Solid-pseudopapillary tumor (SPT) of the pancreas is characterized by a discohesive appearance of the neoplastic cells. This has been linked to the displacement of E-cadherin and beta-catenin from ...their normal membrane location, which prevents adherens junctions to form. The nuclear localization of beta-catenin is also a feature of SPT that helps in differential diagnosis. This latter includes pancreatic endocrine tumor (PET) as SPT may show neuroendocrine differentiation, and pancreatic acinar cell carcinoma (ACC) and pancreatoblastoma (PB) that may often show nuclear beta-catenin staining. However, the role of additional cell-cell adhesion systems remains to be elucidated in SPT, particularly that of claudins that are essential components of tight junctions showing modulated expression in diverse tumor types. We studied 20 SPT, 20 nonfunctioning PET, 7 ACC, 2 PB, and their matched normal pancreas for the immunohistochemical expression of claudin family members 1, 2, 3, 4, 5, and 7, beta-catenin and E-cadherin. All SPT showed intense membrane claudin 5 and cytoplasmic claudin 2 staining, lack of claudins 3 and 4, and positive cytoplasmic claudins 1 and 7 in few cases. Conversely, PET, ACC, and PB showed strong membrane expression of claudin 7 and lack of claudin 5, whereas claudins 1, 2, 3, and 4 showed variable expression among samples. All SPT showed nuclear beta-catenin and lack of E-cadherin membrane staining, whereas PET, ACC, and PB only showed nuclear beta-catenin in 1, 2, and 2 cases, respectively. SPT shows a peculiar claudin expression profile and the highly specific pattern of claudins 5 and 7 differentiates SPT from PET, ACC, and PB.
Advances in the interpretation and understanding of cancer behaviour, particularly of its ability to evade the host immunosurveillance, deregulating the balance between inhibitory and stimulatory ...factors, led to the development of an innovative category of immunotherapeutic agents, currently under investigation. Although the disappointing data deriving from the employment of vaccines in non-small cell lung cancer (NSCLC), more promising results have been obtained in the early phase trials with immune checkpoint inhibitors, such as cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), programmed cell death protein-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors. This review delineates the main features of the available immunotherapeutic agents, focusing the discussion on immune checkpoint inhibitors, those that have already demonstrated a relevant clinical activity (such as Ipilimumab and Nivolumab) and those molecules still in early development phase. Moreover, we underline the possible emerging issues deriving from the progressive diffusion of Immuno-Oncology into the standard clinical practice. The careful and accurate identification and management of immune-related toxicities, the validation of more reliable immune response criteria and the increasing research of potential predictive biomarkers are key points of discussion. The perspective is that immunotherapy might represent an effective 'magic bullet', able to change the treatment paradigm of NSCLC, particularly of those subgroups featured by a heavily mutant cancer (squamous histology and smokers), where the immunologic agents contribute in cancer development and progression seems to be strong and, concurrently, the efficacy of standard therapies particularly limited.
The hallmark of chromophobe renal cell carcinoma is multiple chromosomal losses from among chromosomes 1, 2, 6, 10 and 17. Chromophobe renal cell carcinoma with distant metastases or sarcomatoid ...transformation are uncommon and little is known about their chromosomal abnormalities. We collected six sarcomatoid chromophobe renal cell carcinomas and three primary chromophobe renal cell carcinomas with distant metastases. A cytogenetic analysis by fluorescent in situ hybridization on paraffin-embedded tissue was performed using centromeric probes for chromosomes 1, 2, 6, 10 and 17. We found more than one signal in four of six (66%) sarcomatoid chromophobe renal cell carcinomas, in both sarcomatoid and adjacent epithelial components. Both primary chromophobe renal cell carcinomas and matched metastases showed single signals for all chromosomes studied in two cases and no abnormalities in the remaining case. We concluded that: (1) both epithelial and sarcomatoid components of sarcomatoid chromophobe renal cell carcinoma show different genetic abnormalities from those characteristic of chromophobe renal cell carcinoma; (2) sarcomatoid chromophobe renal cell carcinomas frequently have multiple gains (polysomy) of chromosomes 1, 2, 6, 10 and 17; (3) distant metastases show the same genetic patterns, usually chromosomal losses (monosomy), found in the primary tumors.
Adjuvant chemotherapy for non-small-cell lung carcinoma (NSCLC) is a debated issue in clinical oncology. Although it is considered a standard for resected stage II-IIIA patients according to the ...available guidelines, many questions are still open. Among them, it should be acknowledged that the treatment for stage IB disease has shown so far a limited (if sizable) efficacy, the role of modern radiotherapies requires to be evaluated in large prospective randomized trials and the relative impact of age and comorbidities should be weighted to assess the reliability of the trials' evidences in the context of the everyday-practice. In addition, a conclusive evidence of the best partner for cisplatin is currently awaited as well as a deeper investigation of the fading effect of chemotherapy over time. The limited survival benefit since first studies were published and the lack of reliable prognostic and predictive factors beyond pathological stage, strongly call for the identification of bio-molecular markers and classifiers to identify which patients should be treated and which drugs should be used. Given the disappointing results of targeted therapy in this setting have obscured the initial promising perspectives, a biomarker-selection approach may represent the basis of future trials exploring adjuvant treatment for resected NSCLC.
