Malignant pleural mesothelioma immune microenvironment and checkpoint expression: correlation with clinical-pathological features and intratumor heterogeneity over time.

Background: Tumor immune microenvironment (TME) plays a key role in malignant pleural mesothelioma (MPM) pathogenesis and treatment outcome, supporting a role of immune checkpoint inhibitors as anticancer approach. This study retrospectively investigated TME and programmed death ligand 1 (PD-L1) expression in naïve MPM cases and their change under chemotherapy. Patients and methods: Diagnostic biopsies of MPM patients were collected from four Italian and one Slovenian cancer centers. Pathological assessment of necrosis, inflammation, grading, and mitosis was carried out. Ki-67, PD-L1 expression, and tumor infiltrating lymphocytes were detected by immunohistochemistry. When available, the same paired sample after chemotherapy was analyzed. Pathological features and clinical characteristics were correlated to overall survival. Results: TME and PD-L1 expression were assessed in 93 and 65 chemonaive MPM samples, respectively. Twenty-eight samples have not sufficient tumor tissue for PD-L1 expression. Sarcomatoid/biphasic samples were characterized by higher CD8+ T lymphocytes and PD-L1 expression on tumor cells, while epithelioid showed higher peritumoral CD4+ T and CD20+ B lymphocytes. Higher CD8+ T lymphocytes, CD68+ macrophages, and PD-L1 expression were associated with pathological features of aggressiveness (necrosis, grading, Ki-67). MPM cases characterized by higher CD8+ T-infiltrate showed lower response to chemotherapy and worse survival at univariate analysis. Patients stratification according to a combined score including CD8+ T lymphocytes, necrosis, mitosis, and proliferation index showed median overall survival of 11.3 months compared with 16.4 months in cases with high versus low combined score (P < 0.003). Subgroup exploratory analysis of 15 paired samples before and after chemotherapy showed a significant increase in cytotoxic T lymphocytes in MPM samples and PD-L1 expression in immune cells. Conclusions: TME enriched with cytotoxic T lymphocytes is associated with higher levels of macrophages and PD-L1 expression on tumor cells and with aggressive histopathological features, lower response to chemotherapy and shorter survival. The role of chemotherapy as a tumor immunogenicity inducer should be confirmed in a larger validation set.

Primitive squamous cell carcinoma of the breast (SCCB): case report of an uncommon variant of metaplastic carcinoma.

INTRODUCTION: Metaplastic carcinoma of the breast includes a heterogeneous group of neoplasms characterized by admixture of adenocarcinoma with area of squamous, chondroid and osseous differentiation. If the tumor shows pure squamous differentiation, it is designated as squamous carcinoma. SCCB accounts for less than 1% of all invasive breast carcinoma. It can present as cystic lesions and simulate a breast abscess. CASE REPORT: A 75-year old woman was visited at our General Surgery Unit for a palpable lump, about 5 cm in size, at the lower inner quadrant of right breast. Mammography revealed 3cm oval opacity with micro calcifications and US appearance as isoechogenic lump with lesion solid-cystic appearance; cytology deposes for cystic inflammatory lesion(C2) to be monitored. A subsequent ultrasound check one year later confirmed an increase of volume, so micro histology sampling was made with suspect malignancy(B4). After biopsy, the patient underwent excision of cyst. Final histological examination showed SCCB with diffuse positivity for Cytokeratin 34beta-E12 and p63; negative reactions to ER and PR; monoclonal antibody Ki67 > 40%; HER2/neu with score 2+ and FISH examination negative. Subsequently, the patient underwent radical Madden mastectomy which confirmed the histological diagnosis and the negativity of the lymph nodes. DISCUSSION: In literature, prognosis and therapy are still discussed; SCCB has shown very little responsiveness to common chemotherapy. CONCLUSION: A quadrantectomy or a radical mastectomy with lymph node dissection must be considered the best treatment for this rare neoplasia.

Primary intestinal choriocarcinoma in a patient with long-standing Crohn's disease.

Extra-gonadal choriocarcinoma is an extremely rare highly malignant neoplasm with a poor prognosis. In the gastrointestinal tract it usually arises in stomach, esophagous, bowel intestine and colon. Only few cases are pure and not associated with a classic adenocarcinoma. The correlation of Crohn's disease with choriocarcinoma is not reported. We describe a case of 47-year old man with primary choriocarcinoma of the colon in a previously documented Crohn's disease.

Complement Alternative Pathway Deficiency in Recipients Protects Kidney Allograft From Ischemia/Reperfusion Injury and Alloreactive T Cell Response.

