Levels of soluble vascular endothelial growth factor receptor 1 are elevated in the exudative pleural effusions

Purpose : Vascular endothelial growth factor (VEGF) plays a critical role in the production of malignant pleural effusions. In the present study, we examined the levels of soluble VEGF receptor-1 (sVEGFR-1) and angiopoietin-2 (Ang-2), as possible regulators of VEGF activity, in transudative and exudative pleural effusions. Methods : Forty-two patients were included in this study : 4 with transudative pleural effusions due to heart failure (HF), 38 with exudative pleural effusions (lung cancer [LC], 22 ; other malignant diseases [MD], 10 ; tuberculosis [TB], 6) . The levels of VEGF, Ang-2, and sVEGFR-1 in the pleural effusions were measured by an enzyme-linked immunosorbent assay. Results : The levels of VEGF, Ang-2, and sVEGFR-1 in exudative effusions were higher than those in transudative effusions. Interestingly, the levels of VEGF and Ang-2 in bloody effusions were significantly higher than those in non-bloody effusions (p < 0.05), but the level of sVEGFR-1 in bloody effusions was lower than that in non-bloody effusions. The levels of VEGF and Ang-2 were significantly higher in the malignant effusions, compared with effusion from HF and TB (p < 0.05). In addition, sVEGFR-1 was significantly higher in the effusion from LC, MD, and TB compared with effusion from HF (p < 0.05). In the malignant effusions, direct correlations were observed among VEGF, sVEGFR-1, and Ang-2. Conclusions : The sVEGFR-1 levels were elevated in exudative pleural effusions, and were lower in bloody effusions than in non-bloody effusions, thus suggesting the regulatory role of sVEGFR-1 in the exudative pleural effusions

GAD1 EXPRESSION AND DNA METHYLATION IN THYMIC EPITHELIAL TUMORS

Thymic epithelial tumors (TETs) comprise thymomas and thymic carcinoma (TC). TC has more aggressive features and a poorer prognosis than thymomas. Genetic and epigenetic alterations in thymomas and TC have been investigated in an attempt to identify novel target molecules for TC. In the present study, genome‑wide screening was performed on aberrantly methylated CpG islands in thymomas and TC, and the glutamate decarboxylase 1 gene (GAD1) was identified as the 4th significantly hypermethylated CpG island in TC compared with thymomas. GAD1 catalyzes the production of γ‑aminobutyric acid from L‑glutamic acid. GAD1 expression is abundant in the brain but rare in other tissues, including the thymus. A total of 73 thymomas and 17 TC tissues were obtained from 90 patients who underwent surgery or biopsy at Tokushima University Hospital between 1990 and 2017. DNA methylation was examined by bisulfite pyrosequencing, and the mRNA and protein expression levels of GAD1 were analyzed using reverse transcription‑quantitative PCR and immunohistochemistry, respectively. The DNA methylation levels of GAD1 were significantly higher in TC tissues than in the normal thymus and thymoma tissues, and GAD1 methylation exhibited high sensitivity and specificity for discriminating between TC and thymoma. The mRNA and protein expression levels of GAD1 were significantly higher in TC tissues than in thymomas. Patients with TET with high GAD1 DNA hypermethylation and high mRNA and protein expression levels had significantly shorter relapse‑free survival rates than those with low levels. In conclusion, significantly more epigenetic alterations were observed in TC tissues compared with in thymomas, which may contribute to the clinical features and prognosis of patients

EXPRESSION OF GHRELIN SYSTEM CONSTITUENTS IN THYMIC EPITHELIAL TUMORS

Our previous study reported that the DNA methylation of growth hormone secretagogue receptor (GHSR) was significantly higher in thymoma or thymic carcinoma (TC) than in normal thymic tissue samples. Thymic epithelial tumors (TETs) with higher GHSR DNA methylation were associated with significantly worse prognosis than those with lower levels of DNA methylation. Diversified components of the ghrelin‑GHSR axis may exert opposing effects in cancer progression, depending on the cancer type in question. However, the precise function of the axis remains unclear. In the present study, the mRNA expression of five key components of the ghrelin system [native ligand ghrelin, variant ligand In‑1 ghrelin, native receptor GHSR1a, variant receptor GHSR1b and acylation enzyme ghrelin O‑acyltransferase (GOAT)] were examined in 58 TET samples by reverse transcription‑quantitative PCR, and protein expression of GHSR1a and GHSR1b was assessed in 20 TETs using immunohistochemistry. The results revealed that In‑1 ghrelin, GHSR1b (variant forms) and GOAT were more strongly expressed in thymoma compared with thymic‑adjacent tissue. By contrast, no significant differences were observed in the expression of ghrelin and GHSR1a (native forms) between thymoma and thymic tissue. The mRNA expression of In‑1 ghrelin and GHSR1b (variant forms) was positively associated with GHSR methylation in thymoma tissue samples. However, a relationship was not found between ghrelin, GHSR1a or GOAT expression (native forms) and GHSR methylation in thymoma. Immunohistochemical analysis revealed that mRNA expression of GHSR1a and GHSR1b generally correlated with expression of the corresponding protein, and that the expression of GHSR1b was increased in advanced‑stage TETs. These results indicate that the DNA methylation of GHSR is associated with a shift from native expression (ghrelin and GHSR1a) to variant expression (In‑1 ghrelin and GHSR1b), which induces the tumorigenesis of thymoma, but not TC

