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We assessed the clinical impact of MMP-9 expression on long-term survival in patients with operable non-small cell lung cancer (NSCLC). Primary tumors of 143 consecutive patients with NSCLC resected completely and without overt distant metastases (pT1-4, pN0-2, M0, R0) were examined for MMP-9 expression using immunohistochemistry with a polyclonal, affinity-purified rabbit antibody that recognizes both latent and active MMP-9. Immunohistochemical staining of tumor cells was evaluated in comparison to normal bronchiolar epithelium that served as an internal positive control. MMP-9 expression was categorized into negative, <5% tumor cells stained; heterogeneous, >5% and <95% tumor cells stained; and homogeneous, >95% The standard treatment for early stage NSCLC is surgery resulting in a 5-year survival rate of only 50 -60% in Stage I and II. 5,6 A better understanding of the molecular mechanisms of lung cancer progression might help to identify patients at risk for an unfavorable outcome with potential consequences for adjuvant therapy.Penetration of basement membranes and degradation of extracellular matrix are essential steps in the dissemination of tumor cells from primary tumors to distant organs. 7 One group of proteolytic enzymes that has been associated with these abilities is the matrix metalloproteinase family (MMP). Matrix metalloproteinase 9 (MMP-9) (92 kDa Type IV collagenase or gelatinase B) has the potency to degrade gelatin and Type IV collagen, 8 which is a major component of basement membranes. The clinical relevance of MMP 9 in NSCLC remains in discussion. First clinical trials investigating the efficacy of MMP-inhibitors in advanced cancer were rather disappointing. 9 Furthermore, previous studies examining the prognostic impact of immunohistochemical detection of MMP-9 in NSCLC 10,11 are discussed controversially because they did not demonstrate an independent prognostic impact of MMP-9 considering all standard prognostic factors included in the international system for staging lung cancer. 6 To clarify the prognostic impact of MMP 9 in operable NSCLC, we applied a new immunohistochemical evaluation system, focusing on homogeneous expression of MMP-9. The prognostic value was analyzed in relation to established prognostic factors of the TNM-system. Our study shows that the prognostic impact of homogeneous MMP-9 expression remains independent from possible prognostic joint effects of pT-status, pN-status, tumor histology and tumor grading. Because of this independence, MMP-9 may be considered as an interesting target for adjuvant anticancer therapy in operable NSCLC using selective MMP-inhibitors with high specificity for MMP-9. MATERIAL AND METHODS PatientsAfter approval by the ethical committee of the University of Munich and after written informed consent, tissue specimens of 147 consecutive patients with completely resected NSCLC were collected. The tumors were classified according to the international union against cancer (UICC) TNM-classification. 6 The preoperative staging of all patient...

To prevent postpneumonectomy bronchopleural fistula, coverage of the bronchial stump is recommended, especially for patients treated with neoadjuvant and adjuvant chemotherapy or radiochemotherapy. We compared outcomes after proximal pericardial fat pad coverage and coverage with pleura and surrounding tissues, by retrospective analysis of the records of 243 patients. Postpneumonectomy bronchopleural fistula occurred in 7/143 (4.9%) patients who had pericardial fat pad coverage, and in 6/100 (6.0%) treated by pleural covering. Bronchopleural fistula occurred in 11 patients within 21 days, in one after 2 months, and one after 6 months. Univariate analysis of comorbidities and risk factors did not show any significant differences between the groups. Advanced T stage and carcinomatous lymphangiosis at the resection margin were associated with a higher risk of bronchopleural fistula development, independent of the technique. Reinforcement of the bronchial stump by proximal pericardial fat pad coverage appears to be safe and feasible. It is comparable to coverage with pleura and surrounding tissues.

Congenital cystic adenomatoid malformation (CCAM) of the lung is a congenital lesion that is sometimes complicated by bronchioloalveolar adenocarcinoma (BAC). In some cases foci of atypical goblet cell hyperplasia (AGCH) can be found within the cysts. It has been proposed that CCAM and AGCH predispose to the development of BAC. The present study used comparative genomic hybridization (CGH) to screen 22 cases of CCAM (epithelium, surrounding normal lung tissue, and both preneoplastic and neoplastic lesions) for chromosomal imbalances. Of these 22 cases, 10 were CCAM type 1, 10 were type 2, and 2 were type 3. Of the 10 cases of CCAM type 1, 2 were associated with AGCH, 1 was associated with atypical adenomatous hyperplasia (AAH) and associated tubular adenocarcinoma (AC), and 2 were associated with BAC (1 mucinous and 1 predominantly nonmucinous). The present study also involved immunohistochemistry for interleukin (IL)-13, IL-4 receptor-alpha (IL-4r alpha), cytokines involved in the differentiation of goblet cells, and mucin 2 protein (Muc2). Chromosomal aberrations were not detected in the epithelium or the surrounding normal lung tissue, whereas varying aberrations were found in the neoplastic lesions. The most frequent genomic imbalances observed in both AGCH and the carcinomas were gains in chromosomes 2 and 4. Interestingly, a predominance of gains was also reported in AC of nonsmokers. Chromosomal aberrations in AGCHs arising in CCAMs support their preneoplastic status. Nuclear expression of IL-13, IL-4r alpha, and Muc2 was detected in AGCH, whereas a cytoplasmic and nuclear reaction was seen in normal epithelium. This likely reflects an association with goblet cell differentiation, but it also drives proliferation in AGCH.

SummaryExtranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) comprises 7-8% of B-cell lymphomas and commonly originates from a background of long-standing chronic inflammation. An association with distinct bacteria species has been confirmed for several anatomical sites of MALT lymphoma. For pulmonary MALT lymphoma, however, a clear link with an infectious agent or autoimmune disorder has not yet been reported. Using a 16S rRNA gene-based approach, we have recently identified Achromobacter (Alcaligenes) xylosoxidans in eight of nine cases of pulmonary MALT lymphoma. A. xylosoxidans is a gram-negative betaproteobacterium with low virulence, but high resistance to antibiotic treatment. To further examine a potential association with A. xylosoxidans, 124 cases of pulmonary MALT lymphoma and 82 control tissues from six European countries were analysed using a specific nested PCR. Although prevalence rates for A. xylosoxidans varied significantly from country to country, they were consistently higher for MALT lymphoma as compared to controls. Overall, 57/124 (46%) pulmonary MALT lymphomas and 15/ 82 (18%) control tissues were positive for A. xylosoxidans (P = 0Á004). Whether the significant association of A. xylosoxidans with pulmonary MALT lymphoma demonstrated in our study points to a potential causal role in the pathogenesis of this lymphoma will require further studies.