The diagnosis of infiltrative diffuse lung disease may require invasive procedures after all noninvasive tools have failed. The clinical context in which these diseases develop and the radiological ...patterns are crucial for defining the timing and the methods to be used. Immunocompromised hosts are usually acutely ill with fever, cough, shortness of breath, and often with progressive hypoxemia. In this context a prompt diagnosis is necessary to decrease mortality. Bronchoalveolar lavage especially in cases that show ground-glass attenuation or alveolar opacification in high-resolution CT scan (HRCT) is the most important invasive procedure allowing the identification of infectious agents, neoplastic elements and characteristic cytological and phenotypical profiles (for drug injury) in the majority of cases. Less frequently transbronchial lung biopsy, transbronchial needle aspiration and biopsy or surgical lung biopsy are necessary. In immunocompetent patients the clinical spectrum of diffuse lung disease is quite broad. Furthermore, in the last two decades HRCT, used in conjunction with clinical and other noninvasive investigative modalities, has increased the accuracy of diagnosis for some diseases without the need of surgical biopsy. Also in these patients bronchoalveolar lavage, frequently in combination with transbronchial lung biopsy, is sufficient to achieve a definitive diagnosis in the majority of cases. Surgical lung biopsy is, however, still relevant in cases with idiopathic interstitial pneumonias. In this article invasive diagnostic procedures in patients with diffuse lung infiltrates are discussed from the perspective of their clinical context and their imaging characteristics.
On the basis of these considerations and previous clinical observations,6 we vaccinated several patients with SM without observing important side effects. ...almost all of them achieved a relevant ...protection and decreased their grade of reaction from IV to I. The 2 patients who maintained a grade IV reaction on maintenance SIT could achieve a benefit by increasing the maintenance dose.8 We are aware that the population evaluated in our study is small, but if we take into account the rarity of SM and the low frequency of severe HVA, this study includes the largest cohorts of patients with HVA and SM treated with SIT. An accessory observation is that SM was indeed diagnosed in 16 of 121 patients with severe HVA. ...it can be supposed that severe HVA could be a clinical manifestation of underlying SM, as reported with idiopathic anaphylaxis.9 This would support the usefulness of tryptase assay screening in patients with Hymenoptera-induced anaphylaxis.
Squamous lung carcinoma lacks specific "ad hoc" therapies. Amplification of chromosome 3q is the most common genomic aberration and this region harbours genes having role as novel targets for ...therapeutics. There is no standard definition on how to score and report 3q amplification. False versus true 3q chromosomal amplification in squamous cell lung carcinoma may have tremendous impact on trials involving drugs which target DNA zones mapping on 3q. Forty squamous lung carcinomas were analyzed by FISH to assess chromosome 3q amplification. aCGH was performed as gold-standard to avoid false positive amplifications. Three clustered patterns of fluorescent signals were observed. Eight cases out of 40 (20%) showed ≥8 3q signals. Twenty out of 40 (50%) showed from 3 to 7 signals. The remaining showed two fluorescent signals (30%). When corrected by whole chromosome 3 signals, only cases with ≥8 signals maintained a LSI 3q/CEP3 ratio >2. Only the cases showing 3q amplification by aCGH (+3q25.3-3q27.3) showed ≥8 fluorescent signals at FISH evidencing a 3q/3 ratio >2. The remaining cases showed flat genomic portrait at aCGH on chromosome 3. We concluded that: 1) absolute copy number of 3q chromosomal region may harbour false positive interpretation of 3q amplification in squamous cell carcinoma; 2) a case results truly "amplified for chromosome 3q" when showing ≥8 fluorescent 3q signals; 3) trials involving drugs targeting loci on chromosome 3q in squamous lung carcinoma therapy have to consider false versus true 3q chromosomal amplification.
IgG4 -related disease was first described in adults with autoimmune pancreatitis but is now known to affect multiple organs. Lung involvement has never been described in children to our knowledge. ...Here, we report an adolescent presenting with recurrent dry cough and hemoptysis who was found to have venous ectasia in the left upper lobe, and diffuse bronchiectasis. Sustained high levels of IgG4 (1,090 mg/dL) were found, and the endobronchial biopsy revealed a marked infiltration of plasma cells producing IgG4 (ratio of IgG4 plasma cells to IgG plasma cells >50%). This unique case highlights the occurrence of IgG4 -related disease in a child and underscores the importance of careful scrutiny of all investigations in complex pediatric respiratory cases.
The accumulation of T cells and monocytes at sites of ongoing inflammation represents the earliest step in the series of events that lead to granuloma formation in sarcoidosis. In this study, we ...evaluated the pulmonary production of IFN-inducible protein 10 (IP-10), a CXC chemokine that stimulates the directional migration of activated T cells. Striking levels of IP-10 were demonstrated in the bronchoalveolar lavage (BAL) fluid of 24 patients with pulmonary sarcoidosis and lymphocytic alveolitis, as compared with patients with inactive disease or control subjects. A positive correlation was demonstrated between IP-10 levels and the number of sarcoid CD45R0+/CD4+ cells in the BAL. Immunochemistry, performed with an anti-human IP-10 polyclonal Ab in lymph nodes displaying prominent sarcoid granulomas, showed that cells bearing IP-10 were mainly epithelioid cells and CD68+ macrophages located inside granulomatous areas. Macrophages recovered from the BAL of sarcoid patients stained positive for IP-10 protein. Furthermore, alveolar macrophages isolated from sarcoid patients with T cell alveolitis and cultured for 24 h in presence of IFN-gamma secreted definite levels of IP-10 capable of inducing T cell chemiotaxis. Interestingly, alveolar lymphocytes recovered from patients with active sarcoidosis were CD4+ T cells expressing Th1 cytokines (IL-2 and IFN-gamma) and high levels of CXCR3. Taken together, these data suggest the potential role of IP-10 in regulating the migration and activation of T cells toward sites of sarcoid inflammatory process and the consequent granuloma formation.
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