MDM2 copy number increase: a poor prognostic, molecular event in esophageal squamous cell carcinoma.

The present study aimed to elucidate the clinicopathological significance of molecular alterations in MDM2 in esophageal squamous cell carcinoma (ESCC). A total of 399 resected cases of ESCC were examined by dual-color in situ hybridization for MDM2 and immunohistochemistry for p53 using tissue microarrays. Clinicopathological features were correlated with the MDM2 status. Among 362 cases with a successful dual-color in situ hybridization analysis, 19 (5%) and 13 (4%) had MDM2 amplification and chromosome 12 polysomy, respectively, and these were examined as an MDM2-positive group. A comparison between amplified and polysomic cases revealed that the latter were more strongly associated with preoperative chemotherapy than the former. Sixteen (50%) of 32 MDM2-positive cases had positive results in all tissue cores examined, indicating diffuse MDM2 alterations. Cases with the diffuse alteration of MDM2 were characterized by an advanced pT stage and extensive vascular infiltration. The relationship between MDM2 copy number increases and p53 mutations was weak, with the overexpression of p53 being similarly detected in MDM2-positive and MDM2-negative cases (59% versus 49%; P = .267). Overall survival was shorter in patients with MDM2-positive ESCC than in those without MDM2 alterations (P = .033). The poor prognostic value of MDM2 alterations became more obvious when only diffusely altered cases were counted (P = .005). In conclusion, the present study revealed that MDM2 copy number increases occurred in 9% of ESCC cases, and MDM2 alterations, particularly diffuse abnormalities, were associated with a poor prognosis. MDM2-altered ESCC may achieve beneficial effects from MDM2-targeted therapy.

Significance of Additional Gastrectomy Including Endoscopic Submucosal Dissection Scar for Gastric Cancer.

BACKGROUND/AIM: The aim of the study was to evaluate the necessity of gastrectomy including endoscopic submucosal dissection (ESD) scar with margin-negative early gastric cancer (EGC). PATIENTS AND METHODS: We analyzed 83 patients with EGC who received additional gastrectomy after non-curative ESD and evaluated the risk factors for residual cancer (RC) and lymph node (LN) metastasis. RESULTS: In addition to positive ESD margin, ulceration was a risk factor for RC. Among cases with deep submucosal invasion (sm), 3 were diagnosed as having negative margins in ESD specimens, but the surgical specimens were positive for cancer. The rate of LN metastasis was 12.0%. There was no significant difference in LN metastasis between tumor characteristics. CONCLUSION: LN dissection is recommended after non-curative ESD. Gastrectomy including the ESD scar should be performed not only for cases with positive margin in ESD, but also for cases with invasion deeper than sm2, even though the margin is negative.

[A Case of Gastric Carcinoma with Peritoneal Dissemination Treated with Curative Resection Following Trastuzumab plus Capecitabine plus Cisplatin Combined Therapy].

A 67-year-old man was referred to our hospital with a diagnosis of type 3 gastric cancer in lower third of the stomach. Computed tomography(CT)scan showed no distant metastasis, but peritoneal dissemination from gastric cancer. A laparoscopic exploration diagnosed pStage IV gastric cancer with peritoneal dissemination. Trastuzumab, capecitabine and cisplatin therapy was administered for initially unresectable gastric cancer. After 6courses of chemotherapy, primary lesion and lymph node metastasis shrank, and the peritoneal dissemination did not worsen by CT scan. The second laparoscopic exploration showed no apparent dissemination or metastatic cancer cells. Total gastrectomy with D2 lymph node dissection, partial colectomy and cholecystectomy were performed with curative intent. The pathological diagnosis was ypT3N1P0CY0, Stage II B, and the histological response of primary tumor after chemotherapy was categorized as Grade 1a. The patients is alive during 24 months after surgery with no evidence of recurrence.

SOX2-silenced squamous cell carcinoma: a highly malignant form of esophageal cancer with SOX2 promoter hypermethylation.

