High-Dose Immunoglobulin Therapy for Multiple Thromboembolism in Persisting Heparin-Induced Thrombocytopenia.

This report presents a case of an 81-year-old male with acute respiratory distress syndrome secondary to aspiration pneumonia who developed heparin-induced thrombocytopenia (HIT). His platelet count remained persistently low despite discontinuing unfractionated heparin and initiating intravenous argatroban. Multiple thromboembolisms, including a new aortic mural thrombus in the descending aorta, were observed on contrast-enhanced computed tomography (CT), resulting in a diagnosis of autoimmune HIT (aHIT). Subsequent high-dose intravenous immunoglobulin (IVIG) therapy substantially improved the platelet count and resolved thromboembolisms. This case is notable owing to the improvement of aHIT complicated by multiple thromboembolisms, including an aortic mural thrombus, following high-dose IVIG therapy. In recent years, a growing number of reports have documented the effectiveness of high-dose IVIG therapy for aHIT. However, reports on whether high-dose IVIG therapy could improve an aortic mural thrombus complicating aHIT are lacking. The successful use of high-dose IVIG therapy in the current case highlights its potential efficacy in treating aHIT complicated by multiple thromboembolisms. Further studies are required to clarify the role of IVIG in the management of aHIT with thromboembolism.

Post-traumatic giant thrombosis of inferior vena cava induced right-sided blunt traumatic diaphragmatic injury: a case report.

BACKGROUND: Inferior vena cava thrombosis is a severe disease as it carries a higher risk of developing pulmonary embolism associated with a high mortality rate. The incidence of inferior vena cava thrombosis is extremely low and is commonly associated with outflow obstruction of the inferior vena cava. The frequency of traumatic diaphragmatic injuries is less than 1% of all traumatic injuries. In addition, it was not a typical cause of inferior vena cava obstruction. We report the case of the patient who presented with giant thrombosis of the inferior vena cava, which required surgical treatment-induced right-sided blunt traumatic diaphragmatic injury. CASE PRESENTATION: A 60-year-old male presented to the emergency department with pelvic and lower leg pain. He was working on a dump truck with the bed raised position. Suddenly, the bed came down, and his body was crushed and injured. Primary CT showed a right lung contusion and elevation of the right diaphragm but no apparent liver injury. The right pleural effusion gradually worsened after admission, as the traumatic diaphragmatic injury was highly suspected. Repeat CT showed aggravation of elevation of the right-sided diaphragm, narrowing of the inferior hepatic vena cava due to left cephalic deviation of the liver, and formation of a giant thrombus in the inferior vena cava. No adverse hemodynamic effects were observed due to thrombus formation, and we performed thrombolytic therapy. The day after starting thrombolytic therapy, the patient developed pulmonary embolism due to a dropped in SpO2 needed oxygen, and dyspnea triggered by coughing. Thrombolytic therapy was continued after the diagnosis of pulmonary embolism. However, thrombolytic therapy was ineffective, so we decided on surgical thrombectomy and inferior vena cava filter placement. The postoperative course was not eventful, and an anticoagulant was started. The patient was transferred to the hospital on the 62nd day for rehabilitation. CONCLUSIONS: When a diaphragmatic hernia is suspected of causing hepatic hernia and narrowing of the inferior vena cava, it may be necessary to consider emergency surgical treatment to prevent secondary inferior vena cava thrombosis and fatal pulmonary embolism.

Stroke volume variation as a predictor of intravascular volume depression and possible hypotension during the early postoperative period after esophagectomy.

