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The histological classifications of invasive lung adenocarcinoma subtypes are considered to predict patient prognosis after surgical treatment. The objectives of this study were to evaluate cytomorphological characteristics and proliferative activities among the histological predominant patterns by performing cytomorphometric and flow cytometric analyses using liquid-based cytology materials.Cytological samples fixed by liquid-based cytology preservatives from 53 surgically-resected lung adenocarcinoma specimens were obtained between August 2018 and November 2019. The Papanicolaou-stained and paired Ki-67-stained slides were analyzed for calculating nuclear morphology (nuclear area, nuclear perimeter and nuclear circularity) and Ki-67 labeling index using software. The cell proliferation index (CPIx) was calculated and cellular information including cell cycle stage of tumor cells was obtained by flow cytometry.The 53 cases included papillary (n = 29), acinar (n = 8), lepidic (n = 5), and solid (n = 4) subtypes, and invasive mucinous adenocarcinoma (n = 7) were also included. In the lepidic pattern, nuclear area (79.6 ± 28.8 μmBy revealing the differences of cytomorphological characteristics, these methodologies might be used for diagnosing cytopathological materials using digital cytopathology.

Thymic epithelial tumors are the most common adult mediastinal tumors; however, their growth mechanism remains relatively unknown. Among the JAK/STAT pathway-related proteins, which control various intracellular events, STAT3 is deeply involved in cell proliferation. Constitutive activation of STAT3 and the resulting overexpression of cyclin D1 have been confirmed in various tumors, but have not been thoroughly investigated in thymic epithelial tumors. In this study, we immunohistochemically examined STAT3 activation, cyclin D1 expression, and JAK3 activation in thymic epithelial tumors and statistically analyzed their correlation with clinicopathological features. Formalin-fixed paraffin-embedded specimens of 94 thymic epithelial tumors surgically resected at Kyorin University Hospital between 2005 and 2018 were included in this study. pSTAT3, cyclin D1, and pJAK3 were immunohistochemically examined, and the correlation with histology, Masaoka stage, and survival time was statistically analyzed. Cyclin D1 was found to be significantly overexpressed in the STAT3-activated group. This phenomenon was associated with histology and Masaoka stage. JAK3 was also activated in thymic epithelial tumors; however, JAK3 and STAT3 activation were not always correlated. Using survival time analysis, the STAT3-activated group, cyclin D1-expressed group, and JAK3-activated group had significantly lower progression-free survival times than those for both the non-activated and non-expressed groups. STAT3 activation may promote cyclin D1 overexpression in thymic epithelial tumors, and intracellular signaling pathways other than JAK3 may be involved in STAT3 activation. STAT3 activation, cyclin D1 overexpression, and JAK3 activation are biomarker candidates that indicate clinically poor prognosis.

BACKGROUND Liquid-based cytology (LBC) allows immunohistochemistry (IHC), fluorescence in situ hybridization, and molecular testing to be performed in fixed cell materials. We examined the feasibility of subtyping and EGFR mutation testing of bronchoscopic samples from patients with lung cancer using cell blocks (CB) based on LBC fixation (LBC-CB). METHODS We included 35 consecutive patients with peripheral lung nodules who underwent endobronchial ultrasonography with a guide sheath in our hospital. Thirty of these patients were diagnosed with lung cancer by obtaining cytological samples. Cytological subtyping was performed with IHC using LBC-CB, and the Cobas EGFR Mutation Test ver. 2 was performed using extracted genomic DNA from the LBC-CB, formalin-fixed paraffin-embedded (FFPE) tissue, and matched plasma. RESULTS Of the 30 cases, 25 were classified cytomorphologically as adenocarcinoma (ADC, n = 17) and squamous-cell carcinoma (SQCC, n = 8). The remaining five cases were classified by IHC as favor ADC (n = 3) and favor SQCC (n = 2) according to the WHO criteria. In the final ADC group (n = 20), EGFR mutations on the LBC-CB were identified in eight cases (40%; 1 exon 19 deletion, 6 L858R, and 1 L861Q). Mutations in FFPE samples were identified in seven cases (35%) at the same site in each case. Plasma EGFR mutations were identified in four cases (20%) at the same site. The CB detection rate was higher than for FFPE and plasma. CONCLUSION LBC-CB is suitable for subtyping and EGFR mutation testing in lung cancers.

