A case study of pyloric stenosis caused by metastatic lobular carcinoma of breast.

Metastasis to the gastrointestinal tract is rare. A 59-year-old woman who had a history of an invasive lobular carcinoma of breast with clinical complete response visited our hospital and complained of an upper abdominal pain and distension. We performed an upper gastrointestinal endoscopy which showed only a gastric ulcer without any malignant findings. She experienced a recurrence of symptoms 2 months after this visit. An endoscopy revealed pyloric stenosis, which did not improve with balloon dilatation. We performed a gastro-jejunal and cecal-transverse colonic bypass surgery. Diffuse wall thickening of the antrum was verified during the surgery, and a biopsy sample was collected. The diagnosis of gastric metastasis from breast was confirmed since it showed the same immunohistochemistry pattern as the prior breast lesion. Pyloric stenosis has still been confirmed with an endoscopy, she has been alive with satisfactory oral food intake for >10 years.

Laparoscopic repair of diaphragmatic hernia associating with radiofrequency ablation for hepatocellular carcinoma: A case report.

BACKGROUND: Radiofrequency ablation (RFA) is an effective treatment for early-stage hepatocellular carcinoma (HCC). Although RFA is a relatively safe technique compared with surgery, several complications have been reported to be following/accompanying this treatment. Delayed diaphragmatic hernia caused by RFA is rare; however, the best surgical approach for its treatment is uncertain. We present a case of laparoscopic repair of diaphragmatic hernia due to RFA. CASE SUMMARY: An 80-year-old woman with segment VIII HCC was treated twice in 5 years with RFA; 28 mo after the second RFA, the patient complained of right hypochondriac pain. Computed tomography revealed that the small intestine was incarcerated in the right thorax. The patient was diagnosed with diaphragmatic hernia and underwent laparoscopic repair by non-absorbable running sutures. The patient's postoperative course was favorable, and the patient was discharged on postoperative day 12. The diaphragmatic hernia has not recurred 24 mo after surgery. CONCLUSION: Laparoscopic treatment of iatrogenic diaphragmatic hernia is effective and minimally invasive.

Regulation of MRE11A by UBQLN4 leads to cisplatin resistance in patients with esophageal squamous cell carcinoma.

Resistance to standard cisplatin-based chemotherapies leads to worse survival outcomes for patients with esophageal squamous cell carcinoma (ESCC). Therefore, there is an urgent need to understand the aberrant mechanisms driving resistance in ESCC tumors. We hypothesized that ubiquilin-4 (UBQLN4), a protein that targets ubiquitinated proteins to the proteasome, regulates the expression of Meiotic Recombination 11 Homolog A (MRE11A), a critical component of the MRN complex and DNA damage repair pathways. Initially, immunohistochemistry analysis was conducted in specimens from patients with ESCC (n = 120). In endoscopic core ESCC biopsies taken from 61 patients who underwent neoadjuvant chemotherapy (NAC) (5-fluorouracil and cisplatin), low MRE11A and high UBQLN4 protein levels were associated with reduced pathological response to NAC (P < 0.001 and P < 0.001, respectively). Multivariable analysis of surgically resected ESCC tissues from 59 patients revealed low MRE11A and high UBLQN4 expression as independent factors that can predict shorter overall survival [P = 0.01, hazard ratio (HR) = 5.11, 95% confidence interval (CI), 1.45-18.03; P = 0.02, HR = 3.74, 95% CI, 1.19-11.76, respectively]. Suppression of MRE11A expression was associated with cisplatin resistance in ESCC cell lines. Additionally, MRE11A was found to be ubiquitinated after cisplatin treatment. We observed an amplification of UBQLN4 gene copy numbers and an increase in UBQLN4 protein levels in ESCC tissues. Binding of UBQLN4 to ubiquitinated-MRE11A increased MRE11A degradation, thereby regulating MRE11A protein levels following DNA damage and promoting cisplatin resistance. In summary, MRE11A and UBQLN4 protein levels can serve as predictors for NAC response and as prognostic markers in ESCC patients.

IL-8/CXCR2 Signalling Promotes Cell Proliferation in Oesophageal Squamous Cell Carcinoma and Correlates With Poor Prognosis.

