Yoshiyuki Susaki

IL-6 amplifier activation in epithelial regions of bronchi after allogeneic lung transplantation

The IL-6 amplifier, a positive feedback loop for NFκB signaling, which was originally found to be activated by IL-17A and IL-6 stimulation in non-immune cells, is molecularly a simultaneous activator of NFκB and signal transducer and activator of transcription 3 (STAT3), functionally a local chemokine inducer and pathologically a machinery for inflammation development. It has been shown that IL-6 amplifier activation in epithelial cells contributes to rejection responses in a mouse chronic rejection model that develops a bronchiolitis obliterans (BO)-like disease. We investigated whether the IL-6 amplifier is activated in BO regions of a human lung graft after allogeneic transplantation. NFκB and STAT3 molecules were phosphorylated in the epithelial regions of bronchi that localized in the BO regions. Additionally, chemokine ligand 2 (CCL2), and CD4(+) T cells and macrophages increased in these regions. Furthermore, human lung epithelial cells expressed CCL2 after stimulation by IFNγ in the presence of IL-6 and epidermal growth factor via enhanced STAT3 signaling, which parallels behavior seen in the mouse model. Thus, our results suggest that the IL-6 amplifier in the epithelial cells of grafts is involved in chronic rejection after lung transplantation, suggesting that the amplifier may be a valuable therapeutic target to prevent chronic rejection after lung transplantation.

An accurate and rapid detection of lymph node metastasis in non-small cell lung cancer patients based on one-step nucleic acid amplification assay

A sublobar resection is currently recognized as an option for early small-sized non-small cell lung cancer (NSCLC), and intraoperative rapid and accurate lymph node assessment is required for a complete resection. To solve this issue, we investigated the clinical utility of one-step nucleic acid amplification (OSNA) assay, an automated rapid molecular diagnostic method and its optimal mRNA marker for detection of lymph node metastasis in lung cancer. We extracted 16 target candidate mRNA markers with high expression in lung cancer from a genetic database, and then quantified their expression levels by quantitative RT-PCR using surgically dissected lymph nodes with or without metastasis. Cytokeratin 19 (CK19), cytokeratin 7 (CK7), stratifin (SFN), and anterior gradient homolog 2 (AGR2) showed significant differences for mRNA expression between metastasis-negative and -positive lymph nodes in quantitative-RT-PCR screening. CK19 and CK7 were finally selected as potential target markers and were quantified using OSNA assay findings of 165 dissected lymph nodes obtained from 49 lung cancer patients. The OSNA assay with CK19 and CK7 were completed within 40 min and their positive predictive value, negative predictive value, and accuracy comparing to pathological diagnosis with hematoxylin-eosin staining and immunohistochemistry were shown to be 95.0%, 99.3%, and 98.8%, and 85.0%, 97.9%, and 96.4%, respectively, using a cut-off value of 250 copies/μL. Among the 165 lymph nodes tested, 1 false negative result was due to massive necrosis of cancer cells and 1 false positive was caused by the allocation bias of cancer cells in the sampling in patient with pleural dissemination. The best performance was observed when CK19 was used as a marker, while the addition of CK7 mRNA as a marker did not increase sensitivity or specificity. In conclusion, an OSNA assay using CK19 could be effective for molecular diagnosis of lymph node metastasis in lung cancer. This is the first report suggesting the potential clinical utility of OSNA assay for intraoperative rapid diagnosis of nodal status in lung cancer.

Clinical predictor of pre- or minimally invasive pulmonary adenocarcinoma: possibility of sub-classification of clinical T1a

