Phase I/II study of adding intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis.

BACKGROUND: Intraperitoneal chemotherapy using paclitaxel is considered an experimental approach for treating peritoneal carcinomatosis. This study aimed to determine the recommended dose, and to evaluate the clinical efficacy and safety, of the combination of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel in patients with pancreatic cancer and peritoneal metastasis. METHODS: The frequencies of dose-limiting toxicities were evaluated, and the recommended dose was determined in phase I. The primary endpoint of the phase II analysis was overall survival rate at 1 year. Secondary endpoints were antitumour effects, symptom-relieving effects, safety and overall survival. RESULTS: The recommended doses of intravenous gemcitabine, intravenous nab-paclitaxel and intraperitoneal paclitaxel were 800, 75 and 20 mg/m2 respectively. Among 46 patients enrolled in phase II, the median time to treatment failure was 6·0 (range 0-22·6) months. The response and disease control rates were 21 of 43 and 41 of 43 respectively. Ascites disappeared in 12 of 30 patients, and cytology became negative in 18 of 46. The median survival time was 14·5 months, and the 1-year overall survival rate was 61 per cent. Conversion surgery was performed in eight of 46 patients, and those who underwent resection survived significantly longer than those who were not treated surgically (median survival not reached versus 12·4 months). Grade 3-4 haematological toxicities developed in 35 of 46 patients, whereas non-haematological adverse events occurred in seven patients. CONCLUSION: Adding intraperitoneal paclitaxel had clinical efficacy with acceptable tolerability.

ANTECEDENTES: La quimioterapia intraperitoneal con paclitaxel se considera una terapia experimental para el tratamiento de la carcinomatosis peritoneal. Este estudio tuvo como objetivo determinar la dosis recomendada y evaluar la eficacia clínica y la seguridad de la combinación de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal en pacientes con cáncer de páncreas y metástasis peritoneales. MÉTODOS: Se evaluaron las frecuencias de las toxicidades limitantes de la dosis, y la dosis recomendada se determinó en la fase I. El objetivo principal de la fase II fue la tasa de supervivencia global a 1 año. Los objetivos secundarios fueron los efectos antitumorales, los efectos de alivio de los síntomas, la seguridad y la supervivencia global. RESULTADOS: Las dosis recomendadas de gemcitabina intravenosa, nab-paclitaxel intravenoso y paclitaxel intraperitoneal fueron de 800, 75 y 20 mg/m2 , respectivamente. De los 46 pacientes incluidos en la fase II del estudio, la mediana de tiempo hasta el fracaso del tratamiento fue de 6,0 meses (rango, 0-22,6). Las tasas de respuesta y de control de la enfermedad fueron del 45% y 95%, respectivamente. La ascitis desapareció en el 40% de los pacientes, y la citología se negativizó en el 39% de los pacientes. La mediana del tiempo de supervivencia fue de 14,5 meses y la tasa de supervivencia global a 1 año del 60,9%. La cirugía de rescate se realizó en ocho (17%) pacientes, y los que se sometieron a cirugía sobrevivieron significativamente más tiempo que los que no fueron tratados quirúrgicamente (mediana de supervivencia no alcanzada versus 12,4 meses). Las toxicidades hematológicas de grado 3/4 ocurrieron en el 76% de los pacientes, mientras que los eventos adversos no hematológicos se presentaron en el 15% de los pacientes. CONCLUSIÓN: Agregar paclitaxel intraperitoneal tuvo eficacia clínica con una tolerabilidad aceptable. (UMIN000018878).

Laparoscopic intraoperative navigation surgery for gastric cancer using real-time rendered 3D CT images.

