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.

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.

Variation of microvascular blood flow augmentation--supercharge in esophageal and pharyngeal reconstruction.

AIM OF THE STUDY: A gastric tube is commonly used in thoracic esophageal reconstruction. When a gastric tube is not available, pedicled jejunum transfer and colonic interposition are alternative methods. Oral end of the reconstructed esophagus occasionally has poor blood flow and may result in partial necrosis of the oral segment. We performed additional microvascular blood flow augmentation, the "supercharge" technique, to improve a blood flow circulation in the oral segment of the reconstructed esophagus. METHODS: A series of 86 esophageal reconstructions with microvascular blood flow augmentation using the "supercharge" technique were performed. Reconstructive methods included a gastric tube in five patients, a gastric tube combined with a free jejunual graft in one, an elongated gastric tube in eight, a pedicled colonic interposition in 22, and a pedicled jejunum in 50. Recipient vessels were used in neck or chest region. RESULTS: The color and blood flow of the transferred intestine appeared greatly improved after microvascular blood flow augmentation. Thrombosis was noticed in three patients during the surgery, and all thrombosies were salvaged by re-anastomosis. There were only three patients with partial graft necrosis of oral segment, two patients with anastomotic leakage, one anastomotic stricture. CONCLUSIONS: Augmentation of microvascular blood flow by this "supercharge" technique can be expected to reduce the risk of leakage and partial necrosis of the transferred intestine. This technique contributes to the successful reconstruction of esophageal defect.

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.

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.

Fusion of HIV-1 Tat protein transduction domain to poly-lysine as a new DNA delivery tool.

Effective gene therapy depends on the efficient transfer of therapeutic genes to target cells. None of the current technologies, however, satisfy all of the requirements necessary for gene therapy, because the plasma and nuclear membranes of mammalian cells are tight barriers against gene transfer using synthetic delivery systems. The protein transduction domain (PTD) of human immunodeficiency virus type 1 (HIV-1) Tat protein greatly facilitates protein transfer via membrane destabilisation. We synthesised polylysine peptides containing Tat PTD (TAT-pK), or other sequences, and investigated their potential as agents for gene transfer. The synthesised polypeptide TAT-pK retains DNA binding function and mediates delivery of a reporter gene to cultured cells. RGD motif binds with low affinity to alpha integrins which induce cell activation. Two control polypeptides, GGG-pK and RGD-pK, were synthesised and tested, but their gene transfer abilities were weaker than those of TAT-pK. TAT-pK-mediated gene transfer was enhanced in the presence of chloroquine or ammonium chloride, to a greater extent than that of cationic lipid-mediated gene transfer in most cancer cell lines tested. These data suggest that TAT-pK may be a potent candidate delivery vehicle that promotes gene transfer, dependent on the endocytic pathway. We conclude that the TAT-pK/DNA complex is useful as a minimal unit to package therapeutic genes and to transduce them into mammalian cells.

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.

Portal vein resection and reconstruction prior to hepatic dissection during right hepatectomy and caudate lobectomy for hepatobiliary cancer.

BACKGROUND: Hepatobiliary cancer invading the hilar bile duct often involves the portal bifurcation. Portal vein resection and reconstruction is usually performed after completion of the hepatectomy. This retrospective study assessed the safety and usefulness of portal vein reconstruction prior to hepatic dissection in right hepatectomy and caudate lobectomy plus biliary reconstruction, one of the common procedures for radical resection. METHODS: Clinical characteristics and perioperative results were compared in patients who underwent right hepatectomy and caudate lobectomy plus biliary reconstruction with (ten patients) and without (11 patients) portal reconstruction from September 1998 to March 2002. RESULTS: All ten portal vein reconstructions were completed successfully before hepatic dissection; the portal cross-clamp time ranged from 15 to 41 (median 22) min. Blood loss, blood transfusion during the operation, postoperative liver function, morbidity and length of hospital stay were similar in the two groups. No patient suffered postoperative hepatic failure or death. CONCLUSION: This study demonstrates that portal vein reconstruction does not increase the morbidity or mortality associated with right hepatectomy and caudate lobectomy with biliary reconstruction. This approach facilitates portal vein reconstruction for no-touch resection of hepatobiliary cancer invading the hilar bile duct.