Background Perioperative atrial fibrillation (POAF) in noncardiac surgeries is common. However, it is unclear whether such atrial fibrillation (AF) recurs in the long term. Methods This study was a prospective, single-center, observational study that included patients who underwent noncardiac surgeries for malignancies. Patients were followed up for 1 year to evaluate the incidence of AF, ischemic stroke, and mortality. An event-triggered recorder was used in patients with POAF. The incidences were compared according to the presence of POAF. Results Of 752 consecutive patients, 77 (10.2%) developed POAF and wore an event recorder for 19 (12-30) days. AF and ischemic stroke at 1 year were observed in 24 patients (31.1%) and 2 patients (2.6%) with POAF and 4 patients (0.6%) and 3 patients (0.4%) without POAF, respectively. Of the 24 patients with POAF and AF recurrence, 22 (92%) were asymptomatic. Anticoagulation was prescribed in 67 patients (87%) with POAF. Multivariate Cox regression analysis demonstrated that a higher AF recurrence rate in patients with POAF was associated with hypertension (hazard ratio, 2.79; 95% confidence interval, 1.06-7.38) and serum creatinine level (hazard ratio for 20 μmol/L increase, 2.32; 95% confidence interval, 1.16-4.62). Conclusions AF recurs in approximately 30% of patients with POAF with malignancy in the subsequent year; most recurrences are asymptomatic.

Our report presents the smallest bronchial carcinoid thus far associated with peripheral squamous cell carcinoma. A 79‐year‐old Japanese man presented with an abnormal shadow on chest radiography. Chest computed tomography revealed an ill‐defined nodule at the left S9a area without lymph node involvement. At the time of bronchoscopy, a nodule of ~1 mm in diameter with a smooth surface was observed at the orifice of the left B8. Left lower lobectomy was performed. Pathologically, the S9a tumour was keratinizing squamous cell carcinoma with surgical stage IA3, and the left B8 tumour was a typical bronchial carcinoid. The patient was alive without recurrence 2 years after the surgery. Cases of combined carcinoid and lung cancer are rare. It may be possible to identify bronchial carcinoids early by careful observation of the bronchi during bronchoscopy for peripheral neoplastic lesions., Our report presents the smallest bronchial carcinoid thus far associated with peripheral squamous cell carcinoma. Cases of combined carcinoid and lung cancer are rare. It may be possible to identify bronchial carcinoids early by careful observation of the bronchi during bronchoscopy for peripheral neoplastic lesions.

Perioperative complications have been reported to be associated with a lower incidence of cancer-free survival. Perioperative atrial fibrillation (POAF) is one of occasionally observed complications in patients with malignancies who undergo noncardiac surgeries. However, the long-term clinical impact of POAF on those with malignancies have remained unknown. This was a prospective, single-center, observational study. Patients who underwent noncardiac surgeries for definitive malignancies between 2014 and 2017 were included. The primary and secondary endpoints were 3-year recurrence of malignancies and cancer death, respectively. The present study included consecutive 752 patients (mean age, 68 ± 11 years; males, 62%), and POAF was observed in 77 patients. The follow-up duration was 1037 (interquartile range, 699–1408) days. The 3-year recurrence of malignancies was observed in 239 (32%) patients (POAF, 32 [42%]; non-POAF, 207 [31%]) and 3-year mortality was 130 patients (17%). Cardiac, noncardiac, and cancer deaths were observed in 4 (0.5%), 126 (17%), and 111 (15%) patients, respectively. Multivariate Cox regression analysis demonstrated that POAF was associated with 3-year recurrence of malignancies (hazard ratio [HR], 1.70; 95% confidence interval [CI], 1.15–2.52). Landmark analysis demonstrated that POAF tended to be correlated with the incidence of 3-year cancer death (HR, 1.79; 95% CI, 0.96–3.31). In conclusion, POAF is associated with the subsequent recurrence of malignancies. The association of arrhythmia with cancer death may be revealed under longer follow-up durations. Clinical Trial Registration: https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018270 . UMIN ID: UMIN000016146.

BACKGROUND Liquid-based cytology (LBC) samples allow immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and molecular testing of nucleic acids to be performed in the remaining fixed cells. The current study aimed to examine the relationship between gene mutational status and cytomorphological features in primary lung adenocarcinoma (ADC) using LBC materials. METHODS Forty consecutive patients with primary lung ADC underwent surgical resection in our hospital. Cytological material was obtained by scraping the cut-surface of the lesion, and samples were fixed and stored as LBC materials using CytoRich Red. Epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations, anaplastic lymphoma kinase (ALK), and c-ros oncogene 1 (ROS1) gene rearrangements were detected, and cytomorphological studies were performed. RESULTS Twenty cases (50%) were positive for EGFR mutation and four (10%) were positive for KRAS mutation. ALK gene rearrangement was identified in one case (2.5%) by IHC and FISH, and ROS1 gene rearrangement was identified in one case (2.5%) by IHC and real-time polymerase chain reaction. The KRAS-positive group included higher proportions of cases with an inflammatory background (100%), predominantly papillary architecture (75%), and papillary-type ADC pattern (75%) compared with the EGFR-positive group and the other group, which included ALK and ROS1 gene rearrangements. CONCLUSIONS LBC material is suitable for use in molecular testing. Differences in major gene aberrations detected by this method might predict specific cytomorphological features.

