Increased expression of beta-catenin predicts better prognosis in nonsmall cell lung carcinomas

BACKGROUND: beta-Catenin has been shown to function as a Wnt signaling molecule to stimulate cyclin D1 expression and cell growth in several kinds of tumors. METHODS: The authors immunohistochemically examined specimens of 217 surgically resected primary nonsmall cell lung carcinomas (NSCLCs) for beta-catenin expression and classified them semiquantitatively into three categories, including those with high, moderate, and low scores of expression. RESULTS: High, moderate, and low scores of expression were found in 37 (17.1%), 145 (66.8%), and 35 (16.1%) tumors, respectively. beta-Catenin expression was not correlated with cyclin D1 expression, but was positively correlated with the Ki-67 cell growth fraction (P = 0.04). The direct sequencing analysis for the beta-catenin gene mutation of 13 specimens of 217 tumors for the current study revealed no mutations. The relation between survival and beta-catenin expression was evaluated in 148 potentially curatively resected tumors with pathologic Stages I-IIIA. A trend toward better survival was found in patients with tumors having higher scores. In multivariate analysis, high beta-catenin expression was a significant and independent favorable prognostic factor (hazards ratio, 0.31; P = 0.007) as was pathologic stage. Analyzed by cell type, in nonsquamous cell carcinomas, patients with tumors having high scores survived a significantly longer time than those with tumors having moderate or low scores (5-year survival rates, 84%, 55%, and 32%, respectively; P = 0.02), and high beta-catenin expression tended to be a favorable prognostic factor (hazards ratio, 0.32; P = 0.052). CONCLUSIONS: These results indicate that, in NSCLCs, increased expression of beta-catenin can predict favorable prognosis of patients with resected tumors, suggesting that accumulation of beta-catenin has no or little oncogenic effect via activation of the Wnt pathway, unlike in colon carcinomas or hepatomas.     

Three-dimensional intrafractional movement of prostate measured during real-time tumor-tracking radiotherapy in supine and prone treatment positions

To quantify three-dimensional (3D) movement of the prostate gland with the patient in the supine and prone positions and to analyze the movement frequency for each treatment position.

The real-time tumor-tracking radiotherapy (RTRT) system was developed to identify the 3D position of a 2-mm gold marker implanted in the prostate 30 times/s using two sets of fluoroscopic images. The linear accelerator was triggered to irradiate the tumor only when the gold marker was located within the region of the planned coordinates relative to the isocenter. Ten patients with prostate cancer treated with RTRT were the subjects of this study. The coordinates of the gold marker were recorded every 0.033 s during RTRT in the supine treatment position for 2 min. The patient was then moved to the prone position, and the marker was tracked for 2 min to acquire data regarding movement in this position. Measurements were taken 5 times for each patient (once a week); a total of 50 sets for the 10 patients was analyzed. The raw data from the RTRT system were filtered to reduce system noise, and the amplitude of movement was then calculated. The discrete Fourier transform of the unfiltered data was performed for the frequency analysis of prostate movement.

No apparent difference in movement was found among individuals. The amplitude of 3D movement was 0.1–2.7 mm in the supine and 0.4–24 mm in the prone positions. The amplitude in the supine position was statistically smaller in all directions than that in the prone position (p < 0.0001). The amplitude in the craniocaudal and AP directions was larger than in the left-right direction in the prone position (p < 0.0001). No characteristic movement frequency was detected in the supine position. The respiratory frequency was detected for all patients regarding movement in the craniocaudal and AP directions in the prone position. The results of the frequency analysis suggest that prostate movement is affected by the respiratory cycle and is influenced by bowel movement in the prone position.

The results of this study have confirmed that internal organ motion is less frequent in the supine position than in the prone position in the treatment of prostate cancer. RTRT would be useful in reducing uncertainty due to the effects of the respiratory cycle, especially in the prone position.     

Intrinsic angiotensin II-generating system in human pancreatic cancer tissues

To clarify whether an intrinsic angiotensin II-generating system exists in human advanced pancreatic cancer tissues, we measured angiotensin II concentration and angiotensin converting enzyme (ACE) activity in tissues of normal pancreas, pancreatic cancers, colon cancers and hepatocellular carcinomas. After the surgically resected specimens were homogenized, angiotensin II concentration and ACE activity in tissues were measured using the florisil method and Kasahara's method, respectively. Tissue angiotensin II levels in pancreatic cancers (n = 13) were significantly higher than those of normal pancreas (n = 7), colon cancers (n = 7), or hepatocellular carcinomas (n = 7). However, there was no significant difference in tissue ACE activity between them. This study provides in vivo evidence of ACE-independent angiotensin II-generating system in human pancreatic cancer tissues and suggests that this locally-formed angiotensin II influences the microenvironment of pancreatic cancer tissues in a paracrine fashion.     

Genetic alterations of the ornithine decarboxylase gene in human colorectal cancers

Ornithine decarboxylase (ODC), a critical regulatory enzyme for polyamine biosynthesis, is strictly regulated in human cells. Several studies suggested the importance of elevated enzymatic activity and altered biochemical characteristics of ODC in malignant cells. Because mutation of ODC in primary human hepatocellular carcinoma has been reported, we examined whether the genetic alterations, such as mutations or structural alterations of the gene, also account for the alteration of ODC activity in human colorectal cancer. No mutation or structural alteration in the ODC was detected in any of the colorectal tumors and normal tissues examined. These results suggest that a mutation or structural alteration of the ODC may not be involved in human colorectal carcinogenesis.     

