A glycolysis-based ten-gene signature correlates with the clinical outcome,molecular subtype and IDH1 mutation in glioblastoma

Reprogrammed metabolism is a hallmark of cancer. Glioblastoma (GBM) tumor cells predominantly utilize aerobic glycolysis for the biogenesis of energy and intermediate nutrients. However, in GBM, the clinical significance of glycolysis and its underlying relations with the molecular features such as IDH1 mutation and subtype have not been elucidated yet. Herein, based on glioma datasets including TCGA (The Cancer Genome Atlas), REMBRANDT (Repository for Molecular Brain Neoplasia Data) and GSE16011, we established a glycolytic gene expression signature score (GGESS) by incorporating ten glycolytic genes. Then we performed survival analyses and investigated the correlations between GGESS and IDH1 mutation as well as the molecular subtypes in GBMs. The results showed that GGESS independently predicted unfavorable prognosis and poor response to chemotherapy of GBM patients. Notably, GGESS was high in GBMs of mesenchymal subtype but low in IDH1-mutant GBMs. Furthermore, we found that the promoter regions of tumor-promoting glycolytic genes were hypermethylated in IDH1-mutant GBMs. Finally, we found that high GGESS also predicted poor prognosis and poor response to chemotherapy when investigating IDH1-wildtype GBM patients only. Collectively, glycolysis represented by GGESS predicts unfavorable clinical outcome of GBM patients and is closely associated with mesenchymal subtype and IDH1 mutation in GBMs.     

Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: Case report

Background

Adnexal masses are not uncommon in patients with breast cancer. Breast cancer and ovarian malignancies are known to be associated. In patients with breast cancer and co-existing pleural effusions, ascites and adnexal masses, the probability of disseminated disease is high. Nevertheless, benign ovarian masses can mimic this clinical picture when they are associated with Meigs' syndrome making the work-up and management of these patients challenging. To our knowledge, there are no similar reports in the literature and therefore we present this case to highlight this entity.

Case presentation

A 56-year old woman presented with a 4 cm, grade 2, invasive ductal carcinoma of her left breast. Pre-treatment staging investigations showed a 13.5 cm mass in her left ovary, a small amount of ascites and a large right pleural effusion. Serum tumour markers showed a raised CA125 supporting the malignant nature of the ovarian mass. The cytology from the pleural effusion was indeterminate but thoracoscopic biopsy failed to show malignancy. The patient was strongly against mastectomy and she was commenced on neo-adjuvant Letrozole 2.5 mg daily with a view to perform breast conserving surgery. After a good response to the hormone manipulation, the patient had breast conserving surgery, axillary sampling and laparoscopic excision of the ovarian mass which was eventually found to be a benign ovarian fibroma.

Conclusion

Despite the high probability of disseminated malignancy when an ovarian mass associated with ascites if found in a patient with a breast cancer and pleural effusion, clinicians should be aware about rare benign syndromes, like Meigs', which may mimic a similar picture and mislead the diagnosis and management plan.     

Co-deletion of chromosome 1p/19q and IDH1/2 mutation in glioma subsets of brain tumors in Chinese patients

Objective

To characterize co-deletion of chromosome 1p/19q and IDH1/2 mutation in Chinese brain tumor patients and to assess their associations with clinical features.

Methods

In a series of 528 patients with gliomas, pathological and radiological materials were reviewed. Pathological constituents of tumor subsets, incidences of 1p/19q co-deletion and IDH1/2 mutation in gliomas by regions and sides in the brain were analyzed.

