Addition of MR imaging features and genetic biomarkers strengthens glioblastoma survival prediction in TCGA patients.

PURPOSE: The purpose of our study was to assess whether a model combining clinical factors, MR imaging features, and genomics would better predict overall survival of patients with glioblastoma (GBM) than either individual data type. METHODS: The study was conducted leveraging The Cancer Genome Atlas (TCGA) effort supported by the National Institutes of Health. Six neuroradiologists reviewed MRI images from The Cancer Imaging Archive (http://cancerimagingarchive.net) of 102 GBM patients using the VASARI scoring system. The patients' clinical and genetic data were obtained from the TCGA website (http://www.cancergenome.nih.gov/). Patient outcome was measured in terms of overall survival time. The association between different categories of biomarkers and survival was evaluated using Cox analysis. RESULTS: The features that were significantly associated with survival were: (1) clinical factors: chemotherapy; (2) imaging: proportion of tumor contrast enhancement on MRI; and (3) genomics: HRAS copy number variation. The combination of these three biomarkers resulted in an incremental increase in the strength of prediction of survival, with the model that included clinical, imaging, and genetic variables having the highest predictive accuracy (area under the curve 0.679±0.068, Akaike's information criterion 566.7, P<0.001). CONCLUSION: A combination of clinical factors, imaging features, and HRAS copy number variation best predicts survival of patients with GBM.

Accuracy of MRI for the diagnosis of metastatic cervical lymphadenopathy in patients with thyroid cancer.

PURPOSE: The aim of this study was to systematically compare a comprehensive array of magnetic resonance (MR) imaging features in terms of their sensitivity and specificity to diagnose cervical lymph node metastases in patients with thyroid cancer. MATERIALS AND METHODS: The study included 41 patients with thyroid malignancy who underwent surgical excision of cervical lymph nodes and had preoperative MR imaging ≤4weeks prior to surgery. Three head and neck neuroradiologists independently evaluated all the MR images. Using the pathology results as reference, the sensitivity, specificity and interobserver agreement of each MR imaging characteristic were calculated. RESULTS: On multivariate analysis, no single imaging feature was significantly correlated with metastasis. In general, imaging features demonstrated high specificity, but poor sensitivity and moderate interobserver agreement at best. CONCLUSIONS: Commonly used MR imaging features have limited sensitivity at correctly identifying cervical lymph node metastases in patients with thyroid cancer. A negative neck MR scan should not dissuade a surgeon from performing a neck dissection in patients with thyroid carcinomas.

Transcriptional regulator PRDM12 is essential for human pain perception.

Pain perception has evolved as a warning mechanism to alert organisms to tissue damage and dangerous environments. In humans, however, undesirable, excessive or chronic pain is a common and major societal burden for which available medical treatments are currently suboptimal. New therapeutic options have recently been derived from studies of individuals with congenital insensitivity to pain (CIP). Here we identified 10 different homozygous mutations in PRDM12 (encoding PRDI-BF1 and RIZ homology domain-containing protein 12) in subjects with CIP from 11 families. Prdm proteins are a family of epigenetic regulators that control neural specification and neurogenesis. We determined that Prdm12 is expressed in nociceptors and their progenitors and participates in the development of sensory neurons in Xenopus embryos. Moreover, CIP-associated mutants abrogate the histone-modifying potential associated with wild-type Prdm12. Prdm12 emerges as a key factor in the orchestration of sensory neurogenesis and may hold promise as a target for new pain therapeutics.

Avaliação da resposta bioquímica no câncer inicial de próstata: experiência uninstitucional comparando teleterapia exclusiva ou associada à braquiterapia de alta taxa de dose