PURPOSE: Recent advances in laparoscopic surgical technology have made it possible to perform advanced high-level surgery, such as lymph node dissection for malignancy. Grasping the anatomy during such procedures is important for a safe operation. We have developed a new image information system that provides three-dimensional (3D) reconstructed CT images synchronized with the motion of the laparoscope. This study assesses this new navigation system. METHODS: Enhanced CT using a custom-made software program can provide 3D angiography images reconstructed as a laparoscopic view. A motion sensor mounted on the laparoscope can detect the direction angle of the laparoscope. The real-time rendered 3D CT images are synchronized with the laparoscopic video images according to the motion of the scope. These 3D CT images are projected on another monitor close to the laparoscopic video monitor. Lymph node dissection can be performed with the help of the real-time navigation system that provides a detailed 3D view of the vasculature. RESULTS: Ten laparoscopic gastrectomies were performed using this navigation system. Real-time intraoperative navigation of the vasculature was available, allowing for an excellent surgical outcome. No complications occurred in this series. CONCLUSION: Our intraoperative navigation system allows for safe laparoscopic gastric lymph node dissection.

Heterogeneity of colorectal cancers and extraction of discriminator gene signatures for personalized prediction of prognosis.

Dissected specimens of colorectal cancer (CRC) have been intensively studied using molecular sketches (gene signatures) to obtain a set of discriminator gene signatures for accurate prognosis prediction in individual patients. The discriminators obtained so far are not universally applicable, as the gene sets reflect the method and site of the study. In this study, we show that dissected stage II and III CRC samples are significantly heterogeneous in molecular sketches, and are not appropriate sources for discriminator extraction unless handled individually. To search for an accurate discriminator gene set for prediction of metastases, we need to start with less heterogeneous stage II CRC. We examined 198 (92 stage II and 106 stage III) CRC dissected samples for the predictability of discriminator gene signatures by analyzing stage II CRC alone, stage III alone, or in combination. The best predictive power of discriminator genes was obtained only when these genes were extracted and validated with stage II CRC samples. An accurate discriminator gene set for the prediction of CRC metastases can be obtained by focusing on stage II CRC samples.

Risk-adjusted assessment of incidence and quantity of blood use in acute-care hospitals in Japan: an analysis using administrative data.

BACKGROUND AND OBJECTIVES: Continuous monitoring of blood use and feedback on transfusions are effective in decreasing inappropriate blood transfusions. However, traditional methods of monitoring have practical challenges, such as the limited availability of experts and funding. Administrative data including a patient classification system may be employed for risk-adjusted assessment of hospital-wide blood use. MATERIALS AND METHODS: We conducted an audit of blood use at two hospitals and determined proportions of appropriate blood use at each hospital. We then used administrative data of 587,045 cases provided by 73 hospitals to develop two mathematical models to calculate risk-adjusted use of blood products. The first model is a logistic regression model to predict the percentage of transfused patients. Patient demographics, surgery and diagnostic groups were utilized as predictors of transfusion. The second model is a case-mix adjusted model which predicts hospital-wide use of units of blood products from the distribution of diagnosis-related groups. For each model, the observed to expected (O/E) ratio of blood use in each hospital was calculated. We compared resultant ratios with proportions of appropriate blood use in two of the hospitals studied. RESULTS: Both models showed good prediction abilities. O/E ratios calculated using the two models were relevant to proportions of appropriate transfusions. CONCLUSIONS: Risk-adjusted assessments of blood product use based on administrative data allow hospital-wide evaluation of transfusion use. Comparing blood use between different hospitals contributes toward establishing appropriate transfusion practices.

Abnormal expression of TRIB3 in colorectal cancer: a novel marker for prognosis.

