Melanoma is the most deadly tumor of the skin, and systemic therapies for the advanced stage are still limited. Recent genetic analyses have revealed the molecular diversity of melanoma and potential therapeutic targets. By screening a cohort of 142 primary nonepithelial tumors, we discovered that about 10% of melanoma cases (4/39) harbored an IDH1 or IDH2 mutation. These mutations were found to coexist with BRAF or KIT mutation, and all IDH1 mutations were detected in metastatic lesions. BRAF-mutated melanoma cells, additionally expressing the cancer-related IDH1 mutant, acquired increased colony-forming and in vivo growth activities and showed enhanced activation of the MAPK and STAT3 pathways. Genome-wide gene expression profiling demonstrated that mutant IDH1 affected the expression of a set of genes. Especially, it caused the induction of growth-related transcriptional regulators (Jun, N-myc, Atf3) and the reduction of Rassf1 and two dehydrogenase genes (Dhrs1 and Adh5), which may be involved in the carcinogenesis of IDH1-mutated tumors. Our analyses demonstrate that IDH1 mutation works with other oncogenic mutations and could contribute to the metastasis in melanoma. Melanoma is the most malignant tumor of the skin, and the median survival rate of patients with metastatic tumors is less than 1 year.1 Although the incidence of melanoma has been increasing around the world, systemic therapies for the advanced stage are still limited. 2Recent studies have provided a clearer picture of the molecular events leading to melanoma development and progression.3,4 Since the identification of prevalent activating mutations of BRAF kinase, 5 further molecular studies have clarified the role of this pathway and others in melanomagenesis. 6 Recent genetic investigations have also demonstrated specific genotype-phenotype correlations that would be potentially informative in the context of the molecular subclassification of melanoma and therapeutic target molecules.7 For example, the c-kit gene mutations have been frequently reported in acral lentiginous/mucosal melanomas and are associated with better responsiveness to the inhibitor, imatinib. -10Recently, unbiased whole-exon resequencing analysis of glioblastoma multiforme has revealed recurrent mutation of the two IDH (isocitrate dehydrogenase) isoforms, IDH1 and IDH2.11 Subsequent analysis showed that these mutations are frequent in glioma and associated with better prognosis 12,13 ; furthermore, they have also been detected in a subset (about 8% to 16%) of acute myeloid leukemia (AML).14 -17 These enzymes convert isocitrate to ␣-ketoglutarate (␣-KG) with concurrent reduction of NADPH, but IDH1 is localized in the cytosol 18 whereas IDH2 is localized in mitochondria. 19 Mutations of the two genes affect the residues responsible for hydrophilic interactions with the substrate, and have been shown to impair the enzymatic activity, and therefore they are considered to be loss-of-function alleles.12 However, because the mutations are clustered in specific residues and only...

A retrospective analysis was carried out to identify risk factors for survival and relapse in patients with FIGO stage I -IIB cervical adenocarcinoma (AC), who underwent radical hysterectomy, and to compare outcome and spread pattern with those of squamous cell carcinoma (SCC). One hundred and twenty-three FIGO stage I -IIB patients with AC and 455 patients with SCC, who all underwent primary radical hysterectomy, were reviewed. Among the patients with AC, Cox model identified tumour size (95% CI: 1.35 -30.71) and node metastasis (95% CI: 5.09 -53.44) as independent prognostic factors for survival, and infiltration to vagina (95% CI: 1.15 -5.76) and node metastasis (95% CI: 6.39 -58.87) as independent prognostic factors for relapse. No significant difference was found in survival or relapse between the AC and SCC groups, after adjusting for other clinicopathological characteristics using Cox model. No significant difference was found in the positive rates of lymph nodes or location of initial failure sites between the two groups, but ovarian metastatic rate was significantly higher in patients with pathologic stage IIB AC (P ¼ 0.02). Positive node is a common independent prognostic factor for survival and relapse of patients with AC. FIGO stage I -IIB patients with AC or SCC, who underwent radical hysterectomy, have similar prognosis and spread pattern, but different ovarian metastasis rates. At present, standard treatment options for patients with invasive carcinoma of the uterine cervix are as follows: radical hysterectomy followed by adjuvant radiotherapy or primary radiotherapy with concurrent cisplatin-containing chemotherapy, for the patients with the International Federation of Gynecology and Obstetrics (FIGO) stage IB -IIA disease, with equivalent results; and primary radiotherapy with concurrent chemotherapy for the patients with FIGO stage IIB -IVA disease. These therapeutic strategies have been widely accepted. On the other hand, approximately 85% of the patients with carcinoma of the uterine cervix have squamous lesions, and most of the remaining 10% have adenocarcinoma (AC) lesions (Benedet et al, 2003). To our knowledge, no practice guideline has referred to the treatment option based on the difference of histological types between AC and squamous cell carcinoma (SCC) It is not clear whether these histological types influence outcome or spread pattern, and there is still controversy, as conflicting results have appeared in the literature because of potential limitations of small cohorts of patients with AC. The question whether standard treatment for patients with SCC is also suitable for patients with AC remains unanswered. Additionally, over the last decade, the proportion of AC relative to SCC has doubled, and the rate of AC per population at risk has also increased (Smith et al, 2000). To establish a framework for designing therapeutic strategies, the present retrospective study was undertaken firstly to clarify the clinicopathological features of the surgically treated patients with common typ...

