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Introduction The safety and efficacy of combination therapy comprising immune checkpoint inhibitors and cancer‐specific peptide vaccines have not yet been established. Case presentation A 71‐year‐old ... female metastatic renal cell carcinoma patient with multiple lung and pleural metastases. She had been treated with interferon alpha, sunitinib, axitinib, and pazopanib sequentially, but no clinical efficacy was observed. She participated in a clinical trial using cancer‐specific peptide vaccine therapy. Initially no antitumor effect was observed, and vaccine therapy was ceased after two courses. But 3 months after the start of nivolumab, remarkable tumor shrinkage was observed at all metastatic sites, which resulted in almost complete response at 6 months. At 10 months, nivolumab was stopped due to cellulitis at the peptide vaccine inoculation site. Intriguingly, even after nivolumab discontinuation, complete response was maintained for more than 1 year. Conclusion We experienced a remarkable antitumor effect by nivolumab in a patient who was previously treated with vaccine therapy. more

Introduction Paraganglioma of the urinary bladder is a very rare disease accounting for 0.06% of all bladder tumors. Owing to their rarity and symptomatic variability, preoperative diagnosis is often ... difficult. Case presentation A 70‐year‐old male was referred to our department for hematuria. Cystoscopy showed a non‐papillary broad‐based tumor. Computed tomography and magnetic resonance imaging revealed a 32‐mm bladder tumor at the top of the bladder, which suggested muscle‐invasive bladder tumor. We diagnosed muscle‐invasive bladder cancer or urachal carcinoma, and transurethral resection of the bladder tumor was performed. At the initiation of transurethral resection of the bladder tumor, the systolic blood pressure was elevated to over 200 mmHg. The pathological findings revealed paraganglioma of the urinary bladder, and afterward, a partial cystectomy was performed. Conclusion We herein reported the case of paraganglioma in the bladder whose blood pressure became extremely elevated during transurethral resection of the bladder tumor. In addition, we analyzed important factors for preoperative diagnosis using 162 cases reported in Japan. more

The aim of this clinical trial was to investigate the toxicity and immunological responses of personalized peptide vaccination for cytokine‐refractory metastatic renal cell carcinoma patients. ... Patients were confirmed to be human leukocyte antigen (HLA)‐A24 or HLA‐A2 positive and had histologically confirmed renal cell carcinoma. Ten patients were enrolled in the present study. The peptides to be administered were determined based on the presence of peptide‐specific cytotoxic T lymphocyte precursors in peripheral blood mononuclear cells (PBMC) and peptide‐specific IgG in the plasma of cancer patients. Patients received subcutaneous injections of four different peptides (3 mg/peptide) every 2 weeks. Vaccinations were well tolerated without any major adverse events. A minimal increase in peptide‐specific interferon‐γ production in postvaccination PBMC was observed, regardless of higher levels of cytotoxic T lymphocyte activity in prevaccination PBMC. In contrast, an increase in peptide‐specific IgG levels of postvaccination (sixth) plasma was observed in the majority of patients. After progression, five patients received interleukin‐2 therapy and continuous vaccination, with survival of 31, 25, 23, 17, and 15 months, but interleukin‐2 did not impede humoral responses boosted by the vaccination. These results encourage further clinical trials of personalized peptide vaccinations. (Cancer Sci 2007; 98: 1965–1968) more

