Mutation of PPP2R1A: a new clue in unveiling the pathogenesis of uterine serous carcinoma

Uterine carcinoma is composed mainly of two distinct types: serous and endometrioid. Uterine serous carcinoma, while not as common as endometrioid carcinoma, is a highly aggressive disease and is associated with high mortality. Although the molecular genetic alterations of uterine endometrioid carcinoma have been well established, molecular genetic changes in uterine serous carcinoma are largely unclear. Two recent papers have analysed PPP2R1A mutations among different types of gynaecological neoplasia. Both studies report a surprisingly high frequency of somatic mutations of PPP2R1A in uterine serous carcinomas. PPP2R1A encodes a scaffolding subunit of a major serine/threonine phosphatase, protein phosphatase 2A (PP2A), which plays a critical role in diverse cellular functions, including negative regulation of cellular proliferation and potential tumour suppression. As PPP2R1A is essential for the phosphatase activity of PP2A, this observation should create a new research road map toward elucidating how PPP2R1A mutations and alterations of the PP2A pathway contribute to the pathogenesis of uterine serous carcinoma.     

甲状腺球蛋白抗体对电化学发光免疫分析法测定甲状腺球蛋白的影响

采用电化学发光免疫分析法(ECLIA)同时测定甲状腺球蛋白(Tg)、自身甲状腺球蛋白抗体(TgAb)值,并用回收实验研究TgAb对Tg测定值的影响。甲状腺疾病患者血样84例,测定Tg、TgAb。回收实验分为三组。第一组分别加入50、100和200 ng/ml的标准Tg;第二组TgAb≥4 000 IU/ml的血样对倍稀释5次,分别测定Tg、TgAb值,并加入100 ng/ml标准Tg;第三组TgAb浓度梯度组,分别加入100 ng/ml标准Tg。计算回收率(R)。结果显示血清对倍稀释后,TgAb实测值逐渐下降;Tg实测值、Tg计算值逐渐上升,两者的差值随稀释倍数的增加而增大。当R<80%时,有22人(91.7%)TgAb>115 IU/ml。ECLIA测定Tg时,TgAb的干扰导致Tg测定值低于真实值,并呈浓度依赖性。TgAb的存在是导致回收率降低的主要原因。     

Mitochondrial UCP4 and bcl-2 expression in imprints of breast carcinomas: relationship with DNA ploidy and classical prognostic factors

Mitochondria are the bioenergetic and metabolic centers of cells and play an important role in the regulation of cell death. The mitochondrial apoptosis pathway is controlled by the bcl-2 protein family. Overexpression of mitochondrial uncoupling protein 4 (UCP4) can promote proliferation and inhibit apoptosis and differentiation. Imprint smears obtained from 124 tumors were studied immunocytochemically, and results were correlated with prognostic markers. There were 112 ductal and 12 lobular carcinomas. The positivity of UCP4 was correlated with lymph node metastases (p = 0.005), positive ER and PR expression (p < 0.0001 for both), as well as positivity for p53 (p < 0.0001) and Ki-67 (p < 0.0001). Decreased expression of bcl-2 correlated with increased expression of UCP4 (p = 0.001). Regarding DNA ploidy, UCP4 positivity was correlated with aneuploid tumors (p = 0.002). Negative expression of bcl-2 was correlated with poorly differentiated carcinomas (p < 0.0001), as well as with positive expression of p53 (p < 0.0001) and Ki-67 (p < 0.0001). Logistic regression revealed that ploidy and p53 expression had an impact on UCP4. These findings encourage future investigations regarding the potential role of UCPs not only into mechanisms underlying breast cancer, but also as a novel candidate to the design and development of more effective therapeutic strategies.     

Prospective, non-randomized phase 2 clinical trial of carboplatin plus paclitaxel with sequential radical pelvic radiotherapy for uterine papillary serous carcinoma

Objective

Uterine Papillary Serous Carcinoma (UPSC) is uncommon and accounts for less than 5% of all uterine cancers. Therefore the majority of evidence about the benefits of adjuvant treatment comes from retrospective case series. We conducted a prospective multi-centre non-randomized phase 2 clinical trial using four cycles of adjuvant paclitaxel plus carboplatin chemotherapy followed by pelvic radiotherapy, in order to evaluate the tolerability and safety of this approach.

Methods

This trial enrolled patients with newly diagnosed, previously untreated patients with stage 1b-4 (FIGO-1988) UPSC with a papillary serous component of at least 30%. Paclitaxel (175 mg/m²) and carboplatin (AUC 6) were administered on day 1 of each 3-week cycle for 4 cycles. Chemotherapy was followed by external beam radiotherapy to the whole pelvis (50.4 Gy over 5.5 weeks). Completion and toxicity of treatment (Common Toxicity Criteria, CTC) and quality of life measures were the primary outcome indicators.

Results

Twenty-nine of 31 patients completed treatment as planned. Dose reduction was needed in 9 patients (29%), treatment delay in 7 (23%), and treatment cessation in 2 patients (6.5%). Hematologic toxicity, grade 3 or 4 occurred in 19% (6/31) of patients. Patients' self-reported quality of life remained stable throughout treatment. Thirteen of the 29 patients with stages 1-3 disease (44.8%) recurred (average follow-up 28.1 months, range 8-60 months).

Conclusion

This multimodal treatment is feasible, safe and tolerated reasonably well and would be suitable for use in multi-institutional prospective randomized clinical trials incorporating novel therapies in patients with UPSC.     

