Clinicopathological relevance of tumor expression of NK group 2 member D ligands in resected non-small cell lung cancer.

UL16-binding protein (ULBP) 1-6 and MHC class I chain-related molecule A and B (MICA/B) are NK group 2, member D (NKG2D) ligands, which are specifically expressed in infected or transformed cells and are recognized by NK cells via NKG2D-NKG2D ligand interactions. We previously reported that MICA/B overexpression predicted improved clinical outcomes in patients with resected non-small cell lung cancer (NSCLC). However, the clinicopathological features and prognostic significance of ULBPs in NSCLC remain unclear. Here,ULBP1-6 expression was evaluated based on immunohistochemistry of 91 NSCLC samples from patients following radical surgery. ULBPs were expressed by the majority of NSCLC. Either ULBP1 or ULBP2/5/6 overexpression was associated with squamous-cell carcinoma histology, whereas ULBP4 overexpression was associated with younger age and adenocarcinoma histology. Although overexpression of ULBP1-6 did not impact clinical outcomes in NSCLC patients, integrative profiling with cluster analysis classified patients into 3 subgroups based on the expression pattern of NKG2D ligands. The subgroup characterized by ULBP1 or ULBP2/5/6 high expressing but ULBP4 low expressing tumors showed poor overall survival. Taken together with previous results, NSCLC histological subtype strongly correlates with NKG2D ligands expression pattern. NKG2D ligands expression levels assessed by multiple immune parameters could predict clinical outcomes of patients with NSCLC.

Effect of platinum­based chemotherapy on the expression of natural killer group 2 member D ligands, programmed cell death­1 ligand 1 and HLA class I in non­small cell lung cancer.

Platinum­based chemotherapy improves the clinical outcome of patients with non­small cell lung cancer (NSCLC), although tumors often become refractory after treatment. Immunohistochemical staining was performed to investigate the expression levels of natural killer group 2 member D (NKG2D) ligands, programmed cell death­1 ligand 1 (PD­L1), and human leucocyte antigen (HLA)­class I in tissue samples collected from 10 NSCLC patients who received platinum­based chemotherapy followed by surgery. Additionally, the effects of repeated exposure to cisplatin on the expression of NKG2D ligands, PD­L1 and HLA­class I in NSCLC cell lines were assessed by flow cytometry. We found upregulation of PD­L1 or downregulation of NKG2D ligands in 5 of the 10 NSCLC cases, leading to the attenuation of NK cell­mediated tumor cell death. Moreover, upregulation of PD­L1 or downregulation of HLA­class I were observed in 6 cases, supporting tumor escape from T cell immunity. An in vitro assay showed that repeated exposure to cisplatin enhanced the expression of PD­L1 and NKG2D ligands in NSCLC cell lines. Notably, interferon gamma (IFNγ) stimuli enhanced PD­L1 expression while attenuated that of NKG2D ligands in NSCLC cell lines, which mimicked the results of the clinical study. Both IFNγ­induced upregulation of PD­L1 and downregulation of NKG2D ligands were blocked by the JAK­STAT inhibitor tofacitinib. These findings suggested that the expression levels of NKG2D ligands, PD­L1 and HLA­class I in residual tumors after chemotherapy were affected by host immunity, resulting in an immunoescape phenotype. Blocking IFNγ­induced tumor immunoescape by a JAK­STAT inhibitor might be a promising treatment strategy for NSCLC.

Comparative study of the PD-L1 expression and CD8+ tumor-infiltrating lymphocyte between surgically resected and matched re-biopsy specimens in recurrent non-small cell lung cancer.

