Simultaneous detection of genetic and immunological markers in non-small cell lung cancer: prediction of metastatic potential of tumor

The restriction fragment length polymorphism of c-Ha-ras-1 and L-myc genes and expression of cell surface effector molecules were studied to determine their potential utility as markers for assessing risk of metastasis in 84 lung cancer patients. We performed a comparative study of primary lung carcinomas, metastases, adjacent tissues and blood samples in a group of patients with lung cancer of different histological types, grade of differentiation and presence of regional and distant metastasis. No differences in the frequency of c-Ha-ras-1 rare alleles were found between lung cancer patients and unaffected controls. The detection of common a4-allele seems to be associated with metastasis and low differentiation of lung carcinomas. S-allele of L-myc was observed in 82.6% of patients with metastatic lesions. Homozygosity of L-allele patients was not evidence for distant metastasis and only 17.4% of these patients have metastatic lesions of the lymph nodes. The expression of HLA class I and receptor of transferrin (TrRec) were tested immunohistochemically in the same patients. In the group of squamous cell carcinomas with regional metastases the expression of HLA class I antigens was decreased [7/21 (33.3%) positive staining tumors versus 13/20 (65.0%) in the group without metastases]. The opposite situation was observed for TrRec. The data of restriction fragment length polymorphism of oncogenes and expression of two cell surface effector molecules, identified in the same patients, were combined. The registration of more than one poor marker, tested in individuals with squamous cell carcinoma, closely correlated with dissemination and advanced stage of the disease. Nearly 90% (20/22) of patients with well and moderately differentiated tumor revealed metastatic lesions versus 6.6% (1/15) of patients with manifestation of a single poor marker. Finally, proposals could be made for the development of a risk group that incorporates both clinical and molecular biology features in the prediction of metastasis.     

Diagnosis of extension and treatment of carcinoma of the gallbladder

Diagnosis of extension by intraoperative ultrasonography (IOUS) and treatment based on the degree of histological extension in carcinoma of the gallbladder are discussed. IOUS is a useful technique for the diagnosis of the depth of wall invasion and direct invasion of the liver. The authors diagnose the depth of wall invasion based on the layer structure, unequal width, and discontinuity of the layer echogram. By this technique, mucosal cancer (m cancer) or cancer extending to the proper muscle layer (mp cancer) can be differentiated from cancer with submucosal invasion (ss cancer), and also ss cancer from cancer exposing the serosa (se) or cancer infiltrating to the serosa (si). However, differentiation between m cancer and mp cancer is not possible by IOUS or by other diagnostic techniques. In terms of histological extension, lymph node metastasis or vascular and nerve invasion is not found in m cancer, but in some cases of mp cancer vascular invasion is present. As a radical operative procedure for early m and mp cancer, full-thickness cholecystectomy or partial resection of the liver bed and dissection of lymph nodes 8, 12, and 13 should be conducted. As lymph node metastasis and vascular and nerve invasion are frequent in ss or more advanced cancer, complete lymph node dissection should be performed. Cholecystectomy, partial resection of the liver bed, bile duct resection, and dissection of lymph nodes 8, 12, and 13 is the preferred radical operative procedure for ss cancer. In the cases with in metastasis to lymph nodes 8 and 13, pancreatoduodenectomy is combined. The basic operative procedure for se and si cancer has not been established, but is should be radical and safe. Considering the poor prognosis and frequency of lethal postoperative complications, at present we should not only expand the resected area but select a reasonable and well-balanced operative procedure depending on the degree of cancer extension.     

