A Rare Case of Olmesartan-Associated Enteropathy Successfully Managed With Steroid Taper.

Olmesartan is a commonly used antihypertensive medication belonging to the class of angiotensin II receptor blockers. Though generally well-tolerated, olmesartan can rarely cause olmesartan-associated enteropathy (OAE) with non-bloody diarrhea, weight loss, abdominal pain, and vomiting. Patients may develop enteropathy months to years after drug initiation. In severe cases, patients may develop complications that require hospitalization. Diagnosis is often delayed due to unfamiliarity of OAE, nonspecific presenting symptoms, and normal-appearing gross endoscopic findings. Esophagogastroduodenoscopy (EGD) with biopsy is essential to the diagnosis, showing sprue-like enteropathy with intestinal villous atrophy and mucosal inflammation. This report describes a case of a 70-year-old man who presented with three months of profuse watery diarrhea and 40-pound unintentional weight loss. After an extensive workup, including EGD with duodenal biopsies, the patient was diagnosed with OAE. The biopsies showed findings consistent with acute and chronic duodenitis, mucosal desquamation and ulceration, blunting of villi, and a sprue-like pattern with neutrophils. Celiac serologies and anti-enterocyte antibodies were negative, further supporting the diagnosis of OAE. Complete resolution of symptoms was achieved by discontinuing olmesartan and administering a steroid taper. Considering the frequent use of olmesartan, the increasing occurrence of OAE, and the wide range of associated symptoms, it is crucial for providers to recognize OAE and consider early discontinuation of olmesartan. This approach can help prevent further intestinal damage, protracted symptoms, unnecessary diagnostic tests, and financial burdens on both patients and the healthcare system.

Tocilizumab as a Therapeutic Agent for Critically Ill Patients Infected with SARS-CoV-2.

Tocilizumab is an IL-6 receptor antagonist with the ability to suppress the cytokine storm in critically ill patients infected with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2). We evaluated patients treated with tocilizumab for a SARS-CoV-2 infection who were admitted between March 13, 2020, and April 16, 2020. This was a multicenter study with data collected by chart review both retrospectively and concurrently. Parameters evaluated included age, sex, race, use of mechanical ventilation (MV), usage of steroids and vasopressors, inflammatory markers, and comorbidities. Early dosing was defined as a tocilizumab dose administered prior to or within 1 day of intubation. Late dosing was defined as a dose administered > 1 day after intubation. In the absence of MV, the timing of the dose was related to the patient's date of admission only. We evaluated 145 patients. The average age was 58.1 years, 64% were men, 68.3% had comorbidities, and 60% received steroid therapy. Disposition of patients was 48.3% discharged and 29.3% died, of which 43.9% were African American. MV was required in 55.9%, of which 34.5% died. Avoidance of MV (P = 0.002) and increased survival (P < 0.001) was statistically associated with early dosing. Tocilizumab therapy was effective at decreasing mortality and should be instituted early in the management of critically ill patients with coronavirus disease 2019) COVID-19).

Primary Osseous Low-Grade Myxofibrosarcoma of Clavicle Presenting With Multiple Skeletal Metastases.

Myxofibrosarcoma is a soft tissue neoplasm that usually affects the extremities of the elderly. It usually presents as a slow-growing painless mass that can metastasize to the lung and bone. However, the reported incidence of primary osseous myxofibrosarcoma is very low. Moreover, the metastatic pattern of these bone tumors is largely unknown. We describe a unique case of a young Caucasian male with symptomatic low-grade myxofibrosarcoma arising in the left clavicle, who presented with multiple bone metastases.

Molecular Profiling of Advanced Malignancies: A Community Oncology Network Experience and Review of Literature.