Objective In Japan, pleurodesis is often performed using OK-432. However, OK-432 may cause severe chest pain and fever. The risk factors for these complications are unclear. The aim of this study was to identify the risk factors for chest pain and fever caused by pleurodesis with OK-432. Methods The clinical data of 94 patients who underwent pleurodesis with OK-432 were retrospectively analyzed. Patients who developed chest pain (indicated by a record of rescue pain medication) and/or fever (a recorded temperature of >38°C) were identified. A logistic regression analysis was performed to determine the risk factors for these complications. Results Rescue medication for chest pain was required by 43.6% of the patients and 40.4% developed pyrexia after pleurodesis with OK-432. The univariate analysis showed that the likelihood of requiring rescue medication for chest pain was significantly increased in patients of

Adjuvant cisplatin-vinorelbine chemotherapy has been shown to be effective in patients with completely resected non-small cell lung cancer (NSCLC) in several Phase III trials, but not yet in the Japanese population. Pharmacists are expected to assist patients with completion of adjuvant chemotherapy. The aim of this retrospective study was to evaluate the compliance with and safety of adjuvant cisplatin-vinorelbine chemotherapy in Japanese patients and to evaluate the contribution of pharmacists to completion of treatment. Thirty-four patients with NSCLC who received adjuvant cisplatin-vinorelbine chemotherapy at Kyorin University Hospital between January 2006 and June 2015 were reviewed. The treatment schedule comprised cisplatin 80 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks. Four 3-week cycles were planned. A pharmacist provided guidance to all patients and monitored them for adverse effects thereafter. The pharmacist intervened with advice to doctors as necessary. The 4 cycles were administered in 67.6% of cases. There were no treatment-related deaths. The main grade 3 or 4 toxicities were neutropenia (76.5%) and anorexia (38.2%). The most common reason for discontinuation and dose reduction was anorexia. There were 56 instances of pharmacist intervention. In total, 96.4% of the pharmacist interventions were implemented by doctors, which included administration of an antiemetic on 15 occasions and hot fomentation for prevention of vasculitis on 7 occasions. Adjuvant cisplatin-vinorelbine chemotherapy was tolerated by most patients but was discontinued because of adverse events in some. Pharmacist intervention aids completion of planned chemotherapy and management of treatment-related adverse events.

Solitary pulmonary capillary hemangioma (SPCH) is a rare disease, first described about autopsy cases in 2000 and about surgically resected cases in 2006. To date, only 9 surgically resected cases have been published in English. Here, we report 7 original cases with surgery (median age, 54 y; 4 females, 2 never-smokers). All patients were asymptomatic, and all nodules were detected by computed tomography (CT). The median (range) size of nodule was 11 (8 to 16) mm. Six of 7 cases showed the part-solid nodule appearance and 1 showed pure ground-glass nodule appearance in CT findings. The growth speed was very slow. No abnormal uptake of fluorine-18 fluorodeoxyglucose was observed in systemic positron-emission CT in all 3 cases we examined. No patients died from SPCH. Histologically, SPCH manifested as a solitary lesion composed of densely proliferating and dilated capillaries without cytologic atypia within the alveolar septa. In addition, capillaries of SPCH spread into the vascular lumen and involved the walls of bronchioles with protrusion into the lumen. Immunohistochemically, capillaries of SPCH uniformly expressed endothelial markers, such as CD31, CD34, and Factor VIII; and α-smooth muscle actin positive cells were also observed. To be accurately diagnosed, especially in intraoperative frozen sections, SPCH should be conceived as an entity that presents as a solitary nodule in CT. We propose that SPCH is an unrecognized benign capillary proliferative disease.

Various complications can cause hypoxemia after pulmonary resection for lung cancer, but intracardiac shunt that becomes symptomatic and causes severe hypoxemia postoperatively is very rare. We report a case that presented platypnea-orthodeoxia syndrome (POS) due to right-to-left shunt via patent foramen ovale (PFO). A 71-year-old man with a lung cancer in the left upper lobe was referred to our hospital. Left upper lobectomy was performed. Dyspnea developed postoperatively, which was worsened by sitting or standing and relieved in a recumbent position. Contrast transesophageal echocardiogram (TEE) and right intracardiac catheterization revealed a right-to-left shunt via PFO. Open-heart closure of PFO was performed and the patient was free from POS. Postoperative intracardiac shunt via PFO can cause severe hypoxemia after lung resection. POS suggests the possibility of intracardiac shunt and careful observation is needed.

