MicroRNA and Brain Tumors

MicroRNAs(miRNAs)were first described in 1993 by Lee and col eagues,and the term microRNA was only introduced in 2001 in a set of three articles in Science[1].One of the biggest surprises in the past few years has been the emergence of miRNAs as a major new class of gene expression regulators.Recent studies suggest that miRNA alterations are involved in the initiation and progression of human cancer.The brain tumor, glioblastoma multiforme,is the most malignant and deadly form of gliomas. The prognosis is poor and the median survival with combined radiotherapy and chemotherapy is only 14.6 months.With the discovery of miRNA,the miRNA profiles may become useful biomarkers for brain tumor diagnostics, and miRNA therapy could be a powerful tool for brain tumor prevention and therapeutics.This review outlines the background of miRNA and its expression and therapeutic potential for brain tumors.     

Phosphatase of Regenerating Liver and Its Association with Tumors

Protein kinases and protein phosphatases play key roles in regulating functions of diverse proteins which control numerous     

Diagnosis and Treatment of Gastric Stromal Tumors： Report of 70 Cases

Objective  To investigate the diagnosis and treatment of gastric stromal tumors (GSTs). Methods  The clinical data from 70 cases with GSTs were analyzed retrospectively. Results  Wedge resections were performed on 32 patients and major gastrectomies on 38 patients. The median tumor size was 5.4cm in diameter and 2 out of 70 cases (2.9% ) indicated positive lymph node metastasis. Immunohistochemical staining showed 66 out of 70 (94.3%) were positive for CD117, 53 (75.7%) positive for CD34, 24 positive for SMA and 8 positive for Desmin and S100. Ten out of 70 cases recurred or metastasized. The 5-year survival rate in this series was 71.3%. The 5-year survival rate of benign and malignant GSTs were 92.3% and 61.8% (P<0.05) respectively. The 5-year survival rate for tumors of size <5 cm and ≥5 cm were 95.0% and 48.4% (P< 0.05), respectively. Conclusion  The primary treatment for gastric stromal tumors is surgery. Tumor size and mitotic counts were observed to be important prognostic indicators.     

Clinical Features and Mid-Term and Long-Term Outcomes of Surgical Treatment of 8 Patients with Primary Ventricular Tumors

OBJECTIVE To summarize the clinical features and surgical treatment of primary ventricular tumors. METHODS Eight patients with primary ventricular tumor, aged 3 to 52 years, underwent surgical treatment. There were 6 males and 2 females. The pathological diagnoses were as follows: multiple left ventricular myxomas in 2 cases; left ventricular rhabclomyoma, fibroma and malignant neurolemmoma in 1 case for each; right ventricular myxoma and malignant neurolemmoma in 1 case for each; intraseptal fibroma in 1 case. The operations were performed through median sternotomy with moderate hypothermic cardiopulmonary bypass in 7 cases; via left anterolateral thoracotomy without extracorporeal circulation in 1 case. Tumors were totally removed in 7 cases and subtotally resectecl in 1 case. RESULTS Cardiac arrest after anaesthetization occurred in 1 case with postoperative coma for 10 days. One case died of massive gastro-intestinal hemorrhage postoperatively. Seven cases survived, During a follow-up period of 1 to 21 years, there was no recurrence or metastasis in the 6 cases who received complete tumor resection including 2 cases with malignant tumor. One case of partial tumor removal had a mild heart murmur without tumor progression. All patients were asymptomatic with cardiac functiongrade I. CONCLUSION Primary ventricular tumors showed diversity in their histological characteristics. The mid- and long-term outcomes of surgical treatment for primary ventricular tumors appear to be satisfactory.     

Non-Functioning Pancreatic Neuroendocrine Tumors—A Case Report and Review of Literature

Purpose

Neuroendocrine tumors of pancreas (PNET) are rare pancreatic neoplasms comprising 1–2% of all pancreatic tumors. The overall prognosis and long-term survival for PNET patients is far better than for patients with exocrine pancreatic cancer. PNETs are classified as functional or nonfunctional based on the presence or absence of a specific clinical syndrome associated with hormone oversecretion.

