Alpha-fetoprotein subfractions in amniotic fluid identified by a modification of the method of concanavalin A, lentil lectin or phytohemagglutinin-E affinity crossed-line immunoelectrophoresis

Using a modified method of concanavalin A (Con A), lentil lectin (LCH) or phytohemagglutinin-E (PHA-E) affinity crossed-line immunoelectrophoresis, alpha-fetoprotein (AFP) subfractions were studied in 33 samples of human amniotic fluid obtained between 41 and 287 days of gestation. Fetal tissues (yolk sac, liver, stomach and small intestine) obtained from a fetus of 68 days' gestation were incubated for 24 hours and AFP subfractions in the culture fluid examined. AFP in control amniotic fluids yielded two subfractions (types a and b) with Con A, three subfractions (types A, B and C) with LCH, and four subfractions (types W, X, Y and Z) with PHA-E. Serial changes of AFP subfractions in the amniotic fluid, as well as in the incubation study, indicated that the yolk sac and the gastrointestinal tract were responsible for the production of the Con A non-reactive subfraction (type b), the LCH weakly-reactive subfraction (type B) and the PHA-E reactive subfraction (types W and X), at an early stage of gestation. The Con A reactive subfraction (type a), LCH reactive subfraction (type A), PHA-E weakly-reactive subfraction (type Y) and PHA-E non-reactive subfraction (type Z) were assumed to be produced mainly by yolk sac, liver or gastrointestinal tract. We also found that the LCH non-reactive subfraction (type C) was synthesized either by liver or by the gastrointestinal tract at an early stage of gestation. At term, type a of Con A, type C of LCH and types Y and Z of PHA-E were the main subfractions in amniotic fluid, assumed to be produced by the fetal liver.     

Analysis of lectin affinity immunoelectrophoretic profiles of serum alpha-fetoprotein from patients with yolk sac tumors and carcinomas of the gastrointestinal tract: correlations with molecular structures

Profiles of concanavalin A (Con A) and lentil agglutinin (LCH) affinity immunoelectrophoresis were compared for serum alpha-fetoprotein (AFP) from patients with yolk sac tumors and carcinomas of the gastrointestinal tract, in order to find some correlations between peaks of AFP subfractions detectable by two different lectins, and to investigate whether or not it is possible to prove that the binding of AFP to LCH is weakened to some extent if a fucosylated sugar chain has, in addition, a bisect N-acetylglucosamine (GlcNAc) attached to the beta-linked mannose. The results obtained with our improved techniques tend to indicate that a Con A-reactive AFP subfraction (peak a) corresponds to an LCH strongly reactive AFP (peak A), while a Con A-nonreactive AFP (peak b) corresponds to an LCH weakly reactive AFP (peak B). the authors consider the present data sufficient to support the above explanation.     

Three cases of effective hepatic arterial infusion with OK-432, mitomycin C and 5-fluorouracil in liver metastasis from gastric cancer

A combined therapy with OK-432. mitomycin C (MMC) and 5-fluorouracil (5-FU) by administration through hepatic arterial infusion was performed in three patients with liver metastasis from gastric cancers. A catheter was introduced into hepatic artery by laparotomy. The dosage was 250 mg/day for 5-FU continuously, 10 mg/week for MMC and 5 KE/week for OK-432, respectively. Two cases with advanced gastric cancer and synchronous hepatic metastasis were treated by hepatic arterial infusion after surgical removal of primary lesion. Metastatic lesion in liver was completely eliminated. Another case with metastatic liver tumor from gastric cancer was also treated by the same protocol. The reduction rate of this case was 70% by CT scan. These results suggested that combined therapy with OK-432, MMC and 5-FU by hepatic arterial infusion is a good modality for liver metastases from gastric cancers.     

