Heme Oxygenase-1/High Mobility Group Box 1 Pathway May Have a Possible Role in COVID-19 ARDS (Acute Respiratory Distress Syndrome): A Pilot Histological Study.

COVID-19 is a pandemic disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The persistent and excessive inflammatory response can build up a clinical picture that is difficult to manage and potentially fatal. Potent activators of inflammatory phenomena are damage-associated molecular patterns (DAMPs) and, in particular, the high-mobility group box 1 (HMGB1). HMGB1 is an intranuclear protein that is either passively released during hypoxia-related necrosis or actively released by macrophages. Heme oxygenase (HO-1) has an anti-inflammatory effect by inhibiting HMGB1, which could be a therapeutic target to reduce COVID-19 inflammation. In our study, we evaluated CD3, CD4, CD8, HMGB1 and HO-1 in the COVID-19 lung and correlated it to clinical data.

Splenic abscesses as a first manifestation of Crohn's disease: a case report.

BACKGROUND: Splenic nodules are uncommon entities that occur rarely in the general population. Although an infectious etiology (primarily bacteria, followed by mycobacteria) is usually found, noninfectious diseases, including malignancies and autoimmune disorders, can also be involved. For instance, in course of inflammatory bowel diseases (IBDs), in particular Crohn's Disease, aseptic splenic abscesses have been reported in patients with a long history of illness, or in those unresponsive to medical treatments, while are only anecdotally reported in the early phase of the disease. Hence, we presented the case of aseptic splenic nodules as a first manifestation of Crohn's Disease. CASE PRESENTATION: A 21-year-old woman with a silent medical history was admitted to the Emergency Department of our hospital complaining of fever of 38-39 °C (mainly in the evening) for the past 10 days and left flank abdominal pain, accompanied by sweating and fatigue. An abdominal computed tomography showed multiple splenic nodules of unknown origin. Because of the absence of clinical improvement after several antibiotic therapiesand a positron emission tomography (PET) with hypercaptation strictly localized to spleen, she underwent splenectomy, in suspicion of lymphoma. For persistence of symptoms after splenectomy, she underwent many instrumental examination, including a colonoscopy with bowel and intestinal biopsies that poses diagnosis of Crohn's disease. A second PET confirmed this diagnosis showing this time also the gastrointestinal involvement. CONCLUSION: An unusual onset of Crohn's disease with multiple splenic nodules is reported. This case suggests that in light of splenic nodules of unknown etiology attention should be paid to all possible diagnoses of aseptic abscesses, including IBDs (primarily Crohn's Disease).

Interleukin-17 and -22 synergy linking inflammation and EMT-dependent fibrosis in Sjögren's syndrome.

Primary Sjögren's syndrome (pSS) is a chronic inflammatory, autoimmune and systemic disorder commonly associated with dry eyes and a dry mouth. Recently, the hypothetical link between epithelial-mesenchymal transition (EMT)-dependent salivary gland (SG) fibrosis and chronic inflammatory conditions has been suggested. In this study, we present data demonstrating a negative correlation of the epithelial marker E-cadherin expression and a positive correlation of mesenchymal vimentin and collagen type I expression with increasing degrees of tissue inflammation in pSS SG specimens. In addition, as it is not clear whether dysregulated cytokines in pSS, interleukin (IL)-17 and IL-22 may also contribute to the EMT-dependent fibrosis process, the effect of IL-17 and IL-22 treatment on EMT-dependent SG fibrosis was evaluated in primary human salivary gland epithelial cells (SGEC) isolated from healthy subjects. Here we present data demonstrating that IL-17 and IL-22 can induce SGEC to undergo a morphological and phenotypical transition to a mesenchymal phenotype. In support of this, vimentin and collagen type I were up-regulated while a decreased expression of E-cadherin occurs after interleukin treatment, and co-operation between IL-17 and Il-22 was required to induce the EMT.

Dissection of DLBCL microenvironment provides a gene expression-based predictor of survival applicable to formalin-fixed paraffin-embedded tissue.

