Achiral Molecular Recognition of Substituted Aniline Position Isomers by Crown Ether Type Chiral Stationary Phase.

To understand the selectivity of the crown ether type chiral stationary phase (CSP), the retention selectivity for aniline and the positional isomers of substituted anilines were studied. In various substituted isomers, except nitroaniline, a remarkable decrease of retention due to steric hindrance was observed for the 2-substituted isomer. To determine the detailed molecular recognition mechanism, quantum chemical calculations were performed for the aggregates between the crown ether and the anilines. The results suggested that the 20-Crown-6, which includes a phenyl-substituted 1,1'-binaphthyl moiety, interacts with alkyl and aryl amines in an unconventional form different from the proposed one for 18-Crown-6.

Thin-section computed tomography findings of lung adenocarcinoma with inherent metastatic potential.

PURPOSE: The solid component of lung ground-glass nodules on thin-section computed tomography (TSCT) reflects cancer cell progression and invasiveness. The purpose of this study was to clarify the cut-off value of preoperative TSCT findings in treating a lesion suspected of being adenocarcinoma and to recognize the timing of surgical resection for lung nodules. METHODS: We reevaluated the TSCT findings in 392 patients with clinical stage IA lung adenocarcinoma who underwent surgical resection between 2003 and 2007. We identified the clinical parameters that were most useful for predicting recurrence and identified a cut-off level for each parameter. RESULTS: Recurrence was observed in 75 (19 %) of 392 patients (median follow-up: 7 years). The size of internal consolidation of a lung nodule (SCL) and the ratio of the SCL to the maximum tumor diameter (C/T ratio) were extracted as independent factors that predicted recurrence. Only 1 (0.3 %) patient each with a lung nodule C/T ratio ≤0.5 and SCL ≤10 mm recurred. These conditions were associated with a significantly better overall survival and recurrence-free survival. CONCLUSION: In patients with clinical stage I lung adenocarcinoma with a C/T ratio ≤0.5 and/or SCL ≤10 mm on TSCT, surgery is extremely likely to achieve a cure.

Podoplanin-expressing cancer-associated fibroblasts lead and enhance the local invasion of cancer cells in lung adenocarcinoma.

Cancer-associated fibroblasts (CAFs) communicate with cancer cells and play important roles in cancer invasion. We previously reported that local invasion of cancer cells was frequently observed in lung adenocarcinoma patients with podoplanin (PDPN)-expressing CAFs. However, the underlying mechanisms of this phenomenon have remained unclear. In this study, we established a novel collagen invasion assay model in which cancer cells and CAFs were cocultured; we analyzed the mechanisms governing how cancer cell invasion was promoted by PDPN(+)CAFs. By observing the dynamic movement of both CAFs and cancer cells in the collagen matrix, we found that PDPN(+)CAFs invaded the matrix to a greater extent, with more cancer cells invading within the "tracks" created by the CAFs, compared with control CAFs. The knockdown of PDPN in CAFs decreased the invasion of both the CAFs and the cancer cells. PDPN(+)CAFs displayed a higher RhoA activity and treatment with a ROCK inhibitor cancelled the increased invasion ability of PDPN(+)CAFs and subsequently decreased the number of invaded cancer cells. After intravenous injection in the mouse tail vein, PDPN(+)CAFs invaded and promoted cancer cell invasion into the lung parenchyma, compared with control CAFs. Among the patients with lung adenocarcinoma, we observed some cases with PDPN(+)CAFs at the invasive front of the tumor. These cases predominantly exhibited pleural invasion of cancer cells, known as pathological invasiveness. Our results indicated that PDPN(+)CAFs were tumor-promoting CAFs that lead and enhance the local invasion of cancer cells, suggesting that the invasion activity of CAFs themselves could be rate-determining for cancer cell invasion.

Postoperative radiotherapy is effective for thymic carcinoma but not for thymoma in stage II and III thymic epithelial tumors: the Japanese Association for Research on the Thymus Database Study.

