Preoperative fibrinogen to prealbumin ratio as a novel predictor for clinical outcome of hepatocellular carcinoma.

AIM: To investigate prognostic value of preoperative inflammatory biomarkers in hepatocellular carcinoma (HCC). PATIENTS & METHODS: Preoperative circulating fibrinogen, prealbumin, fibrinogen to prealbumin ratio (FPR), neutrophil to lymphocyte ratio, derived neutrophil to lymphocyte ratio, lymphocyte to monocyte ratio, platelet to lymphocyte ratio were detected and calculated in 230 HCC patients. X-tile software, Kaplan-Meier curve, Cox regression, time-dependent receiver-operating characteristic were used to explored prognostic roles of them in HCC. RESULTS: Multivariate Cox regression showed that high FPR was significantly associated with decreased recurrence-free survival (p = 0.034) and overall survival (p < 0.001) within HCC patients. FPR generated the largest area under curve of time-dependent receiver-operating characteristic comparing to the other biomarkers. Overall survival of HCC patients receiving chemotherapy was superior to the cases without receiving chemotherapy only in high FPR subgroup (p = 0.028). CONCLUSION: Preoperative FPR was superior to other biomarkers to independently predict survival of HCC patients, and it could identify the patients who could benefit from adjuvant chemotherapy.

Exosomes derived from imatinib-resistant chronic myeloid leukemia cells mediate a horizontal transfer of drug-resistant trait by delivering miR-365.

Chronic myeloid leukemia (CML) is a malignant disorder of hematopoietic stem/progenitor cells. Majority of patients can be effectively treated with tyrosine kinase inhibitors (TKIs) such as imatinib, but a portion of patients will develop drug resistance. Accumulated evidences have identified exosomes in cancer as promoters of tumor progression. Herein, we found that exosomes derived from imatinib resistant CML cells can be internalized into sensitive CML cells and confer drug-resistance traits. We also demonstrated a significant higher level of miR-365 in exosomes derived from drug-resistant CML cells compared with those from sensitive ones using microarray and qRT-PCR. The imatinib sensitive CML cells transfected with pre-miR-365 displayed lower chemosensitivity and apoptosis rate compared with controls. We further confirmed that exosomal transfer of miR-365 induced drug resistance by inhibiting expression of pro-apoptosis protein in sensitive CML cells. In conclusion, our study reveals that exosomes mediate a horizontal transfer of drug-resistant trait in chronic myeloid leukemia cell by delivering miR-365.

Circulating fibrinogen to pre-albumin ratio is a promising biomarker for diagnosis of colorectal cancer.

BACKGROUND: Inflammation and nutrition are closely associated with initiation and progression of colorectal cancer (CRC). This study aimed to investigate the diagnostic value of the FAR (FAR = 100*Fibrinogen/Albumin) and FPR (FPR = Fibrinogen/pre-Albumin) in CRC. METHODS: Neutrophil-to-lymphocyte ratio (NLR), FPR, and FAR were calculated in 455 newly diagnosed CRC patients, 455 healthy individuals, and 455 benign controls with colorectal polyp. The diagnostic value of biomarker for CRC was evaluated by receiver operating characteristic curve (ROC). Logistic regression analysis was adopted to assess the risk factors for telling CRC apart from benign disease. Moreover, the combined biomarkers were used for discriminating between CRC and benign disease. RESULTS: Neutrophil-to-lymphocyte ratio, FAR, and FPR were significantly higher in CRC patients compared with the benign or healthy controls (P < 0.05). ROC analysis showed that the diagnostic efficacy of FAR and FPR were better than NLR for CRC. Besides, FPR, NLR, carcinoembryonic antigen (CEA), and carbohydrate antigen 19-9 (CA199) were markedly associated with differentiation of benign disease and CRC in the logistic regression analysis. And the combination of FPR, CEA, and CA199 had the maximum area under the ROC curve (AUC) in separating CRC from benign disease (AUC = 0.845, Sensitivity = 67.9%, Specificity = 85.3%, Positive Predictive Value = 83.5%, Negative Predictive Value = 70.9%). CONCLUSIONS: Fibrinogen/pre-Albumin could be a useful CRC diagnostic biomarker, and the combination of FPR, CEA, and CA199 could significantly improve the diagnostic efficacy in discriminating CRC from the benign colorectal disease.

