Risk Factors and Clinical Outcomes of Recurrent Laryngeal Nerve Paralysis After Esophagectomy for Thoracic Esophageal Carcinoma.

BACKGROUND: The objectives of this study were to assess the incidence of recurrent laryngeal nerve paralysis (RLNP) using laryngoscopy after esophagectomy for thoracic esophageal carcinoma and to clarify the risk factors influencing postoperative RLNP. METHODS: A total of 299 patients who underwent laryngoscopic examination after esophagectomy were retrospectively reviewed. Patients who were found to have postoperative RLNP were followed up every 1­3 months, with a median follow-up period of 3 months. Recovery from paralysis was also evaluated on the basis of each affected nerve. Multivariate analyses using logistic regression were used to identify independent risk factors for RLNP. Cumulative recovery rate was calculated using Kaplan­Meier method. RESULTS: A total of 178 (59.5%) patients were diagnosed with RLNP by first laryngoscopy [bilateral in 59 (33.1%) patients, right in 15 (8.4%), and left in 104 (58.4%)]. In 206 patients who underwent transthoracic and thoracoscopic esophagectomy, independent risk factors for RLNP were lymph node dissection along the right RLN (odds ratio [OR] 3.01, 95% confidence interval [CI] 1.06­8.54, P = 0.04) and cervical anastomosis (OR 5.94, 95% CI 1.78­19.80, P < 0.01). Cumulative recovery rate from RLNP was 61.7% at 12 months after esophagectomy with 91 nerves eventually recovering from paralysis. Median recovery time was 6 months. CONCLUSIONS: RLNP developed in 60 % of patients after esophagectomy and may be associated with lymphadenectomy around the right RLN and cervical esophageal mobilization. Although 62% of affected nerves recovered within 12 months, great attention should be given when performing these procedures.

[Three cases of esophageal carcinoma achieved a pathological complete response after neoadjuvant chemotherapy with cisplatin and 5-fluorouracil].

We report three cases of esophageal carcinoma all of which achieved a pathological complete response after neoadjuvant chemotherapy (NAC) with cisplatin and 5-fluorouracil (CF). All three patients were men with clinical stage II squamous cell carcinoma of the middle thoracic esophagus. We administered 2 courses of CF treatment as NAC and then performed radical esophagectomy. Pathologic examination revealed no viable tumor cells in the resected esophagus. The patients are currently alive with no evidence of disease.

Intra-abdominal mucinous adenocarcinoma of urachal origin: report of a case.

Intra-abdominal mucinous cystic tumors can be difficult to diagnose preoperatively. We report a case of histologically diagnosed primary urachal adenocarcinoma: a rare type of bladder tumor. This case report is interesting for clinicians. The patient was an 86-year-old man who presented with acute abdominal pain. Computed tomography (CT) showed a large cystic mass with calcification, near the apex of the urinary bladder. Laparotomy revealed a large intra-abdominal cystic mass adherent to the anterior abdominal wall and superior to the urinary bladder. We performed laparoscopic-assisted resection and partial cystectomy. The cystic mass measured approximately 15 × 14 × 11 cm and contained mucinous material. Histological examination revealed that it extended to the muscle of the bladder wall and that its epithelium was composed of atypical cells with increased papillary morphology. The mucinous material was glycoprotein with degenerative fatty tissue, and calcification was recognized partly in the specimen. Thus, we comprehensively diagnosed a mucinous cystic adenocarcinoma of urachal origin.

Functional role of CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia.

Cancer development is often preceded by the appearance of preneoplastic lesions. In gastric carcinogenesis, chronic inflammation and histopathologic progression of the stomach epithelium lead to the development of metaplasia and eventually adenocarcinoma. The cell surface protein CD44, especially its variant isoforms (CD44v), has been implicated in metaplasia-carcinoma sequence progression in the stomach. We recently found that CD44v interacts with and stabilizes xCT, a subunit of the cystine transporter system xc(-), in cancer cells and thereby increases cystine uptake and confers resistance to various types of cellular stress in vivo. The functional relevance of CD44v and xCT in the development of preneoplastic lesions, however, has remained unknown. We have now examined the role of the CD44v-xCT system in the development of spasmolytic polypeptide-expressing metaplasia (SPEM) in mouse models of gastric carcinogenesis. CD44v was found to be expressed de novo in SPEM, and CD44v(+) metaplastic cells manifested upregulation of xCT expression compared with CD44v(-) cells. Genetic ablation of CD44 or treatment with sulfasalazine, an inhibitor of xCT-dependent cystine transport, suppressed the development of SPEM and subsequent gastric tumor growth. Therapy targeted to CD44v-xCT could thus prove effective for prevention or attenuation of the CD44v-dependent development of preneoplastic lesions and cancer.