Results

Overall, 1p and 19q was detected in 339 patients by FISH method while the sequence of IDH1/2 was determined in 280 patients. Gliomas of frontal, temporal and insular origin had significantly different pathological constituents of tumor subsets (P<0.001). Gliomas of frontal origin had significantly higher incidence of 1p/19q co-deletion (50.4%) and IDH1/2 mutation (73.5%) than those of non-frontal origin (27.0% and 48.5%, respectively) (P<0.001), while gliomas of temporal origin had significantly lower incidence of 1p/19q co-deletion (23.9%) and IDH1/2 mutation (41.7%) than those of non-temporal origin (39.9% and 63.2%, respectively) (P = 0.013 and P = 0.003, respectively). Subgroup analysis confirmed these findings in oligoastrocytic and oligodendroglial tumors, respectively. Although the difference of 1p/19q co-deletion was not statistically significant in temporal oligodendroglial tumors, the trend was marginally significant (P = 0.082). However, gliomas from different sides of the brain did not show significant different pathological constituents, incidences of 1p/19q co-deletion or IDH1/2 mutation.

Conclusion

Preferential distribution of pathological subsets, 1p/19q co-deletion and IDH1/2 mutation were confirmed in some brain regions in Chinese glioma patients, implying their distinctive tumor genesis and predictive value for prognosis.     

Postoperative extracranial metastasis from glioblastoma: a case report and review of the literature

Background

Glioblastoma is the most common primary malignant brain tumor. Extraneural metastases are rarely reported in the literature.

Case presentation

We report a case of a 38-year-old patient who was diagnosed with glioblastoma in 2015. Four months after surgery, local relapse was found and the patient received a second surgery. After another 4 months, we found a hard mass in the right posterior neck when she admitted to our department for fourth cycle of adjuvant chemotherapy. Immunohistochemical investigation supported the diagnosis of glioblastoma metastases to the neck after resection of the right neck mass. A few days later, spinal vertebral magnetic resonance imaging (MRI) confirmed multiple metastases in the thoracic, lumbar, sacral, and bilateral iliac bones.

Conclusions

Glioblastoma is the most common primary malignant brain tumor. Whole tumor resection and early radiotherapy and chemotherapy can delay recurrence and prolong survival. Extracranial metastases are extremely rare. We report this case with the aim of bringing attention to extracranial metastasis of brain glioma.

     

原发性肝癌患者肠道菌群变化与内毒素和炎性因子水平的关系

目的探讨原发性肝癌患者肠道菌群变化及其与内毒素、炎性因子水平的相关性。方法选取2018年2月至2019年10月我院收治的80例原发性肝癌患者为观察组,另选同时期80例健康体检者为对照组。观察两组对象肠道菌群情况,同时检测两组对象血清内毒素和白细胞介素6(IL-6)、白细胞介素1(IL-1)及肿瘤坏死因子α(TNF-α)水平。采用Pearson检验进行相关性分析。结果观察组患者肠道双歧杆菌、乳杆菌和拟杆菌数量低于对照组;而肠杆菌和酵母菌数量高于对照组(均P0.05)。观察组患者血清内毒素、IL-6、IL-1、TNF-α水平均高于对照组(均P0.05)。Pearson相关性分析显示,肠道双歧杆菌、乳杆菌和拟杆菌数量与血清内毒素和IL-6、IL-1、TNF-α水平呈负相关,肠道肠杆菌和酵母菌数量与内毒素和IL-6、IL-1、TNF-α水平呈正相关(均P0.05)。结论原发性肝癌患者肠道菌群紊乱与内毒素和炎症因子水平具有相关性,肠道菌群失衡可能是促进该病病情发展的原因之一。     

IDH1 and IDH2 mutations are frequent in Chinese patients with acute myeloid leukemia but rare in other types of hematological disorders

Frequent mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1 and IDH2) have been identified in gliomas and acute myeloid leukemia (AML). Our aim is to assess whether IDH mutations were presented in Chinese patients with various hematological disorders. In this study, we screened the IDH1 and IDH2 mutations in a cohort of 456 Chinese patients with various hematological malignancies and disorders. We found three missense (p.R132C, p.R132G, and p.I99M; occurred in five patients) and one silent mutation (c.315C>T; occurred in two patients) in the IDH1 gene and two missense mutations (p.R140Q and p.R172K; occurred in four AML patients) and one silent mutation (c.435G>A) in the IDH2 gene. Except for one non-Hodgkin lymphoma (NHL) patient harboring IDH1 mutation p.R132C, all IDH1 and IDH2 missense mutations were observed in patients with AML. Intriguingly, the IDH2 mutation p.R140Q and novel IDH1 mutation p.I99M co-occurred in a 75-year-old patient with AML developed from myelodysplastic syndromes (MDS). The frequency of IDH1 and IDH2 missense mutations in Chinese AML patients reached 5.9% and 8.3%, respectively. Our results supported the recent findings that IDH gene mutations were common in AML. Conversely, IDH mutations were rather rare in Chinese patients with other types of hematological disorders.     

