Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: a randomized, double-blind, hypothesis-generating study.

Cytomegalovirus is highly prevalent in glioblastomas. In 2006, we initiated a randomized, double-blind, placebo-controlled, hypothesis-generating study to examine the safety and potential efficacy of Valganciclovir as an add-on therapy for glioblastoma. Forty-two glioblastoma patients were randomized in double-blind fashion to receive Valganciclovir or placebo in addition to standard therapy for 6 months. Magnetic resonance images were obtained before and immediately and 3 and 6 months after surgery to evaluate treatment efficacy by measuring contrast enhancing tumor volume (primary end point). Survival data were analyzed for patients and controls in explorative analyses to aid the design of future randomized trials. Trends but no significant differences were observed in tumor volumes in Valganciclovir and placebo patients at 3 (3.58 vs. 7.44 cm3, respectively, p = 0.2881) and 6 (3.31 vs. 13.75 cm3, p = 0.2120) months. Median overall survival (OS) was similar in both groups (17.9 vs. 17.4 months, p = 0.430). Patients could take Valganciclovir for compassionate use after the study phase. Explorative analyses showed an OS of 24.1 months (95% CI, 17.4-40.3) in patients receiving >6 months of Valganciclovir (Val > 6M) versus 13.1 months (95% CI, 7.9-17.7, p < 0.0001) in patients receiving Valganciclovir for 0 or <6 months, and 13.7 months (95% CI, 6.9-17.3, p = 0.0031) in contemporary controls. OS at 4 years was 27.3% in Val>6M patients versus 5.9% in controls (p = 0.0466). Prolonged OS in Val>6M patients suggest that future randomized trials are warranted and should evaluate whether continuous antiviral treatment can improve outcome in glioblastoma patients.

Prepubertal follow-up after hypospadias repair with autologous in vitro cultured urothelial cells.

AIM: To evaluate the long-term effects on hypospadias repair with cultured autologous urothelial cells. METHODS: From 2000 to 2002, six patients with scrotal or perineal hypospadias and pronounced chordee were treated surgically with cultured autologous urothelial cell transplants. All patients were evaluated at 6-8 years postoperatively, that is, in the prepubertal period. The outcome was assessed with respect to cosmetic appearance, voiding function, urinary flow, artificial erection, urethroscopy and biopsies. RESULTS: Median follow-up time was 7.25 years. Up to date, all patients present with a good cosmetic appearance. One of the boys prefers a sitting voiding position. Urinary flow curves are bell-shaped in all but one. All have straight erections, urethroscopy reveals an even, non-hair-bearing surface on the transplanted side and 2/6 present with urothelial cells in biopsies. Limitations of this follow-up study include a small group of patients and lack of controls. However, patients with severe hypospadias have high complication rates, and our results are equal or better than expected for the phenotype. CONCLUSION: Tissue engineering for severe hypospadias repair can be performed in a safe manner. The method is feasible for treatment of a selected group of hypospadias, where pronounced chordee and shortage of preputial and penile skin complicates the creation of a neourethra.

Nerve growth factor receptor immunohistochemistry has a limited additional value to diagnose Hirschsprung's disease.

PURPOSE: The diagnosis of Hirschsprung's disease (HSCR) is based on the histopathological evaluation of rectal suction biopsies (RSB), using haematoxylin and eosin (H&E) stains and acetylcholinesterase (AChE) histochemistry. The use of different immunohistochemical markers, such as nerve growth factor receptor (NGFR), has been suggested to facilitate the diagnosis of HSCR. The aim of this study was to evaluate the addition of NGFR immunohistochemistry to diagnose HSCR. METHODS: RSB from 23 HSCR patients and 16 patients investigated for, but not diagnosed with, HSCR were retrospectively reviewed. The histopathology report supported or did not support the diagnosis of HSCR. RESULTS: In patients with HSCR, the primary biopsies confirmed the diagnosis in 21 of 23 cases with H&E staining, in 16 of 23 cases with AChE histochemistry, and in 8 of 23 cases with NGFR immunohistochemistry. Due to inadequate biopsies or equivocal interpretation, the biopsies were repeated in seven of the patients with HSCR and two patients underwent biopsies a third time. In the 16 patients investigated for but not diagnosed with HSCR, the three tests were normal in all cases. CONCLUSION: We conclude that NGFR immunohistochemistry has limited additional value to diagnose HSCR.

