Eren D. Yeh

Paclitaxel decreases the interstitial fluid pressure and improves oxygenation in breast cancers in patients treated with neoadjuvant chemotherapy: clinical implications.

PURPOSE It has been hypothesized that tumors with high interstitial fluid pressure (IFP) and/or hypoxia respond poorly to chemotherapy (CT) because of poor drug delivery. Preclinical studies have shown that paclitaxel reduces the IFP and improves the oxygenation (pO(2)) of tumors. Our aim is to evaluate the IFP and pO(2) before and after neoadjuvant CT using sequential paclitaxel and doxorubicin in patients with breast cancer tumors of >/= 3 cm. PATIENTS AND METHODS Patients were randomly assigned, according to an institutional review board-approved phase II protocol, to receive neoadjuvant sequential CT consisting of either four cycles of dose-dense doxorubicin at 60 mg/m(2) every 2 weeks followed by nine cycles of weekly paclitaxel at 80 mg/m(2) (group 1) or vice versa, with paclitaxel administered before doxorubicin (group 2). Patients were re-evaluated clinically and radiologically. The IFP (wick-in-needle technique) and pO(2) (Eppendorf) were measured in tumors at baseline and after completing the administration of the first and second drug. RESULTS IFP and pO(2) were measured in 54 patients at baseline and after the first CT. Twenty-nine and 25 patients were randomly assigned to groups 1 and 2, respectively. Paclitaxel, when administered first, decreased the mean IFP by 36% (P = .02) and improved the tumor pO(2) by almost 100% (P = .003). In contrast, doxorubicin did not have a significant effect on either parameter. This difference was independent of the tumor size or response measured by ultrasound. CONCLUSION Paclitaxel significantly decreased the IFP and increased the pO(2), whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.

Physiologic Changes in Breast Magnetic Resonance Imaging during the Menstrual Cycle: Perfusion Imaging, Signal Enhancement, and Influence of the T1 Relaxation Time of Breast Tissue

Abstract:  This study was undertaken to determine the best time during the menstrual cycle to perform dynamic breast magnetic resonance imaging (MRI). The contralateral “normal” breast of 50 premenopausal women (mean age 40.4 ± 6.4 years, range 30–52 years) were enrolled in a protocol designed to correlate an ipsilateral suspicious breast lesion with pathology. The contralateral breast in each patient was examined with palpation and mammography prior to MRI on a 1.5T scanner using gradient echo and dynamic contrast‐enhanced echo‐planar without and following gadolinium diethylenetriaminepentaacetic acid (Gd‐DTPA) injection. Pre‐contrast T1 relaxation times were measured before calculating extraction flow product (EFP) maps using a multicompartmental model. T1, EFP, and enhancement were measured in the control breast on four slices centered around the nipple and recorded as a function of the phases of the menstrual cycle. Lesions or areas with focal enhancement were excluded. Analysis of variance and Fishers tests were performed. The cyclic changes in T1 relaxation time were not significant (p > 0.2). EFP and enhancement varied significantly during the cycle (p < 0.003 and p < 0.004, respectively), with low values during the first half of the cycle and high values during the second half. The lowest values of EFP and enhancement (5.5 ± 2.9 ml/100 g/min and 26 ± 17%) were observed during the proliferative phase (days 3–7), and the highest values (17 ± 10.2 ml/100 g/min and 104 ± 28%) were observed during the secretory phase (days 21–27) (p < 0.0006 and p < 0.0008, respectively). Dynamic breast MRI should be performed during first half of the menstrual cycle (days 3–14) in order to minimize interpretative difficulties related to the uptake of gadolinium in normal breast tissue due to hormonal fluctuations during the menstrual cycle.

Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients.

