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Viable and stable human cancer cell lines and animal models combined with adequate clinical information are essential for future advances in cancer research and patient care. Conventional in vitro cancer cell lines are commonly available; however, they lack detailed information on the patient from which they originate, including disease phenotype and drug sensitivity. Patient-derived xenografts (PDX) with clinical information (so-called 'cancer xenopatients') are a promising advance that may accelerate the development of anticancer therapies. We established 61 PDX lines from 116 surgically removed tumor tissues inoculated subcutaneously into NOG mice (53% success rate). PDX lines were established from various types of epithelial tumors and also from sarcomas, including gastrointestinal stromal tumors and Ewing/PNET sarcomas. The metastatic tumors yielded PDX lines more effectively (65%) than the primary tumors (27%, P<0.001). In our PDX models, morphological characteristics, gene expression profiles, and genetic alteration patterns were all well preserved. In eight cases (7%), the transplantable xenografts for several generations were composed of large monotonous nonepithelial cells of human origin, revealed to be Epstein-Barr virus infection-associated lympho-proliferative lesions. Despite this, PDX linked with clinical information offer many advantages for preclinical studies investigating new anticancer drugs. The fast and efficient establishment of individual PDX may also contribute to future personalized anticancer therapies.

Background: Gangliocytic paraganglioma (GP) is an extremely rare benign tumor that commonly arises from the second part of the duodenum. Since GP exhibit neither prominent mitotic activity nor Ki-67 immunoreactivity, this tumor is often misdiagnosed as neuroendocrine tumor (NET) G1 (carcinoid tumor). However, patients with GP may have a better prognosis than patients with NET G1. This fact emphasizes the importance of differentiating GP from NET G1, but few studies have reported the epidemiology and histopathology of GP because of its rarity. To differentiate GP from NET G1 with ease, we conducted a multi-institutional retrospective study analyzing the morphometric and immunohistochemical features of this tumor., Methods: Since only a limited number of patients with GP could be identified in our institute, we conducted a multi-institutional retrospective study of GP in Japan, which was approved by the Ethics Committee of our medical institute. The obtained tissue sections underwent detailed morphometric and immunohistochemical analyses. Additionally, to differentiate GP from NET G1 with ease, immunohistochemical findings were compared., Results: In our examination of 12 cases of duodenal GP, we found that epithelioid cells of GP exhibited positive reactivity for progesterone receptor and pancreatic polypeptide, whereas tumor cells of NET G1 were completely negative reactivity for both. Additionally, although GP is considered to be an extremely rare NET, we found that four (40.0%) of the ten patients at our institute with duodenal NET G1 actually had GP., Conclusions: Although GP is regarded as a rare NET, our results suggest that it accounts for a substantial percentage of duodenal NETs. Additionally, confirmation of immunoreactivity for progesterone receptor and pancreatic polypeptide can assist in differentiating GP from NET G1.

Background: Patients with pathologic stage (p-Stage) IA non-small cell lung cancer (NSCLC) have a good survival rate because of possible curative resection. However, up to 10% of these patients relapse postoperatively. To identify unfavorable prognostic factors, we retrospectively analyzed the clinicopathological features of p-Stage IA disease, focusing on vascular invasion., Methods: Of 467 patients with p-Stage I NSCLC, 335 were diagnosed with p-Stage IA or IB disease based on a lesion size ≤3 cm and the presence of pleural invasion (PL). Univariate and multivariate analyses of recurrence-free survival (RFS) were performed with age, sex, PL, and vascular invasion (blood vessel invasion [v] and lymphatic vessel invasion [ly]) as variables. To examine vascular invasion, hematoxylin-eosin (HE), Elastica van Gieson staining, and immunostaining with anti-podoplanin antibody were performed. The presence or absence of v and ly was recorded; the number of involved vessels was counted. Survival rates were obtained using the Kaplan-Meier method and log-rank test. Multivariate analyses were performed using the Cox proportional hazards model., Results: RFS differed significantly between patients with no or one involved blood vessel (0 v or 1 v) and those with ≥2 involved vessels (≥2 v). Similarly, RFS differed significantly between patients with no lymphatic vessel involvement (0 ly) and those with one involved lymphatic vessel (1 ly). Thus, BVI(+) and BVI(-) were defined as ≥2 v and 0 v + 1 v, and LVI(+) and LVI(-) as ≥1 ly and 0 ly, respectively. BVI and LVI together represented tumor vessel invasion (TVI). On multivariate analyses, PL and TVI were independently associated with recurrence. Additionally, patients with p-Stage IA TVI(+) disease had a comparable recurrence rate to those with p-Stage IB disease., Conclusions: Similar to PL, TVI is an important factor increasing the likelihood of recurrence. As HE staining alone is insufficient for evaluating vascular invasion, specific staining is necessary. Moreover, patients with p-Stage IA TVI(+) disease had a recurrence rate comparable to those with p-Stage IB disease; therefore, further studies should aim to elucidate whether patients with p-Stage IA TVI(+) disease should be administered postoperative chemotherapy similar to that received by p-Stage IB patients., Virtual Slides: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/5213064891369688.

Background: Detailed reports on mucinous adenocarcinoma (formerly "mucinous bronchioloalveolar carcinoma") have not been published. We evaluated the correlation between thin-section computed tomography findings and the clinicopathologic characteristics and prognosis of mucinous adenocarcinoma., Methods: From April 1997 to March 2008, 45 resected lung carcinomas were diagnosed as mucinous adenocarcinoma. Five cases of multiple lung cancers or ambiguous mucinous adenocarcinoma were excluded. Tumors were classified as "solitary-type" or "pneumonic-type" tumors according to the thin-section computed tomography findings. We evaluated the clinicopathologic characteristics and the epidermal growth factor receptor and KRAS gene mutation statuses and correlated the thin-section computed tomography findings with patient prognoses., Results: Thirty patients had solitary-type and 10 had pneumonic-type tumors. The lesions in 23, 14, and 3 patients were classified as pathologic stage I, stage II, and stage III, respectively. Five patients had adenocarcinoma in situ, 9 had minimally invasive adenocarcinoma, and 26 had invasive mucinous adenocarcinoma. Thirteen patients showed recurrences, which were classified as intrapulmonary metastases in all patients. The 5-year overall and relapse-free survival rates were 83.3% and 88.8%, respectively, in patients with solitary-type tumors and 20.0% and 0%, respectively, in patients with pneumonic-type tumors (p < 0.001). The median follow-up time for surviving patients was 81 months. KRAS mutations were detected in 30 patients, but epidermal growth factor receptor mutations were absent in all patients., Conclusions: Our results indicated that thin-section computed tomography findings for mucinous adenocarcinoma were useful in predicting prognosis before surgical resection. Further studies are required to improve the treatment strategy for mucinous adenocarcinoma., (Copyright © 2015 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Plexiform schwannoma is an infrequent variant of schwannoma characterized grossly and microscopically by multi-nodular growth. Although plexiform schwannoma has such growth patterns, it is a benign tumor as well as a conventional schwannoma. It rarely infiltrates adjacent organs or arises from the organ itself. In this report, we describe a case in which plexiform schwannoma involved the tracheal wall and left recurrent laryngeal nerve to a great extent. As it was expected to be difficult to achieve complete resection even if the longer tracheal resection were performed, we preserved the trachea and resected as much of the tumor as possible. This report is thought to be the first to describe plexiform schwannoma infiltrating or growing from the trachea. Although the treatment decisions we made might be controversial, we believed we could make an accurate diagnosis and adequate treatment decision through surgery.

Introduction: In octogenarians with early stage of lung cancer, sublobar resection has been shown to be no inferior survival to lobectomy. However, some octogenarians remain physically and mentally active., Methods: We retrospectively studied 65 octogenarians who underwent curative resection for clinical stage I NSCLC (excluding adenocarcinoma in situ). All patients were assessed by cardiologists and underwent stair-climbing tests (five flights, 18 m) and cognitive function tests. Lobectomy was performed in patients who could climb 5 flights of stairs without stopping or oxygen desaturation of >4%., Results: The actuarial survival rate was 68.6% at 5 years, and the median survival time was 109.2 months. Forty-three patients met the criteria for lobectomy. As compared with sublobar resection, lobectomy was associated with significantly higher rates of overall survival (78.4% vs. 48.5%; p = 0.02) and disease-specific survival (88.4% vs. 61.7%; p = 0.02) at 5 years. On multivariate analysis, male sex (hazard ratio, 3.827; 1.382-10.596) and sublobar resection (2.261; 1.054-5.360) were independent risk factors for survival. Mental disorders occurred in 6 patients (9.2%), and their score on preoperative cognitive function tests was significantly lower than that of patients without mental disorders (22.7 vs. 26.0, p <0.01)., Conclusion: Outcomes of lobectomy are good in physically and mentally competent octogenarians.