Since the prognosis of small cell lung cancer (SCLC) remains poor, development of new therapeutic approaches, including immunotherapies, would be desirable. In the current study, to evaluate ... immunological responses in refractory SCLC patients, we conducted a small scale phase II clinical trial of personalized peptide vaccination (PPV), in which vaccine antigens are selected based on pre‐existing host immunity. Ten refractory SCLC patients, who had failed to respond to chemo‐ and/or chemoradiotherapies (median number of regimens, 2.5; median duration, 20.5 months), were enrolled. A maximum of four human leukocyte antigen (HLA)‐matched peptides showing higher antigen‐specific humoral responses were subcutaneously administered (weekly for six consecutive weeks and then bi‐weekly thereafter). PPV was terminated before the 3rd administration in four patients because of rapid disease progression, whereas the remaining six patients completed at least one cycle (six times) of vaccinations. Peptide‐specific immunological boosting was observed in all of the six patients at the end of the first cycle of vaccinations, with their survival time of 25, 24.5 (alive), 10 (alive), 9.5, 6.5, and 6 months. Number of previous chemotherapy regimens and frequency of CD3+CD26+ cells in peripheral blood were potentially prognostic in the vaccinated patients (hazard ratio HR = 2.540, 95% confidence interval CI = 1.188–5.431, P = 0.016; HR = 0.941, 95% CI = 0.878–1.008, P = 0.084; respectively). Based on the feasible immune responses in refractory SCLC patients who received at least one cycle (six times) of vaccinations, PPV could be recommended for a next stage of larger‐scale, prospective clinical trials. (Cancer Sci 2012; 103: 638–644) more

Although numerous studies have reported that a positive surgical margin (PSM) is the most important predictive factor for biochemical recurrence (BCR) of prostate cancer (PCa), only a small number of ... studies have evaluated the predictive value of the Gleason score (GS) of the tumor at the margin in radical prostatectomy (RP). The present study aimed to investigate the preoperative factors that predict PSM and the significant predictive factors for BCR in cases with PSM. In addition, it was examined whether documenting the GS of the tumor at the margin in pathological reports is useful as a predictive factor for BCR. Data of 241 patients with PCa who underwent RP at Kurume University Hospital (Kurume, Japan) between January 2007 and December 2011 were retrospectively reviewed. The median follow-up period was 72 months and 122 patients had at least one PSM. The time to BCR was significantly shorter in patients with PSM than in those with a negative surgical margin. Multivariate analysis demonstrated that >10 ng/ml prostate-specific antigen at diagnosis (P=0.024) and >25% positive core at biopsy (P= 0.041) were independent prognostic preoperative factors for PSM. The GS of the tumor at the margin was equal, lower and higher than those of the main tumor in 74 (60.7%), 16 (13.1%) and 32 (26.2%) RPs, respectively. The BCR rates were 35.7, 55.1 and 82.1% in patients whose GS of the tumor at the margin was 6, 7 and 8-10, respectively (P=0.0017). The GS of the tumor at the PSM (P=0.038) and anatomic location of the PSM (P=0.04) were identified as independent prognostic preoperative factors for BCR, whereas the GS of the main tumor and margin length were not. These results suggest that documenting the GS at the margin in pathological reports is useful as a predictive factor for BCR. Key words: prostate cancer, positive surgical margin, Gleason score at the margin, biochemical recurrence, radical prostatectomy more

（緒言）男性の夜間多尿に伴う夜間頻尿に対して低用量デスモプレシンが使用可能となり，用量依存性の有効性が報告されているが，低Na血症等の副作用の報告も比較的高頻度に認めるため，年齢などを考慮し初期投与量を25μgとしている症例も少なくない．今回我々は高齢者に対するデスモプレシン初期投与量50μgの有効性と安全性について検討した．（対象・方法）当院にて夜間多尿に伴う夜間頻尿に対してデスモプレシンを50μgで初期投与開始した45例を対象とした．1週後，4週後の有効性，安全性を排尿日誌に基づく夜間排尿回数，夜間多尿指数，就寝後夜間第一排尿までの時間，就寝後夜間第一尿量，夜間尿量，IPSS，OABSS，アテネ不眠尺度，身体診察，血液検査を用いて検討した．（結果）平均年齢は78.3歳で既知の報告と比較し高齢であった．投与前と比較し1週後から夜間排尿回数の減少，夜間尿量の減少，就寝後第一排尿までの時間の延長，夜間多尿指数の改善，IPSS，IPSS-QOL，OABSS，アテネ不眠尺度の有意な改善を認めた．安全性に関しては有害事象を8例（17.8%）で認め，そのうち低Na血症は7例（15.6%）に認め，既知の報告と同等であった．（結論）デスモプレシンは高齢患者に対しても初期投与量50μgで有用であり，定期的な観察を行い，適宜休薬，減量することで安全に投与可能であった．

