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Supplementary Table 1 from Differential Gene Expression Analysis Reveals Generation of an Autocrine Loop by a Mutant Epidermal Growth Factor Receptor in Glioma Cells

The epidermal growth factor receptor (EGFR) gene is commonly amplified and rearranged in glioblastoma multiforme leading to overexpression of wild-type and mutant EGFRs. Expression of wild-type EGFR ligands, such as transforming growth factor-α (TGF-α) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells. Glioblastoma multiformes express a characteristic EGFR mutant (EGFRvIII, de 2-7) that does not bind ligand, signals constitutively, and is more tumorigenic than the wild-type receptor. However, the downstream signals that mediate this increased tumorigenicity are not well understood. We hypothesized that signals induced specifically by EGFRvIII and not the wild-type receptor are more likely to mediate its increased tumorigenic activity and examined the gene expression profiles resulting from inducible expression of comparable levels of either wild-type EGFR or EGFRvIII in a U251-MG glioma cell line. Expression of EGFRvIII resulted in specific up-regulation of a small group of genes. Remarkably, all these genes, which include TGFA, HB-EGF, EPHA2, IL8, MAP4K4, FOSL1, EMP1, and DUSP6, influence signaling pathways known to play a key role in oncogenesis and function in interconnected networks. Increased expression of EGFRvIII-induced genes was validated by real-time PCR. The mutant receptor does not bind ligand, and EGFRvIII-induced expression of TGF-α and HB-EGF suggests that EGFRvIII plays a role in generating an autocrine loop using the wild-type EGFR in glioma. It also raises the possibility that EGFRvIII may signal, at least in part, through the wild-type receptor. Indeed, we show that inhibiting the activity of HB-EGF, a potent mitogen, with neutralizing antibodies reduces cell proliferation induced by expression of EGFRvIII. This suggests that the EGFRvIII-HB-EGF-wild-type EGFR autocrine loop plays an important role in signal transduction by EGFRvIII in glioma cells. We also show by immunohistochemistry that HB-EGF expression correlates with the presence of EGFRvIII in glioblastoma multiforme. Thus, our study provides a new insight into oncogenic signaling by EGFRvIII and improves our understanding of how autocrine loops are generated in glioma. (Cancer Res 2006; 66(2): 867-74)

BACKGROUND Primary meningeal melanocytic neoplasms are exceedingly rare tumors, representing only 0.06% to 0.1% of all primary brain tumors and ranging in spectrum from benign localized tumors to highly aggressive malignant lesions. The diagnosis of these tumors is often challenging from clinical, radiological, and pathologic standpoints. Equally challenging is the distinction between primary meningeal melanocytic neoplasm and metastatic melanoma. OBSERVATIONS The authors reported the case of a 41-year-old man with imaging findings diagnostic of neurofibromatosis type 2: bilateral internal auditory canal lesions (most consistent with bilateral vestibular schwannomas), two dura-based lesions presumed to be meningiomas, multiple spinal lesions consistent with peripheral nerve sheath tumors, and one intramedullary spinal lesion consistent with an ependymoma. Biopsy of these lesions revealed melanocytic neoplasms with mild to moderate atypia and a mildly elevated proliferation index, which made the distinction between benign and malignant challenging. In addition, the disseminated nature of these tumors made it difficult to determinate whether they arose from the meninges or represented metastases from an occult primary melanoma. LESSONS This case illustrated the challenges presented by the diagnosis of meningeal melanocytic neoplasms and highlighted the importance of integrating the clinical and radiographic findings with histologic appearance and molecular studies.

Dynamic alterations in the unique brain extracellular matrix (ECM) are involved in malignant brain tumors. Yet studies of brain ECM roles in tumor cell behavior have been difficult due to lack of access to the human brain. We present a tunable 3D bioengineered brain tissue platform by integrating microenvironmental cues of native brain-derived ECMs and live imaging to systematically evaluate patient-derived brain tumor responses. Using pediatric ependymoma and adult glioblastoma as examples, the 3D brain ECM-containing microenvironment with a balance of cell-cell and cell-matrix interactions supports distinctive phenotypes associated with tumor type-specific and ECM-dependent patterns in the tumor cells’ transcriptomic and release profiles. Label-free metabolic imaging of the composite model structure identifies metabolically distinct sub-populations within a tumor type and captures extracellular lipid-containing droplets with potential implications in drug response. The versatile bioengineered 3D tumor tissue system sets the stage for mechanistic studies deciphering microenvironmental role in brain tumor progression., The brain extracellular matrix (ECM) is altered in brain tumors, but its role in cancer progression and drug sensitivity are difficult to study. Here the authors develop a 3D bioengineered brain tissue model using patient-derived samples and tunable brain-derived ECM to examine the interplay between cells and the ECM.