Background: Surgical treatment has become the mainstay of treatment for multiple primary lung cancers. In particular, the prevalence of synchronous primary lung adenocarcinomas (SPLA) has recently increased, but few studies have evaluated surgical outcomes of patients with SPLA. We reviewed the clinicopathologic features and surgical outcomes of SPLA to identify factors related to survival., Methods: Data on 2,041 consecutive patients with primary non-small cell carcinoma who underwent surgical resection in our hospital from 1995 through 2009 were retrospectively analyzed., Results: The SPLA was pathologically diagnosed in 93 patients, including 26 with bilateral tumors. The rates of overall survival and recurrence-free survival at 5 years were 87.0% and 81.8%, respectively. There was no surgical mortality at 30 days. On univariate analysis, lymph node metastasis (p = 0.0000), nonlepidic predominant histologic subtype (p = 0.0018), and a solid appearance of the largest tumor on computed tomography (p = 0.0088) were significantly related to poor overall survival. On multivariate analysis, bilateral distribution of tumors (p = 0.031), lymph node metastasis (p = 0.004), and sublobar resection (p = 0.042) were independent predictors of poor survival., Conclusions: Surgery has good outcomes and should be aggressively performed for patients with SPLA. The evaluation of lymph node status has an important role in deciding whether surgery is indicated. Bilateral tumors are a predictor of poor outcomes, requiring that caution be exercised. Lobectomy has a high cure rate and should be performed whenever possible. However, sublobar resection should be considered for patients likely to have poor residual lung function postoperatively., (Copyright © 2014 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Loss of human leukocyte antigen (HLA)-DR expression may be related to a poor prognosis of diffuse large B-cell lymphoma (DLBCL), and tumor-associated macrophages (TAMs) may influence tumor progression. We retrospectively reviewed 36 patients with newly diagnosed DLBCL who received R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) therapy at Kanagawa Cancer Center in Japan from 2004 to 2010. HLA-DR expression by lymphoma cells was evaluated using flow cytometry, and TAMs in lymphoma tissue were detected by immunohistochemistry for CD68 as a marker of macrophages and CD163 as a marker of M2 TAMs. Three-year overall survival was, respectively, 100% versus 69.6% in the HLA-DR "bright" and "not bright" groups (p = 0.012). Patients from the HLA-DR "not bright" group with strong CD163 expression had a much worse prognosis than other patients. The HLA-DR status shown by flow cytometry can be used to predict the prognosis of patients with DLBCL receiving R-CHOP therapy and prognostic accuracy can be increased by also assessing TAMs.

We report the case of a solitary pulmonary tumor, which was diagnosed as recurrent early gastric cancer by detailed pathological examinations. A 59-year old man initially underwent total gastrectomy for gastric adenocarcinoma located at the esophago-gastric junction. A pathological examination indicated a papillary adenocarcinoma (pap ) that had invaded the submucosal layer (sm²), but had not metastasized to the regional lymph nodes (n0). The final diagnosis was P0H0M0T1bN0, Stage IA. Chest computed tomography (CT) 30 months after primary surgery indicated a solitary tumor with a diameter of 9 mm at S3 of the left lung. A positron emission tomography (PET)-CT scan showed an accumulation of ¹⁸F-fluordeoxy-glucose (FDG18) at the same location. Lung cancer was suspected and the patient was given a left upper lobectomy. The resected tumor was diagnosed as gastric cancer metastatic adenocarcinoma by permanent pathological examination. The tumors showed similar histology and immuno histochemical findings for CK7, CK20, TTF-1, SP-A, CDX-2, and HER2 . Early gastric cancer is an almost curable disease and recurrence is very rare. We report the details of this case and review the literature.

Background and Purpose: Acute exacerbation of interstitial pneumonia is a life-threatening complication after lung cancer surgery. Dorsal subpleural fibrotic changes occupying 3 or more segments of both lower lobes on high-resolution computed tomography indicate a very high risk. We conducted a prospective phase II study to assess the efficacy of prophylactic treatment., Methods: Patients with lung cancer underwent high-resolution computed tomography preoperatively to assess the risk of acute exacerbations of interstitial pneumonia. Before induction of general anesthesia, high-risk patients received 125 mg of methylprednisolone as an intravenous bolus and sivelestat sodium hydrate 300 mg ·day(-1) as a continuous intravenous infusion. From January 2010 through August 2011, a total of 327 patients underwent surgery for lung cancer, and 31 (9.5%) were enrolled., Results: There was no case of acute exacerbation. No adverse events were associated with prophylaxis. Usual interstitial pneumonia was confirmed histopathologically in 25 (80.6%) patients. Four (12.9%) patients had major complications. Usual interstitial pneumonia was diagnosed postoperatively in 4 (1.4%) of 327 patients who did not meet the inclusion criteria, and 1 of these patients died due to acute exacerbation of occult interstitial pneumonia., Conclusion: Perioperative use of sivelestat sodium hydrate and low-dose methylprednisolone may be useful as prophylaxis for acute exacerbation of interstitial pneumonia., (© The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: The rapid aging of the population in Japan has been accompanied by an increased rate of surgery for lung cancer among elderly patients. It is thus an urgent priority to map out a treatment strategy for elderly patients with primary lung cancer. Although surgical resection remains standard treatment for early stage non-small-cell lung cancer (NSCLC), it is now essential to confirm the status of epidermal growth factor receptor (EGFR) gene mutations when planning treatment strategies. Furthermore, several studies have reported that EGFR mutations are an independent prognostic marker in NSCLC. However, the relations between age group and the molecular and pathological characteristics of NSCLC remain unclear. We studied the status of EGFR mutations in elderly patients with NSCLC and examined the relations of EGFR mutations to clinicopathological factors and outcomes according to age group., Methods: A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene exons 19, 20, and 21 and KRAS gene exons 12 and 13 were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method., Results: EGFR mutations were detected in 185 (47.7%) and KRAS mutations were detected in 33 (8.5%) of the 388 patients. EGFR mutations were found in a significantly higher proportion of patients younger than 80 years (younger group; 178/359, 49.6%) than in patients 80 years or older (older group; 7/29, 24.1%) (P = 0.008). In contrast, KRAS mutations were more common in the older group (6/29, 20.7%) than in the younger group (27/359, 7.5%) (P = 0.014). The older group showed a trend toward a higher rate of 5-year overall survival among elderly patients with EGFR mutations (100%) than among those with wild-type EGFR (66.2%), but the difference was not significant., Conclusions: Our results suggest that the EGFR status of patients with NSCLC differs between patients 80 years or older and those younger than 80 years. EGFR mutation status might be a prognostic marker in elderly patients with completely resected NSCLC.

