Stability of cervical esophagogastrostomy via hand-sewn anastomosis after esophagectomy for esophageal cancer.

The aim of the present study is to evaluate the outcome of hand-sewn esophagogastric anastomosis during radical esophagectomy for esophageal cancer. The outcomes of 467 consecutive esophageal cancer patients who underwent cervical esophagogastric anastomosis using interrupted and double-layered sutures after radical esophagectomy via right thoracotomy or thoracoscopic surgery were retrospectively reviewed. Anastomotic leakage, including conduit necrosis, occurred in 11 of 467 patients (2.4%); 7 of 11 (63.6%) cases experienced only minor leakage, whereas the other four (36.4%) patients had major leakage that required surgical or radiologic intervention, including two patients of conduit necrosis. Anastomotic leakages were more frequently observed after retrosternal reconstruction compared with the posterior mediastinal route (P < 0.0001). The median time to healing of leakage was 40 days (range: 14-97 days). Two patients (2/467, 0.4%) died in the hospital due to sepsis caused by the leakage and conduit necrosis. Twelve patients (2.6%) developed anastomotic stenosis, which was improved by dilatation in all patients. Hand-sewn cervical esophagogastric anastomosis is a stable and highly safe method of radical esophagectomy for esophageal cancer.

Hypoxia-induced Jagged2 promotes breast cancer metastasis and self-renewal of cancer stem-like cells.

Notch signaling is often and aberrantly activated by hypoxia during tumor progression; however, the exact pathological role of hypoxia-induced Notch signaling in tumor metastasis is as yet poorly understood. In this study, we aimed to define the mechanism of Notch-ligand activation by hypoxia in both primary tumor and bone stromal cells in the metastatic niche and to clarify their roles in tumor progression. We have analyzed the expression profiles of various Notch ligands in 779 breast cancer patients in GEO database and found that the expression of Jagged2 among all five ligands is most significantly correlated with the overall- and metastasis-free survival of breast cancer patients. The results of our immunohistochemical (IHC) analysis for Jagged2 in 61 clinical samples also revealed that both Jagged2 and Notch signaling were strongly upregulated at the hypoxic invasive front. Activation of Jagged2 by hypoxia in tumor cells induced EMT and also promoted cell survival in vitro. Notably, a γ-secretase inhibitor significantly blocked Notch-mediated invasion and survival under hypoxia by promoting expression of E-cadherin and inhibiting Akt phosphorylation. Importantly, Jagged2 was also found to be upregulated in bone marrow stroma under hypoxia and promoted the growth of cancer stem-like cells by activating their Notch signaling. Therefore, hypoxia-induced Jagged2 activation in both tumor invasive front and normal bone stroma has a critical role in tumor progression and metastasis, and Jagged2 is considered to be a valuable prognostic marker and may serve as a novel therapeutic target for metastatic breast cancer.

Laparoscopy-assisted appendectomy through an umbilical port in children.

INTRODUCTION: We report surgical techniques for single-incision laparoscopy-assisted surgery (SILAS) in the treatment of pediatric acute appendicitis. METHODS: We performed SILAS in 15 cases of acute appendicitis between January and September of 2009. SILAS is a surgical method that involves making the incision at the umbilicus, inserting a wound retractor XS, suspending the abdominal wall with a hook, and appendectomy with the same procedures as conventional appendectomy. RESULTS: SILAS appendectomy was performed in all 15 cases with the exception of one case where one 3-mm port was added. Compared to open appendectomy, blood loss was significantly lower and postoperative hospitalization time was shorter, although there was no significant decrease in operative time, or postoperative fasting time. No postoperative complications, such as wound infection, intestinal obstruction, intra-abdominal abscess, or bleeding, were encountered. CONCLUSION: SILAS was safely performed and is superior to open appendectomy with regard to cosmetic outcome.

Minimally invasive surgical enucleation for esophageal leiomyoma: report of seven cases.

Benign esophageal tumor is a rare entity, with leiomyoma being the most common lesion. We present our experience with enucleation of esophageal leiomyomas using a minimally invasive approach. Between March 1998 and June 2008, seven patients with esophageal leiomyoma underwent right thoracosopic enucleation (n=4) or laparoscopic transhiatal enucleation (n=3). A Dor (n=2) or Toupet fundoplication (n=1) were added for laparoscopic procedure. The mean tumor size was 3.9 cm (range, 1.5-5.5 cm). Tumor locations were upper (n=2), middle (n=1), and lower (n=4) thirds of the esophagus. No major morbidities including postoperative leakage or mortalities occurred. At a mean follow-up period of 60.1 months (range, 14-260 months), no evidence of recurrences were observed. Thoracoscopic and laparoscopic transhiatal enucleation for esophageal leiomyomas is a safe and feasible procedure. The optimal approaches should be tailored based on the location and size of the tumor.

