Isolated Celiac Artery Vasculitis Presenting as Ileus in a Patient With Ulcerative Colitis.

There is a known association between inflammatory bowel disease (IBD) and vasculitis, which can present with mesenteric ischemia or cutaneous manifestations. Infliximab, an anti-tumor necrosis factor (anti-TNF) used to treat IBD, has been implicated as a potential culprit. We present a unique case of a patient with ulcerative colitis who developed isolated celiac artery vasculitis presenting with abdominal pain and ileus after decreasing his dosage of azathioprine. Vasculitis resolved with steroids and increasing azathioprine dosage, while continuing anti-TNF therapy, suggesting that anti-TNF agents are not the only cause of vasculitis in patients with IBD or that thiopurines may be protective.

The role of next-generation sequencing in the differential diagnosis of composite neoplasms.

Composite neoplasms (CNs) are rare and diagnostically challenging lesions that require differentiating between mixed clonal tumors with divergent phenotypes (MT), collision of 2 independent tumors adjacent to each other (CT), and tumor-to-tumor metastasis (TTM). To that end, pathologists have traditionally used immunohistochemistry and limited molecular studies, such as Sanger sequencing. Herein we evaluate the potential application of NGS in the differential diagnosis of these rare neoplasms. Four CNs were included in the study. Two were diagnosed as MT (mixed adenoneuroendocrine carcinoma of the gallbladder and metastatic papillary thyroid carcinoma with squamous dedifferentiation) and 2 were interpreted as TTM (esophageal adenocarcinoma to lung adenocarcinoma and small cell carcinoma of the lung to meningeal melanoma). Diagnoses were made using clinical, histologic, and immunophenotypic information, with the aid of limited molecular studies in 2 cases. Formalin-fixed, paraffin-embedded tissue was dissected for DNA and RNA extraction, and NGS was performed using the Oncomine Comprehensive Panel. The 2 tumors initially interpreted as MT showed shared genetic aberrations in the different neoplastic components, supporting the pathologic diagnosis. NGS results for the lesion diagnosed as esophageal adenocarcinoma metastatic to lung adenocarcinoma did not support the histopathologic interpretation and were deemed inconclusive. However, the identification of an identical CDKN2A mutation in all components and in the adjacent benign lung parenchyma suggests a possible germline aberration. Sequencing results in the last case were clearly supportive of TTM. This study illustrates the role of NGS in the diagnostic workup of CNs, as an adjunct to light microscopy and immunohistochemistry.

Detailed Histologic Evaluation of Eosinophilic Esophagitis in Pediatric Patients Presenting with Dysphagia or Abdominal Pain and Comparison of the Histology between the Two Groups.

EoE in children presents with four main symptoms. Most common symptoms exhibited by our clinic population are dysphagia (D) and abdominal pain (AP). Despite similar treatments, we found in an earlier study that the outcomes between these two groups were different. Therefore, we investigated if there exist any histological differences between these groups that could further our knowledge of EoE. Aim. To compare esophageal histology in detail, apart from the eosinophil count, between EoE-D and EoE-AP. Method. Biopsies of patients with EoE-D and EoE-AP were reevaluated for 10 additional histological criteria, in addition to the eosinophil count. Results. Both groups had 67 patients; peak mean eosinophil was 33.9 and 31.55 for EoE-D and EoE-AP (p < 0.05). Eosinophilic microabscesses, superficial layering of eosinophils, and epithelial desquamation were twice as common and significant in EoE-D group than EoE-AP. Eosinophil distribution around rete pegs was also significantly higher in EoE-D group. The remaining criteria were numerically higher in EoE-D, but not significant, with the exception of rete peg elongation. Conclusion. EoE-D patients have significantly higher eosinophils compared to EoE-AP, and the level of inflammation as seen from eosinophil microabscesses, superficial layering, desquamation, and the distribution around rete pegs is significantly higher.

14-3-3ζ as a predictor of early time to recurrence and distant metastasis in hormone receptor-positive and -negative breast cancers.

The 14-3-3ζ gene, on 8q22, is often amplified in breast cancer and encodes a survival factor that interacts with and stabilizes many key signaling proteins. We examined the relationship between the expression of 14-3-3ζ, estrogen receptor α (ERα), and other parameters ( tumor size, grade, nodal status, progesterone receptor, HER2, EGFR, and p53) in matched primary and recurrence tumor tissue and how these factors impact time to recurrence, properties of the recurred tumors, and site of metastasis. In this cohort of over 100 patients, median time to recurrence was 3 years (range 1-17 years). Our analyses of primary tumor microarray cores revealed that 14-3-3ζ status was significantly correlated with tumor grade, size, and ERα. Women with 14-3-3ζ-positive and ERα-negative tumors had the earliest time to recurrence (median 1 yr, p < 0.001, hazard ratio 2.89), while median time to recurrence was 7 years for 14-3-3ζ-negative and ER-positive tumors. Of recurred tumors, 70-75 % were positive for 14-3-3ζ, up from the 45 % positivity of primary tumors. High expression of 14-3-3ζ also correlated with site of recurrence and showed a propensity for distant metastases to lung and chest wall. Multifactor correlation regression analysis revealed 14-3-3ζ to be a non-redundant, independent variable that adds clinical strength in predicting risk for early recurrence in ER-positive and -negative breast cancers, providing information beyond that of all other clinical pathological features examined. Thus, high expression of 14-3-3ζ in the primary tumor was significantly associated with earlier time to recurrence and with distant metastasis. Furthermore, even when the primary breast cancers were negative-low for 14-3-3ζ, the majority acquired increased expression in the recurrence. The findings underscore the detrimental role played by 14-3-3ζ in tumor aggressiveness and suggest that reducing its expression or interfering with its actions might substantially improve the clinical outcome for breast cancer patients.

Estrogen promotes breast cancer cell survival in an inhibitor of apoptosis (IAP)-dependent manner.

The estrogen receptor (ER) is a major prognostic and therapeutic marker that is expressed in nearly 75% of breast tumors. We have previously shown that the presence of inflammatory mediators can alter the genomic function of the estrogen receptor (ER) in a gene specific manner. In particular, 17ß-estradiol (E2) works in combination with the pro-inflammatory cytokines to enhance the expression of a number of pro-survival factors, including the Inhibitor of Apoptosis (IAP) family member, cIAP2. Here we confirm that mRNA and protein levels for cIAP2, but not the related family members cIAP1 and XIAP, are highly up-regulated in MCF-7 breast cancer cells by E2 and cytokines. Similar regulation of cIAP2 is evident in other ER positive but not ER negative cell lines. In agreement with its role as a pro-survival factor, cIAP2 is highly expressed in a subset of invasive breast carcinomas but not in normal breast tissue or ductal carcinoma in situ. Antagonizing IAPs with mimetics of SMAC, which is a known endogenous IAP antagonist, or knockdown of IAPs by siRNA led to greater cell death by TNFα and prevented E2 from promoting cell survival. In addition, a SMAC mimetic reversed TNFα resistance in ER positive breast cancer cells that express high levels of endogenous IAPs. In summary, our findings indicate a new mechanism by which E2 allows breast cancer cells to evade cell death and suggest that an antagonist of IAPs may be a potential therapeutic option for a subset of ER positive breast tumors.