Ana M. Grau

Diagnostic accuracy of endoscopic ultrasound-guided fine-needle aspiration in patients with presumed pancreatic cancer

Endoscopic ultrasound (EUS)-guided fine-needle aspiration (FNA) of the pancreas allows the diagnosis of pancreatic cancer to be established without exploratory surgery. We reviewed our recent experience with EUS-FNA in patients with presumed pancreatic cancer and report the diagnostic accuracy and complications of this procedure. Data were reviewed from all patients who presented with CT evidence of a pancreatic mass or a malignant biliary stricture and underwent EUS-FNA at our institution between November 1, 1999, and October 1, 2001. Based on the findings of contrast-enhanced, multislice CT scanning, patients were categorized as having resectable, locally advanced, or metastatic disease. EUS-FNA was performed in 233 patients. A final diagnosis of cancer was established in 216 patients (93%), 15 patients (6%) were found to have benign disease, and the final diagnosis remains unknown in two patients (1%). The sensitivity, specificity, and accuracy of EUS-FNA for diagnosis of a pancreatic malignancy were 91%, 100%, and 92%, respectively. For the 216 patients subsequently proven to have cancer, the results of EUS-FNA were diagnostic in 197 (91%); 96 (90%) of 107 patients with resectable disease, 62 (97%) of 64 with locally advanced disease, and 39 (87%) of 45 with metastatic disease. Four patients (2%) developed a clinically apparent complication that required hospital admission, including two patients who required surgery for duodenal perforation. There were no EUS-related deaths. We conclude that EUS-FNA can safely and accurately establish a cytologic diagnosis in patients with both early-stage and advanced pancreatic cancer. This enables consideration of all treatment options including protocol-based therapy

Short Preoperative Treatment With Erlotinib Inhibits Tumor Cell Proliferation in Hormone Receptor–Positive Breast Cancers

PURPOSE To administer the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib to patients with operable untreated breast cancer during the immediate preoperative period and to measure an antiproliferative and/or a proapoptotic effect in the post-therapy specimen and determine a biomarker profile associated with evidence of erlotinib-mediated cellular activity. PATIENTS AND METHODS Newly diagnosed patients with stages I to IIIA invasive breast cancer were treated with erlotinib 150 mg/d orally for 6 to 14 days until the day before surgery. Erlotinib plasma levels were measured by tandem mass spectrometry the day of surgery. Drug-induced changes in tumor cell proliferation and apoptosis were assessed by Ki67 immunohistochemistry and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick-end labeling analysis, respectively, in biopsies from the pretherapy and surgical specimens. Biopsies were also evaluated for P-EGFR, P-HER-2, P-MAPK, P-Akt, P-S6, and S118 P-ER alpha. RESULTS In drug-sensitive PC9 xenografts, 5 days of treatment with erlotinib were enough to induce a maximal inhibition of cell proliferation and induction of apoptosis. Forty-one patients completed preoperative treatment with erlotinib. Grade <or= 2 rash and diarrhea were the main toxicities. Erlotinib inhibited tumor cell proliferation (Ki67), P-EGFR, and P-HER-2. The inhibition of proliferation occurred in estrogen receptor (ER) -positive but not in human epidermal growth factor receptor 2 (HER-2) -positive or triple-negative cancers. Treatment was associated with a significant reduction of P-MAPK, P-Akt, P-S6, and S118 P-ER alpha in hormone receptor-positive cancers. CONCLUSION A presurgical approach to evaluate cellular responses to new drugs is feasible in breast cancer. EGFR inhibitors are worthy of testing against ER-positive breast cancers but are unlikely to have clinical activity against HER-2-positive or triple-negative breast cancers.

DCE-MRI analysis methods for predicting the response of breast cancer to neoadjuvant chemotherapy: Pilot study findings

The purpose of this pilot study is to determine (1) if early changes in both semiquantitative and quantitative DCE‐MRI parameters, observed after the first cycle of neoadjuvant chemotherapy in breast cancer patients, show significant difference between responders and nonresponders and (2) if these parameters can be used as a prognostic indicator of the eventual response.

Multiparametric magnetic resonance imaging for predicting pathological response after the first cycle of neoadjuvant chemotherapy in breast cancer.

