Exploration of advanced cellulosic material for membrane filtration with outstanding antifouling property.

Membranes, at times, have issues due to membrane fouling. The membrane fouling leads to performance deterioration and poses a potential to clog the membrane. Here we present experimental works carried out with emphasis on the antifouling properties, chlorine resistance, and mechanical properties of cellulose triacetate (CTA) and cellulose esters. We present that antifouling performance of cellulose esters evaluated by means of the VCG theory decreases with increasing carbon number in the substituent because of the high electron-donating nature of short aliphatic ester groups. When a long aliphatic ester group is required in terms of other properties such as resistance to chlorine, introducing it together with another substituent with an electron-donating nature such as an ethylene glycol moiety may strike a balance between antifouling and other performances.

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.

Highly selective and straightforward recovery of gold and platinum from acidic waste effluents using cellulose-based bio-adsorbent.

Recovery of precious metals (PMs: AuIII and PtIV) from waste resources is of high importance due to the environmental concern and imbalance in the supply-demand ratio. A new approach has been explored for the recovery of PM using earlier developed bio-adsorbent, dithiocarbamate-modified cellulose (DMC). The adsorbent exhibits excellent adsorption efficiency (~99%) over a wide range of pH (< 1-6) and high selectivity towards AuIII and PtIV extraction from acidic solutions ([H+]: ≥ 0.2 mol L-1). The adsorption capacity (mmol g-1; AuIII: 5.07, PtIV: 2.41) and rate to reach equilibrium (≤ 30 min) were significantly higher than most of the reported bio-adsorbents. The AuIII or PtIV, after captured in DMC, was subsequently recovered as Au0 and Pt0 (yield > 99%) via incineration. The protocol was verified using real waste samples containing AuIII and PtIV in a mixed matrix of base metal ions, and a quantitative (~100%) and selective extraction of AuIII and PtIV were observed. The proposed technique is more effective and straightforward than the typical adsorption-desorption-reduction based method, because of the advantages like no-use of toxic eluents, and no-addition of any reductants to collect the PMs in elemental form.

Low-dose CT lung cancer screening in never-smokers and smokers: results of an eight-year observational study.

BACKGROUND: This was an observational study of Japanese participants who underwent low-dose computed tomographic (LDCT) lung cancer screening between February 2004 and March 2012, to evaluate the lung cancers in never-smokers and smokers. METHODS: The study population consisted of a total of 12,114 subjects [never-smokers, 6,021 (49.70%); smokers with <30 pack-years of smoking, 3,785 (31.24%); smokers with ≥30 pack-years of smoking, 2,305 (19.03%); unknown smoking status, 3 (0.02%)]. The odds ratio (OR) of lung cancer detection according to the smoking status adjusted for age and gender was evaluated. RESULTS: A total of 152 lung cancers were diagnosed in 133 patients [never-smokers, 66 (49.6%); smokers with <30 pack-years of smoking, 31 (23.3%); smokers with ≥30 pack-years of smoking, 36 (27.1%)]; therefore, 72.9% of lung cancer patients did not meet the National Lung Screening Trial (NLST) criterion of smokers with ≥30 pack-years of smoking. The OR of lung cancer detection in smokers with ≥30 pack-years of smoking was higher than that in the never-smokers (OR =1.71, 95% CI: 1.04-2.82, P=0.03) and that in smokers with <30 pack-years of smoking (OR =1.71, 95% CI: 1.04-2.80, P=0.03), while the OR of lung cancer detection in smokers with <30 pack-years of smoking was the same as that in the never-smokers (OR =1.00, 95% CI: 0.62-1.61, P=0.99). CONCLUSIONS: Although the OR of lung cancer detection in smokers with ≥30 pack-years of smoking was higher than that in the never-smokers and smokers with <30 pack-years of smoking, approximately 70% of lung cancer patients might be missed if we only adopted the NLST criterion of smokers with ≥30 pack-years of smoking. Therefore, never-smokers and smokers with <30 pack-years of smoking should be included in the target population for LDCT lung cancer screening in Japan.

Poly(4-vinylpyridine) based novel stationary phase investigated under supercritical fluid chromatography conditions.

