Recurrent Wnt Pathway and ARID1A Alterations in Sinonasal Olfactory Carcinoma.

Sinonasal tumors with neuroepithelial differentiation, defined by neuroectodermal elements reminiscent of olfactory neuroblastoma (ONB) and epithelial features such as keratin expression or gland formation, are a diagnostically challenging group that has never been formally included in sinonasal tumor classifications. Recently, we documented that most of these neuroepithelial neoplasms have distinctive histologic and immunohistochemical findings and proposed the term "olfactory carcinoma" to describe these tumors. However, the molecular characteristics of olfactory carcinoma have not yet been evaluated. In this study, we performed targeted molecular profiling of 23 sinonasal olfactory carcinomas to further clarify their pathogenesis and classification. All tumors included in this study were composed of high-grade neuroectodermal cells that were positive for pankeratin and at least 1 specific neuroendocrine marker. A significant subset of cases also displayed rosettes and neurofibrillary matrix, intermixed glands with variable cilia, peripheral p63/p40 expression, and S100 protein-positive sustentacular cells. Recurrent oncogenic molecular alterations were identified in 20 tumors, including Wnt pathway alterations affecting CTNNB1 (n = 8) and PPP2R1A (n = 2), ARID1A inactivation (n = 5), RUNX1 mutations (n = 3), and IDH2 hotspot mutations (n = 2). Overall, these findings do demonstrate the presence of recurrent molecular alterations in olfactory carcinoma, although this group of tumors does not appear to be defined by any single mutation. Minimal overlap with alterations previously reported in ONB also adds to histologic and immunohistochemical separation between ONB and olfactory carcinoma. Conversely, these molecular findings enhance the overlap between olfactory carcinoma and sinonasal neuroendocrine carcinomas. A small subset of neuroepithelial tumors might better fit into the superseding molecular category of IDH2-mutant sinonasal carcinoma. At this point, sinonasal neuroendocrine and neuroepithelial tumors may best be regarded as a histologic and molecular spectrum that includes core groups of ONB, olfactory carcinoma, neuroendocrine carcinoma, and IDH2-mutant sinonasal carcinoma.

Mucoepidermoid carcinoma may be devoid of squamoid cells by immunohistochemistry: expanding the histologic and immunohistochemical spectrum of MAML2- rearranged salivary gland tumours.

Mucoepidermoid carcinoma (MEC) is historically defined by a mix of squamoid, intermediate, and mucous cells, but we have recently encountered several cases lacking immunoreactivity for squamous markers p40, p63, and CK5/6 despite MAML2 fusions. This study will characterise these unique tumours. Ten MEC were collected arising from the parotid gland (n = 4), submandibular gland (n = 2), nasopharynx (n = 1), base of tongue (n = 1), bronchus (n = 1), and trachea (n = 1). Six tumours were low-grade, two intermediate-grade, one high-grade, and one demonstrated low-grade areas with high-grade transformation. Four cases were oncocytic, four had clear-cell features, two had spindle cell features, and one high-grade MEC had prominent solid, cord-like, and micropapillary features. The tumours were negative for p40 (10/10), p63 (10/10), and CK5/6 (9/9). Targeted RNA sequencing demonstrated CRTC1::MAML2 in five cases, CRTC3::MAML2 in two, and a novel MAML2::CEP126 in the unusual high-grade case. In two cases with insufficient RNA, MAML2 fluorescence in situ hybridisation (FISH) showed rearrangement. Genetically-confirmed MEC may lack overt squamous differentiation by histology and immunohistochemistry. While most cases harboured canonical fusions and fit within the spectra of MEC variants with oncocytic, clear cell, and/or spindle cell features, one had a novel MAML2::CEP126 fusion and unusual morphology. In MEC without squamoid cells, the use of immunohistochemistry may hinder, rather than aid, the correct diagnosis. In such cases, MAML2 analysis is most useful. The historical definition of MEC as a carcinoma with squamoid, intermediate and mucous cells should be revisited.

Salivary Gland Intraductal Carcinoma: How Do 183 Reported Cases Fit Into a Developing Classification.