Background: Many genomic alterations have been identified that are critical to the malignant phenotype. Some of these, termed "driver mutations," are critical for tumor proliferation and progression. The landscape of targeted therapy has expanded as well. Next-generation sequencing (NGS) of tumors reveals cancer-related genomic alterations and provides therapeutic recommendations for specific targeted therapy. We analyzed our experience with FoundationOne, a validated NGS genomic profiling test, in a community oncology network. Methods: NGS results from May 2014 to September 2016 from a community oncology network in Western Pennsylvania were analyzed. Medical records were reviewed for primary site, stage, biopsy site, time of testing, prior treatment, FDA-approved therapy in patient's and other tumor types and potential clinical trials based upon mutations detected. Two co-primary endpoints for this study were to determine the percentage of patients having mutations with a FDA-approved targeted agent and the percentage of patients in whom a treatment decision was made based on these NGS results. Results: One Fifty-Seven NGS results were available for analysis. 82% patients had a mutation with a FDA-approved targeted agent available while 18% patients had no FDA-approved targeted agent for the mutation detected. Clinical trials were available for 93% cases. The NGS results were utilized in treatment decisions in 18% patients (n = 28) with, 7% (n = 11) initiating a targeted agent, 6% (n = 9) were on an appropriate targeted agent prior to testing and 5% (n = 8) being unable to start a targeted agent because of insurance denial, clinical deterioration or patient preference. 38% cases were tested early in the disease course (at diagnosis, during or shortly after first-line treatment) and 62% at progression. Conclusions: NGS is a valuable tool to identify molecular targets for personalizing cancer care. From our experience, the actual number of patients starting a targeted agent based on NGS results is low but it provides substantial information in terms of providing additional treatment options, identifying resistance conferring mutations and facilitating clinical trial enrollment. Optimal time of testing, early or late in disease course, financial implications of testing and using targeted therapy and survival benefit of targeted therapy need further studies.

Incremental utility of expanded mutation panel when used in combination with microRNA classification in indeterminate thyroid nodules.

INTRODUCTION: Focused and expanded mutation panels were assessed for the incremental utility of using an expanded panel in combination with microRNA risk classification. METHODS: Molecular results were reviewed for patients who underwent either a focused mutation panel (ThyGenX®) or an expanded mutation panel (ThyGeNEXT®) for strong and weak oncogenic driver mutations and fusions. microRNA results (ThyraMIR®) predictive of malignancy, including strong positive results highly specific for malignancy, were examined. RESULTS: Results of 12 993 consecutive patients were reviewed (focused panel = 8619, expanded panel = 4374). The expanded panel increased detection of strong drivers by 8% (P < .001), with BRAFV600E and TERT promoters being the most common. Strong drivers were highly correlated with positive microRNA results of which 90% were strongly positive. The expanded panel increased detection of coexisting drivers by 4% (P < .001), with TERT being the most common partner often paired with RAS. It increased the detection of weak drivers, with RAS and GNAS being the most common. 49% of nodules with weak drivers had positive microRNA results of which 33% were strongly positive. The expanded panel also decreased the number of nodules lacking mutations and fusions by 15% (P < .001), with 8% of nodules having positive microRNA results of which 22% were strongly positive. CONCLUSIONS: Using expanded mutation panels that include less common mutations and fusions can offer increased utility when used in combination with microRNA classification, which helps to identify high risk of malignancy in the cases where risk is otherwise uncertain due to the presence of only weak drivers or the absence of all drivers.

Endoscopic ultrasound guided fine-needle aspiration vs core needle biopsy for solid pancreatic lesions: Comparison of diagnostic accuracy and procedural efficiency.

BACKGROUND: Endoscopic ultrasound (EUS) guided core needle biopsies (CNB) are increasingly being performed to diagnose solid pancreatic lesions. However, studies have been conflicting in terms of CNB improving diagnostic accuracy and procedural efficiency vs fine-needle aspiration (FNA), which this study aims to elucidate. METHODS: Data were prospectively collected on consecutive patients with solid pancreatic or peripancreatic lesions at a single tertiary care center from November 2015 to November 2016 that underwent either FNA or CNB. Patient demographics, characteristics of lesions, diagnostic accuracy, final and follow-up pathology, use of rapid on-site evaluation (ROSE), complications, and procedure variables were obtained. RESULTS: A total of 75 FNA and 48 CNB were performed; of these, 13 patients had both. Mean passes were lower with CNB compared to FNA (2.4 vs 2.9, P = .02). Use of ROSE was higher for FNA (97.3% vs 68.1%, P = .001). Mean procedure time was shorter with CNB (34.1 minutes vs 51.2 minutes, P = .02) and diagnostic accuracy was similar (89.2% vs 89.4%, P = .98). There was no difference in diagnostic accuracy when ROSE was performed for CNB vs not performed (93.5% vs 85.7%, P = .58). Additionally, diagnostic accuracy of combined FNA and CNB procedures was 92.3%, which was comparable to FNA (P = .73) or CNB (P = .52) alone. CONCLUSION: FNA and CNB had comparable safety and diagnostic accuracy. Use of CNB resulted in less number of passes and shorter procedure time as compared to FNA. Moreover, diagnostic accuracy for CNB with or without ROSE was similar.

