Maiko Niki

Microparticles as Biomarkers of Blood Coagulation in Cancer

Cancer is associated with hypercoagulopathy and increased risk of thrombosis. This negatively influences patient morbidity and mortality. Cancer is also frequently complicated by the development of venous thromboembolism (VTE). Tumor-derived tissue factor (TF)-bearing microparticles (MPs) are associated with VTE events in malignancy. MPs are small membrane vesicles released from many different cell types by exocytic budding of the plasma membrane in response to cellular activation or apoptosis. MPs may also be involved in clinical diseases through expression of procoagulative phospholipids. The detection of TF-expressing MPs in cancer patients may be clinically useful. In lung and breast cancer patients, MPs induce metastasis and angiogenesis and may be indicators of vascular complications. Additionally, MPs in patients with various types of cancer possess adhesion proteins and bind target cells to promoting cancer progression or metastasis. Overexpression of TF by cancer cells is closely associated with tumor progression, and shedding of TF-expressing MPs by cancer cells correlates with the genetic status of cancer. Consequently, TF-expressing MPs represent important markers to consider in the prevention of and therapy for VTE complications in cancer patients.

Phase II study of pemetrexed and carboplatin plus bevacizumab, followed by maintenance pemetrexed and bevacizumab in Japanese patients with non‑squamous non‑small cell lung cancer

The present study evaluated the efficacy and safety of pemetrexed, carboplatin and bevacizumab, followed by maintenance pemetrexed and bevacizumab, in chemotherapy-naïve patients with stage IIIB/IV non-squamous non-small cell lung cancer (NSCLC). The patients were administered pemetrexed (500 mg/m2), carboplatin (area under the concentration-time curve, 6.0 mg/ml × min) and bevacizumab (15 mg/kg) intravenously every three weeks for up to six cycles. Patients who did not experience tumor progression remained on maintenance pemetrexed and bevacizumab until disease progression or unacceptable toxicity occurred. The primary endpoint was the overall response rate. Of the 26 patients enrolled between March 2010 and April 2011, three were excluded due to brain metastases, therefore the intention-to-treat (ITT) population consisted of 23 patients. The median age was 64 years (range, 40–74 years) and 15 patients were male. In total, six patients had a performance status of 0, and 20 had stage IV tumors. The response rate was 69.6% [95% confidence interval (CI), 47.1–86.8], the disease control rate was 100% and the time to response was 1.2 months (95% CI, 0.72–1.93). The median progression-free survival time was 8.6 months (95% CI, 5.9–10.9) and the median overall survival time was 18.6 months (95% CI, 12.9–24.8). There were no grade 3 or worse hemorrhagic events and the feasibility was modest. Overall, pemetrexed and carboplatin plus bevacizumab, followed by maintenance pemetrexed and bevacizumab, was effective and tolerable in the patients with non-squamous NSCLC, and the time to response was relatively short.

Immunohistochemical analysis of NANOG expression and epithelial-mesenchymal transition in pulmonary sarcomatoid carcinoma

Pulmonary sarcomatoid carcinomas (PSCs) are defined as a group of poorly differentiated non-small cell lung cancers that demonstrate sarcoma-like differentiation. The mechanism of mesenchymal differentiation in PSC is epithelial-mesenchymal transition (EMT). The expression of homeobox protein NANOG (NANOG), which regulates the pluripotency of embryonic stem cells, is associated with the EMT process. Therefore, the present study aimed to assess the expression level of NANOG and the status of the EMT process in PSC. The data of patients with PSC were retrospectively reviewed and immunohistochemical analyses were performed on patient samples to examine the expression of NANOG and EMT-associated proteins. The comparator group included randomly selected patients with matched clinicopathological characteristics who had pulmonary adenocarcinoma (PA). In the present study, 12 patients with PSC (4 females and 8 males) were enrolled; their median age was 65 years (range, 36-79 years), and the number of patients with stage IB, IIB, IIIA, IIIB and IV disease were 1, 1, 1, 1 and 8, respectively. The immunoreactive score (IRS) for E-cadherin was significantly lower in the PSC group compared with the PA group (P<0.0001), whereas the IRS for vimentin was significantly higher in the PSC group compared with the PA group (P<0.0001). However, the IRS for NANOG was significantly decreased in the PSC group compared with the PA group (P<0.0001), which suggests that NANOG does not serve an essential role in EMT in PSC. In addition, the overall survival of patients with PSC was significantly lower compared with that of patients with PA (median survival time, 7.0 vs. 35.6 months, respectively; P=0.0256). However, no significant difference was observed in the OS of patients who expressed low compared with high levels of NANOG (P=0.4416). In conclusion, it was clearly demonstrated that cytoplasmic NANOG expression was significantly lower in PSC compared with PA, and that the EMT process in PSC was accelerated, compared with that in PA.

