Increased IgA Expression in Lung Lymphoid Follicles in Severe Chronic Obstructive Pulmonary Disease.

RATIONALE: Accumulation of B cells and lymphoid follicles (LFs) has been described in chronic obstructive pulmonary disease (COPD) airways, but the functional status of lung B cells remains poorly known. OBJECTIVES: To characterize LFs for expression of IgA, the main mucosal antibody. METHODS: The presence of B cells and LFs, including intrafollicular IgA expression, were determined in the lung from patients with COPD (n = 37) versus control subjects (n = 34) by immunohistochemistry. We also evaluated follicular IgA responses in the lungs from mice infected with Pseudomonas aeruginosa (PAO1) (n = 10 per group) and in smoking mice. MEASUREMENTS AND MAIN RESULTS: Whereas in smokers B-cell numbers slightly increased, robust increases in B-cell and LF numbers (mainly in distal airways) were only observed in severe COPD. Most follicular B cells were IgM+ (70-80%), but IgA+ (and not IgG+) B-cell numbers were increased in LFs from severe COPD compared with control subjects (twofold, 44.7% vs. 25.2%), and this was significant in distal but not proximal airways. Follicular IgA response was also observed in PAO1-infected mouse lungs, but not after smoke exposure. Moreover, follicular IgA expression associated with expression of IL-21, which was very potent to activate immunoglobulin production in vitro. CONCLUSIONS: This study shows that IgA production occurs in peribronchiolar LFs from severe COPD, where IL-21-producing T cells are present, and presumably represents a feature of exacerbated mucosal adaptive immune responses against microbial and/or self-antigens.

Diagnostic Accuracy and Safety of CT-Guided Percutaneous Transthoracic Needle Biopsies: 14-Gauge versus 22-Gauge Needles.

PURPOSE: To compare the diagnostic accuracy and safety of a 14-gauge core needle versus a 22-gauge fine needle in the evaluation of thoracic lesions by CT-guided percutaneous transthoracic needle biopsy (TTNB). MATERIALS AND METHODS: Medical charts of all patients who underwent CT-guided percutaneous transthoracic core-needle biopsies (CNBs) with a 14-gauge Spirotome device (99 patients, 102 procedures) and fine-needle biopsies (FNBs) with a 22-gauge Rotex needle (92 patients, 102 procedures) between 2007 and 2013 at a single academic institution were retrospectively reviewed. Variables that could influence diagnostic accuracy and safety were collected. RESULTS: The overall and cancer-specific diagnostic accuracy rates were 90% and 94%, respectively, with CNB, versus 82% and 89% with FNB. Precise cancer type/subtype was provided by 97% of CNBs versus 65% of FNBs (P < .001). In patients with lung cancer considered for targeted therapy, biomarker analyses were feasible in 80% of CNBs versus 0% of FNBs (P < .001). The rate of pneumothorax was significantly higher with CNB versus FNB (31% vs 19%; P = .004), but chest tube insertion rates were similar (10% vs 11%, respectively). Major bleeding complications occurred in 1% of CNBs versus 2% of FNBs and were associated with one death in the CNB group. CONCLUSIONS: Percutaneous transthoracic CNB with a 14-gauge Spirotome needle provided better characterization of cancer lesions and allowed biomarker analyses without a significant increase in major procedural complications.

IL-1α induces CD11b(low) alveolar macrophage proliferation and maturation during granuloma formation.

Macrophages play a central role in immune and tissue responses of granulomatous lung diseases induced by pathogens and foreign bodies. Circulating monocytes are generally viewed as central precursors of these tissue effector macrophages. Here, we provide evidence that granulomas derive from alveolar macrophages serving as a local reservoir for the expansion of activated phagocytic macrophages. By exploring lung granulomatous responses to silica particles in IL-1-deficient mice, we found that the absence of IL-1α, but not IL-1ß, was associated with reduced CD11b(high) phagocytic macrophage accumulation and fewer granulomas. This defect was associated with impaired alveolar clearance and resulted in the development of pulmonary alveolar proteinosis (PAP). Reconstitution of IL-1α(-/-) mice with recombinant IL-1α restored lung clearance functions and the pulmonary accumulation of CD11b(high) phagocytic macrophages. Mechanistically, IL-1α induced the proliferation of CD11b(low) alveolar macrophages and differentiated these cells into CD11b(high) macrophages which perform critical phagocytic functions and organize granuloma. We newly discovered here that IL-1α triggers lung responses requiring macrophage proliferation and maturation from tissue-resident macrophages.

