Karen J. Fritchie

Clinical, endoscopic, and histologic findings distinguish eosinophilic esophagitis from gastroesophageal reflux disease.

BACKGROUND & AIMS Features of eosinophilic esophagitis (EoE) and gastroesophageal reflux disease (GERD) overlap; because they cannot be differentiated on the basis of eosinophil counts alone, it can be a challenge to distinguish these disorders. We aimed to characterize the clinical, endoscopic, and histologic features of EoE and GERD and to identify factors that might be used to differentiate them. METHODS We performed a retrospective case-control study on data collected from 2000 to 2007. Cases were patients of any age with EoE, as defined by recent consensus guidelines; controls were patients of any age with GERD. Clinical and endoscopic data were collected, and all esophageal biopsy specimens were reassessed by gastrointestinal pathologists. Cases and controls were compared, unconditional logistic regression was performed to develop a model to predict EoE, and receiver operator characteristic curves were constructed. RESULTS Data from 151 patients with EoE and 226 with GERD were analyzed. Compared with GERD, features that independently predicted EoE included younger age; symptoms of dysphagia; documented food allergies; observations of esophageal rings, linear furrows, white plaques, or exudates by upper endoscopy; an absence of a hiatal hernia, observed by upper endoscopy; a higher maximum eosinophil count; and the presence of eosinophil degranulation observed in biopsy specimens. The area under the curve for this model was 0.934. CONCLUSIONS We identified a set of readily available and routinely measured variables that differentiate EoE from GERD. Use of this type of analysis with patients suspected to have EoE might lead to more accurate diagnoses.

Clinical and endoscopic characteristics do not reliably differentiate PPI-responsive esophageal eosinophilia and eosinophilic esophagitis in patients undergoing upper endoscopy: A Prospective Cohort Study

OBJECTIVES:Proton-pump inhibitor-responsive esophageal eosinophilia (PPI-REE) is a newly recognized entity that must be differentiated from eosinophilic esophagitis (EoE). Little is known about this condition. We aimed to determine the prevalence of PPI-REE and EoE in patients undergoing upper endoscopy and determine features that distinguish the two groups.METHODS:This prospective study conducted at the University of North Carolina from 2009 to 2011 enrolled consecutive adult patients undergoing outpatient upper endoscopy. Subjects had esophageal biopsies to quantify the maximum eosinophil count per high-power field (eos/hpf; hpf=0.24 mm2). If biopsies revealed ≥15 eos/hpf, subjects were treated with twice daily PPI for 8 weeks and endoscopy was repeated. If ≥15 eos/hpf persisted despite PPI therapy, EoE was diagnosed. If there were <15 eos/hpf, PPI-REE was diagnosed. The proportion of patients in each group was calculated, and patients with EoE and PPI-REE were compared.RESULTS:Of the 223 subjects enrolled, 173 had dysphagia and 50 did not. Of those with dysphagia, 66 (38%) had ≥15 eos/hpf. After the PPI trial, 40 (23%) were confirmed to have EoE, and 24 (14%) had PPI-REE. Of those without dysphagia, 2 (4%) had ≥15 eos/hpf, and after the PPI trial, 1 (2%) had EoE. Compared with EoE, PPI-REE patients were more likely to be older and male and less likely to have typical endoscopic findings of EoE. However, none of the individual factors was independently predictive of PPI-REE status on multivariable analysis. Similarly, although some endoscopic findings were differentially distributed between PPI-REE and EoE, none were significantly associated with disease status on multivariable analysis.CONCLUSIONS:Esophageal eosinophilia is common among patients undergoing esophagogastroduodenoscopy for dysphagia. Although EoE was seen in nearly a quarter of patients with dysphagia, PPI-REE was almost as common, and accounted for over one-third of those with ≥15 eos/hpf. No clinical or endoscopic features independently distinguished PPI-REE from EoE before the PPI trial.

Molecular subtypes in head and neck cancer exhibit distinct patterns of chromosomal gain and loss of canonical cancer genes.

