Preventive Effects of Melatonin on Delirium in Intensive Care Unit Patients: A Meta-Analysis of Randomized Controlled Trials.

Aims: To investigate the preventive efficacy of melatonin on the incidence of delirium and other clinical outcomes of subjects in the intensive care unit (ICU). Methods: Randomized controlled trials concerning the effects of melatonin on delirium published from inception to July 2022 were identified from PubMed, Embase, and the Cochrane Library. The primary outcome was delirium incidence. The secondary outcome was the length of ICU stay, the duration of mechanical ventilation, and the mortality in ICU. A meta-analysis was performed. Estimates were presented as risk ratio (RR) or standard mean difference (SMD) with 95% confidence interval (CI). Results: Eleven RCTs with 2002 patients were included. The forest plots showed that the delirium incidence did not significantly decrease after melatonin administration (RR 0.85; 95% CI, 0.61~1.18, P = .32, I2=60%, P for heterogeneity = .01). The subgroup analyses confirmed that melatonin significantly reduced the incidence of delirium (RR 0.70; 95% CI, 0.56~0.89, P = .003, I2 = 32%, P for heterogeneity = .22) for the special ICU patients. Also, for ICU patients, the length of ICU stays, duration of mechanical ventilation, and mortality were not significantly decreased after melatonin treatment (all P > .05). Conclusion: Melatonin may decrease the incidence of delirium for special ICU patients. PROSPERO registration number: CRD42022354874.

Candidate Oligo Therapeutic Target, miR-330-3p, Induces Tamoxifen Resistance in Estrogen Receptor-Positive Breast Cancer Cells via HDAC4.

Tamoxifen is a drug used for treating breast cancer (BC), especially for individuals diagnosed with estrogen receptor-positive (ER+) BC. Its prolonged use could reduce the risk of recurrence and significantly lengthen the survival rate of BC patients. However, an increasing number of patients developed resistance to tamoxifen treatment, which reduced therapeutic efficiency and caused substandard prognosis. Therefore, the exploration of the molecular processes involved in tamoxifen resistance (TR) is urgently required. This investigation aimed to elucidate the relationship of microRNA-330 (miR-330-3p) with the TR of BC. There is little information on miR-330-3p's link with drug-resistant BC, although it is well known to regulate cell proliferation and apoptosis. Primarily, miR-330-3p expression in parental BC (MCF7/T47D), TR (MCF7-TR), and T47D/TR cell lines was detected by qRT-PCR. Then, the impact of miR-330-3p on the TR of BC cells was assessed by a cell proliferation assay. Lastly, dual-luciferase reporter, qRT-PCR, and western blot assessments were carried out to identify histone deacetylase 4 (HDAC4) as the potential miR-330-3p target gene. The data indicated that miRNA-330 was overexpressed in TR ER+ BC cells and its overexpression could induce TR. Furthermore, miRNA-330 could also reduce the expression of HDAC4, which is closely linked to TR, and overexpression of HDAC4 could reverse miRNA-330-induced drug resistance. In summary, miR-330-3p could induce TR of ER+ BC cells by downregulating HDAC4 expression, which might be a novel marker of TR and a possible treatment target against BC patients who are tamoxifen-resistant.

Ischemic Stroke and Dysbiosis of Gut Microbiota: Changes to LPS Levels and Effects on Functional Outcomes.

