Preoperative Prediction of Ki-67 Labeling Index By Three-dimensional CT Image Parameters for Differential Diagnosis Of Ground-Glass Opacity (GGO)

The aim of this study was to predict Ki-67 labeling index (LI) preoperatively by three-dimensional (3D) CT image parameters for pathologic assessment of GGO nodules. Diameter, total volume (TV), the maximum CT number (MAX), average CT number (AVG) and standard deviation of CT number within the whole GGO nodule (STD) were measured by 3D CT workstation. By detection of immunohistochemistry and Image Software Pro Plus 6.0, different Ki-67 LI were measured and statistically analyzed among preinvasive adenocarcinoma (PIA), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IAC). Receiver operating characteristic (ROC) curve, Spearman correlation analysis and multiple linear regression analysis with cross-validation were performed to further research a quantitative correlation between Ki-67 labeling index and radiological parameters. Diameter, TV, MAX, AVG and STD increased along with PIA, MIA and IAC significantly and consecutively. In the multiple linear regression model by a stepwise way, we obtained an equation: prediction of Ki-67 LI=0.022*STD+0.001* TV+2.137 (R=0.595, R’s square=0.354, p<0.001), which can predict Ki-67 LI as a proliferative marker preoperatively. Diameter, TV, MAX, AVG and STD could discriminate pathologic categories of GGO nodules significantly. Ki-67 LI of early lung adenocarcinoma presenting GGO can be predicted by radiologic parameters based on 3D CT for differential diagnosis.     

肺磨玻璃结节中ki-67的表达及与P53,EGFR,CEA相关性研究

目的:为探究不同病理类型的肺磨玻璃结节(ground-glass opacity,GGO)中ki-67的表达情况及其与肺癌相关标志物p53、p63、EGFR等表达的相关性。方法:收集从2012年10月至2014年10月我院胸外科收治的254例GGO病人的临床病史、影像、病理及血常规等资料予以回顾性分析。结果:Ki-67表达量从良性组(n=66),不典型腺瘤样增生(atypical adenomatous hyperplasia,AAH,n=27),到原位癌(adenocarcinoma in situ,AIS,n=11),微浸润腺癌(minimally invasive adenocarcinoma,MIA,n=108),最后到浸润性腺癌(invasive adenocarcinoma,IAC,n=42)即随着早期肺癌的演进过程不断增高。Ki-67与各标志物的相关系数为0.386(p53,P0.001)、0.227(EGFR,P=0.024)、0.441(CEA,P0.001)。通过ROC曲线分析得到ki-67来判别良恶性GGO的曲线下面积和最佳阈值,也得到了早期肺癌演进过程中ki-67阈值变化。恶性GGO组全血细胞中平均单核细胞含量低于良性组GGO,且差异有统计学意义。结论:ki-67表达量在不同病理类别的GGO中有显著性差异,且在肺癌演进过程中依次增高,可作为鉴别早期肺癌不同病理类型的参考依据和预后因子;ki-67与P53、EGFR及CEA的表达具有一定的相关性。     

Quantitative CT Analysis of Pulmonary Ground-Glass Opacity Nodules for the Distinction of Invasive Adenocarcinoma from Pre-Invasive or Minimally Invasive Adenocarcinoma

Objectives

We aimed to analyze the CT findings of ground-glass opacity nodules diagnosed pathologically as adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma in order to investigate whether quantitative CT parameters enable distinction of invasive adenocarcinoma from pre-invasive or minimally invasive adenocarcinoma.

Methods

We reviewed CT images and pathologic specimens from 191 resected ground-glass opacity nodules with little or no solid component at CT. Nodule size, volume, density, mass, skewness/kurtosis, and CT attenuation values at the 2.5^th–97.5^th percentiles on histogram, and texture parameters (uniformity and entropy) were assessed from CT datasets.

Results

Of 191 tumors, 38 were AISs (20%), 61 were MIAs (32%), and 92 (48%) were invasive adenocarcinomas. Multivariate logistic regression analysis helped identify the 75^th percentile CT attenuation value (P = 0.04) and entropy (P<0.01) as independent predictors for invasive adenocarcinoma, with an area under the receiver operating characteristic curve of 0.780.