Fulminant Herpes Simplex Hepatitis Secondary to Adalimumab in Crohn's Disease: A Case Report.

Herpes simplex virus (HSV) hepatitis is an uncommon cause of fulminant hepatic failure, seen mostly in immunocompromised patients. Conventional treatment modalities for inflammatory bowel disease (IBD), such as steroids and azathioprine, have been known to cause HSV hepatitis. However, the reported incidence of HSV hepatitis in IBD patients undergoing tumor necrosis factor (TNF)-α inhibitor therapy is very rare. In this case report, we describe a rare case of fulminant HSV hepatitis that developed in a patient with Crohn's disease after treatment with the TNF-α inhibitor, adalimumab.

Loss of Heterozygosity (LOH) at 17p13 and 22q13 are Shared by Breast and Thyroid Carcinomas for Metastasis.

Many genomic mutations have been identified to be related to the metastasis of malignancies from various primary sites. In this study, we attempted to identify the loss of heterozygosity (LOH) that might be involved in metastasis of breast ductal carcinoma (BDC) and papillary thyroid carcinoma (PTC). We retrieved 14 BDC cases with metastasis and 19 BDC cases without metastasis as well as 12 PTC cases with metastasis and 14 PTC cases without metastasis. Analysis of 13 polymorphic microsatellite repeat markers targeting 1p34-36, 3p24-26, 9p21, 10q23, 17p13, 17q21, 21q22, and 22q13 was performed on DNA isolated from primary tumors. The results showed that LOH at 17p13 and 22q13 was shared by both BDC and PTC for metastasis. More detailed studies to identified genes in these shared loci of LOH may provide further insight into the molecular mechanisms underlying metastases in these 2 tumor types, and possibly other malignancies as well.

Fine needle aspiration and core needle biopsy of metastatic malignancy of unknown primary site.

Metastatic malignancies of unknown primary site (MUP) is the eighth most common form of malignancy, with an estimated 10-15% of oncology patients having a MUP. Fine needle aspiration cytology (FNA) and core needle biopsy (CNB) are often the first procedures utilized in the work-up of these cases and have a pivotal role for the diagnosis of metastases. There is an increasing emphasis on the precise classification of malignancy and determination of primary site of origin, utilizing smaller specimens. Recent available data suggest that there is a management benefit in identifying the primary site and/or specific cell lineage of MUP. In addition, the pathologists are asked to preserve the limited diagnostic material for potential molecular testing, as selected patients may benefit from targeted therapy. However, these tasks can become extremely challenging, especially if there is no previous history of malignancy, prior pathology is not available for review, or there is an unpredictable pattern of metastasis. In this review, we present a contemporary clinicopathologic approach to the work-up of MUP that includes cytomorphology, ancillary studies, and clinicopathologic correlation. The cytohistologic subclassification of malignancies into specific cell lineages and/or morphologic categories is presented. Knowledge of the various patterns of metastasis to common and unusual sites can help narrow down the location of a primary site. The use of ancillary studies with particular emphasis on IHC utilizing an algorithmic approach and the role of molecular analysis as a diagnostic and theranotic test are also discussed. When the cell block and/or CNB lacks sufficient material for ancillary testing, the cell transfer technique may be utilized.

The utility of combined mutation analysis and microRNA classification in reclassifying cancer risk of cytologically indeterminate thyroid nodules.

