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Doxorubicin is a first-line therapy for patients with unresectable advanced soft tissue sarcoma (STS). However, because of cardiotoxicities, it is not used for patients with cardiac problems. Eribulin has exhibited efficacy for advanced STS in second- or later-line treatments. In the present study, we retrospectively analyzed the efficacy and safety of first-line eribulin therapy for patients with advanced STS unable to receive doxorubicin. Six of 28 patients who received eribulin as any line treatment received eribulin as a first-line treatment. The reasons for avoiding doxorubicin were as follows: cardiac problems for four patients and advanced age for two. Median progression-free survival (PFS) of the patients who received eribulin as first-line and, second or later-line therapy were 9.7 months (95% CI: 1.0-not reached) and 3.9 months (95% CI: 2.7-5.9), which were not significantly different. The reasons for discontinuation of eribulin were disease progression and adverse events (2 fatigue and 1 neuropathy) for three patients each. No treatment-related cardiotoxicity was observed. The findings of this study indicated that eribulin exhibits meaningful efficacy for the patients with contraindications for doxorubicin as a first-line treatment without cardiac adverse events. However, appropriate safety management is necessary because older patients are typically among those intolerable of doxorubicin.

Human anti-programmed death-1 (PD-1) antibody possesses the capability to revitalize host T cells and has been an effective therapy for metastatic malignant melanoma (MM). The precise subsets of T cells predominantly activated by anti-PD-1, however, have not yet been clarified. In this study, peripheral blood mononuclear cells obtained from MM patients scheduled to receive anti-PD-1 (nivolumab) therapy, and healthy subjects (HS), were systematically examined on flow cytometry to identify changes in the proportion of immune cell subsets. Compared with HS, MM patients prior to therapy had an increased proportion of activated CD8+ T cells with effector memory phenotypes (Tem), and PD-1 positive subsets of CD4+ central memory T cells (Tcm) and T-helper (Th)17 cells. After a single course of anti-PD-1 therapy, MM patients had an increase in activated Tem and Tcm subsets of CD4+ and CD8+ T cells, and activated Th1 plus T-helper follicular 1 cells. There was no consistent change in the proportion of Tfh cells, B cells, natural killer cells, or dendritic cells. The observed activated phenotypes were attenuated during the course of therapy, but regulatory T cells belonging to the CD3+CD4+CD45RO+CD25high fraction increased at disease progression. Taken together, anti-PD-1 therapy modulates systemic immune reactions and exerts anti-tumor effects, not only by revitalizing Tem and Tcm of CD4+ and CD8+ T cells, but also via a shift to a Th1 phenotype., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Rationale: The multi-targeted tyrosine kinase inhibitors such as cediranib, sunitinib and pazopanib have been reported to be effective for alveolar soft part sarcoma (ASPS). The efficacy of pazopanib for the patient with lingual ASPS has yet to be reported., Patient Concerns: A 23-year old man presented with articulation disorder and swelling of the tongue. Diagnosis of lingual ASPS was made after incisional biopsy and complete excision of the mass was performed. Three months later, he presented with a protruding mental region., Diagnoses: Computed tomography revealed mental region mass and lung metastasis., Interventions: After the failure of combination therapy of doxorubicin and ifosfamide, pazopanib was administered., Outcomes: Shrinkage of both the mental region and lung mass continued for more than two months, but regrowth was confirmed at the fourth month., Lessons: Lingual ASPS is an exceedingly rare subset of ASPS with distinct molecular and histological characteristics and appropriate therapy remains to be established. Our findings suggest a possible therapeutic strategy for lingual ASPS.

Rationale: Regorafenib is effective for metastatic colorectal cancer but its toxicity such as hemorrhage should be considered. The safety of regorafenib for the patient with the liver disease is not known., Patient Concerns: Seventy-one-year old man of colon cancer had myodesopsia and blood stool after 14 days from the initiation of regorafenib administration with 50% dose reduction due to liver dysfunction., Diagnoses: Fundus examination revealed hemorrhage of the retinal vein., Interventions: Regorafenib treatment was discontinued and observational therapy was pursued., Outcomes: Retinal and gastrointestinal hemorrhage resolved in 1 week., Lessons: Retinal hemorrhage should be considered as the differential diagnosis of myodesopsia in the patient treated by regorafenib. Safety and pharmacokinetic of continuous regorafenib administration for patients with liver dysfunction remains to be clarified.