Conclusion

Quantitative analysis of preoperative CT imaging metrics can help distinguish invasive adenocarcinoma from pre-invasive or minimally invasive adenocarcinoma.     

DNA methylation changes in atypical adenomatous hyperplasia, adenocarcinoma in situ, and lung adenocarcinoma

Background

Aberrant DNA methylation is common in lung adenocarcinoma, but its timing in the phases of tumor development is largely unknown. Delineating when abnormal DNA methylation arises may provide insight into the natural history of lung adenocarcinoma and the role that DNA methylation alterations play in tumor formation.

Methodology/Principal Findings

We used MethyLight, a sensitive real-time PCR-based quantitative method, to analyze DNA methylation levels at 15 CpG islands that are frequently methylated in lung adenocarcinoma and that we had flagged as potential markers for non-invasive detection. We also used two repeat probes as indicators of global DNA hypomethylation. We examined DNA methylation in 249 tissue samples from 93 subjects, spanning the putative spectrum of peripheral lung adenocarcinoma development: histologically normal adjacent non-tumor lung, atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS, formerly known as bronchioloalveolar carcinoma), and invasive lung adenocarcinoma. Comparison of DNA methylation levels between the lesion types suggests that DNA hypermethylation of distinct loci occurs at different time points during the development of lung adenocarcinoma. DNA methylation at CDKN2A ex2 and PTPRN2 is already significantly elevated in AAH, while CpG islands at 2C35, EYA4, HOXA1, HOXA11, NEUROD1, NEUROD2 and TMEFF2 are significantly hypermethylated in AIS. In contrast, hypermethylation at CDH13, CDX2, OPCML, RASSF1, SFRP1 and TWIST1 and global DNA hypomethylation appear to be present predominantly in invasive cancer.

Conclusions/Significance

The gradual increase in DNA methylation seen for numerous loci in progressively more transformed lesions supports the model in which AAH and AIS are sequential stages in the development of lung adenocarcinoma. The demarcation of DNA methylation changes characteristic for AAH, AIS and adenocarcinoma begins to lay out a possible roadmap for aberrant DNA methylation events in tumor development. In addition, it identifies which DNA methylation changes might be used as molecular markers for the detection of preinvasive lesions.     

Deep learning for predicting subtype classification and survival of lung adenocarcinoma on computed tomography

ObjectivesThe subtype classification of lung adenocarcinoma is important for treatment decision. This study aimed to investigate the deep learning and radiomics networks for predicting histologic subtype classification and survival of lung adenocarcinoma diagnosed through computed tomography (CT) images.MethodsA dataset of 1222 patients with lung adenocarcinoma were retrospectively enrolled from three medical institutions. The anonymised preoperative CT images and pathological labels of atypical adenomatous hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, invasive adenocarcinoma (IAC) with five predominant components were obtained. These pathological labels were divided into 2-category classification (IAC; non-IAC), 3-category and 8-category. We modeled the classification task of histological subtypes based on modified ResNet-34 deep learning network, radiomics strategies and deep radiomics combined algorithm. Then we established the prognostic models in lung adenocarcinoma patients with survival outcomes. The accuracy (ACC), area under ROC curves (AUCs) and C-index were primarily performed to evaluate the algorithms.ResultsThis study included a training set (n = 802) and two validation cohorts (internal, n = 196; external, n = 224). The ACC of deep radiomics algorithm in internal validation achieved 0.8776, 0.8061 in the 2-category, 3-category classification, respectively. Even in 8 classifications, the AUC ranged from 0.739 to 0.940 in internal set. Further, we constructed a prognosis model that C-index was 0.892(95% CI: 0.846–0.937) in internal validation set.ConclusionsThe automated deep radiomics based triage system has achieved the great performance in the subtype classification and survival predictability in patients with CT-detected lung adenocarcinoma nodules, providing the clinical guide for treatment strategies.     

