Sigmoid colon perforation induced by the vascular type of Ehlers-Danlos syndrome: report of a case.

The vascular type of Ehlers-Danlos syndrome (vEDS) is a rare inherited disease of the connective tissues, and is caused by abnormal type III collagen resulting from heterogeneous mutations of the type III collagen COL3A1 gene. We herein report the case of a vEDS patient who developed a sigmoid colon perforation and was given a definitive diagnosis by a genetic and biomolecular assay. The patient demonstrated clinical manifestations caused by tissue weakness such as frequent pneumothorax events and a detached retina. During the operation, we noticed easy bruising and thin skin with visible veins on the patient's abdominal wall. Finally, a diagnosis was confirmed by the reduction of type III collagen synthesis and by the identification of a mutation in the gene for type III collagen. We conclude that it is difficult to diagnose a vEDS patient without clinical experiences and specialized genetic methods. Furthermore, all organs must be treated gently during therapy, because the tissues of vEDS patients are extremely fragile.

Placement of an expandable metallic stent improves the efficacy of chemoradiotherapy for pancreatic cancer with malignant portal vein stenosis or obstruction.

BACKGROUND: Advanced or recurrent pancreatic cancer can sometimes cause obstruction or stenosis of the portal vein (PV), resulting in various symptoms of portal hypertension (PH), such as ascites, pancytopenia, hemorrhagic tendencies and liver dysfunction. We placed an expandable metallic stent into the PV to improve PH-associated complications and liver function. The placement of the PV stent was beneficial for administering chemotherapeutic agents and radiotherapy (RT) safely, and resulted in an improved response rate (RR) and survival. PATIENTS AND METHODS: In the present study, 14 patients with malignant portal obstruction due to advanced or recurrent pancreatic cancer received PV stent placement to manage their PH-associated symptoms. After a mini-laparotomy at the ileocecal region, the ileocecal vein was cut and an expandable metallic stent (6-8 mm in diameter and 6-8 cm in length) was inserted into the PV under image roentgenography. After placement of the PV stent, the patients received anti-coagulation treatment with heparin and biaspirin for 1-3 months. All patients received chemotherapy with UFT, cyclophosphamide (CPA) and gemcitabine (GEM), and 11 patients also received RT. RESULTS: The RR was 43% (3 complete (CR), 3 partial (PR), 3 stable disease (SD), and 5 progressive disease (PD)), and the mean survival times (MST) after the initiation of therapy or placement of the PV-stent were 12.6 and 9.5 months, respectively, while the 1-year survival rates were 54.5% and 35.1%, respectively. In the 3 CR patients, 2 died of carcinomatous ascites 13 and 21 months later, and 1 is still disease free. In the PR and SD patients, pain and PH-associated symptoms such as ascites and hyperglycemia were also improved. CONCLUSION: The placement of a PV stent is beneficial for improving PH-associated symptoms as well as facilitating chemo-RT and the efficacy of therapy.

High incidence of synchronous or metachronous breast cancer in patients with malignant and benign thyroid tumor or tumor-like disorders.

BACKGROUND: Although many reports indicated an association between thyroid diseases and breast cancer, such an association still remains controversial. The present study was aimed to clarify the association of thyroid diseases with the breast cancer incidence. In the patients with benign and malignant thyroid tumor or tumor-like disorders, the incidence of other malignancies was surveyed, and the frequency of thyroid cancer in patients with breast cancer was also surveyed. PATIENTS AND METHODS: Between 1982 and 2005, a total of 201 female patients received surgery for tumor or tumor-like disorders, including 65 carcinoma, 68 adenoma, 61 adenomatous goiter and 7 chronic thyroiditis cases. Their outcomes were surveyed in December 2006. Furthermore, during the same periods, 340 female patients underwent breast cancer surgery and their outcomes were also surveyed in December 2006. RESULTS: The overall incidence rate of breast cancer was 16.4% (33/201) in the patients, who received thyroid surgeries and was much higher than other malignancies: 2.0% gastric cancer, 1.0% uterine and colorectal cancer. The incidence rate of breast cancer in each disease was 13.8% for thyroid cancer, 16.2% for adenoma and 21.3% for adenomatous goiter, but no incidence for chronic thyroiditis. On the other hand, in the patients with breast cancer during the same period in our department, the frequency of thyroid cancer was only 2.1% (7/340). CONCLUSION: It appears that thyroid cancer, adenoma and adenomatous goiter were associated with the risk of breast cancer, but chronic thyroiditis was not related.

