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This randomized, double-blind, placebo-controlled, crossover study was the first to determine the effects of luseogliflozin in combination with a low-carbohydrate diet (LCD) on 24-h glucose variability, assessed by continuous glucose monitoring (CGM). A total of 18 Japanese patients with type 2 diabetes were randomized into two groups, in which patients first received luseogliflozin 2.5 mg once daily then placebo for 8 days each, or vice versa. Patients took luseogliflozin or placebo with a normal-carbohydrate diet (NCD) on day 7 and with the LCD on day 8. CGM was performed on both days. Luseogliflozin significantly reduced glucose exposure in terms of the area under the curve over the course of 24 h when administered with the NCD (difference vs placebo: -555.6 mg/dl·h [1 mg/dl = 0.0556 mmol/l]; p

This study was aimed for development of vapour-grown carbon nano-fibre(VGCNF)-reinforced aluminium matrix composites by the low-pressure infiltration process. First, VGCNF and Al powder (VGCNF + Alp) preforms for low-pressure infiltration were fabricated by spark sintering process at pressures of 5, 10, 20 and 40 MPa, respectively. Porosity of the preforms fabricated at pressures of 5 and 10 MPa was 44·89 and 40·87%, respectively. However, porosity of the preforms fabricated by spark sintering at pressures of 20 and 40 MPa was approximately 20%. Therefore, VGCNF + Alp/Al composites with the preform sintered at pressures of 5 and 10 MPa were fabricated by the low-pressure infiltration process under an applied pressure of 0·4 MPa, and the relative density was 81·4 and 76·0%, respectively. Moreover, the microstructure, porosity and electrical conductivity of the VGCNF + Alp/Al composites were estimated. Their electrical conductivities reduced with increasing porosity of VGCNF + Alp/Al composites.

The aim of the present study was to determine the effects of luseogliflozin on 24-h glucose levels, assessed by continuous glucose monitoring, and on pharmacodynamic variables measured throughout the day. In this double-blind, placebo-controlled, crossover study, 37 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized into two groups. Patients in each group first received luseogliflozin then placebo for 7 days each, or vice versa. After 7 days of treatment, the mean 24-h glucose level was significantly lower with luseogliflozin than with placebo [mean (95% confidence interval) 145.9 (134.4-157.5) mg/dl vs 168.5 (156.9-180.0) mg/dl; p

