Wakako Hamanaka

RET, ROS1 and ALK fusions in lung cancer

Through an integrated molecular- and histopathology-based screening system, we performed a screening for fusions of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1, receptor tyrosine kinase (ROS1) in 1,529 lung cancers and identified 44 ALK-fusion–positive and 13 ROS1-fusion–positive adenocarcinomas, including for unidentified fusion partners for ROS1. In addition, we discovered previously unidentified kinase fusions that may be promising for molecular-targeted therapy, kinesin family member 5B (KIF5B)-ret proto-oncogene (RET) and coiled-coil domain containing 6 (CCDC6)-RET, in 14 adenocarcinomas. A multivariate analysis of 1,116 adenocarcinomas containing these 71 kinase-fusion–positive adenocarcinomas identified four independent factors that are indicators of poor prognosis: age ≥50 years, male sex, high pathological stage and negative kinase-fusion status.

Mutation (Ser284Leu) of neuronal nicotinic acetylcholine receptor α4 subunit associated with frontal lobe epilepsy causes faster desensitization of the rat receptor expressed in oocytes

To date five mutations in two major constituents of neuronal nicotinic acetylcholine receptor (nAChR) in the brain, i.e. alpha4 and beta2 subunits, have been identified to be associated with autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE). Among them, only Ser284Leu, a point mutation in alpha4 subunit identified in ADNFLE as well as in a sporadic case with nocturnal frontal lobe epilepsy, remains to be characterized electrophysiologically. We examined the properties of rat nAChR harboring Ser284Leu reconstituted on Xenopus oocytes. Currents elicited in response to application of acetylcholine to oocytes expressing wild type or mutant nAChR were measured by a standard two-microelectrode voltage clamp method. Compared with wild-type nAChR, the mutant nAChR had a comparable EC(50) value for acetylcholine whereas it showed faster desensitization and lower Cs(+)/Na(+) permeability ratio. Ser284Phe, a putative mutation constructed for comparison, exhibited similar properties. These findings indicate that Ser(284) plays an important role in gating of nAChR along with Thr(276) and Ser(280), and suggest that mutation at Ser(284) could reduce nAChR activity similar to other mutations of alpha4 subunit found in ADNFLE.

A subset of small cell lung cancer with low neuroendocrine expression and good prognosis: a comparison study of surgical and inoperable cases with biopsy

Patients with small cell lung carcinoma (SCLC) rarely demonstrate long-term survival. We previously reported that gene expression profiling identified a subset of SCLC with good prognosis in surgical cases. To find an easier way to routinely identify SCLC belonging to this subset, we conducted the present study with a hypothesis that neuroendocrine (NE) or basaloid (BA) phenotypes may influence prognosis. To confirm the subset, we used an array platform to analyze fresh samples. Because inoperable cases may differ from surgical cases, we enrolled 51 biopsy cases and 43 resected samples. To evaluate NE and BA phenotypes, we used NE (synaptophysin, chromogranin A, and CD56) and BA (p63 and CK34βE12) markers. To varying extents, expression profiling based on the array platform duplicated the subsets. For NE phenotypes, 77% of surgical cases and 100% of biopsy cases were positive for at least 1 marker. For BA phenotypes, only 19% of surgical cases were positive for at least 1 marker, whereas there were no positive biopsy cases. Cases undergoing surgery were categorized based on NE and BA immunoreactivity; 58% into NE+BA-, 19% into NE+BA+, 23% into NE-BA-, and 0 into NE-BA+ groups. NE- patients (n = 10) demonstrated a significantly better prognosis (P = .0306) than their NE+ counterparts (n = 33), whereas no survival difference was evident between the BA+ and BA- groups. Multivariate analyses showed that NE positivity was an independent prognostic factor. In conclusion, the SCLC subset with good prognosis is identified by low NE marker expression, which was found only in surgical cases.

Alpha-fetoprotein (AFP)-producing adrenocortical carcinoma — Long survival with various therapeutic strategies including a lung resection: Report of a case

We experienced a very rare case of late pulmonary metastasis from ACC. The patient was a 40-year-old woman who had undergone a left adrenectomy 12 years earlier. Instead of a large metastatic lung tumor with hemothorax and the existence of metastases in other organs, combined therapy of repeated resections for metastases and adjuvant therapy allowed for almost a 36-month survival following the first recurrence and a good quality of life. In addition, a blood and pathological study revealed that the tumor in this case was an alpha-fetoprotein-producing ACC, which is, as far as we could ascertain, the first case of its kind.