念珠菌血症的危险因素和预后分析

目的了解念珠菌血症的临床特点、分布及预后危险因素。方法回顾性调查2012年1月至2014年5月浙江大学医学院附属第一医院所有血培养念珠菌阳性的患者资料,分析其临床特征、治疗和预后等,采用χ2检验或Fisher精确概率法进行预后单因素分析,采用多元Logistic回归进行预后多因素分析。结果 97例念珠菌血症患者入选,其中男性64例,女性33例,平均年龄（59.6±16.8）岁。包括白色念珠菌51例（52.6%）,非白色念珠菌46例（47.4%）,非白色念珠菌中热带念珠菌17例（17.5%）、近平滑念珠菌12例（12.4%）、光滑念珠菌7例（7.2%）、无名念珠菌4例（4.1%）、其他念珠菌6例（6.2%）。念珠菌培养阳性后30 d内死亡37例,30 d病死率为38.1%。Logistic多因素回归分析显示：年龄（OR=1.104,95%CI：1.041~1.170,P=0.001）、血液系统肿瘤（OR=63.256,95%CI：2.898~1380.833,P=0.008）、APACHEⅡ评分（OR=1.176,95%CI：1.053~1.313,P=0.004）、感染性休克（OR=12.032,95%CI：2.389~60.587,P=0.003）及合并细菌性血流感染（OR=26.016,95%CI：4.002~169.127,P=0.001）是其死亡的独立危险因素;而拔除或更换深静脉置管（OR=0.118,95%CI：0.025~0.559,P=0.007）是念珠菌血症死亡的独立保护性因素。结论念珠菌血症患者分布科室范围广、基础疾病重、侵入性操作多。年龄、高APACHEⅡ评分、感染性休克及合并细菌血流感染是影响念珠菌血症死亡的独立危险因素,拔除或更换深静脉置管是念珠菌血症死亡的独立保护性因素。     

IDH1/IDH2 Mutations Define the Prognosis and Molecular Profiles of Patients with Gliomas: A Meta-Analysis

Background

Isocitrate dehydrogenase isoforms 1 and 2 (IDH1 and IDH2) mutations have received considerable attention since the discovery of their relation with human gliomas. The predictive value of IDH1 and IDH2 mutations in gliomas remains controversial. Here, we present the results of a meta-analysis of the associations between IDH mutations and both progression-free survival (PFS) and overall survival (OS) in gliomas. The interrelationship between the IDH mutations and MGMT promoter hypermethylation, EGFR amplification, codeletion of chromosomes 1p/19q and TP53 gene mutation were also revealed.

Methodology and Principal Findings

An electronic literature search of public databases (PubMed, Embase databases) was performed. In total, 10 articles, including 12 studies in English, with 2,190 total cases were included in the meta-analysis. The IDH mutations were frequent in WHO grade II and III glioma (59.5%) and secondary glioblastomas (63.4%) and were less frequent in primary glioblastomas (7.13%). Our study provides evidence that IDH mutations are tightly associated with MGMT promoter hypermethylation (P<0.001), 1p/19q codeletion (P<0.001) and TP53 gene mutation (P<0.001) but are mutually exclusive with EGFR amplification (P<0.001). This meta-analysis showed that the combined hazard ratio (HR) estimate for overall survival and progression-free survival in patients with IDH mutations was 0.33 (95% CI: 0.25–0.42) and 0.38 (95% CI: 0.21–0.68), compared with glioma patients whose tumours harboured the wild-type IDH. Subgroup analyses based on tumour grade also revealed that the presence of IDH mutations was associated with a better outcome.