Introduction: Numerous studies conducted until date have reported that the chemotherapy regimen could affect the programmed cell death ligand 1 (PD-L1) expression status in patients with non-small cell lung cancer (NSCLC). Materials and methods: A total of 36 NSCLC patients for whom both the surgically resected specimens of the primary tumors and re-biopsy specimens of the recurrent tumors were available were enrolled in this study. The PD-L1 expression status and tumor-infiltrating CD8-positive T lymphocytes (CD8+TILs) count were measured in paired samples by immunohistochemistry. The concordance rate in the tumor immune microenvironment (TIME) classification based on the PD-L1 expression status and CD8+TILs count was analyzed. Results: While the PD-L1 expression levels were similar between the surgical and re-biopsy specimens in 77.8% of cases, in 16.7% of cases, the expression levels were higher in the re-biopsy specimens. When the analysis was confined to patients who had received platinum-based chemotherapy, the percentage increased to 42.9%. The TIME classification changed in the re-biopsy specimens as compared to the surgical specimens in one-third of the patients, especially in those who had received chemotherapy previously. The TIME classification in the re-biopsy specimens more closely resembled that in the metastatic lymph nodes as compared to that in the primary tumor. Conclusion: In patients with recurrent NSCLC, especially those who have received chemotherapy previously, a recent re-biopsy sample is required to determine whether PD-1/PD-L1 inhibitors should be used for treatment or not.

Prognostic value of Cox-2 and PD-L1 expression and its relationship with tumor-infiltrating lymphocytes in resected lung adenocarcinoma.

Programmed cell death-1 ligand 1 (PD-L1), tumor-infiltrating CD8-positive T lymphocytes (CD8-positive TILs), and cyclooxygenase-2 (Cox-2) have been used as prognostic tools in patients with lung adenocarcinoma. We conducted a retrospective review of data from 170 patients who had undergone pulmonary resection as an initial treatment for clinical T1-2 N0 lung adenocarcinoma. We then investigated the expressions of three biomarkers using immunohistochemical analyses and compared the expression levels with the clinicopathological characteristics and outcomes of the patients. Next, we classified the tumors into four groups based on the PD-L1 and CD8-positive TILs statuses and evaluated the prognostic significance of Cox-2 expression according to the tumor immune microenvironment classification. Tumors with positive PD-L1 expression levels had a significantly larger number of CD8-positive TILs than tumors with negative PD-L1 expression levels, whereas tumors with high Cox-2 expressions had significantly fewer CD8-positive TILs than tumors with low Cox-2 expressions. A multivariate analysis showed that histological subtype, nodal metastasis, CD8-positive TILs count, and PD-L1 expression were independent predictors of patient outcome. Using a classification based on the PD-L1 and CD8-positive TILs statuses, the outcomes of patients with a negative PD-L1 expression and a high CD8-positive TIL count were significantly better than those with other classifications. In patients with negative PD-L1 and low CD8-positive TILs, the rate of EGFR mutation was significantly higher than that in other classifications, and Cox-2 expression was a powerful predictor of outcome. Clinical and pathological features in conjunction with the tumor immune microenvironment classification indicate that lung adenocarcinoma should be divided into different subgroups for prognosis and treatment. Classification according to the PD-L1 and CD8-positive TILs statuses might enable the effects of Cox-2 inhibitor to be predicted.

Urinary levels of prostaglandin E2 are positively correlated with intratumoral infiltration of Foxp3+ regulatory T cells in non-small cell lung cancer.

The immune microenvironment of primary tumors has been reported to be one of the factors influencing the prognosis of patients with cancer. The tumor-infiltrating regulatory T cell (Treg) count has previously been revealed to be positively correlated with intratumoral cyclooxygenase-2 (Cox-2) expression, and was also associated with poor survival among patients with non-small cell lung cancer (NSCLC). In addition, the urinary levels of a prostaglandin E2 (PGE2) metabolite (PGE-M) were used as a biomarker in clinical trials of the Cox-2 inhibitor celecoxib. In the current prospective study, the association of urinary PGE2 and PGE-M levels with intratumoral Cox-2 expression and Treg count was examined in patients with NSCLC. A total of 21 patients with NSCLC who underwent complete resection of the tumor at Kawasaki Medical School Hospital (Kurashiki, Japan) were enrolled. Urine specimens were obtained prior to surgery in order to examine urinary PGE2 and PGE-M levels. A significant positive association was observed between urinary PGE2 levels and the intratumoral Treg count (P=0.023), but not the intratumoral Cox-2 expression levels. No significant associations were identified between urinary PGE2 levels and any of the other clinicopathological characteristics examined, including age, sex, smoking history, histology, tumor size, nodal status and disease stage. However, no significant association was observed between urinary PGE-M levels and the intratumoral Treg count (P=0.069) or Cox-2 expression. In conclusion, urinary PGE2 levels were positively correlated with intratumoral Treg counts in patients with NSCLC in the current study. This indicates that urinary PGE2 may be an improved biomarker, compared with PGE-M, for the prediction of intratumoral Treg numbers.