Objectives We developed a modified pleural tent (m-tent) procedure and used it in our hospital in almost 30 consecutive patients with spontaneous pneumothorax. The objective of this study was to clarify the feasibility and effectiveness of a thoracoscopic m-tent for the treatment of spontaneous pneumothorax. Methods From July 2013 to November 2014, 107 patients with spontaneous pneumothorax were treated in our institution. Eighty-nine of these patients were analysed retrospectively. The inclusion criteria for thoracoscopic m-tent for spontaneous pneumothorax were multiple and widespread bullae, postoperative relapse and secondary spontaneous pneumothorax. The surgical procedures were usually performed through three ports. After bullectomy, an m-tent is made to strip the parietal pleura off the chest wall from about the level of the fourth or fifth rib to the apex, and two or three ligations are then applied to fix the pleural tent and lung parenchyma. Patients in whom an m-tent was not indicated underwent bullectomy plus coverage using absorbable materials. Results Twenty-seven patients underwent bullectomy plus m-tent (m-tent group) and 62 underwent bullectomy plus coverage over a staple line using an absorbable material such as a polyglycolic acid sheet or nitrocellulose sheet (coverage group). No severe postoperative complications were observed in either group. The m-tent and coverage groups showed significant differences in operation time (129 vs 86 min, mean), haemorrhage (12.8 vs 7.2 ml), postoperative hospital stay (3.7 vs 2.9 days) and postoperative painkiller intake (8.6 vs 6.8 days). Recurrence was observed in 1 (3.7%) and 2 patients (3.2%), respectively. Conclusions The thoracoscopic m-tent procedure requires a longer operation, a longer hospital stay and greater painkiller intake. However, these differences are acceptable, and an m-tent should be considered as an option for pleural reinforcement in spontaneous pneumothorax, especially in patients who are complicated with severe pulmonary emphysema, widespread bullae or recurrent pneumothorax.

Severe combined immunodeficiency disease (SCID) mice with human lepidic adenocarcinoma were established by the intrabronchial implantation of fresh surgically resected specimens. Human pulmonary adenocarcinoma tissue from 16 different cases was transplanted into SCID mice, and SCID mouse tumors were established from four of these cases (25%). Among the four tumors, the tumor cells of two SCID mice showed replacement lepidic growth of mouse alveolar structures accompanied by multiple intrapulmonary lesions. Human lung carcinoma cell lines showing lepidic growth are rare and the xenograft models using the SCID mouse model developed in the current study will be useful for analyzing the growth and/or progression patterns and clinical behavior of lepidic adenocarcinoma, the major histological subtype of human carcinoma of the lung.

“Definition of outcome” and “Details of SPIDER FLASH-t AFib®”. (DOCX 19 kb)

Table S1. The settings of automatic detection function (DOCX 13 kb)

Background: Distinguishing the histological subtype of lung cancer is extremely important because chemotherapy agents may have different chemotherapeutic effects in different histological subtypes. This study retrospectively evaluated the characteristic differences in the cytomorphological and radiological features of nonsmall cell lung cancer. Methods: This study population included 50 lung cancer patients who were diagnosed based on bronchoscopic biopsy findings and underwent surgery from April 2011 to May 2016. Cyotological specimens (Papanicolaou’s staining) were separately analyzed by two experienced cytotechnicians. The associations between the clinicopathological data, as well as the preoperative radiological features on computed tomography (CT) and positron emission tomography (PET) and cytomorphological analyses were analyzed. Results: Forty-five specimens were analyzed (adenocarcinoma [ADC] [n=38], squamous cell carcinomas [SQCC] [n=7]). The ADCs were cytomorphologically sub-classified as follows: acinar (n=25), solid (n=10), lepidic (n=2) and papillary (n=1). Among specimens with a solid pattern of ADC, there was a significantly greater percentage of samples with a necrotic background (50%), predominant 3D clusters (100%) and conspicuous nucleoli (80%) compared to specimens with a nonsolid pattern of ADC. The CT images of patients with solid ADC (90%) and SQCC (100%) tended to show solid nodules on CT. On PET, the maximum standardized uptake values at 120 minutes in solid ADC and SQCC were significantly higher in comparison to nonsolid ADC (12.8 ± 6.1 and 17.2 ± 7.3 versus 8.9 ± 4.4, respectively). Conclusions: The differentiation of the cytomorphological characteristics might predict the values of radiological features, and thereby provide information that can be used when determining the treatment strategies.

In lung tumors, the association between carcinoids and high-grade neuroendocrine tumors (HGNETs) is controversial. To understand the phenotypic similarities/differences between lung carcinoids and HGNETs, we comparatively investigated the expression of three kinds of developing neural transcription factors (DNTFs: BRN2, TTF1 and ASCL1) and multiple endocrine neoplasia type 1 (MEN1) as well as RB1 and P53 using 18 carcinoids and 16 HGNETs. The DNTFs were expressed in 10 of the 18 carcinoids and in all the HGNETs, while normal neuroendocrine cells, which are considered the major cell origin of lung carcinoids and small cell carcinomas, did not express DNTFs. Both the DNTF(-) and DNTF(+) carcinoids contained typical and atypical carcinoids. All the DNTF(-) carcinoids examined were formed in the bronchial wall. All the MEN1(-) carcinoids examined were classified into the DNTF(-) carcinoids, while all the HGNETs expressed MEN1. This finding suggests that DNTF(-) MEN1(-) carcinoids are unlikely to be precursors of HGNETs. Although the status of RB1 and P53 between carcinoids and HGNETs were apparently different, the DNTF(+) carcinoids of two male patients and one female patient revealed morphologies resembling HGNET cells and relatively high Ki67 indices. Further investigation of DNTF expression in carcinoids might provide important clues to understand the association between carcinoids and HGNETs.

