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The article presents information on medical study of a 69-year old woman suffering from breast cancer. The woman underwent quadrantectomy with sentinel lymph node dissection for a differentiated intraductal carcinoma of the left breast. It was concluded after this study that the pathologist should be aware of the potential for occurrence of thyroid type papillary carcinoma not only in struma ovarii but also in strumal carcinoid.

A letter to the editor is presented in response to the article "Cetuximab for the Treatment of Colorectal Cancer" by D. J. Jonker, C. J. O'Callaghan and C. S. Karapetis in a previous issue.

The article focuses on the issue concerning malignancy mimicry of nodal benign hyperplastic mesothelial cells in lymph nodes. It discusses the case of a 74-year-old Hispanic man who underwent an incidental mediastinal lymph node biopsy at the time of aortic and mitral valve replacement surgery. It is advisable that pathologists should be aware of the malignancy mimicry of nodal benign hyperplastic mesothelial cells to avoid administering inappropriate treatments.

Focuses on a study which examined an exact line-integral representation of the physical optics near-field expression scattered in near zone by a penetrable planar structure in terms of a line integral. Derivation of the field-integral representation; Comparison of numerical results obtained by applying line integration; Use of Dyadic theorem of divergence.

In this paper an antenna array operating in circular polarization in the C-band is presented. The array is based on the sequential rotation architecture, applied to six elements, and arranged in hexagonal shape. Thanks to its geometry, the array is suitable for tiling of surfaces as well as for regular solid arrangement. Satisfying experimental validation of a prototype based on the proposed design is observed, with a peak gain of 10.4 dB at 5.8 GHz maintained within 3 dB over a 500 MHz band, a 10 dB return loss bandwidth of 500 MHz, and a 3dB axial ratio bandwidth of almost 400 MHz, meaning 6.5% of fractional bandwidth. [ABSTRACT FROM AUTHOR]

The article presents a microscopic image of micronodular epithelial hyperplasia in ectopic thymus. Ectopic thymus with an entirely normal microscopic appearance may be detected in the lateral aspects of the neck due to branchial pouch anomalies. The case of a 53-year-old Caucasian man who underwent radical surgery for thyroid papillary carcinoma with laterocervical lymph node metastases is presented.

A finite-element implementation for the analysis of propagation constants and fields in a guiding structure is presented in this paper. The solution explicitly takes into account the field divergence on the edges of the internal wedges by exploiting substitutive divergent bases. © 2005 Wiley Periodicals, Inc. Microwave Opt Technol Lett 44: 327–328, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.20624 [ABSTRACT FROM AUTHOR]

Examines the problem of two-dimensional scattering from a transparent wedge with thin resistive faces with the parabolic equation method in conjunction with the finite difference method. Determination of the complex constant for nontransparent wedges.

Provides information on the March 2000 issue of the "International Journal of Numerical Modelling: Electronic Networks, Devices and Fields."

A numerical analysis of plane-wave scattering from the edge of a penetrable wedge illuminated at normal incidence is presented. The wedge is formed by a perfectly conducting half-plane and a resistive sheet joining at an arbitrary angle. The diffracted field is determined through the application of the parabolic equation method in conjunction with a finite-difference (FD) scheme. The solution obtained is valid in the high-frequency region. © 1998 John Wiley & Sons, Inc. Microwave Opt Technol Lett 18: 85–86, 1998. [ABSTRACT FROM AUTHOR]

Discusses how a hybrid numerical technique based on the finite-element method (FEM) is exploited to define a numerical diffraction coefficient for irregular wedge configurations. Formulation; Numerical results.

ABSTRACT This article presents a modular reciprocal multiplexer in which the number of channels can be reduced or expanded. The proposed configuration is based on reactive loads designed to substitute channel filters. This is at the same time easy to manufacture and easy to reconfigure as reactive loads are conceived, so as not to modify the characteristics of the active channels if a channel is added or removed. Additional filter tuning after a reconfiguration is not required. The proposed reciprocal design allows for both low costs and low losses since it does not require circulators or additional components, such as hybrid junctions, usually present in reconfigurable multiplexers, although maintaining a good degree of flexibility. A prototype of the proposed design has been fabricated and measured. © 2016 Wiley Periodicals, Inc. Int J RF and Microwave CAE 26:538-546, 2016. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to an article on bronchioloalveolar carcinoma in the January 10, 2002 issue.