PD-L1 overexpression is partially regulated by EGFR/HER2 signaling and associated with poor prognosis in patients with non-small-cell lung cancer.

Immunocheckpoint inhibitors targeting the programmed cell death-1 (PD-1) and PD-1 ligand 1 (PD-L1) axis have shown promising results in patients with non-small-cell lung cancer (NSCLC). Recent research has shown that epidermal growth factor receptor (EGFR) signaling affects PD-L1 expression in NSCLC cells; however, the mechanism regulating PD-L1 expression in tumor cells remains unclear. Using immunohistochemistry, we evaluated the impact of expression of PD-L1 and EGF family receptors EGFR and human epidermal growth factor receptor 2 (HER2) in tumor cells from 91 patients with pathological Stage IA-IIIA NSCLC. Overexpression of PD-L1 was observed in 14% of the resected tumors, and associated with poor recurrence-free survival (p = 0.021) and overall survival (p = 0.033). PD-L1 expression is positively correlated with EGFR expression and inversely correlated with HER2. NSCLC cell lines were treated in vitro with the EGFR ligand EGF with or without inhibition of EGFR or HER2, after which PD-L1 expression was evaluated using flow cytometry. Consistent with previous reports, PD-L1 expression was clearly enhanced by EGF. EGFR-tyrosine kinase inhibitors or EGFR small interfering RNA (siRNA) blocked EGF-induced PD-L1 overexpression in NSCLC cell lines, but HER2 siRNA did not. Moreover, our findings suggest that PD-L1 expression could be partially regulated via the PI3K/AKT and JAK/STAT pathways. We conclude that PD-L1 overexpression is associated with poor prognosis and is positively correlated with EGFR expression but inversely correlated with HER2 expression in NSCLC. We also showed that EGFR and HER2 have different effects on EGF-induced PD-L1 expression in NSCLC cell lines.

Clinicopathological and immunohistochemical features of lung invasive mucinous adenocarcinoma based on computed tomography findings.

BACKGROUND: We performed an analysis to clarify differences in clinicopathological and molecular features of lung invasive mucinous adenocarcinoma (IMA) based on computed tomography (CT) findings and their impact on prognosis. PATIENTS AND METHODS: On the basis of CT findings, we divided lung IMA into three subtypes: solid, bubbling, and pneumonic. We then investigated differences in clinicopathological characteristics, prognosis, and the expressions of well-identified biomarkers, including cyclooxygenase-2 (Cox-2), excision repair cross-complementation group 1 (ERCC1), ribonucleotide reductase M1 (RRM1), class III beta-tubulin, thymidylate synthase (TS), secreted protein acidic and rich in cysteine (SPARC), programmed cell death-1 ligand-1 (PD-L1), and epidermal growth factor receptor mutation, among the three subtypes. RESULTS: A total of 29 patients with resected lung IMA were analyzed. Compared with the solid or bubbling type, the pneumonic type had a higher proportion of symptoms, a larger tumor size, a higher pathological stage, and a significantly worse prognosis. The immunohistochemical findings tended to show high expression of RRM1, class III beta-tubulin, and Cox-2 in the tumor and of SPARC in the stroma, but not of ERCC1, TS, and PD-L1 in the tumor. None of the biomarkers with high expression levels in the tumor were prognostic biomarkers, but the expression of SPARC in the stroma was correlated with a poor outcome. CONCLUSION: Clinical and pathological features, in conjunction with molecular data, indicate that IMA should be divided into different subgroups. In our results, the pneumonic type was correlated with a significantly worse outcome. Further studies should be performed to confirm our conclusion and to explore its molecular implications.

Pneumatosis intestinalis after gefitinib therapy for pulmonary adenocarcinoma: a case report.