The predictive and prognostic role of a novel ADS score in esophageal squamous cell carcinoma patients undergoing esophagectomy.

BACKGROUND: Chronic inflammation is deemed to play a significant effect on initiation and progression of esophageal squamous cell carcinoma (ESCC). In current study, we investigated the prognostic and predictive role of albumin (Alb) to fibrinogen (Fib) ratio (AFR) and a novel AFR-Alb-derived neutrophil/lymphocyte ratio (dNLR) score (ADS) in ESCC patients undergoing esophagectomy and compared them with Fib, Alb, neutrophil to lymphocyte ratio (NLR), dNLR, platelet to lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR). MATERIALS AND METHODS: A total of 153 clinical confirmed ESCC patients undergoing esophagectomy between January 2011 and December 2013 were included in present study. We detected preoperative Alb, Fib and neutrophil, monocyte, lymphocyte and platelet count, and obtained overall survival (OS) by 3 years' follow-up in the cases. X-tile software, Kaplan-Meier curve, Cox regression and predicted nomogram were used to evaluate the predictive and prognostic role of them in ESCC patients. RESULTS: The optimal cut-off values of Fib, Alb, AFR, NLR, dNLR, PLR and LMR were 3.2 mg/dL, 38.2 g/L, 9.3, 2.1, 4.3, 145.9 and 2.3, respectively. High levels of Fib [(adjusted hazard ratio (HR) = 2.148, 95% confidential interval (CI) (1.229-3.753)], dNLR (adjusted HR = 2.338, 95% CI 1.626-5.308) and PLR (adjusted HR = 1.964, 95% CI 1.129-3.415) as well as low AFR (adjusted HR = 2.381, 95% CI 1.152-4.926) and Alb (adjusted HR = 2.398, 95% CI 1.342-4.273) were significantly associated with decreased OS in ESCC patients. The survival predictive areas under the time-dependent receiver operating characteristics curve of AFR, dNLR and Alb were higher than Fib and PLR, respectively. High ADS score was significantly associated with short 3 years' OS of ESCC patients (adjusted HR = 2.94, 95% CI 1.70-5.08). Moreover, OS of ESCC patients receiving adjuvant radio-chemotherapy was longer than those without the treatment in high ADS score subgroup (p = 0.001), however, no significant survival difference was observed in the patients with or without treatment radio-chemotherapy (p = 0.297). Additionally, a significant difference was observed in c-index values of the nomograms including or without ADS (0.720 vs. 0.670, p < 0.05). CONCLUSIONS: Preoperative ADS was a prospective biomarker to predict clinical efficacy of adjuvant radio-chemotherapy and clinical prognosis of ESCC patients undergoing esophagectomy, and the score could apparently improve predicted efficacy of the nomogram.

Differential expression of urinary exosomal microRNAs in IgA nephropathy.

BACKGROUND: Immunoglobulin A nephropathy (IgAN) is the most common type of primary glomerulonephritis in the world. Reliable biomarkers are required for the non-invasive diagnosis and monitoring of IgAN. This study aims to investigate the difference in urinary exosomal microRNA (miRNA) expression profiles between patients with IgA nephropathy (IgAN) and healthy controls, which may provide clues to identify novel potential non-invasive miRNA biomarkers for renal diseases. METHODS: Urine samples were collected from eighteen healthy controls and eighteen patients with IgAN. Differential centrifugation was performed to isolate exosomes from urine samples. High-throughput sequencing and real-time quantitative polymerase chain reaction (RT-qPCR) were sequentially used to screen and further validate miRNA expression profiles in urinary exosomes of patients with IgAN in two independent cohorts. RESULTS: Urinary exosomes were successfully isolated to obtain exosomal miRNAs. MiR-215-5p and miR-378i were significantly upregulated in urinary exosomes of patients with IgAN compared with healthy controls (P<.01), while miR-29c and miR-205-5p were significantly downregulated (P<.05). MiR-215-5p, miR-378i, miR-365b-3p and miR-135b-5p were found to have altered expression in patients with IgAN from validation cohorts, which was consistent with the high-throughput sequencing analysis. CONCLUSION: This study suggests that there is a significant difference in urinary exosomal miRNA profiles between patients with IgAN and healthy controls. These exosomal miRNAs, such as miR-29c, miR-146a and miR-205 may potentially serve as novel non-invasive biomarkers for IgAN.