OBJECTIVES: Real-world clinical results of (1) Bethesda categorization, (2) mutation analysis, and (3) a microRNA classifier were correlated to show the utility of molecular analysis in assessing malignancy risk of indeterminate thyroid nodules. METHODS: Cytology and molecular results of clinically tested thyroid nodules were compared. An additional microRNA threshold was determined based on nodules with known disease status, establishing a 3-tiered microRNA approach to clinical risk assessments. Expected rate of malignancy given mutation panel and 3-tiered microRNA approach was validated in an independent cohort of atypia of undetermined significance or follicular lesion of undetermined significance (AUS/FLUS) and follicular neoplasm or suspicious for follicular neoplasm (FN/SFN) nodules with surgically derived outcomes. RESULTS: In 2685 patients clinically tested, PIK3CA, PAX8/PPARγ, and RET/PTC mutations occurred in less than 1%. Of note, 2% had BRAFV600E mutation and 82% lacked mutations. The maximum expected risk of malignancy in nodules lacking mutations was 9% and 17% for AUS/FLUS and FN/SFN nodules, respectively. Positive microRNA status further increased risk, with the most worrisome status (level-3) elevating risk to 36% and 54%, respectively. RAS mutations occurred in 15% of nodules tested clinically, including in 8% of those that were cytologically benign. The maximum expected risk of malignancy in nodules with RAS or PAX8/PPARγ mutations was 49% and 65% for AUS/FLUS and FN/SFN nodules, respectively. Positive microRNA status further increased risk, with the most worrisome microRNA status (level-3) elevating risk to 85% and 91%, respectively. CONCLUSIONS: Mutation panels alone do not sufficiently risk stratify thyroid nodular disease. microRNA classification complements cytology and mutation analysis with the capacity to better differentiate nodules at high risk of malignancy.

The Dynamic and Transient Immune Microenvironment in Locally Advanced Esophageal Adenocarcinoma Post Chemoradiation.

OBJECTIVE: The aim of this study was to assess the impact of chemoradiation on the immune microenvironment to influence and optimally design future neoadjuvant clinical trials. SUMMARY BACKGROUND DATA: Programmed death (PD)-1 inhibitors in metastatic gastroesophageal cancer have demonstrated response rates of approximately 25% in programmed death ligand-1 (PD-L1+) tumors. Unfortunately, the majority of patients do not respond. Therefore, a rationale strategy of combining immunotherapeutic agents with chemoradiation in earlier stage esophageal cancer may prevent metastatic disease in patients. METHODS: To determine the effects of chemoradiation on resected esophageal adenocarcinomas, we examined the immune microenvironment pre- and post-chemoradiation using immunohistochemistry, quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and functional analysis of tumor-infiltrating lymphocytes. Additionally, to assess the duration and dependency of radiation-induced PD-L1 upregulation, a surgical rat reflux model of esophageal adenocarcinoma is used. First, tumor-bearing animals were dosed with single-fraction 13Gy or 16Gy radiation to determine safety, dose correlation, and PD-L1 upregulation using qRT-PCR post-radiation. Next, longitudinal PD-L1 expression levels within individual animals were determined using serial endoscopic biopsies at baseline, 1, 5, and 9 weeks post 16Gy radiation. RESULTS: The majority of cancers displayed enhanced interferon γ and activated CD8+ T lymphocytes at the tumor stroma interface. These tumors also demonstrated enhanced upregulation of PD-L1 and multiple other immune checkpoints including TIM3, GITR, IDO1, LAG3, OX40, and KIR. The animal model results indicated PD-L1 upregulation is dose-dependent and transiently elevated post radiation exposure. CONCLUSIONS: Collectively, these findings provide insights into the evolving immune landscape after chemoradiation and have significant implications for neoadjuvant trial designs that will combine radiotherapy with immune checkpoint inhibitors.

Diagnostic yield from colon biopsies in patients with inflammatory bowel disease and suspected cytomegalovirus infection: is it worth it?

