Efficacy and safety of bone management agents administered at 12 weeks vs. 4 weeks in patients with bone metastases: A systematic review.

BACKGROUND: Bone modifying agents (BMAs) have been used to prevent skeletal-related events (SRE) in cancer patients with bone metastases. In this meta-analysis, efficacy and adverse events (AEs) were studied based on a de-escalation strategy in which the BMA dosing interval was prolonged from 4 to 12 weeks. METHODS: PubMed, Cochrane, ICHUSHI, and CINAHL were searched for articles on BMA dosing intervals from outcomes measured were the incidence of SRE and related various AEs. A quantitative meta-analysis was performed using a random-effects model to calculate relative risk ratios (RRs) and 95% confidence intervals (CIs). RESULT: The meta-analysis included three randomized controlled studies (RCTs) of Zoledronic acid hydrate (ZA) (n = 2663) and six RCTs (n = 141) on BMA other than ZA. There was no difference in the incidence of SREs when comparing the dosing frequency of 12 versus 4 weeks for BMA (RR = 1.21, 95% CI [0.82-1.78], p = 0.33). Further, AEs related to treatment discontinuation were significantly less frequent with ZA given every 12 weeks than when given every 4 weeks (RR = 0.51 [0.30-0.89], p = 0.02). In particular, renal dysfunction leading to grade ≥3 or discontinuation of treatment with ZA occurred significantly less frequently with every 12-week dosing (RR = 0.33 [0.12-0.91], p = 0.33). CONCLUSION: This meta-analysis showed no influence of BMA de-escalation on the incidence of SRE; nevertheless, AEs appeared to reduce with the de-escalated usage of ZA.

Tolerability and efficacy of durvalumab in Japanese patients with advanced solid tumors.

Blockade of programmed cell death ligand-1 with durvalumab has shown efficacy and safety in large, international studies of patients with advanced solid tumors. A phase 1, non-randomized, open-label multicenter study was initiated to evaluate durvalumab in a Japanese population. The first part of this study used a standard 3 + 3 dose-escalation design to determine the optimal dosing schedule of durvalumab. Primary objective was evaluation of safety and tolerability of durvalumab monotherapy. Secondary objectives were to evaluate maximum tolerated dose (MTD), immunogenicity, pharmacokinetics, and efficacy. Twenty-two patients (median age, 61.5 years; range, 41-76; 64% male) received durvalumab at doses of 1, 3, or 10 mg/kg every 2 weeks (q2w), 15 mg/kg q3w, or 20 mg/kg q4w. Twenty patients discontinued before completing 12 months of treatment as a result of progressive disease and two due to adverse events (AE). The most common treatment-related AE (trAE) were rash (18%) and pruritus (14%); two patients had grade ≥3 trAE including one patient each with hyponatremia and hypothyroidism. No patient experienced a dose-limiting toxicity (DLT) during the DLT evaluation period and the MTD was not identified. There were no AE leading to a fatal outcome during study treatment. Durvalumab showed dose-proportional pharmacokinetics across the 1-20 mg/kg dose range; incidence of positive titers for antidrug antibodies was 9%. One patient with lung cancer had a partial response and disease control rate at 12 weeks was 36%. In conclusion, durvalumab at the doses and regimens evaluated was safe and well tolerated in Japanese patients with advanced solid tumors.

Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy: a retrospective study and systematic review.

BACKGROUND: While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy. METHODS: To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions. RESULTS: The study population consisted of 277 patients who had received a median of 10 doses (range, 1-79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77-4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF. CONCLUSIONS: We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

Phase II clinical trial of peptide cocktail therapy for patients with advanced pancreatic cancer: VENUS-PC study.