BACKGROUND: The efficacy of postoperative radiotherapy (PORT) for thymic epithelial tumors is still controversial. Using the Japanese Association for Research on the Thymus (JART) database, this study was aimed at clarifying the efficacy of PORT for Masaoka stage II and III thymic carcinoma and thymoma. METHODS: The JART database registered the records of 2835 patients collected from 32 Japanese institutions from 1991 to 2010. Thymic carcinoma and thymoma at stage II or III were extracted. The efficacy of PORT with respect to relapse-free survival (RFS) and overall survival (OS) was evaluated with the Kaplan-Meier method and Cox regression analysis. RESULTS: There were 1265 patients in all: 155 thymic carcinoma cases (12.3%) and 1110 thymoma cases (87.7%). Eight hundred ninety-five (70.8%) were at stage II, and 370 (29.2%) were at stage III. Four hundred three cases (31.9%) underwent PORT. PORT for stage II and III thymic carcinoma was associated with increasing RFS (hazard ratio, 0.48; 95% confidence interval, 0.30-0.78; P = .003) but was not associated with OS (hazard ratio, 0.94; 95% confidence interval, 0.51-1.75; P = .536). PORT for stage II and III thymoma was not associated with RFS or OS (P = .350). A subgroup analysis of stage III thymoma showed no factor associated with the efficacy of PORT. CONCLUSIONS: In this study, PORT did not increase RFS or OS for stage II or III thymoma but increased RFS for stage II and III thymic carcinoma.

Surgical Outcomes of Lung Cancer in Patients with Combined Pulmonary Fibrosis and Emphysema.

PURPOSE: Lung cancers in patients with combined pulmonary fibrosis and emphysema (CPFE) are increasing. Objective of this investigation was to identify which clinicopathological features significantly affected surgical outcome of these patients. METHODS: Among 4313 patients with primary lung cancers who underwent surgery between January 2008 and December 2010 in nine institutions in Japan, 265 had CPFE. We retrospectively compared 2176 and 157 patients without and with CPFE, respectively, and further analyzed 233 patients with CPFE whose detailed information was available. CPFE was defined as upper lobe emphysema and lower lobe fibrosis. RESULTS: The rates of postoperative morbidity and mortality were higher and overall survival was poorer in patients with, than without CPFE. Among 233 patients with CPFE, the median values of %VC and FEV1.0 % were 98.4 and 71.5 %, respectively. The histological types comprised 111 squamous cell carcinomas and 84 adenocarcinomas. Surgical procedures included 203 standard lobectomies/pneumonectomies and 30 lesser resections. Five patients (2 %) developed postoperative acute exacerbation of interstitial pneumonia. Six and 15 patients (3 and 6 %) died within 30- and 90-postoperative-day, respectively. Cancer was the cause of death at 90-day in only one patient. The 3-year overall survival rate for all patients was 58.4 %. Multivariate analysis showed that male sex, advanced age, advanced clinical stage and lower %VC predict a poor prognosis. CONCLUSIONS: Patients with lung cancer and CPFE had poor prognoses regardless of apparently good pulmonary function and showed quite high postoperative mortality rates. A lower %VC that might reflect the severity of pulmonary fibrosis was associated with poor prognoses.

Limited resection trial for pulmonary ground-glass opacity nodules: case selection based on high-resolution computed tomography-interim results.

OBJECTIVE: Our previous trial for small ground-glass opacity nodule on high-resolution computed tomography suggested all these cancers might have been radically managed with limited resection. Good correlation between radiologic and pathologic findings in early lung adenocarcinomas has been reported. We aimed to confirm limited resection efficacy as radical surgery in patients with high-resolution computed tomography-indicated minimally invasive lung cancer. The purpose of this interim analysis is to report the details of the patient and nodule characteristics, intraoperative cytology capability as a negative margin indicator, and patient outcome with the median follow-up period of 7 years and 4 months. METHODS: Enrollment required patients with a tumor ≤2 cm, diagnosed or suspected as a cT1N0M0 carcinoma in the lung periphery and depicted on high-resolution computed tomography as a sub-solid nodule with tumor disappearance ratio ≥0.5. We performed a wedge or segmental resection as appropriate. The primary endpoint is 10 year local recurrence-free survival rate. RESULTS: This study started in November 2003, and 101 patients were enrolled as of November 2009. Of them, 95 were eligible for analysis. There were 38 men and 57 women, aged 30-75, averaging 62 years. Tumor sizes ranged from 7 to 20 mm on computed tomography, averaging 15 mm. There were 11 Noguchi type A tumors, 54 type B tumors, 24 type C tumors, one malignant lymphoma and 5 non-cancerous lesions. All cancers showed no vessel invasion. With a median follow-up period of 88 months, there have been no recurrences. CONCLUSION: So far, high-resolution computed tomography appears to predict non- or minimally invasive ground-glass opacity lung cancers with high reliability, warranting limited resection as curative surgery in this cohort.

