[A Case of Malignant Peritoneal Mesothelioma Resected Four Times in Five Years].

We report a long-surviving case of malignant peritoneal mesothelioma requiring 4 operations in 5 years. A 63-year-old man was diagnosed with gastrointestinal stromal tumor(GIST)that was excised for the first time in June 2011. The pathological diagnosis was malignant peritoneal mesothelioma. Thereafter, we excised recurrences of the tumor in the hepatic hilum in December 2011. Similar operations were performed in March 2012 and August 2015 because of tumors in the small bowel mesentery and the segment 8 of the liver. The pathological diagnosis was malignant peritoneal mesothelioma. It is an extremely rare variant of malignant peritoneal mesothelioma. There is no record of multiple excision of malignant peritoneal mesothelioma for recurrences. In this case, the cause of long survival was considered to be the excision of recurrent tumors.

[Eight Cases of Primary Carcinoma of the Vermiform Appendix].

Primary carcinoma of the vermiform appendix is a rare neoplasm, and its treatment strategy has not yet been established. We retrospectively analyzed 8 cases of primary carcinoma of the vermiform appendix from 2007 to 2017. Six cases were male and two were female, with a median age of 60.5 years. Ileocecal resection and right hemicolectomy were performed in 7 cases and 1 case, respectively. Regarding pathological staging, 5 cases were of pStage Ⅱ, 2 were of pStage Ⅲa, and 1 was of pStage Ⅳ. Three cases had recurrences after curative resection. The postoperative median overall survival time was 45 months. Three cases with a tumor diameter of 20mm were alive without any recurrence; however, 3 of 5 cases with a tumor diameter of B21mm had recurrences. Although only 1 of 3 cases with adjuvant chemotherapy(pStage Ⅲa case)had recurrence, 2 of 4 cases without adjuvant chemotherapy, including a pStage Ⅱ case, had recurrences. Early diagnosis, surgery, and adjuvant chemotherapy could improve the long-term outcomes of patients with primary carcinoma of the vermiform appendix.

Perivascular epithelioid cell tumor of the rectum: report of a case and review of the literature.

We report a case of perivascular epithelioid cell tumor arising in the rectum of a 55-year-old woman. The tumor was treated by transanal endoscopic microsurgery. After 1 year follow-up, the patient is alive with no radiologic or endoscopic evidence of recurrence. Perivascular epithelioid cell tumor is a rare mesenchymal tumor characterized by co-expression of melanocytic and smooth muscle markers. This rare tumor can arise in various organs, including the falciform ligament, uterus, uterine cervix, liver, kidney, lung, breast, cardiac septum, pancreas, prostate, thigh, and gastrointestinal tract. Perivascular epithelioid cell tumor of the gastrointestinal tract is very rare, with only 23 previously reported cases. We review the literature on perivascular epithelioid cell tumors arising in the gastrointestinal tract.

[Clinical efficacy and safety of CPT-11+CDDP therapy as third-line chemotherapy for advanced and recurrent gastric cancer].

The clinical efficacy and safety of CPT-11+CDDP therapy were studied retrospectively in 34 patients with advanced and recurrent gastric cancer. The overall response rate was 5. 9%; MST was 209 days. The adverse effects observed were grade 3 in 7 patients(20. 6%). CPT-11+CDDP therapy could be useful and safe as third-line chemotherapy.

Rare MDM4 gene amplification in colorectal cancer: The principle of a mutually exclusive relationship between MDM alteration and TP53 inactivation is not applicable.

MDM4, a homolog of MDM2, is considered a key negative regulator of p53. Gene amplification of MDM4 has been identified in a variety of tumors. MDM2 or MDM4 gene amplification is only associated with the wild-type TP53 gene in retinoblastomas, thus the amplification of the two genes is mutually exclusive. Previously, we demonstrated that MDM2 amplification and TP53 alteration were not mutually exclusive in colorectal cancer, and we identified a subset of colorectal cancer patients without alterations in either the TP53 or the MDM2 gene. In this study, we investigated the gene amplification status of MDM4 in the same set of colorectal cancer cases. Unexpectedly, MDM4 amplification was rare, detected in only 1.4% (3 out of 211) of colorectal cancer cases. All the three gene-amplified tumors also harbored TP53-inactivating mutations. This contradicts the simple mutually exclusive relationship observed in retinoblastomas. Surprisingly, two of the three MDM4-amplified tumors also demonstrated MDM2 amplification. Paradoxically, the MDM4 protein levels were decreased in the tumor tissue of the gene-amplified cases compared with levels in the matched normal mucosa. We speculate that MDM4 might play a role in colorectal carcinogenesis that is not limited to negative regulation of p53 in combination with MDM2. The functional significance of MDM4 is still unclear and further studies are needed.

MDM2 gene amplification in colorectal cancer is associated with disease progression at the primary site, but inversely correlated with distant metastasis.

