Expression of BMP-7 in human gastric cancer and its clinical significance.

BACKGROUND: Bone morphogenetic protein-7 (BMP-7) is a signalling molecule belonging to the transforming growth factor--superfamily. Recent studies have demonstrated the clinical impact of BMP-7 expression in various human cancers. However, there have been few reports detailing this in gastric cancer. METHODS: We immunohistochemically investigated the expression of BMP-7 in 233 gastric cancer patients to disclose the clinicopathological features of BMP-7-positive gastric cancer. RESULTS: Immunohistochemically, in human gastric cancer, BMP-7 expression was identified in cellular membranes but also in the cytoplasm of cancer cells. Bone morphogenetic protein-7-positive expression was found in 129 of 233 patients (55%). Bone morphogenetic protein-7 expression was correlated with tumour size, nodal involvement, lymphatic invasion, venous invasion and histology (P<0.05). Bone morphogenetic protein-7 expression was significantly correlated with patient postoperative outcome, especially in the undifferentiated group. Multivariate analysis revealed BMP-7 expression as one of the independent prognostic factors next to the depth of invasion and nodal involvement (P<0.01). CONCLUSIONS: From the data collected, it would be appropriate to conclude on the possible regulation of gastric cancer progression by autocrine or paracrine BMP-7 loops. We can use BMP-7 expression as one of the strong predictors of risk of tumour recurrence in gastric cancer.

The role of salvage surgery for recurrence of esophageal squamous cell cancer.

AIM: A consensus treatment strategy for recurrent esophageal squamous cell cancer (ESCC) has not been established. The purpose of the present study was to analyse the mode of recurrence, and evaluate the role of surgical salvage treatment in recurrence of ESCC. METHODS: Recurrence was detected in 131 of 367 consecutive patients with ESCC. We retrospectively analysed the mode of recurrence and treatment for recurrence. Recurrence was divided into four types; lymph node, hematogeneous, mixed and local. Treatments were classified into four groups; chemotherapy alone (C group), radiation therapy +/- chemotherapy (R group), surgery +/- other therapy (S group), and no therapy (N group). RESULTS: Of the 131 recurrences, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 43, 44, 40 and 4, respectively. The number of patients in the C, R, S, N groups was 35, 35, 24 and 37, respectively. Of the 24 patients who received surgical treatment for recurrence, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 11, 6, 6 and 1, respectively. The number of lesions in hematogeneous recurrence was 2 or less. The survival rate from recurrence to death in the C, R, S and N groups was 0, 3.9, 6.7 and 0%, respectively. A statistically significant difference was found in these groups (p < 0.0001). CONCLUSIONS: Salvage surgery is one of the useful treatment tools for resectable metastatic lesions. In such cases, the number of lesions, recurrent sites and effectiveness of chemotherapy and/or radiotherapy should be carefully evaluated.

Localization of cytochrome P-450-linked mixed function oxidase and steroid hydroxylations within zones of bovine adrenocortices.

The localization of contents and activities of components of cytochrome P-450-linked mixed function oxidase system and the hydroxylation of steroids in mitochondria and microsomes within zones of adrenocortices was investigated. NADPH-adrenodoxin reductase activity was higher in the zona glomerulosa than in the other zones. Adrenodoxin content was present at high concentration in the zona fasciculata. The localization of cytochrome P-450 within zones of adrenocortices has already been reported (Ichikawa, Y., Kuroda, M. and Yamano, T. (1970) J. Cell Biol 45, 640--653). The zona fasciculata contained more mitochondrial and microsomal cytochromes P-450 than the zona glomerulosa or zona reticularis. Cleavage activity of the side chain of cholesterol was found in three zones. However, particularly high activity was observed in the zona fasciculata and zona reticularis. 11beta-Hydroxylation was found in the zona glomerulosa. 21-Hydroxylation activity was especially higher in the zona fasciculata than in the other zones.

