Nuclear cyclin D1 overexpression is a critical event associated with cell proliferation and invasive growth in gallbladder carcinogenesis

Cyclin D1 overexpression is remarkably frequent in several human carcinomas and is believed to be a critical event in oncogenesis. We examined cyclin D1 expression, p53 expression, and the Ki-67 labeling index by immunostaining in human gallbladder mucosa in conditions varying from normal to malignant tissue. We also examined K-ras codon 12 mutations in these tissues with a two-step polymerase chain reaction. Nuclear cyclin D1 overexpression was observed in 48% of carcinomas occurring independently of adenoma, but not in adenomas, carcinomas arising in adenomas, or nonneoplastic lesions. Cytoplasmic cyclin D1 overexpression was observed in about 15% of abnormal specimens, irrespective of the type of epithelial abnormality. Carcinomas showing nuclear cyclin D1 overexpression had significantly higher Ki-67 labeling indexes than those with no overexpression. Moderately to poorly differentiated adenocarcinomas showed a higher incidence of nuclear cyclin D1 overexpression than papillary to well differentiated carcinomas. Specimens with cyclin D1 overexpression showed a high incidence of lymph permeation, venous permeation, and lymph node metastasis. We conclude that nuclear cyclin D1 overexpression is a critical event importantly associated with cell proliferation and invasive growth in gallbladder carcinogenesis, and that cyclin D1 immunostaining may become a useful marker for evaluating gallbladder carcinomas. Received: March 9, 1999 / Accepted: July 23, 1999     

Radioactive choline metabolism in guinea pig gallbladder

Acetylcholine may be released from gallbladder intrinsic nerves in response to cholecystokinin stimulation. This study characterized metabolites of [¹⁴C]choline produced in the gallbladder and released during incubation, with or without cholecystokinin-octapeptide. Radiolabeled [¹⁴C]choline was applied to the mucosal or muscle surface of intact guinea pig gallbladders in an organ bath. After radiolabeling, gallbladders were incubated with or without the contractile agonist cholecystokinin-octapeptide. Metabolites of [¹⁴C]choline were identified in gallbladder tissue and incubation buffers using HPLC and thin-layer chromatography. The major metabolites of [¹⁴C]choline were betaine and phosphocholine. [¹⁴C]Phosphocholine was incorporated slowly into [¹⁴C]phosphatidylcholine. [¹⁴C]Choline was released into buffers during incubation. [¹⁴C]Acetylcholine constituted less than 1% of radiolabel in the gallbladder. There was no identifiable [¹⁴C]acetylcholine released in buffers. Cholecystokinin-octapeptide did not affect choline metabolism. These studies showed that choline in the gallbladder is metabolized along pathways similar to those in the liver. Gallbladders released mostly choline, rather than acetylcholine, even during hormonally induced contraction.This project was supported by the Research and Development Office of the Department of Veterans Affairs.     

Percutaneous transhepatic gallbladder stenting for recurrent acute acalculous cholecystitis after failed endoscopic attempt

Endoscopic gallbladder stenting is useful palliative therapy for acute cholecystitis in high‐risk patients. Although the success rate of endoscopic gallbladder stenting is 79%–100%, an alternative method has not been reported. We succeeded in employing a method for percutaneous gallbladder stenting (PTGS) and herein describe this new method. A patient with acute acalculous cholecystitis related to ischemic atherosclerotic vascular disease, cholangitis due to Lemmel syndrome, and severe congestive heart failure underwent PTGS through the cystic duct from the gallbladder to the duodenal papilla, because an endoscopic method failed in the treatment of Lemmel syndrome. Because we were unable to place endoscopic transpapillary gallbladder drainage, percutaneous transhepatic gallbladder drainage (PTGBD) was performed and both the cholecystitis and cholangitis ceased. PTGS was performed as an alternative to endoscopic gallbladder stenting. Access to the cystic duct and gallbladder was obtained by the PTGBD route, using a guidewire (0.035‐inch diameter) and seeking catheter (6.5 Fr) under fluoroscopic control. A 7‐Fr 12‐cm double‐pigtail biliary polyethylene stent was placed. The patient remained asymptomatic for 3 months after the PTGS until he died, of an acute recurrent myocardial infarction. This new PTGS placement is an alternative treatment for symptomatic gallbladder disease in patients with increased operative risk when the endoscopic method is unsuccessful.     

Renal cell carcinoma with unusual metastasis to the gallbladder

Gallbladder involvement in patients with renal cell carcinoma (RCC) is extremely rare. We present a report of a 61-year-old man with a synchronous RCC metastasis to the gallbladder presenting as an intraluminal polypoid mass simulating primary gallbladder carcinoma. Enhanced abdominal computed tomography demonstrated a well-enhanced polypoid lesion in the gallbladder. Intraoperative rapid pathological examination of the gallbladder tumor showed clear cell-type cancerous cells. Microscopically, tumor cells of both the resected kidney and gallbladder had round uniform nuclei, clear cytoplasm, and well-defined cytoplasmic borders, forming alveolar patterns. Immunohistochemically, the tumor cells were negative for cytokeratin 7 (CK7) and carcinoembryonic antigen (CEA), which is usually positive in primary clear cell carcinoma of the gallbladder. Therefore, the final diagnosis was RCC with a synchronous gallbladder metastasis.     