BACKGROUND: TRIB3 is a human homologue of Drosophila tribbles. Previous studies have shown that TRIB3 controls the cell growth through ubiquitination-dependent degradation of other proteins, whereas its significance in the prognosis of colorectal cancer (CRC) is not yet fully understood. MATERIALS: This study comprised 202 patients who underwent surgery for CRC, as well as 22 cell lines derived from human gastrointestinal cancer. The correlation of gene expression with clinical parameters in patients was assessed. The biological significance was evaluated by knockdown experiments in seven colorectal cancer cell lines. RESULTS: A total of 20 cancer cell lines (90.9%) expressed the TRIB3 gene. The assessment in surgical specimens indicated that the gene expression was significantly higher in the cancerous region than in the marginal non-cancerous region. Patients with high TRIB3 expression were statistically susceptible to a recurrence of the disease, and showed poorer overall survival than those with low expression. The assessment of TRIB3 knockdown in five cell lines showed that small interfering RNA (siRNA) inhibition resulted in a statistically significant reduction in cell growth. CONCLUSION: These data strongly suggest the usefulness of TRIB3 as a marker for predicting the prognosis of CRC patients, showing a basis for the development of effective treatments for CRC.

Evaluation of acute myocardial infarction in-hospital mortality using a risk-adjustment model based on Japanese administrative data.

This study aimed to develop a new risk-adjustment method to assess acute myocardial infarction (AMI) in-hospital mortality. Risk-adjustment was based on variables obtained from administrative data from Japanese hospitals, and included factors such as age, gender, primary diagnosis and co-morbidity. The infarct location was determined using the criteria of the International Classification of Diseases (10th version). Potential comorbidity risk factors for mortality were selected based on previous studies and their critical influence analysed to identify major co-morbidities. The remaining minor co-morbidities were then divided into two groups based on their medical implications. The major co-morbidities included shock, pneumonia, cancer and chronic renal failure. The two minor co-morbidity groups also demonstrated a substantial impact on mortality. The model was then used to assess clinical performance in the participating hospitals. Our model reliably employed the available data for the risk-adjustment of AMI mortality and provides a new approach to evaluating clinical performance.

Evaluation of the technical difficulty performing laparoscopic resection of a rectosigmoid carcinoma: visceral fat reflects technical difficulty more accurately than body mass index.

BACKGROUND: In general, visceral fat and adhesion greatly influence the technical difficulty in performing abdominal surgery. Body mass index (BMI) has been widely used to express the degree of obesity, but it does not always properly reflect the degree of visceral fat. This retrospective study investigated the impact of visceral fat on the operation time to examine whether a quantified visceral fat area (VFA) could be used as a sensitive predictor of technical difficulty in performing a laparoscopic resection of rectosigmoid carcinoma. METHODS: Between February 1999 and April 2004, 58 consecutive patients underwent a laparoscopically assisted sigmoidectomy or anterior resection. After a review of the medical charts, the relationship between the operation time and the following variables was analyzed: sex, depth of invasion, approach (medial-to-lateral, lateral-to-medial), subjectively graded degree of visceral fat and adhesion, history of previous abdominal surgery, and BMI. The correlations between VFA, VFA/body surface area (BSA) measured by the "FatScan," software package for quantifying the VFA from the preoperative CT images, and operation time were investigated. Next, the impact of the VFA amount on the early surgical outcome was examined. RESULTS: According to the intraoperative findings, two patients with a severe adhesion required a significantly longer operation time. A history of previous abdominal surgery was not a significant factor in the operation time. Instead, the VFA/BSA had a stronger correlation with the operation time than the BMI. A significantly longer operation time (209 +/- 42 vs 179 +/- 37 min; p = 0.031) was observed for the patients in the high VFA/BSA group (> or =85 cm(2)/m(2)) group than in the normal VFA/BSA group (<85 cm(2)/m(2)). CONCLUSION: For predicting the technical difficulty of performing a laparoscopic resection of rectosigmoid carcinoma, VFA/BSA may be a more useful index than BMI.

Unicentric and multicentric Castleman's disease.

Castleman's disease (CD) appears at ubiquitous lymph nodes. To date, detection of the lesion focus for CD has mainly been carried out by physical examination and radiological findings, such as X-ray analysis, CT and MRI. 18F-FDG PET visualizes the active focus of glucose metabolism and the clinical value has been investigated for many different tumours. Previous studies of 18F-FDG PET for CD have only reported four cases of unicentric CD and no cases of multicentric CD. In this paper, we report two cases of CD, one with unicentric CD and one with multicentric CD. We demonstrate that the use of 18F-FDG PET for the detection and monitoring of patients with CD, especially multicentric CD, would be effective.