BACKGROUND: Patients with inflammatory bowel disease (IBD) are often immunosuppressed and are at risk for reactivation of latent cytomegalovirus (CMV) infection. We examined the diagnostic yield from colon biopsies in IBD patients with suspected CMV infection. METHODS: Patients above 18 years of age who underwent testing for CMV on colon biopsies between January 1st, 2012, and December 31st, 2015, were identified from a pathology data base. A positive CMV result was included only if testing included both hematoxylin/eosin staining and immunohistochemistry from two or more biopsy samples. RESULTS: One hundred twenty-five patients met the inclusion criteria. Of these, 99 had a diagnosis of IBD: 30 with Crohn's disease, 63 with ulcerative colitis, and 6 with indeterminate colitis. As regards treatment, 21.2% of the patients had biologic therapy alone, 13.1% received immunomodulators, and 11.1% were treated with combined biologic and immunomodulator therapy within 3 months of the colon biopsy. In addition, 32.3% of the patients were on steroids. Of the 99 IBD patients, only 1 had biopsy-proven CMV colitis. CONCLUSION: The yield from colon biopsies with hematoxylin/eosin staining and immunohistochemistry to test for CMV in IBD flare is very low. Further multicenter studies with large numbers of patients are needed to compare all testing modalities in the same cohort of patients. This may help identify which subgroup of IBD patients are likely to benefit from specific modalities of CMV testing, with potential cost-saving implications.

GRB7 Expression and Correlation With HER2 Amplification in Invasive Breast Carcinoma.

Growth factor receptor-bound protein 7 (GRB7) gene is located adjacent to the HER2 gene on the 17q12-21 amplicon, is often coamplified with HER2 in a subset of breast cancers, and has been implicated in resistance to anti-HER2 and antiestrogen therapy. This study investigated the correlation of GRB7 expression by immunohistochemistry with HER2 expression, HER2 amplification, increased chromosome 17 copy number, and other prognostic and predictive factors in invasive breast cancer, including histologic grade, pathologic stage, and ER, PR, and p53 status. Paraffin-embedded samples of 188 invasive breast carcinomas with documented HER2, ER, and PR testing were collected and divided into 3 groups: cases positive for HER2 overexpression/gene amplification (n=60), negative for HER2 overexpression (n=97), and cases with increased chromosome 17 copy number without HER2 amplification (n=31). GRB7 expression was evaluated on all 188 cases. In addition, p53 immunohistochemistry was performed on 13 HER2+/GRB7+ cases and 39 HER2+/GRB7- cases. GRB7 expression correlated strongly with HER2 overexpression. GRB7 expression was present in 20/60 (33.33%) of HER2+ cases, compared with 1/97 (1.03%) HER2- cases, and 1/31 (3.22%) increased chromosome 17 copy number cases (P<0.0001). In HER2+ cases, GRB7 expression was found to correlate significantly with a greater degree of HER2 amplification. The mean±SEM HER2 copy number was 21.14±2.59 in GRB7+ cases, compared with 9.8±1.38 in GRB7- cases (P=0.0001). GRB7 expression correlated significantly with ER negativity (P=0.012) and p53 positivity (P=0.03). GRB7 expression did not correlate with histologic grade, pathologic stage, or PR expression. Our data shows that GRB7 expression in invasive breast cancer correlates with markers of a more aggressive phenotype, including HER2 overexpression, a greater degree of HER2 amplification, ER negativity, and p53 positivity.

A Rare Case of Metastatic Choriocarcinoma of Lung Origin.

Choriocarcinoma is part of the spectrum of gestational trophoblastic disease that occurs in women of reproductive age. Although the most common metastatic site of choriocarcinoma is the lung, primary pulmonary choriocarcinoma is rare. To diagnose primary pulmonary choriocarcinoma, the patient should have no previous gynecologic malignancy, have elevated human chorionic gonadotropin, and have pathological confirmation of the disease excluding gonadal primary site of the tumor. Due to the paucity of data, there are no guidelines for treatment. Prognosis of this malignancy is extremely poor. We report a rare case of metastatic primary lung choriocarcinoma in a 69-year-old postmenopausal woman who was treated with combination of surgery, chemotherapy, and radiation. The patient had a good outcome and is doing well after 1-year follow-up.

