Clustering of esophageal cancer among white men in the United States.

Studies of the geographic distribution of esophageal cancer in the United States have been limited. We aimed to examine geographic clustering of esophageal cancer in the United States and assess whether that clustering is explained by the distribution of known risk factors for esophageal cancer. We conducted cluster analyses derived from county mortality rates of esophageal cancer, using publicly available datasets. State incidence rates of esophageal adenocarcinoma were from the National Program of Cancer Registries, and county esophageal-cancer mortality rates were from the Vital Statistics Cooperative Program. County prevalences of cigarette use, alcohol use, obesity, education, and income were published estimates derived from the Behavioral Risk Factor Surveillance System and the American Community Survey. The primary outcomes were clusters of high and low esophageal-cancer mortality rates among non-Hispanic white men, both unadjusted and adjusted for risk factors. Age-standardized county rates of esophageal-cancer mortality among non-Hispanic white men ranged from 4.8 to 21.2 per 100,000/year. There was a cluster of high mortality in the Great Lakes states and New England and a cluster of low mortality in the Southeastern United States. State incidence rates of esophageal adenocarcinoma were consistent with this pattern. Adjusting for risk factors did little to change the pattern of observed rates or the clusters derived from them. Among non-Hispanic white men, there are clusters of high and low mortality rates with esophageal cancer within the United States, likely representing esophageal adenocarcinoma; but those clusters were not explained by several known risk factors. Focusing future efforts in the high-cluster areas might improve the efficiency of cancer screening and control.

GPR133 (ADGRD1), an adhesion G-protein-coupled receptor, is necessary for glioblastoma growth.

Glioblastoma (GBM) is a deadly primary brain malignancy with extensive intratumoral hypoxia. Hypoxic regions of GBM contain stem-like cells and are associated with tumor growth and angiogenesis. The molecular mechanisms that regulate tumor growth in hypoxic conditions are incompletely understood. Here, we use primary human tumor biospecimens and cultures to identify GPR133 (ADGRD1), an orphan member of the adhesion family of G-protein-coupled receptors, as a critical regulator of the response to hypoxia and tumor growth in GBM. GPR133 is selectively expressed in CD133+ GBM stem cells (GSCs) and within the hypoxic areas of PPN in human biospecimens. GPR133 mRNA is transcriptionally upregulated by hypoxia in hypoxia-inducible factor 1α (Hif1α)-dependent manner. Genetic inhibition of GPR133 with short hairpin RNA reduces the prevalence of CD133+ GSCs, tumor cell proliferation and tumorsphere formation in vitro. Forskolin rescues the GPR133 knockdown phenotype, suggesting that GPR133 signaling is mediated by cAMP. Implantation of GBM cells with short hairpin RNA-mediated knockdown of GPR133 in the mouse brain markedly reduces tumor xenograft formation and increases host survival. Analysis of the TCGA data shows that GPR133 expression levels are inversely correlated with patient survival. These findings indicate that GPR133 is an important mediator of the hypoxic response in GBM and has significant protumorigenic functions. We propose that GPR133 represents a novel molecular target in GBM and possibly other malignancies where hypoxia is fundamental to pathogenesis.

The Combined Performance of ADC, CSF CXC Chemokine Ligand 13, and CSF Interleukin 10 in the Diagnosis of Central Nervous System Lymphoma.

BACKGROUND AND PURPOSE: CXC chemokine ligand 13 and interleukin 10 have emerged as CSF biomarkers for the diagnosis of CNS lymphoma. Our hypothesis is that the combined use of ADC, CXC chemokine ligand 13, and interleukin 10 will result in increased diagnostic performance compared with the use of ADC values alone. MATERIALS AND METHODS: Eighty-seven patients were included in this study, including 43 with CNS lymphoma and 44 without CNS lymphoma (21 metastases, 14 high-grade gliomas, 9 tumefactive demyelinating lesions) who had undergone CSF proteomic analysis and had a new enhancing mass on brain MR imaging. Average ADC was derived by contouring the contrast-enhancing tumor volume. Group means were compared via t tests for average ADC, CXC chemokine ligand 13, and interleukin 10. Receiver operating characteristic analysis was performed for each individual variable. Multiple-variable logistic regression with receiver operating characteristic analysis was performed, and the multiple-variable receiver operating characteristic was compared with single-variable receiver operating characteristics. RESULTS: The average ADC was lower and CSF CXC chemokine ligand 13 and interleukin 10 values were higher in CNS lymphoma (P < .001). Areas under the curve ranged from 0.739 to 0.832 for single-variable ROC. Multiple-variable logistic regression yielded statistically significant individual effects for all 3 variables in a combined model. Multiple-variable receiver operating characteristics (area under the curve, 0.928) demonstrated statistically significantly superior diagnostic performance compared with the use of single variables alone. CONCLUSIONS: The combined use of ADC, CSF CXC chemokine ligand 13, and interleukin 10 results in increased diagnostic performance for the diagnosis of CNS lymphoma. This finding highlights the importance of CSF analysis when the diagnosis of CNS lymphoma is considered on the basis of MR imaging.

