%, and 99.6%, respectively. Inaccurate intraoperative diagnosis of LPA, VPI, or hilar node metastasis did not lead to inaccurate prediction of node-negative status. CONCLUSIONS: This is the first prospective trial validating the specific mediastinal LN metastasis pattern in cT1N0 invasive NSCLC, which provides important evidence for clinical applications of selective LN dissection strategy.

Prognostic implication of tumor spread through air spaces in patients with pathologic N0 lung adenocarcinoma.

OBJECTIVES: Tumor spread through air spaces (STAS) has been identified as an invasive pattern in lung adenocarcinoma (ADC), but the prognostic implication of STAS has not been well studied in patients with pathologic N0 lung ADC. The purpose of this study was to evaluate the prognostic implication of STAS in pathologic N0 lung ADC patients after radical surgery. MATERIALS AND METHODS: Between January 2017 and December 2018, 796 patients with completely resected pathologic N0 lung ADC were reviewed. Pearson's chi-square test or Fisher exact test was used for comparing the relationship between STAS and clinicopathological features. The log-rank test and multivariate Cox regression models were used to explore prognostic factors. RESULTS: Among the 796 patients, STAS was positive in 201 patients (25.3%). The presence of STAS was significantly associated with patients with solid nodules (P < 0.001), micropapillary pattern-predominant adenocarcinoma/solid pattern-predominant adenocarcinoma (P < 0.001), larger tumor size (P < 0.001), visceral pleural invasion (P < 0.001) and lymphovascular invasion (P < 0.001). Multivariable analysis showed that STAS was an independent prognostic factor for recurrence-free survival (RFS) in pathologic N0 lung ADC patients (P = 0.014). For patients with acinar pattern-predominant adenocarcinoma (APA) / papillary pattern-predominant adenocarcinoma (PPA) / invasive mucinous adenocarcinoma (IMA) and patients who underwent lobectomy, STAS was an independent prognostic factor for RFS (P = 0.015, P = 0.011; respectively) and overall survival (OS) (P = 0.038, P = 0.020; respectively). CONCLUSION: In this study, STAS was an independent prognostic factor for RFS in pathologic N0 lung adenocarcinomas, and it was also an independent prognostic factor for RFS and OS in patients with APA/PPA/IMA and those who received lobectomy.

The Prognostic Value of Preoperative Serum Tumor Markers in Non-Small Cell Lung Cancer Varies With Radiological Features and Histological Types.

OBJECTIVES: To assess the association between common-used serum tumor markers and recurrence of lung adenocarcinoma and squamous cell carcinoma separately and determine the prognostic value of serum tumor markers in lung adenocarcinoma featured as ground glass opacities. METHODS: A total of 2,654 non-small cell lung cancer patients undergoing surgical resection between January 2008 and September 2014 were analyzed. The serum levels of carcinoma embryonic antigen (CEA), cytokeratin 19 fragment (CYFRA21-1), neuron-specific enolase (NSE), carbohydrate antigen 125 (CA125), carbohydrate antigen 153 (CA153) and carbohydrate antigen 199 (CA199) were tested preoperatively. Survival analyses were performed with COX proportional hazard regression. RESULTS: Among patients with lung adenocarcinoma, elevated preoperative serum CEA(HR=1.246, 95%CI:1.043-1.488, P=0.015), CYFRA21-1(HR=1.209, 95%CI:1.015-1.441, P=0.034) and CA125(HR=1.361, 95%CI:1.053-1.757, P=0.018) were significantly associated with poorer recurrence free survival (RFS). Elevated preoperative serum CA199 predicted worse RFS in patients diagnosed with lung squamous cell carcinoma (HR=1.833, 95%CI: 1.216-2.762, P=0.004). Preoperative serum CYFRA21-1(HR=1.256, 95%CI:1.044-1.512, P=0.016) and CA125(HR=1.373, 95%CI: 1.050-1.795, P=0.020) were independent prognostic factors for patients with adenocarcinoma presenting as solid nodules while serum CEA (HR=2.160,95%CI:1.311-3.558, P=0.003) and CA125(HR=2.475,95%CI:1.163-5.266, P=0.019) were independent prognostic factors for patients with adenocarcinoma featured as ground glass opacities. CONCLUSIONS: The prognostic significances of preoperative serum tumor markers in non-small cell lung cancer were associated with radiological features and histological types.

