Kosuke Chayama

Bio: Kosuke Chayama is an academic researcher from Okayama University. The author has contributed to research in topics: Myeloid leukemia & Imatinib mesylate. The author has an hindex of 4, co-authored 8 publications receiving 155 citations.

Identification of the HERV-K gag antigen in prostate cancer by SEREX using autologous patient serum and its immunogenicity

Abstract: The prostate cancer HERV-K gag-related NGO-Pr-54 antigen was identified by SEREX analysis using autologous patient serum. NGO-Pr-54 mRNA was observed to be faintly expressed in normal prostate and strongly expressed in a variety of cancers, including ovarian cancer (5/8), prostate cancer (6/9), and leukemia (5/14). A phage plaque assay showed that a strong reaction was constantly observed with clone ZH042 in which the 5' end of NGO-Pr-54 is deleted, suggesting that it contained the sequence coding for the protein product. A TI-35 mAb was produced using a recombinant protein (438 aa) deduced from the sequence of ZH042. Transfection of clone ZH042 into 293T cells resulted in the production of an approximately 50-kDa molecule visualized by Western blotting. Natural production of the molecule was confirmed in a SK-MEL-23 melanoma cell line. An indirect immunofluorescence assay showed that NGO-Pr-54 protein was expressed on the cell surface as well as in the cytoplasm. Cell surface expression was confirmed by flow cytometry using the TI-35 mAb. The antibody response against NGO-Pr-54 was observed in patients with bladder (5.1%), liver (4.1%), lung (3.4%), ovarian (5.6%), and prostate (4.2%) cancer, as well as with malignant melanoma (13.2%).

Activation of Akt is associated with poor prognosis and chemotherapeutic resistance in pediatric B-precursor acute lymphoblastic leukemia.

Abstract: Background Activation of the phosphoinositide 3-kinase (PI3K)/Akt pathway, a pro-survival pathway, plays important roles in tumor cell growth. However, the role of Akt in the pathogenesis of pediatric B-precursor acute lymphoblastic leukemia (B-pre ALL) remains to be clarified. This study was undertaken to explore the clinical relevance and molecular mechanisms underlying the activation of Akt (i.e., phosphorylated Akt, P-Akt) in pediatric B-pre ALL. Procedure We evaluated the activation status of Akt in bone marrow samples from 21 children with newly diagnosed B-pre ALL and correlated the expression level of P-Akt with clinicopathologic and prognostic features. Additionally, we transfected the myristoylated Akt cDNA into the B-pre ALL cell line, Nalm-6, and examined the effect, in vitro, of Akt activation on the response to antitumor drugs. Results P-Akt expression in B-pre ALL blast cells at diagnosis was associated significantly with poor response to induction chemotherapy including prednisolone, dexamethasone, vincristine, and adriamycin in B-pre ALL patients. Both overall survival and relapse-free survival in patients with P-Akt expression were reduced significantly more than in patients without P-Akt expression. Activation of Akt reduced the extent of apoptosis induced by the antitumor drugs in Nalm-6 listed above. Activation of Akt did not induce expression of P-glycoprotein, a drug transporter that is capable of conferring multidrug resistance. Conclusion These results support the contention that Akt activation is a mechanism of chemotherapeutic resistance in B-pre ALL and suggest that Akt can be a therapeutic target for the treatment of relapsed or refractory pediatric B-pre ALL. Pediatr Blood Cancer 2012; 59: 83–89. © 2011 Wiley Periodicals, Inc.

Successful chemotherapy for congenital malignant gliomas: a report of two cases.

Abstract: We describe the cases of 2 patients with a congenital malignant glioma that responded to chemotherapy. In the first case, a 2-month-old boy had a conjugate deviation to the right side and nystagmus. A T(1)-weighted gadolinium-enhanced magnetic resonance image showed a large tumor in his right frontal lobe. The tumor was partially resected, and the histological diagnosis was malignant ganglioglioma. The child then underwent 6 cycles of chemotherapy (mainly carboplatin and etoposide), and the residual tumor shrank. The tumor was then partially resected during a second operation, after which the patient underwent 5 cycles of chemotherapy (a combination of carboplatin, etoposide, vincristine, ifosfamide, cisplatin and cyclophosphamide). The tumor has not recurred in more than 8.5 years. In the second case, a 2-month-old boy had bulging of the anterior fontanel. The T(1)-weighted gadolinium-enhanced magnetic resonance image showed a large suprasellar tumor. The tumor was partially resected, and the histological diagnosis was anaplastic astrocytoma. The patient underwent 8 cycles of chemotherapy (MCNU, carboplatin and etoposide) and the tumor has not recurred in more than 7.5 years. Our experience indicates that, if surgical removal and chemotherapy are done aggressively for malignant gliomas in neonates and infants, long-term survival is possible.