Combined chemotherapy with temozolomide (TMZ), bevacizumab (BEV) and irinotecan (IRI) [TBI] has been used in patients with recurrent or progressive high-grade gliomas. Patients tolerated the regimen well with increased frequency of reversible clinical myelosuppression (CM), hypertension and proteinuria. However, organ-specific toxicities have never been evaluated by post-mortem examination. From 2009 to 2019, post-mortem examinations were performed in seventy-six decedents, including gliomas (N=68, 44/M and 24/F, median age: 59, ranging 23–80 years old) and brain metastases (N=8, 5/M and 3/F, ranging 39–75 years old). Twenty-four glioma subjects were treated with 1–25 cycles TBI (median 5.5) at glioma recurrence. All subjects’ clinical information, treatment histories and adverse events were collected. Five (7.7%, 5/65) glioma decedents (excluding three glioma patients who never received TMZ) permanently discontinued TMZ due to severe CM during concurrent chemoradiation therapy. There is no significantly elevated severity of CM from TBI when compared to standard of care therapies, nor when comparing extended TMZ treatment to the standard 12 cycles of TMZ. However, exposure to IRI significantly increased the CM occurrence (p< 0.05). Among glioma decedents, the most common cause of death was tumor progression (63.2 %, N=43), followed by aspiration pneumonia (48.5%, N=33). No deaths were attributed to acute toxicity from TBI. An electromicroscopic (EM) examination was performed in addition to routine autopsy procedures to investigate the cause of hypertension and proteinuria frequently developing in patients received BEV therapy. Ultrastructural evidence of thrombotic microangiopathy was observed in the kidneys among BEV users; however, it is difficult to conclude such changes were related to BEV due to rapid autolytic changes and artifacts. CONCLUSION: IRI, not the extended use of TMZ, significantly increased the frequency of reversible CM in recurrent glioma patients. There are no unexpected adverse events or organ-specific toxicities detected among glioma decedents who received the TBI regimen.

Aims and objectives To assess the willingness of nurses to receive vaccines as recommended by Taiwan's "Immunization Recommendations for Healthcare Personnel" (IRHCP), as well as the factors associated with their willingness. Background Immunisation for healthcare personnel (HCP) is a means of reducing pathogen transmission. Also, vaccinating HCP reduces personnel and labour costs during an epidemic. Methods A cross-sectional study was conducted. A self-administered questionnaire survey targeting nurses working in various service units at three hospitals was used. In total, 413 nurses completed the questionnaire. The main outcome measure was the willingness to receive vaccines recommended by the IRHCP, and the variables we assessed included knowledge regarding the IRHCP, individual perceptions (perceived risk of contracting the infection, perceived severity of the infection and perceived transmissibility after disease onset), perceived benefits and barriers to the vaccination, cues to the vaccination and demographics. This study followed the STROBE checklist for reporting this study. Results The willingness of nurses to receive vaccines recommended by the IRHCP was high; the highest level of willingness was for the hepatitis B vaccine. The nurses' willingness to receive various vaccines recommended by the IRHCP was predicted by the knowledge regarding the IRHCP and perceived transmissibility after disease onset. Except the diphtheria-tetanus-acellular pertussis vaccine, perceived benefits and perceived barriers were also predictors of the willingness to receive vaccines. Conclusions Our results showed that interventions focusing on increasing the knowledge regarding the IRHCP and perceived transmissibility after disease onset, emphasising the benefits of the vaccination and reducing the perceived barriers to the vaccination are needed to increase nurses' willingness to receive vaccines. Relevance to clinical practice It is suggested using health education courses and mass media broadcasts at the individual and societal levels to raise awareness regarding the benefits of vaccines and enhance nurse' confidence in vaccination programs.