Despite the introduction of novel and more targeted immunosuppressive drugs, the long-term survival of kidney transplants has not improved satisfactorily. Early antigen-independent intragraft inflammation plays a critical role in the initiation of the alloimmune response and impacts long-term graft function. Complement activation is a key player both in ischemia/reperfusion injury (IRI) as well as in adaptive antigraft immune response after kidney transplantation. Since the alternative pathway (AP) amplifies complement activation regardless of the initiation pathways and renal IR injured cells undergo uncontrolled complement activation, we speculated whether selective blockade of AP could be a strategy for prolonging kidney graft survival. Here we showed that Balb/c kidneys transplanted in factor b deficient C57 mice underwent reduced IRI and diminished T cell-mediated rejection. In in vitro studies, we found that fb deficiency in T cells and dendritic cells conferred intrinsic impaired alloreactive/allostimulatory functions, respectively, both in direct and indirect pathways of alloantigen presentation. By administering anti-fB antibody to C57 wt recipients in the early post Balb/c kidney transplant phases, we documented that inhibition of AP during both ischemia/reperfusion and early adaptive immune response is necessary for prolonging graft survival. These findings may have implication for the use of AP inhibitors in clinical kidney transplantation.

[Web Babel Syndrome and false expectations during own multimedia oncological search]. / La sindrome di Babele del Web: fonte di false aspettative durante la ricerca della terapia oncologica multimediale personalizzata.

Nowadays Internet has become the new gold standard, for most of web users, when performing a screening on medical updates and/or cares. Although provided with some scientific background most of websites, blogs and videos (which as main source have Youtube) lack some institution that can garantee their contents and quality; thus one generates ambiguities among users giving light to a particular pathology called "Web Babel Syndrome"

Perioperative anaphylactic risk score for risk-oriented premedication.

Basing on the current knowledge, this paper is aimed to review the core characteristics of the most relevant therapeutic agents (steroids and antihistamines), administered to prevent perioperative anaphylaxis. Moreover, the Authors propose the validation of a Global Anaphylactic Risk Score, built up by recording the individual scores related to the most relevant anaphylaxis parameters (i.e. medical history, symptoms and medication for asthma, rhinitis and urticaria etc) and by adding them on all together; the score could be used in the preoperative phase to evaluate the global anaphylactic risk and to prescribe risk-oriented premedication protocols.

CD34+ hemopoietic precursor and stem cells traffic in peripheral blood of celiac patients is significantly increased but not directly related to epithelial damage severity.

Celiac disease (CD) is a chronic inflammatory enteropathy of the small bowel resulting from a local TH1-mediated reaction to wheat gliadins and barley, rye and oat prolamins with the development of auto-antibodies to transglutaminases. As well as for other chronic inflammatory diseases, genetic background and environmental factors participate to pathogenesis. An increased traffic of CD34+ hemopoietic precursor and stem cells (HPC) has been reported in peripheral blood (PB) of subjects with allergic diseases that share in their pathogenesis immuno-mediated reactions, genetic and environmental factors. The aim of the present work was to investigate the CD34+ cell traffic and H2/H1 polarization of lymphoid T-cell lineage, in the peripheral blood of subjects with CD, by means of flow-cytometric techniques. Group A of control was of 20 healthy subjects, aged 5 to 58 years. Study population (Group B) was of twenty-eight patients, all females aged 13 to 70, receiving firstly a CD diagnosis at the SS Annunziata Hospital Digestive Physiopathology Out-standings' by means of clinical, serologic and small intestinal biopsy findings. Peripheral CD34+ HPCs were significantly increased in Group B (median value 0.16) when compared with Group A (median value 0.03) (p 0.0001) but did not correlate either with anti-transglutaminase (tTG) antibody levels (IgA: p 0.226; IgG: p 0.810) or with histological damage severity (p 0.41) that, on the contrary, was significantly related with anti-tTG IgA antibodies (p 0.027). Celiac circulating CD3+CD4+ lymphocytes expressed a chemokine-receptor pattern Th2-skewed in all but three patients investigated. Concluding, the CD34+ HPC highly increased peripheral traffic observed in celiac disease appears more related to a basic and emerging as common defect shared by chronic inflammatory diseases than to the gliadin-specific Th1 local reactions. Data are consistent with a potential NFkappaB deficiency and consequent prevalence of apoptotic versus survival programs leading to excessive cell-death; to replace lost cells a supplementary bone-marrow derived precursors supply, further to that physiologically provided by the gut stem cell "niches" that are cryptopatches, could be required.

Practice parameters for sublingual immunotherapy.

The efficacy and safety of sublingual immunotherapy (SLIT) are currently supported by clinical trials, meta-analysis and post-marketing surveys. Practice parameters for clinical use of SLIT are proposed here by a panel of Italian specialists, with reference to evidence based criteria. Indications to SLIT include allergic rhinoconjunctivitis, asthma, and isolated conjunctivitis (strength of recommendation: grade A). As to severity of the disease, SLIT is indicated in moderate/severe intermittent rhinitis, persistent rhinitis and mild to moderate asthma (grade D). SLIT may be safely prescribed also in children aged three to five years (grade B), and its use in subjects aged more than 60 years is not prevented when the indications and contraindication are ascertained (grade D). The choice of the allergen to be employed for SLIT should be made in accordance with the combination of clinical history and results of skin prick tests (grade D). Polysensitisation, i.e. the occurrence of multiple positive response does not exclude SLIT, which may be done with the clinically most important allergens (grade D). As to practical administration, co-seasonal, pre co-seasonal, and continuous schedules are available, being the latter recommended for perennial allergens or for pollens with particularly prolonged pollination, such as Parietaria (grade D). For pollens with relatively short pollination, such as grasses and trees (cypress, birch, alder, hazelnut, olive) the pre co-seasonal and perennial schedules are preferred (grade C). The build-up phases suggested by manufacturers can be safely used (grade A), but they can be modified according to the patient's tolerance (grade C). A duration of SLIT of 3-5 years is recommended to ensure a long-lasting clinical effect after the treatment has been terminated (grade C).