Improved Accuracy and Sensitivity in Diagnosis and Staging of Lung Cancer with Systematic and Combined Endobronchial and Endoscopic Ultrasound (EBUS-EUS): Experience from a Tertiary Center.

BACKGROUND: Combined endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided tissue acquisition (EUS-TA) are accurate procedures for the diagnosis and staging of mediastinal lymph nodes (MLNs) in lung cancer. However, the respective contribution of separate and combined procedures in diagnosis and staging has not been fully studied. The aim of this study was to assess their respective performances. METHODS: Patients with suspected malignant MLNs in lung cancer or recurrence identified by PET-CT who underwent combined EBUS-TBNA and EUS-TA were retrospectively reviewed. RESULTS: A total of 141 patients underwent both procedures. Correct diagnosis was obtained in 82% with EBUS-TBNA, 91% with EUS-TA, and 94% with the combined procedure. The overall sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of EBUS-TBNA, EUS-TA, and the combined procedure for diagnosing malignancy were [75%, 100%, 100%, 58%], [87%, 100%, 100%, 75%], and [93%, 100%, 100%, 80%], respectively, with a significantly better sensitivity of the combined procedure (p < 0.0001). Staging (82/141 patients) was correctly assessed in 74% with EBUS-TBNA, 68% with EUS-TA, and 85% with the combined procedure. The overall sensitivity, specificity, PPV, and NPV of EBUS-TBNA, EUS-TA, and the combined procedure for lung cancer staging were [62%, 100%, 100%, 55%], [54%, 100%, 100%, 50%], and [79%, 100%, 100%, 68%], respectively, significantly better in terms of sensitivity for the combined procedure (p < 0.001). CONCLUSION: The combined EBUS-EUS approach in lung cancer patients showed better accuracy and sensitivity in diagnosis and staging when compared with EBUS-TBNA and EUS-TA alone.

The memory of airway epithelium damage in smokers and COPD patients.

Chronic obstructive pulmonary disease (COPD), a devastating and irreversible lung disease, causes structural and functional defects in the bronchial epithelium, the (ir)reversibility of which remains unexplored in vitro. This study aimed to investigate the persistence of COPD-related epithelial defects in long-term airway epithelial cultures derived from non-smokers, smokers, and COPD patients. Barrier function, polarity, cell commitment, epithelial-to-mesenchymal transition, and inflammation were evaluated and compared with native epithelium characteristics. The role of inflammation was explored using cytokines. We show that barrier dysfunction, compromised polarity, and lineage abnormalities observed in smokers and COPD persisted for up to 10 wk. Goblet cell hyperplasia was associated with recent cigarette smoke exposure. Conversely, increased IL-8/CXCL-8 release and abnormal epithelial-to-mesenchymal transition diminished over time. These ex vivo observations matched surgical samples' abnormalities. Cytokine treatment induced COPD-like changes in control cultures and reactivated epithelial-to-mesenchymal transition in COPD cells. In conclusion, these findings suggest that the airway epithelium of smokers and COPD patients retains a multidimensional memory of its original state and previous cigarette smoke-induced injuries, maintaining these abnormalities for extended periods.

Treatment and Prognosis of Patients with Lung Cancer and Combined Interstitial Lung Disease.