Background: Significant efficacy of oxaliplatin-based chemotherapy has been demonstrated for advanced gastric cancer (AGC). However, the appropriate dose of oxaliplatin, and the efficacy and toxicity of administration of oxaliplatin subsequent to cisplatin therapy still remain unclear., Patients and Methods: In total, 55 patients with AGC that were scheduled to receive oxaliplatin-based chemotherapy were prospectively examined., Results: The median age was 67 years and oxaliplatin was administered to 39 (71%) patients as first-line and in 16 (29%) patients as second-line therapy. An initial dose of 130 or 100 mg/m 2 of oxaliplatin was administered to 11 and 36 patients, respectively. The overall response rates (ORR) and median progression free survival (mPFS) were 86 and 33%, and 7.2 and 7.8 months, respectively. Compared to 100 mg/m 2 , the relative dose intensity was significantly lower and severe toxicity tended to increase with oxaliplatin at 130 mg/m 2 A total of 10 patients (18%) had a prior cisplatin-based therapy. The ORR of the patients pretreated with cisplatin was 14% and the mPFS was 6.1 months., Conclusion: An initial oxaliplatin dose of 130 mg/m 2 resulted in a good response, but tended to increase the risk of toxicity. Subsequent oxaliplatin-based therapy after cisplatin exhibited modest efficacy, especially in cases with cisplatin intolerance., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: TAS-102 is an anti-metabolite which demonstrated activity against multidrug-resistant advanced colorectal cancer. Its major toxicities are hematological disorders., Patients and Methods: Background, TAS-102 efficacy, toxicities and outcomes for patients with multidrug-resistant advanced colorectal cancer from six Institutions of the Kyushu Medical Oncology Group were retrospectively surveyed., Results: Forty-three patients, including fragile patients due to declining performance status and other comorbidities (37%) were analyzed. Efficacy was reflected in an objective overall response of 3%, median progression-free survival of 74 days (2.5 months) and median overall survival of 229 days (7.6 months). The most frequent Common Terminology Criteria for Adverse Events grade 3/4 adverse events were neutropenia (44%), leukopenia (26%) and anemia (23%). Febrile neutropenia was found in 7%. Sub-group analysis demonstrated an improved outcome on treatment with the sequence regorafenib-TAS-102., Conclusion: TAS-102 was safely administered to modestly fragile patients with equivalent efficacy to that for the non-fragile population. Further investigation of sequential treatment using regorafenib and TAS-102 is needed., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Salvage-line regorafenib monotherapy exhibited a marked survival benefit for metastatic colorectal cancer (mCRC). However, the toxicity of this regimen has resulted in the clinical use of a reduced dose of regorafenib., Patients and Methods: Thirty-two Japanese mCRC patients (median age=61 years) who had been treated with regorafenib were retrospectively examined., Results: Best objective response rate was 0% and stable disease (SD) was 31%. Median progression-free survival was 81 days and median overall survival was 233 days. Adverse events of any grade were observed in all patients: 17 (53%) patients suffered grade 3 or 4 adverse events including fatigue (13%), anorexia (13%), hand-foot skin reaction (22%) and elevations of alanine aminotransferase/aspartate aminotransferase (19%/16%). One patient with grade 5 liver dysfunction was identified (3%). Twenty-nine (91%) patients required treatment dose reduction or a delay in treatment. The relative dose intensity was 59%. Regorafenib treatments were terminated because of disease progression (59%) or adverse events (34%)., Conclusion: Despite a decrease in the intensity of regorafenib treatment, because of severe adverse events, a fairly favorable efficacy was achieved in Japanese patients., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Retroperitoneal sarcomas (RPS), such as pleomorphic leiomyosarcoma, often invade or displace vital organs in the abdominal cavity and exhibit an aggressive clinical course. Complete surgical resection of the tumor and preoperative radiotherapy and chemotherapies can be used for non-metastatic RPS. However, in case of huge retroperitoneal sarcoma fully occupying the abdominal cavity, surgical resection tends to be insufficient, resulting in poor outcomes. This report describes a case of rapidly progressive retroperitoneal pleomorphic leiomyosarcoma that was favorably controlled by debulking surgery followed by combination chemotherapy and radiotherapy., Case Presentation: A 65-year-old Japanese woman developed abdominal discomfort due to a huge retroperitoneal tumor fully occupying the abdominal cavity. The immunohistochemical diagnosis was pleomorphic leiomyosarcoma with high-grade malignancy and aggressive proliferative features. Debulking surgery could be performed, but the small residual tumor had rapidly grown to an approximately 22 cm in length on the major axis within 38 days after the operation. The patient's general condition progressively declined. Combination chemotherapy, consisting of doxorubicin and ifosfamide, was successfully administered for six cycles while maintaining dose intensity. The best objective response was a partial response, and the chemotherapy was well tolerated. Approximately 50 Gy of radiotherapy was delivered to the remaining tumor. This multimodal strategy resulted in progression-free survival for more than 17 months and achieved sustained symptomatic relief., Conclusions: Multimodal therapy with debulking surgery, combination chemotherapy and radiotherapy controlled a rapidly progressive retroperitoneal pleomorphic leiomyosarcoma. Maintaining dose intensity of the chemotherapy and radiotherapy might contribute to overall tumor control.