Is flexible bronchoscopy necessary in the preoperative workup of patients with peripheral cT1N0 subsolid lung cancer? -a prospective multi-center cohort study.

BACKGROUND: Necessity of flexible bronchoscopy (FB) examination as a routine preoperative work-up for peripheral clinical T1N0 subsolid lung cancer was unknown. METHODS: This was a prospective, multi-center clinical trial (NCT03591445). Patients with peripheral GGO nodules (GGNs) who were candidates for surgical resection were enrolled. FB examination was performed preoperatively. Surgical plan could be changed if any aberrant histologic and anatomic findings were detected by FB examination. Primary endpoint was the rate that surgical plan was changed by positive FB findings. Secondary endpoints were rate of positive FB findings and rate of procedural complications. RESULTS: Six hundred and fifteen patients with peripheral subsolid nodules detected by thoracic CT were enrolled. There were 187 (30.4%) male and 428 (69.6%) female patients, mean age was 54.85±10.41 y (range, 26-78). 262 (42.6%) patients had pure GGNs and 353 (57.4%) patients had part-solid nodules. Mean size of nodules was 13.87±6.37 mm (range, 5-30). FB examinations confirmed one (0.16%) adenocarcinoma, seven (1.14%) bronchial variations, one (0.16%) segmental bronchostenosis, one (0.16%) segmental bronchial occlusion and one (0.16%) bronchial inflammation. No complications of FB examinations occurred. 568 (92.35%) thoracoscopic and 47 (7.65%) open surgeries were performed. No established surgical plan was changed by positive FB findings. Final pathologies revealed 26 (4.2%) adenocarcinoma in situ (AIS), 240 (39%) minimal invasive adenocarcinomas (MIAs), 343 (55.8%) invasive adenocarcinomas (IADs), one (0.2%) adenosquamous cell carcinoma, one (0.2%) squamous cell carcinoma, two (0.3%) atypical adenoid hyperplasia and two (0.3%) inflammations. CONCLUSIONS: FB examination was unnecessary in the preoperative assessment of peripheral clinical T1N0 subsolid lung cancer.

Ground glass opacity featured lung adenocarcinoma in teenagers.

INTRODUCTION: Ground glass opacity (GGO) nodules were found incidentally by computed tomography (CT) scan in some teenagers, which turned out to be lung cancer. The purpose of this study is to summarize the characteristics of teenage patients with GGO featured lung adenocarcinoma. METHODS: Patients aging from 13 to 20 who were incidentally diagnosed with lung cancer were reviewed between February 2015 to December 2020. The clinical, radiological and pathological characteristics were analyzed. RESULTS: Totally 12 patients were included. All of them were diagnosed as GGO featured lung cancer through CT scan, with no presenting symptom. The median surveillance before surgery was 5.5 months, and none of these GGO lesions enlarged or altered in the property during the surveillance. The mean tumor diameter was 0.93 ± 0.25 cm. Ten patients underwent wedge resection by video-assisted thoracoscopic surgery (VATS), 9 of which were minimally invasive adenocarcinoma (MIA) and 1 of which were invasive adenocarcinoma (IAC) in the pathological analysis. One patient underwent VATS left-upper sublobectomy, pathologically diagnosed as MIA and 1 patient underwent VATS left-upper lobectomy with systematic mediastinal lymphadenectomy, pathologically diagnosed as IAC. The median postoperative hospital stay was 3 days. All patients survived without recurrence during a median follow-up of 12.5 months. CONCLUSIONS: GGO nodules could be a sign of early-stage teenage lung adenocarcinoma. We proposed a screening strategy with long intervals based on a baseline CT scan for the teenage population, and a treatment strategy for diagnosed teenage patients.

Intrinsic soil property effects on Cd phytotoxicity to Ligustrum japonicum 'Howardii' expressed as different fractions of Cd in forest soils.