Carbachol induces hepatocyte proliferation, but only in the presence of hepatic nonparenchymal cells.

Vagal hyperactivity correlates with enhanced DNA synthesis and cell proliferation in the peripheral tissues of ventromedial hypothalamic (VMH)-lesioned rats. The infusion of an ACh receptor agonist, carbachol (Cch), induces rat duodenal and pancreatic cell proliferation to a degree comparable to the VMH lesions. Whereas the VMH lesions also induce the proliferation of hepatic cells, it is unclear whether Cch can also do this. Here we attempted to clarify the mechanism of hepatic cell proliferation induction by cholinergic stimulation. First, hepatic cell proliferation was examined in rats previously vagotomized and intraperitoneally administered with Cch via an osmotic minipump. Second, the sera from the Cch-infused rats were examined for a proliferative effect on isolated hepatic cells. And last, the effect of the presence of hepatic nonparenchymal cells (NPCs) on the proliferation of the cultured hepatocytes treated with Cch was investigated. Immunohistochemistry for proliferating cell nuclear antigen (PCNA) showed that the 3-day Cch infusion significantly increased the number of PCNA-immunoreactive cells in the liver. Moreover, the sera from the Cch-infused rats increased the number of PCNA-immunoreactive hepatocytes in culture. However, Cch alone did not induce proliferation in monocultured hepatocytes. When compared with the monoculture of hepatocytes, the coculture of those with hepatic NPCs resulted in enhanced PCNA immunoreactivity after a 4-day treatment with 3 mM Cch. These findings suggest that ACh induces hepatocyte proliferation, which is mediated by unidentified humoral factor(s) possibly secreted from hepatic NPCs, and that it also participates in liver hypertrophy in the VMH-lesioned animals.

Continuous carbachol infusion promotes peripheral cell proliferation and mimics vagus hyperactivity in a rat model of hypothalamic obesity.

Lesions of the ventromedial hypothalamus (VMH) result in obesity and enhanced cellular proliferation in various organs, including the pancreas, gastrointestinal tract, and liver. Previous studies have suggested that vagal hyperactivity, rather than overeating, induces the peripheral cell proliferation in VMH-lesioned rats. The goal of the present study was to investigate the mechanism of peripheral cell proliferation in VMH-lesion-induced obesity by infusing rats with the acetylcholine agonist, carbachol, and then measuring cellular proliferation in the pancreas and duodenum using immunohistochemistry. The ventromedial hypothalamus was bilaterally lesioned in five rats. In other rats, the bilateral vagus nerves were ligated (vagotomized), and saline or carbachol was continuously administered by an osmotic minipump (n = 5 in each group). Three days later, rats were killed, and cell proliferation was assessed in the pancreas and the duodenum using immunohistochemistry for proliferating cell nuclear antigen (PCNA). Additionally, cellular proliferation in the duodenum was more precisely examined by assessing incorporation of 5-bromo-2'-deoxyuridine (BrdU). Cellular proliferation was higher in rats that received carbachol infusions and in rats with VMH-lesions when compared with control rats (P < 0.05, respectively). The pancreatic PCNA-expressing cells were predominantly identified as the B-cells of the islets of Langerhans. These data demonstrate that carbachol infusion can induce pancreatic and duodenal cell proliferation to a degree that was comparable to that in vagal hyperactivity induced by VMH lesions.

Immunohistochemical expression of receptor-tyrosine kinase c-kit protein and TGF-beta1 in invasive ductal carcinoma of the pancreas.

