Early skin toxicity predicts better outcomes, and early tumor shrinkage predicts better response after cetuximab treatment in advanced colorectal cancer.

Cetuximab-containing treatments for metastatic colorectal cancer have been shown to have higher overall response rates and longer progression-free and overall survival than other systemic therapies. Cetuximab-related manifestations, including severe skin toxicity and early tumor shrinkage, have been shown to be predictors of response to cetuximab. We hypothesized that early skin toxicity is a predictor of response and better outcomes in patients with advanced colorectal carcinoma. We retrospectively evaluated 62 patients with colorectal adenocarcinoma who had unresectable tumors and were treated with cetuximab in our institution. Skin toxicity grade was evaluated on each treatment day. Tumor size was evaluated using computed tomography prior to treatment and 4-8 weeks after the start of treatment with cetuximab.Patients with early tumor shrinkage after starting treatment with cetuximab had a significantly higher overall response rate (P = 0.0001). Patients with early skin toxicity showed significantly longer overall survival (P = 0.0305), and patients with higher skin toxicity grades had longer progression-free survival (P = 0.0168).We have shown that early tumor shrinkage, early onset of skin toxicity, and high skin toxicity grade are predictors of treatment efficacy and/or outcome in patients with advanced colorectal carcinoma treated with cetuximab.

Immunohistochemical analysis of nuclear survivin expression in esophageal squamous cell carcinoma.

Despite advances in the treatment of esophageal carcinoma, the prognosis for this disease remains poor. Therefore, it is important to obtain a better understanding of the molecular basis of esophageal carcinogenesis. The purpose of this study was to clarify the roles of survivin in esophageal squamous cell carcinoma (ESCC). One hundred 22 ESCC surgical specimens resected from 1989 to 1999 were examined. Survivin expression was assessed by immunohistochemistry. Tumor cells were considered survivin-positive if the immunoreactivity was confined to the nucleus, and a scoring method was applied. Survivin-positive immunostaining was detected in 68 patients (56%). There was a significant association between survivin expression and pN (P = 0.0472). Moreover, the overall survival rate was worse in patients with survivin-positive tumors than in patients with survivin-negative tumors (P = 0.0189). The overexpression of survivin was associated with the overall survival rate and poor prognosis in patients with ESCC. Survivin may be targeted during cancer therapy because of its selective expression in malignant tissue.

Salvage of a massive esophago-tracheal fistula resulting from a stenting treatment.

We report the successful surgical resolution of a case of massive esophago-tracheal fistula (ETF) caused by a stenting treatment for stricture of an esophago-gastric anastomosis. A 54-year-old man was admitted to our hospital due to serious pneumonia secondary to ETF. He had previously received esophagectomy and post-operative chemo-radiation therapy for esophageal cancer, followed by stenting treatments for a benign stricture of the esophago-gastric anastomosis. For surgical treatment of the resulting ETF, serial operations were required. The first operation, performed under percutaneous cardiopulmonary support, included removal of the stents followed by tracheotomy, were with the coverage of the tracheal defect achieved using both major pectoral muscle flaps. A salivary fistula was also generated and an enteral nutrition tube was placed. Six months after the first operation, a pedicled ileocolic interposition was performed in order to effect reconstruction of the digestive tube, with an additional microvascular anastomosis of the ileocolic and internal thoracic artery and vein. After the second operation, the patient's ability to ingest food was restored, and he was discharged from the hospital. Thus, ETF was successfully treated by successive surgical operations with delicate intra- and post-operative respiratory management.

Transcriptional targeting of adenovirus vectors with the squamous cell carcinoma-specific antigen-2 promoter for selective apoptosis induction in lung cancer.

