Gut microbiota and fecal volatilome profile inspection in metabolically healthy and unhealthy obesity phenotypes.

BACKGROUND: People with metabolically healthy (MHO) and metabolically unhealthy obesity (MUO) differ for the presence or absence of cardio-metabolic complications, respectively. OBJECTIVE: Based on these differences, we are interested in deepening whether these obesity phenotypes could be linked to changes in microbiota and metabolome profiles. In this respect, the overt role of microbiota taxa composition and relative metabolic profiles is not completely understood. At this aim, biochemical and nutritional parameters, fecal microbiota, metabolome and SCFA compositions were inspected in patients with MHO and MUO under a restrictive diet regimen with a daily intake ranging from 800 to 1200 kcal. METHODS: Blood, fecal samples and food questionnaires were collected from healthy controls (HC), and an obese cohort composed of both MHO and MUO patients. Most impacting biochemical/anthropometric variables from an a priori sample stratification were detected by applying a robust statistics approach useful in lowering the background noise. Bacterial taxa and volatile metabolites were assessed by qPCR and gas chromatography coupled with mass spectrometry, respectively. A targeted GC-MS analyses on SCFAs was also performed. RESULTS: Instructed to follow a controlled and restricted daily calorie intake, MHO and MUO patients showed differences in metabolic, gut microbial and volatilome signatures. Our data revealed higher quantities of specific pro-inflammatory taxa (i.e., Desulfovibrio and Prevotella genera) and lower quantities of Clostridium coccoides group in MUO subset. Higher abundances in alkane, ketone, aldehyde, and indole VOC classes together with a lower amount of butanoic acid marked the faecal MUO metabolome. CONCLUSIONS: Compared to MHO, MUO subset symptom picture is featured by specific differences in gut pro-inflammatory taxa and metabolites that could have a role in the progression to metabolically unhealthy status and developing of obesity-related cardiometabolic diseases. The approach is suitable to better explain the crosstalk existing among dysmetabolism-related inflammation, nutrient intake, lifestyle, and gut dysbiosis.

Connective tissue nevus misdiagnosed as juvenile localized scleroderma.

BACKGROUND: Connective tissue nevi (CTN) are congenital hamartomas caused by excessive proliferation of dermis components. In children, CTN can mimic juvenile localized scleroderma (JLS), an immune mediated skin disorder that requires aggressive immunosuppression. OBJECTIVES: Aim of our study was to describe a series of pediatric patients with CTN misdiagnosed as JLS and the discerning characteristics between the two conditions. METHODS: Retrospective analysis of children referred to our Center during the last two decades for JLS who received a final diagnosis of CTN. Clinical, laboratory, histopathological and instrumental data (MRI and thermography) were collected and compared with those with JLS. RESULTS: Seventeen patients with mean age at onset 4.6 years entered the study. All came to our Center with a certain diagnosis of JLS (n = 15) or suspected JLS (n = 2). The indurated skin lesions were flat and resembled either circumscribed morphea or pansclerotic morphea. In 14 patients (82.4%) they were mainly localized at the lower limbs and in three (17.6%) at the upper limbs. No patient had laboratory inflammatory changes or positive autoantibodies. Skin biopsies confirmed the diagnosis of CTN: non-familial collagenoma in eleven (64.7%), mixed CTN in four (23.5%) and familial CTN in two (11.8%). Mean age at final diagnosis was 9.5 years, with a mean diagnostic delay of 4.8 years (range 1-15 years). Sixteen patients underwent musculoskeletal MRI that was normal in all except two who showed muscle perifascial enhancement. Thermography was normal in all patients. At our first evaluation, eleven patients (64.7%) were on systemic treatment (methotrexate 11, corticosteroids 7, biologics 2), three (17.6%) on topical corticosteroids and three untreated. CONCLUSIONS: CTN can be misdiagnosed as JLS and therefore aggressively treated with prolonged and inappropriate immunosuppression. The absence of inflammatory appearance of the skin lesions, normal instrumental and laboratory findings and the accurate evaluation of skin biopsy are crucial to address the right diagnosis.

Real-world EGFR testing practices for non-small-cell lung cancer by thoracic pathology laboratories across Europe.

