Search

OBJECTIVE: In this study, we aimed to assess the reproducibility and reliability of a three-dimensional laser scanner (3DLS) in measuring the upper limb volume of BRCL women undergoing a 2-week complete decongestive therapy (CDT). PATIENTS AND METHODS: 3DLS and CM were used to measure the upper limb volume in a cohort of BCRL women before (T0) and after (T1) a 2-week CDT. We evaluated: a) correlation between 3DLS and CM at both time points; b) level of agreement and the consistency of the different measurements at both time points; c) correlation between the inter-rater operator analysis in terms of total limb volume differences before and after rehabilitative treatment of both circumferential method and laser scanning 3D in breast cancer related lymphedema patients. RESULTS: Taken together, 43 BCRL women (age 51.1 ± 5.4 years) were included. Both 3DLS and CM showed a significant inter and intra-operator correlation in the arm volume measurement at both time-points (T0: r2=0.99, p

Recently, it has been hypothesized that the oral administration of specific live probiotic strains may have therapeutic potential in the treatment of allergic inflammation. The aim of this study was to evaluate the effect of the oral L. reuteri DSM 17938 administration (1X108CFU), in airways allergic inflammation in mild persistent asthmatic children. In this DBPC randomized study we selected 50 children (6-14 years old), affected by mild persistent asthma (GINA step 2) and allergic to HDM. At the run-in period (T-2), the children were submitted to medical examination, prick tests for the main respiratory allergens, spirometry and children asthma control test (C-ACT). We selected only the children with well controlled asthma (C-ACT19 and FEV180%). After two weeks (T0) the children were allocated into two groups, the FeNO was measured and the breath condensate was collected. Group A children were treated with the placebo (5 drops per day) and Group B children with L. reuteri (108CFU =5 drops per day) for 60 days. After the treatment period (T1), all patients were evaluated by medical examination, C-ACT, spirometry, FeNO measurement and exaled breath condensate analysis. The FeNO values showed a significant reduction (p=0,045) in L. reuteri group but not in the placebo group at the end of the treatment (T1). Furthermore, the cytokines exam showed an increase in IL-10 levels (p less than 0.05) and a significant reduction in IL-2 levels (p less than 0.05) only in L. reuteri group at T1. No significant differences in FEV1 values and C-ACT score were found in both groups. In conclusion, these data showed that L. reuteri (108 CFU) was effective in reducing bronchial inflammation in asthmatic children. No significant effect was found on FEV1 values and C-ACT score, probably because we selected children with well controlled asthma.

Gastroesophageal adenocarcinoma (GEA) is a global health issue with a high fatality-to-case ratio and a 5-year overall survival that has only slightly improved. High-throughput molecular profiling has uncovered a profound complexity and heterogeneity in GEA biology, which limits considerably the treatment advances. Liquid biopsy with circulating tumor (ct)DNA analysis could elucidate GEA molecular heterogeneity and provide diagnostic, prognostic and predictive information to guide clinical decision-making. However, only a handful of studies have shown positive results for the application of ctDNA analysis in GEA clinical management. As a result, no comprehensive information is available to date on this continuously evolving topic. Here, we discuss the current state of knowledge, along with promises and challenges related to ctDNA analysis in GEA.

AimsVery recent papers proposed a possible role for the expression of terminal deoxynucleotidyl transferase (TdT) in the tumourigenesis of gonadal and extragonadal germ cell-derived tumours (GCTs). Our multicentric study evaluated the magnitude of the immunoreactivity for TdT in GCTs, encompassing seminoma, dysgerminoma, mature teratoma and mixed GCTs.Methods and resultsThe histological series was stained with both monoclonal and polyclonal antibodies, yielding a positivity of 80% of cases with well-defined nuclear reactivity. A significant difference in staining intensity between monoclonal and polyclonal antibodies was observed (p=0.005). However, exploiting western blot and more innovative proteomic approaches, no clear-cut evidence of the TdT protein was observed in the neoplastic tissues of the series.ConclusionsAlternatively to the pathogenetic link between TdT expression and GCTs tumourigenesis, we hypothesised the occurrence of a spurious immunohistochemical nuclear cross-reaction, a well-known phenomenon with important implications and a possible source of diagnostic pitfalls in routine practice for pathologists.

