Development and validation of a nomogram for predicting in-hospital mortality in ICU patients with infective endocarditis.

BACKGROUND: Infective endocarditis (IE) is a disease with high in-hospital mortality. The objective of the present investigation was to develop and validate a nomogram that precisely anticipates in-hospital mortality in ICU individuals diagnosed with infective endocarditis. METHODS: Retrospectively collected clinical data of patients with IE admitted to the ICU in the MIMIC IV database were analyzed using the Least Absolute Shrinkage and Selection Operator (LASSO) regression to identify potential hazards. A logistic regression model incorporating multiple factors was established, and a dynamic nomogram was generated to facilitate predictions. To assess the classification performance of the model, an ROC curve was generated, and the AUC value was computed as an indicator of its diagnostic accuracy. The model was subjected to calibration curve analysis and the Hosmer-Lemeshow (HL) test to assess its goodness of fit. To evaluate the clinical relevance of the model, decision-curve analysis (DCA) was conducted. RESULTS: The research involved a total of 676 patients, who were divided into two cohorts: a training cohort comprising 473 patients and a validation cohort comprising 203 patients. The allocation ratio between the two cohorts was 7:3. Based on the independent predictors identified through LASSO regression, the final selection for constructing the prediction model included five variables: lactate, bicarbonate, white blood cell count (WBC), platelet count, and prothrombin time (PT). The nomogram model demonstrated a robust diagnostic ability in both the cohorts used for training and validation. This is supported by the respective area under the curve (AUC) values of 0.843 and 0.891. The results of the calibration curves and HL tests exhibited acceptable conformity between observed and predicted outcomes. According to the DCA analysis, the nomogram model demonstrated a notable overall clinical advantage compared to the APSIII and SAPSII scoring systems. CONCLUSIONS: The nomogram developed during the study proved to be highly accurate in forecasting the mortality of patients with IE during hospitalization in the ICU. As a result, it may be useful for clinicians in decision-making and treatment.

Analysis of Combustion Instability of Methane-Air Premixed Swirling Flame Based on OH-PLIF Measurements.

A method for determining combustion instability using flame structure parameters is presented. A speaker is used to provide controllable external excitation for the combustion system. The experimental object is a methane-air swirl premixed flame. The flame structure parameters such as height, width, and flame surface density extracted from the hydroxyl planar laser-induced fluorescence image were used to analyze combustion instability at different equivalence ratios (0.8-1.2) and inlet flow rates. It is confirmed that the inflection point of the flame structure parameters corresponds to the evolution of combustion instability verified by the flame transfer function. The results show that with the increase of inlet velocity v, the flame aspect ratio h/b, average OH* concentration, and surface density Σ gradually decrease. The thickness δ of the flame brush shows an increasing trend under the same conditions. With the increase of equivalence ratio Φ, the average OH* concentration and flame surface density Σ increase continuously. The changing trend of flame brush thickness decreases first and then increases to a peak. Finally, it continues to decline after reaching the peak. The flame responds strongly to the sound field when the equivalence ratio is 0.9 and 1.0. In the range of 80-240 Hz, the flame response near 110 and 190 Hz is stronger at each equivalence ratio (0.8-1.0). When the equivalent ratio is 0.9 and 1.0, the amplitude fluctuations of the flame transfer function are much larger than those under other conditions. Meanwhile, the specific performances of the flame structure parameters are that the flame height, average OH* concentration, and flame surface density decrease, and the flame brush thickness increases. These results can be used as a basis for judging combustion instability. This method proves that the parameter information monitored during the flame combustion process can be used to judge the changes in combustion conditions and can adjust the corresponding conditions more accurately and quickly.

Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model.