This study originally aimed to investigate whether the overexpression of SOX2 is associated with the poor prognosis of patients with squamous cell carcinoma of the esophagus. However, we unexpectedly found that esophageal squamous cell carcinomas completely lacking SOX2 expression showed distinct pathologic features and highly aggressive clinical courses. The study cohort consisted of 113 consecutive patients with esophageal squamous cell carcinoma who underwent surgical resection without neoadjuvant therapy. Immunostaining on tissue microarrays and whole sections revealed that 8/113 (7%) cases were entirely negative for this transcriptional factor. SOX2-negative cancers were histologically less differentiated (P=0.002) and showed higher pT and pStages (P=0.003 and 0.007, respectively) than SOX2-positive cases. A remarkable finding was widespread lymphatic infiltration distant from the primary invasive focus, which was observed in 4 SOX2-negative cancers (50%), but none of the SOX2-positive cases. All separate dysplastic lesions observed in SOX2-negative cases were also SOX2-negative. The negative expression of SOX2 appeared to be an independent poor prognostic factor (OR=7.05, 95% CI=1.27-39.0). No mutations were identified in the coding or non-coding regions of SOX2. Fluorescent in situ hybridization did not show any copy-number variations in this gene. Since the SOX2 promoter contains an extensive CpG island, SOX2-negative cases underwent methylation-specific PCR, which disclosed promoter hypermethylation in all cases. In conclusion, SOX2-silenced squamous cell carcinomas of the esophagus appear to be a minor, but distinct form of malignancy characterized by extensive lymphatic invasion, a poor prognosis, and potential association with multiple SOX2-negative neoplastic lesions. The hypermethylation of the promoter region is seemingly a critical epigenetic event leading to SOX2 silencing.

Epigenetic down-regulation of SOX2 is an independent poor prognostic factor for hypopharyngeal cancers.

AIMS: We recently reported that a small subset (7%) of oesophageal squamous cell carcinomas completely lacking SOX2 expression had unique clinicopathological features and a dismal prognosis. The aim of the present study was to elucidate whether the findings obtained in oesophageal cancers are applicable to hypopharyngeal squamous cell carcinomas (HPSCCs) or oropharyngeal squamous cell carcinomas (OPSCCs). METHODS AND RESULTS: The study cohort consisted of consecutive patients with HPSCC (n = 130) and OPSCC (n = 65) who underwent surgery without preoperative therapy. On immunostaining, SOX2 was almost entirely negative in 10 of 130 HPSCCs (8%) and seven of 65 OPSCCs (11%). No significant differences were observed in clinicopathological features, including p16 status, between SOX2-positive and SOX2-negative cancers. However, patients with SOX2-negative HPSCC had significantly worse overall and recurrence-free survival than those with SOX2-positive HPSCC, whereas such a prognostic relationship was not confirmed in patients with OPSCC. In a multivariate analysis, the loss of SOX2 expression appeared to be an independent poor prognostic factor for patients with HPSCC. In a sequencing analysis, no mutation was found in SOX2. As SOX2 is known to contain an extensive CpG island before the transcription start site, methylation-specific polymerase chain reaction for the SOX2 promoter was performed. Methylated alleles were found in nine of 10 SOX2-negative HPSCCs but in none of SOX2-positive HPSCCs. CONCLUSIONS: Similarly to oesophageal cancers, a small subset (8%) of HPSCCs characteristically almost completely lacking SOX2 expression appeared to be aggressive neoplasms with high recurrence rates. Promoter hypermethylation was determined to be a major mechanism underlying epigenetic SOX2 silencing.

Laparoscopy-assisted distal gastrectomy in a patient with situs inversus totalis.

INTRODUCTION: We report on a patient with situs inversus totalis who underwent laparoscopic-assisted distal gastrectomy (LADG) involving standard lymph node dissection (LND) for early gastric cancer. CASE DESCRIPTION: A 42-y-old man presented at the Department of Internal Medicine in our hospital with the diagnosis of early gastric cancer detected elsewhere by upper endoscopy. Endoscopic submucosal dissection for this early gastric cancer was performed at our hospital. Histopathological examination of the resected specimen yielded the diagnosis of type 0-IIc, T1b1(SM), ly (+), v (-), UL (-), HM0, VM0, R0, according to the Japanese Classification of Gastric Carcinoma. Additional surgery was deemed necessary, and he was referred to our department. Preoperative computed tomography showed no liver or lung metastasis. The preoperative diagnosis was cStage IA (pT1b1, cN0, cH0, cP0, and cM0). Standard LADG with LND (D1 + No.7, 8a, 9) was performed successfully. Histological examination disclosed stage IB (pT1b1, pN1, sH0, sP0, and sM0). The patient was discharged on postoperative day 14 after an uneventful postoperative course. Eighteen months after the operation, he is doing well without recurrent gastric cancer. CONCLUSION: Laparoscopic surgery for gastric cancer with SIT should be considered a feasible, safe, and curative procedure.