A nomogram to predict lymph node metastasis before resection in intrahepatic cholangiocarcinoma.

BACKGROUND: In this study, we developed and validated a nomogram to predict lymph node metastasis before surgery in patients with intrahepatic cholangiocarcinoma (ICC). METHODS: Using the data from January 2006 to January 2015, we enrolled a total of 218 eligible patients with clinicopathologically confirmed ICC as a primary cohort to develop the nomogram. After various variables before surgery were analyzed by multivariable logistic regression, we combined the preoperative carbohydrate antigen 19-9, primary site of tumor, lymphonodus size on computed tomography imaging, tumor growth pattern, and (if applicable) histologic grade to make two different predictive nomograms. Then, the results were validated in 62 consecutive ICC patients from February 2015 to December 2016. We also compared the performance of the different nomograms via calibration, discrimination, and clinical use. RESULTS: The nomogram displayed fine discrimination (the concordance index, 0.761) and fine calibration in the primary cohort. When applied to the validation cohort, the nomogram also showed fine discrimination (concordance index, 0.794) and fine calibration. After adding the histologic grade to the nomogram, the integrated discrimination for predictive performance improved significantly. Finally, the clinical usefulness of predictive nomogram was proven via the decision curve analysis. CONCLUSIONS: The proposed nomograms can be selectively used to achieve more accurate lymph node metastasis predictions before surgery in patients with ICC, and this information can help with clinical management.

Risk Factors for Cholangiocarcinoma After Initial Hepatectomy for Intrahepatic Stones.

BACKGROUND: Aggressive hepatectomy is effective in treating intrahepatic stones and may minimize the deleterious consequences of subsequent cholangiocarcinoma (S-CCA). The risk factors of S-CCA after different methods of hepatectomy may vary with the resection scope of stone-affected segments. METHODS: We reviewed the records of 981 patients of primary intrahepatic stones with elective hepatectomy from January 2000 to December 2010. The clinical characteristics of patients in the S-CCA group (n = 55) and the control group (n = 926) were compared. The uniformity between extent of liver resection (ELR) with stone-affected segments (SAS) was segmented into 2 varieties: ELR = SAS with ELR < SAS according to the different hepatic resection scopes. Cox regression model with forward selection was used to identify the risk factors of S-CCA. RESULTS: In the univariate analysis, significant differences were observed between the S-CCA and control groups concerning stone location (unilateral 43.6 and 65.2 %, bilateral 56.4 and 34.8 %), residual stones (32.7 and 11.6 %), hepaticojejunostomy (43.6 and 30.9 %), and uniformity between ELR with SAS (ELR = SAS 20.0 and 42.6 %, ELR < SAS 80.0 and 57.4 %). Residual stones [hazard ratio (HR) 2.101, P = 0.016], hepaticojejunostomy (HR 1.837, P = 0.026) and uniformity between ELR and SAS (HR 2.442, P = 0.013) were independent prognostic factors for S-CCA by a Cox regression analysis with forward selection. In the subsection of ELR = SAS group, the 5- and 10-year postoperative tumor occurrence rates of unilateral and bilateral stones group were 0.9 versus 1.9 % and 3.0 versus 4.1 %, respectively (P = 0.663, log-rank). In the other subsection of ELR < SAS group, the 5- and 10-year postoperative tumor occurrence rates of unilateral and bilateral stones group were 3.4 versus 3.9 % and 6.8 versus 13.2 %, respectively (P = 0.047, log-rank), and the 5- and 10-year postoperative tumor occurrence rates of residual stones and non-residual stones group were 5.8 versus 3.0 % and 16.0 versus 7.9 %, respectively (P = 0.015, log-rank). CONCLUSIONS: Patients who underwent aggressive hepatectomy and had ELR = SAS had better outcomes than those with ELR < SAS. In the patients with ELR = SAS, the S-CCA rates of unilateral and bilateral stones were low and comparable. However, patients with ELR < SAS and bilateral intrahepatic or residual stones should be monitored more carefully for high-risk factors of S-CCA.

AZD-4547 exerts potent cytostatic and cytotoxic activities against fibroblast growth factor receptor (FGFR)-expressing colorectal cancer cells.