Benign metastasizing leiomyoma and 18‑FDG‑PET/CT: A case report and literature review

Pulmonary benign metastasizing leiomyoma (PBML) is a rare disease entity that usually occurs in females of reproductive age with a previous history of uterine myoma. It is typically characterized by multiple pulmonary tumors consisting of benign leiomyoma cells. In the present study, two cases of PBML are discussed. The patient in each case underwent 2-deoxy-2-(fluorine-18)-fluoro-D-glucose positron emission tomography/computed tomography (18-FDG-PET/CT) scans. One patient demonstrated a lack of 18-FDG uptake and a quiescent clinical course. However, the second patient exhibited a markedly high uptake of 18-FDG and aggressive cell proliferation. The two tumors revealed significant differences in metabolic behavior and in clinical course; however, they were similar with regard to cellular appearance. A review of previous studies concerning the findings of 18-FDG-PET/CT in published cases of PBML was also conducted and is presented here.

Retrospective analysis of single‑agent nab‑paclitaxel in patients with platinum‑resistant non‑small cell lung cancer

A retrospective study was conducted to investigate the efficacy and toxicity of single-agent nab-paclitaxel in 67 patients with platinum-resistant non-small cell lung cancer in Kansai Medical University Hospital from August 2013 to December 2015. Overall, 25% of patients experienced disease progression, 48% exhibited a partial response, 27% had stable disease and 0% had a complete response. The median progression-free survival (PFS) time was 4.8 months and the median overall survival time was 18.2 months. There was no statistically significant difference in PFS between patients with non-squamous carcinoma and squamous carcinoma, or between second-line use and post-second-line use. The most common severe adverse event was neutropenia, followed by interstitial lung disease, infection and fatigue. The results revealed that single agent nab-paclitaxel was associated with an acceptable level of toxicity and a favorable response. This regimen has been developed recently, thus it has not been sufficiently evaluated its toxicity and efficacy. Additional studies to evaluate these parameters in non-small cell lung cancer are warranted.

Immune checkpoint inhibitor re-challenge in patients with advanced non-small cell lung cancer

Background Immune checkpoint inhibitors have dramatically changed lung cancer treatment, demonstrating an overall survival benefit. There are limited data about re-challenge in patients with non-small cell lung cancer. We attempted to address this question for re-challenge of immune checkpoint inhibitor in patients with advanced non-small cell lung cancer. Methods We retrospectively analyzed 11 patients with advanced non-small cell lung cancer treated with nivolumab and re-challenged with nivolumab/pemblorizumab at Kansai Medical University Hospital from December 2015 to December 2017. Results Three patients achieved PR and two patients were in SD. These patients were apt to be good responders to the initial treatment, to develop immune-related adverse events and to be immediately started on re-challenge with immune checkpoint inhibitor. The median PFS was 2.7 (range, 0.5–16.1) months. Five patients (45%) had mild to moderate immune-related adverse events. Conclusion Our study shows the effectiveness of re-challenge of immune checkpoint inhibitors in a subset of non-small cell lung cancer patients. Re-challenge might become one of treatment option for advanced non-small cell lung cancer.

Interstitielle Lungenerkrankung nach Monotherapie mit an Albumin-Nanopartikel gebundenem Paclitaxel bei Patienten mit fortgeschrittenem nicht-kleinzelligem Bronchialkarzinom

Eine Interstitielle Lungenerkrankung (interstitial lung disease, ILD) ist ein schwerwiegendes und lebensbedrohendes unerwünschtes Ereignis in der Behandlung von Lungenkrebs. Nab-PTX (an Albumin-Nanopartikel gebundenes Paclitaxel) ist eine neuartige, lösungsmittelfreie Formulierung von Paclitaxel (PTX). Die Inzidenz der nab-PTX-induzierten ILD ist zwar nicht bekannt, man geht jedoch davon aus, dass diese Formulierung mit einem vergleichbaren ILD-Risiko verbunden ist wie PTX. Wir berichten hier über 3 Patienten, die nach der Behandlung mit nab-PTX eine schwere ILD entwickelten. Wir unterstreichen damit das Risiko für das Auftreten einer medikamenteninduzierten ILD nach einer nab-PTX-Therapie und heben hervor, dass diese neue Formulierung in Bezug auf das ILD-Risiko möglicherweise weniger sicher ist als PTX. Übersetzung aus Case Rep Oncol 2017;10:683-688 (DOI: 10.1159/000479148).