Head and neck squamous cell carcinoma (HNSCC) is a frequently fatal heterogeneous disease. Beyond the role of human papilloma virus (HPV), no validated molecular characterization of the disease has been established. Using an integrated genomic analysis and validation methodology we confirm four molecular classes of HNSCC (basal, mesenchymal, atypical, and classical) consistent with signatures established for squamous carcinoma of the lung, including deregulation of the KEAP1/NFE2L2 oxidative stress pathway, differential utilization of the lineage markers SOX2 and TP63, and preference for the oncogenes PIK3CA and EGFR. For potential clinical use the signatures are complimentary to classification by HPV infection status as well as the putative high risk marker CCND1 copy number gain. A molecular etiology for the subtypes is suggested by statistically significant chromosomal gains and losses and differential cell of origin expression patterns. Model systems representative of each of the four subtypes are also presented.

Esophageal dilation in eosinophilic esophagitis: safety and predictors of clinical response and complications

BACKGROUND Esophageal strictures resulting from eosinophilic esophagitis present management challenges, and high rates of rents and perforation have been reported. OBJECTIVE To assess the safety of esophageal dilation in eosinophilic esophagitis and to characterize predictors of both clinical response and complications of the procedure. DESIGN Retrospective study of the University of North Carolina eosinophilic esophagitis database. SETTING Tertiary care referral center. PATIENTS Cases of eosinophilic esophagitis were defined as per consensus guidelines. INTERVENTION Dilation with either Savary or through-the-scope balloon techniques. MAIN OUTCOME MEASUREMENTS Complications (deep mucosal rents, contained or free perforation, and chest pain requiring medical attention or hospitalization) and the global clinical symptom response. RESULTS Of 130 eosinophilic esophagitis cases identified, 70 dilations (12 Savary, 58 balloon) were performed in 36 patients. Esophageal size improved from 12 to 16 mm (P < .001), with an overall symptom response rate of 83%. The only predictor of clinical response was final dilation diameter. There were 5 complications (7%): 2 deep mucosal rents and 3 episodes of chest pain. There were no perforations. There was one hospitalization for chest pain. All complications occurred in patients being treated with topical steroids, who underwent balloon dilation. Complications were associated with younger age (23 vs 42; P = .02) and more dilations (4 vs 1.7; P = .009). LIMITATIONS Single center, retrospective study. CONCLUSIONS Esophageal dilation can be performed in eosinophilic esophagitis with low rates of tears, chest pain, and hospitalization. No perforations were found in our database. The effectiveness of dilation was best when a larger esophageal caliber was achieved, but patients undergoing more procedures was associated with complications.

The prognostic contribution of clinical breast cancer subtype, age, and race among patients with breast cancer brain metastases

Brain metastases (BM) arising from triple‐negative breast cancer (TNBC) portend a poor prognosis. TNBC is more common in premenopausal and African‐American (AA) patients; both of these characteristics also confer a poor prognosis. In a single‐institution cohort study, the authors attempted to determine whether the inferior outcome noted with TNBC brain metastases is more reflective of a higher risk population or the subtype itself.

Tryptase staining of mast cells may differentiate eosinophilic esophagitis from gastroesophageal reflux disease

OBJECTIVES:Mast cells may contribute to the pathogenesis of eosinophilic esophagitis (EoE), but their role in diagnosis is unknown. Our aim was to determine whether tryptase staining of esophageal mast cells differentiates EoE from gastroesophageal reflux disease (GERD) and has utility for diagnosis of EoE.METHODS:We performed a case–control study comparing patients with EoE, defined by consensus guidelines, to GERD patients with eosinophils on esophageal biopsy. Immunohistochemistry was performed with mast cell tryptase. The density (mast cells/mm2) and intensity (0–4 scale) of mast cell staining was compared between groups after masking the diagnosis. Receiver operating characteristic (ROC) curves were constructed, and the area under the curve (AUC) was calculated to assess mast cell staining as both a stand-alone diagnostic test and an adjunctive assay with eosinophil counts.RESULTS:Fifty-four EoE (mean age 24 years; 69% male; mean 146 eosinophils per high-power field (eos/hpf)) and 55 GERD (mean age 34 years; 60% male; mean 20 eos/hpf) patients were analyzed. The maximum epithelial tryptase density was higher in EoE than in GERD (162±87 mast cells/mm2 vs. 67±54; P<0.001). Mast cells were diffusely distributed throughout the biopsy in more EoE than GERD patients (41 vs. 7%; P<0.001). Tryptase density and eosinophil count were only weakly correlated (R2=0.09; P=0.002). The AUC was 0.84 for tryptase staining alone, and 0.96 for the combination of mast cells and eosinophils.CONCLUSIONS:Patients with EoE have higher levels of tryptase-positive mast cells compared with GERD patients, improving the diagnostic value of biopsies beyond eosinophil counts alone. Mast cell tryptase may have utility as a diagnostic assay for EoE.

