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Background: HER2 status assessment is a prerequisite for the establishment of an appropriate treatment strategy in gastric cancer. Gastric cancers are very heterogeneous and separate evaluations of gene amplification and protein expression lead to uncertainties in localizing distinct clones and are time consuming. This study evaluates the equivalence of the novel method combining both gene and protein platforms on one slide.
Methods: Immunohistochemistry (IHC) and HER2 dual-colour silver in situ hybridization (SISH) as single methods (IHC/SISH) and gene-protein platform combining both methods on one slide (gene/protein) were performed in randomly collected 100 cases of gastric adenocarcinoma. Results of IHC/SISH were compared with gene/protein staining.
Results: 96 of 100 samples were assessable. In the gene/protein staining, pathologists were able to assess gene amplification and consequent protein expression at the single cell level. In comparison trials, gene amplification was observed in 14.6% by both, conventional SISH and gene/protein platform (agreement 100%; Kappa-coefficient κ = 1.0). Protein expression scores by IHC were 70.8% (0), 10.4% (1+), 9.4% (2+), and 9.4% (3+). Protein expression by gene/protein method were: 70.8% (0), 11.5% (1+), 7.3% (2+) and 10.4% (3+) of patients. There were complete concordances in IHC assessment of cases with score 0 (100.0%; κ = 1). High concordances are shown in score 1+ (98.96%; κ = 0.947) and 3+ (96.88%; κ = 0.825) cases and good concordances in 2+ cases (95.83%; κ = 0.728).
Conclusions: This novel combined platform has the advantage of being able to evaluate both gene and the protein status in the same cancer cell and may be of particular interest for research and patient's care.
Injury of the sciatic nerve results in regulations of pro- and anti-oxidative enzymes at sites of nociceptive signaling including the injured nerve, dorsal root ganglia (DRGs), dorsal horn of the spinal cord, thalamus and somatosensory cortex (Valek et al., 2015) [1]. The present DiB paper shows immunohistochemistry of redoxins including peroxiredoxins (Prdx1–6), glutaredoxins (Glrx1, 2, 3, 5), thioredoxins (Txn1, 2) and thioredoxin reductases (Txnrd1, 2) in the DRGs, spinal cord and sciatic nerve and thalamus in naïve mice and 7 days after Spared sciatic Nerve Injury (SNI) in control mice (Hif1α-flfl) and in mice with a specific deletion of hypoxia inducible factor 1 alpha (SNS-HIF1α−/−) in DRG neurons. The sciatic nerves were immunostained for the respective redoxins and counterstained with hematoxylin. The redoxin immunoreactivity was quantified with ImageJ. For the DRGs and spinal cord the data show the quantitative assessment of the intensity of redoxin immunoreactivity transformed to rainbow pseudocolors. In addition, some redoxin examples of the ipsi and contralateral dorsal and ventral horns of the lumbar spinal cord and some redoxin examples of the thalamus are presented.
Background: HER2 (ERBB2 or HER2/neu) is a tyrosine-kinase increasing cell proliferation. Overexpression/amplification of HER2 is correlated with worse prognosis in solid malignancies. Consequently, HER2 targeting is established in breast and upper gastrointestinal tract cancer. There are conflicting data concerning the impact of HER2 overexpression on esophageal adenocarcinoma (EAC), as most studies do not differ between cancers of the esophagus/gastroesophageal junction and the stomach. The aim of this study was to analyze the expression/amplification of HER2 in EAC in correlation to clinicopathological data to verify its prognostic impact.
Methods: We analyzed 428 EAC patients that underwent transthoracic thoraco-abdominal esophagectomy between 1997 and 2014. We performed HER2 immunohistochemistry (IHC) according to the guidelines and fluorescence-in-situ-hybridization (FISH) for IHC score2+, using tissue micro arrays (TMA) with up to eight biopsies from the surface and infiltration area of a single tumor for evaluating HER2-heterogeneity and single-spot TMA. The HER2-status was correlated with clinicopathological data.
Results: HER2-positivity was found in up to 14.9% in our cohort (IHC score 3+ or IHC score 2+ with gene amplification) and demonstrated a significantly better overall survival (OS) in correlation to HER2-negative tumors (median OS 70.1 vs. 24.6 months, p = 0.006). HER2-overexpression was more frequently seen in lower tumor stages (pT1/pT2, p = 0.038), in the absence of lymphatic metastases (pN0/pN+, p = 0.020), and was significantly associated with better histological grading (G1/G2) (p = 0.041).
Conclusion: We demonstrated a positive prognostic impact of HER2 overexpression in a large cohort of EAC, contrary to other solid malignancies including gastric cancer and breast cancer, but consistent to the results of a large study on EAC from 2012.
Primary breast lymphoma accounts for 0.04%-0.5% of all breast malignancies. Primary non-Hodgkin’s lymphomas of the breast are extremely rare and represent approximately 0.38%-0.7% of all cases. Epstein-Barr virus (EBV) has been postulated to play an important role in the pathogenesis of Hodgkin’s lymphoma. We present a case of EBV-positive primary Hodgkin’s lymphoma of the breast. Although there is no sufficient data on this challenging diagnosis, it is known that it could be misdiagnosed with inflammatory breast carcinoma. A crucial part of the proper histopathologic diagnosis is immunohistochemistry. Different modalities of treatment include operative procedure, chemotherapy and radiotherapy. Recent studies suggest chemotherapy and radiotherapy to be initial treatment for patients with primary breast lymphomas.