Background The standard of care for LA-NSCLC is a definitive concurrent chemoradiotherapy (CRT). In addition, durvalumab shows significant survival benefit as a consolidation therapy. However, the role of EGFR tyrosine kinase inhibitors (TKIs) in this setting has not been established, despite their efficacy in metastatic disease. The aim of this prospective phase II trial was to evaluate the efficacy and safety of induction gefitinib followed by CRT in EGFR-mutant LA-NSCLC. Methods Patients with unresectable stage III NSCLC harboring activating EGFR mutations received induction gefitinib monotherapy (250 mg/body) for 8 weeks. Patients whose disease had not progressed during induction therapy received cisplatin (40 mg/m2) and docetaxel (40 mg/m2) on days 1, 8, 29, and 36, and concurrent radiotherapy with a total dose of 60 Gy. The primary endpoint was 2-year overall survival (OS) rate. We assumed an expected 2-year OS rate of 85%; a rate of 60% was the threshold of the lower limit. Results Between 2011 and 2017, 20 patients (median age, 65.5 years; male/ female, 9/11; histology, all adenocarcinoma; stage IIIA/IIIB, 9/11; exon 19 / 21 mutations, 10/10) were enrolled. The overall response rate was 75.0% in the induction phase and 85.0% in the entire phase. The 1 and 2-year progression-free survival rates were 58.1% and 36.9%, respectively. The 2-year OS rate was 90% (95% confidence interval, 65.6-97.4), indicating this trial met the primary objective. Grade (Gr) 3 or worse adverse events (>10%) in the induction phase included transient AST elevation (25%) and ALT elevation (45%), and those in the CRT phase included neutropenia (64.7%) and febrile neutropenia (10.8%). In the 6-month follow-up period after completion of CRT, Gr > 2 radiation pneumonitis occurred in 11.8% of patients. The completion rate of the protocol therapy was 80%. No treatment-related death was observed. Conclusions This is the first prospective study to show favorable efficacy and tolerable safety of induction EGFR-TKIs in addition to standard CRT in EGFR-mutant LA-NSCLC. Further confirmatory research is warranted. Clinical trial identification UMIN000005086: 15/Feb/2011 jRCTs071180036: March/2019. Legal entity responsible for the study The authors. Funding LOGIK (Lung Oncology Group In Kyushu, Japan). Disclosure S. Saeki: Research grant / Funding (institution): Pfizer; Honoraria (institution): ONO; Research grant / Funding (institution): MSD; Research grant / Funding (institution): Takeda. K. Hotta: Honoraria (self), Research grant / Funding (self), Relevant financial activities OUTSIDE the submitted work.: AstraZeneca; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Nippon Kayaku. M. Yamaguchi: Honoraria (self): AstraZeneca; Honoraria (self): Daiichi Sankyo; Honoraria (self): Eli Lilly; Honoraria (self): Taiho. D. Harada: Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Chugai; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: MSD; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Kyowa Hakko; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: ONO; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Bristol-Myers Squibb; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Eli Lilly; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: TAIHO; Honoraria (self), Relevant financial activities OUTSIDE the submitted work.: Boehringer Ingelheim; Honoraria (self), Research grant / Funding (self), Research grant / Funding (institution), Relevant financial activities OUTSIDE the submitted work.: AstraZeneca; Research grant / Funding (self), Relevant financial activities OUTSIDE the submitted work.: Novartis; Research grant / Funding (self), Relevant financial activities OUTSIDE the submitted work.: Kissei ; Research grant / Funding (self), Relevant financial activities OUTSIDE the submitted work.: Takeda. A. Bessho: Honoraria (self), Research grant / Funding (institution): AstraZeneca. K. Tanaka: Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution): Chugai; Honoraria (self), Honoraria (institution): AstraZeneca; Honoraria (self), Honoraria (institution): Taiho; Honoraria (self), Honoraria (institution): Pfizer; Honoraria (self), Honoraria (institution): MSD; Honoraria (self), Honoraria (institution): Eli Lilly; Honoraria (self), Honoraria (institution): Bristol-Myers Squibb; Honoraria (self), Honoraria (institution): Novartis; Honoraria (self), Honoraria (institution): Kyowa-Kirin; Honoraria (self), Honoraria (institution): AbbVie; Honoraria (self), Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution): ONO; Honoraria (institution): Daichi-Sankyo; Honoraria (institution), Research grant / Funding (self), Research grant / Funding (institution): Boehringer Ingelheim. K. Inoue: Honoraria (self): AstraZeneca. E. Ichihara: Honoraria (self): AstraZeneca; Research grant / Funding (institution): Eli Lilly. T. Sasaki: Honoraria (self): AstraZeneca. Y. Shioyama: Full / Part-time employment: FUJIFILM Corporation/FUJIFILM Medical Co., Ltd. K. Katsui: Full / Part-time employment: Tsuyama Chuo Hospital. J. Sasaki: Honoraria (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Chugai; Honoraria (self): MSD; Honoraria (self): Daiichi Sankyo; Honoraria (self): Shionogi; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self): Kyowa Kirin; Honoraria (self), Research grant / Funding (self): ONO; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (self): Yakult. K. Kiura: Honoraria (self): AstraZeneca; Honoraria (self): Eli Lilly; Honoraria (self): Novartis; Honoraria (self), Research grant / Funding (self): Taiho; Honoraria (self), Research grant / Funding (self): Chugai; Honoraria (self), Research grant / Funding (self): Pfizer; Honoraria (self), Research grant / Funding (self): ONO; Honoraria (self), Research grant / Funding (self): Bristol-Myers Squibb; Honoraria (self): MSD; Honoraria (self), Research grant / Funding (self): Boehringer Ingelheim; Advisory / Consultancy, Research grant / Funding (self): Daiichi Sankyo; Research grant / Funding (self): Kyorin; Research grant / Funding (self): Nippon Kayaku. K. Sugio: Research grant / Funding (institution): MSD. All other authors have declared no conflicts of interest.

Background Tivantinib (formerly ARQ 197) is a selective inhibitor of c-Met mainly metabolized by CYP2C19. CYP2C19 is known for genetic polymorphisms, and ∼20% of Asians are poor metabolizers (PMs), while others are extensive metabolizers (EMs). In this study, we examined the safety, pharmacokinetics (PK), and preliminary efficacy of tivantinib as a single agent to determine recommended phase II doses (RPIIDs). Patients and methods Forty-seven patients (EMs, 33; PMs, 14) with solid tumors were orally treated with tivantinib, from 70 to 360 mg bid in a 3 + 3 dose-escalation scheme. EMs and PMs were separately enrolled at the doses >120 mg bid. Results Tivantinib was well tolerated up to 360 mg bid for EMs and 240 mg bid for PMs. Neutropenia, leukopenia, anemia, fatigue, and anorexia were the frequent adverse events related to tivantinib and were commonly observed in both EMs and PMs. PMs had 1.9-fold higher AUC0–12 compared with EMs at 240 mg bid. Regardless of CYP2C19 phenotype, Gr.4 neutropenia occurred in patients with relatively high exposure to tivantinib. A confirmed partial response was achieved in two non-small-cell lung cancer (NSCLC) patients. Conclusion Two different settings of RPIIDs, 360 mg bid for EMs and 240 mg bid for PMs, were determined.

The aim of the present study was to determine the effects of luseogliflozin on 24‐h glucose levels, assessed by continuous glucose monitoring, and on pharmacodynamic variables measured throughout the day. In this double‐blind, placebo‐controlled, crossover study, 37 patients with type 2 diabetes mellitus inadequately controlled with diet and exercise were randomized into two groups. Patients in each group first received luseogliflozin then placebo for 7 days each, or vice versa. After 7 days of treatment, the mean 24‐h glucose level was significantly lower with luseogliflozin than with placebo [mean (95% confidence interval) 145.9 (134.4–157.5) mg/dl vs 168.5 (156.9–180.0) mg/dl; p

A comparative study on the effect of neoadjuvant chemotherapy was performed for small cell lung cancer, by radiographic and histopathological examinations. Four patients with small cell lung cancer were preoperatively treated with the combination of cyclophosphamide, doxorubicin, vincristine, nimustine, cisplatin and vindesine, for 2 to 3 cycles. The clinical responses to the neoadjuvant chemotherapy included 2 complete, one partial response and one no change. All four patients underwent a planned operation. Based on microscopical evidence, the two complete responders had a residual tumor in the resected specimens. One was tumor-free after 28 months, while the other succumbed to operation-related death at 2 months. The remaining two inadequate responders relapsed and died shortly following operation. We believe a clinically complete responder should be differentiated from a 'true' complete responder by histopathological examination.