Laparoscopic Heller myotomy with Dor fundoplication for achalasia: long-term outcomes and effect on chest pain.

The aim of the present study was to evaluate the long-term outcomes of laparoscopic Heller myotomy with Dor fundoplication (LHD) and its effect on chest pain. Between June 1995 and August 2009, a total of 35 patients with achalasia underwent an LHD. The symptom scores were calculated by combining the frequency and the severity. Pre- and postoperative evaluations included symptom score, radiology, manometry, and 24-hour pH manometry. Median total symptom score was significantly lower than the preoperative score (19 vs 4, P < 0.001) at a median follow-up of 94 months. Among the 35 patients, 18 (51%) had chest pain. The frequency of chest pain was similar for the pre- and postoperative scores, but the severity tended to be less. Median esophageal diameter (5.4 cm vs 3.5 cm, P < 0.001) and lower esophageal sphincter pressure (41 mmHg vs 8.9 mmHg, P < 0.001) were significantly reduced after surgery. Median age, duration of symptoms, esophageal diameter, and lower esophageal sphincter pressure were similar between patients with and without chest pain prior to surgery. No significant differences were observed between the two groups in terms of amplitude, duration, and frequency of contractions from the findings of postoperative 24-hour esophageal manometry. Chest pain resolved in three patients (17%) and improved in seven patients (39%) after surgery. LHD can durably relieve achalasic symptoms of both dysphagia and regurgitation, and it can be considered the surgical procedure of choice. However, achalasic chest pain does not always seem to be related with patient characteristics and manometric findings.

Cytokine profile of serum and bronchoalveolar lavage fluids following thoracic esophageal cancer surgery.

OBJECTIVES: The body's response to stress is comprised of two opposing reactions, namely inflammation and immunosuppression. The balance between these two reactions not only changes over time, but also varies among different cells or organs. Limited information is available regarding the cytokine balance of circulating blood and inflammatory sites after thoracic surgical stress. DESIGN: The subjects of the present study were 10 patients undergoing esophageal cancer surgery which requires thoracolaparotomic manipulation. The postoperative levels of interleukin (IL)-8, IL-10, IL-1 receptor antagonist (IL-1ra) and soluble tumor necrosis factor receptor I (sTNF-RI) in bronchoalveolar lavage fluids (BALFs) and peripheral blood were measured by enzyme-linked immunosorbent assay. The absolute concentration of cytokines in lower respiratory tract ([cytokine](LRT)) was estimated by using the ratio of urea concentration in BALF and serum. RESULTS: The levels of these cytokines in peripheral blood peaked within 24 h of start of the surgery (IL-8 85.6 +/- 29.8 pg/ml; IL-10 65.1 +/- 10.6 pg/ml; IL-1ra 2,807.8 +/- 652.8 pg/ml, and sTNF-RI 3,996.3 +/- 380.1 pg/ml). The level of [IL-8](LRT) immediately after surgery was approximately 20 times higher than that in peripheral blood, and the level of [IL-1ra](LRT) was approximately 4 times higher. In contrast, the level of [IL-10](LRT) immediately after surgery was comparable to that in peripheral blood, but the level of [sTNF RI](LRT) immediately after surgery was approximately one fifth of that in peripheral blood. CONCLUSIONS: The balance between pro- and anti-inflammatory reactions varies from one part of the body to the next, and changes over time after surgery. The profile of stress-induced pro-inflammatory cytokines and anti-inflammatory cytokines should be analyzed further to establish appropriate and effective cytokine modulatory therapeutic approaches.

Chemoradiotherapy followed by surgery for thoracic esophageal cancer potentially or actually involving adjacent organs.

The objective of this study was to evaluate the therapeutic usefulness of chemoradiotherapy (CRT) followed by surgery in patients with clinically T4 (cT4) esophageal cancer involving adjacent organs such as the trachea, main bronchi, and large vessels. Thirty-seven patients with cT4 squamous cell carcinoma of the thoracic esophagus were enrolled in this study. The CRT regimen comprised cisplatin (70 mg/m2) on day 1, 5-fluorouracil (700 mg/m2) on days 1-4 and external irradiation (200 cGy/day, total 30 Gy) on either days 8-26 (sequential schedule, n=15) or days 1-19 (concurrent schedule, n022). Two courses of CRT were given. The results of CRT were complete response in nine patients, partial response in 19, no change in three (minor response in two), and progressive disease in six patients. The median response duration in all responders was 172 days (range: 56-2469, n=19). After CRT, 13 patients received surgery. In 12 of these patients, tumors were completely resected. Histopathologic examination of the resected specimen revealed a discrepancy between clinical response and histopathologic effect. The median duration of survival and the 1-, 2- and 5-year survival rates were 304 days (84-3155), 45%, 35% and 23% in all patients, respectively, 866 days (190-3155), 83%, 83% and 57% in the 13 patients whose tumors were resected, and 187 days (84--2630), 25%, 5% and 5% in the 24 patients whose tumors were not resected. Grade 3 toxicity, especially hematological reactions, was noted in 13.5% (5/37) of the patients. There was one toxicity-related death (sepsis). A good outcome may be obtained with CRT, followed by surgery when feasible. However, CRT can cause toxic reactions, and close monitoring of patients is required.