BACKGROUND: Pneumatosis intestinalis (PI) is defined as the presence of gas in the bowel wall and is a relatively rare finding. PI has been associated with various pathological conditions and medications. Although several chemotherapeutic agents and molecular targeted therapy agents are reported to be associated with PI, there have been few reports describing the association between the anti-epidermal growth factor receptor agent gefitinib, a tyrosine kinase inhibitor (TKI), and PI. The present report describes a case of PI secondary to gefitinib therapy. CASE PRESENTATION: An 80-year-old woman who had been diagnosed with recurrent lung adenocarcinoma presented with remarkable appetite loss, abdominal distension, and constipation after starting gefitinib therapy. A computed tomography (CT) scan of the abdomen revealed PI extending from the small intestine to the rectum. The patient was managed conservatively, and gefitinib therapy was discontinued. Subsequently, the symptoms improved and a follow-up abdominal X-ray showed a reduction in intramural air. After gefitinib was restarted, PI occurred three more times. CONCLUSIONS: Although PI is extremely rare, physicians should be aware of the risk of PI in patients undergoing gefitinib therapy.

MHC class I chain-related molecule A and B expression is upregulated by cisplatin and associated with good prognosis in patients with non-small cell lung cancer.

MHC class I chain-related molecule A and B (MICA/B) are NK group 2 member D (NKG2D) ligands, which are broadly expressed in transformed cells. Both DNA damage-induced ataxia-telangiectasia-mutated (ATM)- and ATM and Rad3-related protein kinases (ATM-ATR) signaling and oncogene-induced PI3K-AKT signaling regulate the expression of NKG2D ligands, which promote NK cell-mediated cytotoxicity via NKG2D-NKG2D ligand interactions. NKG2D ligand overexpression was recently reported to be correlated with good prognosis in several types of cancer. However, the prognostic significance of NKG2D ligands in non-small cell lung cancer (NSCLC) remains unclear. Here, MICA/B expression was evaluated based on immunohistochemistry of 91 NSCLC samples from patients following radical surgery. In addition, expression of MICA/B was assessed in NSCLC cell lines treated with cisplatin in order to evaluate the regulatory mechanisms of MICA/B expression. Overall, 28 out of 91 (30.8%) specimens showed high expression level of MICA/B, which was associated with low (18)F-fluorodeoxyglucose uptake and manifestation of adenocarcinoma. After a median follow-up of 48.2 months, high MICA/B expression was associated with good recurrence-free survival (p = 0.037). In vitro assays using cell lines revealed that MICA/B expression was upregulated by cisplatin via ATM-ATR signaling, resulting in enhanced NK cell-mediated cytotoxicity. Upregulated MICA/B expressions in patients with radically resected NSCLC are predictive of good disease prognosis. Cisplatin-induced MICA/B upregulation is possibly an indirect mechanism by which the innate immune system eliminates tumor cells. NKG2D-NKG2D ligand-targeting therapy is a promising avenue for future immune-chemotherapy development.

Prognostic nutritional index before adjuvant chemotherapy predicts chemotherapy compliance and survival among patients with non-small-cell lung cancer.

BACKGROUND: Adjuvant chemotherapy after the complete resection of non-small-cell lung cancer (NSCLC) is now the standard of care. To improve survival, it is important to identify risk factors for the continuation of adjuvant chemotherapy. In this study, we analyzed chemotherapy compliance and magnitude of the prognostic impact of the prognostic nutritional index (PNI) before adjuvant chemotherapy. METHODS: We conducted a retrospective review of data from 106 patients who had received adjuvant chemotherapy. The adjuvant chemotherapy consisted of an oral tegafur agent (OT) or platinum-based chemotherapy (PB). The correlations between the PNI values and recurrence-free survival (RFS) were then evaluated. RESULTS: In the PB group, the percentage of patients who completed the four planned cycles of chemotherapy was not correlated with the PNI. In the OT group, however, a significant difference was observed in the percentage of patients who completed the planned chemotherapy according to the PNI before adjuvant chemotherapy. The RFS of patients with a PNI <50 before adjuvant chemotherapy was significantly poorer than that of the patients with a PNI ≥50. A multivariate analysis showed that nodal metastasis and PNI before chemotherapy were independent predictors of the RFS. However, PNI before surgery was not a predictor of the RFS. In the subgroup analysis, PNI before chemotherapy was independent predictor of the RFS in the OT group (P=0.019), but not in the PB group (P=0.095). CONCLUSION: The PNI before adjuvant chemotherapy influenced the treatment compliance with the planned chemotherapy in the OT group, but not the PB group. In addition, a low PNI before adjuvant chemotherapy was associated with a poor RFS in a multivariate analysis, especially in the OT group.