Metastatic adenocarcinoma to the uterine cervix from gastric cancer. A clinicopathologic analysis of 16 cases

BACKGROUND: Metastatic adenocarcinoma to the uterine cervix from gastric cancer is rare, and the clinicopathologic features of this metastasis are unclear. METHODS: A clinicopathologic review of 16 patients with metastatic adenocarcinoma to the uterine cervix from gastric cancer was performed. RESULTS: The ages of the patients ranged from 29 to 57 years, and 81.3% of the patients were premenopausal. Nine of the patients had undergone gastrectomy previously. In 11 patients the histologic type of the gastric cancer was poorly differentiated adenocarcinoma and, in 5 patients, signet ring cell carcinoma. The cervical metastasis was diagnosed 11-121 months (mean, 57.5 months) after the diagnosis of the gastric cancer in 10 of the patients. In six patients, the cervical metastasis was discovered synchronously or before the diagnosis of the gastric cancer. The colposcopic findings were normal in 57.1%, but 56.3% had abnormal cervical smears. In all patients, tumor cells were present in the dilated lymphatics of the cervix. Metastases to the uterine body and bilateral ovaries were common, and half of the patients had metastases to the paraaortic lymph nodes. Extirpation of the cervix was performed in six patients. The prognosis was poor, regardless of the treatment method. CONCLUSIONS: The route of metastasis to the cervix is surmised to be retrograde lymphatic, and this extension is often slow. Periodic gynecologic examinations should be performed indefinitely for premenopausal female patients with advanced gastric cancer.     

Erectile dysfunction

Peanut agglutinin (PNA) lectin-binding site patterns in primary invasive breast ductal not otherwise specified (NOS) carcinomas are related to aggressiveness of the tumor. The present study was designed to compare the expression of PNA-binding sites in the primary tumor and in local lymph node metastases. The expression of lectin-binding sites was studied using the avidin-biotin complex/immunoperoxidase technique and analyzed in relation to age of the patient and size of the breast cancer. Breast cancers and their metastases showed negativity or positivity, the latter being divided into "apical" and "non-apical" (i.e. membrane and/or cytoplasmic) depending on the main localization of staining in tumor cells. No correlation was found between primary tumors and metastases as regards PNA-binding patterns, which confirms the opinion that advanced primary tumors are polyclonal and that selected subclones of malignant cells give rise to metastases. Furthermore, the fact that primary tumors with PNA non-apical expression, a feature related to aggressiveness and poor differentiation, may have lymph node metastases with apical expression, suggests that this pattern, although no longer evident in the primary tumor, is involved in the process of cell metastasis.     

Umbilical metastasis of an endometrial adenocarcinoma: "Sister (Mary) Joseph's nodule". Review of the literature

In the beginning of the XXth century, Sir Hamilton Bailey proposed the name "Sister Joseph's nodule" for the umbilical metastasis of an abdominal cancer. This unusual pathology has multiple primitive etiologies. We report here the 27th case of an umbilical metastasis of an endometrial adenocarcinoma. In case of a malignant umbilical tumor, 75% correspond to a "Sister Joseph's nodule". Their clinical manifestations are quite similar. This secondary localisation could appear before, during or after the diagnosis of the primitive tumor. Adenocarcinoma is the frequently diagnosed histological type. The endometrial origin represents only 1.4% of the cases. Multiple routes of spread exist. Prognosis remains poor. Medico-surgical treatment, in a curative target, will be aggressive and should be adapted at every case. Our case-report recalls a new patho-physiological approach. The extended follow-up of this patient, without further medical treatment, is an additional argument.     

Cellular localization of urokinase-type plasminogen activator, its inhibitors, and their mRNAs in breast cancer tissues

The plasminogen activation (PA) system may participate in cancer invasion and metastasis. A series of breast cancer tissue specimens was analysed using in situ hybridization and immunohistochemistry. Urokinase-type plasminogen activator (u-PA) mRNA was detected in cancer cells and fibroblasts adjacent to them and its expression was found to be more intense in invasive than in intraductal regions. In invasive but not in intraductal regions, especially those with abundant stroma, plasminogen activator inhibitor-1 (PAI-1) mRNA was observed in cancer cells, fibroblasts, macrophages, and endothelial cells, and PAI-2 mRNA was present in cancer cells, and fibroblasts, macrophages, and lymphocytes around them. These PAI-1- and PAI-2-positive cancer cells were localized at the periphery of the invasive front. Immunohistochemistry yielded basically similar results. A retrospective study of surgically resected breast cancers from 73 patients revealed significant clinical differences associated with u-PA and PAI-2 expression in cancer cells, associated with a poor and a good prognosis, respectively. These findings indicate that breast cancer cells and fibroblasts express u-PA initially and then its inhibitors, and that this process is related to invasion. Expression of u-PA and PAI-2 in cancer cells themselves may serve to up-regulate and limit PA-mediated invasion and metastasis, respectively.     