The Japanese guidelines for the proper use of granulocyte-colony stimulating factor(G-CSF)have been revised on the basis of the current international guidelines and latest evidence. The guidelines for primary and secondary prophylactic administration of G-CSF are clearly defined in the revised version. Primary prophylactic administration is recommended as per the incidence of febrile neutropenia(FN): it is highly recommended for patients with an FN rate>20%, but selectively recommended for patients with an FN rate<20%. Secondary prophylactic administration is recommended only for patients who should be maintained on a constant dose of G-CSF for curative purposes. The revised version aims to improve, not limit, the clinical use of G-CSF based on both patient- and evidence-oriented decisions in clinical practice.

Background: Oxaliplatin is a platinum compound that is clinically effective for colorectal cancer (CRC), in combination with 5-fluorouracil (5-FU) and leucovorin (LV), and it is widely used for metastatic disease and for the adjuvant treatment of stage III CRC. With the increasing use of oxaliplatin in Japan, serious adverse events have been experienced other than hematologic and neurologic toxicities., Methods: In order to clarify the clinical features of allergic reactions to oxaliplatin, we retrospectively investigated CRC patients who had received oxaliplatin-based chemotherapies., Results: One hundred and twenty-five CRC patients who had been treated with FOLFOX regimens (containing oxaliplatin, 5-FU, and LV) were examined, and 21 patients (17%) were found to have developed allergic reactions. Sixteen patients (13%) had grade 1/2 adverse events, classified according to the common terminology criteria for adverse events (CTC-AE) version 3.0 and 5 (4%) had grade 3/4 adverse events. The allergic reaction appeared after a median number of nine cycles (range, 2-15 cycles). Previous chemotherapy included 5-FU/LV, CPT-11, and S-1. All of the patients with allergic reactions recovered completely when treated with antiallergy drugs. Oxaliplatin was reintroduced in 11 patients, with the use of prophylactic agents; allergic reaction to the reintroduction was not observed in 8 patients and grade 1/2 allergic reactions developed in 3 patients. No correlation was identified between allergic reaction and patients' background characteristics such as sex, history of allergy, and profile of other adverse events., Conclusion: Allergic reactions to oxaliplatin remain an important issue for patients being able to safely continue effective chemotherapies; further analysis will be needed to establish methods for the prediction and prophylaxis of such reactions.

In order to define the most effective combination schedule of oxaliplatin (L-OHP) and 5-fluorouracil (5-FU), we investigated the in vitro interaction between these drugs in a panel of four human gastric adenocarcinoma cell lines (MKN-1, NUGC-3, NUGC-5 and AZ-521). Cytotoxic activity was determined by the WST-1 assay. Different schedules of the two drugs were compared and evaluated for synergism, additivity or antagonism with a quantitative method based on the median-effect principle of Chou and Talalay. Cell cycle perturbation and apoptosis were evaluated by flow cytometry. Simultaneous and sequential treatments of L-OHP followed by 5-FU exhibited synergistic effects in all four cell lines, whereas the reverse sequence yielded a clear antagonism. 5-FU exclusively arrested cells at the G0/G1 phase, and L-OHP at the G0/G1 and G2/M phases. Apoptosis was most prominent when cells were treated simultaneously or in a sequence of L-OHP followed by 5-FU, producing apoptosis in the majority of treated cells (55.5-61.5%). In contrast, the reverse sequence yielded only 20% induction of apoptosis, the rate being not significantly different from those induced by each drug singly. Moreover, this sequence dependence was further confirmed by the experiment which compared the total number of NUGC-3 cells 7 days after these combination schedules. These findings suggest that the interaction of 5-FU and L-OHP could be highly schedule dependent, with the most efficacious interaction observed in simultaneous combination and that 5-FU followed by L-OHP would not be recommended in clinical trials for patients with advanced gastric cancer.

