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.

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.

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.

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.

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.

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 .

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.

Recent aspects for disseminated carcinomatosis of the bone marrow associated with gastric cancer: What has been done for the past, and what will be needed in future?

Disseminated carcinomatosis of the bone marrow is characterized by widespread bone metastasis (bone marrow infiltration) from solid tumors with hematological disorders coexisted. This disease is frequently complicated with gastric cancer among solid tumors although its incidence is very rare. In recent years, technological innovations in diagnosis and treatment for cancer have remarkably improved, which made survival rates of various cancers prolonged. Prognosis of disseminated carcinomatosis of the bone marrow associated with gastric cancer, however, is still poor (less than a year), possibly because this disease has not been given attention due to low incidence. In this review, I summarize the results obtained for the past, and propose ways to improve the prognosis of this disease.

A Phase I study of MEDI-575, a PDGFRα monoclonal antibody, in Japanese patients with advanced solid tumors.

PURPOSE: MEDI-575 is a fully human monoclonal antibody that selectively binds to platelet-derived growth factor receptor alpha (PDGFRα). This open-label Phase I study assessed the safety and tolerability of MEDI-575 in Japanese patients with advanced solid tumors. METHODS: The study comprised two parts: Part A, dose escalation; Part B, dose expansion in patients with hepatocellular cancer. In Part A, patients were enrolled into three cohorts: MEDI-575 was administered intravenously over a 21-day treatment cycle at doses of 9 and 15 mg/kg/week (cohorts 1, 2) and 35 mg/kg/3-weekly (cohort 3). In Part B, MEDI-575 25 mg/kg/3-weekly was administered. Secondary measures included assessment of the maximum tolerated dose, pharmacokinetics, immunogenicity and anti-tumor activity. RESULTS: Ten and 12 patients were treated in Parts A and B, respectively. There were no dose-limiting toxicities; the maximum tolerated dose was not determined. Common treatment-related adverse events were fatigue (30%) and decreased appetite (20%) in Part A and decreased appetite (33.3%) in Part B. All treatment-related adverse events were grade 1 or 2 in severity. No patients discontinued MEDI-575 because of an adverse event and there were no patient deaths due to adverse events. MEDI-575 binding with PDGFRα resulted in a dose-dependent increase in PDGF-AA ligand, with plateau levels observed within 2 days and sustained during the dosing interval. None of the patients in Part A or B experienced complete or partial responses to treatment. CONCLUSIONS: MEDI-575 once weekly and 3-weekly was well tolerated with a favorable pharmacokinetic profile in Japanese patients with advanced solid tumors. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01102400.

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.

Maximum standardized uptake value in 18F-fluoro-2-deoxyglucose positron emission tomography is associated with advanced tumor factors in esophageal cancer.

Positron emission tomography/computed tomography (PET/CT) with 18F-fluoro-2-deoxyglucose (FDG-PET/CT) has become established in cancer imaging, and derived maximum standardized uptake values (SUVmax) add functional information regarding cancer, including esophageal squamous cell carcinoma (ESCC). The aim of the present study was to determine the clinical significance and association of tumor progression using SUVmax derived from PET/CT images in patients with ESCC. In total, 101 patients with ESCC were assessed using FDG-PET/CT and the SUVmax was then compared with the clinical backgrounds and prognoses of the patients. Endoscopic ESCC biopsy specimens were obtained in order to analyze mRNA expression relative to tumor progression. The results showed that values for SUVmax were significantly higher in patients with tumor progression factors, particularly those with lymph node metastasis. Analysis of receiver operating characteristics curves revealed an optimum SUVmax cut-off value of 10.26 for node-positive disease. Patients with SUVmax ≥10.26 had gene alterations with epithelial-mesenchymal transition (EMT) and significantly worse overall survival (P=0.0012). A higher SUVmax in patients with ESCC was associated with lymph node metastasis and a poorer prognosis. Thus, the SUVmax may reflect the potential of EMT in patients with ESCC.

Involvement of CXCL14 in osteolytic bone metastasis from lung cancer.

To investigate the molecular mechanisms of lung cancer-induced bone metastasis, we established a bone-seeking subclone (HARA-B4) from a human squamous lung cancer cell line (HARA) using an in vivo selection method. We compared comprehensive gene expression profiles between HARA and HARA-B4, and identified the critical factors for the formation of bone metastasis using in vitro and in vivo assays. The number of bone metastatic colonies in the hind legs was significantly higher in HARA-B4-inoculated mice than in HARA-inoculated mice at 4 weeks after inoculation. In addition, visceral (adrenal) metastases were not found in HARA-B4-inoculated mice at autopsy, suggesting an increase in cancer cell tropism to bone in HARA-B4. Based on a comprehensive gene expression analysis, the expression level of CXC chemokine ligand 14 (CXCL14) was 5-fold greater in HARA-B4 than in HARA. Results of a soft agar colony formation assay showed that anchorage-independent growth ability was 4.5-fold higher with HARA-B4 than with HARA. The murine pre-osteoblast cell line MC3T3-E1 and the pre-osteoclast/macrophage cell line RAW264.7 migrated faster toward cultured HARA-B4 cells than toward HARA cells in a transwell cell migration assay. Interestingly, CXCL14 was shown to be involved in all events (enhancement of cancer cell tropism to the bone, anchorage-independent growth and/or recruitment of bone marrow cells) based on siRNA experiments in HARA-B4 cells. Furthermore, in clinical specimens of lung cancer-induced bone metastasis, expression of CXCL14 was observed in the tumor cells infiltrated in bone marrow in all specimens examined. CXCL14 was able to promote bone metastasis through enhancement of cancer cell tropism to the bone and/or recruitment of bone marrow cells around metastatic cancer cells.