Patterns and treatment of recurrence following pulmonary resection for colorectal metastases.

BACKGROUND: Pulmonary resection is the best therapeutic option for lung metastases from colorectal cancer (CRC) today. However, recurrences are frequent following pulmonary resection. We aimed to evaluate the recurrence pattern and treatment of initial pulmonary resection for metastases from CRC. METHODS: Data from 76 patients with recurrence after curative resection of primary CRC and lung metastases were reviewed. The primary outcome measure was overall survival (OS), defined as the interval between the date of recurrence after pulmonary resection and the date of death or last follow-up. Cox regression analyses were performed to identify the factors associated with OS. RESULTS: Recurrence sites after initial pulmonary resection were lung (n = 37), liver (n = 12), others (n = 11), and multiple (n = 16). Treatments for recurrence included surgery (n = 35), chemotherapy (n = 37), and palliative care (n = 4). Of 35 patients who underwent surgery, 22 had pulmonary resection, and 11 had hepatic resection, and 2 had other resection. The 3-year OS was 84.1 % for surgery, 38.9 % for chemotherapy, and 0 % for palliative care, respectively (p < 0.001). In the surgery group, there was no difference in survival between surgical treatments for pulmonary and hepatic recurrences (p = 0.503). Cox regression analyses identified three factors: disease-free interval (DFI) (HR 1.99, 95 % CI 1.03-3.83), surgery (HR 0.30, 95 % CI 0.12-0.72), and recurrence site (lung: HR 0.10, 95 % CI 0.04-0.28, liver: HR 0.08, 95 % CI 0.02-0.31). CONCLUSIONS: The most common recurrence site after resection of lung metastases was the lung. Although the relapse rate is high, surgery for isolated recurrences is a promising strategy, especially for patients with long DFI.

Immunophenotypic features of metastatic lymph node tumors to predict recurrence in N2 lung squamous cell carcinoma.

Patients with mediastinal lymph node metastasis (N2) in squamous cell carcinoma (SqCC) of the lung have poor prognosis after surgical resection of the primary tumor. The aim of this study was to clarify predictive factors of the recurrence of pathological lung SqCC with N2 focusing on the biological characteristics of both cancer cells and cancer-associated fibroblasts (CAFs) in primary and metastatic lymph node tumors. We selected 64 patients with pathological primary lung N2 SqCC who underwent surgical complete resection and investigated the expressions of four epithelial-mesenchymal transition-related markers (caveolin, clusterin, E-cadherin, ZEB2), three cancer stem cell-related markers (ALDH-1, CD44 variant6, podoplanin) of cancer cells, and four markers of CAFs (caveolin, CD90, clusterin, podoplanin) in both primary and matched metastatic lymph node tumors in the N2 area. In the primary tumors, the expressions of all the examined molecules were not related to recurrence. However, in the metastatic lymph node tumors, high clusterin and ZEB2 expressions in the cancer cells and high podoplanin expression in the CAFs were significantly correlated with recurrence (P = 0.03, 0.04, and 0.007, respectively). In a multivariate analysis, only podoplanin expression in the CAFs in metastatic lymph node tumors was identified as a significantly independent predictive factor of recurrence (P = 0.03). Our study indicated that the immunophenotypes of both cancer cells and CAFs in metastatic lymph node tumors, but not primary tumors, provide useful information for predicting the recurrence of pathological N2 lung SqCC.

Prognostic impact of microscopic vessel invasion and visceral pleural invasion in non-small cell lung cancer: a retrospective analysis of 2657 patients.

