The role of tissue IgG4 levels in steroid therapy in patients with idiopathic granulomatous mastitis.

Idiopathic granulomatous mastitis (IGM) is a benign, chronic inflammatory lesion of the breast. Immunoglobulin G4 (IgG4) associated disease is rare in the breast. In our study, we aimed to evaluate the efficacy of steroid treatment on IgG4 levels in tissue in patients diagnosed with IGM. Between 2008 and 2017, 55 patients diagnosed with IGM in our clinic were included in the study. Demographic, clinical, microbiologic and histopathologic characteristics, treatment modality and recovery time were evaluated retrospectively. Patients were divided into 3 groups according to tissue IgG4 levels: negative (Group I), infrequently and slightly positive (Group II), and highly positive (Group III). Group I patients had a complete response rate of 77.8%. In the rest of the patients (22.2%), insufficient response was detected from the beginning of the treatment. In Group II, the response rate was 91.3% and the permanent success rate after treatment was 87.0%. Although group III patients had a complete response at the beginning (95.65%), they relapsed in a short period of time (26.1%) after discontinuation of steroid treatment. At least one steroid-related side effect was observed in 47 (85.8%) patients in all groups. There is no consensus on the dose and duration of immunosuppressive treatment in IGM. In this study, responses to steroid treatment according to IgG4 concentration in pathologic breast tissue and recurrences after the end of treatment were determined. We think that high IgG4 concentration in the tissue is associated with recurrence and other immunosuppressive drugs should be added as maintenance after steroid treatment.

Is There Any Association Between Mammographic Features of Microcalcifications and Breast Cancer Subtypes in Ductal Carcinoma In Situ?

RATIONALE AND OBJECTIVES: To analyze the association between mammographic features of microcalcifications and histopathological prognostic factors based on estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2/neu) in ductal carcinoma in situ (DCIS). MATERIALS AND METHODS: We retrospectively determined 66 patients with microcalcification-associated pure DCIS. Distribution and morphological features of the microcalcifications were described using Breast Imaging Reporting and Data System lexicon. All patients were divided into three subgroups: ER-positive, HER-2 positive, and triple-negative according to the immunohistochemical findings. RESULTS: The morphological features of microcalcifications and receptor subtypes were significantly correlated (p = 0.026). Fine pleomorphic and fine linear branching microcalcifications were observed in 85.2% of HER-2 positive cases, whereas this ratio was 71.4 % in ER-positive and 25% in the triple-negative group. Fine linear branching microcalcifications with linear or segmental distribution were more frequently found with comedo necrosis (p < 0.05). Larger tumour sizes were also associated with microcalcification distribution (p < 0.001). Segmental microcalcifications more likely associated with larger tumour sizes. CONCLUSION: Mammographic features in DCIS correlated with immunohistochemical and histopathological prognostic factors.

Evaluation of Plasma Urokinase-Type Plasminogen Activator Receptor (UPAR) in Patients With Chronic Hepatitis B, C and Non-Alcoholic Fatty Liver Disease (NAFLD) as Serological Fibrosis Marker.

BACKGROUND/AIMS: Progressive hepatic fibrosis is the main predictor of outcome and prognosis in chronic liver diseases. The importance of the coagulation cascade has been defined in liver fibrosis; however, the role of the fibrinolytic pathway has not been clear yet. We aimed to evaluate the association between the plasma levels of soluble urokinase Plasminogen Activator Receptor (uPAR) and the severity of liver fibrosis in chronic hepatitis B, C and Non-Alcoholic Fatty Liver Disease (NAFLD). METHODS: 96 chronic hepatitis B, 22 chronic hepatitis C and 11 NAFLD patients together with 47 healthy controls were enrolled in the study. uPAR plasma levels were detected by Enzyme-Linked Immunosorbent Assay (ELISA) method. RESULTS: The plasma levels of uPAR in patients with chronic hepatitis B and C significantly exceeded those of healthy controls (P < 0.001) while mean uPAR levels in patients with NAFLD were not different from healthy controls. Mean uPAR levels in chronic viral hepatitis patients with F1-F3 fibrosis and F4-F6 fibrosis were higher than those of control group (P < 0.001). Mean uPAR level in patients with F4-F6 fibrosis was significantly higher than that of patients with F1-F3 fibrosis (P < 0.001). CONCLUSION: This is the first study that investigated uPAR as a fibrosis marker in NAFLD and chronic hepatitis B patients. It is suggested that plasma levels of uPAR are closely related to the fibrosis stage in chronic hepatitis B and C and that uPAR might be a noninvasive marker of liver fibrosis.

Dual actions of the antioxidant chlorophyllin, a glutathione transferase P1-1 inhibitor, in tumorigenesis and tumor progression.

