Survival data analysis with time-dependent covariates using generalized additive models

We discuss a flexible method for modeling survival data using penalized smoothing splines when the values of covariates change for the duration of the study. The Cox proportional hazards model has been widely used for the analysis of treatment and prognostic effects with censored survival data. However, a number of theoretical problems with respect to the baseline survival function remain unsolved. We use the generalized additive models (GAMs) with B splines to estimate the survival function and select the optimum smoothing parameters based on a variant multifold cross-validation (CV) method. The methods are compared with the generalized cross-validation (GCV) method using data from a long-term study of patients with primary biliary cirrhosis (PBC)

幼児の規範意識の変容過程に関する検討

学位の種別: 課程博士審査委員会委員 : （主査）東京大学教授 秋田 喜代美, 東京大学准教授 藤江 康彦, 東京大学准教授 浅井 幸子, 東京大学教授 遠藤 利彦, 東京大学准教授 野澤 祥子University of Tokyo(東京大学

Expression of Phospho-Akt and PTEN Proteins in Human Breast Cancer in Relation to Tumor Progression and Patient Survival

Phosphatidylinositol 3-kinase (PI3-kinase) controls mitogenesis, cellular growth and transformation in a variety of cancers. The serine-threonine kinase Akt is a downstream target of PI3-kinase, and phosphorylated Akt (Phospho-Akt) inhibits apoptosis. Phosphatase and tensin homolog detected on chromosome ten (PTEN) is a tumor suppressor that antagonizes PI3-kinase activity, negatively regulates its downstream-target, Akt, inhibits phosphorylation of Akt, and medicates cell-cycle arrest and apoptosis. To clarify whether the PI3-kinase/Akt pathway and PTEN relate to breast cancer, we examined the expression of pathway-related proteins such as Phospho-Akt and PTEN in clinical specimens. Immunohistochemical analysis was performed on tissue specimens surgically obtained from 221 patients with breast cancer. The association of Phospho-Akt and PTEN expression with clinicopathological variables and the prognosis of patients were analyzed. Of 221 breast carcinomas, positive Phospho-Akt expression was observed in 91 (41.1%) and positive PTEN expression in 119 (53.8%). Phospho-Akt expression and loss of PTEN expression significantly correlated with tumor staging, tumor size and lymph node metastasis. Patients with Phospho-Akt-positive tumors had significantly inferior disease-free survival or over-all survival to those with Phospho-Akt-negative tumors, while those with PTEN positive tumors were better than those with PTEN negative tumors. Moreover, patients with Phospho-Akt-positive and PTEN-negative tumors had a significantly inferior disease-free survival and over-all survival compared to those with Phospho-Akt-negative and PTEN-positive tumors. Multivariate analysis revealed that expression of Phospho-Akt and tumor size were the independent factors (P = 0.024). We demonstrated that the expression of Phospho-Akt significantly correlated with tumor progression and patients survival with breast cancer. Phospho-Akt/PTEN expression status is possibly a definitive prognostic factor in clinical breast cancer

Interstitial lung disease caused by TS-1: a case of long-term drug retention as a fatal adverse reaction

TS-1 is an oral anti-cancer agent for gastric cancer with a high response rate and low toxicity. We report a case of long-term drug retention of TS-1 causing interstitial lung disease (ILD) as a fatal adverse reaction. A 65-year-old woman underwent a total gastrectomy with pathologic confirmation of gastric adenocarcinoma. She received 6 cycles of TS-1 and low-dose cisplatin for post-operative adjuvant chemotherapy followed by single-agent maintenance therapy with TS-1. After 8 months, the patient complained of a productive cough with sputum and mild dyspnea. A pulmonary evaluation revealed diffuse ILD in the lung fields, bilaterally. In spite of discontinuing chemotherapy and the administration of corticosteroids, the pulmonary symptoms did not improve, and the patient died of pulmonary failure. TS-1-induced ILD can be caused by long-term drug retention that alters the lung parenchyma irreversibly, the outcome of which can be life-threatening. Pulmonary evaluation for early detection of disease is recommended

Dendritic cell density and activation status in human breast cancer – CD1a, CMRF-44, CMRF-56 and CD-83 expression