Tuberculomas of the lung are one of the more common lesions presenting a solitary pulmonary nodule, roentgenographically. We treated 36 patients with such nodules and describe here the radiologic-pathologic correlations and surgical treatment. In 21 patients, lung cancer was suspected preoperatively, based on radiographic findings of an ill-defined margin, pleural indentation and spicular radiation. Histologically, the tuberculous granuloma proliferated in the alveolar septa of the surrounding normal lung, often seen as a spicular radiation resembling lung cancer. In eight patients, tuberculoma was suspected because of radiographic findings of calcification and satellite nodules, and anti-tuberculous chemotherapy was prescribed for a few months. As this treatment was ineffective, surgical resection had to be done. Postoperative complications were nil and all of these patients are doing well at the time of preparation of this report. Anti-tuberculous chemotherapy was prescribed for 28 of 36 patients, postoperatively. We believe that surgical intervention is required for selected patients.

The fast movement of biped robot can be achieved by the fast walking, but the further fast motion can be achieved only by the biped running. To pursue this target, one leg running robot is modeled, analyzed and developed. First, it is theoretically analyzed in the one and two dimensional sagital plane models, secondly, the derived mathematical model is simulated by digital computers, and finally a 3-axis experimental robot is developed.

Thoracoscopic surgery has expanded with advances in endoscopic surgical instrumentation. We report on a 21-year-old woman with a complete thoracoscopic resection of an intercostal neurilemoma, which occurred extrapleurally in the ninth intercostal space of the lateral thoracic wall. The tumor was 70 x 40 x 25 mm in size, but a thoracotomy with a rib resection was avoided. The patient had an uncomplicated postoperative course and was discharged on the fourth postoperative day. Thoracoscopic resection of an intercostal neurilemoma, presenting as a lateral chest wall tumor, may be a safe and useful approach with an improved cosmetic result.

To assess whether a satellite lesion in the primary-tumor lobe is intrapulmonary metastasis from primary cancer (pm 1) or they are double primary lung cancers, we examined the postoperative prognosis of patients with pm 1 and the p 53 genetic differentiation between a satellite lesion and a primary lesion. Of 772 consecutive patients with N0-2M0 non-small cell lung cancer who underwent surgical resections between 1979 and 2000, 31 patients had a satellite lesion in the primary-tumor lobe. The 5-year survival rate was 26.3% in the pm 1 (+) T 4 group (n = 37), 14.7% in the pm 1 (-) T 4 group (n = 43), and 32.5% in the T 3 group (n = 132), suggesting that pm 1 cases should be classified as T 3. We examined 16 of 37 patients with pm 1 for mutations of the p 53 gene occurring exons 5 through 8 by the fluorescence-based polymerase chain reaction single-strand conformation polymorphism. Seven of the 16 patients analyzed had at least one p 53 mutations in their tumors. The mutational status of the p 53 gene was discordant in 5 patients, suggesting they were double primary lung cancers. The mutational status including DNA sequencing of the p 53 gene was concordant in 2 patients, suggesting they were intrapulmonary metastases. It remains arguable in the TNM staging system whether a satellite lesion in the primary-tumor lobe is intrapulmonary metastasis from primary cancer or they are double primary lung cancers.

Transcription factor Y-box binding protein 1 (YB-1) that binds to the inverted CCAAT box is involved not only in transcription of various genes but also in cell proliferation and DNA repair. We determined whether localization of YB-1 in either the nucleus or cytoplasm could serve as a prognostic marker for patients with non-small cell lung cancer (NSCLC). In 196 NSCLC patients, expression of YB-1 protein in the nucleus or cytoplasm was immunohistochemically evaluated. Of the 196 tumors examined, 88 (44.9%) were positive for YB-1 expression in the nucleus. Nuclear YB-1 expression significantly correlated with T factor, lymph node metastasis, and stage of the disease. Patients with a nuclear YB-1 tumor had a poorer prognosis than did those with a cytoplasmic YB-1 tumor in all of the NSCLC patients (P = 0.0494) and in patients with squamous cell carcinoma (P = 0.0313) but not in patients with adenocarcinomas. Nuclear localization of the YB-1 protein may prove to be an important factor of disease progression for patients with NSCLC, in particular, in cases of squamous cell carcinoma.