Preoperative Flexible Bronchoscopy in Patients with Persistent Ground-Glass Nodule

There are no accurate data on the diagnostic value of preoperative flexible bronchoscopy (FB) for persistent ground-glass nodule (GGN) of the lung. We evaluated the value of preoperative FB in patients with suspected GGN-type lung cancer. We retrospectively searched a database for subjects who had ‘ground-glass opacity’, ‘non-solid nodule’, ‘part-solid nodule’, or ‘sub-solid nodule’ on chest computed tomography reports between February 2004 and March 2012. Patients who had infiltrative ground-glass opacity lesions, mediastinal lymphadenopathy, or pleural effusion, focal ground-glass opacity lesions >3 cm, and were lost to follow-up were excluded. We assessed the diagnostic value of preoperative FB in patients with persistent GGNs who underwent surgical resection. In total, 296 GGNs were evaluated by FB in 264 patients with persistent GGNs who underwent preoperative FB and surgical resection. The median size of the GGNs was 18 mm; 135 (46%) were pure GGN and 161 (54%) were part-solid GGN. No visible tumor or unsuspected endobronchial metastasis was identified by preoperative FB. Only 3 (1%, 3/208) GGNs were identified preoperatively as malignant by bronchial washing cytology; all were part-solid GGNs. No other etiology was identified by FB. Of the GGNs, 271 (91%) were subsequently confirmed as malignant and 25 (9%) were confirmed as benign at surgical resection. Consequently, the overall diagnostic sensitivity and negative predictive value of preoperative FB on a per-nodule basis was 1% (3/271) and 8% (25/293), respectively. The preoperative FB did not change the surgical strategy. Preoperative FB did not add much to the evaluation of persistent GGNs of the lung. Routine preoperative FB may have limited value in surgical candidates with small persistent pure GGNs.     

Meningiomas of the Cerebellopontine Angle: Radiological Differences in Tumors with Internal Auditory Canal Involvement and Their Influence on Surgical Outcome

This study explored the clinical, radiological, and pathological characteristics of cerebellopontine angle (CPA) meningiomas with internal auditory canal (IAC) involvement. The pre- and postoperative MR images of 193 consecutive patients with pathologically diagnosed meningioma centered around the IAC were analyzed, focusing on changes in the IAC, maximal axial tumor volume, peritumoral brain edema, and postoperative residual tumor. Patient age, sex, tumor volume, postoperative residual tumor, and pathological subtype were compared in patients with and without IAC involvement by the tumor and among the different types of IAC involvement. The results showed that the 71 patients (36.8%) with IAC involvement had a higher ratio of peritumoral edema (χ²=5.922, P=0.015), postoperative residual tumor (χ²=22.183, P< 0.001), and a predominance of the meningothelial subtype (χ²=5.89, P=0 .015). Peritumoral edema was a risk factor for IAC involvement (P=0.016, OR=2.186). Radiologically, IAC involvement could be distinguished as intruding (31%, 22/71), filled (29.6%, 21/71), and dilated (39.4%, 28/71). Patients with intruding IAC were significantly older (54.5±9.54 years, P=0.021) and had the lowest postoperative residual tumor values (42%, χ²=7.865, P= 0.005), while those with filled IAC were more likely to be female (95%, χ²=9.404, P=0.009).Our observations provide the basis for a morphological classification of IAC involvement by CPA meningiomas and further insight into the clinical features of these tumors.     

Normal Lung Quantification in Usual Interstitial Pneumonia Pattern: The Impact of Threshold-based Volumetric CT Analysis for the Staging of Idiopathic Pulmonary Fibrosis