Prevalence and risk factors for heterotopic gastric mucosa of the upper esophagus among men undergoing routine screening colonoscopy.

The prevalence of heterotopic gastric mucosa of the upper esophagus (inlet patch) has a wide range depending on the method and detail of examination. The inlet patch is believed to be a congenital malformation that rarely leads to symptoms. We aimed to quantify the prevalence of the inlet patch in a non-referred population and determine if there are any risk factors or associated symptoms. Men between ages 50 and 79 presenting for routine colonoscopy at two clinical sites were recruited to undergo an upper endoscopy. Endoscopists were prompted to examine for the presence of the inlet patch. Of the 822 enrolled patients, 795 had data regarding the presence of an inlet patch. Of these, 55 (6.9%) had an inlet patch identified. Education was inversely associated (odds ratio [OR] advanced degree vs. high school or less = 0.310; 95% confidence interval [CI] = 0.111, 0.869), and tobacco use was positively associated with the presence of an inlet patch (current vs. never smokers OR = 2.87; 95% CI = 1.23, 6.69; former vs. never smokers OR = 1.93; 95% CI = 0.922, 4.02). No association between the inlet patch and symptoms of heartburn, globus, or dysphagia was found. In a cross-sectional study of colon cancer screenees, inlet patches were common and were not associated with symptoms. Tobacco use appears to be associated with the presence of an inlet patch.

Comparing trends in esophageal adenocarcinoma incidence and lifestyle factors between the United States, Spain, and the Netherlands.

OBJECTIVES: The incidence of esophageal adenocarcinoma (EAC) in the western world has been rapidly increasing. The trends in obesity and other lifestyle-associated factors have been hypothesized to be important drivers of this increase. We tested this hypothesis by comparing changes in these factors with changes in EAC incidence over time between three western countries. METHODS: Data on EAC incidence trends were abstracted from the SEER-9 registry (1975-2009) for the United States, from multiple cancer registries (1980-2004) in Spain, and from Eindhoven Cancer Registry in the Netherlands (1974-2010). In addition, we collected trend data on obesity, smoking, and alcohol consumption. The trend data were analyzed using log-linear regression. RESULTS: In 1980, the EAC incidence was similar among the three countries ((0.46-0.63) per 100,000). EAC incidence increased in all, with the largest increase observed in the Netherlands, followed by the United States and Spain (estimated annual percentage of change=9.7%, 7.4%, 4.3%, respectively). However, this pattern was not observed in lifestyle factors associated with EAC. With regards to obesity, the United States clearly has had the highest prevalence rates both in the past and in the present. For alcohol, the highest consumption rates are seen in Spain. Smoking showed a reverse trend compared with EAC among all three countries in the last 20 years. CONCLUSIONS: International trends in EAC incidence do not match corresponding trends in lifestyle-associated factors including obesity. Our findings suggest that factors other than obesity must be the important drivers for the increase in EAC incidence.

Beyond high-dose methotrexate and brain radiotherapy: novel targets and agents for primary CNS lymphoma.