Background: Gene expression profiling (GEP) studies recognized a prognostic role for tumor microenvironment (TME) in diffuse large B-cell lymphoma (DLBCL), but the routinely adoption of prognostic stromal signatures remains limited. Patients and methods: Here, we applied the computational method CIBERSORT to generate a 1028-gene matrix incorporating signatures of 17 immune and stromal cytotypes. Then, we carried out a deconvolution on publicly available GEP data of 482 untreated DLBCLs to reveal associations between clinical outcomes and proportions of putative tumor-infiltrating cell types. Forty-five genes related to peculiar prognostic cytotypes were selected and their expression digitally quantified by NanoString technology on a validation set of 175 formalin-fixed, paraffin-embedded DLBCLs from two randomized trials. Data from an unsupervised clustering analysis were used to build a model of clustering assignment, whose prognostic value was also assessed on an independent cohort of 40 cases. All tissue samples consisted of pretreatment biopsies of advanced-stage DLBCLs treated by comparable R-CHOP/R-CHOP-like regimens. Results: In silico analysis demonstrated that higher proportion of myofibroblasts (MFs), dendritic cells, and CD4+ T cells correlated with better outcomes and the expression of genes in our panel is associated with a risk of overall and progression-free survival. In a multivariate Cox model, the microenvironment genes retained high prognostic performance independently of the cell-of-origin (COO), and integration of the two prognosticators (COO + TME) improved survival prediction in both validation set and independent cohort. Moreover, the major contribution of MF-related genes to the panel and Gene Set Enrichment Analysis suggested a strong influence of extracellular matrix determinants in DLBCL biology. Conclusions: Our study identified new prognostic categories of DLBCL, providing an easy-to-apply gene panel that powerfully predicts patients' survival. Moreover, owing to its relationship with specific stromal and immune components, the panel may acquire a predictive relevance in clinical trials exploring new drugs with known impact on TME.

p38alpha blockade inhibits colorectal cancer growth in vivo by inducing a switch from HIF1alpha- to FoxO-dependent transcription.

Colorectal cancer cell (CRC) fate is governed by an intricate network of signaling pathways, some of which are the direct target of DNA mutations, whereas others are functionally deregulated. As a consequence, cells acquire the ability to grow under nutrients and oxygen shortage conditions. We earlier reported that p38alpha activity is necessary for proliferation and survival of CRCs in a cell type-specific manner and regardless of their phenotype and genotype. Here, we show that p38alpha sustains the expression of HIF1alpha target genes encoding for glycolytic rate-limiting enzymes, and that its inhibition causes a drastic decrease in ATP intracellular levels in CRCs. Prolonged inactivation of p38alpha triggers AMPK-dependent nuclear localization of FoxO3A and subsequent activation of its target genes, leading to autophagy, cell cycle arrest and cell death. In vivo, pharmacological blockade of p38alpha inhibits CRC growth in xenografted nude mice and azoxymethane-treated Apc(Min) mice, achieving both a cytostatic and cytotoxic effect, associated with high nuclear expression of FoxO3A and increased expression of its target genes p21 and PTEN. Hence, inhibition of p38alpha affects the aerobic glycolytic metabolism specific of cancer cells and might be taken advantage of as a therapeutic strategy targeted against CRCs.

Gastrointestinal stromal tumors mimicking gynecological masses on ultrasound: a report of two cases.

Gastrointestinal stromal tumors (GISTs) are among the most common mesenchymal tumors of the gastrointestinal tract. Diagnosis of GIST on ultrasound examination can be difficult because of their similarity in appearance to gynecological neoplasms. We present two cases of GIST originating from the small bowel and the stomach, which were preoperatively misdiagnosed as a uterine leiomyoma and an ovarian tumor, respectively. The ultrasonographic differential diagnosis of these pelvic masses is discussed.

A novel cell type-specific role of p38alpha in the control of autophagy and cell death in colorectal cancer cells.

