Takanori Kanematsu

Phosphorylation, but not overexpression, of epidermal growth factor receptor is associated with poor prognosis of non-small cell lung cancer patients.

Epidermal growth factor receptor (EGFR) is commonly overexpressed in non-small cell lung cancer (NSCLC) and its tyrosine kinase phosphorylation is thought to be an ideal target in the treatment of patients with NSCLC. In the present study, we examined surgically obtained specimens from a series of 36 NSCLC patients for expression of EGFR, phosphorylated EGFR (p-EGFR), and HER2 by immunohistochemistry, and also examined the correlation with clinical characteristics. The positive rate of EGFR, p-EGFR, and HER2 was 97.2%, 44.4%, and 88.6%, respectively, and the overexpression rate was 80.6%, 0.0%, and 27.8%, respectively. EGFR overexpression and phosphorylation were seen at almost the same rate in each histological type of squamous and nonsquamous cell carcinoma (squamous vs. nonsquamous; 78.6% vs. 81.8% for EGFR, 35.7% vs. 50.0% for p-EGFR), while HER2 overexpression was seen less frequently in squamous cell carcinoma than in nonsquamous cell carcinoma (0.0% vs. 45.5%, P = 0.003). Univariate analysis revealed that EGFR overexpression was related to good performance status (P = 0.038) but not related to EGFR phosphorylation. EGFR phosphorylation was correlated to short time to progression (TTP) (P = 0.002) and poor prognosis (P = 0.002), although EGFR overexpression, HER2 overexpression, or EGFR-HER2 coexpression were not correlated to TTP or survival. Bivariate analysis showed EGFR phosphorylation was related to short TTP and poor prognosis both in early and advanced stages. Multivariate analyses confirmed that clinical stage, performance status, and p-EGFR expression were independently associated with increasing risk of short TTP and poor prognosis. These results suggest that phosphorylation, but not overexpression, of EGFR may be an important predictor for clinical outcome of NSCLCs.

Multifunctional interleukin‐1β promotes metastasis of human lung cancer cells in SCID mice via enhanced expression of adhesion‐, invasion‐ and angiogenesis‐related molecules

We examined whether interleukin‐1 (IL‐1), a multifunctional proinflammatory cytokine, progresses or regresses metastasis of lung cancer. Exogenous IL‐lβ enhanced expression of various cytokines (IL‐6, IL‐8, and vascular endothelial growth factor (VEGF)) and intracellular adhesion molecule‐1 (ICAM‐1) by A549, PC14, RERF‐LC‐AI, and SBC‐3 cells expressing IL‐1 receptors. A549 cells transduced with human IL‐1β‐gene with the growth‐hormone signaling‐peptide sequence (A549/IL‐1β) secreted a large amount of IL‐1β protein. Overexpression of IL‐1β resulted in augmentation of expression of the cytokines, ICAM‐1, and matrix metallo‐proteinase‐2 (MMP‐2). A549/IL‐1β cells intravenously inoculated into severe combined immunodeficiency (SCID) mice distributed to the lung more efficiently and developed lung metastasis much more rapidly than did control A549 cells. Treatment of SCID mice with anti‐IL‐1β antibody inhibited formation of lung metastasis by A549/IL‐1β cells. Moreover, A549/IL‐1β cells inoculated in the subcutis grew more rapidly, without necrosis, than did control A549 cells, which produced smaller tumors with central necrosis, suggesting involvement of angiogenesis in addition to enhanced binding in the high metastatic potential of A549/IL‐1β cells. Histological analyses showed that more host‐cell infiltration, fewer apoptotic cells, more vascularization, and higher MMP activity were observed in tumors derived from A549/IL‐1β cells, compared with tumors derived from control A549 cells. These findings suggest that IL‐1β facilitates metastasis of lung cancer via promoting multiple events, including adhesion, invasion and angiogenesis. (Cancer Sci 2003; 94: 244–252)

Parathyroid hormone‐related protein (PTHrP) is responsible for production of bone metastasis, but not visceral metastasis, by human small cell lung cancer SBC‐5 cells in natural killer cell‐depleted SCID mice

We previously established an osteolytic bone metastasis model with multiorgan dissemination in natural killer (NK) cell‐depleted severe combined immunodeficient (SCID) mice using human small cell lung cancer cells (SBC‐5), which highly express the parathyroid hormone‐related protein (PTHrP). In our present study, we evaluated the role of PTHrP on bone metastasis by SBC‐5 cells using anti‐PTHrP neutralizing antibody (Ab). Anti‐PTHrP Ab did not affect the proliferation or cytokine production of SBC‐5 cells in vitro. Repeated intravenous injection with anti‐PTHrP Ab inhibited the formation of bone metastasis in a dose‐dependent manner, while the same treatment had no significant effect on the metastasis to visceral organs (lung, liver, kidney and lymph node). In addition, treatment with anti‐PTHrP Ab improved the elevated serum calcium level, associated with inhibition of osteolytic bone metastasis, suggesting that anti‐PTHrP Ab inhibited bone metastasis via suppression of bone resorption probably by neutralizing PTHrP. These findings suggest that PTHrP is essential for bone metastasis, but not visceral metastasis, by small cell lung cancer SBC‐5 cells.

