Causality and signalling of garden-path sentences.

Sheaves are mathematical objects that describe the globally compatible data associated with open sets of a topological space. Original examples of sheaves were continuous functions; later they also became powerful tools in algebraic geometry, as well as logic and set theory. More recently, sheaves have been applied to the theory of contextuality in quantum mechanics. Whenever the local data are not necessarily compatible, sheaves are replaced by the simpler setting of presheaves. In previous work, we used presheaves to model lexically ambiguous phrases in natural language and identified the order of their disambiguation. In the work presented here, we model syntactic ambiguities and study a phenomenon in human parsing called garden-pathing. It has been shown that the information-theoretic quantity known as 'surprisal' correlates with human reading times in natural language but fails to do so in garden-path sentences. We compute the degree of signalling in our presheaves using probabilities from the large language model BERT and evaluate predictions on two psycholinguistic datasets. Our degree of signalling outperforms surprisal in two ways: (i) it distinguishes between hard and easy garden-path sentences (with a [Formula: see text]-value [Formula: see text]), whereas existing work could not, (ii) its garden-path effect is larger in one of the datasets (32 ms versus 8.75 ms per word), leading to better prediction accuracies. This article is part of the theme issue 'Quantum contextuality, causality and freedom of choice'.

Association between pathologic response and survival after neoadjuvant therapy in lung cancer.

Neoadjuvant immunotherapy plus chemotherapy improves event-free survival (EFS) and pathologic complete response (0% residual viable tumor (RVT) in primary tumor (PT) and lymph nodes (LNs)), and is approved for treatment of resectable lung cancer. Pathologic response assessment after neoadjuvant therapy is the potential analog to radiographic response for advanced disease. However, %RVT thresholds beyond pathologic complete response and major pathologic response (≤10% RVT) have not been explored. Pathologic response was prospectively assessed in the randomized, phase 3 CheckMate 816 trial (NCT02998528), which evaluated neoadjuvant nivolumab (anti-programmed death protein 1) plus chemotherapy in patients with resectable lung cancer. RVT, regression and necrosis were quantified (0-100%) in PT and LNs using a pan-tumor scoring system and tested for association with EFS in a prespecified exploratory analysis. Regardless of LN involvement, EFS improved with 0% versus >0% RVT-PT (hazard ratio = 0.18). RVT-PT predicted EFS for nivolumab plus chemotherapy (area under the curve = 0.74); 2-year EFS rates were 90%, 60%, 57% and 39% for patients with 0-5%, >5-30%, >30-80% and >80% RVT, respectively. Each 1% RVT associated with a 0.017 hazard ratio increase for EFS. Combining pathologic response from PT and LNs helped differentiate outcomes. When compared with radiographic response and circulating tumor DNA clearance, %RVT best approximated EFS. These findings support pathologic response as an emerging survival surrogate. Further assessment of the full spectrum of %RVT in lung cancer and other tumor types is warranted. ClinicalTrials.gov registration: NCT02998528 .

Immune microenvironment of basal cell carcinoma and tumor regression following combined PD-1/LAG-3 blockade.

Systemic treatment options for patients with locally advanced or metastatic basal cell carcinoma (BCC) are limited, particularly when tumors are refractory to anti-programmed cell death protein-1 (PD-1). A better understanding of immune checkpoint expression within the BCC tumor microenvironment may inform combinatorial treatment strategies to optimize response rates. CD3, PD-1, programmed death ligand-1 (PD-L1), lymphocyte activation gene 3 (LAG-3), and T-cell immunoglobulin domain and mucin domain 3 (TIM-3)+ cell densities within the tumor microenvironment of 34 archival, histologically aggressive BCCs were assessed. Tumor infiltrating lymphocyte (TIL) expression of PD-1, PD-L1, and LAG-3, and to a lesser degree TIM-3, correlated with increasing CD3+ T-cell densities (Pearson's r=0.89, 0.72, 0.87, and 0.63, respectively). 100% of BCCs (34/34) demonstrated LAG-3 and PD-1 expression in >1% TIL; and the correlation between PD-1 and LAG-3 densities was high (Pearson's r=0.89). LAG-3 was expressed at ~50% of the level of PD-1. Additionally, we present a patient with locally-advanced BCC who experienced stable disease during and after 45 weeks of first-line anti-PD-1 (nivolumab), followed by a partial response after the addition of anti-LAG-3 (relatlimab). Longitudinal biopsies throughout the treatment course showed a graduated increase in LAG-3 expression after anti-PD-1 therapy, lending support for coordinated immunosuppression and suggesting LAG-3 as a co-target for combination therapy to augment the clinical impact of anti-PD-(L)1.