We previously conducted a phase I clinical trial combining the HLA-A*2402-restricted KIF20A-derived peptide vaccine with gemcitabine for advanced pancreatic cancer (PC) and confirmed its safety and immunogenicity in cancer patients. In this study, we conducted a multicenter, single-armed, phase II trial using two antiangiogenic cancer vaccines targeting VEGFR1 and VEGFR2 in addition to the KIF20A peptide. We attempted to evaluate the clinical benefit of the cancer vaccination in combination with gemcitabine. Chemotherapy naïve PC patients were enrolled to evaluate primarily the 1-year survival rate, and secondarily overall survival (OS), progression free survival (PFS), response rate (RR), disease control rate (DCR) and the peptide-specific immune responses. All enrolled patients received therapy without the HLA-A information, and the HLA genotypes were used for classification of the patients. Between June 2012 and May 2013, a total of 68 patients were enrolled. No severe systemic adverse effects of Grade 3 or higher related to these three peptides were observed. The 1-year survival rates between the HLA-A*2402-matched and -unmatched groups were not significantly different. In the HLA-A*2402 matched group, patients showing peptide-specific CTL induction for KIF20A or VEGFR1 showed a better prognosis compared to those without such induction (P = 0.023, P = 0.009, respectively). In the HLA-A*2402-matched group, the patients who showed a strong injection site reaction had a better survival rate (P = 0.017) compared to those with a weak or no injection site reaction. This phase II study demonstrated that this therapeutic peptide cocktail might be effective in patients who demonstrate peptide-specific immune reactions although predictive biomarkers are needed for patient selection in its further clinical application.

Usefulness of positron emission tomography (PET)/contrast-enhanced computed tomography (CE-CT) in discriminating between malignant and benign intraductal papillary mucinous neoplasms (IPMNs).

BACKGROUND/OBJECTIVES: We evaluated the usefulness of positron emission tomography (PET)/contrast-enhanced computed tomography (CE-CT) in discriminating between malignant and benign intraductal papillary mucinous neoplasms (IPMNs). METHODS: PET/CE-CT imaging was conducted on 29 IPMN lesions, which subsequently underwent surgery. Preoperative findings on PET/CE-CT imaging were compared with the histological findings of the resected specimens to determine the diagnostic accuracy of PET/CE-CT imaging for evaluation of the differential diagnosis between benign and malignant IPMNs. RESULTS: The final diagnoses of the 29 IPMN lesions were 9 benign and 20 malignant. Overall, 18 of the 20 malignant cases were positive for FDG uptake, while 7 of 9 benign cases were negative. The sensitivity, specificity, and diagnostic accuracy for benign/malignant differentiation using FDG uptake as a marker were 90.0%, 77.8%, and 86.2%, respectively. When guideline-based high-risk findings were used as markers, sensitivity, specificity, and diagnostic accuracy for mural nodules were 50.0%, 66.7%, and 55.2%, while they were 40.0%, 56%, and 48.3% for main duct dilatation, respectively. CONCLUSIONS: FDG uptake on PET is a useful new marker for malignancy in benign/malignant differentiation. Because PET/CE-CT imaging is a noninvasive imaging modality that can evaluate FDG uptake in addition to the conventional high-risk findings, we believe it should be the first-line method for determining therapeutic approaches to IPMN.

Phase I dose-escalation study evaluating safety, tolerability and pharmacokinetics of MEDI-573, a dual IGF-I/II neutralizing antibody, in Japanese patients with advanced solid tumours.

PURPOSE: This Phase I, open-label, single-arm, dose-escalation study aimed to evaluate the safety and tolerability of the insulin-like growth factor (IGF-I/II) neutralizing antibody, MEDI-573, in Japanese patients with advanced solid tumours refractory to standard therapy or for which no standard therapy exists. The pharmacokinetics, pharmacodynamics and antitumour activity of MEDI-573 were also evaluated. METHODS: Three cohorts of patients received MEDI-573 in escalating order: cohort 1, 5 mg/kg on Day 1, 8 and 15; cohort 2, 15 mg/kg on Day 1, 8 and 15; cohort 3, 45 mg/kg on Day 1, of 21-day cycles. RESULTS: Ten patients who received at least one dose of MEDI-573 were evaluated. The median number of treatment cycles was 2.0 (range 1-6) and the median number of MEDI-573 doses received was 4.0 (range 1-17). The most commonly reported drug-related adverse events were fatigue (n = 2 patients), pyrexia (n = 2), diarrhoea (n = 2) and electrocardiogram QT prolongation (n = 2). No patients experienced a dose-limiting toxicity. Pharmacokinetics of MEDI-573 were linear with a dose-dependent increase. There were no complete or partial responses; four patients had an overall best response of stable disease. CONCLUSIONS: MEDI-573 is well tolerated at the doses investigated.

IL-6 receptor is a possible target against growth of metastasized lung tumor cells in the brain.

