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Objective Previous studies have described several prognostic factors for heart failure (HF); however, these results were derived from registries consisting of conventional age groups, which might not represent the increasingly aging society. The present study explored the prognostic factors for all-cause death in hospitalized patients with HF across different age categories using an acute HF registry that included relatively old patients. Methods From a total of 1,971 consecutive patients with HF, 1,136 patients were enrolled. We divided the patients into 4 groups (≤65, 66-75, 76-85, and >85 years old) to evaluate all-cause death and prognostic factors of all-cause death. Results During the mean follow-up period of 1,038 days, 445 patients (39.2%) had all-cause death. A Kaplan-Meier analysis demonstrated significantly higher incidence of all-cause death in the elderly groups than in the younger groups (log-rank p85 years old group. Conclusions Atrial fibrillation was a notable predictor of HF in young patients, whereas frailty and low-grade albuminemia were essential predictive factors of HF in elderly patients. With the increasing number of elderly patients with HF, comprehensive multidisciplinary treatment will be necessary.

Detecting rare circulating tumor cells (CTCs) in the bloodstream is extremely challenging. We had previously developed a novel polymeric microfluidic device, "CTC-chip," for capturing CTCs and have shown high capture efficiency in lung cancer cell lines by conjugating Abs against epithelial cell adhesion molecules (EpCAM). This study aimed to optimize the EpCAM-chip and clarify the prognostic impact of CTCs in lung cancer patients. Of 123 patients with pathologically proven lung cancer, both progression-free survival (P = .037) and cancer-specific survival (P = .0041) were predominantly poor when CTCs were detected before treatment. After classification into surgical and chemotherapy groups, progression-free survival was worse in CTC-positive patients in both groups (surgery, P = .115; chemotherapy, P = .012), indicating that the detection of baseline CTCs is a risk factor for recurrence and progression. Furthermore, we recovered captured CTCs using micromanipulators and undertook mutation analysis using PCR. Thus, the EpCAM-chip is a highly sensitive system for detecting CTCs that contributes to the prediction of recurrence and progression and enables genetic analysis of captured CTCs, which could open new diagnostic, therapeutic, and prognostic options for lung cancer patients.

Background Few registries have provided precise information concerning incidence rates for acute heart failure syndrome (AHFS) in Japan.Methods and Results:All hospitals with acute care beds in Awaji Island participated in the Kobe University heart failure registry in Awaji Medical Center (KUNIUMI Registry), a retrospective, population-based AHFS registration study, enabling almost every patient with AHFS in Awaji Island to be registered. From 1 January 2015 to 31 December 2017, 743 patients with de novo AHFS had been registered. Mean age was 82.1±11.5 years. Using the general population of Japan as of 2015 as a standard, age- and sex-adjusted incidence rates for AHFS were 133.8 per 100,000 person-years for male and 120.0 for female. In 2015, there were an estimated 159,702 new-onset patients with AHFS, which was predicted to increase to 252,153 by 2040, and reach a plateau. The proportion of patients aged >85 years accounted for 42.6% in 2015, which was predicted to increase up to 62.5% in 2040. The proportion of patients with heart failure with preserved ejection fraction was estimated at 52.0% in 2015, which was predicted to increase gradually to 57.3% in 2055. Conclusions The present analysis suggested that the number of patients with de novo AHFS keeps increasing with progressive aging in Japan. Establishment of countermeasures against the expanding burden of HF is urgently required.

Background: Because the effectiveness of strengthening guideline-based therapy (GBT) to prevent heart failure (HF) rehospitalization of chronic HF patients remains unclear, this study investigated the characteristics of HF patients in the Kobe University Heart Failure Registry in Awaji Medical Center (KUNIUMI) acute cohort. Methods and Results: We studied 254 rehospitalized HF patients from the KUNIUMI Registry. Optimized GBT was defined as a Class I or IIa recommendation for chronic HF based on the guidelines of the Japanese Circulation Society. The primary endpoint was all-cause death or first HF rehospitalization after discharge. Outcomes tended to be more favorable for patients who had rather than had not received optimized GBT (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.57-1.19; P=0.27). Similarly, among New York Heart Association (NYHA) Class IV patients, outcomes tended to be more favorable for those who had rather than had not undergone optimized GBT (HR 0.73; 95% CI 0.47-1.12; P=0.15). Importantly, outcomes were significantly more favorable among NYHA Class IV patients aged

Background: The effect of intraindividual variability in lipid levels on the onset of acute coronary syndrome (ACS) remains uncertain. We evaluated the relationship between intraindividual variability in lipid levels and culprit lesion morphologies by optical coherence tomography (OCT). Methods and Results: Seventy-four consecutive patients with ACS whose cholesterol levels were assessed ≥3 times during outpatient visits before the onset of ACS were enrolled in the study; 222 patients without significant stenotic lesions were used as a control group. Based on OCT findings of culprit lesions, ACS patients were categorized into a plaque rupture ACS (PR-ACS) group (n=44) or a non-plaque rupture ACS (NPR-ACS) group (erosion or calcified nodule; n=30). Visit-to-visit variability in lipid levels was evaluated using the corrected variability independent of the mean (cVIM). Patients with ACS had significantly higher low-density lipoprotein cholesterol (LDL-C) levels and cVIM in LDL-C than the control group. The PR-ACS group had significantly higher mean LDL-C levels and greater cVIM in LDL-C than the control group. The PR-ACS group had a significantly higher cVIM than the NPR-ACS group, despite similar mean LDL-C levels. Multivariate analysis revealed that higher cVIM of LDL-C was an independent predictor of PR-ACS (odds ratio 1.06; P=0.018). Conclusions: In addition to the LDL-C level, greater visit-to-visit variability in LDL-C levels may be associated with the onset of ACS induced by plaque rupture.