BACKGROUND: Perioperative hypotension during esophagectomy results from hypovolemia caused by a shift of extracellular fluid from the intravascular to the extravascular compartment. Fluid management is often difficult to gauge during major surgery because there are no reliable indicators of fluid status, and some patients still experience cardiorespiratory instability. In this retrospective study, we evaluated stroke volume variation (SVV), calculated by using a new arterial pressure-based cardiac output measurement device, as a predictor for fluid responsiveness after esophageal surgery. METHODS: Eighteen patients undergoing esophagectomy with extended radical lymphadenectomy were monitored by the FloTrac sensor/Vigileo monitor system during the perioperative and immediate postoperative period. Fluid responsiveness was assessed and compared with concurrent SVV and central venous pressure (CVP) values, and routine hemodynamic variables. RESULTS: Eleven of 18 patients needed additional volume loading within the first 10 postoperative hours as a result of hypotension. The maximum SVV value of fluid resuscitated patients was >15% in all cases, whereas six of seven patients without postoperative hypotension had maximum SVV values of <15%. The correlation between SVV and the development of hypotension was statistically significant (P = 0.0012). From the linear correlation analysis of hemodynamic variables influenced by additional fluid loading, SVV was significantly correlated to cardiac output (r = 0.638; P = 0.049), whereas CVP was not (P > 0.05). CONCLUSION: We conclude that SVV, as displayed on the Vigileo monitor, is an accurate predictor of intravascular hypovolemia and is a useful indicator for assessing the appropriateness and timing of applying fluid for improving circulatory stability during the perioperative period after esophagectomy.

Perioperative monitoring of fluid responsiveness after esophageal surgery using stroke volume variation.

OBJECTIVE: To assess the utility of a new arterial pressure-based cardiac output (FloTrac) and central venous oximetry (PreSep) monitoring system in the perioperative management of patients undergoing radical esophagectomy. CASE SERIES: From May 2006, a new analyzing device (Vigileo monitor; Edwards Lifesciences LLC, Tokyo, Japan), which can be used in combination with the FloTrac and PreSep sensors, has been used in nine patients who have undergone radical operations for thoracic esophageal cancer at our hospital. Stroke volume variation (SVV), calculated for each respiratory cycle and displayed on the Vigileo monitor, precisely predicted intravascular hypovolemia. The maximum SVV of patients who needed fluid resuscitation was significantly higher than that of patients who had a stable circulation. The mean value of the maximum SVV in the patient with or without fluid resuscitation was 25 +/- 6.9 and 13 +/- 1.4%, respectively (p < 0.04). In addition, continuous monitoring of central venous oxygen saturation enabled evaluation of oxygen supply to tissues to aid in determining the need for red blood cell transfusion. The Vigileo monitor (with Flo Trac and PreSep sensors) provided reliable information for the perioperative management of high-risk patients after highly invasive general surgery without the need for an invasive central or pulmonary catheter.

[A case of advanced gastric cancer successfully treated with TS-1/CDDP combination chemotherapy, able to maintain CR for more than two years against multiple liver metastases].

INTRODUCTION: In recent years, a high success rate of combination chemotherapy with TS-1/CDDP has been reported against advanced gastric carcinoma. We, this time, experienced a case of advanced hemorrhagic gastric cancer with multiple hepatic metastases for which total gastrectomy was performed, followed by postoperative combination chemotherapy with TS-1/CDDP which culminated in achieving CR for the liver metastases. CASE REPORT: The patient was a 59-year-old woman who was hospitalized for a type IV gastric carcinoma in the upper part of the gastric body. Further examination revealed liver (S 2, S 5, S 7) and lymph node metastases. Due to hemorrhage from the tumorous lesion, the treatment strategy selected was total gastrectomy followed by postoperative chemotherapy. Operative and clinicopathological findings revealed a mass lesion of MLU, type IV, 16.0x14.0 cm, sT 3 (SE), sH 1 (bilobular multiple metastases) and CY 0, and por 1, pT 2 (SS), pN 1 (+) [23/38], int, INF beta, ly 3 and v 1, respectively. Combination chemotherapy with TS-1/CDDP was instituted after surgery. As for the dosing method of combination chemotherapy,the patient was treated with a course of TS-1 80 mg daily divided into two doses over 21 days continuously, followed by a 14-day cessation of the drug,together with a dose of CDDP 70 mg on day 8. The patient received a total of four courses. At the completion of the third chemotherapy course, her multiple hepatic metastases disappeared. Further, the preoperative CA 19-9 level of 370 U/mL returned to normal after chemotherapy. Adverse events observed were leukopenia and thrombocytopenia, both of which were judged to be grade 2. At two years and nine months, the patient is being followed on an outpatient basis without any sign of postoperative recurrent disease. CONCLUSION: We experienced a patient who was successfully treated with combination chemotherapy and demonstrated disappearance of her multiple hepatic metastases, showing a clinical response of CR lasting for more than two years against the metastases. It was inferred that this regimen of TS-1/CDDP is an effective treatment modality not only as preoperative but also postoperative chemotherapy after surgery for advanced gastric carcinoma.