BACKGROUND: The receptor tyrosine kinase c-kit is known to play an important role in the progression of gastrointestinal stromal tumors, but its biological significance in other solid malignancies is unclear. Recent publications have suggested a regulatory role for TGF-beta1 in c-kit-mediated cell growth. The present study assessed the clinicopathological significance of c-kit protein (KIT) and TGF-beta1 expression in resectable invasive ductal carcinomas (IDCs) of the pancreas. PATIENTS AND METHODS: This study included 91 pancreatic IDC patients who received a pancreatectomy between 1982 and 2003. The expression of KIT and TGF-beta1 was analyzed by immunohistochemistry. RESULTS: KIT and TGF-beta1 were expressed in 77% (70/91) and 59% (54/91) of the IDC, respectively. The expression of KIT was not correlated with that of TGF-beta1. TGF-beta1 expression correlated inversely with nodal involvement, but KIT expression did not correlate with any clinicopathological factors. KIT expression had no significant influence on the survival of the patients, whereas the survival rate of TGF-beta1 (+) IDC patients was significantly higher than that of TGF-beta1 (-) IDC patients. Co-expression analysis of KIT and TGF-beta1 indicated that, in patients with KIT (+) IDC, the TGF-beta1 (+) group showed a significantly better survival rate than the TGF-beta1 (-) group. Neither KIT expression nor TGF-beta1 expression had a significant effect on the efficacy of adjuvant chemotherapy (ACT). In multivariate analysis, TGF-beta1 expression was one of the significant variables for survival in IDC patients overall, but KIT expression was not. CONCLUSION: TGF-beta1 expression is suggested to have a significant influence on c-kit-mediated cell proliferation in human pancreatic IDCs.

A randomized consent design trial of neoadjuvant chemotherapy with tegafur plus uracil (UFT) for gastric cancer--a single institute study.

OBJECTIVE: Various forms of neoadjuvant chemotherapy (NAC) have been applied in the treatment of gastric cancer. The present study was designed to assess the survival benefits of NAC with UFT (tegafur plus uracil) for gastric cancer, as a randomized consent trial as described by Zelen. PATIENTS AND METHODS: The present study included 295 patients with resectable gastic cancer between 1991 and 1999. After the patients had been pre-randomized into two groups, a control (no-NAC) group (n=120) and a treatment group (n=175), the treatment group patients were then further stratified into two groups, namely those who wished to join the control group and those who wished to receive NAC with UFT (NAC-UFT group). Patient outcome was surveyed in January 2003. RESULTS: Randomization did not necessarily result in an appropriate registration of the patients, and ultimately 193 patients were included in the control group and 102 patients received NAC-UFT. The NAC-UFT was well tolerated by the patients and side-effects were not severe. However, the NAC-UFT group included the patients with significantly higher stages of cancers than the control group. The survival benefit of NAC-UFT was seen in stage 2 or 3 patients, and multivariate analysis also revealed that NAC-UFT was a significant prognostic variable, as were pT, pN, M and the level of nodal dissection, but patient age, gentler and histological grade were not significant variables. CONCLUSION: NAC-UFT may be beneficial in the improvement of survival rate after gastric cancer surgery and this treatment modality is worthy of further study with a larger patient sample size.

A self-expandable metallic stent in combination with cholangioscopic microwave coagulation therapy and chemotherapy with oral TS-1 against obstructive jaundice due to recurrent gastric cancer: a case report of successful treatment.

Obstructive jaundice is a terminal symptom of gastric cancer. A 45-year-old female patient had a recurrent gastric cancer at the pancreas head and it caused obstructive jaundice. She was treated with percutaneous transhepatic cholangio-drainage, followed by radiotherapy and chemotherapy with cisplatin, epirubicin and 5-FU, which resulted in a prominent response and a self-expandable metallic stent was placed into the bile duct. After 11 months, however, the tumor recurred and the bile duct was obstructed again by an invading tumor. She was retreated with percutaneous transhepatic cholangio-drainage for jaundice, followed by chemotherapy with oral TS-1. Her recurrent tumor dramatically responded again, and cholangioscopic microwave coagulation therapy was applied for the first time through a cholangio-drainage route and an additional metallic stent was inserted into the bile duct. After these therapies she has been disease--free for more than 2 years. In conclusion, the placement of a self-expandable metallic stent in combination with cholangioscopic microwave coagulation therapy and TS-1 was very effective in managing the obstructive jaundice due to the local recurrence of gastric cancer.

Immunohistochemical expression of receptor-tyrosine kinase c-kit protein in invasive ductal carcinoma of the pancreas.