Methods

We present the case of a 36-year-old female with epigastric and right upper quadrant abdominal pain for 3 months associated with decreased appetite, early satiety and a 20-lb weight loss. On examination, she was cachectic with hepatomegaly.

Results

Laboratory assays showed elevated liver and pancreatic enzymes. On computed tomography (CT) scan of the abdomen and pelvis, there was a low-attenuation mass in the distal pancreatic tail measuring 4.7?×?2.4 cm with multiple liver masses, omental implants, left ovarian mass, and a small amount of ascites. CT-guided liver biopsy on pathology was consistent with a well-differentiated pancreatic neuroendocrine carcinoma with metastasis to the liver. Assays for biomarkers of pancreatic neuroendocrine tumors showed an elevated chromogranin A with normal to non-specific elevations of the rest.

Conclusions

The patient and her family declined palliative chemoembolization of the liver lesions or palliative chemotherapy and desired home hospice. We describe here the presentation and course of the case as well as a literature review of PNET with particular emphasis on nonfunctioning PNETs.     

Clinical Analysis of Diagnosis and Treatment of Gastrointestinal Stromal Tumors （Report of 96 Cases）

Objective To investigate the pathological diagnosis, surgical treatment and prognosis of gastrointestinal stromal tumors (GIST). Methods The clinicopathological data of 96 post-operative cases with GIST were analyzed retrospectively, and expression of immunohistochemical staining of CD117, CD34, SMA and S -100 was determined. Results Immunohistochemical positive staining showed: CD117, 79.1% (76/96); CD34, 58.3% (56/96); SMA, 35.4% (34/96); S-100, 9.3% (9/96). Twenty-three benign cases and 73 malignant cases were reported. The omentums were resected in 39 malignant cases. For the other 34 malignant cases the omentums were left intact. The recurrent and metastatic rates were 5.1% and 26.5%(P<0.05). The incisai section between the normal bowel and the tumor was >5cm in 46 cases, for the other 27 cases, the section was < 5cm. The recurrent and metastatic rates were 6.5% and 29.6%(P<0.05), respectively. The 5-year survival rates of benign and malignant GIST were 91.5% and 57.3%(P<0.05). Conclusion GIST were the most freuquent mesenchymal tumor seen in the gastrointestinal tract. The application of immunohistochemical markers CD117and CD34 are mutually beneficial for a final correct pathological diagnosis. The adaptation of a primary rational treatment, including the complete tumor resection and preventive omentectomy could reduce the recurrence of GIST.     

Evaluation Expression of Microrna-93 and Integrin Β8 in Different Types of Glioma Tumors

MicroRNAs (miRNAs), are a type of small non-coding RNAs, that induce mRNA degradation or repress translation by binding to the 3′-untranslated region (UTR) of its target mRNA. Some specific miRNAs, e.g. miR-93, have been discovered to be involved in pathological procedures by targeting some oncogenes or tumor suppressors in glioma. In the present study, real-time RT-PCR data was indicated the expression pattern and prognostic value of miR-93 in patients with types of Glioma.MiR-93 expression was significantly decreased in tumor tissue compared with normal group brain tissues (P<0.001). Low miR-93 expression was significantly correlated with progressive tumor grade (P=0.02).Moreover, multivariate analysis showed that miR-93 decreased expression (HR, 4.3; 95% CI, 0.8–17.2, P=0.02), advanced tumor grade (HR, 3.1; 95% CI, 0.2–13.9, P=0.04), for integrinβ8, level expression was inverse. Our data was shown that the down regulation of miR-93 was significantly correlated with unfavorable pathological features in patients with Glioma .Suggesting that decreased expression of miR-93can be used as a novel prognostic factor for this disease.     