Analysis of multispectral imaging with the AstroPath platform informs efficacy of PD-1 blockade.

Next-generation tissue-based biomarkers for immunotherapy will likely include the simultaneous analysis of multiple cell types and their spatial interactions, as well as distinct expression patterns of immunoregulatory molecules. Here, we introduce a comprehensive platform for multispectral imaging and mapping of multiple parameters in tumor tissue sections with high-fidelity single-cell resolution. Image analysis and data handling components were drawn from the field of astronomy. Using this "AstroPath" whole-slide platform and only six markers, we identified key features in pretreatment melanoma specimens that predicted response to anti-programmed cell death-1 (PD-1)-based therapy, including CD163+PD-L1- myeloid cells and CD8+FoxP3+PD-1low/mid T cells. These features were combined to stratify long-term survival after anti-PD-1 blockade. This signature was validated in an independent cohort of patients with melanoma from a different institution.

Neoadjuvant nivolumab plus ipilimumab in resectable non-small cell lung cancer.

BACKGROUND: We conducted the first trial of neoadjuvant PD-1 blockade in resectable non-small cell lung cancer (NSCLC), finding nivolumab monotherapy to be safe and feasible with an encouraging rate of pathologic response. Building on these results, and promising data for nivolumab plus ipilimumab (anti-CTLA-4) in advanced NSCLC, we expanded our study to include an arm investigating neoadjuvant nivolumab plus ipilimumab. METHODS: Patients with resectable stage IB (≥4 cm)-IIIA (American Joint Committee on Cancer Tumor Node Metastases seventh edition), histologically confirmed, treatment-naïve NSCLC received nivolumab 3 mg/kg intravenously plus ipilimumab 1 mg/kg intravenously 6 weeks prior to planned resection. Nivolumab 3 mg/kg was given again approximately 4 and 2 weeks preoperatively. Primary endpoints were safety and feasibility with a planned enrollment of 15 patients. Pathologic response was a key secondary endpoint. RESULTS: While the treatment regimen was feasible per protocol, due to toxicity, the study arm was terminated early by investigator consensus after 9 of 15 patients were enrolled. All patients received every scheduled dose of therapy and were fit for planned surgery; however, 6 of 9 (67%) experienced treatment-related adverse events (TRAEs) and 3 (33%) experienced grade ≥3 TRAEs. Three of 9 patients (33%) had biopsy-confirmed tumor progression precluding definitive surgery. Of the 6 patients who underwent resection, 3 are alive and disease-free, 2 experienced recurrence and are actively receiving systemic treatment, and one died postoperatively due to acute respiratory distress syndrome. Two patients who underwent resection had tumor pathologic complete responses (pCRs) and continue to remain disease-free over 24 months since surgery. Pathologic response correlated with pre-treatment tumor PD-L1 expression, but not tumor mutation burden. Tumor KRAS/STK11 co-mutations were identified in 5 of 9 patients (59%), of whom two with disease progression precluding surgery had tumor KRAS/STK11/KEAP1 co-mutations. CONCLUSIONS: Though treatment was feasible, due to toxicity the study arm was terminated early by investigator consensus. In light of this, and while the long-term disease-free status of patients who achieved pCR is encouraging, further investigation of neoadjuvant nivolumab plus ipilimumab in patients with resectable NSCLC requires the identification of predictive biomarkers that enrich for response.