Familial hypertrophic cardiomyopathy (HCM, OMIM: 613690) is the most common cardiomyopathy in China. However, the underlying genetic etiology of HCM remains elusive. We previously identified a myosin heavy chain 7 (MYH7) gene heterozygous variant, NM_000257.4: c.G2468A (p.G823E), in a large Chinese Han family with HCM. In this family, variant G823E cosegregates with an autosomal dominant disorder. This variant is located in the lever arm domain of the neck region of the MYH7 protein and is highly conserved among homologous myosins and species. To verify the pathogenicity of the G823E variant, we produced a C57BL/6N mouse model with a point mutation (G823E) at the mouse MYH7 locus with CRISPR/Cas9-mediated genome engineering. We designed gRNA targeting vectors and donor oligonucleotides (with targeting sequences flanked by 134 bp of homology). The p.G823E (GGG to GAG) site in the donor oligonucleotide was introduced into exon 23 of MYH7 by homology-directed repair. A silenced p.R819 (AGG to CGA) was also inserted to prevent gRNA binding and re-cleavage of the sequence after homology-directed repair. Echocardiography revealed left ventricular posterior wall (LVPW) hypertrophy with systole in MYH7 G823E/- mice at 2 months of age. These results were likewise validated by histological analysis (Figure 3). These results demonstrate that the G823E variant plays an important role in the pathogenesis of HCM. Our findings enrich the spectrum of MYH7 variants linked to familial HCM and may provide guidance for genetic counseling and prenatal diagnosis in this Chinese family.

Establishment and Evaluation of a Porcine Vein Graft Disease Model.

Venous graft disease (VGD) is the leading cause of coronary artery bypass graft (CABG) failure. Large animal models of CABG-VGD are needed for the investigation of disease mechanisms and the development of therapeutic strategies. To perform the surgery, we enter the cardiac chamber through the third intercostal space and carefully dissect the internal mammary vein and immerse it in normal saline. The right main coronary artery is then treated for ischemia. The target vessel is incised, a shunt plug is placed, and the distal end of the graft vein is anastomosed. The ascending aorta is partially blocked, and the proximal end of the graft vein is anastomosed after perforation. The graft vein is checked for patency, and the proximal right coronary artery is ligated. CABG surgery is performed in minipigs to harvest the left internal mammary vein for its use as a vascular graft. Serum biochemical tests are used to evaluate the physiological status of the animals after surgery. Ultrasound examination shows that the proximal, middle, and distal end of the graft vessel are unobstructed. In the surgical model, turbulent blood flow in the graft is observed upon histological examination after the CABG surgery, and venous graft stenosis associated with intimal hyperplasia is observed in the graft. The study here provides detailed surgical procedures for the establishment of a repeatable CABG-induced VGD model.

Associations of Clinical and Molecular Characteristics with the Response to Immune Checkpoint Blockade in Advanced Gastric Cancers.

Purpose: Immunotherapy provides a new treatment option for advanced gastric cancer (AGC). This study aims to explore the response markers of immunotherapy in AGCs. Methods: Next-generation sequencing was performed on 44 AGC patients who received immune checkpoint inhibitors and the associations between their outcomes after combination immunotherapy, and the clinicopathological/molecular characteristics were analyzed. Results: The current study cohort had a median progression-free survival (PFS) of 5.9 months, an overall survival (OS) of 12.1 months, and an objective response rate (ORR) of 36.4%. Through multivariable analysis of the clinical characteristics, primary tumor resection (HR = 2.66, 95% CI: 1.06-6.70, p=0.037) and increased proportion of lymphocytes after combination immunotherapy (HR = 0.40, 95% CI: 0.16-0.99, p=0.048) were revealed as independent predictors for patient outcomes. All the 18 patients who underwent genetic profiling were microsatellite-stable with a median TMB of four mutations per Mb. ATM alterations, PI3K pathway mutations, increased TMB, and positive PD-L1 expression were associated with the increased trend of PFS and ORR. According to the combination of baseline lymphocyte count, ATM mutation, TMB status, and PD-L1 expression, patients were stratified into higher- and lower-risk groups, with the lower-risk group showing improved PFS (HR = 4.7e-10, 95% CI: 0-inf, p=0.02) and ORR (75% vs. 0%, p=0.007). Conclusion: Several highly relevant potential biomarkers predictive of immunotherapy response in AGC patients have been identified in this research.

Efficacy and safety evaluation of neoadjuvant immunotherapy plus chemotherapy for resectable non-small cell lung cancer in real world.