BackgroundPerioperative atrial fibrillation (POAF) is one of the common arrhythmias in the setting of non-cardiac surgeries for malignancy. As POAF may cause subsequent adverse events, it is important to confirm its characteristics and risk factors.Materials and methodsThe prospective cohort study of surveillance for perioperative atrial fibrillation recurrence (PREDICT AF RECURRENCE) is an ongoing prospective, single-center, observational study that aims to illustrate the clinical impact of POAF in major non-cardiac surgery for malignancy. Patients who planned to undergo non-cardiac surgery for definitive/suspected malignancy were registered. Those with a history of AF and atrial flutter were excluded. Any 30-day complications included acute myocardial infarction, congestive heart failure, bleeding, thrombosis, any infection, and acute kidney injury. The primary endpoint was an incidence of POAF.ResultsThe present study included 799 patients (age, 68 ± 11; male, 62%). Of these, 80 patients (10.0%) developed POAF. Notably, 66 patients (83%) had no symptoms. Any 30-day complications occurred in 180 patients (23%) (with POAF: 34 (43%); without POAF: 146 (20%); p < 0.001). POAF in 17 patients (50%) was preceded by the development of complications. No patient developed cardiogenic shock and/or acute heart failure. The association between 30-day complications and POAF development were analyzed using the multivariate adjusted model (odds ratio: 2.84; 95% confidence interval: 1.74-4.62; p < 0.001).ConclusionTen percent of patients who underwent non-cardiac surgery for malignancy developed POAF, which was strongly associated with perioperative complications. As a majority were asymptomatic, careful observation using electrocardiography monitoring is important to avoid oversights.Clinical trial registrationUMIN ID: UMIN000016146.

Computed tomography-guided percutaneous transthoracic needle biopsy (CTNB) of the lung is a well-established diagnostic technique for the evaluation of thoracic lesions. At our institution, we have performed real-time CTNB using automated biopsy needles since 1998 and we introduced immediate cytology in 2004. We evaluate immediate cytology in CTNB to increase the diagnostic accuracy and to reduce the number of inadequate specimens. We retrospectively reviewed a consecutive series of 270 patients (group A: 98 patients before introduction, group B: 172 patients after introduction) who underwent CTNB between 2002 and 2009. We compared the diagnostic performance and the complication rates between two groups. There were no significant differences between groups A and B in patient and lesion characteristics. The rates of one time biopsy were significantly different: 56.1% (55/98) in group A and 69.2% (119/172) in group B. The rates of diagnostic accuracy in groups A and B were 79.6% (78/98) and 94.8% (163/172), respectively; the sensitivity were 74.0% (57/77) and 94.1% (127/135); the specificity were 100% (21/21) and 97.3% (36/37); the rates of major complications were 14.3% (14/98) and 2.9% (5/172). Group B had significantly higher diagnostic accuracy, sensitivity, and a lower complication rate in comparison with group A. CTNB with immediate cytology can improve diagnostic performance and decrease the complication rate. These improvements may help make CTNB less of a burden for patients. Diagn. Cytopathol. 2013;41:1063–1068. © 2012 Wiley Periodicals, Inc.

Background Signaling mediated by hepatocyte growth factor (HGF)/MET promotes multiple biological activities, including cell proliferation, motility, invasion, angiogenesis, and morphogenesis. Overexpression of HGF and MET and an increase of the MET gene copy number have recently been found in various cancers that had a poor outcome. Here we investigated the copy number of the MET gene and expression of MET and HGF in small pulmonary adenocarcinomas. Methods Tumor tissues were obtained from 106 pulmonary small adenocarcinomas 2cm or less in diameter. MET gene copy number, and the expression of MET and HGF, were analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry, respectively. Results MET FISH-positive signals were observed in 11 (10.4%) of 106 cases. One case (0.9%) showed gene amplification and 10 (9.4%) exhibited high polysomy. High immunoreactivity for MET and HGF in tumor cells was found in 30 (28.3%) and 19 cases (17.9%), respectively. HGF was also expressed in stromal cells in 32 cases (30.2%). No cases of non-invasive adenocarcinoma (adenocarcinoma in situ , localized bronchioloalveolar carcinoma) showed MET FISH-positive signals or high expression of HGF in the tumor cells. Expression of both MET and stromal HGF was stronger in invasive than in non-invasive adenocarcinoma. MET FISH-positive signals and high immunoreactivity for MET and HGF in tumor cells were associated with factors indicative of poor prognosis such as pleural invasion, vascular invasion, lymphatic permeation, lymph node metastasis, and nuclear grading. Univariate and multivariate analyses that included these factors showed that all statuses except for MET and HGF immunoreactivity were significantly associated with an increased risk of death. However, multivariate analysis revealed no independent factors related to poor prognosis. Conclusion Our results suggest that abnormality of the HGF/MET pathway occurs during the course of progression from non-invasive to invasive pulmonary adenocarcinoma. An increased MET gene copy number is indicative of a poor outcome in patients with small pulmonary adenocarcinomas.