BACKGROUND: Interstitial lung disease (ILD) is associated with a higher lung cancer (LC) risk and may impact cancer's clinical characteristics, treatment strategies, and outcomes. This impact's extent is unclear, particularly in Caucasians. METHODS: In this retrospective observational study, we reviewed the files of all LC patients diagnosed in a 38-month period. Expert radiologists reviewed the computed tomography scans performed at diagnosis. Patients with LC and ILD (n = 29, 7%) were compared to those without ILD (n = 363, 93%) for population and cancer characteristics, treatments, and clinical outcomes. RESULTS: Patients with LC and ILD were older (73 ± 8 vs. 65 ± 11 years; p < 0.001). There was no significant difference in LC histology, localization, stage, or treatment modalities. The respiratory complication rate after cancer treatment was significantly higher in the ILD group (39% vs. 6%; p < 0.01). Overall survival rates were similar at 12 (52% vs. 59%; p = 0.48) and 24 months (41% vs. 45%; p = 0.64) but poorer in the ILD group at 36 months, although not statistically significant (9% vs. 39%; p = 0.06). The ILD group had a higher probability of death (hazard ratio (HR) = 1.49 [0.96;2.27]), but this was not statistically significant (p = 0.06). In a Cox regression model, patients with ILD treated surgically had a significantly higher mortality risk (HR = 2.37 [1.1;5.09]; p = 0.03). CONCLUSIONS: Patients with combined LC and ILD have worse clinical outcomes even when similar treatment modalities are offered.

Platelet-derived growth factor-producing CD4+ Foxp3+ regulatory T lymphocytes promote lung fibrosis.

RATIONALE: There is evidence that CD4(+) effector T lymphocytes (T eff) participate in the development of lung fibrosis, but the role of their CD4(+) regulatory T-cell (T reg) counterparts remains to be determined. OBJECTIVES: To elucidate the contribution of T reg cells in a mouse model of lung fibrosis induced by silica (SiO(2)) particles. METHODS: Lung T reg and T eff cells purified from SiO(2)-treated Foxp3-GFP transgenic mice were cocultured with naive lung fibroblasts or transferred to the lungs of healthy mice. DEREG mice, which express the diphtheria toxin receptor under the control of the foxp3 gene, were used to deplete T reg cells during fibrogenesis. MEASUREMENTS AND MAIN RESULTS: CD4(+) Foxp3(+) T reg cells were persistently recruited in the lungs in response to SiO(2). T reg accumulation paralleled the establishment of pulmonary immunosuppression and fibrosis. T reg cells highly expressed platelet-derived growth factor (PDGF)-B via a TGF-ß autocrine signaling pathway, directly stimulated fibroblast proliferation in vitro, and increased lung collagen deposition upon transfer in the lung of naive mice. The direct profibrotic effects of T reg cells were abolished by the inhibitor of the PDGF-B/TGF-ß signaling pathway, imatinib mesylate. Neutralization of T reg-immunosuppressive activity resulted in enhanced accumulation of T eff cells and IL-4-driven pulmonary fibrogenesis, further demonstrating that T reg cells control T eff cell functions during inflammatory fibrosis. CONCLUSIONS: Our study indicates that T reg cells contribute to lung fibrosis by stimulating fibroblasts through the secretion of PDGF-B in noninflammatory conditions and regulate detrimental T eff cell activities during inflammation-related fibrosis.

Combining a new CO2 laser wave guide with transoral robotic surgery: a feasibility study on four patients with malignant tumors.

We present a series of patients treated by transoral robotic surgery (TORS) using a new CO(2) laser wave guide (CO(2) LWG) (Lumenis, Santa Clara, CA). Patients older than 18 years, with malignant pharyngo-laryngeal tumors were enrolled in this prospective study after signing an informed consent. Four patients were enrolled in the study. The mean age was 56 years. One patient had a T1 base of tongue tumor, two patients had supraglottic tumors (T1, T2), and one had a T1 palatine tonsil tumor. All the procedures could be performed using a Maryland forceps, a 0° endoscope and a CO(2) LWG introduced via the robotic arm introducer. The laser parameters were: superpulse or continuous mode, 7-15 W, continuous delivery. The average set-up time was 30 min. The average surgical time was 94 min. No complications were noted due to the intraoperative use of the robot or the CO(2) LWG. One laser fiber was used for each of the surgeries. The mean coagulation depth was 200 µm (range 100-300). The mean hospital stay was 6 days. The CO(2) LWG is a reliable tool for TORS. It allowed more than 1 h of work without any trouble.

Randomized Phase 2 Study Comparing Pathological Responses of Resected Colorectal Cancer Metastases after Bevacizumab with mFOLFOX6 or FOLFIRI (BEV-ONCO Trial).