To develop a peptide vaccine for cancer patients with the HLA‐A26 allele, which is a minor population worldwide, we investigated the immunological responses of HLA‐A26+/A26+ cancer patients to four ... different CTL epitope peptides under personalized peptide vaccine regimens. In personalized peptide vaccine regimens, two to four peptides showing positive peptide‐specific IgG responses in pre‐vaccination plasma were selected from the four peptide candidates applicable for HLA‐A26+/A26+ cancer patients and administered s.c. Peptide‐specific CTL and IgG responses along with cytokine levels were measured before and after vaccination. Cell surface markers in PBMCs and plasma cytokine levels were also measured. In this study, 21 advanced cancer patients, including seven lung, three breast, two pancreas, and two colon cancer patients, were enrolled. Their HLA‐A26 genotypes were HLA‐A26:01 (n = 24), HLA‐A26:03 (n = 10), and HLA‐A26:02 (n = 8). One, 14, and 6 patients received two, three, and four peptides, respectively. Grade 1 or 2 skin reactions at the injection sites were observed in the majority of patients, but no severe adverse events related to the vaccination were observed. Peptide‐specific CTL responses were augmented in 39% or 22% of patients after one or two cycles of vaccination, respectively. Notably, peptide‐specific IgG were augmented in 63% or 100% of patients after one or two cycles of vaccination, respectively. Personalized peptide vaccines with these four CTL epitope peptides could be feasible for HLA‐A26+ advanced cancer patients because of their safety and higher rates of immunological responses. Personalized peptide vaccine with 4 CTL epitope peptides could be feasible for HLA‐A26+ advanced cancer patients because of the safety and higher rates of immunological responses. more

OBJECTIVE To evaluate, in a prospective, single‐blind, randomized trial, the safety and efficacy of a suspension technique for improving early recovery of continence after radical retropubic ... prostatectomy (RRP). PATIENTS AND METHODS We randomly assigned 60 men with clinically localized prostate cancer to RRP; 30 were treated with the suspension technique and the remaining 30 were not. All patients had RRP by the same surgeon followed by early catheter removal on the third day after RRP. The primary outcome measures were the interval to recovery of continence, and the positive margin rates. The continence status was evaluated by a third party using validated questionnaires at baseline before RRP and at 4 and 7 days, and 2 weeks, 1, 3, 6 and 12 months after RRP. RESULTS The suspension technique resulted in significantly greater continence rates at 1, 3 and 6 months after RRP of 53% vs 20%, 73% vs 47% and 100% vs 83%. Kaplan‐Meier curves also showed that patients in the suspension group had a significantly earlier recovery of continence than in the no‐suspension group; the median (95% confidence interval) interval for recovery was 31 (12–74) days in the suspension group and 90 (65–150) days in the no‐suspension group (log rank test, P = 0.002). The groups had no significant differences in their histological status. CONCLUSIONS The suspension technique had a significant effect on the earlier recovery of urinary continence within 6 months after RRP, without compromising the oncological outcome of RRP. more

Vaccine therapies are increasingly being used for the treatment of various diseases, and the antigen molecules themselves are being expanded from whole microorganisms to fine molecules such as ... peptides. Accordingly, there is a need for new adjuvants to support these new applications. In this paper, we used pharmaceutical grade mineral oil and sorbitan monooleate to develop a new oil adjuvant formula, NH2, and investigated its effects on peptide vaccination at both the pre‐clinical and clinical levels. The adjuvant effect of NH2 on peptide‐induced cellular immunity in mice was superior to that of Montanide ISA51VG, a commercially available incomplete Freund’s adjuvant for clinical use, although no significant difference was observed between the two adjuvants on peptide‐induced humoral immunity. The adjuvant effects of NH2 were also confirmed in a Phase‐I clinical trial of peptide vaccines for patients with advanced cancers. These results suggest that NH2 is a suitable adjuvant for peptide vaccination, particularly for cancer vaccines (Phase‐I clinical trial of pan‐HLA type personalized peptide vaccine for advanced cancer patients, UMIN clinical trial registry number: UMIN 000000619). (Cancer Sci 2010) more

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. more