药物敏感试验指导胃癌合并恶性腹水的腹腔内化疗

目的用药物敏感试验预测胃癌腹水癌细胞对抗癌药物的敏感性,观察其在指导胃癌合并恶性腹水腹腔内化疗的价值。方法选择47例腹水癌细胞阳性胃癌患者,随机分离19例的腹水癌细胞,用三磷酸腺苷(ATP)法分别检测其对卡铂、泰素、5氟尿嘧啶、顺铂、阿霉素、羟基喜树碱、甲氨蝶呤、丝裂霉素、氮烯咪胺的敏感性,各选择最敏感的1种药物对患者进行腹腔内化疗。观察治疗后腹水完全缓解率、腹水癌细胞转阴率,并与28例顺铂单药腹腔内化疗组比较。结果19例腹水癌细胞对抗癌药物敏感的例数分别为卡铂7例、泰素6例、5氟尿嘧啶6例、顺铂6例、阿霉素5例、羟基喜树碱5例、丝裂霉素5例,对甲氨蝶呤和氮烯咪胺均不敏感。治疗后药物敏感试验组腹水完全缓解率为57.9%,高于顺铂组的28.6%(P<0.05);药物敏感试验组腹水中癌细胞转阴率为68.4%,高于顺铂组的32.1%(P<0.05)。结论用药物敏感试验指导胃癌合并恶性腹水腹腔内个体化化疗,可提高恶性腹水的完全缓解率和腹水中癌细胞转阴率,该治疗方法具有临床实用价值。     

腹腔热灌注化疗联合静脉化疗治疗胃肠道肿瘤合并恶性腹水的临床研究

目的探讨胃肠肿瘤合并恶性腹水的有效治疗方法,对持续热灌注腹腔化疗＋全身化疗进行临床研究和初步疗效评价。方法我们把2005年9月至2007年12月住院的进展期胃肠肿瘤合并恶性腹水的患者34例,分别接受持续热灌注腹腔化疗十全身化疗18例、常规腹腔化疗＋全身化疗16例2种治疗方法,治疗2个周期以上,分析其疗效差异。结果与常规腹腔化疗＋全身化疗相比,持续热灌注腹腔化疗＋全身化疗组病人缓解率、总体疗效有明显差异（P〈0．05）,且在治疗转移性腹水方面有明显的优势（P〈0．05）。对机体的免疫打击小。患者生活质量改善明显,临床受益率高。结论对于进展期胃肠肿瘤合并恶性腹水患者,持续热灌注腹腔化疗＋全身化疗效好,副作用小,可提高患者的生活质量。     

热灌注基础上腹腔内贝伐珠单抗联合化疗治疗恶性腹水的临床观察

目的观察在热灌注的基础上腹腔内注射贝伐珠单抗(安维汀)联合腔内化疗治疗恶性腹水患者的疗效和安全性。方法 57例恶性腹水患者在热灌注的基础上随机分为腔内贝伐珠单抗联合化疗治疗组(治疗组)和腔内单纯化疗治疗组(对照组)。治疗前均先排尽腹水,以43～45.0℃灭菌0.9%生理盐水注入腹腔,持续有效循环40 min以上,排尽灌注液后治疗组在腹腔内注入贝伐珠单抗300 mg和氟尿嘧啶1 g。对照组除不加入贝伐珠单抗外,其余同治疗组。结果在可评价的57例患者中,治疗组总有效率为85.71%,对照组58.62%,P<0.05。全组患者耐受良好,无严重不良反应。结论热灌注基础上腹腔内贝伐珠单抗联合化疗治疗恶性腹水优于腔内单纯化疗且安全可靠。     

