Time to go functional! Determining tumors' DNA repair capacity ex vivo.

n.a.Non peer reviewe

Virtual clinical trials identify effective combination therapies in ovarian cancer

A major issue in oncology is the high failure rate of translating preclinical results in successful clinical trials. Using a virtual clinical trial simulations approach, we present a mathematical framework to estimate the added value of combinatorial treatments in ovarian cancer. This approach was applied to identify effective targeted therapies that can be combined with the platinum-taxane regimen and overcome platinum resistance in high-grade serous ovarian cancer. We modeled and evaluated the effectiveness of three drugs that target the main platinum resistance mechanisms, which have shown promising efficacy in vitro, in vivo, and early clinical trials. Our results show that drugs resensitizing chemoresistant cells are superior to those aimed at triggering apoptosis or increasing the bioavailability of platinum. Our results further show that the benefit of using biomarker stratification in clinical trials is dependent on the efficacy of the drug and tumor composition. The mathematical framework presented herein is suitable for systematically testing various drug combinations and clinical trial designs in solid cancers.Peer reviewe

Kohdunrunkosyövän kirurgisen ja liitännäishoidon suunnittelu

Teema : gynekologinen syöpä. English summaryPeer reviewe

HE4 in the evaluation of tumor load and prognostic stratification of high grade serous ovarian carcinoma

Objective Human epididymis protein 4 (HE4) is a validated, complementary biomarker to cancer antigen 125 (CA125) for high grade serous ovarian carcinoma (HGSC). Currently, there are insufficient data on the utility of longitudinal HE4 measurement during HGSC treatment and follow up. We set to provide a comprehensive analysis on the kinetics and prognostic performance of HE4 with serial measurements during HGSC treatment and follow up. Methods This prospective study included 143 patients with advanced HGSC (ClinicalTrials.gov identifier: NCT01276574). Serum CA125 and HE4 were measured at baseline, before each cycle of chemotherapy and during follow up until first progression. Baseline biomarker values were compared to the tumor load assessed during surgery and to residual disease. Biomarker nadir values and concentrations at progression were correlated to survival. Results The baseline HE4 concentration distinguished patients with a high tumor load from patients with a low tumor load assessed during surgery (pPeer reviewe

Molecular subtype diagnosis of endometrial carcinoma: comparison of the next-generation sequencing panel and Proactive Molecular Risk Classifier for Endometrial Cancer classifier

The Cancer Genome Atlas -based molecular classification of endometrial carcinoma (EC) has the potential to better identify those patients whose disease is likely to behave differently than predicted when using traditional risk stratification; however, the optimal approach to molecular subtype assignment in routine practice remains undetermined. The aim of this study was to compare the results of two different widely available approaches to diagnosis the EC molecular subtype. EC specimens from 60 patients were molecularly subclassified using two different methods, by using the FoundationOne CDx next-generation sequencing (NGS) panel and using the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE) classifier and performing immunostaining for mismatch repair proteins and p53. POLE mutation status was derived from FoundationOne results in both settings. Molecular classification based on ProMisE was successful for all 60 tumors. Microsatellite instability status could be determined based on the NGS panel results in 53 of 60 tumors, so ProMisE and NGS molecular subtype assignment could be directly compared for these 53 tumors. Molecular subtype diagnosis based on NGS and ProMisE was in agreement for 52 of 53 tumors. One tumor was microsatellite stable but showed loss of MLH1 and PMS2 expression. Molecular subtype diagnosis of EC based on the NGS panel of formalin-fixed paraffin-embedded ECs and based primarily on immunostaining (ProMisE) yields identical results in 98.1% (52/53, kappa Z 0.97) of cases. Although results obtained using these two approaches are comparable, each has advantages and disadvantages that will influence the choice of the method to be used in clinical practice

The feasibility of [F-18]EF5-PET/CT to image hypoxia in ovarian tumors: a clinical study

