Fukuko Moriya

Assessment of immunological biomarkers in patients with advanced cancer treated by personalized peptide vaccination

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.

Overexpression of the myc target gene Mina53 in advanced renal cell carcinoma

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.

Phase II study of personalized peptide vaccination for castration-resistant prostate cancer patients who failed in docetaxel-based chemotherapy.

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.

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. Clin Cancer Res; 22(1); 54–60. ©2015 AACR.

Gene expression profiles in peripheral blood as a biomarker in cancer patients receiving peptide vaccination.

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.

Growth inhibitory effects of interferon-α subtypes vary according to human liver cancer cell lines

Background:  Interferon (IFN)‐α preparations used in the treatment of viral and neoplastic disease consist of single or multiple IFN‐α subtypes that may possess different biological activity, but there are no data on liver cancer cells.

Two Cases of Renal Cell Carcinoma Harboring a Novel STRN-ALK Fusion Gene.

Anaplastic lymphoma kinase (ALK) translocation renal cell carcinomas (RCCs) have been reported by several independent groups in recent times. The clinical behavior and histopathologic characteristics of these carcinomas are not fully understood because of the paucity of cases reported. Here, we describe 2 cases of RCC harboring a novel striatin (STRN)-ALK fusion. The first case was a 33-year-old woman with no sickle cell trait who underwent nephrectomy for right renal mass and had late recurrence in para-aortic lymph nodes twice 10 and 12 years after initial surgery. After the second recurrence, she was carefully observed without any treatment. Twenty-six years after the initial nephrectomy, the second para-aortic lymphadenectomy was performed, and gastrectomy was performed for newly developed primary gastric cancer. The resected para-aortic lymph nodes were largely replaced by metastatic carcinoma. The second case was a 38-year-old man with no sickle cell trait who underwent cytoreductive nephrectomy followed by sunitinib therapy for metastatic RCC. In both cases, the tumor showed solid, papillary, tubular, and mucinous cribriform structures. Psammoma bodies were occasionally seen in the stroma. Tumor cells had a large nucleus and prominent nucleoli with predominantly eosinophilic cytoplasm. Rhabdoid cells and signet-ring cells were also observed. Intracytoplasmic mucin deposition and background mucinous stroma were confirmed. In the second case, tumor necrosis was seen in some areas. Tumor cells exhibited diffuse positive staining for ALK in both cases. ALK translocation was confirmed by fluorescent in situ hybridization, and further gene analysis revealed a STRN-ALK fusion. These cases provide great insights into ALK translocation RCCs.

Dexamethasone did not suppress immune boosting by personalized peptide vaccination for advanced prostate cancer patients.

To evaluate the immunological responses of personalized peptide vaccination combined with low‐dose glucocorticoids for advanced hormone refractory prostate cancer (HRPC) patients (pts).

A useful treatment for patients with advanced mixed-type small cell neuroendocrine carcinoma of the prostate: A case report.

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.

A clinically challenging diagnosis of adenoma of the retinal pigment epithelium presenting with clinical features of choroidal hemangioma

Background 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. Case report 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. Conclusion 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.