A randomized phase III trial of personalized peptide vaccination for castration­resistant prostate cancer progressing after docetaxel.

First­line chemotherapy for men with metastatic castration­resistant prostate cancer (mCRPC) has been employed to improve overall survival (OS) and progression­free survival (PFS). However, several new agents for CRPC after first­line chemotherapy prolonged survival by only a few months. To develop a new treatment modality, we conducted a phase III randomized trial of personalized peptide vaccination (PPV) for human leukocyte antigen (HLA)­A24­positive patients with castration­resistant prostate cancer (CRPC) for whom docetaxel chemotherapy failed. This randomized, double­blind, placebo­controlled, phase III trial was carried out at 68 medical centers in Japan. Patients were randomly assigned at a 2:1 ratio to receive PPV or placebo. Four of 12 warehouse peptides selected based on pre­existing peptide­specific immunoglobulin G levels or the corresponding placebo were subcutaneously injected in 6 doses weekly and then bi­weekly following the maximum of 30 doses until disease progression. The primary end­point was overall survival (OS). Efficacy analyses were performed by the full analysis set. Between August 2013 and April 2016, 310 patients were randomly assigned, and 306 patients were analyzed. Baseline characteristics were balanced between groups. The estimated median OS was 16.1 months [95% confidence interval (CI), 13­18.2] with PPV and 16.9 months (95% CI, 13.1­20.4) with placebo [hazard ratio (HR), 1.04, 95% CI, 0.80­1.37; P=0.77]. Grade ≥3 adverse events were observed in 41% of both groups. The analysis of treatment arm effects among subgroups revealed lower HRs for OS in favor of the PPV arm in patients with <64% neutrophils (HR, 0.55, 95% CI, 0.33­0.93; P=0.03) or ≥26% lymphocytes (HR, 0.70, 95% CI, 0.52­0.92; P=0.02) at baseline. PPV did not prolong OS in HLA­A24­positive patients with CRPC progressing after docetaxel chemotherapy. Subgroup analysis suggested that the patients with a lower proportion of neutrophils or a higher proportion of lymphocytes at baseline can receive survival benefits from PPV treatment.

Testicular sarcoidosis with bilateral scrotal swelling.

INTRODUCTION: Sarcoidosis is a disease in which noncaseating granulomas form in several organs, particularly in the lungs and skin. Male genitourinary involvement in sarcoidosis is uncommon. CASE PRESENTATION: A 32-year-old male with painless bilateral scrotal swelling who was diagnosed with lung sarcoidosis presented to our hospital. Serum tumor marker levels were normal. Scattered hypoechoic mass lesions in both testes were noted on ultrasound examination. Biopsy of both testes revealed pathologically noncaseating epithelioid cell granuloma, and perihilar lymphadenopathy and a granulomatous lung nodule were found on chest computed tomography. Semen examination was performed after the biopsy, demonstrating oligospermia. A corticosteroid regimen was administered. After treatment, no abnormal accumulation in both testes was observed on gallium-67 scintigraphy, and semen examination demonstrated the mild improvement of the sperm count. CONCLUSION: Treatments for testicular sarcoidosis vary, and malignancy and fertility must be considered.

Identification of biomarkers for personalized peptide vaccination in 2,588 cancer patients.

Peptide­based cancer vaccines have failed to provide sufficient clinical benefits in order to be approved in clinical trials since the 1990s. To understand the mechanisms underlying this failure, the present study investigated biomarkers associated with the lower overall survival (OS) among 2,588 patients receiving personalized peptide vaccination (PPV). Survival data were obtained from a database of 2,588 cancer patients including 399 patients with lung, 354 with prostate and 344 with colon cancer. They entered into phase II clinical trials of PPV in which 2 to 4 of 31 warehouse peptides were selected for vaccination on an individual patient basis based on human leukocyte antigen (HLA) class IA­types and pre­existing peptide­specific IgG levels. Higher pre­vaccination neutrophil, monocyte and platelet counts, and lower pre­vaccination lymphocyte and red blood cell counts were inversely associated with OS, with higher sensitivities in the proportions of neutrophils and lymphocytes, respectively. The most potent unfavorable and favorable factors for OS were the median percentage of neutrophils (≥64.8%) or percentage of lymphocytes (≥25.1%) with correlation coefficients (R2) of 0.98 and 0.92, respectively. Higher pre­vaccination levels of c­reactive protein and other inflammatory soluble factors were inversely associated with OS. Pre­vaccination peptide­specific immunity levels had no effect on OS, although lower immune boosting levels were inversely associated with OS. None of the 31 peptides was inversely associated with OS, although a few peptides were positively associated with it. On the whole, the findings of the present study suggested that pre­vaccination inflammatory signatures, but not those of post­vaccination immune induction, were associated with lower clinical benefits of PPV.

Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: a randomized phase II trial.

A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (n = 25) or placebo with docetaxel and dexamethasone (n = 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%; P = 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (P = 0.018) and CTL (P = 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of < 11.2 ng/ml, but further clinical trials comparing OS are required.

Malignant lymphoma of the bladder with bilateral hydronephrosis.

Lymphoma of the urinary bladder is uncommon, and upper urinary tract obstruction due to lymphoma is rare. Herein, we report a case of malignant lymphoma of the bladder with bilateral hydronephrosis in a 67-year-old female who presented with oliguria. Ultrasonography and computed tomography demonstrated a thickened posterior bladder wall and bilateral hydronephrosis. Whole-body positron emission tomography-computed tomography revealed abnormal accumulation in the right iliac internal lymph nodes. Trans-urethral bladder biopsy led to a histopathological diagnosis of non-Hodgkin diffuse large B-cell malignant lymphoma of the bladder. After bilateral nephrostomy, the patient was treated with six cycles of combination chemotherapy including rituximab, cyclophosphamide, daunorubicin, vincristine, and prednisolone (R-CHOP) and two cycles of rituximab alone. Complete remission was maintained during the 3 years of follow-up.

Survival analysis of multiple peptide vaccination for the selection of correlated peptides in urological cancers.

Peptide-based cancer vaccines are able to induce strong immune responses, but their clinical results are unsatisfactory. To determine clinically correlated peptides, we analyzed survival data from urological cancer patients treated by personalized peptide vaccination (PPV), in which different multiple peptides were used for individual patients based on human leukocyte antigen (HLA) type and pre-existing immunity. Survival data were obtained from a database of 265 urological cancer patients treated in 5 clinical PPV trials comprising 154 patients with castration-resistant prostate cancer (CRPC) and 111 patients with advanced urothelial cancer (UC). Expression of tumor-associated antigens (TAA) was evaluated in 10 prostate cancer tissues, 4 metastatic lymph nodes from prostate cancer, and 10 UC tissues using immunohistochemical staining. Clinical efficacy of individual peptides for overall survival was evaluated by the Cox proportional hazards regression model. All TAA coding candidate peptides used in PPV treatment were expressed in tumor cells from prostate cancer and UC samples except for p56Lck in both, and prostate-specific antigen (PSA), prostatic acid phosphatase (PAP) and prostate-specific membrane antigen (PSMA) in the UC samples. Patients with the following peptides had a significantly longer survival than patients without the peptides (hazard ratio <1.0, 95% confidence intervals <1.0 and P < .05): SART3-109, PTHrP-102, HNPRL-140, SART3-302 and Lck-90 in CRPC patients, and EGF-R-800, Lck-486, PSMA-624, CypB-129 and SART3-734 in advanced UC patients, respectively. Correlated peptides selected using both survival data and pre-existing immunity for PPV treatment may enhance the clinical benefits for urological cancer patients.

Female urethral diverticulum containing large calculi.

Urinary stones in female urethral diverticulum are rarely seen. We report a 79-year-old woman who presented with irritative lower urinary tract symptoms and vaginal cystocele with incontinence. The urethral stones in the diverticulum were successfully extracted through the trans-urethral route and anterior tension-free vaginal mesh was applied one month later. The patient has been well, with no lower urinary symptoms or incontinence for 4 months.

Immunological efficacy of herbal medicines in prostate cancer patients treated by personalized peptide vaccine.