Objective: We examined the appropriate measurement for pathological tumor size by comparing radiological and pathological tumor size of resected lung adenocarcinoma in FSE., Materials and Methods: We reviewed records of 59 resected specimens of lung adenocarcinoma for FSE from January to December 2008. Specimens were well-inflated with saline by using an injector before cutting into segments. After selecting the tumor segment of maximal diameter, we compared three ways of measuring pathological tumor size by using paired t-test: (I) macroscopic tumor size (MTS), measured with a metal straight ruler, (II) microscopic frozen section tumor size (FSTS), and (III) microscopic paraffin section tumor size (PSTS). We compared each discrepancy rate (DR) [DR=(CT tumor size-pathological tumor size)/CT tumor size×100] (%) between tumors that were air-containing type and solid-density type on CT scans, and also compared the tumors with lepidic component rates (LCR) ≥50% and LCR <50%, by using Mann-Whitney U-tests., Results: FSE could diagnose malignancy with 100% accuracy. The mean CT tumor size was 18.36mm, and the mean pathological tumor sizes (MTS, FSTS, and PSTS) were 17.81, 14.29, and 14.23mm, respectively. FSTS and PSTS were significantly smaller than CT tumor size (p<0.001). The DR calculated with PSTS was significantly larger in air-containing than in solid-density tumors, and also larger in LCR ≥50% than in LCR <50% tumors., Conclusion: FSE with the inflation method diagnosed malignancy with 100% accuracy. The lung specimen must be sufficiently inflated to prevent tissue shrinking, and we propose MTS as the definition for pathological tumor size in FSE. The greater discordance observed between CT tumor size and microscopic tumor size was assumed to be due to shrinkage of the lepidic component in the tumor., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Solitary pulmonary capillary hemangioma (SPCH) is a rare benign lung tumor that must be distinguished from small and early lung cancers. Here, we report a case of SPCH for which we performed frozen section diagnosis. The patient was a 55-year-old Japanese woman. Five years before the operation, mixed ground-glass opacity was detected by computed tomography in the left posterior basal segment of the lower lobe (S10). Because the interior tumor density of the ground-glass opacity increased slightly, video-assisted thoracic surgery wedge resection was performed. Frozen section diagnosis revealed a benign tumor without proliferation of atypical epithelial cells. The tumor had narrow alveolar lumens, thickened alveolar septa and a clear boundary separating it from normal lung tissue. The proliferated lumens varied in size and were lined with single layers of flat cells. After the operation, immunohistochemical staining of a paraffin section revealed that the thickened alveolar septa resulted from the proliferation of capillary vessels, the flat cells of which were positive for CD31 and CD34 and negative for podoplanin; the tumor was diagnosed as SPCH. Here, we discuss the pathological features of SPCH on frozen sections with reference to this case and review previous related reports., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Background: The prognostic value of maximum standardized uptake value (maxSUV) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is known for localized pulmonary adenocarcinoma, which is most commonly non-mucinous adenocarcinoma. We examined the validity of thin-section computed tomography (TS-CT) and FDG-PET findings in mucinous adenocarcinoma., Materials and Methods: TS-CT and FDG-PET were performed on 25 patients with mucinous lung adenocarcinoma that was subsequently resected between January 2009 and March 2013. Based on the percentage reduction of maximum tumor diameter on the mediastinal window image compared with the diameter on the lung window image on TS-CT, tumors were classified as air-type (≥50%) or solid-type (<50%). All resected specimens were pathologically diagnosed according to the International Association for the Study of Lung Cancer (IASLC) classification, and the diameter of the pathological invasive area was assessed., Results: Most mucinous adenocarcinomas were located in the lower lobe. All except two were classified as solid-type tumor on TS-CT. Multiple regression analysis revealed the correlation of maxSUV with pathological tumor size and diameter of pathological invasive area; these two parameters showed no significant correlation with each other (r=0.354, p=0.083). maxSUV was significantly lower for tumors with invasive area ≤5 mm than for tumors with invasive area >5mm (1.62 vs. 3.77, p=0.01), but no statistically significant difference was found in terms of other pathological invasive findings such as the presence of lymphatic or vascular invasion, pleural involvement, or predominant histological subtype., Conclusions: Most mucinous adenocarcinomas had appearances of solid-type tumor on TS-CT. maxSUV on FDG-PET indicates the pathological invasive area in mucinous adenocarcinoma as well as non-mucinous adenocarcinoma., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Lung cancers harboring epidermal growth factor receptor (EGFR) mutations depend on constitutive activation of the kinase for survival. Although most EGFR-mutant lung cancers are sensitive to EGFR tyrosine kinase inhibitors (TKIs) and shrink in response to treatment, acquired resistance to TKI therapy is common. We demonstrate here that two EGFR-mutated lung adenocarcinoma cell lines, HCC827 and HCC4006, contain a subpopulation of cells that have undergone epithelial-to-mesenchymal transition and survive independent of activated EGFR. These EGFR-independent cancer cells, herein termed gefitinib-resistant (GR) cells, demonstrate higher levels of basal autophagy than their parental cells and thrive under hypoxic, reduced-serum conditions in vitro; this somewhat simulates the hypoxic environment common to cancerous tissues. We show that depletion of the essential autophagy gene, ATG5, by small interfering RNA (siRNA) or chloroquine, an autophagy inhibitor, markedly reduces GR cell viability under hypoxic conditions. Moreover, we show a significant elevation in caspase activity in GR cells following knockdown of ATG5. These results suggest that GR cells can evade apoptosis and survive in hostile, hypoxic environments with constant autophagic flux. We also show the presence of autophagosomes in some cancer cells from patient samples, even in untreated EGFR-mutant lung cancer tissue samples. Together, our results indicate that autophagy inhibitors alone or in combination with EGFR TKIs may be an effective approach for the treatment of EGFR-mutant lung cancers, where basal autophagy of some cancer cells is upregulated.

Purpose: The transcription factor NRF2 plays a pivotal role in protecting normal cells from external toxic challenges and oxidative stress, whereas it can also endow cancer cells resistance to anticancer drugs. At present little information is available about the genetic polymorphisms of the NRF2 gene and their clinical relevance. We aimed to investigate the single nucleotide polymorphisms in the NRF2 gene as a prognostic biomarker in lung cancer., Experimental Design: We prepared genomic DNA samples from 387 Japanese patients with primary lung cancer and detected SNP (c.-617C>A; rs6721961) in the ARE-like loci of the human NRF2 gene by the rapid genetic testing method we developed in this study. We then analyzed the association between the SNP in the NRF2 gene and patients' overall survival., Results: Patients harboring wild-type (WT) homozygous (c.-617C/C), SNP heterozygous (c.-617C/A), and SNP homozygous (c.-617A/A) alleles numbered 216 (55.8%), 147 (38.0%), and 24 (6.2%), respectively. Multivariate logistic regression models revealed that SNP homozygote (c.-617A/A) was significantly related to gender. Its frequency was four-fold higher in female patients than in males (10.8% female vs 2.7% male) and was associated with female non-smokers with adenocarcinoma. Interestingly, lung cancer patients carrying NRF2 SNP homozygous alleles (c.-617A/A) and the 309T (WT) allele in the MDM2 gene exhibited remarkable survival over 1,700 days after surgical operation (log-rank p = 0.021)., Conclusion: SNP homozygous (c.-617A/A) alleles in the NRF2 gene are associated with female non-smokers with adenocarcinoma and regarded as a prognostic biomarker for assessing overall survival of patients with lung adenocarcinoma.

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.

Paclitaxel and carboplatin (TC) chemotherapy is an effective and well-tolerated regimen against advanced endometrial cancer. Organic anion transporting polypeptide 1B3 (OATP1B3) and copper transporter 1 (CTR1) are critical for the uptake of paclitaxel and carboplatin, respectively. This study aimed to address the prognostic impact of OATP1B3 and CTR1 in endometrial cancer patients treated with adjuvant TC chemotherapy. We immunohistochemically evaluated the expressions of OATP1B3 and CTR1 in 47 stage III endometrial cancers. The high expression levels of OATP1B3 were significantly correlated with type I tumor (P = 0.0005). In univariate analysis, high expression levels of OATP1B3 (P = 0.047) and CTR1 (P = 0.009) were significantly associated with longer disease-free survival (DFS) and longer overall survival (OS), respectively. The patients with tumors showing high expression levels of at least one of OATP1B3 and CTR1 had potentially longer DFS (P = 0.058) and significantly longer OS (P = 0.003) sin the univariate analysis. Combined OATP1B3/CTR1 expression was the sole independent prognostic factor for longer OS in the multivariate analysis (P = 0.013). Our findings suggest that combined OATP1B3/CTR1 expression is a possible predictive/prognostic factor for a good outcome in stage III endometrial cancer patients treated with adjuvant TC chemotherapy.