Salivary gland intraductal carcinoma (IDC) is a very uncommon group of neoplasms. Many names, variations in diagnostic criteria, and newly observed molecular findings (including NCOA4 :: RET , TRIM27 :: RET , HRAS point mutations, and PIK3CA pathway alterations) have generated further confusion in being able to recognize and categorize this group of tumors. Different histologic appearances and patterns of growth suggest there is more than one tumor category, with intercalated duct, apocrine, oncocytic, and hybrid features seen. Frankly destructive invasion further complicates the category, as the name "intraductal" would suggest an "in situ" neoplasm. Recent evidence on fusion-positive IDC demonstrates the same molecular underpinnings in both the ductal and the myoepithelial cells, which aids in further separating these tumors. This article summarizes the historical group of 183 neoplasms classified under the umbrella of IDC and highlights the unique histologic, immunohistochemistry, and molecular features that may further guide nomenclature standardization and harmonization.

Analysis of KRAS, BRAF, and EGFR mutational status in respiratory epithelial adenomatoid hamartoma (REAH).

BACKGROUND: Respiratory epithelial adenomatoid hamartoma (REAH) is a sinonasal glandular overgrowth arising from the surface respiratory epithelium and invaginating into the stroma. Clinically, it appears as a polypoid mass that may cause nasal obstruction, anosmia, and epistaxis. The presence of cartilaginous and/or osseous areas move the lesion to a chondro-osseous respiratory epithelial (CORE) hamartoma subtype. Scattered small seromucinous glands may be observed between typical REAH glands and when it is the only feature, it represents seromucinous hamartoma (SH). The molecular pathogenesis of REAH has been poorly explored and remains unclear. Given that KRAS, BRAF, and EGFR mutations have been detected in a variety of sinonasal tumors, we aimed to assess these mutations in REAH and SH. METHODS: Ten REAH (including one CORE subtype), in addition to two SH cases, were Sanger sequenced by standard techniques. The targeted regions included KRAS exons 2-4 (encompassing hotspots codons 12, 13, 61, and 146), BRAF exons 11 and 15 (spanning the V600 codon), and EGFR exons 19 and 20. RESULTS: All REAH and SH samples showed wild-type sequences for KRAS, BRAF, and EGFR genes. CONCLUSION: Our results demonstrate a lack of KRAS, BRAF, or EGFR pathogenic variants with further evaluation of REAH and SH needed to elucidate driver genetic events.

Image analysis reveals differences in tumor multinucleations in Black and White patients with human papillomavirus-associated oropharyngeal squamous cell carcinoma.

BACKGROUND: Understanding biological differences between different racial groups of human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) patients, who have differences in terms of incidence, survival, and tumor morphology, can facilitate accurate prognostic biomarkers, which can help develop personalized treatment strategies. METHODS: This study evaluated whether there were morphologic differences between HPV-associated tumors from Black and White patients in terms of multinucleation index (MuNI), an image analysis-derived metric that measures density of multinucleated tumor cells within epithelial regions on hematoxylin-eosin images and previously has been prognostic in HPV-associated OPSCC patients. In this study, the authors specifically evaluated whether the same MuNI cutoff that was prognostic of overall survival (OS) and disease-free survival in their previous study, TTR , is valid for Black and White patients, separately. We also evaluated population-specific cutoffs, TB for Blacks and TW for Whites, for risk stratification. RESULTS: MuNI was statistically significantly different between Black (mean, 3.88e-4; median, 3.67e-04) and White patients (mean, 3.36e-04; median, 2.99e-04), with p = .0078. Using TTR , MuNI was prognostic of OS in the entire population with hazard ratio (HR) of 1.71 (p = .002; 95% confidence interval [CI], 1.21-2.43) and in White patients with HR of 1.72 (p = .005; 95% CI, 1.18-2.51). Population-specific cutoff, TW , yielded improved HR of 1.77 (p = .003; 95% CI, 1.21-2.58) for White patients, whereas TB did not improve risk-stratification in Black patients with HR of 0.6 (p = .3; HR, 0.6; 95% CI, 0.2-1.80). CONCLUSIONS: Histological difference between White and Black patient tumors in terms of multinucleated tumor cells suggests the need for considering population-specific prognostic biomarkers for personalized risk stratification strategies for HPV-associated OPSCC patients.

Low-grade non-intestinal-type sinonasal adenocarcinoma: a histologically distinctive but molecularly heterogeneous entity.

