Pulmonary invasive mucinous adenocarcinoma.

Invasive mucinous adenocarcinoma (IMA) is a relatively rare subtype of lung adenocarcinoma, composed of goblet and/or columnar tumour cells containing abundant intracytoplasmic mucin vacuoles. While a majority of IMAs are driven by KRAS mutations, recent studies have identified distinct genomic alterations, such as NRG1 and ERBB2 fusions. IMAs also more frequently present as a pneumonic-like pattern with multifocal and multilobar involvement, and comparative genomic profiling predominantly shows a clonal relationship, suggesting intrapulmonary metastases rather than synchronous primary tumours. Accordingly, these unique features require different therapeutic approaches when compared to nonmucinous adenocarcinomas in general. In this article, we review recent updates on the histopathological, clinical, and molecular features of IMAs, and also highlight some unresolved issues for future studies.

Evaluation indices of the temperature difference of subgrade and the optimization of mitigation measures in cold regions.

With the construction and operation of railways in cold regions, the asymmetric deformation of subgrades due to the difference in the transverse ground temperature has become a prominent issue. A comprehensive evaluation of the transverse ground temperature difference and investigation of the corresponding mitigation measures should be conducted to avoid or minimize the damage resulting from this difference, thereby improving subgrade stability and reducing deformation. In this study, the time history variations in the homogeneity and symmetry indices of the ground temperature at typical instances that reflect the spatial and temporal changes in the temperature difference of the subgrade were proposed as evaluation indices. The feasibility of these evaluation indices was verified through numerical models with different types of anti-frost berms. Subsequently, the numerical models were used to analyze the ground temperature evaluation indices of a subgrade with expanded polystyrene (EPS) insulation board and polyurethane (PU) insulation board at different locations. Additionally, the performances of each mitigation measure in eliminating or reducing the ground temperature difference were assessed and compared. The results show that all the mitigation measures could improve the homogeneity and symmetry of the ground temperature distribution. The maximum mitigation rates for the homogeneity and symmetry are 97.87% and 45.90%, respectively. This study provides a comprehensive evaluation method for the temperature difference of subgrades constructed in cold regions and a theoretical reference for the selection of anti-frost measures in the design, operation, and maintenance of subgrades in cold regions.

Correlation between BAP1 Localization, Driver Mutations, and Patient Survival in Uveal Melanoma.

Uveal melanoma (UM) is an uncommon but highly aggressive ocular malignancy. Poor overall survival is associated with deleterious BAP1 alterations, which frequently occur with monosomy 3 (LOH3) and a characteristic gene expression profile. Tumor DNA from a cohort of 100 UM patients from Moorfields Biobank (UK) that had undergone enucleation were sequenced for known UM driver genes (BAP1, SF3B1, EIF1AX, GNAQ, and GNA11). Immunohistochemical staining of BAP1 and interphase FISH for chromosomes 3 and 8 was performed, and cellular localization of BAP1 was correlated with BAP1 mutations. Wildtype (WT) BAP1 staining was characterized by nBAP1 expression with <10% cytoplasmic BAP1 (cBAP1). Tumors exhibited heterogeneity with respect to BAP1 staining with different percentages of nBAP1 loss: ≥25% loss of nuclear BAP1 (nBAP1) was superior to chr8q and LOH3 as a prognostic indicator. Of the successfully sequenced UMs, 38% harbored oncogenic mutations in GNA11 and 48% harbored mutations in GNAQ at residues 209 or 183. Of the secondary drivers, 39% of mutations were in BAP1, 11% were in EIF1AX, and 20% were in the SF3B1 R625 hotspot. Most tumors with SF3B1 or EIF1AX mutations retained nuclear BAP1 (nBAP1). The majority of tumor samples with likely pathogenic BAP1 mutations, regardless of mutation class, displayed ≥25% loss of nBAP1. This included all tumors with truncating mutations and 80% of tumors with missense mutations. In addition, 60% of tumors with truncating mutations and 82% of tumors with missense mutations expressed >10% cBAP1.

Integrated genomics point to immune vulnerabilities in pleural mesothelioma.