Differential miRNA expression in pleural effusions derived from extracellular vesicles of patients with lung cancer, pulmonary tuberculosis, or pneumonia.

MicroRNAs (miRNAs) have been found to play important regulatory roles in various physiological and pathological processes. MiRNAs also exhibit high stability and are present at high concentrations in human bodily fluids. Consequently, miRNAs may represent attractive and novel diagnostic biomarkers for certain clinical conditions. Recently, the capacity for extracellular vesicles, including microvesicles and exosomes, to carry miRNAs that participate in cell-to-cell communication has been described. In the present study, the miRNA expression patterns for three kinds of pleural effusions that were obtained from patients with pneumonia (group A), pulmonary tuberculosis (group B), and lung cancer (group C) were detected with high-throughput sequencing. When the expression levels of these miRNAs were compared among the three groups, three differentially expressed miRNAs were detected between groups A and B, while 27 differentially expressed miRNAs were detected between groups A and C. Notably, miR-378i was significantly elevated only in group B, while miR-205-5p and miR-200b were markedly increased only in group C (p < 0.01). Further studies are needed to confirm whether these differentially expressed miRNAs may serve as prospective diagnostic markers for pulmonary diseases.

Recombinant human endostatin inhibits TNF-alpha-induced receptor activator of NF-κB ligand expression in fibroblast-like synoviocytes in mice with adjuvant arthritis.

Bone loss is a critical pathology responsible for the functional disability in patients with rheumatoid arthritis (RA). It is well known that receptor activator of nuclear factor kappa-B (NF-κB) ligand (RANKL) plays a crucial role in bone loss in RA. The purpose of this study was to determine whether recombinant human endostatin (rh-endostatin) mediates bone erosion in RA by regulation of RANKL expression in an experimental model of RA, consisting of mice with adjuvant-induced arthritis (AA). Cultured AA fibroblast-like synoviocytes (FLSs) obtained from these mice were induced by tumor necrosis factor-α (TNF-α) combined with or without rh-endostatin. The levels of RANKL and osteoprotegerin (OPG) mRNA, soluble and membrane-bound proteins were assessed by real-time PCR, ELISA, and Western blotting. Western blotting and the luciferase reporter assay were used to study related signaling pathways. Rh-endostatin inhibited RANKL mRNA expression, soluble and membrane-bound protein expression in AA FLSs but not in CD4+ T cells. However, OPG expression and secretion was not affected by rh-endostatin in AA FLSs. Molecular analysis demonstrated that rh-endostatin significantly inhibited TNF-α-induced MAPK and AP-1 signaling pathways. Moreover, rh-endostatin attenuated TNF-α-induced NF-κB signaling by suppressing the phosphorylation level of inhibitor kappaBα (IκBα) and nuclear translocation of NF-κB p65 in FLSs from mice with AA. These results provide the first evidence that rh-endostatin inhibits TNF-α-induced RANKL expression in AA FLSs.

Reconstruction of skull and dural defects using anterolateral thigh flaps: A STROBE-compliant article.