In the animal model of brain metastasis using human lung squamous cell carcinoma-derived cells (HARA-B) inoculated into the left ventricle of the heart of nude mice, metastasized tumor cells and brain resident cells interact with each other. Among them, tumor cells and astrocytes have been reported to stimulate each other, releasing soluble factors from both sides, subsequently promoting tumor growth significantly. Among the receptors for soluble factors released from astrocytes, only IL-6 receptor (IL-6R) on tumor cells was up-regulated during the activation with astrocytes. Application of monoclonal antibody against human IL-6R (tocilizumab) to the activated HARA-B cells, the growth of HARA-B cells stimulated by the conditioned medium of HARA-B/astrocytes was significantly inhibited. Injecting tocilizumab to animal models of brain metastasis starting at three weeks of inoculation of HARA-B cells, two times a week for three weeks, significantly inhibited the size of the metastasized tumor foci. The up-regulated expression of IL-6R on metastasized lung tumor cells was also observed in the tissue from postmortem patients. These results suggest that IL-6R on metastasized lung tumor cells would be a therapeutic target to inhibit the growth of the metastasized lung tumor cells in the brain.

Phase II study of erlotinib plus gemcitabine in Japanese patients with unresectable pancreatic cancer.

Erlotinib combined with gemcitabine has not been evaluated in Japanese patients with unresectable pancreatic cancer. This two-step phase II study assessed the safety and pharmacokinetics of erlotinib 100 mg/day (oral) plus gemcitabine 1000 mg/m(2) (i.v. days 1, 8, 15) in a 28-day cycle in the first step, and efficacy and safety in the second step. The primary end-point was safety. One hundred and seven patients were enrolled (first step, n = 6; second step, n = 101). The most common adverse event was RASH (compiled using the preferred terms rash, acne, exfoliative rash, dermatitis acneiform, erythema, eczema, dermatitis and pustular rash) in 93.4% of patients. One treatment-related death occurred. While interstitial lung disease-like events were reported in nine patients (8.5%; grade 1/2/3, 3.8/2.8/1.9%), all patients recovered or improved. The median overall survival, the 1-year survival rate and median progression-free survival were 9.23 months, 33.0% and 3.48 months, respectively. The overall response and disease control rates were 20.3% and 50.0%, respectively. In Japanese patients with unresectable pancreatic cancer, erlotinib plus gemcitabine had acceptable toxicity and efficacy that was not inferior to that seen in Western patients.

Clinical implication of the antidiuretic hormone (ADH) receptor antagonist mozavaptan hydrochloride in patients with ectopic ADH syndrome.

Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline(®)) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life.

[Gemcitabine plus S-1 combination therapy (GS therapy) for pancreatic cancer patients with high-grade hepatic metastasis].

Pancreatic cancer shows the worst prognosis among the solid tumors, and survival for patients with high-grade liver metastasis is estimated at around a few months. We reported the effects of combination therapy with gemcitabine and S-1 (GS therapy) on pancreatic cancer patients with high-grade hepatic metastasis. Patients with severe metastatic pancreatic cancer received chemotherapy comprising S-1 (30mg/m² p.o. b.i.d., days 1-14) and gemcitabine (1000mg/m² on days 1 and 8), repeated every 3 weeks. Fourteen patients (7 men, 7 women) received treatment at a mean age of 56.5 years (range, 39-76 years), achieving complete response in 1 patient, partial response in 5 patients, and stable disease in 3 patients and progressive disease in 5 patients. The response rate was thus 43%. Median progression-free survival was 186 days (95% confidence interval, 40-247 days). Median overall survival was 261 days (95% confidence interval, 162-358 days). GS therapy appears to be well-tolerated and effective in patients with high-grade hepatic metastasis.

A case of small undifferentiated intramucosal gastric cancer with lymph node metastasis.

Early gastric cancer (EGC) has a favorable prognosis after surgical gastrectomy. For intramucosal EGC with little risk of lymph node metastasis, endoscopic mucosal resection (EMR) is an accepted treatment method. Herein we document a noteworthy case of small undifferentiated gastric cancer with nodal metastasis. A 60-year-old Japanese woman underwent gastrectomy with D2 lymph node dissection for the treatment of EGC in the lower gastric body. Histological examination revealed that signet-ring cell carcinoma was located in approximately one-third of the superficial portion of the mucosal layer, with a tumor size of 13 mm. No lymphatic invasion, venous invasion, or fibrosis was observed in the submucosal layer. This case had nodal metastasis and was finally diagnosed as stage IB (T1N1M0) according to the Japanese Classification of Gastric Carcinoma (JCGC). The patient is alive without recurrence 6 years after treatment.