Context: The intestinal microbiota and their metabolites play an important role in acute ischemic stroke (AIS) and modulate brain functions directly or indirectly through immune, endocrine, vagal, and other humoral pathways. However, relatively few investigations have evaluated the gut microbiome and its levels of inflammatory factors or the potential associations of those factors with stroke outcomes in patients who have had acute ischemic stroke (AIS), with different stroke severities. Objective: The study intended to determine if AIS patients would have different gut microbiota and inflammatory-factor levels than healthy individuals and if those levels would be associated with the stroke's severity and the patient's prognosis. Design: The research team performed a prospective observational study. Setting: The study took place in the Department of Rehabilitation at the General Hospital of Wanbei Coal and Electricity Group, which is the Third Affiliated Hospital of Bengbu Medical College in Suzhou, Anhui, China. Participants: Participants were 90 patients who had received a diagnosis and treatment of AIS within 48 hours of the stroke's onset at the hospital, between October 2021 and March 2022. Groups: The research team performed multiple comparisons of the baseline demographic and clinical characteristics, the gut microbiota, and levels of inflammatory factors of a number of groups: (1) the AIS patients, the AIS group, to the healthy controls, the control group; (2) the AIS participants who had had a mild or moderate stroke, the mild-moderate group, and those who had had a severe stroke, the severe group; (3) the AIS participants who had had a good primary outcome, the good outcome group, and those who had had a poor primary outcome, the poor outcome group; (4) the mild-moderate and severe groups to the control group; and (5) the good outcome and poor outcome groups to the control group. Outcome Measures: The research team: (1) obtained participants' fecal samples within 72 hours of admission; (2) collected baseline data for the included AIS patients and controls; (3) used 16S rRNA gene sequencing and an enzyme-linked immunosorbent assay (ELISA) to compare the fecal microbial compositions, lipopolysaccharide (LPS) contents, and inflammatory-factor levels between groups; and (4) evaluated the associations of the fecal microbial compositions with severity of stroke and 90-day functional outcomes, using logistic-regression models. Results: The gut microflora distinguished AIS patients from healthy controls. The LPS and inflammatory-factor levels were associated with an increased risk of poor functional outcomes at day 90. Conclusions: Dysbiosis of gut microbiota and LPS and inflammatory-factor levels can increase AIS patients' subsequent risks for poor functional outcomes, indicating that the dysbiosis and levels could be potential prognostic markers and therapeutic targets for stroke.

Preparation and Characterization of a Novel Morphosis of Dextran and Its Derivatization with Polyethyleneimine.

Dextran, a variant of α-glucan with a significant proportion of α-(1,6) bonds, exhibits remarkable solubility in water. Nonetheless, the precipitation of dextran has been observed in injection vials during storage. The present study aimed to establish a technique for generating insoluble dextran and analyze its structural properties. Additionally, the potential for positively ionizing IS-dextran with polyethyleneimine was explored, with the ultimate objective of utilizing IS-dextran-PEI as a promising support for enzyme immobilization. As a result, IS-dextran was obtained by the process of slow evaporation with an average molecular weight of 6555 Da and a yield exceeding 60%. The calculated crystallinity of IS-dextran, which reaches 93.62%, is indicative of its irregular and dense structure, thereby accounting for its water insolubility. Furthermore, positive charge modification of IS-dextran, coupled with the incorporation of epichlorohydrin, resulted in all zeta potentials of IS-dextran-PEIs exceeding 30 mV, making it a promising supporting factor for enzyme immobilization.

Drug-Coated versus Uncoated Balloon for Side Branch Protection in Coronary Bifurcation Lesions Treated with Provisional Stenting Using Drug-Eluting Stents: A Meta-analysis.

Background: Provisional stenting using drug-eluting stents (DES) has become the preferred treatment for coronary bifurcation lesions (CBLs). We performed a meta-analysis to compare the effects of side branch (SB) protection using a drug-coated balloon (DCB) versus an uncoated balloon (UCB) during the procedure. Methods: Relevant randomized and nonrandomized studies were identified by searching the Medline, Embase, Web of Science, Wanfang, and CNKI databases. We used a random-effect model to pool the data by incorporating the heterogeneity between the included studies. Results: Overall, 803 patients with CBLs treated with provisional stenting using DES were included from seven studies. With a follow-up duration of 6 to 12 months, SB protection with DCB was associated with a lower degree of postoperative diameter stenosis (mean difference (MD): -11.35%, 95% confidence interval (CI): -14.17 to-8.53, p < 0.001; I2 = 0%) and less late lumen loss (MD: -0.19 mm, 95% CI:-0.28 to-0.10, p < 0.001; I2 = 69%) of SB compared to those with UCB. Moreover, SB protection with DCB was associated with reduced risks of target lesion revascularization (risk ratio [RR]: 0.49, 95% CI: 0.27 to 0.88, p = 0.02; I2 = 0%) and major adverse cardiovascular events (RR: 0.42, 95% CI: 0.27 to 0.66, p < 0.01; I2 = 0%). Subgroup analysis according to the study design showed similar results. Conclusions: For patients with CBL treated with provisional stenting using DES, SB protection with DCB was associated with better angiographic and clinical outcomes than those with UCB.