Etiology of intestinal obstruction in patients without a prior history of laparotomy or a detectable external hernia on physical examination.

We evaluated the preoperative determination of the etiology and effectiveness of the diagnostic modalities, as well as the incidence of various causes of intestinal obstruction (IO) from 1981 through 2001 at a university-affiliated emergency center. Patients with a history of prior laparotomy or evidence of hernia on physical examinations were excluded. Eighty-three patients with surgically or endoscopically proven IO were reviewed. The most common cause of IO in the group with enteric obstruction was hernia while that in the group of colonic obstruction was carcinoma. Of the first preoperative diagnostic modalities to correctly determine the cause of obstruction, the most common were contrast enema and colonoscopy. Preoperative determination of the etiology was possible in 67% of the patients and was significantly more common in patients with colonic obstruction than in those with enteric obstruction.

Solid and cystic tumor of the pancreas with massive hemoperitoneum.

A case of a solid cystic tumor (SCT) of the pancreas with massive hemoperitoneum occurring in a 31-year-old woman is reported. She was admitted with abdominal pain and rebound tenderness. Computed tomography (CT) disclosed a large tumor consisting of both solid and cystic components in the body of the pancreas. Within 12 hours after admission, she exhibited exacerbation of pain and hemoperitoneum on CT with deterioration of general condition and anemia. Celiac artery angiography demonstrated the tumor as a hypovascular mass. SCT of the pancreas was suspected, and emergent laparotomy was performed. In the surgical procedure, tumor in the body of the pancreas with rupture was detected. Distal pancreatectomy was performed with removal of the regional lymph nodes. There was no evidence of metastatic disease in the abdomen. The cut surface of the tumor exhibited areas of cystic degeneration containing hemorrhagic friable materials. Microscopically, the tumor cells were mainly cubic or cylindrical peripherally in pseudo-papillary formation. Postoperative recovery was normal and she was discharged on the 15th postoperative day. Three years after operation, she is free of disease without findings of recurrence.

Pulmonary involvement in Crohn's disease report of a case and review of the literature.

Crohn's disease (CD) is a granulomatous systemic disorder of unknown etiology. Obvious pulmonary involvement is exceptional in patients with CD. We report a case of a 38-year-old man who suffered from CD for more than 14 years and was treated with oral steroids for more than 10 years. Surgical excision of parts of the ileum was performed for life-threatening ileal bleeding caused by CD. After acute tapering of oral steroids, pulmonary symptoms and radiologic abnormalities were noted. Lung biopsy through thoracoscopy was performed and revealed signs of chronic inflammation with multiple subepithelial noncaseating and epithelioid granulomas on pathologic examination. Intravenous steroids were required in the initial management of life-threatening pulmonary dysfunction after diagnostic thoracoscopy and led to marked improvement. Tuberculocidal therapy was performed until all microbiological cultures were negative. Oral steroid dosage had slowly been tapered over 1 month. He was discharged with clinical and radiologic improvements. After 36 months, the patient's condition is stable on continued treatment with prednisolone and mesalazine.

Intermittent FLDP: 24-h infusion of 5-FU on days 1, 3 and 5 combined with low-dose cisplatin on days 1-5 for gastric cancer, and its pharmacologic and kinetic rationale.

