Arata Kamimatsuse

Outcome of hepatoblastomas treated using the Japanese Study Group for Pediatric Liver Tumor (JPLT) protocol-2: report from the JPLT

BackgroundIn the recent years, surgical resection with pre- and/or postoperative chemotherapy has markedly improved the survival rate of hepatoblastoma patients. We herein report the results of patients treated with the current protocol of the Japanese Study Group for Pediatric Liver Tumor, JPLT-2.MethodsA total of 279 patients with malignant liver tumor were enrolled in JPLT-2. Data from 212 hepatoblastoma cases were analyzed. PRETEXT I patients were treated with primary resection followed by low doses of cisplatin–pirarubicin (tetrahydropyranyl-adriamycin). Otherwise, patients received preoperative cisplatin–pirarubicin (CITA), followed by surgery and postoperative chemotherapy. Ifosfamide, pirarubicin, etoposide, and carboplatin (ITEC) were given as a salvage treatment. High-dose chemotherapy with hematopoietic stem cell transplantation (SCT) was reserved for patients with metastatic diseases.ResultsThe 5-year overall survival rate (OS) in non-metastatic cases was 100% for PRETEXT I, 87.1% for PRETEXT II, 89.7% for PRETEXT III, and 78.3% for PRETEXT IV. The 5-year OS in metastatic cases was 43.9%. The outcome in non-metastatic PRETEXT IV cases was markedly improved, while the results of metastatic tumors remained poor.ConclusionsJPLT-2 protocol achieved satisfactory survival among children with non-metastatic hepatoblastoma. New approaches are needed for patients with metastatic diseases.

Wnt signaling and telomerase activation of hepatoblastoma: correlation with chemosensitivity and surgical resectability

PURPOSE Recently, it became apparent that telomerase directly modulated Wnt signaling as a cofactor in a β-catenin transcriptional complex. In this study, we investigated Wnt/β-catenin signaling and telomerase activation in hepatoblastoma (HBL). METHODS Tumors derived from 56 HBL cases treated with the Japanese Study Group for Pediatric Liver Tumors (JPLT) Protocol-2 were analyzed for oncogenic mutations (missense mutations and interstitial deletions in the third exon) of the CTNNB1 gene-encoding β-catenin and for the expression levels of telomerase reverse transcriptase (TERT). RESULTS Oncogenic mutations of CTNNB1 were detected in 42 cases (75%). The expression levels of TERT were significantly higher in 14 cases without mutation (P < .05) and in 8 cases with metastasis (P < .01). Interestingly, Wnt/β-catenin target genes were significantly activated in the tumors without mutations (P = .013). In cases with mutations, preoperative chemotherapy was more effective (P = .008), and complete resection rate was higher (P = .034). Consequently, 2 patients with mutations and 4 patients without mutations died of disease (P = .013). High expression of TERT was detected in all tumors of these dead patients. CONCLUSIONS Wnt/β-catenin signaling in the HBLs without CTNNB1 mutations was activated by high expression of TERT. The clinical courses in HBLs without CTNNB1 mutations seemed to be unfavorable because of chemoresistance and low rates of resectability.

Detection of CpG island hypermethylation of caspase-8 in neuroblastoma using an oligonucleotide array.

The caspase‐8 gene (CASP8) is frequently inactivated in unfavorable neuroblastomas through DNA methylation. The present study utilized oligoarrays to evaluate the methylation status of a CpG island located between exons 2 and 3 of caspase 8 in neuroblastomas.

