[Show abstract][Hide abstract] ABSTRACT: Cancer vaccine is one of the attractive treatment modalities for patients with castration-resistant prostate cancer (CRPC). However, because of delayed immune responses, its clinical benefits, besides for overall survival (OS), are not well captured by the World Health Organization (WHO) and Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Several surrogate markers for evaluation of cancer vaccine, including prostate-specific antigen doubling time (PSADT), are currently sought. The purpose of this study was to assess prospectively the PSA kinetics and immune responses, as well as the efficacy, safety, and biomarkers of personalized peptide vaccination (PPV) in progressive CRPC.
One hundred patients with progressive CRPC were treated with PPV using 2-4 positive peptides from 31 candidate peptides determined by both human leukocyte antigen (HLA) class IA types and the levels of immunoglobulin G (IgG) against each peptide. The association between immune responses and PSADT as well as overall survival (OS) was studied.
PPV was safe and well tolerated in all patients with a median survival time of 18.8 months. Peptide-specific IgG and T-cell responses strongly correlated with PSADT (p < 0.0001 and p = 0.0007, respectively), which in turn showed correlation with OS (p = 0.018). Positive IgG responses and prolongation of PSADT during PPV were also significantly associated with OS (p = 0.001 and p = 0.004) by multivariate analysis.
PSADT could be an appropriate surrogate marker for evaluation of the clinical benefit of cancer vaccine. Further randomized trials are needed to confirm these results.Trial registration: UMIN000001850.
BMC Cancer 12/2013; 13(1):613. · 3.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treating extended prostatic small cell neuroendocrine carcinoma (PSCNC) is extremely difficult and no standard treatment has yet been established. We experienced a case of advanced mixed-type PSCNC in which the patient achieved long-term survival and local control following combined therapy. Locally advanced PSCNC causing lower urinary obstruction was detected during androgen-ablation therapy for stage D2 mixed adenocarcinoma PSCNC. The patient was treated with intra-arterial infusion chemotherapy using a reservoir system and external-beam radiotherapy (EBRT) to the whole pelvis and local tumor. After chemoradiotherapy, the patient's lower urinary obstruction was reduced and did not return during the remaining 40 months of the patient's life. The patient survived for 70 months following the start of the androgen-ablation therapy. The present study reports a useful treatment for advanced mixed-type PSCNC, androgen-ablation therapy and chemoradiotherapy. The present results also suggest that the prognostic factors for advanced mixed-type PSCNC are the sensitivity of the conventional adenocarcinoma to androgen-ablation therapy, degree of metastasis and extent of the small cell neuroendocrine carcinoma component.
[Show abstract][Hide abstract] ABSTRACT: In general, only ≤5% of patients with renal cell carcinoma (RCC) develop paraneoplastic erythropoietin (EPO) overproduction-induced polycythemia. However, a number of reports on EPO-producing RCC are available. The present study aimed to report the first case of a patient demonstrating a therapeutic effect on EPO-producing advanced RCC, subsequent to targeted pre-surgical sunitinib therapy, with a review of the literature. The patient involved was a 62-year-old male who presented with a malformation of the left scrotum. Examination revealed a tumor of 73 mm in diameter along with lymph node metastasis. The histological examination indicated a clear cell RCC containing viable cells as well as hemorrhage and necrosis. EPO in cancer cells was confirmed by immunohistochemistry. Subsequently, a case of EPO-producing RCC with polycythemia was diagnosed. The EPO-producing RCC was successfully treated following targeted presurgical therapy with sunitinib.
Molecular and Clinical Oncology 01/2013; 1(1):112-116.
[Show abstract][Hide abstract] ABSTRACT: Adenoma of the retinal pigment epithelium (RPE) is a rare intraocular tumor that can simulate other pigmented tumors such as choroidal melanoma. We report a case of non-pigmented adenoma of the RPE initially diagnosed as choroidal hemangioma.