Differential expression of basement membrane type IV collagen α2 and α6 chains as a prognostic factor in patients with extrahepatic bile duct carcinoma.

BACKGROUND: The destruction of the basement membrane (BM) is the first step in cancer invasion and metastasis. Type IV collagen is a major component of the BM, and is composed of six genetically distinct α(IV) chains; α1(IV) to α6(IV). The loss of α5(IV) and α6(IV) chains from the epithelial BM at the early stage of cancer invasion has been reported in several types of cancers. However, the expression of α5(IV) and α6(IV) chains in extrahepatic bile duct carcinoma (EBDC) remains unclear. METHODS: We examined the expression of α(IV) chains by immunohistochemistry using 71 resected EBDC specimens. Prognostic significance of α(IV) chains was examined by Cox regression and Kaplan-Meier analyses. RESULTS: In the invasive cancer, the expression of α6(IV) chain in the BM was lost partially or completely preceded by the loss of α2(IV) chain. The loss of α6(IV) chain in the BM of the invasive cancer was related to the tumor classification, TNM stages, and the expression of α2(IV) chain. The patients with α2(IV)-negative and α6(IV)-negative chains had significantly poorer prognosis than those with α2(IV)-positive and α6(IV)-positive/negative chains (P = 0.04). CONCLUSIONS: The loss of α2(IV) and α6(IV) chains might be a useful prognostic factor in patients with EBDC.

Preventive effect of sivelestat on postoperative respiratory disorders after thoracic esophagectomy.

PURPOSE: Sivelestat, a selective inhibitor of neutrophil elastase, has been reported to reduce acute lung injury associated with systemic inflammatory response syndrome. This study retrospectively investigated the effect of sivelestat on respiratory function in patients who underwent esophagectomy. METHODS: Patients who underwent esophagectomy for thoracic esophageal cancer between 2005 and 2010 were included in this study. Forty-two were treated perioperatively with sivelestat (4.8 mg/kg/day; sivelestat group) and the remaining 35 were not (control group). Sivelestat was administered continuously from the beginning of surgery until postoperative day 3. All patients were administered methylprednisolone for 3 days. The perioperative clinical and laboratory data, total sequential organ failure assessment score, PaO2/FiO2 ratio (P/F ratio) and postoperative complications were compared between the two groups. RESULTS: There were no significant differences between the groups in the patients' background data. The P/F ratio immediately after surgery was significantly higher in the sivelestat group than in the control group (p < 0.05). The respiratory rate immediately after surgery and the temperature on postoperative day 2 were significantly lower in the sivelestat group than in the control group (p < 0.05). There were no differences in any of the other clinical data or complications. CONCLUSIONS: Perioperative administration of sivelestat improves postoperative respiratory function in patients after esophagectomy.

Usefulness of transcription-reverse transcription concerted reaction method for detecting circulating tumor cells in patients with colorectal cancer.

PURPOSE: The CellSearch system (Veridex, LLC) is useful for detecting circulating tumor cells (CTCs) in various carcinomas, including colorectal cancer (CRC); however, there are some problems associated with its clinical use. A transcription-reverse transcription concerted reaction (TRC) method, which is a PCR-based technique producing more stable and reliable results, because it is a more simplified process compared with the conventional techniques, has been introduced for detecting micrometastasis in some carcinomas. We aimed to demonstrate the effectiveness of TRC method in the CTC detection. METHODS: We compared the two methods for the sensitivity for CTC detection using the colon cancer cell line and 42 whole-blood samples from patients with advanced or metastatic CRC. Furthermore, 25 patients with metastatic CRC were enrolled to investigate the correlation between CTC detection and prognosis in both methods. RESULTS: The sensitivity of the TRC method was similar to that of the CellSearch system. The overall survival rate was significantly worse in the patients diagnosed as CTC-positive by the TRC method than in those diagnosed as CTC-negative; this finding was similar to the prognosis indicated by the CellSearch system. However, clinically, the TRC method could detect CTCs more rapidly and at a reduced cost compared with the CellSearch system. CONCLUSIONS: The TRC method seems to be a useful alternative to the CellSearch system for clinically detecting CTCs in patients with metastatic CRC.