Effects of mirthful laughter on growth hormone, IGF-1 and substance P in patients with rheumatoid arthritis.

OBJECTIVE: Growth hormone (GH) plays an ancillary role in the regulation of immune function. GH has been shown to be associated with joint symptoms such as pain and swelling. On the other hand, mirthful laughter has favorable effects on the neuroendocrine-immune system. We evaluated the levels of serum GH, insulin-like growth factor-1 (IGF-1) in RA patients and evaluated the effect of mirthful laughter on GH and IGF-1. METHODS: We compared with the levels of serum GH, IGF-1 and substance P (SP) in patients with RA and healthy subjects (control group) before and after exposure to "Rakugo", a traditional Japanese comical story that induces mirthful laughter. RESULTS: The basal level of serum GH in the RA group was significantly higher than in the control group. After experiencing mirthful laughter, the level of serum GH in the RA group significantly decreased, approaching that in the control group. The serum IGF-1 level was lower in the RA group than in the control group. There was no significant difference in the level of serum SP between the RA group and the control group. CONCLUSION: The basal level of serum GH in the RA group was significantly higher than in the control group, and the level of serum GH significantly decreased after experiencing mirthful laughter These results suggest that the homeostasis of GH in patients with RA is disturbed, and the increased serum GH levels in RA patients may be associated with their stress condition.

Intranodal antitumor immunocyte infiltration in node-negative gastric cancers.

The status and role of immunocytes and dendritic cells in regional lymph nodes in patients with gastric cancer are examined in this study. Forty-nine patients with gastric cancer who underwent curative resection were enrolled in the present study. These patients had no lymph node metastases according to a histological examination. The infiltration of natural killer (NK) cells, dendritic cells, and MIB-1-positive immunocytes was investigated. Based on the Japanese Classification of Gastric Carcinoma, regional lymph nodes were divided into three compartments: (a) compartment 1 (lymph node station numbers 1-6); (b) compartment 2 (lymph node station numbers 7-12); and (c) compartment 3 (lymph node station numbers 14 and 16). Dendritic cells and MIB-1-positive immunocytes infiltrated compartment 1 lymph nodes in increased numbers compared with the lymph nodes of compartments 2 or 3 (P < 0.05). Conversely, intranodal NK cell infiltration did not differ significantly among the three compartments. The incidence of intranodal dendritic and MIB-1-positive cell infiltration in patients with submucosal gastric cancer was significantly higher than in patients with tumors that invaded beyond the muscularis propria. The decreased expression of these immunological markers correlated well with recurrent disease, regardless of tumor depth. The immunocyte level is higher in lymph nodes near the primary tumor (compartment 1) than in those that are distant from the tumor (compartments 2 and 3). This pertains to all three markers, i.e., NK, dendritic, and MIB-1-positive cells. Unlike dendritic and MIB-1-positive cells, intratumoral infiltration of NK cells did not correlate well with either lymph node compartment or the depth of tumor invasion. The degree of NK cell infiltration may be directly associated with antitumor effects, especially in compartment 1. A decrease in all three markers is associated with tumor recurrence.

Expression of p21WAF1/Cip1 in the p53-dependent pathway is related to prognosis in patients with advanced esophageal carcinoma.

The proteins p53 and p21 are important components that regulate G1-S transition through the cell cycle. We immunohistochemically investigated p53 and p21 expression in 111 patients with esophageal squamous cell carcinoma. We also evaluated whether the expression of either of these proteins is a prognostic factor according to the p53-dependent and -independent pathways. The positive rates of p53 and p21 expression were 42.8 and 43.2%, respectively. Clinicopathological findings according to p53 and p21 expression did not differ significantly. The 5-year-survival rates between p21 positive and negative expression did not differ significantly in the p53-positive group. In the p53-negative group, the 5-year-survival rate of patients with p21-positive expression was 22.9%, which was significantly better than that of patients with p21-negative expression (12.7%; P<0.05). Multivariate analysis revealed that p21 expression in the p53-dependent pathway was an independent prognostic factor. Accordingly, the prognostic values of p21 expression between the p53-dependent and -independent pathways differed. Examination of p21-positive expression in the p53-dependent pathway will help to estimate the favorable prognosis of patients with advanced esophageal carcinoma.