Conclusion

Our study suggests that IDH mutations, which are closely linked to the genomic profile of gliomas, are potential prognostic biomarkers for gliomas.     

High serum alkaline phosphatase cooperating with MMP-9 predicts metastasis and poor prognosis in patients with primary osteosarcoma in Southern China

Background

A malignant fibrous histiocytoma is a soft tissue tumor that most commonly occurs in the extremities, but rarely involves the liver. The clinical characteristics and therapeutic experiences of primary hepatic malignant fibrous histiocytoma are still limited.

Methods

Two cases of primary hepatic malignant fibrous histiocytoma were analyzed retrospectively, and all the literature concerning primary hepatic malignant fibrous histiocytoma was analyzed.

Results

In China, a total of 76 cases had been reported, among which 50 were men, with a male to female ratio of 1.9:1. Mean age of the patients was 51.0 years old, and more than 85 percent were older than 40 years. 82.9 percent (63/76) of hepatic MFH were solitary lesions, with tumor size ranging from 2.5 to 23.5 cm (average 10.3 cm). Major clinical presentation (78.4%) was abdominal pain or discomfort, accompanied with some other non-specific symptoms such as malaise, anorexia, weight loss, jaundice and fever, and small cases (14.9%) were asymptomatic. Computed tomography and ultrasound usually revealed the location of lesions. The rate of pre-operative misdiagnosis was extremely high, and 14.9 percent of patients were even misdiagnosed as a benign liver cyst, liver abscess or hematoma. Integrated resection was performed among the most cases (49/68), among which only a few ones (12 cases) were introduced to have no recurrence or metastasis or be still alive with no detail information provided, while among the cases with palliative operation or only a biopsy, the cases that were followed-up all died.

Conclusions

Hepatic malignant fibrous histiocytoma is a rare malignant mesenchymal tumor. The variable features of clinical presentations and images make the diagnosis difficult. Though the prognosis of primary hepatic malignant fibrous histiocytoma was rather poor, integrated resection might provide a few cases a good opportunity for surviving, suggesting that surgery might be an effective treatment.     

Loss of microRNA-132 predicts poor prognosis in patients with primary osteosarcoma

??₂-glycoprotein I (??₂-GPI) is a plasma glycoprotein with diverse functions, but the impact and molecular effects of ??₂-GPI on vascular biology are as yet unclear. Based on the limited information available on the contribution of ??₂-GPI to endothelial cells, we investigated the effect of ??₂-GPI on cell growth and migration in human aortic endothelial cells (HAECs). The regulation of ??₂-GPI as part of intracellular signaling in HAECs was also examined. Vascular endothelial growth factor (VEGF) is a pro-angiogenic factor that may regulate endothelial functions. We found that ??₂-GPI dose-dependently inhibited VEGF-induced endothelial cell growth using the 3-(4,5-dimethylthiazol-2-yl)-2,5-dipenyl tetrazolium bromide assay and cell counts. Using wound healing and Boyden chamber assays, ??₂-GPI remarkably reduced VEGF-increased cell migration at the physiological concentration. Furthermore, ??₂-GPI suppressed VEGF-induced phosphorylation of VEGF receptor 2 (VEGFR2), extracellular signal-regulated kinase 1/2 (ERK1/2), and Akt. These results suggest that ??₂-GPI plays an essential role in the down-regulation of VEGF-induced endothelial responses and may be a useful component for anti-angiogenic therapy.     