Neuroendocrine tumors (NETs) and gastrointestinal stromal tumors (GISTs) are different tumor categories with no pathogenetic, morphologic, clinical, or therapeutic similarities: NETs are epithelial to neural tumors in contrast to GISTs, which show mesenchymal cell lineage. Both tumors, however, arise more frequently from the gastrointestinal tract and may benefit of specific target therapeutic approaches: imatinib/STI-571 for GISTs and m-Tor pathway inhibitors or somatostatin analogs for NETs. The role of pathologist is crucial when dealing with both NETs and GISTs, as morphological, immunohistochemical, and molecular analysis often provide helpful information on the clinical behavior and management. We here propose a general overview on nomenclature of tumors classification and suggestions for histological report of both NETs and GISTs. Moreover, we will approach in finer details the immunohistochemical analysis on origin and differential diagnosis in NETs as well as the prognosis and resistance to therapy in GISTs. This review emphasized recent literature advances regarding similarities and differences in the managerial pathologist's approach to either tumor type. [ABSTRACT FROM AUTHOR]

A synthesis method for the design of large planar array antennas with phase-only control is here presented. The synthesis is based on the use of Zernike polynomials, as global basis function for the phase, to reduce the number of optimization variables with respect to the number of elements of the array. Invasive weed optimization (IWO) is applied to polynomial coefficients’ optimization to circumvent nonlinearity and local trapping issues typical of phase-only problems. The periodicity of the array factor is exploited to reduce the optimization to a Voronoi cell of the grating-lobes’ lattice and nonuniform meshing is introduced to best adapt the control stations to the beam shape requirements. The technique is applied to the design of shaped beams for continental coverage from geostationary satellites. [ABSTRACT FROM AUTHOR]

Background. A Joint Expert Panel recently published guidelines for adjuvant cisplatin-based chemotherapy, recommending routine use in patients with completely resected stage II (T1-2N1 and T3N0) non-small-cell lung cancer (NSCLC). However, these two tumor subgroups should be considered as different entities. While the effi cacy of adjuvant chemotherapy has been established in patients with T1-2N1 NSCLC, its benefi t in patients with T3N0 tumor remains questionable. Material and methods. We performed an extensive review of the literature using the Joint Expert Panel guidelines as a start point. Altogether, we identifi ed 76 potentially relevant articles. Basing on inclusion and exclusion criteria, 23 of the 76 articles were eventually included in this review. Results. After careful evaluation of the selected articles, we found no information on the effect of adjuvant chemotherapy in patients with T3N0 NSCLC. Discussion. In the absence of evidencebased data, we recommend that the lack of information on the effi cacy of adjuvant chemotherapy for T3N0 tumors be discussed with patients and propose chemotherapy as an individual option. While the effi cacy of adjuvant chemotherapy will be diffi cult to assess prospectively through a large randomized clinical trial, a pooled-analysis of the existing data would quickly and with a limited effort provide a preliminary answer. [ABSTRACT FROM AUTHOR]

A multisegment artificial neural network (ANN) is proposed as an interpolation technique for the evaluation of the electromagnetic field diffracted at the edge of anisotropic impedance wedges under plane wave illumination at oblique incidence. Multisegmentation is needed as the high-frequency wedge diffracted field is characterized by a number of discontinuities at the shadow boundaries of the geometrical optics and surface wave fields. The proposed approach is applied, as a test case, to the problem of an anisotropic impedance right-angled wedge illuminated by a skewly incident plane wave. Some exact analytical solutions valid for specific surface impedance tensors are used to obtain numerical data for the ANN training phase as well as to show the interpolation capabilities of the implemented ANN. Nevertheless, the proposed ANN structure is general and can be trained with data obtained from other available solutions (analytical, perturbative, numerical) valid for more general wedge configurations, eventually leading to a single software tool encompassing all of them and providing accurate approximations of the wedge diffracted field in a relatively short time, comparable to that of a closed form analytical solution. [ABSTRACT FROM AUTHOR]

High-frequency expressions for the field scattered by a half-plane with a perfectly conducting and an anisotropic impedance face are provided in the format of the uniform geometrical theory of diffraction (UTD), when the half-plane is illuminated by an arbitrarily polarized plane wave obliquely incident on its edge. The loaded face is characterized by a tensor surface impedance with principal anisotropy axes arbitrarily oriented with respect to the edge; a vanishing surface impedance is exhibited in one of the principal directions. This kind of tensor surface impedance can be suitably applied for analyzing the effects on the scattered field of corrugated surfaces or grounded dielectric slabs periodically loaded by metallic strips. This solution extends previous high-frequency formulations valid in those cases in which the direction of corrugations or strips is either parallel or perpendicular to the edge. The analysis is performed by resorting to the Sommerfeld-Maliuzhinets method. To determine the spectral solution, a special function is needed that differs from the standard Maliuzhinets one and was originally introduced to study the electromagnetic scattering by a wedge embedded in a gyroelectric medium. [ABSTRACT FROM AUTHOR]