Next generation sequencing detection in archival surgically resected lung adenocarcinoma specimens harbouring the anaplastic lymphoma kinase fusion protein.

OBJECTIVE: To analyse clinical and molecular features in patients with surgically resected patients with lung cancer harbouring anaplastic lymphoma kinase fusion. METHODS: The retrospective study was conducted at Zhejiang Cancer Hospital, Hangzhou, China, and comprised data from November 2013 to August 2015 of lung cancer patients. Anaplastic lymphoma kinase, epidermal growth factor receptor, kirsten rat sarcoma viral oncogene, v-raf murine sarcoma viral oncogene homolog, REarranged during Transfection proto-oncogene, c-ros oncogene 1 receptor kinase, V-Erb-B2 avian erythroblastic leukaemia viral oncogene homolog 2 and mesenchymal epithelial transition factor were noted using next generation sequencing. Clinicopathological parameters were also investigated. All patients were followed up till August 10, 2017. Data was analysed using SPSS 22. RESULTS: Of the 19 patients, 15(79%) were non-smokers. Anaplastic lymphoma kinase rearrangements occurred in the acinar predominant in 6(31.6%), solid predominant 6(31.6%) and mucinous predominant 4(21%) adenocarcinomas. There was 1(5.2%) patient with epidermal growth factor receptor 21 G863D mutation. The 3-year disease-free survival rate in 5(26.3%) cases of anaplastic lymphoma kinase variant 1 was 5(100%), while in the 14(73.7%) cases of non-variant 1 group it was 9(64.3%) (p=0.257). CONCLUSIONS: Anaplastic lymphoma kinase rearrangements did not tend to be accompanied with other driver genes. Difference between variant 1 and non-variant 1 patients was uncertain and needs to be further investigated.

Clinicopathological characteristics of patients with surgically resected lung cancer having tumours harboring anaplastic lymphoma kinase fusion protein.

Platinum-based postoperative adjuvant chemotherapy is the standard treatment for stage II-IIIA non-small cell lung cancer (NSCLC). Novel therapeutic modalities are required to improve the outcome of an early stage NSCLC. Patients with advanced NSCLC having anaplastic lymphoma kinase (ALK) fusion protein are sensitive to ALK inhibitors such as crizotinib. This study aimed to further explore the clinicopathological characteristics of postoperative patients with early-stage lung cancer harboring ALK fusion protein and provide a basis to carry out postoperative adjuvant crizotinib treatment. A total of 19 patients were retrospectively reviewed, and the clinicopathological parameters and follow-up data were collected and analysed. ALK rearrangements easily exist in male and in non-smokers patients with adenocarcinoma histology. Brain metastasis occurs easily, and prognosis of patients with stage IIIA is relatively poor. Detection of ALK fusion protein should be a routine testing. Postoperative adjuvant crizotinib treatment for patients with stage IIIA NSCLC harboring ALK fusion protein is promising.

Features of branch occlusive disease-type intracranial atherosclerotic stroke in young patients.

