Evis Sala

Dynamic contrast-enhanced MRI as a predictor of tumour response to radiotherapy.

A predictive technique in the management of patients with cancer could improve the therapeutic index by allowing better individualisation of treatment. The standard risk factors that are currently used do not adequately account for the unpredictable and substantial variation seen in the treatment response of patients with a similar risk profile. Dynamic contrast-enhanced (DCE) MRI is a non-invasive technique that can provide anatomical and physiological information on the tumour. The DCE-MRI data reflects the tumour microenvironment variables that are known to influence radiation response. The aim of this review is to describe the potential clinical application of DCE-MRI as a predictor of radiation response. We have reviewed the literature and identified 29 studies (total of 1194 patients) that correlate DCE-MRI with histopathological or clinical outcome data relevant to radiotherapy.

MRI of Malignant Neoplasms of the Uterine Corpus and Cervix

OBJECTIVE In this article, we review the role of MRI in the imaging of malignant neoplasms of the uterine corpus and cervix, describing its role in staging, treatment planning, and follow-up. CONCLUSION MRI is not officially incorporated in the International Federation of Gynecology and Obstetrics (FIGO) staging system, but is already widely accepted as the most reliable imaging technique for the diagnosis, staging, treatment planning, and follow-up of both endometrial and cervical cancer. MRI protocols need to be optimized to obtain the best results and avoid pitfalls.

The Added Role of MR Imaging in Treatment Stratification of Patients with Gynecologic Malignancies: What the Radiologist Needs to Know

Many treatment options are available to patients with endometrial, cervical, or ovarian cancer. Magnetic resonance (MR) imaging plays an important role in the patient journey from the initial evaluation of the extent of the disease to appropriate treatment selection and follow-up. The purpose of this review is to highlight the added role of MR imaging in the treatment stratification and overall care of patients with endometrial, cervical, or ovarian cancer. Several MR imaging techniques used in evaluation of patients with gynecologic malignancies are described, including both anatomic MR imaging sequences (T1- and T2-weighted sequences) and pulse sequences that characterize tissue on the basis of physiologic features (diffusion-weighted MR imaging), dynamic contrast agent-enhanced MR imaging, and MR spectroscopy. MR imaging findings corresponding to the 2009 revised International Federation of Gynecology and Obstetrics staging of gynecologic malignancies are also described in detail, highlighting possible pearls and pitfalls of staging. With the growing role of the radiologist as a core member of the multidisciplinary treatment planning team, it is crucial for imagers to recognize that MR imaging has become central in tailoring treatment options and therapy in patients with gynecologic malignancies.

Red clover-derived isoflavones and mammographic breast density: a double-blind, randomized, placebo-controlled trial [ISRCTN42940165]

IntroductionIsoflavones are hypothesized to protect against breast cancer, but it is not clear whether they act as oestrogens or anti-oestrogens in breast tissue. Our aim was to determine the effects of taking a red clover-derived isoflavone supplement daily for 1 year on mammographic breast density. Effects on oestradiol, follicle-stimulating hormone (FSH), luteinizing hormone (LH), lymphocyte tyrosine kinase activity and menopausal symptoms were also assessed.MethodsA total of 205 women (age range 49–65 years) with Wolfe P2 or DY mammographic breast patterns were randomly assigned to receive either a red clover-derived isoflavone tablet (26 mg biochanin A, 16 mg formononetin, 1 mg genistein and 0.5 mg daidzein) or placebo. Change in mammographic breast density, serum oestradiol, FSH, LH, menopausal symptoms and lymphocyte tyrosine kinase activity from baseline to 12 months were assessed.ResultsA total of 177 women completed the trial. Mammographic breast density decreased in both groups but the difference between the treatment and placebo was not statistically significant. There was a significant interaction between treatment group and oestrogen receptor (ESR1) PvuII polymorphism for the change in estimated percentage breast density (mean ± standard deviation): TT isoflavone 1.4 ± 12.3% and TT placebo -9.6 ± 14.2%; CT isoflavone -5.2 ± 12.0% and CT placebo -2.8 ± 10.3%; and CC isoflavone -3.4 ± 9.7% and CC placebo -1.1 ± 9.5%. There were no statistically significant treatment effects on oestradiol, FSH, or LH (assessed only in postmenopausal women), or on lymphocyte tyrosine kinase activity. Baseline levels of menopausal symptoms were low, and there were no statistically significant treatment effects on frequency of hot flushes or other menopausal symptoms.ConclusionIn contrast to studies showing that conventional hormone replacement therapies increase mammographic breast density, the isoflavone supplement did not increase mammographic breast density in this population of women. Furthermore, there were no effects on oestradiol, gonadotrophins, lymphocyte tyrosine kinase activity, or menopausal symptoms.