This study was performed to determine the incidence rates of resistance factors, i.e., high-level hepatocyte growth factor (HGF) expression, epidermal growth factor receptor (EGFR) T790M secondary mutation, and MET amplification, in tumors with intrinsic and acquired EGFR tyrosine kinase inhibitor (TKI) resistance in EGFR mutant lung cancer.Ninety-seven specimens from 93 EGFR mutant lung cancer patients (23 tumors with acquired resistance from 20 patients, 45 tumors with intrinsic resistance from 44 patients [nonresponders], 29 sensitive tumors from 29 patients) from 11 institutes in Japan were analyzed. HGF expression, EGFR T790M secondary mutation, and MET amplification were determined by immunohistochemistry, cycleave real-time polymerase chain reaction, and fluorescence in situ hybridization, respectively.High-level HGF expression, EGFR T790M secondary mutation, and MET amplification were detected in 61, 52, and 9% of tumors with acquired resistance, respectively. High-level HGF expression was detected in 29% of tumors with intrinsic resistance (nonresponders), whereas EGFR T790M secondary mutation and MET amplification were detected in 0 and 4%, respectively. HGF expression was significantly higher in tumors with acquired resistance than in sensitive tumors (p0.001, Student's t test). Fifty percent of tumors with acquired resistance showed simultaneous HGF expression with EGFR T790M secondary mutation and MET amplification.High-level HGF expression was detected more frequently than EGFR T790M secondary mutation or MET amplification in tumors with intrinsic and acquired EGFR-TKI resistance in EGFR mutant lung cancer in Japanese patients. These observations provide a rationale for targeting HGF in EGFR-TKI resistance in EGFR mutant lung cancer.

Immunoglobulin binding protein 1 (IGBP-1) was initially identified as a signal transduction molecule coprecipitating with MB1 (Igα) of the B cell antigen receptor (BCR) complex and was later found to be broadly expressed. Immunoglobulin binding protein 1 has been characterized as an associated and regulatory component of the catalytic subunits of protein phosphatase 2A (PP2A), which is the most abundant phosphatase and plays important roles in cell growth and cell cycle control. The aim of this study was to investigate the expressional characteristics of IGBP-1 and PP2Ac during pulmonary adenocarcinogenesis. The positivity rate of IGBP-1 increased during the course of sequential progression from non-invasive carcinoma (8/30, 26.7%) to invasive adenocarcinoma (37/46, 80.4%) among cases that showed areas of lepidic growth. In contrast, all of the small adenocarcinomas showing a non-lepidic growth pattern were positive for IGBP-1 (20/20, 100%). All cancers that proved ultimately fatal were positive for IGBP-1, and log-rank analysis showed that IGBP-1 positivity was significantly correlated with a poor prognosis. In contrast, atypical adenomatous hyperplasias and lung adenocarcinomas were uniformly positive for PP2Ac. Protein phosphatase 2A was not associated with carcinoma progression. Thus we have demonstrated that IGBP-1 is expressed universally in advanced lung adenocarcinomas, and that its overexpression is significantly related to outcome.

Hepatocyte growth factor induces resistance to epidermal growth factor receptor tyrosine kinase inhibitors. It has been hypothesized that epidermal growth factor receptor tyrosine kinase inhibitors administration may influence the levels of plasma hepatocyte growth factor. Patients with advanced non-small cell lung cancer and relapsed after chemotherapies were eligible. Plasma hepatocyte growth factor levels were analyzed on pretreatment and post-treatment day 15 and 30. We also investigated the correlation between plasma hepatocyte growth factor levels and sensitivity to epidermal growth factor receptor tyrosine kinase inhibitors, tissue immunoreactivity for hepatocyte growth factor and MET gene status. Thirty-one patients were enrolled. Plasma hepatocyte growth factor levels on post-treatment day 15 (630.1 ± 366.9 pg/ml) were significantly higher (p = 0.029) than the pretreatment plasma hepatocyte growth factor levels (485.9 ± 230.2 pg/ml). Plasma hepatocyte growth factor levels on the post-treatment day 30 (581.5 ± 298.1 pg/ml) tend to be higher than those before treatment (p = 0.057). Pretreatment plasma hepatocyte growth factor levels in patients with progressive disease (724.1 ± 216.4 pg/ml) were significantly higher than those in patients with stable disease (396.5 ± 148.3 pg/ml; p = 0.0008) and partial response (381.7 ± 179.0 pg/ml; p = 0.0039). The optimal pretreatment plasma hepatocyte growth factor cut-off value for diagnosis of responder was 553.5 pg/ml, and its sensitivity and specificity were 90% and 65%, respectively. Pretreatment plasma hepatocyte growth factor levels had no correlation with tissue immunoreactivities for hepatocyte growth factor, MET gene status and active EGFR mutations. Administration of epidermal growth factor receptor tyrosine kinase inhibitors significantly increased plasma hepatocyte growth factor levels. High levels of pretreatment plasma hepatocyte growth factor indicated intrinsic resistance to epidermal growth factor receptor tyrosine kinase inhibitors. Plasma hepatocyte growth factor can serve as a useful biomarker for the early diagnosis of tumor relapse treated with epidermal growth factor receptor tyrosine kinase inhibitors.