Preserved Smad4 expression in the transforming growth factor beta signaling pathway is a favorable prognostic factor in patients with advanced gastric cancer.

The signals of the transforming growth factor beta (TGF-beta) superfamily are conveyed through cell surface serine/threonine kinase receptors to the intracellular mediators known as Smads. Activation of Smads causes their translocation from the cytoplasm to the nucleus, where they function to control gene expression. The present study analyzed the expression of Smad4 and TGF-beta1 to determine their prognostic significance in advanced gastric cancer. Of 249 cases of advanced gastric cancer, 41 had invaded the muscular layer, 114 had invaded the subserosal layer, and 94 had invaded the serosa. Anti-Smad4 and TGF-beta1 antibodies were used for immunohistochemical staining. Reduced expression of Smad4 was 75.1%, whereas positive expression of TGF-beta1 was 39.6% in gastric cancer. Smad4 expression was related to the depth of tumor invasion (P < 0.05), and TGF-beta1 expression correlated with tumor gross type (P < 0.05). Postoperative survival analysis indicated that patients who had a tumor with reduced Smad4 expression had a poorer clinical outcome than those with preserved expression (P < 0.05). Furthermore, in patients with TGF-beta1-positive tumors, survival rate was significantly better in patients with preserved Smad4 expression than in those with reduced Smad4 expression (P < 0.05). According to multivariate analysis, Smad4 expression acted as an independent prognostic factor. Smad4 expression, particularly in the TGF-beta pathway, is an effective predictor of outcome for patients with advanced gastric cancer.

Invariant chain expression in gastric cancer.

Invariant chain (Ii) is a chaperone molecule that inhibits the binding of endogenous antigens to HLA class II. The tumor cell with overexpressed Ii chain is thought to escape attacking cytotoxic lymphocytes by suppressing the host immune. However, the relationship between Ii expression by the tumor and clinicopathological factors in gastric cancer remains unclear. We studied 126 patients with gastric cancer who had undergone curative gastrectomy at Kagoshima University Hospital between 1988 and 1997. In order to detect Ii and HLA-DR expression by tumor cells, immunohistochemical staining with anti-CD74 and anti-HLA-DR antibodies were performed by avidin-biotin peroxidase complex method. The 126 patients studied were divided into two groups based on Ii expression. Ii and HLA-DR were expressed both on the surface and in the cytoplasm of tumor cells and tumor infiltrating lymphocytes. A total of 48 patients were identified as Ii positive, while the remaining 78 patients were Ii negative. Ii expression negatively correlated with the depth of invasion of the tumor as well as the patients' clinical stage. Ii expression was negatively correlated with HLA-DR expression. Patients with Ii negative expression had significantly better surgical outcomes than those with Ii positive expression (P<0.05). Ii expression in gastric cancer affected surgical outcome and Ii expression was negatively correlated with depth of invasion and HLA-DR expression. Ii expression in gastric cancer may be a prognostic factor related to suppressive effects on host immune responses to tumor cells.

Effect of neoadjuvant chemotherapy for lymph node micrometastasis and tumor cell microinvolvement in the patients with esophageal carcinoma.

Micrometastasis (MM) and tumor cell microinvolvement (TCM) in the lymph node were immunohistochemically evaluated using the cytokeratin (CK) antibody between a surgery group (n=20; 929 lymph nodes) and a chemotherapy group (n=20; 1052 lymph nodes). The incidence of MM+/-TCM in the surgery and chemotherapy groups was 50.0 (10/20) and 55.0% (11/20), respectively. Limiting the analysis to TCM alone revealed that the incidence in the chemotherapy group (10.0%; 2/20) was significantly lower than that in the surgery group (40.0%; 8/20; P=0.032). Preoperative chemotherapy in this regime was not effective, except for some patients with TCM alone.

