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The reporting of lung neuroendocrine neoplasms (NENs) according to the 2021 World Health Organisation (WHO) is based on mitotic count per 2 mm2, necrosis assessment and a constellation of cytological and immunohistochemical details. Accordingly, typical carcinoid and atypical carcinoid are low‐ to intermediate‐grade neuroendocrine tumours (NETs), while large‐cell neuroendocrine carcinoma (NEC) and small‐cell lung carcinoma are high‐grade NECs. In small‐sized diagnostic material (cytology and biopsy), the noncommittal term of carcinoid tumour/NET not otherwise specified (NOS) and metastatic carcinoid NOS have been introduced with regard to primary and metastatic diagnostic settings, respectively. Ki‐67 antigen, a well‐known marker of cell proliferation, has been included in the WHO classification as a non‐essential but desirable criterion, especially to distinguish NETs from high‐grade NECs and to delineate the provisional category of carcinoid tumours/NETs with elevated mitotic counts (> 10 mitoses per mm2) and/or Ki‐67 proliferation index (≥ 30%). However, a wider use of this marker in the spectrum of lung NENs continues to be highly reported and debated, thus witnessing a never‐subsided attention. Therefore, the arguments for and against incorporating Ki‐67 in the classification and clinical practice of these neoplasms are discussed herein in detail. [ABSTRACT FROM AUTHOR]

A general approach for the synthesis of the optimal sequential network for use in sequentially rotated antenna (SRA) arrays with an arbitrary number of elements is presented. The performance of this class of antennas are strictly bound to the capacity of the feeding network to produce the nominal power distribution and phase progression. Despite the very high interest in the scientific community on SRA architectures, very few papers have addressed the problem of synthesizing a generic network, with an arbitrary number of outputs. In this paper we propose a novel approach based on closed formulas which solves the synthesis problem exactly, for a given frequency. The proposed approach is then validated with a set of simulations and with the fabrication and measurement of a prototype. Both the simulations and the experimental validation confirms the effectiveness of the proposed method. [ABSTRACT FROM AUTHOR]

Little is known as to whether there may be any pathogenetic link between pulmonary carcinoids and neuroendocrine carcinomas (NECs). A gene signature we previously found to cluster pulmonary carcinoids, large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC), and which encompassed MEN1, MYC, MYCL1, RICTOR, RB1, SDHA, SRC and TP53 mutations or copy number variations (CNVs), was used to reclassify an independent cohort of 54 neuroendocrine neoplasms (NENs) [31 typical carcinoids (TC), 11 atypical carcinoids (AC) and 12 SCLC], by means of transcriptome and mutation data. Unsupervised clustering analysis identified two histology-independent clusters, namely CL1 and CL2, where 17/42 (40.5%) carcinoids and all the SCLC samples fell into the latter. CL2 carcinoids affected survival adversely, were enriched in T to G transversions or T > C/C > T transitions in the context of specific mutational signatures, presented with at least 1.5-fold change (FC) increase of gene mutations including TSC2 , SMARCA2 , SMARCA4 , ERBB4 and PTPRZ1 , differed for gene expression and showed epigenetic changes in charge of MYC and MTORC1 pathways, cellular senescence, inflammation, high-plasticity cell state and immune system exhaustion. Similar results were also found in two other independent validation sets comprising 101 lung NENs (24 carcinoids, 21 SCLC and 56 LCNEC) and 30 carcinoids, respectively. We herein confirmed an unexpected sharing of molecular traits along the spectrum of lung NENs, with a subset of genomically distinct aggressive carcinoids sharing molecular features of high-grade neuroendocrine neoplasms. [ABSTRACT FROM AUTHOR]

This study presents a single‐layer via‐less antenna array operating in circular polarisation for wide‐band operation in C‐band. The antenna comprises 2×2 disc based elements arranged in a sequential rotation architecture. Each element is tuned to exhibit multiple resonances with good circular polarisation performance over a broadband of frequencies. A proper feeding network is then designed so that the resulting array is capable of a wide‐band operation and enhanced gain, equalising the frequency response of the set of elements. Simulations are validated by fabricating and measuring a prototype realised on a commercial FR408 dielectric substrate. Notwithstanding a dimension of only 7×7cm2, that is only 1.66λ02 at centre frequency, measured performance of the proposed array can be summarised in a gain better than 7 dB over an operation bandwidth of 24.45%, which is an unmatched result, given the via‐less single‐layer technology and the specific available area. [ABSTRACT FROM AUTHOR]