原发性与转移性肝癌患者血清学检测的临床应用

  目的  探讨血清学检测指标在鉴别原发性与转移性肝癌时的临床应用价值。  方法  分别测定125例原发性肝癌患者组,135例转移性肝癌患者组及135例无肝转移的癌症患者组血清中ALT、AST、ALP、TBIL、DBIL、GGT、CHE、5'-NT、AFP、CEA、CA199的水平,采用方差析和Scheffe检验进行统计学分析。应用ROC曲线分析AFP、CEA和CA199对原发性肝癌及转移性肝癌的诊断价值。  结果  1）原发性肝癌组与转移性肝癌组之间血清AST、ALP、GGT、5'-NT、AFP及CEA水平差异有统计学意义（P < 0.05）。2）根据原发性肝癌组和转移性肝癌组AFP、CEA和CA199的ROC曲线下面积（Area under the ROC curve,AUC）判断,AFP对原发性肝癌诊断有一定的准确性,CEA、CA199对鉴别原发性肝癌与转移性肝癌有一定诊断价值。  结论  检测血清AST、GGT、5'-NT、AFP、CEA、CA199水平可对恶性肿瘤是否发生肝转移进行初步诊断,亦可对原发性肝癌与转移性肝癌的鉴别诊断提供佐证。      

High frequency of c-Met expression in gastric cancers producing alpha- fetoprotein

Gastric cancers producing alpha-fetoprotein (AFP) have a poor prognosis and a high incidence of liver metastasis. Hepatocyte growth factor (HGF) and its receptor, c-Met, are known to induce mitosis and cell movement and to promote tumor progression. In the present study, c-Met and HGF expression in AFP-producing gastric cancer was compared with those gastric cancers that do not produce AFP. Twenty-six patients with AFP-producing gastric cancers [AFP(+)] and 26 patients stage-matched gastric cancers without AFP production [AFP(-)] were evaluated for c-Met and HGF expression and proliferating cell nuclear antigen-labelling index using immunohistochemical analysis. A higher frequency of c-Met expression was observed in the AFP(+) group than in the AFP(-) group (p < 0.01). A higher expression of c-Met might be one explanation for the poorer prognosis of AFP-producing gastric cancers.     

Antitumor effect of the angiogenesis inhibitor TNP-470 on human digestive organ malignancy

The antitumor and antimetastatic effects of TNP-470, an angiogenesis inhibitor, on human gastrointestinal tumors xenotransplanted into nude mice were investigated. When two gastric cancer (MT-2 and MT-5) and two colon cancer (TK-4 and TK-13) xenografts are transplanted orthotopically into nude mice, liver metastasis develops 6 weeks after transplantation. TNP-470 30 mg/kg had a significant inhibitory effect on primary tumor growth of gastric cancers when given on alternate days from 7 days after transplantation. However, when given from 10 days or 14 days after transplantation, no inhibitory effect on the growth of any tumor xenograft was observed. In contrast, liver metastasis of each xenograft type was inhibited significantly by TNP-470. The effect of TNP-470 on prognosis was investigated using a hepatic metastatic model of rat hepatoma. Although all untreated rats that received AH-130 cell implants died within one month of massive hepatic metastasis, >50% of rats treated with TNP-470 survived for 4 months. The number of apoptotic cells in hepatic metastatic foci was significantly increased by TNP-470 administration. These results suggest that TNP-470 may provide a new approach to the treatment of digestive organ malignancies.     

AFP阳性胃癌的研究进展

AFP阳性胃癌(alpha-fetoprotein-producing gastric carcinoma,APGC)发病率文献统计占胃癌的5·1%~15%。其临床病理学特征与普通型胃癌有较大不同,更易发生肝转移和早期淋巴道转移,具有明显的侵袭性和恶性生物学行为,被认为是一个独立的预后因素。了解APGC高侵袭性的分子作用机制对于今后制定出新的诊断治疗方案有着重要的意义。然而,APF的升高与APGC的高侵袭性之间的关系尚不明确。APGC患者血清及肿瘤组织中AFP与血管内皮细胞生长因子(vascular endothelialgrowthfactor,VEGF)和肝细胞生长因子受体C(c-Met)等与肿瘤侵袭性密切相关的基因表达水平呈正相关,而APGC中AT mo-tif binding factor1(ATBF1)等抑癌基因表达水平低于普通型胃癌。这些基因和其他目前尚未明确的因素可能共同参与了APGC高侵袭性的分子作用机制。APGC治疗首选胃癌根治术,无法切除的转移灶,应积极给予化疗等综合措施治疗,但仍有待发现更新的APGC综合治疗模式。总结了APGC的临床病理、分子生物学特点及治疗等方面的进展。     

