A change in the apparent diffusion coefficient after treatment with bevacizumab is associated with decreased survival in patients with recurrent glioblastoma multiforme

Objectives

The aim of this study was to determine the prognostic significance of changes in parameters derived from diffusion tensor imaging (DTI) that occur in response to treatment with bevacizumab and irinotecan in patients with recurrent glioblastoma multiforme.

Methods

15 patients with recurrent glioblastoma multiforme underwent serial 1.5 T MRI. Axial single-shot echo planar DTI was obtained on scans performed 3 days and 1 day prior to and 6 weeks after initiation of therapy with bevacizumab and irinotecan. Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) maps were registered to whole brain contrast-enhanced three-dimensional (3D) spoiled gradient recalled and 3D fluid attenuation inversion recovery (FLAIR) image volumes. Anatomic image volumes were segmented to isolate regions of interest defined by tumour-related enhancement (TRE) and FLAIR signal abnormality (FSA). Mean ADC and mean FA were calculated for each region. A Bland–Altman repeatability coefficient was also calculated for each parameter based on the two pre-treatment studies. A patient was considered to have a change in FA or ADC after therapy if the difference between the pre- and post-treatment values was greater than the repeatability coefficient for that parameter. Survival was compared using a Cox proportional hazard model.

Results

DTI detected a change in ADC within FSA after therapy in nine patients (five in whom ADC was increased; four in whom it was decreased). Patients with a change in ADC within FSA had significantly shorter overall survival (p=0.032) and progression free survival (p=0.046) than those with no change.

Conclusion

In patients with recurrent glioblastoma multiforme treated with bevacizumab and irinotecan, a change in ADC after therapy in FSA is associated with decreased survival.Genotypic heterogeneity within histologically indistinguishable tumours remains a major barrier to successful treatment of patients with high-grade primary brain tumours [1]. Because of this heterogeneity, only a minority of individual tumours are likely to respond to any given chemotherapeutic agent [2]. Early identification of non-responders would allow potentially more effective therapy to be instituted while minimising the morbidity and financial cost associated with prolonged, ineffective treatment. Current assessment of therapeutic efficacy relies on changes in cross-sectional area estimated weeks to months after the completion of a treatment protocol [3,4]. Unfortunately, patients with aggressive tumours may experience significant disease progression with related morbidity and mortality before therapy can be evaluated and altered using this approach. Biomarkers of treatment response that are independent of late changes in tumour volume will be crucial for optimal treatment of this patient group.Diffusion-weighted MRI (DWI) can be used to characterise early tissue microstructural changes associated with cell death [4,5]. Since parameters derived from DWI can provide a quantitative assessment of such effects, there is increasing interest in this technique as a biomarker of therapeutic efficacy. Although there is good evidence that DWI can be used to characterise treatment effects, the optimal parameter and region of interest are yet to be determined [4,6-12].The preponderance of studies on this subject has quantified the apparent diffusion coefficient (ADC) within regions of interest defined by abnormal tumour-related enhancement [6,9,11]. In vivo, the ADC is primarily determined by cell density [4,8,13,14]. As a result, changes in the ADC are sensitive to early alterations in tissue microstructure related to cell death; these changes include cell swelling and loss of membrane integrity associated with early necrosis as well as cell shrinkage due to apoptosis [11,15]. Indeed, it has been demonstrated that changes in the ADC within enhancing regions of interest can be used to identify the response to chemotherapy earlier than standard MRI [9]. Recent evidence, however, suggests the importance of non-enhancing, infiltrative tumour, as defined on fluid attenuation inversion recovery (FLAIR) images, with respect to tumour progression [16,17]. This non-enhancing component of tumour seems to be of particular relevance to patients treated with anti-angiogenesis agents [16,17]. Since the ADC is sensitive to variations in vasogenic oedema (increasing oedema tends to decrease cell density), in addition to the aforementioned direct effects on tumour cells, we hypothesise that the ADC would be an ideal parameter to characterise the effects of treatment within regions of interest defined by abnormal tumour-related FLAIR signals.Although there are few data in patients with brain tumours, there is some evidence that parameters of diffusion anisotropy derived from diffusion tensor imaging (DTI) may more accurately depict early changes in brain tissue microstructure than the ADC in central nervous system (CNS) diseases [18]. Fractional anisotropy (FA) is a measure of the degree of directional variation of the diffusion of water protons. Like the ADC, FA has been shown to correlate with cell density [7,18,19], but FA provides additional information regarding the integrity and alignment of parenchymal fibre tracts [20]. A recent study in patients with primary brain tumours demonstrated increasing FA across the study population within regions of interest defined by tumour-related contrast enhancement as early as 1 day after initiation of chemotherapy [12]. This same study failed to detect a significant change in the ADC at the same time point, raising the possibility that FA may be a more sensitive parameter to early treatment response.Although these preliminary results are promising, the significance of such changes with respect to patient survival has not been widely studied. In addition, there are very few data regarding the test–retest reproducibility of these parameters in patients with primary brain tumours, information which is crucial for understanding whether changes in these parameters can be used to guide therapy. In particular, an understanding of the magnitude of variability intrinsic to the method will be required to ascribe significance to changes in these parameters that occur after therapy in an individual patient.The goal of this study is to use the repeatability of ADC and FA derived from DTI to devise a method by which prognostic significance can be assigned to changes in these parameters that occur after therapy in patients with glioblastoma multiforme. In particular, we prospectively identified the following two null hypotheses:

• Patients with an increase in FA within regions of interest defined by tumour-related enhancement will not survive longer than those with no change or a decrease in FA.
• Patients with a change in ADC within regions of interest defined by an abnormal FLAIR signal will not survive longer than those with no change.

Although it may seem counterintuitive to evaluate the significance of any change in the ADC without respect for direction, there is evidence that both increasing and decreasing the ADC may reflect a clinically relevant treatment response [9,11].     

Primary vaginal cancer: role of MRI in diagnosis,staging and treatment

Primary carcinoma of the vagina is rare, accounting for 1–3% of all gynaecological malignancies. MRI has an increasing role in diagnosis, staging, treatment and assessment of complications in gynaecologic malignancy. In this review, we illustrate the utility of MRI in patients with primary vaginal cancer and highlight key aspects of staging, treatment, recurrence and complications.The incidence of primary vaginal cancer increases with age, with approximately 50% of patients presenting at age greater than 70 years and 20% greater than 80 years.¹ Around 2890 patients are currently diagnosed with vaginal carcinoma in the USA each year, and almost 30% die of the disease.² The precursor for vaginal cancer, vaginal intraepithelial neoplasia (VAIN) and invasive vaginal cancer is strongly associated with human papillomavirus (HPV) infection (93%).^3,4 In situ and invasive vaginal cancer share many of the same risk factors as cervical cancer, such as tobacco use, younger age at coitarche, HPV and multiple sexual partners.^5–7 In fact, higher rates of vaginal cancer are observed in patients with a previous diagnosis of cervical cancer or cervical intraepithelial neoplasia.^7,8As is true for other gynaecologic malignancies, vaginal cancer diagnosis and staging rely primarily on clinical evaluation by the International Federation of Gynecology and Obstetrics (FIGO).⁹ Pelvic examination continues to be the most important tool for evaluating local extent of disease, but this method alone is limited in its ability to detect lymphadenopathy and the extent of tumour infiltration. Hence, FIGO encourages the use of imaging. Fluorine-18 fludeoxyglucose-positron emission tomography (¹⁸F-FDG-PET), a standard imaging tool for staging and follow-up in cervical cancer, can also be used for vaginal tumours, with improved sensitivity for nodal involvement compared to CT alone.¹⁰ In addition to staging for nodal and distant disease, CT [simulation with three dimensional (3D) conformations] is particularly useful for treatment planning and delivery of external beam radiation. MRI, with its excellent soft tissue resolution, is commonly used in gynaecologic malignancies and has been shown to be accurate in diagnosis, local staging and spread of disease in vaginal cancer.^11,12 While no formal studies are available for vaginal cancer, in cervical cancer MRI actually alters the stage in almost 30% of patients.^13–15Treatment planning in primary vaginal cancer is complex and requires a detailed understanding of the extent of disease. Because vaginal cancer is rare, treatment plans remain less well defined, often individualized and extrapolated from institutional experience and outcomes in cervical cancer.^1,16–19 There is an increasing trend towards organ preservation and treatment strategies based on combined external beam radiation and brachytherapy, often with concurrent chemotherapy,^14,20,21 surgery being reserved for those with in situ or very early-stage disease.²² Increasing utilization of MR may provide superior delineation of tumour volume, both for initial staging and follow-up, to allow for better treatment planning.²³     

Simplified rules for everyday delineation of lymph node areas for breast cancer radiotherapy