Carinal Resection and Reconstruction for Primary Carinal Tumors—Report of 9 Cases

From Oct.1989 to Cec.1998,9 patients aged 12-67 years underwent carinal resection and reconstruction through right or left intercostal space thoraotomy.No important postoperative complications occurred and there were no perioperative deaths.Leiomyoma,neurofibroma,carcioid and squamous cell carcinoma was found in one patient respectively,adenocarcioma in 2 patients,adenoid cystic carcinoma in 3 patients.The actuarial 3-year survival rate for patients with malignant tumors was 42.9%.In order to diagnose early and correctly,bronchoscopy and computed tomography should be used.The end-to-end anastomosis of trachea with bilateral bronchi is the optimal choice among the modes of carinal reconstruction.Some principles of surgery and perioperative care are discussed.     

The Treatment of High Grade Gliomas and Diffuse Intrinsic Pontine Tumors of Childhood and Adolescence: A Historical – and Futuristic – Perspective

Summary Pediatric high grade gliomas represent a heterogeneous group of tumors with poor prognoses despite the use of multimodal treatment. Very little progress has been made over the past decades in identifying efficacious therapeutic modalities against both high grade gliomas and diffuse brainstem gliomas in children. The degree of surgical resection is the most important clinical prognostic factor for children with high grade gliomas, and a complete resection should be attempted whenever feasible. The role of radiation therapy in the treatment of older children with high grade gliomas and diffuse brain stem gliomas is undisputed; however the benefit of using radiation for patients less than 6 years of age (with high grade gliomas) might be questionable. Despite the absence of solid evidence to support its use, chemotherapy is routinely used against these tumors. Currently temozolomide is being investigated due to its activity in adult trials and based on preliminary data regarding recurrent disease. A small subgroup of patients can be successfully treated with high dose chemotherapy followed by autologous stem cell rescue. Early trials using this modality in the past had been associated with high morbidity and mortality. High dose chemotherapy with autologous stem cell rescue in selected patients with minimal residual disease, angiogenesis inhibitors, radiosensitizers and other biological modifiers are being currently investigated in phase I/II trials.     

Boron Neutron Capture Therapy of Brain Tumors: Functional and Neuropathologic Effects of Blood–Brain Barrier Disruption and Intracarotid Injection of Sodium Borocaptate and Boronophenylalanine

Sodium borocaptate (BSH) and boronophenylalanine (BPA) are two drugs that have been used clinically for boron neutron capture therapy (BNCT) of brain tumors. We previously have reported that hyperosmotic mannitol-induced disruption of the blood–brain barrier (BBB-D), followed by intracarotid (i.c.) administration of BPA or BSH, either individually or in combination, significantly enhanced tumor boron delivery and the efficacy of BNCT in F98 glioma bearing rats. The purpose of the present study was to determine the short-term neuropathologic consequences of this treatment and the long-term effects on motor and cognitive function, as well as the neuropathologic sequelae 1 year following neutron capture irradiation. BBB-D was carried out in non-tumor bearing Fischer rats by infusing a 25% solution of mannitol i.c. followed by i.c. injection of BPA or BSH, either individually or in combination, immediately thereafter. Animals were euthanized 2 days after compound administration, and their brains were processed for neuropathologic examination, which revealed sporadic, mild, focal neuronal degeneration, hemorrhage, and necrosis. To assess the long-term effects of such treatment followed by neutron capture irradiation, non-tumor bearing rats were subjected to BBB-D after which they were injected i.c. with BPA (25mgB/kg body weight (b.w)) or BSH (30mgB/kg b.w.) either individually or in combination (BPA 12.5mg and BSH 14mgB/kg b.w.). Two and a half hours later they were irradiated at the Medical Research Reactor, Brookhaven National Laboratory, Upton, NY, with the same physical radiation doses (5.79, 8.10 or 10.06Gy), delivered to the brain, as those that previously had been used for our therapy experiments. The animals tolerated this procedure well, after which they were returned to Columbus, Ohio where their clinical status was monitored weekly. After 1 year, motor function was assessed using a sensitive and reliable locomotor rating scale for open field testing in rats and cognitive function was evaluated by their performance in the Morris water maze, the results of which were similar to those obtained with age matched controls. After functional evaluation, the rats were euthanized, their brains were removed, and then processed for neuropathologic examination. Subtle histopathologic changes were seen in the choroid plexuses of irradiated animals that had received BPA, BSH or saline. Radiation related ocular changes consisting of keratitis, blepharitis, conjunctivitis and cataract formation were seen with similar frequency in most rats in each treatment group. Based on these observations, and the previously reported significant therapeutic gain associated with BBB-D and i.c. injection of BSH and BPA, the present observations establish its safety in rats and suggest that further studies in large animals and humans are warranted.     

