[Neutrophil-Lymphocyte Ratio as a Prognostic Indicator in Patients Treated with Nivolumab for Gastric Cancer].

BACKGROUND: Immune checkpoint inhibitors(nivolumab)have been recommended as third-line chemotherapy for advanced gastric cancer(AGC)according to the Guidelines of Gastric Cancer(5th edition). Therefore, they have been used in daily clinical practice. On the other hand, the neutrophil-lymphocyte ratio(NLR)has been reported to be associated with the prognosis of cancer patients. METHODS: Twenty patients treated with nivolumab for AGC between January 2018 and November 2019 were retrospectively examined. RESULTS: Median age of the 20 patients(18 males, 2 females)was 70 years(55- 84 years). Nivolumab was administered as second-, third-, fourth-, and fifth-line therapy in 1, 11, 7, and 1 case, respectively. The best tumor response evaluation was observed in PR 1, SD 7 and PD 10 cases. Median overall survival(OS)was 10 months, and median progression-free survival(PFS)was 3 months. No serious adverse events occurred. Compared to the NLR>2.0 group, OS significantly prolonged(2.2 months vs 21.9 months)and PFS tended to prolong(1.4 months vs 6.2 months)in the NLR≤2.0 group. CONCLUSION: NLR may be an effective prognostic factor in patients with AGC receiving nivolumab treatment.

[A Postoperative Case of Rectal Cancer with Anal Pain Caused by Side Effects of Oxaliplatin].

This case involved a 28-year-old female with rectal cancer in the inner pelvis. Two courses of SOX plus Cmab therapy, and 4 courses of FOLFOX-Cmab therapy were administered as preoperative chemotherapies, which resulted in a reduction in the major lesion. Subsequently, laparoscopic low anterior resection and dissection of the bilateral lymph nodes were performed. After the surgery, adjuvant chemotherapy with FOLFOX was administered. Afterwards, the patient developed severe anal pain and visited us for treatment. The severe anal pain continued even after FOLFOX treatment and increased with defecation. A side effect of oxaliplatin was suspected, and sLV5FU chemotherapy was administered. As a result, the anal pain disappeared. Thus, the pain was considered to be induced by oxaliplatin. While peripheral neuropathy is a widely known side effect of oxaliplatin, this case was considered to be unique because anal pain occurs very rarely with oxaliplatin treatment.

Cerebral air embolism as a complication of peptic ulcer in the gastric tube: case report.

BACKGROUND: The reported incidence of ulcer formation in the gastric tube in esophageal replacement is rare. CASE PRESENTATION: This is the first report of a case of cerebral air embolism as a result of spontaneous perforation of an ulcer in the constructed gastric tube into the pulmonary vein during post-operative follow-up in a patient with esophageal cancer. CONCLUSIONS: Cerebral air embolism is a rare complication of penetrating gastric ulcer, but should be considered in patients with a history of esophagectomy with gastric conduit that present with acute neurologic findings.

[Rupture of ileal varices in a type C liver cirrhosis patient: a case report].

A 74-year-old woman was admitted to our hospital with recurrent massive lower gastrointestinal bleeding. She had a history of type C liver cirrhosis and appendectomy, and had undergone endoscopic ligation of esophageal varices one year before. Three-dimensional CTA revealed ileal varices in the right lower quadrant of the abdomen. Superior mesenteric arteriography demonstrated varices at the corresponding area and collateral veins from the superior mesenteric vein to the right ovarian vein. Ileal varices were diagnosed and ileal resection was performed. At surgery, exposed vessels were present at the mucosal surface of the resected specimen and they were thought to be the origin of hemorrhage. In conclusion, bleeding from small intestinal varices, though uncommon, should be considered when the origin of melena is unidentified in a patient with liver cirrhosis.

[A case of double cancer of sigmoid colon cancer with lung metastases, peritoneal dissemination and early gastric cancer responding to S-1].