Pleural mesothelioma is an aggressive malignancy with limited effective therapies. In order to identify therapeutic targets, we integrated SNP genotyping, sequencing and transcriptomics from tumours and low-passage patient-derived cells. Previously unrecognised deletions of SUFU locus (10q24.32), observed in 21% of 118 tumours, resulted in disordered expression of transcripts from Hedgehog pathways and the T-cell synapse including VISTA. Co-deletion of Interferon Type I genes and CDKN2A was present in half of tumours and was a predictor of poor survival. We also found previously unrecognised deletions in RB1 in 26% of cases and show sub-micromolar responses to downstream PLK1, CHEK1 and Aurora Kinase inhibitors in primary mesothelioma cells. Defects in Hippo pathways that included RASSF7 amplification and NF2 or LATS1/2 mutations were present in 50% of tumours and were accompanied by micromolar responses to the YAP1 inhibitor Verteporfin. Our results suggest new therapeutic avenues in mesothelioma and indicate targets and biomarkers for immunotherapy.

Comparison of Nuclear Grade, Necrosis, and Histologic Subtype Between Biopsy and Resection in Pleural Malignant Mesothelioma: An International Multi-Institutional Analysis.

OBJECTIVES: Numerous studies on malignant mesothelioma (MM) highlight the prognostic importance of histologic subtype, nuclear grade, and necrosis. This study compares these parameters in paired biopsy and resection specimens of pleural MM. METHODS: Histologic subtype, percentage of epithelioid morphology, nuclear grade, and the presence or absence of necrosis were compared in 429 paired biopsies and resection specimens of pleural MM from 19 institutions. RESULTS: Histologic subtype was concordant in 81% of cases (κ = 0.58). When compared with resection specimens, epithelioid morphology at biopsy had a positive predictive value (PPV) of 78.9% and a negative predictive value (NPV) of 93.5%; sarcomatoid morphology showed high PPV (92.9%) and NPV (99.3%), and biphasic morphology PPV was 89.7% and NPV was 79.7%. Agreement of the percentage of epithelioid morphology was fair (κ = 0.27). Nuclear grade and necrosis were concordant in 75% (κ = 0.59) and 81% (κ = 0.53) of cases, respectively. Nuclear grade showed moderate (κ = 0.53) and substantial (κ = 0.67) agreement from patients with and without neoadjuvant therapy, respectively, and necrosis showed moderate (κ = 0.47 and κ = 0.60) agreement, respectively, in the same subsets of paired specimens. CONCLUSIONS: Paired biopsy-resection specimens from pleural MM show overall moderate agreement in pathologic parameters. These findings may help guide postbiopsy management and triage of patients with MM.

The concept of mesothelioma in situ, with consideration of its potential impact on cytology diagnosis.

Diffuse malignant mesothelioma (MM) is an incurable tumour of the serosal membranes, which is often caused by exposure to asbestos and commonly diagnosed at advanced stage. Malignant mesothelioma in situ (MMIS) is now included as diagnostic category by the World Health Organization (WHO). However, our international survey of 34 pulmonary pathologists with an interest in MM diagnosis highlights inconsistency regarding how the diagnosis is being made by experts, despite published guidelines. Whilst the WHO restricts the diagnosis to surgical samples, the very concept has implication for cytological diagnosis, which is already regarded as controversial in itself by some. MMIS is currently only applicable as precursor to MM with an epithelioid component, and raises the possibility for different molecular pathways for different histological MM subtypes. The clinical implications of MMIS at this stage are uncertain, but aggressive therapies are being initiated in some instances. Based on the results of the survey we here present a critical appraisal of the concept, its clinical and conceptual implications and provide practice suggestions for diagnosis. A low threshold for ancillary testing is suggested. The designations of 'malignant mesothelioma, cannot exclude MMIS' or 'atypical mesothelial proliferation with molecular indicators of malignancy, so-called MMIS' could be used on cytology samples, adding 'no evidence of invasion in sample provided' for surgical samples. Clinical and radiological correlation are integral to diagnosis and best done at multidisciplinary meetings. Finally, collaborative studies are required to improve our understanding of MMIS.

Adenoid cystic carcinoma and chronic lymphocytic leukaemia: synchronous presentations in the lung.