Immunotherapy has become the standard-of-care in many solid tumors. Despite the significant recent achievements in the diagnosis and treatment of cancer, several issues related to patients’ selection for immunotherapy remain unsolved. Multiple lines of evidence suggest that, in this setting, the vision of a single biomarker is somewhat naïve and imprecise, given that immunotherapy does not follow the rules that we have experienced in the past for targeted therapies. On the other hand, additional immune-related biomarkers that are reliable in real-life clinical practice remain to be identified. Recently, the immune-checkpoint blockade has been approved in the US irrespective of the tumor site of origin. Further histology-agnostic approvals, coupled with with tumor-specific companion diagnostics and guidelines, are expected in this field. In addition, immune-related biomarkers can also have a significant prognostic value. In this review, we provide an overview of the role of these biomarkers and their characterization in the management of lung cancer, melanoma, colorectal cancer, gastric cancer, head and neck cancer, renal cell carcinoma, urothelial cancers, and breast cancer.

An important harmonization effort was produced by the scientific community to standardize both the preanalytical and interpretative phases of programmed death-ligand 1 (PD-L1) immunohistochemical (IHC) testing in non-small-cell lung cancer (NSCLC). This analysis is crucial for the selection of patients with advanced-stage tumors eligible for treatment with pembrolizumab and potentially with other anti-PD-1/PD-L1 checkpoint inhibitors. This multicentric retrospective study evaluated the reproducibility of PD-L1 testing in the Italian scenario both for closed and open platforms. In the evaluation of the well-known gold-standard combinations (Agilent 22C3 PharmDx on Dako Autostainer versus Roche’s Ventana SP263 on BenchMark), the results confirmed the literature data and showed complete overlapping between the two methods. With regard to the performances by using open platforms, the combination of 22C3 with Dako Omnis or Benchmark obtained good results basically, while the 28,8 clone seemed to be associated with worse scores.

Among the different ancillary immunohistochemical tools that pathologists may employ in thyroid nodules, the so-called Hector Battifora’s ‘MEsothelioma’ 1 (HBME-1) staining is one of the most fascinating, since its real identity is currently unknown. In the present review, the different clinical applications of HBME-1 are analysed, with main emphasis on its role in thyroid pathology with overview on less impactful fields, such as haematopathology or mesothelial lesions. Different acceptable or good diagnostic performances were recorded for HBME-1 in thyroid pathology, being used in routine practice as one of the best tools to screen thyroid malignancy both in terms of sensitivity and specificity. From a speculative point of view, after many attempts to hunt the cryptic target antigen of this antibody, its identity still remains elusive. In this setting, the application of high-throughput technologies (mainly in situ proteomics) may be the exact route to improve the knowledge about the pathophysiology of HBME-1 and to finally unveil its true identity.

Anatomic pathology has changed dramatically in recent years. Although the microscopic assessment of tissues and cells is and will remain the mainstay of cancer diagnosis molecular profiling has become equally relevant. Thus, to stay abreast of the evolving landscape of today's anatomic pathology, modern pathologists must be able to master the intricate world of predictive molecular pathology. To this aim, pathologists have had to acquire additional knowledge to bridge the gap between clinicians and molecular biologists. This new role is particularly important, as cases are now collegially discussed in molecular tumor boards (MTBs). Moreover, as opposed to traditional pathologists, modern pathologists have also adamantly embraced innovation while keeping a constant eye on tradition. In this article, we depict the highlights and shadows of the upcoming “Anatomic Pathology 2.0” by placing particular emphasis on the pathologist's growing role in the management of cancer patients.

Immune Checkpoint Inhibitors (ICIs) have remarkably modified the way solid tumors are managed, including breast cancer. Unfortunately, only a relatively small number of breast cancer patients significantly respond to these treatments. To maximize the immunotherapy benefit in breast cancer, several efforts are currently being put forward for the identification of i) the best therapeutic strategy (i.e. ICI monotherapy or in association with chemotherapy, radiotherapy, or other drugs); ii) optimal timing for administration (e.g. early/advanced stage of disease; adjuvant/ neoadjuvant setting); iii) most effective and reliable predictive biomarkers of response (e.g. tumor-infiltrating lymphocytes, programmed death-ligand 1, microsatellite instability associated with mismatch repair deficiency, and tumor mutational burden). In this article, we review the impacts and gaps in the characterization of immune-related biomarkers raised by clinical and translational research studies with immunotherapy treatments. Particular emphasis has been put on the documented evidence of significant clinical benefits of ICI in different randomized clinical trials, along with preanalytical and analytical issues in predictive biomarkers pathological assessment.

