Metastasis-associated protein S100A4--a potential prognostic marker for colorectal cancer.

BACKGROUND AND OBJECTIVES: Expression of S100A4, a small calcium-binding protein, in breast, oesophagus and gall bladder cancers is shown to be associated with adverse clinical outcome. We retrospectively examined the correlation of S100A4 expression and outcome in patients with colorectal cancer. METHODS: Tissue sections from 54 patients with Dukes B, C and D cancers operated on between 1995 and 1998 were stained with anti-S100A4 antibody. The S100A4 expression profile was correlated to the clinico-pathological details. RESULTS: There were 31 males and 23 females (mean age 65.94 years +/- 12.29). Dukes stage, >4 positive lymph node status and S100A4 expression were significantly associated with poorer survival. The 3 years survival of patients whose tumour stained positive for S100A4 was 62.85% compared to 93.75% for those stained negative (P < 0.012). In patients with <4 involved nodes, S100A4 expression led to poorer survival (57 months vs. 74 months; P < 0.0052). Within a particular Dukes stage, S100A4 expression was associated with poorer outcome. The 5 years survival of Dukes B patients whose tumour stained negative for S100A4 was 92% compared to 54.6% for those with positive tumours. CONCLUSION: Our results suggest that S100A4 expression is associated with adverse clinical outcome. Inclusion of S100A4 expression status may enhance our accuracy to prognosticate in patients with colorectal cancer.

Liver resection after irinotecan, 5-fluorouracil, and folinic acid for patients with unresectable colorectal liver metastases: a multicenter phase II study by the Cancer Therapeutic Research Group.

The main objectives of this study were to assess the use of irinotecan, 5-fluorouracil (5-FU), and leucovorin (FA) as neoadjuvant chemotherapy for patients with unresectable colorectal liver metastases and to determine the response rate and proportion of patients that could be down-staged to resectable tumors. Forty patients were treated with irinotecan (180 mg/m2 over 30 min) on d 1, FA (200 mg/m2 over 30 min) followed by 5-FU (400 mg/m2 bolus and continuous infusion of 600 mg/m2 over 22 h) on d 1 and 2 every 2 wk. The overall response rate was 55% (95% CI: 39.5-70.4%). The progression-free survival was 12.1 mo (95% CI: 11.4-14.8 mo). The median overall survival was 20 mo (95% CI: 17.7-26.6 mo). Four patients (10%) have undergone liver resection after a median of eight cycles. Those patients remained alive with a median follow up period of 33 mo. The principal grade 3-4 toxicity was neutropenia in 20 patients (50%). We conclude that the regimen of irinotecan/5-FU/FA was highly active in patients with colorectal cancer and liver metastases with limited toxicity. In a subgroup of patients with initial inoperable liver metastases, this regimen was able to down-stage the disease to an operable stage.

Mitochondrial respiratory function and antioxidant capacity in normal and cirrhotic livers following partial hepatectomy.

For many liver malignancies, major hepatectomy is the usual therapy. Although a normal liver has a tremendous capacity for regeneration, liver hepatectomy in humans is usually carried out on a diseased liver and, in such cases, liver regeneration takes place in a cirrhotic remnant. Mitochondrial function in cirrhotic livers shows a variety of changes compared to control livers. This study investigated how mitochondrial respiratory function and antioxidant capacity change following partial hepatectomy of cirrhotic livers, because liver regeneration requires greater energy demands and control of oxidative stress. Cirrhosis was induced in male Wistar-Furth rats by administration of thioacetamide. NADH-cytochrome c reductase activity, mitochondrial glutathione peroxidase activity and mitochondrial GSH levels were all significantly lowered in cirrhotic livers and in the cirrhotic remnants up to 72 h after 70% hepatectomy when compared to the corresponding controls. Lower respiratory control ratios with succinate as substrate were also observed from 6 to 48 h post-hepatectomy. At 24 h post-hepatectomy, higher levels of lipid peroxidation were observed. We conclude that, compared to the controls, cirrhotic livers have diminished oxidative phosphorylation capabilities due to changes in NADH and FADH(2)-linked respiration as well as impaired antioxidant defenses following partial hepatectomy. Both of these factors, if critical, could then impede liver regeneration.