It is difficult to repair large skull and dural defects. We observed the therapeutic effects of anterolateral thigh flaps with vascular fascia lata for repairing large skull and dural defects.From December 2008 to June 2019, we repaired large skull and dural defects for 28 cases including 12 cases with scalp malignant tumor and 16 cases requiring removal of titanium mesh which had been once placed due to craniocerebral trauma. The scalp malignant tumor invaded full-thickness skull in 12 cases; and invaded cervical lymph nodes, dura mater or brain tissue in 3 cases. In the 12 cases with scalp malignant tumor, the scalp defects of 12 cm × 9 cm to 22 cm × 18 cm and skull defects of 9 cm × 7 cm to 15 cm × 12 cm after radical tumor resection were repaired using anterolateral thigh flaps of 14 cm × 11 cm to 23 cm × 19 cm with fascia lata of 10 cm × 8 cm to 16 cm × 12 cm. Postoperative radiotherapy and chemotherapy were also performed in the 3 cases with tumor metastasis. In the 16 cases requiring removal of titanium mesh, the skull and dural defects of 8 cm × 7 cm to 15 cm × 11 cm after removal of titanium mesh were repaired using anterolateral thigh flaps of 10 cm × 8 cm to 16 cm × 12 cm.In all cases, the transplanted anterolateral thigh flap with fascia lata survived after surgery and no vascular crisis occurred. During the followup of 8 months to 9 years, the flap appearance in the head-repaired area was fine, no external hernia of brain tissue occurred, the appearance of the femoral donor site was acceptable, and femoral muscle strength and movements were normal in all cases. The 12 cases with scalp malignant tumor had no local recurrence or distant metastasis.Repairing the skull and dural defects caused by radical surgery for scalp malignant tumor or removal of titanium mesh using anterolateral thigh flaps with vascular fascia lata, is effective. The appearance in the head-repaired area is fine without external hernia of brain tissue.

Repair of knee deep burn wound with descending genicular artery-saphenous artery perforator flaps in elderly patients (a STROBE-compliant article).

It is difficult to repair knee deep burn wounds in elderly patients. In this study, we observed the therapeutic effects of descending genicular artery-saphenous artery perforator flaps on knee deep burn wounds in elderly patients.Between December 2013 and February 2018, we repaired knee third-degree burn wounds using descending genicular artery-saphenous artery perforator flaps of 20 × 12 cm to 23 × 13 cm in 56 elderly patients. For the patella and patellar ligament with complete necrosis, the patella and patellar ligament were completely removed, whereas for the patella and patellar ligament with partial necrosis, necrotic parts were removed first. The donor area was repaired using intermediate thickness free skin graft. The 56 patients were 76- to 85 years' old and all had unilateral knee burn.All flaps survived in the 56 patients. After the follow-up of 2 to 36 months, the flaps were excellent in texture and appearance, and exhibited sensory recovery. In the 8 patients with completely necrotic patella and patellar ligament as well as open knee joint, the weight-bearing function of knee joint was retained, which met patients' requirements of limb salvage and weight-bearing function. In the other 48 patients with partially necrotic patella and patellar ligament as well as open joint capsule, the postoperative flexion and extension of the knee joint were good.In elderly patients, it is an effective method to repair knee deep burn wounds using the descending genicular artery-saphenous artery perforator flaps.

Albumin-to-fibrinogen ratio as a promising biomarker to predict clinical outcome of non-small cell lung cancer individuals.

Chronic inflammation is one of the critical causes to promote the initiation and metastasis of solid malignancies including lung cancer (LC). Here, we aimed to investigate the prognostic roles of albumin (Alb)-to-fibrinogen (Fib) ratio (AFR), Fib and Alb in LC and to establish a novel effective nomogram combined with AFR. Four hundred twelve LC patients diagnosed between February 2005 and December 2014 were recruited in this prospective study. The prognostic roles of AFR, Fib, Alb, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and monocyte-to-lymphocyte ratio (MLR) were identified by X-tile software, Kaplan-Meier curve, Cox regression model, and time-dependent ROC. Pretreatment high circulating Fib, low AFR, and Alb were significantly associated with increased risk of death for LC patients, especially for non-small cell lung cancer (NSCLC) patients in all stages. The area under curves (AUCs) of AFR, Fib, and NLR were higher than them within Alb and PLR for predicting the survival of NSCLC patients. Moreover, we found that clinical outcome of high AFR patient with chemo-radiotherapy was superior to low AFR patient; overall survival rate of stage II-III NSCLC patients undergoing chemo-radiotherapy was significantly lower than the surgical patients with treatment of adjuvant chemo-radiotherapy(P = 0.001) in low AFR subgroup. On the contrary, clinical outcome of the patients receiving chemo-radiotherapy was the same to the patients undergoing surgery and adjuvant chemo-radiotherapy (P = 0.405) in high AFR subgroup. In addition, c-index of predicted nomogram including AFR (0.717) for NSCLC patients with treatment of chemo-radiotherapy was higher than that without AFR (0.707). Our findings demonstrated that circulating pretreatment AFR might be a potential biomarker to predict clinical efficacy of surgical resection and adjuvant chemo-radiotherapy and be a prognostic biomarker for NSCLC individuals.