The Ki-67 Proliferation Index as a Marker of Time to Recurrence in Intracranial Meningioma.

BACKGROUND: There are examples of incongruence between the WHO grade and clinical course in meningioma patients. This incongruence between WHO grade and recurrence has led to search for other prognostic histological markers. OBJECTIVE: To study the correlation between the Ki-67 proliferative index (PI), risk of recurrence, and recurrence rates in meningioma patients. METHODS: We prospectively collected pathological diagnosis of de novo consecutive meningiomas. In total, we followed 159 patients with clinical controls until recurrence, death, or emigration. We estimated the correlation between risk of recurrence and Ki-67 PI when adjusted for age at diagnosis, sex, WHO grade, extent of surgical resection, and tumor location. We estimated the cumulative incidence of recurrence when considering death without recurrence a competing risk. We report recurrence rates per 100 person-years. RESULTS: A 1%-point increase of Ki-67 PI yielded a hazard ratio of 1.12 (95% CI: 1.01-1.24) in a multivariate analysis. The cumulative incidence of recurrence was 3% for Ki-67 0% to 4% vs 19% for Ki-67 > 4% meningiomas after 1 yr, but 24% vs 35%, respectively, after 10 yr. There was no significant difference in mean Ki-67 PI between nonrecurrent and recurrent meningioma in a 2-sample t-test (P = .08). The strongest relationship was detected between Ki-67 PI and time to recurrence: Ki-67 < 4% meningiomas recurred after median 4.8 yr, compared to 0.60 to 0.75 yr for patients with higher Ki-67 PI. CONCLUSION: Ki-67 PI was a marker for time to recurrence rather than a predictor of recurrence. Ki-67 PI may be utilized for patient tailored follow-up.

Expression of enzymes and receptors of the leukotriene pathway in human neuroblastoma promotes tumor survival and provides a target for therapy.

The metabolism of arachidonic acid by the cyclooxygenase (COX) or lipoxygenase (LO) pathways generates eicosanoids that have been implicated in the pathogenesis of a variety of human diseases, including cancer. In this study, we examined the expression and significance of components within the 5-LO pathway in human neuroblastoma, an embryonal tumor of the sympathetic nervous system. High expression of 5-LO, 5-LO-activating protein (FLAP), leukotriene A(4) hydrolase, leukotriene C(4) synthase, and leukotriene receptors was detected in a majority of primary neuroblastoma tumors and all cell lines investigated. Expression of 5-LO and FLAP was evident in tumor cells but not in nonmalignant adrenal medulla where neuroblastomas typically arise. Moreover, neuroblastoma cells produce leukotrienes, and stimulation of neuroblastoma cells with leukotrienes increased neuroblastoma cell viability. Inhibitors of 5-LO (AA-861), FLAP (MK-886), or the leukotriene receptor antagonist montelukast inhibited neuroblastoma cell growth by induction of G(1)-cell cycle arrest and apoptosis. Similarly, specific 5-LO and leukotriene receptor silencing by small interfering RNA decreased neuroblastoma cell growth. These findings provide new insights into the pathobiology of neuroblastoma, and the use of leukotriene pathway inhibitors as a novel adjuvant therapy for children with neuroblastoma warrants further consideration.

The frequency of glassy cells in Barrett's mucosa: a study in Baboons.

BACKGROUND: Glands with glassy cells (GGCs) were recently found in 1.8% of patients showing Barrett's mucosa in esophageal biopsies. Similar GGCs were more recently detected in a baboon having glandulo-metaplastic esophageal mucosa (GMEM). The aim was to assess the frequency of baboons with GMEM having GGCs. MATERIALS AND METHODS: GGCs were sought in 68 consecutive baboons having GMEM. Sections were stained with H&E, and with alcian blue (pH 2.5) to detect sialomucins in goblet cells (a marker of Barrett's mucosa in GMEM). RESULTS: Two out of the 68 baboons with Barrett's mucosa (2.9%) showed GGCs. CONCLUSION: In similarity to humans, the Barrett's mucosa in baboons may show GGCs. Although the significance of GGCs in baboons (and in humans) remains poorly understood, their presence might not be a fortuitous event but may be linked to the molecular events leading to the development of intestinal metaplasia in Barrett's mucosa, a known pre-neoplastic mucosal change in the distal esophagus in humans.