BACKGROUND: Young ischemic stroke patients are common while classification and analysis based upon imaging characteristics are rarely reported. We intend to compare the clinical and MRI characteristics of cerebral stroke induced by intracranial atherosclerosis between young patients with branch occlusive disease (BOD) and those with non-branch occlusive disease (non-BOD) or small artery disease (SAD). METHODS: A total of 151 subjects with acute infarction within the middle cerebral artery (MCA) territory were included and patients with ipsilateral internal carotid artery stenosis or cardioembolism were excluded. Based on the distribution characteristics of infarction and the presence of ipsilateral MCA stenosis, the patients were divided into three groups: BOD-striatocapsular area infarction with ipsilateral MCA stenosis; non-BOD -infarction size exceeds the striatocapsular area and accompanied by ipsilateral MCA stenosis; SAD. The clinical and MCA stenosis characteristics of the three groups were compared. RESULTS: The number of BOD patients with hypertension was significantly higher than that of SAD (92.9% vs 53.7%, p = 0.000) and non-BOD (92.9% vs 57.1%, p = 0.001); subjects with smoking history significantly exceeded that of SAD (50% vs 26.9%, p = 0.03) and subjects with family history of cardiovascular disease was significantly less than that of non-BOD (14.3% vs 41.1%). Baseline NIHSS scores and mRS scores at discharge in patients with BOD were significantly lower than those with non-BOD (p = 0.000, p = 0.001). Majority of patients in non-BOD group displayed severe MCA stenosis (39 cases, 69.6%) while that in BOD group displayed mild stenosis (26 cases, 92.9%), and the difference was statistically significant (p = 0.000). Compared with non-BOD group, the stenosis in BOD group located at a relatively distal end in the M1 segment of MCA (S/M1, 58% vs 40%, p = 0.000) and was more localized (stenosis level/ (SL/M1), 1.86 (1.35-2.6) vs 2.9 (2.0-5.0), p = 0.002). CONCLUSION: BOD in young patients with ischemic stroke induced by intracranial atherosclerosis is not rare (33.3%) and its clinical manifestations and prognosis are similar to those of SAD. This may be related to the mild localized stenosis at the distal end in the M1 segment of MCA. Control of hypertension might play a positive role in secondary prevention.

Continuous blood purification ameliorates clinical signs and corrects the plasma phospholipid levels of patients with multiple organ dysfunction syndromes.

BACKGROUND: Multiple organ dysfunction syndromes (MODS) is reported as a leading cause of mortality in intensive care units. Recently, continuous blood purification (CBP) has been mostly applied for MODS treatment. Thus, the purpose of this study was to investigate the effects of CBP on plasma phospholipid level in patients with MODS. METHODS: A total of 126 patients with MODS and 120 healthy people were collected. The serum cytokine levels, blood biochemical parameters, and blood gas indexes were detected, and the correlation among phospholipid compounds with serum cytokine levels, blood biochemical parameters, and blood gas indexes was analyzed. RESULTS: Before CBP, levels of body temperature, RR, HR, CVP, IL-6, IL-10, TNF-α, BUN, SCr, PaCO2 , SM747, and LPC540 were obviously higher, and pH, HCO3- , PaO2 , SaO2 , PE750, PI885, PC792, PC826, PC830, PC854, PC802, and PG747 were lower in the MODS group than those in the control group. During CBP, the MODS group had gradually declined RR, CVP, levels of IL-6, IL-10 and TNF-α, BUN, SCr, PaCO2 , SM747, and LPC540 and increased HCO3- , PaO2 and SaO2 , PE750, PI885, PC792, PC826, PC830, PC854, PC802, and PG747. Besides, levels of PE750, PI885, PC792, PC826, PC830, PC854, PC802, and PG747 had an obvious negative correlation with levels of TNF-α, IL-10, IL-6, BUN, SCr, and PaCO2 , and a significant positive correlation with levels of HCO3- , PaO2 , and SaO2 . CONCLUSION: CBP could effectively ameliorate clinical signs of patients with MODS and correct the plasma phospholipid levels.

MGMT promoter methylation and 1p/19q co-deletion of surgically resected pulmonary carcinoid and large-cell neuroendocrine carcinoma.

BACKGROUND: The response to temozolomide (TMZ) treatment in small-cell lung cancer (SCLC) correlated with O(6)-methylguanine -DNA methyltransferase (MGMT) promoter methylation. 1p/19q co-deletion within oligodendroglioma is a responsive predictor for TMZ. Currently, the status of MGMT promoter methylation and 1p/19q co-deletion in pulmonary carcinoid (PC) and large-cell neuroendocrine carcinoma (LCNEC) is not reported. METHODS: Nine PC [two atypical carcinoids (AC), seven typical carcinoids (TC)] and six LCNEC patients were collected retrospectively. The pyrosequencing and fluorescence in situ hybridization were used to detect the MGMT promoter methylation and 1p/19q co-deletion in surgically resected specimens. Kaplan-Meier analysis was used to assess the rate of disease-free survival (DFS). RESULTS: MGMT promoter methylation was found in two (2/6, 15.3%) LCNEC patients but not in any PC patients. Three (3/6, 50%) 1p and two (2/6, 33.3%) 19q single deletions were found in LCNEC patients. One 1p single deletion was found in AC patients. One (1/7, 14.3%) 1p and two (2/7, 28.6%) 19q single deletions were found in TC patients. After a median follow-up of 38 months, three LCNEC patients developed distant metastasis and one patient died of LCNEC disease. The DFS of PC patients was much longer than LCNEC patients (χ 2 = 7.565, P = 0.006). CONCLUSIONS: MGMT promoter methylation and 1p/19q co-deletion might not be the ideal biomarkers for TMZ treatment in TC/AC patients. Thus, the detection of MGMT promoter methylation and whether it can be used as a medication for TMZ in LCNEC patients necessitates investigation. Furthermore, 1p deletion could be a negative prognostic factor for LCNEC patients.