Quantitative evaluation of vimentin expression in tumour stroma of colorectal cancer.

Recent studies have identified vimentin, a type III intermediate filament, among genes differentially expressed in tumours with more invasive features, suggesting an association between vimentin and tumour progression. The aim of this study, was to investigate whether vimentin expression in colon cancer tissue is of clinical relevance. We performed immunostaining in 142 colorectal cancer (CRC) samples and quantified the amount of vimentin expression using computer-assisted image analysis. Vimentin expression in the tumour stroma of CRC was associated with shorter survival. Overall survival in the high vimentin expression group was 71.2% compared with 90.4% in the low-expression group (P=0.002), whereas disease-free survival for the high-expression group was 62.7% compared with 86.7% for the low-expression group (P=0.001). Furthermore, the prognostic power of vimentin for disease recurrence was maintained in both stage II and III CRC. Multivariate analysis suggested that vimentin was a better prognostic indicator for disease recurrence (risk ratio=3.5) than the widely used lymph node status (risk ratio=2.2). Vimentin expression in the tumour stroma may reflect a higher malignant potential of the tumour and may be a useful predictive marker for disease recurrence in CRC patients.

Expression and mutation of SMAD4 in poorly differentiated carcinoma and signet-ring cell carcinoma of the colorectum.

Poorly differentiated adenocarcinoma (Por) and signet-ring cell carcinoma (Sig) are rare but highly malignant types of colorectal cancer. To explore their genetic backgrounds we investigated TGF-beta type II receptor (TGF-beta RII) and SMAD4 in the TGF-beta signaling pathway, and to identify their mutator phenotype we examined microsatellite instability (MSI) status. Loss of SMAD4 expression was significantly more frequent in Por (12 of 38; 31%) and Sig (4 of 5; 80%) tumors than in well (Well) and moderately differentiated (Mod) carcinomas (p = 0.04, 0.003, respectively). Mutation of the SMAD4 gene was detected in 2 of 26 Por tumors. MSI was positive in 14 of the 38 Por tumors and in 1 of the 5 Sig tumors, but in none of the Well or Mod tumors examined. We also found mutation of TGF-beta RII, a putative target of MSI, in 10 of 35 Por tumors (28.6%), but in none of 3 Sig tumors. As a whole, about 50% of the Por tumors and 80% of the Sig tumors showed abnormalities of either TGF-beta RII or SMAD4 expression. This suggests that disruption of the TGF-beta signaling pathway may play a central role in the pathogenesis of Por and Sig tumors of the colorectum.

Expression of PPARdelta in multistage carcinogenesis of the colorectum: implications of malignant cancer morphology.

Whether peroxisome proliferator-activated receptor (PPAR) delta is a good target for the chemoprevention and/or treatment of colorectal cancer (CRC) remains controversial. Our goal was to examine PPARdelta expression in multistage carcinogenesis of the colorectum and to assess the relevance of PPARdelta in CRC. Immunohistochemical analysis indicated that PPARdelta expression increased from normal mucosa to adenomatous polyps to CRC. In cancer tissues, the PPARdelta protein was accumulated only in those cancer cells with highly malignant morphology, as represented by a large-sized nucleus, round-shaped nucleus, and presence of clear nucleoli. Interestingly, the cancer tissue often contained both PPARdelta-positive and -negative areas, each retaining their respective specific morphological features. Moreover, this pattern persisted even when PPARdelta-positive and -negative cells were aligned next to each other within a single cancer nest or gland and was present in the majority of CRC cases. Immunohistochemistry for Ki-67 proliferation marker showed no significant correlation between Ki-67 and PPARdelta in CRC samples. Based on Western blot analysis and quantitative RT-PCR, high PPARdelta protein expression correlated with high PPARdelta mRNA levels. Peroxisome proliferator-activated receptor delta may have a supporting role in tumorigenesis, and the close association between PPARdelta expression and malignant morphology of CRC cells suggests a pivotal role in cancer tissue.