Clinical feature of anaplastic lymphoma kinase–mutated neuroblastoma

PURPOSE Anaplastic lymphoma kinase (ALK) has recently been identified as a gene conferring a predisposition for neuroblastoma. We have analyzed tyrosine kinase domain mutations and amplification/expression of the ALK gene and focused on clinical features of neuroblastoma cases with ALK aberrations. METHODS The frequency of ALK mutations, copy number gain, and expression were analyzed in 538 neuroblastoma tumors derived from 361 cases, including 161 cases detected by mass screening. These cases were analyzed according to clinicopathologic features including the International Neuroblastoma Staging System and patient outcomes. RESULTS Three cases (0.8%) had ALK amplification, and 16 cases (5.2%) had missense mutations at positions F1174, F1245, D1249, and R1275. Among them, 7 cases were diagnosed at more than 14 months of age, and 11 cases were infants, including 9 cases detected by mass screening and 1 multiple neuroblastoma with a germline mutation. Of the 11 infants, 3 cases relapsed, and 1 case died of disease. Among cases detected by screening, activated ALK cases showed significantly worse prognosis (P = .002). Of 7 older cases, 5 had MYC amplifications, and 5 died of disease. The expression levels of ALK were up-regulated in cases with unfavorable outcomes. In cases with activated ALK neuroblastoma, survival rates of patients detected by screening were significantly better than those in the clinically detected group (P = .025). CONCLUSIONS The results of the present study support the hypothesis that activated ALK tumors represent a specific subset of neuroblastomas. These tumors usually develop in infants and may have a high capacity for recurrence.

Abstract 3820: Wnt signaling and telomerase activation in hepatoblastoma.

Purpose: The abnormal Wnt/β-catenin signaling plays a key role in hepatoblastoma (HBL) development. In HBL, CTNNB1 coding s-catenin protein with mutated or deleted at hot-spot regions involving exon 3 stimulates this pathway. Previously we reported that the levels of telomerase reverse transcriptase (TERT) mRNA and telomerase activities were correlated with outcomes of the patients with HBL. In this study, we examined the correlation between Wnt/β-catenin signaling and telomerase activation in HBL. And, we investigated the location of β-catenin and TERT in HBL and the expression levels of the Wnt signal genes downstream of s -catenin. Methods: Tumors derived from 212 HBL cases treated with the JPLT-2 protocol were analyzed for oncogenic mutations (missense mutations and interstitial deletions in the third exon) of the CTNNB1 gene encoding β-catenin and mutations of Wnt signal genes including APC, AXIN1, and 2. Moreover, these tumors were analyzed for the expression levels of TERT (telomerase reverse transcriptase) and the Wnt signal genes downstream of s -catenin (MYC, cyclin D1 and MMP7) using Real time RT-PCR and immunohistochemistry. Results: Oncogenic mutations of CTNNB1 were detected in 163 cases (76.4%) and more than 80% showed abnormalities of Wnt signal genes. The expression levels of TERT were significantly higher in 49 cases without mutation (P Citation Format: Eiso Hiyama, Yuka Ueda, Arata Kamimatsuse, Yoshiuki Onitake, Kaoru Ogura, Keiko Hiyama. Wnt signaling and telomerase activation in hepatoblastoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3820. doi:10.1158/1538-7445.AM2013-3820

A Case Report of Intramural Gallbladder Abscess after Two Years

壁内型胆嚢周囲膿瘍を形成して, 2年間の経過の後に切除した症例を経験したので報告する. 症例は92歳の男性で, 2000年11月, 右上腹部痛にて来院し, 急性胆嚢炎として保存的治療を受けて退院した. 2002年11月, 前回と同様の右上腹部痛を主訴に再来院し, 胆嚢炎増悪で入院となった. WBC 9,050/mm3, CRP 9.1mg嚢dlと炎症所見を認めた. 腹部超音波検査で胆嚢周囲への限局性の液体貯留および隔壁様構造を認めた. 腹部CTでは腫大した胆嚢様の構造とその内部に隔壁を認めた. 経皮的膿瘍ドレナージ後の造影では胆嚢と交通した膿瘍腔を認め, 無石性胆嚢炎からの胆嚢周囲膿瘍を形成したと診断した. 病理所見では壊疸性胆嚢炎および壁内型胆嚢周囲膿瘍と診断された. 本症例のように壁内型胆嚢周囲膿瘍の長期経過をみた報告例はまれであり, 消炎後の早期の切除が必要であると考えられた.