Lapatinib enhances trastuzumab-mediated antibody-dependent cellular cytotoxicity via upregulation of HER2 in malignant mesothelioma cells.

EGFR/HER2 are frequently expressed in MPM tissues, however, no studies have shown the clinical benefit of using EGFR/HER2-targeting drugs in patients with malignant pleural mesothelioma (MPM). It was reported that the tyrosine kinase inhibitor (TKI) lapatinib enhanced trastuzumab-mediated antibody-dependent cellular cytotoxicity (ADCC) in HER2-positive breast cancer, suggesting that this combination is a promising strategy for MPM treatment. The aim of the present study was to explore the possibility of a TKI combined with trastuzumab to enhance ADCC in MPM cells. Five MPM cell lines were used to test the effects of TKIs targeting EGFR (gefitinib, afatinib and lapatinib) on cell proliferation and the expression of the HER family receptor. The combined effects of TKI with trastuzumab on ADCC were evaluated using the LDH release assay. Additionally, MPM cells were isolated from patients and evaluated for lapatinib-induced upregulation of HER family receptors and trastuzumab- or cetuximab­mediated ADCC. In MPM cell lines, HER2 expression was upregulated by lapatinib, downregulated by afatinib and unaffected by gefitinib. As expected, more trastuzumab bound to MPM cells pretreated with lapatinib than untreated cells, resulting in the enhancement of trastuzumab-mediated ADCC in MPM cells. In patient-derived MPM cells, both HER2 and EGFR were upregulated by lapatinib, resulting in the enhancement of both trastuzumab- and cetuximab-mediated ADCC. Of the three TKIs, only lapatinib enhanced trastuzumab-mediated ADCC via the upregulation of HER2 expression in MPM cells, suggesting that sequential combination of lapatinib and trastuzumab may be a promising strategy for MPM treatment.

Preoperative neutrophil/lymphocyte ratio and prognostic nutritional index predict survival in patients with non-small cell lung cancer.

BACKGROUND: The immunological status, consisting of "inflammation status" and "nutritional condition," is important for the survival of patients with various cancers, including non-small cell lung cancer (NSCLC). The neutrophil/lymphocyte ratio (NLR) reflects the inflammation status, and the prognostic nutritional index (PNI) reflects the immunological nutritional condition. In the present study, the correlation between the NLR and the PNI as well as the consistency and magnitude of the prognostic impact of the NLR and the PNI were investigated. METHODS: We conducted a retrospective review of data from 334 patients who had undergone a curative resection for NSCLC. The NLR and the PNI were calculated, which was routinely performed before surgery. The correlations between the NLR and the PNI and survival were then evaluated. RESULTS: A clear inverse correlation was observed between the NLR and the PNI. The NLR was associated with sex, smoking history, the CEA level, tumor size, and vascular invasion. The PNI was associated with sex, age, smoking history, tumor size, histological type, tumor differentiation, and vascular invasion. Patients with NLR ≥2.5 had a significantly poorer survival outcome, and patients with PNI <50 had a significantly poorer survival outcome. A multivariate analysis demonstrated that age, nodal metastasis, tumor differentiation, NLR, and PNI were independent predictors of disease-free and overall survival. CONCLUSIONS: Our study demonstrated a significant inverse correlation between the NLR and the PNI, and a high NLR and a low PNI were significantly associated with a poor survival among patients who had undergone a complete resection for NSCLC.