Inhibition of bone and muscle metastases of lung cancer cells by a decrease in the number of monocytes/macrophages.

Attention has recently focused on the critical role of inflammatory responses in the tumor stroma that provide favorable conditions for cancer-cell growth and invasion/metastasis. In particular, macrophages recruited into the tumor stroma and activated, known as tumor-associated macrophages, are suggested to promote tumorigenesis. In this study, we examined the effect of a decrease in the number of monocytes/macrophages in peripheral blood and the tumor stroma on the development of bone and muscle metastases by lung cancer cells. Treatment with clodronate encapsulated by liposomes (Cl(2)MDP-LIP) has been developed for the depletion of monocytes/macrophages in an animal model. Subcutaneous administration of Cl(2)MDP-LIP markedly reduced the number of monocytes in peripheral blood, resulting in efficient suppression of both bone metastasis and muscle metastasis when lung cancer HARA-B cells were injected into the left cardiac ventricle of mice. Treatment with Cl(2)MDP-LIP significantly reduced the number of macrophages in tumors and the number of osteoclasts in bone marrow, as well as peripheral monocytes in mice harboring lung cancer cells. In contrast, treatment with an osteoclast-targeting antibiotic, reveromycin A, inhibited bone metastasis by lung cancer cells, but not muscle metastasis. The survival of human macrophages in culture was found to be specifically blocked by Cl(2)MDP-LIP, but not by reveromycin A. Cl(2)MDP-LIP thus exerted antimetastatic effects in both bone and muscle whereas reveromycin A did so only in bone. Liposome-encapsulated bisphosphonate may modulate metastasis through decreasing the number of monocytes/macrophages in both peripheral blood and the tumor stroma, suggesting that tumor-associated macrophages might be suitable targets for antimetastatic therapy.

Human breast adenocarcinoma (MDA-231) and human lung squamous cell carcinoma (Hara) do not have the ability to cause bone resorption by themselves during the establishment of bone metastasis.

Osteolysis is an important process in the establishment of bone metastasis. The role which cancer cells play in this process is not fully understood. In this study, we first established a reproducible in vivo bone metastasis model using two types of tumor cells, human breast adenocarcinoma (MDA-231) and human lung squamous cell carcinoma (Hara cells), and examined in vitro characteristics of the tumor cells. Tumor cells injected into the left heart ventricle of nude mice preferentially metastasized to bone, 6 weeks after the inoculation. Histological observation of the bone metastatic lesion showed that tumor cells invaded the bone marrow, and osteoclasts adjacent to fibroblasts were actively resorbing the bone matrix. In vitro analysis of the tumor cells showed that MDA-231 cells express cathepsin K, matrix metalloproteinase 9 (MMP-9), and membrane type-1 matrix metalloproteinase (MT1-MMP), all of which are believed to play an important role in osteoclastic bone resorption. In contrast, Hara cells do not express cathepsin K and MT1-MMP. MMP-9 was expressed at a low level. To assess the osteolytic activity of the tumor cells, an in vitro pit assay was performed. The rabbit osteoclasts formed numerous pits on a dentin slice after 18 h of incubation, whereas tumor cells by themselves did not. Taken together, we conclude that MDA-231 and Hara cells, which metastasize to the bone in vivo, do not have enough ability to achieve bone resorption by themselves, but rather achieve it through activation of fibroblast like cells and osteoclasts.

SLCO1B1 Polymorphism Is a Drug Response Predictive Marker for Advanced Pancreatic Cancer Patients Treated With Gemcitabine, S-1, or Gemcitabine Plus S-1.

OBJECTIVES: The aim of this study was to evaluate the effects of single-nucleotide polymorphisms (SNPs) on advanced pancreatic cancer risk and overall survival (OS) in a candidate-gene approach. METHODS: Overall, 5438 SNPs in 219 candidate genes encoding several drug-metabolizing enzymes or transporters were analyzed. In the screening study, 3 SNPs were found associated with OS (P ≤ 0.0005). We validated these SNPs as part of the randomized phase 3 study (GEST study). The associations between OS and SNPs were investigated using log-rank test and Cox proportional hazards model. RESULTS: From the GEST study, the SNP rs4149086 in the 3' UTR of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene showed significant interaction with treatment (P = 0.02). In the gemcitabine group, the SNP was associated with short OS (hazard ratio [HR], 3.75; 95% confidence interval [CI], 1.30-10.8; P = 0.008) even after multiple-comparisons adjustment. In contrast, the SNP was not associated with OS in S-1 (HR, 0.77; 95% CI, 0.33-1.81; P = 0.55) or gemcitabine plus S-1 groups (HR, 1.18; 95% CI, 0.46-3.00; P = 0.72). CONCLUSIONS: Patients with advanced pancreatic cancer with the rs4149086 AG or GG genotype may obtain good clinical results when treated with S-1-containing regimens.