BACKGROUND: Testing for epidermal growth factor receptor (EGFR) mutations is an essential recommendation in guidelines for metastatic non-squamous non-small-cell lung cancer, and is considered mandatory in European countries. However, in practice, challenges are often faced when carrying out routine biomarker testing, including access to testing, inadequate tissue samples and long turnaround times (TATs). MATERIALS AND METHODS: To evaluate the real-world EGFR testing practices of European pathology laboratories, an online survey was set up and validated by the Pulmonary Pathology Working Group of the European Society of Pathology and distributed to 64 expert testing laboratories. The retrospective survey focussed on laboratory organisation and daily EGFR testing practice of pathologists and molecular biologists between 2018 and 2021. RESULTS: TATs varied greatly both between and within countries. These discrepancies may be partly due to reflex testing practices, as 20.8% of laboratories carried out EGFR testing only at the request of the clinician. Many laboratories across Europe still favour single-test sequencing as a primary method of EGFR mutation identification; 32.7% indicated that they only used targeted techniques and 45.1% used single-gene testing followed by next-generation sequencing (NGS), depending on the case. Reported testing rates were consistent over time with no significant decrease in the number of EGFR tests carried out in 2020, despite the increased pressure faced by testing facilities during the COVID-19 pandemic. ISO 15189 accreditation was reported by 42.0% of molecular biology laboratories for single-test sequencing, and by 42.3% for NGS. 92.5% of laboratories indicated they regularly participate in an external quality assessment scheme. CONCLUSIONS: These results highlight the strong heterogeneity of EGFR testing that still occurs within thoracic pathology and molecular biology laboratories across Europe. Even among expert testing facilities there is variability in testing capabilities, TAT, reflex testing practice and laboratory accreditation, stressing the need to harmonise reimbursement technologies and decision-making algorithms in Europe.

What's new in mesothelioma.

Malignant pleural mesothelioma is a neoplasm characterized by a very poor prognosis and medico-legal implications. Diagnosis, prognosis and therapy are often challenging and include several issues. Cytological diagnosis is frequently the first step of the diagnostic process, and although its sensitivity may be somewhat lower, diagnostic criteria should be taken into account. When effusion cytology is inconclusive for the diagnosis, tissue biopsies should be taken. Even if the morphologic criteria for deciding whether a mesothelial proliferation is a benign or a malignant process have been defined, the separation of benign from malignant mesothelial proliferation is often a difficult problem for the pathologist, particularly on small biopsies. Thirdly, when the diagnosis is made, despite many efforts have been made to identify possible new biomarkers for early diagnosis, prognostic stratification and also predictive tools should be defined. Nowadays, the main prognostic parameter is still represented by the histological subtype, having the epithelioid MPM a better outcome than the sarcomatoid or biphasic MPM. A nuclear grading system have been also proposed to stratify patient outcome. Reliable predictive biomarkers are still lacking in MPM and a personalized therapeutic concept is eagerly needed. Mesothelioma occurs mostly as sporadic cancer and the main risk factor is asbestos exposure, but it also occurs among blood relatives suggesting possible increased genetic susceptibility besides shared exposures. Recently the study of genetic predisposition syndrome raised new aspect in the occurrence of mesothelioma cases.This review summarize these most important issues.

The role of immune microenvironment in small-cell lung cancer: Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes.

INTRODUCTION: The prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data on immune microenvironment are very limited. METHODS: We retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated. RESULTS: The analysis included 66 stage I-III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I-III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval [CI]: 0.16-0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17-0.81, p: 0.013) for multivariate analysis. CONCLUSIONS: Immune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I-III SCLCs and warrants further investigation.

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.

Immediate and Catastrophic Antibody-Mediated Rejection in a Lung Transplant Recipient With Anti-Angiotensin II Receptor Type 1 and Anti-Endothelin-1 Receptor Type A Antibodies.