We have conducted a pilot study with combined immunotherapy using autologous lymphocytes activated ex vivo and monocyte-derived dendritic cells in combination with low-dose OK-432, a streptococcal preparation, in five patients with peritoneal or pleural carcinomatosis who were resistant to standard chemotherapy. All patients were given 3 to 10 courses of the combined immunotherapy. No severe adverse reactions occurred. Effusion production was decreased in all of the patients. Significant decreases in tumor markers of both effusions and sera as well as effusion volume occurred in all of the patients. Cytological examinations revealed a marked decrease or disappearance of cancer cells in those effusions. Three patients showed increase in IFN-gamma levels in the effusions. The overall prognosis of the patients was acceptable and the mean survival time was more than 9 months. The locoregional immunotherapy seems to be encouraging in view of therapeutic modality in patients who are resistant to standard chemotherapy. Our study provides a new protocol for immunotherapy and warrants further phase I/II clinical study for chemo-resistant patients with malignant effusion.

Background: Patients with advanced gastric cancer (AGC) are often treated with irinotecan monotherapy as salvage-line therapy. However, the survival benefit of this therapy remains to be elucidated.Methods: Medical records of AGC patients who were treated with irinotecan monotherapy as salvage-line treatment in six institutions from 2007 to 2014 were reviewed.Results: A total of 146 patients had prior fluoropyrimidine and taxane therapies, and 75.3% had prior platinum therapy. The median age was 66 (range 27-81) years, and 102 males (69.9%) were included. Performance status (PS) was 0/1/2/3 in 53/70/19/4 patients. Eighty-nine patients (61.0%) had two or more metastatic sites. Irinotecan monotherapy as 3rd-/4th-line therapy was performed in 135/11 (92.5%/7.5%). The median number of administrations was 4 (range 1-62). Forty-six patients (31.5%) required initial dose reduction at the physician’s discretion. The overall response rate was 6.8%, and the disease control rate was 43.1%. The median PFS was 3.19 months [95% confidence interval (CI) 2.30-4.08 months], and the median OS was 6.61 months (95% CI 5.94-7.28 months). Grade 3/4 adverse events were hematological toxicity (46 patients, 31.5%) and non-hematological toxicity (50 patients, 34.2%). Hospitalization due to adverse events was required in 31 patients (21.2%). Patients with relative dose intensity (RDI) less than 80% showed similar survival to those with RDI 80% or higher.Conclusions: Irinotecan monotherapy was relatively safely performed as salvage-line treatment for AGC in Japanese clinical practice. Careful patient selection and intensive modification of the dose of irinotecan might possibly be associated with favorable survival. [ABSTRACT FROM AUTHOR]

Background: Oxaliplatin + S-1 is a recognized treatment regimen in Japan, but there are no Japanese clinical data on an oxaliplatin dose of 130 mg/m2. The current research involves a single-arm, prospective, phase II clinical trial to examine the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130 mg/m2 to treat HER2-negative advanced/recurrent gastric cancer previously untreated with chemotherapy in Japan.Methods/design: The primary endpoint of this trial will be the response rate, and the secondary endpoints will be the safety profile of oxaliplatin + S-1, progression-free survival, the response rate in subjects under the age of 75, overall survival, time to treatment failure, duration of treatment, time to failure of strategy, and dose intensity. The threshold response rate is 45% and the expected response rate is 60%. Assuming that a one-tailed score test will be performed with an α of 0.05, 68 patients are needed to ensure a statistical power of 80%. Planned enrollment is 70 subjects and the total duration of this trial is expected to be 3 years.Discussion: Since replacing cisplatin with oxaliplatin should provide the same level of therapeutic efficacy while limiting adverse events and simplifying treatment, oxaliplatin + S-1 may be increasingly used to treat gastric cancer in Japan. Verifying the efficacy and safety of oxaliplatin + S-1 with an oxaliplatin dose of 130 mg is an important task that the current trial has set out to achieve.Trial Registration: The protocol was registered at the website of the University Hospital Medical Information Network (UMIN), Japan (protocol ID UMIN000017550) on May 29, 2015. The details are available at the following web address: http://www.umin.ac.jp/ctr/ . [ABSTRACT FROM AUTHOR]