Tumor-growth-promoting cyclooxygenase-2 prostaglandin E2 pathway provides medulloblastoma therapeutic targets.

Prostaglandin E(2) (PGE(2)) has been shown to play important roles in several aspects of tumor development and progression. PGE(2) is synthesized from arachidonic acid by cyclooxygenases (COX) and prostaglandin E synthases (PGES) and mediates its biological activity through binding to the four prostanoid receptors EP(1) through EP(4). In this study, we show for the first time that medulloblastoma (MB), the most common malignant childhood brain tumor, expresses high levels of COX-2, microsomal prostaglandin E synthase-1, and EP(1) through EP(4) and secretes PGE(2). PGE(2) and the EP(2) receptor agonist butaprost stimulated MB cell proliferation. Treatment of MB cells with COX inhibitors suppressed PGE(2) production and induced caspase-dependent apoptosis. Similarly, specific COX-2 silencing by small interfering RNA inhibited MB cell growth. EP(1) and EP(3) receptor antagonists ONO-8713 and ONO-AE3-240, but not the EP(4) antagonists ONO-AE3-208 and AH 23848, inhibited tumor cell proliferation, indicating the significance of EP(1) and EP(3) but not EP(4) for MB growth. Administration of COX inhibitors at clinically achievable nontoxic concentrations significantly inhibited growth of established human MB xenografts. Apoptosis was increased, proliferation was reduced, and angiogenesis was inhibited in MBs treated with COX inhibitors. This study suggests that PGE(2) is important for MB growth and that therapies targeting the prostanoid metabolic pathway are potentially beneficial and should be tested in clinical settings for treatment of children with MB.

Quantitative assessment of the subepithelial collagen band does not increase the accuracy of diagnosis of collagenous colitis.

The thickness of eosinophilic band in collagenous colitis (CC) was assessed by 3 methods: histologic estimates (22 observers), conventional measurements using a calibrated micrometric scale (1 observer), and semiautomatic micrometric measurements (1 observer). By the histologic estimate technique, 7.4% of the results failed to diagnose CC; by calibrated micrometry, the failure was 6% and by semiautomatic micrometry, 6%. The main difficulty in measuring the thickness of the CC band is that the deeper border of the band appears fuzzy and hairy-irregular. CC should be defined not exclusively on the basis of the thickness of the collagen table, but as a microscopic constellation characterized by a distorted superficial cell arrangement, with areas of epithelial denudation and inflammatory cells in the superficial epithelium and the lamina propria. In agreement with Lazenby's statement: "Focusing solely on the collagen band can result in both over- and underdiagnosis"

Incidence of lymphocytic esophagitis in baboons.

BACKGROUND: We previously reported a novel histological phenotype of chronic esophagitis, lymphocytic esophagitis, in patients without gastroesophageal reflux. The aim of the present study was to explore the possible occurrence of lymphocytic esophagitis in baboons. MATERIALS AND METHODS: Filed hematoxylin and eosin (H&E)-stained sections from the esophagi of 103 consecutive baboons were reviewed. Lymphocytic esophagitis is characterized by high numbers of intraepithelial lymphocytes (IELs) gathered mainly around papillary areas and by none to occasional CD15+ intraepithelial granulocytes. RESULTS: Forty-five of the 103 baboons (43.7%) had lymphocytic esophagitis. A mean of 52 IELs/high-power field were found around the papillae. Immunostains showed that the IEL population in lymphocytic esophagitis was composed of T-cells, a subset of natural killer cells and of helper and inflammatory T-cells. CONCLUSION: Since lymphocytic esophagitis is by far much more frequent in baboons than in humans, the baboon emerges as a good animal model to study the etiology of this inflammatory disease in humans.

High prevalence of cytomegalovirus infection in surgical intestinal specimens from infants with necrotizing enterocolitis and spontaneous intestinal perforation: A retrospective observational study.