Primary tumor microRNA signature predicts recurrence and survival in patients with locally advanced esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is an aggressive cancer necessitating the development of improved risk stratification tools for personalized care. Previously, microRNAs have been shown to correlate with the progression and prognosis of various cancer types; however, the value in EAC remains largely unexplored. We performed global microRNA profiling on 32 formalin-fixed, paraffin-embedded EAC specimens to identify microRNAs associated with progression. Literature search and pathway analysis further refined output to five significantly deregulated candidate biomarkers. Four of the five microRNAs (miR-652-5p, miR-7-2-3p, miR-3925-3p, and miR-219-3p) were validated by qRT-PCR. Survival outcomes were evaluated in testing set of 26 stage II/III EAC patients to determine the prognostic relevance of the selected microRNAs. In the testing set, miR-652-5p and miR-7-2-3p expressions were significantly associated with progression-free survival (p-value = .00771 and p-value = .00293). The highest area under receiver operating characteristic (ROC) curve was 0.8212 for the combination of miR-652-5p and miR-7-2-3p. Collectively, our findings demonstrated that the miR-652-5p/miR-7-2-3p signature may serve as a promising prognostic marker in patients with locally advanced EAC.

Radiologic-pathologic Correlation-An Advanced Fourth-year Elective: How We Do It.

Traditionally, the radiology elective has been designed to teach medical students the fundamentals of radiologic interpretation. When questioned, many students state that they want to take a radiology elective so they can "interpret images." For the students on radiology, rotation/elective education was often passive, consisting of didactic conferences and observational shadowing of radiologists as they interpreted images. Students had only a superficial appreciation of how radiologists interacted with clinical services, multidisciplinary teams, and pathology. There was very little emphasis on imaging appropriateness or the most efficient and effective imaging for various clinical problems. With the expansion of numerous imaging modalities and the emphasis on patient-centered care, including imaging safety and dose reduction, it is important to change the focus of radiology education from interpretation to the optimal integration of imaging into clinical medicine. Radiology-pathology (rad path) electives were created at Allegheny General Hospital and the Medical University of South Carolina as a new option to provide a high-quality advanced elective for fourth-year medical students. These electives enable students to correlate radiologic images with gross and microscopic pathology specimens, thus increasing their knowledge and understanding of both. The rad path elective combines aspects of surgery, radiology, and pathology and requires students to be active learners. The implementation of this elective is an exciting work in progress that has been evolving over the past 2 and 4 years at Medical University of South Carolina and Allegheny General Hospital, respectively. We will discuss the historical basis for the elective, the advantages and challenges of having such an integrated course, and some different strategies for creating a rad path elective.

Fine-Needle Aspiration Cytology of Intranodal Palisaded Myofibroblastoma of the Inguinal Lymph Node.

BACKGROUND: Intranodal palisaded myofibroblastoma (IPM) is a rare, lymph node mesenchymal neoplasm; the cytologic features are limited in the literature. CASE: The patient was a 51-year-old female who had a firm, palpable mass in the right inguinal region. Fine-needle aspiration (FNA) was performed. The smears revealed large, 3-dimensional clusters of cohesive spindle cells, densely surrounding a central, orange-colored, acellular matrix core. These cells had a single, elongated nucleus and an inconspicuous nucleolus. Also seen were spindle cells in short fascicles with dense cytoplasm. The spindle cells were loosely arranged in a single-cell pattern. In addition to the spindle cells and matrix, hemosiderin granules were scattered in the background. A few lymphocytes were identified. CONCLUSION: A diagnosis of IPM should be considered when FNA smears of lymph node show bland spindle cells in various patterns including single cells, short fascicles, large cohesive clusters with core amianthoid fibers and background hemosiderin granules.

Primary Splenic Angiosarcoma: Clinical and Imaging Manifestations of This Rare Aggressive Neoplasm.

Primary splenic angiosarcoma is a rare and fatal neoplasm arising from vascular endothelial cells within the spleen. With an incidence of 2 cases per 10 million people worldwide, the diagnosis and treatment of this rare entity is unfamiliar and challenging. We describe the case of a previously healthy 45-year-old woman who presented with vague upper-abdominal pain and was found to have a splenic mass on computed tomography. The patient underwent laparoscopic splenectomy and was found to have splenic angiosarcoma on microscopic evaluation. Although specific radiologic diagnosis is not possible, bringing the possibility of primary splenic angiosarcoma to the ordering clinician's attention has the potential to hasten treatment and improve patient outcomes. This case highlights the importance for radiologists to be aware of this rare neoplasm and to consider it in the differential when encountering a heterogeneously enhancing splenic mass.