Tumors Involving Skin,Soft Tissue and Skeletal Muscle: Benign,Primary Malignant or Metastatic?

Background: Metastatic cancer with invasion of skin, soft tissue and skeletal muscle is not common. Examplespresenting as soft tissue masses could sometimes lead to misdiagnosis with delayed or inappropriate management.The purpose of current study was to investigate clinical characteristics in the involvement of metastatic cancer.Materials and Methods: A total of 1,097 patients complaining of skin or soft tissue masses and/or lesions wereretrospectively reviewed from January 2012 to June 2013. Tumors involving skin, soft tissue and skeletal muscleof head and neck, chest wall, abdominal wall, pelvic region, back, upper and lower extremities were includedin the study. Results: Fifty-seven (5.2%) patients were recognized as having malignancies on histopathologicalexamination. The most common involvement of malignancy was basal cell carcinoma, followed by cutaneoussquamous cell carcinoma, sarcoma and melanoma. The most common anatomical location in skin and soft tissuemalignancies was head and neck (52.6% of the malignancies). Four (0.36%) of the malignant group were identifiedas metastatic cancer with the primary cancer source from lung, liver and tonsil and the most common site wasupper extremities. One of them unexpectedly expired during the operation of metastatic tumor excision at thescalp. Conclusions: Discrimination between benign and malignant soft tissue tumors is crucial. Performanceof imaging study could assist in the differential diagnosis and the pre-operative risk evaluation of metastatictumors involving skin, soft tissue and skeletal muscle.     

Investigation of ICAM-1 and β3 Integrin Gene Variations in Patients with Brain Tumors

Background: Primary brain tumors constitute a small percent of all malignant cancers, but their etiologyremains poorly understood. β3 integrin (ITGB3) has been recognized to play influential roles in angiogenesis,tumor growth and metastasis. Intercellular adhesion molecule-1 (ICAM-1) is a surface glycoprotein important fortumor invasion and angiogenesis. The aim of this study was to investigate whether specific genetic polymorphismsof ICAM-1 and ITGB3 could be associated with brain cancer development and progression in a Turkishpopulation. Our study is the first to our knowledge to investigate the relationship between brain tumor riskand ICAM-1 and β3 integrin gene polymorphisms. Materials and Methods: The study covered 92 patients withprimary brain tumors and 92 age-matched healthy control subjects. Evaluation of β3 integrin (Leu33Pro (rs5918))and ICAM-1 (R241G (rs1799969) and K469E (rs5498)) gene polymorphisms was performed by polymerasechain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: According to results of ourresearch, the A allele of the ICAM-1 R241G gene polymorphism appeared to be a risk factor for primary braintumors (p<0.001). Similarly, the frequency of the A mutant allele of ICAM-1 R241G was statistically significantin patients with brain tumors classified as glioma (p<0.001). When allele and genotype distributions of ICAM-1 K469E, ICAM-1 R241G and β3 integrin Leu33Pro gene polymorphisms were evaluated with age, sex, andsmoking, there were no statistically significant differences. Haplotype analysis revealed that the frequencies ofGAC (rs1799969-rs5498-rs5918) and GAT (rs1799969-rs5498-rs5918) haplotypes were significantly lower inpatients as compared with controls (p=0.001; p=0.036 respectively). Conclusions: This study provides the firstevidence that ICAM-1 R241G SNP significantly contributes to the risk of primary brain tumors in a Turkishpopulation. In addition, our results suggest that ICAM-1 R241G in combination ICAM-1 K469E may haveprotective effects against the development of brain cancer.     