Background: Over the last 2 decades, great progress has been made in the understanding of the clinical aspects and pathogenesis of lymphangioleiomyomatosis (LAM), leading to publication of guidelines and approval of an effective therapy. Objectives: Aim of our study was to describe how the management and the natural history of this rare disease have changed after the publication of the ERS and American Thoracic Society/Japanese Respiratory Society guidelines and the introduction of sirolimus. Methods: We examined 162 LAM patients followed at our center between 2001 and 2017, reporting clinical characteristics and diagnostic approach. Response to sirolimus in patients undergoing long-term treatment and mortality risk, estimated in terms of cumulative incidence taking into account organ transplantation as a competing cause of the event, were evaluated. The difference in the cumulative incidence between the patients admitted to the observation before 2011 and after 2011, year of the publication of the MILES trial for the efficacy of sirolimus, has also been estimated. Results: Sixty-one patients had a histological diagnosis (22 from 2010 onward). 101 patients received a radiological diagnosis according to the guidelines criteria. Pulmonary function tests remained stable over a 3-year treatment period in patients who received sirolimus for over 12 months. The cumulative incidence of mortality after 10 years in the whole population was 25.5%. The cumulative incidence of mortality after 5 years was significantly lower in patients who entered the study since 2011 (after publication of the MILES trial) than in patients who entered the study before. Conclusions: We provide the data supporting the long-term efficacy of sirolimus therapy in a large cohort of patients with functional impairment and other manifestations of the disease. Our results also suggest that the advent of sirolimus and the publication of international guidelines changed the natural history of the disease lowering the mortality and reducing the need of invasive diagnostic techniques. [ABSTRACT FROM AUTHOR]

This paper deals with many different neural network architectures that have been introduced to simulate the electromagnetic behavior of complex microwave devices and antennas. Many issues linked to the peculiarities of such devices are addressed. Furthermore, the inverse problem of designing a microwave device, once the required characteristics are given, is also developed by using a neural network approach. © 2002 John Wiley & Sons, Inc. Int J RF and Microwave CAE 12: 90–97, 2002. [ABSTRACT FROM AUTHOR]

Presents a study which examined the artificial neural network approach for the analysis and synthesis of profiled circular corrugated horn. Geometrical aspects of the profiled corrugated circular horns; Analysis and synthesis procedure; Conclusion.

Examines the time-domain physical optics heuristic approach to passive intermodulation scattering. Proposal of an equivalent nonlinear impedance boundary condition; Suitability of the approach for embedding into electromagnetic computer-aided design software; Approval of additional electromagnetic compatibility pattern of complex nature.

The robustness of straight and curved tetrahedral elements with higher order basis functions is tested against mesh quality with respect to some test cases. Results show not only an overall and expected better performance of higher order basis functions, but also an increased robustness to element distortion. © 2000 John Wiley & Sons, Inc. Microwave Opt Technol Lett 27: 17–20, 2000. [ABSTRACT FROM AUTHOR]

Deals with a study which analyzed electromagnetic scattering by a perfectly conducting dihedral corner with deformed faces. Model developed to study the case in which one face is deformed according to a parabolic law; Verification of the effectiveness of the model.

This study introduces the conic section arc elements in 2D and 2.5D finite element method (FEM). Elements are obtained by deforming an edge in a standard triangular element through a coordinate transformation. This allows to completely eliminate the geometrical error in structures composed of circular, elliptical, hyperbolic and parabolic arcs. The element order is defined independently of the geometrical description of the boundary, allowing the use of simple meshers. Previously available FEM codes can be straightforwardly modified to introduce the conic section boundaries. [ABSTRACT FROM AUTHOR]

Synthesis of phased array antennas generating shaped patterns by exploiting phase tapering only is a challenging problem. A phase‐only tapering permits maximizing the DC to RF power efficiency and results to be particularly useful in satellite applications with stringent constraints on the available power. Such a synthesis is a highly nonlinear problem most effectively addressed via stochastic optimization techniques. In this paper several basis functions to represent the phase distribution are traded‐off and compared, within an invasive weed optimization paradigm. [ABSTRACT FROM AUTHOR]

Presents a study which proposed an algorithm for the analysis of a complete feeding system in corrugated circular waveguide. Overview of the analysis method; Computation of the generalized scattering matrix; Analysis of a typical mode launcher through the generalized admittance matrix approach; Conclusions.