Objectives: The combination of immunotherapy and chemotherapy has shown great efficacy in stage IV non-small cell lung cancer (NSCLC) and is now widely used in clinical treatment strategy. This study retrospectively analyzed the efficacy and safety of neoadjuvant immunotherapy plus chemotherapy for resectable NSCLC in real world. Methods: We retrospectively analyzed patients with NSCLC who received neoadjuvant immunotherapy plus chemotherapy and underwent complete tumor resection in Zhejiang Cancer Hospital between January 2019 and January 2021. Tumor staging was based on the eighth TNM classification system of the American Joint Committee on Cancer staging criteria. The safety and toxicity (including operative and postoperative complications) and the efficacy [including objective response rate (ORR), disease control rate (DCR), tumor major pathological remission (MPR), and pathological complete response (pCR)] were evaluated. Results: In total, 368 patients with NSCLC were administered with neoadjuvant immunotherapy. Of them, 211 patients were included in this retrospective study. Most patients had stage II-III disease, with 75 (35.5%) and 88 (41.7%) patients diagnosed with clinical stages IIB and IIIA, respectively. A total of 206 patients (97.6%) received at least two doses of neoadjuvant immunotherapy plus chemotherapy. In addition, 121 patients (57.3%) have achieved MPR, and 80 patients (37.9%) have achieved pCR, with ORR at 69.2% and DCR at 97.7%. Treatment-related adverse events occurred in 46.4% of patients, and the incidence rate of grade 3 or 4 treatment-related adverse events was 13.3% (13/98). Moreover, adverse events of any grade of surgical complication occurred in 15.6% of patients. One-year disease-free survival was 80.6% (170/211). Conclusions: Neoadjuvant immunotherapy plus chemotherapy has significant efficacy with a high pCR and tolerable adverse effects for patients with resectable stage II-III NSCLC in real world.

Protein Tyrosine Kinase 7 Regulates EGFR/Akt Signaling Pathway and Correlates With Malignant Progression in Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is associated with high invasiveness, high metastatic occurrence and poor prognosis. Protein tyrosine kinase 7 (PTK7) plays an important role in multiple cancers. However, the role of PTK7 in TNBC has not been well addressed. This study was performed to evaluate the role of PTK7 in the progression of TNBC. METHODS: Correlation of PTK7 expression with clinicopathological parameters was assessed using tissue microarray immunohistochemistry (IHC) staining in 280 patients with breast cancer. PTK7 expression in TNBC (MDA-MB-468, MDA-MB-436 and MDA-MB-231) and non-TNBC (MCF7 and SK-BR-3) breast cancer cell lines were examined using immunoblotting assay. PTK7 correlated genes in invasive breast carcinoma were analyzed using cBioPortal breast cancer datasets including 1,904 patients. PTK7 overexpressed or knockdown TNBC cell lines (MDA-MB-468 and MDA-MB-436) were used to analyze the potential roles of PTK7 in TNBC metastasis and tumor progression. A TNBC tumor bearing mouse model was established to further analyze the role of PTK7 in TNBC tumorigenicity in vivo. RESULTS: PTK7 is highly expressed in breast cancer and correlates with worse prognosis and associates with tumor metastasis and progression in TNBC. Co-expression analysis and gain- or loss-of-function of PTK7 in TNBC cell lines revealed that PTK7 participates in EGFR/Akt signaling regulation and associated with extracellular matrix organization and migration genes in breast cancer, including COL1A1, FN1, WNT5B, MMP11, MMP14 and SDC1. Gain- or loss-of-function experiments of PTK7 suggested that PTK7 promotes proliferation and migration in TNBC cell lines. PTK7 knockdown MDA-MB-468 cell bearing mouse model further demonstrated that PTK7-deficiency inhibits TNBC tumor progression in vivo. CONCLUSION: This study identified PTK7 as a potential marker of worse prognosis in TNBC and revealed PTK7 promotes TNBC metastasis and progression via EGFR/Akt signaling pathway.

Integrative clinical and molecular analysis of advanced biliary tract cancers on immune checkpoint blockade reveals potential markers of response.