Hepatocellular Tumors:Immunohistochemical Analyses for Classification and Prognostication

Following the classification of hepatocellular nodules by the International Working Party in 1995 and further elaboration by the International Consensus Group for Hepatocellular Neoplasia in 2009,entities under the spectrum of hepatocellular nodules have been better characterized.Research work hence has been done to answer questions such as distinguishing high-grade dysplastic nodules from early hepatocellular carcinoma (HCC),delineating the tumor cell origin of HCC,identifying its prognostic markers,and su...     

Gastrointestinal Stromal Tumors—A Morphological and Immunohistochemical Study

Purpose

The rationale of this study was to assess the morphological and immunohistochemical characteristics of gastrointestinal stromal tumor (GIST) along with their risk stratification.

Methods

Record of 36 cases diagnosed as GIST over a period of 2 years (January 2007 to December 2008) was retrieved. Slides were reviewed for histological typing, immunohistochemical staining, and mitotic count. Cases were divided into very low, low, intermediate, and high-risk groups according to the Fletcher method of risk stratification (Table 1; Fletcher et al. (Int J Surg Pathol 10:81–89, 2002)). Mean, median, and mode were calculated for quantitative variables like age, tumor size, and mitotic count by using SPSS version 14. Frequencies and percentages were also calculated for qualitative variables like results of immunohistochemistry, tumor site, and histological subtypes.

Results

Out of 36 patients, 14 patients were male, and 22 were female. A total of 14 (39%) patients had tumor size between 2 and 5 cm, 13 (36%) patients had size between 5 and 10 cm, and 9 (25%) patients had size >10 cm. There was no tumor less than 2 cm in size. Twenty-one patients (58%) had mitoses <5/50 high power fields (HPF) while seven (20%) had mitoses between 5 and 10/50 HPF and eight (22%) >10/50 HPF. Thirty-one (86%) of cases were strongly positive for CD117 while CD34 was positive in 81% of the cases. Most frequent histological type was hypercellular spindle cell type, and most frequent site of presentation was stomach. Seven patients fell into low risk, ten patients intermediate risk, and 19 patients in high risk groups. There were no patients in very low risk group.

Conclusion

By using microscopy and immunohistochemical techniques, GISTs can be diagnosed accurately and treated efficiently. Risk stratification and histological subtyping have emerged as efficient tools to predict malignant behavior.     

Pancreatic Neuroendocrine and Carcinoid Tumors: What’s New,What’s Old,and What’s Different?

Well-differentiated neuroendocrine tumors (NETs) can be subdivided into carcinoid and pancreatic NETs (panNETs). Recently, two therapies have been FDA approved for progressive well-differentiated pancreatic NETs but have not been submitted for use in carcinoid tumors (Yao, Shah, Ito, et al. N Engl J Med 364:514–23, 2011??; Raymond, Dahan, Raoul, et al. N Engl J Med 364:501–13, 2011??). The first is sunitinib (Sutent®, Pfizer, Inc.), an orally administered, multitargeted receptor kinase inhibitor. The second targeted agent is everolimus (Afinitor®, Novartis Pharmaceuticals), a mammalian target of rapamycin (mTOR) inhibitor (Yao, Shah, Ito, et al. N Engl J Med 364:514–23, 2011??). Both agents demonstrated improved progression-free survival but can also result in non-trivial toxicities and therefore, should only be considered in patients with progressing or symptomatic pancreatic NET. This review will discuss “new” NET therapies and provides an overview of liver directed and “older” cytotoxic treatment options. We also briefly outline “what’s different” by describing a recent genetics report identifying genetic mutations in panNETs. Such a discovery could potentially be used to stratify treatment and such studies are currently being investigated.     