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Purpose: Standard therapy for advanced small bowel adenocarcinoma (SBA) has not yet been established. The present study assessed the efficacy and safety of chemotherapy (CT) in association with molecular targeting approaches for SBA.Methods: The histories of 33 advanced SBA patients from six different institutions in Japan, who received CT from 2008 to 2016, were retrospectively examined for background, clinical course and outcome.Results: Median patient age was 65 years (range 39-83). Primary tumor was located in the duodenum in 21 patients (67%), the ampulla of Vater in three patients (9%), the jejunum in seven patients (21%) and the ileum in one patient (3%). Histologically, well-to-moderately and poorly differentiated adenocarcinoma were identified in 20 (61%) and nine (27%) patients, respectively. Thirteen patients received a single CT regimen, seven patients received two types of CT regimen, and 13 patients received three or more CT regimens. As first-line CT, modified FOLFOX6, capecitabine plus oxaliplatin, and S-1 plus cisplatin were employed in 13, 1, and 4 patients, respectively. The response rate (RR) and median progression-free survival (PFS) were 25% and 6.0 months, respectively. Median overall survival (OS) was 13.0 months. Nine out of the 33 patients received bevacizumab-containing CT and three received cetuximab-containing CT. Median OS of bevacizumab-containing CT patients was 21.9 months. No unexpected serious adverse events were observed.Conclusions: The analysis indicates that combination CT for advanced SBA is associated with modest efficacy and safety, and bevacizumab-containing CT may contribute to favorable outcome in these patients. [ABSTRACT FROM AUTHOR]

Background: Patients with advanced gastric cancer (AGC) often suffer weight loss, which can be used to predict prognosis. Few reports have assessed the correlation between weight loss during chemotherapy and survival in patients with AGC. Methods: Fifty-three patients with histologically proven AGC, who started systemic chemotherapy from September 2010 to March 2014, were retrospectively examined for body weight, inflammatory status, and survival. Correlation analyses were performed between weight change and survival. Correlations between weight loss and the patient characteristics were analyzed by stepwise multiple regression analyses. Results: The mean age of the patients was 64.4 years; 64% of the patients were males. Initial chemotherapy included fluoropyrimidine plus cisplatin (62%), fluoropyrimidine alone (26%), and other medications (12%); 72% of the patients exhibited weight loss during the initial therapy. Poorer mean overall survival and mean progression-free survival were observed in patients with weight loss of higher-than-average values than in those with weight loss of lower-than-average values. Serum C-reactive protein levels were significantly correlated with weight loss. Conclusions: Weight loss during initial chemotherapy for AGC may predict survival. Systemic inflammation is suggested to be associated with weight loss. [ABSTRACT FROM AUTHOR]

Purpose: Although gefitinib, a selective inhibitor of epidermal growth factor receptor (EGFR) tyrosine kinase, has been demonstrated to exhibit its antitumor activity by the blockade of EGF receptor, the role of signaling pathways downstream of EGFR in gefitinib sensitivity remains unknown. In this study, we investigated the mechanistic role of Src and Ras, major oncogene products implicated in the pathogenesis of many human cancers in gefitinib sensitivity. Methods: Using parental and v- src- or c-H- ras-transfected HAG-1 human gallbladder adenocarcinoma cell lines, effects of gefitinib on cytotoxicity, cell cycle purtubation and apoptosis, and tyrosine phosphorylation of EGFR, Akt, and Erk were determined by WST-1 assay, flow cytometry, and Western blots, respectively. Results: Activated Ras and Src conferred a strong resistance to gefitinib by nearly 30-fold and 200-fold, respectively. Gefitinib induced accumulation of cells in the G0/G1 phase of the cell cycle at 24-h, with progressive expansion of apoptotic cell population in parental HAG-1 cells, but these effects were completely abolished in v- src- or c-H- ras-transfected cell line. Upon gefitinib treatment, EGFR activation and subsequent downstream activation through Erk and Akt were significantly inhibited in HAG-1 cells. By contrast, gefinitib failed to inhibit the activation of both Akt and Erk in v-src-transfected cells and Erk, but not Akt in c-H-ras-transfected cells, despite the blockade of EGFR activation in these respective cell lines. Treatment of v-src-transfected cells with herbimycin A, a Src tyrosine kinase inhibitor, partially reversed the gefitinib resistance, with concomitant inhibition of Akt and Erk. Conclusion: Our results suggest that activated Ras and Src could induce gefitinib resistance by activating either or both of Akt and Erk signaling pathways, thus providing a strategic rationale for assessment of these specific signaling molecules downstream of EGFR to customize treatment. [ABSTRACT FROM AUTHOR]