A report of two bronchioloalveolar carcinoma cases which were rapidly improved by treatment with the epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 (“Iressa”1

Bronchioloalveolar carcinoma (BAC), a form of pulmonary adeno‐carcinoma, presents unique clinical features, such as endobron‐chial spread and bronchorrhea in advanced stages. The prognosis for BAC patients in advanced stages is poor, as is the case for patients with other non‐small‐cell lung cancer (NSCLC) types, because of low susceptibility to conventional chemotherapy. Recently, an orally active, selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (EGFR‐TKI), ZD1839 (“Iressa”), has been investigated in phase II clinical studies (IDEAL 1 and IDEAL 2) as monotherapy against chemotherapy‐refractory NSCLC, and provided clinically significant antitumor activity. In this study, we examined the therapeutic efficiency of ZD1839 in chemotherapy‐refractory BAC patients with bronchorrhea. Two female BAC patients with bronchorrhea were treated once daily with ZD1839 (250 mg/day). In both cases, serous sputum production was dramatically reduced within 3 days of starting the treatment, and hypoxia and radiographic signs of bilateral lung consolidation were visibly improved within 7 days. Following more than 8 months of treatment, no evidence of recurrence or severe adverse events has been observed. These results suggest that this selective EGFR‐TKI, ZD1839, may be a powerful agent for treatment of chemotherapy‐refractory BAC patients with bronchorrhea. (Cancer Sci 2003; 94: 453–458)

Complicated paraneoplastic neurological syndromes: a report of two patients with small cell or non-small cell lung cancer

Paraneoplastic neurological syndromes are frequently associated in patients with small cell lung cancer (SCLC) and antineuronal antibodies are involved in the autoimmune mechanism. Multiple syndromes are sometimes complicated in a single patient with SCLC. However, little is known about non-SCLC-associated neurological manifestations. We report two patients with complicated paraneoplastic neurological syndromes. Patient 1 showed paraneoplastic limbic encephalitis (PLE), paraneoplastic sensory neuropathy (PSN) and Lambert-Eaton myasthenic syndrome (LEMS) associated with SCLC. Patient 2 developed opsoclonus-ataxia and probable PLE associated with non-SCLC. Analysis of various antineuronal antibodies revealed that anti-Hu and P/Q-type voltage-gated calcium channel (VGCC) antibodies were positive in Patient 1 but any antibodies were not in Patient 2. Brain MRI demonstrated high intensity signals in temporal lobes particularly on fluid-attenuated inversion recovery (FLAIR) or diffusion-weighted images. These findings suggest that complicated paraneoplastic neurological syndromes occur in non-SCLC as well as SCLC and that unidentified antineuronal autoantibodies may underlie the pathophysiology.

Lysophosphatidic acid stimulates the proliferation and motility of malignant pleural mesothelioma cells through lysophosphatidic acid receptors, LPA1 and LPA2

Lysophosphatidic acid (LPA) is one of the simplest natural phospholipids. This phospholipid is recognized as an extracellular potent lipid mediator with diverse effects on various cells. Although LPA is shown to stimulate proliferation and motility via LPA receptors, LPA1 and LPA2, in several cancer cell lines, the role of LPA and LPA receptors for malignant pleural mesothelioma (MPM) has been unknown. MPM is an aggressive malignancy with a poor prognosis and the incidence is increasing and is expected to increase further for another 10–20 years worldwide. Therefore, the development of novel effective therapies is needed urgently. In this study, we investigated the effect of LPA on the proliferation and motility of MPM cells. We found that all 12 cell lines and four clinical samples of MPM expressed LPA1, and some of them expressed LPA2, LPA3, LPA4 and LPA5. LPA stimulated the proliferation and motility of MPM cells in a dose‐dependent manner. Moreover, LPA‐induced proliferation was inhibited by Ki16425, an inhibitor of LPA1, and small interfering RNA against LPA1, but not LPA2. Interestingly, LPA‐induced motility was inhibited by small interfering RNA against LPA2, but not LPA1, unlike a number of previous reports. These results indicate that LPA is a critical factor on proliferation though LPA1, and on motility though LPA2 in MPM cells. Therefore, LPA and LPA receptors, LPA2 as well as LPA1, represent potential therapeutic targets for patients with MPM. (Cancer Sci 2008; 99: 1603–1610)

A rare case of gradual enlargement of a multifocal myelolipoma of the posterior mediastinum for 12 years after surgical resection of an adrenal myelolipoma

Highlights • A myelolipoma is a rare benign tumor comprising adipose tissue and normal hematopoietic cells.• A myelolipoma commonly occurs in the unilateral adrenal gland.• This is the first rare case of multifocal myelolipomas of the mediastinum and adrenal gland.

Outcome of intravascular stent in superior vena cava syndrome

Background: Superior vena cava (SVC) syndrome is one of the oncologic emergency. The patients under life-threatening conditions require urgent treatment such as chemotherapy, radiation therapy and stent placement. It has been reported that stent placement provide a palliative benefit. However, indication for treatment of stenting are not well defined. Objective: The aim of this study was to evaluate the outcome of intravascular stent in SVCsyndrome. Methods: The subjects consisted of 11 patients who were undergone stent placement in Matsuyama Red Cross Hospital between June 2010 and April 2013. Contrast enhanced CT was made in all patients. Stent placement was made with self-expanding stent. Results: All patients had lung cancer (5 in adenocarcinoma, 4 in small cell carcinoma and 2 in non-small lung cancer). Seven patients previously had received chemotherapy and /or radiation therapy. In all patients, correct positioning of stents was achieved. Their symptoms completely disappeared within 6.8 hours. The median survival time was 133 days (range, 31 to 573 days). Major side effects were not observed. Conclusion: In our study, stent placement dramatically improved symptoms and quality of life. Stenting increased the survival benefit, especially in patients with improved performance status.