洛沙坦对人类卵巢癌裸鼠模型腹水的抑制作用

目的研究洛沙坦是否可以通过改善淋巴引流抑制卵巢癌裸鼠模型腹水的形成。方法8周龄雌性裸鼠,随机分3组,每组24只鼠。空白对照组不给予任何处理。另两组给予原位移植SKOV3 IP1-Gluc卵巢癌细胞,根据外周血Gluc水平监测腹腔内肿瘤生长情况,达到1×106相对光单位时入组。对照组为卵巢癌无治疗组,22只鼠入组,卵巢癌洛沙坦治疗组23只鼠入组。注射肿瘤后第28天处死,取出腹腔内肿瘤及膈肌,抽吸腹水测量。免疫组化方法检测sirius red、αSMA、Collagen 1,了解细胞外基质胶原蛋白及纤维母细胞含量。用淋巴管造影方法观察膈肌淋巴管形态,腹腔内注射荧光微球观察膈肌及纵膈淋巴结荧光微球分布情况,了解膈肌淋巴管引流功能。结果洛沙坦治疗可以明显减少卵巢癌裸鼠模型腹水形成(P<0.05)。洛沙坦治疗组肿瘤内胶原蛋白含量(sirius red阳性区域,Collagen 1含量)及纤维母细胞(αSMA阳性区域)均明显减少(均P<0.05)。与正常裸鼠比较,卵巢癌无治疗组裸鼠膈肌淋巴管扩张,结构紊乱;洛沙坦治疗组裸鼠膈肌淋巴管形态和分布情况改善,趋于正常化,而淋巴管引流功能也得到明显改善。结论洛沙坦可以抑制细胞外基质形成,减少卵巢癌细胞外基质含量,降低固态压力,解除对淋巴管的压迫作用,改善淋巴引流,减少腹水形成,使临床获益。     

Clinical experience of Pseudo-Meigs＇ Syndrome due to colon cancer

We report a rare case of Pseudo-Meigs＇ Syndrome caused by ovarian metastasis from sigmoid colon cancer, which was accompanied by peritoneal dissemination. A 58-year-old female patient presented with massive right pleural effusion, ascites and a huge pelvic mass. Under the diagnosis of an advanced ovarian tumor, bilateral oophorectomy was performed and sigmoidectomy was also carried out after intraoperative diagnosis of peritoneal dissemination involving the sigmoid colon. How- ever, immunohistochemical staining revealed that the ovarian lesions were metastasis from the primary advanced colon cancer. Postoperatively, ascites and pleural effusion subsided, and the diagnosis of Pseudo-Meigs＇ Syndrome due to a metastatic ovarian tumor from colon cancer was determined. The patient is now undergoing a regimen of chemotherapy for colon cancer without recurrence of ascites or hydrothorax 10 mo after the surgery. Pseudo-Meigs＇ Syndrome due to a metastaticovarian tumor from colon cancer is rare but clinically important because long-term alleviation of symptoms can be achieved by surgical resection. This case report suggests that selected patients, even with peritoneal dissemination, may obtain palliation from surgical resection of metastatic ovarian tumors.     

Pseudo-Meigs&rsquo; syndrome secondary to metachronous ovarian metastases from transverse colon cancer

Pseudo-Meigs’ syndrome associated with colorectal cancer is extremely rare. We report here a case of pseudo-Meigs’ syndrome secondary to metachronous ovarian metastases from colon cancer. A 65-year-old female with a history of surgery for transverse colon cancer and peritoneal dissemination suffered from metachronous ovarian metastases during treatment with systemic chemotherapy. At first, neither ascites nor pleural effusion was observed, but she later complained of progressive abdominal distention and dyspnea caused by rapidly increasing ascites and pleural effusion and rapidly enlarging ovarian metastases. Abdominocenteses were repeated, and cytological examinations of the fluids were all negative for malignant cells. We suspected pseudo-Meigs’ syndrome, and bilateral oophorectomies were performed after thorough informed consent. The patient’s postoperative condition improved rapidly after surgery. We conclude that pseudo-Meigs’ syndrome should be included in the differential diagnosis of massive or rapidly increasing ascites and pleural effusion associated with large or rapidly enlarging ovarian tumors.     

Hepatobiliary and Pancreatic: Rapid growing cystic ovarian metastasis from pancreatic cancer

Pancreatic cancer rarely develops cystic ovarian metastasis. We present a 63‐year‐old female patient with unresectable pancreas head cancer. Seven months after the introduction of the chemoradiotherapy, a giant intrapelvic cystic tumor with rapid growth was found. The tumor was resected because the patient complained of severe bloating and no other new metastatic sites could be identified. Postoperative pathological examination diagnosed it as an ovarian metastasis from the pancreas cancer.     