A novel poly(4-vinylpyridine) based stationary phase was investigated for its performance under supercritical fluid chromatography (SFC) mode. Due to its unique structure, this stationary phase has high molecular planarity recognition ability for aromatic samples possessing the same number of aromatic rings and π-electrons. Taking advantage of the planarity recognition ability observed, separations of structurally similar polycyclic aromatic hydrocarbons and steroids were achieved. This novel stationary phase afforded good peak symmetry for both acidic and basic active pharmaceutical ingredients even when excluding the use of additives such as acids, bases, and salts. These findings may be attributed to the polymeric pyridyl groups covalently-attached on silica gel, which will effectively shield the undesirable interaction between residual silanol groups on the surface and the analytes. Moreover, the properties of pyridyl group on the selector can be reversibly tuned to cationic pyridinium form by eluting trifluoroacetic acid containing modifier. Column robustness toward cycle durability testing was also confirmed.

Poly(butylene terephthalate) based novel achiral stationary phase investigated under supercritical fluid chromatography conditions.

Poly(butylene terephthalate) based novel stationary phase (SP), composed of planar aromatic phenyl group together with ester group monomer units, was designed for supercritical fluid chromatography (SFC) use. As expected from its structure, this phase shows planarity recognition of isomeric aromatics and closely similar compounds. Interestingly, for most analytes, the retention behavior of this SP is significantly distinct from that of the 2-ethylpyridine based SPs which is among the most well-known SFC dedicated phases. Although the poly(butylene terephthalate) is coated on silica gel, the performance of the column did not change by using extended range modifiers such as THF, dichloromethane or ethyl acetate and column robustness was confirmed by cycle durability testing.

Effectiveness of Bone Suppression Imaging in the Detection of Lung Nodules on Chest Radiographs: Relevance to Anatomic Location and Observer's Experience.

OBJECTIVE: To evaluate the effectiveness of bone suppression imaging (BSI) software in lung-nodule detection on chest radiographs (CXRs) in relation to nodule location and observer's experience. MATERIALS AND METHODS: The CXRs of 80 patients, of which 40 had a lung nodule (8 to 30 mm in diameter) and 40 did not have any nodules, were interpreted by 20 observers comprising of 7 pulmonologists with >10 years of experience and 13 pulmonology residents. Each patient's image was sequentially read, first using the standard CXR and thereafter with the BSI software. The nodule location and confidence level with regard to the presence of a lung nodule were recorded. Receiver operating characteristic analysis was used to evaluate observer performance. RESULTS: The average area under the curve (AUC) for the observers' receiver operating characteristic significantly improved from 0.867 to 0.900 (P=0.004) with the use of the BSI software. The average AUC for experienced pulmonologists improved from 0.877 to 0.924 (P=0.017) for lung nodules located in the apical and peripheral areas but not for those in the inner area. The average AUC for residents improved regardless of nodule location. CONCLUSION: The use of BSI software improved the performance in lung-nodule detection on CXRs regardless of observer's experience and was more effective for observers with limited experience.

Genomic Profiling of Large-Cell Neuroendocrine Carcinoma of the Lung.

PURPOSE: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations. EXPERIMENTAL DESIGN: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases). RESULTS: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P = 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%). CONCLUSIONS: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies. Clin Cancer Res; 23(3); 757-65. ©2016 AACR.

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.

The novel one-step nucleic acid amplification (OSNA) assay for the diagnosis of lymph node metastasis in patients with non-small cell lung cancer (NSCLC): Results of a multicenter prospective study.