Pyroptosis in glioblastoma: A crucial regulator of the tumour immune microenvironment and a predictor of prognosis

Recent studies have shown that pyroptosis, an inflammatory form of cell death, has a dual role in tumorigenesis and tumour progression and affects the prognosis of patients; however, the role of pyroptosis in glioblastoma (GBM) is still unclear. In this study, based on GBM patients'' data from two independent cohorts, we performed a comprehensive analysis of the expression and prognostic value of 33 pyroptosis‐associated genes (PAGs) in GBM, as well as their role in the tumour immune microenvironment (TIME) of GBM. We identified 29 PAGs that were differentially expressed between GBM and normal brain tissue, 18 of which were upregulated in GBM tissue. Most of the 33 PAGs were strongly correlated with the levels of immune cell infiltration. Based on the 33 PAGs, the GBM samples can be divided into two clusters (C1‐C2), with C1 having a ‘hot’ but immunosuppressive TIME and C2 having a ‘cold’ TIME, suggesting different immunotherapeutic responses in the two clusters. In addition, we identified four PAGs that were strongly associated with GBM prognosis and constructed a risk model based on these four PAGs. This risk model is an independent prognostic factor for GBM patients, and there is a different immune status between high‐ and low‐risk groups. In conclusion, this study demonstrates that pyroptosis is closely associated with the prognosis and TIME of GBM and provides an important basis for further studies on the relationship between pyroptosis and GBM.     

First report of glucose transporter 1 deficiency syndrome in Korea with a novel splice site mutation

Glucose transporter type 1 deficiency syndrome (Glut-1DS) is caused by autosomal dominant haplodeficiency or autosomal recessive with homozygous mutation of the glucose transporter 1 (SLC2A1) gene and is characterized by severe seizures, developmental delay, ataxia and acquired microcephaly. We describe the first known Korean patient with glucose transporter 1 deficiency syndrome, who had a novel mutation in the splice site. The patient began having intractable seizures at 4days of age that initially presented as eye blinking and apnea, evolving into generalized tonic seizures. A lumbar puncture revealed low glucose concentration in the cerebrospinal fluid (CSF) in the setting of normoglycemia (blood glucose, 106mg/dl; CSF glucose 21mg/dl, and CSF to blood glucose ratio 0.20). The results of a 3-O-methylglucose uptake study in erythrocytes (RBC) revealed that glucose uptake reduced to 48% of his parents in the patient. The patient responded to a ketogenic diet that was initiated at 4months of age and currently is on the modified Atkins diet (MAD) without seizures. He does not require antiepileptic medication. We diagnosed the first Glut-1 patient in Korea with a novel splice site mutation on the basis of clinical features, deficient glucose uptake and a mutation in the SLC2A1 gene.     

老年患者脓毒性休克液体复苏速度与预后的关系

目的探讨老年患者脓毒性休克液体复苏过程中输液速度与预后的相关性。方法回顾性分析92例严重感染病人液体复苏效果。按液体复苏期间的输液速度分为慢速组（〈500ml/h）和快速组（≥500ml/h）,并对两组患者的心率、有创及无创血压、血氧饱和度、呼吸、中心静脉压（CVP）、每小时尿量、尿比重、血乳酸、ScVO2及有无发生肺水肿、急性心功能不全、急性肾功能不全、MODS和7天死亡率、28天死亡率及入住ICU时间、住院时间等指标进行分析比较。结果两组患者在液体复苏过程中CVP和MAP两项指标比较无统计学意义。慢速组的尿量达标时间耗时较长（P〈0.05）;ScVO2及乳酸清除率比较无明显差异。快速组对液体的需求量多,而应用血管活性药物的病例数则少于慢速组;发生肺水肿、急性心功能不全的比例高于慢速组（P〈0.05）。两组急性肾功能不全的发生率相近,但慢速组出现MODS的例数少（P〈0.05）。7天死亡率和28天死亡率比较,慢速组低于快速组,但无统计学意义。两组患者住院时间无显著统计学意义,入住ICU时间慢速组明显短于快速组（P〈0.05）。结论在脓毒性休克复苏过程中不可一味靠加快输液速度来保证组织灌注,尤其对于老年患者,更应控制单位时间内的输液量,避免给储备能力较差的心功能造成更大的负担。在保证主要脏器灌注的情况下可以适当应用血管活性药物。     

Risk factors of household transmission of pandemic (H1N1) 2009 among patients treated with antivirals: a prospective study at a primary clinic in Japan

Background

Household transmission of influenza can affect the daily lives of patients and their families and be a trigger for community transmission, thus it is necessary to take precautions to prevent household transmission. We aimed to determine the risks of household transmission of pandemic (H1N1) 2009 influenza virus from an index patient who visited a primary clinic and was treated with antiviral drugs.