This article applies a new method to analyze modes in empty waveguides having perfectly conducting walls and a rather generic cross‐section. The method is based on a coordinate transformation that maps the generic profile of the waveguide cross‐section to a circular waveguide (CW) filled with an anisotropic material. Modes in this latter waveguide can be represented as a series over the corresponding free‐space CW modes. This representation is particularly useful if used as a modal expansion over the port of a 2.5D or 3D device treated with a transformation optics approach. The method is particularly efficient when the waveguide is "similar" to a CW. Applications are shown to the analysis of some waveguides of arbitrary cross‐section with a view on practical applications. [ABSTRACT FROM AUTHOR]

This paper presents a novel approach to the localization of moving targets in a complex environment based on the measurement of the perturbations induced by the target presence on an independently‐generated time‐varying electromagnetic field. Field perturbations are measured via a set of sensors deployed over the domain of interest and used to detect and track a possible target by resorting to a particle Bernoulli filter (PBF). To comply with real‐time operation, the PBF works along with an artificial neural network (ANN) model of the environment trained offline via finite elements (FEs). The performance of the proposed algorithm is assessed via simulation experiments. [ABSTRACT FROM AUTHOR]

Zones with nonlinear behavior on an object cause intermodulated components in the scattered electromagnetic field. This problem is relevant both for satellite communications and for radio-astronomical applications. Recently, a heuristic model for the passive intermodulation analysis has been derived in a time domain physical optics framework. The heuristic approach proposed requires the determination of few coefficients. Here, a genetic algorithm is introduced for the computation of the optimum values for these coefficients. [ABSTRACT FROM AUTHOR]

This letter proposes a quasi‐elliptical passband filter in via‐less microstrip technology. The filter is based on the Archimedean spiral, enabling a compact and low‐loss response with sharp transitions to stop bands. The developed filters fabricated on a commercial substrate, present losses below 2 dB within a 3 dB bandwidth of 500 MHz, and isolation exceeding 20 dB. Its extremely compact dimension, about 0.018 λ02, and the low‐cost of fabrication, permits the integration within compact front‐end PCB. [ABSTRACT FROM AUTHOR]

NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56brightCD16dim/-CD9+CD49+ subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; among which, angiogenin and invasion-associated enzymes related to the MMP9-TIMP1/2 axis. Here, we describe, for the first time, to our knowledge, the expression of angiogenin, MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 or MMP inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti-tumor antimetastatic ones. [ABSTRACT FROM AUTHOR]

This paper describes a new method to analyze elliptical horns. The method is based on a coordinate transformation, which maps the elliptical shape to a circular shape, allowing to use the 2.5-D body-of-revolution finite-element method formulation with a greatly improved efficiency over 3-D methods. Applications are shown to the analysis and design of shaped arbitrary axial ratio horns. [ABSTRACT FROM AUTHOR]

Aims The association between lung cancer and idiopathic pulmonary fibrosis ( IPF) is well known, but the significance of this association is poorly understood. Bronchiolar honeycomb cysts have been proposed as possible precursors for the development of carcinoma, but limited evidence in support of this hypothesis is available. The aim of this study was to investigate this hypothesis analysing a series of carcinomas arising in IPF by immunohistochemistry. Methods and results Thirty-three lung carcinomas arising in patients with IPF were analysed with a panel of immunohistochemical markers. The antibodies included those against pneumocyte markers [thyroid transcription factor 1 ( TTF1), napsin-A, and surfactant protein A], the goblet cell marker mucin 5 AC, markers of basal/squamous cell differentiation [cytokeratin ( CK) 5/6 and ΔN-p63], and markers related to enteric differentiation ( CDX2, mucin 2, CK20, and villin). A series of 100 consecutive lung adenocarcinomas arising in smokers without IPF were investigated as controls. All carcinomas arising in IPF patients were peripherally located on imaging analysis. The diagnoses were: eight squamous cell carcinomas, 20 adenocarcinomas, three small-cell carcinomas (including one composite small-cell carcinoma and adenocarcinoma), and two large-cell carcinomas. Among adenocarcinomas, a 'pneumocyte' profile ( TTF1/napsin-A/ SPA1-triple-positive) was observed in seven of 20 (35% versus 84% in non- IPF controls, P = 0.0001). The remaining 13 adenocarcinomas (65%) showed rare histotypes: four invasive mucinous adenocarcinomas (20% in IPF patients versus 1% in non- IPF controls, P = 0.002), seven tumours (35%) that were characterized by variable expression of markers of enteric differentiation, and two tumours (10%) that showed a peculiar basaloid component. Conclusions The immunohistochemical characterization of carcinomas arising in IPF patients shows striking divergence from that in non- IPF smokers. The prevalence of rare entities showing bronchiole-related markers is in line with the hypothesis that these tumours arise from transformed small airways in honeycomb lung areas where abnormal bronchiolar proliferation takes place. [ABSTRACT FROM AUTHOR]

