Mizuhiko Terasaki

Phase I Trial of a Personalized Peptide Vaccine for Patients Positive for Human Leukocyte Antigen–A24 With Recurrent or Progressive Glioblastoma Multiforme

PURPOSE Personalized selection of suitable peptides for patients could offer a novel approach to developing cancer vaccines that boost anticancer immunity. We present the results of a phase I trial of 14 kinds of vaccine candidates (ITK-1) in patients with recurrent or progressive glioblastoma multiforme (GBM). PATIENTS AND METHODS From January 2006 to January 2008, 12 patients from eight Japanese hospitals who were positive for human leukocyte antigen-A24, including 10 patients refractory to temozolomide (TMZ), were enrolled. The dose escalation trial included three dose groups (1, 3, and 5 mg) to determine the safety and tolerability of ITK-1 peptides. Immunologic response was monitored by measuring levels of cytotoxic T-lymphocyte precursors and peptide-specific immunoglobulin G. In another ITK-1 phase I trial for advanced prostate cancer, the vaccination schedule was skipped or discontinued in all three patients receiving the highest dose (5 mg/peptide) because of injection site reactions. This trial was therefore ended without enrollment for the highest dose, and data were analyzed by intention to treat. RESULTS No serious adverse drug reactions were encountered, and treatment was well tolerated. The vaccine induced dose-dependent immune boosting. The recommended dose of ITK-1 peptides is 3 mg/peptide. CONCLUSION Personalized vaccination with ITK-1 peptides could be recommended in further stages of clinical trials. The safety and increased frequency of immune boosting offers potential clinical benefits in cases of recurrent or progressive GBM, even in TMZ-refractory settings.

CXCL12/CXCR4 signaling in malignant brain tumors: a potential pharmacological therapeutic target

Chemokines are 8- to 12-kDa peptides that function as chemoattractant cytokines involved in cell activation, differentiation, and trafficking. Chemokines bind to specific G-protein-coupled, seven-span transmembrane receptors on the plasma membrane of target cells. Chemokine (C-X-C motif) ligand 12 (CXCL12), an alpha-chemokine that binds to G-protein-coupled chemokine (C-X-C motif) receptor 4 (CXCR4), plays an important and unique role in the regulation of stem/progenitor-cell trafficking. As CXCR4 is expressed on several cancer cells, these CXCR4-positive cancer cells may metastasize to organs that secrete/express CXCL12. Regarding brain tumors, recent data demonstrate that glioma tumor stem-like cells promote tumor angiogenesis and vasculogenesis via the CXCL12/CXCR4 pathway. In addition, CXCL12/CXCR4 have recently been shown to be expressed in primary central nervous system (PCNS) lymphomas, and a role for chemokines in the pathogenesis of PCNS lymphomas was suggested. This review focuses on current knowledge regarding the biology of the CXCL12/CXCR4 pathway in the context of understanding their potential role in malignant gliomas and PCNS lymphoma development. The CXCL12/CXCR4 interaction as a therapeutic target for malignant brain tumors is also discussed.

Acute focal demyelinating disease simulating brain tumors: histopathologic guidelines for an accurate diagnosis.

The object of the present study was to determine the histopathological guidelines for accurate diagnosis of cases of acute focal demyelinating disease that simulates brain tumors. The surgical pathology of three such cases is assessed. Histopathological keys to the diagnosis of such cases are as follows. First, a pattern of sheets of atypical gemistocytic astrocytes in the white matter that show well‐formed processes and that are adequately distanced from each other argues against a diagnosis of neoplasm. Second, uniform distribution of foamy macrophages aligned along axons, with occasional focal collections surrounding blood vessels and in the absence of any associated coagulative necrosis argues against the presence of a tumor. Third, perivascular chronic inflammatory infiltration, especially a mixture of lymphocytes and macrophages, favors the diagnosis of demyelination plaque. In such cases the lymphocytes will be predominantly T cells. Fourth, pleomorphic astrocytic proliferation with a lack of vascular endothelial proliferation should raise the suspicion that the lesion may not be a brain tumor. These diagnostic keys should be followed when diagnosing cases that are suspected to be demyelination processes rather than brain tumors. The presence of demyelination plaque should then be confirmed by imaging modalities such as staining with myelin‐and axon‐specific stains.