A 73-year-old man was referred to our hospital with complaints of constipation and defecation caused by a sigmoid colon tumor. After examination, he was diagnosed as sigmoid colon cancer with lung metastasis, peritoneal dissemination and early gastric cancer. To prevent bowel obstruction, a sigmoid colon resection was performed. On postoperative day 20, S-1 (100 mg/body for 4 weeks followed by 2 drug-free weeks) treatment was started. After 13 courses of treatment, gastrointestinal fiberscope revealed that the gastric cancer was remarkably reduced, and after 16 courses, computed tomography revealed that the lung metastasis was remarkably reduced. Although after 12 courses, elevation of bilirubin, the treatment could be possible to continued on a lowered dose of S-1 from 100 mg to 80 mg/body. Twenty-four months after the operation, good control of cancer has been maintained, and the treatment is continuing. S-1 treatment was proved effective for double cancer of the advanced colorectal cancer and the gastric cancer.

Gamma-secretase inhibitor prevents Notch3 activation and reduces proliferation in human lung cancers.

Notch receptors are key regulators of development by controlling cell-fate determination in many multicellular organisms. Genes that are important for normal differentiation play a role in cancer when their normal functions became dysregulated. Notch signaling has been shown to promote and maintain survival of many types of cancers, and we previously have shown that Notch3 plays an important role in lung cancer. In this study, we showed that a high percentage of lung cancer lines expressed Jagged1, Notch receptors, and their transcriptional target genes (HES1, Hey1), suggesting that the Notch pathway plays an important role in lung cancer biology. Thus, inhibition of Notch receptor activation represents a compelling treatment strategy. Notch activation requires proteolytic cleavage of the receptor by gamma-secretase protein complex. In this study, we determined the ability of MRK-003, a gamma-secretase inhibitor, to inhibit Notch3 signaling, growth, and apoptosis of lung cancer cell lines in vitro and in vivo using mouse xenograft models. We also found that MRK-003 inhibited Notch3 signaling, reduced tumor cell proliferation, inhibited serum independence, and induced apoptosis. This drug had no effect when Notch3 expression was knocked down using small interfering RNA (siRNA), suggesting that the observed effects were mediated by specific action on this receptor. In conclusion, these results support the hypothesis that inhibition of Notch activation using a gamma-secretase inhibitor represents a potential new approach for the targeted therapy of lung cancer.

Aberrant nuclear localization of beta-catenin without genetic alterations in beta-catenin or Axin genes in esophageal cancer.

BACKGROUND: beta-catenin is a multifunctional protein involved in two apparently independent processes: cell-cell adhesion and signal transduction. beta-catenin is involved in Wnt signaling pathway that regulates cellular differentiation and proliferation. In this study, we investigated the expression pattern of beta-catenin and cyclin D1 using immunohistochemistry and searched for mutations in exon 3 of the beta-catenin gene and Axin gene in esophageal squamous cell carcinoma. MATERIALS AND METHODS: Samples were obtained from 50 esophageal cancer patients. Immunohistochemical staining for beta-catenin and cyclin D1 was done. Mutational analyses of the exon3 of the beta-catenin gene and Axin gene were performed on tumors with nuclear beta-catenin expression. RESULTS: Four (8%) esophageal cancer tissues showed high nuclear beta-catenin staining. Overexpression of cyclin D1 was observed in 27 out of 50 (54%) patients. All four cases that showed nuclear beta-catenin staining overexpressed cyclin D1. No relationship was observed between the expression pattern of beta-catenin and cyclin D1 and age, sex, tumor size, stage, differentiation grade, lymph node metastasis, response to chemotherapy, or survival. No mutational change was found in beta-catenin exon 3 in the four cases with nuclear beta-catenin staining. Sequencing analysis of the Axin cDNA revealed only a splicing variant (108 bp deletion, position 2302-2409) which was present in the paired normal mucosa. CONCLUSION: A fraction of esophageal squamous cell carcinomas have abnormal nuclear accumulation of beta-catenin accompanied with increased cyclin D1 expression. Mutations in beta-catenin or axin genes are not responsible for this abnormal localization of beta-catenin.

Expression and prognostic roles of PABPC1 in esophageal cancer: correlation with tumor progression and postoperative survival.