Background: Nuclear protein in testis (NUT) midline carcinoma is a rarely diagnosed and potentially under-recognized type of squamous carcinoma that is considered one of the most aggressive human solid tumors. Alpha-fetoprotein elevation has been associated with chronic liver diseases and a limited number of cancers. In particular, in presence of a mediastinal mass in a young man, alpha-fetoprotein elevation is considered nearly pathognomonic of a non-seminoma germ-cell tumor.Case Presentation: A 22-year old man without any comorbidity was diagnosed with a large mediastinal mass with skeletal and lymph node metastases. The clinical picture was dominated by a life-threatening superior vena cava syndrome with elevated alpha-fetoprotein and lactate dehydrogenase that supported the diagnostic suspicion of mediastinal germ-cell tumor. However, a biopsy showed a poorly-differentiated and diffusely necrotic carcinoma. We eventually reached the diagnosis of the peculiar entity of NUT midline carcinoma, but the differential diagnosis was quite challenging also because alpha-fetoprotein is not reported as a marker of NUT midline carcinoma. Notably, alpha-fetoprotein levels correlated with disease course.Conclusions: The life-threatening aggressiveness of NUT midline carcinoma mandates to reach the right diagnosis in the shortest possible time. In this regard, poorly differentiated carcinomas lacking glandular differentiation mandate testing for NUT expression by immunohistochemistry. Awareness of a potentially misleading tumor marker elevation can help to broaden the differential diagnosis and establish the most appropriate treatment. [ABSTRACT FROM AUTHOR]

A letter to the editor about the article "Successful Chemotherapy and 90Y-DOTATOC in a Patient With Mediastinal Highly Aggressive Neuroendocrine Carcinoma" is presented.

A correlation between osteopontin, E-cadherin, β-catenin, and cyclooxygenase 2 overexpression and poor clinicopathological features and prognosis has been previously suggested in gastric cancer. This translational study was aimed at assessing the correlation of these immunohistochemical biomarkers with outcome in patients with radically resected gastric cancer. We analyzed osteopontin, E-cadherin, β-catenin, and cyclooxygenase 2 expression by immunohistochemistry in 346 primary gastric tumor tissue samples from patients enrolled in the ITACA-S trial. This phase III study randomized patients with radically resected gastric cancer to receive adjuvant chemotherapy with either 5-fluorouracil and leucovorin or a sequential regimen of infusional 5-fluorouracil and leucovorin plus irinotecan followed by cisplatin and docetaxel. High expression of osteopontin was correlated with high histological grade, diffuse histotype, and peritoneal relapse, but not with TNM stage. Moreover, osteopontin overexpression was associated with higher risk of tumor recurrence and metastases, and was an independent prognostic factor for both relapse-free and overall survival of gastric cancer patients following adjuvant chemotherapy. Abnormal E-cadherin expression and abnormal β-catenin expression were correlated with more advanced disease stage, and as a consequence, with poor outcome. Our results suggest that osteopontin overexpression is a valuable independent predictor of tumor recurrence and survival in patients with radically resected gastric cancer. [ABSTRACT FROM AUTHOR]

An estimated 20% to 30% of all neuroendocrine tumours originate in the bronchial tree and lungs. According to the 2015 World Health Organization categorization, these tumours are separated into four subtypes characterized by increasing biological aggressiveness: typical carcinoid, atypical carcinoid, large-cell neuroendocrine carcinoma and small-cell carcinoma. Although typical and atypical lung carcinoids account for less than 1–5% of all pulmonary malignancies, the incidence of these neoplasms has risen significantly in recent decades. Surgery is the treatment of choice for loco-regional disease but for advanced lung carcinoids there is no recognized standard of care and successful management requires a multidisciplinary approach. The aim of this review is to provide a useful guide for the clinical management of lung carcinoids. [ABSTRACT FROM AUTHOR]