Clinical usefulness of oral granisetron hydrochloride for alleviation of delayed nausea and vomiting induced by CPT-11.

This open label pilot study evaluated the safety and efficacy of the oral 5-HT3 receptor antagonist granisetron for prophylaxis of delayed chemotherapy-induced nausea and vomiting (CINV) in 30 patients with advanced or recurrent colorectal cancer. Patients were studied during two cycles of a 5-week regimen with irinotecan (CPT-11) and UFT. Patients received prophylactic anti-emetic therapy that included intravenous granisetron. If Grade 1 or higher severity gastrointestinal symptoms occurred during 6 days after CPT-11 administration in Cycle 1, then oral granisetron was administered daily for the following 5 days of CPT-11 in Cycle 2. Sixteen patients (53.3%) experienced delayed CINV in Cycle 1. The incidence of Grade 2 or higher vomiting was 32.1% and 27.7% in Cycles 1 and 2 in males (P = 0.554) respectively, and 54.6% and 32.4% in females (P = 0.001) respectively. Granisetron is effective against delayed Grade 2 or higher vomiting induced by CPT-11/UFT in female patients, although granisetron alone may not sufficiently control nausea induced by this regimen.

Feasibility of autonomic nerve-preserving surgery for advanced rectal cancer based on analysis of micrometastases.

BACKGROUND: Autonomic nerve preservation has been advocated as a means of preserving urinary and sexual function after surgery for rectal cancer, but may compromise tumour clearance. The aim of this study was to determine the incidence of micrometastasis in the connective tissues surrounding the pelvic plexus. METHODS: The study included 20 consecutive patients who underwent rectal surgery with bilateral lymph node dissection for advanced cancer. A total of 78 connective tissues medial and lateral to the pelvic plexus and 387 lymph nodes were sampled during surgery. All connective tissue samples and 260 lymph nodes were examined for micrometastases by reverse transcriptase-polymerase chain reaction (RT-PCR) after operation. All patients were followed prospectively for a median of 36.0 months. RESULTS: Of 245 histologically negative lymph nodes, 38 (15.5 per cent) were shown by RT-PCR to harbour micrometastases. However, micrometastases to tissues surrounding the pelvic plexus were detected in only two (3 per cent) of 78 tissues, that is in two of 20 patients. Clinical follow-up showed that the two patients had a poor prognosis owing to distant metastases. CONCLUSION: Autonomic nerve-preserving surgery may be feasible for advanced rectal cancer, but study of more patients positive for micrometastases is required.

Cyber visual training as a new method for the mastery of endoscopic surgery.

BACKGROUND: We devised a new method incorporating cyber visual training whereby novices in endoscopic surgery are instructed via repetition of a video-recorded procedure. We then conducted a study designed to investigate the impact of this cyber visual training on the mastery of intracorporeal knot-tying as an endoscopic technique. METHODS: For the cyber visual training a 10-min video of the same procedure was replayed at normal, slow, and rapid speeds or presented in a series of still images. The training was undertaken by 36 medical students and 1st year trainee doctors who had had no experience of endoscopic surgery. They were divided into three groups, each of all received the same introductory lecture. Group A was only given training with the instructor for 15 min. Group B trained with the instructor for 15 min and was allowed self-training for 10 min. Group C viewed the cyber video beforehand and then underwent training with the instructor for 15 min. For all participants, the time required to complete a knot-tying task was measured and the level of endoscopic skill before and after the training was assessed using a virtual reality system the minimally Invasive Surgical Trainer-Virtual Reality (MIST-VR), in terms of the following three parameters: time, errors, and efficiency of hand movements. The Steel-Dwass test was used to evaluate the differences among the three groups in task performance. RESULTS: Group C completed the knot-tying task faster than group A (p = 0.0375), but there were significant differences between groups A and B and groups B and C. There were no significant differences in the parameters assessed using the MIST-VR. CONCLUSIONS: Our new concept of cyber visual training is effective for mastering the knot-tying technique. This type of training should be widely applicable to other procedures, such as dissection, clipping, and hemostasis.

