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On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed. Cancer Prev Res; 7(5); 496–504. ©2014 AACR.

PDF file - 3911KB, Supplementary Figure S1. Examples of classifications of nevomelanocytic neoplasms histopathologically evaluated for the primary endpoint of the study. Supplementary Figure S2. Examples of a target atypical nevus photographed pre and post treatment. Supplementary Figure S3. Examples of back photos pre and post treatment. Supplementary Figure S4. CONSORT Flowchart for all study subjects. Supplementary Figure S5. Bland-Altman plot of histopathologic regression of atypical nevi. Supplementary Figure S6. Assessment of clinical regression of atypia. Supplementary Figure S7. Bland-Altman plots of (A) HIF-1 percent of nuclear staining, (B) e-Cadherin percent of cytoplasmic staining, (C) N-Cadherin percent of cytoplasmic staining and (D) VEGF percent of cytoplasmic staining. Supplementary Figure S8. Bland-Altman plots of (A) RelA percent of cytoplasmic staining, (B) p21 percent of nuclear staining, and (C) ki-67 percent of nuclear staining.

Perspective on This Article from Phase IIa Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia

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Supplementary Figure S1 from Phase IIa Clinical Trial of Curcumin for the Prevention of Colorectal Neoplasia

Perspective from Difluoromethylornithine Plus Sulindac for the Prevention of Sporadic Colorectal Adenomas: A Randomized Placebo-Controlled, Double-Blind Trial

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PDF file - 64KB, Supplementary Table S1. Descriptive statistics for concordance evaluation of positive control slides. Supplementary Table S2. Evaluation of laboratory data.

Accrual table by institution.

The prospective multicenter ACRIN 6691 trial was designed to evaluate whether changes from baseline to mid-therapy in a diffuse optical spectroscopic imaging (DOSI)–derived imaging endpoint, the tissue optical index (TOI), predict pathologic complete response (pCR) in women undergoing breast cancer neoadjuvant chemotherapy (NAC). DOSI instruments were constructed at the University of California, Irvine (Irvine, CA), and delivered to six institutions where 60 subjects with newly diagnosed breast tumors (at least 2 cm in the longest dimension) were enrolled over a 2-year period. Bedside DOSI images of the tissue concentrations of deoxy-hemoglobin (ctHHb), oxy-hemoglobin (ctHbO2), water (ctH2O), lipid, and TOI (ctHHb × ctH2O/lipid) were acquired on both breasts up to four times during NAC treatment: baseline, 1-week, mid-point, and completion. Of the 34 subjects (mean age 48.4 ± 10.7 years) with complete, evaluable data from both normal and tumor-containing breast, 10 (29%) achieved pCR as determined by central pathology review. The percent change in tumor-to-normal TOI ratio (%TOITN) from baseline to mid-therapy ranged from −82% to 321%, with a median of −36%. Using pCR as the reference standard and ROC curve methodology, %TOITN AUC was 0.60 (95% CI, 0.39–0.81). In the cohort of 17 patients with baseline tumor oxygen saturation (%StO2) greater than the 77% population median, %TOITN AUC improved to 0.83 (95% CI, 0.63–1.00). We conclude that the combination of baseline functional properties and dynamic optical response shows promise for clinical outcome prediction. Cancer Res; 76(20); 5933–44. ©2016 AACR.

List of Chemotherapy regimens used in this study.

The purpose of this study was to determine the distribution of and potential significance of laminin 332 (LM332) in breast cancer. Specimens from a population-based cohort (N = 297) from 1994 to 1995 were stained for estrogen receptor (ER), progesterone receptor (PgR), HER2 and the LM332 β3 chain. Seventy-five tumors were LM332-positive and 222 were negative. LM332 β3 stained 16.0% of ER and/or PgR-positive tumors and 73.2% of triple-negative breast cancers (TNBC). Immunoblotting revealed LM332 in TNBC and HER2-positive samples, but not in an ER-positive breast carcinoma or a phyllodes tumor. After 20 years, 172 patients were alive, 43 had died of breast cancer and 82 of other causes. Patients with LM332-positive tumors had significantly worse 5 (P

BACKGROUND: Preterm birth remains the leading cause of neonatal morbidity and mortality, with complex biochemical pathways requiring continued understanding and assessment. OBJECTIVE: To assess the associations between maternal cortisol and placental corticotropin releasing hormone (placental CRH) concentrations with birth outcomes when stratified by placental histopathology. MATERIALS & METHODS: We conducted an analysis of 112 singleton pregnancies who received betamethasone between 23 and 34 weeks’ gestation. Maternal blood and saliva were collected prior to betamethasone administration and samples assayed for plasma cortisol (pCort), salivary cortisol (sCort), and placental CRH levels. Placental findings were characterized as inflammatory, maternal vascular underperfusion (MVU), or no pathology, and compared for the outcomes of placental CRH, pCort and sCort levels, gestational age at birth (GAB), and birthweight percentiles (BWP). RESULTS: Thirty-six subjects were characterized as inflammatory, 38 as MVU and 38 without placental abnormalities. Histopathology groups differed significantly on placental CRH levels, GAB, and BWP. Post hoc tests suggested that the MVU group had higher placental CRH than the inflammatory or no pathology groups and, despite delivering earlier than the other two groups, the inflammatory group had infants with significantly higher BWP. No differences existed between groups in terms of mean plasma or sCort levels. Higher placental CRH and pCort levels were associated with earlier GAB in the overall sample but, when split by group, these associations remained significant only among the MVU group. Higher placental CRH was also associated with lower BWP in the overall sample but did not remain significant when split by group. Higher sCort was associated with lower BWP only in the MVU group. CONCLUSION: There is differentiation of placental CRH, cortisol and birth outcomes when evaluated by placental histopathology. This highlights the importance of evaluating birth outcomes within the context of placental histopathology.