Background Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. Methods After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

Background Standard therapy for glioblastoma includes surgery, radiotherapy, and temozolomide. This Phase 3 trial evaluates the addition of an autologous tumor lysate-pulsed dendritic cell vaccine (DCVax®-L) to standard therapy for newly diagnosed glioblastoma. Methods After surgery and chemoradiotherapy, patients were randomized (2:1) to receive temozolomide plus DCVax-L (n = 232) or temozolomide and placebo (n = 99). Following recurrence, all patients were allowed to receive DCVax-L, without unblinding. The primary endpoint was progression free survival (PFS); the secondary endpoint was overall survival (OS). Results For the intent-to-treat (ITT) population (n = 331), median OS (mOS) was 23.1 months from surgery. Because of the cross-over trial design, nearly 90% of the ITT population received DCVax-L. For patients with methylated MGMT (n = 131), mOS was 34.7 months from surgery, with a 3-year survival of 46.4%. As of this analysis, 223 patients are ≥ 30 months past their surgery date; 67 of these (30.0%) have lived ≥ 30 months and have a Kaplan-Meier (KM)-derived mOS of 46.5 months. 182 patients are ≥ 36 months past surgery; 44 of these (24.2%) have lived ≥ 36 months and have a KM-derived mOS of 88.2 months. A population of extended survivors (n = 100) with mOS of 40.5 months, not explained by known prognostic factors, will be analyzed further. Only 2.1% of ITT patients (n = 7) had a grade 3 or 4 adverse event that was deemed at least possibly related to the vaccine. Overall adverse events with DCVax were comparable to standard therapy alone. Conclusions Addition of DCVax-L to standard therapy is feasible and safe in glioblastoma patients, and may extend survival. Trial registration Funded by Northwest Biotherapeutics; Clinicaltrials.gov number: NCT00045968; https://clinicaltrials.gov/ct2/show/NCT00045968?term=NCT00045968&rank=1; initially registered 19 September 2002

Stereotactic radiosurgery (SRS) represents a treatment option for patients with brain metastases from small cell lung cancer (SCLC) following prior cranial radiation. Inferior local control has been described. We reviewed our failure patterns following SRS treatment to evaluate this concern.Individuals with SCLC who received SRS for brain metastases from 2004 to 2011 were identified. Central nervous system (CNS) disease was detected and followed by gadolinium-enhanced, high-resolution magnetic resonance (MR) imaging. SRS dose was prescribed to the tumor periphery. Local recurrence was defined by increasing lesion size or enhancement, MR-spectroscopy, and perfusion changes consistent with recurrent disease or pathologic confirmation. Any new enhancing lesion not identified on the SRS planning scan was considered a regional failure. Overall survival (OS) and CNS control were evaluated using the Kaplan-Meier method. Factors predicted to influence outcome were tested by univariate log-rank analysis and Cox regression.Fifteen males and 25 females (median age of 61 years [range, 36-79]) of which 39 received prior brain irradiation were identified. In all, 132 lesions (3.3 per patient) between 0.4 and 4.7 cm received a median dose of 16 Gy (12-22 Gy). Thirteen metastases (10%) ultimately recurred locally with 6- and 12-month control rates of 81% and 69%, respectively. Only 1 of 110 metastases2 cm recurred. Local failure was more likely for size2 cm (P.001) and dose16 Gy (P.001). The median OS was 6.5 months, and the time to regional CNS recurrence was 5.2 months. For patients with single brain metastases, both OS (P = .037) and regional CNS recurrence (P = .003) were improved. CNS control (P = .001), and survival (P = .057), were also longer for patients with controlled systemic disease.Local control following SRS for SCLC metastases is achievable for lesions2 cm. For metastases2 cm, local failure is more common than expected. Patients with controlled systemic disease and limited CNS involvement would benefit most from aggressive treatment.

Silk solvent casting, electrospinning, and electrogelation techniques were used to create a biodegradable, biocompatible silk fibroin dural substitute. The all-silk system was designed and produced to improve on currently available materials, grafts and tissue sealants used for dural closure in neurosurgery. The silk biomaterial was successfully fabricated as a dual layer adhesive system designed to seal durotomies while also functioning as a dural regeneration scaffold. The mechanical characteristics, biocompatibility, biodegradability, and hydrodynamic sealing capability of the material were evaluated. Results showed that the biomaterial was biocompatible with neural cells and fibroblasts, had mechanical properties mimicking the natural dura, was biodegradable with controllable degradation, and was able to seal against a hydrodynamic pressure of 205 mmHg, which greatly exceeds the maximum cerebrospinal fluid pressure seen in both cranial and spinal dural closures of 50 mmHg. Based on its design and experimental results, the adhesive silk dual layer composite biomaterial shows potential as a sutureless dural repair system that would improve on current dural closure techniques.