OBJETIVO: Análise comparativa da resposta bioquímica em pacientes submetidos à teleterapia exclusiva ou associada à braquiterapia de alta taxa de dose para tumores localizados da próstata. MATERIAIS E MÉTODOS: De novembro de 1997 a janeiro de 2000, 74 pacientes foram submetidos à teleterapia com 45 Gy e reforço com braquiterapia de alta taxa de dose com irídio-192 e dose de 16 Gy em quatro inserções (BT). Estes foram comparados a 29 pacientes submetidos à teleterapia com 45 Gy e reforço com arcoterapia e dose mediana de 24 Gy (RT) entre outubro de 1996 e fevereiro de 2000. Nos dois grupos houve associação ocasional de hormonioterapia neoadjuvante. Sobrevida atuarial livre de doença em três anos (SB3) e fatores prognósticos pré-tratamento da resposta bioquímica, como o antígeno prostático-específico inicial (PSAi), escore de Gleason da biópsia de próstata (EG) e estádio clínico (EC), foram analisados. RESULTADOS: O seguimento mediano foi de 25 meses para o grupo RT e 37 meses para o BT. Na análise atuarial, a SB3 foi de 51% e 73% (p = 0,032) para RT e BT, respectivamente. Na análise estratificada pelo PSAi, a SB3 para RT e BT foi de 85,7% e 79,1% (p = 0,76) para PSAi < 10 ng/mL e de 38% e 68% (p = 0,023) para PSAi > 10 ng/mL, respectivamente. Quando estratificado pelo EG, a SB3 para RT e BT foi de 37% e 80% (p = 0,001) para EG < 6 e 78% e 55% para EG > 6 (p = 0,58); estratificando-se pelo EC, a SB3 para RT e BT foi de 36% e 74% (p = 0,018) para EC < T2a e 73% e 69% para EC > T2a (p = 0,692), respectivamente. O risco relativo bruto de recidiva bioquímica foi de 2,3 (95% IC: 1,0-5,1) para os pacientes tratados com RT, em relação à BT; quando ajustado pelo PSAi e EG, o risco relativo de recidiva bioquímica foi de 2,4 (95% IC: 1,0-5,7). CONCLUSÃO: A modalidade de tratamento foi fator prognóstico independente de recidiva bioquímica, com maior controle bioquímico associado à BT. Nossos resultados preliminares sugerem que o maior benefício com BT foi obtido nos pacientes com PSAi > 10 ng/mL, EC < T2a e EG < 6.

Characterization and genetic mapping of eceriferum-ym (cer-ym), a cutin deficient barley mutant with impaired leaf water retention capacity.

The cuticle covers the aerial parts of land plants, where it serves many important functions, including water retention. Here, a recessive cuticle mutant, eceriferum-ym (cer-ym), of Hordeum vulgare L. (barley) showed abnormally glossy spikes, sheaths, and leaves. The cer-ym mutant plant detached from its root system was hypersensitive to desiccation treatment compared with wild type plants, and detached leaves of mutant lost 41.8% of their initial weight after 1 h of dehydration under laboratory conditions, while that of the wild type plants lost only 7.1%. Stomata function was not affected by the mutation, but the mutant leaves showed increased cuticular permeability to water, suggesting a defective leaf cuticle, which was confirmed by toluidine blue staining. The mutant leaves showed a substantial reduction in the amounts of the major cutin monomers and a slight increase in the main wax component, suggesting that the enhanced cuticle permeability was a consequence of cutin deficiency. cer-ym was mapped within a 0.8 cM interval between EST marker AK370363 and AK251484, a pericentromeric region on chromosome 4H. The results indicate that the desiccation sensitivity of cer-ym is caused by a defect in leaf cutin, and that cer-ym is located in a chromosome 4H pericentromeric region.

Comprehensive Molecular Portraits of Invasive Lobular Breast Cancer.

Invasive lobular carcinoma (ILC) is the second most prevalent histologic subtype of invasive breast cancer. Here, we comprehensively profiled 817 breast tumors, including 127 ILC, 490 ductal (IDC), and 88 mixed IDC/ILC. Besides E-cadherin loss, the best known ILC genetic hallmark, we identified mutations targeting PTEN, TBX3, and FOXA1 as ILC enriched features. PTEN loss associated with increased AKT phosphorylation, which was highest in ILC among all breast cancer subtypes. Spatially clustered FOXA1 mutations correlated with increased FOXA1 expression and activity. Conversely, GATA3 mutations and high expression characterized luminal A IDC, suggesting differential modulation of ER activity in ILC and IDC. Proliferation and immune-related signatures determined three ILC transcriptional subtypes associated with survival differences. Mixed IDC/ILC cases were molecularly classified as ILC-like and IDC-like revealing no true hybrid features. This multidimensional molecular atlas sheds new light on the genetic bases of ILC and provides potential clinical options.

Radioterapia adjuvante no tratamento do câncer de endométrio: experiência com a associação de radio-terapia externa e braquiterapia de alta taxa de dose