Sensitivity and usefulness of anti-phosphohistone-H3 antibody immunostaining for counting mitotic figures in meningioma cases

According to current World Health Organization (WHO) criteria, counting mitotic figures (MF), which is equal to the mitotic index (MI), on paraffin sections stained with hematoxylin and eosin (HE) is one of the recognized classification methods for meningiomas. However, it is not always easy to find the area of highest mitotic activity, and there are different perspectives among pathologists with regard to differentiating MF from non-MF, i.e., which are apoptotic figures and which are crushed or distorted cells. Moreover, there is an issue of overgrading in meningiomas with preoperative feeder embolization. Recently, anti-phosphohistone-H3 (PHH3) antibody has been reported as a mitosis-specific marker for meningioma grading. In this study, we attempted PHH3 immunostaining for our meningioma cases and verified not only the sensitivity of PHH3 immunostaining but also that of its usefulness in grading meningiomas. Forty-five initial histologically confirmed meningiomas (37 benign, 7 atypical, and 1 anaplastic) were reviewed according to current WHO criteria based on counting MF on HE-stained slides. PHH3-immunostained MF were counted in the same way, and the MIB-1 labeling index (LI) was calculated for each sample. PHH3-labeled MF were easily identified and permitted rapid recognition of the areas of highest mitotic activity. As a result, significant increase of PHH3 mitotic index (PHH3-MI) in comparison with HE mitotic index (HE-MI) and strong correlations with HE-MI to PHH3-MI as well as PHH3-MI to MIB-1 LI were demonstrated. Furthermore, no significant differences of PHH3-MI between cases with and without feeder embolization were demonstrated. As such, PHH3 may be a sensitive and useful marker for meningioma grading as based on the MF.

Astroblastoma with unusual signet‐ring‐like cell components: A case report and literature review

We report a case of astroblastoma with unusual signet‐ring‐like cell components. A 33‐year‐old‐woman presented with occasional partial seizures of the face. Radiological studies revealed an enhanced frontal mass lesion. At surgery, a gray, soft, well‐circumscribed mass was seen and shelled out. Histologically, the tumor showed a perivascular arrangement and papillary‐like patterns with compact cellularity. The tumor cells radiating from the hyalinized vessels showed broader, shorter, less tapered processes. A part of each tumor cell displayed prominent islands of signet‐ring‐like cells. Glial fibrillary acidic protein reaction revealed strongly positive staining of tumor cells and signet‐ring‐like cells. Eight years after the operation the patient remains well with no tumor recurrence. It remains to be determined whether, in this astroblastoma, the unusual signet‐ring‐like cell components were related to benign biological characteristics or to the tumors low‐grade form with incidental signet‐ring‐like cell appearance.

Development of the Japanese version of the Pediatric Quality of Life Inventory™ Brain Tumor Module

BackgroundThe Pediatric Quality of Life Inventory™ (PedsQL™) is a widely-used modular instrument for measuring health-related quality of life in children aged 2 to 18 years. The PedsQL™ Brain Tumor Module is comprised of six scales: Cognitive Problems, Pain and Hurt, Movement and Balance, Procedural Anxiety, Nausea, and Worry. In the present study, we developed the Japanese version of the PedsQL™ Brain Tumor Module and investigated its feasibility, reliability, and validity among Japanese children and their parents.MethodsTranslation equivalence and content validity were verified using the standard back-translation method and cognitive debriefing tests. Participants were recruited from 6 hospitals in Japan and the Childrens Cancer Association of Japan, and questionnaires were completed by 137 children with brain tumors and 166 parents. Feasibility of the questionnaire was determined based on the amount of time required to complete the form and the percentage of missing values. Internal consistency was assessed using Cronbachs coefficient alpha. Test-retest reliability was assessed by retesting 22 children and 27 parents. Factorial validity was verified by exploratory factor analyses. Known-groups validity was described with regard to whole brain irradiation, developmental impairment, infratentorial tumors, paresis, and concurrent chemotherapy. Convergent and discriminant validity were determined using Generic Core Scales and State-Trait Anxiety Inventory for children.ResultsInternal consistency was relatively high for all scales (Cronbachs coefficient alpha > 0.70) except the Pain and Hurt scale for the child-report, and sufficient test-retest reliability was demonstrated for all scales (intraclass correlation coefficient = 0.45-0.95). Factorial validity was supported through exploratory factor analysis (factor-item correlation = 0.33-0.96 for children, 0.55-1.00 for parents). Evaluation of known-groups validity confirmed that the Cognitive Problems scale was sensitive for developmental impairment, the Movement and Balance scale for infratentorial tumors or paresis, and the Nausea scale for a patient currently undergoing chemotherapy. Convergent and discriminant validity with the PedsQL™ Generic Core Scales and State-Trait Anxiety Inventory for children were acceptable.ConclusionsThe Japanese version of the PedsQL™ Brain Tumor Module is suitable for assessing health-related quality of life in children with brain tumors in clinical trials and research studies.