OBJECTIVES: The precise and rapid diagnosis of the presence or absence of lymph node (LN) metastasis is essential for deciding upon an appropriate therapeutic strategy for patients with non-small cell lung cancer (NSCLC). We conducted a prospective multicenter clinical trial in Japan to evaluate a rapid, automated and objective assay system, the one-step nucleic acid amplification (OSNA) assay (Sysmex Corp), which targets cytokeratin 19 mRNA, to detect LN metastasis of NSCLC. MATERIALS AND METHODS: A total of 410 Lymph nodes (LNs) from 111 patients with clinical stage IB to IIIA NSCLC who underwent lung resection with LN dissection were included in this study. The LNs were divided into 4 blocks and examined by either the OSNA assay or a 3-level histological examination. The results of each method were compared and further analyses were performed for discordant cases. The primary endpoint was a concordance rate of more than 85% between the two methods. RESULTS: The concordance rate between the two methods was 92.7% (95% CI, 89.7-95.0%), with a sensitivity of 79.7% (95% CI, 67.2-89.0%). Discordant results were observed in 30 LNs (5.8%), and were mainly due to a tissue allocation bias and/or contamination by CK19-expressing alveolar cells in LNs. CONCLUSION: The OSNA assay gave a diagnosis that was as accurate as a 3-level histological examination, which is more detailed than a histological examination in routine clinical practice. The OSNA assay might be useful in intraoperative decision-making in personalized lung cancer surgery based on the LN status.

Long-term outcome of surgical resection for residual or regrown advanced non-small cell lung carcinomas following EGFR-TKI treatment: report of four cases.

We report the long-term outcome of 4 patients who underwent pulmonary resection for residual or regrown primary lesion of non-small cell lung cancer (NSCLC) treated with a epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) gefitinib. Two patients underwent surgical resection for localized regrown primary lesion after gefitinib for stage IV disease. The remaining two patients underwent surgery for localized residual primary lesion that was downstaged to N0 after gefitinib for initially inoperable cN2 (stage IIIA) disease. Three patients developed recurrence with a median progression-free period of 1.2 years (0.2-2.2), but they survived more than 5 years postoperatively with good local control. One patient who initially had cN2 disease is alive without recurrence after 4 years with continued postoperative gefitinib. Although our series is small, the relatively favorable long-term survival indicates the need for further investigation of the role of surgery during molecular-targeted therapy for advanced NSCLC.

Long-term outcome and prognostic factors of surgically treated thymic carcinoma: results of 306 cases from a Japanese Nationwide Database Study.

OBJECTIVES: Thymic carcinoma is a rare thymic malignancy. The purpose of this study was to evaluate the prognostic impact of clinicopathological variables and perioperative therapy for surgically treated thymic carcinoma using a nationwide database. METHODS: Of 2835 patients with surgically treated thymic epithelial tumours collected from 32 Japanese institutions, a total of 306 patients with thymic carcinomas, excluding neuroendocrine tumours, were enrolled in this retrospective study. Multivariable Cox regression analyses were performed for overall (OS) and recurrence-free survival (RFS) after R0 resection. RESULTS: Of 306 patients, 228 (75%) patients presented with Masaoka stage III-IV. Squamous cell carcinoma was the most common histological type (n = 216, 71%). R0 resection was performed in 181 (61%) patients, R1 in 46 (16%), R2 sub-total (≥80% tumour resection) in 43 (14%) and R2 non-resection in 27 (9%). The 5-year OS rate was 61%. Prognostic factors for OS were Masaoka stage and resection status. R0 resection was associated with most improved OS; however, both R1 and R2 sub-total resection resulted in superior OS compared with R2 non-resection [hazard ratio (95% confidence interval) for R0, R1 and R2 sub-total, 0.27 (0.15-0.48), 0.40 (0.22-0.74) and 0.38 (0.20-0.72), respectively]. Histological type and perioperative therapy did not affect OS, whereas tumour size and postoperative radiotherapy were associated with improved RFS after R0 resection. CONCLUSIONS: R0 resection is essential for prolonged OS for surgically treated thymic carcinoma, but maximal debulking surgery might be beneficial and worth evaluating for advanced disease deemed difficult for R0 resection. The benefit of postoperative radiotherapy after R0 resection should also be evaluated prospectively.

Postoperative oligo-recurrence of non-small-cell lung cancer: clinical features and survival†.