A 42-year-old woman presented to Kurume University Hospital in November 1992 with an orange-yellow tumor nasal to the optic disc in the left fundus. The tumor was 9.0 × 9.0 mm in diameter, 6.0 mm thick, and was characterized by high intensity on T1-weighted magnetic resonance imaging (MRI), low intensity on T2-weighted MRI, and enhancement on gadolinium MRI. Fluorescein angiography revealed early hypofluorescence and late hyperfluorescence of the tumor and retinal feeder vessels. By April 1996, exudate had developed around the tumor margins. The patient was treated with external beam radiation therapy (20 Gy) in July 1996, but the tumor did not diminish in size. Subsequently, she developed extensive loss of vision due to total retinal detachment. Accordingly, her left eye was enucleated in June 2005 because of severe ocular pain due to absolute glaucoma. Histopathological examination indicated that the tumor was contiguous with the normal surrounding RPE and was composed of cords and tubules of mostly non-pigmented spindle-shaped cells with round to oval nuclei and a small amount of cytoplasm containing melanin granules. The tumor cells were immunoreactive for vimentin, S-100 protein, and cytokeratin 18. The final diagnosis was adenoma of the RPE.
Adenoma of the retinal pigment epithelium may be associated with incompetent vessels leading to serous retinal detachment and extensive visual loss, and may exhibit clinical characteristics similar to choroidal hemangioma.
[Show abstract][Hide abstract] ABSTRACT: Because only a subset of patients show clinical responses to peptide-based cancer vaccination, it is critical to identify biomarkers for selecting patients who would most likely benefit from this treatment.
The authors characterized the gene expression profiles in peripheral blood of vaccinated patients to identify biomarkers to predict patient prognosis. Peripheral blood was obtained from advanced castration-resistant prostate cancer patients, who survived for >900 days (long-term survivors, n = 20) or died within 300 days (short-term survivors, n = 20) after treatment with personalized peptide vaccination. Gene expression profiles in prevaccination and postvaccination peripheral blood mononuclear cells (PBMCs) were assessed by DNA microarray.
There were no statistically significant differences in the clinical or pathological features between the 2 groups. Microarray analysis of prevaccination PBMCs identified 19 genes that were differentially expressed between the short-term and long-term survivors. Among the 15 up-regulated genes in the short-term survivors, 13 genes, which were also differentially expressed in postvaccination PBMCs, were associated with gene signatures of granulocytes. When a set of 4 differentially expressed genes were selected as the best combination to determine patient survival, prognosis was correctly predicted in 12 of 13 patients in a validation set (accuracy, 92%).
These results suggested that abnormal granulocytes present in the PBMC faction may contribute to poor prognosis in advanced prostate cancer patients receiving personalized peptide vaccination. Gene expression profiling in peripheral blood might thus be informative for devising better therapeutic strategies by predicting patient prognosis after cancer vaccines.
Cancer 11/2011; 118(12):3208-21. · 5.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Docetaxel-based chemotherapy (DBC) showed limited clinical efficacy for castration-resistant prostate cancer (CRPC) patients. To explore cancer vaccine as a new treatment modality, we conducted a phase II study of personalized peptide vaccine (PPV) for DBC-resistant CRPC patients.
Twenty DBC-resistant CRPC patients and 22 patients with no prior DBC, as a control, were treated with PPV using peptides chosen from 31 peptides in patients, respectively. Cytokines, inflammatory markers, and immune responses were measured as candidate biomarkers. DBC-resistant CRPC patients without PPV was set as a historical control for evaluation of clinical benefit of PPV.
Median overall survival (OS) time from the first vaccination was 14.8 months or not reached in DBC-resistant CRPC patients and patients with no prior DBC (log-rank; P = 0.07), respectively. Median OS time from the first day of progression disease was 17.8 and 10.5 months in DBC-resistant CRPC patients receiving PPV and those with no PPV (P = 0.1656), respectively. Elevated IL-6 levels before vaccination was an unfavorable factor for OS of DBC-resistant CRPC patients (P = 0.0161, hazard ratio (HR): 0.024, 95% CI:0.001-0.499) as well as all 42 patients with PPV(P = 0.0011, HR: 0.212, 95% CI:0.068-0.661) by multivariable analysis.
Further clinical study of PPV is recommended for DBC-resistant CRPC patients, because of the safety and possible prolongation of MST. Control of elevated IL-6 by combined therapy may provide much better clinical outcome.