BackgroundAlthough several computer-aided computed tomography (CT) analysis methods have been reported to objectively assess the disease severity and progression of idiopathic pulmonary fibrosis (IPF), it is unclear which method is most practical. A universal severity classification system has not yet been adopted for IPF.ObjectiveThe purpose of this study was to test the correlation between quantitative-CT indices and lung physiology variables and to determine the ability of such indices to predict disease severity in IPF.MethodsA total of 27 IPF patients showing radiological UIP pattern on high-resolution (HR) CT were retrospectively enrolled. Staging of IPF was performed according to two classification systems: the Japanese and GAP (gender, age, and physiology) staging systems. CT images were assessed using a commercially available CT imaging analysis workstation, and the whole-lung mean CT value (MCT), the normally attenuated lung volume as defined from −950 HU to −701 Hounsfield unit (NL), the volume of the whole lung (WL), and the percentage of NL to WL (NL%), were calculated.ResultsCT indices (MCT, WL, and NL) closely correlated with lung physiology variables. Among them, NL strongly correlated with forced vital capacity (FVC) (r = 0.92, P <0.0001). NL% showed a large area under the receiver operating characteristic curve for detecting patients in the moderate or advanced stages of IPF. Multivariable logistic regression analyses showed that NL% is significantly more useful than the percentages of predicted FVC and predicted diffusing capacity of the lungs for carbon monoxide (Japanese stage II/III/IV [odds ratio, 0.73; 95% confidence intervals (CI), 0.48 to 0.92; P < 0.01]; III/IV [odds ratio. 0.80; 95% CI 0.59 to 0.96; P < 0.01]; GAP stage II/III [odds ratio, 0.79; 95% CI, 0.56 to 0.97; P < 0.05]).ConclusionThe measurement of NL% by threshold-based volumetric CT analysis may help improve IPF staging.     

Left Ventricular Diastolic Dysfunction Assessment with Dual-Source CT

PurposeTo assess the impact of left ventricular (LV) diastolic dysfunction on left atrial (LA) phasic volume and function using dual-source CT (DSCT) and to find a viable alternative prognostic parameter of CT for LV diastolic dysfunction through quantitative evaluation of LA phasic volume and function in patients with LV diastolic dysfunction.ResultsLA ejection fraction (LAEF), LA contraction, reservoir, and conduit function in patients in impaired relaxation group were not different from those in the normal group, but they were lower in patients in the pseudonormal and restrictive LV diastolic dysfunction groups (P < 0.05). For LA conduit function, there were no significant differences between the patients in the pseudonormal group and restrictive filling group (P = 0.195). There was a strong correlation between the indexed maximal left atrial volume (LAVmax, r = 0.85, P < 0.001), minimal left atrial volume (LAVmin, r = 0.91, P < 0.001), left atrial volume at the onset of P wave (LAVp, r = 0.84, P < 0.001), and different stages of LV diastolic function. The LAVi increased as the severity of LV diastolic dysfunction increased.ConclusionsLA remodeling takes place in patients with LV diastolic dysfunction. At the same time, LA phasic volume and function parameters evaluated by DSCT indicated the severity of the LV diastolic dysfunction. Quantitative analysis of LA phasic volume and function parameters using DSCT could be a viable alternative prognostic parameter of LV diastolic function.     

Evaluation of CT Perfusion Biomarkers of Tumor Hypoxia

BackgroundTumor hypoxia is associated with treatment resistance to cancer therapies. Hypoxia can be investigated by immunohistopathologic methods but such procedure is invasive. A non-invasive method to interrogate tumor hypoxia is an attractive option as such method can provide information before, during, and after treatment for personalized therapies. Our study evaluated the correlations between computed tomography (CT) perfusion parameters and immunohistopathologic measurement of tumor hypoxia.MethodsWistar rats, 18 controls and 19 treated with stereotactic radiosurgery (SRS), implanted with the C6 glioma tumor were imaged using CT perfusion on average every five days to monitor tumor growth. A final CT perfusion scan and the brain were obtained on average 14 days (8–22 days) after tumor implantation. Tumor hypoxia was detected immunohistopathologically with pimonidazole. The tumor, necrotic, and pimonidazole-positive areas on histology samples were measured. Percent necrotic area and percent hypoxic areas were calculated. Tumor volume (TV), blood flow (BF), blood volume (BV), and permeability-surface area product (PS) were obtained from the CT perfusion studies. Correlations between CT perfusion parameters and histological parameters were assessed by Spearman’s ρ correlation. A Bonferroni-corrected P value < 0.05 was considered significant.ResultsBF and BV showed significant correlations with percent hypoxic area ρ = -0.88, P < 0.001 and ρ = -0.81, P < 0.001, respectively, for control animals and ρ = -0.7, P < 0.001 and ρ = -0.6, P = 0.003, respectively, for all animals, while TV and BV were correlated (ρ = -0.64, P = 0.01 and ρ = -0.43, P = 0.043, respectively) with percent necrotic area. PS was not correlated with either percent necrotic or percent hypoxic areas.ConclusionsPercent hypoxic area provided significant correlations with BF and BV, suggesting that CT perfusion parameters are potential non-invasive imaging biomarkers of tumor hypoxia.     

