Masaki Ueno

Wnt5a Expression Is Associated With the Tumor Proliferation and the Stromal Vascular Endothelial Growth Factor—An Expression in Non–Small-Cell Lung Cancer

PURPOSEnThe Wnt gene family encodes the multifunctional signaling glycoproteins. We performed the present study to investigate the clinical significance of Wnt5a expression in non-small-cell lung cancer (NSCLC).nnnPATIENTS AND METHODSnOne hundred twenty-three patients with NSCLC who had undergone resection were investigated. Real-time quantitative reverse transcriptase polymerase chain reaction was performed to evaluate the Wnt5a gene expression. Immunohistochemistry was performed to investigate the Wnt5a protein expression, the Ki-67 proliferation index, tumor angiogenesis, and the expression of beta-catenin and vascular endothelial growth factor-A (VEGF-A).nnnRESULTSnWnt5a gene expression in squamous cell carcinoma was significantly higher than that in adenocarcinoma (P < .0001). There was a significant correlation between the normalized Wnt5a gene expression ratio and the intratumoral Wnt5a protein expression (r = 0.729; P < .0001). The intratumoral Wnt5a expression was significantly correlated with the Ki-67 proliferation index (r = 0.708; P < .0001). In contrast, no correlation was observed between the intratumoral Wnt5a expression and tumor angiogenesis. Furthermore, the intratumoral Wnt5a expression was significantly correlated with the stromal expression of beta-catenin (r = 0.729; P < .0001) and VEGF-A (r = 0.661; P < .0001). In addition, the stromal VEGF-A expression was also correlated with Ki-67 proliferation (r = 0.627; P < .0001). Cox regression analyses demonstrated Wnt5a status to be a significant prognostic factor for NSCLC patients (P = .0193), especially for patients with squamous cell carcinomas (P = .0491).nnnCONCLUSIONnThe present study revealed that an overexpression of Wnt5a could produce more aggressive NSCLC, especially in squamous cell carcinomas, during tumor progression.

The tumour–stromal interaction between intratumoral c-Met and stromal hepatocyte growth factor associated with tumour growth and prognosis in non-small-cell lung cancer patients

Immunohistochemical analyses of the effects of hepatocyte growth factor (HGF) and c-Met expression on tumour growth and angiogenesis were performed on 88 patients with non-small-cell lung cancers (NSCLCs). In all, 22 carcinomas (25.0%) were intratumoral HGF-positive, 14 carcinomas (15.9%) were stromal HGF-positive, and 36 carcinomas (40.9%) were intratumoral c-Met-positive. None of the carcinomas were stromal c-Met-positive. Examination of tumour growth revealed that the frequency of tumours with a high Ki-67 index was significantly greater for stromal HGF-positive tumours than for stromal HGF-negative tumours (P=0.0197). The frequency of tumours with a high Ki-67 index was also significantly greater for intratumoral c-Met-positive tumours than for intratumoral c-Met-negative tumours (P=0.0301). However, there was no significant difference in tumour vascularity with relation to intratumoral HGF status, stromal HGF status, and intratumoral c-Met status. The survival rate of patients with intratumoral c-Met-positive tumours was significantly lower than for patients with c-Met-negative tumours (P=0.0095). Furthermore, the survival rate of patients with both intratumoral c-Met-positive and stromal HGF-positive tumours was significantly lower than for patients with either positive tumours, and that of patients with both negative tumours (P=0.0183 and P=0.0011, respectively). A univariate analysis revealed that intratumoral c-Met expression was a significant prognostic factor of NSCLC patients (relative risk=2.642, P=0.0029). The present study demonstrates that tumour–stromal interaction between tumour cell-derived c-Met and stromal cell-derived HGF affects tumour growth and the prognosis of NSCLC patients.