A 59-year-old male active smoker presented with a 6-month history of cough and breathlessness and was found to have a right upper lobe mass. Histology revealed this to be an adenoid cystic carcinoma (ACC) of the lung, while local lymph node dissection revealed a synchronous diagnosis of chronic lymphocytic leukaemia (CLL). The connection between CLL and solid organ malignancy is well documented, but the reporting of ACC in this context is novel. Mechanisms linking the two processes are revealed with the possibility of causality, and heightened vigilance for the development of primary lung tumours in CLL, and their management, is recommended.

Mucinous adenocarcinoma arising in congenital pulmonary airway malformation: clinicopathological analysis of 37 cases.

AIMS: Mucinous adenocarcinoma arising in congenital pulmonary airway malformation (CPAM) is a rare complication, with little being known about its natural course. The aims of this article are to describe a series of mucinous adenocarcinomas arising from CPAMs, and present their clinicopathological features, genetics, and clinical outcome. METHODS AND RESULTS: Thirty-seven cases were collected within a 34-year period, and the subtype of adenocarcinoma and CPAM, tumour location, stage, growth patterns, molecular data and follow-up were recorded. The cohort comprised CPAM type 1 (n = 33) and CPAM type 2 (n = 4). Morphologically, 34 cases were mucinous adenocarcinomas (21 in situ; 13 invasive), and three were mixed mucinous and non-mucinous adenocarcinoma. Seventeen cases showed purely extracystic (intra-alveolar) adenocarcinoma, 15 were mixed intracystic and extracystic, and five showed purely intracystic proliferation. Genetically, nine of 10 cases tested positive for KRAS mutations, four with exon 2 G12V mutation and five with exon 2 G12D mutation. Residual disease on completion lobectomy was observed in two cases, and three cases recurred 7, 15 and 32 years after the original diagnosis. Two patients died of metastatic invasive mucinous adenocarcinoma. CONCLUSIONS: Most adenocarcinoma that arise in type 1 CPAMs, are purely mucinous, and are early-stage disease. Intracystic proliferation is associated with lepidic growth, an absence of invasion, and indolent behaviour, whereas extracystic proliferation may be associated with more aggressive behaviour and advanced stage. Most cases are cured by lobectomy, and recurrence/residual disease seems to be associated with limited surgery. Long-term follow-up is needed, as recurrence can occur decades later.

Prognostic Impact of Histopathologic Features in Pulmonary Invasive Mucinous Adenocarcinomas.

OBJECTIVES: The prognostic significance of pathologic features and invasive size has not been well studied for invasive mucinous adenocarcinoma (IMA). This study evaluates the significance of pathologic features and invasive size in relation to clinical outcome. METHODS: We reviewed the pathologic features in 84 IMAs, including histologic pattern, nuclear atypia, mitosis, necrosis, and lymphovascular invasion. The invasive size was calculated from the total size using the percentage of invasive components. Cases were subdivided into two pathologic grades based on five pathologic features, and the pathologic grade and adjusted T (aT) stage were correlated with disease-free and overall survival (OS). RESULTS: Necrosis and N stage were significantly associated with aT stage, and a significant association was noted between OS and aT stage. Nuclear atypia, mitosis, and lymphovascular and pleural invasion also showed a significant association with OS. High-grade tumors showing a significantly worse OS compared with low-grade tumors, as well as pathologic grade (hazard ratio [HR], 2.337; P = .043) and aT stage (HR, 1.875; P = .003), were independent prognostic factors in multivariate analysis. CONCLUSIONS: The pathologic grading system stratified IMAs into high- and low-grade tumors with significant differences in OS. Invasive size may provide a better prognostic stratification for OS.

The important role of the histopathologist in clinical trials: challenges and approaches to tackle them.