Aims Increased left atrial pressure leads to pulmonary congestion. Although the B-lines in lung ultrasound (LUS) are useful in detecting pulmonary congestion, data regarding the association between B-lines and invasive haemodynamics are inconsistent. This study aimed to explore the correlation of the B-line count by LUS with pulmonary capillary wedge pressure (PCWP) stratified for preserved and reduced ejection fraction (EF) in acute heart failure patients. Methods and results We performed a prospective observational study on 116 hospitalized patients with acute heart failure (mean age, 75.2 ± 10.3 years), who underwent right heart catheterization before discharge. LUS was performed in eight zones within 4 h of right heart catheterization and compared with PCWP separately in each EF group. Cardiac events were recorded 1 year after discharge. PCWP revealed a clear pivot point at which the B-lines began to increase in the overall cohort and each EF. Specific thresholds of the increase in B-lines were identified at 19 and 25 mmHg for preserved and reduced EF, respectively. Residual congestion at discharge was defined as the presence of ≥6 B-lines. Patients with residual congestion had a higher risk for cardiac events than those without residual congestion (hazard ratio, 12.6; 95% confidence interval, 4.71–33.7; log-rank, P < 0.0001). Conclusion A clear pivot point was associated with increased B-lines count in PCWP at 19 and 25 mmHg for preserved and reduced EF, respectively. Moreover, the increased B-line count above the defined cut-off used to quantify residual congestion was associated with significantly worse outcomes.

A 73-year-old woman was diagnosed by bronchoscopic examination with primary left lung cancer (Adenocarcinoma, cT3N0M0, stage IIB), which was closely adjacent to the descending aorta in contrast enhanced computed tomography (CT). This CT did not reveal any invasion of a tumor into the descending aorta, and a dynamic fourth dimension CT (4D-CT) indicated that there was no invasion of the aorta by this tumor, so we decided to perform surgery. The operative procedure was a left lower lobectomy and lymph node dissection with the use of a thoracoscope. An intraoperative finding was that the tumor had not invaded the aorta. There are few reports about the evaluation of vascular invasion using the dynamic 4D-CT. We consider that the dynamic 4D-CT gave very useful information about vascular invasion.

There is little evidence to demonstrate the impact of heparin bridging (HB) in major surgery. This study aimed to evaluate the benefits and risks of HB in lung cancer surgery by comparing HB and non-HB (NHB) groups. We extracted patients who were taking an anticoagulant, were diagnosed with lung cancer, and underwent lung resection between April 2014 and March 2018 from a nationwide database in Japan. We compared the HB and NHB groups to determine the benefits and risks of HB. The proportion of postoperative thromboembolism and bleeding events between the HB and NHB groups was the primary outcome. We performed propensity score matching to remove any HB assignment bias. We selected 2416 patients, and among these, 1068 patients had HB and 1348 did not. Propensity score matching extracted 1500 patients: 750 with HB and 750 without HB. After matching, a Chi-square test showed no significant difference in the incidence of postoperative thromboembolism (1.5% vs 0.9%, p value = 0.343) and bleeding events (5.9% vs 4.0%, p value = 0.124) between the two groups. There was no significant difference in the incidence of postoperative thromboembolism and bleeding in the patients with and those without HB.

Background: In-stent neoatherosclerosis (NA) is a risk for future cardiovascular events through atherosclerotic progression in non-stented lesions. Using optical coherence tomography, this study assessed the efficacy of intensive therapy with 10 mg/day rosuvastatin plus 1,800 mg/day eicosapentaenoic acid (EPA) vs. standard 2.5 mg/day rosuvastatin therapy on native coronary plaques in patients with NA. Methods and Results: This was a subgroup analysis of the randomized LINK-IT trial, which was designed to compare changes in the lipid index in NA between intensive and standard therapy for 12 months. In all, 42 patients with native coronary plaques and NA were assessed. Compared with standard therapy, intensive therapy resulted in greater decreases in serum low-density lipoprotein cholesterol concentrations and greater increases in serum 18-hydroxyeicosapentaenoic acid concentrations, with significantly greater decreases in the lipid index and macrophage grade in both NA (-24 vs. 217 [P

Background: The clinical frailty scale (CFS) predicts late mortality in patients undergoing transcatheter aortic valve replacement. We evaluated the CFS and other parameters associated with 1-year mortality after balloon aortic valvuloplasty (BAV). Methods and Results: Between January 2013 and May 2018, 148 patients with severe aortic stenosis (AS) who underwent BAV at the present hospital were enrolled. We recorded pre-procedural CFS grade, baseline characteristics, echocardiographic, and hemodynamic parameters. To investigate the potential risk to patients before BAV, we evaluated the Society of Thoracic Surgeons (STS) score. After patients who underwent surgical aortic valve replacement, transcatheter aortic valve replacement or repeat BAV were excluded, we investigated 1-year survival. Of 127 patients, 41 (32.3%) died ≤1 year after BAV, 8 of whom (19.5% of all-cause deaths) had cardiac deaths. Higher grade of CFS and STS score significantly correlated with 1-year mortality. Severe frailty and the high operative risk group (CFS ≥7 and STS score ≥8.7%) had an extremely poor prognosis (1-year mortality, 81.2%). Conclusions: In this BAV cohort, severe frailty was a predictor of 1-year mortality in elderly patients with severe AS.

Background: Cholesterol efflux from atherosclerotic lesion is a key function of high-density lipoprotein (HDL). Recently, we established a simple, high-throughput, cell-free assay to evaluate the capacity of HDL to accept additional cholesterol, which is herein referred to as "cholesterol uptake capacity (CUC)". Objective: To clarify the cross-sectional relationship between CUC and coronary plaque properties. Methods: We enrolled 135 patients to measure CUC and assess the morphological features of angiographic stenosis by optical coherence tomography (OCT). We estimated the extent of the lipid-rich plaque by multiplying the mean lipid arc by lipid length (lipid index). The extent of the OCT-detected macrophage accumulation in the target plaque was semi-quantitatively estimated using a grading system. Results: Lipid-rich plaque lesions were identified in 125 patients (92.6%). CUC was inversely associated with the lipid index (R = -0.348, P < 0.0001). In addition, CUC was also inversely associated with macrophage score (R = - 0.327, P < 0.0001). Conversely, neither circulating levels of HDL cholesterol nor apoA1 showed a similar relationship. Conclusions: We demonstrated that CUC was inversely related to lipid-rich plaque burden and the extent of macrophage accumulation, suggesting that CUC could be useful for cardiovascular risk stratification.