PURPOSE: To improve the therapeutic efficacy and minimize the toxicity of 5-fluorouracil (5-FU), intermittent therapy consisting of alternate 24-h intravenous infusion and based on differences in generation time (T(G)) between normal cells and tumor cells was investigated. METHODS: Two human gastric cancer cell lines MKN-7 and MKN-74 with T(G) of 35 h and 17 h, respectively, were used in an in vitro cytotoxic assay. The drug exposure schedule consisted of a continuous 144-h exposure and alternate 24-h exposures. In a clinical trial, a total of 23 patients with advanced or recurrent gastric cancer were treated with intermittent therapy consisting of 24-h intravenous infusion with 5-FU 700 mg/m(2) per day on days 1, 3 and 5 in combination with low-dose cisplatin (CDDP) at 3.3 mg/m(2) per day on days 1 to 5. One cycle of the combined chemotherapy lasted for four consecutive weeks, followed by withdrawal over 1-2 weeks. Plasma 5-FU concentrations were measured by high-performance liquid chromatography in 15 patients and dihydropyrimidine dehydrogenase (DPD) activity in peripheral blood mononuclear cells (PBMC) was measured in 13 patients. RESULTS: The in vitro study revealed no statistically significant difference in cytotoxicity of 5-FU between the two drug exposure schedules in MKN-7 cells. In MKN-74 cells, however, a statistically significant decrease in cytotoxicity was found with the alternate 24-h exposure. In a clinical trial, plasma 5-FU concentrations showed a trapezoidal pattern. There was a significant correlation between DPD activity in PBMC and total body clearance of 5-FU. There were eight partial responders (8/22, 36%). Toxicities were very mild in severity, with no grade 3 or 4 toxicity. In particular, diarrhea and stomatitis were infrequent (one patient), and none of the patients developed thrombocytopenia. CONCLUSIONS: Toxicities which may be observed in rapidly growing cells such as bone marrow cells and gastrointestinal epithelial cells following continuous intravenous infusion of 5-FU seemed to be reduced by intermittent therapy of 5-FU consisting of alternate 24-h intravenous infusions.

Peliosis hepatis during postpartum period: successful embolization of hepatic artery.

Peliosis hepatis is a rare disorder characterized by the presence of blood-filled spaces in the liver, and it usually has a chronic presentation pattern. It has been reported mainly in adult patients in association with various pharmacological agents and infections. The present report concerns a postpartum patient in whom peliosis hepatis initially presented as active intraperitoneal hemorrhage from peliotic liver lesions, with no obvious etiology. We report here a 31-year-old woman who developed symptomatic peliosis hepatis and underwent superselective hepatic artery embolization, with control of the bleeding. We also present the sonographic, computed tomographic, and magnetic resonance images and laparoscopic findings. The patient recovered well and was discharged without any complaints. The pathogenesis in this patient remains unclear, but it is suggested that in her case estrogens and progesterone could not have been responsible for the development of peliosis hepatis.

Evaluation of the ratio of lymph node metastasis as a prognostic factor in patients with gastric cancer.

BACKGROUND: Lymph node metastasis in patients with gastric cancer is one of the important prognostic factors. However, there is no consensus concerning the best classification for lymph node metastasis as a prognostic factor. So, to evaluate the ratio of the number of metastatic lymph nodes to the total number of dissected lymph nodes (the ratio of LN meta) as a prognostic factor, we compared the ratio of LN meta with lymph node status according to the Japan Classification of Gastric Carcinoma and the total number of metastatic lymph nodes with multivariate analysis.METHODS: Between 1991 and 1997, a total of 360 patients with primary gastric cancer who underwent gastrectomy with D2 or more extended lymph node dissection were included in this study. Ten kinds of prognostic factors and three types of different classifications for lymph node metastasis were analyzed by multivariate analysis using the Cox regression.RESULTS: The average number of dissected lymph nodes and metastatic lymph nodes were 55.0 (range, 11-184) and 2.6 (range, 0-86), respectively. There were significant differences of the 5-year cumulative survival rates among each group of the ratio of LN meta (0%, 1%-9%, 10%-24%, and more than 25%). Age, tumor size, curability, and the ratio of LN meta were selected as independent prognostic factors by forward stepwise selection. The ratio of LN meta showed the highest hazard ratio by Cox regression.CONCLUSION: The ratio of LN meta appears to be an important prognostic factor and the best classification factor for lymph node metastasis.

Laparoscopic paracecal hernia repair.