Chronic immune checkpoint inhibitor pneumonitis.

BACKGROUND: Pneumonitis from immune checkpoint inhibitors (ICI) is a potentially fatal immune-related adverse event (irAE) from antiprogrammed death 1/programmed death ligand 1 immunotherapy. Most cases of ICI pneumonitis improve or resolve with 4-6 weeks of corticosteroid therapy. Herein, we report the incidence, clinicopathological features and management of patients with non-small cell lung cancer (NSCLC) and melanoma who developed chronic ICI pneumonitis that warrants ≥12 weeks of immunosuppression. METHODS: Patients with ICI pneumonitis were identified from institutional databases of ICI-treated patients with advanced melanoma and NSCLC between January 2011 and July 2018. ICI pneumonitis was defined as clinical/radiographic evidence of lung inflammation without alternative diagnoses, adjudicated by a multidisciplinary team. Chronic ICI pneumonitis was defined as pneumonitis that persists or worsens with steroid tapering, and necessitates ≥12 weeks of immunosuppression, after ICI discontinuation. Serial chest CT was used to assess radiological features, and tumor response by Response EvaluationCriteria for Solid Tumors V.1.1. Bronchoalveolar lavage fluid (BALF) samples were assessed by cell differential. Lung biopsy samples were evaluated by H&E staining and multiplex immunofluorescence (mIF), where available. RESULTS: Among 299 patients, 44 developed ICI pneumonitis (NSCLC: 5/205; melanoma: 1/94), and of these, 6 experienced chronic ICI pneumonitis. The overall incidence of chronic ICI pneumonitis was thus 2%. Of those who developed chronic ICI pneumonitis: the majority had NSCLC (5/6), all sustained disease control from ICIs, and none had other concurrent irAEs. Timing of chronic ICI pneumonitis development was variable (range: 0-50 months), and occurred at a median of 12 months post ICI start. Recrudescence of ICI pneumonitis occurred at a median of 6 weeks after initial steroid start (range: 3-12 weeks), with all patients requiring steroid reintroduction when tapered to ≤10 mg prednisone/equivalent. The median total duration of steroids was 37 weeks (range: 16-43+weeks). Re-emergence of radiographic ICI pneumonitis occurred in the same locations on chest CT, in most cases (5/6). All patients who developed chronic ICI pneumonitis had BALF lymphocytosis on cell differential and organising pneumonia on lung biopsy at initial ICI pneumonitis presentation, with persistent BALF lymphocytosis and brisk CD8+ infiltration on mIF at pneumonitis re-emergence during steroid taper. CONCLUSIONS: A subset of patients who develop pneumonitis from ICIs will develop chronic ICI pneumonitis, that warrants long-term immunosuppression of ≥12 weeks, and has distinct clinicopathological features.

Comparison of Biomarker Modalities for Predicting Response to PD-1/PD-L1 Checkpoint Blockade: A Systematic Review and Meta-analysis.