The impact of perioperative heparin bridging (HB) for lung surgery in patients on anti-clotting drugs remains unclear. We performed a retrospective study to assess its effect on surgical safety by comparing HB and non-HB groups. This study included 274 consecutive patients on anti-clotting drugs who underwent surgery for lung cancer. Of these, 77 received HB and 197 did not. Propensity score matching extracted 124 patients, consisting of 62 patients with HB and 62 patients without HB. Endpoints were surgical safety. There was no statistically significant difference in the outcomes of surgical safety outcomes between the HB and non-HB group after propensity-score matching, operative time (172 vs. 203 min, p = 0.131), volume of blood loss (60 vs. 70 ml, p = 0.335), need for intraoperative RBC transfusion (3.2 vs. 6.5%, p = 0.680), chest tube drainage volume on the 1st postoperative day (200 vs. 200 ml, p = 0.796), and chest tube placement duration (3 vs. 3 days, p = 0.606). The influence of perioperative HB on postoperative thromboembolic or bleeding events in lung cancer surgery is not obvious, but its surgical safety appears to be acceptable.

Both extrapleural pneumonectomy (EPP) and pleurectomy/decortication (P/D) are used for the surgical treatment of malignant pleural mesothelioma (MPM). This study aimed to compare the operative and clinical outcomes and survival between EPP and P/D.We performed a retrospective analysis of the surgical and clinical data of 40 patients who underwent either EPP (n = 18) or P/D (n = 22) for MPM at our institution between January 2000 and December 2018.In comparison to EPP, P/D was associated with a higher intraoperative bleeding volume (1175 vs 1805 ml, p = 0.0020) and greater duration of postoperative thoracic drainage (3 vs 16 days, p 0.0001). Adjuvant chemotherapy was more common after P/D (81.8%) than after EPP (33.3%; p = 0.0024). For epithelioid-type MPM, overall survival (OS) and recurrence-free survival (RFS) were significantly better in patients who underwent P/D in comparison to those who underwent EPP (p = 0.040 and p = 0.015, respectively), with no difference for the biphasic and sarcomatoid types of MPM. A Cox proportional hazards regression model identified P/D as a significant favorable prognostic factor for OS [hazard ratio (HR), 0.391; 95% confidence interval (CI), 0.175-0.871; p = 0.022] and RFS (HR, 0.418; 95% CI, 0.190-0.920; p = 0.030).Based on our findings, P/D may be superior to EPP for improving the prognosis of patients with resectable epithelioid-type MPM.

We report the case of a 70-year-old man who developed a splenic infarction due to a thrombus in the pulmonary vein (PV) stump after left upper lobectomy (LUL). Preoperative imaging showed a mass measuring > 5 cm in the upper lobe of the left lung, and sputum cytology revealed squamous cell carcinoma. Therefore, video-assisted thoracoscopic LUL was performed. The postoperative course was uneventful but biochemical blood tests showed an increased inflammatory response. Contrast-enhanced computed tomography revealed splenic infarction and a thrombus in the left superior PV stump. Prompt treatment with anticoagulants was administered, and the patient was discharged with mild recovery. However, the patient developed cerebral infarction after discharge and died 33 days after the surgery. Splenic infarction is a rare postoperative complication, with only three reported cases, including this report. However, this condition should be considered along with PV thrombus when evaluating an increased inflammatory response after LUL.

Detection of rare tumor cells circulating in the blood (CTCs) presents technical challenges. CellSearch, the only approved system for clinical use, fails to capture epithelial cell adhesion molecule‐negative CTCs such as malignant pleural mesothelioma (MPM). We have developed a novel microfluidic device (CTC‐chip) in which any Ab to capture CTCs is conjugated. The CTC‐chip was coated with an Ab against podoplanin that is abundantly expressed on MPM. Circulating tumor cell‐detection performance was evaluated in experimental models in which MPM cells were spiked in blood sampled from a healthy volunteer and in clinical samples drawn from MPM patients. The CTC‐chip showed superior CTC‐detection performance over CellSearch in experimental models (sensitivity, 63.3%‐64.5% vs 0%‐1.1%; P

Introduction Patients with undiagnosed anterior mediastinal tumors commonly undergo surgery for diagnosis and treatment. However, determining the optimal therapeutic strategy is difficult for tumors with substantial invasion, such as lesions touching the aortic arch (AA). Case presentation A 76-year-old man of Asian descent presented to our hospital because chest computed tomography (CT) revealed an anterior mediastinal tumor. This tumor surrounded the left subclavian vein and touched the AA. We suspected the tumor to be malignant. We therefore decided to resect the tumor with preparation for total arch replacement (TAR). The operation was performed in three steps. First, we performed a mediastinal sternotomy. However, the tumor had invaded the subclavian vein, so we resected this vein after adding a transmanubrial approach. However, because of invading the AA we needed next step. Second, we shifted the patient to the right lateral decubitus position. We performed partial resection of the left upper lobe and exfoliated the distal AA. Third, we shifted the patient to the dorsal position and implanted an artificial cardiopulmonary device, after which we performed TAR, and pulmonary artery (PA) trunk plasty with a pericardial patch. The operation was successful, with no major adverse events. Pathologically, the tumor was diagnosed as diffuse large B-cell lymphoma. Discussion If oncologically complete resection is preferable for tumors with substantial invasion, complete resection should be attempted even if the surgery is difficult. Conclusion We performed complete resection of an anterior mediastinal tumor with TAR and PA trunk plasty using a pericardial patch., Highlights • We performed complete resection of a malignant tumor through TAR and PA trunk plasty with a pericardial patch. • Discrimination between ML and thymoma is frequently difficult. • If complete resection is preferable for tumors, the surgery should be attempted even if the surgery is difficult.