Lymphatic vessel invasion detected by the D2-40 monoclonal antibody is an independent prognostic factor in node-negative esophageal squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: D2-40 staining has been reported to be useful for both identifying lymphatic vessel invasion (LVI) and counting lymphatic vessel density (LVD) in various cancers. The aim of this study was to clarify the prognostic significance of D2-40 staining in patients with esophageal squamous cell carcinoma (ESCC). METHODS: A total of 159 consecutive patients with ESCC who underwent an esophagectomy with lymph node dissection were eligible. LVI was diagnosed by both hematoxylin-eosin (LVI-HE) and D2-40 staining (LVI-D2-40) in the largest central sections of the entire tumors, while both the intratumoral and peritumoral LVD were counted by D2-40 staining. The correlation between the prognosis and clinicopathological factors was investigated. RESULTS: An univariate analysis revealed that tumor invasion beyond the muscularis propria, lymph node metastasis (LNM), LVI-HE, LVI-D2-40, high intratumoral LVD, and blood vessel invasion correlated with worse patients' prognosis (P < 0.05). A multivariate analysis revealed LNM to be the only independent prognostic factor in all cases (P = 0.0083). On the other hand, when the prognostic factors of 83 patients without LNM were investigated, LVI-D2-40 was revealed to be the only independent prognostic factor (P = 0.048). CONCLUSIONS: LVI detected by D2-40 staining was an independent prognostic factor in patients with node-negative ESCC.

Induction chemotherapy with docetaxel/cisplatin/5-fluorouracil for patients with node-positive esophageal cancer.

BACKGROUND: Despite improvements in the surgical management of esophageal cancer, the prognosis of patients with lymph node metastases is still unsatisfactory. Recently, survival benefit of neoadjuvant or induction chemotherapy for patients with esophageal cancer has been highlighted. METHODS: Efficacy and toxicity of induction chemotherapy for esophageal cancer were reviewed. In addition, our experience on modified docetaxel/cisplatin/5-FU (DCF) as induction chemotherapy was also demonstrated. The modified DCF consisted of 60 mg/m² of docetaxel on day 1, and 350 mg/m² of 5-FU and 6 mg/m² of cisplatin on days 1-5. Two courses have been administered as induction chemotherapy in 51 patients with node-positive esophageal cancer. Response was evaluated by RECIST v1.0 and changes in standardized uptake value by ¹8F-fluorodeoxyglucose positron emission tomography. RESULTS: Induction chemotherapy may be beneficial for node-positive esophageal cancer, although the consensus has not yet been established. A regimen of induction chemotherapy should have a high response rate and cisplatin/5-FU may be underpowered as an induction setting. DCF can be a candidate for the regimen of induction chemotherapy for esophageal cancer, although severe adverse events have been reported. Several modified regimens to reduce the toxicity have been reported. The response rate of our series was 61% and a significant decrease in standardized uptake values was observed after the induction chemotherapy. Although high-grade neutropenia was still observed with this regimen, neither treatment-related death nor delay in the following treatment was observed. CONCLUSIONS: Modified DCF can be a regimen of induction chemotherapy for node-positive esophageal cancer because of its high efficacy, although an adequate care for severe neutropenia is needed.

Adenoviral oncolytic suicide gene therapy for a peritoneal dissemination model of gastric cancer in mice.