We report a rare case of lung adenocarcinoma in which micropapillary components were considered to cause stump recurrence. A woman in her fifties was diagnosed with lung cancer in the right middle lobe with invasion to the upper lobe, which was treated by a right middle lobectomy together with upper lobe partial resection. The cancer was pathologically diagnosed as adenocarcinoma and had a free surgical margin. There was no recurrence during the following 5 years and 8 months, and thus periodical surveillance, including computed tomography, was stopped. However, 2 years and 7 months after this, she was discovered to have an abnormal shadow on chest radiography, and a thorough examination revealed a 3-cm-sized tumor involving the previous surgical margin. Therefore, she underwent right upper lobectomy. We pathologically re-evaluated the first tumor and found that it was an adenocarcinoma with a micropapillary component in the periphery, 6mm away from the surgical margin. In addition, a few tiny clusters of tumor cells were found to be floating within the alveolar spaces near the margin. The first and second tumors showed almost the same histological mixture of components of adenocarcinoma and the same EGFR mutation. From these results, we concluded the second tumor was a stump recurrence originating from the first tumor resection. This case illustrates the importance of careful pathological investigation when an autosuture instrument is used for a partial resection in a case of lung adenocarcinoma with micropapillary components. In such cases, it is particularly important to clarify if micropapillary components are floating near a stump., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Well-differentiated papillary mesothelioma (WDPM) is a distinct subtype of mesothelial tumor from diffuse malignant mesothelioma (DMM), with an uncertain malignant potential. The relationship between WDPM and DMM, with regard to the ability of the former to develop into the latter, is also unknown. A 58-year-old woman, diagnosed with a rectal carcinoid tumor, underwent removal of the lymph nodes via the abdomen in 2004. A large number of white miliary nodules were identified on the mesentery and peritoneum, which were histologically diagnosed as WDPM. No further therapy was administered, but the patient was followed-up using imaging methods. Seven years later, an abdominal wall mass was discovered using positron emission tomography-computed tomography, and a laparotomy biopsy was performed. DMM was diagnosed, because mesothelioma with extended invasion had been histologically identified. Mesothelioma similar to papillary proliferation was present on the outer layer of the peritoneum, and an infiltrating lesion with continuous restiform or solid-like structures was noted. WDPM was believed to have undergone malignant transformation. Compared to DMM, WDPM has a good prognosis and is considered a benign or borderline neoplasm. Our findings suggest that WDPM does have malignant potential, however, because histological findings indicated a malignant transformation of WDPM to DMM., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

Aim: To analyse the correlation between computed tomography (CT) findings of small lung adenocarcinomas and the International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society Classification of Lung Adenocarcinoma., Materials and Methods: A retrospective review of 300 lung adenocarcinoma lesions (size ≤20 mm) after surgical resection in 295 consecutive patients was performed. Tumours were defined as air-containing type if the ratio of the maximum dimension of the tumour on mediastinal windows to the maximum dimension of the tumour on lung windows was ≤50%, and as solid-density type if the ratio was >50%. The incidence between CT findings (air bronchogram, vascular involvement, pleural tags, notches, and spiculation) and pathological findings were investigated., Results: Of the 142 air-containing lesions, 114 were adenocarcinoma in situ (AIS), 28 were minimally invasive adenocarcinoma (MIA), and none of the lesions were invasive adenocarcinoma. Of the 158 solid-density lesions, 30 were AIS, 24 were MIA, and 104 were invasive adenocarcinoma. Notches and pleural tags were commonly observed in cases of invasive adenocarcinoma (p < 0.05)., Conclusions: In the air-containing type of small lung adenocarcinomas, AIS and MIA were observed but no cases of invasive adenocarcinoma were found. The presence of notches and pleural tags were a significant factor in invasive adenocarcinoma., (Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: Maximum standardized uptake value (SUVmax) of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been found to have prognostic value. We previously reported the correlation between SUVmax and pathological invasive area, and determined an SUVmax cut-off value of 2.15 for predicting the recurrence potential of an invasive area of diameter 5mm. Here, we evaluate the validity of FDG-PET for prediction of recurrence in pathological stage IA lung adenocarcinoma., Methods: From February 2006 to May 2008, 100 patients with pathological stage IA lung adenocarcinoma underwent complete resection at our hospital. Tumors were classified as air-type or solid-type based on thin-section computed tomography (TS-CT) findings and the influence of TS-CT classification, SUVmax, and clinicopathologic features were evaluated in terms of the incidence of recurrence., Results: Unlike air-type adenocarcinomas, recurrent disease was detected in 8 of 62 solid-type adenocarcinomas. SUVmax and diameter of invasive area were significantly correlated with recurrence and a shorter time to recurrence. All 8 recurrent cases had pathological invasive area >5mm. All except one case of recurrence were solid-type adenocarcinomas with SUVmax≥2.15. Three-year disease-free survival rates were 100% in air-type adenocarcinomas, 97.1% in solid-type adenocarcinomas with SUVmax<2.15, and 74.1% in solid-type adenocarcinoma with SUVmax≥2.15., Conclusion: Combined evaluation of TS-CT classification and SUVmax had significant value in predicting recurrence in stage IA lung adenocarcinoma, reflecting the aggressiveness of primary lung adenocarcinoma. Prediction of tumor aggressiveness could contribute to decision-making regarding the choice of surgical procedure and treatment after surgery., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Introduction: To study the characteristics of lung cancer, appearing as small solid nodules on initial computed tomography (CT) findings, and to determine an appropriate follow-up duration so as to differentiate between malignancy and benign tumor., Methods: We analyzed the records of 34 patients who had undergone surgical resection of lung cancer, which appeared as small solid nodules on initial CT findings. We studied the CT findings, volume doubling times (VDT), follow-up durations, pathological and clinical findings., Results: VDT is classified as follows: (1) slow growth group (SGG), with a VDT of more than 700 days and (2) rapid growth group (RGG), with a VDT of less than 700 days. The median VDT of the SGG was 1083 days, and the RGG was 256 days (p<0.01). The median duration for follow-up of the SGG was 1218 days, and 179 days for the RGG. A statistical difference was noted in the follow-up durations (p<0.01). There were no statistical differences in the preoperative thin-section CT (TSCT) findings, or in the pathological findings. The RGG included more patients with smoking histories. The CT findings of RGG tended to reveal changed in base lung field such as emphysema, and lung fibrosis., Conclusions: Generally, lung cancer appearing as small solid nodules on initial CT findings grew rapidly, but there were some cases which displayed slow growth patterns. These cases required follow up for over two years, before diagnosis was possible. We concluded the appropriate maximum followup duration is three years., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Although cardiac fibroma has been regarded as benign tumor, it presents various symptoms and may lead to death. Unfortunately, only a few studies have reported the epidemiology, embryology, and histopathology of the tumor, and the factors predicting poorer outcome are still obscured., Methods: In July 2011 we searched for English and Japanese cases of cardiac fibroma using the PubMed and IgakuChuoZasshi databases. We then extracted and sampled raw data from the selected publications in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) style as much as was possible., Results: Details of a total of 178 patients with cardiac fibroma were retrieved. The mean age was 11.4 years (median: 2.8 years). Tumor sizes ranged from 8.0 to 150.0 mm (mean 53.1 mm). The left ventricle was found to be the most common site associated with the tumor at a rate of 57.3%, followed by the right ventricle, and interventricular septum. The highest mortality was found in patients with septal involvement (58.6%). In all, 111 patients survived among the 160 patients with a recorded outcome. A younger age of the patient at the time of diagnosis was associated with a decreased survival rate. In addition, a significant positive association was found between ages for patients younger than 17 years of age and the diameter of the tumor at the time of diagnosis (r = 0.341, P = 0.006)., Conclusions: Both the younger age of patients at the time of diagnosis and septal involvement can be regarded as factors significantly indicating a poor prognosis. Furthermore, our statistical analyses support the following hypotheses. First, the high ratio of tumor-to-heart size may generate low cardiac output and therefore lead to poor outcome. Second, the ratio of the sites where cardiac fibroma occurred corresponds with the ratio of the muscular weight of the cardiac chamber. Third, cardiac fibroma involving the interventricular septum more frequently induces conduction system disease.