Preexisting donor-specific anti-HLA antibodies (DSAs) have been associated with reduced survival of lung allografts. However, antibodies with specificities other than HLA may have a detrimental role on the lung transplant outcome. A young man with cystic fibrosis underwent lung transplantation with organs from a suitable deceased donor. At the time of transplantation, there were no anti-HLA DSAs. During surgery, the patient developed a severe and intractable pulmonary hypertension associated with right ventriular dysfunction, which required arteriovenous extracorporeal membrane oxygenation. After a brief period of clinical improvement, a rapid deterioration in hemodynamics led to the patient's death on postoperative day 5. Postmortem studies showed that lung specimens taken at the end of surgery were compatible with antibody-mediated rejection (AMR), while terminal samples evidenced diffuse capillaritis, blood extravasation, edema, and microthrombi, with foci of acute cellular rejection (A3). Immunological investigations demonstrated the presence of preexisting antibodies against the endothelin-1 receptor type A (ETA R) and the angiotensin II receptor type 1 (AT1 R), two of the most potent vasoconstrictors reported to date, whose levels slightly rose after transplantation. These data suggest that preexisting anti-ETA R and anti-AT1 R antibodies may have contributed to the onset of AMR and to the catastrophic clinical course of this patient.

TL1A/DR3 axis involvement in the inflammatory cytokine network during pulmonary sarcoidosis.

BACKGROUND: TNF-like ligand 1A (TL1A), a recently recognized member of the TNF superfamily, and its death domain receptor 3 (DR3), firstly identified for their relevant role in T lymphocyte homeostasis, are now well-known mediators of several immune-inflammatory diseases, ranging from rheumatoid arthritis to inflammatory bowel diseases to psoriasis, whereas no data are available on their involvement in sarcoidosis, a multisystemic granulomatous disease where a deregulated T helper (Th)1/Th17 response takes place. METHODS: In this study, by flow cytometry, real-time PCR, confocal microscopy and immunohistochemistry analyses, TL1A and DR3 were investigated in the pulmonary cells and the peripheral blood of 43 patients affected by sarcoidosis in different phases of the disease (29 patients with active sarcoidosis, 14 with the inactive form) and in 8 control subjects. RESULTS: Our results demonstrated a significant higher expression, both at protein and mRNA levels, of TL1A and DR3 in pulmonary T cells and alveolar macrophages of patients with active sarcoidosis as compared to patients with the inactive form of the disease and to controls. In patients with sarcoidosis TL1A was strongly more expressed in the lung than the blood, i.e., at the site of the involved organ. Additionally, zymography assays showed that TL1A is able to increase the production of matrix metalloproteinase 9 by sarcoid alveolar macrophages characterized, in patients with the active form of the disease, by reduced mRNA levels of the tissue inhibitor of metalloproteinase (TIMP)-1. CONCLUSIONS: These data suggest that TL1A/DR3 interactions are part of the extended and complex immune-inflammatory network that characterizes sarcoidosis during its active phase and may contribute to the pathogenesis and to the progression of the disease.

Iron supplementation in young iron-deficient females causes gastrointestinal redox imbalance: protective effect of a fermented nutraceutical.

The aim of this study was to assess whether the concomitant supplementation of certified fermented papaya preparation (FPP, ORI, Gifu, Japan) together with iron supplementation could beneficially affect lipid peroxidation either systemically and at a intraluminal gut level in women with low iron stores. Treatment compliance and iron absorption was assessed as well. Fifty-two non-pregnant, fertile, non-smokers, healthy women with iron deficiency were recruited. The women were given iron supplements (100 mg Fe/d as ferrous sulfate) to be taken daily for 12 weeks (group A). Group B patients were also supplemented with 6g/day of a FPP. A detailed life style questionnaire was administered to all subjects. Iron, ferritin, transferrin receptors (Tf R) and malondialdehyde (MDA) in plasma were measured. The RBCs lysate was used for the estimation of superoxide dismutase (SOD) and glutathione peroxidase (GPx). The total and free iron concentration as well as analysis of oxidative stress in the feces was measured. FPP-supplemented subjects showed a significantly lower degree of gastrointestinal discomfort (p less than 0.05) and abolished the iron supplementation-induced increase of MDA (p less than 0.001) and the depletion of SOD and GPx (p less than 0.01). Moreover, the nutraceutical co-administration brought about a significant reduction of gut oxidative damage and lower fecal content of either total and free iron (p less than 0.05 vs group A). Overall, group B showed a better TfR/ferritin ratio response (p less than 0.05 vs group A). While iron supplementation maintains its clinical relevance considering the prevalence of iron deficiency among females, a careful clinical evaluation and a protective nutraceutical co-administration, as our data suggest with FPP, should be considered.

