CCNE1 and survival of patients with tubo-ovarian high-grade serous carcinoma: An Ovarian Tumor Tissue Analysis consortium study

BACKGROUND: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo-ovarian high-grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 amplification and CCNE1 overexpression with survival, but to date no large-scale, histotype-specific validation has been performed. The hypothesis was that high-level amplification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. METHODS: Within the Ovarian Tumor Tissue Analysis consortium, amplification status and protein level in 3029 HGSC cases and mRNA expression in 2419 samples were investigated. RESULTS: High-level amplification (>8 copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression (>60% with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high-level amplification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26; 95% CI, 1.08-1.47, p = .034, and HR, 1.18; 95% CI, 1.05-1.32, p = .015, respectively). This was also true for cases with combined high-level amplification/overexpression (HR, 1.26; 95% CI, 1.09-1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1-SD increase; 95% CI, 0.94-1.06; p = .58). CCNE1 high-level amplification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. CONCLUSION: This study provides large-scale validation that CCNE1 high-level amplification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC

Gene expression profiling of mucinous ovarian tumors and comparison with upper and lower gastrointestinal tumors identifies markers associated with adverse outcomes.

PURPOSE: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. EXPERIMENTAL DESIGN: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). RESULTS: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77; 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25; 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21; 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) amplification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). CONCLUSIONS: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC samples clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies

Updating the approaches to define susceptibility and resistance to anti-tuberculosis agents: implications for diagnosis and treatment

11 páginas, 2 figuras, 1 tablaInappropriately high breakpoints have resulted in systematic false-susceptible AST results to anti-TB drugs. MIC, PK/PD and clinical outcome data should be combined when setting breakpoints to minimise the emergence and spread of antimicrobial resistance.I. Comas was supported by PID2019-104477RB-I00 from the Spanish Science Ministry and by ERC (CoG 101001038)Peer reviewe

Risk of persistent and recurrent cervical neoplasia following incidentally detected adenocarcinoma-in-situ.

BACKGROUND: Adenocarcinoma-in-situ (AIS) of the uterine cervix is a precursor to cervical adenocarcinoma and may co-exist with both adenocarcinoma and high-grade squamous dysplasia (cervical intraepithelial neoplasia (CIN) 2 and 3). Up to 60% of AIS lesions are detected incidentally following excisional biopsies performed for the treatment of CIN 2/3. To date there are no data regarding risk factors for persisting or progressive cervical neoplasia in these patients. OBJECTIVE: To investigate patient outcomes following incidentally detected cervical AIS after loop electrosurgical excision procedure (LEEP) or cold knife cone (CKC) biopsy performed for the treatment of high-grade cervical intraepithelial neoplasia (CIN). STUDY DESIGN: A retrospective, population-based cohort study of Western Australian patients with an incidental diagnosis of AIS between 2001 and 2012. Primary outcomes were persistent or recurrent CIN 2/3 and or AIS, and invasive adenocarcinoma during follow-up (<12 months) and surveillance (=12 months) periods. RESULTS: The cohort comprised 298 patients, with 228 (76.5%) treated initially by LEEP and 70 (23.5%) treated by CKC biopsy. The mean age was 31.2 years (range 18 to 68 years) and the median length of follow-up was 2.4 years (range 0.3 to 12.2 years). Overall, 11 (3.7%) patients had CIN 2/3, 23 (7.7%) had AIS and 3 (1.0%) had adenocarcinoma diagnosed during the follow-up and surveillance periods. Age over 30 years, pure AIS lesions and larger lesions (>8mm) were associated with a greater risk of disease persistence or recurrence. CONCLUSION(S): Following the incidental detection of AIS, age >30 years, pure AIS lesions and lesions >8mm, were significantly associated with disease persistence/recurrence. In younger women, incidentally detected AIS which co-exists with CIN 2/3 and is <8mm extent with clear margins may not require re-excision