血清甲胎蛋白阳性胃癌患者临床病理特征与预后关系的研究

  目的  探讨血清AFP阳性胃癌（alpha-fetoprotein producing gastric cancer ,AFPGC）与普通型胃癌的差异以及其临床病理特征和预后的关系。  方法  回顾性分析2013年1月至2018年12月在中国人民解放军联勤保障部队第九四〇医院行胃癌手术的患者1 321例,经筛选纳入研究1 144例,分为血清AFP阳性组（53例）与血清AFP阴性组（1 091例）。  结果  AFPGC占同期胃癌患者的4.6%,AFPGC与血清AFP阴性胃癌1、3、5年累计生存率分别为64.2%与92.2%、20.8%与45.1%、13.2%与25.7%,两者术前血清AFP、肿瘤大小、免疫组织化学HER2、肿瘤部位、浸润深度、淋巴结转移、临床分期、脉管侵犯、手术方式、术后肝转移相比,均差异具有统计学意义（P<0.05）。AFPGC单因素以及Cox多因素生存分析显示:临床分期、脉管侵犯、手术方式、术后肝转移以及术后血清AFP再次升高是影响AFPGC预后的危险因素。  结论  AFPGC是一种特殊性的胃癌,具有临床分期晚、易发生术后肝转移和脉管侵犯且预后差,AFPGC患者即使肿瘤原发灶被切除后,仍有较高的肝转移风险,且术前血清AFP水平与患者预后无关,而术后监测血清AFP水平可及时发现肿瘤复发及术后肝转移,此外,早期行胃癌根治术有助于改善患者预后。      

Immunohistochemical Type Distinction of a-Fetoprotein in Various a-Fetoprotein-secreting Tumors

In order to clarify the histogenesis of a -fetoprotein(AFP)-secreting tumor tissues, formalin-fixed, paraffin-embedded serial sections of 148 tumors in various organs were examined by the peroxidase-antiperoxidase method for AFP, and paradoxical concanavalin A staining. Yolk sac-type AFP was found in yolk sac tumors, embryonal carcinomas, solid teratomas, (yolk sac) endodermal cell tumors, adenocarcinomas (stomach, ovary or lung) and metastatic liver cancers. Hepatic-type AFP was demonstrated in hepatocellular carcinomas, hepatoblastomas, solid teratomas and a stomach cancer. Yolk sac-type AFP was observed in the neighboring liver cells of metastatic liver cancers without relation to the type of AFP in primary cancers. The results from serum analyses of preoperative tumor-bearing patients (68 cases) were coincident with those from immunohistochemical stainings.     

血清CEA、SF、AFP联合检测对肝转移癌的诊断价值

目的　探讨肝转移癌患者血清中CEA、SF、AFP检测及临床意义。方法　检测 134例肝转移癌和183例原发性肝癌血清的CEA、SF、AFP。结果　原发性肝癌的CEA、SF和AFP阳性率分别为 2 0 2 2 % ,81 4 2 %和 6 1 75 % ,肝转移癌的CEA、SF和AFP阳性率分别为 87 31% (P <0 0 1) ,72 39% (P >0 0 5 )和5 2 2 % (P <0 0 1)。肝转移癌化疗前后的血清CEA有显著性差异 (P <0 0 1)。结论　检测CEA对肝转移的诊断、治疗及预后有明显的指导意义。     

A case of AFP-producing gastric cancer with hepatic metastases that accompanied early gastric cancer treated effectively by chemotherapy