OBJECTIVE: We aimed to assess the prognostic significance of microscopic vessel invasion (MVI) and visceral pleural invasion (VPI) in non-small cell lung cancer (NSCLC). BACKGROUND: VPI is included in the current tumor-node-metastasis (TNM) classification in NSCLC; however, MVI is not incorporated in TNM classification. METHODS: From August 1992 to December 2009, 2657 consecutive patients with pathological T1-4N0-2M0 NSCLC underwent complete resection. In addition to conventional staging factors, we evaluated MVI histologically and analyzed its significance in NSCLC recurrence prognosis. The recurrence-free period in several NSCLC subgroups was analyzed using the Kaplan-Meier method and Cox regression analysis. RESULTS: The proportion of patients with a 5-year recurrence-free period was 52.6% and 87.5%, respectively, in those with and without MVI (P < 0.001). Multivariate analysis showed that MVI, similarly to VPI, was found to be an independently significant predictor of recurrence [hazard ratio (HR): 2.78]. In particular, MVI and VPI were the 2 strongest significant independent predictors of recurrence in 1601 patients with pathological stage I disease treated without adjuvant chemotherapy (HR: 2.74 and 1.84, respectively). In each T subgroup analysis, evident and significant separation of the recurrence-free proportion curves were observed among the 3 groups (VPI and MVI absent, VPI or MVI present, and VPI and MVI present). CONCLUSIONS: This study demonstrated that MVI was a significant independent risk factor for recurrence in patients with a resected T1-4N0-2M0 NSCLC. Further data on MVI prognostic impact should be collected for the next revision of the TNM staging system.

Precision synthesis of bio-based acrylic thermoplastic elastomer by RAFT polymerization of itaconic acid derivatives.

Bio-based polymer materials from renewable resources have recently become a growing research focus. Herein, a novel thermoplastic elastomer is developed via controlled/living radical polymerization of plant-derived itaconic acid derivatives, which are some of the most abundant renewable acrylic monomers obtained via the fermentation of starch. The reversible addition-fragmentation chain-transfer (RAFT) polymerizations of itaconic acid imides, such as N-phenylitaconimide and N-(p-tolyl)itaconimide, and itaconic acid esters, such as di-n-butyl itaconate and bis(2-ethylhexyl) itaconate, are examined using a series of RAFT agents to afford well-defined polymers. The number-average molecular weights of these polymers increase with the monomer conversion while retaining relatively narrow molecular weight distributions. Based on the successful controlled/living polymerization, sequential block copolymerization is subsequently investigated using mono- and di-functional RAFT agents to produce block copolymers with soft poly(itaconate) and hard poly(itaconimide) segments. The properties of the obtained triblock copolymer are evaluated as bio-based acrylic thermoplastic elastomers.

Surgical outcomes after initial surgery for clinical single-station N2 non-small-cell lung cancer.

OBJECTIVE: Single-station N2 (Stage IIIA) non-small-cell lung cancer has been reported to have a relatively favorable prognosis after surgery. However, most previous studies examined surgical outcomes in N2 disease by pathologic nodal status but not by clinical nodal status. The objective of this study was to clarify the surgical outcomes in clinical single-station N2 non-small-cell lung cancer patients. METHODS: A total of 125 consecutive patients with clinical single-station N2 non-small-cell lung cancer were treated in our institution between 1992 and 2008. Among them, 97 (78%) patients underwent thoracotomy, and were included in this retrospective study. We defined clinical single-station N2 node as a node measuring 1-2 cm in a single mediastinal station observed on contrast-enhanced computed tomography. The median follow-up period was 5.9 years (range, 1.8-12.6). RESULTS: Eighty-eight (91%) patients underwent lung resection. Of them, 17 (19%) had true (pathologic) single-station N2 disease. Twenty-eight (32%) had pathologic multistation N2 and 43 (49%) had pN0-1 disease with favorable prognoses. The overall survival of the clinical single-station N2/pathologic N2 patients after initial surgery was unsatisfactory with a 5-year overall survival of 23.6%, but their prognoses were heterogeneous. True single-station pathologic N2 status (hazard ratio = 0.35, P = 0.008) and negative subcarinal node status (hazard ratio = 0.34, P = 0.022) were independent favorable prognostic factors after initial resection for clinical single-station N2/ pathologic N2 patients. The patients with both factors revealed a relatively favorable 5-year overall survival of 43.8%. CONCLUSION: Clinical single-station N2 status does not always correspond with pathologic true N2 status. From a prognostic point of view, initial surgery for clinical single-station N2 patients is indicated if their true single-station N2 status and negative subcarinal involvement are preoperatively confirmed.