Lymphatic Vessels in Colorectal Cancer and Their Relation With Inflammatory Infiltrate

PURPOSE: The aim of this study was to determine why colorectal tumors confined to submucosa rarely metastasize. Under normal conditions, the submucosa contains many large lymphatic vessels with thin walls that would presumably favor the spread of cancer cells through the lymphatic system. METHODS: Specimens of colorectal cancer tissue, the border between tumor and normal tissue, and normal tissue were obtained from patients undergoing radical resection of colorectal cancer. The material was embedded in methacrylate resin for light microscopy and Epon® for transmission electron microscopy examination. Light microscopy observations were routinely performed on serial sections. RESULTS: No lymphatic vessels were ever found in the tumor mass. The border area contained peritumoral inflammatory infiltrate of variable thickness. Where submucosal lymphatic vessels came into contact with peritumoral inflammatory infiltrate, they were profoundly altered: their endothelium was fragmented, and their walls were disrupted. These altered lymphatic vessels were almost always accompanied by mast cells, which were observed in the process of degranulating toward the lymphatic endothelium. No such alterations were detected in blood vessels. CONCLUSION: Our results suggest that mast cells, probably influenced by inflammatory infiltrate and/or colorectal cancer cells, destroy lymphatic vessels, which prevents cancer cells from spreading through the lymphatic system.     

Chemotherapy for murine ovarian cancer: a rationale for ip therapy with adriamycin.

The metastatic spread of a trnasplantable murine ovarian cancer is similar to the spread of ovarian cancer in patients with advanced disease, making it a useful model to investigate novel experimental therapies. The ip inoculation of 10(6) tumor cells into C3HeB/FeJ mice leads to the formation of ascites, sub-diaphragmatic tumor deposits, intra-abdominal tumors, and death within 25 days. Adriamycin (ADR) was found to be an active agent against this murine ovarian cancer. The effects of ADR were dependent upon the route of administration. A single ip LD10 dose of ADR (5 mg/kg) administered 2 days after inoculation with 10(6) tumor cells produced long-term survival (greater than 60 days) in 70% of the mice. An iv LD10 dose had no effect on survival. The survival advantage of ip ADR (compared to the iv route) was found to be related to: (a) a greater suppression of DNA synthesis in the tumor; (b) a rapid penetration of ADR into the nuclei of ascites tumor cells and into sub-diaphragmatic tumor deposits; and (c) significantly higher levels of ADR in tumor cells following ip administration. The ip route may also be less cardiotoxic since the peak levels after an iv dose were three times greater than after an equal ip dose. If local toxicity does not prove to be a major problem, then ip ADR may be a useful mode of therapy in patients with intra-abdominal tumors.     

Pseudo-Meigs syndrome: particular management of ovarian metastases in colorectal cancer

Ascites and/or pleural effusion with ovarian metastases in colorectal cancer are usually related to peritoneal carcinomatosis. Pseudo-Meigs syndrome is a characterized by non-malignant ascites and/or pleural effusion caused by pelvic tumors other than solid benign ovarian tumors. We treated two patients who developed this syndrome in a context of colorectal cancer. After ovarian metastasis resection, ascites and pleural diffusion disappeared. In the presence of acellular ascites with ovarian metastases from colorectal cancer, diagnosis of pseudo-Meigs syndrome may allow surgical treatment with curative intent.     

Pseudo-Meigs' syndrome secondary to metachronous ovarian metastases from transverse colon cancer

Pseudo-Meigs' syndrome associated with colorectal cancer is extremely rare. We report here a case of pseudo-Meigs' syndrome secondary to metachronous ovarian metastases from colon cancer. A 65-year-old female with a history of surgery for transverse colon cancer and peritoneal dissemination suffered from metachronous ovarian metastases during treatment with systemic chemotherapy. At first, neither ascites nor pleural effusion was observed, but she later complained of progressive abdominal distention and dyspnea caused by rapidly increasing ascites and pleural effusion and rapidly enlarging ovarian metastases. Abdominocenteses were repeated, and cytological examinations of the fluids were all negative for malignant cells. We suspected pseudo-Meigs' syndrome, and bilateral oophorectomies were performed after thorough informed consent. The patient's postoperative condition improved rapidly after surgery. We conclude that pseudo-Meigs' syndrome should be included in the differential diagnosis of massive or rapidly increasing ascites and pleural effusion associated with large or rapidly enlarging ovarian tumors.     