Preparation, characterization and in vitro and in vivo evaluation of a solid dispersion of Naringin.

Naringin (NA) is one of typical flavanone glycosides widely distributed in nature and possesses several biological activities including antioxidant, anti-inflammatory, and antiapoptotic. The aim of this study was to develop solid dispersion (SD) and to improve the dissolution rate and oral bioavailability of NA. NA-SD was prepared by the traditional preparation methods using PEG6000, F68, or PVP K30 as carrier at different drug to carrier ratios. According to the results of solubility and in vitro dissolution test, the NA-PEG6000 (1:3) SD was considered as an optimal formulation to characterize by Fourier transform infrared spectroscopy (FT-IR), differential scanning calorimetry and powder X-ray diffraction. Furthermore, oral bioavailabilities of NA-PEG6000 (1:3) SD and NA-suspension with the same dosage were investigated in SD rats. The results confirmed the formation of SD and the pharmacokinetic parameters of NA-PEG6000 (1:3) SD (Cmax = 0.645 ± 0.262 µg/ml, AUC0-t = 0.471 ± 0.084 µg/ml h) were higher than that of NA-suspension (Cmax = 0.328 ± 0.183 µg/ml, AUC0-t = 0.361 ± 0.093 µg/ml h). Based on the results, the SD is considered as a promising approach to enhance the dissolution rate and oral bioavailability of NA.

Lentivirus-mediated angiopoietin-2 gene silencing decreases TNF-α induced apoptosis of alveolar epithelium cells.

OBJECTIVE: To investigate the role of angiopoietin-2 (Ang-2) in tumor necrosis factor-α (TNF-α) induced apoptosis of alveolar epithelium cells (AECs). METHODS: TNF-α was used to induce human alveolar epithelial HPAEpiC cells, and Ang-2 siRNA vector was transfected to the HPAEpiC cells. RT-PCR and Western blot were used. TUNEL staining was applied to observe apoptosis, and annexin V-FITC-PI staining was used to calculate apoptosis rate. RESULTS: mRNA and protein expressions of Ang-2, activated Bax, and cleaved caspase-3 in HPAEpiC cells were up-regulated, but the expression level of Bcl-2 decreased (P < 0.05). After transfection of Ang-2 siRNA, mRNA and protein expressions of Ang-2, activated Bax, and cleaved caspase-3 in HPAEpiC cells were down-regulated, but the expression level of Bcl-2 increased (P < 0.05). The number of apoptotic cells increased after TNF-α treatment; however, the number decreased after Ang-2 siRNA transfection. Annexin V-FITC-PI staining verified that the total number of apoptotic cells was elevated with TNF-α treatment, but declined after transfection of Ang-2 siRNA. CONCLUSIONS: The expression level of Ang-2 increased during TNF-α-induced apoptosis. Inhibiting Ang-2 expression may suppress the early stages of cell apoptosis and the degree of TNF-α-induced apoptosis.

Evaluation of N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine as an irreversible inhibitor of mammalian thioredoxin reductase1.