The Prostate 09/2011; 72(8):834-45. · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The majority of peptide-based cancer vaccines under development are for human leukocyte antigen (HLA)-A2- or -A24-positive patients. To overcome this limitation, we conducted a phase I clinical study of peptide vaccines designed for cancer patients with six different HLA-A types. Eligible patients were required to have failed prior standard cancer therapies and to be positive for the HLA-A2, -A24 or -A3 (A3, A11, A31 and A33) supertype. Three sets of 8 candidate peptides (24 peptides in total) were provided for vaccination to HLA-A2(+), HLA-A24(+) and HLA-A3(+) patients, respectively. Personalization of the vaccination peptides from the candidate pool was made by considering the patients' HLA types and pre-existing levels of IgGs to the candidate peptides. Seventeen patients were enrolled in this study. The peptide vaccinations were well tolerated in all patients with no vaccine-related severe adverse events. Augmentation of cytotoxic T lymphocyte (CTL) or IgG responses specific to the vaccinated peptides was observed in 11 or 10 out of 13 cases tested, respectively. This new type of vaccine is recommended for phase II clinical trial because of its tolerability and the immune responses to the vaccinated peptides.
Experimental and therapeutic medicine 01/2011; 2(1):109-117. · 0.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Since the introduction of targeted therapy, treatment of metastatic renal cell carcinoma (RCC) has undergone dramatic changes. Responses to targeted therapy within the primary tumor and metastatic lesions are novel findings not seen with immunotherapeutic-based strategies. We report here a case of T4 RCC in which cytoreductive nephrectomy became possible after a neoadjuvant targeted therapy using sunitinib. Our experience with the present case suggests that targeted therapy in the neoadjuvant setting may have a variety of potential applications. Further investigations should be encouraged.
[Show abstract][Hide abstract] ABSTRACT: To investigate immunological biomarkers to predict overall survival of advanced cancer patients under treatment with personalized peptide vaccination, correlations between overall survival and biomarkers, including cytotoxic T lymphocyte (CTL) and immunoglobulin G (IgG) responses to the vaccinated peptides, were investigated in 500 advanced cancer patients who received personalized peptide vaccination from October 2000 to October 2008. The best clinical response was assessed for in 436 patients, 43 patients (10%) had partial response, 144 patients (33%) had stable disease and 249 patients (57%) had progressive, with a median overall survival of 9.9 months. Both lymphocyte counts prior to the vaccination (P = 0.0095) and increased IgG response (P = 0.0116) to the vaccinated peptides, along with performance status (P < 0.0001), well correlated with overall survival. To confirm the superiority of IgG response to CTL response, the samples from advanced castration-resistant prostate cancer patients who survived more than 900 days (n=20) and those who died within 300 days (n=23) were analyzed further. As a result, both the numbers of peptides, to which increased IgG responses were observed, and the fold increases in IgG levels were significantly higher in long-term survivors (P = 0.000282 and P = 0.00045). In contrast, CTL responses were not statistically different between the two groups. Both lymphocyte numbers and IgG response were thus suggested to be biomarkers of cancer vaccine for advanced cancer patients.
Cancer biology & therapy 12/2010; 10(12):1266-79. · 3.29 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.
Cancer Immunology and Immunotherapy 02/2010; 59(7):1001-9. · 3.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To facilitate the development of a peptide-based cancer vaccine for prostate cancer patients, we examined whether any of the 13 peptides previously reported to induce HLA-class I-restricted cytotoxic T lymphocyte (CTL) activity in HLA-A3 supertype (-A3, -A11, -A31 and -A33)-positive prostate cancer patients are also capable of inducing CTLs restricted to HLA-A2, HLA-A24 or HLA-A26 alleles. Among the 13 peptides tested, a peptide at positions 309 to 318 of β-tubulin 5 exhibited binding activity to the HLA-A(*)2402 molecule and induced HLA-A24-restricted CTL activity against prostate cancer cells derived from peripheral blood mononuclear cells of prostate cancer patients. The CTL activity was determined to be specific to this peptide and was mediated by CD8(+) T cells in an HLA-class I-restricted manner. These results suggest that this peptide could be applicable as a peptide vaccine, not only for HLA-A3 supertype-positive, but also for HLA-A24-positive prostate cancer patients.