Colorectal cancer (CRC) causes significant mortalities worldwide. Fibroblast growth factor (FGF) receptor (FGFR) signaling is frequently dysregulated and/or constitutively activated in CRCs, contributing to cancer carcinogenesis and progression. Here, we studied the activity of AZD-4547, a novel and potent FGFR kinase inhibitor, on CRC cells. AZD-4547 inhibited CRC cell growth in vitro, and its activity correlated with the FGFR-1/2 expression level. AZD-4547 was cytotoxic and pro-apoptotic in FGFR-1/2-expressed CRC cell lines (NCI-H716 and HCT-116), but not in FGFR-1/2 null HT-29 cells. Further, AZD-4547 inhibited cell cycle progression and attenuated the activation of FGFR1-FGFR substrate 2 (FRS-2), ERK/mitogen-activated protein kinase (MAPK), and AKT/mammalian target of rapamycin (AKT/mTOR) signalings in NCI-H716 and HCT-116 cells. In vivo, AZD-4547 oral administration at effective doses inhibited NCI-H716 (high FGFR-1/2 expression) xenograft growth in nude mice. Phosphorylation of FGFR-1, AKT, and ERK1/2 in xenograft specimens was also inhibited by AZD-4547 administration. Thus, our preclinical studies strongly support possible clinical investigations of AZD-4547 for the treatment of CRCs harboring deregulated FGFR signalings.

Analysis of HYAL3 gene mutations in Chinese lung squamous cell carcinoma patients.

PURPOSE: In a previous study, we found a hyaluronidase 3 (HYAL3) gene mutation in exon 2 at position 188 by genome sequencing in a lung squamous cell carcinoma patient. The mutation results in substitution of serine for alanine. The aim of the study was to screen the HYAL3 gene mutation in Chinese lung squamous cell carcinoma patients and explore the correlation between mutation of HYAL3 with clinical and pathological characteristics in lung squamous cell carcinoma patients in China. METHODS: We applied polymerase chain reaction to examine the HYAL3 gene mutations in cancer tissues and their adjacent normal tissues from 39 cases of lung squamous cell carcinoma patients. RESULTS: 1) The incidence rate of HYAL3 mutation in 39 cases of lung squamous cell carcinoma was 10.26% (4/39) and none in adjacent normal lung tissues (0/39). 2) The mutations of HYAL3 in the 4 cases were all heterozygous: 3 of them were located in exon 1 (G-T) and one in exon 2 (G-T). 3) Mutations of the HYAL3 gene were not correlated with the distribution of patient gender, age, tumor size, histological grade, smoking history, TNM stage or distant metastasis (P >0.05). The gene mutation was correlated with lymph node status (P = 0.044). CONCLUSION: Mutations of the HYAL3 gene are rare in Chinese lung squamous cell carcinoma patients and might contribute to lymph node metastasis.

Reduced expression of SK3 and IK1 channel proteins in the cavernous tissue of diabetic rats.

The small (SK3) and intermediate (IK1) conductance calcium-activated potassium channels could have key roles in the endothelium-dependent hyperpolarization factor pathway, which is believed to contribute to normal penile erection function. We aimed to investigate the expression of SK3 and IK1 in diabetic rodents. The experimental diabetes model was induced in 8-week-old male Sprague-Dawley rats (250-300 g) by a single administration of streptozotocin. Both the diabetes mellitus group (DM group, n = 20) and the control group (NDM group, n = 10) were injected with a low dose of apomorphine to allow for the measurement and comparison of the corresponding penile erections. The mRNA and protein expression levels of SK3 and IK1 were measured by reverse transcription polymerase chain reaction and western blot, respectively. Erectile function was significantly decreased in the DM group compared with control group (P < 0.05). The mRNA and protein expression levels of SK3 and IK1 were reduced in the cavernous tissue of diabetic rats compared with the control group (P < 0.05). Diabetes inhibits mRNA and protein expression of both SK3 and IK1 in the cavernous tissue of diabetic rats. This could play a key role in the development of erectile dysfunction in diabetic rats.

[Diabetes mellitus reduces the expression of SK3 in rat cavernous tissues].

OBJECTIVE: SK3, one of the small conductance calcium-activated potassium channels, is the key substance of the endothelium-derived hyperpolarizing factor (EDHF) passway. This study aimed to investigate the expression of SK3 in the cavernous tissue of rats with diabetes mellitus (DM). METHODS: Twenty-six DM models were made by injection of streptozocin (STZ) out of 50 male Sprague-Dawley rats, and another 15 that failed to be modeled were included in an STZ group. Ten healthy male rats were taken as blank controls. Eight weeks later, the penile erectile function of the rats was detected by injection of apomorphine (APO) at 80 microg/kg, and the expression of SK3 in the cavernous tissue was determined by RT-PCR and Western blot. RESULTS: Penile erection was observed in 14 (54%) of the 26 DM rat models and in all the rats of the STZ and blank control groups. Both the mRNA and protein expressions of SK3 were significantly lower in the DM (0.50 +/- 0.09 and 0.65 +/- 0.06) than in the STZ (1.15 +/- 0.03 and 1.28 +/- 0.04) and blank control groups (1.21 +/- 0.04 and 1.34 +/- 0.05) (P < 0.05). There were no significant differences between the STZ and blank control groups in either penile erection or mRNA and protein expressions of SK3 (P > 0.05). CONCLUSION: Diabetes mellitus can significantly reduce erectile function in rats, which may be related to the decreased expression of SK3 in the corpus cavernosum.