OBJETIVO: Analisar, retrospectivamente, os resultados da radioterapia externa (RT) combinada a braquiterapia de alta taxa de dose (BATD), adjuvantes à cirurgia para o carcinoma de endométrio. MATERIAIS E MÉTODOS: Avaliamos 141 pacientes tratados com RT e BATD adjuvantes à cirurgia, no período de janeiro de 1993 a janeiro de 2001. RT pélvica foi realizada com dose mediana de 45 Gy, e BATD realizada na dose mediana de 24 Gy, em quatro inserções semanais de 6 Gy. A idade mediana das pacientes foi de 63 anos e a distribuição por estádio clínico (EC) foi: EC I (FIGO), 52,4%; EC II, 13,5%; EC III, 29,8%; EC IV, 4,3%. RESULTADOS: Com seguimento mediano de 53,7 meses, a sobrevida livre de doença (SLD) em cinco anos foi: EC I, 88,0%; EC II, 70,8%; EC III, 55,1%; EC IV, 50,0% (p = 0,0003). A sobrevida global em cinco anos foi: EC I, 79,6%; EC II, 74,0%; EC III, 53,6%; EC IV, 100,0% (p = 0,0062). Fatores que influíram na SLD foram grau histológico e histologia seropapilífera. Dos 33 casos que apresentaram recidiva da doença, em 13 (9,2%) esta ocorreu na pelve, vagina ou cúpula vaginal. RT + BATD do fundo vaginal permitiram o controle da doença em 90,8% dos casos. CONCLUSÃO: A RT exerce papel fundamental no controle loco-regional do câncer de endométrio e permite excelentes taxas de cura nos estádios iniciais. Para os estádios mais avançados, a falha terapêutica tende a ser a distância, sugerindo a necessidade de complementação terapêutica sistêmica, com introdução de novas modalidades de tratamento, em particular a quimioterapia.

Meta-analysis of correlated traits via summary statistics from GWASs with an application in hypertension

Genome-wide association studies (GWASs) have identified many genetic variants underlying complex traits. Many detected genetic loci harbor variants that associate with multiple-even distinct-traits. Most current analysis approaches focus on single traits, even though the final results from multiple traits are evaluated together. Such approaches miss the opportunity to systemically integrate the phenome-wide data available for genetic association analysis. In this study, we propose a general approach that can integrate association evidence from summary statistics of multiple traits, either correlated, independent, continuous, or binary traits, which might come from the same or different studies. We allow for trait heterogeneity effects. Population structure and cryptic relatedness can also be controlled. Our simulations suggest that the proposed method has improved statistical power over single-trait analysis in most of the cases we studied. We applied our method to the Continental Origins and Genetic Epidemiology Network (COGENT) African ancestry samples for three blood pressure traits and identified four loci (CHIC2, HOXA-EVX1, IGFBP1/IGFBP3, and CDH17; p < 5.0 × 10(-8)) associated with hypertension-related traits that were missed by a single-trait analysis in the original report. Six additional loci with suggestive association evidence (p < 5.0 × 10(-7)) were also observed, including CACNA1D and WNT3. Our study strongly suggests that analyzing multiple phenotypes can improve statistical power and that such analysis can be executed with the summary statistics from GWASs. Our method also provides a way to study a cross phenotype (CP) association by using summary statistics from GWASs of multiple phenotypes.

Tratamento do câncer de pequenas células de pulmão: doença limitada: resultados de uma única instituição

OBJETIVO: Relatar os resultados de tratamento de pacientes com câncer de pulmão de pequenas células com doença limitada (CPPC-DL), num período de dez anos, numa única instituição, para controle de qualidade e comparação com dados de literatura. MATERIAIS E MÉTODOS: Entre janeiro de 1992 e dezembro de 2002, 101 pacientes portadores de CPPC-DL completaram tratamento em nossa instituição. Seus resultados foram revistos e incluíram quimioterapia, radioterapia, a seqüência dos dois tratamentos e o uso de irradiação profilática cerebral (PCI). A radiação foi administrada com dose mediana de 45 Gy em 1,8 a 2 Gy por fração. A dose mediana de PCI foi de 25 Gy em dez frações. RESULTADOS: O seguimento mediano foi de 50,6 meses e a idade mediana dos pacientes foi de 63 anos. Houve 85 mortes confirmadas, 5 pacientes foram perdidos de seguimento e 11 estavam vivos. O tempo de sobrevida mediano foi de 11 meses, a sobrevida global em dois e cinco anos foi de 25,5% e 10%, respectivamente. Não houve diferença significante na sobrevida global em dois ou cinco anos segundo a idade e sexo dos pacientes. Também não houve diferença significante na sobrevida global entre os pacientes que realizaram PCI ou não, ou foram tratados em dois períodos diferentes (1997-2002 vs. 1992-1996). CONCLUSÃO: Os resultados de tratamento dos pacientes portadores de CPPC-DL na nossa instituição refletem as constantes mudanças no manuseio do CPPC. Nossa sobrevida global em dois anos de 25,5% é semelhante a outros resultados uni-institucionais publicados, mas menor que os resultados de 47% a 54% recentemente publicados por grupos cooperativos.

Drosophila Ionotropic Receptor 25a mediates circadian clock resetting by temperature.