Clinical impact of intratumoral natural killer cell and dendritic cell infiltration in gastric cancer.

Intratumoral natural killer cells (NKC) and dendritic cells (DC) may affect the clinical features of various gastrointestinal cancers. However, the relationship between intratumoral NKC and DC remains unclear. We examined 169 patients with gastric cancer who underwent gastrectomy at Kagoshima University Hospital. Immunohistochemical staining of CD57 and S-100-protein was performed to evaluate NKC and DC infiltration, respectively. A total of 25 areas containing pericancerous tissue were selected for determining the number of NKC and DC under high power microscopy (x400). Patients were classified into two groups according to NKC and DC population. Intratumoral lymphocytic infiltration was also calculated in 15 areas with a high power (x400) objective. The degree of NKC and DC infiltration was gradually decreased according to the progression of nodal involvement. Patients with many NKC infiltration had a lower positivity of lymph node metastasis and lymphatic invasion than patients with little NKC infiltration. DC infiltration was also negatively correlated with depth of invasion, lymph node metastasis and curativity. DC infiltration was positively correlated with lymphocytic infiltration (P=0.01. r=0.6). The 5-year survival rates of patients with many NKC infiltration and patients with DC many infiltration were 75 and 78%, respectively, both of which were significantly better than that of patients with little NKC and DC infiltration (P<0.05). NKC may be activated without DC or intratumoral lymphocytes. Intratumoral NKC may act as an independent immunologic effector against tumor cells, unlike DC.

Ureteric obstruction after allogeneic bone marrow transplantation: an unusual complication.

A patient with acute myeloid leukemia (M4) in the first complete remission received a bone marrow transplantation (BMT) from an HLA-compatible sibling. Sustained engraftment was achieved, but she developed colicky pain at the back and lower quadrant of both sides on days 19-21 post-BMT, followed by hemorrhagic cystitis 13 days later. Ultrasonogram, intravenous pyelogram and computed tomogram of the abdomen showed hydronephrosis and ureteric obstruction of both sides. There was no stone in the urinary tract or abnormality of the bladder. The cortex of the right kidney was rather hypertrophic in spite of the persistent presence of hydronephrosis. Viral culture of urine and electron microscopic examination of urine sediments revealed the presence of adenovirus type II. Infection of the urinary tract with adenovirus type II may have been the underlying cause of the hemorrhagic cystitis and possibly also of the otherwise unexplained ureteric obstruction.

Hemorrhagic cystitis after bone marrow transplantation: importance of a thin sectioning technique on urinary sediments for diagnosis.

We used a thin-sectioning technique for the electron microscopic detection of viral particles within the cells of urinary sediments in three recipients who developed hemorrhagic cystitis after allogeneic bone marrow transplantation. Results of viral cultures of urine and electron microscopic (EM) observations on urinary sediments were consistent in only one recipient. In this recipient, EM observations revealed many viral particles within the cells of urinary sediments with diameter of about 80 nm corresponding to adenovirus, of which type 11 was produced in viral cultures. In one of the other two recipients many viral particles with a mean diameter of 41.6 nm corresponding to papovavirus were observed, but viral cultures using conventional cells were negative. Re-cultures using HEK cells produced polyomavirus BK. EM observation was a clue to the correct diagnosis. In the remaining recipient, no viral particles were observed within the cells of urinary sediments, suggesting the hemorrhagic cystitis to be of non-viral origin, despite a positive result of viral culture. These results suggest that a thin-sectioning technique on the cells of urinary sediments is important for the differential diagnosis between a viral-induced and non-viral hemorrhagic cystitis.

Immunohistochemical study of heparan sulfate proteoglycan in adenocarcinomas of the pancreas.