The prognosis of patients with esophageal cancer remains poor. TNM classification is not sufficient to predict their prognosis, and novel predictive markers of the prognosis of esophageal cancer patients are therefore needed. Poly A binding protein, cytoplasmic 1 (PABPC1) plays a role in post-transcriptional control of mRNA and may be involved in tumorigenesis. PABPC1 expression has not been studied in esophageal cancer. Expression of PABPC1 was quantified by real-time reverse transcription polymerase chain reaction (RT-PCR) using LightCycler in 41 primary esophageal squamous cell carcinomas (ESCCs) and their paired normal esophageal mucosa. We examined the correlation between PABPC1 expression and the clinicopathological factors and prognosis of ESCC patients. Reduced expression of PABPC1 was accompanied by locally invasive tumors (t-factor, p=0.0145) and more advanced tumors (pathologic stage, p=0.0264). Moreover, ESCC patients with low PABPC1 mRNA expression had a significantly shorter postoperative survival time than those with high expression (median survival, 3.1 vs. 6.5 months, p=0.002). In esophageal cancer, reduced expression of PABPC1 was correlated with local tumor progression and poor prognosis after surgery.

Thioredoxin-1 modulates transcription of cyclooxygenase-2 via hypoxia-inducible factor-1alpha in non-small cell lung cancer.

Hypoxic induction of gene expression occurs mainly via the hypoxia-inducible factor-1 (HIF-1) transcription factor and is a critical step in tumor growth. Cyclooxygenase-2 (COX-2) is commonly overexpressed in non-small cell lung cancer (NSCLC). In this study, we sought to determine the role of HIF-1 in the induction of COX-2 expression during hypoxia. Through sequence comparison of hypoxia-responsive genes, COX-2 promoter deletion analysis, and site-directed mutagenesis, we identified a hypoxia-responsive element within the COX-2 promoter that interacts with HIF-1alpha and underlies the mechanism of hypoxic activation of COX-2 in lung cancer cells. Proteomic analysis of NSCLC identified thioredoxin-1 as a redox protein overexpressed in NSCLC correlated with poor prognosis. We also show that thioredoxin-1 stabilizes HIF-1alpha to induce hypoxia-responsive genes under normoxic conditions. Our results identify two new mechanisms for regulation of COX-2 expression in NSCLC.

Dominant-negative Notch3 receptor inhibits mitogen-activated protein kinase pathway and the growth of human lung cancers.

Notch3 is a member of an evolutionarily conserved family of cell surface receptors important in cell-fate determination in both vertebrates and invertebrates. Significant data support the role of Notch pathway in cancer development, although the conflicting role of Notch signaling pathways in tumorigenesis suggests that its action is highly context-dependent. Furthermore, although Notch receptors signal primarily through the regulation of hairy enhancer of split (HES) and HES-related (HRT) genes, they are known to crosstalk with other signaling pathways, including the epidermal growth factor (EGF) and the mitogen-activated protein kinase pathways. Whereas much is known about the role of Notch1 in human cancer, the role of Notch3 in epithelial tumors, such as lung carcinomas, has not been well established. In this study, we show that Notch3 is expressed in 80 of 207 (39%) resected human lung tumors and that its expression is positively correlated with EGF receptor expression. Inhibition of the Notch3 pathway using a dominant-negative receptor dramatically reduces growth in soft agar and increases growth factor dependence. We also find that Notch inhibition increases sensitivity to EGF receptor tyrosine kinase inhibition and decrease in phosphorylation of the mitogen-activated protein kinase. These observations support a role for Notch3 signaling in lung cancer, and one potential mechanism of maintaining the neoplastic phenotype is through the modulation of the EGF pathway.

Excision repair cross complementing 3 expression is involved in patient prognosis and tumor progression in esophageal cancer.