Circadian clocks are endogenous timers adjusting behaviour and physiology with the solar day. Synchronized circadian clocks improve fitness and are crucial for our physical and mental well-being. Visual and non-visual photoreceptors are responsible for synchronizing circadian clocks to light, but clock-resetting is also achieved by alternating day and night temperatures with only 2-4 °C difference. This temperature sensitivity is remarkable considering that the circadian clock period (~24 h) is largely independent of surrounding ambient temperatures. Here we show that Drosophila Ionotropic Receptor 25a (IR25a) is required for behavioural synchronization to low-amplitude temperature cycles. This channel is expressed in sensory neurons of internal stretch receptors previously implicated in temperature synchronization of the circadian clock. IR25a is required for temperature-synchronized clock protein oscillations in subsets of central clock neurons. Extracellular leg nerve recordings reveal temperature- and IR25a-dependent sensory responses, and IR25a misexpression confers temperature-dependent firing of heterologous neurons. We propose that IR25a is part of an input pathway to the circadian clock that detects small temperature differences. This pathway operates in the absence of known 'hot' and 'cold' sensors in the Drosophila antenna, revealing the existence of novel periphery-to-brain temperature signalling channels.

The DYRK-family kinase Pom1 phosphorylates the F-BAR protein Cdc15 to prevent division at cell poles.

Division site positioning is critical for both symmetric and asymmetric cell divisions. In many organisms, positive and negative signals cooperate to position the contractile actin ring for cytokinesis. In rod-shaped fission yeast Schizosaccharomyces pombe cells, division at midcell is achieved through positive Mid1/anillin-dependent signaling emanating from the central nucleus and negative signals from the dual-specificity tyrosine phosphorylation-regulated kinase family kinase Pom1 at the cell poles. In this study, we show that Pom1 directly phosphorylates the F-BAR protein Cdc15, a central component of the cytokinetic ring. Pom1-dependent phosphorylation blocks Cdc15 binding to paxillin Pxl1 and C2 domain protein Fic1 and enhances Cdc15 dynamics. This promotes ring sliding from cell poles, which prevents septum assembly at the ends of cells with a displaced nucleus or lacking Mid1. Pom1 also slows down ring constriction. These results indicate that a strong negative signal from the Pom1 kinase at cell poles converts Cdc15 to its closed state, destabilizes the actomyosin ring, and thus promotes medial septation.

Maintenance Therapy With Tumor-Treating Fields Plus Temozolomide vs Temozolomide Alone for Glioblastoma: A Randomized Clinical Trial.

IMPORTANCE: Glioblastoma is the most devastating primary malignancy of the central nervous system in adults. Most patients die within 1 to 2 years of diagnosis. Tumor-treating fields (TTFields) are a locoregionally delivered antimitotic treatment that interferes with cell division and organelle assembly. OBJECTIVE: To evaluate the efficacy and safety of TTFields used in combination with temozolomide maintenance treatment after chemoradiation therapy for patients with glioblastoma. DESIGN, SETTING, AND PARTICIPANTS: After completion of chemoradiotherapy, patients with glioblastoma were randomized (2:1) to receive maintenance treatment with either TTFields plus temozolomide (n = 466) or temozolomide alone (n = 229) (median time from diagnosis to randomization, 3.8 months in both groups). The study enrolled 695 of the planned 700 patients between July 2009 and November 2014 at 83 centers in the United States, Canada, Europe, Israel, and South Korea. The trial was terminated based on the results of this planned interim analysis. INTERVENTIONS: Treatment with TTFields was delivered continuously (>18 hours/day) via 4 transducer arrays placed on the shaved scalp and connected to a portable medical device. Temozolomide (150-200 mg/m2/d) was given for 5 days of each 28-day cycle. MAIN OUTCOMES AND MEASURES: The primary end point was progression-free survival in the intent-to-treat population (significance threshold of .01) with overall survival in the per-protocol population (n = 280) as a powered secondary end point (significance threshold of .006). This prespecified interim analysis was to be conducted on the first 315 patients after at least 18 months of follow-up. RESULTS: The interim analysis included 210 patients randomized to TTFields plus temozolomide and 105 randomized to temozolomide alone, and was conducted at a median follow-up of 38 months (range, 18-60 months). Median progression-free survival in the intent-to-treat population was 7.1 months (95% CI, 5.9-8.2 months) in the TTFields plus temozolomide group and 4.0 months (95% CI, 3.3-5.2 months) in the temozolomide alone group (hazard ratio [HR], 0.62 [98.7% CI, 0.43-0.89]; P = .001). Median overall survival in the per-protocol population was 20.5 months (95% CI, 16.7-25.0 months) in the TTFields plus temozolomide group (n = 196) and 15.6 months (95% CI, 13.3-19.1 months) in the temozolomide alone group (n = 84) (HR, 0.64 [99.4% CI, 0.42-0.98]; P = .004). CONCLUSIONS AND RELEVANCE: In this interim analysis of 315 patients with glioblastoma who had completed standard chemoradiation therapy, adding TTFields to maintenance temozolomide chemotherapy significantly prolonged progression-free and overall survival. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00916409.