The prognosis for carcinoma of the pancreas is extremely poor. One of the characteristics of this tumor is its invasion of the surrounding tissues. Reduction of glycoprotein is considered to be conducive to invasion of the basement membrane by carcinoma cells. Heparan sulfate proteoglycan (HSPG), a kind of glycoprotein, is an important component of basement membrane. In this study, the relation between HSPG and carcinoma of the pancreas was examined by using the immunohistochemical method, and the survival rate of pancreatic adenocarcinoma was evaluated. We found that some carcinomas contained little or no HSPG. The poorer the differentiation of an adenocarcinoma of the pancreas, the lower was its content of HSPG. The level of HSPG was significantly different in carcinomatous and in noncarcinomatous cells. There was a close correlation among the content of HSPG, the degree of differentiation of carcinomas of the pancreas, and the survival time. HSPG seems to be useful in prognosis of adenocarcinoma of the pancreas.

Quantitative analysis of collagen and collagen subtypes I, III, and V in human pancreatic cancer, tumor-associated chronic pancreatitis, and alcoholic chronic pancreatitis.

The collagen content in human pancreatic cancer tissue, tissue of tumor-associated chronic pancreatitis (TACP), and normal pancreatic tissue was determined in 14 patients with pancreatic cancer by measuring the amount of 4-hydroxyproline. Four patients with alcoholic chronic pancreatitis (AlCP) were also analyzed. The mean collagen content in both pancreatic cancer tissue and TACP tissue was approximately threefold higher than in normal pancreatic tissue. Cyanogen bromide peptides of type I, III, and V collagens from invasive ductal carcinomatous tissue of the pancreas and from TACP tissue of eight patients were analyzed sequentially using high-performance liquid chromatography with ion-exchange and gel-permeation columns. No difference in the proportion of type I, III, and V collagens was detected between pancreatic cancer tissue and TACP tissue. The mean collagen content in AlCP tissue was significantly lower than that in TACP tissue, but no difference in the proportion of type I, III, and V collagens was detected between these two tissues. These results indicate a similar quantity and distribution pattern of fibrillar collagen in human pancreatic cancer and TACP.

Clinical and pathologic features of early gastric cancer in elderly patients.

BACKGROUND/AIMS: The purpose of this study was to review the Clinicopathologic features of early gastric cancer in elderly patients. METHODOLOGY: Three hundred and seventy-two patients who underwent resection for early gastric cancer were divided into groups of patients younger and older than 70 years. The clinical and pathologic findings surgical treatment, and perioperative complications in the group of elderly patients with early gastric cancer were reviewed and compared to those of the younger group. RESULTS: Gastric cancer involving the lower third of the stomach, as well as histopathologically well-differentiated carcinomas, were significantly more prevalent in the older group. Pre-operatively, the older patients had a higher incidence of respiratory dysfunction and hypertension. D1 lymph node dissections were chosen frequently for older patients. Six older patients died within 2 months of hospitalization, while no younger patients died within this period. The mortality rate mas 11% in older patients undergoing D2 or greater extents of node dissection, although the mortality rate was only 2% in older patients undergoing a D1 or less dissection. The 5-year survival rate for older patients, including deaths unrelated to cancer, was 71%, which was significantly lower than that in the younger group. However, when only mortality from gastric cancer was considered, patient survival did not differ according to age. CONCLUSION: Given the high mortality in elderly patients unrelated to early gastric cancer, we concluded that node dissection should be limited to perigastric nodes according to tumor location in such patients.

Strategy of gastric cancer in patients 85 years old and older.