OBJECTIVES: Postoperative recurrences of non-small-cell lung cancer (NSCLC) are usually disseminated and systemic. Recently, the concept of oligo-recurrence, which is theoretically curable by definitive local therapy (DLT), has been proposed in several cancers. The aim of this study was to clarify clinical features and outcomes of patients with postoperative oligo-recurrence of NSCLC. METHODS: From 3275 patients with resected pathological stage IA-IIIB NSCLC between 1993 and 2011, a total of 768 patients who developed recurrence were included in this study. Oligo-recurrence was defined as 1-3 loco-regional or distant recurrent lesions restricted to a single organ. Other recurrences were classified as poly-recurrence. Second primary lung cancers and suspected lesions were excluded. DLT included surgery, stereotactic radiotherapy and radiotherapy with a 45 Gy or higher dose, performed with curative intent. RESULTS: Oligo-recurrence was identified in 162 (21%) patients, mainly as a solitary recurrence (n = 129, 80%) in regional lymph nodes, brain, lung, bone and adrenal gland, and the proportion of patients with oligo-recurrence increased gradually year by year. The patients with oligo-recurrence had more early-staged disease at initial surgery and a longer time to recurrence than those with poly-recurrence. The entire population of oligo-recurrence patients had better post-recurrence survival (PRS) than those with poly-recurrence (5-year PRS: 32.9 vs 9.9%, P < 0.001). For oligo-recurrence, DLT was totally conducted in 105 (65%) patients as initial treatment. Multivariate analyses revealed that the initial DLT was associated with improved PRS [odds ratio (OR) 0.44; 95% confidence interval (CI) 0.29-0.68]. The recurrence location and initial pathological stage did not affect PRS. The 5-year PRS and postoperative progression-free survival rates after DLT were 38.6 and 22.3%, respectively. Of the 10 long-term (≥5-year) progression-free survivors, 9 were those with a solitary recurrence. CONCLUSIONS: Initial DLT for oligo-recurrence achieved favourable PRS in a selected population. Oligo-recurrence curable by DLT was found in a subset of patients who received DLT, mostly as a solitary recurrence.

Expression profiling of receptor tyrosine kinases in high-grade neuroendocrine carcinoma of the lung: a comparative analysis with adenocarcinoma and squamous cell carcinoma.

BACKGROUND: As the comprehensive genomic analysis of small cell lung cancer (SCLC) progresses, novel treatments for this disease need to be explored. With attention to the direct connection between the receptor tyrosine kinases (RTKs) of tumor cells and the pharmacological effects of specific inhibitors, we systematically assessed the RTK expressions of high-grade neuroendocrine carcinomas of the lung [HGNECs, including SCLC and large cell neuroendocrine carcinoma (LCNEC)]. PATIENTS AND METHODS: Fifty-one LCNEC and 61 SCLC patients who underwent surgical resection were enrolled in this research. As a control group, 202 patients with adenocarcinomas (ADCs) and 122 patients with squamous cell carcinomas (SQCCs) were also analyzed. All the tumors were stained with antibodies for 10 RTKs: c-Kit, EGFR, IGF1R, KDR, ERBB2, FGFR1, c-Met, ALK, RET, and ROS1. RESULTS: The LCNEC and SCLC patients exhibited similar clinicopathological characteristics. The IHC scores for each RTK were almost equivalent between the LCNEC and SCLC groups, but they were significantly different from those of the ADC or SQCC groups. In particular, c-Kit was the only RTK that was remarkably expressed in both LCNECs and SCLCs. On the other hand, about 20 % of the HGNEC tumors exhibited strongly positive RTK expression, and this rate was similar to those for the ADC and SQCC tumors. Intriguingly, strongly positive RTKs were almost mutually exclusive in individual tumors. CONCLUSIONS: Compared with ADC or SQCC, LCNEC and SCLC had similar expression profiles for the major RTKs. The exclusive c-Kit positivity observed among HGNECs suggests that c-Kit might be a distinctive RTK in HGNEC.

Mediastinal nodal involvement in patients with clinical stage I non-small-cell lung cancer: possibility of rational lymph node dissection.