Circulating tumor cell (CTC) is a potentially useful surrogate of micro-metastasis, but detection of rare tumor cells contaminated in a vast majority of normal hematologic cells remains technical challenges. To achieve effective detection of a variety of CTCs, we have developed a novel microfluidic system (CTC-chip) in which any antibody to capture CTCs is easily conjugated. In previous studies, we employed an antibody (clone E-1) against podoplanin that was strongly expressed on mesothelioma cells. The CTC-chip coated by the E-1 antibody (E1-chip) provided a modest sensitivity in detection of CTCs in malignant pleural mesothelioma (MPM). Here, to achieve a higher sensitivity, we employed a novel anti-podoplanin antibody (clone NZ-1.2). In an experimental model, MPM cells with high podoplanin expression were effectively captured with the CTC-chip coated by the NZ-1.2 antibody (NZ1.2-chip). Next, we evaluated CTCs in the peripheral blood sampled from 22 MPM patients using the NZ1.2-chip and the E1-chip. One or more CTCs were detected in 15 patients (68.2%) with the NZ1.2-chip, whereas only in 10 patients (45.5%) with the E1-chip. Of noted, in most (92.3%, 12/13) patients with epithelioid MPM subtype, CTCs were positive with the NZ1.2-chip. The CTC-count detected with the NZ1.2-chip was significantly higher than that with the E1-chip (p = 0.034). The clinical implications of CTCs detected with the NZ1.2-chip will be examined in a future study.

In patients with lung cancer invading the left atrium, performing complete resection is difficult. In many cases of complete resection, pneumonectomy is performed. We herein report two techniques in which complete resection with negative margins at the intrapericardial pulmonary vein and left atrium was achieved without pneumonectomy. In the first technique, the groove of the pericardium between the right and left atrium was dissected and an atrial cuff was made in a manner that elongated the intrapericardial pulmonary vein. In the second technique, traction was applied to the atrial cuff, and only the middle lobe vein of the elongated pulmonary vein was resected, to perform atrial cuff plasty. The upper lobe vein and inferior pulmonary vein could be preserved. These techniques of PV elongation and atrial cuff plasty are suitable for both achieving complete resection and lung preservation for lung cancer patients with invasion of the left atrium.

Background Surgery for lung cancer invading the spine remains challenging associated with high morbidity and mortality. However, recent advances in surgical techniques as well as in perioperative care may improve outcomes of lung cancer surgery with vertebrectomy. We describe our surgical approach and assess the outcome lung cancer invading the spine. Methods We retrospectively reviewed our recent experiences of lung cancer with vertebral invasion, in which we have performed total or partial vertebrectomy from January 2011 through April 2015. Results We experienced eight patients who were treated with partial or total vertebrectomy for lung cancer. Vertebral invasion was evaluated by chest CT and MRI findings. All cases were no distant metastasis. N factors were all patients N0 revealed by chest CT and PET-CT. Two patients were treated preoperative induction therapy (CDDP + TS-1, Radiation 50 Gy). For the surgery, total vertebrectomy was performed two patients, hemi vertebrectomy was two patients, transverse-process resection was four patients. In all of eight cases, complete resection were perfomed with total or partial vertebrectomy. Morbidity was observed in six patients (75%); no mortality occurred. Six patients (75%) were survived after surgery (range: 12–62 months) and four patients (50%) were no recurrence. Five years overall survival rate was 71.4%. Conclusions In our experience, Lung cancer surgery combined with vertebrectomy is highly aggressive surgery associated with high morbidity. But, this procedure is a promising treatment option for selected patients, for example N0M0 disease with lung cancer invading the spine., Highlights • Surgery for lung cancer invading the spine remains challenging. • We describe our surgical approach and assess the outcome. • We experienced eight patients who were treated with partial or total vertebrectomy. • Five years overall survival rate was 71.4%.

Background Balloon aortic valvuloplasty (BAV) offers an alternative to conventional aortic valve replacement in elderly and frail patients with severe aortic stenosis (AS) for whom there are no other effective options. We aimed to investigate the mid-term effect of BAV on mitral regurgitation (MR) in patients with severe AS. Methods Our analysis was based on the data from 83 patients with severe AS (mean age, 86 ± 5 years; female, 68) treated using BAV. Echocardiography was performed before the procedure and at 1 and 3 months after. MR was quantified by measuring the MR jet area, with more-than-moderate MR being clinically significant. Results Forty patients were classified in this group (MR group). Significant reduction of MR was observed in the MR group at 1 month and 3 months after procedure, with no improvement in patients in the non-MR group. At 3 months, 15 of the 40 patients in the MR group still had significant MR, with the change at 1 month in the left ventricular end-systolic dimension (OR: 1.36; 95% CI: 1.05–1.76; P = 0.022) and MR jet area (OR: 1.95; 95% CI: 1.16–3.29; P = 0.012) being predictive of persisting significant MR at 3 months after BAV. The prevalence of New York Heart Association functional class III or IV decreased at 1 and 3 months after BAV in both groups. Conclusions BAV provides a useful therapeutic strategy for elderly patients with severe AS who are not candidates for surgical or transcatheter aortic valve replacement, especially in those with significant MR.

Patient: Male, 50 Final Diagnosis: Lung cancer Symptoms: None Medication: — Clinical Procedure: Surgery and chemotherapy Specialty: Oncology Objective: Challenging differential diagnosis Background: Circulating tumor cells (CTCs) are tumor cells that are shed from primary tumors and circulate in the peripheral blood. CTCs, as a surrogate of micro-metastasis, can be a useful clinical marker, but their clinical significance remains unclear in lung cancer. We now report a case of lung cancer in which the count of CTCs was useful in monitoring postoperative recurrence. Case Report: A 50-year-old man had undergone right upper lobectomy for lung cancer (pT1bN2M0, stage IIIA adenocarcinoma), followed by cisplatin-based adjuvant chemotherapy. After the patient’s operation, we initiated monitoring of CTCs using CellSearch, and documented the change in the CTC count along with the development of cancer recurrence and response or progression to chemotherapy given for recurrent disease. Conclusions: The CTC count may be useful in monitoring blood of patients with lung cancer.