A better comprehensive understanding of the influence of soil/solution properties on cadmium (Cd) phytotoxicity is essential for soil Cd ecological risk assessment. The toxicity of soil spiked Cd to Ligustrum japonicum 'Howardii' seedling growth was conducted by the greenhouse pot experiments using 13 typical forest soils selected from mainland of China. The results showed that the ranges of Cd toxicity thresholds of 10% seedling growth inhibition (EC10) and 50% inhibition (EC50) followed the order: soil pore water Cd (EC10 on average 0.88 mg L-1 with the variation of 54.9 folds and EC50 on average 2.28 mg L-1 with variation of 41.8 folds), DTPA extractable Cd (EC10 on average 5.4 mg kg-1 with 20.9 folds variation and EC50 on average 17.86 mg kg-1 with 6.6 folds variation), total added Cd (EC10 on average 6.55 mg kg-1 with 16.7 folds variation and EC50 on average 22.11 mg kg-1 with 5.1 folds variation), which suggested that whatever the available Cd expressed, its toxicity is largely affected by soil properties. The empirical multiple equations were well developed between different fractions of Cd toxicity thresholds ECx (x = 10 or 50) and soil/solution. The results also showed that the pH inversely correlated with EC10 (r2 = 0.54, P < 0.01) and EC50 (r2 = 0.63, P < 0.001) based on soil pore water, indicating the ECx decreased with more toxicity as pH increased. No single significant soil solution properties were found for ECx in DTPA extractable Cd. For the ECx of DTPA extractable and total Cd, the content of aluminum oxides in soil and soil pH were the two significant factors inversely related with ECx, which explained 68%-79% of the inter-soil variation, respectively. Overall, soil or solution pH was the most important factor controlling Cd toxicity thresholds. Meanwhile, significant negative correlations existed between the soil solution pH and the slopes of parameter (b) of the dose-response curves for different fractions of Cd, implying that the growth of toxic effect enhanced as unit Cd dosage increased in low pH soils. These results will be helpful to evaluate the metal ecological risk in forest soils.

Cell-Cycle-Dependent Phosphorylation of PRPS1 Fuels Nucleotide Synthesis and Promotes Tumorigenesis.

Nucleotide supply is essential for DNA replication in proliferating cells, including cancer cells. Ribose-phosphate diphosphokinase 1 (PRPS1) is a key enzyme to produce the consensus precursor of nucleotide synthesis. PRPS1 participates in the pentose phosphate pathway (PPP) by catalyzing the phosphoribosylation of D-ribose 5-phosphate (R-5P) to 5-phosphoribosyl-1-pyrophosphate. Therefore, PRPS1 not only controls purine biosynthesis and supplies precursors for DNA and RNA biosynthesis but also regulates PPP through a feedback loop of the PRPS1 substrate R-5P. However, it is still elusive whether PRPS1 enhances nucleotide synthesis during cell-cycle progression. In this study, we explore the role and activation mechanism of PRPS1 in cell-cycle progression of colorectal cancer, and observed a peak in its enzymatic activity during S phase. CDK1 contributes to upregulation of PRPS1 activity by phosphorylating PRPS1 at S103; loss of phosphorylation at S103 delayed the cell cycle and decreased cell proliferation. PRPS1 activity in colorectal cancer samples is higher than in adjacent tissue, and the use of an antibody that specifically detects PRPS1 phosphorylation at S103 showed consistent results in 184 colorectal cancer tissues. In conclusion, compared with upregulation of PRPS1 expression levels, increased PRPS1 activity, which is marked by S103 phosphorylation, is more important in promoting tumorigenesis and is a promising diagnostic indicator for colorectal cancer. SIGNIFICANCE: These findings show that the enzymatic activity of PRPS1 is crucial for cell-cycle regulation and suggest PRPS1 phosphorylation at S103 as a direct therapeutic target and diagnostic biomarker for colorectal cancer.

ETS variant 5 promotes colorectal cancer angiogenesis by targeting platelet-derived growth factor BB.

ETS transcription factors play important roles in tumor cell invasion, differentiation and angiogenesis. In this study, we initially demonstrated that ETS translocation variant 5 (ETV5) is abnormally upregulated in colorectal cancer (CRC), is positively correlated with CRC tumor size, lymphatic metastasis and tumor node metastasis (TNM) stage and indicates shorter survival and disease-free survival in CRC patients. In vitro and in vivo experiments revealed that the downregulation of ETV5 could significantly suppress CRC cell proliferation. Moreover, overexpression of ETV5 could stimulate CRC angiogenesis in vitro and in vivo, which is consistent with RNA-seq results. Then, we identified platelet-derived growth factor BB (PDGF-BB) as a direct target of ETV5 that plays an important role in ETV5-mediated CRC angiogenesis through an angiogenesis antibody microarray. Additionally, PDGF-BB could activate VEGFA expression via the PDGFR-ß/Src/STAT3 pathway in CRC cells and appeared to be positively correlated with ETV5 in CRC tissues. Finally, we revealed that ETV5 could bind directly to the promoter region of PDGF-BB and regulate its expression through ChIP and luciferase assays. Overall, our study suggested that the transcription factor ETV5 could stimulate CRC malignancy and promote CRC angiogenesis by directly targeting PDGF-BB. These findings suggest that EVT5 may be a potential new diagnostic and prognostic marker in CRC and that targeting ETV5 might be a potential therapeutic option for inhibiting CRC angiogenesis.