Pediatric chronic lower respiratory disorders: microbiological and immunological phenotype.

The role of infectious agents in children with recurrent/chronic lower respiratory disorders (R/CLRDs) is not clear, whereas it has been largely studied in acute respiratory diseases. The purpose of the study was to evaluate the frequency of infections, in particular viral infections, in children with R/CLRDs correlating their presence with clinical/biohumoral parameters. Eighty children affected by R/CLRDs underwent bronchoscopy and analysis of bronchoalveolar lavage (BAL) for cells, mediators (eosinophil cationic protein-ECP, interleukin-IL-8, tumor necrosis factor-TNFα) and pathogens (viruses and bacteria). Viral genomes were detected in 50/80 (62.5%) children. Rhinovirus, the principal detected virus (26/50, 52%), occurred more frequently in male children. Higher percentages of BAL neutrophils and IL-8 values were detected in virus positive than negative children. ECP values resulted significantly higher in the children with rhinovirus than in those with other viruses. No other statistically significant correlation between viral findings and clinical/biohumoral data were found. Respiratory viruses, especially rhinovirus, seem to play an important role in children with R/CLRDs. They are associated with changes in BAL cellularity and inflammatory cytokines. Further studies are needed to confirm the persistence of viruses in these patients and to identify eventual therapeutic strategies.

Activating c-KIT mutations in a subset of thymic carcinoma and response to different c-KIT inhibitors.

BACKGROUND: To analyze a multi-institutional series of type C thymic carcinomas (TCs) (including neuroendocrine tumors), focusing on the expression and mutations of c-KIT. MATERIALS AND METHODS: Immunohistochemical expression of c-KIT/CD117, p63, CD5 and neuroendocrine markers, as well as mutational analysis of c-KIT exons 9, 11, 13, 14, 17 by direct sequencing of 48 cases of TCs. Immunohistochemical and molecular data were statistically crossed with clinicopathological features. RESULTS: Overall, 29 tumors (60%) expressed CD117, 69% were positive for CD5 and 85% (41 cases) for p63. Neuroendocrine markers stained all six atypical carcinoids and five poorly-differentiated thymic squamous cell carcinomas. Overall, six CD117-positive cases (12.5%) showed c-KIT mutation. No mutation was detected in CD117-negative tumors and carcinoids. All the mutations were found in poorly-differentiated thymic squamous cell carcinomas expressing CD117, CD5, p63 and lacking neuroendocrine markers (6 of 12 cases with these features). Mutations involved exon 11 (four cases: V559A, L576P, Y553N, W557R), exon 9 (E490K) and exon 17 (D820E). CONCLUSIONS: All TCs need an immunohistochemical screening with CD117, while c-KIT mutation analysis is mandatory only in CD117-positive cases, particularly when coexpressing CD5 and p63, lacking neuroendocrine differentiation. The finding of c-KIT mutation can predict efficacy with different c-KIT inhibitors.

Synovial colony-stimulating factor-1 mRNA expression in diffuse pigmented villonodular synovitis.

OBJECTIVES: To delineate the molecular mechanisms underlying the process of the diffuse-type giant cell tumours, also called pigmented villonodular synovitis, a rare, aggressive condition of the synovium, the knee synovial tissue expression of colony-stimulating factor-1 gene, as detected by real-time polymerase chain reaction, was compared between patients affected with pigmented villonodular knee synovitis and knee meniscal tears, or persistent gonoarthitis. METHODS: Multiple synovial biopsies of the knee were performed by arthroscopy in five consecutive patients affected by diffuse pigmented villonodular knee synovitis and in 12 patients affected by knee meniscal tears (n. 6) or persistent active gonarthritis (n. 6), recruited from the patients attending the Rheumatology Day Surgery Outpatient Clinic of the University of Padova Hospital. The ethics committee approved the study protocol and the participants signed consent statements after being informed about the content of the study. The diagnosis was made on the basis of a histological examination. The colony-stimulating factor-1 gene expression was assessed by reverse transcription followed by real-time polymerase chain reaction. RESULTS: The detection by RT-PCR of synovial colony-stimulating factor-1 mRNA showed a wide spectrum of expression in the three groups of distinct knee joint disease affected patients, with significantly higher level of colony-stimulating factor-1 mRNA expression in synovial tissue of pigmented villonodular synovitis, in comparison to that of knee meniscal injuries and persistent gonoarthritis patients. CONCLUSIONS: Our findings point out to an important role of colony-stimulating factor-1 in pigmented villonodular knee synovitis disease process and support the idea that colony-stimulating factor-1/colony-stimulating factor-1 receptor interaction may represent a potential therapeutic target of this disease.