The expression of receptor tyrosine kinase c-kit and its biologic significance in pancreatic cancer are unclear. We studied the expression of c-kit protein (c-KIT) in resectable invasive ductal carcinomas (IDCs) of the pancreas, in order to assess whether a selective c-kit inhibitor, STI571 (Glivec), may be applied for the treatment of pancreatic IDCs. This study included 72 pancreatic IDC patients who received a pancreatectomy between 1982 and 2002. The expression of c-KIT was analyzed retrospectively by immunohistochemistry. c-KIT was expressed in 78% (56/72) of the pancreatic IDCs. c-KIT expression did not correlate with any clinicopathological factor of pancreatic IDC and c-KIT expression had no significant influence on the survival of the patients. The survival rate of the adjuvant chemotherapy (ACT) (+) group was significantly higher than that of the ACT (-) group, but c-KIT expression had no significant effects on the efficacy of the ACT. Multivariate analysis indicated that the pTNM stage, grade and ACT were all significant variables for survival in IDCs overall. As c-KIT was expressed in 78% of the pancreatic IDCs, it suggests that STI571 may be a beneficial agent for chemotherapy against human pancreatic IDCs.

Problems in the N-classification of the new 1997 UICC TNM stage classification for gastric cancer: an analysis of over 10 years' outcome of Japanese patients.

BACKGROUND: One of the major changes in the new TNM classification (5th edition, 1997) for gastric cancer was made in the classification of N category: the 5th edition employs the number of involved nodes and a minimum of 15 examined nodes is required for N0 classification. The validity of the new TNM classification was assessed by comparing the survivals according to the number of nodal involvement and especially the cut-off point of number of involved nodes and the problems in N0 classification in T1 were focused. PATIENTS AND METHODS: Between 1982 and 1999, a total of 641 patients underwent gastrectomy for gastric cancer in our department. The stage and the degree of subcategories were classified according to the pathological assessment after surgery, and the survival and its correlation with clinicopathological factors were statistically analyzed. RESULTS: pT classification included 325 pT1, 103 pT2, 102 pT3 and 111 pT4 cases, while pN classification included 448 pN-classifiable cases (223 pNO, 149 pN1, 52 pN2 and 24 pN3); 193 were unclassifiable (pNx), 123 of which were classified pNx due to the examined lymph nodes being less than 15. In 448 pTNM-classifiable cases the pN2 and pN3 groups showed almost the same survivals, while the pN1 included subgroups with a significant difference in prognosis. The pN1 category should be classified into two categories: pN1a, 1-3 involved nodes and pN1b, 4-6 involved nodes. Furthermore, out of 325 pT1 cases, 151 (46.5%) were pN-unclassifiable (pNx): 123 were due to the examined number being less than 15 for pN0 classification and 28 where the number of examined nodes were not reported. Although the mean number of examined nodes in pT1 was 24.7 for pN0 and 8.3 for pNx, there were no differences in survival rates between the pT1pN0 group and the pT1pNx group. This suggests the over-requirement of the number of examined nodes for pN0 classification in pT1 cases. We propose that pN0 classification in pT1 should be required for a minimum of 6 examined nodes. CONCLUSION: The pN1 category should be subclassified into pN1a and pN1b. Furthermore, pN0 classification in pT1 should be required for a minimum of 6 examined nodes.

Implication of HER-2/neu overexpression for the efficacy of oral fluoropyrimidine-based adjuvant chemotherapy in the patients with estrogen receptor negative breast cancer after surgery.

BACKGROUND: The implications of HER-2/neu overexpression for the efficacy of adjuvant chemotherapy (ACT) and endocrine therapy (AET) have been controversial. The present study retrospectively assessed the effects of HER-2/neu overexpression on the efficacy of oral fluoropyrimidine-based ACT and AET after breast cancer surgery. PATIENTS AND METHODS: The expression of HER-2/neu protein and estrogen receptor (ER) in 217 primary breast cancers was assessed immunohistochemically using the HercepTest and an anti-ER monoclonal antibody. The overexpression of HER-2/neu was classified into 4 categories (0-3+) according to standard criteria, and 3+ was categorized as HER-2/neu-overexpression. Of the 217 patients, 26 received surgery alone (SA), 32 received ACT, 20 received AET alone and 139 received both AET and ACT. The regimen of the ACT included oral fluoropyrimidines in all patients. RESULTS: HER-2/neu (3+) overexpression and ER expression were seen in 31.8% (69 out of 217) and 47.5% (103 out of 217) of the patients, respectively. The survival of the HER-2/neu (3+) group was significantly lower than other groups (p = 0.0134), especially in the ER (+) patients (p = 0.0229). However, in the ER (+) patients, HER-2/neu overexpression had no significant effect. The effects of HER-2/neu overexpression and ER expression on the efficacy of the ACT and AET were analyzed by patient survival. In the ER (-) patients, the ACT (+) group had a significantly higher survival rate than the ACT (-) group (p = 0.0459), and this was noted especially in the HER-2/neu-overexpressing cases (p = 0.0485). In the ER (+) patients, ACT and AET did not have any significant influence on the survival regardless of the HER-2/neu status. CONCLUSION: Fluoropyrimidines-based ACT improves the long-term outcome of patients with HER-2/neu-overexpression (3+) and ER (-) breast cancer after surgery.