The diagnosis and treatment of internal abdominal hernia usually require laparotomy. We report a case of preoperative diagnosis and laparoscopic repair of paracecal hernia. A 90-year-old woman was referred with features of a well-established small bowel obstruction (SBO). Computed tomography and a small bowel contrast examination showed a paracecal hernia. With the patient under general anesthesia, laparoscopic surgery was carried out with the use of pneumoperitoneum, and an easy reduction of the incarcerated intestinal loop was achieved by gentle traction of the intestine. The bowel was assessed for viability and showed no evidence of nonviability. The abnormal orifice in the paracecal region was observed. The orifice was closed with 3-0 PDS II (polydiaxonone) sutures laparoscopically. A laparotomy was avoided, and the patient recovered without significant complications. We conclude that laparoscopy can play a useful role in the treatment of internal hernia causing SBO when an obstructive lesion has been detected and decompression accomplished preoperatively.

Selective application of laparoscopic intervention in the management of isolated bowel rupture in blunt abdominal trauma.

BACKGROUND: Recently, laparoscopy has been used as an effective diagnostic and therapeutic modality for traumatic injury and peritonitis. However, its clinical benefits are still under evaluation. The aim of this study was to assess the feasibility and safety of this technique, in comparison with traditional laparotomy, in the management of isolated bowel rupture. A further aim was to evaluate possible predictive clinical factors in the management of isolated bowel rupture. INDICATIONS: Patients with definite or suspected isolated gastrointestinal perforation who were hemodynamically stable underwent laparoscopic surgery for diagnosis and treatment. METHODS AND RESULTS: The traditional laparotomy control group (Group A, historical controls) included patients from a prior study. In this previous study, carried out between 1993 and 1997, 23 consecutive cases of traumatic gastrointestinal perforation were treated with traditional laparotomy. Retrospectively, 13 of these 23 cases would have been eligible for laparoscopic intervention. The laparoscopic group (group B) was made up of cases seen at our institution from 1998 to 2000. Of the 13 consecutive cases of traumatic gastrointestinal perforation, only one required immediate traditional laparotomy. Just one of the 12 cases of gastrointestinal perforation approached laparoscopically had to be converted to a traditional laparotomy. The following variables were evaluated in both groups: patient background, time from accident to onset of operation, operative time, blood loss, time to oral intake, incidence of peritoneal contamination, length of hospital stay, mortality, and intraoperative and postoperative complications. There were no statistical differences in age, gender ratio, and injury severity score (ISS). The mean operative times were 132.3 +/- 58.7 minutes and 143.6 +/- 27.3 minutes in group A and group B, respectively. The mean blood loss was 266.8 +/- 277.8 mL in group A and 57.6 +/- 57.1 mL in group B. The blood loss in group B was significantly lower (P =.0084) than that in group A. There were no significant differences in intraoperative and postoperative complications, hospital stay, and mortality between the two groups. CONCLUSIONS: Laparoscopic intervention offers better results in the management of patients with blunt abdominal trauma and isolated bowel rupture.

Pneumothorax as a presenting manifestation of early sarcoidosis.

Pneumothorax rarely develops sarcoidosis. A 21-year-old man with early sarcoidosis presenting as pneumothorax is reported. The patient came to our institute with severe chest pain and dyspnea. Plain chest roentgenograms revealed pneumothorax in the left lung. A chest tube was inserted to inflate the lung. Subsequent computed tomography demonstrated subpleural blebs in the upper lobe of the left lung. Continuous treatment with tube drainage was performed. However, surgical intervention was needed since long-term tube drainage turned out to be unsuccessful. Thoracoscopic partial extirpation on the left upper lobe was performed. The histology of the obtained lung tissue showed non-caseating granulomas composed of epithelioid cells and occasional giant cells. A diagnosis of sarcoidosis was made on the basis of the histological report. Although early sarcoidosis presenting as pneumothorax is rare in young patients, the possibility of a sarcoidosis should be considered.

[Combination chemotherapy with intra-perioneal infusion of CDDP and continuous intravenous infusion of 5-FU for peritoneal metastasis in gastric cancer--analysis of long-term survivors].