Role of VEGF and CD44v6 in differentiating benign from malignant ascites

AIM: To detect the vascular endothelial growth factor (VEGF) and soluble splice variant 6 of CD44 (sCD44v6) levels in ascites and to explore their role in differentiating benign from malignant ascites. METHODS: Cirrhotic ascites (n=36), tuberculosis ascites (n=8) and malignant ascites (n=23) were collected and studied. Concentrations of soluble VEGF and sCD44v6 in various kinds of ascites (n=67) were measured using a sandwich enzyme-linked immunoadsorbent assay. RESULTS: VEGF and sCD44v6 levels in malignant ascites were 640.74+/-264.81 pg/ml and 89.22+/-38.20 ng/ml, respectively, both of which were significantly higher than those in cirrhotic ascites and tuberculous ascites (q=18.98, 11.89 and q=8.92, 5.09; P<0.01). However, the levels of VEGF and sCD44v6 in cirrhotic and tuberculous ascites had no significant difference (q=0.48, 0.75; P>0.05). Furthermore, VEGF levels in malignant ascites in patients with ovarian cancer were higher than those with gastric and colon cancer (q=5.03, 6.79; P<0.01, respectively). But differences of VEGF levels between gastric and colon cancer were not significant (q=1.90, P>0.05). Whereas, sCD44v6 levels in malignant ascites from patients with ovarian, gastric and colon cancer had no significant difference (q=0.06, 0.91, 0.35; P>0.05, respectively). In comparison with cirrhotic and tuberculous ascites, when the upper limit of its VEGF mean levels 119.44 pg/ml (70.90+/-48.54) and sCD44v6 mean levels 63.59 ng/ml (44.42+/-19.17) was taken as the minimum cutoff limit, the sensitivity and specificity of VEGF and sCD44v6 of this assay to the diagnosis of malignant ascites were 91.3%, 90.9% and 73.9%, 88.7% respectively. CONCLUSION: Elevated levels of VEGF and sCD44v6 may be useful in differential diagnosis of benign and malignant ascites.     

Study of hepatic venous wedge and intraperitoneal pressures in cirrhotic patients with refractory ascites treated by dialytic ultrafiltration

Abstract Three cirrhotic patients with intractable ascites and one patient with malignant ascites received dialytic ultrafiltration of ascitic fluid by a haemofilter system for symptomatic relief. The haemofilter removes fluid and substances with a molecular weight less than 50 000 daltons and the concentrated ascitic fluid was reinfused into the pertioneal cavity after ultrafiltration. The changes in intraperitoneal and hepatic venous wedge pressures were studied in these patients. Dialytic ultrafiltration of ascites was associated with a parallel fall of both intraperitoneal and hepatic venous wedge pressures in cirrhotic patients but not in the patient with malignant ascites. The intraperitoneal and hepatic venous wedge pressures remained low for 18 h after completion of dialytic ultrafiltration. The mean arterial pressure and central venous pressure remained unchanged despite rapid removal of ascitic fluid. The interrelationships between the intraperitoneal pressure, hepatic venous wedge pressure, and vascular volume are discussed.     

Detection of type Ⅳ collagenase activity in malignant ascites

AIM: Type Ⅳ collagenase participates in invasion and metastasis of cancer cells. Malignant ascites is a manifestation of advanced malignant disease that is associated with invasion and metastasis of the peritoneal cavity. Thus, it is reasonable to hypothesize that type Ⅳcollagenase is linked to malignant ascites. The purpose of our study was to detect type Ⅳ collagenase activity in malignant ascites so as to provide the scientific basis for clinic diagnosis and treatment of malignant ascites.METHODS: Cirrhotic ascites (n=36), tuberculous ascites (n=8) and malignant ascites (n=23) from patients with gastric cancer (n=6), colon cancer (n=5), ovarian cancer (n=8) and other cancers (n=4), including 2 hepatocellular cancers, 1 pancreatic cancer, 1 primary peritoneal carcinoma were collected by paracentesis. The ascites were made cellfree by centrifugation and stored frozen at -70℃ before determination. Type Ⅳ collagenase activity was determined by gelatin zymography.RESULTS: The activity of matrix metalloproteinases-2 and -9 could not be detected in ascites of hepatic cirrhosis and tuberculous peritonitis but could be detected in 20 and 18 out of 23 malignant ascites respectively. The positive rate of type Ⅳ collagenase (MMP-2, 87.0 % and MMP-9, 78.3 %) was higher than that by routine ascites tests (P<0.01) in malignant ascites. Furthermore, the activity of MMP-2 was higher than that of MMP-9 (P=0.022<0.05).CONCLUSION: Type Ⅳ collagenase is positive in malignant ascites. Detection of type Ⅳ collagenase activity is useful in qualitative diagnosis of ascites. Type Ⅳ collagenase may play an important role in malignant ascites formation.     