Clinical and oncologic outcomes of single-incision laparoscopic surgery for right colon cancer: a propensity score matching analysis.

BACKGROUND: Single-incision laparoscopic surgery (SILS) for right colon cancer is going to be considered as a new option. The potential benefits, clinical, and oncologic outcomes are still controversial. The aim of this study was to investigate clinical and oncologic outcomes of single-incision laparoscopic surgery (SILS) compared to conventional laparoscopic surgery (CLS) for right colon cancer using propensity score matching analysis. METHODS: From December 2013 to June 2017, 174 patients underwent laparoscopic radical right hemicolectomy through a single-incision (n = 32) or a conventional (n = 142) approach. The data were prospectively collected and the patients were matched at a radio of 1:1 according to age, sex, body mass index (BMI), previous abdominal surgeries, comorbidities, ASA score (≤ 2/> 2), and pathologic stage. RESULTS: No significant differences were observed in estimated blood loss, time to diet, postoperative pain score, length of hospital stay between the SILS and CLS groups. However, the SILS group showed longer operation time (175 (40) vs 145 (52.5), p = 0.011) and shorter incision length (4 (1.4) vs 7 (1.9), p < 0.001). There were 2 (6.3%) postoperative complications in the SILS group and 5 (15.6%) in the CLS group (p = 0.426). The pathologic outcomes were similar between two groups. The median follow-up period was 26.5 months in the SILS group and 34.9 months in the CLS group (p = 0.002). There were 3 recurrences (9.4%) in the SILS group and 3 (9.4%) in the CLS group. The 3-year disease-free survival rates were 92.4 and 93.8% (p = 0.984), and overall survival rates were 92.3 and 93.0% (p = 0.884) in the SILS and the CLS groups, respectively. No incisional hernia was observed during the follow-up period. CONCLUSIONS: Though single-incision laparoscopic surgery for right colon cancer showed longer operation time in this study, it appears to be a safe and feasible option with comparable clinical and oncologic outcomes to conventional laparoscopic surgery.

Resection of Liver Metastases: A Treatment Provides a Long-Term Survival Benefit for Patients with Advanced Pancreatic Neuroendocrine Tumors: A Systematic Review and Meta-Analysis.

PURPOSE: Nonsurgical therapies, including biotherapy, chemotherapy, and liver-directed therapy, provided a limit survival benefit for PNET patients with hepatic metastases. With the development of liver resection technique, there was a controversy on whether to perform a liver resection for these patients. METHODS: A computerized search was made of the Medline/PubMed, EMbase, Cochrane Library, and SinoMed (CBM) before March 2018. A meta-analysis was performed to investigate the differences in the efficacy of liver resection and nonliver resection treatments based on the evaluation of morbidity, 30-day mortality, symptom relief rate, and 1-, 3-, and 5-year survival. Two investigators reviewed all included articles and extracted the data of them. The meta-analysis was performed via Review Manager 5.3 software. RESULTS: A total of 13 cohort studies with 1524 patients were included in this meta-analysis. Compared with the nonliver resection group, liver resection group had a longer 1-, 3-, and 5-year survival time and a higher symptom relief with an acceptable mortality and morbidity. CONCLUSIONS: Liver resection is a safe treatment and could significantly prolong the long-term prognosis for highly selected patients with resectable liver metastases from PNET. Further randomized, controlled trials are needed.

MLLT10 promotes tumor migration, invasion, and metastasis in human colorectal cancer.