Melanoma-associated antigen-A4 (MAGE-A4) is one of the candidates for a target of immunotherapy and is expressed in non-small cell lung cancer (NSCLC). However, tumors sometimes lose human leukocyte antigen (HLA) class I expression, and tumor-specific T cells cannot eliminate the tumor with loss of HLA. However, the relationship between MAGE-A4 expression and HLA loss has remained unclear. Among 363 NSCLC patients who consecutively underwent curative surgery, 187 cases whose material could be analyzed were reviewed. The expression of HLA class I molecules was assessed by immunohistochemical staining. The expression of MAGE-A4 was analyzed by RT-PCR. Seventy-seven tumors expressed HLA normally; however, 110 tumors lost HLA. The proportion of patients with a smoking habit and expressing the MAGE-A4 gene in patients with HLA loss was higher than those with HLA expression (p = 0.04 and 0.028, respectively). Five-year overall survival (OS) rate in the patients expressing MAGE-A4 but with loss of HLA was 52.4 %, and OS was significantly poorer than their counterparts (74.0 %, p = 0.036). Multivariate analysis indicated that advanced stage or history of smoking and HLA loss was an independently poor prognostic predictor of OS in NSCLC (p

OBJECTIVES: Immune therapy targeting cancer/testis (CT) antigens improve the survival in several types of solid tumours. The expression of CT antigens is related to poor survival in non-small-cell lung cancer (NSCLC). The epidermal growth factor receptor (EGFR) mutation is the best predictive factor for the sensitivity to tyrosine kinase inhibitors in lung adenocarcinoma. The aim of this study was to elucidate the correlation between the expression of CT antigens and clinicopathological factors, including the EGFR mutation, and to analyse the prognosis in lung adenocarcinoma. METHODS: Data were collected from a total of 281 lung adenocarcinoma patients who underwent surgery. Among them, 125 cases, whose specimens were too small to extract sufficient DNA and/or RNA, and 2 cases with the coexistence of another histological lung cancer were excluded. A total of 154 patients were reviewed. The expression of CT antigens (melanoma-associated antigen gene [MAGE]-A4 and KK-LC-1) and the EGFR-activating mutation (L858R point mutation in exon 21 and inframe deletion in exon 19) was evaluated by using polymerase chain reaction amplification. RESULTS: The expression of MAGE-A4 and KK-LC-1 was detected in 14 (9%) and 54 patients (35%) with adenocarcinoma. The EGFRactivating mutation was found in 64 patients (42%). Univariate and multivariate analyses demonstrated that tumours expressing at least one CT antigen were associated with no EGFR mutation (odds ratio = 0.3; 95% confidence interval, 0.14–0.71; P< 0.01). A survival analysis was performed in 135 patients who underwent complete resection and the 5-year overall survival rate was 71.1% in those with any expression of CT antigens and 83.2% in those without expression of the genes (P< 0.04). CONCLUSION: Two different therapeutic targets, EGFR-activating mutation and CT antigen, have a negative relationship with each other.

Background: The standard therapy for brain metastasis (BM) in non-small cell lung cancer (NSCLC) is radiation therapy (RT), although it is associated with complications such as leukoencephalopathy. In the current report, we retrospectively review data from eight patients who had NSCLC and harbored epidermal growth factor receptor (EGFR) mutations, and who were received erlotinib plus bevacizumab (E+B) as first-line therapy for BM. Methods: Patients were given E+B as first therapy for BM until August 2017 at our institution. Patients receiving local therapy for BM, such as surgery or radiotherapy, were excluded. Patients were administered erlotinib orally (once daily at 150 mg/body) plus bevacizumab by intravenous infusion (15 mg/kg on day 1 of a 21- or 28-day cycle). Results: Eight NSCLC patients who were diagnosed with BM received E+B, including 2 men and 6 women with a median age of 65 years (range, 46–84 years). Four patients had an L858R EGFR mutation, while the other four had an exon 19 deletion. Seven patients had a partial response to E+B treatment, and one had a complete response. The 2-year survival rate was 62.5%. Three patients who were pre-treated with gefitinib had an E+B treatment duration of less than 1 year. At the time of this analysis, four patients had BM-related neurologic symptoms and multiple BMs, and were still receiving E+B with no evidence of treatment failure after more than 1 year. Conclusions: E+B can be used as first-line therapy for BM, even in patients with BM-related neurologic symptoms and multiple BMs.

The purpose of the present study was to identify a novel tumor-specific antigen capable of inducing a specific cellular immune response in lung cancer patients. The co-culture of regional lymph node lymphocytes and the CD80-transfected autologous lung adenocarcinoma cell line H1224L resulted in a successful induction of bulk cytotoxic T lymphocytes (CTL). CTL clone L7/8 was established by the limiting dilution method from these bulk CTLs and lysed H1224L but not autologous Epstein–Barr virus-transformed B cells or K562. The CTL clone also recognized allogeneic lung cancer cell lines in an HLA-A*31012-restricted manner. Using the CTL clone, an antigen-coding gene was identified using the cDNA expression cloning technique, which encodes ribosomal protein L19 (RPL19). Finally, a 9 mer antigenic peptide was identified by means of construction of mini-genes. RPL19 was overexpressed in the lung cancer tissue from patient H1224. All of the normal tissues examined expressed lower levels of RPL19 mRNA than that of the lung cancer tissue. RPL19 was also found to be overexpressed in 12 of 30 (40%) non-small-cell lung cancer tissues by immunohistochemical staining. The expression level of RPL19 in tumor cell lines correlated positively with the production of interferon (IFN)-γby CTL clone L7/8 in response to such cell lines. In addition, the suppression of RPL19 expression by transfection with small interfering RNA resulted in the suppression of cyclinD1, D3 synthesis, and the growth inhibition of lung cancer cell lines overexpressing RPL19. Therefore, this growth suppression could be ascribed to the inhibition of the cell cycle. These results may indicate that RPL19 is a novel overexpressed antigen which may therefore be a useful candidate as a target for specific immunotherapy. (Cancer Sci 2009)