Detection of type IV collagenase activity in malignant ascites

AIM: Type IV collagenase participates in invasion and metastasis of cancer cells. Malignant asdtes is a manifestation of advanced malignant disease that is associated with invasion and metastasis of the peritoneal cavity. Thus, it is reasonable to hypothesize that type IV collagenase is linked to malignant ascites. The purpose of our study was to detect type IV collagenase activity in malignant ascites so as to provide the scientific basis for clinic diagnosis and treatment of malignant ascites. METHODS: Cirrhotic ascites (n=36), tuberculous ascites (n=8) and malignant ascites (n=-23) from patients with gastric cancer (n=6), colon cancer (n=5), ovarian cancer (n=8) and other cancers (n=4), including 2 hepatocellular cancers, 1 pancreatic cancer, 1 primary peritoneal carcinoma were collected by paracentesis. The ascites were made cellfree by centrifugation and stored frozen at -70℃ before determination. Type IV collagenase activity was determined by gelatin zymography. RESULTS: The activity of matrix metalloproteinases-2 and -9 could not be detected in ascites of hepatic cirrhosis and tuberculous peritonitis but could be detected in 20 and 18 out of 23 malignant ascites respectively. The positive rate of type IV collagenase (MMP-2, 87.0% and MMP-9, 78.3%) was higher than that by routine ascites tests (P&lt;0.01) in malignant ascites. Furthermore, the activity of MMP-2 was higher than that of MMP-9 (P=0.022&lt;0.05). CONCLUSION: Type IV collagenase is positive in malignant ascites. Detection of type IV collagenase activity is useful in qualitative diagnosis of ascites. Type IV collagenase may play an important role in malignant ascites formation.     

Evaluation and treatment of malignant ascites secondary to gastric cancer

Malignant ascites affects approximately 10% of patients with gastric cancer(gC), and poses significant difficulties for both patients and clinicians. In addition to the dismal general condition of affected patients and the diversity of associated complications such as jaundice and ileus, problems in assessing scattered tumors have hampered the expansion of clinical trials for this condition. However, the accumulation of reported studies is starting to indicate that the weak response to treatment in g C patients with malignant ascites is more relevant to their poor prognosis rather than to the ascites volume at diagnosis. Therefore, precise assessment of initial state of ascites, repetitive evaluation of treatment efficacy, selection of suitable treatment, and swift transition to other treatment options as needed are paramount to maximizing patient benefit. Accurately determining ascites volume is the crucial first step in clinically treating a patient with malignant ascites. Ultrasonography is commonly used to identify the existence of ascites, and several methods have been proposed to estimate ascites volume. Reportedly, the sum of the depth of ascites at five points(named "five-point method") on three panels of computed tomography images is well correlated to the actual ascites volume and/or abdominal girth. This method is already suited to repetitive assessment due to its convenience compared to the conventional volume rendering method. Meanwhile, a new concept, "Clinical Benefit Response in g C(CBR-GC)", was recently introduced to measure the efficacy of chemotherapy for malignant ascites of g C. CBR-GC is a simple and reliable patient-oriented evaluation system based on changes in performance status and ascites, and is expected to become an important clinical endpoint in future clinical trials. The principal of treatment for g C patients with ascites is palliation and prevention of ascites-related symptoms. The treatment options are various, including a standard treatment based on the available guidelines, cytoreductive surgery with hyperthermic intraperitoneal chemotherapy(HIPEC), laparoscopic HIPEC alone, intravenous chemotherapy, intraperitoneal chemotherapy, and molecular targetingtherapy. Although each treatment option is valid,further research is imperative to establish the optima choice for each patient.     