We report a case of alphafetoprotein (AFP)-producing gastric cancer that accompanied early gastric cancer and was treated effectively by chemotherapy. The patient was a 73-year-old male. A type 1 tumor was observed in the upper gastric body and a 0-IIa tumor was noted on the anterior wall of the lower gastric body. Abdominal CT showed multiple metastatic lesions in the liver. A subtotal gastrectomy was performed, and the pathological examination revealed that the type 1 tumor was positive for AFP and the 0-IIa tumor was negative for AFP. After 5 courses of postoperative administration of S-1, hepatic metastatic lesions disappeared on imaging. The serum AFP level, which had increased to the maximum of 49,660 ng/ml, was normalized. After 60 months, there has been no sign of recurrence. We encountered a case of AFP-producing gastric cancer that accompanied early gastric cancer and was treated effectively by S-1. Various therapies for AFP-producing gastric cancer have been reported; however, a standardized regimen has not been established. Since the concurrence of AFP-producing gastric cancer and tubular adenocarcinoma is rare, and hepatic metastatic lesions disappeared, the case under study is considered to be of interest. Therefore, we report this case with a review of the literature.     

Clinical evaluation of intra-arterial infusion of hyperthermo-chemotherapy in gastric cancer]

We performed intra-arterial infusion hyperthermochemotherapy by retaining an intra-arterial reservoir in 17 lesions of 12 patients with non-resectable, metastatic or recurrent gastric cancers. The 12 patients consisted of one with a primary gastric cancer lesion, 6 with a solitary gastric cancer lesion metastasizing to the liver, 4 with gastric cancer accompanied by hepatic metastasis, lymph node metastasis or local recurrence, and one with a gastric cancer lesion metastasizing to Douglas' pouch. A catheter was retained in the hepatic artery of all 6 patients with a solitary gastric cancer lesion metastasizing to the liver, and a catheter was retained in the aorta of the patient with a primary lesion, 3 of the 4 patients with two or more metastatic lesions, and the patient with a lesion metastasizing to Douglas' pouch. The duration of each hyperthermia session was 50 minutes, and one or two sessions were performed within a week. One course consisting of 5 or 6 sessions was repeated. Antineoplastic drugs such as MMC, 5-FU, ADR, epi-ADR, CDDP and VP-16 were injected in bolus form or administered serially through the reservoir. Nine of the 12 patients had polypharmacy. One to 3 courses or 4 to 20 sessions at maximum (average 9.8 sessions) were given. The rate of efficacy of intra-arterial infusion hyperthermochemotherapy was 44% for hepatic metastasis and 25% for lymph node metastasis. The local recurrent lesions, the lesion metastasizing to Douglas' pouch and the primary lesion did not respond to therapy.     

AFP-producing gastric cancer--analyses of 17 cases

Serum AFP levels were increased in 17 of 446 patients with primary gastric cancer, No liver metastasis was detected in 11 of them. In all patients who underwent gastrectomy, the post-operative AFP levels were significantly lowered. In patients with recurrence, the increase of AFP levels was detected before the diagnosis of recurrent tumor could be achieved by US or CT. The tumor invasion in most of these patients was graded as ss. Lymph node metastasis was found in all patients. Most tumors were histologically classified as tub 2. The histochemical demonstration of AFP in carcinoma cells of the stomach and metastatic lesions of the liver suggests tht AFP may be produced within cancer cells. The prognosis was generally poor.     

Hepatic arterial injection therapy (HAI) for metastatic liver tumor from gastric cancer

The results and problems of hepatic artery infusion therapy (HAI) for gastric carcinoma with synchronous liver metastasis were evaluated. The response rate of HAI with CDDP and 5-FU for metastatic liver tumor was 55% (1 CR + 5 PR/11). The median survival time for responders was 16.5 months, which was statistically longer than that of non-responders at only 5.5 months. Histologically, most responder cases were with AFP producing tumors and NSE positive tumors without distant lymph node involvement. Non-responder cases developed marked distant lymph node involvement besides the liver metastasis. Most of responder patients died of lymph node recurrence or distant metastasis other than liver tumor. It may be concluded that additional therapy to HAI is needed to improve the prognosis of gastric cancer patients with multiple liver metastases.     