IMPORTANCE: PD-L1 (programmed cell death ligand 1) immunohistochemistry (IHC), tumor mutational burden (TMB), gene expression profiling (GEP), and multiplex immunohistochemistry/immunofluorescence (mIHC/IF) assays have been used to assess pretreatment tumor tissue to predict response to anti-PD-1/PD-L1 therapies. However, the relative diagnostic performance of these modalities has yet to be established. OBJECTIVE: To compare studies that assessed the diagnostic accuracy of PD-L1 IHC, TMB, GEP, and mIHC/IF in predicting response to anti-PD-1/PD-L1 therapy. EVIDENCE REVIEW: A search of PubMed (from inception to June 2018) and 2013 to 2018 annual meeting abstracts from the American Association for Cancer Research, American Society of Clinical Oncology, European Society for Medical Oncology, and Society for Immunotherapy of Cancer was conducted to identify studies that examined the use of PD-L1 IHC, TMB, GEP, and mIHC/IF assays to determine objective response to anti-PD-1/PD-L1 therapy. For PD-L1 IHC, only clinical trials that resulted in US Food and Drug Administration approval of indications for anti-PD-1/PD-L1 were included. Studies combining more than 1 modality were also included. Preferred Reporting Items for Systematic Reviews and Meta-analysis guidelines were followed. Two reviewers independently extracted the clinical outcomes and test results for each individual study. MAIN OUTCOMES AND MEASURES: Summary receiver operating characteristic (sROC) curves; their associated area under the curve (AUC); and pooled sensitivity, specificity, positive and negative predictive values (PPV, NPV), and positive and negative likelihood ratios (LR+ and LR-) for each assay modality. RESULTS: Tumor specimens representing over 10 different solid tumor types in 8135 patients were assayed, and the results were correlated with anti-PD-1/PD-L1 response. When each modality was evaluated with sROC curves, mIHC/IF had a significantly higher AUC (0.79) compared with PD-L1 IHC (AUC, 0.65, P < .001), GEP (AUC, 0.65, P = .003), and TMB (AUC, 0.69, P = .049). When multiple different modalities were combined such as PD-L1 IHC and/or GEP + TMB, the AUC drew nearer to that of mIHC/IF (0.74). All modalities demonstrated comparable NPV and LR-, whereas mIHC/IF demonstrated higher PPV (0.63) and LR+ (2.86) than the other approaches. CONCLUSIONS AND RELEVANCE: In this meta-analysis, tumor mutational burden, PD-L1 IHC, and GEP demonstrated comparable AUCs in predicting response to anti-PD-1/PD-L1 treatment. Multiplex immunohistochemistry/IF and multimodality biomarker strategies appear to be associated with improved performance over PD-L1 IHC, TMB, or GEP alone. Further studies with mIHC/IF and composite approaches with a larger number of patients will be required to confirm these findings. Additional study is also required to determine the most predictive analyte combinations and to determine whether biomarker modality performance varies by tumor type.

Correction to: 33rd Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2018).

After publication of this supplement [1, 2], it was brought to our attention that due to an error authors were missing in the following abstracts. This has now been included in this correction.

Traditional Medicines and Kidney Disease in Low- and Middle-Income Countries: Opportunities and Challenges.

Traditional medicines are a principal form of health care for many populations, particularly in low- and middle-income countries, and they have gained attention as an important means of health care coverage globally. In the context of kidney diseases, the challenges and opportunities presented by traditional medicine practices are among the most important considerations for developing effective and sustainable public health strategies. However, little is known about the practices of traditional medicines in relation to kidney diseases, especially concerning benefits and harms. Kidney diseases may be caused, treated, prevented, improved, or worsened by traditional medicines depending on the setting, the person, and the types, modes, and frequencies of traditional medicine use. Given the profound knowledge gaps, nephrology practitioners and researchers may be uniquely positioned to facilitate more optimal public health strategies through recognition and careful investigation of traditional medicine practices. Effective implementation of such strategies also will require local partnerships, including engaging practitioners and users of traditional medicines. As such, practitioners and researchers investigating kidney diseases may be uniquely positioned to bridge the cultural, social, historical, and biologic differences between biomedicine and traditional medicine, and they have opportunities to lead efforts in developing public health strategies that are sensitive to these differences.

Traditional medicine practices among community members with diabetes mellitus in Northern Tanzania: an ethnomedical survey.