Enhanced spontaneous and aflatoxin-induced liver tumorigenesis in xeroderma pigmentosum group A gene-deficient mice

Xeroderma pigmentosum (XP) is an autosomal recessive hereditary disease featuring defective nucleotide excision repair (NER). XP patients are highly sensitive to sunlight and develop skin cancer at an early age. While the fact that XP patients have a large increase in mortality from skin cancers has been extensively documented, the relation between XP and internal tumors has received little attention. We therefore analyzed development of spontaneous and aflatoxin B(1) (AFB(1))-induced liver tumors in XPA-deficient congenic mice, originally created by repeated back-crosses with inbred C3H/HeN mice. Spontaneous liver tumors were assessed at the age of 16 months in two separate experiments using F5 and F10 lines. The incidence of and average number of spontaneous tumors per mouse were significantly higher in XPA-/- than in XPA+/+ and +/- mice. Similarly, F10 XPA-/- mice receiving i.p. injection of 0.6 or 1.5 mg/kg b.w. AFB(1) at 7 days of age demonstrated more liver tumors than their heterozygous or homozygous positive counterparts when examined at month 11. These results demonstrate that XPA-deficient mice have increased susceptibility to both spontaneous liver tumor development and AFB(1)-induced hepatocarcinogenesis.     

Prognostic Value of Loss of Heterozygosity around three Candidate Tumor Suppressor Genes on Chromosome 10q in Astrocytomas

We thoroughly examined loss of heterozygosity (LOH) around three candidate tumor suppressor genes on chromosome 10q to determine whether LOH of each tumor suppressor gene is associated with the previously defined clinical prognostic indices. We also examined whether LOH can help predict prognostic variables in astrocytomas.We selected samples from 40 astrocytomas (grades 2–4), performed Ki-67 immunostaining, and counted positive cells. Using DNA from aliquots of tumor blocks and leukocytes, we investigated LOH around the PTEN, NEURL, and DMBT1 genes (10q23.3–26.1) with the silver staining procedure. We then statistically evaluated the relationship among histological features, regional LOH on chromosome 10q, and survival. The mean survival period for patients with LOH around PTEN was 7.2 months after surgery, while that for patients without LOH around PTEN was 21.4 months. Thus, LOH around PTEN was closely associated with a reduced overall survival (p = 0.0020) but LOH at NEURL or DMBT1 was not (p > 0.05).The combined features of an increase in histological grading and Ki-67-positive cells and the presence of LOH around PTEN significantly correlated with poor prognosis. These factors may be useful predictors of survival, and LOH analysis of tumor suppressor genes on chromosome 10q can contribute greatly to the treatment of patients with astrocytoma.     

Expression of dystroglycan and the laminin-alpha 2 chain in the rat peripheral nerve during development

In Schwann cells, the transmembrane glycoprotein beta-dystroglycan comprises the dystroglycan complex, together with the extracellular glycoprotein alpha-dystroglycan, which binds laminin-2 (alpha 2/beta 1/gamma 1), a major component of the Schwann cell basal lamina. To provide clues to the biological functions of the interaction of the dystroglycan complex with laminin-2 in peripheral nerves, we investigated the expression of beta-dystroglycan and the laminin-alpha 2 chain in rat sciatic nerve during development by immunoblot, immunofluorescence, and immunoelectron microscopic studies. The expression of beta-dystroglycan and the laminin-alpha 2 chain in the rat sciatic nerve was low and not confined to the Schwann cell outer membrane from embryonic day 18 to birth, when there was only an immature basal lamina assembly and no compact myelin formation by Schwann cells. However, the expression of these proteins increased markedly and became clearly localized to the Schwann cell outer membrane between birth and postnatal day 7, when both basal lamina assembly and compact myelin formation by Schwann cells progressed rapidly. From postnatal day 7 to adult, there was no remarkable change in the expression of these proteins. Our results support the hypothesis that the dystroglycan complex functions as an adhesion apparatus, binding the Schwann cell outer membrane with the basal lamina, and suggest that the dystroglycan complex plays a role in Schwann cell myelination through its interaction with laminin-2.     

Distal myopathy with rimmed vacuoles: novel mutations in the GNE gene

The authors present three novel missense mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene, the causative gene for hereditary inclusion body myopathy, in Japanese patients with distal myopathy with rimmed vacuoles. Seven out of nine patients had homozygous V572L mutation, one was a compound heterozygote with C303V and V572L mutations, and the remaining patient bore homozygous A631V mutation.     

Colocalization of CA19-9 and KL-6 to epithelial cells in dilated bronchioles in a patient with idiopathic pulmonary fibrosis complicated by diffuse alveolar damage

A 73-year-old woman with idiopathic pulmonary fibrosis (IPF) had an elevated serum CA19-9 level, but not KL-6. Her condition worsened and she subsequently died and this was associated with a rise in the serum KL-6 level. At autopsy, the lung showed a honeycomb appearance macroscopically and, microscopically, hyaline membrane formation was seen. Immunohistochemical staining revealed partial colocalization of KL-6 and CA19-9 to dilated bronchiolar cells. These features suggest that the mechanisms that cause the synthesis and release of CA19-9 and KL-6 from damaged lung tissue in IPF are likely to differ from those in diffuse alveolar damage. In addition, serum KL-6 levels may reflect the severity of disease more sensitively than CA19-9 levels.