Although low-grade non-intestinal-type sinonasal adenocarcinoma (SNAC) is formally a diagnosis of exclusion defined by the absence of salivary or intestinal differentiation, most tumors in this category comprise a distinctive histologic group that are increasingly thought to derive from seromucinous glands. However, the molecular underpinnings of SNAC remain poorly understood, and it is unclear if diverse genetic alterations recently reported in isolated cases should delineate separate subgroups. This study aims to perform comprehensive evaluation of gene fusions and mutations and their histologic correlates in low-grade SNAC to clarify its pathogenesis and classification. We identified 18 non-intestinal-type SNAC that all displayed characteristic tubulopapillary architecture and low-grade cytology, although several cases had other unique histologic features and 3 showed intermixed high-grade areas. Among tumors stained with S100 protein, SOX10, and DOG1, 86% expressed at least one of these seromucinous markers. Of 17 cases with sufficient RNA or DNA available for analysis, likely oncogenic molecular alterations were identified in 76% of cases, most notably including CTNNB1 p.S33F mutations in 2 cases, concomitant BRAF p.V600E and AKT1 p.E17K mutations in 2 cases, and ETV6::NTRK3, PRKAR1A::MET, FN1::NRG1, and DNAJB1::PRKACA fusions in 1 case each. While tumors with most genetic alterations were histologically indistinguishable, cases with CTNNB1 mutations had intermixed squamoid morules and cases with BRAF and AKT1 mutations showed a myoepithelial cell population and prominent papillary to micropapillary architecture. Overall, these findings confirm previous reports of frequent seromucinous differentiation in low-grade SNAC. However, these tumors display striking molecular diversity with involvement of multiple kinase fusions, leading to frequent activation of signaling cascades including the MAPK pathway. While most genetic alterations are not associated with sufficiently distinctive histologic features to suggest separate classification, biphasic tumors with BRAF p.V600E mutations are more unique and may represent a distinctive subgroup.

Alterations in key signaling pathways in sinonasal tract melanoma. A molecular genetics and immunohistochemical study of 90 cases and comprehensive review of the literature.

Sinonasal mucosal melanoma is a rare tumor arising within the nasal cavity, paranasal sinuses, or nasopharynx (sinonasal tract). This study evaluated 90 cases diagnosed in 29 males and 61 females with median age 68 years. Most tumors involved the nasal cavity and had an epithelioid morphology. Spectrum of research techniques used in this analysis includes targeted-DNA and -RNA next-generation sequencing, Sanger sequencing, fluorescence in situ hybridization and immunohistochemistry. Sinonasal melanomas were commonly driven by RAS (38/90, 42%), especially NRAS (n = 36) mutations and rarely (4/90, 4%) displayed BRAF pathogenic variants. BRAF/RAS mutants were more frequent among paranasal sinuses (10/14, 71%) than nasal (26/64, 41%) tumors. BRAF/RAS-wild type tumors occasionally harbored alterations of the key components and regulators of Ras-MAPK signaling pathway: NF1 mutations (1/17, 6%) or NF1 locus deletions (1/25, 4%), SPRED1 (3/25, 12%), PIK3CA (3/50, 6%), PTEN (4/50, 8%) and mTOR (1/50, 2%) mutations. These mutations often occurred in a mutually exclusive manner. In several tumors some of which were NRAS mutants, TP53 was deleted (6/48, 13%) and/or mutated (5/90, 6%). Variable nuclear accumulation of TP53, mirrored by elevated nuclear MDM2 expression was seen in >50% of cases. Furthermore, sinonasal melanomas (n = 7) including RAS/BRAF-wild type tumors (n = 5) harbored alterations of the key components and regulators of canonical WNT-pathway: APC (4/90, 4%), CTNNB1 (3/90, 3%) and AMER1 (1/90, 1%). Both, TERT promoter mutations (5/53, 9%) and fusions (2/40, 5%) were identified. The latter occurred in BRAF/RAS-wild type tumors. No oncogenic fusion gene transcripts previously reported in cutaneous melanomas were detected. Eight tumors including 7 BRAF/RAS-wild type cases expressed ADCK4::NUMBL cis-fusion transcripts. In summary, this study documented mutational activation of NRAS and other key components and regulators of Ras-MAPK signaling pathway such as SPRED1 in a majority of sinonasal melanomas.

Scalar Signatures of Chaotic Mixing in Porous Media.