High-quality histopathology is essential for the success of clinical trials. Histopathologists have a detailed understanding of tumour biology and mechanisms of disease, as well as practical knowledge of optimal tissue handling and logistical service requirements for study delivery, such as biomarker evaluation, tissue acquisition and turnaround times. As such, histopathologist input is essential throughout every stage of research and clinical trials, from concept development and study design to trial delivery, analysis and dissemination of results. Patient recruitment to trials takes place among all healthcare settings, meaning that histopathologists make an invaluable contribution to clinical trials as part of their routine day-to-day work that often goes unrecognised. More complex evaluation of surgical specimens in the neoadjuvant setting and ever-expanding minimum data sets add to the workload of every histopathologist, not just academic pathologists in tertiary centres. This is occurring against a backdrop of increasing workload pressures and a worldwide shortage of histopathologists and biomedical scientists. Providing essential histopathology support for trials at grassroots level requires funding for adequate resources including histopathologist time, education and training, biomedical scientist and administrative support and greater recognition of the contribution made by histopathology. This paper will discuss the many ways in which histopathologists are involved in clinical trials and the challenges faced in meeting the additional demands posed by trial participation and potential ways to address this, with a special emphasis on the UK model and the Cellular-Molecular Pathology Initiative (CM-Path).

Utility of Nuclear Grading System in Epithelioid Malignant Pleural Mesothelioma in Biopsy-heavy Setting: An External Validation Study of 563 Cases.

Nuclear grading systems for epithelioid malignant pleural mesothelioma (MPM) have been proposed but it remains uncertain if they could be applied in a biopsy-heavy setting. Using the proposed system, we conducted an independent, external validation study using 563 consecutive cases of epithelioid MPM diagnosed at our institution between 2003 and 2017, of which 87% of patients underwent biopsies only. The median number of sites sampled was 1, with a median maximum tissue dimension of 17 mm (biopsy) and 150 mm (resection). The median overall survival (OS) was 14.7 months. The frequencies of grade I, II, and III tumors were 31% (132/563), 52% (292/563), and 17% (94/563). Grade I tumors were associated with the most favorable median OS (24.7 mo) followed by grades II (12.7 mo) and III (7.2 mo). The 2-tier nuclear grade separated tumors into low grade (19.3 mo) and high grade (8.9 mo). In multivariate analysis, 3-tier nuclear grade, 2-tier nuclear grade, and mitosis-necrosis score predicted OS independent of age, procedural type, solid-predominant growth pattern, necrosis, and atypical mitosis (all P<0.001 except 2-tier nuclear grade, P=0.001). In the scenario of a single- site biopsy with tissue dimension ≤10 mm, none but age (P=0.002) were independently predictive. Our data also suggested sampling 3 sites or a maximum tissue dimension of at least 20 mm from a single site is optimal for nuclear grade assessment. In conclusion our study confirmed the utility of nuclear grade in epithelioid MPM using a biopsy-heavy cohort provided the tissue sample met minimum dimensional criteria.

Localized malignant mesothelioma, an unusual and poorly characterized neoplasm of serosal origin: best current evidence from the literature and the International Mesothelioma Panel.

Localized malignant mesotheliomas (LMM) is an uncommon and poorly recognized neoplasm. Its pathologic diagnosis is often surprising in patients with serosal/subserosal based localized tumors that are clinically suspicious for metastatic lesions or primary sarcomas. Once a tumor is diagnosed as "mesothelioma", LMM is often mistaken for diffuse malignant mesothelioma (DMM). Best currently available evidence about LMM was collected from the literature and cases diagnosed by members of the International Mesothelioma Panel (IMP). One hundred and one (101) LMM have been reported in the English literature. Patients had localized tumors with identical histopathologic features to DMM. Patients ranged in age from 6 to 82 years; 75% were men. Most (82%) of the tumors were intrathoracic. Others presented as intrahepatic, mesenteric, gastric, pancreatic, umbilical, splenic, and abdominal wall lesions. Tumors varied in size from 0.6 to 15 cm. Most patients underwent surgical resection and/or chemotherapy or radiation therapy. Median survival in a subset of patients was 29 months. Seventy two additional LMM from IMP institutions ranged in age from 28 to 95 years; 58.3% were men. Sixty tumors (83.3%) were intrathoracic, others presented in intraabdominal sites. Tumors varied in size from 1.2 to 19 cm. Median survival for 51 cases was 134 months. Best evidence was used to formulate guidelines for the diagnosis of LMM. It is important to distinguish LMM from DMM as their treatment and prognosis is different. A multidisciplinary approach is needed for the diagnosis of LMM as it shows identical histopathology and immunophenotype to DMM.