Cancer immunotherapy is now recognized to be fundamental in modern oncology, because immune system recruitment may represent a powerful and innovative strategy in cancer therapy. Pembrolizumab, a highly selective humanized monoclonal antibody directly blocking the interaction between programmed cell death-1 expressed by tumor-associated T-cells and its ligand programmed cell death-L1 present on tumor and stromal cells, was recently approved by US Food and Drug Administration for the treatment of patients with unresectable or metastatic melanoma and disease progression upon ipilimumab and BRAF inhibitor. This review will focus on the clinical development and use of pembrolizumab in the clinical practice and in the management of advanced melanoma. [ABSTRACT FROM AUTHOR]

Biomarkers predicting which patients with advanced radioiodine-resistant differentiated thyroid cancer (DTC) may benefit from multi-kinase inhibitors are unavailable. We aimed to describe molecular markers in DTC that correlate with clinical outcome to axitinib. Pretreatment thyroid cancer blocks from 18 patients treated with axitinib were collected and genomic DNA was isolated. The OncoCarta™ Mutation Panel was used to test for 238 oncogenic mutations. Copy number of VEGFR1-3 and PIK3CA was determined using qPCR on enriched tumor samples. Genomic DNA was analyzed for all coding regions of VEGFR1-3 with custom primers. Protein expressions of VEGFR1-3, c-Met, and PIK3CA were evaluated with immunohistochemistry. Clinical response to axitinib, including best response (BR) and progression free survival (PFS), was ascertained from corresponding patients. Fisher's exact test and logistic regression models were used to correlate BR with molecular findings. Cox proportional hazards regression was used to correlate PFS with molecular defects. A total of 22 pathology samples (10 primary, 12 metastatic) were identified. In patients with 2 samples (n = 4), genetic results were concordant and only included once for analysis. Tumors from 4 patients (22%) harbored BRAF V600E mutations, 2 (11%) had KRAS mutations (G12A, G13D) and 2 (11%) had HRAS mutations (Q61R, Q61K). One metastatic sample with mutated KRAS also harbored a PIK3CA (H1047R) mutation. qPCR showed increased copy numbers of PIK3CA in 6 (33%) tumors, VEGFR1 in 0 (0%) tumors, VEGFR2 in 4 (22%) tumors, and VEGFR3 in 6 (33%) tumors. VEGFR sequencing was significant for a possibly damaging non-synonymous SNP in VEGFR2 (G539R) in 2 samples (11%), a possibly damaging SNP in VEGFR3 (E350V) in 1 sample (6%), and a potentially novel mutation in VEGFR2 (T439I) in 2 samples (11%). Immunohistochemistry (VEGFR1, -2, -3; c-MET; PIK3CA) revealed positive staining in the majority of samples. No significant relationship was seen between BR or PFS and the presence of molecular alterations. Molecular evaluation of DTC specimens did not predict clinical response to axitinib but our data were limited by sample size. We did identify molecular changes in VEGFR that should be further explored. While DTC is genetically heterogeneous, primary and metastatic lesions showed identical oncogenic alterations in four cases. [ABSTRACT FROM AUTHOR]

Pulmonary mucin-producing adenocarcinomas may be indistinguishable on conventional histology from a metastasis, as thyroid transcription factor-1 (TTF-1) expression often is lacking and KRAS mutations are widely present even in extrapulmonary sites. Few data have been reported on the diagnostic role of napsin-A and epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) gene alterations in this challenging differential diagnosis. Seventy-seven surgically resected cases, including 53 primary and 24 metastatic tumors from different sites, were evaluated for napsin-A, TTF-1, and ALK by immunohistochemistry and for EGFR mutations by direct sequencing. Overall, napsin-A expression in primary lung mucin-producing adenocarcinomas was 36% (8% mucinous, 17% colloid, 87.5% solid, and 100% signet ring cell) and TTF-1 expression reached an overall figure of 42% (12.5% mucinous, 33% colloid, 87.5% solid, and 100% signet ring cell). Metastatic mucinous adenocarcinomas did not react with napsin-A or with TTF-1. All primary and metastatic tumors lacked EGFR mutations, while a single case of signet ring cell lung adenocarcinoma showed ALK expression and rearrangement at fluorescent in situ hybridization analysis. Napsin-A has a lower sensitivity compared with TTF-1 in primary mucin-producing adenocarcinomas of the lung. However, both antibodies have an absolute specificity, being always negative in metastatic mucinous adenocarcinomas. EGFR mutations and ALK translocation or expression are exceedingly rare in mucin-producing adenocarcinomas of the lung, resulting unnecessary as diagnostic tool in this setting. [ABSTRACT FROM AUTHOR]