Utility of contrast-enhanced FDG-PET/CT in the clinical management of pancreatic cancer: impact on diagnosis, staging, evaluation of treatment response, and detection of recurrence.

OBJECTIVES: Fluorodeoxyglucose (FDG)-positron emission tomography/contrast-enhanced computed tomography (PET/CE-CT) involving whole-body scanning first by non-CE-CT and FDG-PET followed by CE-CT has been used for detailed examination of pancreatic lesions. We evaluated PET/CE-CT images with regard to differential diagnosis, staging, treatment response, and postoperative recurrence in pancreatic cancer. METHODS: Positron emission tomography/CE-CT was conducted in 108 patients with pancreatic cancer and in 41 patients with other pancreatic tumor diseases. RESULTS: The maximum standardized uptake value (SUV(max)) overlapped in benign and malignant cases, suggesting that differential diagnosis of pancreatic tumors based on the SUV(max) is difficult. In the evaluation of staging in 31 resectable pancreatic cancer by PET/CE-CT, the diagnostic accuracy rate was more than 80% for most factors concerning local invasion and 94% for distant metastasis but only 42% for lymph node metastasis. Significant positive correlations were found between the SUV(max) and tumor size/markers, suggesting that SUV(max) may be a useful indicator for the treatment response. Regarding the diagnosis of the postoperative recurrence, PET/CE-CT correctly detected local recurrence in all the 11 cases of recurrence, whereas abdominal CE-CT detected only 7 of 11 cases, suggesting that PET/CE-CT is superior in this context. CONCLUSIONS: Positron emission tomography/CE-CT is useful for the clinical management of pancreatic cancer.

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.

The bisphosphonate incadronate inhibits intraperitoneal dissemination in an in vivo pancreatic cancer model.

Pancreatic cancer is characterized by intraperitoneal dissemination and often by large volumes of ascites. Aminobisphosphonates exhibit potent antitumor effects and are currently being tested against human solid tumors. Several aminobisphosphonates inhibit cancer cell migration by preventing the activation of Rho through inhibition of the mevalonate pathway. We evaluated the ability of an aminobisphosphonate, incadronate, to inhibit the growth of disseminated pancreatic cancer in vivo. We established an in vivo pancreatic cancer model with i.p. carcinomatosis in nude mice. Incadronate administration started from the day of tumor inoculation, and reduced tumor burden and ascites accumulation. Further, we evaluated the effect of incadronate on the inhibition of pancreatic cancer cell proliferation, migration and invasion in vitro. Incadronate induced growth inhibition and apoptotic death of pancreatic cancer cells. It also inhibited migration presumably by preventing the activation of Rho by lysophosphatidic acid. Thus, the in vivo antitumor effect may result from the inhibition of cancer cell proliferation and migration. The potent effects of incadronate in reducing tumor burden and ascites suggest that it will be of value in regimens for the treatment of pancreatic cancer.

[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.

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.

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.

Interaction between lung cancer cells and astrocytes via specific inflammatory cytokines in the microenvironment of brain metastasis.

The incidence of brain metastasis is increasing, however, little is known about molecular mechanism responsible for lung cancer-derived brain metastasis and their development in the brain. In the present study, brain pathology was examined in an experimental model system of brain metastasis as well as in human brain with lung cancer metastasis. In an experimental model, after 3-6 weeks of intracardiac inoculation of human lung cancer-derived (HARA-B) cells in nude mice, wide range of brain metastases were observed. The brain sections showed significant increase in glial fibrillary acidic protein (GFAP)-positive astrocytes around metastatic lesions. To elucidate the role of astrocytes in lung cancer proliferation, the interaction between primary cultured mouse astrocytes and HARA-B cells was analyzed in vitro. Co-cultures and insert-cultures demonstrated that astrocytes were activated by tumor cell-oriented factors; macrophage migration inhibitory factor (MIF), interleukin-8 (IL-8) and plasminogen activator inhibitor-1 (PAI-1). Activated astrocytes produced interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and interleukin-1 ß (IL-1ß), which in turn promoted tumor cell proliferation. Semi-quantitative immunocytochemistry showed that increased expression of receptors for IL-6 and its subunits gp130 on HARA-B cells. Receptors for TNF-α and IL-1ß were also detected on HARA-B cells but down-regulated after co-culture with astrocytes. Insert-culture with astrocytes also stimulated the proliferation of other lung cancer-derived cell lines (PC-9, QG56, and EBC-1). These results suggest that tumor cells and astrocytes stimulate each other and these mutual relationships may be important to understand how lung cancer cells metastasize and develop in the brain.