Because tumor cell motility is a requirement for metastasis, we hypothesized that lung tissue harbors substances that induce tumor cell migration. MCF‐7 breast carcinoma cells exposed to small airway epithelial cells and conditioned medium exhibited dose‐dependent tumor cell migration. Among the extracellular matrix proteins in the conditioned medium identified by mass spectrometry, laminin 332 (LM332) had the greatest contribution to the migration of MCF‐7 cells. Immunoblotting and immunohistochemistry for LM332‐specific chains identified LM332 in the lung and in pulmonary epithelial cells. Antibodies to either LM332 or its integrin receptor inhibited MCF‐7 motility, and knockdown of LM332 chains also reduced its migration‐inducing activity. Taken together, these findings implicate LM332 as a component of lung tissue that can induce motility in breast carcinoma cells that have been transported to lung during metastasis. Earlier studies on LM332 in tumor progression have examined LM332 expression in tumor cells. This investigation, in comparison, provides evidence that the tumor promoting potential of LM332 may originate in the lung microenvironment rather than in tumor cells alone. Furthermore, this study provides evidence that the motility‐inducing properties of the microenvironment can reside in epithelial cells. The findings raise the possibility that LM332 plays a role in the pulmonary metastases of breast carcinoma and may provide a target for antimetastasis therapy.

Spindle cell carcinoma (SpC), also known as metaplastic carcinoma—spindle cell type, is a subtype of metaplastic carcinoma. Metaplastic carcinomas of the breast are rare but are thought to be more aggressive than invasive ductal carcinomas. Due to their rarity, there are few randomized trials that can inform any standardized approaches to treatment. Treatment is instead extrapolated from other types of breast cancer or metaplastic carcinomas of different locations. Here we present the first known case report of a patient with spindle cell carcinoma of the breast successfully treated with a standard sarcoma neoadjuvant regimen of doxorubicin, ifosfamide, and mesna (AIM) that resulted in >99% necrosis of the tumor and negative margins at the time of resection.

Background Molecular characterisation of non-squamous non-small-cell lung cancer (NSCLC) is required to direct optimal treatment. Treatment of NSCLC with inhibitors of epidermal growth factor receptor (EGFR) tyrosine kinase (EGFR-TKI) should be guided by the presence of activating mutations of the EGFR gene. Aim To gain insight into the rate of testing, the range of tissues samples, test utility and outcome when cost of testing as a barrier to access is removed in the Australian setting. Methods In October 2010, a sponsored programme was commenced to gather data on EGFR gene mutation testing in Australia. Partnering laboratories were funded for provision of de-identified results. For participating patients, the programme supported the test charge. Mutation testing was performed using Sanger sequencing of exons 18–21 of the EGFR. Results Samples 2013 were submitted from 2012 patients. Full sequencing was achieved in 1717 (85%). Failure of full sequencing was more likely in samples derived from fine needle aspiration(FNA) biopsy than tissue biopsy or pleural/pericardial fluid cell blocks OR 3.1 (95% CI 1.9–5.2). There were 359 mutations seen in 337 patients. 14.5% of cases had a classical mutation conferring sensitivity to EGFR-TKI. In addition there was a range of less common mutations – some predicting responses and others of uncertain significance. 1.4% of cases had mutations associated with non-responsiveness to EGFR-TKI. Conclusions EGFR gene mutation testing is feasible on local and interstate lung cancer samples. The rate of valid test outcomes is high, but FNA samples are associated with more frequent test failure.

On the basis of large cardiovascular clinical trials of lipid-lowering agents that showed a considerable decrease in the incidence of primary melanomas in the active agent arm, we have carried out a randomized, double-blind clinical trial examining the impact of lovastatin on various biomarkers of melanoma pathogenesis. Subjects with at least two clinically atypical nevi were randomized to receive oral lovastatin or placebo for a 6-month period. Clinical, histopathologic, and molecular biomarkers were evaluated for change in the two groups. Eighty subjects were randomized, evaluable, and included in the analyses. Lovastatin showed no benefit in comparison with placebo in the primary endpoint of decreasing the level of histopathologic atypia, nor in any of the secondary endpoints of decreasing clinical atypia, impact on nevus number, nor in showing significant changes in any of the molecular biomarkers. There were no significant differences in adverse event profiles for lovastatin compared with placebo. The lovastatin arm did show a significant and considerable decrease in total serum cholesterol and serum low-density lipoprotein (LDL) levels compared with placebo, an expected result. This finding bolsters confidence in subject compliance. Given the results of this trial, it is concluded that if lovastatin were to lower the incidence of melanoma, it would appear not to be doing so by reversing atypia of precursor atypical nevi over the 6-month time frame studied. Further research into the pathogenesis of melanoma and in other potential chemopreventive agents is needed. Cancer Prev Res; 7(5); 496–504. ©2014 AACR.