Steady laminar flows through porous media spontaneously generate Lagrangian chaos at pore scale, with qualitative implications for a range of transport, reactive, and biological processes. The characterization and understanding of mixing dynamics in these opaque environments is an outstanding challenge. We address this issue by developing a novel technique based upon high-resolution imaging of the scalar signature produced by push-pull flows through porous media samples. Owing to the rapid decorrelation of particle trajectories in chaotic flows, the scalar image measured outside the porous material is representative of in situ mixing dynamics. We present a theoretical framework for estimation of the Lyapunov exponent based on extension of Lagrangian stretching theories to correlated aggregation. This method provides a full characterization of chaotic mixing dynamics in a large class of porous materials.

Emerging Entities and New Diagnostic Markers for Head and Neck Soft Tissue and Bone Tumors.

Bone and soft tissue tumors of the head and neck are relatively uncommon tumors that often represent a diagnostic challenge because of the wide range of entities that must be considered in the differential diagnosis. Over the past few years, classification of bone and soft tissue tumors has evolved primarily because of substantial contributions from molecular genetics, with the identification of new markers that are increasingly used to complement histopathologic findings in the routine diagnostic workup. This review focuses on the recently described mesenchymal tumors that preferentially involve the head and neck region, with a focus on the most relevant novel immunohistochemical and molecular findings, including gene fusions and mutations, that can help in the diagnosis and in the assessment of clinical behavior.

Fungal prostatitis due to endemic mycoses and Cryptococcus: A multicenter case series.

BACKGROUND: Fungal prostatitis is exceedingly rare with mostly case reports. METHODS: Electronic medical records at three medical centers were searched for cases of fungal prostatitis due to endemic mycoses and Cryptococcus over the preceding 10 years. RESULTS: Seven cases were identified from 105 600 prostate biopsies within the Southern California Permanente Medical Group for an incidence of 0.0066%. An additional eight cases were identified from two other health care systems. Excluding four patients without available clinical data, 11 patients were reviewed, most of whom underwent biopsy due to elevated prostate-specific antigen. Four were asymptomatic and the remainder had nonspecific signs or symptoms. All biopsies revealed granulomatous inflammation and fungal organisms. Seven patients had coccidioidomycosis, three patients had cryptococcosis (confirmed in two cases and suspected by organism morphology in the other), and one patient had likely histoplasmosis based on organism morphology. Prolonged antifungal treatment was standard; outcomes were favorable. CONCLUSION: Fungal prostatitis due to endemic mycoses and Cryptococcus is uncommon and associated with favorable outcomes but generally involves prolonged therapy.

Sinonasal Undifferentiated Carcinoma (SNUC): From an Entity to Morphologic Pattern and Back Again-A Historical Perspective.

Since the first description of sinonasal undifferentiated carcinoma (SNUC) as a distinctive highly aggressive sinonasal neoplasm with probable origin from the sinonasal mucosa (Schneiderian epithelium), SNUC has been the subject of ongoing study and controversy. In particular, the SNUC category gradually became a "wastebasket" for any undifferentiated or unclassifiable sinonasal malignancy of definite or probable epithelial origin. However, with the availability of more specific and sensitive immunohistochemical antibodies and increasing implementation of novel genetic tools, the historical SNUC category became the subject of progressive subdivision leading to recognition of specific genetically defined, reproducible subtypes. These recently recognized entities are characterized by distinctive genetic aberrations including NUTM1-rearranged carcinoma (NUT carcinoma) and carcinomas associated with inactivation of different members of the SWI/SNF chromatin-remodeling gene complex such as SMARCB1-deficient and less frequently SMARCA4-deficient carcinoma. The ring became almost closed, with recent studies highlighting frequent oncogenic IDH2 mutations in the vast majority of histologically defined SNUCs, with a frequency of 82%. A review of these cases suggests the possibility that "true SNUC" probably represents a distinctive neoplastic disease entity, morphologically, phenotypically, and genetically. This review addresses this topic from a historical perspective, with a focus on recently recognized genetically defined subsets within the SNUC spectrum.

Early squamous cell carcinoma of the oral tongue with histologically benign lymph nodes: A model predicting local control and vetting of the eighth edition of the American Joint Committee on Cancer pathologic T stage.