OBJECTIVES: Colorectal cancer (CRC), one of the most aggressive gastrointestinal malignancies, is a frequently diagnosed life-threatening cancer worldwide. Most CRC patients have poor prognosis mainly because of frequent metastasis and recurrence. Thus, it is crucial to find out some new biomarkers and to show deeper insights into the mechanisms of CRC. MLLT10, Myeloid/lymphoid or mixed-lineage leukemia translocated to 10, also known as AF10, a recurrent MLL partner. In this study, we found that MLLT10 promotes CRC tumor invasion and metastasis both in vitro and in vivo. METHODS: Here, the expression of MLLT10 was evaluated by immunohistochemistry. Then, the plasmid and lentivirus particles for MLLT10 overexpression or knockdown were designed and constructed into SW620 and HT29 cells. Finally, cell proliferation assay, cell adhesion assay, transwell migration, and invasion assay were used to detect the migration and invasion ability of MLLT10 in CRC cells. A tail vein injection assay was employed to evaluate the role of MLLT10 in tumor metastases. RESULTS: MLLT10 expression was significantly higher in CRC tissues than in noncancerous tissues and was associated with some clinicopathological factors. In vitro, the overexpression of MLLT10 promoted CRC cell migration and invasion, while after MLLT10 was knocked down, the opposite results were observed. Furthermore, we used animal metastasis models to detect the function of MLLT10 in vivo, the results are same with the outcomes in vitro. In lung metastasis sites, the knockdown of MLLT10 in SW620 cells significantly inhibited Vimentin expression, whereas the E-Cadherin was increased. CONCLUSIONS: These results indicate that MLLT10 regulates the metastasis of CRC cells via EMT.

[Factors affecting the difficulty of laparoscopy-assisted triple-port anterior resection].

OBJECTIVE: To explore the factors affecting the operative difficulty of triple-port laparoscopic surgery (TLS) in anterior resection. METHODS: A retrospective case-control study was carried out. Clinical and MRI imaging data of 106 colorectal cancer cases undergoing TLS anterior resection at Department of Colorectal Surgery of Ruijin Hospital between 2013 and 2016 were retrospectively analyzed. INCLUSION CRITERIA: (1) patients receiving TLS anterior resection (Dixon operation); (2) preoperative stageI( to III( malignant tumor;(3) distance of 5-15 cm from inferior margin of tumor to anal verge; and (4) available preoperative rectal MRI. EXCLUSION CRITERIA: (1) patients receiving preoperative adjuvant therapy; (2) patients with low rectal cancer or with local advanced disease; (3) T4b tumor. Rectal MRI was introduced to measure the structure of pelvis. In sagittal view, superior margin of the first sacral vertebrae, superior margin of the third sacral vertebrae, apex of coccyx, and the line of superior margin of pubic symphysis were used to form a pentagon. The 5 lines were marked as N, O, P, Q, R, and the 5 included angles were marked as angle 1, 2, 3, 4, 5. Organs (uterus and prostate) and tumor (transverse diameter, longitudinal diameter, section area, lesion length, distance to circumference cutting edge) were also measured on MRI. The operative time was applied to be the indicator of operative difficulty and patients were divided into 2 groups according to median operative time. Baseline information (age, gender, BMI, distance from inferior margin of tumor to anal verge, operative history, length of tumor), preoperative tumor staging, and MRI measurements (pelvis, tumor, uterus, prostate), etc were compared between two groups. Factors affecting operative difficulty of TLS were analyzed with logistic regression model. RESULTS: Of 106 enrolled patients, 73 were male and 33 female with mean age of (59.8±12.2) years and mean BMI of (22.8±3.3) kg/m2; 25 patients had previous abdominal surgery; distance from inferior margin of tumor to anal verge was (7.4±2.0) cm and the tumor diameter was (3.7±1.4) cm; 24, 36 and 46 patients were in stage I(, II( and III( respectively. All operations were completed successfully. The median number of harvested lymph node was 13(11-16); the median length of distal resection margin was 2.5(2.0-3.1) cm; the median operative time was 2.0(1.5-2.6) hours; the median intraoperative blood loss was 50(0-100) ml; the median time to liquid diet was 4(3-5) days; the median hospital stay was 7(6-10) days. Ten cases (9.4%) developed complications within 30 days after surgery. Patients were divided into ≤2 h group and > 2 h group according to median operative time, and both groups had 53 patients. As compared to ≤2 h group, >2 h group had shorter distance from inferior margin of tumor to anal verge [(6.8 ± 1.5) cm vs. (8.0 ± 2.4) cm, t = 3.174, P = 0.004], lower ratio of (R+N)/(O+P)(1.61±0.27 vs. 1.73±0.19, t = 2.494, P = 0.014), larger transverse distance of tumor [(3.45±0.72) cm vs. (3.05±0.89) cm, t = 0.224, P = 0.027]. Multivariate logistic regression analysis showed the distance from inferior margin of tumor to anal verge was the independent factor affecting operative difficulty(OR=0.584, 95%CI:0.429-0.796, P = 0.001). CONCLUSIONS: Surgeons may have less difficulty in performing TLS anterior resection for patients with longer distance from inferior margin of tumor to anal verge. In preoperative assessment of operative difficulty of TLS, comprehensive evaluation should be performed. Distance from inferior margin of tumor to anal verge should be regarded as the main factor, and MRI (R+N)/(O+P) and transverse diameter of tumor should be used as important reference, leading to reasonable choice of cases for TLS and smooth pass of study curve.