This randomized phase II study investigated the immunological efficacy of herbal medicines (HM) using Hochu-ekki-to and Keishi-bukuryo-gan in combination with personalized peptide vaccination (PPV) for castration-resistant prostate cancer (CRPC). Seventy patients with CRPC were assigned to two arms; PPV plus HM or PPV alone. Two to four peptides were chosen from 31 peptides derived from cancer antigens for a s.c. injection of PPV given eight times according to the patient's human leukocyte antigen type and levels of antigen-specific IgG titer before PPV treatment. Peptide-specific CTL, IgG, regulatory T cells (Treg), monocytic myeloid-derived suppressor cells (Mo-MDSC), and interleukin-6 (IL-6) responses were measured before and at the eighth vaccination. Clinical outcomes were also analyzed. Combination therapy of PPV with HM was well tolerated without severe adverse events. There was no significant change in antigen-specific IgG, CTL, Treg or clinical outcomes. Combination therapy of PPV with HM stabilized the frequency of Mo-MDSC (1.91%-1.92%, P = 0.96) and serum levels of IL-6 (19.2 pg/mL to 16.1 pg/mL, P = 0.63) during the treatment. In contrast, the frequency of Mo-MDSC and levels of IL-6 in the PPV-alone group were significantly increased (0.91%-1.49% for Mo-MDSC and 9.2 pg/mL to 19.4 pg/mL for IL-6, respectively). These results suggest that the combined use of HM has the potential to prevent the immunosuppression induced by Mo-MDSC or IL-6 during immunotherapy. More research is needed to validate the findings of the present study.

Personalized peptide vaccination as second-line treatment for metastatic upper tract urothelial carcinoma.

This study investigated the applicability of personalized peptide vaccination (PPV) for patients with metastatic upper tract urothelial cancer (mUTUC) after failure of platinum-based chemotherapy. In this single arm, open-label, phase II clinical trial, patients with mUTUC received PPV at a single institution. Personalized peptide vaccination treatment used a maximum of four peptides chosen from 27 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for six s.c. injections weekly as one cycle. The safety of PPV, as well as its influence on host immunity and effect on overall survival were assessed. Forty-eight patients were enrolled in this study. Personalized peptide vaccinations were well tolerated without severe adverse events. Median survival time was 7.3 months (95% confidence interval [CI], 5.3-13.1) with 13.0 months for patients receiving combined salvage chemotherapy (95% CI, 5.7-17.5) and 4.5 months for patients receiving PPV alone (95% CI, 1.7-10.1) (P = 0.080). Patients with positive CTL responses showed a significantly longer survival than patients with negative CTL responses (hazard ratio, 0.37; 95% CI, 0.16-0.85; P = 0.019). Multivariate Cox regression analysis showed that lower numbers of Bellmunt risk factors and lower levels of B-cell activating factor were significantly associated with favorable overall survival for patients under PPV treatment. This study indicated that PPV for patients with mUTUC after failure of platinum-based chemotherapy induced substantial peptide-specific CTL responses without severe adverse events and has the potential to prolong survival when combined with salvage chemotherapy. UMIN Clinical Trials Registry ID: 000001854.

Clinical development of immunotherapy for prostate cancer.

Prostate cancer is the most common cancer in men, and the second leading cause of cancer-related death in Western countries. Prostate cancer-related death occurs in patients with metastatic castration-resistant prostate cancer. Although several new drugs for castration-resistant prostate cancer have been approved, each of these has prolonged survival by just a few months. Consequently, new therapies are sorely needed. Recently, it has been recognized that immunotherapy is an effective treatment for prostate cancer patients. Several strategies, such as cancer vaccines and immune checkpoint inhibitors, have been investigated in clinical studies for prostate cancer patients. In the present review, the results of the most recent clinical studies investigating immunotherapy in prostate cancer patients are reported, and the future clinical development of immunotherapy for prostate cancer is discussed.

Feasibility Study of Personalized Peptide Vaccination for Advanced Small Cell Lung Cancer.

