Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/or gene products between invading and noninvading glioma cells may identify potential targets for new therapies. To look for genes associated with glioma invasion, we first employed Affymetrix microarray Genechip technology to identify genes differentially expressed in migrating glioma cells in vitro and in invading glioma cells in vivo using laser capture microdissection. We observed upregulation of a variety of genes, previously reported to be linked to glioma cell migration and invasion. Remarkably, major histocompatiblity complex (MHC) class I and II genes were significantly downregulated in migrating cells in vitro and in invading cells in vivo. Decreased MHC expression was confirmed in migrating glioma cells in vitro using RT-PCR and in invading glioma cells in vivo by immunohistochemical staining of human and murine glioblastomas for beta2 microglobulin, a marker of MHC class I protein expression. To the best of our knowledge, this report is the first to describe the downregulation of MHC class I and II antigens in migrating and invading glioma cells, in vitro and in vivo, respectively. These results suggest that the very process of tumor invasion is associated with decreased expression of MHC antigens allowing glioma cells to invade the surrounding brain in a 'stealth'-like manner.     

Thirty-Day Readmission After Laparoscopic Sleeve Gastrectomy—a Predictable Event?

Background

Thirty-day readmission post-bariatric surgery is used as a metric for surgical quality and patient care. We sought to examine factors driving 30-day readmissions after laparoscopic sleeve gastrectomy (LSG).

Methods

We reviewed 1257 LSG performed between March 2012 and June 2014. Readmitted and nonreadmitted patients were compared in their demographics, medical histories, and index hospitalizations. Multivariable regression was used to identify risk factors for readmission.

Results

Forty-five (3.6 %) patients required 30-day readmissions. Forty-seven percent were readmitted with malaise (emesis, dehydration, abdominal pain) and 42 % with technical complications (leak, bleed, mesenteric vein thrombosis). Factors independently associated with 30-day readmission include index admission length of stay (LOS) ≥3 days (OR 2.54, CI?=?[1.19, 5.40]), intraoperative drain placement (OR 3.11, CI?=?[1.58, 6.13]), postoperative complications (OR 8.21, CI?=?[2.33, 28.97]), and pain at discharge (OR?8.49, CI?=?[2.37, 30.44]). Patients requiring 30-day readmissions were 72 times more likely to have additional readmissions by 6 months (OR?72.4, CI?=?[15.8, 330.5]).

Conclusions

The 30-day readmission rate after LSG is 3.6 %, with near equal contributions from malaise and technical complications. LOS, postoperative complications, drain placement, and pain score can aid in identifying patients at increased risk for 30-day readmissions. Patients should be educated on postoperative hydration and pain management, so readmissions can be limited to technical complications requiring acute inpatient management.

     

Laparoscopic gastric banding resolves the metabolic syndrome and improves lipid profile over five years in obese patients with body mass index 30–40 kg/m

Background

Obesity, metabolic syndrome (MS) and dyslipidemia are independent risk factors for cardiovascular disease. Bariatric surgery is increasingly recognized as an effective intervention for improving each of these risk factors. There are sparse data on the long-term durability of metabolic changes associated with bariatric surgery, in particular with laparoscopic gastric banding (LGB). Our objective was to evaluate the durability of metabolic changes associated with LGB in nonmorbid obesity.

Methods

Fifty obese patients (BMI 30–40) with ≥1 obesity-related comorbidity were prospectively followed for five years. At follow-up, subjects underwent fasting blood measures, including lipid NMR spectroscopy and standard lipid profile.

Results

Forty-seven patients (45 female, mean age 43.8 years) completed four years follow-up (46 completed five years). Baseline BMI was 35.1 ± 2.6. Subjects exhibited mean weight loss of 22.3 ± 7.9 kg (22.9 ± 7.4%) at year one and maintained this (19.8 ± 10.2%) over five years. At baseline, 43% (20/47) of subjects met criteria for MS. This was reduced to 15% (7/47) at year one and remained reduced over five years (13%, 6/46) (p < 0.001). There were reductions in triglycerides (p < 0.001) and increases in HDL cholesterol (HDL-C, p < 0.001) and HDL particle concentration (p = 0.02), with a trend toward increased HDL particle size (p = 0.06) at year five. Changes in triglycerides and HDL-C were more prominent in patients with MS at baseline, but unassociated with weight loss or waist circumference. Changes in HDL particle size and concentration were not associated with MS status, weight loss, waist circumference, or statin use.

Conclusions

LGB produces significant weight loss, resolution of MS and changes in lipid profile suggestive of beneficial HDL remodeling. These changes persist five years following LGB.     

Leptomeningeal dissemination in children with progressive low-grade neuroepithelial tumors

Our purpose is to describe the incidence and clinical features of leptomeningeal dissemination (LM) in children with progressive low-grade neuroepithelial tumor (LGN). We have continuously tracked all patients with primary CNS tumors since 1986. Satisfactorily followed data were obtained on 427 of the 588 patients with localized LGN at diagnosis between 1986 and 1998, 177 (42%) of whom developed progressive or recurrent disease. LM was identified in 13/177 (7%). The median age at initial diagnosis was 5 years and at LM diagnosis was 8.5 years. The primary tumor sites were diencephalon (6), brainstem (3), cerebellum (2), cerebrum (1), and spinal cord (1). The histologies were pilocytic astrocytoma (4), ganglioglioma (4), fibrillary astrocytoma (3), mixed glioma (1), and glioneurofibroma (1). Management included chemotherapy (2) or radiotherapy (3) or both (7); 1 patient received only radical resections of symptomatic lesions. The 5-year progression-free survival rates for patients with localized versus LM disease at recurrence were 22% (95% confidence interval [CI], 13%-25%) versus 15% (95% CI, 0.1%-36%), respectively ( P = 0.28). The 5- and 10-year overall survival rates for patients with localized disease versus LM were 87% (95% CI, 82%-92%) and 83% (95% CI, 77%-89%) versus 68% (95% CI, 39%-91%) and 68% (95% CI, 39%-91%), respectively ( P = 0.05). The 7% incidence of LM is a low estimate because patients were not routinely staged at recurrence. Tumors arising from the diencephalon appeared to predispose to LM; no other predisposing features were identified. We strongly urge that for optimum treatment planning all patients with recurrent LGN be staged with an enhanced spine and brain MRI before adjuvant therapy is initiated. The good survival of patients with LGN and LM reflects a more indolent disease than malignant CNS tumors with LM.     