症例は52歳，女性．左乳房腫瘤を指摘され当院を受診した．左乳房に30mm大の腫瘍が認められ，生検にて浸潤性乳管癌と診断された．PET-CTにて左乳腺および左腋窩にFDGの集積が見られた．また，左肺S10に9mm大の結節が見られた．肺結節にFDGの集積は見られなかったが，乳癌の転移性肺腫瘍が疑われた．病期判定のために確定診断が必要と判断され，胸腔鏡下左下葉部分切除術を行った．病理所見では，明るい細胞質を有する立方状から多角形の腫瘍細胞が充実性に認められた．免疫・特殊染色では，S-100が陽性でHMB-45とサイトケラチンとCD10が陰性であった．形態および免疫染色の結果より，肺良性淡明細胞腫瘍と診断された．肺良性淡明細胞腫は比較的稀な腫瘍である．自験例を含めた本邦報告例32例を集計して報告する．

背景．腸型肺腺癌は稀な組織型であり，大腸癌の転移性肺腫瘍との鑑別が重要となる．症例．74歳，男性．咳嗽を主訴に近医を受診したところ，胸部CTで右S3に57 mm大の腫瘍を指摘された．気管支鏡では右B3aから突出する腫瘍が認められ，組織学的には高円柱上皮が腺管を形成する病変であった．免疫組織化学的にはCK20（+），CK7（-），TTF-1（-）であり，大腸癌の転移が疑われた．上部内視鏡および下部内視鏡を行ったが肺野以外に病変がないため，原発性肺腺癌として右上葉切除術+ND2aを行った．永久標本の組織像も内視鏡下生検と同様で大腸癌に類似した組織像であり，CK20（+），CDX-2（+），MUC2（partly+），CK7（-），TTF-1（-），SP-A（-）から転移が疑われる所見であったが，臨床的な総合判断より腸型肺腺癌と診断した．結論．腸型肺腺癌は組織学的あるいは免疫組織化学的に確定診断が困難であり，消化管の精査が重要である．

症例は38歳女性．月経に一致した左気胸を発症し当センターを紹介された．月経22日後に行った胸腔鏡下手術にて，肺瘻の部位や気腫性嚢胞は確認できなかったが，左胸腔内の臓側，壁側胸膜にびまん性に多発する褐色の結節を認めた．病理学的に臓側，壁側胸膜ともに子宮内膜組織を認め，月経随伴性気胸と診断した．術後第3病日に月経が開始し右気胸を併発したが胸腔ドレナージにより改善した．後にホルモン療法を施行し，術後1年の経過では気胸の再発を認めていない．本症例は月経直前に手術を施行したため脱落する前の病変が観察されたと考えられた．発症機序は腹腔からの子宮内膜組織の侵入と臓側胸膜病変の脱落による気胸発症と推測された．壁側胸膜に子宮内膜組織を認めることはまれであり，月経随伴性気胸の発症機序を考えるうえで，本症例は興味深く貴重な症例と思われた．

In lung tumors, the association between carcinoids and high-grade neuroendocrine tumors (HGNETs) is controversial. To understand the phenotypic similarities/differences between lung carcinoids and HGNETs, we comparatively investigated the expression of three kinds of developing neural transcription factors (DNTFs: BRN2, TTF1 and ASCL1) and multiple endocrine neoplasia type 1 (MEN1) as well as RB1 and P53 using 18 carcinoids and 16 HGNETs. The DNTFs were expressed in 10 of the 18 carcinoids and in all the HGNETs, while normal neuroendocrine cells, which are considered the major cell origin of lung carcinoids and small cell carcinomas, did not express DNTFs. Both the DNTF(-) and DNTF(+) carcinoids contained typical and atypical carcinoids. All the DNTF(-) carcinoids examined were formed in the bronchial wall. All the MEN1(-) carcinoids examined were classified into the DNTF(-) carcinoids, while all the HGNETs expressed MEN1. This finding suggests that DNTF(-) MEN1(-) carcinoids are unlikely to be precursors of HGNETs. Although the status of RB1 and P53 between carcinoids and HGNETs were apparently different, the DNTF(+) carcinoids of two male patients and one female patient revealed morphologies resembling HGNET cells and relatively high Ki67 indices. Further investigation of DNTF expression in carcinoids might provide important clues to understand the association between carcinoids and HGNETs.