MRP-1/CD9 gene transduction downregulates Wnt signal pathways

Motility-related protein-1 (MRP-1/CD9) is a transmembrane glycoprotein that has been implicated in cell adhesion, motility, proliferation, and differentiation. It has a functional role as a tumor metastatic suppressor. During tumor progression, a reduction of MRP-1/CD9 gene expression results in tumor cells with a high metastatic potential. However, the mechanism of action of MRP-1/CD9 is still unclear. We studied changes of gene expression in relation to MRP-1/CD9 gene transduction into tumor cell lines, HT1080 and A549, using microarray assays and real-time PCR. Consequently, we have demonstrated that MRP-1/CD9 gene transduction can downregulate expression of several Wnt family genes, such as Wnt1, Wnt2b1 and Wnt5a, and their target genes, including WISP-1 (Wnt-1 induced secreted protein 1), WISP-3, c-Myc, vascular endothelial growth factor-A, and matrix metalloproteinase-26. Western blot analyses also showed that MRP-1/CD9 gene transduction downregulated expression of Wnt1 protein and its target proteins. In addition, a neutralizing anti-MRP-1/CD9 monoclonal antibody inhibited the downregulation of Wnt signal pathways in MRP-1/CD9-transfected cells. The present study has revealed that the MRP-1/CD9 signal is located upstream of the Wnt signal pathways. Therefore, MRP-1/CD9 could suppress cell transformation including epithelial to mesenchymal transition through downregulation of Wnt1, and might suppress tumor metastasis through downregulation of Wnt5a.

The HAUSP gene plays an important role in non-small cell lung carcinogenesis through p53-dependent pathways

Herpesvirus‐associated ubiquitin‐specific protease (HAUSP) directly stabilizes the tumour suppressor p53 by de‐ubiquitination. Therefore, the HAUSP gene might play an important role in carcinogenesis. In this paper, HAUSP expression and p53 gene status have been studied in relation to the expression of p53 target genes in 131 patients with non‐small cell lung cancer (NSCLC). p53 gene status was evaluated by polymerase chain reaction‐single‐strand conformation polymorphism (PCR‐SSCP) followed by sequencing. Quantitative reverse‐transcription polymerase chain reaction (RT‐PCR) was performed to evaluate the gene expression of HAUSP, p21, and bax. Immunohistochemistry was performed to evaluate the protein expression of p53, HAUSP, mdm2, p21, and bax. Fifty‐nine carcinomas (45.0%) showed reduced expression of HAUSP, and 58 carcinomas (44.3%) had mutations of p53. Concerning tumour histology, HAUSP mRNA expression was significantly lower in adenocarcinomas than in squamous cell carcinomas (p = 0.0038), while the frequency of p53 mutation was significantly higher in squamous cell carcinomas than in adenocarcinomas (p = 0.0461). There was no significant difference in HAUSP mRNA expression according to p53 gene status. In total, 93 carcinomas (71.0%) showed either mutant p53 or reduced HAUSP expression. The down‐regulation of HAUSP was associated with reduced p53 protein expression (p = 0.0593 in tumours with wild‐type p53 and p = 0.0004 in tumours with mutant p53). Furthermore, p21 and bax protein expression was significantly lower in tumours with either mutant p53 or reduced HAUSP expression than in tumours with both wild‐type p53 and positive HAUSP expression (p = 0.0440 and p = 0.0046, respectively). In addition, the simultaneous evaluation of both HAUSP expression and p53 gene status was a significant indicator of poor prognosis in adenocarcinoma patients (hazard ratio 4.840, p = 0.0357). These results suggest that reduction of HAUSP gene expression may play an important role in NSCLC carcinogenesis, especially in adenocarcinomas, through p53‐dependent pathways. Copyright

Triple positive tumor markers for hepatocellular carcinoma are useful predictors of poor survival.