BACKGROUND: Peritoneal dissemination of gastric cancer is often refractory to systemic therapies. Although adenoviral gene therapy has been reported to be a potentially useful therapeutic modality, the adenovirus itself has a dose-limiting toxicity. A novel system was constructed using adenoviral oncolytic suicide gene therapy targeting carcinoembryonic antigen (CEA), and its therapeutic effect and the possibility to reduce the total viral dose while still preserving the antitumor effect were assessed. METHODS: Three types of adenoviruses were prepared for this novel system: (A) Ad/CEA-Cre, (B) Ad/lox-CD::UPRT for a Cre/loxP system, and (C) Ad/CEA-E1 for conditionally replicating adenovirus. The antitumor effect of the oncolytic suicide gene therapy (A + B + C) was then evaluated in vitro. Mice bearing peritoneal dissemination of human gastric cancer were treated with either this system (A + B + C) or with a tenfold viral dose of suicide gene therapy (A + B). The adverse effects in terms of hepatotoxicity were then evaluated between the two groups. RESULTS: The current system (A + B + C) demonstrated significantly better cytotoxic effect for CEA-producing cell lines than did suicide gene therapy (A + B) at the same viral dose in vitro. The effect of oncolytic suicide gene therapy was almost equal to that of the tenfold viral dose of suicide gene therapy in vivo. The hepatotoxicity of the two treated groups was also found to be equivalent. CONCLUSION: It was possible to reduce the total adenoviral dose of oncolytic suicide gene therapy while still preserving the antitumor effect.

Phosphorylated mTOR expression is associated with poor prognosis for patients with esophageal squamous cell carcinoma.

BACKGROUND: The mammalian target of rapamycin (mTOR) plays central roles in the regulation of cell growth and proliferation by monitoring nutrient availability, cellular energy level, oxygen level, and mitogenic signals. The aberrant activation of mTOR in relation to clinical outcome has been reported in several types of cancers. mTOR is increasingly important as a potential target for anticancer therapy. Nonetheless, a prognostic feature of mTOR activation in esophageal squamous cell carcinoma (ESCC) remains uncertain. MATERIALS AND METHODS: First, in order to validate phospho-specific mTOR antibody (Ser2448), phosphorylated mTOR (p-mTOR) expression levels in five ESCC cell lines under cultural conditions with or without everolimus (mTOR inhibitor, also known as RAD001) were evaluated by in vitro immunohistochemistry and immunoblotting. Second, we examined p-mTOR expression by immunohistochemistry using 143 resected ESCC specimens. Prognostic significance of p-mTOR expression was examined by Cox regression and Kaplan-Meier analyses. RESULTS: Among 143 patients, 71 (49.7%) were classified into p-mTOR-positive and 72 (50.3%) were classified into p-mTOR-negative. Compared with p-mTOR-negative patients, p-mTOR-positive patients experienced high overall mortality [hazard ratio (HR) 2.44; 95% confidence interval (CI), 1.24-4.83; P = 0.008], which persisted in multivariate analysis (multivariate HR 2.92; 95% CI, 1.48-5.78; P = 0.002). A similar finding was observed for esophageal cancer-specific mortality. p-mTOR expression was not related with any clinical or pathologic variables including age, sex, tumor location, histological grading, operative procedure, T classification (tumor invasion), or lymph-node metastasis. CONCLUSIONS: p-mTOR overexpression was independently associated with poor prognosis in ESCC, supporting the potential for mTOR as a therapeutic target for ESCC.

Extensive lymphatic spread of cancer cells in patients with thoracic esophageal squamous cell carcinoma: detection of CEA-mRNA in the three-field lymph nodes.

BACKGROUND AND OBJECTIVES: The aim of this study is to clarify the extent of lymphatic spread of cancer cells using a novel genetic test to examine patients with thoracic esophageal squamous cell carcinoma (ESCC). METHODS: A total of 35 patients who underwent an esophagectomy with three-field lymph node (LN) dissection were eligible. The regional LN stations were categorized into the cervical (C), recurrent nerve (RN), paraesophageal (PE), tracheo-bronchial (TB), and perigastric (PG) nodes. Lymphatic spread was pathologically diagnosed with Hematoxylin-Eosin (HE) and anti-cytokeratin immunohistochemistry (IHC) staining, and CEA-mRNA expression was examined using the transcription-reverse transcription concerted (TRC) reaction. RESULTS: The rates of lymphatic spread with HE, IHC, and TRC were 7.2%, 10.1%, and 55.5%, respectively. The number of CEA-mRNA(+) LN stations significantly correlated with tumor depth, LN metastasis diagnosed by HE, and vascular invasions. CEA-mRNA expression was observed in 42.9%, 94.3%, 77.1%, 80.0%, and 82.9% of C, RN, TB, PE, and PG nodes, respectively. CONCLUSIONS: The high frequency of CEA-mRNA expression suggests that systemic therapy is necessary in addition to esophagectomy with adequate LN dissection. Conversely, a relatively low frequency of CEA-mRNA expression in the C node does not support the routine dissection of the LNs in this area.