Prognosis of lung cancer patients with a past history of colorectal cancer.

OBJECTIVES: The prognosis in lung cancer patients with a prior history of extrapulmonary cancer is controversial. In the current multicenter joint research in Japan, we focused on the relationship between a history of colorectal cancer and its prognostic impact in patients with subsequent lung cancer. METHODS: Between 2000 and 2013, we designed a retrospective multicenter study at three institutes in Japan to evaluate the prognostic factors in lung cancer patients with a previous surgery for colorectal cancer. RESULTS: The cohorts consisted of 123/4431 lung cancer patients with/without a previous history of surgery for colorectal cancer. The median follow-up period was 6.1 years after lung cancer surgery. The 5-year overall survival in lung cancer patients with/without colorectal cancer was not significantly different, regardless of the stage of lung cancer (overall: 71.3 versus 74.7%, P = 0.1426; Stage I lung cancer: 83.3 versus 84.8%, P = 0.3779; Stage II or more lung cancer: 47.7 versus 54.4%, P = 0.1445). Based on multivariate Cox regression analysis in 4554 lung cancer patients, a past history of colorectal cancer was not a significant prognostic factor (P = 0.5335). Among the 123 lung cancer patients with colorectal cancer, age and absence of adjuvant chemotherapy for colorectal cancer were significant prognostic factors based on multivariate analysis (P = 0.0001 and 0.0236). Furthermore, there was no difference in the overall survival of lung cancer patients according to the stage of colorectal cancer (Stage I: 74.7%; Stage II/III: 66.5%, P = 0.7239). CONCLUSIONS: A history of antecedent colorectal cancer did not contribute to the prognosis in patients with subsequent lung cancers.

Tumor-size-based morphological features of metastatic lymph node tumors from primary lung adenocarcinoma.

Most primary lung adenocarcinomas show histological diversity, however, histological diversity in the metastatic lymph node tumors (LNT) is not well defined. The aim of this study was to explore the histological characteristics of the metastatic LNT based on their sizes. We analyzed 163 primary tumors and 509 metastatic LNTs. When the primary tumor showed papillary-predominant subtype, the most frequent histological subtype in the metastatic LNT that were ≤2 mm in diameter was solid subtype (49%), followed by papillary subtype (35%); on the other hand, in the metastatic LNT measuring >2 mm in size, the frequency of tumors showing papillary-predominant subtype increased significantly to 52% (P = 0.04). When the primary tumor showed acinar-predominant subtype, the most predominant subtype in the ≤2 mm metastatic LN tumors was acinar subtype (55%), followed by solid subtype (40%), with the frequency of acinar subtype increasing significantly to 76% in the metastatic LNT that were >2 mm in diameter (P = 0.04). These results indicate that solid subtype is the characteristic histological subtype in the early phase of the LN metastatic process, and that as the metastatic LNT grow larger, they develop morphological features resembling those in the primary tumor.

Stereospecific cyclic poly(methyl methacrylate) and its topology- guided hierarchically controlled supramolecular assemblies.

In this study, the stereocomplexation between a novel stereospecific cyclic vinyl polymer, that is, cyclic syndiotactic poly(methyl methacrylate) (st-PMMA), with the complementary linear isotactic (it-) PMMA was investigated. Surprising new insight into the effects of the topology (i.e., end groups), size, and tacticity of the assembling components on stereocomplex formation was obtained. Characterization of the stereocomplexes revealed that the self-assembly of cyclic st-PMMAs and linear it-PMMAs resulted in the formation of an unprecedented "polypseudorotaxane-type" supramolecular assembly. This stereocomplex exhibited remarkably different physical properties as compared to the conventional PMMA triple-helix stereocomplex as a result of the restricted topology imposed by the cyclic st-PMMA assembling component.

Forkhead box P3 regulatory T cells coexisting with cancer associated fibroblasts are correlated with a poor outcome in lung adenocarcinoma.