BACKGROUND/AIMS: There is little information about the clinical and pathological features of patients with gastric cancer aged 85 years old and older. METHODOLOGY: We analyzed data of 197 gastric cancer patients aged 75 years and older. The patients were dividing into three age groups and we retrospectively studied 25 gastric cancer patients aged 85 years old and older and compared their clinical courses with those of 94 patients in their late 70s and 78 patients in their early 80s. RESULTS: The patients aged 85 years and older had a significantly higher rate of symptoms on admission such as gastric outlet obstruction and progressive anemia (64%), than did the other two age groups (p<0.05). Twenty-five percent of the oldest age group did not have surgery, and none had a D2 lymph node dissection. Perioperative complications were more frequent in the oldest group than in the youngest group (p<0.05). Survival in the oldest patients was not affected by surgical resection. CONCLUSIONS: These results indicate curative gastric surgery has a less positive impact in patients aged 85 years and older than younger patients. Treatment for gastric cancer in patients 85 years old and older should emphasize the palliation of symptoms but not curative resection.

Visualization of jugular vein on a thallium-201 scan for thyroid cancer.

A 52 year-old woman with recurrent thyroid cancer showed an accumulation of Tl-201 chloride in the left side of the neck. This proved to be reflux and retention of Tl-201 chloride in the left internal jugular vein and was verified with a Tc-99m HSA flow study. This phenomenon could be mistaken for metastases of thyroid cancer.

Comparison of delayed imaging with Tc-99m PMT and Tc-99m DEIDA for visualization of hepatoma.

Delayed imaging was performed after the intravenous administration of Tc-99m DEIDA and Tc-99m PMT in 18 patients with hepatocellular carcinoma. Using Tc-99m DEIDA imaging, sharp uptake by liver tumors was observed in four patients (22%), but the uptake was similar to that of the surrounding normal liver in eight patients (44%). Using Tc-99m PMT imaging, the uptake by the tumor was notable in ten patients (56%) and normal in two (11%). Tc-99m PMT and Tc-99m DEIDA were both concentrated in hepatocellular carcinomas, but the former showed intense uptakes more frequently, and thus is suggested to be useful in the diagnosis of hepatocellular carcinoma.

Clinical study of urinary excretion of Ga-67.

Ga-67 urinary excretion was examined in 59 patients. The 72-hour urinary excretion rate ranged from 4.3 to 67.8% of the injected dose. Within the first 24 hours, 60.9% of the 72-hour urinary excretion was excreted. There was no significant difference in the Ga-67 urinary excretion rate between males and females, nor between the Ga-67 positive and negative cases. A significant negative correlation was found between the 72-hour Ga-67 urinary excretion rate and the unsaturated iron binding capacity. Notably, four patients with hyperferremia, which was considered secondary to leukemia and/or chemotherapy or liver cirrhosis, excreted more than 46.8% of Ga-67 within 72 hours. A significant negative correlation was also found between the 72-hour Ga-67 urinary excretion rate and age. Urinary excretion of Ga-67 may be related to the glomerular filtration rate, which decreases with age.

[Early phase II study of PL-AC [N4-palmitoyl-(1-beta-D-arabinofuranosyl) cytosine] on hematopoietic malignancies].

Twenty-one patients with hematopoietic malignancies including 6 previously untreated, 9 pretreated, and in relapse, 5 in complete remission and one in partial remission all were treated with PL-AC. The patients consisted of 12 acute myelocytic leukemias, 4 acute monocytic leukemias, 2 acute lymphocytic leukemias, one erythroleukemia, one malignant lymphoma and one chronic monocytic leukemia. PL-AC was given orally at a dosage of 50-1200 mg daily. Mean total dosage was 4.74 g (0.6-15.25), and the mean administration period was 3.43 days (1-122). days Responses were observed in 4 out of 9 pretreated patients by a decrease of blast cells in the peripheral blood. Partial remission was obtained in one case which lasted 8 months. Out of 5 previously untreated acute leukemias, one partial remission and 4 hematological responses were observed. The plasma concentration of Ara-C was maximal at 3 hours and was not detectable after 12 hours. Side effects observed were nausea in 5 patients vomiting in one patient and liver dysfunction in one patient. These side effects however were not so severe as to stop drug administration. PL-AC may be administered in doses ranged 150-250 mg for 2-3 weeks without any severe side effects, and with some clinical effects.