Identification of differentially expressed genes involved in colorectal carcinogenesis using a cDNA microarray.

To identify candidate genes involved in human colorectal carcinogenesis, we constructed the gene expression profiles of 50 colorectal cancers (CRCs) and 12 normal colorectal epithelia using a cDNA microarray specially constructed for CRC. Hierarchical clustering analysis and principal component analysis could clearly distinguish the gene profiles of cancer tissues from those of normal tissues. Our results confirm there are indeed differences in gene expression between cancer and normal mucosa. Our cDNA microarray identified 22 up-regulated genes and 32 down-regulated genes in CRC. Many of these genes have been previously identified in relation to human carcinogenesis, 68% and 78%, respectively. Subsequent validation of selected genes by serial analysis of gene expression and reverse transcription polymerase chain reaction, demonstrated expression patterns that were almost identical to our microarray analysis. Using a four-fold larger sample relative to that used in our previous study, candidate genes involved in human colorectal carcinogenesis were reproducibly identified. Further studies of comprehensive gene expression using our technique may elucidate the mechanism of CRC tumorigenesis.

Laparoscopic lymph node dissection for gastric cancer with intraoperative navigation using three-dimensional angio computed tomography images reconstructed as laparoscopic view.

BACKGROUND: Laparoscopic extended lymph node dissection for gastric cancer is difficult to perform because it requires dissection with preservation of vessels. Therefore, an intraoperative navigation system for the angioarchitecture would be helpful. Recent enhanced volume-rendering computed tomography (CT) can produce clear intraluminal three-dimensional (3D) images. This advanced radiological technology can provide 3D angiographic images reconstructed in the same view as would be observed from a laparoscope inserted into the abdominal cavity. We report our experience with laparoscopic gastrectomy with radical lymph node dissection using this advanced radiological technology. METHODS: 3D CT angiographic images from the celiac axis to the proper hepatic artery were reconstructed in two ways preoperatively. The first was only 3D angiographic images that were reconstructed as the laparoscopic view (LapView 3D CT angiography). The second was LapView 3D CT angiography with images of the body of the pancreas, which was more useful for intraoperative navigation in comprehensing anatomy. Two monitors were placed over the shoulder of the patient during surgery. One monitor, which was controlled by the image mixer, projected the laparoscopic images with picture in picture of 3D CT angiographic images. The surgeon performed the surgery with reference to this monitor during lymph node dissection. RESULTS: 3D angiographic CT clearly showed all vessels of interest in laparoscopic lymph node dissection for gastric cancer in 10 cases. The anatomy of vessels appeared as if looking beyond visible surface. LapView 3D CT angiography was useful for laparoscopic navigation surgery.

Laparoscopic intragastric surgery for gastric tube cancer following esophagectomy.

As a result of the recent improvement of the prognosis of esophageal cancer, the reporting frequency of gastric tube cancer following esophageal cancer has increased. Gastric tube total resection following median sternotomy, a highly invasive surgical procedure, is applied to the cases of advanced gastric tube cancer, whereas endoscopic mucosal resection is selected for the cases of early gastric tube cancer. If endoscopic mucosal resection is not applicable for some reason, partial or total resection of the gastric tube following median sternotomy has been selected. We applied laparoscopic intragastric surgery to such a case: The patient, a 59-year-old man with esophageal cancer, had undergone subtotal esophagectomy followed by gastric tube reconstruction through the retrosternal route 6 years before. Since endoscopy revealed early gastric cancer in the body of the stomach, we tried to perform mucosal resection but failed because of anastomotic stenosis. However, we successfully performed intragastric surgery, in which a camera and forceps were inserted directly into the gastric tube. Thus, laparoscopic intragastric surgery is a useful technique in cases to which endoscopic mucosal resection is not applicable.