Spatial and Temporal Heterogeneity in High-Grade Serous Ovarian Cancer: A Phylogenetic Analysis

Background The major clinical challenge in the treatment of high-grade serous ovarian cancer (HGSOC) is the development of progressive resistance to platinum-based chemotherapy. The objective of this study was to determine whether intra-tumour genetic heterogeneity resulting from clonal evolution and the emergence of subclonal tumour populations in HGSOC was associated with the development of resistant disease. Methods and Findings Evolutionary inference and phylogenetic quantification of heterogeneity was performed using the MEDICC algorithm on high-resolution whole genome copy number profiles and selected genome-wide sequencing of 135 spatially and temporally separated samples from 14 patients with HGSOC who received platinum-based chemotherapy. Samples were obtained from the clinical CTCR-OV03/04 studies, and patients were enrolled between 20 July 2007 and 22 October 2009. Median follow-up of the cohort was 31 mo (interquartile range 22–46 mo), censored after 26 October 2013. Outcome measures were overall survival (OS) and progression-free survival (PFS). There were marked differences in the degree of clonal expansion (CE) between patients (median 0.74, interquartile range 0.66–1.15), and dichotimization by median CE showed worse survival in CE-high cases (PFS 12.7 versus 10.1 mo, p = 0.009; OS 42.6 versus 23.5 mo, p = 0.003). Bootstrap analysis with resampling showed that the 95% confidence intervals for the hazard ratios for PFS and OS in the CE-high group were greater than 1.0. These data support a relationship between heterogeneity and survival but do not precisely determine its effect size. Relapsed tissue was available for two patients in the CE-high group, and phylogenetic analysis showed that the prevalent clonal population at clinical recurrence arose from early divergence events. A subclonal population marked by a NF1 deletion showed a progressive increase in tumour allele fraction during chemotherapy. Conclusions This study demonstrates that quantitative measures of intra-tumour heterogeneity may have predictive value for survival after chemotherapy treatment in HGSOC. Subclonal tumour populations are present in pre-treatment biopsies in HGSOC and can undergo expansion during chemotherapy, causing clinical relapse.

The role of dynamic contrast-enhanced and diffusion weighted magnetic resonance imaging in the female pelvis

Functional imaging by means of dynamic multiphase contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion weighted magnetic resonance imaging (DW-MRI) is now part of the standard imaging protocols for evaluation of the female pelvis. DCE-MRI and DW-MRI are important MR imaging techniques which enable the radiologist to move from morphological to functional assessment of diseases of the female pelvis. This is mainly due to the limitations of morphologic imaging, particularly in lesion characterization, accurate lymph node staging, assessment of tumour response and inability to differentiate post-treatment changes from tumour recurrence. DCE-MRI improves the accuracy of T2WI in staging of endometrial cancer. It also helps differentiate tumour recurrence from radiation fibrosis in patients with cervical cancer. DCE-MRI improves characterization of cystic adnexal lesions and detection of small peritoneal implants in patients with ovarian cancer. DW-MRI is valuable in preoperative staging of patients with endometrial and cervical cancer, especially in detection of extra-uterine disease. It does increase readers confidence for detection of recurrent disease in gynaecological malignancies and improves detection of small peritoneal implants in patients with ovarian cancer. In this review article we give an overview of both DCE-MRI and DW-MRI techniques, concentrating on their main clinical application in the female pelvis, and present a practical approach of the added value of these techniques according to the main pathological conditions, highlighting the pearls and pitfalls of each technique.

Semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging measurements predict radiation response in cervix cancer

PURPOSE To evaluate semiquantitative and quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) measurements in predicting the response to radiotherapy in cervix cancer. METHODS AND MATERIALS Patients with cervix cancer treated radically with chemoradiotherapy had DCE-MRI at three time points: before starting treatment, after 2 weeks of radiotherapy, and in the 5th week of radiotherapy. Semiquantitative measurements obtained from the signal intensity vs. time plots included arrival time of contrast, the slope and maximum slope of contrast uptake, time for peak enhancement, and the contrast enhancement ratio (CER). Pharmacokinetic modeling with a modeled vascular input function was used for the quantitative measurements volume transfer constant (K(trans)), rate constant (k(ep)), fraction plasma volume (fPV), and the initial area under gadolinium-time curve. The correlation of these measurements at each of the three time points with radiologic tumor response was investigated. RESULTS Thirteen patients had a total of 38 scans. There was no correlation between the DCE-MRI measurements and the corresponding tumor volumes. A statistically significant correlation with percentage tumor regression was shown with the pretreatment DCE-MRI semiquantitative parameters of peak time (p = 0.046), slope (p = 0.025), maximum slope (p = 0.046), and CER (p = 0.025) and the quantitative parameters K(trans) (p = 0.043) and k(ep) (p = 0.022). Second and third scan measurements did not show any correlation. CONCLUSIONS This is the first study to show that pretreatment DCE-MRI quantitative parameters predict the radiation response in cervix cancer. These measurements may allow a more meaningful comparison of DCE-MRI studies from different centers.