Retrospective studies reported that preoperative oxaliplatin-based chemotherapy increased pathological response (PR) in patients resected for colorectal liver metastases (CRLM). This multicenter prospective randomized (1/1) phase II trial evaluated PR on resected CRLM after preoperative mFOLFOX6 (arm A) or FOLFIRI (arm B) + bevacizumab. The primary endpoint was the major pathological response rate (MPRR), defined as the percentage of patients presenting CRLMs with mean tumor regression grade (TRG) < 3. Secondary endpoints included safety, progression-free survival (PFS) and overall survival (OS). Out of 65 patients, 57 patients (28 and 29 in arm A/B) were resected for CRLM (one patient with lung metastases). Clinical and treatment characteristics were similar in both arms. One-month postoperative complications were 39.3%/31.0% in arm A/B (p = 0.585). MPRR and complete PR were 32.1%/20.7% (p = 0.379) and 14.3%/0.0% (p = 0.052) in arm A/B, respectively. PFS and OS were not different. Patients with PR among all CRLMs (max TRG ≤ 3; 43.8% of patients) had a lower risk of relapse (PFS: HR = 0.41, 95%CI = 0.204−0.840, p = 0.015) and a tendency towards better survival (OS: HR = 0.34, 95%CI = 0.104−1.114, p = 0.075). The homogeneity of PR was associated with improved PFS/OS. This trial fails to demonstrate a significant increase in MPRR in patients treated with mFOLFOX6-bevacizumab but confirms PR as an important prognostic factor.

Incidence and Prognosis of Biliary Tract and Gallbladder Cancers in a Belgian Academic Hospital.

BACKGROUND: Biliary tract and gallbladder cancers are rare tumors with a poor prognosis (except the ampulla type). The evolution of hepatobiliary cancer incidence varies widely around the world. According to the Belgian Cancer Registry, the number of hepatobiliary cancers has increased every year since 2004. MATERIALS AND METHODS: This retrospective study included patients diagnosed with cholangiocarcinoma, ampulla cancer, or gallbladder cancer at the university hospital, CHU UCL, Godinne site, in Namur, Belgium, between 1997 and 2017. The evolution of cancer incidence was evaluated with the Mann-Kendall method, by analyzing 7 consecutive 3-year periods. We calculated survival with the Kaplan-Meier method, and we determined prognostic factors with the log-rank test and Cox models. RESULTS: Between 1997 and 2017, we included 128 patients that were newly diagnosed in our center. According to the Mann-Kendall test, the evolution of the incidence of these cancers in our hospital increased significantly over the study period (Sen's slope = 7; p = 0.003). The 1-year overall survival was 53.0 ± 4.7%. Poor prognostic factors included age, cancer stage, local cancer extension, and metastatic disease. The independent prognostic factors of survival were age (p = 0.002), ampulla cancer (p < 0.001), and metastatic disease (p < 0.001). CONCLUSIONS: We found that the incidence of biliary tract and gallbladder cancers increased over a period of 20 years in our center. Further investigations are needed to determine the reasons for this increase. Although new therapies are emerging, the prognosis remains poor for these cancers. Determining risk factors might promote the development of preventive approaches.

Is frozen section reliable in transoral CO(2) laser-assisted cordectomies?

Endoscopic resection of laryngeal tumors is replacing external approaches. One drawback of endoscopic resection is the difficulty of interpretation of histological specimens because of thermal effect of laser on tissues. Our goal is to assess the reliability of frozen section in this setting by comparing its results with those of routine histology. We, retrospectively, reviewed the charts of all consecutive patients, who underwent cordectomies in our institution between January 2000 and 2008, using the CO(2) laser Acublade system (Lumenis, Santa Clara, CA). Age, sex, staging of the tumor, previous treatments, type of cordectomy, frozen section and routine histology results were analyzed. Ninety-seven patients fulfilled the inclusion criteria; 22.7% had severe dysplasia, 54.6% had T1 epidermoid carcinoma, 17.5% had T2 carcinoma and finally 5.2% had T3 carcinoma. We performed type I cordectomy in 36.1% of patients, type II cordectomy in 18.6%, type III cordectomy in 10.3%, type IV cordectomy in 5.2%, type V cordectomy in 28.9% and type VI cordectomy in 1% of patients. Most of the patients did not have any previous treatment. The mean number of margins per surgery was 2. Routine histological examination confirmed frozen section in 94.8% of the interventions. Frozen section is reliable in laser-assisted cordectomies, when performed by an experienced team; it has a high negative-predictive value. It can limit the need, cost and emotional stress of second look surgeries.