Preclinical Study of AUY922, a Novel Hsp90 Inhibitor, in the Treatment of Esophageal Adenocarcinoma.

OBJECTIVE: To assess the efficacy of heat-shock protein 90 (Hsp90) inhibitor, NVP-AUY922-AG (AUY922), in the treatment of esophageal adenocarcinoma (EAC) in vitro and in vivo. BACKGROUND: EAC is a leading cause of cancer death, and current treatment options are limited. Hsp90, a chaperone protein that regulates several oncoproteins, is upregulated in EAC, and may be a novel target for therapy. METHODS: In vitro, EAC cell lines were utilized to evaluate AUY922, alone and in combination with 5-fluorouracil (5-FU) and cisplatin. BrdU ELISA and flow cytometry were used to assess proliferation and measure apoptosis, respectively. Western blot and RT-PCR were performed to quantitate Hsp90 pathway expression. In vivo, esophagojejunostomy was performed on rats and treatment animals received AUY922 32 to 40 weeks postoperatively. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, gross histological evaluation, and Hsp90 pathway expression. RESULTS: In vitro, AUY922 demonstrated antiproliferative activity in both cell lines and showed enhanced efficacy with cisplatin and 5-FU. Western Blot and RT-PCR demonstrated downregulation of CDK1 and CDK4 and upregulation of Hsp72. In vivo, AUY922 showed decrease in tumor volume in 36.4% of rats (control = 9.4%), increase in 9.1% (control = 37.5%), and stable disease in 54.5% (control = 43.7%). Necropsy confirmed the presence of EAC in 50% of treatment animals and 75% of control animals. mRNA expression, pre- and posttreatment, demonstrated significant downregulation of MIF, Hsp70, Hsp90ß, and CDK4, and upregulation of Hsp72. CONCLUSIONS: AUY922 exhibits antitumor efficacy in vitro and in vivo for EAC, suggesting the need for human clinical trials.

GATA3 immunohistochemistry expression in histologic subtypes of primary breast carcinoma and metastatic breast carcinoma cytology.

GATA3 plays a role in cell proliferation and differentiation in many tissues, including breast, and it has been suggested that GATA3 expression correlates with ER expression. However, little is known on GATA3 expression in various subtypes of breast carcinoma, its utilization in cytology, and on how GATA3 performs in comparison with GCDFP-15 and mammaglobin. Eighty-four histology cases of breast carcinoma of various subtypes, including 28 triple-negative breast carcinomas, along with 20 cytology cases of metastatic breast carcinoma and 12 cytology cases of ER-positive metastatic gynecologic malignancies, were stained for GATA3, GCDFP-15, and mammaglobin. In non-triple-negative breast carcinomas (n=56), GATA3 showed 100% sensitivity, higher than GCDFP-15 (42.8%; P<0.0001) and mammaglobin (58.9%; P<0.0001), whereas staining patterns were similar for all the histologic subtypes examined. Staining scores were determined by multiplying the percentage of cancer cells staining with an intensity score of 1+, 2+, or 3+ (range, 0 to 300). In non-triple-negative carcinomas, GATA3 showed a mean score of 273.7, higher than GCDFP-15 (107.5; P<0.0001) and mammaglobin (147.7; P<0.0001). In triple-negative breast carcinomas (n=28), GATA3 showed a sensitivity of 60.7%, greater than GCDFP-15 (17.9%; P=0.0022) and mammaglobin (7.1%; P<0.0001). These results were consistent irrespective of the subtype examined. In breast carcinoma cytology cases, 100% stained with GATA3, higher than GCDFP-15 (20%; P<0.0001) and mammaglobin (45%; P<0.0001). None of the metastatic endometrial or ovarian carcinomas were positive for GATA3. Although GATA3 expression correlates with ER expression in breast, no correlation is observed in gynecologic malignancies. Thus, in working up ER-positive metastatic malignancies GATA3 demonstrates specificity for breast.