The aim of this study was to present the simplified rules of delineation of lymph node (LN) volumes in breast irradiation. Practical rules of delineation of LN areas were developed in the Department of Radiation Oncology of the Institut Curie. These practical guidelines of delineation were based on different specific publications in the field of breast and LN anatomy. The principal characteristic of these rules is their clearly established relationship with anatomical structure, which is easy to find on CT slices. The simplified rules of delineation have been published in pocket format as the illustrated atlas “Help of delineation for breast cancer treatment”. In this small pocket guide, delineation using the practical rules is illustrated, with examples from anatomical CT slices. It is shown that there is an improvement in delineation after the use of these simplified rules and the guide. In conclusion, this small guide is useful for improving everyday practice and decreasing the differences in target delineation for breast irradiation between institutions and observers.The value of lymph node irradiation has already been demonstrated by various studies and meta-analyses [1–3]. In the age of new conformal techniques, there is a real need for a clear definition of treated volumes, such as breast, tumour bed, lymph node areas and organs at risk (OAR) [4–10]. Many teams have been working for several years on the definition of treated volumes. Some delineation studies are exclusively theoretical and some provide a good anatomical atlas, but this information is difficult to use in everyday practice [4–15]. The treatment position has also been shown to be an important factor of variability in the depth and situation of lymph node volumes [5, 6]. Conformal and intensity-modulated radiotherapy (IMRT) require an exact definition of target volumes in terms of their anatomical limits for delineation on CT scans. Some authors have proposed anatomically based landmarks specific for breast cancer radiotherapy in order to delineate all regional lymph nodes and the breast [5, 6, 8, 10, 15, 16]. Despite this work, two recent papers have demonstrated the individual interobserver variability and differences in target and OAR delineation for breast irradiation, especially in lymph node areas [7, 8].This study was designed to propose a practical method to improve and facilitate the everyday delineation process for the clinicians of our department.     

Comparison of mammography, sonography, MRI and clinical examination in patients with locally advanced or inflammatory breast cancer who underwent neoadjuvant chemotherapy

Objectives

The purpose of this study was to determine the relative accuracies of mammography, sonography, MRI and clinical examination in predicting residual tumour size and pathological response after neoadjuvant chemotherapy for locally advanced or inflammatory breast cancer. Each prediction method was compared with the gold standard of surgical pathology.

Methods

43 patients (age range, 25–62 years; mean age, 42.7 years) with locally advanced or inflammatory breast cancer who had been treated by neoadjuvant chemotherapy were enrolled prospectively. We compared the predicted residual tumour size and the predicted response on imaging and clinical examination with residual tumour size and response on pathology. Statistical analysis was performed using weighted kappa statistics and intraclass correlation coefficients (ICC).

Results

The ICC values between predicted tumour size and pathologically determined tumour size were 0.65 for clinical examination, 0.69 for mammography, 0.78 for sonography and 0.97 for MRI. Agreement between the response predictions at mid-treatment and the responses measured by pathology had kappa values of 0.28 for clinical examination, 0.32 for mammography, 0.46 for sonography and 0.68 for MRI. Agreement between the final response predictions and the responses measured by pathology had kappa values of 0.43 for clinical examination, 0.44 for mammography, 0.50 for sonography and 0.82 for MRI.

Conclusion

Predictions of response and residual tumour size made on MRI were better correlated with the assessments of response and residual tumour size made upon pathology than were predictions made on the basis of clinical examination, mammography or sonography. Thus, the evaluation of predicted response using MRI could provide a relatively sensitive early assessment of chemotherapy efficacy.The advantages of neoadjuvant chemotherapy are multiple and it has been used widely during the past few years [1]. Its primary role is to induce tumour shrinkage and permit breast-conserving surgery, primarily in patients with advanced breast cancer [2-4]. Neoadjuvant chemotherapy allows earlier treatment of micrometastatic disease and the study of biological markers that might predict tumour response [5]. The effectiveness of chemotherapeutic agents in treating both primary breast cancer and potential metastatic disease may be enhanced by the presence of tumour neovascularity. If chemotherapy is given before surgery, while tumour vascularity remains intact, the chemotherapeutic agents may be better able to reach the tumour and thus be more effective.Neoadjuvant chemotherapy of locally advanced breast cancer (LABC) has also been shown to improve the resectability rate, offering disease-free and overall survival rates that are at least equivalent to those offered by surgery alone [6,7]. Pathological complete response (pCR) is clinically significant because it is associated with improved long-term prognosis and decreased risk of recurrence [6,8]. Decisions regarding the continuation of current regimens and the appropriate type and timing of surgery depend on the radiological and clinical assessment of residual tumour size during neoadjuvant chemotherapy [9,10]. Until now, many studies have shown that physical examinations, mammography and sonography provide suboptimal evaluations of lesion extent that do not allow accurate assessments of pathological response or residual tumour size [5^,11-13]. In the case of LABC, physical examination, mammography or sonography may be suitable for detecting the larger lesions of non-responders, but they have limited sensitivity for responders with smaller residual lesions [14,15]. For mammography, calcifications may persist or even increase in patients who respond to neoadjuvant chemotherapy [14,16,17].Many previous studies have shown that MRI is the most reliable technique for evaluating residual disease after neoadjuvant chemotherapy, although initial reports described frequent false-negatives with smaller-volume disease [18-27]. Recent studies have increased the sensitivity of MRI, with increased resolution, reduced slice thickness and lower enhancement thresholds being used to minimise the underestimation of residual disease [15^,22-27]. It is still difficult, however, to distinguish residual scarring, necrosis and fibrosis from viable residual malignancy and to predict accurate response after neoadjuvant chemotherapy, especially in responders. Few published studies have described work with patients with inflammatory breast cancer who underwent neoadjuvant chemotherapy because the incidence of this disease is very low [28,29]. The purpose of our study was to determine the relative accuracies of mammography, sonography, MRI and clinical examination in predicting residual tumour size and pathological response after neoadjuvant chemotherapy for locally advanced and inflammatory breast cancer. We compared each prediction method with the gold standard of surgical pathology.     

Prognostic factors associated with a subchondral insufficiency fracture of the femoral head

Objective

The aim of this study was to identify the risk factors associated with the prognosis of a subchondral insufficiency fracture of the femoral head (SIF).

Methods

Between June 2002 and July 2009, 25 patients diagnosed with SIF were included in this study. Sequential radiographs were evaluated for the progression of collapse. Clinical profiles, including age, body mass index, follow-up period and Singh’s index, were documented. The morphological characteristics of the low-intensity band on T₁ weighted MRI were also examined with regards to four factors: band length, band thickness, the length of the weight-bearing portion and the band length ratio (defined as the proportion of the band length to the weight-bearing portion of the femoral head in the slice through the femoral head centre).

Results

Radiographically, a progression of collapse was observed in 15 of 25 (60.0%) patients. The band length in patients with progression of collapse [22.5 mm; 95% confidence interval (CI) 17.7, 27.3] was significantly larger than in patients without a progression of collapse (13.4 mm; 95% CI 7.6, 19.3; p<0.05). The band length ratio in patients with progression of collapse (59.8%; 95% CI 50.8, 68.9) was also significantly higher than in patients without a progression of collapse (40.9%; 95% CI 29.8, 52.0; p<0.05). No significant differences were present in the other values.

Conclusion

These results indicate that the band length and the band length ratio might be predictive for the progression of collapse in SIF.Subchondral insufficiency fractures of the femoral head (SIF) often occur in osteoporotic elderly patients [1-9]. Patients usually suffer from acute hip pain without any obvious antecedent trauma. Radiologically, a subchondral fracture is seen primarily in the superolateral portion of the femoral head [4,5,10]. T₁ weighted MRI reveal a very low-intensity band in the subchondral area of the femoral head, which tends to be irregular, disconnected and convex to the articular surface [2,4,5,7,9,11]. This low-intensity band in SIF was histologically proven to correspond with the fracture line and associated repair tissue [5,9]. Some cases of SIF resolve after conservative treatment [5,11-14]; other cases progress until collapse, thereby requiring surgical treatment [4-10,15]. The prognosis of SIF patients remains unclear.The current study investigated the risk factors that influence the prognosis of SIF based on the progression to collapse.     

Diffusion tensor imaging of normal prostate at 3 T: effect of number of diffusion-encoding directions on quantitation and image quality

Objective

The purpose of this study was to prospectively investigate differences of diffusion tensor imaging (DTI) using a different number of diffusion-encoding directions and to evaluate the feasibility of tractography in healthy prostate at 3 T.