Structural defects play a major role in the acute lung toxicity of multiwall carbon nanotubes: toxicological aspects.

Experimental studies indicate that carbon nanotubes (CNTs) have the potential to induce adverse pulmonary effects, including alveolitis, fibrosis, and genotoxicity in epithelial cells. Here, we explored the physicochemical determinants of these toxic responses with progressively and selectively modified CNTs: ground multiwall CNTs modified by heating at 600 degrees C (loss of oxygenated carbon functionalities and reduction of oxidized metals) or at 2400 degrees C (annealing of structural defects and elimination of metals) and by grinding the material that had been heated at 2400 degrees C before (introduction of structural defects in a metal-deprived framework). The CNTs were administered intratracheally (2 mg/rat) to Wistar rats to evaluate the short-term response (3 days) in bronchoalveolar lavage fluid (LDH, proteins, cellular infiltration, IL-1beta, and TNF-alpha). The long-term (60 days) lung response was assessed biochemically by measuring the lung hydroxyproline content and histologically. In vitro experiments were also performed on rat lung epithelial cells to assess the genotoxic potential of the modified CNTs with the cytokinesis block micronucleus assay. The results show that the acute pulmonary toxicity and the genotoxicity of CNT were reduced upon heating but restored upon grinding, indicating that the intrinsic toxicity of CNT is mainly mediated by the presence of defective sites in their carbon framework.

Current state of scanning micromanipulator applications with the carbon dioxide laser.

OBJECTIVES: The development of the scanning system AcuBlade has considerably enhanced carbon dioxide laser energy delivery, improving cutting and ablation modes. The scanning system can be applied with the 2 available high-powered pulsed waves, SuperPulse and UltraPulse. This study was conducted to determine whether there are any differences in phonosurgery between the SuperPulse and UltraPulse lasing applications with regard to thermal diffusion into the surrounding tissues, healing time, and clinical results. METHODS: Thirteen patients with bilateral and similar vocal fold lesions underwent operation--one side in SuperPulse mode and the other side in UltraPulse mode. The parameters for phonosurgery were depth of 0.2 mm, 10 W, single pulse, and 0.10 second for SuperPulse, and 2 passes, 10 W, single pulse, and 0.10 second for UltraPulse. RESULTS: Incisions were sharper with UltraPulse, making the surgery easier, but at the first postoperative follow-up visit, after 8 to 10 days, no differences were observed in the presentation, the healing, or the vibration of the 2 vocal folds. Coagulation along the incision line was 25 microm for SuperPulse and 15 microm for UltraPulse (median values). CONCLUSIONS: In comparison with SuperPulse, the UltraPulse carbon dioxide laser made the procedure easier, but did not improve the clinical outcome.

Clinical application of targeted next-generation sequencing for colorectal cancer patients: a multicentric Belgian experience.

International guidelines made RAS (KRAS and NRAS) status a prerequisite for the use of anti-EGFR agents for metastatic colorectal cancer (CRC) patients. Daily, new data emerges on the theranostic and prognostic role of molecular biomarkers; this is a strong incentive for a validated, sensitive, and broadly available molecular screening test. Next-generation sequencing (NGS) has begun to supplant other technologies for genomic profiling. We report here our 2 years of clinical practice using NGS results to guide therapeutic decisions. The Ion Torrent AmpliSeq colon/lung cancer panel, which allows mutation detection in 22 cancer-related genes, was prospectively used in clinical practice (BELAC ISO 15189 accredited method). The DNA of 741 formalin-fixed paraffin-embedded CRC tissues, including primary tumors and metastasis, was obtained from 14 different Belgian institutions and subjected to targeted NGS. Of the tumors tested, 98% (727) were successfully sequenced and 89% (650) harbored at least one mutation. KRAS, BRAF and NRAS mutations were found in 335 (46%), 78 (11%) and 32 (4%) samples, respectively. These mutation frequencies were consistent with those reported in public databases. Moreover, mutations and amplifications in potentially actionable genes were identified in 464 samples (64%), including mutations in PIK3CA (14%), ERBB2 (0.4%), AKT1 (0.6%), and MAP2K1 (0.1%), as well as amplifications of ERBB2 (0.3%) and EGFR (0.3%). The median turnaround time between reception of the sample in the laboratory and report release was 8 calendar days. Overall, the AmpliSeq colon/lung cancer panel was successfully applied in daily practice and provided reliable clinically relevant information for CRC patients.