INTRODUCTION: The prognosis of patients with small cell lung cancer (SCLC) remains very poor. Therefore, the development of new therapeutic approaches, including immunotherapies, is desirable. PATIENTS AND METHODS: We conducted a phase II study of personalized peptide vaccination (PPV), in which a maximum of 4 human leukocyte antigen-matched peptides were selected from 31 pooled peptides according to the pre-existing peptide-specific IgG responses before vaccination. The PPV was subcutaneously administered. RESULTS: Forty-six patients were enrolled (median age, 63 years; 40 patients were men). Grade 1 (n = 13), 2 (n = 10), or 3 (n = 1) skin reactions at the injection sites were observed; however, no other severe adverse events related to the PPV were observed. The median survival time was 466, 397, 401, and 107 days in the subgroups with 0 (n = 5), 1 (n = 15), 2 (n = 12), and ≥ 3 (n = 14) previous chemotherapy regimens, respectively. Peptide-specific IgG responses to the vaccinated peptides were augmented in 70% and 95% of patients after 1 and 2 vaccination cycles, respectively. The overall survival (OS) of patients with augmented IgG responses to a greater number of nonvaccinated peptides after the second cycle of vaccination was significantly longer (median survival time, 1237 days vs. 382 days; P = .010). In addition, augmentation of IgG responses specific to 6 peptides, including Lck-derived peptides, was significantly related to better OS (P < .05, in each peptide). CONCLUSION: These results suggest the feasibility of PPV for SCLC patients from the viewpoints of safety, immune boosting, and possible prolongation of OS. Therefore, further evaluation of PPV for advanced SCLC in prospective randomized trials is warranted.

Immunological evaluation of peptide vaccination for cancer patients with the HLA -A11+ or -A33+ allele.

The HLA-A11 or -A33 allele is found in approximately 18% or 10% of the Asian population, respectively, but each of which is a minor allele worldwide, and therefore no clinical trials were previously conducted. To develop a therapeutic peptide vaccine for each of them, we investigated immunological responses of advanced cancer patients with the HLA-A11+ /A11+ (n = 18) or -A33+ /A33+ (n = 13) allele to personalized peptide vaccine (PPV) regimens. The primary sites of HLA-A11+/A11+ or -A33+/A33+ patients were the colon (n = 4 or 2), stomach (2 or 3), breast (3 or 2), lung and pancreas (2 or 2), and so on. For PPV, a maximum of four peptides were selected from nine different peptides capable of binding to HLA-A11 and -A33 molecules based on the pre-existing peptide-specific IgG responses. There were no severe adverse events related to PPV. At the end of the first cycle, peptide-specific CTL responses were augmented in 4/12 or 2/9 of HLA-A11+ /A11+ or -A33+ /A33+ patients, while peptide-specific IgG responses were augmented in 6/14 or 4/10 patients, respectively. Clinical responses consisted of four stable diseases and 14 progressive diseases in HLA-A11+ /A11+ patients, versus seven and six in -A33+ /A33+ patients, respectively. Further clinical study of PPV could be recommended because of the safety and positive immunological responses.

Immunological evaluation of personalized peptide vaccination for patients with histologically unfavorable carcinoma of unknown primary site.

The immunological characteristics of carcinoma of unknown primary site (CUP) are not well established due to inclusion of heterogeneous types of metastatic tumors with the absence of any detectable primary site. We evaluated the immune responses in patients with histologically unfavorable CUP during personalized peptide vaccination (PPV). Ten patients with histologically unfavorable CUP who had been treated by PPV after chemotherapy failure were analyzed. In PPV treatment, up to four human leukocyte antigen-matched peptides of a total 31 peptides were selected according to preexisting host immunity before vaccination and administered subcutaneously. Peptides derived from the Lck antigen were most often chosen for use among all patients. CTL responses were increased in 8 of the 10 and 5 of the five patients tested at the end of the first and second PPV cycles, respectively. Increases in humoral responses after vaccination, including IgG, IgG1, IgG3, IgA, and IgM, were observed against not only the vaccinated peptides but also the non-vaccinated peptides. Severe adverse events due to PPV were not observed. Median overall survival was 13.9 months (95 % CI 4.0-22.5 months). PPV activated both cellular and humoral immune responses to short peptides derived from CTL epitopes in the majority of CUP patients. PPV with Lck-derived peptides may be a feasible, new treatment modality for histologically unfavorable CUP patients due to its safety and strong ability to boost immune responses, although its clinical efficacy remains to be investigated in larger-scale trials.