Objective:To determine the importance of the expression pattern of multiple tumor markers for hepatocellular carcinoma (HCC) with regard to the tumor malignancy and patient survival. Background:Several studies have indicated that HCC tumor markers, including alpha-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP and des-&ggr;-carboxy prothrombin were predictors of HCC malignancy. However, few reports have shown the relevance of the expression pattern of these 3 tumor markers with regard to patient prognosis. We herein reported the influence of the expression pattern of these 3 tumor markers on HCC malignancy and patient prognosis. Methods:This retrospective study analyzed 185 patients who underwent hepatectomy for HCC between January 1999 and May 2009. The relationships between clinical parameters and these 3 tumor markers were analyzed. Cox proportional hazards regression analyses were performed to estimate risk factors for recurrence and survival. Furthermore, the relationships between pathological parameters and the expression patterns of the 3 tumor markers were analyzed. Results:From clinical parameters, expression patterns of 3 tumor markers were related to maximum tumor size and macrovascular invasion in image findings. Multivariate analyses revealed independent risk factors for recurrence or survival to be the Child-Pugh score, the presence of multiple tumors, and triple positive tumor marker expression. From pathological findings, microvascular invasion and an Edmondson-Steiner classification of III or IV were related to the expression patterns of the 3 tumor markers. Conclusions:Triple positive tumor markers for HCC showed poor prognosis and invasive characteristics in pathological findings. Examination of these markers would be useful for predicting the degree of HCC malignancy.

Anatomical considerations of the infrapyloric artery and its associated lymph nodes during laparoscopic gastric cancer surgery

BackgroundLittle is known about the vascular and lymphatic distribution of the pyloric antrum in the stomach. We focused on the infrapyloric region containing the infrapyloric artery (IPA) and lymph nodes.MethodsThe anatomy of the IPA and its associated lymph nodes was clinically elucidated during 156 laparoscopic gastrectomies.ResultsMost of the arteries originated from the anterior superior pancreatoduodenal artery (ASPDA, 64.2xa0%) or the root of the right gastroepiploic artery (RGEA, 23.1xa0%), but a small portion originated from the gastroduodenal artery (GDA, 12.7xa0%). The average lengths from the pyloric ring to the IPA proximal branch were 21.8xa0mm from the ASPDA, 20.6xa0mm from the RGEA and 9.0xa0mm from the GDA, a significantly shorter length than the other 2 variations. On average, 2.5 out of 10.0 nodes existed along the IPA. One patient, whose tumor was located close to the pylorus, had a metastatic node in this section.ConclusionThe IPA most commonly originates from the ASPDA and is associated with a certain number of lymph nodes. Vascular distribution from the IPA depends on the anatomic variation.

Treatment Strategy for Borderline Resectable Pancreatic Cancer With Radiographic Artery Involvement.

Objectives We evaluated whether neoadjuvant therapy followed by surgical resection improves the clinical outcome for patients with borderline resectable pancreatic cancer with radiologic artery involvement (BRPC-A). Methods We reviewed 143 BRPC-A patients from among 330 pancreatic cancer patients, including 111 potentially resectable pancreatic cancer patients and 76 borderline resectable pancreatic cancer with portal/superior mesenteric vein involvement patients, who underwent surgery at Wakayama Medical University Hospital. We compared the clinicopathological factors of 40 BRPC-A patients treated with neoadjuvant therapy followed by surgery and those of 103 BRPC-A patients treated with upfront surgery. Results The R0 rate and progression-free survival of BRPC-A patients who received neoadjuvant therapy and subsequent surgical resection were significantly better compared to those who received upfront surgery (R0: P = 0.041; progression-free survival: P = 0.033), but overall survival was not significantly different. A multivariate analysis showed that intraoperative transfusion (P = 0.007), moderately or poorly differentiated pathological adenocarcinoma (P = 0.019), and failure to complete postoperative adjuvant therapy (P < 0.001) independently predicted a poor prognosis for BRPC-A patients who underwent surgical resection. Conclusions Neoadjuvant treatment followed by surgery might provide clinical benefits for BRPC-A patients; however, the establishment of the most appropriate neoadjuvant therapy is needed by further studies.