Cancer develops when molecular pathways that control the fine balance between proliferation, differentiation, autophagy and cell death undergo genetic deregulation. The prospects for further substantial advances in the management of colorectal cancer reside in a systematic genetic and functional dissection of these pathways in tumor cells. In an effort to evaluate the impact of p38 signaling on colorectal cancer cell fate, we treated HT29, Caco2, Hct116, LS174T and SW480 cell lines with the inhibitor SB202190 specific for p38alpha/beta kinases. We report that p38alpha is required for colorectal cancer cell homeostasis as the inhibition of its kinase function by pharmacological blockade or genetic inactivation causes cell cycle arrest, autophagy and cell death in a cell type-specific manner. Deficiency of p38alpha activity induces a tissue-restricted upregulation of the GABARAP gene, an essential component of autophagic vacuoles and autophagosomes, whereas simultaneous inhibition of autophagy significantly increases cell death by triggering apoptosis. These data identify p38alpha as a central mediator of colorectal cancer cell homeostasis and establish a rationale for the evaluation of the pharmacological manipulation of the p38alpha pathway in the treatment of colorectal cancer.

[Subareolar injection for sentinel lymph node biopsy in multiple breast cancer]. / L'iniezione subareolare per la biopsia del linfonodo sentinella nei tumori multipli della mammella

In this study we performed subdermal injection of 99mTc-labeled albumin combined with subareolar (SA) injection of blue dye to axillary lymphatic mapping and sentinel lymph node biopsy (SNLB) in patients with multifocal and multicentric breast cancer (MC) to evaluate the feasibility and accuracy of this technique. We compared the results with a group of patients with unifocal breast cancer. From January 1999 to March 2006 axillary lymph node mapping and SLNB was performed on 250 patients followed by a complete axillary lymph node dissection. Retrospective analysis showed that 32 (12.8%) of these patients have MC on final histopathologic examination and 218 (87.2%) have unifocal cancer. In statistical analysis tumor size shows a significant difference (p=.01) with largest lesions in MC. In MC often histological type is invasive lobular with or without in situ cancer (p= .001). Metastatic lymph node involvement was significantly higher in the MC group compared to unifocal cancer group (p=.001). False negative (FN) rate was 5.8% in MC and 9.6% in unifocal cancers. The overall accuracy of lymphatic mapping was 96.8% in MC and 97.6% in unifocal cancers. Sensitivity was 94.4% in MC and 91.2% in unifocal cancers. In this study we provide further evidence that lymphatic mapping may be reliable even in patients with MC. SA injection technique demonstrates a high sentinel lymph node identification rate and low FN rate; therefore this technique should been recommended to SLNB in patients with MC of the breast.

Malignant fibrous histiocytoma arising on chronic osteomyelitis.

We present a case of a primary malignant fibrous histiocytoma of the skin (MFH) arising on chronic osteomyelitis in a 67-year-old woman. Although this condition seems to be a predisposing factor for the onset of the malignancy, MFH complicating chronic osteomyelitis is generally localized at the level of the bone tissue. In the case we report the neoplasm was primitively localized at the dermal and subcutaneous level and presented as a rapidly growing mass.

[The stereotaxic core breast biopsy using the Mammotome: an alternative to intraoperative examination]. / La core-biopsy mammaria stereotassica con Mammotome: un'alternativa all'esame intraoperatorio.

The aim of this work was to evaluate the accuracy of vacuum-assisted biopsy by comparing it with frozen biopsy. 141 stereotaxic biopsies were performed by Mammotome (Ethicon Endo-Surgery, Hamburg) from January 2000 to March 2001. Biopsies were performed for microcalcifications (n = 105, 74.5%), irregular opacities (n = 20, 14.2%), regular opacities (n = 6, 4.2%), stellate lesions (n = 10, 7.1%). Histological analysis showed 85 (60.3%) benign lesions, 46 (32.6%) malignant lesions including (21 cases of carcinoma in situ and 25 invasive carcinomas) and 10 (7.1%) atypical lesions. All malignant lesions were subjected to surgery. In three cases (1 in situ and 2 invasive), core biopsy was excisional and no residual lesion was observed. Two of the carcinomas in situ revealed invasive features on the surgical biopsy. One of the atypical lesions was underestimated and the final diagnosis was "well differentiated carcinoma in situ." Only three of benign lesions underwent surgery after Mammotome biopsy. Among the 55 frozen-section biopsies of mammographically detected breast lesions performed in the same period, were one false-positive and 3 false-negative cases, while in 4 cases the diagnosis was deferred after paraffin embedding. Our results confirmed Mammotome biopsy as an effective alternative and a more reliable method than frozen-section examination.