BACKGROUND: Necrotizing enterocolitis (NEC) is a severe, often fatal gastrointestinal emergency that predominantly affects preterm infants, and there is evidence that neonatal cytomegalovirus (CMV) infection may in some cases contribute to its pathogenesis. OBJECTIVES: This study aimed to evaluate the prevalence of CMV in infants with NEC. STUDY DESIGN: Seventy intestinal specimens from 61 infants with NEC, spontaneous intestinal perforation (SIP), or related surgical complications were collected at Karolinska University Hospital and Uppsala University Hospital, Sweden. Ten specimens from autopsied infants without bowel disease served as controls. Samples were analyzed for CMV immediate-early antigen (IEA), CMV late antigen (LA), 5-lipoxigenase (5LO) and CMV-DNA by immunohistochemistry (IHC) and in situ hybridization (ISH), respectively. In 10 index samples, CMV DNA was analyzed with Taqman PCR after laser capture microdissection (LCM) of cells positive for CMV IEA by IHC. RESULTS: CMV IEA was detected by IHC in 57 (81%) and CMV LA in 45 (64%) of 70 intestinal specimens from index cases; 2 (20%) of 10 control specimens were positive for both antigens. 5LO was detected in intestinal tissue section obtained from all examined index and controls. CMV DNA was detected in 4 of 10 samples (40%) after LCM. By ISH, all 13 IHC-IEA-positive samples were positive for CMV DNA; however, 3 of 5 IHC-IEA-negative samples (60%) were also positive. CONCLUSIONS: CMV-specific antigens and CMV DNA were highly prevalent in intestinal specimens from infants with NEC, SIP, and related surgical complications. Our findings provide further evidence that neonatal CMV infection contributes to the pathogenesis of these diseases and may affect patient outcome.

Reliability of the reported size of removed colorectal polyps.

BACKGROUND: The size of colorectal polyps is important in the clinical management of these lesions. AIM: To audit the accuracy in calculating the size of "polyps" by various specialists. MATERIALS AND METHODS: Eighteen pathologists and four surgeons measured, with a conventional millimetre ruler, the largest diameter of 12 polyp phantoms. The results of two independent measurements (two weeks apart) were compared with the gold standard-size assessed at The Royal Institute of Technology, Sweden. RESULTS: Thirty-one percent (83/264-trial 1) and 33% (88/264-trial 2) of the measurements underestimated or overestimated the gold standard size by >1 mm. Of the 22 experienced participants, 95% (21/22-trial 1) and 91% (20/22-trial 2) misjudged by >1 mm the size of one or more polyps. Values given by 13 participants (4.9%) in trial 1 and by 15 participants (5.7%) in trial 2, differed by > or = +/-4 mm from the gold standard size. In addition, a big difference between the highest and the lowest values was recorded in some polyps (up to 11.4 mm). Those disparate values were regarded as a human error in reading the scale on the ruler. CONCLUSION: Using a conventional ruler (the tool of pathologists worldwide) unacceptably high intra-observer and inter-observer variations in assessing the size of polyp-phantoms was found. The volume and the shape of devices, as well as human error in reading the scale of the ruler were confounding factors in size assessment. In praxis, the size is crucial in the management of colorectal polyps. Considering the clinical implications of the results obtained, the possibility of developing a method that will allow assessment of the true size of removed clinical polyps is being explored.

Cyclooxygenase-2 is expressed in neuroblastoma, and nonsteroidal anti-inflammatory drugs induce apoptosis and inhibit tumor growth in vivo.

Neuroblastoma is the single most common and deadly tumor of childhood and is often associated with therapy resistance. Cyclooxygenases (COXs) catalyze the conversion of arachidonic acid to prostaglandins. COX-2 is up-regulated in several adult epithelial cancers and is linked to proliferation and resistance to apoptosis. We detected COX-2 expression in neuroblastoma primary tumors and cell lines but not in normal adrenal medullas from children. Treatment of neuroblastoma cells with nonsteroidal anti-inflammatory drugs, inhibitors of COX, induced caspase-dependent apoptosis via the intrinsic mitochondrial pathway. Treatment of established neuroblastoma xenografts in nude rats with the dual COX-1/COX-2 inhibitor diclofenac or the COX-2-specific inhibitor celecoxib significantly inhibited tumor growth in vivo (P < 0.001). In vitro, arachidonic acid and diclofenac synergistically induced neuroblastoma cell death. This effect was further pronounced when lipooxygenases were simultaneously inhibited. Proton magnetic resonance spectroscopy ((1)H MRS) of neuroblastoma cells treated with COX inhibitors demonstrated accumulation of polyunsaturated fatty acids and depletion of choline compounds. Thus, (1)H MRS, which can be performed with clinical magnetic resonance scanners, is likely to provide pharmacodynamic markers of neuroblastoma response to COX inhibition. Taken together, these data suggest the use of nonsteroidal anti-inflammatory drugs as a novel adjuvant therapy for children with neuroblastoma.