Src has a role in the anoikis resistance in lung adenocarcinomas. We focused on two epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cell lines, HCC827 (E746-A750 deletion) and H1975 (L858R+T790M), in suspension to elucidate whether suspended lung adenocarcinoma cells are eradicated by long-term treatment with Src tyrosine kinase inhibitors (TKIs). We also examined metastasis-positive lymph nodes from 16 EGFR-mutant lung adenocarcinoma patients for immunohistochemical expression of mutant-specific EGFR. Almost all suspended HCC827 cells underwent apoptosis after 144 h of combination treatment with AZD0530, trichostatin A (TSA), and ABT-263, whereas many suspended H1975 cells survived the treatment. AZD0530 is a Src TKI, TSA is a histone deacetylase inhibitor, and ABT-263 is a Bcl-2 inhibitor. During the therapy, the phosphorylation of EGFR decreased in HCC827 cells and remained stable in H1975 cells. The phosphorylated EGFR of Src TKI-resistant H1975 cells, as well as HCC827 cells, was completely suppressed by the third generation EGFR TKI, WZ4002. Consequently, both the suspended cell lines were almost completely eradicated within 144 h, with the combined therapy of WZ4002, ABT-263, and TSA. Interestingly, treated suspended cells underwent apoptosis to a greater extent than did adherent cells. Intrasinus floating lung adenocarcinoma cells in the lymph nodes expressed a mutant-specific EGFR. These findings suggest that suspended EGFR-mutant lung adenocarcinoma cells depend significantly more on EGFR activation for survival than attached cells do. The tumor cells circulating in vessels, which express mutant-specific EGFR, would be highly susceptible to the combination therapy of WZ4002, ABT-263, and TSA.

Background: Pulmonary adenocarcinomas with a micropapillary component having small papillary tufts and lacking a central fibrovascular core are thought to result in poor prognosis. However, the component consists of tumor cells often floating within alveolar spaces (aerogenous micropapillary component [AMPC]) rather than invading fibrotic stroma observed in other organs like breast (stromal invasive micropapillary component [SMPC]). We previously observed cases of lung adenocarcinoma with predominant SMPC that was associated with micropapillary growth of tumors in fibrotic stroma observed in other organs. We evaluated the incidence and clinicopathological characteristics of SMPC in lung adenocarcinoma cases., Patients and Methods: We investigated the clinicopathological characteristics and prognostic significance of SMPC in lung adenocarcinoma cases by reviewing 559 patients who had undergone surgical resection. We examined the SMPC by performing immunohistochemical analysis with 17 antibodies and by genetic analysis with epidermal growth factor receptor (EGFR) and KRAS mutations., Results: SMPC-positive (SMPC(+)) tumors were observed in 19 cases (3.4%). The presence of SMPC was significantly associated with tumor size, advanced-stage disease, lymph node metastasis, pleural invasion, lymphatic invasion, and vascular invasion. Patients with SMPC(+) tumors had significantly poorer outcomes than those with SMPC-negative tumors. Multivariate analysis revealed that SMPC was a significant independent prognostic factor of lung adenocarcinoma, especially for disease-free survival of pathological stage I patients (p = 0.035). SMPC showed significantly higher expression of E-cadherin and lower expression of CD44 than the corresponding expression levels shown by AMPC and showed lower surfactant apoprotein A and phospho-c-Met expression level than corresponding expression levels shown by tumor cell components without a micropapillary component. Fourteen cases with SMPC(+) tumors (74%) showed EGFR mutations, and none of them showed KRAS mutations., Conclusions: SMPC(+) tumors are rare, but they may be associated with a poor prognosis and have different phenotypic and genotypic characteristics from those of AMPC(+) tumors.

Alginate is a natural acidic linear polysaccharide that is produced by brown seaweeds. It is currently used in a broad range of commercial enterprises, such as the food and medical products industries. Recent evidence has demonstrated that alginate oligosaccharides may function as growth promoting agents for certain plant cells, including those of some green algae. Chlamydomonas reinhardtii is a green alga that is used as a model organism in fundamental molecular biology studies; it is also a producer of biohydrogen. In the present study, we examined effects of two types of alginate oligosaccharide mixtures (AOMs), which were prepared by either enzymatic degradation (ED) or acid hydrolysis (AH), on the growth of C. reinhardtii. Growth was significantly promoted by AOM (ED) in a concentration-dependent manner. The maximum effect was observed on day 4 of treatment. The fatty acid composition of C. reinhardtii was also influenced by AOM (ED); the levels of C16:0, C18:2 cis and C18:3 n-3 increased in treated cells. AOM (AH) and the other saccharides that we tested did not affect the growth of C. reinhardtii. The effects that we identified could promote efficient biomass production by reducing culture times and by changing cellular fatty acid levels., (Copyright © 2011 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Malignant pleural mesothelioma (MPM) is a fatal tumor. It is often hard to discriminate MPM from metastatic tumors of other types because currently, there are no reliable immunopathological markers for MPM. MPM is differentially diagnosed by some immunohistochemical tests on pathology specimens. In the present study, we investigated the expression of intelectin-1, a new mesothelioma marker, in normal tissues in the whole body and in many cancers, including MPM, by immunohistochemical analysis. We found that in normal tissues, human intelectin-1 was mainly secreted from gastrointestinal goblet cells along with mucus into the intestinal lumen, and it was also expressed, to a lesser extent, in mesothelial cells and urinary epithelial cells. Eighty-eight percent of epithelioid-type MPMs expressed intelectin-1, whereas sarcomatoid-type MPMs, biphasic MPMs, and poorly differentiated MPMs were rarely positive for intelectin-1. Intelectin-1 was not expressed in other cancers, except in mucus-producing adenocarcinoma. These results suggest that intelectin-1 is a better marker for epithelioid-type MPM than other mesothelioma markers because of its specificity and the simplicity of pathological assessment. Pleural intelectin-1 could be a useful diagnostic marker for MPM with applications in histopathological identification of MPM.

Objective: We divided pulmonary adenocarcinoma of ≤ 20 mm into air-containing and solid-density types based on a percentage reduction of the maximum tumor diameter in the mediastinal window image compared to the area in the lung window image on thin-section (TS) CT of ≥ 50% (air-containing type) and <50% (solid-density type). No relapse occurred in patients with air-containing type. The prognosis of solid-density type may be poor even when the tumor size is 20mm or smaller. We investigated whether CT findings for these tumors could serve as prognostic factors., Methods: The subjects were 105 patients with solid-density type pulmonary adenocarcinoma that was identified on TSCT and found to have a diameter of 20mm or smaller after surgical resection during the period from April 1997 to November 2004. Notches, air bronchogram, pleural retraction, spiculation, venous involvement, and ground glass opacity were examined on TSCT, and their associations with pathological findings (i.e., pleural invasion, lymphatic permeation, vascular invasion, lymph node metastasis, and Noguchi's classification) and relapse were investigated using chi-square test and Cox proportional hazards model., Results: The incidence of relapse was significantly higher in cases with notches. The incidence of notches increased with tumor growth and notches were frequent in Noguchi type D tumors, reflecting poorly differentiated adenocarcinoma. Lymphatic permeation and type D cases were independent factors associated with a poor prognosis using Cox proportional hazards model., Conclusions: TSCT findings may be useful for prediction of the prognosis of solid-density type pulmonary adenocarcinoma., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

Generally, adenocarcinomas with micropapillary pattern, featuring small papillary tufts lacking a central fibrovascular core, are thought to have poor prognosis. This pattern has been described in various organs. However, tumor cells with micropapillary pattern of lung adenocarcinoma are more often seen to float within alveolar spaces (aerogenous micropapillary pattern, AMP) than in fibrotic stroma like other organs (stromal micropapillary pattern, SMP) and SMP predominant lung adenocarcinoma (SMPPLA) has not been well described yet. We presented two cases of SMPPLA which were found in the last four years. Both the cases showed more than 50% of SMP in the tumor area. The majority of the stromal micropapillary clusters expressed MUC1 and epithelial membrane antigen along the outer surface of cell membrane. On the other hand, connective tissues surrounding stromal micropapillary clusters showed no reactivity for epithelial markers (thyroid transcription factor-1 and cytokeratin) or endothelial marker (D2-40 and CD34). It means clusters of SMP do not exist within air space or lymphatic or vessel lumens. The tumors with SMP often presented lymphatic permeation and vessel invasion, and intriguingly, one of the two cases showed metastasis to the mediastinal lymph node. Additionally, both the cases showed EGFR point mutations of exon 21. These results suggest that SMPPLA might be associated with poor prognosis and effective for EGFR tyrosine kinase inhibitors.

