膵癌におけるp16癌抑制遺伝子の異常 : 臨床病理学的事項との対比

取得学位：博士(医学), 学位授与番号：医博甲第1478号, 学位授与年月日：平成13年3月31日, 学位授与年：200

Herbal medicine Ninjinyoeito ameliorates ribavirin-induced anemia in chronic hepatitis C: A randomized controlled trial

金沢大学がん研究所Aim: Ribavirin (RBV) shows a strong antiviral effect on hepatitis C virus when used in combination with interferon. However, RBV-induced anemia is a major problem in this therapy. It would be of great clinical importance to ameliorate the anemia without reducing the RBV dose. We report here that, Ninjinyoeito (NYT), a herbal medicine can reduce the RBV-induced anemia. Methods: Twenty-three patients with chronic hepatitis C were treated with interferon alpha 2b plus RBV with (NYT group) or without (control group) NYT by a randomized selection. Eighteen patients completed the treatment schedule, and hemato-biochemical and virological effects were evaluated. Results: There was no significant difference in biochemical and virological responses between the two groups. However, anemia was significantly reduced in the NYT group compared with the control group. The maximal decrease of Hb in the NYT group (2.59±1.10 g/dL) was significantly (P= 0.026) smaller than that in the control group (3.71±0.97 g/dL). There was no significant difference in serum glutathione peroxidase activity, serum RBV concentration, and Th1/Th2 balance between the two groups. There was no specific adverse effect in NYT administration. Conclusion: These results suggest that NYT could be used as a supportive remedy to reduce the RBV-induced anemia in the treatment of chronic hepatitis C. © 2005 The WJG Press and Elsevier Inc. All rights reserved

Multiple factors influencing the release of hTERT mRNA from pancreatic cancer cell lines in in vitro culture

Since telomerase expression is highly prevalent in human cancers, the quantitation of serum/plasma hTERT (human telomerase reverse transcriptase) mRNA levels may be useful for early detection of PCa (pancreatic cancer). To analyse the correspondence between exhTERT (extracellular hTERT) mRNA levels and hTERT expression, we designed a cell culture system to investigate factors modulating the extracellular levels of hTERT mRNA in media conditioned by eight PCa cell lines. We found that the level of exhTERT mRNA was dependent on cell growth rate. MIAPaCa-2, PANC-1, KLM-1 and PK-9 cells expressed high levels of exhTERT mRNA, independent of cell density, whereas proliferating PK-59, BxPC-3 and PK-45H cells released low levels of exhTERT mRNA. The augmented release of mRNA by spontaneous dead MIAPaCa-2 cells was further increased at postconfluence. In Capan-1 cells, low correspondence of marker was also due to RNase secretion. Upon reaching confluence, some PCa cell lines showed down-regulation of hTERT expression. Following cell-cell adhesion, as shown by E-cadherin engagement, PK-59 cells showed levels of extracellular message below the limits of detection, a loss not due to an increase in message degradation. These results suggest that the levels of exhTERT mRNA in the medium of PCa cell lines are altered not only in response to cell growth rate and cell destruction, but are responsive to extracellular cues such as RNases and cell density. A cell-free assay for exhTERT mRNA may therefore not be useful for early detection of PCa. © The Author(s) Journal compilation © 2012 International Federation for Cell Biology

Diagnostic utility of aberrant methylation of tissue factor pathway inhibitor 2 in pure pancreatic juice for pancreatic carcinoma