Video-assisted anatomic mediobasal segmentectomy of lung.

Although video-assisted thoracic surgery (VATS) is now widely accepted, pulmonary segmentectomy is rarely performed. We present a case series of patients undergoing this procedure. The first patient had multiple arteriovenous malformations of the right mediobasal segment and a leiomyoma in the bronchus of the mediobasal segment. The second patient had multiple pulmonary metastases from colon cancer, including one in the right mediobasal segment. The third patient had metastases in the right ventrobasal and mediobasal segments from a solitary fibrous tumor that originated in the contralateral diaphragm. In the first two patients, a solitary mediobasal segmentectomy was done. In the third patient, a combined ventrobasal and mediobasal bisegmentectomy was performed. There were no complications, and visualization was excellent. Because VATS provides such excellent exposure, mediobasal segmentectomy of the lung is feasible, even though this operation is not done as an open procedure.

An extrapleural approach to the anterior mediastinum using video-assisted thoracic surgery (VATS).

A lateral extrapleural approach via video-assisted thoracic surgery (VATS) was used in a patient suspected of having a benign tumor of right lobe of the thymus. The patient previously had undergone lung resection for pulmonary tuberculosis, and the ipsilateral thorax had contracted and dense pleural adhesions were likely to exist. Lateral extrapleural approach by VATS was performed successfully and is an alternative to open surgery in highly selected patients with anterior mediastinal lesions.

Availability of lobe-selective bronchial blockade for video-assisted thoracic surgery: an initial experience with three cases.

BACKGROUND: Stable oxygenation and sufficient collapse of the lung are essential for video-assisted thoracic surgery (VATS). We performed the lobe-selective lung collapse technique with VATS for patients who had deteriorated lung function. METHODS AND RESULTS: CASE 1: A 75-year-old man who had undergone thoracoplasty showed spontaneous pneumothoraces in the contralateral side. Bullae were stapled successfully under complete isolation and collapse of diseased lobe. CASE 2: A 57-year-old woman who had undergone left lower lobectomy for lung cancer presented with another lung cancer in the right lower lobe. The right lower lobe bronchus was closed selectively, and basal segmentectomy was performed. CASE 3: A 60-year-old woman who had lost left lung function presented with right-side spontaneous pneumothoraces. The right upper lobe was collapsed selectively, and bullectomy was performed. CONCLUSION: Lobe-selective bronchial blockade may be beneficial when VATS is performed for selected patients with deteriorated lung function.

Selective occlusion with fibrin glue under fistuloscopy: seven cases of postoperative management for intractable complex fistulas.

BACKGROUND AND STUDY AIM: Fistula occlusion is not achieved in some fistulas with complex branches. To obtain early fistula closure in such cases, we insert a double-lumen catheter into each fistula branch, with the aid of a guide wire positioned using a small-caliber endoscope, and attempt selective infusion of fibrin glue. PATIENTS AND METHODS: Following removal of foreign bodies and necrotic granulation, we applied the selective occlusion method under fistuloscopic control to seven intractable external fistulas with complex branches, in which fistula closure had not been obtained by a simple occlusion method (SOM). All the fistulas were complex with more than two branches. RESULTS: Fistula occlusion was obtained within 2 weeks in six of the seven patients, and there has been no sign of recurrence over a follow-up period of 4 - 59 months (average 29.8 months). CONCLUSION: Selective occlusion under fistuloscopy is highly effective for intractable external fistulas with complex branches.

[Intentional limited operation for minute peripheral adenocarcinoma of the lung].