NSAIDs in neuroblastoma therapy.

Cyclooxygenases (COX) catalyse the conversion of arachidonic acid to prostaglandins. COX-2 is upregulated in several adult epithelial cancers. In neuroblastoma it has been shown that the majority of primary tumours and cell lines express high levels of COX-2, whereas normal adrenal medullas from children do not express COX-2. Treatment of neuroblastoma cells with nonsteroidal anti-inflammatory drugs (NSAIDs), inhibitors of COX, induces caspase-dependent apoptosis via the intrinsic mitochondrial pathway. Established neuroblastoma xenografts in nude rats treated with the dual COX-1/COX-2 inhibitor, diclofenac, or the COX-2 specific inhibitor, celecoxib significantly inhibits neuroblastoma growth in vivo. In vitro, arachidonic acid and diclofenac synergistically induces neuroblastoma cell death. This effect is further pronounced when lipoxygenases is inhibited simultaneously. Proton MR-spectroscopy (1H MRS) of neuroblastoma cells treated with COX-inhibitors demonstrates accumulation of polyunsaturated fatty acids and depletion of choline compounds. Thus, 1H MRS, which can be performed with clinical MR-scanners, is likely to provide pharmacodynamic markers of neuroblastoma response to COX-inhibition. Taken together, these data suggest the use of NSAIDs as a novel adjuvant therapy for children with neuroblastoma.

An audit of immunohistochemical marker patterns in meningioma.

Meningiomas may express a number of potentially growth-promoting receptors including receptors for progesterone, growth hormone and vascular endothelial growth factor (VEGF). These and other receptors are potential targets for chemotherapy. We have prospectively studied a panel of markers as a routine in order to obtain data of individual expression of markers that may provide targets for anti-receptor treatment. One hundred and seventy-five consecutive patients operated on for meningiomas between 2005 and 2008 were prospectively analysed with antibodies against receptors for growth hormone, insulin-like growth factor 1 (IGF-1), androgen receptors, progesterone receptors (PR) and antibodies against CD34, VEGF, Ki-67 and caspase-3. Expression of IGF-1 receptor (IGF-1r), epidermal growth factor receptor (EGFR) E30 and growth hormone receptor (GHr) was conserved across histological grades and found in 88% to 94% of meningiomas. PR were detected in 87%, but expression decreased in aggressive tumours. Angio-markers such as VEGF and CD34 were detected in 69% and 17% of meningiomas, respectively. Androgen receptors and caspase-3 were uncommon. The analyses of a panel were undertaken as a clinical routine in order to assess its feasibility and to provide data that can be utilised in a clinical setting. Three putative therapeutic receptor targets, IGF-1r, GHr and EGFR E30 were expressed in a large majority of tumours and in contrast to PR maintained expression despite increasing pathological grade of meningioma. Our data also suggest that anti-progesterone therapies and anti-angiogenic therapies could be targeted to subsets of meningioma patients who express PR or have CD34-positive tumours.

Increased survival using delayed gamma knife radiosurgery for recurrent high-grade glioma: a feasibility study.

OBJECTIVE: The current study retrospectively assessed delayed gamma knife radiosurgery (GKRS) in the management of high-grade glioma recurrences. METHODS: A total of 55 consecutive patients with high-grade glioma comprising 68 World Health Organization (WHO) III and WHO IV were treated with GKRS for local recurrences between 2001 and 2007. All patients had undergone microsurgery and radiochemotherapy, considered as standard therapy for high-grade glioma. Complete follow-up was available in all patients; median follow-up was 17.2 months (2.5-114.2 months). Median tumor volume was 5.2 mL, prescription dose was 20 Gy (14-22 Gy), and median max dose was 45 Gy (30-77.3 Gy). RESULTS: The patients with WHO III tumors showed a median survival of 49.6 months with and a 2-year survival of 90%. After GKRS of the recurrences, these patients showed a median survival of 24.2 months and a 2-year survival of 50%. The patients with WHO IV tumors had a median survival of 24.5 months with a 2-year survival of 51.4%. After the recurrence was treated with GKRS, the median survival was 11.3 months and a 2-year survival: 22.9% for the WHO IV patients. CONCLUSION: The current study shows a survival benefit for high-grade glioma recurrences when GKRS was administered after standard therapy. This is a relevant improvement compared with earlier studies that had had not been able to provide a beneficial effect timing radiosurgery in close vicinity to EBRT.