Validation and comparison of three newly-released Thyroid Imaging Reporting and Data Systems for cancer risk determination.

PURPOSE: To validate and compare diagnostic value of three newly-released Thyroid Imaging Reporting and Data Systems (TIRADS) for cancer risk determination. METHODS: Total 2031 patients with 2465 thyroid nodules were recruited for this study. Ultrasound (US) images were categorized based on three TIRADS editions established by Korean Society of Thyroid Radiology (KSThR), European Thyroid Association (ETA) and American College of Radiology (ACR). ROC curves were established to compare diagnostic value. RESULTS: Total 1460 benign and 1005 malignant nodules were enrolled. The malignancy rates of each category in KSThR-TIRADS were 2.8%, 5.1%, 33.7% and 79.6%, respectively. For European-TIRADS, 0, 3.1, 22.8, and 73.5% of nodules categorized as 2 to 5 were malignant. Distribution of carcinomas among ACR-TIRADS categories was 0%, 2.3%, 7.5%, 40.1% and 81.4%, respectively. In terms of diagnostic value, KSThR-TIRADS had highest AUC (0.855) and specificity (87.4%), while lowest (71.4%) sensitivity. ACR-TIRADS showed best sensitivity (96.6%) with lowest specificity (52.9%) and the AUC (0.846) was slightly lower than KSThR-TIRADS. Total 56.1, 45.4, and 37.4% fine-needle aspiration biopsy (FNAB) were recommended by KSThR, ETA and ACR, revealing 42.8%, 44.5% and 53.6% malignant lesions, respectively. The rate of unnecessary FNAB was lowest with the ACR (17.3%), followed by ETA (25.2%) and KSThR (32.1%). CONCLUSION: All these US models showed great value in predicting thyroid malignancy. Among them, KSThR-TIRADS showed the most effective diagnostic performance in specificity, while ACR-TIRADS yielded best sensitivity. As for FNAB criteria, ACR-TIRADS showed the lowest rate of unnecessary FNAB and highest rate of malignancy in FNAB.

VO2 Thermochromic Films on Quartz Glass Substrate Grown by RF-Plasma-Assisted Oxide Molecular Beam Epitaxy.

Vanadium dioxide (VO2) thermochromic thin films with various thicknesses were grown on quartz glass substrates by radio frequency (RF)-plasma assisted oxide molecular beam epitaxy (O-MBE). The crystal structure, morphology and chemical stoichiometry were investigated systemically by X-ray diffraction (XRD), atomic force microscopy (AFM), Raman spectroscopy and X-ray photoelectron spectroscopy (XPS) analyses. An excellent reversible metal-to-insulator transition (MIT) characteristics accompanied by an abrupt change in both electrical resistivity and optical infrared (IR) transmittance was observed from the optimized sample. Remarkably, the transition temperature (TMIT) deduced from the resistivity-temperature curve was reasonably consistent with that obtained from the temperature-dependent IR transmittance. Based on Raman measurement and XPS analyses, the observations were interpreted in terms of residual stresses and chemical stoichiometry. This achievement will be of great benefit for practical application of VO2-based smart windows.

Application of high-resolution ultrasound, real-time elastography, and contrast-enhanced ultrasound in differentiating solid thyroid nodules.

High-resolution ultrasound (HRUS) is a sensitive tool for identifying thyroid nodules. Real-time elastography (RTE) and contrast-enhanced ultrasound (CEUS) are newly developed methods which could measure tissue elasticity and perfusion features. The aim of the present study was to evaluate and compare the diagnostic efficiency of HRUS, RTE, CEUS and their combined use in the differentiation of benign and malignant solid thyroid nodules.In total, 111 consecutive patients with 145 thyroid nodules who were scheduled for surgery were included in the study. All of them underwent HRUS, RTE, and CEUS examination. The independent ultrasound (US) predictors for malignancy were determined and quantified using logistic regression analysis, based on which a risk-scoring model was established for each method. The diagnostic efficiency of each method was assessed by receiver operating characteristic (ROC) curve analysis.HRUS showed the best diagnostic efficiency among the 3 US methods, with 74.6% sensitivity and 87.8% specificity. CEUS had higher sensitivity (85.7%), whereas RTE alone did not show much advantage. Combined use of RTE and HRUS increased the sensitivity (92.1%). The HRUS-RTE-CEUS combination could increase both the sensitivity and specificity (87.3%, 91.5%), with the best AUC (0.935) among all the methods.The overall diagnostic value of HRUS in predicting malignancy is the best among the 3 US methods. Combined use of RTE and CEUS and HRUS could improve the diagnostic efficiency for solid thyroid nodules.