BACKGROUND: The aim of this study is to elucidate the optimal candidate of selective lymph node dissection (LND) that reduces the extent of mediastinal LND according to clinical information including radiological evaluation in primary non-small-cell lung cancer (NSCLC) patients. METHODS: Eight hundred and seventy-six patients with clinical(c)-stage I NSCLC (adenocarcinoma and squamous cell carcinoma), who underwent complete surgical resection between January 2003 and December 2009 were included in this study. We elucidated the lymph node metastatic incidence and distribution according to the primary tumor lobe location and extracted the associated clinicopathological factors, especially thin-section computed tomographic findings, with mediastinal lymph node involvement. RESULTS: The total incidence of mediastinal lymph node metastasis was 9.1%. There were no cases with hilar and mediastinal lymph node metastasis in ground glass opacity-predominant tumors. There was no significant association of clinical factors with subcarinal lymph node metastasis in right upper-lobe and left upper-division adenocarcinoma. An elevated preoperative serum carcinoembryonic antigen level (p < 0.001) showed significant associations with upper mediastinal lymph node metastasis in the patients with bilateral lower-lobe primary lung adenocarcinoma. CONCLUSIONS: It would be acceptable to perform selective LND in patients with c-stage I NSCLC with ground glass opacity- predominant tumor. Elevated serum carcinoembryonic antigen was associated with upper mediastinal lymph node involvement in lower-lobe primary lung adenocarcinoma with radiologically solid-predominant tumor. We should be careful when applying selective LND to patients with solid-predominant tumor, especially located in the lower lobe.

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.

Clinicopathological significance of cancer stem-like cell markers in high-grade neuroendocrine carcinoma of the lung.

PURPOSE: This study aimed to evaluate the clinicopathological significance of cancer stem-like cell (CSLC) markers in high-grade neuroendocrine carcinoma (HGNEC) of the lung, including small cell lung carcinoma (SCLC) and large cell neuroendocrine carcinoma (LCNEC). METHODS: We retrospectively studied patients who underwent surgical resection of SCLC (n = 60) and LCNEC (n = 45) to analyze their clinicopathological profiles and the immunohistochemical expression of putative CSLC markers (Caveolin, Notch, CD44, CD166, SOX2, ALDH1, and Musashi1). Staining scores for these markers in tumor cells were calculated by multiplying the percentage of positive tumor cells per lesion by the staining intensity level (0, 1, and 2); a score of ≥ 10 represented positive expression. RESULTS: There was a difference between SCLC and LCNEC with respect to both SOX2 (55 vs. 27 %, p = 0.003) and CD166 (27 vs. 47 %, p = 0.034) expression. ALDH1 expression was equally observed in SCLC and LCNEC (67 vs. 73 %, p = 0.46), and patients with ALDH1-positive HGNEC had significantly worse recurrence-free survival (RFS) and overall survival (OS) rates than those with ALDH1-negative HGNEC (5-year RFS: 39 vs. 67 %, p = 0.009; 5-year OS: 50 vs. 79 %, p = 0.021). A multivariate analysis revealed that positive ALDH1 expression was an independent unfavorable prognostic factor with respect to both RFS and OS. CONCLUSIONS: The differences in the expression profiles of CSLC markers might reflect morphological differences between SCLC and LCNEC. Positive ALDH1 expression in lung HGNEC was associated with an unfavorable patient prognosis, which suggested that ALDH1-positive tumor cells might be future therapeutic targets for the treatment of lung HGNEC.

Podoplanin-expressing cancer-associated fibroblasts inhibit small cell lung cancer growth.

Cancer-associated fibroblasts (CAFs) expressing podoplanin (PDPN) are a favorable prognosticator in surgically resected small cell lung cancer (SCLC). Here we explore whether CAFs expressing PDPN influence proliferation of SCLC cells. Compared with control group (SCLC cells co-cultured with CAFs-Ctrl), numbers of SCLC cells co-cultured with CAFs overexpressing PDPN were decreased. Suppression of PDPN expression by shRNA in CAFs resulted in increased numbers of SCLC cells. In surgically resected human SCLC specimens, the frequency of Geminin-positive cancer cells was significantly higher in the cases with PDPN-positive CAFs than in the cases with PDPN-negative CAFs. Thus CAFs expressing PDPN inhibit growth of SCLC cells, suggesting that CAFs expressing PDPN represent a tumor inhibitory stromal cell component in SCLC.

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.

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.