Cancer-derived VEGF plays no role in malignant ascites formation in the mouse

AIM: Vascular endothelial growth factor (VEGF) is a potent mediator of peritoneal fluid accumulation following tumor progression. This study investigated the role of VEGF secreted by cancerous cells in the formation of malignant ascites. METHODS: VEGF expression was eliminated by knockdown in the pancreas cancer cell-line PancO2 using vector-based short-hairpin type RNA interference (RNAi). Malignant ascites formation in the mouse was analyzed by intraperitoneal injection of PancO2 cells expressing VEGF or with expression knockdown. RESULTS: The VEGF knockdown PancO2 cell was successfully established. Knockdown of VEGF did not affect cancer cell proliferation in vitro or in vivo. The volume of ascites following peritoneal expansion of the tumor in VEGF knockdown cells and control cells did not differ statistically in this in vivo study. Moreover, the VEGF concentration in the ascites did not differ statistically. CONCLUSION: Malignant ascites formation might be mediated by VEGF production in noncancerous tissues, such as stromal compartments. An anti-VEGF strategy against malignant ascites could be applied to various tumors regardless of whether they secrete VEGF.     

Retrovirus-mediated in vivo gene therapy using the herpes simplex virus thymidine kinase gene against carcinomatous peritonitis

BACKGROUND: Carcinomatous peritonitis is characterized by massive malignant ascites, while peritoneally disseminated carcinomatosis is characterized by a large number of metastatic solid tumors in the peritoneal cavity. Although both are fatal end-stage manifestations of malignancies derived from the digestive system, the former is usually more serious than the latter due to massive malignant ascites. Although the effectiveness of gene therapy against peritoneally disseminated carcinomatosis has been shown in animal experiments, its effectiveness against carcinomatous peritonitis remains to be examined. METHODS: A carcinomatous peritonitis model was made by inoculating murine hepatocellular carcinoma cells, MH134, into the peritoneal cavity of syngeneic C3H/He mice, resulting in production of massive malignant ascites without development of intraperitoneal solid tumors. Model animals were injected intraperitoneally with retroviruses carrying the herpes simplex virus thymidine kinase (HSV-tk) gene followed by ganciclovir (GCV) treatment. RESULTS: Retrovirus-mediated in vivo gene therapy with the HSV-tk/GCV system was shown to have a significant impact on survival of animals with carcinomatous peritonitis not only at an early stage, but also at an advanced stage. Furthermore, repeated injections of HSV-tk-carrying retroviruses significantly prolonged the survival of animals with carcinomatous peritonitis compared with a single injection protocol. When intraperitoneal administration of recombinant interleukin-2 (IL-2) was added to the HSV-tk/GCV system, levels of IL-1beta and IL-2 in malignant ascites were significantly increased, resulting in significantly reduced ascite volume and prolonged survival. CONCLUSIONS: Our results indicate the feasibility of retrovirus-mediated in vivo gene therapy with the HSV-tk/GCV system plus IL-2 treatment against carcinomatous peritonitis.     

Pharmacokinetic study of paclitaxel in malignant ascites from advanced gastric cancer patients

AIM: To examine the paclitaxel concentrations in plasma and ascites after its intravenous administration in patients with ascites due to peritonitis carcinomatosa resulting from advanced gastric cancer. METHODS: Two patients with ascites due to peritonitis carcinomatosa resulting from gastric cancer were included in this study. The paclitaxel concentrations in plasma and ascites were investigated for 72 h in case 1 and 168 h in case 2 after intravenous administration. RESULTS: The paclitaxel concentration in plasma peaked immediately after administration, followed by rapid decrease below the threshold value of 0.1μmol (85 ng/mL) within 24 h. In contrast, the paclitaxel concentration in ascites increased gradually for 24 h after administration to a level consistent with the level found in plasma. After 24 h the level of paclitaxel in ascites and plasma became similar, with the optimal level being maintained up to 72 h following administration. CONCLUSION: The concentration of paclitaxel in ascites is maintained within the optimal level for the treatment of cancer cells for up to 72 h after intravenous administration. Paclitaxel is a promising drug for the treatment of malignant ascites of gastric cancer.     

