Matrix metalloproteinase-2 status in stromal fibroblasts, not in tumor cells, is a significant prognostic factor in non-small-cell lung cancer.

PURPOSE: The purpose is to assess clinical significance of matrix metalloproteinase (MMP)-2 and MMP-9 status, especially MMP-2 status, in stromal cells in non-small-cell lung cancer (NSCLC) because experimental studies have revealed that stromal MMP-2 plays important roles in progression of malignant tumors, but most clinical studies focused on tumoral MMP-2 expression, not stromal MMP-2 expression. EXPERIMENTAL DESIGN: We conducted a retrospective study on MMP-2 and MMP-9 expression as evaluated immunohistochemically in a total of 218 consecutive patients with completely resected pathological stage I-IIIA, NSCLC. RESULTS: Strong MMP-2 expression in tumor cells and stromal fibroblasts were documented in 54 (24.8%) and 132 (60.6%) patients, respectively. Strong MMP-2 expression in stromal fibroblasts was more frequently seen in squamous cell carcinoma (72.7%) than in adenocarcinoma (54.9%; P = 0.016). Tumors showing strong MMP-2 expression in stromal fibroblasts showed a significantly higher intratumoral microvessel density (IMVD) than weak stromal MMP-2 tumors (mean intratumoral microvessel density, 50.9 versus 32.4, P = 0.003). In addition, postoperative prognosis of strong stromal MMP-2 patients was significantly poorer than that of weak stromal MMP-2 patients (5-year survival rate, 77.5 versus 60.2%, P = 0.032), and the prognostic significance was enhanced in squamous cell carcinoma patients but disappeared in adenocarcinoma patients. Multivariate analyses confirmed that strong stromal MMP-2 expression was a significant factor to predict a poor prognosis in squamous cell carcinoma patients, not in adenocarcinoma patients. In contrast, MMP-2 or MMP-9 status in tumor cells was not a significant prognostic factor. CONCLUSIONS: MMP-2 status in stromal fibroblasts, not in tumor cells, was a significant prognostic factor associated with angiogenesis in NSCLC.     

Biological features and preoperative evaluation of mediastinal nodal status in non-small cell lung cancer

Background. To examine whether biological features of primary tumor can help preoperative evaluation of mediastinal nodal status in non-small cell lung cancer.

Methods. A total of 450 patients who underwent tumor resection and mediastinal dissection were reviewed. p53 status and proliferative fraction (PI) were evaluated immunohistochemically.

Results. The accuracy of preoperative evaluation of mediastinal nodal status with computed tomography (CT) was 72.2%; mediastinal nodal metastases had not been revealed until operation in 59 patients (13.1%) (false-negative), and no metastasis was revealed in 66 patients (14.7%) although mediastinal nodal enlargement had been demonstrated by CT (false-positive). The number of false-negative patients was significantly larger when p53 aberrant expression was positive or when PI was higher. Combined with p53 status and PI, there were 27 false-negatives (24.1%) among patients with aberrant p53 expression and higher PI, whereas only two false-negatives (1.5%) among those with negative p53 expression and lower PI.

Conclusions. Mediastinoscopy may be recommended for tumor showing aberrant p53 expression and higher PI, even when CT demonstrates no mediastinal nodal enlargement.     

Improved PCR amplification for molecular analysis using DNA from long-term preserved formalin-fixed,paraffin-embedded lung cancer tissue specimens

Archival tissue specimens are valuable resources of materials for molecular biological analyses in retrospective studies, especially for rare diseases or those associated with exposure to uncommon environmental events. Although successful amplification with PCR is essential for analysis of DNA extracted from archival formalin-fixed, paraffin-embedded (FFPE) tissue specimens, we have often encountered problems with poor PCR amplification of target fragments. To overcome this, we examined whether heat treatment in alkaline solution could efficiently restore the PCR template activity of DNA that had already been extracted from FFPE lung cancer tissue specimens. The effect of the heat treatment was assessed by PCR for the TP53 gene and other lung cancer-related gene loci. The heat treatment of DNA samples in borate buffer resulted in successful PCR amplification of DNA fragments ranging from 91 to 152 bp. This technique for restoration of template activity of DNA for PCR amplification is very simple and economical, and requires no special apparatus, so it may be applicable for molecular analysis of DNA samples from FFPE tissue specimens at various laboratories.     