Preoperative circulating FPR and CCF score are promising biomarkers for predicting clinical outcome of stage II-III colorectal cancer patients.

INTRODUCTION: Inflammation and nutrition are considered as two important causes leading to the progression and poor survival of colorectal cancer (CRC). The objective of this study is to investigate the prognostic significance of preoperative albumin-to-fibrinogen ratio (AFR), fibrinogen-to-pre-albumin ratio (FPR), fibrinogen (Fib), albumin (Alb), and pre-albumin (pre-Alb) in CRC individuals. MATERIALS AND METHODS: In this study, 3 years' follow-up was carried out in 702 stage I-III resected CRC patients diagnosed between January 2008 and December 2013. The optimal cutoff points and prognostic values of AFR, FPR, Fib, Alb, pre-Alb, and a novel carcinoembryonic antigen (CEA)-carbohydrate antigen 19-9 (CA199)-FPR (CCF) score were assessed by X-tile software, Kaplan-Meier curve, and Cox regression model. We established the CRC prognostic nomogram, and its predictive efficacy was determined by Harrell's concordance index (c-index). RESULTS: Our results showed that high FPR was obviously correlated with poor survival of CRC patients. The prognostic predictive efficacy of CCF score was superior to FPR, CEA, CA199, CEA-CA199 (CCI), and CEA-FPR (CFI) score. Moreover, stage II-III patients harboring high FPR or elevated CCF (score≥1) could benefit from adjuvant chemotherapy, rather than those with low FPR or CCF (score=0). Additionally, the c-index (0.728) of the nomogram containing CCF score was significantly higher than that (0.626) without it (p<0.01). CONCLUSION: These findings illustrated that FPR and CCF score were promising biomarkers to predict the prognosis of CRC and to classify the stage II-III patients who could benefit from the adjuvant chemotherapy.

Association Between TNF-α -308G/A Polymorphism and Risk of Immune Thrombocytopenia: A Meta-Analysis.

OBJECTIVE: Previous studies have investigated the association between tumor necrosis factor-alpha (TNF-α) -308G/A polymorphism and risk of immune thrombocytopenia (ITP), but the reported results have been inconsistent. Thus, a systematic meta-analysis was performed to resolve this discrepancy. METHODS: Electronic databases and the cited references of the obtained published articles were manually searched. Quality assessment of each study was conducted using the Newcastle-Ottawa Scale (NOS). All case-control studies were used to assess the strength of the association. Statistical analysis was performed using Stata version 12.0. RESULTS: Eight high-quality studies, including 947 patients and 1911 controls, were selected for the final meta-analysis. There was no significant association between TNF-α -308G/A polymorphism and ITP in overall and Asian populations. However, a significant positive association was observed between them in the dominant genetic model (AA+AG versus GG) in the Caucasian population (OR = 1.35, 95% confidence interval [CI]: 1.07-1.71, PH = 0.173). CONCLUSIONS: Our finding suggested that TNF-α -308G/A might be involved in development of ITP in the Caucasian population, but not in the Asian population. Among Caucasians the A allele (AA+AG) was associated with ITP. However, larger-scale studies are required to confirm our findings.

Identification of differential expressed PE exosomal miRNA in lung adenocarcinoma, tuberculosis, and other benign lesions.