[Significance of liver resection for multiple hepatic metastases from colorectal cancer].

In colorectal cancer, liver metastasis is the most common and most important prognostic factor. To elucidate the significance of liver resection, we examined 72 cases (H2: 29 cases, H3: 43 cases). The 3-year survival rate for H2 and H3 patients was 71.5% and 4.5%, respectively. The liver resection rate in H2 and H3 patients was 58.6% (17/29) and 16.3% (7/43), respectively. In H2 patients the 3-year survival rate of those with liver resection and non-resection was 71.3% and 9.2%, respectively (p < 0.001). However, in H3 patients the 3-year survival rate in liver resection and non-resection patients was 80.0% and 43.9%, respectively (not significant). Many therapies, such as liver resection, hepatic arterial infusion, and systemic chemotherapy, were attempted for patients with hepatic metastases. Our data show that liver resection can prolong the survival of H2 patients only. On the other hand, hepatic arterial infusion therapy prolongs the survival of H3 patients only. Systemic chemotherapy does not prolong the survival of either H2 or H3 patients.

[Tumor markers for colorectal cancer].

CEA and CA19-9 are the two most common tumor markers for colorectal cancer that are currently utilized clinically. The positive rate of CEA is 40-60% and that of CA19-9 is 30-50%. Simultaneous use of the two markers is useful in evaluating the therapeutic effect and monitoring the recurrence of advanced colorectal cancer. Surgical specimens may also provide useful information for the appropriate treatment of patients. Using surgically resected lymph nodes, we examined micrometastasis to assess the spread of the cancer cells and the malignant potential of colorectal cancer. Immunohistochemical analysis using anti-cytokeratin antibody revealed no significant impact of micrometastasis on patient prognosis, while RT-PCR assay using CEA as a genetic marker suggested a positive value in predicting a rapid recurrence. Among various molecular markers, we found that CDC25B phosphatase was a powerful prognostic factor for colorectal cancer. Diagnosis of the existence and malignant potential of cancer cells, together with serum tumor marker levels, may help to construct a more useful system for the better treatment of colorectal cancer.

Correlation of beta-catenin and cyclin D1 expression in colon cancers.

OBJECTIVE: Beta-catenin activates transcription by TCF/LEF and has been regarded as an oncogene in a wide range of malignant tumors. Among various molecules regulated by beta-catenin/Tcf, cyclin D1 is the most likely candidate for stimulation of the oncogenic pathway. The association between beta-catenin and cyclin D1 was investigated using clinical samples from colorectal cancers. METHODS: The expression of beta-catenin and cyclin D1 was investigated by immunohistochemical analyses of samples from 70 patients with colorectal cancers. In 28 of the fresh tumor samples, beta-catenin protein was separated into soluble and insoluble fractions and quantitatively correlated with cyclin D1 protein by Western blot analysis. RESULTS: Compared with noncancerous epithelium, beta-catenin and cyclin D1 were overexpressed (+) in 35 (50%) and 30 cases (43%), respectively. Cyclin D1 (+) was observed in 74% (26/35) of beta-catenin (+) cases, but only in 11% (4/35) of the beta-catenin (-) cases. Thus, there was a strong association between the expression of beta-catenin and that of cyclin D1 (p < 0.001). In the Western blot analysis, the amount of cyclin D1 correlated well with beta-catenin expression in the soluble fraction (p = 0.0016), but not with beta-catenin in the insoluble fraction or with E-cadherin expression. Beta-catenin (-)/cyclin D1 (-) cases displayed less tumor invasion than the remaining cases. However, there were no significant differences in lymph node metastasis or other clinicopathological findings. CONCLUSION: Our results indicate that beta-catenin overexpression in the cytoplasm may promote malignant transformation by triggering cyclin D1 expression in colorectal cancers.