Method

12 healthy volunteers underwent DTI with single-shot echo-planar imaging at 3 T using a phased-array coil. Diffusion gradients of each DTI were applied in 6 (Group 1), 15 (Group 2) and 32 (Group 3) non-collinear directions. For each group, the mean apparent diffusion coefficient (ADC), fractional anisotrophy (FA) and signal-to-noise ratio (SNR) were measured in the peripheral zone (PZ) and central gland (CG). The quality of diffusion-weighted and tractographic images were also evaluated.

Results

In all three groups, the mean ADC value of the CG was statistically lower than that of the PZ (p<0.01) and the mean FA value of the CG was statistically greater than that of the PZ (p<0.01). For the mean FA value of the CG, no statistical difference was seen among the three groups (p=0.052). However, the mean FA value of the PZ showed a statistical difference among the three groups (p=0.035). No significant difference in SNR values was seen among the three groups (p>0.05). Imaging quality of diffusion-weighted tractographic images was rated as satisfactory or better in all three groups and was similar among the three groups.

Conclusion

In conclusion, prostate DTI at 3 T was feasible with different numbers of diffusion-encoding directions. The number of diffusion-encoding directions did not have a significant effect on imaging quality.Diffusion tensor imaging (DTI) is a common non-invasive method of assessing the anisotropy and organisation of structures in neurological and musculoskeletal imaging [1-4]. Generally, water diffusion in tissues without a well-organised microstructure shows isotropic direction whereas that in structures with a high degree of structural order has a preferential direction or anisotropy [5,6]. The prostate consists of histologically different components—glandular and fibromuscular elements. A few studies reported the potential of prostate tractography in evaluating the microstructural organisation of the prostate [7,8], but the role of tractography in the prostate has not been yet determined.With the recent introduction of ultra-fast echo-planar sequences and parallel imaging techniques, DTI could be applied to the prostate [7-12]. Several studies have reported the results of DTI in a healthy prostate or prostate cancer at 1.5 T [9,11,12]. However, 1.5 T MR scanners have major limitations, such as poor signal-to-noise ratio (SNR), which may affect the accuracy of measuring the apparent diffusion coefficient (ADC) or fractional anisotropy (FA) values. More recently, 3 T MR scanners have been introduced into clinical practice and DTI at 3 T has been a feasible tool in the prostate [7,8,10]. 3 T MR scanners have several benefits over 1.5 T MR scanners, such as a twofold increase in SNR, resulting in improved spatial and temporal resolution [13]. However, few studies have investigated the prostate DTI at 3 T [7,8,10].The possible applications of DTI in prostate tissue investigated so far [7-12] have focused on differentiating between benign prostate tissue and cancer and determining normative FA and ADC values in the prostate. No studies for optimising DTI parameters such as number of diffusion-encoding directions in the prostate have been published, and there is no consensus for optimal diffusion-encoding directions in prostate DTI. To estimate the diffusion tensor, one needs diffusion-weighted imaging (DWI) with high b-values along at least six non-collinear directions in addition to a low b-value DWI or a T₂ weighted image (T2WI) (b=0) [5]. The rationale for sampling more directions is that this reduces the orientational dependence and increases the accuracy and precision of DTI parameters such as FA or mean diffusivity. However, more diffusion-encoding directions may need relatively longer imaging times and the amount of imaging time is limited in most clinical situations. The choice of optimal diffusion-encoding directions gives a trade-off between minimising directions bias and minimising scanning time.Optimising image acquisition parameters is an essential step for producing high-quality DTI. Among several parameters, the number of diffusion-encoding gradient directions has been reported as one of several important factors for calculating DTI parameters, especially in neurological imaging [14,15]. In prostate DTI, 6 or 32 diffusion-encoding directions were applied in several previous studies to date [9,11,12]. To the best of our knowledge, there have as yet been no studies into the optimal numbers of diffusion-encoding directions for prostate DTI.Therefore, the purpose of this study was to prospectively investigate differences of DTI using a different number of diffusion-encoding directions and to evaluate the feasibility of tractography in healthy prostates at 3 T.     

Characterisation of breast papillary neoplasm on automated breast ultrasound

Intraductal papillary neoplasms of the breast form a wide spectrum of pathological changes with benign intraductal papilloma and papillary carcinoma. They can occur anywhere within the breast ductal system. This review illustrates some characteristic appearances of breast papillary neoplasms on coronal planes reconstructed by automatic breast volume scan. Such manifestations are not uncommon in papillary neoplasms, and familiarity will enable confident diagnosis.Papillary lesions of the breast are a heterogeneous group of breast lesions, including intraductal papilloma, atypical papilloma and intraductal papillary carcinoma [1,2]. Although the management of intraductal papillomas is varied, surgical excision is generally recommended as a precaution against the risk of a subsequent carcinoma [3,4]. Recently, some studies have suggested that patients with a tumour measuring <1.5 cm and an ultrasound Breast Imaging—Reporting and Data System (BI-RADS) category of 3 or 4a can be potentially selected for vacuum-assisted biopsy, but only if the tumour does not extend into the branching ducts [5,6]. Ueng et al [2] recommended that localised papillary lesions should be excised completely with a small rim of uninvolved breast tissue without any prior needle instrumentation if and when the papillary nature can be determined by imaging. Therefore, a careful imaging evaluation is necessary because it could help to identify the papillary neoplasm nature and select the high-risk lesions for proper treatment.Ultrasound has a greater sensitivity for detecting all papillary lesions than mammography [7]. Recently, automated breast ultrasound scanners have been developed, and the ultrasound volume data set of the whole breast can be acquired in a standard manner [8]. They have already shown potential for characterisation of breast tumours [9,10]. However, these studies did not detail the ultrasound features of intraductal papillary neoplasms on automated breast ultrasound. The reconstructed coronal views are also expected to provide more information and thus help to differentiate these lesions from other focal breast abnormalities.     

Estimation of percentage breast tissue density: comparison between digital mammography (2D full field digital mammography) and digital breast tomosynthesis according to different BI-RADS categories

Objective:

To compare breast density estimated from two-dimensional full-field digital mammography (2D FFDM) and from digital breast tomosynthesis (DBT) according to different Breast Imaging–Reporting and Data System (BI-RADS) categories, using automated software.

Methods:

Institutional review board approval and written informed patient consent were obtained. DBT and 2D FFDM were performed in the same patients to allow within-patient comparison. A total of 160 consecutive patients (mean age: 50±14 years; mean body mass index: 22±3) were included to create paired data sets of 40 patients for each BI-RADS category. Automatic software (MedDensity^©, developed by Giulio Tagliafico) was used to compare the percentage breast density between DBT and 2D FFDM. The estimated breast percentage density obtained using DBT and 2D FFDM was examined for correlation with the radiologists'' visual BI-RADS density classification.

Results:

The 2D FFDM differed from DBT by 16.0% in BI-RADS Category 1, by 11.9% in Category 2, by 3.5% in Category 3 and by 18.1% in Category 4. These differences were highly significant (p<0.0001). There was a good correlation between the BI-RADS categories and the density evaluated using 2D FFDM and DBT (r=0.56, p<0.01 and r=0.48, p<0.01, respectively).

Conclusion:

Using DBT, breast density values were lower than those obtained using 2D FFDM, with a non-linear relationship across the BI-RADS categories. These data are relevant for clinical practice and research studies using density in determining the risk.

Advances in knowledge:

On DBT, breast density values were lower than with 2D FFDM, with a non-linear relationship across the classical BI-RADS categories.To tailor screening and diagnosis protocols, it is important to identify females with an increased risk of breast cancer [1–3]. It has been estimated that females with dense breasts (breast densities of >75%) have 4–6 times higher risk of breast cancer than females with low breast densities [4] and that breast density is increasingly recognised as an independent determinant of breast cancer risk and possibly in prognosis [5]. Assessment of breast density is becoming crucial in epidemiological studies, including the estimation of breast cancer risk and assessing breast density-related risk over time, radiation dose monitoring and monitoring drug-related response [6,7].Different methods and classifications have been reported to assess breast density: the Tabar classification [8], Wolfe''s parenchymal patterns [9], and both semi-quantitative and quantitative computer-aided techniques [10–16]. The Breast Imaging–Reporting and Data System (BI-RADS) classification, considered as the additional quantitative scheme, is routinely used in the USA and was introduced to standardise reporting. Initially, it was based on four qualitative categories but an additional quantitative scheme was added in 2003, based on the extent of fibroglandular tissue [17]. Mammographic breast density estimation may be limited by the two-dimensional (2D) nature of the imaging technique, whereas a three-dimensional (3D) imaging modality, such as digital breast tomosynthesis (DBT), reduces the appearance of the overlapping parenchymal tissue and may therefore influence or alter density assessments [13,14]. In DBT, high-spatial-resolution tomographic images of the breast are reconstructed from multiple low-dose projection images acquired within a limited range of X-ray tube angles [15]. It has been demonstrated in a few studies that the automated estimation of breast density eliminates subjectivity between comparisons of full-field digital mammography (2D FFDM) and DBT and is more reproducible than a quantitative BI-RADS evaluation [14,16]. However, previous research mainly considered patients with relatively high breast density, with the possibility of the results not being applicable across all density categories and showing whether published percentage breast density differences between 2D FFDM and DBT apply to less dense or non-dense breasts. The purpose of our study was to compare the breast tissue density estimated using 2D FFDM and DBT among patients in a balanced data set of the four BI-RADS categories, using fully automated software.     