Hepatocellular carcinoma: from bedside to proteomics.

Hepatocellular carcinoma (HCC or hepatoma) is the most common primary cancer of the liver. It is responsible for approximately one million deaths each year, mainly in underdeveloped and developing countries. The aetiological factors identified in the development of HCC included persistent infection by hepatitis B and hepatitis C viruses, and exposure to aflatoxins. Although immunization can protect individuals from being infected by the hepatitis B virus, the early detection of HCC in those who have been infected by the virus remains a challenge. Thus most HCCs present late and are not suitable for curative treatment. Hence there is a tremendous interest and urgency to identify novel HCC diagnostic marker(s) for early detection, and tumour specific disease associated proteins as potential therapeutic targets in the treatment of HCC. Screening for these HCC proteins has been facilitated by proteomics, a key technology in the global analysis of protein expression and understanding gene function. Present and earlier proteome analyses of HCC have used predominantly experimental in vitro systems. The protein expression profiles of several hepatoma cell lines such as HepG2, Huh7, SK-Hep1, and Hep3B have been compared with normal liver, and nontransformed cell lines (Chang and WRL-68), while a comprehensive proteome analysis to create a protein database was carried out for the cell line HCC-M. In the future, proteome analyses utilizing tumour tissues, which reflect the pathological state of HCC more closely, will be undertaken. This work will complement the gene expression studies of HCC which are already underway. Efforts have also been directed at the proteome analysis of hepatic stellate cells, as these cells play an important role in liver fibrosis. Since liver fibrosis is reversible but not cirrhosis, it is of considerable importance to identify therapeutic targets that can slow its progression.

Appendicitis in the elderly.

BACKGROUND: Acute appendicitis in the elderly (i.e. those over 60 years of age) is associated with high morbidity and mortality rates. The present retrospective study reviews 10 years ( 1986-1996) of experience and outcome in treating acute appendicitis in patients aged 60 or above. METHODS: One hundred and thirty patients with acute appendicitis were identified and their case notes reviewed. RESULTS: Acute appendicitis was diagnosed at admission in 84 patients (64.6%). The remaining patients were observed for a median duration of 9.4 h prior to diagnosis and treatment. Patients with an underlying perforated acute appendix had a significantly longer period of pain prior to admission (P = 0.029; Mann-Whitney U-test) but perforation per se was not associated with a significantly higher rate of morbidity and longer length of hospital stay. In contrast, the use of midline or paramedian incisions was associated with a higher wound infection rate (P=0.003; Pearson chi-squared test) and a longer hospital stay (P<0.001; Mann Whitney U-test). None of the patients were subsequently found to have an underlying colonic neoplasm. The overall morbidity rate was 28%. The mortality rate was 2.3% and all three patients who died had a severe comorbid medical condition prior to developing acute appendicitis. CONCLUSIONS: Acute appendicitis in the elderly is still associated with significant morbidity. But once acute appendicitis is diagnosed, then expedient surgery, appropriate use of perioperative antibiotics and a right lower quadrant incision can help to minimize the morbidity. Pre-existing severe comorbid medical condition(s) is a major contributory factor to mortality in these patients.

Cholangiographic features in the diagnosis and management of obstructive icteric type hepatocellular carcinoma.