Lung cancer with a solitary metastasis to the stomach occurred in a 65-year-old man, surgically treated for gastric metastasis was followed by pulmonary resection. The gastric metastasis accompanied by upper gastrointestinal hemorrhage. After total gastrectomy to control this hemorrhage, a left lower lobectomy with a partial resection of the lingular segment and combined resection of the chest wall were done. Histopathological features of both the primary tumor in the left lower lobe and the gastric tumor were poorly differentiated adenocarcinoma, and showed the same immunoreactivities of p53 protein, carcinoembryonic antigen and keratin. These results indicate that the gastric tumor was a metastasis originated from the lung cancer.

Although human lung adenocarcinoma has diverse histological subtypes, the correlation between histological subtypes and occurrence of the p53 gene mutation has been given less attention. We investigated 145 surgically resected lung adenocarcinomas to search for the incidence of p53 mutations and for record data on survival in each histological subtype, according to the new WHO criteria (1999). The frequency of p53 mutation in bronchioloalveolar carcinoma (BAC; 0% in 17 cases) and BAC with invasive growth component (BAC-invasive; 11% in 27 cases), which is conventionally categorized as the mixed subtype in WHO typing, were apparently significantly lower than in other types (non-BAC including acinar, papillary, solid, or mixed histology with these subtypes; 48% in 101 cases; P0.01). Multivariate analysis revealed that the histological subtype including BAC-invasive was a strong, independent, and significant prognostic factor (P0.03), as were tumor size and pathological stage (P0.001 and 0.002, respectively) for overall survival. However, the occurrence of p53 mutation itself was seen to be significant only in case of the univariate analysis. Therefore, histological subtyping may be a better prognostic indicator than is p53 mutation. These findings suggest that the WHO classification with the BAC and BAC-invasive from other histological subtypes may prove useful to predict the outcome for surgically treated patients with lung adenocarcinoma.

Although the tumor suppressor p53 protein (P53) immunoreactivity and its gene (p53) mutation were reported to be significant prognostic indicators for human lung adenocarcinomas, little is known regarding the relationship between the heterogeneous distribution of P53 and its genetic status in each tumor focus and the clinicopathological significance. To determine how P53 is heterogeneously stabilized in patients, we compared P53 expression to both the p53 allelic mutation in exon 2 approximately 9 by polymerase chain reaction-single strand conformation polymorphism using microdissected DNA fractions, and the immunohistochemical MDM2 expression. Of the 48 positive to P53 in 118 lung adenocarcinomas examined, 10 with heterogeneous P53 expression were closely examined. The higher P53 expression foci in 7 of 10 cases were less differentiated, histologically in respective cases, and were frequently associated with fibrous stroma. Two had genetic mutations in exon 7 of the p53 gene in both the high and low P53 expression foci of cancer tissue indicating no apparent correlation between heterogeneous P53 expression and the occurrence of gene mutation. Immunohistochemical expression of MDM2 was significantly lower in high P53 expression areas (p0.05, the mean labeling indices of high and low P53 expression areas being 4.2 +/- 5.4% and 13.6 +/- 12.2%, respectively). In addition, among all the 118 cases examined, MDM2 expression was significantly suppressed in cases of p53 gene mutation, simultaneously with P53 overexpression, as compared with cases without both the p53 mutation and expression (p0.001). These findings suggest that the heterogeneous stabilization of P53 in human lung adenocarcinomas could be partly due to suppressed MDM2 expression. The overexpression of non-mutated P53 may afford a protective mechanism in human lung adenocarcinomas.

We herein report a case of a pulmonary metastatic tumor with an endobronchial growth pattern. A 75-year-old female was operated on for pulmonary metastasis which originated from a malignant melanoma of the upper gum. Computed tomography (CT) of the chest demonstrated a solitary mass in right S6 region and a preoperative bronchoscopic examination revealed an endobronchial tumor in rtB6b. A retrospective analysis of the chest CT showed a thickened bronchial wall extending to the entrance of rtB6b. Therefore, not a wedge resection but a segmentectomy (rtS6) was performed. When the surgical margin is determined, we should therefore keep in mind the possibility of an endobronchial growth pattern if only a solitary mass is recognized on the CT, even though pulmonary metastatic tumors showing an endobronchial growth pattern is uncommon.

A tumor-like lesion in the anterior mediastinum was recognized in a 21-year-old female patient with Graves' disease. A CT examination and MRI suggested a thymoma. A subtotal thyroidectomy and a total thymectomy were therefore performed simultaneously. A pathological study of the thymic mass showed thymic hyperplasia. These findings suggest that an enlarged anterior mediastinal mass in a Graves' disease could thus sometimes turn out to be thymic hyperplasia and not a thymoma.

We present a case of thymoma arising in the wall of the thymic cyst. A 77-year-old asymptomatic woman demonstrated an approximately 3.5 cm sized cystic mass in the left anterior mediastinum in the CT scan. The tumor was extirpated by a total thymectomy. Histologically, the cyst wall was lined by low cuboidal cells, but a markedly thickened wall was observed at the upper site of the mass, which was found to be thymoma. These findings may suggest that the thymoma originated from the wall of the thymic cyst.