Immunological evaluation of personalized peptide vaccination in refractory small cell lung cancer

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)

High-grade adenoid cystic carcinoma originating from the lacrimal gland

Among primary lacrimal gland tumors, adenoid cystic carcinoma (ACC) is the most common malignant epithelial neoplasm; it is characterized by local intracranial invasion. A case with unusual dumbbell-type intracranial extension representing cavernous sinus syndrome is described. A 49-year-old woman was admitted to our hospital with right cavernous sinus syndrome. Computerized tomographic (CT) scans and magnetic resonance (MR) imaging demonstrated well-enhanced intraorbital and middle fossa tumors mimicking multifocal mass lesions. Operative findings revealed an ACC originating from the lacrimal gland and extending into the right cavernous sinus and middle fossa along the nerve sheath in the superior orbital fissure. Although MR image findings of intracranial ACC often resemble the image findings for meningiomas, intracranial ACC is very aggressive in comparison with meningioma. It is best treated surgically and aggressively.

Chordoid meningioma arising in the pineal region: a case report

We report a rare case of chordoid meningioma arising in the pineal region, which presented in a 22-year-old woman. Her only complaint was headache, and neurological examination revealed no deficits. She had suffered from prolonged fever a few weeks earlier, and her hematological findings included hypochromic microcytic anemia and a high serum level of C-reactive protein (CRP). Cranial magnetic resonance (MR) images demonstrated a 25 × 30 mm mass in the pineal region, which showed iso-to low intensity on T1-weighted images (T1WI), high to low intensity on T2-weighted images (T2WI), and homogeneous enhancement with gadolinium-diethylenetriaminepentaacetic acid (Gd-DTPA). We performed subtotal removal of the tumor with an occipital transtentorial approach (OTA), and all her preoperative symptoms completely abated. Histological examination of this tumor specimen showed the typical pattern of chordoid meningioma. Chordoid meningioma has been known to correspond with Castleman’s disease, and pineal meningiomas are extremely rare among intracranial meningiomas. The details of this case are presented with a review of the literature.

Primary choroid plexus T-cell lymphoma and multiple aneurysms in the CNS.

Although primary central nervous system lymphoma (PCNSL) accounts for 2.3% of all primary intracranial tumors, incidence is increasing and correlates to the rising number of immunosuppressed patients [1,2]. Most PCNSLs are of B-cell origin; only 1 – 3.6% have the T-cell phenotype [3]. Because of its rarity, T-cell PCNSL has been less well-defined. We describe a patient with primary choroid plexus T-cell PCNSL and multiple aneurysms; we also provide a systemic review of the literature. A 56-year-old man presented with headaches that had progressively worsened during the 2 days. His medical history was unremarkable with no evidence of immunodeficiency. Computed tomography (CT) and axial T1-weighted magnetic resonance (MR) images without contrast showed a homogeneous mass with intraventricular hemorrhage at the inferior horn of the lateral ventricle and aneurysms as a signal-void area in the bifrontal region but no subarachnoid hemorrhage (Figure 1A); we were able to differentiate that the blood on the MR images came from the tumor and not from the aneurysms. Rim-enhanced mass was observed in the choroid plexus. (Figure 1B). Angiograms showed multiple intracranial aneurysms located at the anterior choroidal artery (AchoA), the posterior communicating artery (PcoA), the terminus of the right internal carotid artery (ICA), and the carotid terminus of the left ICA (Figure 1C and 1D). Cerebrospinal fluid (CSF) from lumber puncture contained 2676 red blood cells/ml and a protein level of 299 mg/dl. We found no evidence of viral or other infectious disease; b2-microgloblin levels in the CSF were high (4.55 mg/l). CSF cytology indicated atypical lymphocytes that appear to be small with irregular nuclear membrane. Atypical lymphoid cells were immunoreactive for T-cell lymphocyte markers but not for B-cell markers (Figure 1E). We did ophthalmologic examination, whole body CT, as well as gastroscopic, bone marrow biopsies, Ga-67 scintigraphy, and F-fluoro-deoxy-D-glucose-positron emission tomography (FDG-PET) to confirm that our patient had no systemic disease and that the choroids plexus was the primary tumor site. We performed endovascular coiling on the AchoA, the PcoA, and the left ICA aneurysms, but not the small (52 mm in diameter) aneurysm at the terminal portion of the right ICA because of its size, nonbleb shape, and location. One week after embolization, we gave two cycles of MTX chemotherapy (100 mg/kg). After the completion of chemotherapy, we administered 40 Gy of whole-brain field irradiation and 10 Gy of locally involved field irradiation to prevent tumor relapse and the spread of tumor cells. CSF samples were collected during chemotherapy and examined for residual disease. After the completion of adjuvant therapy, we found no evidence of tumor cells in the CSF and no residual neoplastic disease on MR images (Figure 1F). After 19 months of outpatient follow-up that included serial MR scans and repeated CSF cytological examinations, we found no recurrence of disease. Medline literature searches were performed for articles involving TPCNSL and ventricular PCNSL. The search encompassed the years 1970 – 2005. Articles published in languages in other than English were analyzed and reviewed if an abstract in English