In 11 years and 3 months, 2,037 patients with HCC were seen and 48 patients (2.4%) were diagnosed to have obstructive icteric type HCC. Five patients were terminally ill and were not investigated further. Forty three patients were initially investigated by endoscopic retrograde cholangiography (ERC) or percutaneous transhepatic cholangiogram (PTC) and classified as having obstructive icteric type 1, 2, or 3 HCC based on the cholangiographic findings. The obstruction in type 1 HCC was due to intraluminal tumour casts and/or tumour fragments obstructing the hepatic ductal confluence or common bile duct, while intraluminal blood clots, from haemobilia, filling the biliary tree was the cause in type 2 HCC. The pathology in type 3 HCC was extraluminal obstruction by extensive tumour encasement of the intra-hepatic biliary ductal system and/or extrinsic compression of the hepatic and common bile ducts by tumour(s) and/or malignant lymph nodes. At the initial ERC/PTC, 10 patients (5 resected, 50%) had obstructive icteric type 1 and 23 patients (0 resected) had obstructive icteric type 3 HCC. Of the 10 patients initially classified according to cholangiography to have obstructive icteric type 2 HCC, subsequent investigations revealed that 6 patients had type 1 HCC (4 resectable,67%) and 4 patients had type 3 HCC (0 resectable). The classification of the obstructive icteric type HCC into types 1, 2, and 3, based on the initial cholangiographic appearances has simplified and rationalized our management strategy for this condition.

Spontaneous rupture of hepatocellular carcinoma: conservative management and selective intervention.

HYPOTHESIS: A conservative approach using selective intervention is better than an aggressive approach using nonselective intervention for ruptured hepatocellular carcinoma. DESIGN: Nonrandomized controlled trial. SETTING: A university hospital. PATIENTS AND INTERVENTIONS: From 1984 to 1990, an aggressive approach was adopted in which 29 and 8 of a total of 40 patients underwent surgical intervention or attempted transarterial embolization (TAE), respectively. From 1991 to 1997, a more conservative approach was used. The initial treatment for 72 patients was conservative with close monitoring. Additional hemostatic procedures consisting of TAE (n = 13) or surgical intervention (n = 9) were given, depending on the clinical progress, disease status, and liver function of the patients. MAIN OUTCOME MEASURES: In-hospital mortality, survival. RESULTS: In-hospital mortality rate was 62% (25 of 40 patients) in the first period and 51% (37 of 72 patients) in the second period. The respective median survival times were 7 and 12 days. If 36 patients with end-stage malignant neoplasms were excluded, the in-hospital mortality rate became 60% (18 of 30 patients) in the first period and 35% (16 of 46 patients) in the second period (P = .03, chi2 test). The respective median survival times became 8 and 72 days (P = .02, log rank test). In the second period, 7 (54%) of 13 patients who underwent TAE and 1 (11%) of 9 patients who underwent surgical intervention died within the same hospital admission (P = .07, Fisher exact test). CONCLUSIONS: Selective intervention was cost-effective and gave better results than an aggressive approach. When intervention was indicated for hemostasis, surgery seemed better than TAE although the difference was not statistically significant.

An unusual case of breast metastasis from an anorectal melanoma.

An unusual case of solitary breast metastasis from a primary anorectal melanoma in a 59-year-old post-menopausal woman is reported. The course and management of melanotic breast metastases is discussed.

Frequent allelic loss on chromosome 9 in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignancy worldwide and highly associated with chronic virus-B or -C infection and cirrhosis. Molecular studies have shown high frequency of loss of heterozygosity (LOH) in some specific chromosome regions, but LOH on chromosome 9 in HCC has not been thoroughly investigated. In our investigation of chromosome 9 with 19 polymerase-chain-reaction (PCR)-based polymorphic microsatellite markers, 30 of 48 HCC tissue samples (63%) had LOH, and a distinct common deletion region and a region of loss were identified. The first region was located at the 9p21 region and the minimal deletion region was located between loci D9S1747 and D9S1748. This is a region of approximately 200 kb which includes the p16 tumor-suppressor gene. A region of loss was located on 9p13 to 9q33. The putative tumor-suppressor gene for nevoid-basal-cell-carcinoma syndrome (NBCCS) at 9q22.3 resides within this region. In addition to LOH, 4 HCC cases showed possible homozygous deletions at 9p21 with markers D9S1748, D9S1752 and D9S171 by multiplex PCR analysis. In 3 cases, the minimal region of possible homozygous deletion was approximately 300 kb and was defined between markers D9S1747 and D9S1752. Since this deletion region includes both the p15 and the p16 tumor-suppressor genes, these genes were possibly inactivated by homozygous deletion in HCC. In addition, a second region of possible homozygous deletion was present on the centromeric side of 9p21. However, these changes are not associated with age, gender, size or tumor-cell differentiation. Our data also suggest that inactivation of the p16 and the p15 genes and the possibility of other unknown tumor-suppressor genes located on these defined deleted regions of chromosome 9 may be involved in the pathogenesis of HCC.