Clinical Outcome After Pulmonary Resection for Lung Cancer Patients on Hemodialysis

BACKGROUND The number of operations for patients with malignant tumors receiving long-term hemodialysis has been increasing; however, there are only few reports about pulmonary resection for the patients with lung cancer. METHODS Between 1995 and 2009, 11 hemodialysis patients (6 men, 5 women; mean age, 66.4 years) with non-small cell lung cancer underwent pulmonary resection at our institution. We retrospectively evaluated their postoperative clinical outcomes and long-term results. RESULTS The underlying kidney conditions included nephrosclerosis in 3, diabetic nephropathy in 3, glomerulonephritis in 1, and polycystic kidney in 1; 3 patients had undergone nephrectomy. The median duration of hemodialysis preoperatively was 5.0 years. Three patients had been treated for previous carcinoma. The histopathologic diagnoses were adenocarcinoma in 9 patients and squamous cell carcinoma in 2. Procedures included lobectomy in 9, pneumonectomy in 1, and wedge resection in 1. There were no in-hospital deaths. Postoperative morbidity included 2 cases of pneumonia and 1 of chylothorax. At the time of our investigation, 6 patients were dead; 2 of cancer and 4 of noncancer causes. The overall 5-year survival rate of 11 patients was 28.0%. CONCLUSIONS Hemodialysis is not a contraindication to lung resection, despite the high morbidity rate. Surgical treatments, including lobectomy, remain one of effective treatments for patients on hemodialysis with lung cancer.

Does Pneumothorax Occurrence Correlate with a Change in the Weather

PurposeThere has been speculation that weather changes correlate with the incidence of spontaneous pneumothorax, although this has not been verified. Moreover, there are no significant data available on the meteoropathic pneumothorax in Asia. The aim of this study was to investigate the possible correlation and to compare our results to those of the United States and Europe.MethodsFrom January 2000 to December 2009, 317 spontaneous pneumothorax cases with clear dates of onset were treated in our institution. Using the meteorological data of Fukuoka, Japan, the days with and without an occurrence of pneumothorax were statistically compared in terms of atmospheric pressure, the amount of precipitation, temperature, humidity, hours of sunshine, and occurrence of a typhoon and lightning.ResultsMultivariate analysis revealed that a decrease in the hours of sunshine, an increase in mean temperatures 2 days before the incidence, and the days following a day with lightning were all significantly correlated with the occurrence of pneumothorax (P = 0.2 days before the incidence, and the days following a day with lightning were all significantly correlated with the occurrence of pneumothorax (P = 0.0083, 0.0032, 0.0351, respectively). However, typhoons, as an “unusual” weather condition, did not influence the incidence of pneumothorax (P = 0.983).ConclusionsOur results show strong similarities with reports from European countries despite the different climates. We conclude that the occurrence of pneumothorax appears to correlate with some weather conditions in Japan.

Clinicopathological findings of non-small-cell lung cancer with high serum progastrin-releasing peptide concentrations

Although progastrin-releasing peptide (proGRP) is used as a serum tumor marker for small cell lung cancer (SCLC), high serum pro-GRP concentrations are observed in some non-small-cell lung cancers (NSCLCs). The characteristics of these NSCLCs are not well known. To determine the clinicopathological features of NSCLC in patients with elevated serum proGRP concentrations, serum proGRP values were assessed in 654 advanced lung cancer patients, and positive (>46pg/mL) NSCLC specimens were subjected to cytological and histopathological reevaluation. Serum proGRP concentrations were positive in 34 of 421 NSCLC patients (8.1%) and 186 of 233 SCLC patients (80%). Histological subtypes of the 34 NSCLC patients at diagnosis were 20 adenocarcinomas, 5 squamous cell carcinomas, 4 large cell carcinomas, and 5 large cell neuroendocrine carcinomas. Six of 27 cytology specimens contained characteristic neuroendocrine morphology. Immunohistochemical analysis showed that 11 of 17 tumors were positive for neuroendocrine markers (64.7%). Twenty of 34 serum proGRP-positive NSCLC patients received platinum-based chemotherapy, and the response rate was 55.0%. These results suggest that serum proGRP-positive NSCLCs may have neuroendocrine differentiation. In addition, serum proGRP-positive NSCLCs may have clinical characteristics that are different from other NSCLCs.

Off-the-job training for VATS employing anatomically correct lung models

We evaluated our simulated major lung resection employing anatomically correct lung models as “off-the-job training” for video-assisted thoracic surgery trainees. A total of 76 surgeons voluntarily participated in our study. They performed video-assisted thoracic surgical lobectomy employing anatomically correct lung models, which are made of sponges so that vessels and bronchi can be cut using usual surgical techniques with typical forceps. After the simulation surgery, participants answered questionnaires on a visual analogue scale, in terms of their level of interest and the reality of our training method as off-the-job training for trainees. We considered that the closer a score was to 10, the more useful our method would be for training new surgeons. Regarding the appeal or level of interest in this simulation surgery, the mean score was 8.3 of 10, and regarding reality, it was 7.0. The participants could feel some of the real sensations of the surgery and seemed to be satisfied to perform the simulation lobectomy. Our training method is considered to be suitable as an appropriate type of surgical off-the-job training.

Video-assisted thoracic surgery for lung cancer in hemodialysis patients

Introduction: In recent years, the number of hemodialysis patients has been continuously increasing. At the same time, the use of video‐assisted thoracic surgery (VATS) for lung cancer has also increased. However, reports of the outcome of VATS in hemodialysis patients are still quite rare.