OBJECTIVES A new pathological classification for pre- and minimally invasive adenocarcinoma has been established, with distinction prior to surgery crucial because of the extremely good prognosis. METHODS Of 412 patients who underwent surgery for lung cancer from 2008 to 2011, 110 classified as c-stage I had each of the following four parameters assessed for predictive power for pre- or minimally invasive adenocarcinoma and relapse-free survival (RFS): (i) whole tumour size (WS) shown by computed tomography (CT) , (ii) size of the solid (SS) component in CT findings, (iii) maximum standard uptake value in fluorodeoxyglucose positron emission tomography (FDG-PET)/CT scan images (SUVmax) and (iv) serum level of carcinoembryonic antigen. RESULTS For prediction of pre- or minimally invasive adenocarcinoma, the area under the receiver-operating curve was >0.7 for all the four parameters, while only SS was found to be an independent factor in multivariate logistic regression analysis. In Cox proportional hazard model analysis, SS and SUVmax were statistically significant, and SS was exclusively independent in multivariate analysis. Differences in RFS between T1a and T1b were more pronounced when using SS compared with WS. In the sub-classification of T1a, we used a breakpoint of 1.0 cm in SS (T1a-α and T1a-β), which resulted in a 2-year RFS rate of 1.00 for T1a-α (n=21), 0.89 for T1a-β (n=27) and 0.68 for T1b (n=26) (P=0.002 between T1a-β and T1b). CONCLUSIONS The SS parameter was useful to distinguish pre- and minimally invasive adenocarcinoma from other types of lung cancer, and set a T1a sub-classification.

A Double-Blind Placebo-Controlled Study of the Effects of Olprinone, a Specific Phosphodiesterase III Inhibitor, for Preventing Postoperative Atrial Fibrillation in Patients Undergoing Pulmonary Resection for Lung Cancer.

BACKGROUND We previously reported that patients with elevated preoperative B-type natriuretic peptide (BNP) levels have an increased risk for postoperative atrial fibrillation following lung cancer surgery. The present study evaluated whether the specific phosphodiesterase III inhibitor olprinone can reduce the incidence of postoperative atrial fibrillation in patients with elevated BNP levels undergoing pulmonary resection for lung cancer. METHODS A prospective randomized study was conducted with 40 patients who had elevated preoperative BNP levels (≥ 30 pg/mL) and underwent scheduled lung cancer surgery. All patients were in sinus rhythm at surgery. Low-dose olprinone or placebo was continuously infused for 24 h and started just before anesthesia induction. The primary end point was the incidence of postoperative atrial fibrillation. The secondary end points were perioperative hemodynamics and levels of BNP, WBC counts, and C-reactive protein. RESULTS The incidence of postoperative atrial fibrillation was significantly lower in the olprinone group than in the placebo group (10% vs 60%, P < .001). Patients in the olprinone group showed significantly lower BNP, WBC counts, and C-reactive protein levels after surgery. CONCLUSIONS Continuous infusion of olprinone during lung cancer surgery was safe and reduced the incidence of postoperative atrial fibrillation following pulmonary resection in patients with elevated preoperative BNP levels. TRIAL REGISTRY Japan Primary Registries Network; No.: JPRN-UMIN2404; URL: http://www.umin.ac.jp/ctr/.

Lymphatic invasion of micropapillary cancer cells is associated with a poor prognosis of pathological stage IA lung adenocarcinomas.

The cancer cells of lung adenocarcinoma with a micropapillary pattern (MPP) have been found to frequently invade lymphatic vessels, and the prognosis of patients with lung adenocarcinoma with an MPP is poor. In the present study, the cancer cells of lung adenocarcinomas containing an MPP were found to express vimentin more extensively than those in lung adenocarcinoma without an MPP. The contribution of cancer cells in the MPP component to adenocarcinoma lymphatic invasion was assessed using vimentin as a marker. Vimentin expression was analyzed in the cancer cells present in each lymphatic vessel and compared with the expression of vimentin in the cancer cells in the adenocarcinomas without an MPP component. The results showed that the cancer cells in the lymphatic vessels expressed vimentin more extensively than those in the adenocarcinoma components without an MPP, suggesting that cancer cells derived from an MPP component are present in the lymphatic vessels. By contrast, the area of the MPP component in each adenocarcinoma was <25%. These findings suggest that cancer cells in MPP components have a high capacity to invade lymphatic vessels and that their high invasive capacity may be associated with a poor prognosis in patients with adenocarcinoma with an MPP component.