Cytochrome P450 (CYP) signalling pathway has been shown to play a vital role in the vasoreactivity of wild type mouse ophthalmic artery. In this study, we determined the expression, vascular responses and potential mechanisms of the CYP-derived arachidonic acid metabolites. The expression of murine CYP (Cyp2c44) and soluble epoxide hydrolase (sEH) in the wild type ophthalmic artery was determined with immunofluorescence, which showed predominant expression of Cyp2c44 in the vascular smooth muscle cells (VSMC), while sEH was found mainly in the endothelium of the wild type ophthalmic artery. Artery of Cyp2c44−/− and sEH−/− mice were used as negative controls. Targeted mass spectrometry-based lipidomics analysis of endogenous epoxide and diols of the wild type artery detected only 14, 15-EET. Vasorelaxant responses of isolated vessels in response to selective pharmacological blockers and agonist were analysed ex vivo. Direct antagonism of epoxyeicosatrienoic acids (EETs) with a selective inhibitor caused partial vasodilation, suggesting that EETs may behave as vasoconstrictors. Exogenous administration of synthetic EET regioisomers significantly constricted the vessels in a concentration-dependent manner, with the strongest responses elicited by 11, 12- and 14, 15-EETs. Our results provide the first experimental evidence that Cyp2c44-derived EETs in the VSMC mediate vasoconstriction of the ophthalmic artery.
Objectives: To immunohistochemically characterize and correlate macrophage M1/M2 polarization status with disease severity at peri-implantitis sites.
Materials and methods: A total of twenty patients (n = 20 implants) diagnosed with peri-implantitis (i.e., bleeding on probing with or without suppuration, probing depths ≥ 6 mm, and radiographic marginal bone loss ≥ 3 mm) were included. The severity of peri-implantitis was classified according to established criteria (i.e., slight, moderate, and advanced). Granulation tissue biopsies were obtained during surgical therapy and prepared for immunohistological assessment and macrophage polarization characterization. Macrophages, M1, and M2 phenotypes were identified through immunohistochemical markers (i.e., CD68, CD80, and CD206) and quantified through histomorphometrical analyses.
Results: Macrophages exhibiting a positive CD68 expression occupied a mean proportion of 14.36% (95% CI 11.4–17.2) of the inflammatory connective tissue (ICT) area. Positive M1 (CD80) and M2 (CD206) macrophages occupied a mean value of 7.07% (95% CI 5.9–9.4) and 5.22% (95% CI 3.8–6.6) of the ICT, respectively. The mean M1/M2 ratio was 1.56 (95% CI 1–12–1.9). Advanced peri-implantitis cases expressed a significantly higher M1 (%) when compared with M2 (%) expression. There was a significant correlation between CD68 (%) and M1 (%) expression and probing depth (PD) values.
Conclusion: The present immunohistochemical analysis suggests that macrophages constitute a considerable proportion of the inflammatory cellular composition at peri-implantitis sites, revealing a significant higher expression for M1 inflammatory phenotype at advanced peri-implantitis sites, which could possibly play a critical role in disease progression.
Clinical relevance: Macrophages have critical functions to establish homeostasis and disease. Bacteria might induce oral dysbiosis unbalancing the host’s immunological response and triggering inflammation around dental implants. M1/M2 status could possibly reveal peri-implantitis’ underlying pathogenesis.
The prognostic impact of epidermal growth factor receptor in patients with metastatic gastric cancer
(2012)
Background: The epidermal growth factor receptor (EGFR) is a potential target of anticancer therapy in gastric cancer. However, its prognostic role in metastatic gastric or gastroesophageal junction (GE) cancer has not been established yet.
Methods: EGFR status was analyzed by immunohistochemistry (IHC) in paraffin-embedded samples from 357 patients who received chemotherapy in 4 first-line trials. Automated RNA extraction from paraffin and RT-quantitative PCR were additionally used to evaluate EGFR mRNA expression in 130 patients.
Results: EGFR protein expression (any grade) and overexpression (3+) were observed in 43% and 11% of patients, respectively. EGFR positivity correlated with intestinal type histology (p = 0.05), but not with other clinicopathologic characteristics. Median follow-up was 18.2 months. Median overall survival (OS) was similar in patients with EGFR positive vs. those with EGFR negative tumors, regardless whether positivity was defined as ≥1+ (10.6 vs. 10.9 months, p = 0.463) or as 3+ (8.6 vs. 10.8 months, p = 0.377). The multivariate analysis indicated that EGFR status is not an independent prognostic factor (hazard ratio 0.85, 0.56 to 1.12, p = 0.247). There were also no significant differences in overall survival when patients were categorized according to median (p = 0.116) or quartile (p = 0.767) distribution of EGFR mRNA gene expression. Similar distributions of progression-free survival according to EGFR status were observed.
Conclusions: Unlike different cancer types where EGFR-positive disease is associated with an adverse prognostic value, EGFR positivity is not prognostic of patient outcome in metastatic gastric or GE cancer.