Circulating nucleosomes as new blood-based biomarkers for detection of colorectal cancer.

BACKGROUND: Colonoscopy is currently widely accepted as the gold standard for detection of colorectal cancer (CRC) providing detection of up to 95% of pre-cancerous lesions during the procedure. However, certain limitations exist in most countries including cost and access to the procedure. Moreover, colonoscopy is an invasive technique with risk inherent to the endoscopic procedure. For this reason, alternative screening tests, in particular, fecal occult blood-based tests, have been widely adopted for frontline screening. Limited compliance to colonoscopy and fecal screening approaches has prompted research on blood-based tests as an alternative approach to identifying individuals at risk who could then be referred for colonoscopy. Increased total levels of nucleosomes in the blood have been associated with tumor burden and malignancy progression. Here, we report for the first time, CRC-associated epigenetic profiles of circulating cell-free nucleosomes (cf-nucleosomes). METHODS: Levels of 12 epigenetic cf-nucleosome epitopes were measured in the sera of 58 individuals referred for endoscopic screening for CRC. RESULTS: Multivariate analysis defined an age-adjusted panel of four cf-nucleosomes that provided an AUC of 0.97 for the discrimination of CRC from healthy controls with high sensitivity at early stages (sensitivity of 75 and 86 at 90% specificity for stages I and II, respectively). A second combination of four cf-nucleosome biomarkers provided an AUC of 0.72 for the discrimination of polyps from the healthy group. CONCLUSIONS: This study suggests that a combination of different cf-nucleosome structures analyzed in serum samples by a simple ELISA is a promising approach to identify patients at risk of CRC.

Azithromycin reduces spontaneous and induced inflammation in DeltaF508 cystic fibrosis mice.

BACKGROUND: Inflammation plays a critical role in lung disease development and progression in cystic fibrosis. Azithromycin is used for the treatment of cystic fibrosis lung disease, although its mechanisms of action are poorly understood. We tested the hypothesis that azithromycin modulates lung inflammation in cystic fibrosis mice. METHODS: We monitored cellular and molecular inflammatory markers in lungs of cystic fibrosis mutant mice homozygous for the DeltaF508 mutation and their littermate controls, either in baseline conditions or after induction of acute inflammation by intratracheal instillation of lipopolysaccharide from Pseudomonas aeruginosa, which would be independent of interactions of bacteria with epithelial cells. The effect of azithromycin pretreatment (10 mg/kg/day) given by oral administration for 4 weeks was evaluated. RESULTS: In naive cystic fibrosis mice, a spontaneous lung inflammation was observed, characterized by macrophage and neutrophil infiltration, and increased intra-luminal content of the pro-inflammatory cytokine macrophage inflammatory protein-2. After induced inflammation, cystic fibrosis mice combined exaggerated cellular infiltration and lower anti-inflammatory interleukin-10 production. In cystic fibrosis mice, azithromycin attenuated cellular infiltration in both baseline and induced inflammatory condition, and inhibited cytokine (tumor necrosis factor-alpha and macrophage inflammatory protein-2) release in lipopolysaccharide-induced inflammation. CONCLUSION: Our findings further support the concept that inflammatory responses are upregulated in cystic fibrosis. Azithromycin reduces some lung inflammation outcome measures in cystic fibrosis mice. We postulate that some of the benefits of azithromycin treatment in cystic fibrosis patients are due to modulation of lung inflammation.