Intrapericardial vessel management is one of the necessary techniques for respiratory surgeons. We collected cases that had undergone intrapericardial vessel management for lung cancer, and herein discuss the practical performance and safety of this treatment method. We identified 23 (5.6%) of 413 patients who had undergone lung cancer surgery during the 30-month period from January 2011 to June 2013 at our institution. Twenty cases had large sized tumors near the hilum. Three cases demonstrated severe adhesion in the intrathoracic region due to a previous operation. The lung cancer staging was stage ⅠA in 1 case, stage ⅠB in 4 cases, stage ⅡB in 5 cases, stage ⅢA in 11 cases, stage ⅢB in 1 case, and stage Ⅳ in 1 case. We performed lobectomy in 11 cases, bilobectomy in 6 cases, and pneumonectomy in 6 cases. The average operation time was 366 minutes (137-965). Post operative complications were observed in five cases, including two cases of air-leakage and three cases of arrhythmia. All cases were able to walk on foot at discharge. It is important to clearly understand intrapericardial anatomy in order to carry out successful intrapericadial vessel management.

The difficulty in the induction and preparation of a large number of autologous tumor‐specific cytotoxic T lymphocytes (CTL) from individual patients is one of major problems in their application to adoptive immunotherapy. The present study tried to establish the useful antitumor effectors by using γδ T cells through tumor‐specific TCRαβ genes transduction, and evaluated the efficacy of their adoptive transfer in a non‐obese diabetic/severe combined immunodeficiency (NOD/SCID) mice model. The TCRαβ gene was cloned from the HLA‐B15‐restricted CTL clone specific of the Kita‐Kyushu Lung Cancer antigen‐1 (KK‐LC‐1). The cloned TCRαβ as well as the CD8 gene were transduced into γδ T cells induced from peripheral blood lymphocytes (PBL). Cytotoxic T lymphocyte activity was examined using a standard 4 h (51) Cr release assay. Mice with a xenotransplanted tumor were treated with an injection of effector cells. Successful transduction of TCRαβ was confirmed by the staining of KK‐LC‐1‐specific tetramers. The γδ T cells transduced with TCRαβ and CD8 showed CTL activity against the KK‐LC‐1‐positive lung cancer cell line in a HLA B15‐restricted manner. Adoptive transfer of the effector cells in a mice model resulted in marked growth suppression of KK‐LC‐1‐ and HLA‐B15‐positive xenotransplanted tumors. Co‐transducing TCRαβ and CD8 into γδ T cells yielded the same antigen‐specific activity as an original CTL in vitro and in vivo. The TCRαβ gene transduction into γδ T cells is a promising strategy for developing new adoptive immunotherapy. (Cancer Sci, doi: 10.1111/j.1349‐7006.2012.02337.x, 2012)

The human lung cancer cell line, C831L, lost HLA class I expression due to a mutation of the β2-microglobulin (β2m) gene, and it may have been the result of immunoediting by CTL cytotoxicity. By restoration of HLA class I expression, we could identify the antigen that may be associated with HLA downregulation. Such an antigen might be a promising target of immunotherapy because it potentially may induce a sufficient immune response to eradicate cancer cells. The CTL clone could be established from lymph node lymphocytes in patient C831 by stimulation with wild-type β2m-transduced C831L (C831L-wβ2m). The CTL clone showed reactivity against C831L-wβ2m in a HLA-B*0702-restricted manner, but not Parental-C831L or autologous normal cells. The cDNA expression cloning method was used to identify the antigen coding gene recognized by the CTL clone. The cDNA clone exhibited a homology with a part of the mRNA that codes for leucine rich repeat containing eight family member A (LRRC8A). A transfection analysis of minigenes indicated that the antigen peptide was derived from protein translated from the downstream of the registered open reading frame in LRRC8A mRNA. The antigenic 9-mer peptide (GPRESRPPA) was identified. The present methodology should be useful to find the crucial tumor antigens, which are potentially associated with loss of HLA expression. Furthermore, such an antigen may help in achieving a better understanding of the immunological escape mechanisms and it may also provide a favorable immune response in cancer immunotherapy.

Malignant pleural mesothelioma (MPM) is difficult to diagnose at an early stage. The present study attempted to obtain a tumor-specific antibody against MPM derived from tumor-infiltrating B lymphocytes in MPM by using a xenotransplanted severe combined immunodeficiency (SCID) mouse model, and to identify the antigens recognized by the antibodies. Among the antigen-antibody relationships, the clinical usefulness of antibody titers in the sera was evaluated from the viewpoint of diagnosis of MPM and monitoring of therapeutic effects. Tumor tissue specimens from two patients with MPM were engrafted subcutaneously in SCID mice and blood samples were obtained and pooled every 2 weeks after xenotransplantation until 14 weeks when the mice were killed. A cDNA library was constructed from the mRNA of a MPM cell line (K921MSO). Immunoscreening of the libraries was carried out by serological identification of antigens by a recombinant expression cloning method (SEREX) and four antigens were identified as MPM-associated antigens. Among them, antibody titers against two antigens, Gene-X and thrombospondin-2 (THBS-2), were analyzed by phage plaque assay as the first step. ELISA systems correlated with the phage plaque assay to detect antibody titers against the two antigens were constructed using 20-mer peptides of the antigen-coding genes. The cut-off value was decided by the average and standard deviation of normal healthy persons. Antibody against Gene-X was detected in 10 out of 18 (55.6%) mesothelioma patients and antibody against THBS-2 was detected in 16 out of 18 (88.9%) mesothelioma patients. No patients with lung cancer regardless of asbestos exposure exhibited positive antibody titer against the two antigens. Furthermore, the serum antibody titers decreased after surgical treatment of MPM and increased after recurrence of the disease. The titers of the antibodies against Gene-X and THBS-2 could be used as tumor markers for the diagnosis and follow up of patients with MPM.