Squamous cell carcinoma antigens SCCA1 and SCCA2 are highly homologous serine proteinase inhibitors which have been widely utilized as serological markers for squamous cell cancers, but it has recently been demonstrated that only SCCA2 is truly specific for certain forms of lung cancer. Using a construct containing the 5'-flanking region of the SCCA2 gene between -460 and +0 bp and the luciferase reporter gene, SCCA2 promoter activity was detected in SCCA2-producing SCC cell lines (LK-2, LC-1), but not in SCCA2-nonproducing lung adenocarcinoma cell lines (A549, ABC-1, and RERF-LC-MS) or normal cells (WI-38, SAEC, and NHEK-Adult). Infection with a recombinant adenovirus vector, Ad-SCCA2-DsRed, resulted in cell-specific expression of the SCCA2 promoter-driven DsRed marker gene only in LK-2 and LC-1 cells. The same strategy was used for SCCA2-driven expression of a proapoptotic gene, (KLAKLAK)2, which can cause mitochondrial disruption by triggering mitochondrial permeabilization and swelling, resulting in the release of cytochrome c and induction of apoptosis. Infection with Ad-SCCA2-KLAKLAK2 specifically reduced the growth of the two human lung SCC cell lines compared to the SCCA2 nonproducing cell lines both in vitro and in vivo, suggesting that the SCCA2 promoter had a tumor-specific effect. These results suggest that transduction of SCCA2 promoter-controlled suicide genes by adenoviral vectors can confer transcriptionally targeted cytotoxicity in SCCA2-producing lung SCC cells, and represents a novel strategy for gene transfer specifically targeted to SCC in the lung.

Esophageal pemphigus vulgaris with carcinoma: postoperative steroid therapy based on pemphigus-related antibodies.

A 71-year-old man had been treated as an outpatient for pemphigus vulgaris. Endoscopic examination disclosed an ulcerated lesion in the middle of the esophagus. A biopsy specimen was diagnosed pathologically as squamous cell carcinoma. At surgery, the esophageal mucosa beyond the resection margin appeared edematous and blistered. We carried out anastomosis with sutures rather than staples at the site where the epithelium was least damaged, to minimize likelihood of anastomotic breakdown from poor blood flow. Histopathologic examination of the resected specimen additionally showed blisters and acantholytic cells throughout the esophageal mucosa, so esophageal pemphigus was diagnosed in addition to carcinoma. The patient's general condition deteriorated from worsening of pemphigus. We initiated steroid therapy, making adjustments according to changes in titers of anti-intercellular bridge antibody and antibodies to the cell adhesion molecules (desmoglein 1 and 3). Fever and extensive blistering subsided dramatically, and the patient was discharged in good condition on hospital day 103. When performing esophagectomy in the presence of esophageal pemphigus, the anastomosis must be fashioned cautiously because any mechanical stress can abrade the friable edematous esophageal mucosa. While steroid therapy is known to be effective for pemphigus vulgaris, our findings indicate that in patients with postoperative deterioration of their general condition, marked improvement can be obtained by using antibody titers to guide timing and dose in steroid administration.

Cyclin D1, E2F1 expression levels are associated with characteristics and prognosis of esophageal squamous cell carcinoma.

SUMMARY. We performed a multi-institutional analysis of E2F1 and cyclin D1 expression in cases of esophageal squamous cell carcinoma (ESCC). Cyclin D1 and E2F1 are involved in the transition of cell cycle phases and associated with tumor progression. However, no previous studies have concurrently analyzed combined E2F1 and cyclin D1 expression. The purpose of this study was to clarify the relationship of E2F1 and cyclin D1 in ESCC. We studied 122 patients with primary ESCC who underwent surgical tumor resection. Immunohistochemical analyses were performed for E2F1 and cyclin D1. A statistical analysis of immunohistochemistry results, clinicopathological features, and prognosis was performed. E2F1/cyclin D1 (-/-) tumors were present in 31 patients (25.4%) and correlated with reduced tumor progression. In these patients, pT (P=0.0001), pN (P<0.0001), p-Stage (P=0.0019), and survival rates were better than in patients who were positive for either E2F1 or cyclin D1 (P=0.0232). The expression of E2F1 and cyclin D1 is an indicator of tumor progression and prognosis in patients with ESCC. Combined analysis of E2F1 and cyclin D1 expression helps to determine the characteristics and prognosis of ESCC.