Human epidermal growth factor receptor 2 (HER2) status is useful for predicting response to trastuzumab. Fluorescence in situ hybridization (FISH) for HER2 gene amplification is accurate but limited because of cost, the need for fluorescence microscopy, the limited assessment of histology, and the fading of its signal over time. Dual-color in situ hybridization (Dual ISH) is fully automated, is viewable by bright-field microscopy, has a stable signal, and has separate colors for HER2 and chromosome 17 signals. HER2 immunohistochemistry (IHC), FISH, and Dual ISH were performed on 101 breast cancer cases. Sixteen of 17 cases with 3+ HER2 by IHC showed gene amplification by FISH, and 15 showed amplification by Dual ISH. Three of the 2+ IHC cases were either amplified or equivocal by Dual ISH. None of the IHC-negative cases were amplified by either FISH or Dual ISH. Dual ISH agreed with FISH in 93% of cases. Among the 6 discrepancies, 4 were for an equivocal result for 1 test compared with either a positive or a negative result for the other test. The average differences in readings between Dual ISH and FISH in the discrepant cases were only 0.02, with a range of -1.37 to 1.85. Turnaround time for FISH as a send-out test from test ordering to reporting averaged 8.27 workdays, whereas the turnaround time for Dual ISH performed in-house averaged 4.94 workdays (P < .0000001). Our results indicated that automated Dual ISH is a useful method for evaluating HER2 status in a clinical setting.

Author(s): Chen, Jeon-Hor; Bahri, Shadfar; Mehta, Rita S; Carpenter, Philip M; McLaren, Christine E; Chen, Wen-Pin; Fwu, Peter T; Hsiang, David JB; Lane, Karen T; Butler, John A; Su, Min-Ying | Abstract: Background and objectivesTo investigate accuracy of magnetic resonance imaging (MRI) for measuring residual tumor size in breast cancer patients receiving neoadjuvant chemotherapy (NAC).MethodsNinety-eight patients were studied. Several MRI were performed during NAC for response monitoring, and the residual tumor size was measured on last MRI after completing NAC. Covariates, including age, tumor characteristics, biomarkers, NAC regimens, MRI scanners, and time from last MRI to operation, were analyzed. Univariate and Multivariate linear regression models were used to determine the predictive value of these covariates for MRI-pathology size discrepancy as the outcome measure.ResultsThe mean (±SD) of the absolute difference between MRI and pathological residual tumor size was 1.0 ± 2.0 cm (range, 0-14 cm). Univariate regression analysis showed tumor type, morphology, HR status, HER2 status, and MRI scanner (1.5 T or 3.0 T) were significantly associated with MRI-pathology size discrepancy (all P l 0.05). Multivariate regression analyses demonstrated that only tumor type, tumor morphology, and biomarker status considering both HR and HER-2 were independent predictors (P = 0.0014, 0.0032, and 0.0286, respectively).ConclusionThe accuracy of MRI in evaluating residual tumor size depends on tumor type, morphology, and biomarker status. The information may be considered in surgical planning for NAC patients.

Focal segmental glomerulosclerosis (FSGS) causes glomerular lesions that can progress to end-stage renal disease. It is suspected to be caused by a circulating factor that is amenable to plasmapheresis removal and exhibits a risk for recurrence in the renal allograft. We present two patients with FSGS recurrence in their allograft kidneys diagnosed by biopsy after significant proteinuria developed in the posttransplant setting. Treatment with therapeutic plasma exchange induced long-term remission in both patients. Spot urine protein:creatinine ratios were monitored and treatment was continued until a target of

This study aimed to evaluate the influence of hormone receptor (HR) and Ki-67 proliferation markers in predicting the accuracy of magnetic resonance imaging (MRI) for measuring residual tumor size in patients with HER2-negative (HER2(-)) breast cancer receiving neoadjuvant chemotherapy (NAC).Fifty-four women were studied. Patients received AC (doxorubicin (Adriamycin)/cyclophosphamide) and/or taxane-based regimens. The accuracy of MR-determined clinical complete response (CCR) was compared to pathological complete response (pCR). The size of detectable residual tumor on MRI was correlated with pathologically diagnosed tumor size using the Pearson correlation.MRI correctly diagnosed 16 of the 17 cases of pCR. There were 8 false-negative diagnoses: 7 HR(+) and 1 HR(-). The overall sensitivity, specificity, and accuracy of MRI were 78%, 94%, and 83%, respectively. The positive predictive value was 97% and the negative predictive value was 67%. For MRI vs. pathologically determined tumor size correlation, HR(-) cancers showed a higher correlation (R = 0.79) than did HR(+) cancers (R = 0.58). A worse MRI/pathology size discrepancy was found in HR(+) cancer than in HR(-)cancer (1.6 ± 2.8 cm vs. 0.56 ± 0.9 cm; P = .05). Tumors with low Ki-67 proliferation (40%) showed a larger size discrepancy than did those with high Ki-67 proliferation (≥ 40%) (1.2 ± 2.0 cm vs. 0.4 ± 0.8 cm; P = .05).The results showed that the diagnostic performance of MRI for patients with breast cancer undergoing NAC is associated with a molecular biomarker profile. Among HER2(-)tumors, the accuracy of MRI was worse in HR(+)cancers than in HR(-)cancers and was also worse in low-proliferation tumors than in high-proliferation tumors. These findings may help in surgical planning.