Background Third ventricular ependymomas in adults are rare lesions for which the optimal management strategy has not been determined. Objectives We describe our results using a strategy of endoscopic biopsy followed by gamma knife radiosurgery in two patients with low-grade (World Health Organization [WHO] grade II) third ventricular ependymomas. Methods A retrospective analysis of clinical notes, operative records, and neuroimaging was performed for the two patients in this study. The patients both presented with obstructive hydrocephalus and had endoscopic third ventriculostomy performed along with endoscopic tumor biopsy. In both patients the pathology revealed papillary ependymoma WHO grade II. In one patient the endoscopic third ventriculostomy failed, and ventriculoperitoneal shunt placement was necessary. Postoperatively, gamma knife radiosurgery was performed at 1 and 4 months, respectively. Results Both patients in the study experienced symptom resolution following treatment of the hydrocephalus. They returned to their preoperative level of social and occupational function. There was tumor enlargement in one patient in the interval between the initial surgery and the gamma knife treatment. However, neither tumor has enlarged since gamma knife treatment with follow-up of 35 and 41 months, respectively. Conclusions The strategy of endoscopic biopsy followed by gamma knife radiosurgery for adult WHO grade II third ventricular ependymomas has produced acceptable clinical results 3 years posttreatment. Stereotactic radiosurgery without prior microsurgical resection has not previously been reported in these tumors. Longer follow-up is required to evaluate the durability of this treatment.

Background This study aimed to evaluate the prevalence of parvovirus B19 antibodies in children and young adults aged = 30 years old in Taiwan. Methods Stored serum samples from healthy volunteers aged 1-29 years in Taipei were randomly selected and tested for antiparvovirus B19 immunoglobulin G by enzyme immunoassay. Results A total of 277 serum samples were tested. The overall seroprevalence of parvovirus B19 in Taiwanese children and young adults was 23.1% (64/277) in 2004. The positive rate increased slightly with age; it ranged from 15.0% in those aged 1-4 years to 30.8% in those aged 25-29 years (trend test, p = 0.01). The age-adjusted anti-B19 immunoglobulin G seropositive rate was slightly higher in males (27.8%) than in females (18.8%; adjusted odds ratio: 0.56; 95% confidence interval: 0.32-0.99). Conclusion Most children and young adults in Taipei City are not immune to parvovirus B19, suggesting that no parvovirus B19 epidemic has occurred in the last few decades.

Soft tissue sarcomas (STS) are a heterogeneous group of uncommon tumors that show a broad range of differentiation that may reflect etiologic distinction. Routine tabulations of STS are not morphology-specific. Further, the lack of inclusion of sarcomas arising in all organs in most standard evaluations underestimates the true rates. We analyzed the 1978–2001 Surveillance, Epidemiology and End Results program incidence rates of STS regardless of primary site, except bones and joints, using the 2002 criteria of the WHO classification. There were 26,758 cases available for analysis. Leiomyosarcomas accounted for 23.9%, malignant fibrous histiocytomas 17.1%, liposarcomas 11.5%, dermatofibrosarcomas 10.5%, rhabdomyosarcomas 4.6% and angiosarcomas 4.1%. Almost half (47.9%) of the sarcomas arose in the soft tissues, 14.0% in the skin and 7.0% in the uterus. Overall, incidence rates were highest among black women (6.26/100,000 woman-years) and the lowest among white women (4.60/100,000). Age-adjusted rates increased at 1.2% and 0.8% per year among white males and females, respectively, both trends statistically significant, while rates among blacks declined slightly. About 40% of leiomyosarcomas among women were uterine in origin, with a black/white rate ratio of 1.7. This rate ratio increased to 2.0 when we accounted for the lower prevalence of intact uteri among black compared to white women. Total STS rates rose exponentially with age. Rates for both uterine leiomyosarcoma and dermatofibrosarcoma increased rapidly during the childbearing years, peaking at about age 40 and 50, respectively. Incidence patterns of STS varied markedly by histologic type, supporting the notion that these tumors may be etiologically distinct. © 2006 Wiley-Liss, Inc.