BACKGROUND/AIM: The inflammatory cytokine IL-8 and its receptor CXCR2 are key signalling pathway molecules in cancer development. We hypothesized that IL-8/CXCR2 signalling promotes tumour progression in oesophageal squamous cell carcinoma (ESCC) patients. MATERIALS AND METHODS: We examined the relationship between IL-8/CXCR2 expression and clinicopathological factors by immunohistochemistry in samples from 63 patients with resectable ESCC. The effects of IL-8/CXCR2 signalling on cell proliferation and gene expression were examined in vitro and in vivo using ESCC cell lines. RESULTS: Increased IL-8/CXCR2 signalling was associated with shorter overall survival (p<0.05) and recurrence-free survival (p<0.05) in ESCC patients. Multivariate analysis identified IL-8/CXCR2 expression as a prognostic factor for surgically treated ESCC (p<0.05). In vitro, IL-8 exposure or over-expression significantly enhanced ESCC cell proliferation. SB225002, a CXCR2-specific antagonist, and IL-8 siRNA significantly suppressed cell proliferation. CONCLUSION: IL-8/CXCR2 expression is an independent prognostic factor for surgically treated ESCC, and IL-8/CXCR2 signalling contributes to ESCC cell proliferation.

Recurrence after ESD curative resection for early gastric cancer.

BACKGROUND: Endoscopic submucosal dissection (ESD) is gaining ground as a minimally invasive treatment for early gastric cancer (EGC) that has a negligible risk of lymph node metastasis. According to the 5th edition of Japanese gastric cancer treatment guidelines, annual or biannual follow-up with endoscopy is recommended, but follow-up with abdominal ultrasonography or computed tomography (CT) for surveillance of metastases is not recommended after the eCuraA resection. However, we experienced a case of lymph node recurrence following ESD resulting in eCuraA. CASE PRESENTATION: A 76-year-old female received ESD for EGC in a previous hospital 4 years ago. Pathological findings were tub1, 30 mm, T1a (M), UL0, Ly0, V0, pHM-, pVM- (eCuraA) according to the 15th edition of Japanese Classification of Gastric Carcinoma. Follow-up esophagogastroduodenoscopy revealed submucosal tumor, which was suspected as a swollen lymph node by CT and endoscopic ultrasound fine-needle aspiration revealed the recurrence of gastric cancer. We performed total gastrectomy with D2 lymph node dissection. Postoperative pathological examination revealed no local recurrent tumor at the ESD site in the stomach. Swollen lymph node was diagnosed as metastasis and lymph node metastasis was limited near the cardia. CONCLUSION: This case provides valuable information about tumor with a minimum poorly differentiated adenocarcinoma component may develop lymph node metastasis even satisfying the guidelines criteria for curative resection.

Validation Study of Fibrinogen and Albumin Score in Esophageal Cancer Patients Who Underwent Esophagectomy: Multicenter Prospective Cohort Study.

PURPOSE: To arrange multidisciplinary treatment for esophageal cancer, a simple and accurate predictive marker for prognosis is required. The current multicenter prospective study aims to validate the prognostic significance of fibrinogen and albumin score (FA score) for esophageal cancer patients. PATIENTS AND METHODS: Patients who were planned to undergo surgical resection for esophageal cancer at four participating institutions were enrolled in this study. Patient background, clinicopathological factors, and blood concentration of plasma fibrinogen and albumin were collected. Patients with elevated fibrinogen and decreased albumin levels were allocated a score of 2; those with only one of these abnormalities were allocated a score of 1; and those with neither of these abnormalities were allocated a score of 0. Recurrence-free survival (RFS) and overall survival (OS) were evaluated as a primary endpoint. RESULTS: From four participating institutions, 133 patients were registered for the current analysis. The distribution of FA score of 0/1/2 was 84 (63%)/34 (26%)/15 (11%), respectively. In the analysis of primary endpoint, the preoperative FA score significantly classified RFS (FA score 1/2: HR 2.546, p = 0.013/6.989, p < 0.001) and OS (FA score 1/2: HR 2.756, p = 0.010/6.970, p < 0.001). We further evaluated the prognostic significance of FA score under stratification by pStage. As a result, with increasing FA score, RFS and OS were significantly worse in both pStage 0-I and II-IV groups. CONCLUSIONS: The prognostic impact of preoperative FA score was confirmed for esophageal cancer patients in the current multicenter prospective trial. FA score can be considered to predict postoperative survival and rearrange the treatment strategy before esophagectomy.