Delayed esophageal reconstruction for aortoesophageal fistula caused by an aortic arch aneurysm with microvascular anastomosis of the left gastric artery and vein.

SUMMARY: We report a case of aorto esophageal fistula (AEF) with delayed esophageal reconstruction employing microvascular anastomosis. We demonstrate here that our method is useful for delayed esophageal reconstruction following AEF.

Over-expression of E2F-1 in esophageal squamous cell carcinoma correlates with tumor progression.

The transcription factor E2F-1, a downstream regulator of the p16-cyclinD-Rb pathway, is required for cell cycle progression. Evidence shows that overexpression of E2F-1 can either promote or inhibit the development of tumors, depending on tissue or experimental conditions. However, the clinical impact of E2F-1 expression on esophageal squamous cell carcinoma (ESCC) remains unknown. To analyze E2F-1 expression in ESCC, we investigated the immunoreactivity of E2F-1 and its correlation with clinicopathological features in 122 patients who underwent surgical resection for ESCC. Positive E2F-1 immunostaining was detected in 73 patients (59.8%). Positive E2F-1 immunostaining correlated positively with pathologic stage (P = 0.0103), p-Grade (P = 0.0014) and pT (P = 0.0192). The overall survival rate was worse in patients with E2F-1-positive tumors than in patients with E2F-1-negative tumors (P = 0.0290). Over-expression of E2F-1 is associated with tumor progression and a worse prognosis after surgery in ESCC.

DARPP-32 expression arises after a phase of dysplasia in oesophageal squamous cell carcinoma.

This is the first report to correlate DARPP-32 immunoreactivity (dopamine and cAMP-regulated phosphoprotein, M(r) 32 000) to clinicopathological status in human cancer. DARPP-32 is recognised as a neuronal protein. A recent study demonstrated that DARPP-32, and a truncated isoform t-DARPP, are overexpressed in gastric carcinoma during the process of carcinogenesis. The biological function of DARPP-32, however, is still unclear. The purpose of this study was to clarify the roles of DARPP-32 and t-DARPP in oesophageal squamous cell carcinoma (OSCC). Initially, we investigated DARPP-32 and t-DARPP expression in OSCC cell lines by Reverse transcription-polymerase chain reaction and Western blot. DARPP-32 expression was observed in four out of seven (57.1%) cell lines, but t-DARPP expression was not observed in any cell lines. In oesophageal tissue sample, DARPP-32 expression was observed in four out of seven (57.1%) tumour tissues, while t-DARPP was not observed in any tissues. Subsequently, DARPP expression was assessed by immunohistochemistry, using a polyclonal antibody, in tissue sections from 122 patients with primary OSCC. DARPP immunoreactivity was not observed in any normal oesophageal mucous membranes. On the other hand, positive DARPP immunostaining was detected in 37 patients (30.3%) and correlated inversely with pathologic stage (P=0.0284), pT (P=0.0438), pN (P=0.0303) and tumour size (P=0.012). The overall survival rate was worse in patients with DARPP-negative tumours than in patients with DARPP-positive tumours (P=0.0453). Interestingly, DARPP expression was observed in only one out of 45 cases of dysplasia. These observations suggest that DARPP-32 (rather than t-DARPP) expression arises after a phase of dysplasia in OSCC, and that tumours expressing DARPP-32 progress less rapidly than DARPP-32-negative tumours.

Mediastinal bronchial artery aneurysm with hematemesis.

Mediastinal bronchial artery aneurysm is a rare condition which can lead to potentially fatal hemorrhage. In most cases it presents respiratory symptoms due to rupture into pleural parenchyma. But when it develops mediodorsally and compresses the esophagus, it may cause dysphagia or hematemesis. Here we report a case of mediastinal bronchial artery aneurysm which presented with hematemesis. Computed tomography and endoscopic ultrasound showed what seemed to be a submucosal tumor on the esophagus. We were able to correctly diagnose the aneurysm using magnetic resonance imaging and probe thoracoscopy, and were able to successfully treat with transluminal artery embolization.