AYA-generation lung cancer in a patient presenting with spontaneous pneumothorax : A case report

Background : Surgery for young patients（i.e., <２０ years of age）with early-stage lung cancer is extremely rare. To the best of our knowledge, only a few cases of lung cancer initially presented with spontaneous pneumothorax. Here, we report a case of AYA（adolescent and young adult）-generation lung cancer in a patient who presented with spontaneous pneumothorax. Case : An １８-year-old male was admitted to our hospital for new-onset left pneumothorax. Chest computed tomography incidentally revealed a pure ground-glass nodule（pGGN）in the left lower lobe（S８）with a bulla near the nodule. While chest tube drainage improved his condition, pneumothorax recurred two weeks later, prompting surgical for video-assisted partial resection of the left lung. Intraoperative findings showed that the bulla and nodule were distant. Histopathologic analysis was consistent with a diagnosis of adenocarcinoma in situ with a bleb. Conclusion : This study highlights the importance of considering the possibility of lung cancer in patients with irregular chest shadows, even those less than２０years of age. Computed tomography plays an important role in the diagnosis of lung cancer in patients with spontaneous pneumothorax

Intensification therapy with anti-parathyroid hormone-related protein antibody plus zoledronic acid for bone metastases of small cell lung cancer cells in severe combined immunodeficient mice

金沢大学附属病院がん高度先進治療センターBone metastases occur in more than one-third of patients with advanced lung cancer and are difficult to treat. We showed previously the therapeutic effect of a third-generation bisphosphonate, minodronate, and antiparathyroid hormone-related protein (PTHrP) neutralizing antibody on bone metastases induced by the human small cell lung cancer cell line, SBC-5, in natural killer cell-depleted severe combined immunodeficient mice. The purpose of our current study was to examine the effect of the combination of PTHrP antibody and zoledronic acid, which has been approved to treat bone metastases, against bone metastases produced by SBC-5 cells expressing PTHrP. Treatment with PTHrP antibody and/or zoledronic acid did not affect the proliferation of SBC-5 cells in vitro. Repeated treatments with either PTHrP antibody or zoledronic acid inhibited the formation of osteolytic bone metastases of SBC-5 cells but had no effect on metastases to visceral organs. Importantly, combined treatment with PTHrP antibody and zoledronic acid further inhibited the formation of bone metastases. Histologic assays showed that, compared with either PTHrP antibody or zoledronic acid alone, their combination decreased the number of tumor-associated osteoclasts and increased the number of apoptotic tumor cells. These findings suggest that this novel dual-targeting therapy may be useful for controlling bone metastases in a subpopulation of small cell lung cancer patients. Copyright © 2009 American Association for Cancer Research.全文公開20100

横隔膜縫縮術により著明な呼吸機能改善を得た横隔膜弛緩症の１例

A woman in her seventies visited the hospital two months after experiencing dyspnea on exertion. After chest radiographs and computed tomography of the chest showed elevation of the right diaphragm, she was referred to our department for further examination and management. Respiratory function tests revealed restricted ventilatory impairment with a vital capacity （VC） of 1.28 L and a %VC of 54.0%. Since there was no evidence of organic disease causing diaphragmatic paralysis and a slight movement of the diaphragm, we diagnosed the patient with right diaphragmatic eventration. Since she was symptomatic, we decided to treat her surgically. She was operated under general anesthesia, left lateral recumbency, single lung ventilation, and lateral open chest between the eighth ribs. The relaxed diaphragm was elevated, horizontal mattress sutures were placed. Considering the risk of diaphragm rupture, a 2-mm thick Gore-Tex sheet was fixed to the chest wall and diaphragm in a tent-like manner. The patient was discharged from the hospital on the fourth postoperative day. A chest radiograph postoperatively showed good diaphragmatic movement. Respiratory function tests also showed marked improvement, with a VC of 2.00 L and %VC of 86.3%. The patient’s subjective symptoms have disappeared, and she is currently outpatient observation