Methods

We followed up all the patients who were diagnosed with influenza A by rapid diagnostic test with a questionnaire or interview from July 2009 to April 2010. Secondary cases were defined as patients visiting the clinic or other clinics and being positive for influenza A by rapid diagnostic test within 7 days of onset of an index patient. Logistic regression analysis was used to explore the association between household transmission and the studied variables.

Results

We recruited 591 index patients and 1629 household contacts. The crude secondary attack rate was 7.3% [95% confidence interval (CI): 6.1–8.7]. Age of index patients (0–6 years old: odds ratio 2.56; 95% CI: 1.31–4.01; 7–12 years old: 2.44, 1.31–3.72; 30–39 years old 3.88; 2.09–5.21; 40 years old or more 2.76; 1.17–4.53) and number of household members with five or more (3.09, 2.11–4.07), medication started ≥48 hours from the onset of fever (2.38, 1.17–3.87) were significantly associated with household transmission.

Conclusions

Household transmission was associated with index patients aged ≤12 years old and adults ≥30 years with children, with more than five persons in the household, and medication initiated ≥48 hours from the onset of fever among the population, in which, antiviral treatment was given to all patients. We need to warn patients at high risk of household transmission to take additional precautions.     

Low expression of ENC1 predicts a favorable prognosis in patients with ovarian cancer

Ectodermal-neural cortex 1 (ENC1) belongs to a member of the kelch family of genes. It is an actin-binding protein and plays a pivotal role in neuronal and adipocyte differentiation. Here, we found that lower expression of ENC1 in the ovarian cancer patients was associated with favorable prognosis. In addition, ENC1 was heterogeneously expressed in various ovarian cancer cells. The messenger RNA and protein expression levels of ENC1 in HO-8910PM and NIH:OVCAR-3 cells were obviously higher than that in the other types of ovarian cancer cells. Knockdown of ENC1 in HO-8910PM or NIH:OVCAR-3 cells could significantly increase the reactive oxygen species levels, resulting in inhibition of in vitro proliferation, migration, and invasion. Our findings suggest that decreasing expression of ENC1 may be a new approach that can be used for ovarian cancer treatment.     

WT1 mutations in patients with Denys-Drash syndrome: a novel mutation in exon 8 and paternal allele origin

Denys-Drash syndrome (DDS) is characterized by early onset nephropathy, pseudohermaphroditism in males and a high risk for developing Wilms' tumour (WT). The exact cause of DDS is unknown but germline mutations in the Wilms' tumour suppressor gene (WT1) have recently been described in the majority of DDS patients studied. These mutations occur de novo and are clustered around the zinc finger (ZF) coding exons of the WT1 gene. Analysis of exons 2–10 of the WT1 gene in constitutional DNA from five patients with DDS was carried out using the polymerase chain reaction (PCR) and direct DNA sequencing. In four out of the five patients, heterozygous germline mutations were found: a novel point mutation in exon 8 (ZF₂) at codon 377 altering the wild-type histidine to arginine, and three previously described point mutations in exon 9 (ZF₃) in the codons corresponding to amino acids ³⁹⁴Arg and ³⁹⁶Asp. In one patient, no mutations could be demonstrated. In three patients where parental DNA was available, the mutations were shown to have occurred de novo. Furthermore, since tumour DNA in two of these cases had lost the wild-type allele, polymorphic markers from the short arm of chromosome 11 were used to determine the parental origin of the mutant chromosome. In both cases, the mutant chromosome was shown to be of paternal origin. Since the majority of published WT1 mutations in DDS patients alter a RsrII restriction site in exon 9, we were able to perform PCR-based diagnosis in a female patient with early renal insufficiency and normal external genitalia.