The purpose of this report is to evaluate the limited operation for peripheral minute adenocarcinoma of the lung. Firstly, 44 cases (47 lesions) of surgically resected minute peripheral lung adenocarcinoma, 10 mm or less in diameter, were reviewed using Noguchi's classification, and the correlation between high resolution CT (HRCT) images and the clinicopathological features was examined retrospectively. All type A and B adenocarcinomas (n = 14) had no recurrence and all cases were the air containing type by HRCT. Lymph node metastasis and lymphatic/vascular involvement were detected with type C, D, E, F and 3 cases among them were died for recurrence. Based on those results, from April 2000, intentional limited operation was prospectively performed for 14 patients (16 lesions) with peripheral nodule showing ground-glass opacity on HRCT. The pathological findings were type A (n = 9), type B (n = 5), and atypical adenomatous hyperplasia was one case (If the findings were confirmed type C, D, E, F by permanent section diagnosis, VATS lobectomy will be performed). We recommend limited operation should be performed in only type A or B adenocarcinoma and permanent section diagnosis is necessary to determine whether or not.

A case of spindle cell carcinoma of the breast--long survival achieved by multiple surgical treatment.

Spindle cell carcinoma of the breast was formerly called carcinosarcoma, and is relatively rare. We report a case of spindle cell carcinoma of the breast. The patient was treated with multiple surgeries and achieved long-term survival. The patient was a 52-year-old woman, in whom small induration developed at the areola of the nipple of the right breast. The lesion was resected, and benign tumor was diagnosed pathologically. Four years later, she had recurrence at the scar, and a typical mastectomy was performed. A tumor developed again 5 years later; the lesional focus was at the scar of the right chest wall and invasion of the ribs and the sternum was noted. The sternum and the right costal cartilage of ribs 3-9 were dissected together. The right chest wall was reconstructed and adjuvant radiation therapy performed. Four years after this operation, tumor recurred near the scar and chest wall resection including part of the pericardial cavity and the left lung was performed. However, 6 months later, invasion of the mediastinum, heart and lung were noted. The patient died 16 years after the first surgery. Dermatofibrosarcoma protuberance of the breast was diagnosed at the second operation. However, the diagnosis was changed to spindle cell carcinoma of the breast following immunohistochemical studies. Spindle cell carcinoma of the breast is rare, and definitive histopathological diagnosis is often difficult. When spindle cell carcinoma is suspected, comprehensive diagnostic studies including immunohistochemical examinations should be performed. Even in case with multiple recurrences correctly performed operations may contribute to prolongation of survival.

Esophageal reconstruction using a stomach roll following endoscopic mucosal resection.

A 73-year-old male patient presenting with synchronous triple cancer of the hypopharynx, esophagus and stomach is herein reported. To pursue safety by reducing surgical stress and better postoperative quality of life, we preserved the stomach by treating the gastric cancer by endoscopic mucosal resection and subsequently used the stomach for making an elongated stomach roll during the esophageal reconstruction. Postoperatively, no complications occurred and the patient has been on oral feeding for 23 months with no recurrence of primary cancer.

Analysis of predictive factors for recurrence after hepatectomy for colorectal liver metastases.

Hepatectomy for liver metastases from colorectal cancer has recently received general acceptance as a safe, potentially curative treatment. Most patients, however, die of recurrent disease after hepatectomy. The predictive factors for recurrence after first resection of liver metastases have not yet been clarified. The authors aimed to determine the factors that can predict recurrence, especially hepatic-only recurrence after hepatectomy for colorectal liver metastases. Seventy-six patients who underwent liver resection of colorectal metastases were studied retrospectively. Forty-seven (61.8%) of the patients had a recurrence. The patients' disease-free survival after first hepatectomy and the second recurrence sites were univariately and multivariately analyzed using 16 clinicopathologic variables. Wall invasion, lymph node metastases, lymphatic invasion, venous invasion of the primary tumor, 24 months or longer disease-free interval after resection of the primary colorectal cancer, and bilateral liver metastases significantly influenced the disease-free survival (log-rank test: p < 0.05). The multivariate analysis revealed that venous invasion of the primary tumor and bilateral hepatic metastases were independent risk factors for recurrence after hepatectomy. The liver was the only site of second recurrence in 23 patients. Patients with lymph node metastases and venous invasion of the primary tumor had a significant difference between hepatic-only and extrahepatic recurrence after first hepatectomy (chi-square test or Fishers' exact test: p < 0.05). Recurrence after hepatectomy was influenced more by factors associated with the primary colorectal cancer than factors surrounding the first liver metastases. Venous invasion of the primary colorectal cancer was the most important predictable factor for hepatic-only second recurrence.