Cellular adjustment of gastric cancer for hepatic metastasis in successive orthotopic implantation model

In order to examine the mechanisms of hepatic metastasis in gastric cancer, a repeated orthotopic implantation method was used in nude mice with YCC-16, which was isolated from the blood of a gastric cancer patient. This study compared the biological and cytogenetic phenotypes of the five cell lines, the parental YCC-16, the orthotopic primary S1L0 and the 3 subsequent liver metastatic clones of S1L1, S2L2 and S3L3. E-cadherin and DAG1 gene expression levels were measured using real-time PCR. The parental YCC-16 showed multiple metastases, whereas the liver metastatic clones metastasized to the liver only. The liver metastatic rate showed increased trend with subsequent passages (passageII: 2/5, 40%; passageIII: 3/5, 60%; passageIV: 4/5, 80%). Otherwise, the liver metastatic clones had phenotype with a higher motility than that of the cell line from the orthotopic primary tumor (S1L0), and clonogenecity increased with subsequent passages in liver metastatic cell lines. The five cell lines had similar and additional chromosomal abnormalities were found in the selected clones. The E-cadherin expression level was decreased in all of the five cell lines, which was comparable to the common chromosomal changes. YCC-16 presented the lowest DAG1 expression level while S1L0 presented the highest. In the liver metastatic clones, the DAG1 expression level increased gradually with passages. Both the genetic alteration and cellular adjustment to the microenvironment are required for hepatic metastasis in gastric cancer. This model offers an opportunity to study the mechanisms of a hepatic metastasis of gastric cancer at the genetic and cellular level.     

Hepatic metastases from alpha-fetoprotein producing colorectal cancer that responded remarkably to transcatheter arterial chemo-embolization

Although alpha-fetoprotein (AFP)-producing colorectal cancer is extremely rare, its potential for liver metastasis is high and the prognosis of the patient is very poor. We report a case of metastatic liver tumor from an AFP producing sigmoid colon cancer that was successfully treated with transcatheter arterial chemo-embolization (TACE). A 48-year-old female was admitted to our hospital complaining of anal bleeding, and was diagnosed as harboring a type 2 advanced tumor with two metastatic lesions in the lateral segment of the liver. Serum AFP measured 948.2 ng/ml before surgery. We performed sigmoidectomy and lateral segmentectomy of the liver. Pathological examination revealed moderately differentiated adenocarcinoma both in the primary and the metastatic lesions, and AFP-stain positive nests were seen on immunohistochemical staining. The serum AFP value returned to normal soon after the surgery. Five months later, a recurrent lesion was discovered in the right lobe of liver, and it was surgically removed. Another 4 months later, multiple liver metastases were recognized and the patient's serum AFP level was found to be 593.3 ng/ml. For the re-recurrent hepatic lesions of 5.5 cm in diameter, she underwent two courses of TACE using Lipiodol and epirubicin hydrochloride. Following the treatment, the tumor shrank rapidly and almost disappeared. The patient has been in good health for 24 months since the last TACE, and the serum AFP level has been within the normal range.     

Liver resection for metastatic gastric cancer: experience with 42 patients including eight long-term survivors

BACKGROUND: The indication for liver resection for gastric metastases remains controversial and few previous studies have reported the outcome of surgery in the treatment of liver metastases of gastric cancer. The aim of this study is to clarify the effectiveness of surgical resection for liver metastases arising from gastric cancer. METHODS: A retrospective analysis was performed on the outcome of 42 consecutive patients with synchronous (n = 20) or metachronous (n = 22) gastric liver metastases that were curatively resected. RESULTS: The overall 1, 3 and 5 year survival rates after hepatic resection were 76, 48 and 42%, respectively, and the median survival was 34 months. Univariate analysis revealed that survival significantly differed between cases of solitary and multiple metastases (P = 0.03). Multivariate analysis revealed that solitary liver metastasis and the absence of serosal invasion by primary gastric cancer were favorable independent prognostic factors (P = 0.005 and P = 0.02, respectively). All eight patients who survived for more than 5 years after initial hepatectomy had a solitary metastasis, and six of these had no serosal invasion by the primary gastric cancer. No patient with multiple metastatic diseases survived beyond 3 years. CONCLUSIONS: Patients with a solitary liver metastasis are good candidates for surgical resection, whereas those with multiple gastric liver metastases should be treated by multimodal approaches.     