Randomized Phase II Study of Docetaxel plus Personalized Peptide Vaccination versus Docetaxel plus Placebo for Patients with Previously Treated Advanced Wild Type EGFR Non-Small-Cell Lung Cancer.

Objectives. To evaluate the efficacy and safety of personalized peptide vaccination (PPV) combined with chemotherapy for patients with previously treated advanced non-small-cell lung cancer (NSCLC). Patients and Methods. Previously treated PS0-1 patients with IIIB/IV EGFR (epidermal growth factor receptor) wild genotype NSCLC were randomly assigned to docetaxel (60 mg/m(2) on Day 1) plus PPV based on preexisting host immunity or docetaxel plus placebo. Docetaxel administration was repeated every 3 weeks until disease progression. Personalized peptides or placebo was injected subcutaneously weekly in the first 8 weeks and biweekly in subsequent 16 weeks. The primary efficacy endpoint was progression-free survival (PFS). Results. PPV related toxicity was grade 2 or less skin reaction. The median PFS for placebo arm and PPV arm was 52 days and 59 days, respectively. There was no significant difference between two arms by log-rank test (p = 0.42). Interestingly, PFS and overall survival (OS) in humoral immunological responder were significantly longer than those in nonresponder. Conclusion. PPV did not improve the survival in combination with docetaxel for previously treated advanced NSCLC. However, PPV may be efficacious for the humoral immunological responders and a further clinical investigation is needed.

Prospect and progress of personalized peptide vaccinations for advanced cancers.

INTRODUCTION: The field of cancer immunotherapy has made dramatic progress in the past 20 years, in part due to the identification of numerous tumor-associated antigens (TAAs). We have developed a novel immunotherapeutic approach called the personalized peptide vaccine (PPV), in which a maximum of four human leukocyte antigen (HLA)-matched vaccine peptides are selected based on the pre-existing host immunity before vaccination. AREAS COVERED: This review describes recent progress in the use of PPV for various types of advanced cancer. EXPERT OPINION: Although various approaches for therapeutic cancer immunotherapies, including peptide-based vaccines, have been developed and clinically examined, the diverse and heterogeneous characteristics of tumor cells and host immunity seem to limit their therapeutic efficacy. Selection of suitable peptide vaccines for individual patients based on the pre-existing host immunity before vaccination could resolve this limitation and could be a rational approach for developing effective cancer vaccines.

A randomized phase II clinical trial of personalized peptide vaccination with metronomic low-dose cyclophosphamide in patients with metastatic castration-resistant prostate cancer.

This study investigated the effect of metronomic cyclophosphamide (CPA) in combination with personalized peptide vaccination (PPV) on regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC), and whether it could improve the antitumor effect of PPV. Seventy patients with metastatic castration-resistant prostate cancer were randomly assigned (1:1) to receive PPV plus oral low-dose CPA (50 mg/day), or PPV alone. PPV treatment used a maximum of four peptides chosen from 31 pooled peptides according to human leukocyte antigen types and antigen-specific humoral immune responses before PPV, for 8 subcutaneous weekly injections. Peptide-specific cytotoxic T lymphocyte (CTL) and immunoglobulin G responses were measured before and after PPV. The incidence of grade 3 or 4 hematologic adverse events was higher in the PPV plus CPA arm than in the PPV alone arm. Decrease in Treg and increase in MDSC were more pronounced in PPV plus CPA treatment than in PPV alone (p = 0.036 and p = 0.048, respectively). There was no correlation between the changes in Treg or MDSC and CTL response. There was no difference in positive immune responses between the two arms, although overall survival in patients with positive immune responses was longer than in those with negative immune responses (p = 0.001). Significant differences in neither progression-free survival nor overall survival were observed between the two arms. Low-dose CPA showed no change in the antitumor effect of PPV, possibly due to the simultaneous decrease in Treg and increase in MDSC, in patients under PPV.