E-cadherin, a calcium-dependent cell-cell adhesion molecule, plays a key role in the maintenance of tissue integrity. The function of this molecule is partly mediated by alpha-/beta-/gamma-catenin. Loss or dysfunction of E-cadherin is associated with an invasive phenotype. We analyzed the expression of E-cadherin and beta-catenin in human lung cancer to determine the relationship to clinicopathological factors and prognosis. E-cadherin and beta-catenin expressions were evaluated in 331 lung cancer tissues in a immunohistochemical analysis. Reduced E-cadherin expression was evident in 138 (42%), and reduced beta-catenin expression was noted in 122 (37%). Reduced E-cadherin expression significantly correlated with lymph nodes metastasis (P = 0.0199). E-cadherin expression significantly correlated with increasing histological differentiation (P = 0.0403). Although reduced E-cadherin did not correlate with the prognosis (P = 0.0652), reduced beta-catenin expression did significantly correlate with a poor prognosis (P = 0.0001). When both were reduced, there was a significant unfavorable prognosis compared with either the reduced expression (P = 0.0493) and preserved expression (P = 0.0003). Multivariate analysis showed a significantly lower survival rate for patients with reduced beta-catenin (P0.0001). We interpret these data to mean that dysfunction of the cell-cell adhesion molecule has a role in the progression of lung cancer and that analysis of E-cadherin and beta-catenin expression can provide clinically important evidence on which to base treatment.

The purpose of this study was to elucidate the characteristic high-resolution CT (HRCT) findings of poorly differentiated adenocarcinoma (PDA) in comparison with those of well differentiated adenocarcinoma (WDA).We investigated the HRCT features of surgically resected PDAs (n=21) and WDAs (n=31). We analyzed the margin, CT attenuation, and internal architecture of the tumor and findings in the surrounding lung field, comparing them with the corresponding pathologic findings.Smoothness of the greater part (full-1/2 round) of the tumor and solid appearance were more prevalent in PDAs than WDAs (81% vs. 32%, 100% vs. 35%) [p0.01]. Air-bronchogram was prevalent in WDAs (58%), but was never seen in PDAs [p0.01]. Ground-glass opacity in PDAs pathologically corresponded to inflammation and edema in the alveolar space.Smoothness of the tumor margin and solid appearance without air-bronchogram were more commonly found in PDA than in WDA. HRCT may predict the histological differentiation of adenocarcinoma in selected cases in which differentiation is inconclusive by sputum cytology and transbronchial or CT-guided biopsy.

We reported a case of catamenial pneumothorax that was recurrent after surgical treatment. A 43-year-old woman had sudden chest pain and dyspnea during menstruation. Right pneumothorax and pleural effusion were pointed out on chest X-ray films. When the patient was 31 years old, she received a diagnosis of catamenial pneumothorax and underwent thoracotomy for resection of diaphragmatic endometriosis. However, after surgery she experienced recurrence of right pneumothorax, and was accordingly treated with danazol. The patient decided to terminate medication by herself because her symptoms had disappeared. Several years after the cessation of medication, she experienced chest pain frequently during menstruation, but did not seek a medical check-up. She visited our department because of persistent chest pain in 1997. After the patient was hospitalized, pneumothorax was diagnosed and continuous drainage was performed. Although pneumothorax was alleviated by drainage, it recurred during the patient's next menstrual period. Open lung surgery was performed. Diaphragmatic endometriosis with a small hole and inflammatory thickened lesions on the visceral pleura of the lower lobe (S 6) were found and excised. Microscopic examination of the excised specimens showed endometriosis. Visceral pleural endometriosis has been histologically demonstrated in very few cases. After surgery, hormonal therapy was started. The patient has been well for 12 months without recurrence of pneumothorax. Both surgical and hormonal treatment were considered necessary for the treatment of catamenial pneumothorax in this case.

This study was designed to evaluate p53 alterations in occult lymph node metastases.We examined 41 patients with stage I non-small-cell lung cancer. We investigated p53 gene mutation by polymerase chain reaction and single-strand conformation polymorphism analysis of exons 5-8, p53 protein accumulation by immunostaining with monoclonal antibody DO-7, and detection of tumor cells in lymph nodes by immunohistochemistry with monoclonal antibodies to cytokeratin (CK).p53 gene mutation was detected in 34% of tumors and nuclear p53 accumulation in 46%. CK-positive cells in the hilar and mediastinal region lymph nodes were detected in 43.9% of patients and 29.3%, respectively. Of the 14 cases with p53 mutation and the 19 cases with p53 accumulation, 12 and 15 had micrometastases in the hilar or mediastinal lymph nodes, respectively. However, p53 alterations were not significantly associated with occult lymph node metastases. In cases with occult lymph node metastases, the 5-year survival was 81. 9% for the p53 wild-type group and 45.8% for the p53 mutation group.p53 alterations are not correlated with occult lymph node metastases, while p53 gene mutation is considered to be an unfavorable prognostic marker in patients with occult lymph node metastases. J. Surg. Oncol. 2000;73:143-147.