High IL-6 levels in ascitic fluid correlate with reactive thrombocytosis in patients with epithelial ovarian cancer

Summary. Non-haematopoietic malignancies are commonly associated with thrombocytosis. The aetiology of tumour-associated thrombocytosis is still unclear but may be related to tumour-derived thrombopoietin-like factors. Epithelial ovarian tumour cells have been shown to release IL-6 in vitro and high IL-6 levels have been identified in ascites of patients with ovarian cancer. Since IL-6 is a potent stimulator of megakaryocytopoiesis we examined IL-6 production at the tumour site and its relationship to serum IL-6 levels and circulating platelet counts in patients with ovarian cancer. Forty patients undergoing exploratory laparotomy for epithelial ovarian cancer [stage I + II: 6 (15%); stage III: 25 (62.5%); stage IV: 9 (22.5%)] and 24 women with benign ovarian conditions were evaluated. Sera were available from 39 cases with ovarian cancer and from 19 cases with benign ovarian tumours. Ascites was obtained from 35 patients with ovarian cancer. IL-6 activity in serum and ascitic fluid was determined by the standard B9 proliferation assay (detection level: 1 pg/ml). IL-6 bioactivity was detectable in 22 (56%) sera from patients with ovarian cancer, but in only five (26%) of the serum samples obtained from benign cases (P < 0.001). Serum IL-6 levels in patients with ovarian cancer were significantly higher (median 3 pg/ml; range < 1 to 1221 pg/ml) than in patients with benign ovarian conditions (median 0 pg/ml; range < 1 to 4 pg/ml) (P < 0.001). However, much higher concentrations of IL-6 were measured in malignant ascites specimens (median 22 100 pg/ml; range < 1 to 182 600 pg/ml). IL-6 bioactivity in serum and ascites samples was completely inhibited by a neutralizing goat antihuman IL-6 antiserum. Thrombocytosis (platelet counts > 400 × 10⁹/l) occurred in 25 (62.5%) of the 40 patients with ovarian cancer, but in only two (8%) of the 24 cases with benign ovarian tumours. In eight (20%) cases with malignant disease platelet counts ranged between 600 × 10⁹/l and 1060 × 10⁹/l. IL-6 bioactivity in ascitic fluid correlated significantly with circulating platelet counts (r = 0.5916; P < 0.001). Maximum IL-6 bioactivity in ascites and highest platelet counts occurred in patients with undifferentiated ovarian adenocarcinoma or advanced disease. In conclusion, these observations strongly suggest a role for IL-6 in the development of tumour-associated thrombocytosis.     

Pancreatic cancer: who benefits from curative resection?

Surgical resection is the only chance for cure of pancreatic cancer. Unfortunately, the majority of patients have grossly unresectable disease. Patients with stage I or II disease according to the criteria of the International Union Against Cancer (UICC) should be considered for potentially curative surgery. The goal of surgery is to remove the entire tumour with no residual disease (oncological R0 resection), which requires extensive resection of the surrounding tissues. Even if lymph nodes are histologically free of disease, molecular biological techniques reveal infiltration with cancer cells in 50% of cases. Therefore, extensive local resection combined with radical resection of lymphatic tissue, including lymph nodes around the head of the pancreas, retroperitoneal tissue and neural plexus around the great vessels, affords a longer median survival time than standard resection alone. Even patients with UICC stage III disease can undergo aggressive surgical treatment, but their chances for long term survival are low. Some patients develop severe diarrhea after circumferential removal of nerve tissue around the superior mesenteric artery. Adjuvant radiochemotherapy also provides a modest prolongation of survival. Despite these advances, the prognosis for pancreatic cancer is still poor, and spread of tumour within the peritoneum and to the liver is common postoperatively.     

Surveillance of patients after initial treatment of ovarian cancer

The surveillance of ovarian cancer patients after initial treatment is a challenging question in clinical practice. Serum CA 125 assay, physical examination, and imaging examinations have been employed with different time schedules for the follow-up of asymptomatic patients. Rising serum CA 125 levels may precede the clinical detection of relapse in 56-94% of cases with a median lead time of 3-5 months. An ongoing randomised phase III European trial is comparing the benefits of early administration of chemotherapy based on serum CA 125 assay alone versus delaying treatment until clinical or radiological detection of recurrent disease. Physical examination, with or without ultrasound, is very useful for the surveillance of these patients, since approximately 25-50% of relapses involve the pelvis. Additional radiological imaging techniques, such as computed tomography (CT) and magnetic resonance imaging (MRI), are usually performed in asymptomatic patients with rising CA 125 levels as well as in patients with suspicious symptoms or signs. Integrated positron emission tomography (PET) and CT scanners (PET/CT) can identify recurrent disease in tissues that appear normal at CT imaging as well as metastatic lesions intimately associated with the bowel wall that are difficult to detect with CT or MRI, so that in most series PET/CT has a higher diagnostic reliability than that of conventional imaging techniques. Moreover, PET/CT can disclose unusual supra-diaphragmatic spreading of the disease and may be very helpful for treatment planning, especially for the selection of patients suitable for secondary surgical cytoreduction. A prospective, randomised trial of therapeutic interventions based on stratification by PET/CT disease status could elucidate the real impact of this diagnostic procedure in the management of patients with recurrent ovarian cancer.     