Evaluation of Depth of Myometrial Invasion and Overall Staging in Endometrial Cancer: Comparison of Diffusion-weighted and Dynamic Contrast-enhanced MR Imaging

PURPOSE To compare the diagnostic performance of diffusion-weighted (DW) magnetic resonance (MR) imaging with that of dynamic contrast material-enhanced (DCE) MR imaging in evaluating the depth of myometrial invasion and overall stage in patients with endometrial cancer. MATERIALS AND METHODS The institutional review board approved this retrospective study; patient consent was not required. From May 2008 to February 2010, 48 women with endometrial cancer underwent preoperative MR imaging, including T1- and T2-weighted imaging, DW MR imaging (b=0 and 800 sec/mm2) and DCE MR imaging. Two radiologists independently interpreted the depth of myometrial invasion, overall stage, and presence of pitfalls associated with inaccurate assessment of myometrial invasion at T1- and T2-weighted imaging, DW MR imaging, and DCE MR imaging. Myometrial invasion and overall stage were compared by using the McNemar test, and κ statistics were used for reader agreement. RESULTS For assessing the depth of myometrial invasion, diagnostic accuracy, sensitivity, and specificity, respectively, were as follows: DW MR imaging-reader 1, 90%, 84%, and 100%; reader 2, 85%, 84%, and 88%; DCE MR imaging-reader 1, 71%, 61%, and 88%; reader 2, 79%, 77%, and 82%. The improvement in diagnostic accuracy for reader 1 was significant (P=.035). For myometrial invasion, κ values were 0.75 with DW MR imaging and 0.26 with DCE MR imaging. There was no association between inaccurate assessment of myometrial invasion and standard pitfalls with DW MR imaging. Readers 1 and 2 correctly staged more patients by using DW MR imaging (39 and 38 patients, respectively) than by using DCE MR imaging (29 and 30 patients, respectively) (P<.05). For overall stage, κ values were 0.74 with DW MR imaging and 0.22 with DCE MR imaging. CONCLUSION DW MR imaging has superior diagnostic accuracy in the assessment of myometrial invasion and significantly higher staging accuracy compared with DCE MR imaging.

Mammographic parenchymal patterns and mode of detection: implications for the breast screening programme

Objectives To assess the effects of mammographic parenchymal patterns on the risk of breast cancer detected at first screen, second screen, and in the interval between these two screens. Settings A nested case-control study within a screening cohort in East Anglia was designed. The study group comprised 502 patients with cancer at the prevalence screening round, 198 patients with interval cancer, and 175 with cancer at the first incidence screen. These patients were matched with 2601 controls. Methods The mammographic parenchymal patterns of breast tissue were assessed according to Wolfes classification. Statistical analysis was by conditional logistic regression. Results Overall, 67% of patients and 59% of controls were considered to have high risk pattern (P2+DY) mammogram. The risk associated with P2 or DY mammographic patterns compared with N1 was higher for interval cancers (odds ratios (ORs) 2.2 and 2.4 respectively) than for screen detected cancers (ORs 1.7 and 1.1 respectively). For interval cancers in the first 18 months after the last negative mammogram, the risk was particularly high (ORs 3.8 for P2 and 4.1 for DY compared with N1). The high risk associated with P2 and DY patterns was concentrated on invasive ductal grade III cancers (ORs 2.7 and 3.8) rather than grade I or II cancers (ORs 1.6 and 1.2). Conclusions The study strongly suggests that screening effectiveness is reduced for high risk parenchymal patterns which are associated with high grade cancers. Changes should aim at improving screening sensitivity for dense parenchymal patterns, and the diagnosis of high grade tumours.

Associations among Mammographic Density, Circulating Sex Hormones, and Polymorphisms in Sex Hormone Metabolism Genes in Postmenopausal Women

Mammographic density and serum sex hormone levels are important risk factors for breast cancer, but their associations with one another are unclear. We studied these phenotypes, together with single nucleotide polymorphisms (SNP) in genes related to sex hormone metabolism, in a cross-sectional study of 1,413 postmenopausal women from the European Prospective Investigation into Cancer and Nutrition-Norfolk. All women were >1 year postmenopausal and had not taken hormone replacement therapy for >3 months before sampling. Serum levels of 7 sex hormones [estradiol, testosterone, sex hormone-binding globulin (SHBG), androstenedione, 17-OH-progesterone, estrone, and estrone sulfate] and 15 SNPs in the CYP17, CYP19, EDH17B2, SHBG, COMT, and CYP1B1 genes were studied. Mammograms nearest in time to the blood sampling were identified through the national breast screening program and visually assessed by three radiologists using the Boyd six-category and Wolfe four-category scales. We found a weak positive association between mammographic density and SHBG levels (P = 0.09) but no association with any other hormones. None of the SNPs, including those shown previously to be associated with estradiol or SHBG, showed significant associations with density. We conclude that mammographic density is largely independent of postmenopausal steroid hormone levels, indicating that these risk factors have, to a large extent, an independent etiology and suggesting that they may be independent predictors of breast cancer risk. (Cancer Epidemiol Biomarkers Prev 2006;15(8):1502-08)