Laminin 332 (LN332) is a basally expressed extracellular matrix protein that enhances the migration and invasion of breast carcinoma cells. The goal of this study was to examine LN332 expression breast carcinoma. Triple negative breast carcinomas lack estrogen receptor (ER), progesterone receptor (PR) expression and HER2 positivity. Immunohistochemistry for ER, PR, HER2, and dual silver in situ hybridization for the HER2 gene were used to define the phenotype of 243 breast cancers in biopsies or arrays. Immunohistochemistry for LN332 revealed that 70% of triple negative carcinomas stained for LN332. Cytokeratins 5/6 (CK5/6), epidermal growth factor receptor and p63 alone stained fewer triple negative breast carcinomas each, but the combination of LN332 and CK5/6 or epidermal growth factor receptor identified 92% of triple negative breast carcinoma. Of the 163 non-triple negative cases, LN332 was expressed in only 15%. The identification of LN332 in triple negative breast carcinomas is consistent with gene profiling studies showing its expression among breast carcinomas with a basal phenotype. The observation that a proinvasive protein such as LN332 is expressed in breast cancer suggests another mechanism by which the triple negative phenotype could be aggressive.

Background Imaging technologies monitoring and predicting breast cancer response to neoadjuvant chemotherapy (NAC) are of increasing interest. The utility of conventional imaging approaches varies and identifies the need for alternate functional imaging strategies. The use of model-based photon migration methods to quantitatively separate light absorption from scattering in multiply-scattering tissues is a type of near-infrared spectroscopy (NIRS) broadly referred to as diffuse optical spectroscopy (DOS) [Bevilacqua, et al. Applied Optics, 2000; Jakubowski, et al., J of Applied Optics, 2009]. DOSI is a promising experimental technology that allows patients undergoing NAC to be followed with a “no significant risk” device meeting Food and Drug Administration criteria for exempt status. The current design is a mobile device which offers increased accessibility and is relatively simple to perform and interpret, as compared to mammography, magnetic resonance imaging, and positron emission tomography. Due to its size and portability, DOSI is a low barrier-to-access technology, creating new opportunities for patients to receive personalized treatment and for physicians to gain new insight into response mechanisms. The long-term goal is to provide oncologists with a relatively simple, risk-free bedside tool that can be used to help inform medical decisions on chemotherapy regimen, duration, and timing of surgery, thereby maximizing therapeutic response and minimizing unnecessary toxicity. Trial design: In this phase I/II prospective single arm study, patients will receive SOC NAC at five (5) NCI Network for Translational Research in Optical Imaging (NTROI) clinical sites with identical DOSI instruments and procedures. Patients will receive four DOSI exams: at baseline before chemotherapy, at early therapy 5–10 days after NAC initiation, at mid therapy, and at post therapy prior to surgery. The protocol will evaluate a harmonized DOSI technology platform that has been standardized for NAC monitoring. Eligibility: Women who have been diagnosed with breast cancer, have had confirmation by pre-treatment biopsy, and are scheduled to receive NAC followed by surgery are eligible for this trial. Specific aims: The primary aim of this clinical trial is to determine whether the baseline to mid-therapy changes in the DOSI measurement of the quantitative tumor tissue optical index can predict final pathologic complete response in patients with breast cancer undergoing NAC. The secondary aims investigate the correlation between additional DOSI quantitative measurements of tumor biochemical composition obtained at other timepoints, the full range of pathologic response (i.e. complete, partial, and non-response), and any corresponding imaging measurements. Statistical methods: Logistic regression models will be used to study the relationships between pathological complete response and percent change in tissue optical index tumor to normal ratio at different imaging time points. Study size: A total of sixty (60) patients will be enrolled in this imaging study. Currently, one patient has accrued. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr OT2-05-02.

To assess how the molecular biomarker status of a breast cancer, including human epidermal growth factor receptor 2 (HER2), hormone receptors, and the proliferation marker Ki-67 status, affects the diagnosis at 3.0-T magnetic resonance (MR) imaging.This study was approved by the institutional review board and was HIPAA compliant. Fifty patients (age range, 28-82 years; mean age, 49 years) receiving neoadjuvant chemotherapy were monitored with 3.0-T MR imaging. The longest dimension of the residual cancer was measured at MR imaging and correlated with pathologic findings. Patients were further divided into subgroups on the basis of HER2, hormone receptor, and Ki-67 status. Pathologic complete response (pCR) was defined as when there were no residual invasive cancer cells. The Pearson correlation was used to correlate MR imaging-determined and pathologic tumor size, and the unpaired t test was used to compare MR imaging-pathologic size discrepancies.Of the 50 women, 14 achieved pCR. There were seven false-negative diagnoses at MR imaging. The overall sensitivity, specificity, and accuracy for diagnosing invasive residual disease at MR imaging were 81%, 93%, and 84%, respectively. The mean MR imaging-pathologic size discrepancy was 0.5 cm ± 0.9 (standard deviation) for HER2-positive cancer and 2.3 cm ± 3.5 for HER2-negative cancer (P = .009). In the HER2-negative group, the size discrepancy was smaller for hormone receptor-negative than for hormone receptor-positive cancers (1.0 cm ± 1.1 vs 3.0 cm ± 4.0, P = .04). The size discrepancy was smaller in patients with 40% or greater Ki-67 expression (0.8 cm ± 1.1) than in patients with 10% or less Ki-67 expression (3.9 cm ± 5.1, P = .06).The diagnostic accuracy of breast MR imaging is better in more aggressive than in less aggressive cancers. When MR imaging is used for surgical planning, caution should be taken with HER2-negative hormone receptor-positive cancers.