医薬保健研究域医学系The tissue factor pathway inhibitor 2 (TFPI-2) is a Kunitz-type serine proteinase inhibitor. Recently, the aberrant methylation of TFPI-2 was detected frequently in pancreatic carcinoma (PCa) tissues but not in normal pancreatic tissues. We analyzed the aberrant methylation of TFPI-2 in the pure pancreatic juice (PPJ) aspirated endoscopically from patients with various pancreatic diseases. Using the highly sensitive methylation-specific polymerase chain reaction (MSP) and quantitative MSP (Q-MSP) assay, we investigated the aberrant methylation of TFPI-2 in nine human PCa cell lines and in the PPJ from patients with PCa, intraductal papillary mucinous neoplasms (IPMN) and chronic pancreatitis (CP). The incidence of aberrant TFPI-2 methylation was seven (77.8%) of nine PCa cell lines by Q-MSP. In cell lines, the expression of TFPI-2 mRNA by quantitative reverse transcription-polymerase chain reaction showed an inverse correlation to the aberrant methylation of TFPI-2. The incidence of aberrant TFPI-2 methylation in the PPJ was 21 (58.3%) of 36 PCa patients, three (17.6%) of 17 IPMN and one (4.8%) of 21 CP by MSP assay. Using a suitable cut-off value of 2.5 according to the receiver operating characteristic curve, the incidence of aberrant TFPI-2 methylation in the PPJ by real-time MSP was 18 (62.1%) of 29 PCa patients, one (5.1%) of 17 IPMN and three (14.3%) of 21 CP, respectively. The incidence of quantitative TFPI-2 hypermethylation in the PPJ with PCa was significantly higher than that with IPMN (P < 0.001) or CP (P < 0.001). Moreover, the aberrant methylation rate of TFPI-2 in the PPJ was 100%, as observed (6/6) in the PCa patients with liver metastasis, and 86.7% (26/30) in stages IVa + IVb of PCa by Q-MSP assay. These results suggest that promoter methylation of TFPI-2 in the PPJ may be a useful marker in the diagnosis and progression of PCa using an endoscopically feasible approach. © 2006 Japanese Cancer Association

慢性膵炎の診断における超音波内視鏡の有用性

金沢大学附属病院消化器内科金沢大学がん研究所We report usefulness of endoscopic ultrasonography (EUS) for the diagnoses of chronic pancreatitis (CP). We evaluated EUS features of hyperechoic foci, hyperechoic strand, lobular out gland margin, lobularity, cyst, stone, ductal dilatation, side branch dilatation, duct irregularity, hyperechoic duct margins, atrophy, localized swelling in cases with CP (30 definite and 6 probable) diagnosed by computed tomography (CT) or endoscopic retrograde cholangiopancreatography (ERCP). Hyperechoic foci, hyperechoic strand, lobularity, hyperechoic duct margins in definite or probable CP were recognized in more than 80 % cases. Lobular out gland margin was observed in 14 (47 %) of 30 cases with definite CP, although none with probable CP (P = 0.06). In conclusions, hyperechoic foci, hyperechoic strand, lobularity, hyperechoic duct margins are useful for screening of CP, and lobular out gland margin would be reliable finding in definite CP. 目的：慢性膵炎の診断における超音波内視鏡 (EUS) の有用性につき検討した。 対象と方法：対象は内視鏡的逆行性胆道膵管造影 (ERCP)、CTにて慢性膵炎と診断され、EUSを施行した36例 (確診30例、準確診6例) で、hyperechoic foci, hyperechoic strand, lobular out gland margin, lobularity, cyst, stone, ductal dilatation, side branch dilatation, duct irregularity, hyperechoic duct margins, atrophy, localized swellingの各種EUS所見について評価し、retrospectiveに検討した。 結果：慢性膵炎確診例、準確診例では、いずれもhyperechoic foci, hyperechoic strand, lobularity, hyperechoic duct marginsが、80％以上の症例でみられた。lobular out gland marginは確診例で47%に認めたが、準確診例ではみられず、確診例で多い傾向が見られた (p=0.06)。 結語：hyperechoic foci, hyperechoic strand, lobularity, hyperechoic duct marginsは慢性膵炎の拾い上げに有用であり、lobular out gland marginは慢性膵炎の確診所見になる可能性が示唆された