Expression of cell adhesion molecule CD44 and sialyl Lewis A in gastric carcinoma and colorectal carcinoma in association with hepatic metastasis

To clarify the role of the expression of adhesive molecules [CD44 (standard form) and sialyl Lewis A (sialyl Lea)] on hepatic metastasis, 108 advanced gastric carcinomas and 94 advanced colorectal carcinomas were investigated immunohistochemically. Multivariate analysis demonstrated that CD44 expression and lymph node metastasis in gastric cancer and CD44 and sialyl Lea expression in colorectal cancer were significantly related to hepatic metastasis. The incidence of hepatic metastasis was highest in patients with the expression of both CD44 and sialyl Lea. The expression of CD44 standard form as well as sialyl Lea may have a major role as adhesion molecules in the process of hepatic metastasis.     

Management of the neck in thyroid cancer

The incidence of nodal metastasis in differentiated thyroid cancer ranges between 40% to 75%. Elective neck dissection is generally not advised in patients with differentiated thyroid cancer; however, if clinically apparent nodal disease is noted in the tracheoesophageal groove during surgery, central compartment clearance is advised. If clinically apparent nodal disease is present in the lateral compartment of the neck, modified neck dissection preserving the sternomastoid, accessory nerve, and jugular vein is advised. The "berry picking procedure" is generally not recommended because of the higher incidence of regional recurrence. Due consideration should be given for parathyroidal transplantation if the blood supply to the parathyroids is damaged during central compartment clearance. The incidence of lymph node metastasis is highest in young patients, however, lymph node metastasis has no bearing on long-term survival. There seems to be a higher incidence of regional recurrence in elderly individuals. If patients present with bulky nodal disease, consideration may be given for postoperative radioactive iodine dosimetry and ablation if necessary. Differentiated thyroid cancer represents a unique disease in the human body, where lymph node metastasis has no prognostic implication. Aggressive surgical clearance is advised in patients with medullary thyroid cancer in the central compartment and the jugular chain lymph nodes.     

Double cancer of the stomach, one AFP-producing tumor

In recent years, many cases of alpha-fetoprotein-producing gastric cancer (AFPGC) characterized by increased serum levels of alpha-fetoprotein (AFP) and AFP positivity of the gastric cancer have been reported. Here we present a case of AFPGC coexistent with a different histological type of gastric cancer: The AFPGC was Borrmann type 1 advanced gastric cancer with multiple liver metastasis and appeared to produce both AFP and des-gamma-carboxy prothrombin (PIVKA-II). The second cancer was IIc type early gastric cancer and did not produce AFP. Despite receiving palliative chemotherapy, the patient died, due to hepatic failure, 45 days after admission.     

Analysis of the factors influencing the quality of life of patients with advanced or recurrent breast cancer

To investigate the factors influencing the quality of life (QOL) of Japanese patients with advanced or recurrent breast cancer, a newly developed QOL questionnaire, "The QOL Questionnaire for Cancer Patients Treated with Anticancer Drugs" (QOL-ACD), was answered by 23 patients, and a multiple regression analysis was performed. The demographic and medical factors relating to the overall QOL score and to the four categories of the QOL-ACD, namely (1) activity, (2) physical condition, (3) psychological condition, and (4) social relationships, were analyzed. The results indicated that skin metastasis, a heavier body weight, and bone metastasis had a strong negative influence on the overall QOL scroe, whereas endocrine therapy, the existence of a primary lesion, and more extensive first surgery had a strong positive influence on it. With regard to the analysis of the four categories, endocrine therapy was found to be positively related to all four categories. The multiple correlation coefficient (R) between the estimated overall QOL score and the observed overall QOL score was about 0.77. The results of this analysis showed that endocrine therapy can improve the QOL of patients with advanced or recurrent breast cancer, and that the QOL-ACD questionnaire could prove extremely useful for predicting the QOL of individual patients and for aiding clinicians in deciding on the most appropriate type of therapy for each patient.     