BACKGROUND: While there has been significant progress in outcomes for patients diagnosed with primary central nervous system (CNS) lymphoma (PCNSL), survival rates will likely plateau with the current armamentarium of agents used to treat these patients. Moreover, given that PCNSL increasingly impacts an older population, a significant proportion of patients are not eligible for intensive therapies such as high-dose chemotherapy or whole-brain radiation. There is a need for the development of novel agents, which target key survival pathways in order to continue to make progress in this disease. PATIENTS AND METHODS: We reviewed the key molecular pathways and genomic aberrations in PCNSL in order to identify candidate targets. We focused on molecules and pathways that have been identified and confirmed by more than one investigator or methodology. RESULTS: While PCNSL tumors usually express a BCL6+, MUM1+ 'activated, germinal center' immunophenotype, they exhibit multiple shared genetic properties with ABC-type diffuse large B-cell lymphomas. Candidate targets and pathways include NFkB, the B-cell receptor, the JAK/STAT pathway, IRF4, BCL-6 as well as PIM kinases. Elements of the tumor microenvironment that may be exploited therapeutically include chemokine pathways, as well as macrophage and T-cell responses. CONCLUSIONS: There is a significant need for developing novel therapies in PCNSL, given that an increasing proportion of patients are not eligible for high-dose chemotherapy and brain radiation is associated with detrimental cognitive side-effects. We provide an overview of potential drug targets and novel agents that may be integrated with existing strategies in order to make further progress in this disease.

Systematic review with meta-analysis: race-specific effects of alcohol and tobacco on the risk of oesophageal squamous cell carcinoma.

BACKGROUND: Oesophageal squamous cell carcinoma (OSCC) is associated with alcohol use, tobacco use and African or Asian descent. However, little is known about how racial background modifies the effects of alcohol or tobacco. AIM: To investigate how racial and geographical background modifies the effect of alcohol and tobacco on OSCC via a systematic review and meta-analysis of published literature. METHODS: We performed a literature search in multiple online databases regardless of language. Eligible studies were population-based assessments of the effect of tobacco and/or alcohol on the risk of OSCC allowing stratification by race. The quality of studies was assessed by the Newcastle-Ottawa Scale. Meta-analyses were performed to estimate summary effects using random effect models. RESULTS: Systematic review identified 9668 unique citations of which 34 were eligible. The majority were of high quality. The effect of current smoking vs. never-smoking was weaker among Asians than among Europeans [European: odds ratio (OR) = 4.21, 95% confidence interval (CI) 3.13, 5.66; Asian: OR = 2.31, 95% CI 1.78, 2.99], with the 95% CIs not crossing, indicating statistical significance. Asians also trended towards weaker effects of long-duration cigarette use and of heavy daily cigarette use. There was no difference in the effect of alcohol on OSCC risk by race. CONCLUSIONS: Contrary to our hypothesis, a weaker effect of tobacco for OSCC was observed among Asians than among Europeans. Differences in other factors must explain the higher incidence of OSCC among Asians. More studies are needed to understand the cause of the disparate incidence of OSCC between races.

Combined diffusion and perfusion MR imaging as biomarkers of prognosis in immunocompetent patients with primary central nervous system lymphoma.

BACKGROUND AND PURPOSE: ADC derived from DWI has been shown to correlate with PFS and OS in immunocompetent patients with PCNSL. The purpose of our study was to confirm the validity of ADC measurements as a prognostic biomarker and to determine whether rCBV measurements derived from DSC perfusion MR imaging provide prognostic information. MATERIALS AND METHODS: Pretherapy baseline DWI and DSC perfusion MR imaging in 25 patients with PCNSL was analyzed before methotrexate-based induction chemotherapy. Contrast-enhancing tumor was segmented and coregistered with ADC and rCBV maps, and mean and minimum values were measured. Patients were separated into high or low ADC groups on the basis of previously published threshold values of ADC(min) < 384 × 10(-6) mm(2)/s. High and low rCBV groups were defined on the basis of receiver operating curve analysis. High and low ADC and rCBV groups were analyzed independently and in combination. Multivariate Cox survival analysis was performed. RESULTS: Patients with ADC(min) values < 384 × 10(-6) mm(2)/s or rCBV(mean) values < 1.43 had worse PFS and OS. The patient cohort with combined low ADC(min)-low rCBV(mean) had the worst prognosis. No other variables besides ADC and rCBV significantly affected survival. CONCLUSIONS: Our study reinforces the validity of ADC values as a prognostic biomarker and provides the first evidence of low tumor rCBV as a novel risk factor for adverse prognosis in immunocompetent patients with PCNSL.

Inter-rater reliability between musculoskeletal radiologists and orthopedic surgeons on computed tomography imaging features of spinal metastases.