In order to inhibit the occurrence of airborne metastasis of bronchioloalveolar cell carcinoma (BAC), we tried to activate alveolar macrophages by the inhalation of aerosolized OK-432, which is a heat and penicillin-treated lyophilized preparation of the Su strain of Streptococcus pyogenes.Alveolar macrophages were obtained from resected specimens of lung cancer patients and cultured for 24 h in the presence of various concentrations of OK-432 (0.001-1 KE/ml). The cytotoxic activity against a lung cancer cell line was augmented in a dose dependent manner and reached a plateau level at 0.1 KE/ml of OK-432. Furthermore, the alveolar macrophages produced various cytokines, i.e., IL-1, TNF-alpha, and IL-6 after 72 h cultivation with 0.1 KE/ml of OK-432. Based on the in vitro experiments, six patients with intrapulmonary metastatic BAC were therefore treated by the inhalation of aerosolized OK-432. All 6 patients inhaled aerosolized OK-432 (0.1 KE/ml) twice a day for 5 days. The inhalation therapy regimen was repeated either weekly or monthly unless the tumor markedly progressed. No adverse events were observed in any patients. Either an augmentation of antitumor cytotoxicity or TNF-alpha production by the alveolar macrophages was observed in the two of three patients examined.OK-432 inhalation therapy was found to be safe and thus warrants further investigation to determine its clinical effectiveness for BAC.

We report a case of squamous cell carcinoma of the lung in which a left pneumonectomy combined resection of the pulmonary artery and aorta was performed using a cardiopulmonary bypass. The bifurcation of the pulmonary artery was repaired with a pericardial patch and the descending aorta was replaced with an artificial vessel Eleven months later, the patient underwent dissection of the contralateral mediastinal lymph nodes because of a recurrence of the disease. Even though pulmonary metastases have again recently appeared, he is alive and doing well two years after operation. To obtain a better prognosis in cases demonstrating an involvement of the bifurcation of pulmonary artery, more effective combined treatment still needs to be developed.

99mTc-hexakis-2-methoxyisobutyl isonitrile (MIBI) has been reported to accumulate in various tumors and to be a transport substrate for P-glycoprotein (Pgp). The aim of this study was to evaluate the usefulness of 99mTc-MIBI SPECT for in vivo assessment of lung cancer chemosensitivity. Also examined was the relationship between 99mTc-MIBI uptake and Pgp expression.Ten lung cancer patients who had undergone surgery were examined. Before surgery, 99mTc-MIBI SPECT was performed 15 and 120 min after injection, and the early uptake (L/Ne), delayed uptake (L/Nd) and washout rate (L/Nwr) of 99mTc-MIBI were calculated by the count ratio of lesion to contralateral normal lung tissue. The results were then compared with chemosensitivity determined by the succinate dehydrogenase inhibition test using six antitumor drugs (doxorubicin, mitomycin C [MMC], vindesine, etoposide [VP-16], cyclophosphamide and cisplatin). Pgp expression was determined by immunohistochemical staining.Sensitivity to MMC correlated significantly with L/Ne (P0.01) and L/Nwr (P0.05). Sensitivity to VP-16 correlated weakly and insignificantly with L/Nwr. L/Nd showed no correlation with sensitivity to any drug. Neither L/Ne, L/Nd nor L/Nwr was significantly different between the Pgp-positive group (n = 2) and the Pgp-negative group (n = 8).The results suggest that 99mTc-MIBI SPECT, a noninvasive in vivo examination, can predict the chemosensitivity of lung cancer to MMC and VP-16 independently of Pgp expression.

A 63-year-old man was admitted to our hospital because of left back pain and dysesthesia in his left arm. On physical examination, the patient had ptosis, myosis, and anhydrosis on the left side, suggesting Horner's syndrome. A chest computed tomographic scan disclosed a mass lesion adjoining to the left posterior mediastinum. Although the mass lesion showed a slight decrease in size after the systemic administration of corticosteroids, no further improvement was obtained. Open chest examination revealed extended thickening of the parietal pleura with massive involvement of the upper thoracic sympathetic trunk. The diagnosis was malignant mesothelioma of sarcomatous type. Horner's syndrome is a rare but possible complication in the clinical course of malignant pleural mesothelioma.

Ras gene mutations are associated with a poor prognosis in patients with adenocarcinoma of the lung. However, the association between cases with ras gene mutation and an occurrence of second primary cancer is unknown.We examined 89 adenocarcinoma of the lung obtained from patients treated by curative resection, and four second primary cancers, for mutation at codons 12, 13, and 61 of three ras oncogenes using polymerase chain reaction and oligonucleotide hybridization techniques.Ras gene mutations were detected in 13 cases. Six patients died from recurrent disease within 3 years. Of the seven patients who survived over 5 years, three patients demonstrated a metachronous second primary cancer after the operation for lung cancer, and one patient had synchronous laryngeal cancer. Two of the cases with second primary cancer demonstrated the ras gene mutation. One had the same mutation as that of the primary lung cancer, and the other had a different mutation from the first lung cancer.Ras gene mutations play an important role in tumor progression of lung adenocarcinoma and also might have an role in the carcinogenesis in respiratory tract cancer.

We report an extremely rare case of intrapulmonary lymphangioma. A 41-year-old woman was admitted to our hospital for complete medical evaluation of a pulmonary nodule on chest X-ray, which was found during an annual check-up. Chest radiograph showed a well-circumscribed spherical mass adjacent to the right border of the heart in the right lower lung field. Although a cystic tumor of the lung was suspected based on computed tomogram and magnetic resonance imaging findings, a histologic diagnosis could not be made on transbronchial biopsy. In addition, the nodule had increased in size compared with a chest X-ray taken 1 year previously. Enucleation was performed. Histological examination revealed numerous cysts with thin walls lined by a single layer of cells in which immunoreactivity to von Willebrand factor was weakly positive. Intrapulmonary lymphangioma was subsequently diagnosed.