Purpose: Neuroendocrine tumors of the lung (LNETs) encompass a heterogeneous group of lesions, including tumors with no or low metastatic potential, such as typical (TCs) and atypical (ACs) carcinoids, and highly aggressive neuroendocrine carcinomas. To date, only a few biomarkers with prognostic impact have been identified in LNETs. Previous experimental studies have suggested that the cytokine CXCL12 might have a role in stratifying the outcome of lung cancer as well as LNET patients. However, the reliability of immunohistochemical (IHC) tissue expression of CXCL12 in evaluating the prognosis of resected LNETs is currently not known. Methods: Here, we subjected a cohort of 112 resected LNETs specifically enriched for ACs to IHC for CXCL12 and Ki67 using routine procedures. The clinical value of CXCL12 was assessed by applying the Cox proportional-hazards model to overall and disease-free survival rates. Results: We found that CXCL12 was expressed in 8.3 to 38% of LNETs, depending on the different diagnostic categories. Upon survival analysis, when considering the whole cohort, we found that CXCL12-positive cases exhibited shorter disease-free survival rates compared to CXCL12-negative cases. Among ACs, tumors overexpressing CXCL12 showed significantly shorter disease-free survival rates. Finally, we found that the Ki67 index in ACs was higher in the CXCL12-positive cases. Conclusion: CXCL12 immunohistochemistry may serve as a potentially useful tool to better stratify LNETs, and more specifically ACs, in clinical practice.

Background: The need to integrate the classification of cancer with information on the genetic pattern has emerged in recent years for several tumors. Methods: The genomic background of a large series of 208 papillary thyroid cancers (PTC) followed at a single center was analyzed by a custom MassARRAY genotyping platform, which allows the simultaneous detection of 19 common genetic alterations, including point mutations and fusions. Results: Of the PTCs investigated, 71% were found to have pathognomonic genetic findings, with BRAF V600E and TERT promoter mutations being the most frequent monoallelic alterations (42% and 23.5%, respectively), followed by RET/PTC fusions. In 19.2% of cases, two or more point mutations were found, and the co-occurrence of a fusion with one or more point mutation(s) was also observed. Coexisting BRAF V600E and TERT promoter mutations were detected in a subgroup of aggressive PTCs (12%). A correlation between several aggressive features and mutation density was found, regardless of the type of association (i.e., only point mutations, or point mutations and fusions). Importantly, Kaplan-Meier curves demonstrated that mutation density significantly correlated with a higher risk of persistent disease. In most cases, the evaluation of the allelic frequencies normalized for the cancer cell content indicated the presence of the monoallelic mutation in virtually all tumor cells. A minority of cases was found to harbor low allelic frequencies, consistent with the presence of the mutations in a small subset of cancer cells, thus indicating tumor heterogeneity. Consistently, the presence of coexisting genetic alterations with different allelic frequencies in some tumors suggests that PTC can be formed by clones/subclones with different mutational profiles. Conclusions: A large mono-institutional series of PTCs was fully genotyped by means of a cost- and time-effective customized panel, revealing a strong impact of mutation density and genetic heterogeneity on the clinical features and on disease outcomes, indicating that an accurate risk stratification of thyroid cancer cannot rely on the analysis of a single genetic event. Finally, the heterogeneity found in some tumors warrants attention, since the occurrence of this phenomenon is likely to affect response to targeted therapies.

INTRODUCTION: A pathologic grading system (PGS) for malignant pleural mesothelioma (MPM) is warranted to better identify different risk categories of patients, plan therapeutic options, and activate clinical trials. METHODS: A series of 940 patients with MPM (328 in a training set and 612 in a validation set) that was diagnosed between October 1980 and June 2015 at the participant institutions was retrospectively assembled. A PGS was constructed by attributing to each histologic parameter, independent at multivariate analysis with excellent reproducibility (κ > 0.75), different scores based on the increase in corresponding hazard ratios. The relevant PGS score thus ranged from 0 to 8 points for individual patients with MPM. CONCLUSIONS: The PGS was constructed by taking into consideration the histological subtyping of MPM (epithelioid/biphasic = 0 points; sarcomatoid = 2 points), necrosis (absent = 0 points versus present = 1 point), mitotic count per 1 mm2 (cutoffs as follows: 1-2 = 0 points, 3-5 = 1 point, 6-9 = 2 points, or ≥10 = 4 points), and Ki-67 labeling index based on 2000 cells (