Targeting autophagy enhances apatinib-induced apoptosis via endoplasmic reticulum stress for human colorectal cancer.

Apatinib, a novel tyrosine kinase inhibitor (TKI), has been confirmed for its efficacy and safety in the treatment of advanced gastric carcinoma and some other solid tumors. However, the direct functional mechanisms of tumor lethality mediated by apatinib have not yet been fully characterized, and the precise mechanisms of drug resistance are largely unknown. Here, in this study, we demonstrated that apatinib could induce both apoptosis and autophagy in human colorectal cancer (CRC) via a mechanism that involved endoplasmic reticulum (ER) stress. Moreover, activation of the IRE1α pathway from apatinib-induced ER stress is responsible for the induction of autophagy; however, blocking autophagy could enhance the apoptosis in apatinib-treated human CRC cell lines. Furthermore, the combination of apatinib with autophagy inhibitor chloroquine (CQ) tends to have the most significant anti-tumor effect of CRC both in vitro and in vivo. Overall, our data show that because apatinib treatment could induce ER stress-related apoptosis and protective autophagy in human CRC cell lines, targeting autophagy is a promising therapeutic strategy to relieve apatinib drug resistance in CRC.

LIFR promotes tumor angiogenesis by up-regulating IL-8 levels in colorectal cancer.

Leukemia inhibitory factor receptor (LIFR) has been documented as a cancer promoter and to be present at high levels in various types of tumor tissues. In our search for molecules prognostic of colorectal cancer (CRC), we found high levels of LIFR in CRC tissue samples. Further analyses revealed that LIFR was indeed prognostic of CRC patient survival, and was associated with tumor size, lymphatic metastasis and stages. LIFR was found to promote tumor growth, metastasis and angiogenesis both in vitro and in vivo. High levels of LIFR in CRC facilitated proliferation and migration of endothelial cells, resulting in an increase in angiogenic activity. Moreover, interleukin 8 (IL-8) was found to play a role in the LIFR induced angiogenesis. IL-8 levels were correlated with LIFR levels in CRC tissues, whereas depletion of IL-8 led to a reduced angiogenic activity of LIFR in CRC cells. In addition, LIFR increased phosphorylation level of Erk, which regulates il-8 transcription. We conclude that LIFR is possibly a valuable prognostic marker for CRC. Our results also implicate a mechanism by which LIFR regulates tumor angiogenesis through Erk/IL-8 pathway, and that LIFR could be a potential therapeutic target for CRC.

Cortactin promotes colorectal cancer cell proliferation by activating the EGFR-MAPK pathway.

Cortactin (CTTN) is overexpressed in various tumors, including head and neck squamous cell carcinoma and colorectal cancer (CRC), and can serve as a biomarker of cancer metastasis. We observed that CTTN promotes cancer cell proliferation in vitro and increases CRC tumor xenograft growth in vivo. CTTN expression increases EGFR protein levels and enhances the activation of the MAPK signaling pathway. CTTN expression also inhibits the ubiquitin-mediated degradation of EGFR by suppressing the coupling of c-Cbl with EGFR. CoIP experiments indicate CTTN can interact with c-Cbl in CRC cells. These results demonstrate that CTTN promotes the proliferation of CRC cells and suppresses the degradation of EGFR.