The microenvironment of human neuroblastoma supports the activation of tumor-associated T lymphocytes.

Tumor infiltration by lymphocytes has been linked to improved clinical outcome in children with neuroblastoma (NB) but T-cell activation has never been demonstrated to occur within the NB microenvironment. Here we show that tumor-associated lymphocytes (TALs) obtained from lesions representing all genetic subsets of NB and autologous peripheral blood lymphocytes (PBLs) analyzed on the day of tumor excision differed in composition, phenotype and functional characteristics. The NB microenvironment appeared to promote the accumulation of CD3+CD8+ T cells and contained a larger proportion of T cells expressing the interleukin-2 receptor α chain (CD25) and manifesting an effector memory (CCR7-CD45RA-) phenotype. Accordingly, the stimulation of PBLs with autologous tumor cells in short-term cultures increased the proportion of effector memory T cells, upregulated CD25, stimulated the expression of the TH1 cytokines interferon γ and tumor necrosis factor α, and reduced the expression of transforming growth factor ß. In situ proliferation as well as a characteristic pattern of T-cell receptor aggregation at the contact sites with malignant cells was revealed by the immunohistochemical staining of TALs in primary tumors, indicating that the NB milieu is compatible with the activation of the immune system. Our results are compatible with the hypothesis that CD8+ T cells are specifically activated within the NB microenvironment, which appears to be permissive for effector memory responses.

Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival.

BACKGROUND: Patients with glioblastoma multiforme (GBM) generally live 12-15 months after diagnosis, despite maximal surgical resection, adjuvant radiotherapy, and chemotherapy. HCMV has been detected in 90-100% of GBMs. We recently found that low grade HCMV infection in GBM tumours was highly associated with survival over 18 months (case-control study). Here, we sought to determine whether low-grade HCMV infection in GBMs is associated with prolonged survival in a consecutive patient cohort, analysed retrospectively. STUDY DESIGN: Tumour samples from 75 consecutive GBM patients treated surgically at Karolinska University Hospital in 2004-2005 were examined by immunohistochemistry (IHC) and in situ hybridization for HCMV proteins and DNA, respectively. Tumours were graded 1-4, depending on the percentage of positive cells by IHC. Low-grade HCMV was defined as grade 1 (< 25% of HCMV infected tumour cells). Time to tumour progression (TTP) and survival data were analysed with Cox regression and Kaplan-Meier models. RESULTS: HCMV infection was detected in 74 of 75 tumours (99%). In patients with low-grade HCMV infection, median survival was 20 months longer than in patients with high-grade infections (P = 0.036, HR: 2.2), and TTP was 8 months longer (P = 0.1, HR: 1.8). Two-year survival was much higher in patients with low-grade HCMV infection (63.6% vs. 17.2%, P = 0.003). CONCLUSION: The longer survival in patients whose tumours had low-grade HCMV infection suggests that the level of HCMV infection in GBMs has a prognostic value and that HCMV may contribute to the pathogenesis of GBM.

Low levels of Human Cytomegalovirus Infection in Glioblastoma multiforme associates with patient survival; -a case-control study.

BACKGROUND: Glioblastoma multiforme (GBM) represent the most aggressive brain tumor with a median overall survival of about 12-15 months. Over 90% of GBM tumors have recently been shown to be infected with human cytomegalovirus (HCMV). In this case-control study, we evaluated whether there was an association between the grade of HCMV infection and long-term survival (> 18 months) in GBM patients. MATERIAL AND METHODS: Brain tumor tissue sections from consecutive GBMs patients who survived more than 18 months (n = 40), and an equal number of GBM patients, matched to date of diagnosis and surgery, operated at Karolinska University Hospital in 2000-2005 were selected. HCMV infection grade was determined by estimation of the number of HCMV positive cells (scored negative or grade 1-4) in tumor tissue specimens. Using Chi-Square test and logistic regression analysis, we analyzed whether there was an association between long-term survival and HCMV low-grade infection or other clinical parameters known to be associated with prolonged survival of GBM patients; age under 50 years, radical surgery or low recursive partition analysis (RPA) subclass. RESULTS: HCMV infection was detected in tumor samples from 79 of 80 patients (99%). Among patients surviving > 18 months, HCMV infection grade 1 in the GBM tumor was predominant. A low grade HCMV infection was found in 19 patients, of these 16 survived > 18 months. Thus, 16 of 40 (40%) GBM patients who lived > 18 months had low-grade HCMV infection while only 3 of 40 (8%) GBM patients who lived < 18 months did (p .0006, Chi-Square test). Multiple logistic regression analyses yielded an odds ratio estimate of 6.604 with 95% confidence interval (1.36-32.1) (p .019) for low grade HCMV after adjustment for RPA class III and IV, radical surgery, age and gamma knife treatment. CONCLUSION: In conclusion, we found that low-grade HCMV infection was strongly associated with long-term survival in GBM patients.