A fractal dimension analysis: a new method for evaluating the response of anticancer therapy.

BACKGROUND: The therapeutic effects of various anticancer therapies on malignant tumors are evaluated as objective response (OR) by comparing the tumor size before and after the therapy However, it is difficult to evaluate the OR because malignant tumors frequently have very irregular or stellate shapes. In the present study we investigated a new method for evaluating the response of esophageal cancer to radio-chemotherapy using the fractal dimension (FD). PATIENTS AND METHODS: The changes in tumor size or shape during therapy were recorded in 6 patients with esophageal cancer by esophageal fluoroscopy. The OR was evaluated by WHO standard criteria by calculating the tumor regression rate (TRR), while the FD was calculated by a standard compass-counting method. RESULTS: All 6 patients complained of dysphagia before therapy, but the food passage improved after therapy in all patients. The TRR after therapy ranged between -90% and 43.4%, and the OR was evaluated as no change (NC) in 5 patients and progressive disease (PD) in one patient. On the other hand, the RD gradually decreased in all 6 patients during the therapy. Furthermore, 5 patients underwent esophagectomy and the histological effect was evaluated as grade-2 response in two patients and grade-1 response in three patients. The decreases in the FD were 0.069 and 0.079 in grade-2 responses and 0.022-0.034 in grade-1 responses. By contrast, 4 NCs included 2 grade-2 responses and 2 grade-1 responses, and PD was evaluated as grade-1 response. These results suggested that the standard criteria for an OR could not accurately evaluate the therapeutic effect in some cases, and the changes in FD correlated with the improvement in the symptoms and histological effect more precisely than the TRR or the OR. CONCLUSION: The FD represented the therapeutic effect of radio-chemotherapy well for esophageal cancer, and may be widely applied for evaluating the therapeutic effect of cancer therapy.

Oral UFT (uracil plus futrafur) for neoadjuvant chemotherapy of gastric cancer.

BACKGROUND: Neoadjuvant chemotherapy has become one of the topics of interest in chemotherapy of gastric cancer; the present study assessed the clinical benefits of neoadjuvant chemotherapy with oral uracil and futrafur (UFT) for gastric cancer.METHODS: Between 1991 and 1997, 82 patients with gastric cancer (36 with early and 46 with advanced cancers) received UFT at 300-600 mg/day orally for 1-6 weeks before surgery. Objective responses, histological effects, and postsurgical survival rates were assessed.RESULTS: In 69 of the 82 patients, the objective responses of the primary lesions were assessed by endoscopy or upper gastrointestinal series examination, and 2 complete responses (CR)s, 25 partial responses (PRs), and 42 no changes (NCs) were seen (39.1% response). Histological effects were evaluated in 82 patients, and 2 grade 3, 11 grade 2, 11 grade 1b, 27 grade 1a, and 31 grade 0 effects were seen. A longer period of UFT administration was associated with a CR or PR. However, the objective responses did not correlate with the histological effects. All the patients underwent gastrectomy, and during the median follow-up period of 41 months, 3-year survival rates were 97.1% for pTNM stage 1, 75% for stage 2, 86.7% for stage 3, and 41.6% for stage 4. The survival rates of stage 3 and stage 4 patients were higher than those of the historical controls in our department. However, CR or PR did not correlate with the improvement in survival. Side effects before surgery were not serious; they included slight myelotoxicity, liver dysfunction, and anorexia; however, 3 patients (3.7%) had suture insufficiency, 3 patients (3.7%) had methicillin-resistant Staphylococcus aureus (MRSA) enteritis, and 7 patients (8.5%) had liver dysfunction.CONCLUSIONS: Preoperative chemotherapy for gastric cancer with oral UFT was safe and resulted in a good local response (macro- and microscopically) which may indicate the possibility of improved survival with neoadjuvant chemotherapy with UFT. Furthermore, preoperative chemotherapy with oral UFT is easy and patients can receive this treatment on an outpatient basis.