Sequential steps in hematogenous metastasis of cancer cells studied by in vivo videomicroscopy

Understanding metastatic spread of cancer is of upmost importance to developing successful strategies to treat this disease. In this review, we present a picture of the process of hematogenous metastasis from the initial arrest of cancer cells, their extravasation, postextravasation migration, and their replication to form tumors, based on experimental results using in vivo videomicroscopy. The cancer cells are initially arrested by size constraints within minutes of entering the circulation and with little hemodynamic destruction. Within 24-48 h >80% of these cancer cells extravasate as single cells by adhesion to and spreading along the vessel wall, often using pseudopodial projections to move into the surrounding tissue without disrupting the microcirculation. Some of the extravasated cells also use pseudopodial projections to migrate to specific structures in the tissue where they can replicate. Many cancer cells can persist as dormant cells, neither dividing nor undergoing apoptosis. Only a small fraction of extravasated cells begin to divide to form micrometastases, and only a very small fraction of these micrometastases continue to grow to form tumors. Possible clinical implications are that (1) initial arrest and extravasation may be difficult to prevent and thus may be poor therapeutic targets; (2) dormant single cells will not be affected by conventional cancer therapies which are designed to treat actively growing cells; and (3) regulation of growth of cells after extravasation is key to determining whether clinically evident metastases form - this stage of metastasis thus offers promising targets for new antimetastasis drugs.     

Clinical outcome of surgical treatment for invasive early colorectal cancer in Japan

BACKGROUND/AIMS: Despite the high frequency of early colorectal cancer, little is known about the clinicopathologic features of invasive early colorectal cancer for which endoscopic polypectomy is not indicated. We wanted to determine the clinicopathologic features of these early colorectal cancers. MATERIALS AND METHODS: From 1973 to 1994, a total of 728 patients with colorectal cancer were reviewed retrospectively from hospital records. The clinicopathologic features of the 90 invasive early colorectal cancer patients who underwent major surgeries were compared with those of 626 patients with advanced colorectal cancer. RESULTS: The frequency of early colorectal cancer increased significantly from the periods 1973-1979 to 1990-1994: 0% in the former period and 18.3% in the later period. Minimally invasive surgery was chosen more frequently for the treatment of early colorectal cancers than for the treatment of advanced cancers (p < 0.005). Lymph node metastasis, lymph vessel invasion, and vascular invasion were more prevalent in advanced cancer cases than in early cancer cases (p < 0.005). Lymph node metastasis was found in 7 patients with early colorectal cancer (7.8%). There was no difference in histologic type between the early and advanced colorectal cancers. The 5-year survival rates of early colorectal cancer patients were higher than those of advanced cancer patients: 97.5% in early colon cancer patients; 93.5% in early rectal cancer patients; 59.8% in advanced colon cancer patients; 55.4% in advanced rectal cancer patients. Three early colorectal cancer patients died of recurrence. CONCLUSION: Minimally invasive surgery such as laparoscopic colectomy should be performed on patients with invasive early colorectal cancer when it is impossible for the cancer to be removed by endoscopic polypectomy.     

Results of resection of gastric cancer with distant metastases

BACKGROUND/AIMS: The present study was carried out in order to examine the outcome of resection in cases of gastric cancer with distant metastases. METHODOLOGY: The survival rates of two hundred and eighty-one patients who had undergone resection for primary carcinomas of the stomach, and who had distant metastases according to the TNM classification, were studied. RESULTS: The 5-year survival rates for patients with metastasis to the peritoneum or group 3 nodes were 8.9% and 15.3% respectively and were significantly higher than the survival rates for patients with metastasis to the liver (0%), to group 4 nodes (2.2%) or to more than one site among the liver, lymph nodes and peritoneum (3.5%). Moreover, the 5-year survival rates for patients with metastasis to the peritoneum and N3 nodes increased significantly to 29.4% and 24.2%, respectively, when curative surgery was performed. CONCLUSIONS: The findings of the present study suggests that metastases to the adjacent peritoneum or group 3 nodes have a greater chance of being cured using radical surgery, and that gastrectomy with extended lymphadenectomy (D2-D3) may be used for advanced gastric cancer if there is no gross evidence of metastasis to the distant peritoneum, liver or group 4 nodes.     