Quantitative expression of the major homing integrins alphaL and alpha4 on human cord blood hematopoietic progenitor and stem cells.

An increased traffic of hematopoietic progenitor cells (HPC) between bone marrow and peripheral organs is a peculiar feature of the allergic inflammation. It has been recently reported that the sublingual form of specific immunotherapy (SLIT) is capable of reducing such an increased HPC traffic. The House Dust Mite major antigen Der p1 has been proved to up-regulate the expression of the ICAM-1 and VCAM-1 endothelial addressins, supporting the view of an inflammatory cell recruiting at the site of allergen extract administration. In the present work we have investigated, by flow-cytometric techniques, the expression of the two major integrins CD11a (LFA-1) and CD49d (VLA-4) that are the homing receptor cognate for ICAM-1 and VCAM-1 on human cord blood CD34 hematopoietic progenitor and stem cells. Even if both the investigated molecules resulted detectable on CD34+ HPC surfaces, being the system redundant, the density of the cellular expression was significantly higher for CD49d (median value: 158) than CD11a (median value: 20.5), suggesting a preferential usage of the homing axis VLA-4/VCAM-1. Results consistency with outcomes of clinical trials that relate SLIT efficacy to allergen dosage is discussed.

Epidemiology of allergic occupational diseases induced by Tetranychus urticae in greenhouse and open-field farmers living in a temperate climate area.

BACKGROUND: The role of Tetranychus urticae (TU) as an occupational allergen has thus far been investigated only in selected farmer samples. METHODS: The prevalence of TU-induced sensitization and occupational diseases in a randomized sample of farmers living in a temperate climate area was investigated. Occupational/nonoccupational symptoms, skin prick test (SPT) results with common allergens and TU, specific occupational test results, and greenhouse or open-field sources of TU exposure were assessed. The study design was cross-sectional. RESULTS: The prevalence of positive SPT to TU was 6%. TU-induced allergic/nonallergic complaints accounted for 65% of farmers with challenge-confirmed occupational disease. In all farmers, sensitization to common allergens was a risk factor for both current occupational and nonoccupational complaints, while TU sensitization was a prominent risk factor for occupational complaints. Furthermore, in SPT-positive farmers, only the presence of seasonal occupational complaints was significantly associated with TU sensitization. Common allergen sensitization was a risk factor for development of TU sensitization, which was more frequent in greenhouse than in open-field workers. CONCLUSIONS: TU was a common nontraumatic, allergic occupational hazard for farmers. Since occupational seasonal symptoms could be directly related to the presence of TU sensitization, allergy to this mite should be routinely investigated in farmers.

Long-term absence of sensitization to mepivacaine as assessed by a diagnostic protocol including patch testing.

BACKGROUND: Prospective assessment of non-reactivity to local anaesthetics is a frequent reason for allergy consultation. OBJECTIVES: To investigate the clinical profiles of subjects referred for allergy evaluation; to prospectively reduce the frequency of evaluation by assessing the persistence, during clinical use, of non-reactivity to contaminant/additive-free mepivacaine; and to determine the usefulness of a diagnostic protocol involving patch testing. METHODS: In a prospective study, 198 consecutive patients underwent collection of clinical data, skin prick tests and patch tests using allergens/antigens relevant for the investigation, and an intradermal/subcutaneous challenge procedure using contaminant/additive-free mepivacaine, as appropriate. Patients were followed up for 3 years for assessment of non-reactivity persistence using the same diagnostic protocol. RESULTS: Only one-third of the patients had a history of previous adverse local anaesthetic reactions. Absence of sensitization to contaminant/additive-free mepivacaine persisted in all subjects completing the follow-up. Controlled challenge with mepivacaine was negative in 196 patients with both negative specific skin prick tests and patch tests but it was eventful in two subjects with positive specific patch tests. A few subjects displayed positive skin prick tests and/or patch tests for latex and/or additives. CONCLUSIONS: A few patients had a relevant history for potential local anaesthetic-induced adverse reactions. Upon assessment of absence of sensitization and reactivity, contaminant/additive-free mepivacaine could safely be given for as long as 3 years. The patch testing was shown to be useful and safe for prediction of challenge outcomes. True allergic reactions to contaminant/additive-free mepivacaine were not observed in our patient series.