Both cytotoxic T lymphocytes (CTL) and natural killer (NK) cells may play major roles in the host defense against cancer. However, their relationship against the same tumor remains to be elucidated. Among 26 human lung cancer cell lines established in our laboratory, 10 (38%) exhibited human leukocyte antigen (HLA)-class I haplotype loss and three (12%) lost HLA-class I expression totally by flow cytometry analysis. The two cell lines (E522L and C831L) that lost their expression of HLA-class I in vitro and in vivo were applied for further evaluations. Genetic abnormalities of β2-microglobulin gene were observed in both E522L (loss of mRNA) and C831L (point mutation). Transduction of the wild-type β2-microglobulin gene rendered them positive for HLA-class I expression. The CTL were induced from autologous peripheral blood mononuclear cells or regional lymph node lymphocytes by stimulation with wild-type β2-microglobulin transduced-E522L or -C831L, and they showed tumor-specific cytotoxicity against wild-type β2-microglobulintransductant, but not parental cells. In NK cell cytotoxicity, E522L showed high sensitivity to NK cells; however, C831L showed resistance despite loss of HLA-class I expression. E522L expressed MHC class I chain related molecules A/B, but C831L did not. The transduction of the MHC class I chain related molecule A gene from E522L rendered C831L positive for expression and sensitive to NK cell cytotoxicity. Reconstruction of HLA-class I and MHC class I chain related molecules A expression could abrogate evasion from cellular attack by CTL and NK cells, and it may lead to a breakthrough in the development of cancer immunotherapy. (Cancer Sci 2007; 98: 1795–1802)

The kinetics of the solid-state isothermal transition of bromovalerylurea polymorphic forms (I, II and III) at high temperature were investigated by means of differential scanning calorimetry. Kinetic analysis according to the method of Hancock and Sharp indicated that the transition of form I to form II follows the one-dimensional diffusion mechanism. The activation energy for this transition calculated from the Arrhenius plots was 826.2 kJ/mol. On the other hand, it was found that the transition of form III to form I conforms with the mechanism of random nucleation and two-dimensional growth of nuclei (Avrami-Erofeev equation). This activation energy was estimated to be 185.2 kJ/mol. It was concluded that the mechanism and the value of activation energy were both different between the two kinds of isothermal transitions of bromovalerylurea polymorphic forms.

Refractive indices and related optical properties of 3 polymorphs and 2 solvates of sulfamethoxydiazine were determined by a polarizing microscope. A morphological measurement was also made for form I and III by a goniometer. All these data were useful for the simple and rapid identification of each form of sulfamethoxydiazine in a hospital pharmacy using a polarizing microscope. Especially the differences in key refractive indices between form II, the most active one, and form I or III are advantageous for discriminating form II from other less active forms in pharmaceutical preparations. Transition behaviors were also examined using a heating stage, from which the stability of 3 polymorphic forms were determined.

The influence of 6-thioxanthine (6TX) on the thermal transformation of 6-mercaptopurine (6MP) crystals was investigated using scanning electron microscopy and X-ray diffraction. The crystal lattice of 6MP and 6TX molecules can include up to 10% of the counterpart molecules to form a solid solution. Monohydrate crystals (form I) of pure 6MP were directly transformed into anhydrate crystals (form II) by heating at 150-220°C, but similar crystals (form ITX) of 6MP containing more than 2% 6TX were converted into another form of anhydrate crystals (form III) via an amorphous state by the same treatment. These phase transformations were kinetically studied and there was a clear difference in mechanism under the present experimental conditions. The transformations of form I into form II and form ITX into an amorphous state were assumed to proceed according to the contracting cube equation whereas that of the amorphous state into form III appeared to follow the Prout-Tompkins equation. The reason for the transformation into different crystal forms, from form I into form II and from form ITX into form III, is discussed on the basis of the experimental results.

Form I, form II, and CHCl3-II type of acetohexamide are obtained by recrystallization from different solvents. X-ray diffraction patterns, infrared spectra, and differential scanning calorimeter curves of the CHCl3-II type are identical with those of form II, but CHCl3-II type contains a chloroform molecule, which cannot be removed by normal drying condition, and CHCl3-II type seems unsuitable for medical use. The solubility of form II is 1.2 times that of form I.

The plasma concentration of indomethacin (IM) after administration of sustained-release suppositories containing microencapsulated IM was analyzed by means of the compartment model method and the statistical moment method. The plasma concentration-time course after rectal administration of conventional suppositories followed a two-compartment model with first-order absorption for all doses examined, 6.25, 12.5 and 25 mg. The pharmacokinetic constants did not show dose-dependency. It was presumed that the plasma concentration-time course after rectal administration of sustained-release suppositories could be accounted for by a two-compartment model with two consecutive first-order input steps. The release rate constants (k1) of these dosage forms were very small compared with the absorption rate (ka). Consequently, the release process from sustainedrelease suppositories was the rate-determining step. This conclusion was confirmed by statistical moment analysis.

The different crystal forms of benoxaprofen were obtained by recrystallization from several solvents. These crystal forms were identified by using X-ray diffractometry, infrared spectroscopy, differential scanning calorimetry and thermogravimetry. It was found that benoxaprofen exists in two polymorphic forms and that form II is more stable than form I. The thermodynamic values of the two polymorphic forms of benoxaprofen were calculated from solubility measurements. The transition temperature and the free energy difference (ΔG) were estimated to be 98.0°C and-232cal/mol, respectively. The solubility of form I was about 1.5 times greater than that of form II. However, there was no significant difference in the bioavailability of the two polymorphic forms in rabbits.