[SIRS in surgical stress].

It has been suggested that SIRS are triggered by superfluous pro-inflammatory cytokine production, and that organ injury is caused by uncontrolled inflammatory responses. However, the results of clinical studies, on the usefulness of specific cytokine antagonists and anti-TNF antibodies for the treatment of septic shock, have been unsatisfactory. The reason for this might have been that when uncontrolled inflammatory reactions progressed locally, anti-inflammatory reactions were elevated in the circulated blood by way of CARS, thus the timing of administration and pharmacokinetics did not match clinical course. Recent research has shown that SIRS is always accompanied by CARS, and since it seems to do the amplitude of SIRS and CARS to each other so that there may be a deep valley, if there is a high mountain. We introduce the recent knowledge which indicates that SIRS is a preliminary alert for not only organ dysfunction but also immunosuppression after severe injury or major surgery.

Problems in neoadjuvant chemoradiotherapy preceding surgery for advanced squamous cell carcinoma of the thoracic esophagus.

The adverse effect of neoadjuvant chemoradiotherapy on the postoperative course in esophageal cancer was studied in 9 patients undergoing neoadjuvant chemoradiotherapy preceding surgery for thoracic esophageal carcinoma possibly involving adjacent organs (neoadjuvant group), and 13 patients undergoing surgery without neoadjuvant therapy for same disease (control group). The two groups were compared for volume of intraoperative hemorrhage, surgical duration, frequency of postoperative morbidity, and for postoperative changes in blood platelet counts, and serum thrombopoietin and interleukin-6 levels. Mean intraoperative blood loss was 1121 g (580-1,662 g) in the neoadjuvant group and 546.5 g (274.7-778.3 g) in controls group (Student's T test: p < 0.01). No significant difference was seen found between the two groups in the degree of postoperative deterioration in cardiopulmonary function or in interleukin-6 levels. Blood platelet counts decreased in both groups until postoperative day 7, but recovery on postoperative day 14 was significantly depressed in the neoadjuvant group compared to controls. Serum thrombopoietin levels were higher in the neoadjuvant group than in controls (Mann-Whitney U-test: p < 0.05). We found that neoadjuvant chemoradiotherapy induces latent postoperative myelosuppression and may lead to intractable infection.

Infrequent frameshift mutations of polynucleotide repeats in multiple primary cancers affecting the esophagus and other organs.

Frequent frameshift mutations of simple nucleotide repeats in the protein-encoding regions, as well as replication errors (RERs) at microsatellite loci, have recently been demonstrated in gastrointestinal tumors. These genetic instabilities have been considered indicative of an increased risk of accumulating mutations in cancer-associated genes and of developing multiple cancers. We studied frameshift (or insertion/deletion) mutations of simple nucleotide repeats in five genes (TGFbeta type II receptor [TGFbetaRII], E2F4, MSH2, MSH3, and MSH6) in 23 tumors from 12 patients who had synchronous cancers of the esophagus and other organs. Genetic instability at four microsatellite loci, as well as mutations in the TP53, APC, and KRAS2 genes, were also studied. No frameshift mutations were observed in the TGFbetaRII, MSH3, and MSH6 genes. RER and a deletion mutation of BAT26 in MSH2 were present in one (1/23; 4%) gastric cancer. This tumor also carried a deletion mutation in the serine (AGC) repeat of the E2F4 gene. Mutation screening of the TP53, APC, and KRAS2 genes revealed that the synchronous cancers did not carry the same mutations. Our results suggested that genetic instability, such as insertion/deletion mutations in simple nucleotide repeats, is not significantly associated with the development of multiple primary cancers of the esophagus and other organs, and that these synchronous cancers developed independently according to their different environmental factors.

Pharmacokinetics of cisplatin in combined cisplatin and 5-fluorouracil therapy: a comparative study of three different schedules of cisplatin administration.