BACKGROUND: While there have been encouraging preliminary clinical results for immune checkpoint inhibitors (ICIs) in BTCs, it remains a challenge to identify the subset of patients who may benefit. In this study, we evaluated the efficacy of ICI treatment in patients with advanced BTCs, and explored potential biomarkers that are predictive of response. METHODS: The study enrolled 26 patients with advanced microsatellite stable BTCs (15 with gallbladder cancers [GCs] and 11 with intrahepatic cholangiocarcinoma [ICCs]) who received ICI treatment. Targeted next-generation sequencing (NGS) was performed on tumor tissue samples collected from 17 patients. Clinical and genomic characteristics were assessed for the correlation with clinical outcome. RESULTS: Analysis of the baseline clinical characteristics showed that performance score (PS) of 0 was associated with a better prognosis than PS of 1 (HR = 1.08 × 109 ; 95% CI, 0∼Inf; P = .002). No significant correlations were found between clinical outcome and inflammation-related indicators. NGS profiling of the available tumor tissues, revealed largely non-overlapping somatic alterations between GCs and ICCs. Mutations in LRP1B (HR = 0.26; 95% CI, 0.06-1.21; P = .067), ERBB2 (HR = 0.15; 95% CI, 0.02-1.19; P = .04), or PKHD1 (HR < 0.01; 95% CI, 0-Inf; P = .04) showed strong association with increased progression-free survival (PFS) benefit. Subsequent analysis showed that alterations in the RTK-RAS pathway were associated with improved outcomes (HR = 0.12; 95% CI, 0.02-0.63; P = .003). Tumor mutation burden (TMB) was higher in patients with GC than those with ICC, and was associated with LRP1B mutations (P = .032). We found that patients with 19q amplification (19q Amp) and 9p deletion (9p Del) had poor PFS outcome (19q Amp, HR = 15.4; 95% CI, 2.7-88.5; P < .001; 9p Del; HR = 4.88 × 109 ; 95% CI, 0-Inf; P < .001), while those with chromosomal instability derived PFS benefit (HR = 0.24; 95% CI, 0.05-1.17; P = .057). CONCLUSION: Our study identified several potential clinical and genomic features that may serve as biomarkers of clinical response to ICIs in advanced BTCs patients. A larger sample size is required for further verification.

Multi-region exome sequencing reveals genomic evolution from preneoplasia to lung adenocarcinoma.

There has been a dramatic increase in the detection of lung nodules, many of which are preneoplasia atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA) or invasive adenocarcinoma (ADC). The molecular landscape and the evolutionary trajectory of lung preneoplasia have not been well defined. Here, we perform multi-region exome sequencing of 116 resected lung nodules including AAH (n = 22), AIS (n = 27), MIA (n = 54) and synchronous ADC (n = 13). Comparing AAH to AIS, MIA and ADC, we observe progressive genomic evolution at the single nucleotide level and demarcated evolution at the chromosomal level supporting the early lung carcinogenesis model from AAH to AIS, MIA and ADC. Subclonal analyses reveal a higher proportion of clonal mutations in AIS/MIA/ADC than AAH suggesting neoplastic transformation of lung preneoplasia is predominantly associated with a selective sweep of unfit subclones. Analysis of multifocal pulmonary nodules from the same patients reveal evidence of convergent evolution.

Genomic analysis of oesophageal squamous-cell carcinoma identifies alcohol drinking-related mutation signature and genomic alterations.

Approximately half of the world's 500,000 new oesophageal squamous-cell carcinoma (ESCC) cases each year occur in China. Here, we show whole-genome sequencing of DNA and RNA in 94 Chinese individuals with ESCC. We identify six mutational signatures (E1-E6), and Signature E4 is unique in ESCC linked to alcohol intake and genetic variants in alcohol-metabolizing enzymes. We discover significantly recurrent mutations in 20 protein-coding genes, 4 long non-coding RNAs and 10 untranslational regions. Functional analyses show six genes that have recurrent copy-number variants in three squamous-cell carcinomas (oesophageal, head and neck and lung) significantly promote cancer cell proliferation, migration and invasion. The most frequently affected genes by structural variation are LRP1B and TTC28. The aberrant cell cycle and PI3K-AKT pathways seem critical in ESCC. These results establish a comprehensive genomic landscape of ESCC and provide potential targets for precision treatment and prevention of the cancer.

Improving the Accuracy of Mesothelioma Diagnosis in China.