Differential role of gonadotropin-releasing hormone on human ovarian epithelial cancer cell invasion

Ovarian cancer is the most lethal of all gynecological cancers. Most deaths from ovarian cancer are due to widespread intraperitoneal metastases and malignant ascites. However, mechanisms of invasion in ovarian cancer remain poorly understood. In this study, we examined the effects of gonadotropin-releasing hormone (GnRH)-I (the classical mammalian GnRH), GnRH-II (a second form of GnRH), and GnRH receptor on invasion using two human ovarian carcinoma cell lines, OVCAR-3 and SKOV-3. Here we demonstrated that in OVCAR-3, GnRH-I and GnRH-II promoted cell invasion, whereas in SKOV-3, GnRH-I and GnRH-II inhibited cell invasion. Transfection of small interfering RNA to abrogate the gene expression of GnRH receptor reversed GnRH-I and GnRH-II-mediated invasion activities, suggesting that the same receptor, type I GnRH receptor, is essential for the effects of GnRH-I and GnRH-II in both OVCAR-3 and SKOV-3. Treatment of SKOV-3 cells with GnRH-I or GnRH-II resulted in a decrease in matrix metalloproteinase 2 but an increase in tissue inhibitor of metalloproteinase 2 secretions. In addition, we found that GnRH-I and GnRH-II interfered with activation of the phosphatidylinositol-3-kinase/AKT pathway that is well documented to stimulate proteolysis and invasion of ovarian cancer cells. Taken together, these observations suggest that GnRH-I and GnRH-II play key regulatory roles in ovarian tumor cell invasion and extracellular matrix degradation.     

Presence of bone marrow-derived circulating progenitor endothelial cells in the newly formed lymphatic vessels

Bone marrow (BM)-derived circulating endothelial precursor cells (CEPCs) have been reported to incorporate into newly formed blood vessels under physiologic and pathologic conditions. However, it is unknown if CEPCs contribute to lymphangiogenesis. Here we show that in a corneal lymphangiogenesis model of irradiated mice reconstituted with enhanced green fluorescent protein (EGFP)-positive donor bone marrow cells, CEPCs are present in the newly formed lymphatic vessels. Depletion of bone marrow cells by irradiation remarkably suppressed lymphangiogenesis in corneas implanted with fibroblast growth factor-2 (FGF-2). Further, transplantation of isolated EGFP-positive/vascular endothelial growth factor receptor-3-positive (EGFP+/VEGFR-3+) or EGFP+/VEGFR-2+ cell populations resulted in incorporation of EGFP+ cells into the newly formed lymphatic vessels. EGFP+/CEPCs were also present in peritumoral lymphatic vessels of a fibrosarcoma. These data suggest that BM-derived CEPCs may play a role in "lymphvasculogenesis."     

Resection of paraaortic lymph node metastasis of colon cancer with graft replacement

The metastasis sites of colon cancer are the liver, lungs, bones, peritoneum, and lymph nodes. Lymph node recurrences, however, are seldom resected metachronously. We report here a case of en-bloc resection of paraaortic lymph node recurrence together with the invaded abdominal aorta, left kidney and ureter 4 years after curative resection of sigmoid colon cancer. Combined resection of the metastatic lymph nodes and the abdominal aorta would be an even more radical procedure and treatment for cancer because of lymphatic spread around the aorta. The slow growth of the cancer might justify this aggressive resection. This is the first report of resection of late paraaortic lymph node metastasis and simultaneous abdominal aortic graft replacement.     

Structural changes of the diaphragmatic peritoneum in patients with schistosomal hepatic fibrosis: its relation to ascites

The histopathologic changes of the peritoneum of the hemidiaphragm were studied in 30 patients with schistosomal liver disease and compared with ten control subjects. The diaphragmatic peritoneum of patients with ascites was markedly thickened with infiltration of inflammatory cells and collagen bundles resembling the interstitial changes of peripheral lymphedema. Obliteration of diaphragmatic lymphatic stomata with restricted lymph flow as well as excess lymph formation from portal hypertension are both major factors in the magnitude and intractability of ascites associated with schistosomal hepatic fibrosis.     