VEGF、CEA联合检测在腹水鉴别诊断中的价值

目的 探讨测定腹水中血管内皮生长因子(VEGF)、癌胚抗原(CEA)在良、恶性腹水鉴别诊断中的价值,以及二者联合检测的临床意义.方法 收集腹水标本61例,分为良性腹水组和恶性腹水组,采用ELISA的方法测定VEGF,放免法测定CEA.结果 恶性腹水组VEGF水平明显高于良性腹水组(P＜0.01);恶性腹水组CEA水平明显高于良性腹水组(P＜0.01).卵巢癌引起的腹水中VEGF的水平显著高于肝癌、胃癌、结肠癌组(P＜0.05).不同肿瘤引起的腹水中CEA的含量无明显差异(P＞0.05).VEGF诊断恶性腹水的敏感性为82.1%,特异性为87.9%,准确率为85.2%.CEA诊断恶性腹水的敏感性为64.3%,特异性为90.9%,诊断准确率为78.7%.同时检测患者腹水VEGF和CEA,其诊断恶性腹水的敏感性为92.9%,特异性为84.8%,诊断准确率为88.5%.结论 腹水中VEGF、CEA测定有助于良、恶性腹水的鉴别诊断;恶性腹水中VEGF的含量对恶性腹水的组织来源可能有一定的鉴别诊断作用;联合检测恶性腹水中的VEGF、CEA水平,可明显提高诊断恶性腹水的敏感性.     

Unusual anodic migrating isoamylase differentiates selected malignant from nonmalignant ascites

Ascitic fluid from nine patients with nonmalignant ascites and nine patients with malignant ascites was subjected to isoamylase analysis. Unusual isoamylase bands that migrate to the anode were demonstrated in seven of eight patients with ovarian carcinoma and in one patient with gastric carcinoma. In no case of nonmalignant ascites was anodic isoamylase found, despite the presence of normal amylase in all samples. This is the first report of anodic isoamylase from ascitic fluid in gastric carcinoma and the first series comparing isoamylase patterns in malignant and nonmalignant ascites. Anodic isoamylase on electrophoresis of ascitic fluid may prove to be useful as a tumor marker in differentiating selected malignancies from nonmalignant ascites.     

Treatment of cancerous ascites and radical gastrectomy with intraperitoneal hyperthermic double-distilled water and cis-diaminodichloro-platinum perfusion

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Increase of Cholesterol Level in the Surface Membrane of Lymphoma Cells and Its Inhibitory Effect on Ascites Tumor Development

An ascites form of malignant transformed lymphoma cells were treated in vitro with liposomes of 1:1 lecithin-cholesterol in order to increase the cholesterol level of the cell-surface membranes and thereby to increase the rigidity of the lipid layer. This treatment was found to inhibit the rate of killing by ascites tumor after intraperitoneal inoculation into adult mice of 10(4) and 10(5) treated cells per animal. With 10(3) treated cells per animal, full survival was observed up to 90 days after inoculation, whereas with the same number of untreated cells all infected mice died within 30 days after inoculation. An analogous treatment of the malignant lymphoma cells with liposomes of pure lecithin did not result in any appreciable inhibitory effect on the ascites tumor development in vivo, as initiated by inoculation of 10(5), 10(4), or 10(3) cells per animal.     

Effects of lymphokine-activated killer cells and interleukin-2 on the ascites formation and the survival time of nude mice bearing human ovarian cancer cells

Summary The effect of intraperitoneal instillations of interleukin-2 (IL-2) and/or lympokine-activated killer (LAK) cells on the ascites formation and the survival time was examined using nude mice as a model, with malignant ascites produced by intraperitoneal inoculation of human ovarian cancer cells derived from ascites of a patient with serous cystadenocarcinoma of the ovary. Twenty-eight days after tumor inoculation, all nude mice in the untreated group and in the group treated with spleen cells alone formed ascites. Two of ten nude mice treated with IL-2 alone after tumor inoculation survived without forming ascites during the experimental period. On the other hand, all nude mice treated with LAK cells alone had formed ascites 14 days after tumor inoculation. When LAK cells and IL-2 were combined, five of ten mice survived without forming ascites during the experimental period. The survival time of the group treated with IL-2 alone was significantly prolonged compared to the groups that received medium alone, spleen cells alone and LAK cells alone. When administration of LAK cells was followed by IL-2, the survival time was further prolonged.Supported in part by a grant from the Special Scientific Research Program of the Defense Agency in Japan Offprini requests to: Y. Kikuchi     