Overexpression of hypoxia-inducible-factor 1alpha(HIF-1alpha) in oesophageal squamous cell carcinoma correlates with lymph node metastasis and pathologic stage.

The purpose of this study is to investigate the clinical and histopathologic significance of hypoxia-inducible-factor 1alpha (HIF-1alpha) expression in oesophageal squamous cell carcinoma. One hundred and thirty surgically resected specimens of OSCC were immunohistochemically assessed for HIF-1alpha expression with monoclonal antibody. High HIF-1alpha immunostaining was detected in 40 specimens. The percentage of high HIF-1alpha expression cases increased with tumour stage according to pTNM system. High HIF-1alpha expression correlated with pTNM stage, depth of tumour invasion, lymph node metastasis, distant metastasis, lymphatic invasion and positive surgical margin. The overall survival rate was worse in patients with high HIF-1alpha pattern than in patients with low-expression pattern. Univariate analyses identified high HIF-1alpha positivity, depth of tumour invasion, lymph node metastasis, distant metastasis, lymphatic invasion, and a positive surgical margin as risk factors. Multivariate analyses indicated that depth of tumour invasion, lymph node metastasis and positive surgical margin, but not HIF-1alpha, were independent prognostic factors. Survival in patients with a high HIF-1alpha expression was significantly worse than in those with low expression in patient treated with adjuvant therapy.

Behavioral effect of herbal glycoside in the forced swimming test.

We investigated the behavioral effects of Chinese herbal medicines in the forced swimming test. One of these medicines, Kami-shoyo-san, induced an antidepressive climbing behavior in mice. An effective substance detected to be an O-linked glycoside with the sugar chain structure GalNAc alpha 1-3GalNAc was separated. The behavioral effect was dose-dependently decreased by the dopamine 2 antagonist sulpiride, but not by the dopamine 1 antagonist SCH-233960. Investigated Chinese herbal medicines, including Kami-shoyo-san, have been used for human depression. These facts suggest that glycoside is one of the antidepressant-like substances of Chinese herbal medicines.

Lithium affects the reactivities of GalNAcalpha1-3GalNAc-lipid and fibrinopeptide A in mice.

The relationship between lithium and the reactivities of GalNAcalpha1-3GalNAc-lipid and fibrinopeptide A were investigated in mice. Lithium strongly decreased glycolipid reactivity and slightly increased peptide reactivity in a dose- and time-dependent manner. These substances showed antidepressive behavioral effects in mice via different neurological activities. This many suggest a mechanism of two different clinical effects of lithium: one of which is a strong antimanic effect and one of which is a weak antidepressive effect.

NK- and CD8(+) T cell-mediated eradication of established tumors by peritumoral injection of CpG-containing oligodeoxynucleotides.

Unmethylated cytosine-phosphorothioate-guanine (CpG) containing oligodeoxynucleotides (CpG-ODN) are known to act as adjuvants and powerful activators of the innate immune system. We investigated the therapeutic effect of CpG-ODN on a variety of established mouse tumors including AG104A, IE7 fibrosarcoma, B16 melanoma, and 3LL lung carcinoma. These tumors are only weakly immunogenic and notoriously difficult to treat. Repeated peritumoral injection of CpG-ODN resulted in complete rejection or strong inhibition of tumor growth, whereas systemic application had only partial effects. The CpG-ODN-induced tumor rejection was found to be mediated by both NK and tumor-specific CD8(+) T cells. Comparison of parental tumors and variants rendered more antigenic by transfection with tumor Ags suggested that the efficiency of the CpG-ODN therapy correlated with the antigenicity of the tumors. Peritumoral CpG-ODN treatment was even effective in a situation where the immune system was tolerant for the tumor Ag, as shown by breakage of tolerance and tumor elimination. These results suggest that peritumoral application of CpG-ODN acts locally by inducing NK cells, and also leads to efficient presentation of tumor Ags and stimulation of CD8(+) effector and memory T cells, thus providing a powerful antitumor therapy that can be also applied without knowledge of the tumor Ag.