Response of severe HIV-associated thrombocytopenia to highly active antiretroviral therapy including protease inhibitors.

OBJECTIVE: To investigate the response of HIV-associated severe thrombocytopenia (STP) to highly active antiretroviral therapy (HAART) including protease-inhibitors. METHODS: In this retrospective study, 15 patients with HIV-associated STP (platelet count < 50 x 10(9)/l mostly antiretroviral experienced (13/15), underwent HAART for at least 6 months (median 21; range 6-41 months) during which the platelet (PLT) count and plasmatic HIV-RNA were monitored. The PLT response was compared to that observed in 19 patients previously treated with zidovudine (AZT) monotherapy. RESULTS: HAART induced a significant increase in the PLT count (chi(2)=10.53, P=0.01) within the third month which was sustained up to the sixth month of therapy. No STP relapse was observed among eight PLT responders followed for longer than 6 months (median 27; range 7-41 months). The PLT increase after HAART was similar to that observed with AZT monotherapy, but a greater number of HAART patients were antiretroviral-experienced. HAART determined a PLT response in 10/13 subjects whose thrombocytopenia had not improved after previous AZT monotherapy. After 6 months of HAART, a complete platelet response occurred more frequently in patients with undetectable plasma HIV-RNA levels (P=0.01). CONCLUSIONS: HAART induces a sustained PLT response in HIV-associated STP, even in antiretroviral-experienced subjects and in those with AZT-resistant thrombocytopenia. An undetectable plasma HIV viraemia induced by HAART is necessary for STP recovery.

[Prevalence and distribution of congenital cardiopathy at birth and in pregnancy termination: impact of prenatal diagnosis in 4 years of experience]. / Prevalenza e distribuzione delle cardiopatie congenite alla nascita e nelle interruzioni di gravidanza: impatto della diagnosi prenatale in quattro anni di esperienza.

OBJECTIVE: To evaluate in two time intervals the potential impact of prenatal diagnosis on prevalence and spectrum of CHD at birth and in aborted fetuses. PATIENTS AND METHODS: At the University Hospital of Bari, south-east Italy, in the period between January 1st 1996 and December 31st 1999 a retrospective study was performed of all newborns and termination of pregnancy (TOP) beyond 18 weeks' gestation with postnatally diagnosed CHD. An antenatal fetal ultrasonic evaluation had been always performed between 18-22 weeks' gestation. The prevalence, distribution and detection rate of CHD at birth and in TOP were assessed and compared between two different periods of time (96-97 vs 98-99) to verify an eventual improvement in the prenatal diagnosis due to the learning curve and to new technologies. RESULTS: Prevalence of severe CHD in livebirths and aborted fetuses showed no significant changes between the two study periods (respectively 4.6@1000 vs 5.4@1000, at birth; 10% vs 11%, in TOP) and the same was observed as for as distribution of CHD. Maternal or fetal risk factors were found in 23% of cases of CHD at birth and in 74% of cases of CHD in aborted fetuses. The antenatal detection rate of CHD did not change between the two study periods in newborns (25% vs 27%, NS) while in aborted fetuses it was higher and showed a significant longitudinal improvement (53% vs 85%, p < 0.05), which was more evident if only selected cases were considered (56% vs 93%, p < 0.03). DISCUSSION: Our data show that gain in experience in fetal echocardiography has increased the prenatal diagnostic accuracy for congenital cardiac malformations only in selected cases, evaluated by more expert operators. In conclusion the impact of antenatal routine screening for congenital heart disease appears still relatively small.