Introduction: Squamous cell carcinomas (SqCCs) of the lung can be divided into two types according to the location of primary site; one is central type and another is peripheral type. Many reports on the central type revealed the clinicopathological characteristics relating carcinogenesis, therapeutics and prognosis. On the other hand, those on the peripheral type are very a few and prognostic indicators of peripheral type have not been enough elucidated. The aim of this study was to clarify clinicopathological prognostic factors of small peripheral SqCCs of the lung 30 mm or less., Materials and Methods: We evaluated various 15 clinicopathological parameters in 81 patients with peripheral type SqCCs, which are defined as tumors located in or more peripheral from the third branching bronchus, measuring 30 mm or less in diameter., Results: Univariate analyses were performed using the log lank test and multivariate analyses using logistic regression model. As a result, two factors had a statistically significant influence on outcome of the patients in the univariate analysis; no relapse was observed in the patients with the ratio of alveolar space filling (ASF) area to tumor area of 70% or more and the maximum diameter of invasive area measuring 10 mm or less in size (P=0.0214, P=0.0373, respectively). Meanwhile, multivariate analysis showed that the ASF ratio of 70% or more significantly affected the outcome of the patients (P=0.0337), however the maximum diameter of invasive area did not (P=0.2136). We could not show the unfavorable prognostic factor contributory to tumor relapse., Conclusions: We have shown that the ASF ratio is a significantly favorable prognostic factor for small peripheral type. Especially the focally invasive tumors with ASF ratio of 70% or more might be classified as "a microinvasive carcinoma" of the peripheral SqCCs of the lung and tumors with ASF ratio 100% as noninvasive carcinoma., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

We report a case of papillary adenoma of the lung with a peculiar raw macroscopic feature at intraoperative consultation. A 52-year-old man was admitted to our hospital for the evaluation of a solitary peripheral nodule in the left lower lobe which was detected with chest CT. When we took staples off from the stump of the partially resected lung in order to make a frozen section diagnosis, granular fragments leaked out from the stump. On the cut surface, the dark reddish and granular tumor grew expansively; however, hemorrhage and necrosis were absent. Histologically, granular fragments were mainly composed of papillary structures, which consisted of a single layer of cuboidal to low columnar cells with round to oval nuclei lining the surface of the fibrovascular cores. Characteristically, papillary structures lacked elastic fibers in the stroma and were packed within an elastic fiber framework derived from pre-existing alveolar structures. We considered that high intratumoral pressure might have made the granular fragments leak out of the stump as soon as we removed staples and that peculiar macroscopic findings before fixation may be a diagnostic clue for papillary adenoma., (© 2011 The Authors. Pathology International © 2011 Japanese Society of Pathology and Blackwell Publishing Asia Pty Ltd.)

Background: Although gangliocytic paraganglioma (GP) has generally been regarded as a neuroendocrine tumor, its origin remains unclear. We therefore aimed to investigate the details of this disease by carefully analyzing and extracting common features of the disease as presented in selected publications., Methods: We searched for English and Japanese cases of GP using the PubMed and IgakuChuoZasshi databases on August 2010. We then extracted and sampled raw data from the selected publications and performed appropriate statistical analyses. Additionally, we evaluated the expression of hormone receptors based on our previously reported case., Results: 192 patients with GP were retrieved from the databases. Patient ages ranged from 15 y to 84 y (mean: 52.3 y). The gender ratio was 114:76 (male to female, 2 not reported). Maximum diameter of the tumors ranged from 5.5 mm to 100 mm (mean: 25.0 mm). The duodenum (90.1%, 173/192) was found to be the most common site of the disease. In 173 patients with duodenal GP, gastrointestinal bleeding (45.1%, 78/173) was found to be the most common symptom of the disease, followed by abdominal pain (42.8%, 74/173), and anemia (14.5%, 25/173). Rate of lymph node metastasis was 6.9% (12/173). Our statistical analysis indicated that significant differences were found for gender between GP within the submucosal layer and exceeding the submucosal layer. Furthermore, our immunohistochemical evaluation showed that both epithelioid and pancreatic islet cells showed positive reactivity for progesterone receptors., Conclusions: Our literature survey revealed that there were many more cases of GP exceeding the submucosal layer than were expected. Meanwhile, our statistical analyses and immunohistochemical evaluation supported the following two hypotheses. First, vertical growth of GP might be affected by progesterone exposure. Second, the origin of GP might be pancreatic islet cells. However, it is strongly suspected that our data have been affected by publication bias and to confirm these hypotheses, further investigation is required.

Background: Pulmonary tumor thrombotic microangiopathy (PTTM) has been known as a rare and serious cancer-related pulmonary complication. However, the pathogenesis and pathophysiology of this debilitating condition still remains obscure and no effective management was recommended. The present study aims to elucidate the pathophysiology of PTTM., Methods: Autopsy records were searched to extract cases of pulmonary tumor embolism induced by metastasis of gastric carcinoma in the Toho University Omori Medical Center from 2000 to 2006. And then, tissue sections of extracted cases were prepared for not only light microscopic observation but morphometric analysis with the use of selected PTTM cases., Results: Six autopsies involved PTTM and clinicopathological data of them were summarized. There was a significant negative association between pulmonary arterial diameter and stenosis rate in four cases. Although all cases showed an increase of stenosis rate to some degree, the degree of stenosis rate varied from case to case. Significant differences were found for average stenosis rate between the under 100 micrometer group or the 100 to 300 micrometer group and the 300 micrometer group in four cases. However, no significant differences were found for average stenosis rate between the under 100 micrometer group and the 100 to 300 micrometer group in all cases. Meanwhile, all cases showed positive reactivity for tissue factor (TF), five showed positive reactivity for vascular endothelial growth factor (VEGF), and three showed positive reactivity for osteopontin (OPN)., Conclusions: In the present study, we revealed that the degree of luminal narrowing of the pulmonary arteries varied from case to case, and our results suggested that pulmonary hypertension in PTTM occurs in selected cases which have a widespread pulmonary lesion with severe luminal narrowing in the smaller arteries. Furthermore, our immunohistochemical examination indicated that gastric carcinoma indicating PTTM shows a higher TF-positive rate than typical gastric carcinoma. However, it remains still obscuring whether gastric carcinoma indicating PTTM shows a higher VEGF or OPN-positive rate as determined by immunohistochemistry.

Background: Postoperative interstitial pneumonitis is a life-threatening complication after lung cancer surgery. We conducted this study to identify risk factors for postoperative interstitial pneumonitis in patients with no clinical evidence of interstitial lung disease., Methods: We retrospectively studied patients who underwent lung cancer resection. The characteristics of patients were analyzed by reviewing their clinical and surgical records and preoperative chest high-resolution computed tomographic scans. Postoperative interstitial pneumonitis was defined as acute severe hypoxemia accompanied by radiographic diffuse interstitial infiltrates of the lung with no apparent cause within a few weeks after surgery., Results: From 2002 through 2005, 651 patients were evaluated, operated on, and managed by the same team. Postoperative interstitial pneumonia developed in 7 patients (7 of 651, 1.1%). Five of these patients had local, but not diffuse, dorsal subpleural honeycombing occupying three or more segments in both lower lobes on high-resolution computed tomography (CT honeycombing). During the same period, 46 patients had CT honeycombing. The incidence of postoperative interstitial pneumonia was 10.9% (5 of 46) among patients with CT honeycombing and 0.3% (2 of 605) among those without CT honeycombing. Four of the 7 (57%) patients with postoperative interstitial pneumonia died of respiratory failure. Mortality among the patients who had postoperative interstitial pneumonia as well as CT honeycombing was 80% (4 of 5); in contrast, none of the patients without CT honeycombing died. Multivariate analyses showed that the presence of CT honeycombing and prolonged operation time were significant risk factors., Conclusions: Subpleural honeycombing on high-resolution computed tomography is a significant predictor of postoperative interstitial pneumonia in asymptomatic patients who undergo resection for lung cancer., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Study Objectives: Previously, we reported that small pulmonary adenocarcinomas (tumor diameter 20 mm or less) could be classified according to attenuation on thin-section CT (TS-CT) images as either 'air-containing type' or 'solid-density type' (Lung Cancer 2002;36:49-57). Air-containing type was defined as having areas where TOM (tumor opacity on mediastinal window images) was half or less than half the size of those noted on lung window images. Solid-density type was defined as having areas where TOM was greater than half the size of those noted on lung window images. Our findings indicated that there was no microscopic evidence of metastasis with air-type nor any relapses nor deaths, after resection. By contrast, patients with solid-density types demonstrated a poor prognosis. At this time, the histopathological characteristics of areas of TOM have not been fully investigated. The purpose of this study is to define the correlations between TOM and histopathological findings of small lung adenocarcinomas., Method: We retrospectively reviewed the records and CT scans of 134 patients, who had undergone surgical resection of peripheral adenocarcninomas. All tumor diameters were 20 mm or less in size. All 134 patients had undergone TS-CT prior to surgery. TS-CT Images were acquired by a model X-Vigor/Real or an Aquillion CT scanner (Toshiba Medical Systems). Thin-section images of tumors were obtained at 135 kVp at 250 mAs with 1-2 mm section thicknesses. All images were photographed using mediastinal (level, 40 HU; width, 400 HU) and lung (level, -600 HU; width, 1600 HU) window settings. We researched the histopathological components corresponding to the areas of TOM., Results: Areas of TOM demonstrated five possible histopathological findings; (1) collapse (C), (2) collapse with bronchioloalveolarcell carcinoma (CwB), (3) adenocarcinoma cells (Cells), (4) fibroblasts (F), and (5) mucus (M). Areas of TOM in air-containing type adenocarcinomas (52 cases) demonstrated predominantly C and/or CwB (C/CwB type, 44 cases). Areas of TOM in solid-density type adenocarcinomas (82 cases), in comparison, demonstrated predominantly Cells and/or Cells/F (Cell/F type, 67 cases). We noted a statistically significant difference between the histopathological findings of the areas of TOM of air-containing type and solid-density type tumors. The 39 cases of Cell/F type adenocarcinomas revealed microscopic evidence of metastasis (pleural involvement, vascular invasion, lymphatic permeation, or lymphnode metastasis). Whereas, no C/CwB type adenocarcinomas cases revealed any microscopic metastasis. The prognosis of C/CwB type after resection is better than for Cell/F type., Conclusion: We found that air-containing type adenocarcinomas demonstrated C/CwB type, and that solid-density type adenocarcinomas demonstrated Cell/F type. The histopathological findings of small pulmonary adenocarcinomas could be classified into three groups: C/CwB type, Cell/F type and M type. The prognosis of C/CwB type is better than for Cell/F type. Our results indicate that there are clear correlations between the areas of TOM and the histopathological components of small pulmonary adenocarcinomas. Therefore TS-CT findings are a useful aid in determining the best surgical methods., (Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.)