INTRODUCTION: The primary objective of this pilot study was to examine the inter-rater reliability in scoring the computed tomography (ct) imaging features of spinal metastases in patients referred for radiotherapy (rt) for bone pain. METHODS: In a retrospective review, 3 musculoskeletal radiologists and 2 orthopedic spinal surgeons independently evaluated ct imaging features for 41 patients with spinal metastases treated with rt in an outpatient radiation clinic from January 2007 to October 2008. The evaluation used spinal assessment criteria that had been developed in-house, with reference to osseous and soft tissue tumour extent,presence of a pathologic fracture,severity of vertebral height loss, andpresence of kyphosis.The Cohen kappa coefficient between the two specialties was calculated. RESULTS: Mean patient age was 69.2 years (30 men, 11 women). The mean total daily oral morphine equivalent was 73.4 mg. Treatment dose-fractionation schedules included 8 Gy/1 (n = 28), 20 Gy/5 (n = 12), and 20 Gy/8 (n = 1). Areas of moderate agreement in identifying the ct imaging appearance of spinal metastasis included extent of vertebral body involvement (κ = 0.48) and soft-tissue component (κ = 0.59). Areas of fair agreement included extent of pedicle involvement (κ = 0.28), extent of lamina involvement (κ = 0.35), and presence of pathologic fracture (κ = 0.20). Areas of poor agreement included nerve-root compression (κ = 0.14) and vertebral body height loss (κ = 0.19). CONCLUSIONS: The range of agreement between musculoskeletal radiologists and orthopedic surgeons for most spinal assessment criteria is moderate to poor. A consensus for managing challenging vertebral injuries secondary to spinal metastases needs to be established so as to best triage patients to the most appropriate therapeutic modality.

Meta-analysis: the association of oesophageal adenocarcinoma with symptoms of gastro-oesophageal reflux.

BACKGROUND: Endoscopic screening has been proposed for patients with symptoms of gastro-oesophageal reflux disease (GERD) in the hope of reducing mortality from oesophageal adenocarcinoma. Assessing the net benefits of such a strategy requires a precise understanding of the cancer risk in the screened population. AIM: To estimate precisely the association between symptoms of GERD and oesophageal adenocarcinoma. METHODS: Systematic review and meta-analysis of population-based studies with strict ascertainment of exposure and outcomes. RESULTS: Five eligible studies were identified. At least weekly symptoms of GERD increased the odds of oesophageal adenocarcinoma fivefold (odds ratio = 4.92; 95% confidence interval = 3.90, 6.22), and daily symptoms increased the odds sevenfold (random effects summary odds ratio = 7.40, 95% confidence interval = 4.94, 11.1), each compared with individuals without symptoms or less frequent symptoms. Duration of symptoms was also associated with oesophageal adenocarcinoma, but with very heterogeneous results, and unclear thresholds. CONCLUSIONS: Frequent GERD symptoms are strongly associated with oesophageal adenocarcinoma. These results should be useful in developing epidemiological models of the development of oesophageal adenocarcinoma, and in models of interventions aimed at reducing mortality from this cancer.

Diffusion-weighted MR imaging derived apparent diffusion coefficient is predictive of clinical outcome in primary central nervous system lymphoma.

BACKGROUND AND PURPOSE: There is evidence that increased tumor cellular density within diagnostic specimens of primary central nervous system lymphoma (PCNSL) may have significant prognostic implications. Because cellular density may influence measurements of apparent diffusion coefficient (ADC) by using diffusion-weighted MR imaging (DWI), we hypothesized that ADC measured from contrast-enhancing regions might correlate with clinical outcome in patients with PCNSL. MATERIALS AND METHODS: PCNSL tumors from 18 immunocompetent patients, treated uniformly with methotrexate-based chemotherapy, were studied with pretherapeutic DWI. Enhancing lesions were diagnosed by pathologic analysis as high-grade B-cell lymphomas. Regions of interest were placed around all enhancing lesions allowing calculation of mean, 25th percentile (ADC(25%)), and minimum ADC values. Histopathologic tumor cellularity was quantitatively measured in all patients. High and low ADC groups were stratified by the median ADC value of the cohort. The Welch t test assessed differences between groups. The Pearson correlation examined relationships between ADC measurements and tumor cellular density. Single and multivariable survival analysis was performed. RESULTS: We detected significant intra- and intertumor heterogeneity in ADC measurements. An inverse correlation between cellular density and ADC measurements was observed (P < .05). ADC(25%) measurements less than the median value of 692 (low ADC group) were associated with significantly shorter progression-free and overall survival. Patients with improved clinical outcome were noted to exhibit a significant decrease in ADC measurements following high-dose methotrexate chemotherapy. CONCLUSIONS: Our study provides evidence that ADC measurements within contrast-enhancing regions of PCNSL tumors may provide noninvasive insight into clinical outcome.