Aims Primary Ewing sarcoma of the ileum has rarely been documented. Little is known about its pathogenesis and clinical implications, and it would be helpful to identify novel molecular markers. EWSR1-FEV translocation is exceedingly rare in Ewing sarcoma, as FEV expression is restricted to prostate, brain and serotonin neuroendocrine cells ( NE) and related tumours. Methods and Results Paraffin sections or snap-frozen material were used in this investigation. Tumours were investigated by means of immunohistochemistry, RT-PCR ( EWSR1- FLI1, EWSR1- ERG and EWSR1- FEV transcripts), FISH analysis ( EWSR1 break-apart and specific EWSR1- FEV translocation) and spectral karyotyping ( SKY). Ten ileal neuroendocrine tumours ( INET) made up the control group for EWSR1- FEV translocation. Among 445 Ewing sarcomas cases spanning a period of 20 years, seven (1.6%) arose in the ileum. All tumours were immunoreactive for synaptophysin, CD99, FLI1 and vimentin. FISH identified EWSR1 rearrangement in all cases, with EWSR1-FLI1 transcripts being detected in all but one tumour showing the uncommon EWSR1- FEV rearrangement, with SKY, RT- PCR and FISH confirmation. The mean survival of EWSR1- FLI1 patients was 14 months, whereas the EWSR1- FEV patient was alive after 15 years despite several recurrences controlled by surgery alone. No INET showed EWSR1 translocation. Conclusions Most primary Ewing sarcomas of the ileum show the common EWSR1- FLI1 translocation, but EWSR1- FEV could be specific for tumours arising in the ileum and showing better prognosis. [ABSTRACT FROM AUTHOR]

Introduction: Although cetuximab and panitumumab show an increased efficacy for patients with KRAS-NRAS-BRAF and PI3KCA wild-type metastatic colorectal cancer, primary resistance occurs in a relevant subset of molecularly enriched populations. Patients and Methods: We evaluated the outcome of 68 patients with advanced colorectal cancer and RAS, BRAF and PI3KCA status according to ALK gene status (disomic vs. gain of ALK gene copy number – defined as mean of 3 to 5 fusion signals in ≥10% of cells). All consecutive patients received cetuximab and irinotecan or panitumumab alone for chemorefractory disease. Results: No ALK translocations or amplifications were detected. ALK gene copy number gain was found in 25 (37%) tumors. Response rate was significantly higher in patients with disomic ALK as compared to those with gain of gene copy number (70% vs. 32%; p = 0.0048). Similarly, progression-free survival was significantly different when comparing the two groups (6.7 vs. 5.3 months; p = 0.045). A trend was observed also for overall survival (18.5 vs. 15.6 months; p = 0.885). Conclusion: Gain of ALK gene copy number might represent a negative prognostic factor in mCRC and may have a role in resistance to anti-EGFR therapy. [ABSTRACT FROM AUTHOR]

Somatostatin receptors (SSTRs) may be used in lung carcinoids (LCs) for diagnosis and therapy, although additional targets are clearly warranted. This study aimed to investigate whether olfactory receptor 51E1 (OR51E1) may be a potential target for LCs. OR51E1 coding sequence was analyzed in LC cell lines, NCI-H727 and NCI-H720. OR51E1 transcript expression was investigated in LC cell lines and frozen specimens by quantitative real-time PCR. OR51E1, SSTR2, SSTR3, and SSTR5 expression was evaluated by immunohistochemistry on paraffin-embedded sections of 73 typical carcinoids (TCs), 14 atypical carcinoids (ACs), and 11 regional/distant metastases and compared with OctreoScan data. Immunohistochemistry results were rendered semiquantitatively on a scale from 0 to 3, taking into account the cellular compartmentalization (membrane vs cytoplasm) and the percentage of tumor cells (!50 vsO50%). Our results showed that WT OR51E1 transcript was expressed in both LC cell lines. OR51E1 mRNA was expressed in 9 out of 12 TCs and 7 out of 9 ACs (PZNS). Immunohistochemically, OR51E1, SSTR2, SSTR3, and SSTR5 were detected in 85, 71, 25, and 39% of TCs and in 86, 79, 43, and 36% of ACs respectively. OR51E1 immunohistochemical scores were higher or equal than those of SSTRs' in79%of TCsand86%of ACs. Furthermore, in the LC caseswhere all SSTR subtypes were lacking,membraneOR51E1 expressionwas detected in 10 out of 17 TCs and 1 out of 2 ACs. Moreover, higher OR51E1 immunohistochemical scores were detected in 5 out of 6 OctreoScan-negative LC lesions. Therefore, the high expression of OR51E1 in LCs makes it a potential novel diagnostic target in SSTR-negative tumors. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: To assess changes in survival over time in patients affected by thoracic soft tissue sarcomas treated at a single institution. Patients and Methods: Patients with localised adult-type deep thoracic soft tissue sarcoma surgically treated at our institution between 1980 and 2012 were retrospectively reviewed. Patients were categorised into two groups according to timing of their first operation, i.e. surgery done before or after 31st December 2001 (so called ‘early years’ and ‘recent years’ groups, respectively), since a more extended surgery was used in the second interval. Overall survival (OS) and crude cumulative incidence (CCI) of local recurrence (LR) and distant metastases (DM) were calculated for each time period. Results: Three-hundred-thirty-seven patients were identified. Median follow-up was 4.7years. Tumour size and rate of critical site involvement were larger in ‘recent years’, while the distribution of all other tumour- and patient-related factors was identical in the two periods. Despite this, OS and CCI of LR were significantly better in ‘recent years’ as compared to ‘early’ ones, the 5-year OS increasing from 58% to 72% and the CCI of LR dropping from 22% to 11%. CCI of DM was equal in the two periods. Conclusion: Reference institutions for sarcomas may have improved their outcome in the last years. Although biases of retrospective analyses need to be discounted, it is possible that optimal exploitation of a series of subtle improvements in sarcoma treatment may make a difference in results achievable today. [Copyright &y& Elsevier]