The purpose of the study was to retrospectively characterize diffusion-weighted magnetic resonance imaging (DWI) and positron emission tomography for differentiating among the various cytological subtypes of primary lung adenocarcinomas. The maximum diffusion signal intensities and the maximum standardized uptake value (SUV max) of 31 lesions were analyzed after delineation of regions of interest on the images. Diffusion intensities were 0.934 for Clara type, 0.938 for type II type, 1.473 for nongoblet type, and 1.617 for poorly differentiated adenocarcinoma type based on Shimosato's cytological classification ( P =.020). The SUV max values were 4.926, 5.491, 5.709, and 12.132, respectively ( P =.044). DWI might reflect some of the cytological characteristics of the tumor cells for differentiating the subtypes of lung adenocarcinomas.

Computed tomography-guided percutaneous transthoracic needle biopsy (CTNB) of the lung is a well-established diagnostic technique for the evaluation of thoracic lesions. At our institution, we have performed real-time CTNB using automated biopsy needles since 1998 and we introduced immediate cytology in 2004. We evaluate immediate cytology in CTNB to increase the diagnostic accuracy and to reduce the number of inadequate specimens. We retrospectively reviewed a consecutive series of 270 patients (group A: 98 patients before introduction, group B: 172 patients after introduction) who underwent CTNB between 2002 and 2009. We compared the diagnostic performance and the complication rates between two groups. There were no significant differences between groups A and B in patient and lesion characteristics. The rates of one time biopsy were significantly different: 56.1% (55/98) in group A and 69.2% (119/172) in group B. The rates of diagnostic accuracy in groups A and B were 79.6% (78/98) and 94.8% (163/172), respectively; the sensitivity were 74.0% (57/77) and 94.1% (127/135); the specificity were 100% (21/21) and 97.3% (36/37); the rates of major complications were 14.3% (14/98) and 2.9% (5/172). Group B had significantly higher diagnostic accuracy, sensitivity, and a lower complication rate in comparison with group A. CTNB with immediate cytology can improve diagnostic performance and decrease the complication rate. These improvements may help make CTNB less of a burden for patients.

Immunoglobulin binding protein 1 (IGBP-1) was initially identified as a signal transduction molecule coprecipitating with MB1 (Igα) of the B cell antigen receptor (BCR) complex and was later found to be broadly expressed. Immunoglobulin binding protein 1 has been characterized as an associated and regulatory component of the catalytic subunits of protein phosphatase 2A (PP2A), which is the most abundant phosphatase and plays important roles in cell growth and cell cycle control. The aim of this study was to investigate the expressional characteristics of IGBP-1 and PP2Ac during pulmonary adenocarcinogenesis. The positivity rate of IGBP-1 increased during the course of sequential progression from non-invasive carcinoma (8/30, 26.7%) to invasive adenocarcinoma (37/46, 80.4%) among cases that showed areas of lepidic growth. In contrast, all of the small adenocarcinomas showing a non-lepidic growth pattern were positive for IGBP-1 (20/20, 100%). All cancers that proved ultimately fatal were positive for IGBP-1, and log-rank analysis showed that IGBP-1 positivity was significantly correlated with a poor prognosis. In contrast, atypical adenomatous hyperplasias and lung adenocarcinomas were uniformly positive for PP2Ac. Protein phosphatase 2A was not associated with carcinoma progression. Thus we have demonstrated that IGBP-1 is expressed universally in advanced lung adenocarcinomas, and that its overexpression is significantly related to outcome.

7531 Background: This study was performed to determine the incidence rates of resistance factors, i.e., high-level hepatocyte growth factor (HGF) expression, epidermal growth factor receptor (EGFR)...

Introduction Nuclear grading involves an evaluation of the size and shape of nuclei and the percentage of tumor cells that are in the mitotic phase. To estimate the degree of aggressiveness, this approach has been applied to various types of carcinomas, such as breast carcinoma and pulmonary adenocarcinoma (Nakazato et al.). In the present study, we estimated and evaluated the interobserver variability of nuclear grading in primary pulmonary adenocarcinomas. Methods We selected 122 primary pulmonary adenocarcinomas measuring 2 cm or less in diameter. Eight pathologists independently evaluated the nuclear factors, using the nuclear grading system reported previously by Nakazato et al. The same pathologists also used both the international multidisciplinary classification of pulmonary adenocarcinoma (2011 International Association for the Study of Lung Cancer classification) and Noguchi's classification, and assessed the extent of the lepidic pattern in the largest cut surface of the tumor. Interobserver agreement was evaluated using the κ statistic. The disease-free survival curves of the patients were obtained using the Kaplan–Meier method and analyzed with the log-rank test. Results The mean (±SD) κ values for the two histological classifications, the extent of the lepidic pattern, and nuclear grading were 0.46 ± 0.09, 0.48 ± 0.09, 0.45 ± 0.16, and 0.58 ± 0.09, respectively. The cases judged as negative on the basis of nuclear grading showed a significantly better prognosis (5-year disease-free survival rate; 91.8% ± 2.7) than the positive cases did (68.6% ± 3.1). Conclusion Nuclear grading is practical for prognostic evaluation of pulmonary adenocarcinoma. The interobserver agreement for nuclear grading is significantly higher than for histological classifications and the extent of the lepidic pattern. Nuclear grading is a reliable prognostic indicator for small adenocarcinomas.