Value of TIRADS, BSRTC and FNA-BRAF V600E mutation analysis in differentiating high-risk thyroid nodules.

The thyroid imaging reporting and data system (TIRADS) and Bethesda system for reporting thyroid cytopathology (BSRTC) have been used for interpretation of ultrasound and fine-needle aspiration cytology (FNAC) results of thyroid nodules. BRAF(V600E) mutation analysis is a molecular tool in diagnosing thyroid carcinoma. Our objective was to compare the diagnostic value of these methods in differentiating high-risk thyroid nodules. Total 220 patients with high-risk thyroid nodules were recruited in this prospective study. They all underwent ultrasound, FNAC and BRAF(V600E) mutation analysis. The sensitivity and specificity of TIRADS were 73.1% and 88.4%. BSRTC had higher specificity (97.7%) and similar sensitivity (77.6%) compared with TIRADS. The sensitivity and specificity of BRAF(V600E) mutation (85.1%, 100%) were the highest. The combination of BSRTC and BRAF(V600E) mutation analysis significantly increased the efficiency, with 97.8% sensitivity, 97.7% specificity. In patients with BSRTC I-III, the mutation rate of BRAF(V600E) was 64.5% in nodules with TIRADS 4B compared with 8.4% in nodules with TIRADS 3 or 4A (P < 0.001). Our study indicated that combination of BSRTC and BRAF(V600E) mutation analysis bears a great value in differentiating high-risk thyroid nodules. The TIRADS is useful in selecting high-risk patients for FNAB and patients with BSRTC I-III for BRAF(V600E) mutation analysis.

Antibiotic stewardship programmes in intensive care units: Why, how, and where are they leading us.

Antibiotic usage and increasing antimicrobial resistance (AMR) mount significant challenges to patient safety and management of the critically ill on intensive care units (ICU). Antibiotic stewardship programmes (ASPs) aim to optimise appropriate antibiotic treatment whilst minimising antibiotic resistance. Different models of ASP in intensive care setting, include "standard" control of antibiotic prescribing such as "de-escalation strategies"through to interventional approaches utilising biomarker-guided antibiotic prescribing. A systematic review of outcomes related studies for ASPs in an ICU setting was conducted. Forty three studies were identified from MEDLINE between 1996 and 2014. Of 34 non-protocolised studies, [1 randomised control trial (RCT), 22 observational and 11 case series], 29 (85%) were positive with respect to one or more outcome: These were the key outcome of reduced antibiotic use, or ICU length of stay, antibiotic resistance, or prescribing cost burden. Limitations of non-standard antibiotic initiation triggers, patient and antibiotic selection bias or baseline demographic variance were identified. All 9 protocolised studies were RCTs, of which 8 were procalcitonin (PCT) guided antibiotic stop/start interventions. Five studies addressed antibiotic escalation, 3 de-escalation and 1 addressed both. Six studies reported positive outcomes for reduced antibiotic use, ICU length of stay or antibiotic resistance. PCT based ASPs are effective as antibiotic-stop (de-escalation) triggers, but not as an escalation trigger alone. PCT has also been effective in reducing antibiotic usage without worsening morbidity or mortality in ventilator associated pulmonary infection. No study has demonstrated survival benefit of ASP. Ongoing challenges to infectious disease management, reported by the World Health Organisation global report 2014, are high AMR to newer antibiotics, and regional knowledge gaps in AMR surveillance. Improved AMR surveillance data, identifying core aspects of successful ASPs that are transferable, and further well-conducted trials will be necessary if ASPs are to be an effective platform for delivering desired patient outcomes and safety through best antibiotic policy.