Low CD1a-positive putative dendritic cell numbers in human breast cancer has recently been described and may explain the apparent ‘poor immunogenicity’ previously reported in breast cancer. Little attention has been given to dendritic cell activation within the tumour microenvironment, which is another reason why the in-situ immune response may be severely deficient. We have therefore examined CD1a expression as a marker for dendritic cells, together with CMRF-44 and -56 as markers of dendritic cell activation status, in 40 human breast cancers. The results demonstrate few or no CD1a-positive putative dendritic cells and minimal or no expression of the dendritic cell activation markers. Both dendritic cell number and dendritic cell activation appear substantially deficient in human breast cancers, regardless of tumour histological grade

Hypoxia and Etanidazole Alter Radiation-Induced Apoptosis in HL60 Cells but Not in MOLT-4 Cells

培養細胞において放射線照射誘発アポトーシスに対する低酸素状態での照射の影響を検討した。HL60及びMolt4細胞を空気中及び低酸素下で15GyのX線を照射した。放射線増感剤としてEtanidazoleを用いた。アポトーシスの検出は核の形態観察と電気泳動によるラダーの検出により行った。HL60細胞では低酸素下での照射ではアポトーシスによる細胞死が減少し、カスパーゼ8、9及び3の活性誘導も減少した。低酸素下でEtanidazoleはX線誘発アポトーシスとカスパーゼの活性を高めた。しかし、Molt4細胞ではEtanidazoleの影響は認められなかった。この2細胞におけるX線誘発DNA二重鎖切断（DSB）は低酸素下での照射ではともに空気中での照射に比べて有意に減少した。低酸素下でEtanidazoleはX線誘発DSBを増加させた。これらの結果からHL60においてはX線誘発アポトーシスはDSBによって引導されること、Molt4では他の損傷が引き金になってアポトーシスが誘発されることが示唆された

Plasma Leptin Level, the Adipocyte-Specific Product of the Obese Gene, Is Associated with Tumor Progression and Is a Marker of the Nutritional Status of Patients with Gastric Cancer

Leptin, a product of the obese gene, is synthesized and released into the circulation in response to increased energy storage in adipose tissue. Leptin plays an important role in the regulation of body weight and energy balance. However, leptin levels in patients with malignant tumor have not been fully examined. The purpose of the present study is to clarify the clinical implications of leptin levels in the circulation in patients with gastric cancer. The subjects were 103 patients with gastric cancer at various stages. Levels of leptin in the plasma were determined with a commercially available human leptin-selective quantitative enzyme immunoassay kit. There were clear decreasing trends in leptin levels along with tumor progression in both males and females, and statistically significant differences were observed in males between stages II and IV, and in females between stages I and IV. Plasma leptin levels of females were consistently higher than those of males when we compared them with patients in the same stages. Moreover, statistically significant decreases in leptin levels were observed postoperatively. However, there were no statistically significant relationships between leptin levels and clinicopathological findings. There was a positive correlation between levels of plasma leptin and values of the body mass index. These findings may indicate that plasma leptin levels do not involve factors relevant to specific tumor growth but involve some tumor-related nutritional status due to tumor progression. We conclude that leptin levels are reflected during tumor-bearing status, and these are also useful markers for both indicating tumor progression and discovering the nutritional status of patients with gastric cancer

Immunohistochemical Detection of Occult Serosal Microinvasion in Primary Lesions of Gastric Cancer with Subserosal Invasion

In gastric cancer, the presence or absence of serosal invasion by cancer in the primary lesion is an important prognostic factor. Pathological findings are routinely determined by hematoxylin-eosin (H&E) staining, but it is well known that micrometastasis or microinvasion are easily overlooked by H&E staining. Cytokeratin (CK) proteins serve as reliable markers for cells from epithelial origins. The purpose of this study was to clarify the usefulness of CK immunohistochemical staining in the detection of serosal microinvasion in gastric cancer with subserosal invasion. We examined 50 primary lesions from 50 gastric cancer patients with subserosal invasion. Two consecutive sections were prepared for simultaneous staining with ordinary H&E and CK immunostaining with anticytokeratin antibody (CAM 5.2), respectively. Although there were no differences in the postoperative survival rates between patients with or without microinvasion, serosal microinvasion was 0detected in 8 (16%) of 50 patients by CK staining, including 1 patient whose invasion was detected by both H&E and CK stainings. CK immunostaining enabled us to make an accurate and detailed diagnosis which we believe to be useful for detecting serosal microinvasion in the primary lesion in gastric cancer with subserosal invasion