Contrasting Effects of the Cytotoxic Anticancer Drug Gemcitabine and the EGFR Tyrosine Kinase Inhibitor Gefitinib on NK Cell-Mediated Cytotoxicity via Regulation of NKG2D Ligand in Non-Small-Cell Lung Cancer Cells.

INTRODUCTION: Several cytotoxic anticancer drugs inhibit DNA replication and/or mitosis, while EGFR tyrosine kinase inhibitors inactivate EGFR signalling in cancer cell. Both types of anticancer drugs improve the overall survival of the patients with non-small-cell lung cancer (NSCLC), although tumors often become refractory to this treatment. Despite several mechanisms by which the tumors become resistant having been described the effect of these compounds on anti-tumor immunity remains largely unknown. METHODS: This study examines the effect of the cytotoxic drug Gemcitabine and the EGFR tyrosine kinase inhibitor Gefitinib on the expression of NK group 2 member D (NKG2D) ligands as well as the sensitivity of NSCLC cells to the NK-mediated lysis. RESULTS: We demonstrate that Gemcitabine treatment leads to an enhanced expression, while Gefitinib downregulated the expression of molecules that act as key ligands for the activating receptor NKG2D and promote NK cell-mediated recognition and cytolysis. Gemcitabine activated ATM and ATM- and Rad-3-related protein kinase (ATR) pathways. The Gemcitabine-induced phosphorylation of ATM as well as the upregulation of the NKG2D ligand expression could be blocked by an ATM-ATR inhibitor. In contrast, Gefitinib attenuated NKG2D ligand expression. Silencing EGFR using siRNA or addition of the PI3K inhibitor resulted in downregulation of NKG2D ligands. The observations suggest that the EGFR/PI3K pathway also regulates the expression of NKG2D ligands. Additionally, we showed that both ATM-ATR and EGFR regulate MICA/B via miR20a. CONCLUSION: In keeping with the effect on NKG2D expression, Gemcitabine enhanced NK cell-mediated cytotoxicity while Gefitinib attenuated NK cell killing in NSCLC cells.

Clinical significance of dual-time-point 18F-FDG PET imaging in resectable non-small cell lung cancer.

OBJECTIVE: The maximal standardized uptake value (SUVmax) of pulmonary lesions on dual-time-point (DTP) fluorodeoxyglucose positron emission tomography (FDG-PET) has been shown to be useful for differentiation between malignant and non-malignant pulmonary lesions, and also to be of value for intrathoracic nodal staging of non-small cell lung cancer (NSCLC). However, a few NSCLC lesions have been found to show decreased FDG uptake on delayed images, and the significance of this finding remains unknown. PATIENTS AND METHODS: We conducted a retrospective review of the data of 284 patients with NSCLC who underwent DTP FDG-PET before surgery. Cases of adenocarcinoma in situ and minimally invasive adenocarcinoma were excluded, because these lesions show little FDG uptake. Each patient was scanned at 60 min (early acquisition; SUV-E) and 115 min (delayed acquisition; SUV-D) after the radiopharmaceutical injection. The intratumoral retention index (RI) of 18F-FDG was measured for each examination by the DTP method. Recurrence-free survival (RFS) was determined by the Kaplan-Meier method and compared in relation to the SUV-E, SUV-D, and RI by univariate and multivariate analysis using models including the clinico-pathological prognostic factors. RESULTS: Of the 284 cases, the RI ≤ 0 was in 49 cases (17.3%). This group of patients showed lower values of SUV-E and SUV-D, a smaller tumor size, and a lower rate of lymphatic invasion or vascular invasion. It was particularly noteworthy that lymph node metastasis was not histopathologically confirmed in any of these patients. Univariate analysis identified the RI, SUV-E and SUV-D, besides age, tumor size, lymph node metastasis, and tumor differentiation grade as predictors of the RFS. On the other hand, multivariate analysis identified the RI and lymph node metastasis, but not the SUV-E and SUV-D, as independent predictors of the RFS. CONCLUSIONS: This study demonstrated that DTP FDG-PET of the primary tumor in NSCLC can be useful to predict the RFS of the patients. In addition, this method may also be useful to predict the presence/absence of intrathoracic lymph node metastasis in these patients.