In order to evaluate the utility of combination chemotherapy with intra-peritoneal infusion of CDDP and continuous intravenous infusion of 5-FU, we performed this therapy in 23 primary gastric cancer patients with peritoneal metastasis. CDDP was administered intraperitoneally at a dose of 70 mg/m2 over 2 hours on day 1, and 5-FU was continuously administered intravenously at a dose of 700 mg/m2 for 5 consecutive days from day 1, respectively. This treatment was given twice. Median survival time with this treatment was 343 days, and the depth of invasion was selected as an independent prognostic factor according to multivariate analysis. Five patients (21.7%) have survived more than 3 years. Major toxicities were less than Grade 2 except for two patients with each anemia (Grade 3) and venous thrombosis (Grade 3), respectively. This regimen appears to be feasible and effective for gastric cancer patients with peritoneal metastases. Long term survival may be obtained in patients without adjacent organ invasion.

[A case of advanced gastric cancer which became operable after chemotherapy with combination of TS-1/CDDP and in which complete disappearance of liver metastasis was histopathologically confirmed].

We encountered a patient in whom TS-1/cisplatin (CDDP) combination chemotherapy was effective. The cancer became operable, and complete disappearance of liver metastasis was histopathologically confirmed. The patient was a 65-year-old man who presented with complaints of epigastric discomfort and anorexia. Based on upper GI endoscopy and abdominal CT, type 1 gastric cancer associated with liver and abdominal lymph node metastases was diagnosed. The cancer was judged to be inoperable, and chemotherapy with a combination of TS-1 and CDDP was initiated. One course of treatment consisted of administration of 120 mg/day of TS-1 for 21 days followed by 14 days of withdrawal, and administration of 100 mg/body/day of CDDP on day 8 (80 mg/body/day in the second course). After two courses of treatment, the primary lesion and the liver and lymph node metastatic lesions decreased in size (reduction ratios were 42.3%, 90.5% and 85.2%, respectively). The tumor marker values became normal. Subsequently, the cancer was judged to have become operable. After consultation with the patient, total gastrectomy, splenectomy, partial hepatectomy, and D3 dissection were performed, and curability B was achieved. The only adverse event of Grade 2 or more severity observed during drug administration was anorexia. Liver metastasis was judged from pathological findings to have disappeared. The postoperative course was uneventful and the patient was discharged from the hospital. To date, there have been no signs of recurrence. TS-1/CDDP therapy is believed to provide effective treatment against liver metastasis and lymph node metastasis of gastric cancer.

Pneumoperitoneum without perforation of the gastrointestinal tract.

Pneumoperitoneum (PP) is usually the result of perforation of the gastrointestinal (GI) tract with associated peritonitis. However, other rare causes, including spontaneous PP incidental to intrathoracic, intra-abdominal, gynecologic, and miscellaneous other origins not associated with a perforated GI tract have been described in the literature. Six cases of PP without any perforated GI tract are reported. Three patients with generalized peritonitis underwent exploratory laparotomy or laparoscopy when clinical examinations suggested an acute abdomen. At surgical procedure, perforated pyometra, perforated liver abscess and a ruptured necrotic lesion of a liver metastasis were documented in these patients, respectively. We also saw 3 PP patients not associated with peritonitis. Two patients with PP caused by pneumatosis cystoides intestinalis were encountered, 1 was managed conservatively and the other received diagnostic laparoscopy. A patient in whom pneumomediastinum and pneumoretroperitoneum were accompanied by PP caused by an alveolar rupture based on decreased pulmonary compliance due to malnutrition was managed conservatively. The history of the patient and knowledge of the less frequent causes of PP can possibly contribute towards refraining from exploratory laparotomy in the absence of peritonitis.

Intussusception in adults: a 21-year experience in the university-affiliated emergency center and indication for nonoperative reduction.