CONTEXT: Thioredoxin reductase (TrxR) is up-regulated in a number of human malignant cells and becomes a promising target for anticancer drug development. OBJECTIVE: To evaluate N-acetyl-S-(p-chlorophenylcarbamoyl)cysteine (NACC), a potent anticancer agent against melanoma, as an inhibitor of mammalian TrxR1. MATERIAL AND METHODS: The mechanism of inhibition against TrxR1 was investigated using substrate protection, dialysis and liquid chromatography-tandem mass spectrometry. RESULTS: NACC inhibits TrxR1 in a time and concentration dependent manner. The K(I) and k(inact) of NACC against TrxR1 were determined to be 80 µM and 0.178 min(-1), respectively. The inhibition occurred only in the presence of NADPH and persisted after extensive dialysis. The tandem mass spectrometric analysis demonstrated that the selenocysteine rather than cysteine residue at the active site was p-chlorophenyl carbamoylated by NACC. Inhibition of intracellular TrxR by NACC in cultured melanoma cells was observed. DISCUSSION AND CONCLUSION: NACC which irreversibly inhibits TrxR1 by forming a covalent bond with selenocysteine can be an effective tool in the study of TrxR1.

[Liposclerosing myxofibrous tumor of bone: a clinicopathologic analysis].

OBJECTIVE: To explore the clinicopathologic features and imaging diagnosis of 17 cases of liposclerosing myxofibrous tumor (LSMFT) and to discuss the mechanism of the disease. METHODS: Cases of LSMFT diagnosed in 2014 were included in this retrospective study. The clinicopathologic features and imaging findings were evaluated. RESULTS: There were 17 cases of LSMFT, occurring in 11 men and 6 women with a mean age of 46 years (range, 26-67 years). Patients were asymptomatic or presented with pain localized over the lesions. Most (13/17) lesions were located in the intertrochanteric region. Radiographs showed well-defined and often extensively sclerotic margin. MRI showed the lesions to be relatively heterogeneous on T1W, and heterogeneous with high signal intensity on T2W with fat suppression. Microscopically, LSMFT was characterized by a complex mixture of histologic elements, including myxofibrous and collagen tissues, lipomatous areas, xanthoma cells, calcification, irregular ossification and pseudo-Paget's bone. CONCLUSIONS: LSMFT is a benign fibro-ossesous lesion with unique imaging characteristics and histologic features, occurring preferentially in some locations. It might represent end-stage degenerative changes in other benign bone lesions such as fibrous dysplasia, simple bone cyst and intraosseous lipoma secondary to trauma from forces and ischemic bone injury exerted on the intertrochanteric region of the femur.

Establishment and Characterization of a CD20-Positive NK/T-Cell Lymphoma Cell Line.

BACKGROUND: CD20 positive NK/T-cell lymphoma is extremely rare and difficult for clinical treatment. Due to the lack of an established cell model for this disease, less is known about its biological characterization and potential therapeutic options. METHODS: A cell line of NK/T-cell lymphoma, which was enriched by magnetic sorting with proper cell surface markers (CD56) from peripheral blood mononuclear cells (PBMCs) drawn from a 21-year-old male patient with nasal angiocentric NK/T-cell lymphoma, was designated as ZQNK-29. Immunophenotypic analysis of ZQNK-29 was performed by flow cytometric and immunohistochemical analysis. Comparative genomic hybridization (CGH) analysis was used for cytogenetic analysis of ZQNK-29. Potential rearrangements of the immunoglobulin gene and Epstein-Barr virus (EBV) infection were examined by PCR and RT-PCR, respectively. RESULTS: ZQNK-29 cells express the phenotypic T-cell marker (CD3), T cell activation markers (HLA-DR), markers for both NK and cytotoxic T lymphocytes (TIA-1), and B-lineage marker CD20; however, expression of CD56 was not detected in expanded ZQNK-29 cells although this NK cell surface marker was used as one of selective cell surface markers for the initial isolation of NK/T cells. RT-PCR analysis showed that the pattern of gene expressions for infected EBV was latency type III, with the expressions of LMP1, EBNA-1, and EBNA-2; no rearrangements were found in the heavy-chain of the immunoglobulin gene or in the y chain of the T cell receptors (TCRs) gene. CGH analysis demonstrated that ZQNK-29 possessed an abnormal karyotype, 46XY, 1p (dist)+, 4p (dist)+, 4q (mid)-, 5q (mid)-, 9q (dist)+, 16p (dist)+, 16q (dist)+, 17p+, 17q (dist)+, 19q (dist)+, 20p+, 20q+, 21q+, and 22q+. Of these, 1p (dist)+, which has been confirmed to be mitochondrial DNA amplification, is believed to be mainly caused by EBV infection. CONCLUSIONS: ZQNK-29 is a well characterized premature human NK/T-cell lymphoma cell line with expression of the B-cell marker CD20 and will provide a useful pre-clinic model for characterization and potential therapeutic studies of the aggressive NK/T-cell lymphoma.