The role of pro- and anti-inflammatory responses in silica-induced lung fibrosis.

BACKGROUND: It has been generally well accepted that chronic inflammation is a necessary component of lung fibrosis but this concept has recently been challenged. METHODS: Using biochemical, histological, immunohistochemistry, and cellular analyses, we compared the lung responses (inflammation and fibrosis) to fibrogenic silica particles (2.5 and 25 mg/g lung) in Sprague-Dawley rats and NMRI mice. RESULTS: Rats treated with silica particles developed chronic and progressive inflammation accompanied by an overproduction of TNF-alpha as well as an intense lung fibrosis. Dexamethasone or pioglitazone limited the amplitude of the lung fibrotic reaction to silica in rats, supporting the paradigm that inflammation drives lung fibrosis. In striking contrast, in mice, silica induced only a limited and transient inflammation without TNF-alpha overproduction. However, mice developed lung fibrosis of a similar intensity than rats. The fibrotic response in mice was accompanied by a high expression of the anti-inflammatory and fibrotic cytokine IL-10 by silica-activated lung macrophages. In mice, IL-10 was induced only by fibrotic particles and significantly expressed in the lung of silica-sensitive but not silica-resistant strains of mice. Anti-inflammatory treatments did not control lung fibrosis in mice. CONCLUSION: These results indicate that, beside chronic lung inflammation, a pronounced anti-inflammatory reaction may also contribute to the extension of silica-induced lung fibrosis and represents an alternative pathway leading to lung fibrosis.

[A-leukemic caecal myeloid sarcoma: a difficult diagnosis]. / Localisation caecale d'un sarcome myéloïde a-leucémique: un diagnostic difficile.

Myeloid sarcoma is a malignant neoplasia composed of abnormal myeloid or monocytic cells, often localized in bones, but also rarely in extra-medullary sites such as lymph nodes, skin and soft tissue. We report a case of caecal myeloid sarcoma, diagnosed in a 60 year old woman who complained from abdominal pain and weight loss, in absence of any medullary disorder. Initially misdiagnosed as a B lymphoma because of a weak positivity for CD79a, the diagnosis of primitive caecal myeloid sarcoma was eventually established after further investigations showing a positivity for lysozyme and myeloperoxidase. This report of such a rare clinical and pathological presentation of a myeloid sarcoma underlines a difficult differential diagnosis for which adequate immunohistochemistry, including lysozyme and myeloperoxydase is mandatory.

Small bowel adenocarcinomas complicating Crohn's disease are associated with dysplasia: a pathological and molecular study.

BACKGROUND: Crohn's disease (CD) is associated with an increased risk of small bowel adenocarcinoma (SBA). However, there are no guidelines for the screening and early diagnosis of SBA. Colorectal cancer associated with chronic colitis arises from dysplasia. High-risk patients benefit from surveillance colonoscopies aimed to detect dysplasia. The dysplasia-carcinoma sequence remains poorly documented in CD-associated SBA. Moreover, molecular data about SBA complicating CD and associated dysplasia are very limited. We therefore assessed dysplasia and several key molecular markers of carcinogenesis in SBA and dysplasia developed in patients with CD. METHODS: Forty-five SBA complicating CD and 4 specimens with dysplasia without SBA were screened. In SBA, we looked for dysplasia and determined their pathological characteristics (type, grade, distribution). We also stained for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), p53, ß-catenin, and p16 and looked for KRAS, BRAF and PIK3CA mutations. RESULTS: All neoplastic lesions, except 1 lesion, were found in inflamed mucosal areas. Dysplasia was found in 20 of 41 patients with SBA (49%). Dysplasia was flat or raised, low grade or high grade, and adjacent or distant to concomitant SBA. Molecular markers of SBA carcinogenesis complicating CD were similar to those observed in chronic colitis-related colorectal cancer (KRAS, BRAF, p53, MSI), although differences were observed for ß-catenin and p16. No PIK3CA mutations were observed. CONCLUSIONS: These results suggest that there is an inflammation-dysplasia-adenocarcinoma sequence in at least half of CD-related SBA, similar to what is observed in chronic colitis-related colorectal cancer and may have implications for the prevention and treatment of this cancer.