High frequency of p16INK4A gene alterations in hepatocellular carcinoma.

The tumor suppressor gene p16 (CDKN2/MTS-1/INK4A) is an important component of the cell cycle and inactivation of the gene has been found in a variety of human cancers. In order to investigate the role of p16 gene in the tumorigenesis of hepatocellular carcinoma (HCC), 48 cases of HCC were analysed for p16 alterations by: methylation-specific PCR (MSP) to determine the methylation status of the p16 promoter region; comparative multiplex PCR to detect homozygous deletion; PCR-SSCP and DNA sequencing analysis to identify mutation of the p16 gene. We found high frequency of hypermethylation of the 5' CpG island of the p16 gene in 30 of 48 cases (62.5%) of HCC tumors. Moreover, homozygous deletion at p16 region were present in five of 48 cases (10.4%); and missense mutation were detected in three of 48 cases (6.3%). The overall frequency of p16 alterations, including homozygous deletion, mutation and hypermethylation, in HCC tumors was 70.8% (34 of 48 cases). These findings suggest that: (a) the inactivation of the p16 is a frequent event in HCC; (b) the p16 gene is inactivated by multiple mechanisms including homozygous deletion, promoter hypermethylation and point mutation; (c) the most common somatic alteration of the p16 gene in HCC is de novo hypermethylation of the 5' CpG island; and (d) in contrast to other studies, high frequency of genomic alterations are not uncommon in the 9p21 of the p16 gene. Our results strongly suggest that the p16 gene plays an important role in the pathogenesis of HCC.

The lateral thyroid ligament of Berry.

Division of the lateral thyroid ligament is essential for total thyroid lobectomy. The exact extent of this ligament, first described by Berry in 1888, was studied in a series of 25 cadaveric and post-mortem subjects. The ligament was attached to the inferior margin of the cornu of the cricoid cartilage, near its pole, and extended infero-medially onto the tracheal wall, reaching the midline in 4 of the 50 lobes examined. At the level of the cricoid cartilage, the mean distance between the attachment of the ligament to the cricoid cartilage and the recurrent laryngeal nerve (RLN) entry point into the larynx was 1.9 mm. This region corresponds to the area where RLNs are mostly injured during thyroid surgery. Awareness of the extent of this ligament and the proximity of the RLN to it should lessen the risk of injury to the RLN during thyroid lobectomy and total thyroidectomy.

Subclavian arterio-esophageal fistula secondary to fish bone impaction: report of a case.

A 48-year-old Indian man swallowed a fish bone and presented 1 week later with dysphagia, following a single episode of fresh hematemesis. A barium swallow demonstrated a horizontal mucosal tear at the level of the aortic arch, and computed tomography (CT) showed mediastinal emphysema and a bleeding point medial to the left subclavian artery which appeared to be contained by a surrounding hematoma. Subsequently, he developed sudden massive hematemesis and collapsed. Despite emergency surgery, the patient died. At the postmortem examination, a 1.2-cm fistula tract was found connecting the esophagus to the left subclavian artery. This case report emphasizes that a diagnosis of arterio-esophageal fistula should be considered if a patient presents with fresh hematemesis and a recent history of foreign body ingestion.