BACKGROUND: While intussusception is relatively common in children, it is rare in adults. METHODS: We retrospectively reviewed the records of all patients older than 18 years with the diagnosis of intussusception between 1981 and 2001. RESULTS: Eleven patients with surgically or endoscopically proven intussusception were encountered at the University-affiliated emergency center. The patients ranged in age from 19 to 88 years with a mean age of 45 years. Males predominated by a ratio of 7:4. Most patients (82%) presented with symptoms of bowel obstruction. The mean duration of symptoms was 4.5 days with a range of 4 h to 25 days. Correct pre-treatment diagnosis was made in 82% of the patients using abdominal ultrasonography and computed tomography (CT). The causes of intussusception were organic lesions in 64% of the patients, postoperative in 18% and idiopathic in 18%, respectively. 73% of patients had emergency operations, and an attempt at nonoperative reduction was performed and completed successfully in 3 patients with ileo-colic or colonic type of intussusception. There have been no cases of morbidity or mortality in our series and no recurrence has occurred up to the present time. CONCLUSIONS: Abdominal ultrasonography and CT were effective tools for the diagnosis of intussusception. Patients with ileo-colic and colonic intussusception without malignant lesions could be good candidates for nonoperative reduction prior to definitive surgery.

Quantitative measurement of thymidylate synthase and dihydropyrimidine dehydrogenase mRNA level in gastric cancer by real-time RT-PCR.

We used real-time reverse-transcription polymerase chain reaction (RT-PCR) to assay expression of the mRNA of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in gastric cancer tissue with the objective of establishing a system to measure TS and DPD in ultra-low-volume samples. Nude mouse xenografts of 5 human gastric cancer cell lines and 85 clinical samples were used as the specimens in this study. Sensitivity to 5-fluorouracil (5-FU) was determined on the basis of the relative tumor proliferation rate in mice and the results of ATP assay using serum-free cultures of the clinical samples. mRNA expression was measured in tumor tissue by real-time RT-PCR using the ABI PRISM 7700 system. The values for expression of the mRNA for TS and DPD were corrected according to the level of glyceraldehyde-3-phosphate dehydrogenase mRNA expression. The xenografts yielded correlations between TS and DPD mRNA expression and the activity of the enzymes (TS: rs=0.700, DPD: rs=0.900), and an inverse correlation was noted between the mRNA levels and sensitivity to 5-FU (TS: rs=-0.900, DPD: rs=-0.800). The clinical samples showed an inverse correlation between 5-FU sensitivity and mRNA expression (TS: rs=-0.518, DPD: rs=-0.564). Sensitivity to 5-FU was noted only in cases in which TS mRNA expression and DPD mRNA expression were both low. Real-time RT-PCR can provide a highly sensitive assessment of TS and DPD mRNA expression in gastric cancer, and it was useful for predicting 5-FU sensitivity.

Prediction of sensitivity to fluoropyrimidines by metabolic and target enzyme activities in gastric cancer.

BACKGROUND: This study was designed to investigate the role of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and thymidine phosphorylase (TP) in tumor progression and sensitivity to 5-fluorouracil (5-FU). METHODS: A total of 275 tumor samples from 275 patients with gastric cancer were utilized in this study. TS activity was determined in 130 samples by 5-fluorodeoxyuridine monophosphate binding assay. DPD activity was measured in 140 samples by radioenzymatic assay, and TP protein level was determined in 157 samples by an enzyme-linked immunosorbent assay (ELISA) system. These parameters were compared with several clinicopathologic factors and sensitivity to 5-FU determined by in-vitro ATP assay. The antitumor activities of 5-FU, uracil plus tegafur (UFT), and 1M tegafur--0.4 M 5-chloro-2,4-dihydroxypyridine--1 M potassium oxonate (S-1 [TS-1]) were also compared, using three human gastric cancer xenografts in nude mice. RESULTS: There was no correlation between either TS or TP and sensitivity to 5-FU. However, a weak inverse correlation was found between DPD activity and sensitivity to 5-FU. High DPD activity in tumor resulted in poor prognosis, especially in patients who received 5-FU-based adjuvant chemotherapy. Although TP was significantly correlated with depth of tumor invasion and with lymphatic and venous invasions, TP alone had no impact on survival. On the other hand, TS, as well as peritoneal, hepatic, and lymph node metastases, was selected as an independent prognostic factor in gastric cancer. In the animal model, there was no significant difference in antitumor activities among the drugs in a tumor with low DPD activity. However, S-1 showed superior antitumor activity to 5-FU or UFT in tumors with high DPD activity. CONCLUSION: DPD is considered to be a most important predictive factor of 5-FU sensitivity. The use of DPD inhibitory fluoropyrimidines is strongly recommended for tumors with high DPD activity.