Ideally, neoadjuvant chemotherapy (NAC) assessment should predict pathologic complete response (pCR), a surrogate clinical endpoint for 5-year survival, as early as possible during typical 3- to 6-month breast cancer treatments. We introduce and demonstrate an approach for predicting pCR within 10 days of initiating NAC. The method uses a bedside diffuse optical spectroscopic imaging (DOSI) technology and logistic regression modeling. Tumor and normal tissue physiological properties were measured longitudinally throughout the course of NAC in 33 patients enrolled in the American College of Radiology Imaging Network multicenter breast cancer DOSI trial (ACRIN-6691). An image analysis scheme, employing [Formula: see text]-score normalization to healthy tissue, produced models with robust predictions. Notably, logistic regression based on [Formula: see text]-score normalization using only tissue oxygen saturation ([Formula: see text]) measured within 10 days of the initial therapy dose was found to be a significant predictor of pCR ([Formula: see text]; 95% CI: 0.82 to 1). This observation suggests that patients who show rapid convergence of tumor tissue [Formula: see text] to surrounding tissue [Formula: see text] are more likely to achieve pCR. This early predictor of pCR occurs prior to reductions in tumor size and could enable dynamic feedback for optimization of chemotherapy strategies in breast cancer.

Neuroendocrine (NE) phenotype, seen in >30% of prostate adenocarcinomas (PCa), and NE prostate tumors are implicated in aggressive prostate cancer. Formation of NE prostate tumors in the TRAMP mouse model was suppressed in mice lacking the ubiquitin ligase Siah2, which regulates HIF-1alpha availability. Cooperation between HIF-1alpha and FoxA2, a transcription factor expressed in NE tissue, promotes recruitment of p300 to transactivate select HIF-regulated genes, Hes6, Sox9, and Jmjd1a. These HIF-regulated genes are highly expressed in metastatic PCa and required for hypoxia-mediated NE phenotype, metastasis in PCa, and the formation of NE tumors. Tissue-specific expression of FoxA2 combined with Siah2-dependent HIF-1alpha availability enables a transcriptional program required for NE prostate tumor development and NE phenotype in PCa.

Angiogenesis, the formation of blood vessels, is necessary for a tumor to grow, but when angiogenesis first appears in the progression of breast ductal carcinomas is unknown. To determine when this occurs, the authors examined microvessel density (MVD) by CD31 and CD105 immunostaining in normal ducts, 32 cases of usual hyperplasia, 19 cases of atypical hyperplasia, and 29 cases of ductal carcinoma in situ (DCIS). Simple hyperplasia had a 22-fold greater MVD than normal ducts ( P < .0001). An increase during the progression of ductal changes was highly significant ( P < .0001). To determine a possible mechanism, immunohistochemistry for vascular endothelial growth factor (VEGF) was evaluated. VEGF staining intensity of ductal epithelium increased during the progression from normal to hyperplastic to DCIS. This study shows that the first significant increase in angiogenesis occurs very early in the evolution of ductal proliferations as ductal cells become hyperplastic.

We demonstrate successful treatment of recurrent chondroid-metaplastic breast cancer. Breast cancer recurrence was diagnosed when a patient with a history of metaplastic breast cancer presented with recurrent acute strokes. A diagnosis of tumor embolism was suspected when a chest radiograph performed as part of a work-up for stroke demonstrated several lung nodules, with 1 lung nodule invading the pulmonary vein and extending into the left atrium-the source of tumor emboli. This was followed by timely surgery to remove the embolizing metastatic lesion and local radiation to prevent growth and recurrent embolization. Subsequently, the patient received carboplatin and albumin-bound paclitaxel and experienced complete remission.

INTRODUCTION After exposure of the retropubic space, the surgeon commonly dissects the fat overlying the prostate and usually discards it. We have previously described the importance of dissecting this fat to completely visualize the dorsal venous complex (DVC) and prostatic apex. In this study, we describe a technique to dissect and remove the anterior prostatic fat pad (APF) and its anatomic and pathologic significance. TECHNICAL CONSIDERATIONS After the retropubic space was prepared, we dissected the fat overlying the puboprostatic ligaments and the DVC to fully expose these structures. The superficial branch of the DVC was then transected, and the fat was dissected cephalad to the junction with the bladder. The fat was then further dissected laterally toward the lateral pelvic sidewall. Video analysis of the lateral dissection of the fat revealed a direct link to the obturator lymph node chain, where it was transected. Pathologic analysis demonstrated that 30 (14.7%) of 204 patients had one or more APF lymph nodes, of which four were positive for metastatic prostate cancer. The cancer of 3 of these 4 patients was upstaged as a result of the detection of these positive nodes. CONCLUSIONS The dissection of the APF facilitates visualization of the apex and bladder neck. Anatomically, we have demonstrated that the APF contains lymph nodes approximately 15% of the time that are in communication with the obturator lymph node chain and DVC. We found that removal of the APF and its pathologic analysis can result in pathologic upstaging.