Association of Radiologic Findings with Mortality in Patients with Avian Influenza H7N9 Pneumonia

Background

The novel H7N9 virus causes severe illness, including pneumonia and acute respiratory distress syndrome, with high rates of mortality. We investigated the association of initial radiologic characteristics obtained at admission with clinical outcomes in patients with avian influenza H7N9 pneumonia.

Methods

Demographics, comorbidities, clinical findings, radiologic appearance and scores of the affected lung parenchyma were compared between survivor group (n = 15) and mortality group (n = 7). Two radiologic scores were calculated, one using chest radiography and one using CT. Follow-up CT scans at discharge were analyzed in 12 patients of the survival group.

Results

All the patients in mortality group developed acute respiratory distress syndrome and required mechanical ventilation, while in the survival group 33% (5/15) developed acute respiratory distress syndrome (P<0.05) and 27% (4/15) required mechanical ventilation (P<0.05). The mean radiographic and CT scores of the mortality group were 50% higher compared to the survival group (P<0.05). ROC analysis revealed an area under curve of 0.738 for the radiographic score with an optimal cutoff value of a score of 19 for prediction of mortality, with a sensitivity of 71% and a specificity of 67%, and an area under curve of 0.833 for the CT score with an optimal cutoff value of a CT score of 21 for prediction of mortality, with a sensitivity of 86% and a specificity of 73%. The mean CT score of the affected lung parenchyma at discharge was 30% lower than the initial CT examination (P<0.05).

Conclusion

High initial radiologic score is associated with mortality in patients with avian influenza H7N9 pneumonia.     

How Have We Diagnosed Early-Stage Lung Cancer without Radiographic Screening? A Contemporary Single-Center Experience

Background

The National Lung Screening Trial (NLST), which demonstrated a reduction in lung cancer mortality, may result in widespread computed tomography (CT)-based screening of select populations. How early-stage lung cancer has been diagnosed without screening, and what proportion of these cases would be captured by a screening program modeled on the NLST, is not currently known. We therefore evaluated current patterns of early-stage lung cancer presentation.

Methodology/Principal Findings

We performed a single-institution retrospective analysis of patients diagnosed with stage I–II non-small cell lung cancer (NSCLC) from 2000–2009. Associations between patient and imaging characteristics were assessed using univariate and multivariate analyses. A total of 412 patients met criteria for analysis. Among those with available reason for initial imaging, the reason was symptoms in 51%, follow-up of other conditions in 43%, and screening in 6%. Reason for imaging was associated with race (P<0.001), insurance type (P = 0.005), and disease stage (P<0.001). Type of initial imaging was associated with reason for imaging (P<0.001), year (chest x-ray 67% in 2000–2004 vs. 49% in 2005–2009; P<0.001), and disease stage (P = 0.005). Among patients with available quantified smoking history, 48% were age 55–74 years and smoked 30-plus pack-years, therefore meeting NLST entry criteria.

Conclusions/Significance

Symptoms remain a dominant but declining reason for detection of early-stage NSCLC. The proportion of cases detected initially by CT scan without antecedent chest x-ray has increased considerably. Because as few as half of cases meet NLST eligibility criteria, clinicians should remain aware of the diverse circumstances of early-stage lung cancer presentation to expedite therapy.     