New prognostic biomarkers and therapeutic effect of bevacizumab for patients with non-small-cell lung cancer

Background Several biomarkers have emerged as potential prognostic and predictive markers for non-small-cell lung cancer (NSCLC). Successful inhibition of angiogenesis with the antivascular endothelial growth factor antibody, bevacizumab, has improved the efficacy seen with standard cytotoxic therapy of NSCLC. However, despite such enhanced treatment strategies, the prognosis for patients with advanced NSCLC remains poor. Patients and methods We assessed potential biomarkers in 161 NSCLC patients and 42 control patients. Enzyme-linked immunosorbent assay methods were used to evaluate three biomarkers: platelet-derived microparticle (PDMP), high-mobility group box-1 (HMGB1), and plasminogen activator inhibitor-1 (PAI-1). We studied the effects of bevacizumab on the expression of these markers. We also analyzed the relationship of the newly designed risk factor (NDRF) to overall survival and disease-free survival. The NDRF classification of patients was determined from the levels of PDMP, HMGB1, and PAI-1. To determine the individual prognostic power of PDMP, HMGB1, and PAI-1, we evaluated associations between their levels and patient outcomes by Kaplan–Meier survival analysis in a derivation cohort. Results PDMP, HMGB1, and PAI-1 levels were higher in NSCLC patients compared with control patients. Notably, the difference in PDMP levels exhibited the strongest statistical significance (p<0.001). Multivariate analysis showed that HMGB1 and PAI-1 levels were significantly correlated with PDMP levels. Patients who received standard chemotherapy with bevacizumab exhibited significantly reduced levels of all three markers compared with patients who received standard chemotherapy. NDRF3 status (high levels of all three markers) was significantly correlated with a poor prognosis (p<0.05 for overall survival and disease-free survival). Conclusion Our results demonstrate that abnormal levels of PDMP, HMGB1, and PAI-1 are related to each other in NSCLC. Moreover, our findings suggest that the vascular complications associated with these markers may contribute to a poor prognosis for NSCLC patients.

Interstitial Lung Disease Following Single-Agent Nanoparticle Albumin-Bound Paclitaxel Treatment in Patients with Advanced Non-Small Cell Lung Cancer

Interstitial lung disease (ILD) is a serious and potentially fatal adverse event in lung cancer therapy. Nanoparticle albumin-bound paclitaxel (nab-PTX) is a novel, solvent-free formulation of paclitaxel (PTX). Although the incidence of nab-PTX-induced ILD is not clear, it is generally considered that this formulation presents a similar risk of developing ILD as PTX. Here, we report 3 patients who developed severe ILD following treatment with nab-PTX. We draw attention to the risk of developing drug-induced ILD following nab-PTX treatment, and highlight that this novel formulation might therefore not be as safe as PTX with respect to the development of ILD.

O2-5-6Neutrophil to lymphocyte ratio (NLR) as an early marker for outcome in patients treated with nivolumab in advanced NSCLC

CD4þCD25þFoxp3þ regulatory T cells (Tregs) are known to suppress immune responses. Treg-mediated immunosuppression is a key mechanism for tumor immune-evasion, which could lead cancer immunotherapies to failures. Systemic depletion of Tregs has been tried by using antibodies against them; however, intravenously delivering these antibodies might not sufficiently deplete Tregs in tumor microenvironment or could deplete effector cells. Furthermore, systemic severe autoimmune responses could cause potential side effects. To address these problems, we exploited near infrared photoimmunotherapy (NIR-PIT) to deplete only intratumoral Tregs with anti-CD25-antibody aiming to induce anti-tumor immune activation within manageable side effects. NIR-PIT is a recently developed cancer treatment that combines the specificity of intravenously injected antibodies that target tumors/cells with the toxicity induced by photosensitizers activated by NIR-light.