Inflammatory stimuli from macrophages and cancer cells synergistically promote tumor growth and angiogenesis.

The focus of the present study was whether and how infiltrating macrophages play a role in angiogenesis and the growth of cancer cells in response to the inflammatory cytokine interleukin (IL)-1beta. Lewis lung carcinoma cells overexpressing IL-1beta grew faster and induced greater neovascularization than a low IL-1beta-expressing counterpart in vivo. When macrophages were depleted using clodronate liposomes, both neovascularization and tumor growth were reduced in the IL-1beta-expressing tumors. Co-cultivation of IL-1beta-expressing cancer cells with macrophages synergistically augmented neovascularization and the migration of vascular endothelial cells. In these co-cultures, production of the angiogenic factors vascular endothelial growth factor-A and IL-8, monocyte chemoattractant protein-1, and matrix metalloproteinase-9 were increased markedly. The production of these factors, induced by IL-1beta-stimulated lung cancer cells, was blocked by a nuclear factor (NF)-kappaB inhibitor, and also by the knockdown of p65 (NF-kappaB) and c-Jun using small interference RNA, suggesting involvement of the transcription factors NF-kappaB and AP-1. These results demonstrated that macrophages recruited into tumors by monocyte chemoattractant protein-1 and other chemokines could play a critical role in promoting tumor growth and angiogenesis, through interactions with cancer cells mediated by inflammatory stimuli.

Identification of N-ethylglycine in urine of cancer patients with metastatic bone disease.

BACKGROUND: Previously, a HPLC method for the determination of N-terminal prolyl dipeptides, proline and hydroxyproline in urine with fluorescence detection after pre-column derivatization with 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride (DMS-Cl) [Inoue H, Iguchi H, Kono A, Tsuruta Y. Highly sensitive determination of N-terminal prolyl dipeptides, proline and hydroxyproline in urine by high-performance liquid chromatography using a new fluorescent labelling reagent, 4-(5,6-dimethoxy-2-phthalimidinyl)-2-methoxyphenylsulfonyl chloride. J Chromatogr 1999;724:221-230] was developed to study the relation between those analytes and bone diseases. When the urinary analytes were measured, a large peak due to an unknown substance was recognized in the chromatograms of cancer patients with metastatic bone disease, although it was scarcely present in normal subjects. In this study, we identified the unknown substance. METHODS: The fluorescent fraction based on the unknown substance was collected using HPLC and the structure of the fluorescence product was analyzed with MS, (1)H NMR and (13)C NMR. RESULTS: The fluorescence product based on the unknown substance was established to be a DMS-derivative of N-ethylglycine. CONCLUSIONS: Excretion of N-ethylglycine in the urine of cancer patients with metastatic bone disease is recognized, although N-ethylglycine is scarcely excreted in the urine of normal subjects.

[Molecular mechanism and potential targets for bone metastasis].

The incidence of bone metastasis has been increasing in all cancers in recent years. Bone metastasis is associated with substantial morbidity, including bone pain, pathological fracture, neurological deficit and/or hypercalcemia. Thus, the management of bone metastasis in patients is a clinically significant issue. In the process of bone metastasis, the primary mechanism responsible for bone destruction is cancer cell-mediated stimulation of osteoclastic bone resorption, which results in osteolysis and release of various growth factors from the bone matrix. These growth factors are prerequisites for successful colonization and subsequent invasive growth of cancer cells in bone, which is called a "vicious cycle." Thus, it is important to elucidate what molecules are involved in this step of bone destruction, and the understanding of these molecular mechanisms could lead to develop molecular-target therapies for bone metastasis. Bisphosphonates introduced in the treatment for bone metastasis have been shown to reduce skeletal morbidity. In Japan, the most potent bisphosphonate, zoledronate (ZOMETA), was introduced in this past April, and a phase III clinical trial of humanized anti-RANKL monoclonal antibody (Denosumab) against bone metastasis is under way as a global study. These new agents, which are targeted to osteoclasts, are considered to be standard management in the care of bone metastasis patients in combination with chemotherapy and/or hormone therapy.