Optimal Dose Levels in Screening Chest CT for Unimpaired Detection and Volumetry of Lung Nodules,with and without Computer Assisted Detection at Minimal Patient Radiation

Objectives

The aim of this phantom study was to minimize the radiation dose by finding the best combination of low tube current and low voltage that would result in accurate volume measurements when compared to standard CT imaging without significantly decreasing the sensitivity of detecting lung nodules both with and without the assistance of CAD.

Methods

An anthropomorphic chest phantom containing artificial solid and ground glass nodules (GGNs, 5–12 mm) was examined with a 64-row multi-detector CT scanner with three tube currents of 100, 50 and 25 mAs in combination with three tube voltages of 120, 100 and 80 kVp. This resulted in eight different protocols that were then compared to standard CT sensitivity (100 mAs/120 kVp). For each protocol, at least 127 different nodules were scanned in 21–25 phantoms. The nodules were analyzed in two separate sessions by three independent, blinded radiologists and computer-aided detection (CAD) software.

Results

The mean sensitivity of the radiologists for identifying solid lung nodules on a standard CT was 89.7%±4.9%. The sensitivity was not significantly impaired when the tube and current voltage were lowered at the same time, except at the lowest exposure level of 25 mAs/80 kVp [80.6%±4.3% (p = 0.031)]. Compared to the standard CT, the sensitivity for detecting GGNs was significantly lower at all dose levels when the voltage was 80 kVp; this result was independent of the tube current. The CAD significantly increased the radiologists’ sensitivity for detecting solid nodules at all dose levels (5–11%). No significant volume measurement errors (VMEs) were documented for the radiologists or the CAD software at any dose level.

Conclusions

Our results suggest a CT protocol with 25 mAs and 100 kVp is optimal for detecting solid and ground glass nodules in lung cancer screening. The use of CAD software is highly recommended at all dose levels.     

Prognostic Importance and Therapeutic Implications of PAK1, a Drugable Protein Kinase,in Gastroesophageal Junction Adenocarcinoma

Gastroesophageal junction (GEJ) adenocarcinoma is a lethal cancer with rising incidence, yet the molecular biomarkers that have strong prognostic impact and also hold great therapeutic promise remain elusive. We used a data mining approach and identified the p21 protein-activated kinase 1 (PAK1), an oncogene and drugable protein kinase, to be among the most promising targets for GEJ adenocarcinoma. Immunoblot analysis and data mining demonstrated that PAK1 protein and mRNA were upregulated in cancer tissues compared to the noncancerous tissues. Immunohistochemistry revealed PAK1 overexpression in 72.6% of primary GEJ adenocarcinomas (n = 113). A step-wise increase in PAK1 levels was noted from paired normal epithelium, to atypical hyperplasia and adenocarcinoma. PAK1 overexpression in tumor was associated with lymph node (LN) metastasis (P<0.001), advanced tumor stage (P<0.001), large tumor size (P = 0.006), residual surgical margin (P = 0.033), and unfavorable overall survival (P<0.001). Multivariate analysis showed PAK1 overexpression is an independent high-risk prognostic predictor (P<0.001). Collectively, PAK1 is overexpressed during tumorigenic progression and its upregulation correlates with malignant properties mainly relevant to invasion and metastasis. PAK1 expression could serve as a prognostic predictor that holds therapeutic promise for GEJ adenocarcinoma.     

A Minor (<50%) Signet-Ring Cell Component Associated with Poor Prognosis in Colorectal Cancer Patients: A 26-Year Retrospective Study in China

Background

We performed a retrospective study to determine the cancer-specific survival of colorectal cancer patients with a component of signet-ring cells or mucin comprising < 50% of the tumor mass.

Methods

A total of 2454 patients seen in our hospital from 1985 to 2011 were retrospectively studied. The patients were divided into five groups according to type of cancer: signet-ring cell carcinoma (with > 50% signet-ring cell, n = 36), partial signet-ring cell carcinoma (with < 50% signet-ring cell, n = 28), mucinous adenocarcinoma (with > 50% mucin lacking signet-ring cell, n = 267), partial mucinous adenocarcinoma (with < 50% mucin lacking signet-ring cell, n = 145), and classic adenocarcinoma (with absence of either mucin or signet-ring cell, n = 1978).