Antiangiogenesis – Therapeutic Strategies and Clinical Implications for Brain Tumors

The poor prognosis of patients with malignant brain tumors in spite of aggressive multimodality therapy has led to the search for novel therapeutic strategies. Among the targets for such treatment approaches, tumor angiogenesis has captured the attention of not only the medical field but also of the lay public because of its conceptual departure from traditional methods of cancer therapy. Angiogenesis and vascular proliferation are particularly important in the growth and progression of malignant gliomas and are used as indicators of the degree of malignancy. Recent studies have helped us gain a better understanding of the molecular mediators of this process. It is now evident that after the initial formation of malignancy the continued growth of a glioma is critically dependent on its angiogenic potential. Hence, several approaches to control angiogenesis are being developed and tested. In the present review, we examine some of these approaches from a therapeutic perspective and summarize the findings from early human trials of such agents.     

Expression of Vascular Endothelial Growth Factor-C and Vascular Endothelial Growth Factor Receptor-3 in Ovarian Epithelial Tumors

Objective： To explore the role of vascular endothelial growth factor-C （VEGF-C） in the process of angiogenesis, lymphangiogenesis and lymphatic metastasis in epithelial ovarian tumors. Methods： In situ hybridization and immunohistochemical staining for VEGF-C were performed in 30 epithelial ovarian carcinomas, 9 borderline tumors and 26 benign tumors. Endothelial cells were immunostained with anti-VEGFR-3 pAb and anti-CD31 mAb, and VEGFR-3 positive vessels and microvessel density （MVD） were assessed by image analysis. Results： VEGF-C mRNA and protein expression were detected in cytoplasm of carcinoma cells. VEGF-C mRNA and protein expression in ovarian epithelial carcinomas were significantly higher than those in borderline tumors and benign tumors （P〈0.05 or P〈0.01）. In ovarian epithelial carcinomas, VEGF-C protein expression, VEGFR-3 positive vessels and MVD were significantly higher in the cases of clinical stage Ⅲ-Ⅳ and with lymph node metastasis than those of clinical stage Ⅰ-Ⅱ and without lymph node metastasis respectively （P〈0.05 or P〈0.01）. VEGFR-3 positive vessels and MVD were significantly higher in VEGF-C protein positive tumors than negative tumors （P〈0.05）. VEGFR-3 positive vessels was significantly correlated with MVD（P〈0.01）. Conclusion： VEGF-C might play a role in lymphatic metastasis via lymphangiogenesis and angiogenesis in epithelial ovarian tumors, and VBEGF-C could be used as a biologic marker of metastasis in ovarian epithelial tumors.     

A Retrospective Study of Primary Brain Tumors in Children under 14 Years of Age at PIMS,Islamabad

The aim of present study was to determine the relative frequency of primary brain tumors among childrenunder 14 years of age in Pakistan. A retrospective review of pediatric primary brain tumors, encounteredover 13 years (January 1998 through July 2010) at the Neurosurgical Unit of the Pakistan Institute of MedicalSciences (PIMS), Islamabad, Pakistan, was made covering 231 cases, 142 (61.5%) males and 89 (38.5%) females,with a male to female ratio of 1.69:1. The cases were divided into 5 age groups each covering three years of life(0-2, 3-5, 6-8,9-11 and 12-14 years), with the greatest number in age group 3 i.e. 6-8 years (32%) and the leastnumber of patients in age groups 1 and 5 (10.3% each). The 231 malignancies were categorized by site into twogroups, supratentorial (83 cases; 35.9%) and infratentorial (148 cases; 64.1%). The morphological distributionwas medulloblastoma (33.3%), astrocytoma (24.7%), mixed gliomas (14.7%), craniopharyngioma (11.7%),ependymoma (8.7%), PNET (6.1%) and pineal tumor (0.9%). Since only a single institution was studied, cautiousinterpretation is needed. Ideally, a population-based approach would be adopted to determine the cancerburden due to pediatric malignancies of the brain in this population and for their morphological categorizationin Pakistan.