The main aim of the study was to assess the feasibility of matrix-assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI) in the pathological investigation of Medullary Thyroid Carcinoma (MTC). Formalin-fixed paraffin-embedded (FFPE) samples from seven MTC patients were analysed by MALDI-MSI in order to detect proteomic alterations within tumour lesions and to define the molecular profiles of specific findings, such as amyloid deposition and C cell hyperplasia (CCH). nLC-ESI MS/MS was employed for the identification of amyloid components and to select alternative proteomic markers of MTC pathogenesis. Results highlighted the potential of MALDI-MSI to confirm the classic immunohistochemical methods employed for the diagnosis of MTC, with good sensitivity and specificity. Intratumoural amyloid components were also detected and identified, and were characterised by calcitonin, apolipoprotein E, apolipoprotein IV, and vitronectin. The tryptic peptide profiles representative of MTC and CCH were distinctly different, with four alternative markers for MTC being detected; K1C18, and three histones (H2A, H3C, and H4). Finally, a further 115 proteins were identified through the nLC-ESI-MS/MS analysis alone, with moesin, veriscan, and lumican being selected due to their potential involvement in MTC pathogenesis. This approach represents a complimentary strategy that could be employed to detect new proteomic markers of MTC. Statement of significance: Medullary thyroid carcinoma (MTC) is a rare endocrine malignancy that originates from the parafollicular C-cells of the thyroid. The diagnosis is typically established using a combination of fine-needle aspiration biopsy (FNAB) of a suspicious nodule along with the demonstrable elevation of serum biomarkers, such as calcitonin and carcinoembryonic antigen (CEA). Unfortunately, this combination is often associated with a high degree of false-positive results and this can lead to misdiagnosis and avoidable total thyroidectomy. The current study presents the potential role of MALDI-MSI in the search for new proteomic markers of MTC with diagnostic and prognostic significance. MALDI-MSI was capable of detecting the classic immunohistochemical markers employed for the diagnosis of MTC, with good sensitivity and specificity. Furthermore, the complementary combination of MALDI-MSI and nLC-ESI-MS/MS analysis, using a single tissue section, enabled further potential markers to be identified and their spatial localisation visualised within tumoural regions. Such findings could be a valuable starting point for further studies focused on confirming the data presented here using thyroid FNABs, with the final objective being to provide complimentary assistance for the detection of MTC during the pre-operative phase.

Aims: Pulmonary adenofibromas are rare benign fibroepithelial tumours of the lung with unknown histogenesis and an indolent clinical behaviour. Their stroma resembles that of solitary fibrous tumours, whereas the glands are composed of respiratory epithelium organized in a phyllodes-like architecture. Differentiation of pulmonary adenofibromas from other more aggressive intrathoracic tumours is clinically relevant. However, their biology is unknown. Here, we sought to characterize pulmonary adenofibromas at a clinicopathological level and to define whether they could be underpinned by a highly recurrent somatic genetic alteration akin to tumours with similar morphology. Methods and results: Seven pulmonary adenofibromas were subjected to immunohistochemical analysis for thyroid transcription factor 1 (TTF1), napsin A, cytokeratin 7, E-cadherin, CD99, CD34, CD31, STAT6, oestrogen receptor (ER), progesterone receptor, androgen receptor, bcl-2, and vimentin, as well as electron microscopy and capillary sequencing on microdissected samples to evaluate the presence of NAB2–STAT6 fusion genes and MED12 exon 2 mutations in their discrete components. A control group comprising pulmonary solitary fibrous tumours, pulmonary hamartomas and breast fibroadenomas was also analysed. We confirmed that the stromal elements of pulmonary adenofibromas pertain to the fibroblastic lineage, and show ER overexpression in 71% of cases, whereas the epithelium consists of TTF1-positive, E-cadherin positive bronchiolar elements. A highly recurrent NAB2–STAT6 fusion variant (exon 4–exon 2) was detected in the stroma but not in the epithelium. No MED12 mutations were identified. Conclusions: Here, we demonstrate that pulmonary adenofibromas are neoplastic lesions harbouring the molecular hallmark of solitary fibrous tumours