Results

Patients with > 50% or < 50% signet-ring cell had the lowest 5-year survival rates (35.5% and 29.7%, respectively), followed by patients with > 50% mucin (48.8%). Patients who had partial mucinous adenocarcinoma with < 50% mucin and classic adenocarcinoma patients had the highest 5-year survival rates (64.8% and 65.3%, respectively). Stratified and multivariate analysis showed that signet-ring cell carcinoma, partial signet-ring cell carcinoma and mucinous adenocarcinoma were independent predictors of decreased survival (hazard ratio 1.699, P = 0.016; hazard ratio 2.182, P = 0.005; hazard ratio 1.532, P < 0.001; respectively), and partial mucinous adenocarcinoma was not (hazard ratio 1.137, P = 0.431).

Conclusions

Patients with a component of signet-ring cells, regardless of the extent, had poor prognoses. Patients with mucinous adenocarcinoma containing >50% mucin had poor prognoses as well, whereas those with < 50% mucin had survival rates similar to those of classic adenocarcinoma patients. Therefore, in clinical practice, patients with a component of signet-ring cells, regardless of the extent, should be given significant clinical attention.     

Mismatch Repair Gene MLH3 Pro844Leu and Thr942Ile Polymorphisms and the Susceptibility to Cervical Carcinoma and HPV Infection: A Case-Control Study in a Chinese Population

To investigate the association between MLH3 Pro844Leu, Thr942Ile polymorphisms and potential linkage with the risk of cervical carcinoma and potential effect on protein function, we carried out a case-control study with 400 cervical squamous cell carcinoma, 400 CIN3 and 1200 normal controls in a Chinese population. The results showed that there was an increased risk of cervical carcinoma and CIN3 associated with the genotype 844CT [OR 2.17 (1.61–2.94); P<0.001; OR 1.49 (1.08–2.07), P 0.017, respectively] and a decreased risk with the 942CT genotype [OR 0.56 (0.38–0.82); P<0.001; OR 0.37 (0.24–0.58), P<0.001, respectively]. Most 844CT genotypes were linkage CT(844)-CC(942), which increased the risk of cervical carcinoma and CIN3 [77/83, OR 2.04 (1.48–2.80), P<0.001; 55/61, OR 1.46 (1.03–2.06), P 0.035, respectively]. Most 942CT were linkage CC(844)-CT(942), which decreased the risk of cervical carcinoma [29/35, OR 0.60 (0.40–0.91); P 0.017; 18/24, OR 0.33 (0.20–0.55), P<0.001, respectively]. In some grouping, the 844CT and 942CT were further enriched; especially HR-HPV-positive subjects both in the CIN3 and the cervical carcinoma, the 844CT had greater enrichment. These results included that CT(844)-CC(942) was associated with a high risk of cervical carcinoma and CIN3, and the CC(844)-CT(942) decreased the risk. The 844CT had a higher level of enrichment in HR-HPV positive individuals, which is probably related to HR-HPV susceptibility. There was no significant difference of the MLH3 mRNA expression and these two amino acid substitutions did not impact on the protein function.     

CT Perfusion Imaging as an Early Biomarker of Differential Response to Stereotactic Radiosurgery in C6 Rat Gliomas

Background

The therapeutic efficacy of stereotactic radiosurgery for glioblastoma is not well understood, and there needs to be an effective biomarker to identify patients who might benefit from this treatment. This study investigated the efficacy of computed tomography (CT) perfusion imaging as an early imaging biomarker of response to stereotactic radiosurgery in a malignant rat glioma model.

Methods

Rats with orthotopic C6 glioma tumors received either mock irradiation (controls, N = 8) or stereotactic radiosurgery (N = 25, 12 Gy in one fraction) delivered by Helical Tomotherapy. Twelve irradiated animals were sacrificed four days after stereotactic radiosurgery to assess acute CT perfusion and histological changes, and 13 irradiated animals were used to study survival. Irradiated animals with survival >15 days were designated as responders while those with survival ≤15 days were non-responders. Longitudinal CT perfusion imaging was performed at baseline and regularly for eight weeks post-baseline.