Association of adiponectin multimers with Barrett's oesophagus.

OBJECTIVE: Barrett's oesophagus is associated with abdominal obesity. Adiponectin is a peptide that is secreted from adipocytes and circulates in three multimeric forms: low molecular weight (LMW), middle molecular weight (MMW), and high molecular weight (HMW). The anti-inflammatory effects of adiponectin are specific to individual multimers, with LMW being most anti-inflammatory. We postulated that circulating levels of adiponectin and its multimers would be associated with the risk of Barrett's oesophagus. DESIGN: Cross-sectional study. SETTING: Outpatient clinic in North Carolina, USA. PATIENTS: Cases of Barrett's oesophagus and controls undergoing upper endoscopy for gastro-oesophageal reflux disease (GORD). MAIN OUTCOME MEASURES: Adjusted odds ratios of plasma adiponectin levels and its multimers for Barrett's oesophagus. RESULTS: There were 112 cases of Barrett's oesophagus and 199 GORD controls. Total adiponectin was not associated with Barrett's oesophagus (3(rd) tertile vs 1(st) tertile adjusted odds ratio (aOR) = 0.88; 95% confidence interval (CI) = 0.44 to 1.78). High levels of LMW adiponectin were associated with a decreased risk of Barrett's oesophagus (3(rd) tertile vs 1(st) tertile aOR = 0.33; 95% CI, 0.16 to 0.69), and a high LMW/total ratio appeared particularly inversely associated with Barrett's oesophagus (3(rd) tertile vs 1(st) tertile aOR = 0.27; 95% CI, 0.13 to 0.58). CONCLUSIONS: High levels of LMW adiponectin are associated with a decreased risk of Barrett's oesophagus among patients with GORD. Further human studies are required to confirm these findings, and in vitro studies are needed to understand if there is a mechanism whereby adiponectin may affect Barrett's metaplasia.

Chromosome 8p as a potential hub for developmental neuropsychiatric disorders: implications for schizophrenia, autism and cancer.

Defects in genetic and developmental processes are thought to contribute susceptibility to autism and schizophrenia. Presumably, owing to etiological complexity identifying susceptibility genes and abnormalities in the development has been difficult. However, the importance of genes within chromosomal 8p region for neuropsychiatric disorders and cancer is well established. There are 484 annotated genes located on 8p; many are most likely oncogenes and tumor-suppressor genes. Molecular genetics and developmental studies have identified 21 genes in this region (ADRA1A, ARHGEF10, CHRNA2, CHRNA6, CHRNB3, DKK4, DPYSL2, EGR3, FGF17, FGF20, FGFR1, FZD3, LDL, NAT2, NEF3, NRG1, PCM1, PLAT, PPP3CC, SFRP1 and VMAT1/SLC18A1) that are most likely to contribute to neuropsychiatric disorders (schizophrenia, autism, bipolar disorder and depression), neurodegenerative disorders (Parkinson's and Alzheimer's disease) and cancer. Furthermore, at least seven nonprotein-coding RNAs (microRNAs) are located at 8p. Structural variants on 8p, such as copy number variants, microdeletions or microduplications, might also contribute to autism, schizophrenia and other human diseases including cancer. In this review, we consider the current state of evidence from cytogenetic, linkage, association, gene expression and endophenotyping studies for the role of these 8p genes in neuropsychiatric disease. We also describe how a mutation in an 8p gene (Fgf17) results in a mouse with deficits in specific components of social behavior and a reduction in its dorsomedial prefrontal cortex. We finish by discussing the biological connections of 8p with respect to neuropsychiatric disorders and cancer, despite the shortcomings of this evidence.

Two cases of acrometastasis to the hands and review of the literature.