New Combined Medical Treatment With Etilefrine and Octreotide for Chylothorax After Esophagectomy: A Case Report and Review of the Literature.

AbstractPostoperative chylothorax is a rare but well-known complication of general thoracic surgery. Medical treatment of chylothorax was reported in the past, but there is still considerable controversy on the appropriate management strategies.Two patients with esophageal cancer underwent esophagectomy, 2-field lymph node dissection, and resection of thoracic duct together with ileocolic reconstruction via the retrosternal route at our hospital. Chylothorax developed on the 32nd postoperative day (POD) in 1 patient and the 12th POD in the other, manifesting as a change in the character of thoracic drainage to turbid white. Both were immediately started on octreotide (300u200a&mgr;g/ day) and etilefrine (120u200amg/day). When the amount of pleural effusion decreased to <50u200amL/day, we performed pleurodesis with Picibanil (OK432). Thereafter, the patients gradually made satisfactory progress and resumed oral food intake, and the thoracotomy tubes were eventually removed. They have remained recurrence-free at the time of writing.In this report, we demonstrated the clinical efficacy of etilefrine for the management of postesophagectomy chylothorax. New medical treatment options for this condition are now broad and the usefulness of combined therapy consisting of a sclerosing agent, etilefrine, and octreotide is underscored, regardless of the status of the thoracic duct.

Should lymph nodes along the thoracic duct be dissected routinely in radical esophagectomy

BackgroundAlthough dissection of mediastinal lymph nodes along the thoracic duct is included in standard radical esophagectomy, it is not routinely performed because of the undesirable hemodynamic effects. This study aims to investigate whether dissection of the nodes along the thoracic duct has prognostic benefits.MethodsA total of 778 consecutive patients who underwent radical esophagectomy with three-field lymph node dissection for squamous cell carcinoma of the thoracic esophagus from 1984 to 2011 were included. The incidence of metastasis in thoracic duct nodes and that in nodes within #112 station excluding thoracic duct nodes were studied in relation to the depth of the main tumor. The survival curves of lymph node-positive patients were compared.ResultsThe metastatic incidence was 2.2xa0% in T1b/T2, whereas it was 10.0xa0% in T3/T4. The survival curves in patients with metastasis in the thoracic duct nodes and in the #112 station were not statistically different.ConclusionThe dissection of the nodes along the thoracic duct along with thoracic duct resection should be performed routinely; however, reliable indicator of the necessity of its dissection is awaited in T1b/T2 tumors because of the low metastatic rate and the potential risk associated with resection of the thoracic duct.

Serial pseudoprogression of metastatic malignant melanoma in a patient treated with nivolumab: a case report

BackgroundPseudoprogression refers to a specific pattern of response sometimes observed in malignant melanoma patients receiving treatment with immune-checkpoint inhibitors. Although cases with pseudoprogression documented once have been reported previously, there have been no case reports yet of pseudoprogression events documented twice during treatment.Case presentationA 55-year-old man underwent surgery for locally advanced esophageal malignant melanoma and received postoperative adjuvant interferon therapy. However, he presented with multiple liver and bone metastases at 6xa0months after the surgery, and was initiated on treatment with nivolumab 2xa0mg/kg every 3xa0weeks as the first-line treatment for recurrent disease. Follow-up computed tomography revealed that the liver metastases initially increased transiently in size, but eventually regressed. However, while the liver metastases continued to shrink, a new peritoneal nodule emerged, that also subsequently shrinked during the course of treatment with nivolumab. With only grade 1 pruritus, the patient continues to be on nivolumab treatment at 15xa0months after the induction therapy, with no progression observed after the second episode of pseudoprogression in the liver and peritoneal nodule.ConclusionsWe present the case of a patient with metastatic malignant melanoma who showed the unique response pattern of serial pseudoprogression during treatment with nivolumab. This case serves to highlight the fact that development of a new lesion may not always signify failure of disease control during treatment with nivolumab.