Experimental and therapeutic medicine 01/2010; 1(5):833-839. · 0.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: N-myc downstream regulated gene 1 (NDRG1)/Cap43 is a 43 kDa protein that is widely distributed in the body. Its expression is regulated by nickel, cobalt, hypoxic condition and others; it is reported to be weaker in tumors than normal tissues; and NDRG1/Cap43 is considered to act suppressively to tumor metastasis. This current study immunohistochemically examined NDRG1/Cap43 expression in hepatocellular carcinoma (HCC), and analyzed its relationship to clinicopathologic factors and prognosis. The samples were 105 surgically resected HCC tissue blocks, i.e., 18 well-differentiated HCC, 61 moderately differentiated HCC, 10 poorly differentiated HCC, 9 'nodule-in-nodule' type HCC, and 7 sarcomatous HCC. In all cases, NDRG1/Cap43 was not expressed in normal liver cells. Strong expression was found in 65 of the 105 cases (62%), i.e., in 11.1% of well-differentiated HCC, 72.1% of moderately differentiated HCC, 80.0% of poorly differentiated HCC, and 71.4% of sarcomatous HCC. In the 'nodule-in-nodule' type, its expression was found in 55.6% of their well-differentiated component, and this frequency was significantly higher than that in well-differentiated HCC (11.1%). In the cases showing strong NDRG1/Cap43 expression, frequency of portal vein invasion and of intrahepatic metastasis was significantly high. No clear relationship between the expression and prognosis was observed. NDRG1/Cap43 expression that was found in advanced HCC was thought to accelerate tumor invasion and metastasis. NDRG1/Cap43 could act as a useful biomarker of HCC.
[Show abstract][Hide abstract] ABSTRACT: We report a case of primary mucosa-associated lymphoid tissue (MALT) lymphoma of the prostate. A 67-year-old man presented with urinary obstruction and an elevated prostate-specific antigen (PSA) level. A physical examination revealed mild prostate enlargement and no lymphadenopathy. A needle biopsy and immunohistochemical studies of the prostate were performed, which revealed marginal zone B-cell MALT-type lymphoma. A bone marrow aspiration and biopsy did not show involvement by lymphoma. Magnetic resonance imaging (MRI) of the abdomen and the pelvis revealed no lymphadenopathy or ascites. There was no involvement of other sites by lymphoma. The patient was diagnosed and staged as extranodal marginal zone B-cell MALT-type lymphoma of the prostate, low grade and stage I. The patient received external beam radiation therapy to the prostate with a total dose of 3600cGy in 22 fractions, and became free of disease within the following 15 months.
[Show abstract][Hide abstract] ABSTRACT: We investigated the effects of pegylated IFN-alpha2b (PEG-IFN-alpha2b) alone and PEG-IFN-alpha2b plus 5-fluorouracil (5-FU) in vitro on the proliferation of renal cell carcinoma (RCC) cell lines. After the transplantation of RCC cells into nude mice, we administered IFN (PEG-IFN-alpha2b or IFN-alpha2b) alone, 5-FU alone, or IFN (PEG-IFN-alpha2b or IFN-alpha2b) plus 5-FU; and investigated tumor volume, tumor weight, the numbers of apoptotic cells and artery-like blood vessels, relative mRNA expression levels of enzymes which relate to 5-FU metabolism, angiogenesis factor, and type I interferon receptor. RCC cells in vitro were generally and relatively resistant to the anti-proliferative effects of PEG-IFN-alpha2b, but the addition of 5-FU augmented IFN-induced anti-proliferative effects with the induction of apoptosis. PEG-IFN-alpha2b in vivo presented stronger anti-tumor effects than IFN-alpha2b, and its combination with 5-FU augmented the effects. The significant anti-tumor effect of the combination treatment was the increase in apoptotic cell number, but there were no significant differences in the suppression of angiogenesis, expression of IFN receptor, and the actions of metabolic enzymes of 5-FU. In conclusion, PEG-IFN-alpha2b presents stronger anti-tumor effects than non-pegylated IFN, and the effects are augmented in the combination with 5-FU. Our findings suggest the clinical usefulness of PEG-IFN-alpha2b in the treatment of RCC.