BRCA mutation testing for first-degree relatives of women with high-grade serous ovarian cancer

BackgroundWomen with high-grade serous ovarian cancer (HGSC) have a 20% chance of carrying a BRCA1 or 2 mutation. Not all undergo genetic testing, and there is a large legacy group of untested patients. Their female first-degree relatives (FDR) may not qualify for testing unless they have specific ethnicity, or personal/family cancer history. We conducted a cost-effectiveness analysis to evaluate risk-reducing strategies for these FDR who are ineligible for testing.MethodsA Markov Monte Carlo simulation model estimated the costs and benefits of 3 strategies for female FDR of HGSC patients whose BRCA status is unknown: (1) no BRCA testing; (2) universal BRCA testing, followed by risk-reducing bilateral salpingo-oophorectomy (RRBSO) for mutation carriers; (3) universal RRBSO, without BRCA testing. Effectiveness was estimated in quality-adjusted life year (QALY) gains over a 50-year time horizon. Sensitivity analyses accounted for uncertainty around various parameters.ResultsUniversal BRCA testing for female FDR of women with HGSC yielded a higher average QALY gain at acceptable cost compared to no BRCA testing, with an incremental cost-effectiveness ratio of $7888 per QALY. Universal BRCA testing was more effective and less costly than universal RRBSO (19.20 QALYs vs. 18.52 QALYs, and $10,135 vs. $14,231, respectively). Results were stable over wide ranges of plausible costs and estimates. Compliance with hormone replacement therapy had to exceed 79.3% for universal RRBSO to be the most effective strategy.ConclusionBRCA mutation testing should be offered to all female first-degree relatives of women with high-grade serous ovarian cancer when BRCA mutation status is unknown.     

Neuroendocrine differentiation in carcinoma of the breast. Tyramide signal amplification discloses chromogranin A-positive tumour cells in more breast tumours than previously realized

The aim of the study was to determine if, by means of tyramide signal amplification (TSA), the presence of chromogranin A (CgA)-positive tumour cells could be demonstrated in breast cancer cases found to be negative by conventional immunohistochemical staining. Sections from 44 cases of breast cancer (28 infiltrating ductal carcinomas, 2 lobular carcinomas, 4 ductal carcinomas in situ (DCIS), 7 lobular carcinomas in situ (LCIS), and 3 mucinous carcinomas) were stained for CgA by conventional immunohistochemical methods and by immunohistochemistry with TSA. The sections were also histologically graded and their oestrogen receptor (ER), progesterone receptor (PgR) and HER-2 oncogene status was recorded. Five of the tumours showed CgA-positive staining with the polyclonal antibody 430 with conventional methods. Thirty cases showed CgA-immunoreactive tumour cells after immunohistochemical staining with the polyclonal antibody 430 with TSA. However, eight of these also showed faint staining with the negative control antibody X0936 with TSA. One case showed immunopositivity for CgA using a monoclonal antibody without tyramide amplification and only a further two cases were positive when TSA was applied. The presence of CgA appears to be associated with a lower histological grade and may be more often found in oestrogen receptor-positive tumours.     

Overexpression of β-catenin and cyclinD1 predicts a poor prognosis in ovarian serous carcinomas

Ovarian serous cancer is the most common subtype of epithelial ovarian cancer, and is the leading cause of death from gynecologic cancer. There is an important need for exploration of diagnostic and prognostic markers for this disease. β-catenin and cyclinD1 play central roles in the tumorigenesis for certain cancers. The role of β-catenin and cyclinD1 in diagnosis and prognosis of ovarian serous carcinoma is uncertain. In the present study, the expression of β-catenin and cyclinD1 was examined in 60 ovarian serous carcinomas patients with immunohistochemical staining. The relationship between expression of β-catenin and cyclinD1 and FIGO stage, pathological grade was analyzed. Kaplan-Meier survival function was used to analyze the prognosis. Overexpression of β-catenin is more often detected in patients with FIGO stage III and IV than in those with stage I, and II (P=0.003). No significant relationship was found between expression of β-catenin and pathological grade (P=0.817). Positive expression of β-catenin related to lower survival rate (P=0.034). The expression of cyclinD1 had no relationship with FIGO stage (P=0.829). Overexpression of cyclinD1 was positively to pathological grade (P=0.017) and survival rate (P=0.009). There is a significantly positive relationship between expression of β-catenin and cyclinD1 (P=0.014). No statistical significance was found between expression of β-catenin and cyclinD1 and other pathological parameters. Conclusions: Expression of β-catenin and cyclinD1 may be used as predict markers for poor prognosis.     

Multiple genital tract tumors and mucinous adenocarcinoma of colon in a woman with Peutz-Jeghers syndrome: a case report and review of literatures

We report a very rare case of Peutz-Jeghers syndrome (PJS) composed of multiple genital tract tumors and mucinous adenocarcinoma. A 46-year-old woman presented to our hospital with lower abdominal pain resulting from PJS involves sex cord tumor with annular tubules (SCTAT), ovarian mucinous tumor, ovarian serous tumor, mucinous adenocarcinoma of colon. The CEA concentration is high before surgery, and decreases after the surgery and subsequent chemoradiotherapy. This case demonstrates a classic clinical presentation of a patient with PJS. PJS patients have increased risk of malignancy and early detection and regular surveillance of the high-risk patients with PJS is crucial. Surgery may be required for obstructive gastrointestinal lesions as well as those exhibiting malignant degeneration.