Background: Cell transplantation is safe in animal models and enhances recovery from stroke in rats. Methods: We studied the safety and feasibility of fetal porcine transplantation in 5 patients with basal ganglia infarcts and stable neurological deficits. To prevent rejection, cells were pretreated with an anti-MHC1 antibody and no immunosuppressive drugs were given to the patients. Results: The first 3 patients had no adverse cell, procedure, or imaging-defined effects. The fourth patient had temporary worsening of motor deficits 3 weeks after transplantation, and the fifth patient developed seizures 1 week after transplantation. MRI in both patients demonstrated areas of enhancement remote from the transplant site, which resolved on subsequent imaging. Two patients showed improvement in speech, language, and/or motor impairments over several months and persisted at 4 years. The study was terminated by the FDA after the inclusion of 5 patients. Conclusion: This is the first report on the transplantation of nontumor cells in ischemic stroke patients.

OBJECTIVE The objective of the Brain Tumor Cooperative Group NIH Trial 87-01 trial was to investigate the effect of additional implanted radiation therapy in newly diagnosed patients with pathologically confirmed malignant gliomas.METHODS The study involved a randomized comparison of surgery, extern

PURPOSE: Stereotactic radiosurgery (SRS) following resection of brain metastases is well-tolerated, provides excellent local control and reserves whole-brain radiation therapy for high volume CNS recurrence. We identified criteria to facilitate appropriate candidate selection for SRS based on CNS recurrence and overall survival (OS). METHODS: From 2002-2010, individuals with a KPS >70 who received SRS to the resection cavity for brain metastases were evaluated. The target encompassed the entire cavity defined on MRI, and was treated using Gamma Knife radiosurgery. Follow-up included clinical exam and MRI at 2-3 month intervals. CNS failure was defined by imaging or pathology. Factors predicted to impact OS and CNS control were assessed using log-rank and Cox-regression analyses. RESULTS: 151 consecutive patients with a median follow-up of 5.3 months were identified. Local control was >90% at 1 year and >80% at 2 years. Median OS was 14.2 months with 19% 5-year survival. Patients without systemic disease and those with single metastasis survived significantly longer. Median time to regional CNS failure was 14.5 months. Systemic disease overwhelmingly predicted regional CNS recurrence. Multivariate analysis showed that absence of systemic disease, a single brain metastasis and age were associated with improved OS and regional CNS control. We identified 3 groups: single brain lesion without systemic disease, >2 brain lesions without systemic disease, and those with systemic disease, that predicted OS and CNS control. Median OS was 16.5, 18.3, and 8.1 months, respectively (p < 0.001) and median time to CNS recurrence was 32.8, 15.7 and 8.7 months, respectively (p < 0.001). CONCLUSION: This represents the largest study of SRS following resection of brain metastases. Excellent long-term local control, survival and regional CNS control can be achieved in select patients. Major criteria to identify treatment candidates should include systemic disease status as well as number of brain lesions.

Case A 57 year old female patient presented with a painful right-sided neck mass that on MRI was shown to be adherent to the posterior aspect of the sternocleidomastoid muscle. The mass was surgically resected en bloc without complications. Histopathologic analysis revealed the mass to be a myxoma. Review To date, there have been several case reports of myxomas, although very few involving the head or neck. The majority of the literature available concurs that myxomas are benign neoplasms that exhibit characteristic qualities on MRI imaging. The definitive treatment by consensus is surgical excision. Conclusions Although the incidence of head and neck myxomas is low, it is important to include in the differential of a neck mass with certain radiographic findings.

✓Iophendylate (Pantopaque or Myodil) was commonly used from the 1940s until the late 1980s for myelography, cisternography, and ventriculography. Although such instances are rare, several different long-term sequelae have been described in the literature and associated with intrathecal iophendylate. The authors describe an unusual case of arachnoiditis caused by residual thoracic iophendylate imitating an expansile intramedullary lesion on magnetic resonance images obtained 30 years after the initial myelographic injection.

As of April 14, 2003, Taiwan had had 23 probable cases of severe acute respiratory syndrome (SARS), all imported. Taiwan isolated these first 23 patients with probable SARS in negative-pressure rooms; extensive personal protective equipment was used for healthcare workers and visitors. For the first 6 weeks of the SARS outbreak, recognized spread was limited to one healthcare worker and three household contacts.