This paper reports two cases of acrometastasis to the hands. The first case involved a 78-year-old woman with a permeative osteolytic lesion in her proximal second metacarpal. A biopsy of this lesion suggested a diagnosis of non-small-cell lung carcinoma with secondary osseous metastasis. This was the first presentation of the woman's primary diagnosis. A single 8-Gy fraction of palliative radiotherapy was delivered to the patient's left hand. The treatment proved successful: the woman soon experienced pain relief and regained the use of her hand. The second case involved a 69-year-old woman with extensive lytic destruction involving the proximal two thirds of her third metacarpal. This patient had been diagnosed with carcinoma of the breast in 1990. She also received a single 8-Gy fraction of radiation, which improved both her pain and her hand mobility.An extensive review of the literature uncovered 257 previously reported cases of acrometastasis. Articles were analyzed based on age and sex of the patient, site of the primary carcinoma, metastatic locations within the hand and affected appendage or appendages, the treatment given, and the patient's length of survival. Men were almost twice as likely to experience acrometastasis as women, and the median age of the patients overall was 58 years (range: 18 months-91 years). Lung, kidney, and breast carcinoma were the three most prevalent primary diagnoses reported in the literature. Cancers of the colon, stomach, liver, prostate, and rectum affected the remainder of the population.Overall, the right hand was more often host to the metastatic lesions. In addition, almost 10% of the patients experienced lesions in both hands. The third finger was the digit most affected by osseous metastases reported in the literature. Lesions of the thumb, fourth finger, second finger, and fifth finger were less commonly reported. The region of the digit most often affected within the patient population was the distal phalanx. The metacarpal bones, proximal phalanges, and middle phalanges comprised the remainder of the four most frequent acrometastatic sites. In the literature, single lesions were more prevalent than multiple bony lesions.Based on the reported cases, amputation appeared to be the preferred method of treatment. Radiation, excision, and systemic therapy were the next most frequently used treatments. Patient survival was not well documented within the literature. However, the median survival of patients in the reported cases was 6 months. Thus, our review suggested that a diagnosis of hand metastasis is an indication of poor prognosis.This report serves to emphasize the importance of properly diagnosing acrometastases. Identifying and effectively treating these metastases in a timely manner can lead to a dramatic improvement in a patient's quality of life.

Primary CNS lymphoma with intraocular involvement: International PCNSL Collaborative Group Report.

OBJECTIVE: To describe the demographics, diagnostic details, therapeutic management, and outcome in patients with primary CNS lymphoma (PCNSL) with ocular involvement. METHODS: A retrospective study of 221 patients was assembled from 16 centers in seven countries. Only HIV-negative, immunocompetent patients with brain and ocular lymphoma were included; none had systemic lymphoma. RESULTS: Median age at diagnosis was 60. Fifty-seven percent were women. Median Eastern Cooperative Oncology Group performance status was 2. Ocular disturbance and behavioral/cognitive changes were the most common presenting symptoms. Diagnosis of lymphoma was made by brain biopsy (147), vitrectomy (65), or CSF cytology (11). Diagnosis of intraocular lymphoma was made by vitrectomy/choroidal/retinal biopsy (90) or clinical ophthalmic examination (141). CSF cytology was positive in 23%. Treatment information was available for 176 patients. A total of 102 received dedicated ocular therapy (ocular radiotherapy 79, intravitreal methotrexate 22, and both 1) in addition to treatment for their brain lymphoma. Sixty-nine percent progressed at a median of 13 months; sites of progression included brain 52%, eyes 19%, brain and eyes 12%, and systemic 2%. Patients treated with local ocular therapy did not have a statistically significant decreased risk of failing in the eyes (p = 0.7). Median progression free survival and overall survival for the entire cohort were 18 and 31 months. CONCLUSION: This is the largest reported series of primary CNS lymphoma (PCNSL) with intraocular involvement. Progression free and overall survival was similar to that reported with PCNSL. Dedicated ocular therapy improved disease control but did not affect overall survival.

Impact of intensive PBSC mobilization therapy on outcomes following auto-SCT for non-Hodgkin's lymphoma.