Inflammatory breast cancer associated with amyopathic dermatomyositis: a case report.

BACKGROUND: Dermatomyositis is associated with malignant tumors including breast cancer, and inflammatory breast cancer is considered to have a poorer prognosis than most breast cancers. CASE PRESENTATION: A 74-year-old Asian woman, developed erythema on her face, back, and the back of her hands, 3 weeks before attending our department. At the same time, she had noticed a right breast mass and redness of the skin of the breast. The clinical findings and vacuum aspiration biopsy diagnosed inflammatory breast cancer and neoadjuvant chemotherapy was performed. The mass and enlarged axillary lymph nodes had shrunk, therefore a total mastectomy was performed. The sentinel lymph node biopsy was negative. She was discharged 7 days after surgery without any complications. She has received a postoperative aromatase inhibitor and is alive without recurrence. The dermatomyositis also began to improve with the start of her chemotherapy and has not recurred since the surgery. CONCLUSIONS: Neoadjuvant chemotherapy was performed for inflammatory breast cancer with dermatomyositis, and tumor shrinkage was confirmed. A total mastectomy without axillary lymph node dissection was performed. Dermatomyositis and breast cancer have not recurred. Dermatomyositis may have been a paraneoplastic syndrome due to breast cancer.

Utility of the one-step nucleic acid amplification assay in sentinel node mapping for early gastric cancer patients.

BACKGROUND: To safely perform minimized gastrectomy based on sentinel node (SN) concept for early gastric cancer patients, intraoperative diagnostic accuracy is indispensable. This study aimed to evaluate the clinical utility of the one-step nucleic acid amplification (OSNA) assay in the intraoperative diagnosis of SN metastasis in early gastric cancer patients compared with that of histopathological examination. METHODS: We conducted a prospective study using the OSNA assay for 43 patients with cT1N0M0 gastric cancer undergoing gastrectomy with SN mapping. All the SNs and selected non-SNs were examined by routine histopathological diagnosis, and the OSNA assay. RESULTS: We performed permanent histopathology (PH) in 1732 lymph nodes (LNs) (286 SNs and 1446 non-SNs) obtained from 43 patients. We also evaluated 439 LNs (286 SNs and 153 non-SNs) with the OSNA assay in addition to PH. Intraoperative histopathology (IH) was performed in 214 LNs (213 SNs and 1 non-SN). PH revealed LN metastasis in 6 patients (14%), all of whom showed positive SNs by PH. The diagnostic accuracy to predict the LN status based on the SN concept by histological examination was 100%. The concordance rate between the OSNA assay and the PH and IH were 0.970 and 0.981 respectively. Discordant results between PH and OSNA assay were observed in 13 LNs. The sensitivity and specificity of the OSNA assay compared with those of PH were 0.636, and 0.988, and compared with those of IH were 0.800, and 0.995. CONCLUSION: Our results suggest that the OSNA assay is a useful and convenient tool for the intraoperative detection of SN metastasis in early gastric cancer patients.

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors.

Genomic instability can be a hallmark of both human genetic disease and cancer. We identify a deleterious UBQLN4 mutation in families with an autosomal recessive syndrome reminiscent of genome instability disorders. UBQLN4 deficiency leads to increased sensitivity to genotoxic stress and delayed DNA double-strand break (DSB) repair. The proteasomal shuttle factor UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activity in vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. In line with an HRR defect in these tumors, UBQLN4 overexpression is associated with PARP1 inhibitor sensitivity. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.

CXCR2 expression and postoperative complications affect long-term survival in patients with esophageal cancer.