ObjectivesThe purpose of this study was to determine whether multiparametric magnetic resonance imaging (MRI) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DWI), obtained before and after the first cycle of neoadjuvant chemotherapy (NAC), is superior to single-parameter measurements for predicting pathologic complete response (pCR) in patients with breast cancer. Materials and MethodsPatients with stage II/III breast cancer were enrolled in an institutional review board–approved study in which 3-T DCE-MRI and DWI data were acquired before (n = 42) and after 1 cycle (n = 36) of NAC. Estimates of the volume transfer rate (Ktrans), extravascular extracellular volume fraction (ve), blood plasma volume fraction (vp), and the efflux rate constant (kep = Ktrans/ve) were generated from the DCE-MRI data using the Extended Tofts-Kety model. The apparent diffusion coefficient (ADC) was estimated from the DWI data. The derived parameter kep/ADC was compared with single-parameter measurements for its ability to predict pCR after the first cycle of NAC. ResultsThe kep/ADC after the first cycle of NAC discriminated patients who went on to achieve a pCR (P < 0.001) and achieved a sensitivity, specificity, positive predictive value, and area under the receiver operator curve (AUC) of 0.92, 0.78, 0.69, and 0.88, respectively. These values were superior to the single parameters kep (AUC, 0.76) and ADC (AUC, 0.82). The AUCs between kep/ADC and kep were significantly different on the basis of the bootstrapped 95% confidence intervals (0.018–0.23), whereas the AUCs between kep/ADC and ADC trended toward significance (−0.11 to 0.24). ConclusionsThe multiparametric analysis of DCE-MRI and DWI was superior to the single-parameter measurements for predicting pCR after the first cycle of NAC.

A novel AIF tracking method and comparison of DCE-MRI parameters using individual and population-based AIFs in human breast cancer.

Quantitative analysis of dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) data requires the accurate determination of the arterial input function (AIF). A novel method for obtaining the AIF is presented here and pharmacokinetic parameters derived from individual and population-based AIFs are then compared. A Philips 3.0 T Achieva MR scanner was used to obtain 20 DCE-MRI data sets from ten breast cancer patients prior to and after one cycle of chemotherapy. Using a semi-automated method to estimate the AIF from the axillary artery, we obtain the AIF for each patient, AIF(ind), and compute a population-averaged AIF, AIF(pop). The extended standard model is used to estimate the physiological parameters using the two types of AIFs. The mean concordance correlation coefficient (CCC) for the AIFs segmented manually and by the proposed AIF tracking approach is 0.96, indicating accurate and automatic tracking of an AIF in DCE-MRI data of the breast is possible. Regarding the kinetic parameters, the CCC values for K(trans), v(p) and v(e) as estimated by AIF(ind) and AIF(pop) are 0.65, 0.74 and 0.31, respectively, based on the region of interest analysis. The average CCC values for the voxel-by-voxel analysis are 0.76, 0.84 and 0.68 for K(trans), v(p) and v(e), respectively. This work indicates that K(trans) and v(p) show good agreement between AIF(pop) and AIF(ind) while there is a weak agreement on v(e).

Neoadjuvant Concurrent Paclitaxel and Radiation in Stage II/III Breast Cancer

Purpose: The aim of this study was to determine the safety and pathologic response rates following neoadjuvant paclitaxel and radiation in patients with stage II/III breast cancer and to evaluate the use of sequential biopsies to allow an in vivo assessment of biological markers as potential predictive markers of response to this regimen. Patients and Methods: Patients with high-risk, operable breast cancer were treated with three cycles of paclitaxel 175 mg/m2 every 3 weeks, followed by twice-weekly paclitaxel 30 mg/m2 and concurrent radiation. Core biopsies were obtained at baseline and 24 to 72 hours after the first cycle of paclitaxel. After completing neoadjuvant treatment, patients underwent definitive surgery. The primary end point was pathologic complete response, which is defined as the absence of any invasive cancer at surgery. Potential markers of therapeutic response were evaluated including markers of proliferation, apoptosis, p21, HER2, estrogen receptor, and progesterone receptor status. Results: Of the 38 patients enrolled, 13 (34%) had a pathologic complete response. There was no significant difference in baseline Ki-67 between responders (35%) and nonresponders (28%; P = 0.45). There was also no significant change in Ki-67 following paclitaxel administration. Despite this lack of immunohistologic change in proliferative activity, baseline mitotic index was higher for patients with pathologic complete response over nonresponders (27 versus 10, P = 0.003). Moreover, the increase in mitotic index following paclitaxel administration was associated with pathologic complete response. Conclusions: Neoadjuvant paclitaxel/radiation is effective and well tolerated. Tumor proliferation at baseline and response to chemotherapy as measured by mitotic activity may serve as an important indicator of pathologic response to neoadjuvant paclitaxel/radiation.