There is a close association between SMMN-FGT and LEGH/PGM. Microinvasion and positive peritoneal cytology may not have an influence on outcome.

A retrospective analysis was performed to evaluate the prognostic significance of peritoneal cytology in patients with endometrial carcinoma limited to the uterus. A total of 280 patients with surgically staged endometrial carcinoma that was histologically confined to the uterus were examined clinicopathologically. The median length of follow-up was 62 (range, 12 -135) months. All patients underwent hysterectomy and salpingo-oophorectomy with selective lymphadenectomy, and only three patients received adjuvant postoperative therapy. No preoperative adjuvant therapy was employed. In all, 48 patients (17%) had positive peritoneal cytology. The 5-year survival rate among patients with positive or negative peritoneal cytology was 91 or 95%, respectively, showing no significant difference (log-rank, P ¼ 0.42). The disease-free survival rate at 36 months was 90% among patients with positive cytology, compared with that of 94% among patients with negative cytology, and the difference was not significant (log-rank, P ¼ 0.52). Multivariate proportional hazards model revealed only histologic grade to be an independent prognostic factor of survival (P ¼ 0.0003, 95% CI 3.02 -40.27) among the factors analysed (age, peritoneal cytology, and depth of myometrial invasion). Multivariate analysis revealed that histologic grade (P ¼ 0.02, 95% CI 1.21 -9.92) was also the only independent prognostic factor of disease-free survival. We concluded that the presence of positive peritoneal cytology is not an independent prognostic factor in patients with endometrial carcinoma confined to the uterus, and adjuvant therapy does not appear to be beneficial in these patients.

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Uterine papillary serous carcinoma (UPSC) is a rare and aggressive variant of endometrial carcinoma. Little is known about the pathological and biological features of this tumor. Human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression have an important role in tumor behavior and clinical outcome, but their relevance in UPSC is not clear. In the present study, the immunohistochemical expression of HER2 and HR was assessed in 27 patients with Stage I disease, 13 with Stage II disease, 25 with Stage III disease, and 6 with Stage IV disease. Correlations between HER2 and HR expression and the clinicopathological parameters of UPSC were evaluated using Cox's univariate and multivariate analyses. For all patients, the 5-year recurrence-free survival (RFS) and overall survival (OS) rates were 51% and 66%, respectively; in patients with Stage I, II, III and IV disease, the RFS and OS were 67%/81%, 59%/77%, 43%/54% and 0%/0%, respectively. Of all 71 patients, 14% (10/71) were positive for HER2 and 52% (37/71) were positive for HR. Overexpression of HER2 was correlated with lower OS (P = 0.01), whereas HR overexpression was correlated with higher OS (P = 0.008). In multivariate models, HER2, HR, and histologic subtype were identified as independent prognostic indicators for RFS (P = 0.022, P = 0.018, and P = 0.01, respectively), but HR was the only independent factor associated with OS (P = 0.044). Thus, HER2 and HR are prognostic variables in UPSC, with HR an independent prognostic factor for OS. (Cancer Sci 2012; 103: 926-932) E ndometrial carcinoma is the most common gynecological malignancy in the US and its occurrence in Japan has increased recently.(1,2) Endometrial carcinomas are conventionally divided into two subgroups, Types I and II. Type I endometrial carcinomas is associated with a hyperestrogenic state and tends to be well differentiated, whereas Type II endometrial carcinomas is not associated with a hyperestrogenic status and is high grade.(3) Uterine papillary serous carcinoma (UPSC), initially described by Hendrickson et al.,(4) is one of the Type II endometrial carcinomas. It comprises <10% of all endometrial carcinomas, but accounts for over 50% of all recurrences and deaths caused by this disease.(5-7) Despite aggressive treatment, locoregional and distant failures are common, even in patients treated by surgery for early stage disease. (5,(8)(9)(10) One study reported a 5-year overall survival (OS) rate for 129 patients with UPSC of 45.9%, with recurrence even occurring in four of 21 (19%) patients with Stage IA. Nonetheless, there is little information regarding the molecular basis for the aggressive biological behavior of UPSC.Human epidermal growth factor receptor type 2 (HER2) is a well-established tumor biomarker that is overexpressed in a wide variety of carcinomas, including breast, ovary, prostate, and lung. (11,12) Overexpression of HER2 is a significant factor in aggressive tumor behavior and poor clinical outcome.

A subset of EMPD, both intraepithelial and invasive, showed HER2 overexpression and gene amplification. These HER2 alterations were correlated with biologically aggressive EMPDs, i.e. those with deep invasion and lymph-node metastasis. Clinical trials of HER2-targeted therapy are awaited for improvement of the prognosis of patients with aggressive EMPD.

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