[Accuracy of different preoperative biopsy techniques in diagnosis of osteosarcomas and their value in prognostic evaluation].

OBJECTIVE: To study the difference in pathologic diagnostic accuracy among different histologic subtypes of osteosarcoma and different methods of preoperative biopsy, and the influence of diagnostic accuracy on prognosis of osteosarcoma. METHODS: The preoperative biopsies, complete clinical, radiological and pathological data of 347 pathologically confirmed osteosarcomas were evaluated. According to the Pathological Diagnostic and Technical Specifications, the accuracy of preoperative biopsies was divided into 6 grades. 1: definite diagnosis, 2: basically definite diagnosis, 3: significant diagnosis, 4: descriptive diagnosis, 5:inadequate sampling, 6:misdiagnosis. 1 to 3 were defined as successful diagnosis,while 4 to 6 were defined as unsuccessful diagnosis. RESULTS: Of the 347 biopsies, 252 were CT-guided needle biopsies by the radiologists, and 95 were core-needle biopsies by orthopedic surgeons without CT-guidance. The latter showed a higher overall biopsy success rate (97.9%) in all osteosarcomas. Biopsies by surgeons showed a higher biopsy success rate (95.4%) in conventional osteosarcoma, but lower success rate in telangiectatic (55.6%) and low-grade central osteosarcomas (63.7%). The accuracy of pathologic diagnosis of preoperative biopsy was related to patients' age, serum AKP level, imaging diagnosis, method of biopsy and the subtype of osteosarcoma. Comparing the groups with successful and unsuccessful diagnosis, there were significant differences in recurrence rate and mortality after operation (P<0.01). CONCLUSIONS: The accuracy of pathologic diagnosis of preoperative biopsy are related to recurrence rate and mortality after operation. Biopsy by orthopedic surgeons without CT-guidance is reliable and safe, followed by primary diagnosis at frozen section and final diagnosis by routine pathologic sections for osteosarcomas located in the long bones of the extremities. Close integration of the preoperative pathologic diagnosis with clinical and radiological data will improve the accuracy of diagnosis.

HtrA1 downregulation induces cisplatin resistance in lung adenocarcinoma by promoting cancer stem cell-like properties.

Cisplatin (CDDP) resistance usually develops during lung adenocarcinoma (LAC) therapy. However, the comprehensive mechanisms remain largely unclear. In this study, we first established a CDDP-resistant LAC cell line-A549/CDDP from its parental cell line-A549. The results showed that CDDP resistance in A549/CDDP cells correlates with acquirement of cancer stem cell-like properties (increased percentage of CD133-expressing subpopulation, sphere formation and levels of some pluripotency-associated markers). HtrA1 expression at both mRNA and protein levels was reduced in CDDP-resistant A549/CDDP cells compared with that in A549 cells. Ectopic expression of HtrA1 in A549/CDDP cells reversed cancer stem cell-like properties and CDDP resistance. In A549 cells, stable knockdown of HtrA1 expression promoted cancer stem cell-like properties and CDDP insensitivity, however, these effects were blocked by inhibition of PI3K/Akt pathway using LY294002. Furthermore, HtrA1 knockdown could significantly stimulate PI3K/Akt signaling in A549 cells. In vivo studies, HtrA1 knockdown promoted tumorigenesis and conferred CDDP resistance in xenograft A549 tumors, which were reversed by intraperitoneal injection of LY294002. In conclusion, these results indicate that HtrA1 downregulation confers CDDP resistance by inducing cancer stem cell-like properties via PI3K/Akt-dependent pathway in A549 cells. Therefore, HtrA1 may be a potential target for overcoming CDDP resistance in LAC.

[Clinicopathologic differential diagnosis of giant cell-rich osteosarcoma and giant cell tumor of bone].