Microsatellite instability in gallbladder carcinoma: two independent genetic pathways of gallbladder carcinogenesis

Although the genetic basis for gallbladder carcinogenesis has not been clarified, considerable evidence has shown that genetic alterations play an important role in the development and progression of human cancers. In this study, we analyzed 30 gallbladder carcinomas to investigate the role of genetic alterations in their tumorigenesis, and to study correlations with their clinicopathological features. Tissue samples were obtained from 30 patients with gallbladder carcinoma (11 men and 19 women; mean age, 62 years; age range, 38–80 years). Genomic DNAs were extracted from fresh tumor tissue. We examined loss of heterozygosity (LOH) in the p53, APC, DCC, RB, and NM23-H1 gene regions by polymerase chain reaction (PCR)-LOH assay using an automated fluorescent DNA sequencer employing four microsatellite markers (p53, APC, DCC, NM23-H1). Five additional microsatellite markers were used for the determination of microsatellite instability (MSI). LOH was found at p53 in 9 of 15 informative cases (60%), at DCC in 10 of 22 (45%), at APC in 5 of 15 (33%), at RB in 1 of 8 (13%), and at NM23-H1 in 1 of 15 (7%). MSI was observed in 5 of 30 cases (17%) in at least one chromosomal loci of these nine microsatellite markers. None of the patients with MSI-positive tumors showed lymph node metastasis, and there was an inverse correlation between MSI and the presence of LOH in gallbladder carcinoma. These results suggest that there are two independent genetic pathways in gallbladder carcinogenesis; that is, an MSI pathway and an LOH pathway. Received: December 24, 1999 / Accepted: May 26, 2000     

Effect of nifedipine on interdigestive gallbladder volume and postprandial gallbladder emptying in man

The effect of two oral doses (10 and 20 mg) of nifedipine versus placebo on the fasted gallbladder volume and on the meal-induced gallbladder emptying was assessed according to a double-blind study protocol in 12 healthy volunteers. Eight subjects underwent three studies (with placebo and with both nifedipine doses), whereas in two subjects the effect of a 10-mg nifedipine dose, vs placebo and in two others the effect of a 20-mg nifedipine dose vs placebo was examined. The studies were performed on separate days, and the gallbladder volume was measured by means of real-time ultrasonography. Neither placebo nor 20 mg nifedipine per os elicited any significant change in the fasted gallbladder vlume. With 10 mg nifedipine per os a significant increase in the interdigestive gallbladder volume was observed: 22.9±2.9 cm³ before and 26.2±3.2 cm³ after the drug receipt (P<0.005). A trend towards an inhibition of the postprandial gallbladder emptying was observed with 10 mg nifedipineper os without, however, reaching the level of statistical significance. Following 20 mg nifedipineper os, a marked delay in the meal-stimulated gallbladder emptying occurred as reflected by a decrease in the gallbladder ejection fraction from 48.1±4.5% (placebo) to 26.4±5.0% (nifedipine) (P<0.02) at 30 min and from 54.0±3.6% (placebo) to 33.2±4.6% (nifedipine) (P<0.02) at 40 min after the test meal. We conclude that a therapeutic oral dosage of nifedipine has a significant relaxing effect on the human gallbladder.     

硬质胆道镜联合腹腔镜保胆取石治疗胆囊结石、胆囊息肉的78例疗效观察

目的观察硬质胆道镜联合腹腔镜保胆取石治疗胆囊结石、胆囊息肉的临床疗效。方法 48例胆囊结石与30例胆囊息肉患者行硬质胆道镜保留胆囊、取净结石和息肉手术,术后定期复查腹部彩超。结果 78例患者中1例(1.28%)因结石位于胆囊颈且嵌顿中转行胆囊切除,其余均顺利手术;1例(1.28%)术后2月发现胆囊颈内残余结石,行腹腔镜胆囊切除术;胆囊息肉术后病理检查均为良性息肉。结论硬质胆道镜取石、取息肉术方法简单、安全、可行,是保留胆囊功能的有效方法。     

胆囊癌组织中线粒体DNA含量变化的研究

目的探讨线粒体DNA(mt DNA)含量的改变与胆囊癌的关系。方法通过实时荧光定量PCR检测30例胆囊癌组织、30例胆囊癌旁组织和30例胆囊良性病变组织标本中mt DNA的含量。结果胆囊癌组织中mt DNA的平均含量为(766±143)×10~6拷贝/L,胆囊癌旁组织中mt DNA的平均含量为(343±94)×10~6拷贝/L,胆囊良性病变组织中mt DNA的平均含量为(386±104)×10~6拷贝/L,胆囊癌组织中mt DNA平均含量分别高于胆囊癌旁组织(t=11.583,P<0.001)和胆囊良性病变组织(t=13.320,P<0.001)。胆囊癌组织中mt DNA含量的改变与患者性别、年龄及肿瘤分化程度无关(P>0.05)。胆囊良性病变组织与胆囊癌旁组织中mt DNA的平均含量比较,差异无统计学意义(t=1.673,P=0.107)。结论胆囊癌发生与mtDNA含量增加可能相关,mtDNA含量的检测是胆囊癌诊断的一种方法。     

Breast carcinoma with metastasis to the gallbladder:an unusual case report with a short review of literature

Gallbladder metastases are very rare and usually arise from malignant melanoma, renal cell carcinoma and cervical carcinoma. Breast carcinoma tnetastatic to the gallbladder is extremely rare and only 4 cases have been reported in the English literature. We hereby report a 54-year-old lady who was diagnosed as having breast carcinoma and underwent modified radical mastectomy. One month after the operation, she developed acute abdomenal pain and underwent cholecystectomy after clinical investigation. Histopathological examination revealed metastasis to the gallbladder. Being considered a patient with tnetastatic breast carcinoma she was subjected to taxane and anthracycline-based palliative chemotherapy. Later she had CNS involvement and died of the progressive disease soon after few months.