Noneosinophilic asthma in children: relation with airway remodelling.

Noneosinophilic asthma is increasingly recognised as an important clinical-pathological phenotype in adults. However, this entity has scarcely been investigated in children. In particular, it is unknown whether airway remodelling would develop in children with non-eosinophilic asthma to the same degree as in children with eosinophilic disease. We analysed bronchial biopsies from 80 children undergoing bronchoscopy for appropriate clinical indications: 21 with noneosinophilic asthma, 34 with eosinophilic asthma and 25 control children. Features of airway remodelling - basement membrane thickening, epithelial loss and angiogenesis - and immune activation - inflammatory infiltrate, interleukin (IL)-4, IL-5, transforming growth factor (TGF)-ß, TGF-ß receptor type II - were quantified by histology and immunohistochemistry. The main components of airway remodelling were present in children with noneosinophilic asthma just as in those with eosinophilic disease. Indeed, compared with control children, both noneosinophilic and eosinophilic asthmatic children had thickened basement membrane, increased epithelial loss and higher number of vessels. Moreover, in both groups of asthmatics, expression of IL-4 and IL-5 was increased, while that of TGF-ß receptor type II was reduced, compared with controls. This study demonstrates that structural changes typical of asthma develop in asthmatic children even in the absence of a prominent eosinophilic infiltrate, indicating that other mechanisms, besides eosinophilic inflammation, may promote airway remodelling early in life.

Frozen-section diagnosis in donor livers: error rate estimation of steatosis degree.

A high degree of macrovesicular steatosis is associated with a significant risk of graft dysfunction. Most centers, including ours, consider 60% the limit value for transplantability, while others have adopted 30% as a cutoff. Pretransplant frozen-section (PFS) evaluation is used for reliable quantification of steatosis. However, the accuracy of PFS analysis for the degree of steatosis has largely been debated due to its high grade of variability and subjectivity. The aim of our study was to evaluate the accuracy of PFS diagnosis compared with subsequent paraffin histology samples. We retrospectively analyzed PFS from 52 consecutive liver donors. All PFS were blindly reviewed by two pathologists. The results were graded according to two classifications: (A) lower or higher than 60% steatosis, or (B) mild (0%-30%), moderate (30%-60%), or severe (>60%) steatosis. The rate of error for A (two-grade classification score) was 1.9% with the erroneous discharge of a viable organ. The error rate for B (three-grade classification score) was 7.7% with four discrepancies. In three cases, the discrepancy was related to the mild to moderate cutoff value, leading to a clinical error rate of 5.8% (discharging organs with statosis >30%, when we used more strict criteria). Our study validated PFS analysis as a reliable technique when the maximum value for organ transplantation was 60% steatosis. There was a higher error rate when a cutoff value of 30% was used. This finding suggests the usefulness of another technique to support a more precise steatosis evaluation.

Post-transplant lymphoproliferative disorders in liver transplanted patients: a single-centre experience.

Post-transplant lymphoproliferative disorder (PTLD) is a life-threatening complication after solid organ transplantation. Reduction of immunosuppression (RI) is accepted as a first step treatment with a long-term complete response rate observed in 23-50% of patients. Chemotherapy for diseases refractory to RI is based on small cohorts treated with different regimens. This paper reports on 10 consecutive cases of PTLD after liver transplantation. The median time from transplantation to PTLD diagnosis was 5 years. PTLD was frequently extranodal involving the transplanted liver. Seven monomorphic PTLD, 2 polymorphic and one Hodgkin disease were observed. Epstein Barr virus was present in tumour tissue only in one case. Initial therapy included RI in all patients. Chemotherapy was used in eight patients. No treatment-related mortality was observed and no patient developed graft rejection during chemotherapy. At a median follow-up period of 25 months, 6 of the 10 patients were alive and without evidence of disease.