Hormone receptor status is an integral component of decision-making in breast cancer management. IHC4 score is an algorithm that combines hormone receptor, HER2, and Ki-67 status to provide a semiquantitative prognostic score for breast cancer. High accuracy and low interobserver variance are important to ensure the score is accurately calculated; however, few previous efforts have been made to measure or decrease interobserver variance. We developed a Web-based training tool, called "Score the Core" (STC) using tissue microarrays to train pathologists to visually score estrogen receptor (using the 300-point H score), progesterone receptor (percent positive), and Ki-67 (percent positive). STC used a reference score calculated from a reproducible manual counting method. Pathologists in the Athena Breast Health Network and pathology residents at associated institutions completed the exercise. By using STC, pathologists improved their estrogen receptor H score and progesterone receptor and Ki-67 proportion assessment and demonstrated a good correlation between pathologist and reference scores. In addition, we collected information about pathologist performance that allowed us to compare individual pathologists and measures of agreement. Pathologists' assessment of the proportion of positive cells was closer to the reference than their assessment of the relative intensity of positive cells. Careful training and assessment should be used to ensure the accuracy of breast biomarkers. This is particularly important as breast cancer diagnostics become increasingly quantitative and reproducible. Our training tool is a novel approach for pathologist training that can serve as an important component of ongoing quality assessment and can improve the accuracy of breast cancer prognostic biomarkers.

Computer-assisted image analysis is useful for quantifying the histologic and molecular changes of sun-induced squamous cell carcinoma progression. We used the CAS 200 image analysis system to measure nuclear morphometric parameters, p53 expression, and proliferation markers in actinic keratosis (AK), sun-exposed, and normal skin in 51 patients. Nuclear morphometry revealed significant increases in nuclear absorbance, irregularity of nuclear shape, and nuclear size in AK compared with normal and sun-damaged skin. These parameters showed significantly greater variability in AK nuclei. Argyrophyllic nucleolar organizer area and number were also significantly greater in AK compared with sun-damaged skin and normal skin. Ki67 and p53 expressions were both increased in sun-damaged skin relative to normal and greater still in AK. These data are evidence that sun damage induces proliferation and p53 abnormalities before the appearance of nuclear abnormalities and their associated DNA instability. Following these changes during a skin cancer chemopreventative trial can then help assess the efficacy of the agent and help determine where in the progression of neoplastic changes it exerts its biological effects.

AIM To investigate whether normal thickness cartilage in osteoarthritic knees demonstrate depletion of proteoglycan or collagen content compared to healthy knees. METHODS Magnetic resonance (MR) images were acquired from 5 subjects scheduled for total knee arthroplasty (TKA) (mean age 70 years) and 20 young healthy control subjects without knee pain (mean age 28.9 years). MR images of T1ρ mapping, T2 mapping, and fat suppressed proton-density weighted sequences were obtained. Following TKA each condyle was divided into 4 parts (distal medial, posterior medial, distal lateral, posterior lateral) for cartilage analysis. Twenty specimens (bone and cartilage blocks) were examined. For each joint, the degree and extent of cartilage destruction was determined using the Osteoarthritis Research Society International cartilage histopathology assessment system. In magnetic resonance imaging (MRI) analysis, 2 readers performed cartilage segmentation for T1ρ/T2 values and cartilage thickness measurement. RESULTS Eleven areas in MRI including normal or near normal cartilage thickness were selected. The corresponding histopathological sections demonstrated mild to moderate osteoarthritis (OA). There was no significant difference in cartilage thickness in MRI between control and advanced OA samples [medial distal condyle, P = 0.461; medial posterior condyle (MPC), P = 0.352; lateral distal condyle, P = 0.654; lateral posterior condyle, P = 0.550], suggesting arthritic specimens were morphologically similar to normal or early staged degenerative cartilage. Cartilage T2 and T1ρ values from the MPC were significantly higher among the patients with advanced OA (P = 0.043). For remaining condylar samples there was no statistical difference in T2 and T1ρ values between cases and controls but there was a trend towards higher values in advanced OA patients. CONCLUSION Though cartilage is morphologically normal or near normal, degenerative changes exist in advanced OA patients. These changes can be detected with T2 and T1ρ MRI techniques.

C1qRp is a type I cell surface glycoprotein that has been shown to enhance ingestion of suboptimally opsonized targets by phagocytes in vitro. In this study, we developed and characterized polyclonal antibodies to study the tissue distribution of this receptor targeted to either the N- or C-terminal portion of the molecule. C1qRp was detected in vascular endothelial cells and in a subset of pyramidal neurons in the brain, as well as neutrophils, but it was absent in most tissue macrophages. Analysis of in vitro differentiation of blood monocytes to dendritic cells demonstrated a down-regulation of the receptor as monocytes differentiate to dendritic cells, providing a possible explanation for the lack of reactivity of these cells in tissue. The predominant presence of C1qRp in endothelial cells, while compatible with a phagocytic role in host defense and/or clearance of cellular material, suggests other possible novel roles for this receptor.

A carcinogen (N-ethyl-N-nitrosourea)-induced animal tumor model was established to grow malignant and benign breast tumors. In each tumor the pharmacokinetic characteristics were measured by using three contrast agents, gadolinium-diethylene-triamine-pentaacetic acid (Gd-DTPA

A 29-year-old woman presented with an unusual lesion on the right auricular antihelix. The mass was purple and painful, and it had been present for 17 years. Preoperatively, the presumptive diagnosis was a venous malformation. The mass was resected, and a staged reconstruction was performed. Microscopic analysis of the specimen revealed that the lesion was an angioleiomyoma. Most cases of angioleiomyoma involve the extremities; few have been described in the head and neck region, and very few of those have been reported on the ear. Among those auricular angioleiomyomas that have been reported, most were distinctly painless. We report a new, atypical case of this unusual tumor.