Results

Early signs of radiation-induced injury were observed on histology. There was an overall survival benefit following stereotactic radiosurgery when compared to the controls (log-rank P<0.04). Responders to stereotactic radiosurgery showed lower relative blood volume (rBV), and permeability-surface area (PS) product on day 7 post-stereotactic radiosurgery when compared to controls and non-responders (P<0.05). rBV and PS on day 7 showed correlations with overall survival (P<0.05), and were predictive of survival with 92% accuracy.

Conclusions

Response to stereotactic radiosurgery was heterogeneous, and early selection of responders and non-responders was possible using CT perfusion imaging. Validation of CT perfusion indices for response assessment is necessary before clinical implementation.     

Anemia of Inflammation Is Related to Cognitive Impairment among Children in Leyte,The Philippines

Background

Many studies have addressed the relationship between iron deficiency anemia (IDA) and cognitive impairment, but none have evaluated the role of non-iron deficiency anemia (NIDA). One of the main causes of NIDA in developing countries is AI, largely due to infectious diseases, whereby iron is shunted away from bio-available forms to storage forms, making it less accessible for use by host tissues. The objective of this study was to determine the effect of NIDA, due largely to AI in this context, on cognitive function after adjustment for potential confounders.

Methodology

This cross-sectional study was conducted in Leyte, The Philippines among 322 children ages 7–18 years. Blood samples were collected and analyzed at the time of cognition testing. Three stool samples were collected and evaluated by the Kato Katz method for quantitative assessment for Schistosoma japonicum and geo-helminth infection. Socio-economic status (SES) was evaluated by survey. Linear regression models were used to quantify the adjusted relationship between performance in different cognitive domains and both IDA and NIDA.

Principal Findings

After adjusting for age, sex, SES and nutritional status, children in the NIDA had lower scores on the PNIT (P = <0.05) and the WRAML memory domain (P<0.05) compared to children in the non-anemic group. Children in the IDA had lower performance on the PNIT compared to the non-anemic group after controlling for potential confounders (P<0.05).

Conclusions

NIDA, predominantly due to AI in this context, was related to lower performance on two tests of cognitive function. This is likely due to decreased delivery of iron to host tissues in this context, including the CNS.     

Functional Polymorphisms of CHRNA3 Predict Risks of Chronic Obstructive Pulmonary Disease and Lung Cancer in Chinese

Recently, several genome-wide association studies (GWAS) have identified many susceptible single nucleotide polymorphisms (SNPs) for chronic obstructive pulmonary disease (COPD) and lung cancer which are two closely related diseases. Among those SNPs, some of them are shared by both the diseases, reflecting there is possible genetic similarity between the diseases. Here we tested the hypothesis that whether those shared SNPs are common predictor for risks or prognosis of COPD and lung cancer. Two SNPs (rs6495309 and rs1051730) located in nicotinic acetylcholine receptor alpha 3 (CHRNA3) gene were genotyped in 1511 patients with COPD, 1559 lung cancer cases and 1677 controls in southern and eastern Chinese populations. We found that the rs6495309CC and rs6495309CT/CC variant genotypes were associated with increased risks of COPD (OR = 1.32, 95% C.I. = 1.14–1.54) and lung cancer (OR = 1.57; 95% CI = 1.31–1.87), respectively. The rs6495309CC genotype contributed to more rapid decline of annual Forced expiratory volume in one second (FEV1) in both COPD cases and controls (P<0.05), and it was associated with advanced stages of COPD (P = 0.033); the rs6495309CT/CC genotypes conferred a poor survival for lung cancer (HR = 1.41, 95%CI = 1.13–1.75). The luciferase assays further showed that nicotine and other tobacco chemicals had diverse effects on the luciferase activity of the rs6495309C or T alleles. However, none of these effects were found for another SNP, rs1051730G>A. The data show a statistical association and suggest biological plausibility that the rs6495309T>C polymorphism contributed to increased risks and poor prognosis of both COPD and lung cancer.