BACKGROUND: Diabetes is a growing burden in sub-Saharan Africa where traditional medicines (TMs) remain a primary form of healthcare in many settings. In Tanzania, TMs are frequently used to treat non-communicable diseases, yet little is known about TM practices for non-communicable diseases like diabetes. METHODS: Between December 2013 and June 2014, we assessed TM practices, including types, frequencies, reasons, and modes, among randomly selected community members. To further characterize TMs relevant for the local treatment of diabetes, we also conducted focus groups and semi-structured interviews with key informants. RESULTS: We enrolled 481 adults of whom 45 (9.4 %) had diabetes. The prevalence of TM use among individuals with diabetes was 77.1 % (95 % CI 58.5-89.0 %), and the prevalence of using TMs and biomedicines concurrently was 37.6 % (95 % CI 20.5-58.4 %). Many were using TMs specifically to treat diabetes (40.3 %; 95 % CI 20.5-63.9), and individuals with diabetes reported seeking healthcare from traditional healers, elders, family, friends, and herbal vendors. We identified several plant-based TMs used toward diabetes care: Moringa oleifera, Cymbopogon citrullus, Hagenia abyssinica, Aloe vera, Clausena anisata, Cajanus cajan, Artimisia afra, and Persea americana. CONCLUSIONS: TMs were commonly used for diabetes care in northern Tanzania. Individuals with diabetes sought healthcare advice from many sources, and several individuals used TMs and biomedicines together. The TMs commonly used by individuals with diabetes in northern Tanzania have a wide range of effects, and understanding them will more effectively shape biomedical practitices and public health policies that are patient-centered and sensitive to TM preferences.

A Structural and Functional Comparison Between Infectious and Non-Infectious Autocatalytic Recombinant PrP Conformers.

Infectious prions contain a self-propagating, misfolded conformer of the prion protein termed PrPSc. A critical prediction of the protein-only hypothesis is that autocatalytic PrPSc molecules should be infectious. However, some autocatalytic recombinant PrPSc molecules have low or undetectable levels of specific infectivity in bioassays, and the essential determinants of recombinant prion infectivity remain obscure. To identify structural and functional features specifically associated with infectivity, we compared the properties of two autocatalytic recombinant PrP conformers derived from the same original template, which differ by >105-fold in specific infectivity for wild-type mice. Structurally, hydrogen/deuterium exchange mass spectrometry (DXMS) studies revealed that solvent accessibility profiles of infectious and non-infectious autocatalytic recombinant PrP conformers are remarkably similar throughout their protease-resistant cores, except for two domains encompassing residues 91-115 and 144-163. Raman spectroscopy and immunoprecipitation studies confirm that these domains adopt distinct conformations within infectious versus non-infectious autocatalytic recombinant PrP conformers. Functionally, in vitro prion propagation experiments show that the non-infectious conformer is unable to seed mouse PrPC substrates containing a glycosylphosphatidylinositol (GPI) anchor, including native PrPC. Taken together, these results indicate that having a conformation that can be specifically adopted by post-translationally modified PrPC molecules is an essential determinant of biological infectivity for recombinant prions, and suggest that this ability is associated with discrete features of PrPSc structure.

Examining perceived cancer risk among patients with neurofibromatosis type 1.

Neurofibromatosis 1 (NF1) is a genetic disorder in which patients are at significantly increased risk for developing malignant peripheral nerve sheath tumors (MPNST) and malignant gliomas (brain cancer). We sought to develop a measure for assessing perceived risk of developing MPNST and brain cancer among patients with NF1 and to examine patients' perceived risk of developing these cancers. We assessed 112 NF1 patients' perceived risk of developing MPNST and brain cancer using an 8-item scale we developed that yielded two subscales in a principal component analysis (PCA). Linear regression models examined factors associated with perceived risk of malignancy. 33.9 % and 47.3 % of patients disagreed that having NF1 placed them at increased risk for MPNST and brain cancer, respectively. The PCA of the perceived risk items yielded a 2-factor solution with an MPNST and a brain subscale (total scale α = 0.90). Level of anxiety was the primary factor associated with perceived risk for both cancers. A significant proportion of NF1 patients underestimate their risk of developing MPNST and brain cancer. Perceived risk was associated with emotional distress, in particular anxiety. Clinicians should actively communicate with NF1 patients about their elevated cancer risk.