Molecular pathways involved in synovial cell inflammation and tumoral proliferation in diffuse pigmented villonodular synovitis.

Diffuse-type tenosynovial giant cell tumors, also known as pigmented villonodular synovitis, are unique mesenchymal lesions that arise from the synovial tissue of the joints. They are predominantly intraarticular, aggressive, infiltrative processes, characterized by both inflammatory or neoplastic properties and local destructive progression. The pattern of synovial gene and protein expressions in pigmented villonodular synovitis, similar to those in activated macrophages in rheumatoid arthritis, and the phenotype of multinucleated giant cells, characteristic of osteoclasts, suggest that there is a common autocrine mechanism in osteoclast differentiation in both diseases and indicate the potential utility of tumor necrosis factor (TNF)-alpha blockade. High synovial colony stimulating factor 1 (CSF1) messenger RNA (m RNA) expression in pigmented villonodular synovitis, unrelated to a chromosomal translocation involving CSF1 locus, may indicate that there is a synergic paracrine loop mediated by TNF-alpha and CSF1, as shown in both inflammatory and neoplastic conditions. The effects of a new therapeutic approach consisting in intraarticular TNF-alpha blockade were studied in four pigmented villonodular synovitis knees. Knee injections produced a rapid reduction in clinical and sonographic indexes and immunohistological alterations, confirmed by arthroscopic synovectomy. A delayed relapse in one of the four knees and unaltered synovial CSF1 expression were other important findings. In the light of these observations, CSF1/CSF1R interaction probably represents a more sensible therapeutic target than TNF-alpha blockade in the diffuse form of pigmented villonodular synovitis.

Total duodenectomy with enteric duct drainage: a rescue operation for duodenal complications occurring after pancreas transplantation.

Duodenal graft complications (DGC) occur frequently after pancreas transplantation but rarely cause graft loss. Graft pancreatectomy, however, may be required when DGC compromise recipient's safety. We herein report on two patients with otherwise untreatable DGC in whom the entire pancreas was salvaged by means of total duodenectomy with enteric drainage of both pancreatic ducts. The first patient developed recurrent episodes of enteric bleeding, requiring hospitalization and blood transfusions, starting 21 months after transplantation. The disease causing hemorrhage could not be defined, despite extensive investigations, but the donor duodenum was eventually identified as the site of bleeding. The second patient was referred to us with a duodenal stump leak, 5 months after transplantation. Two previous surgeries had failed to seal the leak, despite opening a diverting stoma above the duodenal graft. Thirty-nine and 16 months after total duodenectomy with dual duct drainage, respectively, both patients are insulin-independent and free from abdominal complaints. Magnetic resonance pancreatography shows normal ducts both basal and after intravenous injection of secretin. The two cases presented herein show that when DGC jeopardize pancreas function or recipient safety, total duodenectomy with enteric duct drainage may become an option.

Small airways diseases.

The histopathology of the small airways is frequently quite subtle, even in cases with clinically severe disease. In the present paper, we will demonstrate some recognizable straightforward pathological changes in the small airways, and also provide a list of clinico-pathological conditions that should be considered when each is encountered. In the second part of the paper, we will briefly overview some general histological patterns of lesions and specific diseases that may involve the small airways. The basic lesions will be subdivided into inflammatory (acute, chronic, granulomatous, with or without necrosis), proliferative (epithelial or mesenchymal), and remodeling reactions. Inflammatory and proliferative reactions may lead to a the third category of remodeling reactions, characterized by a variety of distortions of normal bronchiolar architecture, including occlusion, constriction, dilatation (with or without mucostasis), tortuosity and nodularity. In addition to this schematic distinction, it is important to recognize that these lesions are frequently combined together and evolve with one another. Each of the 3 reaction patterns may be exquisitely bronchiolar, or may extend in the surrounding parenchyma. In this case, it is important to distinguish between lesions that extend from the bronchiole to the parenchyma or vice versa (such as in organizing pneumonia patterns, where the main lesion is in the parenchyma). As most of these lesions are part of a dynamic process, it is important to recognize that a single causative agent may produce distinct pathologic features at different times in the natural history of the disease. In addition, the same clinical disease may result in a variety of pathologic lesions. Accordingly, there may be not always be an unequivocal relationship between the clinical disease/condition and specific histopathologic lesions in the small airways.