INTRODUCTION: In the Western world, malignant mesothelioma (MM) is most prevalent in the pleura of older males who have been professionally exposed to asbestos. Information about MM from rapidly industrializing countries such as China is minimal. There is concern that a proportion of MM diagnoses in China may be incorrect because most Chinese physicians do not have experience diagnosing this rare cancer. We recently reported an unusually high incidence of peritoneal MM among eastern Chinese female patients. Here, we review the accuracy of MM diagnoses in China and provide suggestions to improve the accuracy of diagnosis. METHODS: We reviewed 92 pathological diagnosis of MM in 2002-2015 from two reference centers in the province of Zhejiang in eastern China. We performed a large set of immunohistochemistry analyses to increase the reliability of the diagnosis. RESULTS: We confirmed the MM diagnosis in 12 of 34 of the pleural tumors (35.3%), in 38 of 56 of the peritoneal tumors (67.9%), and in two of two of the MMs of the tunica vaginalis (100%). MMs were characterized by tumor cells showing nuclear Wilms tumor 1 and calretinin staining and by strong membranous staining for cytokeratin CAM5.2. The results of staining for the epithelial markers carcinoembryonic antigen, thyroid transcription factor-1, MOC31, BerEP4, p63, p40, paired box 8, ER and PR were negative. BRCA1 associated protein 1 nuclear staining was lost in percentages similar to what has been reported for samples from Western countries. CONCLUSIONS: Our findings suggest that MM-especially in its pleural localization-is often misdiagnosed in eastern China. Identifying pitfalls and possible solutions in the pathological diagnosis of MM will affect both the standard of care and research in China.

C-Met as a Molecular Marker for Esophageal Squamous Cell Carcinoma and Its Association with Clinical Outcome.

BACKGROUND: Epidermal growth factor receptor (EGFR), c-Met, and human epidermal growth factor receptor 2 (HER2) are overexpressed in a variety of human cancers, and may serve as biomarkers for disease prognosis. We examined whether high expression of these molecular markers correlates with poor disease prognosis in esophageal squamous cell cancer (ESCC). MATERIALS AND METHODS: Expression of EGFR, c-Met, and HER2 protein was detected by immunohistochemistry (IHC) in 180 paraffin-embedded tissue samples from stage IIB-IIIC ESCC patients. The overall survival (OS) rates were calculated according to the Kaplan-Meier method, and the log-rank test was used to evaluate differences between survival curves. The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS: The median survival of all patients was 46 months. There was no significant difference in OS in terms of HER2 and EGFR status (P = 0.177 and P=0.061, respectively). However, there was a significant difference in OS between c-Met high expression patients and c-Met low expression or negative patients (median: 41.9 months vs. 56.7 months; P = 0.001). Multivariate analysis also showed that, of the covariates analyzed, c-Met high expression was the only prognostic factor for OS (HR: 0.459 [95 % confidence interval: 0.287-0.733]; P = 0.001). Patients with ESCC that had concurrent overexpression of EGFR and c-Met had significantly worse survival than ESCC that displayed overexpression of either EGFR or c-Met individually or that did not have overexpression of either protein (P=0.000). CONCLUSIONS: Overexpression of HER2 and EGFR individually is not significantly associated with poor prognosis in ESCC. High expression of c-Met may be indicative of a poorer prognosis in ESCC. In order to promote efficient and rapid development of therapeutic methods in ESCC, further studies are necessary to explore the role of c-Met.

Inhibitor Response to HER2 G776(YVMA) In-frame Insertion in HER2-positive Breast Cancer.

Human epidermal growth factor receptor 2 (HER2/neu or HER2) has long been recognized as an attractive therapeutic target for breast cancer. The YVMA in-frame insertion at the residue G776 (G776(YVMA)) of HER2 kinase domain is a frequently observed mutation that can largely shift drug sensitivity in targeted therapy of HER2-positive breast cancer. Here, the molecular mechanism and biological significance of tyrosine kinase inhibitor (TKI) response to HER2 G776(YVMA) insertion were investigated in detail. An established protocol that integrated bioinformatics modeling and kinase inhibition assay was employed to examine the structural basis, energetic property, and biological implication underlying the intermolecular interaction between HER2 kinase domain and three representative TKIs, i.e. two FDA-approved drugs lapatinib and gefitinib as well as a pan-kinase inhibitor staurosporine. It was found that the insertion mutation can moderately sensitize lapatinib, but cannot influence the inhibitory capability of staurosporine essentially, suggesting that the two inhibitors exhibit differentiated selectivity between the wild-type HER2 (HER2(WT)) and HER2 G776(YVMA) (HER2(YVMA)) variant. In addition, the gefitinib, which was originally developed as EGFR inhibitor, only possesses modest potency against its noncogate target HER2(WT), and the insertion can further impair the potency, causing a strong resistance for the agent to HER2(YVMA) variant.

Vascular invasion is an independent prognostic factor for distant recurrence-free survival in papillary thyroid carcinoma: a matched-case comparative study.