High expression of PRL-3 promotes cancer cell motility and liver metastasis in human colorectal cancer: a predictive molecular marker of metachronous liver and lung metastases.

PURPOSE: Overexpression of PRL-3 has been implicated in colorectal cancer metastases. We investigated the significance of PRL-3 expression in the progression and development of colorectal cancer. EXPERIMENTAL DESIGN: We transfected PRL-3-specific small interfering RNA into human colon cancer DLD-1 cells and analyzed its effect on proliferation, motility, and hepatic colonization. Using an in situ hybridization method, we examined the levels of PRL-3 expression in both primary (177 cases) and metastatic (92 cases) human colorectal cancers and elucidated the relationships with clinicopathological parameters including the incidence of metachronous liver and/or lung metastasis after curative surgery for primary tumor. RESULTS: Transient down-regulation of PRL-3 expression in DLD-1 cells abrogated motility (in vitro) and hepatic colonization (in vivo), but no effect on the proliferation of these cells was observed. In human primary colorectal cancers, the frequency of up-regulated PRL-3 expression in cases with liver (84.4%) or lung (88.9%) metastasis was statistically higher than that in cases without either type of metastasis (liver, 35.9%; lung, 42.3%). In metastatic colorectal cancer lesions, high expression of PRL-3 was frequently detected (liver, 91.3%; lung, 100%). Interestingly, metachronous metastasis was observed more frequently in the cases with high PRL-3 expression (P < 0.0001). CONCLUSIONS: These results indicate that PRL-3 expression in colorectal cancers may contribute to the establishment of liver metastasis, particularly at the step in which cancer cells leave the circulation to extravasate into the liver tissue. In addition, PRL-3 is expected to be a promising biomarker for identifying colorectal cancer patients at high risk for distant metastases.     

A case of gastric cancer associated with synchronous liver metastasis successfully treated with combination therapy of systemic and hepatic arterial infusion chemotherapy

A 56-year-old man who underwent distal gastrectomy at another hospital was admitted to our hospital because of advanced gastric cancer with synchronous liver metastasis. As we considered that the metastatic liver tumor was unresectable one, an intra-arterial catheter was inserted and weekly chemotherapy including methotrexate (MTX) (intra-venous) and 5-fluorouracil (5-FU) (intra-arterial) was started. The metastatic liver tumor was gradually reduced and resulted in partial response (PR) after 12 courses. Eight months later, the size of the metastatic liver tumor increased and lung metastasis occurred, so we started a new regimen of chemotherapy using CPT-11 (intra-venous) and CDDP (intra-arterial). After 4 courses of this regimen, we gained PR both in the metastatic liver and lung tumor. This case indicates that the combination therapy of systemic and hepatic arterial infusion chemotherapy is a treatment option in cases of advanced gastric cancer with liver metastasis.     

Combination of operation, chemotherapy and radiation for AFP producing gastric cancer--a case report

We report a case of AFP producing gastric cancer after a combination of operation, chemotherapy and radiation. A 70-year-old man was admitted complaining of abdominal fullness. He was diagnosed as having type 3 advanced gastric cancer with multiple lymph node metastasis, including No. 8p lymph node, by endoscopy and computed tomography. Distal gastrectomy and D2 lymph node dissection were performed after chemotherapy using S-1, low-dose CDDP and CPT-11. Histopathological study showed moderately differentiated adenocarcinoma, and immunohistochemical study revealed a few AFP-positive tumor cells. Postoperatively, radiation (50 Gy) was performed for paraaortic lymph node metastasis and right hepatic lobectomy for liver metastasis. However, about 2 months after hepatic lobectomy, liver metastasis was diagnosed again by computed tomography, and radiation (30 Gy) was performed. He died 13 months after first surgery.