BACKGROUND: Esophagectomy is one of the most invasive surgical treatments for digestive tract cancer, and the blood levels of inflammatory cytokines such as interleukin-1, interleukin-6, and interleukin-8 are increased for several hours after surgery or in patients experiencing postoperative complications. CXCR2, an interleukin-8 receptor, is reportedly expressed in several carcinomas, and interleukin-8 signaling promotes cancer cell proliferation. The impact of postoperative complications following esophagectomy on long-term survival is controversial. In this study, we demonstrate the significance of CXCR2 expression and validate the effects of CXCR2 expression and postoperative complications on long-term prognosis of esophageal squamous cell carcinoma using resected specimens. METHODS: Eighty-two specimens were sectioned from archived, paraffin-embedded tumor tissues obtained from patients with esophageal squamous cell carcinoma who underwent esophagectomy and extended lymphadenectomy for complete resection of cancer in our institute between 1997 and 2002. Immunohistochemistry was performed using a polyclonal antibody to CXCR2, and the correlation of stainability with clinicopathological factors and long-term survival was examined. RESULTS: CXCR2 was expressed in 33 of 82 (40.2 %) specimens. In the CXCR2-positive group, the recurrence-free survival and overall survival rates of patients who developed postoperative complications were both significantly lower than those for patients who did not develop any complications. In contrast, in the CXCR2-negative group, there was no significant difference in long-term prognosis between patients with and without complications. CXCR2 positivity combined with postoperative complications was an independent risk factor for subsequent tumor recurrence, showing the highest hazard ratio. CONCLUSIONS: Our results suggest that the patients with CXCR2-positive esophageal cancer who develop postoperative complications have a poor prognosis and should be carefully followed. TRIAL REGISTRATION: This study was approved by Keio University School of Medicine Ethics Committee with a trial registration number of 2011-241.

The Impact of Postoperative Complications on Survivals After Esophagectomy for Esophageal Cancer.

The aim of this study was to assess the impact of postoperative complications after esophagectomy on long-term outcome.The treatment of esophageal cancer has recently been improved; however, esophagectomy with thoracotomy and laparotomy carries considerable postoperative morbidity and mortality. The real impact of postoperative complications on overall survival is still under evaluation.A retrospective analysis was performed on patients with esophageal cancer who underwent esophagectomy with thoracotomy and laparotomy, with R0 or R1 resection between January 1997 and December 2012. Of 402 patients, we analyzed the following parameters 284 patients who could be followed up for over 5 years: stage of disease, neoadjuvant therapies, surgical approaches, surgical complications, postoperative medical complications, and overall and relapse-free survivals using medical records.Of the 284 patients, 64 (22.5%) had pneumonia, 55 (19.4%) had anastomotic leakage, and 45 (15.8%) had recurrent laryngeal nerve paralysis (RLNP). Pneumonia had a significant negative impact on overall survival (P = 0.035); however, anastomotic leakage and RLNP did not affect overall survival. Multivariate analysis revealed that the presence of pneumonia was predictive of poorer overall survival; the multivariate hazard ratio was 1.456 (95% confidence interval 1.020-2.079, P = 0.039).Pneumonia has a negative impact on overall survival after esophagectomy. Strategies to prevent pneumonia after esophagectomy should improve outcomes in this operation.

[A case of endocrine cell carcinoma of the ascending colon with liver metastasis treated with hepatectomy after excision of the primary lesion and systemic chemotherapy].

A 77-year-old man who complained of melena was admitted to our department. Colonoscopy revealed a type 2 tumor in the hepatic flexure of the ascending colon. Biopsy examination revealed a poorly differentiated adenocarcinoma. Abdominal computed tomography(CT)revealed 3 tumors within the posterior segment of the right hepatic lobe. Initially, a right hemicolectomy was performed. Immunohistochemically, the tumor was diagnosed as an endocrine cell carcinoma. After surgery, a capecitabine, oxaliplatin, and bevacizumab(CapeOX/BEV)regimen was administered. However, after 5 chemotherapy courses, abdominal CT revealed enlargement of the 3 tumors in the posterior segment of the right hepatic lobe. There was no metastasis besides the liver metastasis. The patient underwent a radical hepatectomy of the posterior segment. At 8 months post-surgery, the patient remains alive and well. Endocrine cell carcinoma of the colon and rectum is usually malignant and is associated with a very poor prognosis because of rapid hematogenous or lymphogenous metastasis. Effective multimodal treatment regimens, including surgery and new chemotherapies such as molecular targeted therapies, should be established to improve the prognosis of patients with endocrine cell carcinomas of the colon and rectum.

Clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma.

BACKGROUND: CXCL-8, known as proinflammatory cytokine interleukin (IL)-8, and its receptor, CXCR-2, are expressed in various cancer cells. CXCL-8/CXCR-2 network is believed to be involved in angiogenesis, growth, and invasion of tumor cells. To date, the clinical significance of CXCL-8/CXCR-2 network in esophageal squamous cell carcinoma (ESCC) remains unclear. Here, we investigated the role of CXCL- 8/CXCR-2 network in ESCC. METHODS: The subjects included 78 patients with primary ESCC. We examined CXCL-8 and CXCR-2 expression in surgically resected specimens using immunohistochemistry. The association between CXCL-8/CXCR-2 expression and level of preoperative serum cytokines, C-reactive protein (CRP), coagulation factors, clinicopathologic background factors, and survival of ESCC patients was assessed. RESULTS: Thirty-seven (47%) and 36 (46%) patients were positive for CXCL-8 and CXCR-2 expression, respectively. Both CXCL-8 and CXCR-2 were expressed in 26 patients (33%). We compared the results of these 26 patients [CXCL-8(+)/CXCR-2(+) group] with those of the other group (n = 52). The depth of invasion (pT factor; P < .001), lymph node metastasis (pN factor; P = .001), pathologic stage (P < .001), lymphatic invasion (P = .010), and venous invasion (P = .001) were significantly more advanced in the CXCL-8(+)/CXCR-2(+) group compared with the other group. Preoperative IL-6, IL-8, CRP, fibrin/fibrinogen degradation product, and fibrinogen levels in the CXCL-8(+)/CXCR-2(+) group were also significantly higher than those in the other group (P = .046, .009, .029, .010, and <.001, respectively). The CXCL-8(+)/CXCR-2(+) group also showed a significantly lower recurrence-free survival (RFS; P < .001) and disease-specific survival (P = .008). As per Cox's hazards model, CXCL-8/CXCR-2 expression (hazard ratio, 2.89; P = .008) was independent predictive factor for RFS. CONCLUSION: Increased expression of both CXCL-8 and CXCR-2 correlated with tumor progression, metastasis, higher preoperative levels of proinflammatory cytokines, CRP, activation of exogenous coagulation factors, and poor prognosis in ESCC patients. These results indicate that overexpression of both CXCL-8 and CXCR-2 may be a useful marker for predicting the outcome in ESCC patients, and more important, has potential in becoming a critical diagnostic marker for selection of appropriate treatments.

Minimally invasive surgery for esophageal epiphrenic diverticulum: the results of 133 patients in 25 published series and our experience.

Esophageal epiphrenic diverticula are uncommon. Traditionally, thoracotomy has been the preferred surgical approach. Recently, minimally invasive approaches have been reported in a few series. However, the best surgical approach remains uncertain. In this study, we review the results of 25 articles discussing laparoscopic or thoracoscopic surgery. From January 1995 to December 2008, there were a total of 133 patients reported in English-language journals in PubMed. Nineteen patients (14 %) underwent thoracoscopic surgery, 112 (84 %) laparoscopic surgery and two patients (2 %) were treated using a combination approach. The diverticulectomy was performed using an endostapler device in all patients. A myotomy was added in 103 patients (83 %). A fundoplication was added in 106 patients (85 %). There were two deaths during surgery (2 %). The post-operative morbidity rate was 21 %. The most severe complication was suture-line leakage, which occurred in 20 patients (15 %). Recently, we successfully treated a patient with an epiphrenic esophageal diverticulum by performing a minimally invasive laparoscopic transhiatal resection and Heller myotomy with Dor fundoplication after observing its enlargement on radiological and endoscopic examinations over 2 years. We believe laparoscopic transhiatal resection and Heller myotomy with Dor fundoplication may therefore become the standard treatment modality for minimally invasive surgery for esophageal epiphrenic diverticulum.