Intratumoral Immune Responses Can Distinguish New Primary and True Recurrence Types of Ipsilateral Breast Tumor Recurrences (IBTR).

Ipsilateral breast tumor recurrence (IBTR) is an increasingly common clinical challenge. IBTRs include True Recurrences (TR; persistent disease) and New Primaries (NP; de novo tumors), but discrimination between these is difficult. We assessed tumor infiltrating leukocytes (TIL) as biomarkers for distinguishing these types of IBTR using primary tumors and matched IBTRs from 24 breast cancer patients, half of which were identified as putative TRs and half as NPs using a previously reported clinical algorithm. Intratumoral lymphocyte populations (CD3, CD8, CD4, CD25, FOXP3, TIA1, CD20) and macrophages (CD68) were quantified by immunohistochemistry in each tumor. Compared to matched primaries, TRs showed significant trends towards increased CD3(+) and CD8(+) TIL, while these populations were often diminished in NPs. Comparison of IBTRs showed that TRs had significantly higher levels of CD3(+) (P = 0.0136), CD8(+) (P = 0.0092), and CD25(+) (P = 0.0159) TIL than NPs. We conclude that TIL may be a novel diagnostic biomarker to distinguish NP from TR IBTRs.

iNOS in cardiac myocytes plays a critical role in death in a murine model of hypertrophy induced by calcineurin.

Transgenic overexpression of calcineurin (CN/Tg) in mouse cardiac myocytes results in hypertrophy followed by dilation, dysfunction, and sudden death. Nitric oxide (NO) produced via inducible NO synthase (iNOS) has been implicated in cardiac injury. Since calcineurin regulates iNOS expression, and since phenotypes of mice overexpressing iNOS are similar to CN/Tg, we hypothesized that iNOS is pathogenically involved in cardiac phenotypes of CN/Tg mice. CN/Tg mice had increased serum and cardiac iNOS levels. When CN/Tg-iNOS(-/-) and CN/Tg mice were compared, some phenotypes were similar: extent of hypertrophy and fibrosis. However, CN/Tg-iNOS(-/-) mice had improved systolic performance (P < 0.001) and less heart block (P < 0.0001); larger sodium current density and lower serum TNF-alpha levels (P < 0.03); and less apoptosis (P < 0.01) resulting in improved survival (P < 0.0003). To define tissue origins of iNOS production, chimeric lines were generated. Bone marrow (BM) from wild-type or iNOS(-/-) mice was transplanted into CN/Tg mice. iNOS deficiency restricted to BM-derived cells was not protective. Calcineurin activates the local production of NO by iNOS in cardiac myocytes, which significantly contributes to sudden death, heart block, left ventricular dilation, and impaired systolic performance in this murine model of cardiac hypertrophy induced by the overexpression of calcineurin.

Celiac disease: are endomysial antibody test results being used appropriately?

BACKGROUND: The aim of this study was to retrospectively examine how positive IgA-endomysial antibody (EMA) test results for celiac disease were being interpreted and acted on by physicians in the Calgary Health Region. METHODS: We reviewed consecutive EMA test results, with or without a serum IgA, obtained during a 17-month period. Seropositive tests were cross-referenced to the surgical database to determine the number of patients who underwent intestinal biopsy and the results of the biopsy. We sent questionnaires to the ordering physicians of positive tests with no record of intestinal biopsy. RESULTS: Among 11,716 EMA tests in 9533 patients, 349 results were positive in 313 patients (3%). Intestinal biopsies were performed in 218 (70%) of the seropositive patients; 194 of them were diagnostic of celiac disease. Celiac disease was also found in 10 EMA-negative patients. Of the 109 positive tests performed in 95 patients with no subsequent biopsy, 28 had appropriate indications to not perform a biopsy; the most common reason being that the test had been ordered to follow up on a previous biopsy-proven diagnosis of celiac disease (n = 21). For 33 other positive test results without a subsequent biopsy, management appeared to be inappropriate, most commonly (n = 21) because of a recommendation to follow a gluten-free diet despite lack of a tissue diagnosis of celiac disease. For the remaining 48 positive EMA results, administrative issues prevented evaluation (n = 19), the patients refused further evaluation (n = 11), or physician surveys were not returned (n = 18). CONCLUSIONS: Celiac disease affected 2% of patients, with a similar prevalence in male and female patients. Most positive EMA tests (77%) were appropriately managed by physicians. Beginning a gluten-free diet without biopsy or failing to follow up on a positive EMA test remain common errors of management.