Inhibitory effect of PPARγ on NR0B1 in tumorigenesis of lung adenocarcinoma

NR0B1, an orphan nuclear receptor, is expressed in side population cells and its knockdown reduces tumorigenic and anti-apoptotic potential in lung adenocarcinoma. Peroxisome proliferator-activated receptor γ (PPARγ) is another member of the nuclear receptor family which induces apoptosis in lung cancer. The interaction of NR0B1 with PPARγ was examined. The transactivation ability of PPARγ was inhibited by NR0B1 in lung adenocarcinoma, and the N-terminal region of NR0B1 containing LxxLL motifs mediated its inhibition. Co-immunoprecipitation experiments revealed that this N-terminal region of NR0B1 was essential for the physical interaction with PPARγ. Aldehyde dehydrogenase (ALDH) activity and ALDH3A1 expression, which are correlated with tumorigenic potential of lung adenocarcinoma, increased when NR0B1 expression was induced, but its increase was inhibited by PPARγ overexpression. ALDH activity increased by treatment with PPARγ inhibitor, and the increase was further enhanced when the expression of NR0B1 was induced. Furthermore, the high NR0B1 and low PPARγ expression was a negative prognostic factor in Pathological-Stage IA clinical cases. These results indicate the reciprocal relationship between NR0B1 and PPARγ on the malignant grade of lung adenocarcinoma.

HER3 expression is enhanced during progression of lung adenocarcinoma without EGFR mutation from stage 0 to IA1: Enhanced HER3 in stage IA1 lung ADC

Activating EGFR mutations, HER2, and HER3 are implicated in lung cancer; however, with the exception of EGFR gene amplification in lung adenocarcinoma harboring EGFR mutations, their involvement in disease progression during the early stages is poorly understood. In this paper, we focused on which receptor is correlated with lung adenocarcinoma progression in the presence or absence of EGFR mutation from stage 0 to IA1.

Ectopic cervical thymoma accompanied by Good's syndrome.

Ectopic cervical thymoma (ECT) is a rare tumor that is frequently misdiagnosed as a thyroid tumor or other malignancy. A 34-year-old male with a right palpable neck mass had been mistakenly diagnosed with T-cell lymphoblastic lymphoma even after an open biopsy. The atypical clinical course, including hypogammaglobulinemia, led us to the correct diagnosis; ECT accompanied by Goods syndrome (GS). After the intravenous infusion of gammaglobulin, tumor resection and a subsequent video-assisted thoracoscopic extended thymectomy were performed. The final diagnosis was type AB thymoma, Masaoka stage I. This report is, to the best of our knowledge, the first description of this extremely rare combination.

Colopleural fistula caused by aspergillus: an extremely rare complication after lung resection-case report.

A colopleural fistula is a rare condition reported to be caused by Crohn’s disease, a malignant tumor of the gastrointestinal tract, and other clinical conditions. Some studies have noted that a sub-diaphragmatic abscess, usually organized following abdominal surgery, may play some role in the formation of this type of fistula. Therefore, a colopleural fistula is a complication very rarely encountered by thoracic surgeons after lung resection.We experienced an extremely rare case of colopleural fistula following a left lower lobectomy for lung aspergillosis. Here, we report a 71-year-old man with a surgical history of proximal gastrectomy for gastric cancer. He underwent left lower lobectomy of the lung for aspergillosis, and a colopleural fistula occurred on the second operative day as a complication. Aspergillus might be responsible for forming a fistula between the colon and lung via the diaphragm, and lung surgery manifested this rare condition. Although some reports suggest that surgical treatment is mandatory to cure this fistula, an immediate colostomy in our case reduced the internal pressure of the colon, thus enabling spontaneous closure of the fistula with appropriate drainage and antibiotics. The patient was discharged in a good condition.

Single-lung transplantation in a chronic pulmonary emphysema patient with a marginal donor who was ABO blood group nonidentical but compatible

Because the number of ideal brain-dead donors is limited, active use of marginal donors is currently one of the major issues discussed in regard to lung transplantation. We report a case in which the patient underwent single-lung transplantation for chronic pulmonary emphysema. The lung came from a marginal, ABO blood group nonidentical, compatible donor. Because the donor was marginal (pneumonia in the right lung and lobar atelectasis in both lungs), all recipient candidates with ABO blood group identical declined. Thus, a nonidentical, compatible recipient had a chance to receive a lung transplant. This 49-year-old man underwent single-lung transplantation for chronic pulmonary emphysema with severe respiratory failure. He had a good postoperative clinical course.