The effects of iron overload on pancreatic iron content and morphology were investigated. Sprague-Dawley rats were randomized into an iron-overloaded group, which received a single subcutaneous injection of 1.2 g/kg elemental iron as iron-dextran complex, and placebo-treated pair-fed controls. Animals were studied after a 10-month observation period. Tissue nonheme iron content was measured, and histologic examination was carried out. Chronic iron-overloaded animals showed significant increases in tissue iron content. There was a statistically significant increase in stainable iron in perivascular, parenchymal, and lymphoid tissue in the iron-overloaded group. Although pancreatic fibrosis was present in the iron-overload group, it was not statistically significant. The iron-overloaded animals showed some islet cell destruction. In contrast, no significant islet cell destruction was seen in the control group. However, the difference was not statistically significant. Moreover, the serum glucose levels were the same in both groups, suggesting that there was no significant impairment of pancreatic endocrine function. Thus, chronic experimental iron overload in rats leads to significant increases in tissue iron content, but no significant morphologic alterations of the pancreas with the dose and route of iron administered in this animal model.

A potentially important tumor-host interaction is increased tumor-cell invasiveness in response to motility factors derived from stromal and lymphoid cells. Conditioned medium of IL-2-stimulated lymphocytes and fractions enriched in either T cells, natural killer (NK) cells, or monocytes induced motility in MCF-7 breast carcinoma cells. ELISA and antibody neutralization studies demonstrated that this effect was due to tumor necrosis factor-alpha (TNF-alpha) secretion by the lymphoid cells or the enriched fractions. Unstimulated leukocytes in direct contact with MCF-7 cells also induced motility that was inhibited by anti-TNF-alpha antiserum. Time-lapse video microscopy of cells exposed to 10 ng/ml TNF-alpha showed that motility was independent of its toxic effects. Immunoperoxidase showed that MCF-7 cells expressed both the 55-kDa and the 75-kDa TNF-alpha receptors (TNFR). Antiserum against the 55-kDa TNFR, like TNF-alpha, induced motility in MCF-7 cells. This was most likely due to cross-linking of the 55-kDa TNFR monomers, since the monomeric F(ab) did not produce this effect. Our results raise the possibility that TNF-alpha-induced motility is one mechanism by which tumor cells overcome the potential anti-tumor immune function of lymphocytes and macrophages in peri-tumoral infiltrates.

To investigate accuracy of magnetic resonance imaging (MRI) for measuring residual tumor size in breast cancer patients receiving neoadjuvant chemotherapy (NAC).Ninety-eight patients were studied. Several MRI were performed during NAC for response monitoring, and the residual tumor size was measured on last MRI after completing NAC. Covariates, including age, tumor characteristics, biomarkers, NAC regimens, MRI scanners, and time from last MRI to operation, were analyzed. Univariate and Multivariate linear regression models were used to determine the predictive value of these covariates for MRI-pathology size discrepancy as the outcome measure.The mean (±SD) of the absolute difference between MRI and pathological residual tumor size was 1.0 ± 2.0 cm (range, 0-14 cm). Univariate regression analysis showed tumor type, morphology, HR status, HER2 status, and MRI scanner (1.5 T or 3.0 T) were significantly associated with MRI-pathology size discrepancy (all P 0.05). Multivariate regression analyses demonstrated that only tumor type, tumor morphology, and biomarker status considering both HR and HER-2 were independent predictors (P = 0.0014, 0.0032, and 0.0286, respectively).The accuracy of MRI in evaluating residual tumor size depends on tumor type, morphology, and biomarker status. The information may be considered in surgical planning for NAC patients.

We introduce a new epithelial ovarian carcinoma cell line (UCI 107) from a patient with papillary adenocarcinoma of the ovary who had not been previously treated. The growth characteristics, chemosensitivity, tumorgenicity, cytogenetics, antigen expression, and receptor status were examined. A standardized photometric assay was implemented to determine the response to single drug agents including doxorubicin (ADR), cisplatin (CDDP), and Taxol. Tumorgenicity was determined utilizing female athymic mice implanted either subcutaneously (sc) or intraperitoneally (ip) with 1 x 10(7) UCI 107 cells. UCI 107 cells grow rapidly in culture with lag phase of approximately 48 hr, population doubling time of 24-36 hr, and saturation density of 4.8 x 10(5) cells/cm2. The 50% inhibitory concentration values for the chemotherapeutic agents were 0.170, 0.029, and 0.330 microM for ADR, Taxol, and CDDP, respectively. Nude mice produced ip tumors within 15 days, resulting in death from carcinomatosis 40-45 days postimplantation. Subcutaneous tumor nodules (100 mm3) were observed in nude mice 12-13 days post-tumor implantation reaching a maximum tumor volume of approximately 10,000 mm3 by Day 30. The cytogenetic composite karyotype is as follows: 46, X, der (X) t (X;7) (p11;q22), inv dup (1) (q12;q32), t (6;6;11;22) (p21.3;q16;q23.3;q13.3), del (13) (q14.1). The cell line expresses progesterone receptor, increased levels of p53 protein, and cytokeratins. It does not appear to express Her-2/neu protein, estrogen receptor, nor the CA 125 tumor marker. In conclusion, UCI 107 displays unique cellular properties which make it an attractive model for the study of ovarian cancer.