Cyclooxygenase-2 expression is a prognostic biomarker for non-small cell lung cancer patients treated with adjuvant platinum-based chemotherapy.

BACKGROUND: Adjuvant chemotherapy after the resection of stage IB-IIIA non-small cell lung cancer (NSCLC) is now the standard of care based on large-scale phase III trials and a meta-analysis. However, chemotherapy has plateaued in terms of its efficacy, and the search for treatment prediction biomarkers is imperative for the further identification of treatable subgroups. Therefore, we investigated the significance of cyclooxygenase-2 (Cox-2) expression and the applicability of a Cox-2 inhibitor in patients who had received adjuvant chemotherapy. METHODS: We conducted a retrospective review of data from 97 patients who had received adjuvant chemotherapy. The adjuvant chemotherapy consisted of an oral tegafur agent (OT) or platinum-based chemotherapy (PB). The criteria for regimen selection were based on a discussion among the cancer board and enrollment in a clinical trial. Immunohistochemical staining (IHC) for Cox-2 was performed, and the correlation between Cox-2 expression and disease-free survival (DFS) was evaluated. RESULTS: IHC showed that 56 cases (57.7%) were positive for Cox-2. The rate of Cox-2 expression was similar for the PB and OT groups. Among the patients who received PB, the DFS of the patients with Cox-2 expression was significantly poorer than that of the patients without Cox-2 expression (P = 0.017), but there was no significant difference among the patients who received OT (P = 0.617). In a multivariate analysis, Cox-2 expression and lymph node metastasis were independent predictors of DFS among patients who received PB. CONCLUSIONS: Cox-2 expression was a powerful predictor of DFS among patients who received PB as an adjuvant chemotherapy. Further study investigating the use of a Cox-2 inhibitor for adjuvant chemotherapy is needed.

Cyclooxygenase-2 genetic variants influence intratumoral infiltration of Foxp3-positive regulatory T cells in non-small cell lung cancer.

The immune microenvironment of primary tumors has been reported to be a prognostic factor. We previously reported that the tumor-infiltrating regulatory T cell (Treg) count was positively correlated with the intratumoral cyclooxygenase-2 (COX-2) expression level and was associated with a poor survival among patients with non-small cell lung cancer (NSCLC). Recently, numerous single nucleotide polymorphisms (SNPs) in the COX-2 gene have been identified, and these SNPs may contribute to differential gene expression and enzyme activity levels. However, whether COX-2 genetic variants influence the functions of COX-2 in NSCLC remains unclear. Eighty NSCLC patients who underwent a complete resection at our institute were enrolled. We extracted DNA from the peripheral blood and identified five different COX-2 SNPs. The correlations between the COX-2 SNPs and the expression levels of COX-2, Tregs and Ki-67 were studied. The prognostic significance of the COX-2 SNPs was also evaluated. COX-2 SNPs were not correlated with the expression of COX-2. However, for the COX-2 -1195G/A polymorphism, the AA genotype group had a significantly higher Treg score. Furthermore, the AA group had a significantly higher Treg score regardless of the COX-2 expression level. The COX-2 -1195AA genotype group tended to have a shorter disease-free survival period than the GA/GG group. In conclusion, the COX-2 -1195G/A polymorphism influences the infiltration of Tregs into NSCLC, and the COX-2 SNP factor may be a prognostic factor reflecting Treg infiltration in NSCLC.

Difference in prognostic values of maximal standardized uptake value on fluorodeoxyglucose-positron emission tomography and cyclooxygenase-2 expression between lung adenocarcinoma and squamous cell carcinoma.