Background With international concern over emerging infectious diseases (EID) and bioterrorist attacks, public health is being required to have early outbreak detection systems. A disease surveillance team was organized to establish a hospital emergency department-based syndromic surveillance system (ED-SSS) capable of automatically transmitting patient data electronically from the hospitals responsible for emergency care throughout the country to the Centers for Disease Control in Taiwan (Taiwan-CDC) starting March, 2004. This report describes the challenges and steps involved in developing ED-SSS and the timely information it provides to improve in public health decision-making. Methods Between June 2003 and March 2004, after comparing various surveillance systems used around the world and consulting with ED physicians, pediatricians and internal medicine physicians involved in infectious disease control, the Syndromic Surveillance Research Team in Taiwan worked with the Real-time Outbreak and Disease Surveillance (RODS) Laboratory at the University of Pittsburgh to create Taiwan's ED-SSS. The system was evaluated by analyzing daily electronic ED data received in real-time from the 189 hospitals participating in this system between April 1, 2004 and March 31, 2005. Results Taiwan's ED-SSS identified winter and summer spikes in two syndrome groups: influenza-like illnesses and respiratory syndrome illnesses, while total numbers of ED visits were significantly higher on weekends, national holidays and the days of Chinese lunar new year than weekdays (p < 0.001). It also identified increases in the upper, lower, and total gastrointestinal (GI) syndrome groups starting in November 2004 and two clear spikes in enterovirus-like infections coinciding with the two school semesters. Using ED-SSS for surveillance of influenza-like illnesses and enteroviruses-related infections has improved Taiwan's pandemic flu preparedness and disease control capabilities. Conclusion Taiwan's ED-SSS represents the first nationwide real-time syndromic surveillance system ever established in Asia. The experiences reported herein can encourage other countries to develop their own surveillance systems. The system can be adapted to other cultural and language environments for better global surveillance of infectious diseases and international collaboration.

This study's objective was to describe: (1) patterns of cancer prevalence and type, (2) patient demographics, and (3) the sources, and cost, of medical care in the military beneficiary population using the Military Health System administrative databases. Calendar year 2002 patient enrollment, inpatient and outpatient encounter, and cost data from the 50 United States were analyzed to determine beneficiary cancer prevalence, demographics, source of care, cost of care, and cancer type. A total of 355,442 military beneficiaries were identified to have a cancer diagnosis (excluding nonmelanoma skin cancers) in 2002. More than two-thirds of these beneficiaries were over the age of 65, 55% were male, and 44% lived in three geographic areas of the country. Cancer of the prostate, breast, lung, and colon were most common. Almost 90% received their care outside of military medical treatment facilities and the overall cost of their care for 2002 was over $1 billion.

The epidermal growth factor receptor (EGFR) gene is commonly amplified and rearranged in glioblastoma multiforme leading to overexpression of wild-type and mutant EGFRs. Expression of wild-type EGFR ligands, such as transforming growth factor-α (TGF-α) or heparin-binding EGF (HB-EGF), is also often increased in gliomas resulting in an autocrine loop that contributes to the growth autonomy of glioma cells. Glioblastoma multiformes express a characteristic EGFR mutant (EGFRvIII, de 2-7) that does not bind ligand, signals constitutively, and is more tumorigenic than the wild-type receptor. However, the downstream signals that mediate this increased tumorigenicity are not well understood. We hypothesized that signals induced specifically by EGFRvIII and not the wild-type receptor are more likely to mediate its increased tumorigenic activity and examined the gene expression profiles resulting from inducible expression of comparable levels of either wild-type EGFR or EGFRvIII in a U251-MG glioma cell line. Expression of EGFRvIII resulted in specific up-regulation of a small group of genes. Remarkably, all these genes, which include TGFA, HB-EGF, EPHA2, IL8, MAP4K4, FOSL1, EMP1, and DUSP6, influence signaling pathways known to play a key role in oncogenesis and function in interconnected networks. Increased expression of EGFRvIII-induced genes was validated by real-time PCR. The mutant receptor does not bind ligand, and EGFRvIII-induced expression of TGF-α and HB-EGF suggests that EGFRvIII plays a role in generating an autocrine loop using the wild-type EGFR in glioma. It also raises the possibility that EGFRvIII may signal, at least in part, through the wild-type receptor. Indeed, we show that inhibiting the activity of HB-EGF, a potent mitogen, with neutralizing antibodies reduces cell proliferation induced by expression of EGFRvIII. This suggests that the EGFRvIII-HB-EGF-wild-type EGFR autocrine loop plays an important role in signal transduction by EGFRvIII in glioma cells. We also show by immunohistochemistry that HB-EGF expression correlates with the presence of EGFRvIII in glioblastoma multiforme. Thus, our study provides a new insight into oncogenic signaling by EGFRvIII and improves our understanding of how autocrine loops are generated in glioma. (Cancer Res 2006; 66(2): 867-74)