BACKGROUND: The eighth edition of the American Joint Committee on Cancer staging manual (AJCC8) added depth of invasion to the definition of pathologic T stage (pT). In the current study, the authors assess pT stage migration and the prognostic performance of the updated pT stage and compare it with other clinicopathologic variables in patients with early squamous cell carcinoma of the oral tongue (OTSCC; tumors measuring ≤4 cm) with histologically benign lymph nodes (pN0). METHODS: A multi-institutional cohort of patients with early OTSCC was restaged as per AJCC8. Primary endpoints were local recurrence (LR) and locoregional recurrence (LRR). Influential variables were identified and an LR/LRR prediction model was developed. RESULTS: There were a total of 494 patients, with 49 LR and 73 LRR. AJCC8 pT criteria resulted in upstaging of 37.9% of patients (187 of 494 patients), including 34.5% (64 of 185 patients) from pT2 to pT3, without improving the prognostication for LR or LRR. Both LR and LRR were found to be similar for patients with AJCC8 pT2 and pT3 disease. On multivariate analysis, LR was only found to be associated with distance to the closest margin (hazard ratio, 0.36; 95% CI, 0.20-0.64 [P = .0007]) and perineural invasion (hazard ratio, 1.92; 95% CI, 1.10-0.64 [P = .046]). Based on these 2 predictors, a final proportional hazards regression model (which may be used similar to a nomogram) was developed. The proposed model appeared to be superior to AJCC pT stage for estimating the probability of LR and LRR for individual patients with early OTSCC. CONCLUSIONS: AJCC8 pT criteria resulted in pT upstaging of patients with pN0 disease without improved LR or LRR prognostication. The proposed model based on distance to the closest margin and perineural invasion, status outperformed pT as a predictor of LR and LRR in patients with early OTSCC.

Can diatom girdle band pores act as a hydrodynamic viral defense mechanism?

Diatoms are microalgae encased in highly structured and regular frustules of porous silica. A long-standing biological question has been the function of these frustules, with hypotheses ranging from them acting as photonic light absorbers to being particle filters. While it has been observed that the girdle band pores of the frustule of Coscinodiscus sp. resemble those of a hydrodynamic drift ratchet, we show using scaling arguments and numerical simulations that they cannot act as effective drift ratchets. Instead, we present evidence that frustules are semi-active filters. We propose that frustule pores simultaneously repel viruses while promoting uptake of ionic nutrients via a recirculating, electroosmotic dead-end pore flow, a new mechanism of "hydrodynamic immunity".

Space-Group Symmetries Generate Chaotic Fluid Advection in Crystalline Granular Media.

The classical connection between symmetry breaking and the onset of chaos in dynamical systems harks back to the seminal theory of Noether [Transp. Theory Statist. Phys. 1, 186 (1918)10.1080/00411457108231446]. We study the Lagrangian kinematics of steady 3D Stokes flow through simple cubic and body-centered cubic (bcc) crystalline lattices of close-packed spheres, and uncover an important exception. While breaking of point-group symmetries is a necessary condition for chaotic mixing in both lattices, a further space-group (glide) symmetry of the bcc lattice generates a transition from globally regular to globally chaotic dynamics. This finding provides new insights into chaotic mixing in porous media and has significant implications for understanding the impact of symmetries upon generic dynamical systems.

Detection of unstable periodic orbits in mineralising geological systems.

Worldwide, mineral exploration is suffering from rising capital costs, due to the depletion of readily recoverable reserves and the need to discover and assess more inaccessible or geologically complex deposits. For gold exploration, this problem is particularly acute. We propose an innovative approach to mineral exploration and orebody characterisation, based on the analysis of geological core data as a spatial dynamical system, using the mathematical tools of dynamical system analysis. This approach is highly relevant for orogenic gold deposits, which-in contrast to systems formed at chemical equilibrium-exhibit many features of nonlinear dynamical systems, including episodic fluctuations on various length and time scales. Feedback relationships between thermo-chemical and deformation processes produce recurrent fluid temperatures and pressures and the deposition of vein-filling minerals such as pyrite and gold. We therefore relax the typical assumption of chemical equilibrium and analyse the underlying processes as aseismic, non-adiabatic, and inherent to a hydrothermal, nonlinear dynamical open-flow chemical reactor. These processes are approximated using the Gray-Scott model of reaction-diffusion as a complex toy system, which captures some of the features of the underlying mineralisation processes, including the spatiotemporal Turing patterns of unsteady chemical reactions. By use of this analysis, we demonstrate the capability of recurrence plots, recurrence power spectra, and recurrence time probabilities to detect underlying unstable periodic orbits as one sign of deterministic dynamics and their robustness for the analysis of data contaminated by noise. Recurrence plot based quantification is then applied to three mineral concentrations in the core data from the Sunrise Dam gold deposit in the Yilgarn region of Western Australia. Using a moving window, we reveal the episodic recurring low-dimensional dynamic structures and the period doubling route to instability with depth, embedded in and originating from higher-dimensional processes of the complex mineralisation system.