B-cell epitopes in GroEL of Francisella tularensis.

The chaperonin protein GroEL, also known as heat shock protein 60 (Hsp60), is a prominent antigen in the human and mouse antibody response to the facultative intracellular bacterium Francisella tularensis (Ft), the causative agent of tularemia. In addition to its presumed cytoplasmic location, FtGroEL has been reported to be a potential component of the bacterial surface and to be released from the bacteria. In the current study, 13 IgG2a and one IgG3 mouse monoclonal antibodies (mAbs) specific for FtGroEL were classified into eleven unique groups based on shared VH-VL germline genes, and seven crossblocking profiles revealing at least three non-overlapping epitope areas in competition ELISA. In a mouse model of respiratory tularemia with the highly pathogenic Ft type A strain SchuS4, the Ab64 and N200 IgG2a mAbs, which block each other's binding to and are sensitive to the same two point mutations in FtGroEL, reduced bacterial burden indicating that they target protective GroEL B-cell epitopes. The Ab64 and N200 epitopes, as well as those of three other mAbs with different crossblocking profiles, Ab53, N3, and N30, were mapped by hydrogen/deuterium exchange-mass spectrometry (DXMS) and visualized on a homology model of FtGroEL. This model was further supported by its experimentally-validated computational docking to the X-ray crystal structures of Ab64 and Ab53 Fabs. The structural analysis and DXMS profiles of the Ab64 and N200 mAbs suggest that their protective effects may be due to induction or stabilization of a conformational change in FtGroEL.

Cofactor molecules induce structural transformation during infectious prion formation.

The spread of misfolded proteins may occur in many neurodegenerative diseases. Mammalian prions are currently the only misfolded proteins in which high specific biological infectivity can be produced in vitro. Using a system that generates infectious prions de novo from purified recombinant PrP and conversion cofactors palmitoyl-oleoyl-phosphatidylglycerol (POPG) and RNA, we examined by deuterium exchange mass spectrometry (DXMS) the stepwise protein conformational changes that occur during prion formation. We found that initial incubation with POPG causes major structural changes in PrP involving all three α helices and one ß strand, with subsequent addition of RNA rendering the N terminus highly exposed. Final conversion into the infectious PrP(Sc) form was accompanied by globally decreased solvent exposure, with persistence of the major cofactor-induced conformational features. Thus, we report that cofactor molecules appear to induce major structural rearrangements during prion formation, initiating a dynamic sequence of conformational changes resulting in biologically active prions.

Appearance concerns among women with neurofibromatosis: examining sexual/bodily and social self-consciousness.

OBJECTIVE: Neurofibromatosis (NF) 1 and 2 have distinct appearance effects, yet little research has examined patients' appearance concerns. We assessed appearance concerns and self-consciousness, self-esteem, and loneliness among women with NF. METHODS: Women with NF1 (n = 79) and NF2 (n = 48) completed the Derriford Appearance Scale to assess appearance concerns and sexual/bodily and social self-consciousness, Rosenberg Self-Esteem Scale, and UCLA Loneliness Scale. Women's appearance concerns were coded to determine whether they were NF-related and whether psychosocial factors contributed to the concerns. RESULTS: A total of 85% of women reported appearance concerns, many of which were NF-related and attributed to psychosocial factors. Women with NF1 reported significantly more sexual/bodily self-consciousness but similar levels of social self-consciousness compared with women with NF2. Significantly higher sexual/bodily self-consciousness was found among married/cohabiting women regardless of NF group. Compared with general population norms and breast cancer survivors (BCS), women with NF1 reported significantly greater sexual/bodily and social self-consciousness. Women with NF2 reported less sexual/bodily self-consciousness compared with population norms, yet tended to report greater sexual/bodily self-consciousness than BCS. Women with NF2 reported significantly greater social self-consciousness compared with population norms and BCS. For both NF1 and NF2, higher levels of sexual/bodily and social self-consciousness were related to lower self-esteem and higher levels of social self-consciousness to more loneliness. CONCLUSIONS: Appearance concerns are prevalent, and social self-consciousness is high, among women with NF1 and NF2. Women with NF1 compared with NF2 experience more sexual/bodily self-consciousness. Providers should assess the impact of NF on women's self-perceptions and address sexual, body image, and social concerns.