The anteroventral temporal lobe integrates visual, lexical, semantic and mnestic aspects of word processing, through its reciprocal connections with the ventral visual stream, language areas, and the hippocampal formation. We used linear microelectrode arrays to probe population synaptic currents and neuronal firing in different cortical layers of the anteroventral temporal lobe, during semantic judgments with implicit priming and overt word recognition. Since different extrinsic and associative inputs preferentially target different cortical layers, this method can help reveal the sequence and nature of local processing stages at a higher resolution than was previously possible. The initial response in inferotemporal and perirhinal cortices is a brief current sink beginning at approximately 120 ms and peaking at approximately 170 ms. Localization of this initial sink to middle layers suggests that it represents feedforward input from lower visual areas, and simultaneously increased firing implies that it represents excitatory synaptic currents. Until approximately 800 ms, the main focus of transmembrane current sinks alternates between middle and superficial layers, with the superficial focus becoming increasingly dominant after approximately 550 ms. Since superficial layers are the target of local and feedback associative inputs, this suggests an alternation in predominant synaptic input between feedforward and feedback modes. Word repetition does not affect the initial perirhinal and inferotemporal middle layer sink but does decrease later activity. Entorhinal activity begins later (approximately 200 ms), with greater apparent excitatory post-synaptic currents and multiunit activity in neocortically projecting than hippocampal-projecting layers. In contrast to perirhinal and entorhinal responses, entorhinal responses are larger to repeated words during memory retrieval. These results identify a sequence of physiological activation, beginning with a sharp activation from lower level visual areas carrying specific information to middle layers. This is followed by feedback and associative interactions involving upper cortical layers, which are abbreviated to repeated words. Following bottom-up and associative stages, top-down recollective processes may be driven by entorhinal cortex. Word processing involves a systematic sequence of fast feedforward information transfer from visual areas to anteroventral temporal cortex followed by prolonged interactions of this feedforward information with local associations and feedback mnestic information from the medial temporal lobe.

Background. Health care workers continued to contract severe acute respiratory syndrome (SARS), even after barrier precautions were widely implemented. Methods. We explored the possible contribution of contaminated hospital surfaces to SARS transmission by swabbing surfaces in 2 hospitals and testing the swab samples by reverse-transcriptase polymerase chain reaction (RT-PCR) and viral culture. Results. Twenty-six of 94 swab samples tested positive for viral RNA. Swab samples of respiratory secretions from each of the 4 patients examined tested positive by RT-PCR, as were 12 of 43 swabs from patient rooms and 10 of 47 swabs from other parts of the hospital, including the computer mouses at 2 nursing stations and the handrail of the public elevator. Specimens from areas with patients with SARS in the most infectious phase of illness (days 5–15 after onset) were more likely to be RNA positive than were swab specimens from elsewhere (24 of 63 samples vs. 2 of 31 samples; P = .001). All cultures showed no growth. Conclusions. Although the viruses identified may have been noninfectious, health care workers should be aware that SARS coronavirus can contaminate environmental surfaces in the hospital, and fomites should be considered to be a possible mode of transmission of SARS.

BACKGROUND: In order to facilitate public health response and to achieve early control of infectious disease epidemics, an adjustable epidemiologic information system (AEIS) was established in the Taiwan public health network in February 2006. METHODOLOGY/PRINCIPAL FINDINGS: The performance of AEIS for the period 2006 through 2008 was evaluated based on a number of response times (RT) and the public health impact. After implementation of the system, the apparent overall shortened RT was mainly due to the shortening of personnel response time (PRT) and the time needed to draft a new questionnaire that incurred as personnel-system interface (PSI); PRT dropped from a fluctuating range of 9.8 ∼28.8 days in the first four months to

Osteoid osteoma is an uncommon benign tumor of bone that rarely involves the cranium. It often causes local pain that is worse at night, characteristically relieved by aspirin, and does not correlate with the size of the lesion. The diagnosis depends on skull radiographs and computed tomography. This report describes a case in which radiographs showed nothing abnormal. The diagnosis and operative localization were accomplished with radionuclide bone scanning. Thus, the possibility of radiographically cryptic lesions must be considered in the evaluation of atypical head pain syndromes.