The fusion gene EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) was recently identified as a novel genetic alteration in non-small-cell lung cancer. The clinicopathological features of EML4-ALK-positive adenocarcinoma are reported to include its high incidence in young, non-smoking patients, tumors that show distinct solid or acinar growth patterns with or without signet-ring cell histology, and its mutually exclusive occurrence with mutations in EGFR and KRAS. However, the clinical findings have not been well described. Here, we report a case of EML4-ALK-positive lung adenocarcinoma that showed multiple metachronous lesions on the pleura and pulmonary field, suspected to be a recurrence of lung adenocarcinoma after a 20-year disease-free interval. The slow clinical course may be characteristic of EML4-ALK-positive lung adenocarcinoma. Therefore, long-term observation of patients with EML4-ALK-positive lung adenocarcinomas is required after surgery., (Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.)

Background: (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) is commonly used to distinguish benign from malignant lesion. Recently, maximum standardized uptake value (SUVmax) on FDG-PET has found to have prognostic value. We examined the relationship between SUVmax and proliferative activities as indicated by maximum diameter of tumor opacity on mediastinal-window images (TOM), Ki-67 index, and diameter of the pathological invasive area in lung adenocarcinomas 5mm was determined as 2.15 by ROC analysis, with sensitivity of 88.3% and specificity of 84.6%., Conclusions: SUVmax correlated significantly with Ki-67 index and diameter of the pathological invasive area. The present results suggest the potential role of FDG-PET in predicting adenocarcinomas with invasive characteristics., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Improved histological typing systems for thymic tumors and advances in induction and adjuvant therapy have created the need to reevaluate strategies for the management of thymoma. We retrospectively studied 73 patients with completely resected thymomas unassociated with myasthenia gravis. The World Health Organization (WHO) histologic classification, clinicopathological features and surgical outcomes were analyzed. Overall survival was 66.2% at 10 years, and the median survival time was 169 months. According to the Masaoka staging system, overall survival rates at 10 years were 94.7% in stage I, 76.1% in stage II, 30% in stage III and 0% in stage IV. In the WHO classification, overall survival rates at 10 years were 91.9% in types A and AB, 50.9% in type B2 and not achieved in type B3. The disease-free interval was slightly shorter in patients with B2 and B3 disease than in those with type A, AB and B1 disease. Advanced thymomas were significantly associated with type B2 and B3 (p<0.01). In stage III and IV disease, adjuvant or neoadjuvant therapy was associated with better survival as compared to no adjuvant therapy (p=0.07). On multivariate analysis, Masaoka stage III and IV disease and extended thymectomy indicated significant, negative and independent risk factors for survival (p<0.01). Masaoka stage I and II thymomas or WHO type A and AB thymomas have favorable prognoses and do not require postoperative adjuvant therapy. Patients with stage III and IV thymomas require additional therapy after surgery.

The effects of fucose-containing sulfated polysaccharides, ascophyllan and fucoidan, isolated from the brown alga Ascophyllum nodosum, on the growth of various cell lines (MDCK, Vero, PtK(1), CHO, HeLa, and XC) were investigated. In a colony formation assay, ascophyllan and fucoidan showed potent cytotoxic effects on Vero and XC cells, while other cell lines were relatively resistant to these polysaccharides. Almost no significant effects of these polysaccharides were observed in the cell lines tested using the Alamar blue cytotoxicity assay over 48 h with varying initial cell densities (2500-20,000 cells/well) in growth medium. Interestingly, a significant growth promoting effect of ascophyllan on MDCK cells was observed, whereas treatment with fucoidan showed growth suppressive effects on this cell line under the same experimental conditions. These results suggest that ascophyllan is distinguishable from fucoidan in terms of their bioactivities. This is the first report of the growth promoting effects of a sulfated fucan on a mammalian cell line under normal growth conditions., (2010 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

We describe a case of duodenal gangliocytic paraganglioma showing lymph node metastasis. A 61-year-old Japanese man underwent pylorus preserving pancreaticoduodenectomy to remove a tumor at the papilla of Vater. The section of the tumor extending from the mucosa to submucosa of the duodenum was sharply demarcated, solid, and white-yellowish. Neither necrosis nor hemorrhage was present. Histological examination confirmed the immunohistochemical identification of three components comprising epithelioid cells, spindle-shaped cells, and ganglion-like cells. Epithelioid cells showed positive reactivity for synaptophysin, somatostatin, and CD56. In contrast, spindle-shaped cells showed positive reactivity for S-100 protein, but not for synaptophysin, somatostatin or CD56. Furthermore, we found lymph node metastasis despite lack of bcl-2 and p53 expression. In addition to the rarity of the tumor, we are describing here the present case suggests the malignant potency of the tumor despite lack of acceptable prognostic indicators for neuroendocrine tumor.

Objective: We reported that adenocarcinomas with a bubblelike appearance (BLA) appear similar to old inflammation (J Comput Assist Tomogr 2009;33:42-48). The histopathological, clinical, and biological characteristics of adenocarcinomas with BLA need more investigation., Methods: We retrospectively reviewed the records of 26 patients who had undergone surgical resection between 1993 and 2008. We analyzed correlations between thin-section computed tomographic (TS-CT), histopathological, and clinical findings. We analyzed epidermal growth factor receptor and K-ras gene mutations., Results: The TS-CT findings are unique with one pattern that was the same in all the 26 cases: (1) polygonal with straight and concave margins, (2) slight peripheral ground-glass opacity areas, (3) 3 or more dilated air bronchograms, and (4) clear pleural indentations. The histopathological findings were identical with our TS-CT findings. The mean tumor doubling time was 1165 days. Epidermal growth factor receptor mutations were observed in 17 cases. There were no K-ras mutations. After resection, the 5-year survival rate is 100%., Conclusion: The adenocarcinomas with BLA have unique TS-CT, histopathological, and clinical findings.