Purpose: To define the most effective combination schedule of paclitaxel and nedaplatin, a new platinum derivative, we investigated the in vitro interaction between these drugs in AZ-521 and NUGC-4 gastric adenocarcinoma and KSE-1 esophageal squamous carcinoma cell lines. Materials and methods: Cytotoxic activity was determined by the WST-1 assay. Different treatment schedules of the two drugs were compared and evaluated for synergism, additivity, or antagonism using a quantitative method based on the median-effect principle of Chou and Talalay. Cell-cycle perturbation and apoptosis were evaluated by means of flow cytometry. Results: Upon 24-h sequential exposure, the sequence paclitaxel followed by nedaplatin induced greater than additive effects in all of the cell lines, with synergistic interactions in NUGC-4 and KSE-1 cells. By contrast, antagonistic effects were observed with the reverse sequence. Simultaneous treatment resulted in either a synergistic or antagonistic effect, depending on the cell line. Therefore, the sequence paclitaxel followed by nedaplatin appears most active, at least in these three cell lines. Flow cytometric analyses at IC50 indicated that paclitaxel induced G2/M arrest with subsequent induction of apoptosis (56%) in the sub-G1 phase. When paclitaxel preceded nedaplatin, apoptosis was most prominent (70%) with pronounced G2/M arrest. By contrast, the reverse sequence yielded only 28% induction of apoptotic cells, with almost identical cell-cycle distribution patterns to those observed with nedaplatin alone, indicating that the activity of paclitaxel is abolished by pretreatment with nedaplatin. Conclusions: Our findings suggest that the interaction of nedaplatin and paclitaxel is highly schedule dependent and that the sequential administration of paclitaxel followed by nedaplatin should be thus incorporated into the design of a clinical trial. [ABSTRACT FROM AUTHOR]

For vaccinations based on dendritic cells (DCs), maturation of DCs is critical to the induction of T-cell responses. We tested the efficacy of streptococcal preparation OK-432 as a Good Manufacturing Practice (GMP)–grade maturation agent. OK-432 is currently used in Japan as a cancer immunotherapy drug. Immature monocyte-derived dendritic cells (imMo-DCs) isolated from human peripheral blood monocytes stimulated with granulocyte-macrophage colony stimulating factor and interleukin-4 were exposed to maturation factors, i.e., lipopolysaccharide (LPS), tumor necrosis factor α (TNF-α) plus prostaglandin E2 (PGE2), and OK-432 for 2 days. OK-432 increased expression of activation- and maturation-related molecules such as HLA-DR, CD80, CD83, and CD86 in imMo-DCs at levels similar to that of TNF-α plus PGE2,and higher than that of LPS. All agents examined induced allogeneic T-cell proliferation at a similar level. Only OK-432 caused significant production of interleukin-12 (IL-12) p70 and interferon γ (IFN-γ) at both the mRNA and protein levels in imMo-DCs. Neutralizing antibody against IL-12 p70 blocked IFN-γ secretion from OK-432–stimulated Mo-DCs. IL-12 p70 produced by OK-432–stimulated imMo-DCs induced secretion of IFN-γ by CD4+ T cells. OK-432 and LPS activated nuclear factor κ B (NF-κB) in imMo-DCs. Both secretion of IL-12 p70 and IFN-γ and activation of NF-κB induced by OK-432 were suppressed when imMo-DCs were pretreated with cytochalasin B. These results indicate that uptake of OK-432 by imMo-DCs is an early critical event for IL-12 p70 production and that NF-κB activation induced by OK-432 also contributes partially to IL-12 p70 production. In conclusion, OK-432 is a GMP-grade maturation agent and may be a potential tool for DC-based vaccine therapies. [ABSTRACT FROM AUTHOR]