To prevent stapled stenosis after laparoscopic local gastric resection by using autosuturing devices, we developed a technique for laparoscopic pylorus-preserving gastrectomy with intracorporeal hand-sewn anastomosis. We describe this procedure and present two case reports. The intracorporeal hand-sewn anastomotic technique is an important advance in the field of minimally invasive laparoscopic surgery.

The distribution of cytochrome P450 2E1 (CYP2E1) genetic polymorphism was compared in 126 patients with non-small cell lung cancer (NSCLC) and 612 control subjects by PCR-based assay. Incidence of C type (c2/c2) of CYP2E1 polymorphism in the patients with squamous cell carcinoma (9.4%) was significantly higher than that in healthy controls (4.1%) or in the patients with adenocarcinoma (2.7%) within the Japanese population. The relative risk (95% confidence limit) of C type compared with A and B type in patients with squamous cell carcinoma was 2.45 (0.92-6.48). The incidence of p53 gene mutation was studied in an association with CYP2E1 polymorphism. When all the NSCLC patients were considered, the incidence of p53 mutations in type C (85.7%) was significantly higher than that of A and B type (32.8%). It is suggested that C type of CYP2E1 may define individuals at an increased risk of squamous cell carcinoma through the impaired metabolism of a certain carcinogen which predisposes to p53 gene mutation.

We examined 110 patients with non-small cell lung cancer who underwent consecutive pulmonary resection for loss of heterozygosity (LOH) at the short arm of chromosome 3 (3p). We performed a PCR-based microsatellite polymorphism analysis for detection of LOH. The microsatellite markers used were D3S966 (3p21.3), D3S1007 (3p21. 3-22), and D3S1228 (3p14.1-14.3). Of 98 informative cases, 3p LOH was found in 45 (46%). 3p LOH was more prevalent in squamous cell carcinoma (24/35, 69%) than in adenocarcinoma (18/52, 35%; P = 0.0019). There was no significant association between 3p LOH and sex, disease stage, or grade of differentiation. However, patients with 3p LOH tended to survive for a shorter period of time (P = 0.0631, log rank test). There was no such tendency in squamous cell carcinoma (P = 0.7513), but in adenocarcinoma, the difference of survival was significant (P = 0.0015). Cox's proportional hazards model also predicted that 3p LOH was an independent poor prognostic marker in adenocarcinoma (P = 0.0502) but not in squamous cell carcinoma or in the entire cohort (P = 0.7866 and 0.1371, respectively). LOH at 3p may help to identify non-small cell lung cancer patients with a poor prognosis, who thus need an intensive postoperative follow-up protocol or who are suitable for novel investigational therapeutic approaches. It is also suggested that the putative tumor suppressor gene at 3p may have a different role in squamous cell carcinoma and adenocarcinoma of the lung.

To clarify the clinical significance of the mutation of p53 gene in hepatocellular carcinoma (HCC), 90 resected specimens from Japanese patients were assayed using a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) analysis. p53 mutations were detected in 25 cases (27.8%) at exons 4, 5, 6, 7, and 8, and the most frequent region of the mutation was at exons 5 and 7. No statistically significant correlation was observed between the p53 mutations and the clinical features except for the preoperative alpha-fetoprotein (AFP) level (P.05). According to the pathological features, prognostic factors, such as size of the tumor, vascular invasion, fibrous capsule infiltration, and intrahepatic metastasis, showed no relationship to the existence of the mutation. However, p53 mutations were significantly associated with the degree of differentiation of HCC; that is, the mutation was found in 19 cases of 53 poorly differentiated HCCs (35.9%) and 2 of 3 cases of anaplastic HCCs (66.7%). The presence of p53 mutations was associated with a shortened cancer-free survival (P.001, by log rank test) and a shortened survival (P.05). A multivariate analysis by the Cox regression analysis showed that the p53 mutations were an unfavorable prognostic factor related to recurrence (P.005), which is especially significant within the first postoperative year. These results suggest that the mutations of p53 gene of HCC might be an independent prognostic predictor to help in the selection of candidates who should undergo more intensive postoperative treatment.

Expression of isoforms of the CD44 is generated by alternative splicing of CD44 gene; CD44H: lacks all 10 alternative exons, CD44R: the alternative exons v8 to v10, CD44V: other group of variants which contains the alternative exon v6. In some tumors such as colorectal cancer, breast cancer, non-Hodgkin lymphoma, and melanoma, over-expressed CD44 isoform which contains such alternative-spliced variant exons may play a causative role in tumor metastasis. In lung cancer, however, the role of CD44 variants in tumor progression and metastasis is uncertain. In our study and reported literature, no definite correlation was observed between the expression of specific CD44 isoform and tumor progression or metastasis of lung cancer.