Image-guided volumetric modulated arc therapy for breast cancer: a feasibility study and plan comparison with three-dimensional conformal and intensity-modulated radiotherapy

Objective:

To test the feasibility of volumetric modulated arc therapy (VMAT) in breast cancer and to compare it with three-dimensional conformal radiotherapy (3D-CRT) as conventional tangential field radiotheraphy (_conTFRT).

Methods:

12 patients (Stage I, 8: 6 left breast cancer and 2 right breast cancer; Stage II, 4: 2 on each side). Three plans were calculated for each case after breast-conserving surgery. Breast was treated with 50 Gy in four patients with supraclavicular lymph node inclusion, and in eight patients without the node inclusion. Multiple indices and dose parameters were measured.

Results:

V95% was not achieved by any modality. Heterogeneity index: 0.16 (VMAT), 0.13 [intensity-modulated radiotherapy (IMRT)] and 0.14 (_conTFRT). Conformity index: 1.06 (VMAT), 1.15 (IMRT) and 1.69 (_conTFRT). For both indices, IMRT was more effective than VMAT (p=0.009, p=0.002). D_mean and V20 for ipsilateral lung were lower for IMRT than VMAT (p=0.0001, p=0.003). D_mean, V2 and V5 of contralateral lung were lower for IMRT than VMAT (p>0.0001, p=0.005). Mean dose and V5 to the heart were lower for IMRT than for VMAT (p=0.015, p=0.002).

Conclusion:

The hypothesis of equivalence of VMAT to IMRT was not confirmed for planning target volume parameter or dose distribution to organs at risk. VMAT was inferior to IMRT and 3D-CRT with regard to dose distribution to organs at risk, especially at the low dose level.

Advances in knowledge:

New technology VMAT is not superior to IMRT or conventional radiotherapy in breast cancer in any aspect.In Western countries, one in every eight females is diagnosed with breast cancer. Breast-conserving surgery with post-operative radiotherapy (RT) is the primary therapeutic strategy for Stages I and II of breast cancer. Systemic therapy is also part of the primary therapeutic strategy in most patients with Stage I and II breast cancer. RT substantially reduces the rate of local relapse and improves long-term survival [1]. However, RT is suggested to be associated with morbidity of the heart [2,3], lung [4,5], subcutaneous tissue and skin [6] and a risk of secondary malignancies [7–9].A large body of available data regarding the potential toxicity of RT was published between 1980 and the end of 1990 [1]. Special clinical interest has been focused on acute and mostly transient lung and skin toxicity, axillary problems and late cardiac events, in addition to the risk of secondary malignancies. This period was characterised by RT delivery using a fluoroscopic technique with two-dimensional planning followed by three-dimensional (3D) conformal techniques with two conventional tangential field radiotherapy (_conTFRT) fields. _conTFRT encompassed the whole breast, skin, minor ipsilateral lung volume, a part of the axillary region at Level 1 and a part of the heart in the case of left-sided cancer [10–12]. These areas have been sites for local toxicity, because RT principles, and thus homogeneous photon flux across treatment fields, remained unchanged.Intensity-modulated radiotherapy (IMRT) has been implemented in the past decade, permitting variation of fluence modulation across fields and allowing optimal dose administration according to an individual''s anatomy. IMRT results in improved avoidance of critical structures such as the heart, skin, axillary region and lung, while facilitating necessary tumour volume coverage [13,14]. Clinical data on IMRT show an improvement in dose homogeneity within the irradiated breast and sparing of the heart and lung [14–17]. However, a disadvantage of IMRT over _conTFRT is the long treatment duration owing to the higher number of fields and monitor units (MUs) involved. In addition, although IMRT reduces the volume of the heart and ipsilateral lung that receive high doses, it is associated with an increase in overall low-dose radiation. Despite the available clinical data, the wider use and specific indications for IMRT for breast cancer have not been established.In volumetric modulated arc therapy (VMAT), technical extension of conventional fixed-field IMRT, an optimised dose distribution is possible with a single gantry rotation. Studies have shown that VMAT reduces the number of MUs and treatment delivery time [18–22], with similar or better planning target volume (PTV) coverage and sparing of organs at risk (OARs) than IMRT. Reports on VMAT for breast cancer are few and mainly concern planning comparisons [20,23–28] and very preliminary clinical data [29].The RapidArc® system (Varian Medical Systems, Palo Alto, CA) has recently been introduced in our department. Accordingly, we have begun examining the potential of RapidArc VMAT for breast cancer treatment in a prospective clinical setting to adequately evaluate dosimetric parameters, treatment planning and clinical implications as well the disadvantages.The present study aimed to compare the use of RapidArc VMAT with IMRT and _conTFRT for breast cancer therapy. We hypothesised that the use of RapidArc under routine clinical circumstances would be equivalent to or better than IMRT and _conTFRT in terms of PTV coverage and OAR sparing, while reducing both treatment time and MUs.     

Diffusion-weighted MRI in the follow-up of chronic periaortitis

Objective:

To evaluate the usefulness of diffusion-weighted MRI (DWI) for the assessment of the intraindividual follow-up in patients with chronic periaortitis (CP) under medication.

Methods:

MRI data of 21 consecutive patients with newly diagnosed untreated disease were retrospectively examined before and after medical therapy, with a median follow-up of 16 weeks. DWI parameters [b800 signal, apparent diffusion coefficient (ADC) values] of the CP and psoas muscle were analysed together with the extent and contrast enhancement. Pre- and post-treatment laboratory inflammation markers were acquired parallel to each MR examination.

Results:

Statistically significant lower b800 signal intensities (p ≤ 0.0001) and higher ADC values (p ≤ 0.0001) were observed after medical treatment within the fibrous periaortic tissue. Extent and contrast enhancement of the CP showed also a statistically significant decrease (p ≤ 0.0001) in the follow-up examinations, while the control parameters within the psoas muscle showed no differences.

Conclusion:

DWI seems to be a useful method for the evaluation of response to treatment without contrast agents. The technique may be helpful in the assessment of disease activity to guide further therapeutic strategies.

Advances in knowledge:

DWI detects significant differences in the intraindividual follow-up of CP under medical therapy.Chronic periaortitis (CP) is a proliferating fibroinflammatory disease of the perivascular retroperitoneal space and aortic wall.^1–4 Owing to adventitial inflammation, some recent theories consider CP as a large vessel vasculitis.⁵ Clinical manifestations of CP include idiopathic retroperitoneal fibrosis, inflammatory aortic aneurysm and perianeurysmal retroperitoneal fibrosis.^2,6,7 The three manifestations with very similar histopathological characteristics are distinguished by the diameter of the abdominal aorta and concomitant ureteral affection.^1,3,7Specific clinical symptoms are caused by extrinsic compression of the ureters or retroperitoneal veins, resulting in hydronephrosis, oliguria, lower extremity oedema and deep vein thrombosis.^1,8Under medical treatment with steroids, CP has a good prognosis.⁷ Today tamoxifen is suggested as a safe and effective therapeutic alternative, and immunosuppressive drugs can be considered in patients with suboptimal responses to these drugs or multiple relapses.^9–11CT and MRI are the modalities of first choice for diagnosis and follow-up of CP.^1,7,12 The fibrotic para-aortic tissue shows significant contrast uptake in gadolinium-enhanced MRI.^12–14 Dynamic contrast-enhanced MRI was suggested for the assessment of the disease activity.^15,16 However, in cases with impaired renal function (e.g. by ureteral compression), gadolinium-independent imaging methods should be preferred owing to the potential development of a nephrogenic systemic fibrosis.¹⁷Diffusion-weighted MRI (DWI) is a non-contrast MR modality that has been successfully applied for the assessment of retroperitoneal masses, inflammatory abdominal aortic aneurysms and for the differentiation between retroperitoneal fibrosis and malignant retroperitoneal neoplasms.^18–21DWI indicates restricted diffusion of water, for example caused by a high cellularity in malignant disease or active inflammation. The apparent diffusion coefficient (ADC) is a quantitative parameter for the level of restricted diffusion, which is calculated from the signals of different diffusion gradients (b-values).²²In the context of untreated CP diffusion-weighted MRI may detect restricted inflammation as a sign of high cellularity caused by active inflammation.There are no data for the evaluation of intraindividual follow-up and the response to treatment by DWI of CP so far. Therefore, the aim of the present study was to analyse differences in DWI signals during follow-up in patients with CP before and after treatment. In addition, we sought to elucidate the potential of DWI in the therapy monitoring of CP.     