Event-related correlates of response suppression as indicators of novelty seeking in alcoholics

We examined amplification of the c-met, c-erbB-2, and epidermal growth factor receptor (EGFR) gene in the patients with primary gastric cancer, and compared the data with clinical features in order to clarify the relationship between oncogenic abnormality and clinical features. Oncogene amplifications were examined by slot blot hybridization using DNAs extracted from formalin-fixed and paraffin-embedded tissues of primary gastric cancers. Seven of the seventy cancers (10.0%) had c-met gene amplification, nine (12.9%) had c-erbB-2 gene amplification, and six (8.6%) had EGFR gene amplification, respectively. Eighteen cases (25.7%) exhibited one or multiple oncogene amplification, and two cases (2.9%) exhibited simultaneous amplification of the three genes. The cases with c-met gene amplification tend to show invasive character and were related to peritoneal dissemination. The cases with c-erbB-2 gene amplification were related to lymph node metastasis. The cases with EGFR gene amplification had large tumors and were in highly advanced stage. The survival rate in patients with oncogene amplification was significantly lower than that in patients without amplification. Our data indicated that these genes were related to growth and metastasis of gastric cancer. Furthermore, this study about the three genes suggested that the type of activated gene might decide on the type of metastasis and clinical features.     

The etiopathogenesis of esophageal cancer

Cancer of the oesophagus is a challenging clinical problem. Overall survival is poor, but patients who present early are eminently curable. Most cancers of the middle and upper oesophagus are squamous cell carcinoma. Adenocarcinoma is the most common cancer of the third of the oesophagus; this is not surprising when the usual distribution of Barrett's mucosa is considered. The geographical variation in the prevalence of oesophagus cancer is important. In most parts of the world, alcohol consumption and tobacco usage are the principal risk factors. Other risk factors have been identified in "the high-risk areas": a diet high in nitrosamines, deficient in trace elements, in vitamins (C.A, E) and the hereditary conditions like: Barrett's oesophagus, achalasia, caustic strictures.     

Effect of CDDP/5'-DFUR combination chemotherapy for advanced or recurrent gastric cancer

CDDP/5'-DFUR combination chemotherapy was performed on 17 patients with non-resected and recurrent gastric cancer (clinical stage were IVb in all patients). They were treated with 1,400 mg/m2 of 5'-DFUR on days 1-4 orally following by withdrawal 10 days, every 2 weeks repeatedly and 80 mg/m2 of CDDP (c. i. v., on day 5, every 4 weeks). This chemotherapy was performed for at least 2 courses on all patients. Eight of 17 patients achieved a partial response and the overall response rate was 47.1% (differentiated type 57.1%, undifferentiated type 45.5%). Response rates of each lesion were as follows: primary foci 42.9%, abdominal lymph nodes 57.1%, hepatic metastasis 60.0% and ascites 33.3%, respectively. Improvement of performance status was seen in 12 of 17 patients (70.6%). The overall median survival time was 227 days. The median outpatient period was 113 days. There was no high-grade toxicity over grade 2. Therapeutic toxicity of grade 2 was manifested as renal dysfunction (23.5%), nausea/vomiting (17.6%), leukopenia (5.9%) and anemia (5.9%). We evaluated the therapeutic effect by visual examination after completion of the second course. However, poor effect and high incidence of renal dysfunction were found in patients treated with this therapy over four times. Therefore, the maximum effect seemed to be revealed after completion of the fourth course. From the present study, CDDP/5'-DFUR combination chemotherapy seems to be effective for patients with high-grade advanced gastric cancer and improved their quality of life.     