Recently, an association between tumor infiltrating Forkhead box P3 regulatory T cells (Treg ) and an unfavorable prognosis has been clinically shown in some cancers, but the mechanism of Treg induction in the tumor microenvironment remains uncertain. The aims of the present study were to examine the relationship between Treg and patient outcome and to investigate whether Treg induction is influenced by the characteristics of cancer-associated fibroblasts (CAF) in lung adenocarcinoma. The numbers of Treg in both the tumor stroma and the tumor nest were counted in 200 consecutive pathological stage I lung invasive adenocarcinoma specimens. To examine whether the characteristics of CAF influence Treg induction, we selected and cultured CAF from low Treg and high Treg adenocarcinoma. The number of Treg was much higher in the stroma than in the nest (P < 0.01). Patients with high Treg had a significantly poorer prognosis than those with low Treg (overall survival: P = 0.03; recurrence-free survival: P = 0.02; 5-year overall survival: 85.4% vs 93.0%). Compared with the CAF from low Treg adenocarcinoma, culture supernatant of the CAF from high Treg adenocarcinoma induced more Treg (P = 0.01). Also, CAF from high Treg adenocarcinoma expressed significantly higher mRNA levels of transforming growth factor-ß (P = 0.01) and vascular endothelial growth factor (P = 0.01), both of which are involved in Treg induction. Our studies suggest the possibility that CAF expressing immunoregulatory cytokines may induce Treg in the stroma, creating a tumor-promoting microenvironment in lung adenocarcinoma that leads to a poor outcome.

Identification of intravascular tumor microenvironment features predicting the recurrence of pathological stage I lung adenocarcinoma.

Histological vascular invasion (VI) by tumors is reportedly a risk factor influencing recurrence or survival after surgical treatment; however, few studies have evaluated which VI features affect recurrence or survival. The objective of this study was to evaluate how VI features affect recurrence in lung adenocarcinoma patients. We selected 106 patients with pathological stage I lung adenocarcinoma who showed VI and examined the properties of intravascular tumors associated with recurrence. First we investigated the relationship between the frequency of VI in a histological cross-section and the incidence of recurrence; however, a significant impact was not observed. Microscopic examination revealed the intravascular tumors were composed of not only cancer cells but also non-cancerous cells. To examine whether the characteristics of intravascular cancer cells and/or non-cancerous cells have prognostic value, we examined the expression levels of epithelial-mesenchymal transition-related markers in cancer cells and the numbers of infiltrating non-cancerous cells, including macrophages, endothelial cells, and fibroblasts. High levels of E-cadherin expression in the intravascular cancer cells were significant predictors of recurrence (P = 0.004), whereas the expressions of CD44, CD44 variant 6, and vimentin were not. Large numbers of intravascular CD204(+) macrophages (P = 0.016), CD34(+) microvessels (P = 0.007), and α-smooth muscle actin (+) fibroblasts (P = 0.033) were also significant predictors of recurrence. Our results indicated VI with abundant stromal cell infiltrates might be a predictor of recurrence and suggested the tumor microenvironment created by cancer cells and stromal cells within the blood vessel may play an important role during the metastatic process.

Impaired mental health among the bereaved spouses of cancer patients.

OBJECTIVE: Few cancer physicians routinely provide bereavement follow-up in clinical practice. The purpose of this study was to identify the prevalence of impaired mental health among the bereaved spouses over several years and explore the indicators for early detection of high-risk spouses during end-of life (EOL) care. METHODS: A cross-sectional mail survey was conducted for the bereaved spouses of patients who had died at the National Cancer Center Hospital of Japan. Bereaved spouses with potential psychiatric disorders were identified by the cut-off score of the 28-item General Health Questionnaire. Associated factors of potential psychiatric disorders were explored by logistic regression analysis. RESULTS: A total of 821 spouses experiencing bereavement from 7 months to 7 years returned the questionnaires. Overall mean prevalence of potential psychiatric disorders was 44% (360/821). Bereaved spouses 'under 55 years' (71%) or '2 years after bereavement' (59%) revealed a significantly higher prevalence (p < 0.01). Associated factors during EOL care were several characteristics such as 'spouses' history of psychiatric disorder (odds ratio (OR) = 3.19), 'patients' with stomach cancer (OR = 1.87), and 'patients' using psychiatric consultation services (OR = 1.52) as well as spouses' dissatisfaction with EOL care such as 'physicians' treatment of physical symptoms' (OR = 3.44) and 'time spent communicating with patients' (OR = 1.55). CONCLUSIONS: Nearly half the bereaved spouses showed potential psychiatric disorders even 7 years after bereavement. Patients' psychological distress, spouses' history of psychiatric disorder, and dissatisfaction with EOL care were indicators of high-risk spouses.