Measurement of breast density with digital breast tomosynthesis—a systematic review

Digital breast tomosynthesis (DBT) has gained acceptance as an adjunct to digital mammography in screening. Now that breast density reporting is mandated in several states in the USA, it is increasingly important that the methods of breast density measurement be robust, reliable and consistent. Breast density assessment with DBT needs some consideration since quantitative methods are modelled for two-dimensional (2D) mammography. A review of methods used for breast density assessment with DBT was performed. Existing evidence shows Cumulus has better reproducibility than that of the breast imaging reporting and data system (BI-RADS®) but still suffers from subjective variability; MedDensity is limited by image noise, whilst Volpara and Quantra are robust and consistent. The reported BI-RADs inter-reader breast density agreement (k) ranged from 0.65 to 0.91, with inter-reader correlation (r) ranging from 0.70 to 0.93. The correlation (r) between BI-RADS and Cumulus ranged from 0.54–0.94, whilst that of BI-RADs and MedDensity ranged from 0.48–0.78. The reported agreement (k) between BI-RADs and Volpara is 0.953. Breast density correlation between DBT and 2D mammography ranged from 0.73 to 0.97, with agreement (k) ranging from 0.56 to 0.96. To avoid variability and provide more reliable breast density information for clinicians, automated volumetric methods are preferred.Breast cancer accounts for approximately 23% of all cancers in females and is the most frequent cause of cancer deaths in females worldwide.^1–3 The exact aetiology of the disease is complex, but many risk factors have been documented in the literature amongst which is breast density.^4–7 Breast density refers to the proportion of the breast that is composed of fibroglandular tissue. Breasts with high density contain more epithelial and stromal cells and collagen, which are significant for tumorigenesis as well as tissue-specific progenitor cells that are at risk of transformation to cancer cells.^8,9 Studies have shown that breast density is a strong, modifiable and measureable risk factor for breast cancer.^10–13 Additionally, the masking effect from breast density reduces the performance of screening mammography and limits early detection and treatment of breast cancer.¹⁴ Encouragingly, breast density is reducible, and its reduction has been shown to mitigate breast cancer risk.¹³ Therefore, mammographic breast density measurement can be used for breast cancer risk prediction and personalization of breast cancer prevention and control strategies, such as the selection of females who may require breast density reduction interventions. It may also be used for selection of more appropriate imaging pathways for earlier detection of breast cancer.^5,13 Utilization of breast density for these purposes requires robust and consistent methods for its assessment.Breast density depicted by the radio-opaque areas on a mammogram can be assessed using qualitative and quantitative (semi-automated and automated) methods.^15–17 Qualitative methods assign breast density grades based on visual assessment of the relative proportions of dense tissue, fat and prominence of ducts and include breast imaging reporting and data system (BI-RADS®), visual analogue scale and Wolfe, Tabar and Boyd assessment methods.^15,18,19 Semi-automated methods use segmentation and thresholding techniques to quantify the percentage of dense tissue on a mammogram and include planimetry and interactive thresholding methods such as Cumulus and Madena.^20,21 Automated methods use mathematical, statistical and physical modelling to calculate breast density; such automated methods include computerized texture-based techniques, calibration approaches and dual X-ray absorptiometry.^22–24 Others are automated thresholding approaches, such as Autodensity and MedDensity,^25,26 and three physical model-based techniques: standard mammographic form (SMF), Volpara and Quantra.^27–29 Irrespective of the method of measurement, breast density has been shown to be a potent risk factor for breast cancer.Many studies on mammographic breast density measurement are based on film–screen mammography and digital mammography (DM), which produce two-dimensional (2D) images of a three-dimensional (3D) breast. Qualitative methods have been shown to be poorly reproducible with these modalities; they have wide inter-reader agreement with Kappa (k) values ranging from 0.37 to 0.91.^26,30 Quantitative methods have better reproducibility with these modalities; however, there are concerns that quantitative area measurement of breast density as percentage mammographic density (PMD) is not representative of the tissue at risk of breast cancer, and that it is more reasonable to measure the volume of only the fibroglandular tissue, which is more related to the dense tissue at risk instead of PMD.^16,31 Another concern is that volumetric breast density measurement with 2D mammography is limited owing to the absence of depth information in such mammograms;³¹ methods estimating mammographic breast density with 2D mammography attempt to take into account variation in breast tissue thickness by modelling; however, with all models, there are assumptions made that may not be necessarily correct for an individual patient.Digital breast tomosynthesis (DBT) has gained acceptance as a tool for imaging of the symptomatic breast and as an adjunct to DM in screening.^32,33 Breast density assessment with DBT needs some consideration since quantitative methods are modelled for 2D mammography. DBT is a 3D imaging modality utilizing the concept of conventional tomography but a limited angle of tube movement (11–60^°) to acquire depth information from the breast (Figure 1a,b).³⁴ With the removal of anatomical noise (superimposed skin and subcutaneous tissue) in DBT images, quantitatively assessed breast density is expected to be lower than DM. On the other hand, more dense tissue becomes apparent to a subjective reader and qualitatively assessed breast density with DBT is expected to be higher relative to DM. It is therefore important to have a standardized robust, reliable and reproducible assessment method to avoid variability in breast density measurement as this will impact on clinical decision-making for females undergoing breast screening. There are several contending methods (Figure 2), each of which has its own merits; this review briefly examines the links between breast density and breast cancer. It also examines methods that have been used for measurement of mammographic breast density with DBT to ascertain which can be considered the best approach.Open in a separate windowFigure 1.Principles of digital breast tomosynthesis: (a) tube rotations relative to the detector and (b) acquired image slices. Image courtesy of Hologic Inc.; Bedford, MA © 2011. All rights reserved.Open in a separate windowFigure 2.Methods of breast density measurement. BI-RADS®, breast imaging reporting and data systems; SMF, standard mammographic form.     

Primary and secondary breast lymphoma: prevalence, clinical signs and radiological features

Objectives

The purpose of this study was to determine the prevalence, clinical signs and radiological features of breast lymphoma.

Methods

This is a retrospective review of 36 patients with breast lymphoma (22 primary and 14 secondary). 35 patients were female and 1 was male; their median age was 65 years (range 24–88 years). In all patients, the diagnosis was confirmed histopathologically.

Results

The prevalence of breast lymphoma was 1.6% of all identified cases with non-Hodgkin lymphoma and 0.5% of cases with breast cancer. B-cell lymphoma was found in 94% and T-cell lymphoma in 6%. 96 lesions were identified (2.7 per patient). The mean size was 15.8±8.3 mm. The number of intramammary lesions was higher in secondary than in primary lymphoma. The size of the identified intramammary lesions was larger in primary than in secondary lymphoma. Clinically, 86% of the patients presented with solitary or multiple breast lumps. In 14%, breast involvement was diagnosed incidentally during staging examinations.

Conclusion

On mammography, intramammary masses were the most commonly seen (27 patients, 82%). Architectural distortion occurred in three patients (9%). In three patients (9%), no abnormalities were found on mammography. On ultrasound, the identified lesions were homogeneously hypoechoic or heterogeneously mixed hypo- to hyperechoic. On MRI, the morphology of the lesions was variable. After intravenous administration of contrast medium, a marked inhomogeneous contrast enhancement was seen in most cases. On CT, most lesions presented as circumscribed round or oval masses with moderate or high enhancement.Ductal and lobular carcinomas are the most frequent tumours of the breast. Breast involvement by lymphoma is very rare. It can occur as a primary breast tumour or as an extranodal manifestation in systemic disease [1-5]. According to the literature, the prevalence of breast lymphoma (BL) ranges from 0.04 to 0.5% of malignant breast neoplasms [1,2]. In addition, the prevalence of primary BL (PBL) varies from 0.85 to 2.2% of extranodal malignant lymphomas [3-5]. Secondary BL (SBL) is more common [6-8]. The rarity of BL can be attributed to the fact that the breast contains very little lymphoid tissue [9,10].Only a few of the published studies focus on the radiological features of BL, and conflicting findings of BL have been reported [1,7,11-13]. Only in one investigation has the distinction between primary and secondary breast involvement been taken into consideration [1]. Therefore, the aim of this study was to determine the prevalence of BL in our population and to analyse its clinical and radiological characteristics.     