Diagnostic utility of aberrant methylation of tissue factor pathway inhibition 2 in pure pancreatic juice for pancreatic carcinoma

Division of Medical Oncology and Surgical Oncolog

Usefulness of endoscopic ultrasonography for the diagnoses of chronic pancreatitis

Division of Medical Oncology and Surgical Oncolog

Combined chemotherapy with carboplatin plus irinotecan showed favorable efficacy in a patient with relapsed small cell carcinoma of the prostate complicated with meningeal carcinomatosis

金沢大学附属病院がん高度先進治療センター金沢大学がん研究所分子標的がん医療研究開発センターWe report the case of a 65-year-old man with recurrent prostate cancer who presented with meningeal carcinomatosis. In September 2007, he had been diagnosed with mixed type small cell carcinoma and adenocarcinoma at clinical stage T4N1M1 (primary prostate tumor with multiple bone, liver, and lymph node metastases) and hormonal therapy had been administered. Following an increase in the level of pro-gastrin-releasing peptide (ProGRP), combined chemotherapy with cisplatin plus etoposide was implemented and showed efficacy in targeting the small cell carcinoma. In March 2008, he presented with signs of meningeal irritation; his condition deteriorated quickly and multiple brain metastases were confirmed by magnetic resonance imaging (MRI). A sample of cerebrospinal fluid collected by lumbar puncture showed cancer cells and an elevated level of ProGRP. Small cell carcinoma of the prostate complicated with meningeal carcinomatosis was diagnosed. A different chemotherapy regimen was then administered, consisting of a combination of carboplatin plus irinotecan, which is one of the most common first-line treatments for extensive-stage small cell lung carcinoma. From day 20 after the initiation of this therapy, he gradually recovered from the signs of meningeal irritation, and brain MRI showed nearly normal findings; also, the serum level of ProGRP was reduced. In conclusion, we report the efficacy of combined treatment with carboplatin plus irinotecan for small cell carcinoma of the prostate complicated with meningeal carcinomatosis. Because this clinical condition is extremely rare, a gold standard treatment has yet to be established. © 2009 Japan Society of Clinical Oncology

Metastatic renal cell carcinoma complicated with diffuse alveolar hemorrhage: a rare adverse effect of sunitinib

金沢大学附属病院がん高度先進治療センターWe report the case of a 67-year-old man with metastatic papillary renal cell carcinoma (RCC) who developed bloody sputum after the administration of sunitinib. Chest computed tomography revealed diffuse ground-glass opacity lesions, and bloody bronchoalveolar lavage fluid was obtained by flexible bronchoscopy. The abnormal shadows promptly regressed after withdrawal of sunitinib. In four cycles of sunitinib treatment, he suffered from controllable diffuse alveolar hemorrhage. Finally, he died of respiratory failure 8 months after onset. This is the first case report of diffuse alveolar hemorrhage as an adverse effect of sunitinib in metastatic papillary RCC. Care should be taken with pulmonary hemorrhage in the use of anti-angiogenesis agents in not only squamous cell lung cancer, but also metastatic lung tumors. © 2010 Japan Society of Clinical Oncology

Androgen replacement therapy for cancer-related symptoms in male advanced cancer patients : study protocol for a randomised prospective trial (ARTFORM study)

Recent studies reveal that hypogonadism with low serum androgen levels is associated with advanced cancer and induction of most cancer-related symptoms.We designed an ARTFORM study to evaluate the efficacy of androgen replacement therapy in male advanced cancer patients. The ARTFORM study is an investigatorinitiated, randomised controlled trial comparing intramuscle injection of testosterone enanthate with non-administration in male advanced cancer patients with non-curative locally advanced or metastatic lesions. Serum total and free testosterone levels are measured and patients with low testosterone level are randomised. The primary endpoint is the difference in validated health-related quality of life questionnaires at week 12. Trial registration of the ARTFORM study is assigned to University hospital Medical Information Network, Center identifier UMIN 000010939