OBJECTIVE: It is still unclear whether the clinicopathological and outcome characteristics of vascular invasion (VI) (+) papillary thyroid carcinoma (PTC) differ from VI (-) PTC. This study aims to establish distinguishing features of patients with VI (+) and VI (-) PTC and to investigate the biological and clinical aggressiveness of the disease in these patient groups. DESIGN: A matched-case comparative study. METHODS: 412 patients (VI (+) PTC study group n=103, and VI (-) PTC control group n=309). These two patient groups were matched 1:3 for variables of age, gender, histological variants, tumour/node/metastasis (TNM) staging and approximate duration of follow-up. Clinicopathological factors and prognosis were compared across the two patient groups. RESULTS: The median age at the time of diagnosis was 42.0 years, and 68.9% were females. Across the patient groups, the incidence of tumour multifocality in patients with VI (+) PTC was slightly higher than in those with VI (-) PTC (p=0.049). In addition, when undergoing more aggressive therapy regimens patients with VI (+) PTC showed decreased distant recurrence-free survival (DRFS), but not regional recurrence-free survival (RRFS) and disease-specific survival (DSS) compared with patients who were VI (-). VI was found to be an independent predictor of DRFS, combined with tumour size >3 cm and total thyroidectomy. CONCLUSIONS: VI was an independent risk factor for DRFS, necessitating the need for appropriate postoperative treatment and careful follow-up.

Expression levels of HER2 and MRP1 are not prognostic factors of long-term survival in 829 patients with esophageal squamous cell carcinoma.

Esophageal squamous cell carcinoma (ESCC) is the eighth most frequent neoplasm in China. However, the expression levels of human epidermal growth factor receptor 2 (HER2) and multidrug resistance protein 1 (MRP1) in patients with ESCC remain to be determined. In the present study, 829 ESCC cases were evaluated using immunohistochemistry. The association between the expression levels of HER2 and MRP1 and the patient's clinicopathological factors was analyzed using Fisher's exact test or χ2 test. Univariate analysis was performed via Kaplan-Meier survival curves, while the Cox proportional hazard model was used for multivariate analysis. A significant correlation was observed between the expression levels of HER2 and the patient's gender (P<0.050), tumor size (P=0.013) and venous/lymphatic invasion (P=0.039). However, no significant correlation was identified between the expression levels of MRP1 and the clinicopathological factors of the patients. In univariate analysis, gender, differentiation, depth of invasion, clinical stage, adjuvant radiotherapy or chemotherapy and lymph node metastasis were significantly correlated with progression-free survival (PFS) and overall survival (OS) in patients with ESCC (P<0.050). The graphical representation of the Kaplan-Meier estimate curves suggested that the expression levels of HER2 or MRP1 did not exert any influence on prognosis (log-rank test, P>0.050). In multivariate analysis, tumor location, gender, clinical stage, differentiation and lymph node metastasis were identified as independent factors of prognosis in patients with ESCC (P<0.050). However, the expression levels of HER2 or MRP1 were not independently associated with PFS or OS in these patients. In conclusion, the present large-scale study demonstrates that the protein expression levels of HER2 and MRP1 does not exert any influence on the prognosis of ESCC.

Epidermal growth factor receptor protein overexpression and gene amplification are associated with aggressive biological behaviors of esophageal squamous cell carcinoma.

Alterations of the epidermal growth factor receptor (EGFR), including overexpression or gene mutations, contribute to the malignant transformation of human epithelial cells. The aim of this study was to assess EGFR overexpression or gene amplification in esophageal squamous cell carcinoma (ESCC) tissue samples and investigate their correlations with biological behaviors. Tissue specimens from 56 patients with surgically resected ESCC were obtained for immunohistochemical analysis of EGFR expression and fluorescence in situ hybridization analysis of EGFR amplification. The data were statistically analyzed to determine the associations with patient clinicopathological and survival data. EGFR was overexpressed in 30 of the 56 (53.6%) ESCC samples and was associated with poor tumor differentiation (P=0.047). EGFR amplification was detected in 13 cases (23.2%) and was associated with advanced pathological stage (P=0.042) and tumor lymph node metastasis (P=0.002). The univariate analysis identified no association between EGFR overexpression and the overall survival (OS) of the patients. By contrast, EGFR amplification predicted ESCC prognosis (P=0.031), while the multivariate analysis revealed a marginal statistical significance for the association between EGFR amplification and OS (P=0.056). EGFR overexpression and increased EGFR copy number were common events in ESCC and contributed to malignant biological behaviors, including tumor dedifferentiation and lymph node metastasis. EGFR amplification may therefore be useful in predicting OS in patients with ESCC.