An Open-Label, Randomized Phase II Trial of Personalized Peptide Vaccination in Patients with Bladder Cancer that Progressed after Platinum-Based Chemotherapy.

PURPOSE: The prognosis of platinum-based chemotherapy-resistant metastatic urothelial cancer of the bladder remains poor. Personalized selection of the right peptides for each patient could be a novel approach for a cancer vaccine to boost anticancer immunity. EXPERIMENTAL DESIGN: In this randomized, open-label, phase II study, patients ages ≥18 years with progressive bladder cancer after first-line platinum-based chemotherapy were randomly assigned (1:1) to receive personalized peptide vaccination (PPV) plus best supportive care (BSC) or BSC. PPV treatment used a maximum of four peptides chosen from 31 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for 12 s.c. injections (8 injections, weekly; 4 injections, bi-weekly). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), immune response, and toxicity. RESULTS: Eighty patients were randomly assigned to receive either PPV plus BSC (n = 39) or BSC (n = 41). No significant improvement in PFS was noted [HR, 0.7; 95% confidence interval (CI), 0.4-1.2, P = 0.17]. For the secondary endpoints, PPV plus BSC significantly prolonged OS compared with BSC (HR, 0.58; 95% CI, 0.34-0.99, P = 0.049), with median OS of 7.9 months (95% CI, 3.5-12.0) in the PPV plus BSC and 4.1 months (95% CI, 2.8-6.9) in the BSC. PPV treatment was well tolerated, without serious adverse drug reactions. CONCLUSIONS: PPV could not prolong PFS, but OS appeared to be improved with low toxicity and immune responses. Further large-scale, randomized trials are needed to confirm these results.

Immunotherapy in prostate cancer: challenges and opportunities.

Although treatment options for castration-resistant prostate cancer (CRPC) have increased over the last decade, there remains a need for strategies that can provide durable disease control and long-term benefit. Recently, immunotherapy has emerged as a viable and attractive strategy for the treatment of CRPC. To date, there are multiple strategies to target the immune system, and several approaches including therapeutic cancer vaccines and immune checkpoint inhibitors have been most successful in clinical trials. With regard to this, we report the results of the most recent clinical trials investigating immunotherapy in CRPC and discuss the future development of immunotherapy for CRPC, as well as the potential importance of biomarkers in the future progress of this field.

Assessment of cell proliferation in renal cell carcinoma using dual-phase 18F-fluorodeoxyglucose PET/CT.

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.

Phase II Study of Personalized Peptide Vaccination with Both a Hepatitis C Virus-Derived Peptide and Peptides from Tumor-Associated Antigens for the Treatment of HCV-Positive Advanced Hepatocellular Carcinoma Patients.

Objective. To evaluate safety and immune responses of personalized peptide vaccination (PPV) for hepatitis C virus- (HCV-) positive advanced hepatocellular carcinoma (HCC). Patients and Methods. Patients diagnosed with HCV-positive advanced HCC were eligible for this study. A maximum of four HLA-matched peptides were selected based on the preexisting IgG responses specific to 32 different peptides, which consisted of a single HCV-derived peptide at core protein positions 35-44 (C-35) and 31 peptides derived from 15 different tumor-associated antigens (TAAs), followed by subcutaneous administration once per week for 8 weeks. Peptide-specific cytotoxic T lymphocyte (CTL) and IgG responses were measured before and after vaccination. Results. Forty-two patients were enrolled. Grade 3 injection site skin reaction was observed in 2 patients, but no other PPV-related severe adverse events were noted. Peptide-specific CTL responses before vaccination were observed in only 3 of 42 patients, but they became detectable in 23 of 36 patients tested after vaccination. Peptide-specific IgG responses were also boosted in 19 of 36 patients. Peptide-specific IgG1 responses to both C-35 and TAA-derived peptides could be potentially prognostic for overall survival. Conclusion. Further clinical study of PPV would be warranted for HCV-positive advanced HCC, based on the safety and strong immune induction.