Comparison of high-dose Cisplatin-based chemoradiotherapy and Cetuximab-based bioradiotherapy for p16-positive oropharyngeal squamous cell carcinoma in the context of revised HPV-based staging.

AIM: To perform a comparison of Cisplatin vs. Cetuximab in p16-positive oropharyngeal squamous cell carcinoma (OPSCC) in the context of the revised HPV-based staging. BACKGROUND: Previous reports comparing these agents in head and neck cancer have included heterogenous disease and p16-status. MATERIALS AND METHODS: A retrospective review was conducted from 2006 to 2016 of patients with p16-positive OPSCC who underwent definitive radiotherapy concurrent with either triweekly Cisplatin (n = 251) or Cetuximab (n = 40). AJCC 8th Edition staging was adapted. RESULTS: Median follow-up for surviving patients was 40 months. On multivariate analysis for all-comers, comparing Cisplatin and Cetuximab, 3-year locoregional recurrence (LRR): 6% vs. 16% (p = 0.07), 3-year distant metastasis (DM): 8% vs. 21% (p = 0.04), 3-year overall recurrence rate (ORR): 11% vs. 29% (p = 0.01), and 3-year cause-specific survival (CSS): 94% vs. 79% (p = 0.06), respectively. On stage-based subgroup analysis, for stage I-II disease, 3-year LRR: 5% vs. 10% (p = 0.51), 3-year DM: 7% vs. 16% (p = 0.32), 3-year ORR: 10% vs. 23% (p = 0.15), and 3-year CSS: 95% vs. 82% (p = 0.38). For stage III disease, 3-year LRR: 10% vs. 40% (p = 0.07), 3-year DM: 9% vs. 43% (p = 0.07), 3-year ORR: 15% vs. 55% (p = 0.04), and 3-year CSS: 94% vs. 57% (p = 0.048). CONCLUSIONS: When given concurrently with radiotherapy, Cetuximab and triweekly Cisplatin demonstrated comparable efficacy for AJCC 8th Edition stage I-II p16-positive OPSCC. However, Cetuximab appeared to be associated with higher rates of treatment failure and cancer-related deaths in stage III disease. Upon availability of the RTOG 1016 trial results, analysis based on the revised HPV-based staging should be performed to confirm these findings.

Subsets of salivary duct carcinoma defined by morphologic evidence of pleomorphic adenoma, PLAG1 or HMGA2 rearrangements, and common genetic alterations.

BACKGROUND: The authors hypothesized that histogenetic classification of salivary duct carcinoma (SDC) could account for de novo tumors and those with morphologic or molecular evidence (pleomorphic adenoma gene 1 [PLAG1], high-mobility group AT hook 2 [HMGA2] rearrangement, amplification) of pleomorphic adenoma (PA). METHODS: SDCs (n = 66) were reviewed for morphologic evidence of PA. PLAG1 and HMGA2 alterations were detected by fluorescence in situ hybridization (FISH). PLAG1-positive tumors were tested by FISH for fibroblast growth factor receptor 1 (FGFR1) rearrangement. Thirty-nine tumors were analyzed using a commercial panel for mutations and copy number variations in 50 cancer-related genes. RESULTS: On the basis of combined morphologic and molecular evidence of PA, 4 subsets of SDC emerged: 1) carcinomas with morphologic evidence of PA but intact PLAG1 and HMGA2 (n = 22); 2) carcinomas with PLAG1 alteration (n = 18) or 3) HMGA2 alteration (n = 12); and 4) de novo carcinomas, without morphologic or molecular evidence of PA (n = 14). The median disease-free survival was 37 months (95% confidence interval, 28.4-45.6 months). Disease-free survival and other clinicopathologic parameters did not differ for the subsets defined above. Combined Harvey rat sarcoma viral oncogene homolog/phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit α (HRAS/PIK3CA) mutations were observed predominantly in de novo carcinomas (5 of 8 vs 2 of 31 tumors; P = .035). Erb-B2 receptor tyrosine kinase 2 (ERBB2) copy number gain was not observed in de novo carcinomas (0 of 8 vs 12 of 31 tumors; P = .08). Tumor protein 53 (TP53) mutations were more common in SDC ex pleomorphic adenomas than in de novo carcinomas (17 of 31 vs 1 of 8 tumors; P = .033). CONCLUSIONS: The genetic profile of SDC varies with the absence or presence of pre-existing PA and its cytogenetic signature. Most de novo SDCs harbor combined HRAS/PIK3CA mutations and no ERBB2 amplification. Cancer 2016;122:3136-44. © 2016 American Cancer Society.