Prognostic Factors in Resectable Pancreatic Cancer: p53 and Bcl-2

The p53 tumor suppressor gene and the Bcl-2 proto-oncogene regulate cell cycle progression and apoptosis. We evaluated the expression of these molecular markers with standard pathologic prognostic variables in patients who received multimodality therapy for resectable adenocarcinoma of the pancreas to study the effect of p53 and Bcl-2 on survival duration. Immunohistochemical staining of archival material was performed to determine levels of expression of p53 and Bcl-2 proteins in 70 patients with adenocarcinoma of pancreatic origin. All patients underwent a potentially curative pancreaticoduodenectomy and standardized pathologic analysis of resected specimens. Potential pathologic and molecular prognostic variables were assessed for their effect on survival duration. Nuclear staining for p53 was observed in 33 (47%) of 70 specimens. Immunostaining for Bcl-2 was observed in 23 specimens (33%). A trend toward improved survival duration was seen in patients whose tumors stained positive for either p53 or Bcl-2. Negative staining for both markers predicted short survival (P = 0.01). By univariate and multivariate analyses, no single pathologic factor was associated with survival duration. Immunohistochemical staging using both p53 and Bcl-2 significantly predicted survival duration by univariate and multivariate analysis; patients whose tumors stained positively for p53 and/or overexpressed Bcl-2 had a significantly longer survival than those whose tumors stained negative for both proteins.

Tumor Suppressor Gene Smad4/DPC4, Its Downstream Target Genes, and Regulation of Cell Cyclea

Abstract: The tumor suppressor gene deleted in pancreatic cancer locus 4 (Smad4/DPC4) is inactivated in about 50% of pancreatic adenocarcinomas. The role of DPC4 in the transforming growth factor‐β (TGF‐β) receptor‐mediated signal transduction cascade in human pancreatic, colon, and breast carcinoma cell lines has been investigated by a number of laboratories. The results demonstrate that Smad4/DPC4 protein functions as a key transcription factor required in regulation of TGF‐β inducible gene expression and subsequent growth inhibition. Many transcription regulators that are involved in cell growth, differentiation, and oncogenesis have been identified and cloned. Yet paradoxically, it is much more difficult to identify the important downstream target genes responsible for the biological effects elicited by these transcription factors. Although numerous attempts have been made and different approaches have been used to identify the target genes, only limited success has been achieved. Our data show that p21waf1 is one of the Smad4/DPC4‐regulated downstream target genes and suggest that overexpression of the Smad4/DPC4 gene can bypass TGF‐β receptor activation and reestablish one of the key regulatory controls of cell proliferation. Identification of the Smad‐regulated downstream target genes responsible for diverse biological processes that they control will extend our understanding of the mechanism for cell cycle regulation and cell differentiation.

Statistical comparison of dynamic contrast-enhanced MRI pharmacokinetic models in human breast cancer.

By fitting dynamic contrast‐enhanced MRI data to an appropriate pharmacokinetic model, quantitative physiological parameters can be estimated. In this study, we compare four different models by applying four statistical measures to assess their ability to describe dynamic contrast‐enhanced MRI data obtained in 28 human breast cancer patient sets: the chi‐square test (χ2), Durbin–Watson statistic, Akaike information criterion, and Bayesian information criterion. The pharmacokinetic models include the fast exchange limit model with (FXL_vp) and without (FXL) a plasma component, and the fast and slow exchange regime models (FXR and SXR, respectively). The results show that the FXL_vp and FXR models yielded the smallest χ2 in 45.64 and 47.53% of the voxels, respectively; they also had the smallest number of voxels showing serial correlation with 0.71 and 2.33%, respectively. The Akaike information criterion indicated that the FXL_vp and FXR models were preferred in 42.84 and 46.59% of the voxels, respectively. The Bayesian information criterion also indicated the FXL_vp and FXR models were preferred in 39.39 and 45.25% of the voxels, respectively. Thus, these four metrics indicate that the FXL_vp and the FXR models provide the most complete statistical description of dynamic contrast‐enhanced MRI time courses for the patients selected in this study. Magn Reson Med, 2012.

Psychosocial Determinants of Mammography Follow-up after Receipt of Abnormal Mammography Results in Medically Underserved Women

This article targets the relationship between psychosocial determinants and abnormal screening mammography follow-up in a medically underserved population. Health belief scales were modified to refer to diagnostic follow-up versus annual screening. A retrospective cohort study design was used. Statistical analyses were performed examining relationships among sociodemographic factors, psychosocial determinants, and abnormal mammography follow-up. Women with lower mean internal health locus of control scores (3.14) were two times more likely than women with higher mean internal health locus of control scores (3.98) to have inadequate follow-up (OR=2.53, 95% CI=1.12–5.36). Women with less than a high school education had lower cancer fatalism scores than women who had completed high school (47.5 vs. 55.2, p-value=.02) and lower mean external health locus of control scores (3.0 vs. 5.3) (p-value<.01). These constructs have implications for understanding mammography follow-up among minority and medically underserved women. Further comprehensive study of these concepts is warranted.