Hepatic resection for metachronous metastases from ovarian carcinoma

Recently, several authors have reported that optimal primary cytoreduction of both hepatic and extrahepatic disease is not only feasible but improves survival. However, the role of hepatic resection in combination with secondary cytoreduction for epithelial ovarian cancer is unclear. Patients with recurrent ovarian cancer and metachronous intrahepatic metastases are often evaluated by a multidisciplinary team at the Mayo Clinic comprising pelvic and hepatobiliary surgeons for consideration of cytoreductive surgery. The purpose of this report is to update the outcome of cytoreductive surgery including hepatic resection for patients with metastatic ovarian carcinoma.     

Gonadotropins and ovarian cancer

Ovarian epithelial cancer (OEC) accounts for 90% of all ovarian cancers and is the leading cause of death from gynecological cancers in North America and Europe. Despite its clinical significance, the factors that regulate the development and progression of ovarian cancer are among the least understood of all major human malignancies. The two gonadotropins, FSH and LH, are key regulators of ovarian cell functions, and the potential role of gonadotropins in the pathogenesis of ovarian cancer is suggested. Ovarian carcinomas have been found to express specific receptors for gonadotropins. The presence of gonadotropins in ovarian tumor fluid suggests the importance of these factors in the transformation and progression of ovarian cancers as well as being prognostic indicators. Functionally, there is evidence showing a direct action of gonadotropins on ovarian tumor cell growth. This review summarizes the key findings and recent advances in our understanding of these peptide hormones in ovarian cancer development and progression and their role in potential future cancer therapy. We will first discuss the supporting evidence and controversies in the "gonadotropin theory" and the use of animal models for exploring the involvement of gonadotropins in the etiology of ovarian cancer. The role of gonadotropins in regulating the proliferation, survival, and metastasis of OEC is next summarized. Relevant data from ovarian surface epithelium, which is widely believed to be the precursor of OEC, are also described. Finally, we will discuss the clinical applications of gonadotropins in ovarian cancer and the recent progress in drug development.     

Breast cancer as a systemic disease: a view of metastasis

Breast cancer is now the most frequently diagnosed cancer and leading cause of cancer death in women worldwide. Strategies targeting the primary tumour have markedly improved, but systemic treatments to prevent metastasis are less effective; metastatic disease remains the underlying cause of death in the majority of patients with breast cancer who succumb to their disease. The long latency period between initial treatment and eventual recurrence in some patients suggests that a tumour may both alter and respond to the host systemic environment to facilitate and sustain disease progression. Results from studies in animal models suggest that specific subtypes of breast cancer may direct metastasis through recruitment and activation of haematopoietic cells. In this review, we focus on data implicating breast cancer as a systemic disease.     

卵巢癌组织中M2型巨噬细胞密度变化及其与卵巢癌预后的关系

目的观察卵巢癌组织中M2型巨噬细胞（M2）的密度变化,并探讨其与卵巢癌预后的关系。方法用CD68标记巨噬细胞M,φCD163标记M2,采用免疫组化法检测42例卵巢癌组织（卵巢癌组）和30例卵巢良性肿瘤组织（对照组）中的Mφ、M2密度。观察Mφ、M2密度及M2细胞百分比与卵巢癌临床病理参数的关系。结果卵巢癌组Mφ密度为（74.4±7.2）/HP,M2密度为（63.8±8.2）/HP,对照组分别为（18.4±4.2）/HP、（14.4±3.6）/HP,两组相比,P均〈0.01。晚期（Ⅲ＋Ⅳ期）卵巢癌组织M2细胞百分比为79.2%±18.2%,高于早期（Ⅰ＋Ⅱ期）卵巢癌组织的48.2%±12.1%（P〈0.05）。M2密度、M2细胞百分比与卵巢癌FIGO分期、淋巴结转移有关（P均〈0.01）。M2高密度组生存时间为（42.77±4.35）个月,低于低密度组的（61.70±3.22）个月（P〈0.01）,M2细胞高百分比组生存时间为（51.32±3.25）个月,低于低百分比组的（65.78±4.19）个月（P〈0.01）。M2细胞百分比与卵巢癌预后有关（P〈0.05）。结论人卵巢肿瘤肿瘤组织中存在Mφ向M2的分化;M2细胞比例与卵巢癌预后有关。