The communication of suicidal intentions: a meta-analysis.

BACKGROUND: Among the myths that are often cited about suicide is that 'people who talk about killing themselves rarely die by suicide', but the evidence seems to contradict this statement. The aim of this study was to conduct a meta-analysis of studies reporting a prevalence of suicide communication (SC), and to examine the diagnostic accuracy of SC towards suicide in case-control reports. METHOD: Eligible studies had to examine data relative to completed suicides and report the prevalence of SC. Data relative to sample characteristics, study definition, modality and recipient of the SC were coded. RESULTS: We included 36 studies, conducted on a total of 14 601 completed suicides. The overall proportion of SC was 44.5% [95% confidence interval (CI) 35.4-53.8], with large heterogeneity (I 2 = 98.8%) and significant publication bias. The prevalence of SC was negatively associated with the detection of verbal communication as the sole means of SC and, positively, with study methodological quality. Based on seven case-control studies, SC was associated with an odds ratio of 4.66 for suicide (95% CI 3.00-7.25) and was characterized by sufficient diagnostic accuracy only if studies on adolescents were removed. CONCLUSION: Available data suggest that SC occurs in nearly half of subjects who go on to die by suicide, but this figure is likely to be an underestimate given the operational definitions of SC. At present, SC seems associated with overall insufficient accuracy towards subsequent suicide, although further rigorous studies are warranted to draw definite conclusions on this issue.

Mixing of discontinuously deforming media.

Mixing of materials is fundamental to many natural phenomena and engineering applications. The presence of discontinuous deformations-such as shear banding or wall slip-creates new mechanisms for mixing and transport beyond those predicted by classical dynamical systems theory. Here, we show how a novel mixing mechanism combining stretching with cutting and shuffling yields exponential mixing rates, quantified by a positive Lyapunov exponent, an impossibility for systems with cutting and shuffling alone or bounded systems with stretching alone, and demonstrate it in a fluid flow. While dynamical systems theory provides a framework for understanding mixing in smoothly deforming media, a theory of discontinuous mixing is yet to be fully developed. New methods are needed to systematize, explain, and extrapolate measurements on systems with discontinuous deformations. Here, we investigate "webs" of Lagrangian discontinuities and show that they provide a template for the overall transport dynamics. Considering slip deformations as the asymptotic limit of increasingly localised smooth shear, we also demonstrate exactly how some of the new structures introduced by discontinuous deformations are analogous to structures in smoothly deforming systems.

Bifurcations and degenerate periodic points in a three dimensional chaotic fluid flow.

Analysis of the periodic points of a conservative periodic dynamical system uncovers the basic kinematic structure of the transport dynamics and identifies regions of local stability or chaos. While elliptic and hyperbolic points typically govern such behaviour in 3D systems, degenerate (parabolic) points also play an important role. These points represent a bifurcation in local stability and Lagrangian topology. In this study, we consider the ramifications of the two types of degenerate periodic points that occur in a model 3D fluid flow. (1) Period-tripling bifurcations occur when the local rotation angle associated with elliptic points is reversed, creating a reversal in the orientation of associated Lagrangian structures. Even though a single unstable point is created, the bifurcation in local stability has a large influence on local transport and the global arrangement of manifolds as the unstable degenerate point has three stable and three unstable directions, similar to hyperbolic points, and occurs at the intersection of three hyperbolic periodic lines. The presence of period-tripling bifurcation points indicates regions of both chaos and confinement, with the extent of each depending on the nature of the associated manifold intersections. (2) The second type of bifurcation occurs when periodic lines become tangent to local or global invariant surfaces. This bifurcation creates both saddle-centre bifurcations which can create both chaotic and stable regions, and period-doubling bifurcations which are a common route to chaos in 2D systems. We provide conditions for the occurrence of these tangent bifurcations in 3D conservative systems, as well as constraints on the possible types of tangent bifurcation that can occur based on topological considerations.