BACKGROUND: Cisplatin is widely used in combination chemotherapy against a variety of tumors; however, the optimal administration schedule of cisplatin is still controversial. To clarify the pharmacokinetic differences according to the administration schedules of cisplatin, we compared three different administration schedules of cisplatin such as single short-term infusion, daily short-term infusion and daily continuous infusion in combination with 5-fluorouracil. Preliminary clinical responses and toxicities were also investigated. METHODS: A total of 12 courses in combination of cisplatin and 5-fluorouracil therapy was studied. The schedules of cisplatin tested were as follows: single short-term infusion (80 mg/m2, day 1,2 h div., n = 4), daily short-term infusion (20 mg/m2, days 1 to 5, 2 h div., n = 4), daily continuous infusion (100 mg/m2, 120 h, n = 4). In all schedules, 5-fluorouracil was continuously administered at a dose of 800 mg/m2/day on days 1 to 5. The area under the time-concentration curve (AUC) and the maximum concentration (Cmax) of total and free Pt were investigated. RESULTS: The highest AUC of total and free Pt and the lowest Cmax of free Pt were observed in the daily continuous infusion (total AUC; 162.53 +/- 18.39 micrograms h/ml, free AUC; 5.50 +/- 0.9 micrograms h/ml, free Cmax; 0.07 +/- 0.01 microgram/ml, mean +/- SEM). Two patients in the single short-term infusion and one patient in the daily continuous infusion indicated partial responses clinically. No nephrotoxicity or ototoxicity was observed. All toxicities were mild and tolerable in all regimens; however, the incidence of GI toxicity in daily continuous infusion seemed to be relatively higher. CONCLUSIONS: Daily continuous infusion of cisplatin gave the best pharmacokinetic results and to evaluate the clinical advantage of this schedule a prospective randomized trial should be conducted with sufficient numbers of patients.

[Treatment of patients with recurrent esophageal carcinoma].

From 1987 to 1997, 211 patients with thoracic esophageal carcinoma underwent radical surgery. The 5 year survival rate was 87% in pTNM stage I, 64% in stage II A, 57% in stage II B, and 31% in stage III. The survival curve was improved by postoperative chemotherapy including CDDP/5-FU as compared with surgery alone. Relapse occurred in 59 of these patients (28%). Lymphatic recurrence was recognized in 32 patients, hematogenic recurrence in 19, mixed type in 4, and intramural or local recurrence in 4 patients. In spite of through lymph node dissection, postoperative lymphatic recurrence was most frequent at the upper mediastinum and neck. Among hematogenic metastases, pulmonary and hepatic metastases were observed at equal incidences. The 1 year survival rate and median survival period of the patients with recurrent carcinoma were 36% and 191 days (26-1,122), respectively. There was no significant difference in prognosis between lymphatic and hematogenic recurrence. The prognosis for patients who underwent active therapy for recurrence (42 cases) was significantly better than for those who underwent only palliative therapy (17 cases). Resection of the site of recurrence was performed in 4 cases. The combination therapy of resection or irradiation and combined chemotherapy with CDDP and 5-FU resulted in a better prognosis (median survival period was 504 days) than irradiation alone or chemotherapy alone. In conclusion, early diagnosis and active multimodality therapy were important to improve the prognosis of recurrent esophageal carcinoma.

[Clinical experiences with the insertion of dynamic stent for the patients with esophago-tracheal fistula due to advanced esophageal carcinoma--two case reports].

We experienced two cases who were inserted dynamic stent (a tracheobronchial silicone stent) to treat esophago-tracheal fistula due to advanced esophageal carcinoma. This procedure permitted to perform esophageal bypass operation under intubated general anesthesia in the first case. After operation, severe coughing improved so much and he could start oral intake and resulted in better performance status. In the second case, by the insertion of dynamic stent general condition recovered well, so he could achieve full course of chemo-radiotherapy and enter in partial response. Esophago-tracheal fistula due to advanced esophageal carcinoma markedly worsens performance status and its treatment is usually very difficult. The insertion of dynamic stent may improved their quality of life, make it possible to achieve further therapy and improve their prognosis.

[Experimental study of biochemical modulation of 5-fluorouracil with l-leucovorin against human esophageal cancer].

Potentiation of cytotoxic effects of 5-fluorouracil (5-FU) were investigated by simultaneous or sequential combination of l-leucovorin (LV) against human esophageal cancer cell line (TE-1, TE-2) and 23 human clinical cancer samples in vitro. LV enhanced the cytotoxic effects of 5-FU on human esophageal cancer cell line as a dose dependent manner, and increased the cytotoxic effect of 5-FU about 1.5-fold with 10 microM and about 2-fold with 100 microM. The incubation time did not affect the effects. The potentiation with LV was also demonstrated against human clinical cancer samples, and the cytotoxic effects of 5-FU increased 7.6% in esophageal cancer, 20.9% in gastric cancer and 25.5% in colorectal cancer. As a result, the potentiating effects of LV against 5-FU seemed to be limited on human esophageal cancer.