The prognosis of patients with esophageal cancer remains poor. TNM classification is not sufficient to predict the prognosis. Therefore, novel predictive markers of the prognosis of esophageal cancer patients are awaited. The abnormality of the nucleotide excision repair (NER) is often involved in human cancers. Excision repair cross complementing 3 (ERCC3) contributes to NER. In esophageal cancer, ERCC3 expression has not been studied. Expression of ERCC3 was quantified by real-time reverse transcription polymerase chain reaction (RT-PCR) using LightCycler in 43 primary esophageal squamous cell carcinomas (ESCCs) and their paired normal esophageal mucosa. We examined the correlation between the ERCC3 expression and the clinicopathological factors and prognosis of ESCC patients. ERCC3 expression level was significantly correlated with the pathologic stage, tumor size and local invasiveness (t-factor) in esophageal cancer tissues. Reduced expression of ERCC3 was accompanied with tumor progression (p=0.0049) and higher pathologic stage (p=0.020). Moreover, ESCC patients with low ERCC3 mRNA expression had significantly shorter post-operative survival time than those with high expression (p=0.0003). In esophageal cancer, reduced expression of ERCC3 was correlated with local tumor progression and poor prognosis after operation.

Expression of PPAR-gamma is correlated with the clinical course of neuroblastoma.

BACKGROUND/PURPOSE: Neuroblastoma is a common pediatric tumor of the sympathetic nervous system. Unlike the ones found in older children, the tumors found in patients younger than one year of age often show spontaneous differentiation and regression. Peroxisome proliferator-activated receptor gamma (PPAR-gamma), a member of the nuclear hormone receptor superfamily is expressed in several human cancers. Recently, PPAR-gamma has been reported to be expressed in neuroblastoma, and the agonist of this receptor caused differentiation of neuroblastoma cells. METHODS: In this report we studied the expression of PPAR-gamma mRNA, using LightCycler in neuroblastoma samples diagnosed in 17 patients under the age of one year. RESULTS: Twelve samples showed PPAR-gamma mRNA expression. There was no significant difference in the PPAR-gamma mRNA expression based on age, histology, staging, and DNA ploidy. The PPAR-gamma mRNA expression level was significantly correlated with the change in urinary vanillyl mandelic acid (VMA). The neuroblastoma samples resected from patients who showed a decrease in their urinary VMA before the operation showed significantly higher PPAR-gamma expression than those from patients who showed an increase in their urinary VMA before the operation. CONCLUSIONS: PPAR-gamma may have played a role in the reduction of VMA and possibly in the regression of early-onset neuroblastoma.

Estrogen receptor alpha mutation (A-to-G transition at nucleotide 908) is not found in different types of breast lesions from Japanese women.

BACKGROUND: An estrogen receptor (ER) alpha variant with an A-to-G transition at nucleotide 908 (A908G) has been identified in typical hyperplastic mammary epithelium. This somatic mutation, which induces a Lys-to-Arg substitution at residue 303 within exon 4 at the border of the hinge and hormone-binding domains of the ER alpha, shows increased sensitivity to estrogen compared with wild-type ER alpha. METHODS: To investigate whether this mutation was present in breast lesions, we performed mutation analyses using the PCR-restriction fragment length polymorphism (RFLP) method in 7 cases of hyperplasia, 18 cases of benign breast tumor, 26 cases of ductal carcinoma in situ (DCIS) and 215 cases of invasive ductal carcinoma (IDC). When we extracted DNA, the hyperplastic epithelium and cancer cells of DCIS were microdissected. We also performed direct sequencing analysis from 7 randomly-selected representative cases of hyperplasia, 9 cases of benign breast tumors, 11 cases of DCIS and 20 cases of IDC. RESULTS: No A908G mutation was found in the ER alpha gene in these breast lesions. CONCLUSION: This mutation might be absent or occur in so few cells as to be undetectable by PCR-RFLP or direct sequencing.

Chfr expression is downregulated by CpG island hypermethylation in esophageal cancer.