Emotional functioning of patients with neurofibromatosis tumor suppressor syndrome.

PURPOSE: Although patients with neurofibromatosis are predisposed to multiple nerve sheath tumors that can develop anywhere in the body and cause significant morbidity (e.g., hearing loss; pain), little research has examined emotional correlates of neurofibromatosis. The purpose of this study was to examine emotional functioning among adult patients with neurofibromatosis. METHODS: A total of 248 patients with neurofibromatosis (neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis) who received care at a specialized clinic completed validated measures to assess symptoms of depression and anxiety, level of perceived stress, and self-esteem. RESULTS: Patients with neurofibromatosis reported significantly more symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem as compared with general population norms. No significant differences were found among patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis, and emotional functioning was not significantly associated with disease severity. However, increased symptoms of depression and anxiety, higher levels of perceived stress, and lower levels of self-esteem were associated with a higher frequency of self-reported medical visits in the past year (P values ≤0.05). CONCLUSION: Neurofibromatosis appears to be associated with reduced emotional functioning. Although further research is needed, these findings suggest a role for a multidisciplinary treatment approach to address emotional distress among adult patients with neurofibromatosis.

Prospective, high-throughput molecular profiling of human gliomas.

Gliomas consist of multiple histologic and molecular subtypes with different clinical phenotypes and responsiveness to treatment. However, enrollment criteria for clinical trials still largely do not take into account these underlying molecular differences. We have incorporated a high-throughput tumor genotyping program based on the ABI SNaPshot platform as well as other molecular diagnostic tests into the standard evaluation of glioma patients in order to assess whether prospective molecular profiling would allow rational patient selection onto clinical trials. From 218 gliomas we prospectively collected SNaPshot genotyping data on 68 mutated loci from 15 key cancer genes along with data from clinical assays for gene amplification (EGFR, PDGFRA, MET), 1p/19q co-deletion and MGMT promoter methylation. SNaPshot mutations and focal gene amplifications were detected in 38.5 and 47.1 % of glioblastomas, respectively. Genetic alterations in EGFR, IDH1 and PIK3CA closely matched frequencies reported in recent studies. In addition, we identified events that are rare in gliomas although are known driver mutations in other cancer types, such as mutations of AKT1, BRAF and KRAS. Patients with genetic alterations that activate signaling pathways were enrolled onto genetically selective clinical trials for malignant glioma as well as for other solid cancers. High-throughput molecular profiling incorporated into the routine clinical evaluation of glioma patients may enable the rational selection of patients for targeted therapy clinical trials and thereby improve the likelihood that such trials succeed.

Acculturation and cross-border utilization of health services.

Health services from Mexico constitute an important source of care for U.S. residents living along the U.S.-Mexico border. Data from The Cross-Border Utilization of Health Care Survey (n = 966) were used to estimate logit models that related acculturation, as measured by generational status, to the use of medication, physician, dental, and inpatient services from Mexico by U.S. residents in the Texas border region. Relative to first-generation Mexican immigrants, later-generation Mexican-Americans were progressively less likely to go to Mexico for health services. This finding holds with or without adjusting for the effects of selected demographic and socioeconomic variables. Addressing unmet needs in medical care in the southwestern U.S. border area should go beyond a simple expansion of health insurance coverage--it is also important to deliver health services that are sensitive to generational differences within the population in terms of linguistic and cultural barriers to health care access.