The next generation interferometric gravitational wave detectors require arm lengths measured in tens of kilometers, with each cavity storing megawatts of optical power. The beams are contained in ultrahigh vacuum pipes. Scattered interferometer light in the pipes may reenter the cavities and inject extra noise. The pipes are, therefore, provided with optical baffles necessary to eliminate the scattered light. The design of the vacuum pipes and of the optical baffles is tightly intertwined. We present a thorough discussion that opens the door to the design of an optimized stepped-diameter vacuum pipe system using novel helical baffles. Our analysis suggests that a more efficient pipe design (with special reference to scattered light) may use spiral baffles and sectioned stepped tubes. [ABSTRACT FROM AUTHOR]

The identify friend or foe antenna is a complement to many radar antennas which allows the discrimination between friendly and hostile targets by receiving identification data. Such antenna must synthesize both a sum and a difference pattern in azimuth to allow target discrimination and must point to the target being inquired, either by mechanical or electronic scanning in azimuth. In this paper, to attain optimal electronic scanning, an array of antennas lying on a generic planar curve is considered. A multi-objective optimization based on the invasive weed optimization algorithm is then applied to the shape of such curve, aimed at maximizing performances. Whereas a conventional linear array of 6 elements can effectively scan ±30°, with respect to broadside, the proposed array, notwithstanding the same number of elements and overall length, can scan ±45° and still synthesize effective sum and difference patterns. [ABSTRACT FROM AUTHOR]

An elementary dipole in presence of a perfectly conducting wedge radiates a field whose analytic expression can be written in terms of a double infinite series. A dipole located at a point characterized by complex coordinates behaves in the real space as a directive source akin to a Gaussian beam in the paraxial region. In this article, the series solution, originally conceived for a dipole located at a point characterized by real coordinates, is extended to the case of a complex coordinates source, hence providing an analytical solution approximating the problem of a wedge illuminated by a Gaussian beam. [ABSTRACT FROM AUTHOR]

• Spread through air spaces is suggested to be invasion way of lung parenchyma. • Spread through air spaces has been described around lung neuroendocrine neoplasms. • Spread through air spaces may be made up by hyperplastic neuroendocrine cells. • Spread through air spaces is likely to be an ex vivo artifact due to tissue manipulation. Spread through air spaces (STAS) is a recently proposed invasion way of lung cancer, including neuroendocrine (NE) neoplasms. However, if this phenomenon is a real one or an artifact while manipulating lung specimens, it is still matter of debate. Three consecutive patients with newly diagnosed diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) were reviewed for STAS. In well-fixed lung specimens, DIPNECH was seen to coexist with atypical carcinoid, bifocal typical carcinoid and adenocarcinoma in the three patients, respectively. While STAS was not observed at the growing edges of tumors, a few freely-floating aggregates of hyperplastic NE cells within air spaces were noticed to emanate from foci of NE hyperplasia and tumorlets and in intimate association with normal bronchiolar cells and erythrocytes to denote artifactual derivation upon tissue manipulation. Traveling of hyperplastic NE cells through air spaces is likely to artifactually occur via knife, surgeon or other way, thus challenging invasion by STAS. [ABSTRACT FROM AUTHOR]

The well‐known symmetry property of the scattering matrix relative to propagating modes becomes tricky in the case of arbitrary polarization or arbitrary complex modal functions, as in the case of waveguide polarizers and ortho‐mode transducers. A straightforward transformation between different modal bases for the guided waves leads to a loss of symmetry. Only by gaining a deeper insight on the properties of the scattering matrices and with separate transformations for the incident and reflected waves is symmetry recovered. [ABSTRACT FROM AUTHOR]

Accrual of metastatic pulmonary carcinoid patients for therapy is usually relied on clinical and histologic characterization, with no role for the proliferation activity as defined by Ki-67 labelling index (LI). A total of 14 carcinoid patients with tumour primaries (TP) and 19 corresponding tumour metastases (TM) were blindly reviewed by 2 different pathologists for necrosis, mitotic count, and Ki-67 LI. Ki-67 LI outperformed histologic subtyping, mitotic count, and necrosis with good to almost excellent (0.40-0.75) inter-observer agreement. About 10% cut-off Ki-67 LI predicted survival better than histology for TP and TM for both observers. The TM patients survived differently according to diverse treatments (somatostatin analogues [SSAs], analogues plus additional treatments except for platinum; platinum-based chemotherapy) in close correlation with <10%, 10% to 20%, and >20% cut-off thresholds of Ki-67 LI, respectively. There was also a trend for an increase in Ki-67 LI in TM as compared with TP. This is the first proof of concept in which a clinical potential is preliminarily suggested for Ki-67 LI to better stratify pulmonary metastatic carcinoid patients for treatment according to a criterion of histology-independent biological aggressiveness. [ABSTRACT FROM AUTHOR]

In this paper, a wide band monopole antenna with a shaped profile is presented. Shaped profile and end-caps allow for a compact antenna with respect to wavelength. Antenna is designed to be as isotropic as possible and with low phase deviation from spherical wave front to allow accurate detection of the direction of arrival of an unknown signal when used in radiogoniometry applications. [ABSTRACT FROM AUTHOR]

