Ryoichi Nakanishi

Brain-derived neurotrophic factor/tropomyosin-related kinase B signaling pathway contributes to the aggressive behavior of lung squamous cell carcinoma

The tropomyosin-related kinase (Trk) family consists of TrkA, TrkB, and TrkC, which play essential roles in tumor progression and/or suppression in various cancers. Little is known about the biological significance of the Trk family in human lung squamous cell carcinoma (SCC). Here we investigated the clinical significance of the protein expression of Trk family members in samples from 99 SCC patients, and we explored the relationship between invasion/proliferation activities and Trk expression using lung SCC cell lines to clarify the biological significance of the Trk family in lung SCC. Immunohistochemical high expression of TrkB was significantly correlated with vascular invasion (P=0.004), lymph node metastasis (P<0.001), and advanced stage (P=0.0015). The overall survival of the patients with TrkB-high expression was significantly shorter than those with TrkB-low expression (P=0.0110). TrkA/TrkC expressions were not predictors of poor prognosis. An in vitro assay demonstrated that the inhibition of brain-derived neurotrophic factor (BDNF) (a TrkB ligand) and TrkB by K252a (a Trk inhibitor) or siRNA (BDNF-siRNA, TrkB-siRNA) suppressed the invasion, migration, and proliferative activities of lung SCC cells. The administration of recombinant human BDNF (rhBDNF) enhanced the invasion, migration, and proliferation activities, which were abrogated by K252a. TrkB-siRNA transfection increased the protein expression of E-cadherin and decreased vimentin expressions in lung SCC cells. Matrix metalloproteinase-2 (MMP-2)-mediated gelatin degradations were decreased in lung SCC cells transfected with TrkB-siRNA. Thus, TrkB-high expression is an indicator of poor prognosis in lung SCC, probably due to invasion/proliferation activities promoted by the BDNF/TrkB signaling pathway, which could become a therapeutic target for lung SCC.

Risk factors for short-term outcomes after thoracoscopic lobectomy for lung cancer

Few studies have analysed postoperative risk factors in patients undergoing thoracoscopic lobectomy, including assessments of preoperative physical function. The objectives of this study were to identify predictors of postoperative deterioration of performance status and cardiopulmonary complications in cases of thoracoscopic lobectomy. Between June 2005 and October 2012, we retrospectively reviewed 188 consecutive subjects who underwent thoracoscopic lobectomy for preoperative stage I nonsmall cell lung cancer. The demographic and clinical parameters, including physical function, were analysed using a multivariate logistic regression to clarify the determinants. The percent predicted diffusing capacity of the lung for carbon monoxide, quadriceps muscle strength and pathologic stage were independent risk factors for deterioration of performance status after surgery in the multivariate analyses. Chronic obstructive pulmonary disease, 6-min walking distance and pathologic stage were also independent risk factors for postoperative cardiopulmonary complications. Our data suggest that, in addition to a greater pathologic stage, lower diffusing capacity and comorbid chronic obstructive pulmonary disease, poor physical function was associated with worse short-term outcomes after thoracoscopic lobectomy. An evaluation of preoperative quadriceps muscle strength and 6-min walk test is easily performed and may therefore be a useful predictor in cases of thoracoscopic lobectomy. Evaluating quadriceps muscle and 6MWT is useful for risk assessment in cases of thoracoscopic lobectomy for NSCLC http://ow.ly/4mIZQR

Exon 7 splicing variant of estrogen receptor α is associated with pathological invasiveness in smoking‑independent lung adenocarcinoma

Patients with smoking-independent lung cancer mainly consist of females, yet the molecular background of this epidemiological feature, other than epidermal growth factor receptor (EGFR) mutation, remains unclear. Several studies have revealed the association between female hormone-associated factors and the prognosis of lung cancer, however the data remain inconsistent. The present study focused on the expression of estrogen receptor (ER)α in order to elucidate this association in smoking-independent lung cancer. Immunohistochemistry staining (IHC) of aromatase, ERα and ERβ was performed against formalin-treated tissues from 38 patients who had never-smoked who underwent complete surgical resection between 2012 and 2013. Among them, adequate RNA of the tumor and adjacent normal lung cancer was extracted from 31 matching deep frozen samples. Considering the IHC results, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was performed to measure the expression level of 2 different exons of ERα, exon 6 and exon 7, which are part of the ligand binding domain of ERα, using the Taqman gene expression assay. Extra-nuclear expression of ERα using IHC demonstrated a statistically significant association with pathological invasiveness. RT-qPCR results exhibited a decreased expression of ERα exon 7 in invasive tumor tissues, compared with their adjacent normal tissues. This is consistent with the findings of previous in vitro studies indicating that extra-nuclear ERα were exon 7 splicing variants. No difference was observed in ERα exon 7 expression between normal and tumor tissues in non-invasive lung cancer tissues. When considering the EGFR mutation status, EGFR wild-type lung cancers exhibited decreased ERα exon 7 expression levels compared with EGFR mutated lung cancers. Extra-nuclear expression of ERα, which may represent exon 7 splicing variants of ERα, showed statistical association with pathological invasiveness in smoking-independent lung cancer. The post-translational splicing mechanism of ERα may be involved in the acquired invasiveness of smoking independent lung cancer.