BACKGROUND: The maximal standardized uptake value (SUVmax) on fluorodeoxyglucose-positron emission tomography (FDG-PET) for primary tumors is correlated with clinicopathological and prognostic factors in patients with non-small cell lung cancer. However, previous investigations have discussed the role of SUVmax without distinguishing among the histological subtypes of lung cancer. Herein, we investigated the correlations among the SUVmax on FDG-PET, clinicopathological or prognostic factors, and the expression of tumor angiogenic biomarkers according to histological subtypes. METHODS: We conducted a retrospective review of data from 52 patients with invasive adenocarcinoma (ADC) and 32 patients with squamous cell carcinoma (SQC) measuring less than 3 cm in diameter. Immunohistochemical staining for cyclooxygenase-2 (Cox-2), Ki-67, and vascular endothelial growth factor, which might influence cancer progression, was performed and the correlations between the expressions of these biomarkers and the SUVmax were evaluated. RESULTS: Among ADC patients, a statistically significant correlation was observed between the SUVmax and the major clinicopathological factors; among SQC patients, however, no statistically significant association was observed. The disease-free survival (DFS) period of the ADC patients with a high SUVmax was significantly poorer than that of the patients with a low SUVmax, but the DFS of the SQC patients with a high SUVmax was not significantly poorer. In a multivariate analysis, the pathological stage and the SUVmax were independent prognostic factors of the DFS among the ADC patients. Among the SQC patients, however, only Cox-2 expression was an independent prognostic factor of DFS. CONCLUSIONS: Some clear differences in prognostic values of the SUVmax on FDG-PET and Cox-2 expression exist between patients with ADC and those with SQC. Based on these relationships between the SUVmax and clinicopathological or biological factors that influence cancer progression, the importance of the SUVmax appears to be quite different for patients with ADC and those with SQC.

A case report of intrapulmonary schwannoma.

A 38-year-old man without any symptoms was admitted to our institution because of an abnormal shadow found incidentally on a chest X-ray. Chest computed tomography showed a round mass in the lingular segment of the left upper lobe. Lingular segmentectomy was performed, and the histopathological diagnosis was intrapulmonary schwannoma. Immunohistochemical staining revealed a positive result for S-100 protein and negative results for CD34 and desmin. We report this case of intrapulmonary schwannoma, which is extremely rare.

Role of 2-[18F]fluoro-2-deoxyglucose positron emission tomography in preoperative management of solid-type small-sized lung cancer.

OBJECTIVE: 2-[18F]Fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is routinely used for the diagnosis of primary lung cancer. However, the role of FDG-PET in the diagnosis and staging of small-sized lung cancer has not been sufficiently evaluated. The purpose of this study was to determine the utility of FDG-PET for preoperative staging of solid-type small-sized lung cancer manifesting as solid-component predominant nodules. METHODS: One-hundred and eighteen patients with solid-type small-sized (≤2 cm) lung cancer diagnosed as clinical stage IA based on thin-slice computed tomography (TS-CT) were included in this study. Before surgery, FDG-PET was performed in 78 patients (CT/PET group), and TS-CT alone was performed in 40 patients (CT group). Clinical and pathological stage and prognosis were retrospectively reviewed according to whether FDG-PET had been performed. RESULTS: No significant differences in clinical factors were observed when comparing the CT/PET group and the CT group. Of the 78 patients in the CT/PET group, 12 (15.4 %) were diagnosed with clinical stage IIA or IIIA disease based on FDG-PET findings, but no advanced cases with contraindications for curative surgery were seen. In the CT/PET group, the pathological stage was IA in 66 patients, IB in eight patients, IIA in one patient, and IIIA in three patients; 16 patients had incorrectly staged disease. The accurate staging rate was 79.5 % for the CT-PET group and 70.0 % for the CT group (P = 0.262). Among patients diagnosed with clinical stage IA disease, the 3-year overall survival rate was 85.5 % for the 66 patients in the CT/PET group and 76.8 % for the 40 patients in the CT group (P = 0.554). No significant difference was observed in accuracy of preoperative staging and prognosis between the two groups. CONCLUSIONS: FDG-PET produced no clear benefit for the preoperative management of patients with solid-type clinical T1aN0M0 lung cancer, in terms of postoperative survival and the concordance rate of clinical and pathological stage.

Lung cancer with sarcoid reaction in the lymph nodes following chemoradiotherapy.

This report describes a case of lung cancer with sarcoid reaction following chemoradiotherapy, showing false-positive accumulation of (18)F-fluorodeoxyglucose on positron-emission tomography in a 55-year-old man. Treatment-related sarcoid reaction should be considered when the accumulation of (18)F-fluorodeoxyglucose shows rapid extension in the course of treatment.