This paper presents an efficient highfrequency analysis framework for studying diffraction occurring at irises, or baffles, in the arms of a Fabry-Perot optical interferometer, relevant to the design and operation of interferometric detectors of gravitational waves like LIGO and Virgo. [ABSTRACT FROM AUTHOR]

ABSTRACT A pentagonal circular polarized subarray composed of five elements is proposed for operation at 2.45 GHz. The array is based on the sequential rotation architecture (SRA), implemented with a sequential phase distribution network. Despite a more complex design in comparison to the canonical 4-elements SRA, a pentagonal subarray is more suited to be packed in a Bucky-ball or icosahedral arrangement, ideal for smart antennas with wide angle spatial coverage. A single-layer via-less prototype is fabricated on a common FR4 substrate. Measurements show a realized gain of 6.15 dBi with a polarization purity exceeding 20 dB at 2.45 GHz. © 2017 Wiley Periodicals, Inc. Microwave Opt Technol Lett 59:1077-1081, 2017 [ABSTRACT FROM AUTHOR]

The scattering problem of the electromagnetic field generated by an elementary dipole in the presence of a perfectly conducting wedge is here addressed in terms of a Sommerfeld integral which can be expressed by an infinite summation. The analytic solution presented is valid also in the case in which the dipole, the observation point, or both are close to the edge of the wedge. Approximations are also presented, and comparison with the uniform geometrical theory of diffraction (UTD) solution provided. [ABSTRACT FROM PUBLISHER]

Large cell carcinoma (LCC) is a merely descriptive term indicating a subtype of lung cancer with no specific features of small-cell lung cancer (SCLC), adenocarcinoma (ADC) or squamous cell carcinoma (SQC). This diagnosis is allowed on surgical specimens only, whereas its counterpart in biopsy/cytology samples is non-small-cell lung carcinoma (NSCLC), not otherwise specified (NOS). Although these two terms do not fulfill the same concept, they can be interchangeable synonyms at the clinical level, reflecting, in different ways, the inability to define a specific subtype. Immunohistochemistry (IHC), next generation sequencing (NGS) analysis and, historically, electron microscopy have been unveiling diverse cell differentiation lineages in LCC, resulting in LCC-favor ADC, LCC-favor SQC and LCC-favor large-cell neuroendocrine carcinoma (LCNEC), the latter hopefully to be included into the neuroendocrine tumor (NET) group in the future. Paradoxically, however, the interpretation issues of LCC/NSCLC-NOS are not diminishing, but even increasing albeight an accurate diagnosis is oncologically required and crucial. Also, rare LCC/NSCLC-NOS cases exhibiting null/unclear phenotype, are difficult to classify, and this terminology could be maintained for the sake of classification (basically these tumors are serendipitous ADC, as also confirmed by the lack of p40). In this review article, seven relevant issues to LCC have been addressed by using a question–answer methodology, with final key points discussing major interpretation issues. In conclusion, most LCC/NSCLC-NOS may be eventually re-classified and addressed by exploiting IHC and/or molecular testing to satisfy the criteria of precision medicine (the right drug, to the right patient, at the right time). [ABSTRACT FROM AUTHOR]

Transformation optics is a powerful tool allowing remapping a generic domain into another yet maintaining a correspondence of the solution of Maxwell's equations within the two domains. Transformation optics has been used in the past to conveniently solve for modes in a generic waveguide by transforming its cross‐section into a circular one. Such a transformation needs particular care in enforcing boundary conditions in the transformed, circular, domain. In this paper, a theoretical treatment of boundary conditions is presented, allowing for an accurate computation of all field components in a generic waveguide. [ABSTRACT FROM AUTHOR]

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]

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]

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: 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 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]

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]

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 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]

Acinar cell carcinoma (ACC) of the pancreas are known to be rare and difficult to be recognize because they mimic other unrelated tumors (neuroendocrine, solid pseudopapillary) with different clinical behavior. Especially in the setting of inoperable patients, fine needle aspiration cytology (FNAC), core needle biopsy (FNAB) and immunocyto/histochemistry (ICC/IHC) play a crucial role in the differential diagnosis. The biological material available for ICC tests obtained by minimal invasive procedures is usually limited. Aim of the current study was to evaluate diagnostic panel based on a limited number of ICC markers for typing preoperatively ACC of the pancreas. Of 1820 needle sampling procedures performed and related to pancreatic lesions, 21 cases were extracted with a confirmed diagnosis of ACC on histology. Of them,12 were pure ACC and 9 mixed acinar-neuroendocrine carcinoma (MANEC). Smears of ACC, MANEC and a control group composed of 34neuroendocrine, 7solid pseudopapillary, 50ductal and 4 adenosquamous carcinoma were assessed with an ICC panel made up of BCL10, trypsin, synaptophysin, chromograninA, β-catenin. On cytology, BCL10 sensitivity and specificity for ACC was 100%. Trypsin correctly recognized 90% of the cases. Synaptophysin was helpful to correctly identify all the cases with a mixed neuroendocrine component. No significant cross-reaction was observed between BCL10 and trypsin in any of the control group case. BCL10 is a determinant marker for the diagnosis of acinar cell carcinoma and mixed acinar neuroendocrine cell carcinoma of the pancreas in a pre-operative citologic/histologic setting. [ABSTRACT FROM AUTHOR]