Gastric metastasis of malignant fibrous histiocytoma diagnosed preoperatively by endoscopic ultrasound-guided fine-needle aspiration biopsy: report of a case.

Metastatic gastric tumors originating from malignant fibrous histiocytoma (MFH) are rare. We herein report the case of a 75-year-old woman who underwent a distal gastrectomy for gastric metastasis of MFH, who was preoperatively diagnosed by an endoscopic ultrasound-guided fine-needle aspiration biopsy.

Multiple gastrointestinal stromal tumors in neurofibromatosis type 1: report of a case.

This report presents a case of multiple gastrointestinal stromal tumors (GIST) with neurofibromatosis type 1 (NF1). A 68-year-old woman was admitted to the hospital because of a tumor close to the head of the pancreas. Imaging studies revealed submucosal tumors of the duodenum. The retroperitoneal tumor was diagnosed before surgery. Besides the main tumor in the duodenum, multiple small submucosal tumors were found in the duodenum and upper part of the jejunum during the operation. All of these tumors were resected. The histological diagnosis of all these tumors was GISTs. These tumors were immunohistochemically positive for KIT, but they demonstrated no mutation in c-kit exons 9, 11, 13, and 17, and platelet-derived growth factor receptor alpha exons 12 and 18. No recurrence occurred for a year after surgery.

Strangulation of the small intestine caused by an intra-mesosigmoid hernia: a case report.

Sigmoid mesocolon hernia is an uncommon type of internal hernia with only a few cases reported to date. This disease entity can progress rapidly to cause vascular disturbance, necrosis, and perforation of the bowel wall; therefore, early diagnosis and surgical treatment are essential. We describe the case of an intra-mesosigmoid hernia in a 60-year-old man without history of previous abdominal surgery who presented with sudden acute abdominal pain and vomiting. Based on computed tomography, which showed ascites and small bowel obstruction, we diagnosed him as having strangulation of the small intestine caused by a sigmoid mesocolic hernia and performed emergency surgery. Laparotomy revealed small intestinal strangulation, extensive engorgement, and discoloration of bowel loops. Approximately 100 cm of the small intestine extending from the ligament of Treitz had undergone strangulation and herniated into the defect of sigmoid mesocolon, leading to a diagnosis of an intra-mesosigmoid hernia. Because the incarcerated portion of the small intestine was viable, we did not perform intestinal resection and reconstruction but closed the defect in the sigmoid mesocolon. His postoperative course was uneventful.

Benign esophageal schwannoma: a brief overview and our experience with this rare tumor.

BACKGROUND: Benign esophageal tumors are uncommon, comprising approximately 2% of esophageal tumors. Esophageal schwannomas constitute an even rarer entity, with few cases reported in the literature. CASE PRESENTATION: We present a 66-year-old male who was referred for dysphagia. A computed tomography scan showed a well-demarcated, enhancing, and homogenous esophageal tumor measuring 50 mm. The tumor was hypermetabolic on positron emission tomography, and an endoscopic ultrasound-guided fine needle aspiration demonstrated the presence of benign spindle cells. We performed an uncomplicated, simple, tumor enucleation through a cervical approach. Histology revealed spindle-shaped cells in a fasciculated, disarrayed pattern. Immunohistochemistry demonstrated positive staining for S-100 protein and negative staining for KIT, CD34, desmin, and α-smooth muscle actin. These findings were consistent with a benign esophageal schwannoma. CONCLUSIONS: We report our experience with esophageal schwannoma, a rare but benign diagnosis of the esophagus.

Internal hernia after laparoscopic-assisted proximal gastrectomy with jejunal interposition for gastric cancer: a case report.