Rationale Evaluation of the feasibility of [F-18]EF5-PET/CT scan in identifying hypoxic lesions in ovarian tumors in prospective clinical setting. Methods Fifteen patients with a suspected malignant ovarian tumor were scanned with [F-18]EF5 and [F-18]FDG-PET/CT preoperatively. The distribution of [F-18]EF5-uptake, total intraabdominal metabolic tumor volume (TMTV), and hypoxic subvolume (HSV) were assessed. Results [F-18]EF5-PET/CT suggested hypoxia in 47% (7/15) patients. The median HSV was 87 cm(3)(31% of TMTV). The [F-18]EF5-uptake was detected in primary tumors and in four patients also in intra-abdominal metastases. The [F-18]EF5-uptake in cancer tissue was low compared to physiological excretory pathways, complicating the interpretation of PET/CT images. Conclusions [F-18]EF5-PET/CT is not feasible in ovarian cancer imaging in clinical setting due to physiological intra-abdominal [F-18]EF5-accumulation. However, it may be useful when used complementarily to FDG-PET/CT.</div

Vulvar malignant pleomorphic adenoma in a patient with lichen sclerosus

Lichen sclerosus (LS) is a chronic inflammatory skin disease presenting mainly on the anogenital area. The relationship between female genital LS and squamous cell carcinoma (SCC) has been established, with a lifetime risk of 4% to 5% for SCC development on female patients.1 Vulvar malignant pleomorphic adenoma, also termed carcinoma ex pleomorphic adenoma, is a rare tumor, with only 2 cases reported previously.2,3 The benign counterpart, pleomorphic adenoma (PA), is a commonly diagnosed benign tumor in the salivary glands but may also occur at a variety of other sites. Only about 10 cases of vulvar PA have been reported in the literature.4 There are no previous reports of PA or malignant PA in a patient with LS. Here we report a third case of vulvar malignant PA, and the first, to our knowledge, in a patient with LS.</p

Diagnostic efficiency of whole-body 18F-FDG PET/MRI, MRI alone, and SUV and ADC values in staging of primary uterine cervical cancer

Background: The use of PET/MRI for gynecological cancers is emerging. The purpose of this study was to assess the additional diagnostic value of PET over MRI alone in local and whole-body staging of cervical cancer, and to evaluate the benefit of standardized uptake value (SUV) and apparent diffusion coefficient (ADC) in staging.Methods: Patients with histopathologically-proven cervical cancer and whole-body F-18-FDG PET/MRI obtained before definitive treatment were retrospectively registered. Local tumor spread, nodal involvement, and distant metastases were evaluated using PET/MRI or MRI dataset alone. Histopathology or clinical consensus with follow-up imaging were used as reference standard. Tumor SUVmax and ADC were measured and SUVmax/ADC ratio calculated. Area under the curve (AUC) was determined to predict diagnostic performance and Mann-Whitney U test was applied for group comparisons.Results: In total, 33 patients who underwent surgery (n = 23) or first-line chemoradiation (n = 10) were included. PET/MRI resulted in higher AUC compared with MRI alone in detecting parametrial (0.89 versus 0.73), vaginal (0.85 versus 0.74), and deep cervical stromal invasion (0.96 versus 0.74), respectively. PET/MRI had higher diagnostic confidence than MRI in identifying patients with radical cone biopsy and no residual at hysterectomy (sensitivity 89% versus 44%). PET/MRI and MRI showed equal AUC for pelvic nodal staging (both 0.73), whereas AUC for distant metastases was higher using PET/MRI (0.80 versus 0.67). Tumor SUVmax/ADC ratio, but not SUVmax or ADC alone, was significantly higher in the presence of metastatic pelvic lymph nodes (P Conclusions: PET/MRI shows higher accuracy than MRI alone for determining local tumor spread and distant metastasis emphasizing the added value of PET over MRI alone in staging of cervical cancer. Tumor SUVmax/ADC ratio may predict pelvic nodal involvement.</div