Pladienolide is active on gastric cancer

The antitumor activity of pladienolide B, a novel splicing inhibitor, against gastric cancer is totally unknown and no predictive biomarker of pladienolide B efficacy has been reported. We investigated the antitumor activity of pladienolide B and its derivative on gastric cancer cell lines and primary cultured cancer cells from carcinomatous ascites of gastric cancer patients. The effect of pladienolide B and its derivative on six gastric cancer cell lines was investigated using a MTT assay and the mean IC50 values determined to be 1.6 ± 1.2 (range, 0.6–4.0) and 1.2 ± 1.1 (range, 0.4–3.4) nM, respectively, suggesting strong antitumor activity against gastric cancer. The mean IC50 value of pladienolide B derivative against primary cultured cells from 12 gastric cancer patients was 4.9 ± 4.7 nM, indicative of high antitumor activity. When 18 SCID mice xenografted with primary cultured cells from three patients were administered the pladienolide B derivative intraperitoneally, all tumors completely disappeared within 2 weeks after treatment. Histological examination revealed a pathological complete response for all tumors. In the xenograft tumors after treatment with pladienolide B derivative, immature mRNA were detected and apoptotic cells were observed. When the expressions of cell-cycle proteins p16 and cyclin E in biopsied gastric cancer specimens were examined using immunohisctochemistry, positivities for p16 and cyclin E were significantly and marginally higher, respectively, in the low-IC50 group compared with the high-IC50 group, suggesting the possibility that they might be useful as predictive biomarkers for pladienolide B. In conclusion, pladienolide B was very active against gastric cancer via a mechanism involving splicing impairment and apoptosis induction

Phosphorylated Smad2 in Advanced Stage Gastric Carcinoma

<p>Abstract</p> <p>Background</p> <p>Transforming growth factor β (TGFβ) receptor signaling is closely associated with the invasion ability of gastric cancer cells. Although Smad signal is a critical integrator of TGFβ receptor signaling transduction systems, not much is known about the role of Smad2 expression in gastric carcinoma. The aim of the current study is to clarify the role of phosphorylated Smad2 (p-Smad2) in gastric adenocarcinomas at advanced stages.</p> <p>Methods</p> <p>Immunohistochemical staining with anti-p-Smad2 was performed on paraffin-embedded specimens from 135 patients with advanced gastric adenocarcinomas. We also evaluated the relationship between the expression levels of p-Smad2 and clinicopathologic characteristics of patients with gastric adenocarcinomas.</p> <p>Results</p> <p>The p-Smad2 expression level was high in 63 (47%) of 135 gastric carcinomas. The p-Smad2 expression level was significantly higher in diffuse type carcinoma (p = 0.007), tumours with peritoneal metastasis (p = 0.017), and tumours with lymph node metastasis (p = 0.047). The prognosis for p-Smad2-high patients was significantly (p = 0.035, log-rank) poorer than that of p-Smad2-low patients, while a multivariate analysis revealed that p-Smad2 expression was not an independence prognostic factor.</p> <p>Conclusion</p> <p>The expression of p-Smad2 is associated with malignant phenotype and poor prognosis in patients with advanced gastric carcinoma.</p

Neutrophils in primary gastric tumors are correlated with neutrophil infiltration in tumor-draining lymph nodes and the systemic inflammatory response

Abstract Background Tumor-Associated Neutrophils (TANs) may be able to induce lymphangiogenesis and angiogenesis, although the detailed roles of TANs remain unclear. The Neutrophil-Lymphocyte Ratio (NLR) is an inflammation-based prognostic factor for gastric cancer. This study aimed to investigate the distribution of CD15+neutrophils in the primary tumor and Tumor-Draining Lymph Nodes (TDLNs), and to examine the association of TANs with the clinicopathological features (including NLR) of patients with gastric cancer. Results Immunohistochemical staining showed that the median number of CD15+TANs was 18 and 24 per high-power field (HPF) in primary tumors and TDLNs, respectively. Patients were divided into high and low infiltration groups based on the median number. A high number of infiltrating CD15+TANs in the primary tumors and in the TDLNs were associated with depth of invasion and lymph node metastasis. Kaplan-Meier analysis revealed that a poor overall survival was associated with high numbers of CD15+TANs, and the multivariate analyses revealed that a high number of CD15+TANs in the TDLNs was an independent prognostic factor. The numbers of CD15+TANs in the primary tumors and TDLNs showed weak positive correlation. The number of CD15+TANs in the primary tumors was positively correlated with the preoperative NLR, (P = 0.001, R = 0.327) and immunohistochemical staining revealed that C-X-C motif chemokine receptor 2 (CXCR2) +neutrophils might be the origin of the CD15+TANs. Flow cytometry analysis indicated that infiltrating neutrophils increased in the tumor and TDLN compared to non-cancerous tissue. Neutrophils treated with cancer supernatant upregulated TWIST and IL-6 genes in vitro. Conclusion Our findings suggested that local infiltration of CD15+TANs may be correlated with inflammation in TDLNs and systemic response to cause metastasis in gastric carcinoma