ABL kinase mutation and relapse in 4 pediatric Philadelphia chromosome-positive acute lymphoblastic leukemia cases

Abstract: The tyrosine kinase inhibitor (TKI) imatinib mesylate (IM) revolutionized the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL), which had showed poor prognosis before the dawn of IM treatment. However, if Ph-ALL patients showed IM resistance due to ABL kinase mutation, second-generation TKI, dasatinib or nilotinib, was recommended. We treated 4 pediatric Ph-ALL patients with both IM and bone marrow transplantation (BMT); however, 3 relapsed. We retrospectively examined the existence of ABL kinase mutation using PCR and direct sequencing methods, but there was no such mutation in all 4 diagnostic samples. Interestingly, two relapsed samples from patients who were not treated with IM before relapse did not show ABL kinase mutation and IM was still effective even after relapse. On the other hand, one patient who showed resistance to 3 TKI acquired dual ABL kinase mutations, F359C at the IM-resistant phase and F317I at the dasatinib-resistant phase, simultaneously. In summary, Ph-ALL patients relapsed with or without ABL kinase mutation. Furthermore, ABL kinase mutation was only found after IM treatment, so an IM-resistant clone might have been selected during the IM treatment and intensive chemotherapy. The appropriate combination of TKI and BMT must be discussed to cure Ph-ALL patients.

A phase III study of the efficacy and safety of meropenem in patients with febrile neutropenia

Abstract: Efficacy, safety and pharmacokinetics of meropenem (MEPM) were assessed when 1 g (40 mg/kg for some of the pediatric patients) t.i.d. was administered every 8hours to 101 adult and 6 pediatric patients with febrile neutropenia (FN) as diagnosed based on the Japanese guideline for FN treatment. The efficacy rate evaluated as antifebrile effect up to Day 4 of treatment was 40.0% (40/100) in adult and 66.7% (4/6) in pediatric patients. The antifebrile effect in adult patients was analyzed after stratifying them according to their neutrophil counts up to Day 4. Treatment with MEPM produced an antifebrile effect not only in patients with higher neutrophil counts (> or = 500/mm3) but also in those with lower counts ( or = 500/mm3 group. The bacteriological efficacy of MEPM evaluated as disappearance rate on Days 3 to 5 and Day 7 was both 100% (8/8 and 4/4, respectively). The time above minimal inhibitory concentration (% T > MIC) in the treatment interval was greater than 90% in 9 out of 10 patients for whom likely causative organism was isolated and identified after MEPM treatment or for whom causative organism emerging after treatment was isolated and identified. The incidence of adverse events was 93.1% in adult and 83.3% in pediatric patients. There were three deaths and one serious adverse event reported among the adult patients; however, all these cases were assessed as not related to the study medication. The incidence of adverse drug reactions was 45.5% and 66.7%, respectively. All the observed adverse drug reactions were mild or moderate in severity and none of them was severe. Adverse drug reactions which were unknown from the previous MEPM clinical studies and investigation of the results of clinical experience include 'chest discomfort', 'blood uric acid decreased', 'lymphocyte deformation', 'blood uric acid increased', 'abnormal funduscopy', 'hypesthesia' and 'hemorrhagic cystitis'. All these events were mild or moderate in severity and resolved without requiring any action or after providing symptomatic treatment. There was no unknown adverse drug reaction that resulted in treatment discontinuation. No nervous system disorders such as convulsion and impaired consciousness were reported. The results show that monotherapy of MEPM 1 g (or 40 mg/kg for some of the pediatric patients) t.i.d. every 8 hours was effective, and was also safe and well tolerated in adult and pediatric patients with FN. Therefore, MEPM monotherapy is expected to be useful as the initial treatment for Japanese patients with FN.