Internal hernia after gastrectomy is a rare complication. It can progress rapidly to vascular disturbance, necrosis, and perforation, therefore early diagnosis and surgical treatment is essential. We present a case of internal hernia following laparoscopic-assisted proximal gastrectomy with jejunal interposition reconstruction in a 68-year-old man, who presented with acute abdominal pain and vomiting. Computed tomography showed a whirl sign, ascites, and a closed-loop formation of the small intestine. We diagnosed an internal hernia and performed emergency surgery. Laparotomy revealed chyle-like ascites and extensive small intestine with poor color. We recognized that about 20 cm of jejunum from the ligament of Treitz was strangulated behind the pedicle of the jejunum lifted during laparoscopic-assisted proximal gastrectomy. We relieved the strangulation, whereupon the color of the strangulated intestine was restored. Therefore, we did not perform intestinal resection and reconstruction. Finally, we fixed the jejunal pedicle and mesentery of the transverse colon. We report this case as there are few reported cases of internal hernia after laparoscopic-assisted proximal gastrectomy.

Prognostic significance of peritoneal lavage cytology at three cavities in patients with gastric cancer.

BACKGROUND: We sought to determine the prognostic significance of intraoperative peritoneal lavage cytology (CY) at 3 different abdominal cavities and establish the optimal treatment for gastric cancer patients with positive peritoneal cytology (CY1). METHODS: A total of 1,039 patients with primary gastric adenocarcinoma who underwent CY at 3 cavities (Douglas' pouch, left subphrenic cavity, and right subhepatic cavity) were enrolled; 116 (11%) patients had at least one positive cavity. We retrospectively analyzed the clinicopathologic characteristics and survival of these 116 patients with CY1. RESULTS: Seventeen (15%) of the patients had negative cytology at Douglas' pouch but positive cytology at one or both of the other cavities. The 116 patients' overall 2-year survival rate was 22.9%, with the median survival time of 11 months. The overall 2-year survival rates for the patients with positive cytology at 1, 2, and 3 cavities were 41.9%, 35.8%, and 15%, with median survival times of 17, 18, and 9 months, respectively (P < .01). A multivariate analysis revealed that macroscopic type 4 tumor, R2 resection, lymph node metastasis, and postoperative chemotherapy were independent prognostic factors. Among the CY1 patients with type 4 tumors, there was no substantial difference in survival between the patients who underwent R1 or R2 resection, although the statistical power of this subgroup analysis was low. CONCLUSION: CY at 3 cavities might be a useful method to decrease the false-negative rate. Palliative gastrectomy for CY1 patients with type 4 tumors is still controversial.

SPINK1 Status in Colorectal Cancer, Impact on Proliferation, and Role in Colitis-Associated Cancer.

UNLABELLED: Colorectal cancer is a major cause of deaths due to cancer; therefore, research into its etiology is urgently needed. Although it is clear that chronic inflammation is a risk factor for colorectal cancer, the details remain uncertain. Serine protease inhibitor, Kazal type 1 (SPINK1) is mainly produced in pancreatic acinar cells. However, SPINK1 is expressed in various cancers and in inflammatory states, such as colon cancer and inflammatory bowel disease. There are structural similarities between SPINK1 and epidermal growth factor (EGF). Hence, it was hypothesized that SPINK1 functions as a growth factor for tissue repair in inflammatory states, and if prolonged, acts as a promoter for cell proliferation in cancerous tissues. Here, immunohistochemical staining for SPINK1 was observed in a high percentage of colorectal cancer patient specimens and SPINK1 induced proliferation of human colon cancer cell lines. To clarify its role in colon cancer in vivo, a mouse model exposed to the colon carcinogen azoxymethane and nongenotoxic carcinogen dextran sodium sulfate revealed that Spink3 (mouse homolog of SPINK1) is overexpressed in cancerous tissues. In Spink3 heterozygous mice, tumor multiplicity and tumor volume were significantly decreased compared with wild-type mice. These results suggest that SPINK1/Spink3 stimulates the proliferation of colon cancer cells and is involved in colorectal cancer progression. IMPLICATIONS: Evidence suggests that SPINK1 is an important growth factor that connects chronic inflammation and cancer.