Hairy polyp can be lethal even when small in size

A case of sudden cardiopulmonary arrest in a 3‐month‐old girl is presented. The patient had barely recovered from hypoxic encephalopathy when she presented with repeated respiratory distress. Computed tomography and endoscopic analysis revealed a shiny polyp in the lateral wall of the nasopharynx, and this polyp was suspected to be the main cause of respiratory distress. After referral to our hospital, surgical removal was performed, and the histopathological diagnosis was hairy polyp. Hairy polyp is a rare congenital benign tumor that sometimes induces respiratory distress. This polyp can potentially induce a life‐threatening event. In a systematic review of 40 reported cases, polyps of ≤3.0 cm in diameter have a higher risk of respiratory distress than do those >3.0 cm in diameter (P = 0.01). Small hairy polyps may be lethal because of delayed diagnosis. To locate small hairy polyps, physicians should not hesitate to perform further examination because there is the possibility of oversight with only physical examination.     

Sudden Onset of Platypnea-Orthodeoxia Syndrome Caused by Traumatic Tricuspid Regurgitation With Ruptured Chordae Tendineae After Blunt Chest Trauma

An 86-year-old man was admitted our hospital because of sudden onset of dyspnea after blunt chest trauma. Because his oxygen saturation deteriorated from 92% in the supine position to 86% in the sitting position, platypnea-orthodeoxia syndrome was suspected. Transesophageal echocardiography showed severe tricuspid regurgitation (TR) caused by anterior papillary muscle rupture. Furthermore, right-to-left shunt with TR through a patent foramen ovale (PFO) was observed. The diagnosis was therefore platypnea-orthodeoxia syndrome with right-to-left shunt through PFO with shunting exacerbated by acute severe TR after blunt chest trauma. The patient underwent urgent tricuspid valve repair and PFO closure and has remained asymptomatic postoperatively.     

IL-1 is required for tumor invasiveness and angiogenesis

Here, we describe that microenvironmental IL-1 beta and, to a lesser extent, IL-1 alpha are required for in vivo angiogenesis and invasiveness of different tumor cells. In IL-1 beta knockout (KO) mice, local tumor or lung metastases of B16 melanoma cells were not observed compared with WT mice. Angiogenesis was assessed by the recruitment of blood vessel networks into Matrigel plugs containing B16 melanoma cells; vascularization of the plugs was present in WT mice, but was absent in IL-1 beta KO mice. The addition of exogenous IL-1 into B16-containing Matrigel plugs in IL-1 beta KO mice partially restored the angiogenic response. Moreover, the incorporation of IL-1 receptor antagonist to B16-containing plugs in WT mice inhibited the ingrowth of blood vessel networks into Matrigel plugs. In IL-1 alpha KO mice, local tumor development and induction of an angiogenic response in Matrigel plugs was less pronounced than in WT mice, but significantly higher than in IL-1 beta KO mice. These effects of host-derived IL-1 alpha and IL-1 beta were not restricted to the melanoma model, but were also observed in DA/3 mammary and prostate cancer cell models. In addition to the in vivo findings, IL-1 contributed to the production of vascular endothelial cell growth factor and tumor necrosis factor in cocultures of peritoneal macrophages and tumor cells. Host-derived IL-1 seems to control tumor angiogenesis and invasiveness. Furthermore, the anti-angiogenic effects of IL-1 receptor antagonist, shown here, suggest a possible therapeutic role in cancer, in addition to its current use in rheumatoid arthritis.