HERV-K(HML-2), the Best Preserved Family of HERVs: Endogenization, Expression, and Implications in Health and Disease

Abstract: Retroviruses that have the ability to infect germ line cells can become an integral and inherited part of the host genome. About 8% of the human chromosomal DNA consists of sequences derived from infections by retroviruses that presumably circulated 2-40 millions of years ago, and some elements are actually much older. Postinsertional recombinations, deletions and mutations have rendered all known human endogenous retroviruses (HERVs) non-infectious. However some, particularly the most recently acquired proviruses of the HERV-K(HML-2) family, can expresses viral proteins and produce viral particles. In this review we will first discuss the major aspects of the endogenisation process and peculiarities of the different HERV-K families. We will then focus on the genes and proteins encoded by HERV-K(HML-2) as well as inactivation of these proviruses by postinsertional mutations and their inhibition by antiretroviral factors. After describing the evolutionary interplay between host and endogenous retrovirus we will delve deeper into the currently limited understanding of HERV-K and its possible association with disease, particularly tumorigenesis.

Ipilimumab for Patients With Advanced Mucosal Melanoma

Abstract: The outcome of patients with mucosal melanoma treated with ipilimumab is not defined. To assess the efficacy and safety of ipilimumab in this melanoma subset, we performed a multicenter, retrospective analysis of 33 patients with unresectable or metastatic mucosal melanoma treated with ipilimumab. The clinical characteristics, treatments, toxicities, radiographic assessment of disease burden by central radiology review at each site, and mutational profiles of the patients' tumors were recorded. Available peripheral blood samples were used to assess humoral immunity against a panel of cancer-testis antigens and other antigens. By the immune-related response criteria of the 30 patients who underwent radiographic assessment after ipilimumab at approximately week 12, there were 1 immune-related complete response, 1 immune-related partial response, 6 immune-related stable disease, and 22 immune-related progressive disease. By the modified World Health Organization criteria, there were 1 immune-related complete response, 1 immune-related partial response, 5 immune-related stable disease, and 23 immune-related progressive disease. Immune-related adverse events (as graded by Common Terminology Criteria for Adverse Events version 4.0) consisted of six patients with rash (four grade 1, two grade 2), three patients with diarrhea (one grade 1, two grade 3), one patient with grade 1 thyroiditis, one patient with grade 3 hepatitis, and 1 patient with grade 2 hypophysitis. The median overall survival from the time of the first dose of ipilimumab was 6.4 months (range: 1.8-26.7 months). Several patients demonstrated serologic responses to cancer-testis antigens and other antigens. Durable responses to ipilimumab were observed, but the overall response rate was low. Additional investigation is necessary to clarify the role of ipilimumab in patients with mucosal melanoma.

Phytochemicals As Chemosensitizers: From Molecular Mechanism to Clinical Significance

Abstract: This review provides an overview of the clinical relevance of chemosensitization, giving special reference to the phenolic phytochemicals, curcumin, genistein, epigallocatechin gallate, quercetin, emodin, and resveratrol, which are potential candidates due to their ability to regulate multiple survival pathways without inducing toxicity. We also give a brief summary of all the clinical trials related to the important phytochemicals that emerge as chemosensitizers. The mode of action of these phytochemicals in regulating the key players of the death receptor pathway and multidrug resistance proteins is also abridged. Rigorous efforts in identifying novel chemosensitizers and unraveling their molecular mechanism have resulted in some of the promising candidates such as curcumin, genistein, and polyphenon E, which have gone into clinical trials. Even though considerable research has been conducted in identifying the salient molecular players either contributing to drug efflux or inhibiting DNA repair and apoptosis, both of which ultimately lead to the development of chemoresistance, the interdependence of the molecular pathways leading to chemoresistance is still the impeding factor in the success of chemotherapy. Even though clinical trials are going on to evaluate the chemosensitizing efficacy of phytochemicals such as curcumin, genistein, and polyphenon E, recent results indicate that more intense study is required to confirm their clinical efficacy. Current reports also warrant intense investigation about the use of more phytochemicals such as quercetin, emodin, and resveratrol as chemosensitizers, as all of them have been shown to modulate one or more of the key regulators of chemoresistance.

Human endogenous retrovirus-K (HML-2): a comprehensive review.

Abstract: The human genome contains a large number of retroviral elements acquired over the process of evolution, some of which are specific to primates. However, as many of these are defective or si...