International Journal of Oncology 11/2008; 33(4):647-55. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To evaluate the immunological responses of personalized peptide vaccination combined with low-dose glucocorticoids for advanced hormone refractory prostate cancer (HRPC) patients (pts).
Eleven pts with advanced HRPC were treated with the vaccination and low-dose glucocorticoids; 6 pts with 10 mg/day of prednisolone (PDL) followed by 1 mg/day of dexamethasone at the time of progression, 1 pt with PDL, and 4 pts with dexamethasone. Peptide-specific cellular and humoral responses were employed to monitor pre- and post- (6th) vaccination samples.
The vaccination combined with glucocorticoids was well tolerated with no severe adverse effects. Increments of IgG responses were observed in 1 of 4 or 8 of 10 pts tested who received PDL or dexamethasone, respectively, increment of cytotoxic T lymphocyte activity was observed in 2 of 4 or 5 of 7 pts tested, respectively. Vaccination with PDL or dexamethasone resulted in a decline of PSA (at least 50%) in 1 of 7 or 6 of 10 pts with significantly longer median TTP in the dexamethasone group, respectively.
Vaccination combined with dexamethasone could be recommended for further clinical trials from both immunological and clinical points of view.
The Prostate 10/2008; 68(16):1753-62. · 3.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fucoidan, the general term for sulfated polysaccharides, is reported to engage in various biological activities having anti-tumor, anti-coagulation and anti-viral effects. Though it has been investigated, the mechanism of its anti-tumor effects remains elusive. The current study examined the anti-tumor effects of fucoidan extracted from Okinawa mozuku on 15 human cancer cell lines (6 hepatocellular carcinomas, 1 cholangiocarcinoma, 1 gallbladder cancer, 2 ovarian cancers, 1 hepatoblastoma, 1 neuroblastoma and 3 renal cancers) using an MTT assay. Changes in apoptosis and the cell cycle were analyzed by flow cytometry. The results revealed that cell proliferation was suppressed in 13 cell lines in a time- and/or dose-dependent manner; this suppression was marked in the hepatocellular carcinoma, cholangiocarcinoma and gallbladder carcinoma cell lines. In contrast, proliferation of the neuroblastoma and 1 of the 2 ovarian carcinoma cell lines was not affected. The ratio of apoptotic cells significantly increased in 5 of the 6 hepatocellular carcinoma cell lines, and the ratio of G2/M cells increased in the 3 hepatocellular cell lines examined. These observations indicate that fucoidan is a potential anti-tumor agent for the treatment of bile duct cancers, such as hepatocellular carcinoma, cholangiocarcinoma and gall-bladder carcinoma.
Molecular Medicine Reports 07/2008; 1(4):537-42. · 1.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The myc target gene Mina53 was reported to be overexpressed in esophageal cancer with a poor prognosis. The purpose of the present study was to examined Mina53 expression and its relationship to clinicopathological parameters in human renal cell carcinoma (RCC). Mina53 and Ki-67 expression was examined on immunohistochemistry for 64 surgically resected RCC and non-cancerous tissue. In addition, the relationship between Mina53 expression and clinicopathological prognostic factors of RCC such as age, stage, microvenous invasion (MVI), histological subtype, Ki-67 labeling index (LI), and prognosis, was examined. Mina53 was expressed in the nuclei of tumor cells and tubular nuclei of normal renal tissue. The expression level of Mina53 was significantly higher in patients with poor prognostic factors (stage IV, MVI-positive, and sarcomatoid RCC, and high Ki-67 LI). The prognosis of high Mina53-expressing tumors was significantly poorer than that of non-Mina53-high tumors (P < 0.0001). In conclusion, Mina53 is overexpressed in RCC tissue from patients with poor prognostic factors, suggesting that Mina53 overexpression is one of the factors for poor prognosis in RCC.
Pathology International 10/2007; 57(10):672-80. · 1.72 Impact Factor