Diffusion-weighted MRI as a potential imaging biomarker reflecting the metastatic potential of upper urinary tract cancer

Objective:

To evaluate the role of diffusion-weighted MRI (DW-MRI) as an imaging biomarker for upper urinary tract cancer (UUTC) that has already metastasized or will metastasize soon.

Methods:

61 patients clinically diagnosed with UUTC were prospectively enrolled in this study. All the patients underwent MRI, including DW-MRI, prior to any interventions. Correlations between apparent diffusion coefficient (ADC) and other clinicopathological variables, including metastasis-free survival, were analysed.

Results:

Median follow-up period was 938 days. Of the 61 patients, 12 had any metastases at the initial diagnosis. 11 patients developed metastases during the follow-up period. These 23 patients were categorized as “Metastatic”. Of the remaining 38 patients, 35 with a follow-up period longer than 400 days were categorized as “Localized”. ADC was significantly lower in the Metastatic category than in the Localized (p = 0.0002) category. Multivariate analysis of pre-operative variables identified ADC (cut-off value, 1.08 × 10⁻³ mm² s⁻¹) and clinical T stage based on T₂ weighted MRI as an independent predictive factor of metastatic UUTC. 46 patients without any metastases during the initial diagnosis were stratified into a high-risk group (16 patients with low ADC and clinical T3–4) and a low-risk group (30 patients with high ADC or clinical Ta-2). The 3-year metastasis-free survivals were 45% and 93%, respectively.

Conclusion:

In the current study, UUTC with lower ADC value is more likely to have metastatic potential. Incorporating ADC with clinical T stage helps to differentiate metastatic UUTC at the initial diagnosis.

Advances in knowledge:

DW-MRI is a potential imaging biomarker reflecting metastatic propensity of UUTC.Upper urinary tract cancer (UUTC) is a potentially lethal disease. The prognosis remains poor even when standard care, radical nephroureterectomy (RNU) is performed, and almost one-third of the patients die within 5 years.^1–3 In the management of localized UUTC, adjuvant chemotherapy has no impact on survival, particularly owing to the impaired post-surgical renal function or comorbidity.⁴ However, neoadjuvant chemotherapy, which showed a survival benefit in bladder cancer,⁵ may have a similar benefit in UUTC.Neoadjuvant chemotherapy can be considered an option for locally advanced disease at diagnosis. Two nomograms are available for predicting locally advanced UUTC in the pre-operative setting: one includes tumour histological grade, architecture and location and the other includes histological grade and radiological clinical stage.^6,7 “Localized disease” at the initial diagnosis that will develop metastasis soon after RNU can also be a candidate for neoadjuvant chemotherapy. However, identifying these occult or developing metastases pre-operatively remains a challenge.Diffusion-weighted MRI (DW-MRI) is a functional imaging technique that reveals physiological information by quantifying the diffusion of water molecules in tissues.⁸ The extent of water diffusion is quantified as the apparent diffusion coefficient (ADC). In 2009, a consensus meeting was held on the use of DW-MRI as a cancer imaging biomarker.⁹ An extraordinary opportunity for DW-MRI to evolve into a clinically valuable imaging tool was indicated. This imaging technique has been incorporated into general oncological imaging practices, including tissue characterization, monitoring the treatment response and predicting treatment outcome, in various cancers.^8,10–14Previous studies demonstrated the role of the ADC as a marker for the biological aggressiveness of UUTC by showing a correlation of the ADC with the histological grade and the Ki-67 labelling index.^14,15 Furthermore, the ADC was significantly associated with the cancer-specific survival after RNU.¹⁵ Therefore, we hypothesized that the ADC can be used as a marker to reflect the metastatic potential of UUTC, as has been reported in bladder cancer.¹⁶ The aim of this study is to show that the ADC can predict UUTC that has already metastasized or will metastasize soon. We first evaluated ADC values of the biologically metastatic UUTC and non-metastatic UUTC. Secondarily, we analysed the potential of the ADC to predict the development of metastasis.     

Correlation between mammographic and sonographic findings and prognostic factors in patients with node-negative invasive breast cancer

Objectives

The purpose of this study was to correlate sonographic and mammographic findings with prognostic factors in patients with node-negative invasive breast cancer.

Methods

Sonographic and mammographic findings in 710 consecutive patients (age range 21–81 years; mean age 49 years) with 715 node-negative invasive breast cancers were retrospectively evaluated. Pathology reports relating to tumour size, histological grade, lymphovascular invasion (LVI), extensive intraductal component (EIC), oestrogen receptor (ER) status and HER-2/neu status were reviewed and correlated with the imaging findings. Statistical analysis was performed using logistic regression analysis and intraclass correlation coefficient (ICC).

Results

On mammography, non-spiculated masses with calcifications were associated with all poor prognostic factors: high histological grade, positive LVI, EIC, HER-2/neu status and negative ER. Other lesions were associated with none of these poor prognostic factors. Hyperdense masses on mammography, the presence of mixed echogenicity, posterior enhancement, calcifications in-or-out of masses and diffusely increased vascularity on sonography were associated with high histological grade and negative ER. Associated calcifications on both mammograms and sonograms were correlated with EIC and HER-2/neu overexpression. The ICC value for the disease extent was 0.60 on mammography and 0.70 on sonography.

Conclusion

Several sonographic and mammographic features can have a prognostic value in the subsequent treatment of patients with node-negative invasive breast cancer. Radiologists should pay more attention to masses that are associated with calcifications because on both mammography and sonography associated calcifications were predictors of positive EIC and HER-2/neu overexpression.The three strongest prognostic factors in invasive breast cancer are widely accepted to be lymph node stage, histological grade and the size of histologically invasive cancer [1–4]. Axillary lymph node stage is an important prognostic factor in invasive breast cancer: the prognosis progressively worsens with an increasing number of involved nodes. Although controversial, micrometastatic disease continues to have clinical significance. Most series have shown that nodal micrometastasis appears to have a more or less adverse effect on disease-g0ree and overall survival [5]. The three strongest prognostic factors in invasive breast cancer provide more valuable information when taken into account altogether than when any single individual factor is used alone. The Nottingham Prognostic Index (NPI) uses these three factors and has been externally validated by several studies [2, 6–8]. In addition, histological grade, tumour size and oestrogen receptor (ER) status are usually used as significant factors in guiding adjuvant systemic chemotherapy in node-negative patients [9].Lymphovascular invasion (LVI) shows a clear relationship with nodal status [10–13] and local recurrence [12, 13]. LVI is also related to distant metastasis and overall survival in node-negative breast cancer [14, 15]. Patients with breast cancers that exhibit a high proportion of intraductal components have a higher risk of local recurrence after conservative surgery [16, 17]. Hence, accurate evaluation of intraductal spread is considered to be a key issue in determining tumour margins before planning breast-conserving surgery [18]. HER-2/neu overexpression in node-negative cancers is related to disease relapse and to disease-related death, regardless of tumour size, histological grade and ER status [19].In terms of treatment, most patients with node-positive invasive breast cancers measuring greater than 2 mm are offered adjuvant chemotherapy, with additional hormone therapy or trastuzumab (Herceptin) based upon necessity according to their hormone receptor and HER-2/neu status. On the other hand, patients with node-negative invasive cancer might not be offered adjuvant therapy, adjuvant hormone therapy or chemotherapy depending on the size, LVI, histological grade, their hormone receptor responsiveness and HER-2/neu status, and their age [20]. Therefore, in patients with node-negative breast cancers, knowing the hormone receptor and HER-2/neu status, histological grade and extent of LVI is very important in guiding the treatment plan and determining the prognosis.Several studies have looked at the correlation between imaging findings and prognostic factors [18, 21–27]. To our knowledge, however, no report has correlated imaging findings in node-negative invasive breast cancers that were analysed according to the Breast Imaging Report and Data System (BI-RADS) lexicon with prognostic factors. The purpose of our study was to correlate sonographic and mammographic findings with prognostic factors in patients with node-negative invasive breast cancer and to determine whether or not the imaging findings could have prognostic value. We also determined the relative accuracy of mammography and sonography in evaluating the extent of disease in patients with node-negative invasive breast cancer.     

Diffusion-weighted imaging in the assessment of tumour grade in endometrial cancer

Objective

Endometrial cancer is the most common gynaecological malignancy in developed countries. Histological grade and subtype are important prognostic factors obtained by pipelle biopsy. However, pipelle biopsy “samples” tissue and a high-grade component that requires more aggressive treatment may be missed. The purpose of the study was to assess the use of diffusion-weighted MRI (DW-MRI) in the assessment of tumour grade in endometrial lesions.