Introduction: In our limited resection trial of pulmonary peripheral ground-glass opacity (GGO) lesions from 1998 to 2002, limited resection of Noguchi type A and B carcinomas seemed to have a positive outcome. However, recently three of the 24 patients, with mixed GGO lesions intraoperatively diagnosed as type B, developed a solid lesion at the cut-end scar., Methods: Medical records and radiology and pathology findings of the three patients were reviewed. We also analyzed epidermal growth factor receptor gene mutations when possible., Results: Radiologically, these three second tumors were clearly cut-end scar area recurrences. However, other pathologic and mutation findings suggest metachronous primary cancers developed in Case 1, cut-end recurrence in Case 2, and needle biopsy implantation in Case 3. It is difficult to definitively conclude whether the second tumors were recurrences or metachronous primaries., Conclusions: These second tumors have convinced us that our initial caution in concluding GGO lesions can be cured by limited resection was very appropriate. The recurrences definitely indicate that continuing follow-up attention for more than 5 years is needed after limited resection even for GGO bronchioloalveolar carcinomas.

The ability to resist anoikis is critical for carcinoma cells to metastasize. Although several lung adenocarcinoma cell lines were shown to repress anoikis through the activation of Src, it remains unknown whether Src actually plays a crucial role in anoikis resistance in lung adenocarcinoma tissues. We examined 20 human lung adenocarcinoma tissues with lymphatic permeation and nine cell lines to investigate whether intralymphatic floating carcinoma cells in the tissues, used as an in vivo model of anoikis resistance, actually suppressed anoikis and whether cell lines in suspension culture, an in vitro model of anoikis resistance, survived through Src activation. We observed that the intralymphatic carcinoma cells aggregated tightly to form nests expressing E-cadherin and phosphorylated Src (p-Src). The apoptotic indices of these cells were comparable to those of extracellular matrix adhesive cells in all tissues, indicating that the intralymphatic cells actually evaded anoikis. Next, we found that the nine cell lines in suspension aggregated loosely (five cell lines) or tightly (four cell lines), and all cells resisted anoikis. Upon detachment, four cell lines (LC-KJ, HCC827, H1650, and H1975) formed compact spheroids that expressed E-cadherin and p-Src. The spheroids were similar to intralymphatic tumour nests and were thus considered to be a suitable model of the nests. The spheroids of the four cell lines underwent apoptosis after treatment with the Src/Abl/Kit inhibitor PP1 or Src/Abl inhibitor bosutinib. On the other hand, the Abl/Kit inhibitor imatinib did not affect cell growth or apoptosis in the four types of spheroids. These results indicate that Src, but not Abl or Kit, plays an essential role in the development of anoikis resistance in lung adenocarcinomas.

We prospectively investigated the outcome of personalized second-line treatment based on epidermal growth factor receptor (EGFR) gene status in previously treated patients with advanced non-small cell lung cancer (NSCLC). EGFR gene status was evaluable by LH-mobility shift assay in registered patients. Gefitinib (Gef) treatment was recommended if the patients had EGFR mutation (mEGFR). EGFR gene status was evaluable in 146 patients. Seventy-four of the patients were female, 82 were smokers, and 122 had adenocarcinoma. Overall, 67 patients had mEGFR and received Gef. Forty-nine of 79 patients with wild-type EGFR (wEGFR) received other chemotherapies or radiation but 30 selected best supportive care only as a second-line treatment. Patients with mEGFR survived significantly longer than patients with wEGFR (p < 0.0001). However, the survival of patients who received other forms of chemotherapy was not different from that of patients who received best supportive care only as a second-line treatment in patients with wEGFR. Examination of the association between overall survival after first-line chemotherapy and prognostic factors using multivariate regression analysis showed that mEGFR and response to first-line chemotherapy were independent factors (p = 0.003 and p = 0.003, respectively). Selection of second-line treatment according to EGFR gene status may be useful for patients with NSCLC.

Diagnostic criteria to identify small lung adenocarcinomas that relapse after resection have yet to be established. For this purpose, we developed a mathematical logistic model in the present study. We collected data for patients with lung adenocarcinoma of 2 cm or less in size: the original cohort comprised 28 men and 25 women and the validation cohort comprised 11 men. By entering five clinicopathological factors (vascular invasion, lymphatic permeation, histological subtype, papillary carcinoma component, and smoking status) into the logistic model, we calculated a predictive function for relapse after surgery. The obtained predictive function accurately classified the patients into a recurrence or non-recurrence group: the overall accuracy of the predictive model for recurrence established from the male patients in the original cohort was 86%. Our predictive model is, however, currently limited to male patients only, because the original cohort included only one female patient with relapse. By applying the logistic model to the validation cohort, six patients were classified into a recurrence group and the other five into a non-recurrence group: four of the six patients in a recurrence group had relapsed, while all five patients in the non-recurrence group were well during their follow-up periods. Although the predictive ability of the logistic model did not reach a statistical significance (P=0.0606), nine of the 11 (82%) patients in the validation cohort were correctly classified. Consequently, using a logistic predictive model consisting of the five clinicopathological factors might enable us to predict the recurrence of resected small-sized lung adenocarcinomas in male patients.

Effects of an alginate oligosaccharide mixture (AOM) on Nannochloropsis oculata, a unicellular marine microalga, were investigated. The growth of N. oculata was significantly promoted by AOM in a concentration-dependent manner. The maximum effect was attained at 20 mg/ml, at which the growth rate of the alga became nearly 5 times higher than that of control without AOM. The growth-promoting effect of AOM decreased slightly at 40 mg/ml. Furthermore, the algicidal effect of Cu(2+) was profoundly alleviated by the addition of AOM. These results suggest that AOM is useful for promoting and/or improving the growth of N. oculata.

Objective: To study the initial findings of lung adenocarcinoma revealed by computed tomography (CT) scanning and observe tumor progression and elucidate appropriate follow-up schedule of tumor diagnosis via CT findings of suspected lung adenocarcinoma., Method: We studied 59 patients who had undergone CT scanning twice or more at intervals of 3 months or longer before surgery. We evaluated the initial CT findings as well as all subsequent changes. The rate of tumor growth was estimated by tumor volume doubling time, using the original method of Schwartz. The histological classifications were evaluated according to the criteria of Noguchi et al (Cancer 1995;75:2844-2852)., Result: The initial appearances of lung adenocarcinoma were divided into 4 types: (1) ground-glass opacity-like lesions, (2) bubble-like appearance, (3) small nodules, and (4) scar-like lesions. Ground-glass opacity-like lesions tended to increase in size over the years, with solid parts appearing in some lesions during follow-up examinations. Bubble-like appearance displayed characteristic CT findings and tended to increase over the years from the time of initial diagnosis, and we therefore tended to consider them as old inflammatory lesions. Small nodules tended to increase in size over the months more rapidly than in other types. Scar-like lesions tended to exist mainly in the lungs already damaged by lung fibrosis and/or emphysema and therefore were difficult to detect on initial CT scans., Conclusion: We categorized 4 types of initial findings of lung adenocarcinomas detected by CT. We determined that each type of lesion had its own unique characteristic growth patterns and required varying follow-up periods.

Pleomorphic carcinoma (PC) of the lung is rare, and it is classified as a subtype of sarcomatoid carcinoma of the lung in the World Health Organization histologic classification of lung tumors. In this study, 70 cases of PC surgically resected were reviewed to identify its clinicopathologic characteristics. There were 57 men and 13 women, and their mean age was 66 years (range: 29 to 80 y). Sixty-eight tumors contained identifiable epithelial components, and the other 2 consisted of spindle cells and giant cells alone. An adenocarcinoma component was found in 34 cases, a squamous cell carcinoma component in 13, and a large cell carcinoma component in 40. The overall survival rate and disease-free survival rate were 36.6% and 40.7%, respectively, and both rates were significantly lower than for other nonsmall cell lung carcinomas. When the PC patients were divided into 3 groups according to the predominant epithelial component, an adenocarcinoma group, squamous cell carcinoma group, and large cell carcinoma group, there were no significant differences in the overall survival rate and median survival time between the 3 groups. Univariate analysis revealed that advanced stage (stage III), mediastinal lymph node metastasis, lymphatic permeation, and histologically diagnosed massive coagulation necrosis (>25% of the tumor) predicted poorer disease-free survival. Multivariate analysis showed that massive necrosis alone was an independent prognostic factor. We concluded that PC should be considered as an aggressive disease and massive necrosis should be routinely reported and used as a factor in clinical assessments.