磁共振动态磁敏感对比增强成像在术前脑胶质瘤分级诊断及IDH突变状态评估中的应用价值

目的:探讨动态磁敏感对比增强磁共振成像在胶质瘤术前分级诊断及IDH突变状态评估中的应用价值。 方法:纳入我院经病理确诊脑胶质瘤71例［30例低级别胶质瘤（low-grade glioma,LGG）,41例高级别胶质瘤（high-grade glioma,HGG）,41例IDH突变型（isocitrate dehydrogenase mutant）,30例IDH野生型（IDH wild type）］。术前均行常规MR平扫、增强、DWI及DSC-MRI,运用后处理工作站对各MR图像进行分析,分别测量肿瘤实质区、瘤周水肿区及对侧正常脑白质区的相对脑血容量（relative cerebral blood volume,rCBV）、相对脑血流量（relative cerebral blood flow,rCBF）、平均通过时间（mean transit time,MTT）以及达峰时间（time to peak,TTP）,并计算规范化（肿瘤实质区/对侧正常脑白质区）肿瘤实质区的各参数值。所得数据经统计软件进行组间比较,并与病理分级及IDH突变状态进行相关性以及各参数诊断效能的分析。 结果:肿瘤实质区,LGG的规范化rCBF和rCBV值低于HGG（P<0.05）,IDH突变型的规范化rCBF和rCBV值低于IDH野生型（P<0.05）。规范化的rCBF,rCBV值与高、低肿瘤级别间呈正相关（P<0.01）,与IDH突变状态呈负相关（P<0.01）。对高、低级别胶质瘤的诊断,以rCBV值的曲线下面积最大（0.849）,诊断阈值为2.2 mL/100 g,敏感性为87.8%,特异性为76.7%。对IDH突变状态的评估,以rCBV值的曲线下面积最大（0.741）,诊断阈值为3.6 mL/100 g,敏感性为62.2%,特异性为90.9%。DSC预测高、低级别胶质瘤分级诊断的准确性为81.7%,预测IDH突变状态的准确性为80.0%。 结论:DSC是脑胶质瘤术前无创分级诊断及评估IDH突变状态的有效影像学技术,可在术前检测胶质瘤灌注信息判断其级别及IDH突变状态,为患者的精确诊治提供帮助。     

Tumor hypoxia: a new PET imaging biomarker in clinical oncology

Tumor hypoxia is associated with tumor progression and resistance to various treatments. Noninvasive imaging using positron emission tomography (PET) and F-18-labeled fluoromisonidazole (FMISO) was recently introduced in order to define and quantify tumor hypoxia. The FMISO uptake was closely correlated with pimonidazole immunohistochemistry and hypoxia-inducible factor 1 expression in basic studies. Tumor hypoxia in head and neck cancers and other tumors in a clinical setting may also indicate resistance to radiation and/or chemotherapy. Hypoxic imaging may thus play a new and important role for suitable radiation planning, including dose escalation and dose reduction based on the image findings. Such radiation-dose painting based on the findings of hypoxia may require high-performance PET imaging to provide high target-to-background ratio images and an optimal quantitative parameter to define the hypoxic region. A multicenter prospective study using data from a large number of patients is also warranted to test the clinical value of hypoxic imaging.     

全身炎症反应指数对胶质瘤患者临床预后影响及与IDH1突变的关系

目的 探讨全身炎症反应指数(SIRI)对胶质瘤患者临床预后影响及与IDH1突变的关系。方法 收集2006年8月—2015年11月于我院神经外科行手术治疗的80例神经胶质瘤患者。应用ROC曲线确定SIRI判断患者术后生存状态的最佳临床分界值,并依此分组。采用Kaplan-Meier和Log-rank法分析两组患者术后生存情况。Cox比例风险回归模型分析临床预后因素。应用免疫组织化学和DNA测序方法检测IDH1突变情况。结果 低SIRI组术后中位无进展生存时间(Progress free survival,PFS)和中位总生存时间(Overall survival,OS)分别为46.90个月和57.90个月,而高SIRI组术后中位PFS和中位OS分别为31.78个月和47.22个月;两组术后中位PFS和中位OS比较差异具有统计学意义(P＜0.05)。经单因素和多因素分析,年龄、手术情况、WHO分级、SIRI、IDH1突变是神经间质瘤独立预后的因素。低SIRI组伴有IDH1突变的神经胶质瘤患者预后较好。结论 SIRI是神经胶质瘤独立的预后因素,具有简单、方便、可重复性强等特点,可用来预测神经胶质瘤患者的预后。     

Influence of selenium-enriched yeast supplementation on biomarkers of oxidative damage and hormone status in healthy adult males: a clinical pilot study.

