We examined the impact of pretreatment neutrophil count on survival in patients with advanced non-small-cell lung cancer (NSCLC). A total of 388 chemo-naïve patients with stage IIIB or IV NSCLC from a randomised controlled trial were evaluated. The effects of pretreatment peripheral blood neutrophil, lymphocyte and monocyte counts and neutrophil-lymphocyte ratio on survival were examined using the proportional hazards regression model to estimate hazard ratios after adjustment for covariates. The optimal cut-off value was determined by proportional hazards regression analysis with the minimum P-value approach and shrinkage procedure. After adjustment for prognostic factors, the pretreatment elevated neutrophil count was statistically significantly associated with short overall (P=0.0008) and progression-free survival (P=0.024), whereas no association was found between prognosis and lymphocyte or monocyte count. The cut-off value selected for neutrophil count was 4500 mm(-3) (corrected hazard ratio, 1.67; 95% confidence interval (CI), 1.09-2.54). The median survival time was 19.3 months (95%CI, 16.5-21.4) for the low-neutrophil group (4500 mm(-3), n=204) and was 10.2 months (95%CI, 8.0-12.3) for the high-neutrophil group (4500 mm(-3), n=184). We confirmed that pretreatment elevated neutrophil count is an independent prognostic factor in patients with advanced NSCLC receiving modern chemotherapy. Neutrophil count is easily measured at low cost, and it may be a useful indicator of patient prognosis.

EML4-ALK-positive lung adenocarcinoma has a tendency to express a characteristic morphological pattern. The combined use of morphological feature analysis and immunohistochemistry may be a useful and cost effective screening method for EML4-ALK lung adenocarcinoma.

We previously reported that the (1®3)-branched (1®6)-bglucan termed D-Fraction, extracted from the fruit body of the maitake mushroom (Grifola frondosa) ( Fig. 1), is a biological response modifier (BRM) like lentinan, which is found in Letinus edodes. [1][2][3] These polysaccharides enhance the activity of immunocompetent cells such as macrophages, helper T cells, and cytotoxic T cells, which attack tumor cells. These effects of BRMs led us to hypothesize that oral administration of D-Fraction would be an effective treatment for cancer patients. Orally administered D-Fraction was shown to reduce tumor size in mice, without causing unwanted side effects.2) Therefore, D-Fraction has been commercialized as a health material, the safety of which has been confirmed by the Consumer Product Testing Co. (New Jersey, U.S.A.) We have already tried a non-randomized clinical trial of D-Fraction therapy for patients with lung and breast cancer in stages II-IV. 4) In this trial, we found that IL-2 production was enhanced in D-Fraction-treated patients, suggesting that macrophages and T cells were activated by DFraction. In addition, D-Fraction is revealed to be effective for human immunodeficiency virus (HIV) infection 5) and listeriosis, 6) by reinforcing the immune system. These results indicate that one network of the immuno-response pathway by which D-Fraction enhances anti-tumor effects is dependent on an adaptive immunity associated with cytotoxic T cell activation.Natural killer (NK) cells rapidly recognize and lyse a large variety of tumor or virus-infected cells, without the need for either prior sensitization or MHC-dependent recognition, which is different from cytotoxic T cell. 7) Pham-Nguyen et al. have reported that the early NK cell response alone is not sufficient for tumor clearance, and that both T cells and NK cells are required in the development of the long-term survival in the hepatic tumor model by IL-12-mediated gene therapy. 8) In our clinical study, we also found that D-Fraction activated NK cells in lung, breast and liver carcinoma patients for long periods of time, exceeding one year (Table 1) MATERIALS AND METHODS MaterialsFor the detection of human NK activity, chromium-51 (Daiichi Kagaku Yakuhin Co., Tokyo) and lymphopacel (dϭ1.077) (IBL Co., U.S.A.) were prepared.Animals Male C3H/HeN mice (4-weeks-old) were obtained (Japan Crea Co., Osaka) and were raised for one week before being used for experiments. Food and water were given freely to these mice until used for experiments.Cells MM-46 carcinoma cells were kindly donated by Dr. Kanki Komiyama. 51Cr labeled K-562 cells were used as target cells of human NK.Preparation of D-Fraction D-Fraction was prepared from the dried powder of the fruit body of maitake mushrooms (Grifola frondosa) (Yukiguni Maitake Co., Niigata), according to the method described in our previous paper. 6)The level of LPS contained in D-Fraction was determined by using Endospecy ES-20S Set (Seikagaku Industry Co., Tokyo), and the ratio (%) of LPS in D-Fraction was less than...