HER2 mutation status in Japanese HER2-positive breast cancer patients

AbstractBackground Human epidermal growth factor receptor 2 (HER2) gene amplification/overexpression is a major therapeutic target in breast cancer, and has been introduced as a predictive biomarker to identify patients who may benefit from therapy with anti-HER2 agents. HER2 somatic mutations have been reported, and these may influence the effect of HER2-targeted drugs.MethodsHere, we sought HER2 mutations in a group of 135 Japanese breast cancer patients with HER2-positive tumors. We analyzed HER2 mutations by direct Sanger sequencing of two major areas, the extracellular domain at position 309–310 and the kinase domain between 755 and 781.ResultsTwo patients with the HER2 somatic mutation S310F in the extracellular domain were found in this series. One patient with the S310F mutation had a node-negative invasive ductal carcinoma classified as HER2 2+ by the HercepTest and fluorescence in situ hybridization (FISH) positive, and which was estrogen receptor (ER)-negative and progesterone receptor (PgR)-negative. Another patient with the S310F mutation had an apocrine carcinoma with seven lymph nodes positive for metastasis, classified as HER2 3+ by the HercepTest, but which was FISH-negative, as well as ER-negative and PgR-negative. Both patients had received adjuvant single-agent trastuzumab therapy, and had no local recurrence or distant metastasis for five and three years after surgery, respectively.ConclusionsOur data show that HER2 mutations are rare in HER2-positive Japanese breast cancer patients. The two mutations found in this study were identical, S310F. We suggest that in vitro experiments to determine whether the S310F mutation could be involved in resistance to anti-HER2 drugs are worthwhile in future.

Long-term survival of a patient with pulmonary metastatic urothelial carcinoma following metastasectomy

Cisplatin-based systemic chemotherapy is the gold standard for the treatment of patients with metastatic urothelial carcinoma (UC), which is a chemosensitive cancer. However, long-term survival has been deemed disappointing. We describe here a case of UC with solitary pulmonary metastasis who had successfully achieved long-term disease-free survival by combination of cisplatin-based chemotherapy and pulmonary metastasectomy. From the finding of this article, we propose that adjuvant chemotherapy may be considered as a viable option after metastasectomy in low volume pulmonary metastatic UC patients.

Blastomatoid pulmonary carcinosarcoma: A rare case report and review of the literature: Blastomatoid pulmonary carcinosarcoma

A 65‐year‐old never‐smoking woman presented to a local hospital, because an abnormal shadow was detected at the right lower lung field by annual chest X‐ray. Computed tomography (CT) revealed a 5‐cm tumor in segment 6 of her right lung and an enlarged subcarinal lymph node, suggesting metastasis. The lung tumor was diagnosed as adenocarcinoma by a CT‐guided percutaneous needle biopsy. She was referred to our hospital and underwent right lower lobectomy with lymph node dissection (ND2a‐2). A histopathological examination of the tumor showed a biphasic proliferation made of carcinomatous and sarcomatous components. The carcinomatous component consisted of glandular structures of atypical cells that possessed chromatin‐rich nuclear and clear cytoplasm, confirming high‐grade fetal adenocarcinoma. The sarcomatous component consisted of immature spindle cells that differentiated into chondrosarcoma. Immunohistochemically, the glandular structures expressed membranous beta‐catenin, and the ultimate diagnosis was blastomatoid variant of pulmonary carcinosarcoma. She received four courses of cisplatin plus vinorelbine as adjuvant chemotherapy and remained alive with neither recurrence nor distant metastasis at two and a half years after the operation. We experienced a rare case of blastomatoid pulmonary carcinoasarcoma.

Thymothymectomy with pulmonary partial resection using the subxiphoid approach: how to do it?