The mechanisms responsible for the protective role of selenium against the development of prostate cancer remain to be determined (L. C. Clark et al., J. Am. Med. Assoc., 276: 1957-1963, 1996). In the present study, we tested the hypothesis that selenium supplementation reduces oxidative stress. A secondary aim was to determine whether selenium-induced changes in testosterone (T) metabolism may also be involved. To this end, we conducted a double-blind, randomized, placebo-controlled trial of 247 micro g selenium/day administered p.o. in the form of Se-enriched yeast. Study subjects were 36 healthy adult males, 11 blacks and 25 whites, 19-43 years of age. Supplementation occurred over the first 9 months, after which all subjects were placed on placebo for an additional 3 months. Blood and urine were collected at baseline and after 3, 9, and 12 months. In the selenium group, plasma selenium levels were 2-fold higher than baseline values after 3 and 9 months and returned to 136% of baseline after 12 months (P < 0.0001), whereas in the placebo group, levels were unchanged. A 32% increase in blood glutathione (GSH) levels was observed after 9 months in the selenium group only (P < 0.05). This change coincided with a 26% decrease in protein-bound GSH (bGSH) and a 44% decrease in bGSH:GSH ratios (P < 0.05). The changes in GSH and bGSH were highly correlated with changes in plasma selenium concentrations and may reflect a decrease in oxidative stress. No changes were observed in either group for plasma T, dihydrotestosterone (DHT) or DHT:T ratios, suggesting that selenium had no effect on the alpha-reductase involved in the conversion of T to DHT. A small but significant decrease in prostate-specific antigen levels was observed after 3 and 9 months (P < 0.001), and this difference disappeared after 12 months. Future trials will test the above hypothesis in prostate cancer patients and in subjects at high risk for prostate cancer.     

Tissue carcinoembryonic antigen and oestrogen receptor status in breast carcinoma: an immunohistochemical study of clinical outcome in a series of 252 patients with long-term follow-up.

Carcinoembryonic antigen (CEA) is a well-known tumour marker whose immunohistochemical expression could be prognostically relevant in breast carcinomas. We evaluated CEA immunohistochemical expression, using the specific T84.66 monoclonal antibody, in a series of 252 consecutive cases of infiltrating breast carcinomas (104 N0, 148 N1/2) with median follow-up of 84 months. Oestrogen receptor (ER) status has been evaluated with the immunohistochemical method (ER1D5 antibody, 10% cut-off value): 121 cases were ER negative, 128 cases were ER positive and in three cases ER status was unknown. CEA staining was cytoplasmic; staining intensity and percentage of reacting cells were combined to obtain a final score (CEA score). The difference between the distribution of CEA score within the modalities of the other variables was not statistically significant. Univariate survival analysis has been performed on the series of node-negative and node-positive patients. In the latter subgroup, this has been performed separately for patients treated with systemic adjuvant hormonal therapy or chemotherapy. A multivariate analysis was only performed for node-positive patients treated with adjuvant therapy. CEA immunoreactivity was not prognostically relevant in any subset of analysed patients. The most important prognostic markers were nodal status and tumour size.     

IgVH genes mutation and usage, ZAP-70 and CD38 expression provide new insights on B-cell prolymphocytic leukemia (B-PLL).

B-prolymphocytic leukemia (B-PLL) is a rare disease with poor prognosis. To further characterize the biological features of this disease, we analyzed immunoglobulin heavy chain (IgVH) mutations, ZAP-70 and CD38 in 19 cases with de novo B-PLL. Immunoglobulin heavy chain genes analysis showed an unmutated pattern (>98% homology to germ line) in 9/17 cases (53%), with 100% homology in eight. In the remaining, it ranged from 90 to 97.4%, with three cases slightly mutated (98-95%) and five heavily mutated (<95%). All B-PLL utilized members of VH3 (11/17) and VH4 (6/17) families, with V3-23, V4-59 and V4-34 gene accounting for more than half of them, regardless of mutational status. ZAP-70, assessed by flow cytometry, ranged from 1 to 91% cells, being > or =20% in 57% of cases. CD38 ranged from 1 to 99% (median 21%). There was no correlation between IgVH status and ZAP-70 or CD38 expression, but male gender and del(17p) were more common in the unmutated group. Neither IgVH mutations, CD38 expression nor del(17p) influenced patients' outcome. Unexpectedly, ZAP-70+ B-PLL patients survived longer (40 months) than ZAP-70- B-PLL (8 months). B-PLL appears biologically heterogeneous regarding IgVH mutations, ZAP-70 and CD38 expression, showing a pattern distinct from that of other lymphoproliferative disorders.     