Clinicopathological characteristics of EGFR mutated adenosquamous carcinoma of the lung.

Adenosquamous carcinoma of the lung (Ad-Sq) is an uncommon subtype with poor prognosis. We analyzed the clinicopathological characteristics of Ad-Sq, focusing the correlation between Epidermal Growth Factor Receptor (EGFR) mutation and clinicopathological factors. A total of 67 cases were selected from September 1992 to May 2011. EGFR mutational analysis (n = 59) was performed by direct sequence. We also performed immunohistochemical staining for EGFR mutated cases using the two mutation-specific antibodies for deletion and L858R. Postoperative 3-year survival rate of Ad-Sq was 58.7%, statistically worse in comparison with adenocarcinoma (58.7% vs. 78.1%, P = 0.038). Twenty-four percent (14/59) were positive for EGFR mutations. Patients who had never been smokers and who were lymphatic permeation positive were seen more frequently in the mutation positive group (P = 0.035, 0.027, respectively). Moreover, the EGFR mutated group tended to have a more positive prognosis than negative. Focusing on the pathological features, the lepidic growth pattern was more frequently seen in the positive group (P = 0.018). Immunoreactivity for the DEL-specific and L858-specific antibody were observed in both adenocarcinoma and squamous cell carcinoma components. Our study demonstrated that EGFR mutated Ad-Sq had similar clinicopathological features as EGFR mutated adenocarcinoma.

Cancer-initiating cell marker-positive cells generate metastatic tumors that recapitulate the histology of the primary tumors.

Cancer-initiating cell (CIC) hypothesis suggests that CICs may be responsible for the generation of tumors that recapitulate the histology of the primary tumor at distant sites. We investigated the distribution of CIC markers (podoplanin (PDPN), CD44, and p63) positive cells of lung squamous cell carcinoma (SqCC) within primary and matched lymph node (LN) metastatic tumors to confirm this hypothesis (n = 113). In 61 cases, the PDPN-positive cells were localized in more peripheral areas of the tumor nests than the CD44- and p63-positive cells. This distribution pattern corresponded to a 'hierarchical distribution (HD)' reported previously. Among the cases with HD-(+) primary tumors (n = 61), the number showing HD-(+) LN metastatic tumors was 31 (51%), while among the cases with HD-(-) primary tumors (n = 52), the number showing HD-(+) LN metastatic tumors was 7 (13%) (p < 0.01). Primary and matched pulmonary metastatic (PM) tumors were also analyzed (n = 31), and a significant relationship of the HD pattern between them was also detected (p = 0.01). These results indicate that PDPN-positive cells might reflect the most immature cells in the differentiation process of metastatic SqCC and might generate metastatic tumors that recapitulate the histologic heterogeneity of the primary tumor.

Aldehyde dehydrogenase 1 expression in cancer cells could have prognostic value for patients with non-small cell lung cancer who are treated with neoadjuvant therapy: identification of prognostic microenvironmental factors after chemoradiation.

Prognostic factors for patients with non-small cell lung cancer (NSCLC) who have been treated with neoadjuvant therapy have not been fully assessed. The purpose of this study was to analyze prognostic biomarkers in NSCLC after treatment with neoadjuvant therapy, with special reference to the immunophenotypes of both the cancer cells and stromal cells. A total of 52 patients with NSCLC who were treated with neoadjuvant therapy followed by complete resection were included. We examined the expressions of nine markers in the cancer cells and stromal cells. The 5-year disease-free survival rate of patients with high aldehyde dehydrogenase 1 (ALDH1) expression levels in their cancer cells was significantly lower than those with a low ALDH1 level (47.3% vs. 21.5%, respectively; P = 0.023). The other molecules expressed in cancer cells did not exhibit any prognostic value. In NSCLC without neoadjuvant therapy (case control, n = 104), expression of ALDH1 in cancer cells was not correlated with prognosis (P = 0.507). A multivariate analysis identified ALDH1 expression in cancer cells as significantly independent prognostic factors for disease-free survival (P = 0.045). The current study indicated that the immunophenotypes of ALDH1 in cancer cells could have prognostic value for patients with NSCLC who are treated with neoadjuvant therapy.