Effects of TS-1 on peritoneal dissemination of gastric cancer in nude mice

BACKGROUND/AIMS: We investigated the effects of TS-1 on the survival of nude mice developing peritoneal dissemination of gastric cancer. METHODOLOGY: MKN-45 cells were injected into the peritoneal cavity of nude mice and a model of peritoneal dissemination was developed. TS-1 was administered orally every day from day 1 to day 10 or day 10 to day 19. RESULTS: Survival time of these treatment groups was significantly longer than untreated controls. In a pharmacokinetic study, TS-1 was administered on day 10 and the 5-fluorouracil levels were retained and maintained for a longer time, in the ascites and tumor than in plasma. The area under the concentration curve for 5-FU in the tumor was higher, than in plasma or ascites. CONCLUSIONS: TS-1 could be effective in treating peritoneal dissemination of gastric cancer, due to the supply of 5-fluorouracil in the tumor by systemic and intraperitoneal circulation.     

两种方案治疗晚期胃癌恶性腹水的临床研究

目的观察比较植入用缓释氟尿嘧啶腹腔给药和腹腔内热灌注氟尿嘧啶化疗治疗晚期胃癌恶性腹水患者的近期疗效、临床获益反应及毒副反应。方法选择30例经病理组织学确诊的晚期胃腺癌腹水患者,随机分为两组,每组15例。植入用缓释氟尿嘧啶腹腔给药组:将按500mg/m2注入植入用缓释氟尿嘧啶,第14天再重复给药;热灌注化疗组:将5-FU1g溶于10%葡萄糖500ml中,加热至45℃,注入腹腔。第7天和第14天再重复给药。2周期治疗后评价疗效。结果植入用缓释氟尿嘧啶给药组和腹腔热灌注组总有效率分别为66.7%和64.2%,两组比较无显著性差异(P0.05)。临床获益率分别为73.37%(11/15)和71.4%(10/14),两者比较无统计学差异(P0.05)。血液系统毒性两组比较无统计学意义(P0.05)。非血液系统毒性两组的腹泻、肾功能损害、周围神经炎、口腔黏膜炎的发生率无统计学差异(P0.05);恶心/呕吐、肝功能损害的发生率有统计学差异(P0.05)。结论两种方案治疗晚期胃癌恶性腹水疗效确切,均能显著改善患者的生活质量,两组对比无明显差异。毒副作用可以耐受,安全性好,但恶心/呕吐和肝功能损害的发生率在植入用缓释氟尿嘧啶腹腔给药组比腹腔内热灌注化疗组低。     

Clinical significance of CT-defined minimal ascites in patients with gastric cancer

AIM: To study the clinical significance of minimal ascites, which was only defined by the CT and whose nature was not determined preoperatively, in the relationship with the peritoneal carcinomatosis. METHODS: The medical records and the dynamic CT films of 118 patients with gastric cancer were reviewed. Factors associated with peritoneal carcinomatosis were analyzed in 40 patients who had CT-defined ascites of which the nature was surgically confirmed. RESULTS: Only 12.5-25% of the CT-defined minimal ascites, whose volume was estimated to be less than 50 mL, were associated with peritoneal carcinomatosis. When the estimated CT-defined ascitic volume was 50 mL or more, peritoneal carcinomatosis was identified in 75-100%. When CT-defined lymph node enlargements were not found beyond the regional gastric area, perigastric invasions were not suspected, and the size of tumor was less than 3 cm, peritoneal carcinomatosis seemed significantly less accompanied at the univariate analysis. However, except for the minimal volume of CT-defined ascites in comparison with the mild or more, other factors were not confirmed multivariately. CONCLUSION: In the patients with gastric cancer, CT-defined minimal ascites alone is rarely associated with peritoneal carcinomatosis, if it does not accompany other signs suggestive of malignant seeding. Therefore, consideration of active curative resection should not be hesitated, if CT-defined minimal ascites is the only delusive sign.