An open approach by sternotomy is still selected for locally advanced anterior mediastinal tumors. Technical and instrumental improvements to video-assisted thoracic surgery (VATS) have enabled the treatment of anterior mediastinal tumor in the last decade, and the indications of VATS for an anterior mediastinal tumor are thus expanding. Recently, a single-port thymectomy procedure using the subxiphoid approach has gained popularity worldwide because of its low invasiveness. Improvements to the thoracoscopic instruments and the development of a single-port device are expanding the adoption of single-port VATS in the thoracic surgical field, including resection of anterior mediastinal tumors. We, herein, report a case of thymothymectomy with pulmonary partial resection using the subxiphoid approach. This approach is useful for extended operation for anterior mediastinal tumors and provides favorable results regarding postoperative pain and cosmetic outcomes.

Four immunohistochemical assays to measure the PD-L1 expression in malignant pleural mesothelioma

Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 pathway are expected to be a novel therapy for combating future increases in numbers of malignant pleural mesothelioma (MPM) patients. However, the PD-L1 expression, which is a predictor of the response to ICIs, is unclear in MPM. We studied the PD-L1 expression using four immunohistochemical assays (SP142, SP263, 28-8 and 22C3) in 32 MPM patients. The PD-L1 expression in tumor cells and immune cells was evaluated to clarify the rate of PD-L1 expression and the concordance among the four assays in MPM. The positivity rate of PD-L1 expression was 53.1% for SP142, 28.1% for SP263, 53.1% for 28-8, and 56.3% for 22C3. Nine cases were positive and 10 were negative for all assays. Discordance among the four assays was found in 13 cases. The concordance rates between SP142 and 22C3 and between 28-8 and 22C3 were the highest (84.4%). The concordance rates between SP263 and the other three assays were low (71.9% to 75.0%). The PD-L1 expression in MPM was almost equivalent for three of the assays. Given the cut-off values set in our study, these findings suggested that these assays, except for SP263, can be used for accurate PD-L1 immunostaining in MPM.

A comparative study of PD-L1 immunohistochemical assays with four reliable antibodies in thymic carcinoma

Currently, four immunohistochemical assays are registered with the US Food and Drug Administration to detect the expression of PD-L1. We investigated the PD-L1 expression in thymic carcinomas using these four diagnostic assays. The cases of 53 patients were reviewed and their specimens were subjected to four PD-L1 assays with different antibodies (SP142, SP263, 22C3, and 28-8). The PD-L1 expression in tumor cells (TCs) and immune cells (ICs) was evaluated. In TCs, the four assays showed similar scores in each case. Histopathologically, high TC scores were observed in squamous cell carcinomas (SqCCs). Meanwhile, there were no significant relationships among the IC scores in the four assays. In SqCCs, the high expression of PD-L1 (defined as ≥50% TC score) in TCs tended to be associated with early stage cancer. The patients with high expression levels of PD-L1 tended to show longer overall survival in the 22C3 assays (p=0.0200). In thymic carcinomas, the staining pattern showed high concordance among the four assays when TCs – rather than ICs – were stained. High PD-L1 positivity in TCs, especially in SqCCs, indicated that PD-1/PD-L1 targeted therapy may be a promising therapeutic approach.

The relationship between the expression of thymidylate synthase, dihydropyrimidine dehydrogenase, orotate phosphoribosyltransferase, excision repair cross‑complementation group 1 and class III β‑tubulin, and the therapeutic effect of S‑1 or carboplatin plus paclitaxel in non‑small‑cell lung cancer

Previous studies have reported that the expressions of specific proteins may predict the efficacy of chemotherapy agents for non-small cell lung cancer (NSCLC) patients. The present study evaluated the expression of proteins hypothesized to be associated with the effect of chemotherapeutic agents in 38 NSCLC patients with pathological stage II and IIIA. The subjects received carboplatin plus paclitaxel (CP) or S-1 as adjuvant chemotherapy following complete resection. The protein expressions evaluated were those of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phsphoribosyltransferase (OPRT), which were suspected to be associated with the effect of S-1 agents, excision repair cross-complementation group 1 (ERCC1), which was suspected to be associated with the effect of platinum-based agents, and class III β-tubulin (TUBB3), which was suspected to be associated with the effect of taxane-based agents. The positive rate of TS was 55.3% (n=21/38), DPD was 57.9% (n=22/38), OPRT was 42.1% (n=16/38), ERCC1 was 47.4% (n=18/38) and TUBB3 was 44.7% (n=17/38). Among the patients who received S-1 adjuvant chemotherapy, TS-negative cases demonstrated a significantly better disease-free survival than positive cases. Thus, TS protein expression may have been a factor that predicted the effect of S-1 agent as adjuvant chemotherapy.