Method

42 endometrial lesions including 23 endometrial cancers and 19 benign lesions were evaluated with DW-MRI (1.5T with multiple b-values between 0 and 750 s mm⁻²). Visual evaluation and the calculation of mean and minimum apparent diffusion coefficient (ADC) value were performed and correlated with histology.

Results

The mean and minimum ADC values for each histological grade were 1.02 ± 0.29×10⁻³ mm² s⁻¹ and 0.74 ± 0.24×10⁻³ mm² s⁻¹ (grade 1), 0.88 ± 0.39×10⁻³ mm² s⁻¹ and 0.64 ± 0.36×10⁻³ mm² s⁻¹ (grade 2), and 0.94 ± 0.32×10⁻³ mm² s⁻¹ and 0.72 ± 0.36×10⁻³ mm² s⁻¹ (grade 3), respectively. There was no statistically significant difference between tumour grades. However, the mean ADC value for endometrial carcinoma was 0.97 ± 0.31, which was significantly lower (p<0.0001) than that of benign endometrial pathology (1.50 ± 0.14). Applying a cut-off mean ADC value of less than 1.28 × 10⁻³ mm² s⁻¹we obtained a sensitivity, specificity, positive predictive value and negative predictive value for malignancy of 87%, 100%, 100% and 85.7%, respectively.

Conclusion

Tumour mean and minimum ADC values are not useful in differentiating histological tumour grade in endometrial carcinoma. However, mean ADC measurement can provide useful information in differentiating benign from malignant endometrial lesions. This information could be clinically relevant in those patients where pre-operative endometrial sampling is not possible.Endometrial carcinoma is the commonest gynaecological malignancy in developed countries [1,2]. The majority of patients present with intermenstrual or post-menopausal bleeding, with approximately 70–80% having early (Stage I) disease at presentation [1,3]. Despite the relatively high incidence, endometrial cancer is not a common cause of cancer death with a 5 year survival of approximately 80% when all stages are considered together [4].The most important prognostic indicators in endometrial cancer are FIGO (International Federation of Gynecology and Obstetrics) stage, lymphovascular invasion, histological subtype and grade, and the presence of lymph node metastases [4-8]. FIGO staging of endometrial cancer is a surgico-pathological staging system that includes total hysterectomy, bilateral salpingo-oophrectomy and peritoneal washings with full pelvic lymphadenectomy [9]. The overall rate of lymph node involvement in endometrial cancer is low (5–8%) and lymphadenectomy carries a reported complication risk of up to 17–19% [10,11], which is particularly marked in patients who are at high surgical risk, such as those who are obese, diabetic or suffer from ischaemic heart disease [12]. As a result, only around 30% of endometrial cancer patients undergo lymphadenectomy in the USA as a whole, increasing to 48.3% in specialised cancer centres [13]. The role of lymphadenectomy in the management of endometrial cancer is currently an area of controversy in gynaecological oncology with no clear evidence regarding the survival benefits associated with the procedure [14-17]. However, in patients who are at high risk of nodal metastases most centres continue to perform lymphadenectomy.Accurate pre-operative identification of patients at high risk of nodal metastases would allow the selection of patients for lymphadenectomy, while those at low risk could be treated with simple hysterectomy. Histological tumour grade is a strong predictor of nodal invasion and thereby prognosis in endometrial cancer [18,19]. In patients with FIGO Stage 1 disease, grade 1 or grade 2 histology carries a less than 10% risk of nodal metastases. However, grade 3 histology carries an overall risk of 18% in Stage 1 disease, which increases to 34% when considering patients with deep myometrial invasion [18,19]. Pre-operative cytology from pipelle or curettage specimens only samples the endometrial tissue and therefore does not always provide accurate assessment [20,21]. In a study of patients with grade 1 histology pre-operatively 19% were upgraded following surgical resection [22].Diffusion-weighted MRI (DW-MRI) is a functional imaging technique that looks at the Brownian motion of water in tissues. In biological tissues this is restricted by interactions with cell membranes and macromolecules on a microscopic level. Increased tissue cellularity, as seen in tumours, restricts Brownian motion, which can be quantified by calculation of the apparent diffusion coefficient (ADC) [23].Previous publications have demonstrated that endometrial carcinoma may be distinguished from normal endometrium on DW-MRI [24-30]. It has also been suggested that DW-MRI may be useful in the pre-operative assessment of tumour grade [26,31]. The purpose of this study is to determine if there is a correlation between histological tumour grade and ADC value in endometrial cancer.     

Use of 99mTc-doxorubicin scintigraphy in females with breast cancer: a pilot study

Objective:

Doxorubicin (Eurofarma, São Paulo, Brazil) is an antitumour agent widely used in the treatment of breast cancer and can be used for tumour tracking when labelled with a radionuclide. Here, we present the results obtained with technetium-99m (^99mTc)-doxorubicin, using the direct method, to evaluate its uptake in breast cancer.

Methods:

Four females with confirmed breast carcinoma diagnosis and breast image reporting and data system Category 5 on mammography underwent whole-body and thorax single-photon emission CT/CT imaging 1 and 3 h after ^99mTc-doxorubicin administration.

Results:

We observed increased uptake in breast carcinoma lesions and elimination via renal and hepatic pathways.

Conclusion:

These preliminary results suggest that ^99mTc-doxorubicin may be a promising radiopharmaceutical for the evaluation of patients with breast cancer. Further studies are ongoing.

Advances in knowledge:

To our knowledge, this is the first study to evaluate the use of a directly labelled doxorubicin tracer in humans. ^99mTc-doxorubicin could provide information on the response of tumours to doxorubicin.Breast cancer is the most common cancer in females worldwide, with an estimated 1.67 million new cases in 2012.¹ In order to improve the treatment and prognosis of breast cancer, early detection is extremely important. However, the techniques most often used for cancer evaluation, such as mammography, ultrasonography and MRI, have limitations and are not always capable of differentiating benign from malignant lesions. Breast scintigraphy has some clinical indications and, in association with other imaging methods, can increase the accuracy of diagnoses and reduce unnecessary biopsies.²Advances in imaging modalities have contributed to the improvement of early breast cancer diagnosis.³ The use of positron emission tomography (PET) and its new radiopharmaceuticals is an important advance in cancer detection.⁴ Hybrid acquisition of PET with CT (PET/CT) allows evaluation of morphological parameters, increasing the sensitivity and specificity of PET findings.⁴ However, the uptake of fluorine-18-fludeoxyglucose (¹⁸F-FDG), the radiopharmaceutical most often used for PET, changes according to different variables, such as the histological type. In breast cancer, infiltrating ductal carcinoma shows higher uptake than infiltrating lobular carcinoma, while in ductal carcinoma, uptake is usually low.^{5–7 18}F-FDG uptake also depends on the grade of breast cancer.^6,8 Hybrid PET/CT has low sensitivity for tumours <1 cm, owing to limitations in spatial resolution and tumour variables,^7,8 and ¹⁸F-FDG uptake may occur in benign lesions such as inflammatory granulomatous mastitis.⁹ Although PET/CT is limited in the evaluation of tumour size and the presence of multifocal disease, this might change with the advent of positron emission mammography (PEM). Eo et al¹⁰ reported that PEM diagnosed more malignant breast lesions than PET/CT, particularly in tumours <2 cm.Unfortunately, PET scanners are not available in all nuclear medicine services, notably in developing countries. Conventional gamma cameras, on the other hand, are widely available and therefore single-photon emission CT (SPECT) radiopharmaceuticals have the potential to benefit a larger number of patients. Another promising tool is the use of dedicated apparatus for conventional nuclear medicine of the breast, called molecular breast imaging (MBI), which can detect malignant breast lesions <1 cm.^11,12Doxorubicin (Eurofarma, São Paulo, Brazil) is a potent antitumour agent that is widely used in chemotherapy for several types of cancer.¹³ It acts by intercalating nucleotide bases, binding to the lipid membrane, and also inhibits the biosynthesis of macromolecules.¹⁴ Among the main side effects of this drug is possible cardiotoxicity.¹⁵ Technetium-99m (^99mTc) is the radionuclide most often used in conventional nuclear medicine; our research group has used ^99mTc to radiolabel different types of cells and molecules.^16–23 We previously reported a technique for labelling the thymidine precursor thymine with ^99mTc, with good specificity and high predictive value.^16–18 We have also used ^99mTc-doxorubicin in dogs and cats in order to evaluate its uptake in different kinds of tumours, with promising results, which led to the approval of this pilot trial.²⁴     

Accessory or additional renal arteries show no relevant effects on the width of the upper urinary tract: a 64-slice multidetector CT study in 1072 patients with 2132 kidneys

Objective

The aim of this study was to find out on an unselected patient group whether crossing vessels have an influence on the width of the renal pelvis and what independent predictors of these target variables exist.