Brain metastases in lung adenocarcinoma: impact of EGFR mutation status on incidence and survival

Background

The brain represents a frequent progression site in lung adenocarcinoma. This study was designed to analyse the association between the epidermal growth factor receptor (EGFR) mutation status and the frequency of brain metastases (BM) and survival in routine clinical practice.

Patients and methods

We retrospectively analysed the medical records of 629 patients with adenocarcinoma in Slovenia who were tested for EGFR mutations in order to analyse the cumulative incidence of BM, the time from the diagnosis to the development of BM (TDBM), the time from BM to death (TTD) and the median survival.

Results

Out of 629 patients, 168 (27%) had BM, 90 patients already at the time of diagnosis. Additional 78 patients developed BM after a median interval of 14.3 months; 25.8 months in EGFR positive and 11.8 months in EGFR negative patients, respectively (p = 0.002). EGFR mutations were present in 47 (28%) patients with BM. The curves for cumulative incidence of BM in EGFR positive and negative patients demonstrate a trend for a higher incidence of BM in EGFR mutant patients at diagnosis (19% vs. 13%, p = 0.078), but no difference later during the course of the disease. The patients with BM at diagnosis had a statistically longer TTD (7.3 months) than patients who developed BM later (3.1 months). The TTD in EGFR positive patients with BM at diagnosis was longer than in EGFR negative patients (12.6 vs. 6.8, p = 0.005), while there was no impact of EGFR status on the TTD of patients who developed BM later.

Conclusions

Except for a non-significant increase of frequency of BM at diagnosis in EGFR positive patients, EGFR status had no influence upon the cumulative incidence of BM. EGFR positive patients had a longer time to CNS progression. While EGFR positive patients with BM at diagnosis had a longer survival, EGFR status had no influence on TTD in patients who developed BM later during the course of disease.     

Circulating nucleosomes and response to chemotherapy: an in vitro,in vivo and clinical study on cervical cancer patients

It is known that cell-free DNA circulates in plasma/serum of patients with cancer and that part of this DNA circulates as nucleosomes that can be quantified by ELISA. We analyzed the effect of tumor and chemotherapy upon the levels of nucleosomes in vitro, in vivo and in cervical cancer patients. The levels of nucleosomes pre- and post-treatment were correlated with response in 11 patients receiving chemotherapy. Nucleosomes were determined in nude mice treated with or without cisplatin and carrying tumors generated with HeLa cells, and in the cell lysate and supernatant of HeLa cells exposed to cisplatin in culture. In addition, nucleosomes were determined at different time points in patients and in rats receiving chemotherapy. Nucleosomes were higher in patients that controls (1,760 vs. 601, p = 0.0001). After 24 hr of treatment with oxaliplatin and gemcitabine, the levels decreased in 6 patients of whom 5 had response. Nucleosome levels differed between mice xenografted and not xenografted (765 vs. 378, p = 0.001) and between xenografted treated with or without cisplatin (650 vs. 765, p = 0.010), but not in tumor-free animals treated and untreated with cisplatin (378 vs. 379, p = 0.99). In vitro, nucleosomes reached at peak 8 hr in cell lysates to decrease thereafter, whereas in supernatant, levels continued to increase up to 24 hr. Serial determination of nucleosomes in patients showed a rise within 6-12 hr and then a reduction to below the basal at 24 hr. In rats, nucleosomes had no major changes in those receiving oxaliplatin or the triple combination of cisplatin, gemcitabine and paclitaxel as compared to untreated controls. An overdose of this triple combination produced a transient elevation of almost 1,000 AU over the basal. Our results demonstrate that most of circulating nucleosomes originate from the tumor and that chemotherapy produces an early rise most likely due to tumor apoptosis and that nucleosomes are rapidly cleared from circulation. On the contrary, chemotherapy within the therapeutic range of doses has no effect on nucleosome levels in healthy mice and rats. This data suggests that the determination of circulating nucleosomes pre- and post-treatment could be a useful test to predict response to chemotherapy in cancer patients.     

Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients

ABSTRACT: BACKGROUND: KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. METHODS: Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n=17) or poor (n=17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. RESULTS: Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model. CONCLUSIONS: Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.     

Quality of life in lung cancer patients: impact of baseline clinical profile and respiratory status

As cure is attainable in very few cases of lung cancer, the imperative issue is to make quality of life (QOL) as good as possible as part of the palliative care package. The aim of this paper was to evaluate the baseline QOL of lung cancer patients and observe its association with various clinical parameters and overall respiratory status. A total of 101 patients were administered the European Organization for Research and Treatment of Cancer core quality of life (EORTC QLQ-C30, version 3) questionnaire. Clinical profile and measures of respiratory status, including spirometry, measures of dyspnoea, and 6-min walk test, were recorded. Higher Karnofsky Performance Status (KPS) significantly correlated with better global health status (P < 0.001) and healthy level of functioning (P < 0.001). The cumulative symptom burden was significantly associated with global QOL (P = 0.01) and physical, role and cognitive function scales (P < 0.05). All dyspnoea measures negatively correlated with global QOL and functioning scales. Spirometric indices showed a positive correlation with all functional scales (P < 0.05) except social. In conclusion, lung cancer patients have unsatisfactory QOL, with the global health status and physical functions being most affected. Number of symptoms, KPS, dyspnoea and spirometry significantly affect QOL.     

Postoperative epilepsy and survival in glioma patients: a nationwide population-based cohort study from 2009 to 2018

Journal of Neuro-Oncology - Postoperative epilepsy is common in glioma patients and has been suggested to indicate disease progression, yet knowledge of its role as a prognostic factor is limited....     

Ki-ras point mutation and p53 expression in human pancreatic cancer: a comparative study among Chinese, Japanese, and Western patients.

The aim of this study was to clarify features of Ki-ras point mutation (PM) and p53 expression in Chinese pancreatic cancer and to compare those with that in other countries. Dot blot hybridization and immunohistochemical methods were performed in 59 Chinese patients. The results showed that Ki-ras PMs at codon 12 and p53 expression were frequent in this group. No relationships were found between Ki-ras PM alone and p53 expression alone, and clinicopathological parameters, including age, gender, clinical stage, and histological grade and classification in Chinese patients. However, their cooperation was significantly associated with a poor prognosis in this group. Comparison showed that there were significant differences in the overall frequency and substitution of Ki-ras PM and in the ratio of transition:transversion in pancreatic cancer among various countries. In addition, the effect of Ki-ras PM and p53 expression on a poor prognosis of pancreatic cancer may be different among various countries. These findings suggested that not only Ki-ras PM and p53 expression are frequent in Chinese pancreatic cancer, but also a gene component to pancreatic cancer may be different between Asian and Western pancreatic cancer. In addition, it seems that cooperation of Ki-ras PM and p53 expression may predict a poor prognosis in Chinese patients with pancreatic cancer.     

Systemic rapamycin alone may not be a treatment option for malignant glioma: evidence from an in vivo study

Concerns about the health effects of radiofrequency (RF) waves have been raised because of the gradual increase in usage of cell phones, and there are scientific questions and debates about the safety of those instruments in daily life. The aim of this study is to evaluate the genotoxic effects of RF waves in an experimental brain cell culture model. Brain cell cultures of the mice were exposed to 10.715 GHz with specific absorbtion rate (SAR) 0.725 W/kG signals for 6 h in 3 days at 25°C to check for the changes in the micronucleus (MNi) assay and in the expression of 11 proapoptotic and antiapoptotic genes. It was found that MNi rate increased 11-fold and STAT3 expression decreased 7-fold in the cell cultures which were exposed to RF. Cell phones which spread RF may damage DNA and change gene expression in brain cells.     