The best method to mobilize PBSCs in patients with non-Hodgkin's Lymphoma (NHL) is uncertain. We hypothesized that PBSC mobilization using an intensive chemotherapy regimen would improve outcomes after autologous hematopoietic stem cell transplantation (ASCT) in NHL patients at high risk for relapse. Fifty NHL patients were prospectively allocated to intense mobilization with high-dose etoposide plus either high-dose cytarabine or CY if they were 'high risk' for relapse, whereas 30 patients were allocated to nonintense mobilization with CY if they were 'standard risk' (all patients, +/-rituximab). All intensely mobilized patients were hospitalized compared with one-third of nonintensely mobilized patients. The EFS after ASCT was the same between the two groups, but overall survival (OS) was better for intensely mobilized patients (<0.01), including the diffuse large B-cell subgroup (P<0.04). We conclude that the intense mobilization of PBSCs in patients with NHL is more efficient than nonintense mobilization, but with greater toxicity. The equalization of EFS and superiority of OS in patients intensely mobilized to those nonintensely mobilized suggests that a treatment strategy using intensive chemotherapy for mobilization may be improving NHL outcomes after ASCT.

Abnormal social behaviors in mice lacking Fgf17.

The fibroblast growth factor family of secreted signaling molecules is essential for patterning in the central nervous system. Fibroblast growth factor 17 (Fgf17) has been shown to contribute to regionalization of the rodent frontal cortex. To determine how Fgf17 signaling modulates behavior, both during development and in adulthood, we studied mice lacking one or two copies of the Fgf17 gene. Fgf17-deficient mice showed no abnormalities in overall physical growth, activity level, exploration, anxiety-like behaviors, motor co-ordination, motor learning, acoustic startle, prepulse inhibition, feeding, fear conditioning, aggression and olfactory exploration. However, they displayed striking deficits in several behaviors involving specific social interactions. Fgf17-deficient pups vocalized less than wild-type controls when separated from their mother and siblings. Elimination of Fgf17 also decreased the interaction of adult males with a novel ovariectomized female in a social recognition test and reduced the amount of time opposite-sex pairs spent engaged in prolonged, affiliative interactions during exploration of a novel environment. After social exploration of a novel environment, Fgf17-deficient mice showed less activation of the immediate-early gene Fos in the frontal cortex than wild-type controls. Our findings show that Fgf17 is required for several complex social behaviors and suggest that disturbances in Fgf17 signaling may contribute to neuropsychiatric diseases that affect such behaviors.

Gene expression profiling suggests primary central nervous system lymphomas to be derived from a late germinal center B cell.

To characterize the molecular origin of primary lymphomas of the central nervous system (PCNSL), 21 PCNSLs of immunocompetent patients were investigated by microarray-based gene expression profiling. Comparison of the transcriptional profile of PCNSL with various normal and neoplastic B-cell subsets demonstrated PCNSL (i) to display gene expression patterns most closely related to late germinal center B cells, (ii) to display a gene expression profile similar to systemic diffuse large B-cell lymphomas (DLBCLs) and (iii) to be in part assigned to the activated B-cell-like (ABC) or the germinal center B-cell-like (GCB) subtype of DLBCL.

Neuronal production and precursor proliferation defects in the neocortex of mice with loss of function in the canonical Wnt signaling pathway.

To better understand the function of the Wnt pathway in the developing telencephalon, we analyzed neocortical development in low density lipoprotein receptor-related protein (LRP) 6 mutants. LRP6 mutant mice are hypomorphic for the canonical Wnt signaling pathway and have hypoplasia of the developing neocortex. While early telencephalic morphogenesis is largely intact in these mice, probably due to compensation by LRP5, the mutant mice develop a dramatically thinner cortical plate. There is a prominent reduction of neurogenesis leading to a thin cortical plate. Reduced proliferation late in gestation probably also contributes to the hypoplasia. Although there are marked decreases in the numbers of layer 6 and layers 2-4 neurons all laminar identities are generated and there is no evidence of compensatory increases in layer 5 neurons. In addition, LRP6 mutants have partial penetrance of a complex of cortical dysmorphologies resembling those found in patients with developmental forms of epilepsy and mental retardation. These include ventricular and marginal zone heterotopias and cobblestone lissencephaly. This analysis demonstrates that canonical Wnt signaling is required for a diverse array of developmental processes in the neocortex in addition to the previously known roles in regulating precursor proliferation and patterning.