Non-invasive diagnostic tools are effective in the histomorphological study of melanocytic lesions. The role of melanoma susceptibility genes on melanocytic nevi histopathological features is not clear. The current study aimed to correlate genetic alterations and histomorphological features of melanocytic nevi. Clinical, dermoscopic and confocal features of 34 multiple melanoma patients and 34 controls were compared. Among patients with melanoma, carriers of CDKN2A mutations and/or MC1R variants, and wild-type genes were also compared. In patients with melanoma, a lighter phototype ( P = 0.051), a higher number of nevi ( P < 0.01) and clinically atypical nevi ( P < 0.01) were observed. At dermoscopy, these nevi showed a complex pattern ( P = 0.011), atypical network ( P = 0.018) and irregular pigmentation ( P = 0.037); at confocal, an irregular meshwork pattern ( P = 0.026) with atypical nests ( P = 0.016) and an inflammatory infiltrate ( P = 0.048) were observed. Among patients with melanoma genetically tested, CDKN2 A G101 W mutation carriers were more frequently younger ( P = 0.023), with clinically atypical nevi ( P = 0.050), with cytological atypia ( P = 0.033) at confocal. G101 W mutation and MC1 R variants carriers showed hypopigmented nevi ( P = 0.002) and, at confocal, roundish cells infiltrating the junction ( P = 0.019). These data suggest an influence of CDKN2 A mutation and MC1 R variants in the development of dysplastic melanocytic lesions. Non-invasive histomorphological evaluation, together with genetic studies, improves melanoma risk identification and early diagnosis, for a patient-tailored management. [ABSTRACT FROM AUTHOR]

BIM is a proapoptotic member of the Bcl-2 family. Here, we investigated the epigenetic status of the BIM locus in NPM/ALK+ anaplastic large cell lymphoma (ALCL) cell lines and in lymph node biopsies from NPM/ALK+ ALCL patients. We show that BIM is epigenetically silenced in cell lines and lymph node specimens and that treatment with the deacetylase inhibitor trichostatin A restores the histone acetylation, strongly upregulates BIM expression, and induces cell death. BIM silencing occurs through recruitment of MeCP2 and the SIN3a/histone deacetylase 1/2 (HDAC1/2) corepressor complex. This event requires BIM CpG methylation/demethylation with 5-azacytidine that leads to detachment of the MeCP2 corepressor complex and reacetylation of the histone tails. Treatment with the ALK inhibitor PF2341066 or with an inducible shRNA targeting NPM/ALK does not restore BIM locus reacetylation; however, enforced expression of NPM/ALK in an NPM/ALK-negative cell line significantly increases the methylation at the BIM locus. This study demonstrates that BIM is epigenetically silenced in NPM/ALK-positive cells through recruitment of the SIN3a/HDAC1/2 corepressor complex and that NPM/ALK is dispensable to maintain BIMepigenetic silencing but is able to act as an inducer of BIM methylation. [ABSTRACT FROM AUTHOR]