Methods

In this cross-sectional study, 1072 patients with arterially contrasted CT scans were included. The 2132 kidneys were supplied by 2736 arteries.

Results

On the right side, there were 293 additional and accessory arteries in 286 patients, and on the left side there were 304 in 271 patients. 154 renal pelves were more than 15 mm wide. The greatest independent factor for hydronephrosis on one side was hydronephrosis on the contralateral side (p<0.0001 each). Independent predictors for the width of the renal pelvis on the right side were the width of the renal pelvis on the left, female gender, increasing age and height; for the left side, predictors were the width of the renal pelvis on the right, concrements, parapelvic cysts and great rotation of the upper pole of the kidney to dorsal. Crossing vessels had no influence on the development of hydronephrosis. Only anterior crossing vessels on the right side are associated with widening of the renal pelvis by 1 mm, without making it possible to identify the vessel as an independent factor in multivariate regression models.

Conclusion

The width of the renal pelvis on the contralateral side is the strongest independent predictor for hydronephrosis and the width of the renal pelvis. There is no link between crossing vessels and the width of the renal pelvis.Obstructions of the ureteropelvic junction (UPJ) can be caused by intrinsic or extrinsic factors [1]. Although there are no studies of this to date, crossing the UPJ by an aberrant crossing vessel is considered the most important [2] of the extrinsic factors [3]. Crossing vessels, which are thought to cause from 40% to over 50% of the extrinsic UPJ obstructions in adults [4, 5], are located ventral more often than dorsal to the UPJ. These are usually normal vessels of the lower pole segment [4, 6–9], which can be divided into additional renal arteries arising from the aorta, and accessoric renal arteries arising from branches of the aorta [10, 11]. The primary surgical therapy of choice is endoscopic endopyelotomy [12]. The success rate of 89–90% [12, 13] is thought to be noticeably poorer in patients with crossing vessels [12, 13]; however, this is not undisputed [14, 15]. Be that as it may, to prevent bleeding complications it is necessary to be familiar with the vascular situation around the UPJ prior to the procedure [3, 16–18]. CT angiography is used for this purpose, as it is highly accurate, quick to perform and shows all relevant anatomical structures in relation to one another [3, 19, 20]. The objective of this study was to determine whether or not there are vascular morphological patterns or other factors that influence the width of the renal collecting system, regardless of the definitions of hydronephrosis.     

MRI features of breast lymphoma: preliminary experience in seven cases

PURPOSE

We aimed to evaluate the imaging features of breast lymphoma using magnetic resonance imaging (MRI).

METHODS

This retrospective study consisted of seven patients with pathologically confirmed breast lymphoma. The breast lymphomas were primary in six patients and secondary in one patient. All patients underwent preoperative dynamic contrast-enhanced MRI and one underwent additional diffusion-weighted imaging (DWI) with a b value of 600 s/mm². Morphologic characteristics, enhancement features, and apparent diffusion coefficient (ADC) values were reviewed.

RESULTS

On MRI, three patients presented with a single mass, one with two masses, two with multiple masses, and one with a single mass and a contralateral focal enhancement. The MRI features of the eight biopsied masses in seven patients were analyzed. On MRI, the margins were irregular in six masses (75%) and spiculated in two (25%). Seven masses (87.5%) displayed homogeneous internal enhancement, while one (12.5%) showed rim enhancement. Seven masses (87.5%) showed a washout pattern and one (12.5%) showed a plateau pattern. The penetrating vessel sign was found in two masses (25%). One patient with two masses underwent DWI. Both masses showed hyperintense signal on DWI with ADC values of 0.867×10⁻³ mm²/s and 0.732×10⁻³ mm²/s, respectively.

CONCLUSION

Breast lymphoma commonly presents as a homogeneously enhancing mass with irregular margins and displays a washout curve pattern on dynamic MRI. A low ADC value may also indicate a possible diagnosis of breast lymphoma.Breast lymphoma, which constitutes only 0.04%–0.5% of all breast malignancies (1), can be divided into primary or secondary breast lymphoma (2). The majority of breast lymphomas are diffuse large B-cell lymphoma (3). The spontaneous regression of a breast lymphoma is rare and the five-year overall survival rate is 53% (1, 4). Early-stage identification and the use of radiotherapy are favorable prognostic factors, while mastectomy is associated with a poorer survival (1, 5). Therefore, a preoperative diagnosis of breast lymphoma would mean an earlier diagnosis and likely avoid unnecessary aggressive procedures.Previous studies demonstrated mammographic and ultrasonographic findings of breast lymphoma (6–8). Most lesions were high-density masses without spiculated margins and calcifications on mammography and noncircumscribed hypoechoic masses on ultrasonography (6–8). However, none were pathognomonic.Data on the magnetic resonance imaging (MRI) of breast lymphoma are limited to some single case reports (4, 7, 9–19) and small sample size case series (8, 20–23). The morphology and time-signal intensity curve (TIC) of breast lymphoma on MRI are variable. Diffusion-weighted imaging (DWI) is a functional imaging technique that is useful for distinguishing lymphoma from other malignant tumors in other systems (24, 25). However, to the best of our knowledge, the value of DWI in differentiating breast lymphoma from other malignant breast lesions has not been discussed. Therefore, the purpose of this study is to assess the MRI and DWI features of breast lymphoma.     

MRI evaluation of neoadjuvant low-dose fractionated radiotherapy with concurrent chemotherapy in patients with locally advanced breast cancer

Objectives

We address the diagnostic performance of breast MRI and the efficacy of neoadjuvant radiochemotherapy (NRC) treatment (NRC protocol) vs conventional neoadjuvant chemotherapy (NAC) in patients with locally advanced breast cancer.

Methods

The NRC protocol consists of six anthracycline/taxane cycles and concomitant low-dose radiotherapy on breast tumour volume. Breast MRI was performed at baseline and after the last therapy cycle in 18 and 36 patients undergoing the NRC protocol or conventional NAC (propensity matching).

Results

In both groups, we observed reduced tumour dimensions after the last cycle (p<0.001), and the response evaluation criteria in solid tumours (RECIST) class directly correlated with the tumour regression grade class after the last cycle (p<0.001). Patients in the NRC group displayed a higher frequency of complete/partial response than those in the NAC group (p=0.034). 17 out of 18 patients in the NRC group met the criteria for avoiding mastectomy based on final MRI evaluation. The RECIST classification displayed a superior diagnostic performance in the prediction of the response to treatment [area under the receiver operating characteristic curve (AUC)=0.72] than time-to-intensity curves and apparent diffusion coefficient (AUC 0.63 and 0.61). The association of the three above criteria yielded a better diagnostic performance, both in the general population (AUC=0.79) and in the NRC and the NAC group separately (AUC=0.82 and AUC=0.76).

Conclusions

The pathological response is predicted by MRI performed after the last cycle, if both conventional MRI and diffusion imaging are integrated. The NRC treatment yields oncological results superior to NAC.

Advances in knowledge

MRI could be used to establish the neoadjuvant protocol in breast cancer patients.Neoadjuvant chemotherapy is currently widely employed in patients with locally advanced breast cancer (LABC) in order to improve the rate of breast-conserving surgery (up to 98% of patients) and systemic control of the disease [1,2]. The coupling of pre-operative radiotherapy (RT) cycles with neoadjuvant chemotherapy has been proposed for other cancer types. In particular, taxanes could have a synergistic effect with RT when administered concurrently [3-5]. Nonetheless, few data are currently available on the efficacy of concurrent neoadjuvant RT in patients with LABC, although evidence exists that such a strategy is safe and feasible [6], and is supported by preliminary investigations [7,8]. Radiation doses below 0.5 Gy have been demonstrated to enhance the effectiveness of continuous-infusion taxanes. This phenomenon has been termed low-dose hyper-radiosensitivity [9,10].MRI is a reliable tool to evaluate the breast cancer response to chemotherapy by measuring tumour diameter changes and by assessing the viability of residual tumour areas [11-13]. Nevertheless, MRI may under- or overestimate the burden of residual tumour by confounding a fibrotic scar with viable tumour tissue, or vice versa. Diffusion-weighted imaging (DWI) has been shown in such contexts to improve the diagnostic performance of MRI [14]. It has not been clarified whether MRI retains its diagnostic performance even in the context of breast RT. The latter is known to trigger tissue oedema, which may potentially impair the diagnostic accuracy [15,16]. The purpose of the present work is to ascertain (1) the diagnostic performance of MRI and DWI-MRI in the context of concurrent low-dose fractionated RT (LD-FRT) and chemotherapy in the prediction of response to neoadjuvant treatment; (2) whether the adoption of concurrent neoadjuvant LD-FRT and chemotherapy yields better oncological results in LABC than neoadjuvant chemotherapy alone.