Influence of the phosphatidylethanolamine (PE) and bovine serum origins on anti-PE antibody detection by ELISA

The long-term results of external irradiation in locally advanced prostate cancer are poor: relapses are local or distant from infra-clinical disease present at diagnosis. Three clinical randomized trials have shown that hormonotherapy with LH-RH analogue with or without antiandrogen has improved: disease-free survival, local recurrence-free survival and metastasis-free survival (P < 0.001). The EORTC trial 22863 has shown a significant improvement of the overall survival (P = 0.001), with an LH-RH analogue (goserilin acetate, Zoladex) was administered the first day of irradiation and then every 4 weeks for 3 years; for the RTOG trial 85-31 the same LH-RH analogue was administered during the last week of irradiation and given until relapse increases survival of patients with poor differentiated tumours with a Gleason score ranging from 8 to 10 (P = 0.03). Adjuvant hormonal treatment with an LH-RH analogue is recommended, but the optimal duration of the treatment remains unclear.     

Characteristics and clinical outcome of proximal-third gastric cancer

BACKGROUND: It is generally accepted that the prognosis of patients with proximal gastric cancer (PGC) is worse than that of patients with more distal gastric cancer. STUDY DESIGN: The aim of this study was to compare the clinical features and outcomes of PGC with those of middle- and distal-third gastric cancers. A total of 646 primary gastric cancers was analyzed as a retrospective study. RESULTS: Proximal gastric cancer occurred in 21.8% of the 646 cancers analyzed, and approximately 21% of PGCs had esophageal invasion. The 5-year survival rate for patients with PGC was significantly lower than that of patients with more distal tumors. When the PGC group was divided into patients with esophageal invasion and without esophageal invasion, patients with esophageal invasion had significantly worse outcomes. When corrected for depth of invasion, lesions with esophageal invasion had significantly worse outcomes than those of other sites in T2 curative cancers. Proximal gastric cancer with esophageal invasion was characterized by a larger tumor, deeper penetration, and a higher incidence of lymph node metastasis compared with tumors in other sites, and in multivariate analysis of all curative cases, these variables were independent prognostic factors for survival. The frequency of positive proximal margins of PGC was higher than those of other sites. CONCLUSIONS: The relatively poor prognosis associated with PGC is mainly from advanced tumor stages of esophageal invasion. Early detection is the most important strategy to improve the survival of patients with PGC. In addition, aggressive lymph node dissection and chemotherapy for esophageal invasion should be considered even if the tumor invasion is moderate (T2 tumor), and a tumor-free margin is important.     

Stromal degradation by the malignant epithelium in pancreatic cancer and the therapeutic potential of proteolytic inhibition

off matrix metalloproteinases (MMPs) and the tissue inhibitors of the metalloproteinases (TIMPs) are described and reviewed. The role of the MMPs and their inhibitors in tumour invasion and metastasis is reviewed and the interaction between the extracellular matrix and these enzymes is discussed. The expression and activity of the MMPs and TIMPs in pancreatic cancer is reported with reference to the literature and the author's own work. The effect of MMP inhibitors (MMPIs) in vivo and the use of batimastat and marimastat (both; British Biotech Pharmaceuticals, Oxford, UK) in animal experiments are also described. Preliminary phase II and III clinical trial data of marimastat in advanced pancreatic cancer is reported.     

氟尿嘧啶缓释剂术中局部植入治疗32例进展期大肠癌

Objective: The aim of our study was to probe into the effect of fluorouracil controlled release formulation in the local implant treatment of patients with advanced colorectal cancer. Methods: Sixty-four cases of patients advanced colorectal cancer from August 2004 to February 2008 were selected for radical surgery, including 32 cases injected with intraoperative fluorouracil controlled release formulation in local implantation for 600 mg (the treatment group). Patients in another 32 cases received abdominal washing surgery by distilled water (the control group). All patients were followed up for 2 years and observed in aspects of the toxicity, 2-year survival rate, local recurrence rate and distant metastasis rate. Results: The 2-year survival rate and local recurrence rate in the treatment group was better than those in the control group (P ＜ 0.05); as for toxicity and distant metastasis rate, no significant difference was observed. Conclusion: The effect of fluorouracil controlled release formulation in local implantation treatment was significant and the patient tolerance was satisfactory. Thus, it is an effective approach in the treatment of advanced colorectal cancer.