Significance Emerging evidence indicates patients who benefit from antiangiogenic therapies have improved vessel function. To determine how bevacizumab modulates vessel morphology to improve vessel function we conducted a phase II trial of preoperative bevacizumab followed by bevacizumab combined with chemotherapy in HER2-negative breast cancer patients. Our results suggest that the clinical response to bevacizumab may occur through an increase in the extent of vascular normalization primarily in patients with a high baseline tumor microvessel density. If validated, these observations suggest approaches to improve antiangiogenic therapy and to identify patients likely to benefit. Preoperative bevacizumab and chemotherapy may benefit a subset of breast cancer (BC) patients. To explore potential mechanisms of this benefit, we conducted a phase II study of neoadjuvant bevacizumab (single dose) followed by combined bevacizumab and adriamycin/cyclophosphamide/paclitaxel chemotherapy in HER2-negative BC. The regimen was well-tolerated and showed a higher rate of pathologic complete response (pCR) in triple-negative (TN)BC (11/21 patients or 52%, [95% confidence interval (CI): 30,74]) than in hormone receptor-positive (HR)BC [5/78 patients or 6% (95%CI: 2,14)]. Within the HRBCs, basal-like subtype was significantly associated with pCR (P = 0.007; Fisher exact test). We assessed interstitial fluid pressure (IFP) and tissue biopsies before and after bevacizumab monotherapy and circulating plasma biomarkers at baseline and before and after combination therapy. Bevacizumab alone lowered IFP, but to a smaller extent than previously observed in other tumor types. Pathologic response to therapy correlated with sVEGFR1 postbevacizumab alone in TNBC (Spearman correlation 0.610, P = 0.0033) and pretreatment microvascular density (MVD) in all patients (Spearman correlation 0.465, P = 0.0005). Moreover, increased pericyte-covered MVD, a marker of extent of vascular normalization, after bevacizumab monotherapy was associated with improved pathologic response to treatment, especially in patients with a high pretreatment MVD. These data suggest that bevacizumab prunes vessels while normalizing those remaining, and thus is beneficial only when sufficient numbers of vessels are initially present. This study implicates pretreatment MVD as a potential predictive biomarker of response to bevacizumab in BC and suggests that new therapies are needed to normalize vessels without pruning.

Background Parenchymal Enhancement at Breast MR Imaging: Normal Patterns, Diagnostic Challenges, and Potential for False-Positive and False-Negative Interpretation

At magnetic resonance (MR) imaging, both normal and abnormal breast tissue enhances after contrast material administration. The morphology and temporal degree of enhancement of pathologic breast tissue relative to normal breast tissue form the basis of MR imagings diagnostic accuracy in the detection and diagnosis of breast disease. Normal parenchymal enhancement at breast MR imaging is termed background parenchymal enhancement (BPE). BPE may vary in degree and distribution in different patients as well as in the same patient over time. Typically BPE is minimal or mild in overall degree, with a bilateral, symmetric, diffuse distribution and slow early and persistent delayed kinetic features. However, BPE may sometimes be moderate or marked in degree, with an asymmetric or nondiffuse distribution and rapid early and plateau or washout delayed kinetic features. These patterns cause diagnostic difficulty because these features can be seen with malignancy. This article reviews typical and atypical patterns of BPE seen at breast MR imaging. The anatomic and physiologic influences on BPE in women undergoing diagnostic and screening breast MR imaging are reviewed. The potential for false-positive and false-negative interpretations due to BPE are discussed. Radiologists can improve their interpretive accuracy by increasing their understanding of various BPE patterns, influences on BPE, and the potential effects of BPE on MR imaging interpretation.

The Lactating Breast: MRI Findings and Literature Review

Abstract: Normal physiologic changes in the breast related to pregnancy and lactation can reduce the sensitivity of imaging modalities, such as mammography. This is likely to be true for other breast imaging techniques such as magnetic resonance imaging (MRI). Although malignancy is relatively uncommon in lactating breasts, patients may develop palpable abnormalities that require imaging evaluation. Physiologic changes from pregnancy and lactation can complicate breast imaging. We report the MRI appearance of the lactating breast and address potential difficulties that may be encountered in this clinical situation.

Invasive Lobular Carcinoma: Spectrum of Enhancement and Morphology on Magnetic Resonance Imaging

Abstract: Invasive lobular carcinoma (ILC) may be a difficult tumor to detect early by physical examination, mammography, or ultrasound. We undertook this study to describe the spectrum of gadolinium enhancement and morphologic features of ILC on magnetic resonance imaging (MRI). Nineteen patients with ILC who presented with a palpable mass, a mammographically visible abnormality, or an unknown primary underwent preoperative MRI of both breasts using a T1‐weighted high‐resolution gradient echo sequence (pre‐ and postcontrast), and an echoplanar sequence during the administration of gadolinium. Using a quantitative measure of gadolinium uptake over time, called the extraction flow (EF) product, and a normal tissue threshold EF level of 25 or less, enhancement for 15 of the 19 cancers was characterized. By consensus, three radiologists categorized the morphologic features of the lesions. For the 15 cases of ILC that had echoplanar data, analysis showed peak EFs ranging between 25 and 120, and the majority showed EFs in the 30s. A substantial portion of two tumors enhanced in a similar fashion to normal breast tissue, with EFs in the low 20s. Morphologically MRI showed a focal mass in eight cases, regional enhancement in five, segmental enhancement in one, segmental enhancement with multiple small nodules in one, a mixture of a focal mass and regional enhancement in one, diffuse enhancement in one, multiple small nodules in one, and bilateral disease in one. Of the focal masses, seven were irregular in shape and one was round; six had ill‐defined margins and two had spiculated margins. All eight enhanced heterogeneously. Four cases had multifocal disease and one case had unsuspected contralateral disease discovered only on MRI. MRI using a combination of morphology and a quantitative measure of gadolinium uptake was able to detect the majority of cases of ILC. However, there was a variable morphologic appearance and contrast enhancement pattern on MRI. A few lesions were difficult to distinguish from normal tissue. This suggests that some cases of ILC may be difficult to detect on MRI. 