Long-term 25-year follow-up of surgically treated parasagittal meningiomas.

BACKGROUND: Parasagittal meningiomas are either treated with conservative surgery or aggressive surgery with extensive vascular reconstructions to achieve radicality. The optimal management is subject to controversy. A prerequisite for good management and for design of relevant studies is the knowledge of natural history after radical and subtotal surgery. METHODS: All patients operated for parasagittal meningiomas at Karolinska Hospital between 1975 and 1979 were identified. This cohort of 51 patients was retrospectively analyzed to obtain 25-year follow-up data. Data were obtained from medical charts at all treating hospitals, the Swedish cancer registry, and the Swedish registry of causes of death. Radiology reports and images were reviewed. All patients still alive were contacted for visits, interviews, and radiologic imaging when indicated. Karnofsky index, Simpson grade, and pathologic examinations were obtained. RESULTS: The total recurrence rate after 25 years was 47%. Ten- and 25-year recurrence rates for radically operated parasagittal meningioma (Simpson grade 1-2) were 13% and 38%, respectively. The recurrence rates increased with increasing Simpson grades; 10- and 25-year recurrence rates in the Simpson grade 4 group were 62% and 69%, respectively. The relative risk for recurrence in Simpson grade 4 patients was 1.78 compared to Simpson grade 1-3 patients. The 10- and 25-year mortality rates were 33% and 63%, respectively. Of the total mortality 50% was caused by the tumor after 10 years and 48% after 25 years. CONCLUSIONS: A 25-year follow-up was necessary to estimate the long-term outcomes of parasagittal meningiomas. It is necessary to consider long-term recurrences and morbidity as important factors when managing patients with parasagittal meningiomas whose life expectancies are not diminished by old age or co-morbidities. The long-term outcomes must also be considered when evaluating different treatment modes, as "cure" of parasagittal meningiomas cannot be evaluated without sufficient follow-up.

Brain abnormalities and glioma-like lesions in mice overexpressing the long isoform of PDGF-A in astrocytic cells.

BACKGROUND: Deregulation of platelet-derived growth factor (PDGF) signaling is a hallmark of malignant glioma. Two alternatively spliced PDGF-A mRNAs have been described, corresponding to a long (L) and a short (S) isoform of PDGF-A. In contrast to PDGF-A(S), the PDGF-A(L) isoform has a lysine and arginine rich carboxy-terminal extension that acts as an extracellular matrix retention motif. However, the exact role of PDGF-A(L) and how it functionally differs from the shorter isoform is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: We overexpressed PDGF-A(L) as a transgene under control of the glial fibrillary acidic protein (GFAP) promoter in the mouse brain. This directs expression of the transgene to astrocytic cells and GFAP expressing neural stem cells throughout the developing and adult central nervous system. Transgenic mice exhibited a phenotype with enlarged skull at approximately 6-16 weeks of age and they died between 1.5 months and 2 years of age. We detected an increased number of undifferentiated cells in all areas of transgene expression, such as in the subependymal zone around the lateral ventricle and in the cerebellar medulla. The cells stained positive for Pdgfr-α, Olig2 and NG2 but this population did only partially overlap with cells positive for Gfap and the transgene reporter. Interestingly, a few mice presented with overt neoplastic glioma-like lesions composed of both Olig2 and Gfap positive cell populations and with microvascular proliferation, in a wild-type p53 background. CONCLUSIONS: Our findings show that PDGF-A(L) can induce accumulation of immature cells in the mouse brain. The strong expression of NG2, Pdgfr-α and Olig2 in PDGF-A(L) brains suggests that a fraction of these cells are oligodendrocyte progenitors. In addition, accumulation of fluid in the subarachnoid space and skull enlargement indicate that an increased intracranial pressure contributed to the observed lethality.