A 65 year old, blood group O, African-American male with 0% CPRA received a blood group O deceased donor kidney transplant with a negative crossmatch (XM). During surgery, the transplanted kidney became dusky within minutes of restoring blood flow. There was no suspicion of anti-HLA or anti-ABO antibodies which could mediate hyperacute rejection, so a thrombotic event or anatomical defect was suspected. The OPO consented to allocate the second kidney from the same donor; it was transplanted within hours, and the same events transpired. Three days later, the recipient had bleeding and pain at the graft site, and donor vein and artery grafts had to be removed. We sought to identify the factors which caused the allografts loss. Both kidneys were sent for microscopic and C4d evaluation. Recipient HLA antibodies were tested by FlowPRA and Luminex Single Antigen Beads (LSAB). XM were performed by CDC and flow cytometry. Recipient serum was tested for MICA antibodies by LSAB, endothelial cell (EC) antibodies by XM, AT1R antibodies by ELISA, and non-ABO blood group antibodies. Molecular blood typing of the donor DNA was performed. Histopathology identified karyorrhectic nuclear debris in the glomeruli, small fibrin thrombi, and neutrophilic infiltrates, consistent with hyperacute rejection, although IHC failed to show definite C4d deposition. All FlowPRA, XM, LSAB, MICA, and EC XM tests were negative. The AT1R result was 14 U/mL (at risk). Molecular testing confirmed the donor as Group O. Testing ruled out the rare Bombay phenotype, and the recipient was negative for all non-ABO blood group antibodies, except for weak cold agglutinins only seen at 4 °C. The events during the surgery and the pathology findings are consistent with humoral hyperacute rejection. Confoundingly, the recipient has no HLA antibodies and had negative CDC and flow XM with the donor. However, none of the other testing has been able to identify an antibody with a strength that would explain hyperacute rejection. The only identified antibodies thus far are anti-AT1R and cold agglutinins. We are continuing to investigate more non-HLA antibodies that may have a synergistic impact on graft rejection.

Metastasis to the lung often leads to the demise of the patient, thus a greater understanding of the process might lead to strategies for better cancer control. Tumor cell metastatic ability is determined by both intrinsic properties of tumor cells and contributions from the microenvironment. The goal of this study was to determine the role of the extracellular matrix protein laminin 332 (LN332) in breast cancer progression. Because tumor cell motility is a requirement for metastasis, we hypothesize that lung tissue harbors substances that induce tumor cell migration. In order to better characterize the interaction of breast carcinoma cells and lung tissue, MCF-7 breast carcinoma cells were added to slides of frozen sections of lung tissue. MCF-7 cells in contact with the lung tissue exhibited properties associated with tumor cell migration, including pseudopodia and lamellipodia. In contrast, MCF-7 cells on glass without lung tissue had smooth borders. Similarly, MCF-7 cells showed migratory properties when co-cultured with small airway epithelial cells (SAEC). LN332 is a component of the basement membrane of lung epithelium, and is thought to induce the migration of several tumor cell types. Immunoblotting revealed all three chains of LN332 in SAEC conditioned medium. To confirm that LN332 was among the components of the lung cells that induced the migration of the breast carcinoma cells, siRNA knockdown of the α3, β3 and γ2 chains of LN332 was performed on SAEC. The conditioned media from knock down and control SAEC was collected for motility assays. Knockdown of the α3 chain alone was sufficient to decrease the expression of the other two chains, but the greatest knockdown of LN332 protein was achieved with simultaneous use of siRNA against the α3, β3 and γ2 chains combined. Conditioned medium from cells with knockdown of LN332 induced tumor cell migration to a lesser extent than conditioned medium from control cells. Taken together, these in vitro data provide evidence that LN332 in the microenvironment has the potential to promote the invasion of metastatic foci into the pulmonary parenchyma. Next, we sought to determine whether LN332 expressed in breast carcinoma cells was associated with any particular phenotype of the tumors, or were associated with tumor prognosis. Tissue microarrays of breast carcinomas excised in 1994 and 1995 from 312 patients were stained for estrogen receptor, progesterone receptor, HER2 and the LN332 β3 chain by immunohistochemistry. LN332 expression was greatest in triple negative and HER2 expressing breast carcinomas. Follow-up for over 20 years on this cohort revealed that patients with tumors expressing LN332 β3 chain had a worse prognosis than patients without LN332 β3 chain in their tumors. Taken together, these studies provide evidence that LN332 in either tumor cells or the microenvironment may be implicated in breast cancer progression. Citation Format: Philip M. Carpenter, Priyanka Sivadas, Argyrios Ziogas, Hoda Anton-Culver. Pulmonary laminin 332 in tumor cell migration and breast cancer survival. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C05.

Two cases of recurrent noninvasive Paget's disease of the vulva in a split-thickness graft without an underlying adenocarcinoma are presented. This is the third report of recurrence of extramammary Paget's disease in a split-thickness graft, and the second of such an occurrence without an underlying dermal adnexa adenocarcinoma. A hypothesis for the possible pathogenetic mechanism of this unusual biological behavior is suggested.

Chromosome studies in a 7-week-old female infant with an intraabdominal malignant fibrosarcoma showed a hyperdiploid karyotype of 50,XX,+der(6)del(6)(p23)add(6)(q11),+8,+10,+11,add(12)(p13). Trisomy 11 appears to be a nonrandom primary cytogenetic abnormality in the congenital or infantile form of this mesenchymal tumor and is also a nonrandom gain in congenital mesoblastic nephroma. A possible developmental link between these two mesenchymal tumors, mediated by a gene or genes on chromosome 11 is postulated.