MDM2 is a crucial negative regulator of the TP53 tumor suppressor and almost 10% of human tumors exhibit MDM2 amplification. Although TP53 pathway perturbation has been extensively examined in colorectal cancer (CRC), only one previous report has evaluated MDM2 amplification in relation to clinicopathological factors. In that report, MDM2 amplification was shown to be associated with disease progression from Dukes' Stages A to D. In this study, we investigated MDM2 amplification by quantitative PCR and fluorescence in situ hybridization (FISH) together with the SNP309 genotypes, and analyzed the correlations with TP53 and KRAS mutations and clinicopathological features in 211 Japanese CRC patients. MDM2 amplification was detected in 8% of the specimens and its incidence was significantly higher in Dukes' stage C than in the combined earlier Stages A and B (P = 0.025). Unexpectedly, the incidence was significantly decreased in Stage D metastatic disease (P = 0.043). The copy number gain ranged from four to eight copies and was generally concordant with gain of centromere 12 using FISH analysis. Together with the results of centromere 1 FISH and TP53 copy number assessment, the MDM2 increment most likely resulted from chromosome 12 gain. The mechanism of the copy number gain and incidence in Dukes' Stage D differed considerably from the previous report. Ethnic or geographic factors could be responsible for these differences. Several promising therapeutic strategies targeting the TP53-MDM2 system are being developed. Further understanding of the significance of MDM2 and MDM2 amplification in CRC is required to facilitate personalized treatment for CRC patients.

Identification of colorectal cancer patients with tumors carrying the TP53 mutation on the codon 72 proline allele that benefited most from 5-fluorouracil (5-FU) based postoperative chemotherapy.

BACKGROUND: Although postoperative chemotherapy is widely accepted as the standard modality for Dukes' stage C or earlier stage colorectal cancer (CRC) patients, biomarkers to predict those who may benefit from the therapy have not been identified. Previous in vitro and clinical investigations reported that CRC patients with wild-type p53 gene (TP53)-tumors benefit from 5-fluorouracil (5-FU) based chemotherapy, while those with mutated TP53-tumors do not. However, these studies evaluated the mutation-status of TP53 by immunohistochemistry with or without single-strand conformation polymorphism, and the mutation frequency was different from study to study. In addition, the polymorphic status at p53 codon 72, which results in arginine or proline residues (R72P) and is thought to influence the function of the protein significantly, was not examined. METHODS: To evaluate the significance of the TP53 mutation as a molecular marker to predict the prognosis of CRC patients, especially those who received postoperative chemotherapy, we examined the mutation by direct sequencing from fresh CRC tumors and evaluated the R72P polymorphism of the mutated TP53 by a combined mutant allele- and polymorphic allele-specific polymerase chain reaction (PCR). RESULTS: The TP53 mutation occurred in 147 (70%) of 211 Japanese CRC tumors. The mutation was observed in 93 (63%) tumors on the R72 allele and in 54 (37%) tumors on the P72 allele. Although the alterations to TP53 have no prognostic significance for CRC patients overall, we found that Dukes' stage C CRC patients who did not receive postoperative chemotherapy and carried the mutated TP53-R72 showed significantly longer survival times than those with the mutated TP53-P72 when evaluated by overall survival (p = 0.012). CONCLUSION: Using a combined mutant allele- and polymorphic allele-specific PCR, we defined the codon 72 polymorphic status of the TP53 mutated allele in Japanese CRC patients. We raised a possibility that Dukes' stage C colorectal cancer patients with tumors carrying TP53 mutation, especially the P72 allele, benefited from 5-FU based postoperative chemotherapy.

Quantitive cytokine mRNA expression profiles in the colonic mucosa of patients with steroid naïve ulcerative colitis during active and quiescent disease.

BACKGROUND: Cytokines have validated roles in the immunopathogenesis of inflammatory bowel disease (IBD). This study was to investigate the expressions of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, and IL-10 mRNAs in the colonic mucosa of patients with ulcerative colitis (UC) during active and quiescent UC. METHODS: At colonoscopy, biopsies were taken from inflamed and non-inflamed mucosa of patients with steroid-naive UC (n = 15), non-IBD inflammatory colitis controls (ICC, n = 6), and non-colitis controls (NCC, n = 14). The presence of extensive mononuclear cells and neutrophils infiltrate in the lamina propria, cryptitis, and epithelial damage defined an inflammatory lesion in the mucosa. Quantitative cytokine mRNA expressions in biopsies were measured by real-time polymerase chain reaction (PCR). RESULTS: Of 15 UC patients, 3 remitted with 5-aminosalicylate and 11 received granulocytapheresis; of these, 10 remitted. At baseline, IL-6, IL-8, TNF-alpha, and IL-10 mRNAs were high in inflamed mucosa compared with NCC (P < 0.01). In active UC, IL-6, IL-8 and IL-10 mRNAs were high compared with non-inflamed mucosa (P = 0.03, P = 0.03, P < 0.05, respectively). Both TNF-alpha mRNA (P = 0.03) and IL-6 mRNA (P = 0.04) were higher in UC compared with ICC. Even in non-inflamed mucosa, IL-8 and TNF-alpha mRNA expressions were high compared with NCC. Both IL-6 and IL-8 mRNAs decreased to normal levels after granulocytapheresis. CONCLUSIONS: During active UC, all 4 cytokine mRNA levels were high; only IL-6 and IL-8 mRNAs decreased to normal levels during remission. IL-8 mRNA was high even at sites of endoscopically quiescent UC during active disease. Steroid naïve patients respond well to granulocytapheresis.