Accuracy of cartilage and subchondral bone spatial thickness distribution from MRI

To assess three‐dimensional measurement accuracy of articular cartilage (AC) and subchondral bone (SB) thickness from MRI.

Analysis of the Mammographic and Sonographic Features of Pseudoangiomatous Stromal Hyperplasia

OBJECTIVE The purpose of this study was to describe the imaging findings in 149 patients with pseudoangiomatous stromal hyperplasia (PASH) who had undergone at least 4 years of clinical follow-up for detection of subsequent malignancy. CONCLUSION PASH is a common entity that presents with benign imaging features without evidence of subsequent malignant potential. At our institution, in the absence of suspicious features a diagnosis of PASH at core biopsy is considered sufficient, and surgical excision has been obviated.

The Mammary Hamartoma Appreciation of Additional Imaging Characteristics

Objective. To determine the mammographic and sonographic findings of hamartomas that were not classic on imaging, how pathologists distinguish the hamartoma from benign breast tissue on core samples, and reasons for discrepancies between core and surgical biopsy. Methods. A retrospective review of all image‐recommended core biopsies between 1993 and 2001 was performed. There were 41 cases of hamartomas found on either core or surgical biopsy. The mammographic, sonographic, and pathologic findings were reviewed. Results. Of 41 hamartomas in 38 patients, 18 went on to surgical biopsy. Of these 18 cases, 4 cases of hamartoma on core biopsy were fibroadenoma after excision; 2 cases of hamartoma on core biopsy were confirmed by surgery; and 12 cases of fibrocystic change after core biopsy were hamartoma after surgical biopsy. The 4 cases of fibroadenoma shown at final pathologic examination were excluded from imaging review, leaving 37 cases. In the 20 patients who underwent only core sampling, 23 hamartomas were diagnosed. Seventeen masses were visible on mammography, and 82% were homogeneously dense. Of 36 masses shown on sonography, 86% were uniformly hypoechoic. At histologic examination, only 16% contained fat within the mass. Conclusions. Hamartomas may appear as homogeneously dense, well‐circumscribed masses, varying in appearance from the classically described encapsulated mixed fatty‐fibroglandular mass. Pathologists can make the diagnosis of hamartoma without the presence of adipose tissue but may have difficulty in distinguishing the hamartoma from fibrocystic change. However, if there is radiologic‐pathologic concordance, further surgical excision is not warranted.

Detecting Nonpalpable Recurrent Breast Cancer: The Role of Routine Mammographic Screening of Transverse Rectus Abdominis Myocutaneous Flap Reconstructions

PURPOSE To perform a retrospective cohort study to determine the rates of recall and cancer detection and then to develop a decision analytic model to evaluate the effectiveness of routine screening of transverse rectus abdominis myocutaneous (TRAM) flap reconstructions. MATERIALS AND METHODS This study was approved by the institutional review board, and the methods comply with HIPAA regulations. A retrospective search of the institutional mammographic results database was done to identify bilateral screening mammographic examinations obtained from January 1, 1999, through July 15, 2005. The search included the term TRAM; the recall and cancer detetion rates were then detected. Subsequently, a decision analytic model was constructed to evaluate a hypothetical cohort of women with TRAM flap reconstructions. RESULTS Of 554 mammograms (265 TRAM flap reconstructions), 546 (98.6%) had negative results (Breast Imaging Reporting and Data System category 1 or 2). Eight (1.4%) had positive test results (Breast Imaging Reporting and Data System category 0, 3, 4, or 5). All suspicious lesions underwent biopsy and had benign pathologic results. No interval breast cancers were identified. The detection rate for nonpalpable recurrent breast cancer was 0% (exact 95% confidence interval: 0.0%, 1.4%). According to decision analysis, screening would help detect an estimated 12 additional recurrent cancers per 1000 women screened, providing an additional 1.6 days of life expectancy for the screened cohort. Under base-case conditions, screening of TRAM flap reconstructions is less effective than screening asymptomatic women in their 40s. Sensitivity analysis revealed that a benefit equivalent to that of screening asymptomatic women in their 40s was achievable under conditions related to estimates of screening effectiveness and cancer detection rate. CONCLUSION Routine screening mammography of TRAM flap reconstructions has a very low detection rate for nonpalpable recurrent breast cancer. Decision analysis indicates that screening such women is less effective than screening asymptomatic women in their 40s for primary breast cancer.