We present a very interesting case of lung adenocarcinoma carrying an uncommon EGFR exon 19 insertion with concomitant PIK3CA mutation showing dramatic and persisting improvement upon erlotinib therapy, after progression during PI3K inhibitor. [ABSTRACT FROM AUTHOR]

Distinguishing between malignant mesothelioma and reactive mesothelial hyperplasia is often inestimable, but may be a challenging gauntlet for pathologists. A 62-year-old man underwent appendectomy after the identification of a peritoneal mass and the histological examination showed mesothelial proliferation along the appendix surface with no clear images of infiltration. After a few months the patient developed mediastinal and supraclavicular lymphadenopathies, and a nodal biopsy showed mesothelial cell proliferation invading lymphatic sinuses, consistent with the cells seen in the abdominal cavity. Since overt morphologic criteria for malignancy were lacking and reactive mesothelial cell deposits have been documented in lymph nodes, a molecular investigation of the CDKN2A (henceforth simply p16) gene status via fluorescence in situ hybridization was performed, which showed homozygous deletion in 100% tumor cells. These data ruled out the hypothesis of reactive mesothelial cells inclusion in lymph nodes, thus confirming the diagnosis of epithelioid malignant mesothelioma. [ABSTRACT FROM AUTHOR]

Background: Prostate cancer (PCa) is a leading cause of cancer-related death in males worldwide. Exacerbated inflammation and angiogenesis have been largely demonstrated to contribute to PCa progression. Diverse naturally occurring compounds and dietary supplements are endowed with anti-oxidant, anti-inflammatory and anti-angiogenic activities, representing valid compounds to target the aberrant cytokine/chemokine production governing PCa progression and angiogenesis, in a chemopreventive setting. Using mass spectrometry analysis on serum samples of prostate cancer patients, we have previously found higher levels of carnitines in non-cancer individuals, suggesting a protective role. Here we investigated the ability of Acetyl-L-carnitine (ALCAR) to interfere with key functional properties of prostate cancer progression and angiogenesis in vitro and in vivo and identified target molecules modulated by ALCAR. Methods: The chemopreventive/angiopreventive activities ALCAR were investigated in vitro on four different prostate cancer (PCa) cell lines (PC-3, DU-145, LNCaP, 22Rv1) and a benign prostatic hyperplasia (BPH) cell line. The effects of ALCAR on the induction of apoptosis and cell cycle arrest were investigated by flow cytometry (FC). Functional analysis of cell adhesion, migration and invasion (Boyden chambers) were performed. ALCAR modulation of surface antigen receptor (chemokines) and intracellular cytokine production was assessed by FC. The release of pro-angiogenic factors was detected by a multiplex immunoassay. The effects of ALCAR on PCa cell growth in vivo was investigated using tumour xenografts. Results: We found that ALCAR reduces cell proliferation, induces apoptosis, hinders the production of pro inflammatory cytokines (TNF-α and IFN-γ) and of chemokines CCL2, CXCL12 and receptor CXCR4 involved in the chemotactic axis and impairs the adhesion, migration and invasion capabilities of PCa and BPH cells in vitro. ALCAR exerts angiopreventive activities on PCa by reducing production/release of pro angiogenic factors (VEGF, CXCL8, CCL2, angiogenin) and metalloprotease MMP-9. Exposure of endothelial cells to conditioned media from PCa cells, pre-treated with ALCAR, inhibited the expression of CXCR4, CXCR1, CXCR2 and CCR2 compared to those from untreated cells. Oral administration (drinking water) of ALCAR to mice xenografted with two different PCa cell lines, resulted in reduced tumour cell growth in vivo. Conclusions: Our results highlight the capability of ALCAR to down-modulate growth, adhesion, migration and invasion of prostate cancer cells, by reducing the production of several crucial chemokines, cytokines and MMP9. ALCAR is a widely diffused dietary supplements and our findings provide a rational for studying ALCAR as a possible molecule for chemoprevention approaches in subjects at high risk to develop prostate cancer. We propose ALCAR as a new possible "repurposed agent' for cancer prevention and interception, similar to aspirin, metformin or beta-blockers. [ABSTRACT FROM AUTHOR]