[Clinical study of irinotecan plus infusional fluorouracil/l-leucovorin (FOLFIRI) in patients with fluoropyrimidine-resistant metastatic colorectal cancer].

The clinical efficacy and safety of irinotecan plus infusional fluorouracil/l-leucovorin (FOLFIRI) in patients with fluoropyrimidine-resistant metastatic colorectal cancer were studied retrospectively. 20 patients were treated with FOLFIRI at our hospital between October 2003 and November 2005. The objective overall response rate was 28% (5/18; 95% confidence interval, 9.7-54%). The disease control rate (CR+PR+SD) was 61%. The most frequent grade 3 to 4 adverse event was neutropenia, and it was seen in 50%. Non-hematological toxicities were mild. The median survival time was 11 months. The 1-year survival rate was 34%. This study showed the activity and safety of FOLFIRI in practice.

Crizotinib, a MET inhibitor, prevents peritoneal dissemination in pancreatic cancer.

Peritoneal dissemination is a frequent occurrence in pancreatic cancer, which is associated with a poor prognosis. MET is associated with the progression of pancreatic cancer; therefore, we evaluated the effect of a MET inhibitor, crizotinib, on peritoneal dissemination of pancreatic cancer. Crizotinib inhibited the growth of 8 pancreatic cancer cell lines with the IC50 ranging from 1.4 to 4.3 µM. Invasion of the pancreatic cancer cell line Suit-2, was suppressed in vitro at a concentration of 1.0 µM, which is sufficient for the inhibition of MET phosphorylation. This effect on cell invasion was also recapitulated by the reduction of MET expression in Suit-2 with siRNA. Crizotinib also inhibited RhoA activation in addition to MET phosphorylation. We further evaluated the effect of crizotinib on peritoneal dissemination of pancreatic cancer in vivo. Crizotinib reduced tumor burden and ascites accumulation due to development of peritoneal dissemination after inoculation of Suit-2. Taken together, crizotinib may be a potent drug for treating peritoneal dissemination of pancreatic cancer by inhibiting cancer cell proliferation and invasion, at least in part through the suppression of HGF/MET signaling and RhoA activation.

Predictive biomarkers for the efficacy of peptide vaccine treatment: based on the results of a phase II study on advanced pancreatic cancer.

BACKGROUND: The purpose of the present study was to explore novel biomarkers that can predict the clinical outcome of patients before treatment or during vaccination. These would be useful for the selection of appropriate patients who would be expected to exhibit better treatment outcomes from vaccination, and for facilitating the development of cancer vaccine treatments. METHODS: From a single-arm, non-randomized, human leukocyte antigen (HLA)-A-status-blind phase II trial of a vaccine treatment using three HLA-A*2402-restricted peptides for advanced pancreatic cancer (PC), we obtained peripheral blood samples from 36 patients of an HLA-A*2402-matched group and 27 patients of an HLA-A*2402-unmatched group. RESULTS: Multivariate analysis (HR = 2.546; 95% CI = 1.138 to 5.765; p = 0.0231) and log-rank test (p = 0.0036) showed that a high expression level of programmed death-1 (PD-1) on CD4+ T cells was a negative predictive biomarker of overall survival in the HLA-A*2402-matched group . Moreover, a high expression level of PD-1 on CD4+ T cells was a negative predictor for the induction of cytotoxic T lymphocytes (p = 0.0007). After treatment, we found that the upregulation of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) expression on CD4+ and CD8+ T cells was significantly associated with a poor clinical outcome in the HLA-A*2402-matched group (p = 0.0330, 0.0282, 0.0046, and 0.0068, respectively). In contrast, there was no significant difference for these factors in the HLA-A*2402-unmatched group. CONCLUSIONS: Our results indicate that the upregulation of PD-1 and Tim-3 expression on CD4+ and CD8+ T cells may restrict T cell responses in advanced PC patients; therefore, combination immunotherapy with blockade of PD-1 and Tim-3 to restore T cell responses may be a potential therapeutic approach for advanced PC patients. TRIAL REGISTRATION: Clinical-Trail-Registration: UMIN000008082 .