Riki Okita

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

BackgroundThe 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.MethodsWe 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.ResultsA 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.ConclusionsOur 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.

Heterogeneity of the EGFR mutation status between the primary tumor and metastatic lymph node and the sensitivity to EGFR tyrosine kinase inhibitor in non-small cell lung cancer

The purpose of this study was to clarify the distribution of epidermal growth factor receptor (EGFR) mutations between primary tumors (PT) and metastatic lymph node (MLN) in patients with resected non-small cell lung cancer (NSCLC) and to identify a better predictive marker of the response to EGFR tyrosine kinase inhibitor (EGFR-TKI). We conducted a retrospective review of the data of 70 lung cancer patients with lymph node metastasis who underwent surgical resection. Analysis to detect EGFR mutations was performed by a peptide nucleic acid–locked nucleic acid polymerase chain reaction clamp method. EGFR mutations were detected in 15.7xa0% of both the PT and MLN and in 14.3xa0% of the PT only. The response rate to EGFR-TKI tended to be higher in patients with EGFR mutations in the MLN, as all patients with EGFR mutations in the MLN showed disease control to treatment with EGFR-TKI. Our results demonstrated that the EGFR mutation status of MLN is a predictive marker of the response to EGFR-TKI therapy in patients with recurrent NSCLC after surgical resection.

Post-recurrence survival of patients with non-small-cell lung cancer after curative resection with or without induction/adjuvant chemotherapy

OBJECTIVESnRecently, the prognosis of patients with non-small-cell lung cancer (NSCLC) has improved, thanks to the standardization of adjuvant chemotherapy and the introduction of molecular-targeted drugs, notably epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors and other new anti-cancer agents. However, the survival characteristics and prognosis of patients with recurrent NSCLC after curative resection are not well understood.nnnMETHODSnOf the 430 consecutive patients with NSCLC who underwent complete surgical resection at our institution between January 2004 and July 2011, we included 76 patients with recurrence whose post-recurrence treatment and outcome could be confirmed. We then retrospectively evaluated the effect of prognostic factors on post-recurrence survival.nnnRESULTSnThere were 50 men and 26 women, and the median age at recurrence was 74.5 years. The median time from surgical resection to recurrence was 12.7 months. Thirty-eight of the 76 (50%) patients underwent multimodality treatment with surgery and preoperative and/or postoperative chemotherapy as their initial treatment. For recurrence, systemic chemotherapy was administered to 64 (84%) patients, and the disease control rate for first-line chemotherapy was 55%. The 1- and 2-year post-recurrence survival rates were 68.3 and 45.8%, respectively, and the median post-recurrence survival time was 17.7 months. Six independent prognostic factors were identified: wild-type EGFR, no adjuvant chemotherapy for the primary lung cancer, age ≥ 80 years at recurrence, a poor Eastern Cooperative Oncology Group performance status at recurrence, symptomatic at recurrence and no systemic chemotherapy for recurrence, which significantly decreased the post-recurrence survival.nnnCONCLUSIONSnThe prognosis of patients with NSCLC recurrence after surgery is currently improving. Our results suggested two new prognostic factors, adjuvant chemotherapy and EGFR mutations, neither of which have been previously reported. Treatment strategies for postoperative recurrence should be established based on a more detailed subdivision of factors, such as histology and molecular markers, in the future.

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 (pu2009=u20090.021) and overall survival (pu2009=u20090.033). 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.

Influence of vascular endothelial growth factor single nucleotide polymorphisms on non-small cell lung cancer tumor angiogenesis

Vascular endothelial growth factor (VEGF) plays an important role in tumor angiogenesis. Several studies have reported that genomic VEGF polymorphisms may influence VEGF synthesis. To evaluate the role of VEGF single nucleotide polymorphisms (SNPs), we examined the expression of several angiogenesis-related proteins [VEGF, hypoxia-inducible factor-1α (HIF-1α) and delta-like ligand 4 (Dll4)] and the spread of microvessels in resected non-small cell lung cancer (NSCLC). Blood and tumor tissue from 83 patients with NSCLC were examined for VEGF −460T/C (rs833061) and VEGF +405G/C (rs2010963) SNPs using the SNaPshot method. Immunohistochemical staining was performed to measure protein expression and microvessel density (MVD). VEGF −460T/C and +405G/C SNPs showed no association with VEGF or HIF-1α expression and MVD. Patients with VEGF −460TT and the TC genotype had significantly higher MVD compared to those with the CC genotypes. Furthermore, patients with the VEGF −460TT genotype had significantly higher Dll4 expression compared to those with the TC or CC genotypes, while the VEGF +405G/C SNP displayed no association with Dll4 expression and MVD. These findings indicate that the VEGF −460T/C SNP may have a functional influence on tumor angiogenesis in NSCLC. We hypothesize that VEGF SNPs may influence angiogenesis through Dll4.

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

Abstract 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 (30.8xa0%) specimens showed high expression level of MICA/B, which was associated with low 18F-fluorodeoxyglucose uptake and manifestation of adenocarcinoma. After a median follow-up of 48.2xa0months, high MICA/B expression was associated with good recurrence-free survival (pxa0=xa00.037). 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.

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

BackgroundAdjuvant 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.MethodsWe 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.ResultsIHC 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 (Pu2009=u20090.017), but there was no significant difference among the patients who received OT (Pu2009=u20090.617). In a multivariate analysis, Cox-2 expression and lymph node metastasis were independent predictors of DFS among patients who received PB.ConclusionsCox-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.

Unknown primary large cell neuroendocrine carcinoma (LCNEC) in the mediastinum

Unknown primary large cell neuroendocrine carcinoma (LCNEC) in the mediastinum is extremely rare. In this report, we present a case of a 53-year-old man with superior vena cava (SVC) syndrome who developed LCNEC in the middle mediastinum. His chief complaint was facial edema. Chest X-ray revealed an abnormal shadow in the right upper mediastinum. Computed tomography (CT) scan of the chest revealed a 67-mm mass in the middle mediastinum. Tumor invasion caused constriction of the SVC. The patient underwent induction chemoradiotherapy with vinorelbin and cisplatin and concurrent radiation therapy. After induction therapy, the tumor size decreased remarkably and was resected completely. The pathological diagnosis was LCNEC.

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

ObjectiveThe 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 methodsWe 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 60xa0min (early acquisition; SUV-E) and 115xa0min (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.ResultsOf the 284 cases, the RIxa0≤xa00 was in 49 cases (17.3xa0%). 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.ConclusionsThis 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.

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 cetuximab-mediated 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.