[Show abstract][Hide abstract] ABSTRACT: The present study aimed to examine the association between 18F-fluorodeoxyglucose (18F-FDG) uptake and cell proliferation markers; in addition, the correlation between 18F-FDG uptake and biological characteristic in patients with renal cell carcinoma (RCC) was investigated using dual-phase 18F-FDG-positron emission tomography/computed tomography (PET/CT). Dual-phase 18F-FDG PET/CT was performed on 31 RCC patients and the maximum standardized uptake values at 1 h (SUV1) and 2 h (SUV2) as well as the retention index (RI; %) in the primary tumors were calculated. Monoclonal antibodies for Ki-67, minichromosome maintenance 2 (MCM2) and topoisomerase II α (topo II α) were used to assess the expression levels of their respective proteins in excised tumor tissue using immunohistochemistry. The results demonstrated that RI and SUV2 in patients with Stage I/II + grade 1 (G1) RCC were significantly decreased compared with all patients with other stages/grades (RI, P=0.0065; SUV2, P=0.043); in addition, significantly increased uptake and RI were detected in patients with metastases compared with patients without metastases (SUV1, P=0.029; SUV2, P=0.0003; RI, P<0.001). All proliferation markers significantly correlated with RI (Ki-67, r=0.501, P=0.004; MCM2, r=0.359, P=0.047; topo II α, r=0.402, P=0.024), while SUV1 and SUV2 correlated with Ki-67 only. In conclusion, the results of the present study demonstrated that dual-phase 18F-FDG-PET/CT was more useful for predicting cell proliferation in RCC compared with single-phase imaging alone. However, follow-ups are required in order to determine whether dual-phase 18F-FDG-PET/CT provides independent prognostic information.
[Show abstract][Hide abstract] ABSTRACT: The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once a week for 6 weeks. KRM-20 was applicable for patients with positive human leukocyte antigen (HLA) A2, A3, A11, A24, A26, A31 or A33 alleles, which cover the majority of the global population. To evaluate the minimum immunological effective dose (MIED), peptide-specific CTL and immunoglobulin G (IgG) responses, and immune suppressive subsets were evaluated during the vaccination. Total of 17 patients was enrolled. No serious adverse drug reactions were encountered. The MIED of KRM-20 in CTL or IgG response calculated by logistic regression model was set as 16 or 1.6 mg, respectively. The frequency of immune suppressive subsets was fewer in the 20 mg cohort than that in 6 or 60 mg cohort. Clinical responses determined by prostate-specific antigen levels were two partial responses (from the 20 mg cohort), five no changes and ten progressive diseases. Twenty milligrams of KRM-20 could be recommended for further studies because of the safety and ability to augment CTL activity.
Cancer Immunology and Immunotherapy 02/2015; 10(4). DOI:10.1007/s00262-015-1660-1 · 3.94 Impact Factor
[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. DOI:10.1186/1471-2407-13-613 · 3.36 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. DOI:10.3892/mco.2012.5
[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 06/2012; 118(12):3208-21. DOI:10.1002/cncr.26636 · 4.89 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 06/2012; 72(8):834-45. DOI:10.1002/pros.21485 · 3.57 Impact Factor
[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: The prognosis of standard therapy-resistant urothelial carcinoma (UC) remains poor. To explore cancer vaccine as a new treatment modality, we conducted a phase II study of personalized peptide vaccine (PPV) for standard therapy-resistant UC patients. Therapeutic cancer vaccine therapy has undergone clinical trials for urothelial carcinoma, and is being developed as a drug so that it can supply. It is expected to become the fourth therapeutic method following surgery, radiotherapy and chemotherapy. Twenty-five standard therapy-resistant UC patients were treated with PPV using peptides chosen from among 31 peptides in the patients. This study protocol was approved by the institutional ethical review boards of Kurume University, and conducted in accordance with the Declaration of Helsinki. Written informed consent was obtained from all patients they participated in this clinical trial. Peptide vaccination was safe and well tolerated, with no severe adverse events in any of the patients. Median overall survival (OS) time from the first vaccination was 11. 3 months in the standard therapy-resistant UC patients. Increased anti-peptide IgG titer was revealed in ten patients (40%) out of twenty-five patients at post 6 th vaccination, and in six patients (100%) out of six patients at post 12 th vaccination. Further clinical study of PPV is recommended for standard therapy-resistant UC patients, with a view of the safety and possible prolongation of MST.
European Urology Supplements 02/2012; 11(1):e863-e863a. DOI:10.1016/S1569-9056(12)60860-4 · 3.37 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. DOI:10.3892/etm.2010.177 · 1.27 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.
The Kurume Medical Journal 01/2011; 58(3):95-8. DOI:10.2739/kurumemedj.58.95
[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.
[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 09/2010; 1(5):833-839. DOI:10.3892/etm.2010.120 · 1.27 Impact Factor