Pleural effusion (PE) is a common clinical complication of many pulmonary and systemic diseases, including lung cancer and tuberculosis. Nevertheless, there is no clinical effective biomarker to identify the cause of PE. We attempted to investigate differential expressed exosomal miRNAs in PEs of lung adenocarcinoma (APE), tuberculous (TPE), and other benign lesions (NPE) by using deep sequencing and quantitative polymerase chain reaction (qRT-PCR). As a result, 171 differentiated miRNAs were observed in 3 groups of PEs, and 11 significantly differentiated exosomal miRNAs were validated by qRT-PCR. We identified 9 miRNAs, including miR-205-5p, miR-483-5p, miR-375, miR-200c-3p, miR-429, miR-200b-3p, miR-200a-3p, miR-203a-3p, and miR-141-3p which were preferentially represented in exosomes derived from APE when compared with TPE or NPE, while 3 miRNAs, including miR-148a-3p, miR-451a, and miR-150-5p, were differentially expressed between TPE and NPE. These different miRNAs profiles may hold promise as biomarkers for differential diagnosis of PEs with more validation based on larger cohorts.

[Repair of tissue defects with free composite anterolateral femoral fascia lata perforator tissue flaps].

OBJECTIVE: To observe the clinical effects of repair of complicated tissue defects of several body parts with composite anterolateral femoral fascia lata perforator tissue flaps (fascial flap or fascial skin flap) with the aid of micro-surgery. METHODS: From February 2008 to August 2012, complicated tissue defects in 12 patients were repaired with composite anterolateral femoral fascia lata perforator tissue flaps. Two of the 12 patients suffered from a defect of scalp, skull, and dura mater as a result of resection of a malignant tumor of the scalp; 3 patients showed a defect of skin and tendo calcaneus in the heel and lower leg; 2 patients showed a defect of skin and extensor tendon in the dorsum of hands; the other 5 patients suffered from defects of skin and extensor tendon in the foot and ankle combined with exposure of bone or internal buttress plate. The size of tissue flaps ranged from 12 cm ×6 cm to 19 cm ×18 cm. The donor sites were closed by immediate suturing or skin grafting. RESULTS: All 12 tissue flaps survived. Patients were followed up for 2 to 36 months. The flaps were shown to have good appearance, texture and function. Two patients with the defect of the scalp, skull and dura mater after a resection of the malignant tumor of the scalp did not have recurrence or herniation of brain tissue. The foot-raising function in 3 patients with the defect of skin and tendo calcaneus in the heel and lower leg was recovered, and according to Arner-Lindholm criteria the result was excellent in 2 cases and good in 1 case. The extension function of fingers of 2 patients with defects of skin and extensor tendon in the dorsum of hands was good according to the evaluation criteria of Chinese Medical Association Society of Hand Surgery for tendon repair of hand. The extension function of toes of 5 patients with defects of skin and extensor tendon in the foot and ankle combined with exposure of bone or internal buttress plate was recovered and improved. CONCLUSIONS: Transplantation of composite anterolateral femoral fascia lata perforator tissue flaps with the aid of micro-surgery is an effective method in repairing the tissue defects of skull, dura mater, and the extensor tendon of hands or feet, with restoration of the extension function.

[Fabricated expanded thoracodorsal artery perforator flap to repair cervical scar in children].

OBJECTIVE: To investigate ideal methods to repair cervical cicatricial contracture in children. METHODS: The expanders were implanted subcutaneously around the cervical scar and above the latissimus. After expansion was completed, the cervical cicatricial contracture was released and the wound was covered with local expanded flaps and free expanded prefabricated thoracodorsal artery perforator flap, leaving no injury to thoracodorsal nerves and latissimus. The wound at the donor site was closed directly. RESULTS: From July 2007 to October 2009, 10 patients were treated. All the flaps survived completely. All the wounds were repaired totally and the deformities were corrected completely. The patients were followed up for 3-30 months. When the patients grew up, the flaps enlarged simultaneously. The flaps were not bulky and had a good color match. The scar at the donor site was inconspicuous with no functional morbidity. CONCLUSION: The fabricated expanded thoracodorsal artery perforator flaps is an ideal method for severe cervical cicatricial contracture in children.