OBJECTIVE: To study the clinicopathologic features and differential diagnosis of giant cell-rich osteosarcoma (GCRO) and giant cell tumor of bone (GCT). METHODS: The clinical, radiologic, pathologic and immunohistochemical features of 18 cases of GCRO and 118 cases of GCT were evaluated. RESULTS: The mean age of patients with GCRO was 24.6 years. Fifteen of the 18 cases arose in the metaphysis of long bones. GCRO presented as a large poorly-defined mixed lytic and blastic mass, associated with cortical destruction and formation of large soft tissue component. Histologically, GCRO was characterized by a predominance of numerous osteoclast-like giant cells admixed with scanty osteoid which was formed by neoplastic cells in different levels of anaplasia and pleomorphism. In the 118 cases of GCT studied, the mean age of patients was 34.5 years. Most of them (108 cases) arose in the epiphyseal region of long bones. They usually presented as expansile eccentric and osteolytic lesions. Invasive GCT displayed local cortical destruction. Histologic examination of GCT revealed the presence of large number of osteoclast-like giant cells and mononuclear stromal cells. The mononuclear stromal cells possessed poorly defined cytoplasm, showed little cytological atypia and did not carry atypical mitotic figures. They were positive for p63 (83.9%, 99/118). Reactive bone could be observed at the periphery. CONCLUSIONS: GCRO represents a special form of osteosarcoma which shows overlapping clinicopathologic features with invasive GCT. The presence of nuclear atypia, atypical mitoses and osteoid matrix produced directly by neoplastic cells are more in favor of GCRO. These features however may not be demonstrated in full in limited small biopsy samples. It is thus important to analyze all clinical, radiologic and pathologic features before a definitive diagnosis is made.

[Benign notochordal cell tumor of cervical vertebrae: a clinicopathologic analysis].

OBJECTIVE: To report 2 rare cases of benign notochordal cell tumor (BNCT), according to WHO classification of tumors of soft tissue and bone (4th edition). Their radiologic and clincopathologic features and differential diagnosis were investigated. METHODS: Two cases of BNCT were studied by retrospective review of the clinical, radiologic, pathologic and immunophenotypical findings. Related literatures were reviewed at the same time. RESULTS: Case 1 was a 53-year-old man, and case 2 was a 61-year-old woman. Radiographically, both patients presented with abnormal imaging findings in the fifth cervical vertebral body with the lesions located within the bone but without extra osseous mass. Histopathologically, the lesions lacked lobular architecture and extracellular myxoid matrix. The tumor cells were vacuolated and had centrally or peripherally placed round or oval nuclei with small nucleoli, mimicking mature adipocytes. No cytological atypia or mitotic figures were seen. The affected bone trabeculae were sclerotic and islands of bone marrow were often entrapped within the tumor. CONCLUSIONS: Although sharing similar anatomic distribution and immunophenotype to those of chordoma, BNCT has distinct radiologic and pathologic features and different treatment and prognosis. The differential diagnosis between BNCT and chordoma requires detailed clinical, radiologic and histopathologic evaluations.

[Clinicopathologic characteristics of primary Schwannoma of the bone].

OBJECTIVE: To evaluate the diagnostic criteria and morphologic difference of primary schwannoma from that of soft tissue schwannoma. METHODS: All neurogenic tumors of the bone in this hospital from 2002 to 2013 were reviewed, four cases of primary schwannoma arising from bone were selected. Their clinical features, radiologic appearance and pathologic findings were evaluated. Immunophenotyping was performed using EnVision method. RESULTS: All four cases had classic morphologic features and immunophenotype of conventional schwannoma. Compared with schwannoma of the soft tissue, primary bone schwannoma had the following features: benign radiological appearance, absence of capsule under light microscope, local infiltration of bone or destruction of bone cortex, occasionally involving extra-osseous soft tissue. Most tumors were solid, with less cystic degeneration. Histologically, the tumors were mainly composed of compact areas of spindle cells (Antoni A), and areas of hypercellularity could often be observed. CONCLUSIONS: Primary schwannoma of the bone is rare, usually arises within the long bones and flat bones. Compared to conventional soft tissue schwannoma, it shows different growth pattern, imaging and pathologic features; thus care should be exercised not to misdiagnose schwannoma of the bone as other primary low-grade malignant spindle cell sarcoma of the bone and to avoid unnecessary over-treatment.