Concurrent radiotherapy with gefitinib in elderly patients with esophageal squamous cell carcinoma: Preliminary results of a phase II study.

The survival rate associated with esophageal cancer is very poor due to diagnosis at advanced stages of disease and insensitivity to chemotherapy. This study investigated the efficacy of gefitinib combination with radiation in 20 elderly patients with esophageal squamous cell carcinoma (ESCC) who were not eligible for platinum-based chemotherapy. Immunohistochemistry was performed to analyze epidermal growth factor receptor (EGFR) expression, and the amplified refractory mutation system was used to detect EGFR mutations. Treatment response was assessed by endoscopy and computed tomography. Treatment toxicity was evaluated using the National Cancer Institute's Common Toxicity Criteria. The data showed that among these 20 patients, 5 experienced a complete response (CR), 13 a partial response (PR), and 2 had stable disease. The overall response rate (CR + PR) was 90%, the median overall survival (OS) was 14.0 months (95% confidence interval [CI]: 10.0-17.9 months), and the median progression-free survival was 7.0 months (95% CI: 0-17.2 months). Patients with good Eastern Cooperative Oncology Group performance status, never smoking, and EGFR mutated tumors had the best OS (14.0, 14.0, and 17.0 months, respectively). Treatment-related grade 3/4 toxicity occurred in five patients. No case of grade 3/4 impaired liver function or hematological toxicity was observed. Concurrent radiotherapy with gefitinib is effective and tolerable in elderly ESCC patients.

Abnormal Expression of DNA Double-Strand Breaks Related Genes, ATM and GammaH2AX, in Thyroid Carcinoma.

ATM and γH2AX play a vital role in the detection of DNA double-strand breaks (DSB) and DNA damage response (DDR). This study aims to investigate ATM and γH2AX expression in thyroid cancer and discuss possible relationship between thyroid function tests and DNA damage. The expression of ATM and γH2AX was detected by immunohistochemistry in 30 cases of benign nodular goiter, 110 cases of well differentiated thyroid cancer, 22 cases of poorly differentiated thyroid cancer, and 21 cases of anaplastic thyroid cancer. Clinicopathological features, including differentiation stages, distant metastasis, lymph node metastasis, T classification, TNM stage, and tests of thyroid functions (TPOAb, Tg Ab, T3, FT3, T4, FT4, TSH, and Tg), were reviewed and their associations with γH2AX and ATM were analyzed. γH2AX and ATM expressed higher in thyroid cancer tissues than in benign nodular goiter and normal adjacent tissues. γH2AX was correlated with ATM in thyroid cancer. Both γH2AX and ATM expression were associated with FT3. γH2AX was also associated with T classification, TNM stage, FT4, TSH, and differentiation status. Therefore both of ATM and γH2AX seem to correlate with thyroid hormones and γH2AX plays a role in the differentiation status of thyroid cancer.

Mesoporous silica nanospheres decorated with CdS nanocrystals for enhanced photocatalytic and excellent antibacterial activities.

Uniform SiO2@CdS mesoporous nanospheres with an average diameter of 300 nm have been synthesized successfully by a facile process. The as-prepared mesoporous composite nanospheres have a BET-specific surface area of 640 m(2) g(-1) and an average pore size of 2.82 nm. The results demonstrated that more than 60% Rhodamine B (RhB) dye in solution (4.8 mg L(-1), 50 mL) could be removed by adsorption in the dark for 30 min using the as-prepared SiO2@CdS mesoporous nanospheres (40 mg). The as-prepared SiO2@CdS mesoporous nanospheres have a mesoporous nanostructure, suggesting a higher specific surface area and resulting in a strong adsorption ability. In addition, the mesoporous silica was decorated with ca. 5 nm CdS nanocrystals, which showed excellent photocatalytic activity under visible light and could rapidly remove most of the RhB molecules from a pollutant solution under visible light irradiation. Furthermore, the mesoporous SiO2@CdS nanospheres synthesized by the present protocol exhibited excellent antibacterial activity.