Maitake D-Fraction, extracted from maitake mushroom, has been reported to exert its antitumor effect in tumor-bearing mice by enhancing the immune system through activation of macrophages, T cells, and natural killer (NK) cells. In a previous study, the combination of immunotherapy with the maitake D-Fraction and chemotherapy suggested that the D-Fraction may have the potential to decrease the size of lung, liver, and breast tumors in cancer patients. In the present study, we administered maitake D-Fraction to cancer patients without anticancer drugs, and at the same time NK cell activity was monitored to investigate whether the activity is closely related with disease progression. The numbers of CD4(+) and CD8(+) cells in the peripheral blood were measured in 10 patients, and NK cell activity was assessed using K-562 cells as target cells. Serum soluble interleukin-2 receptor (sIL-2R) levels in three patients and the expression of tumor markers in four patients were determined by enzyme-linked immunosorbent assay. The slight changes observed in the CD4(+) and CD8(+) cell numbers were independent of disease severity or stage as well as serum sIL-2R levels. In contrast, maitake D-Fraction hindered metastatic progress, lessened the expression of tumor markers, and increased NK cell activity in all patients examined. Thus maitake D-Fraction appears to repress cancer progression and primarily exerts its effect through stimulation of NK activity. In addition, we conclude that measurement of NK cell activity may be a useful clinical parameter in monitoring disease progression during and following immunotherapy with maitake D-Fraction.

Background: This study aimed to investigate the association of computed tomography (CT)-assessed sarcopenia and visceral adiposity with efficacy and prognosis of immune-checkpoint inhibitor (ICI) therapy for pretreated non-small cell lung cancer (NSCLC). Methods: We retrospectively collected 74 patients with pretreated NSCLC who had initiated programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1) inhibitor monotherapy between December 2015 and November 2018 at our hospital. As CT-assessed pretreatment markers, we used psoas muscle index (PMI), intramuscular adipose tissue content (IMAC), visceral-tosubcutaneous ratio (VSR) and visceral fat area (VFA) at lumbar vertebra L3 level. We divided 74 patients into high and low groups according to each Japanese sex-specific cutoff value. Using Kaplan-Meier curves and log-rank tests, we compared overall survival (OS) and progression-free survival (PFS). Adjusted by serum albumin, neutrophil-to-lymphocyte ratio, performance status and driver mutations, multivariate Cox proportional hazard analyses evaluated various variables as independent prognostic factors of OS and PFS. Results: We could not find significant difference in response rate (RR) and disease control rate (DCR) between low and high groups according to any factors. The OS of patients with body mass index (BMI) < 18.5 was significantly shorter than that of patients with BMI ≥ 18.5 (median 3.3 vs. 15.8 months, P < 0.01), while there was no significant difference in OS and PFS according to PMI, IMAC, VSR and VFA. Multivariate analyses detected no significant prognostic factor in OS and PFS, except for low IMAC (hazard ratio 0.43, 95% confidence interval 0.18-0.998, P = 0.0496) as a favorable prognostic factor of longer OS. Conclusions: Neither PMI nor VSR, VFA might be a significant prognostic factor of PFS and OS of ICI monotherapy for pretreated NSCLC. According to our multivariate analyses, IMAC was a significant prognostic factor of OS, but not of PFS. Thus, neither sarcopenia nor visceral adiposity may be associated with the efficacy of ICI therapy.