Although gallbladder carcinoma is one of the most frequent neoplasms in Chile, there is limited information about the molecular changes involved in its pathogenesis. We investigated the incidence of ras gene mutations and loss of heterozygosity (LOH) at the following genes/loci: p53, DCC, rb, 5q 3p, 8p, and 9p. We precisely microdissected 194 relevant areas from paraffin-embedded microslides from 25 gallbladder carcinomas and their accompanying nonneoplastic lesions (which were present in 15 cases) from patients in Chile. The specimens were analyzed by PCR-based assays for LOH, and we designed a RFLP method for ras mutations and immunohistochemistry for p53 protein overexpression. We determined that LOH at p53 (91%), 9p (50%), 8p (44%) and DCC (31%) are frequent events and that LOH at p53, 9p, and DCC are early events, while ras mutations and LOH at 3p, rb, and 5q occurred occasionally. LOH at p53 occurred more frequently and earlier than protein overexpression. The mean number of mutations present in invasive carcinomas was 2.1, and in six cases, LOH at the p53 gene was the sole mutation detected. The same allele was lost in 61 (93%) of 71 nonneoplastic foci as in the corresponding invasive carcinomas for all four mutations studied. The odds of this occurring by chance are approximately 4 x 10(-15). Although clonality cannot be excluded, allelic loss appears to be highly directed, but the mechanism for allele-specific mutations remains to be determined.

Deletions in the short arm of chromosome 3 (3p) are present in most lung carcinomas.To investigate the role of these chromosome 3p deletions in the pathogenesis of non-small cell lung carcinomas.Seven archival, paraffin-embedded, surgically resected lung cancer specimens were studied. Fifty precisely identified malignant and preneoplastic lesions present in bronchi, bronchioles, and alveoli were microdissected from stained slides and analyzed for allele loss using polymerase chain reaction-based assays for dinucleotide repeat polymorphisms at three chromosome 3p loci (3p14, 3p21.3, and 3p25).University-based medical center and affiliated hospitals.Samples were analyzed from seven patients who underwent surgical resection with curative intent for non-small cell lung cancer and whose specimens included extensive multifocal areas of preneoplastic lesions (hyperplasia, metaplasia, dysplasia, or noninvasive cancer).Lymphocytes from all seven cases were heterozygous (ie, informative) for all three microsatellites analyzed. Six (86%) of seven invasive cancers had loss of heterozygosity at one or more chromosome 3p sites. In the accompanying preneoplastic lesions, loss of heterozygosity was detected in none of two normal bronchioles, 13 (76%) of 17 hyperplasias, six (86%) of seven dysplasias, and four (100%) of four noninvasive cancers. Loss of heterozygosity was detected throughout the respiratory tract, in bronchi, bronchioles, and alveoli. In 18 (78%) of 23 preneoplastic lesions, the specific alleles lost were identical to those lost in the corresponding carcinomas. The probability of this happening by chance is 5.3 x 10(-3).Deletions in the short arm of chromosome 3 occur at the earliest stage (hyperplasia) in the pathogenesis of lung cancer and involve all regions of the respiratory tract. Allele loss is highly specific, but its mechanism remains unknown. Our findings may be of considerable biologic, prognostic, and clinical significance.

Background The cell surface receptor tyrosine kinase c-Met and its ligand, the hepatocyte growth factor (HGF), are implicated in tumor cell migration, invasion, survival and proliferation. EMD 1214063 is a novel potent and highly selective reversible, ATP-competitive small molecule c-Met inhibitor. Methods This is a phase I, first in human (FIH) clinical trial with escalating doses of EMD 121406(NCT 01014936). The primary objective is to determine the MTD. Secondary objectives include evaluation of safety, pharmacokinetics, anti-tumor effect and pharmacodynamics (Pd). Eligible patients had advanced solid tumors not amenable to standard therapies. Following a classical 3 + 3 dose escalation scheme, successive cohorts of patients were treated with once daily oral EMD 1214063 according to two 21-day-cycle schedules, either days 1-14 followed by a 7-day rest(regimen 1, R1), or continuous three times weekly administration (regimen 2, R2). Pd markers were evaluated in paired tumor biopsies. Results As of 30 March 2011, a total of 41 patients had been enrolled, 21 in R1 and 20 in R2. The dose was escalated from 30 mg/day to 115 mg/day in R2 and to 230 mg/day in R1. One DLT was reported in R1 at 115 mg/day, an asymptomatic, grade 4 lipase and G3 amylase elevation. No other DLTs or treatment-related SAEs were observed. The remaining treatment-related AEs of grade 2 or higher included nausea (n = 1), vomiting (n = 1), anorexia (n = 1), diarrhea (n = 1), and fatigue (n = 1) in R1, and neutropenia (n = 1) in R2. 37 patients (90%) had no drug-related toxicity greater than grade 1. At the dose levels investigated, median Cmax and AUC values increased with dose. Immunohistochemical analysis of a patient with pre- and on-treatment biopsies showed a decrease in phospho-c-Met staining intensity under treatment. Preliminary anti-tumor activity has been observed, including an unconfirmed PR in one patient and stable disease lasting for at least 4 months in 5 patients. One patient with sarcomatoid bladder carcinoma and multiple MET copies due to polysomy of chromosome 7 achieved SD for 16+ months. Conclusions The MTD has not yet been reached and dose escalation of EMD 1214063 continues. Updated results of this FIH study will be presented.