Cell cycle progression is monitored by checkpoint mechanisms to ensure the integrity of the genome and the fidelity of sister chromatid separation. Failure of such checkpoint functions results in genomic instability, a condition that predisposes cells to neoplastic transformation and tumor progression. Recently, Scolnick and Halazonetis defined a new mitotic checkpoint that acts at prophase and delays chromosome condensation in response to mitotic stress, and identified a gene, named checkpoint with FHA and ring finger (Chfr), that seems to be required for delaying prophase in human cells. In the present study, we examined human Chfr mRNA expression in 15 human esophageal cancer cell lines and 43 primary esophageal cancers to investigate the potential involvement of Chfr in the pathogenesis of esophageal cancers. We report here that a significant proportion of human esophageal cancer has loss of expression of Chfr gene. Furthermore, we found aberrant hypermethylation of the promoter region of this checkpoint gene in four of 15 (26.7%) esophageal cancer cell lines and in seven of 43 (16.3%) primary cancers.

Expression of PTTG (pituitary tumor transforming gene) in esophageal cancer.

BACKGROUND: Recently, a vertebrate securin [pituitary tumor transforming gene (PTTG) in humans] has been identified that inhibits sister chromatid separation and is involved in malignant transformation and tumorigenesis. Abundance of this protein would disrupt cell division, generate chromosomal instability and thereby increase cell susceptibility to acquisition of further mutations during subsequent division. Esophageal cancer is a disease with poor prognosis with early local invasion and lymph node metastasis. It is important to identify factors that influence the aggressiveness of esophageal cancer. METHODS: Expression of PTTG messenger ribonucleic acid (mRNA) was evaluated by real-time reverse transcription polymerase chain reaction in 48 esophageal cancer specimens and matched normal esophageal mucosa. The data were analyzed with reference to clinicopathological factors. RESULTS: Tumor tissue expressed a significantly higher level of PTTG1 mRNA than the corresponding normal tissue (P < 0.0001). PTTG1 mRNA expression was significantly higher in tumors with higher pathological stage (IV vs 0-III, P = 0.0442) or more extensive lymph node metastasis (pathological N factor; N4 vs N0-3, P = 0.003). The median survival for patients with high PTTG1 expression (8.5 months) was less than that for patients with low PTTG1 expression (14.0 months, P = 0.039). PTTG1 expression was one of the significant predictors of survival on univariate analysis (hazard ratio 2.225; 95% confidence interval 1.007-4.915). CONCLUSIONS: Detection of high PTTG1 expression in surgically excised esophagus tumor tissues might help to identify patients with aggressive disease who require adjuvant therapy and provide prognostic information.

Decreased peroxisome proliferator-activated receptor gamma gene expression is correlated with poor prognosis in patients with esophageal cancer.

BACKGROUND: Peroxisome proliferator-activated receptor gamma (PPAR gamma) induces apoptosis by ligand stimulation in various tumor cell lines. In esophageal cancer cell lines, PPAR gamma activation also has suppressed the proliferation. METHODS: In 55 primary esophageal squamous cell carcinomas (ESCCs) we examined the correlation between the expression of PPAR gamma mRNA with prognosis of esophageal cancer patients. The expression of PPAR gamma mRNA was quantified by real-time reverse transcription polymerase chain reaction using LightCycler. Immunohistochemistry was used to study the expression of PPAR gamma protein. RESULTS: The expression of PPAR gamma mRNA was significantly decreased in esophageal cancer cells compared with normal esophageal mucosa (P = 0.0084). Among the clinical factors, PPAR gamma mRNA expression was lower in the tumors with extensive lymph node metastasis (n4) than those with less extensive lymph node metastasis (n0-3) (P = 0.0059). Patients with low PPAR gamma mRNA expression had significantly shorter postoperative survival time than those with high PPAR gamma mRNA expression (P = 0.0191). In immunohistochemistry, PPAR gamma protein was expressed in the nuclei of cells in some cases and expressed in the nuclei and cytoplasm in others. The expression of PPAR gamma protein is decreased in esophageal cancer tissue compared with normal esophageal squamous epithelium. However, we could not deduce the apparent relation for the expression between PPAR gamma mRNA and PPAR gamma proteins in immunohistochemistry (P = 0.284). CONCLUSIONS: In esophageal cancer tissues, the expression of PPAR gamma was decreased compared with normal esophageal epithelium. The mRNA expression level of PPAR gamma may be a marker of prognosis after operation in esophageal cancer patients.