IDH1 mutation as a potential novel biomarker for distinguishing pseudoprogression from true progression in patients with glioblastoma treated with temozolomide and radiotherapy

The purpose of this study was to distinguish pseudoprogression (PP) from early true progression in patients with glioblastoma (GBM) based on the presence of a mutation in isocitrate dehydrogenase 1 (IDH1). We retrospectively surveyed 32 patients with GBM or GBM with oligodendroglioma component (GBMO) who underwent biopsy or maximal tumor resection followed by concurrent radiotherapy and temozolomide (TMZ). We then selected patients with early radiological progression in magnetic resonance imaging within 6 months after concurrent radiotherapy and TMZ treatment. DNA was extracted from their tumor blocks. The IDH1 mutation was analyzed in the genomic region by direct sequencing as a biomarker for PP. Twenty-eight patients were diagnosed with GBM and four with GBMO. Eleven patients were discovered to have early radiological progression. PP was detected in two patients (6.3 %) diagnosed with GBMO and one patient with GBM. Both of the GBMO patients with PP had the IDH1 mutation, the one GBM patient with PP and the other eight patients with early true progression with wild type. The sensitivity and specificity of the IDH1 mutation for detecting PP were 66.7 and 100 %, respectively. This study suggests the IDH1 mutation may become a novel molecular biomarker for PP. Analyzing the IDH1 mutation, in the case of recognizing early radiological progression, may enable distinction of PP from early true progression, and we could determine the need for second-look surgery.     

Promoter methylation and immunohistochemical expression of hMLH1 and hMSH2 in sporadic colorectal cancer: a study from India

To determine the etiological factors of human colorectal cancer (CRC) we assessed the frequency and prognostic significance of hMLH1 and hMSH2 genes in conjunction with hMLH1 and hMSH2 protein expression in 30 Indian CRC patients. The protein expression and promoter methylation of hMLH1 and hMSH2; Mismatch Repair genes (MMR) were analyzed by immunohistochemistry and methylation-specific PCR (MSP), respectively. A loss of hMLH1 expression was recognized in 4(13.3 %) and loss of hMSH2 expression was recognized in 2(6.6 %) of 30 CRC cases whereas 50 % tumors showed reduced expression of hMLH1 and 33.3 % showed reduced expression of hMSH2 protein. One tumor showed a loss of both hMLH1 and hMSH2 expression. Normal nuclear staining pattern of hMLH1 and hMSH2 was observed in almost all the adjoining and normal mucosa. Promoter hypermethylation of the hMLH1 gene was detected in 15 of 30 CRC cases (50 %) and of hMSH2 gene was only in 3 of 30 CRC cases (10 %). No promoter methylation of hMLH1 and hMSH2 genes was observed in adjoining and normal mucosa. Combination of methylation of hMLH1 and hMSH2 gene was observed in two tumors (6.6 %). A significant correlation between histological grade of the tumor, methylation and expression of hMLH1 gene (p?<?0.05) was observed. Normal expression of hMLH1 and hMSH2 was seen in all of the unmethylated tumors (100 %). Nuclear staining and promoter methylation of hMLH1 and hMSH2 did not significantly influence survival. hMLH1 methylation was common and was significantly correlated with loss of hMLH1 protein expression. In contrast, hMSH2 methylation was infrequent. These findings suggest that the inactivation of MMR gene expression probably via hypermethylation may lead to inactivation of their functions which finally leads to tumor aggressiveness and the immunostaining of hMLH1 protein can be used as a prognostic factor for determining the grade of the tumor.     

Preferential expression and frequent IgG responses of a tumor antigen, SOX5, in glioma patients

We previously reported to identify SOX5 as a glioma antigen by serological screening using a testis cDNA library. The present study was designed to analyze SOX5 expression, its immunoreactivity, and the correlation between SOX5 IgG responses and clinical features in glioma patients to evaluate the possibility of its use as a diagnostic marker. Quantitative RT-PCR and Western blot analysis revealed that SOX5 was expressed in glioma tissues, but not in normal adult tissues, except in the testis. An immunohistochemical analysis showed that SOX5 was expressed in glioma cells, but only a few SOX5-positive cells were detected in non-neoplastic tissues from the cerebral cortex. IgG antibodies against SOX5 were detected in sera from 8 of the 27 glioma patients (27.6%), 0 of the 14 patients with other brain diseases (0%), 1 of the 54 other cancer patients (1.9%) and 1 of the 37 healthy individuals (2.7%). Patients with glioblastoma (GBM) who showed IgG responses against SOX5 exhibited significantly better survival periods than GBM patients without SOX5 antibodies. In summary, SOX5 is aberrantly expressed in glioma and can be recognized as a glioma antigen using IgGs from the sera of glioma patients. Furthermore, there is a statistically significant correlation between the presence of SOX5 IgGs and survival in GBM patients, suggesting that the glioma antigen SOX5 may be useful not only as a diagnostic marker, but also as a prognostic marker in glioma patients.