6-Mercaptopurine (6-MP) polymorphs were administered to rabbits as intravenous injection, oral aqueous solution, oral hard capsule and effervescent capsule. When the form III powder was given in hard capsules, the dissolution from the capsule was very slow and the plasma levels after oral administration were also lower than those obtained with form I. On the other hand, the form III effervescent capsule prepared to enhance the dissolution gave an extent of bioavailability (EBA) about 1.5 times greater than that of form I. The time course data after oral administration of each dosage form were analyzed by means of the compartment model method and the statistical moment method. It appears that the difference of EBA after oral administration as the capsule dosage forms was chiefly attributable to the difference of apparent absorption rate. These results could be explained in terms of the differences of the mean disintegration and dissolution time (MDDT) obtained by means of the moment method.

Double layer suppositories (D-15) of nifedipine (NF), prepared by using a solid dispersion system of polyethylene glycol 4000 as a water-soluble carrier and cellulose acetate phthalate as a poorly water-soluble-carrier, were administered to healthy volunteers, and their sustained-release characteristics, bioavailability and clinical utility were investigated. It was found that D-15 was able to maintain a therapeutically effective level of NF from 30 min to 10 h without causing an excessively high peak level and offered good bioavailability. From the results of pharmacokinetic analysis by using the compartment model method, it appeared that the plasma concentration-time course after rectal administration of D-15 is satisfactorily accounted for by a one-compartment model with first-order release and absorption steps. The value of release rate constant of D-15 obtained was smaller than that of absorption rate constant, and the sustained-release effect was apparently attributed to the slow release of NF from the suppository.The plasma level of NF rapidly decreased as removing D-15, and the plasma level showed hardly any irregularities arising from the removal and the renewal of suppositories.Accordingly, it was concluded that D-15 is an effective sustained-release dosage from and represents a convenient mode of therapy with reduced frequency of drug administration and reduced risk of side-effects.

By the use of solid dispersion systems, suppositories having both a fast release and a sustained release of nifedipine were developed. Namely, cellulose acetate phthalate (CAP)-polyethylene glycol (PEG) matrix was prepared as a suppository base by using PEG 4000 as a water-soluble carrier and CAP as a poorly soluble carrier. Conventional suppositories (use of PEG 4000 alone as a base : C-0), three kinds of CAP-PEG matrix suppositories (use of 5, 10 and 15% (w/w) CAP in the matrix : M-5, M-10 and M-15) and double layer suppositories including nifedipine only in the outside layer (use of 15% CAP in the matrix as a base : D-15) were prepared, and the sustained-release effect and bioavailability of each suppository were examined in rabbits. The M-5 as well as C-0 produced a sharp peak of plasma concentration of nifedipine and did not give a sustained-release effect. The M-10 gave a sustained-release effect, but it was not a desirable preparation because it developed many cracks and broke easily. The M-15 gave a low and plateau plasma level of nifedipine and had no cracks, but the extent of bioavailability was very small. The D-15 enhanced the bioavailability of nifedipine and also gave a sustained-release plasma level of nifedipine. Therefore, it appeared that D-15 was a suitable preparation for our purpose.

Indomethacin (IM) sustained-release suppositories were prepared by using a solid matrix of methacrylic acid-methacrylic acid methyl ester copolymer (Eudragit L100[○!R] : EL) as a poorly water-soluble carrier and polyethylene glycol 2000 (PEG 2000) as a readily water-soluble carrier. The rate of IM release from EL-PEG 2000 matrix suppositories decreased with increase of the EL content. The sustained release of IM from these matrix suppositories was attributed to the development of a network structure of EL. Rectal administrations of the matrix suppositories in rabbits resulted in good characteristics for sustained release. The extent bioavailability of the 20% EL-PEG 2000 matrix suppositories (EL-20) was about 50%.

Cytosolic aspartate aminotransferase from rat liver was separated into at least 3 subforms, focused at pH 6.2, 5.9, and 5.7, by isoelectric focusing. Increase of subforms with low pI values was observed in pyridoxine-deficient rat liver. These subforms with low pI values showed low catalytic activities relative to their antigenic activities. The Km values for substrate and optimal pH values of the two main subforms were not significantly different in pyridoxine-deficient and control rat livers. Some conformational change of enzyme in the cytosol of pyridoxine-deficient rat liver was suggested by circular dichroic and fluorescent spectra. The N and C terminals of the enzyme from both pyridoxine-deficient rats and controls were shown to be alanine and glutamine, respectively.

Sustained-release suppositories of indomethacin (IM) were prepared by the use of a solid dispersion system. As the suppository base, we used a solid matrix of polyethylene glycol 2000(PEG) as a water-soluble carrier and hydroxypropylmethylcellulose phthalate (HP55) as a poorly water-soluble carrier. It was observed by X-ray diffractometry that IM was uniformly dispersed in amorphous state in the matrix suppositories. The rectal administration of 20% HP55 matrix suppositories (M-20-5) in rabbits resulted in both fast-release and sustained-release characteristics as well as good bioavailability. The sustained release of IM from the matrix suppositories was attributed to the formation of a network structure of HP55 which dissolved more slowly than PEG.

The kinetics of the isothermal transition of tolbutamide polymorphic forms (form B at 65, 70, 75 and 80°C), as well as mefenamic acid (form I at 142.5, 145, 147.5 and 150°C) were investigated by means of differential scanning calorimetry. Kinetic analysis according to the method of Hancock and Sharp indicated that the transition of form B to form A of tolbutamide proceeds by the mechanism of three-dimensional diffusion (Jander equation). The activation energy for this transition calculated from the slope of the Arrhenius plots was 37.3 kcal/mol. On the other hand, the transition of form I to form II of mefenamic acid appeared to follow the zero-order mechanism (Polany-Winger equation). The activation energy for this transition was calculated to be 86.4 kcal/mol.