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In the original version of this article, the name of the author "Kamesh Ayasolla" was incorrectly given as "Kamesh Ayyasola". This has now been corrected to "Kamesh Ayasolla" in both the PDF and HTML versions of the article.

BACKGROUND:Congenital diaphragmatic hernia (CDH) is a complex birth anomaly with significant mortality and morbidity. Lung hypoplasia and persistent pulmonary hypertension (PPHN) limit survival in CDH. Macrophage migration inhibitory factor (MIF), a key regulator of innate immunity, is involved in hypoxia-induced vascular remodeling and PPHN. We hypothesized that antenatal inhibition of MIF in CDH fetuses, would reduce vascular remodeling, and improve angiogenesis and lung development. METHODS:Pregnant rats were randomized into three groups: Control, nitrofen, and nitrofen + ISO-92. Lung volumes of pups were measured by CT scanning. Right ventricular systolic pressure (RVSP) and vascular wall thickness (VWT) were measured together with MIF concentration, angiogenesis markers, lung morphometry, and histology. RESULTS:Prenatal treatment with ISO-92, an MIF inhibitor, improved normalization of static lung volume, lung volume-to-body weight ratio, decreased alveolar septal thickness, RVSP and VWT and improved radial alveolar count as compared to the non-treated group. Expression of MIF was unaffected by ISO-92; however, ISO-92 increased p-eNOS and VEGF activities and reduced arginase 1, 2 and Sflt-1. CONCLUSION:Prenatal inhibition of MIF activity in CDH rat model improves angiogenesis and lung development. This selective intervention may be a future therapeutic strategy to reduce the morbidity and mortality of this devastating condition.

BACKGROUND:Colorectal carcinomas are one of the most commonly diagnosed malignancies. There are many prognostic factors relating to clinical course and disease progression, including tumor stage, metastasis, and tumor budding. In 2016, the International Tumor Budding Consensus Conference (ITBCC) created a system to uniformly assess tumor budding. This system includes a 3-tier system for the grading of tumor budding. In the past, there lacked uniform consensus, however the general grading practice was based on a 2-tiered system. Given that tumor budding is considered to have prognostic value, the accuracy and reproducibility of its assessment is vital. Our study aims to look at interobserver agreement in the scoring of tumor budding. DESIGN/METHODS:A total of 233 cases of colorectal carcinoma diagnosed in our health system were retrospectively analyzed and routine H&E stained slides of these cases were collected. A representative slide for tumor budding was selected per case. Four investigators with different levels of experience and expertise evaluated the selected slide of each case for tumor budding. Scoring was based on the ITBCC protocol. Clinico-pathological data was collected for each case and analyzed with tumor budding scores. Tumor budding scores per individual investigator and consensus tumor budding score were compared to patient and tumor characteristics including patient survival, tumor grade, tumor stage, and lymph node status. RESULTS:) and associated 95% confidence intervals was used to compare the ratings made by 4 pathologists. Overall, there was variation among pathologists in tumor budding score (Gwet's agreement coefficient = 0.25 and 0.326 for 3-tier and 2-tier grading system, respectively). Results show higher reliability with the 2-tier system compared to the 3-tier system. Tumor stage was significantly associated with budding score for all individual investigators and the consensus value (p value < 0.001). CONCLUSION/CONCLUSIONS:There is low inter-observer agreement in the assessment of tumor budding in colorectal carcinoma. This suggests that it is difficult to uniformly grade tumor budding and that our classification system needs improvement. We found that the older 2-tier system (Hase et al.) results in slightly higher inter-observer agreement than the recently proposed 3-tier grading system (ITBCC, 2016), though both systems lead to suboptimal agreement. Worth noting is that observers with subspecialty GI training and more work experience had higher inter-observer agreement. Our results showed that subspecialty training tends to increase agreement more than overall work experience. In addition, our exploratory results showed that there is an association of tumor budding score to tumor stage. While increasing refinement in classification, the 3-tiered system resulted in decreased agreement in tumor budding assessment. Clearly, there is more work to be done in the identification and quantification of tumor buds.

Low-grade B-cell lymphoma with immunoglobulin (IG) and interferon regulatory factor 4 (IRF4) gene rearrangement is extremely rare, with only 4 cases being previously reported. In this article, we report one additional case that arises from the skull and review the literature. The patient was a 69-year-old man who presented with recurrent and disabling vertigo and was found to have a 5.0 × 1.7 cm lesion within the left posterior parietal bone. Histological examination revealed a bone lesion with diffuse lymphoid infiltrate comprising of mostly small lymphocytes with scant cytoplasm, slightly irregular nuclei and inconspicuous nucleoli, and scattered larger cells resembling prolymphocytes and paraimmunoblasts. Immunohistochemical studies showed that the neoplastic cells were positive for CD20, CD79a, PAX5, CD23, CD43, BCL-2, BCL-6, MUM-1, LEF-1, and IgM and negative for CD5, CD10, cyclinD1, SOX11, and IgD. Flow cytometric analysis identified CD5 negative and CD10 negative monoclonal B cells with lambda light chain restriction. Fluorescence in situ hybridization analysis revealed del(13q) abnormality, but was negative for IGH/BCL2, IGH/CCND1, and BIRC3/MALT1 translocations. Next-generation sequencing identified IGK-IRF4 rearrangement and BRD4 E1113 del abnormalities. Given a low clinical stage (IE) of the disease, the patient did not receive additional treatments and was free of disease at 1 year after the diagnosis.

BACKGROUND/PURPOSE/OBJECTIVE:Tumor heterogeneity is a now well-recognized phenomenon that can affect the classification, prognosis and treatment of human cancers. Heterogeneity is often described in primary breast cancers based upon histologic subtypes, hormone- and HER2-receptor status, and immunolabeling for various markers, which can be seen within a single tumor as mixed cellular populations, or as separate discrete foci. EXPERIMENTAL DESIGN/METHODS/UNASSIGNED:Here, we present a case report of a patient's primary breast cancer that had two separate but adjacent histologic components, one that was estrogen receptor (ER) positive, and the other ER negative. Each component was subjected to whole exome sequencing and compared for gene identity to determine clonal origin. RESULTS:Using prior bioinformatic tools, we demonstrated that both the ER positive and negative components shared many variants, including passenger and driver alterations. Copy number variations also supported the two components were derived from a single common clone. CONCLUSIONS:These analyses strongly suggest that the two ER components of this patient's breast cancer were derived from the same clonal origin. Our results have implications for the evolution of breast cancers with mixed histologies, and how they might be best managed for optimal therapy.

Primary central nervous system T-cell lymphoma (PCNSTCL) is rare, accounting for 2% of CNS lymphomas. We report the first case of PCNSTCL with aberrant expression of CD20 and CD79a in an 81-year-old man with a left periventricular brain mass. A biopsy revealed dense lymphoid infiltrate consisting of medium-sized cells in a background of gliosis and many histiocytes. The lymphoid cells were positive for CD2, CD3, CD7, CD8, T-cell intracellular antigen-1, granzyme B, CD20, and CD79a and negative for CD4, CD5, PAX-5, OCT-2, BOB-1, human herpes virus-8, and Epstein-Barr virus-encoded small RNAs. Molecular studies revealed clonal TCR-β and TCR-γ gene rearrangements and negative immunoglobulin gene rearrangements. The patient was treated with chemotherapy (vincristine and methotrexate) and rituximab, but he died 1 month after the diagnosis. This is a unique case that emphasizes the use of a multimodal approach, including a broad immunohistochemical panel and molecular studies in lineage determination for lymphomas with ambiguous phenotype.