Proton MR spectroscopy of tumefactive demyelinating lesions

BACKGROUND AND PURPOSE: Tumefactive demyelinating lesions (TDLs) can simulate intracranial neoplasms in clinical presentation and MR imaging appearance, and surgical biopsy is often performed in suspected tumors. Proton MR spectroscopy has been applied in assessing various intracranial diseases and is increasingly used in diagnosis and clinical management. Our purpose was to determine if multivoxel proton MR spectroscopy can be used to differentiate TDLs and high-grade gliomas. METHODS: Conventional MR images, proton MR spectra, and medical records were retrospectively reviewed in six patients with TDLs diagnosed by means of biopsy or by documented clinical improvement, with or without supporting laboratory testing and follow-up imaging. Proton MR spectra of 10 high-grade gliomas with similar conventional MR imaging appearances were used for comparison. In contrast-enhancing, central, and perilesional areas of each lesion, peak heights of N-acetylaspartate (NAA), choline (Cho), and creatine (Cr) were measured and the lactate peak noted. Cho/Cr and NAA/Cr ratios of corresponding regions in TDLs and gliomas were compared. RESULTS: No significant differences in mean Cho/Cr ratios were found in the corresponding contrast-enhancing, central, or perilesional areas of TDLs and gliomas. The mean central-region NAA/Cr ratio in gliomas was significantly lower than that of TDLs, but mean NAA/Cr ratios in other regions were not significantly different. A lactate peak was identified in four of six TDLs and three of 10 gliomas. CONCLUSION: In the cases examined, the NAA/Cr ratio in the central region of TDLs and high-grade gliomas differed significantly. However, overall metabolite profiles of both lesions were similar; this finding emphasizes the need for the cautious interpretation of spectroscopic findings.     

Diffusion-tensor MR imaging of intracranial neoplasia and associated peritumoral edema: introduction of the tumor infiltration index

PURPOSE: To determine whether diffusion-tensor magnetic resonance (MR) imaging metrics of peritumoral edema can be used to differentiate intra- from extraaxial lesions, metastatic lesions from gliomas, and high- from low-grade gliomas. MATERIALS AND METHODS: In this study, diffusion-tensor MR imaging was performed preoperatively in 40 patients with intracranial neoplasms, including meningiomas, metastatic lesions, glioblastomas multiforme, and low-grade gliomas. Histograms of mean diffusivity (MD) and fractional anisotropy (FA) were used to analyze both the tumor and the associated T2 signal intensity abnormality. An additional metric, the tumor infiltration index (TII), was evaluated. The TII is a measure of the change in FA presumably caused by tumor cells infiltrating the peritumoral edema. Student t test and least-squares linear regression analyses were performed. RESULTS: Peritumoral MD and FA values indicated no statistically significant difference between intra- and extraaxial lesions or between high- and low-grade gliomas. Regarding intraaxial tumors, the measured mean peritumoral MD of metastatic lesions, 0.733 x 10(-3) mm(2)/sec +/- 0.061 (SD), was significantly higher than that of gliomas, 0.587 +/- 0.093 x 10(-3) mm(2)/sec (P <.05). There was also a statistically significant difference between the TIIs of the edema surrounding meningiomas and metastases (mean, 0 +/- 35) and the TIIs of the edema surrounding gliomas (mean, 64 +/- 59) (P <.05). CONCLUSION: Peritumoral diffusion-tensor MR imaging metrics enable the differentiation of solitary intraaxial metastatic brain tumors from gliomas. In addition, the TII enables one to distinguish presumed tumor-infiltrated edema from purely vasogenic edema.     

Green fluorescent protein immunohistochemistry as a novel experimental tool for the detection of glioma cell invasion in vivo

In vivo animal models of primary brain tumors are necessary to advance knowledge related to the complex interactions between glioma cells and the adjacent brain. A cardinal feature of glioma growth, and a major reason why neurosurgical and adjunctive therapies ultimately fail in most patients is their invasive properties. We have adapted a previously described animal model developed by one of us to give better histological detail while preserving the identification of single infiltrating glioma cells. GL261 glioma cells were first transfected with the plasmid encoding green fluorescent protein (GFP) and then implanted into the brains of syngeneic C57BL/6 mice. Identification of GFP-positive tumor cells in paraffin sections of the brains of tumor-bearing animals utilized an antibody for conventional immunoperoxidase immunohistochemistry. This method is a more powerful technique compared with the prior use of frozen sections and fluorescence microscopy to identify GFP-tagged tumor cells. We find that this new method provides improved morphology and proves to be a sensitive and reliable system for detection of invading glioma cells. Using this methodology with other advanced technologies (eg, laser capture microdissection) holds out the promise of helping to elucidate the molecular mechanisms of glioma cell infiltration and invasion into the surrounding brain.