Urinary copper excretion in type 2 diabetic patients with nephropathy.

BACKGROUND/AIMS: The aim of this study was to examine the relationship between the degree of urinary copper excretion and stages of diabetic nephropathy. METHODS: Copper, ceruloplasmin and albumin concentrations were measured in serum and urine samples from 41 type 2 diabetic outpatients with different stages of nephropathy and from 10 healthy controls. The copper/albumin and copper/ceruloplasmin ratios in serum and urine were determined. Furthermore, we examined whether free copper ions are dissociated from ceruloplasmin under various pH conditions. RESULTS: Urinary copper concentrations significantly increased only in macroalbuminuric patients. The copper/ceruloplasmin and copper/albumin ratios in urine were consistently greater than those in serum which were not different between patients and healthy controls except the copper/albumin ratio in macroalbuminuric patients. The ratios in urine decreased in parallel with the progression of nephropathy. Copper was found to be released from ceruloplasmin under acidic conditions. CONCLUSION: Urinary copper excretion in healthy controls may be the result of dissociation from the albumin-copper complex of serum during its passage through the kidney. In diabetic patients with advanced nephropathy, urinary copper excretion may be due to dissociations from both copper-albumin and ceruloplasmin-copper complexes filtered through the damaged glomerulus. Overloading of urinary copper to damaged renal tubules may play some roles in the progression of nephropathy in patients with advanced nephropathy.

[Optimal lymph node dissection for carcinoma of the biliary tract].

To clarify the optimal lymph node dissection for carcinoma of the biliary tract, we analyzed the mode of lymphatic spread in 86 resected cases with carcinoma of the gallbladder and 139 with carcinoma of the extrahepatic bile duct, and investigated long-term results after resection based on the degree of lymph node metastasis. Of the 86 patients with carcinoma of the gallbladder, 62 (72.1%) had lymph node metastasis. Patients with m and mp tumors (n = 9) had no lymph node metastasis, whereas ss tumors (n = 13) had 23.1% lymph node metastasis. Those with se, si tumors (n = 64) had greater lymph node involvement (92.2%). In 4 patients with advanced carcinomas (ss or more) who survived more than 5 years, only one (limited to periportal lymph nodes) of them had lymph node metastasis. Of the 139 patients with carcinoma of the extrahepatic bile duct, 58 (41.7%) had lymph node metastasis. There was no lymph node metastasis in 15 patients with m or fm tumors. The frequency of metastasis in the ss (n = 39) and se, si (n = 85) tumors was 17.9% and 60.0%, respectively. Twenty-four patients with advanced tumors survived more than 5 years. Curative resection was achieved in all 24 and lymph node metastasis was n0 in 19, n1 in 4 and n2 in 1 patients. Satisfactory long-term result can be achieved in carcinoma of the biliary tract after resection when lymph node metastasis is limited to nodes in the hepatoduodenal ligament. In view of our surgical results and the lymphatic drainage system of the biliary tract, systemic dissection of the regional lymph nodes, including periportal, posterior pancreato-duodenal, and celiac nodes, is necessary in patients with N0-N2 (limited to lymph nodes in the hapatoduodenal ligament) tumors in whom it contributes to good prognosis.

Surgical treatment of pancreatic cancer. Does extended lymphadenectomy provide a better outcome?

The rate of curative resection of pancreatic cancer has increased as a result of extended operations, but this has not led to any significant improvement in postoperative outcome. No definite conclusions were drawn in retrospective studies comparing outcome after standard and extended operations, and there was almost no difference in outcome between the two groups in a recent prospective randomized study. In addition, extended procedures are very stressful operations that, in most instances, impair the patient's quality of life (QOL). As a result, the need for performing extended surgery to treat pancreatic cancer has come into question. The outcome of advanced cancer in patients in whom curative resection cannot be achieved by extended operations is extremely poor, and we believe that, in such patients, priority should be given to QOL, by selecting bypass or limited operations instead. It is hoped that the value of extended surgery will be clarified by a very carefully planned multicenter prospective randomized study in the future.