αB-Crystallin: A Novel Regulator of Breast Cancer Metastasis to the Brain

Purpose: Basal-like breast tumors are typically (ER/PR/HER2) triple-negative and are associated with a high incidence of brain metastases and poor clinical outcomes. The molecular chaperone αB-crystallin is predominantly expressed in triple-negative breast cancer (TNBC) and contributes to an aggressive tumor phenotype in preclinical models. We investigated the potential role of αB-crystallin in brain metastasis in TNBCs. Experimental Design: αB-crystallin expression in primary breast carcinomas and brain metastases was analyzed by immunohistochemistry among patients with breast cancer with brain metastases. αB-crystallin was overexpressed or silenced in two different TNBC cell lines. The effects on cell adhesion to human brain microvascular endothelial cells (HBMEC) or extracellular matrix proteins, transendothelial migration, and transmigration across a HBMEC/astrocyte coculture blood–brain barrier (BBB) model were examined. In addition, the effects of overexpressing or silencing αB-crystallin on brain metastasis in vivo were investigated using orthotopic TNBC models. Results: In a cohort of women with breast cancer brain metastasis, αB-crystallin expression in primary breast carcinomas was associated with poor overall survival and poor survival after brain metastasis, even among patients with TNBC. Stable overexpression of αB-crystallin in TNBC cells enhanced adhesion to HBMECs, transendothelial migration, and BBB transmigration in vitro, whereas silencing αB-crystallin inhibited these events. αB-crystallin promoted adhesion of TNBC cells to HBMECs, at least in part, through an α3β1 integrin–dependent mechanism. αB-crystallin overexpression promoted brain metastasis, whereas silencing αB-crystallin inhibited brain metastasis in orthotopic TNBC models. Conclusion: αB-crystallin is a novel regulator of brain metastasis in TNBC and represents a potential biomarker and drug target for this aggressive disease. Clin Cancer Res; 20(1); 56–67. ©2013 AACR.

Phosphatidylinositol 3-kinase pathway activation in breast cancer brain metastases

IntroductionActivation status of the phosphatidylinositol 3-kinase (PI3K) pathway in breast cancer brain metastases (BCBMs) is largely unknown. We examined expression of phospho(p)-AKT, p-S6, and phosphatase and tensin homologue (PTEN) in BCBMs and their implications for overall survival (OS) and survival after BCBMs. Secondary analyses included PI3K pathway activation status and associations with time to distant recurrence (TTDR) and time to BCBMs. Similar analyses were also conducted among the subset of patients with triple-negative BCBMs.Methodsp-AKT, p-S6, and PTEN expression was assessed with immunohistochemistry in 52 BCBMs and 12 matched primary BCs. Subtypes were defined as hormone receptor (HR)+/HER2-, HER2+, and triple-negative (TNBC). Survival analyses were performed by using a Cox model, and survival curves were estimated with the Kaplan-Meier method.ResultsExpression of p-AKT and p-S6 and lack of PTEN (PTEN-) was observed in 75%, 69%, and 25% of BCBMs. Concordance between primary BCs and matched BCBMs was 67% for p-AKT, 58% for p-S6, and 83% for PTEN. PTEN- was more common in TNBC compared with HR+/HER2- and HER2+. Expression of p-AKT, p-S6, and PTEN- was not associated with OS or survival after BCBMs (all, P > 0.06). Interestingly, among all patients, PTEN- correlated with shorter time to distant and brain recurrence. Among patients with TNBC, PTEN- in BCBMs was associated with poorer overall survival.ConclusionsThe PI3K pathway is active in most BCBMs regardless of subtype. Inhibition of this pathway represents a promising therapeutic strategy for patients with BCBMs, a group of patients with poor prognosis and limited systemic therapeutic options. Although expression of the PI3K pathway did not correlate with OS and survival after BCBM, PTEN- association with time to recurrence and OS (among patients with TNBC) is worthy of further study.

TGFBR3 and MGEA5 rearrangements in pleomorphic hyalinizing angiectatic tumors and the spectrum of related neoplasms

Pleomorphic hyalinizing angiectatic tumor (PHAT) is a rare, locally aggressive tumor of the distal extremities with a proclivity for local recurrence. PHATs contain characteristic ectatic, thin-walled vessels, lined by fibrin, and are surrounded by groups of variably pleomorphic spindled to epithelioid neoplastic cells. The putative precursor lesion of PHAT, originally termed “early PHAT” shares many clinicopathologic features with hemosiderotic fibrolipomatous tumor (HFLT). HFLT, myxoinflammatory fibroblastic sarcoma (MIFS), and tumors showing hybrid features of HFLT and MIFS often show TGFBR3 and MGEA5 gene rearrangements. To date, only a small number of PHATs has been tested for either rearrangement; all have been negative. We hypothesized that PHATs contain TGFBR3 and/or MGEA5 rearrangements. Cases of PHAT (all containing areas of HFLT) (N=10), HFLT (N=7), MIFS (N=6), hybrid HFLT/MIFS (N=3), and PHAT-like undifferentiated pleomorphic sarcomas (N=7) were retrieved from our institutional and consultation archives and analyzed for TGFBR3 and MGEA5 rearrangements using a break-apart probe strategy for FISH. Six of 10 PHATs harbored TGFBR3 and/or MGEA5 gene rearrangements: 4 cases had both TGFBR3 and MGEA5 rearrangements, and 2 cases contained MGEA5 rearrangements. Two of 7 HFLTs were positive: 1 case had a TGFBR3 rearrangement, and 1 case had an MGEA5 rearrangement. One of 6 MIFSs had an MGEA5 rearrangement. All 3 hybrid HFLT/MIFS cases were positive: 2 cases had both TGFBR3 and MGEA5 rearrangements, and 1 case had a TGFBR3 rearrangement. All PHAT-like undifferentiated pleomorphic sarcomas were negative. We report, for the first time, the presence of TGFBR3 and/or MGEA5 rearrangements in tumors showing mixed features of HFLT and PHAT. The presence of such rearrangements strongly suggests that HFLT is related to both PHAT and MIFS and that the latter 2 tumors may represent morphologic variants of a single, genetically defined entity in which only MIFS has acquired the capacity to metastasize.

High XRCC1 Protein Expression Is Associated with Poorer Survival in Patients with Head and Neck Squamous Cell Carcinoma

Purpose: We evaluated X-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1) protein in head and neck squamous cell carcinoma (HNSCC) patients in association with outcome. Experimental Design: XRCC1 protein expression was assessed by immunohistochemical (IHC) staining of pretreatment tissue samples in 138 consecutive HNSCC patients treated with surgery (n = 31), radiation (15), surgery and radiation (23), surgery and adjuvant chemoradiation (17), primary chemoradiation (51), and palliative measures (1). Results: Patients with high XRCC1 expression by IHC (n = 77) compared with patients with low XRCC1 expression (n = 60) had poorer median overall survival (OS; 41.0 months vs. OS not reached, P = 0.009) and poorer progression-free survival (28.0 months vs. 73.0 months, P = 0.031). This association was primarily due to patients who received chemoradiation (median OS of high- and low-XRCC1 expression patients, 35.5 months and not reached respectively, HR 3.48; 95% CI: 1.44–8.38; P = 0.006). In patients treated with nonchemoradiation modalities, there was no survival difference by XRCC1 expression. In multivariable analysis, high XRCC1 expression and p16INK4a-positive status were independently associated with survival in the overall study population (HR = 2.62; 95% CI: 1.52–4.52; P < 0.001 and HR = 0.21; 95% CI: 0.06–0.71; P = 0.012, respectively) and among chemoradiation patients (HR = 6.02; 95% CI: 2.36–15.37; P < 0.001 and HR = 0.26; 95% CI: 0.08–0.92, respectively; P = 0.037). Conclusions: In HNSCC, high XRCC1 protein expression is associated with poorer survival, particularly in patients receiving chemoradiation. Future validation of these findings may enable identification of HNSCC expressing patients who benefit from chemoradiation treatment. Clin Cancer Res; 17(20); 6542–52. ©2011 AACR.