Glutathione (GSH) and enzymes related to this antioxidant molecule are often overexpressed in tumor cells and may contribute to drug resistance. Blockade of glutathione transferases (GSTs) has been proposed to potentiate the efficacy of chemotherapeutic drugs in cancer. The aim of this study was to evaluate the effect of chlorophyllin that has antioxidant properties, and also interferes with the activity of GST P1-1, on breast cancers in vitro and in vivo. The in vivo studies were conducted using an N-methyl- N-nitrosourea (MNU)-induced chemical carcinogenesis model in laboratory rats. DNA damage, GST activity, and GSH levels were determined in liver and tumor tissues. Treatment with chlorophyllin increased the GSH levels in the liver and significantly decreased DNA damage in the blood, liver, and tumor tissues. Even though tumorigenesis was delayed in rats receiving chlorophyllin before MNU injections, once the tumors emerged, the progression of tumor appeared to be faster than in the animals that received the carcinogen only. Out of nine breast cell lines, GST P1-1 expression was detected in MCF-12A, MDA-MB-231, and HCC38. Concomitant incubation with chlorophyllin and docetaxel did not significantly affect cell proliferation and viability. Chlorophyllin displayed genoprotective effects that initially delayed tumorigenesis. However, once the tumors were established, it may act as a promoter that facilitates tumor growth, potentially by a mechanism independent of cell proliferation and viability. Our results underline the pros and cons of antioxidant treatment in cancer, even if it has a capacity to inhibit GST P1-1.

Therapeutic efficacy of folate receptor-targeted amphiphilic cyclodextrin nanoparticles as a novel vehicle for paclitaxel delivery in breast cancer.

PURPOSE: The aim of this study is to test folate-conjugated cyclodextrin nanoparticles (FCD-1 and FCD-2) as a vehicle for reducing toxicity and increasing the antitumor efficacy of paclitaxel especially for metastatic breast cancer. METHODS: For the evaluation of PCX-loaded FCD nanoparticles, animal studies were realised in terms of survival rate, tumour size, weight change, metastazis and histopathological examination. RESULTS: FCD-1 displayed significant advantages such as efficient targeting of folate receptor positive breast cancer cells and having considerably lower toxicity compared to that of Cremophor®. When loaded with paclitaxel, FCD-1 nanoparticles, which have smaller particle size, neutral zeta potential, high encapsulation efficiency and better loading capacity for controlled release, emerged as an effective formulation in terms of cytotoxicity and high cellular uptake. In an experimental breast cancer model, anticancer activity of these nanoparticles were compatible with that of paclitaxel in Cremophor® however repeated administrations of FCD-1 nanoparticles were better tolerated by the animals. These nanoparticles were able to localise in tumour site. Both paclitaxel-loaded FCD-1 and FCD-2 significantly reduced tumour burden while FCD-1 significantly improved the survival. CONCLUSIONS: Folate-conjugated amphiphilic cyclodextrin nanoparticles can be considered as promising Cremophor®-free, low-toxicity and efficient active drug delivery systems for paclitaxel.

ACOX2 deficiency: A disorder of bile acid synthesis with transaminase elevation, liver fibrosis, ataxia, and cognitive impairment.

Acyl CoA Oxidase 2 (ACOX2) encodes branched-chain acyl-CoA oxidase, a peroxisomal enzyme believed to be involved in the metabolism of branched-chain fatty acids and bile acid intermediates. Deficiency of this enzyme has not been described previously. We report an 8-y-old male with intermittently elevated transaminase levels, liver fibrosis, mild ataxia, and cognitive impairment. Exome sequencing revealed a previously unidentified homozygous premature termination mutation (p.Y69*) in ACOX2 Immunohistochemistry confirmed the absence of ACOX2 expression in the patient's liver, and biochemical analysis showed marked elevation of intermediate bile acids upstream of ACOX2. These findings define a potentially treatable inborn error of bile acid biosynthesis caused by ACOX2 deficiency.

Crizotinib-induced toxicity in an experimental rat model.

AIM: The aim of the present study was to evaluate the effect of crizotinib on visceral organs in an experimental rat model. METHODS: Eighteen Wistar albino rats were divided into three groups: experimental toxicity was induced with crizotinib (10 mg/kg) administered for 28 days (Group 1), 42 days (Group 2) orally by gavage. Control group received only distilled water. Rats in Group 1 and Group 2 were sacrificed after the collection of blood and tissue samples on the 28th and 42nd days, respectively. RESULTS: Subjects in Group 1 and Group 2 had abnormal histology mainly in lung and liver. There were intraalveolar hemorrhage in lungs; mild portal inflammation, perivenular focal and confluent necrosis in liver; inflammatory reaction in renal pelvis and periureteral areas, and focal pancreatitis in pancreas. CONCLUSION: This study is the first to evaluate the histopathological features of toxicity of crizotinib in a rat model.

CRAM-A indicates IFN-γ-associated inflammatory response in breast cancer.

Atypical chemokine receptors (ACKRs) function as endpoint regulators of chemokine gradients. These non-signaling receptors that are transiently expressed under inflammatory conditions have critical roles in the control or maintenance of immune responses. Alternatively, here, CCRL2 (ACKR5) expression was determined to be constitutive in breast cancer cells. Increased amount of CCRL2 was also found in breast tumor tissues with high immune infiltration. Its expression was upregulated in the presence of pro-inflammatory cytokines, IL-1ß, TNF-α, IL-6, and especially IFN-γ⋅ Moreover, an alternative transcript of CCRL2 gene, CRAM-A, was specifically expressed in a transient fashion under the influence of IFN-γ. CRAM-A expression was also positively correlated with the presence of IFN-γ mRNA in patient samples. CCRL2-associated chemotactic molecules, chemerin, CCL19 and CCL5, were also detected in cancer tissues and CCL5 mRNA level was correlated with that of CRAM-A and IFN-γ. Hence, in breast cancer, CRAM-A becomes specifically upregulated under inflammatory stimuli and may serve as a potential marker of immune response.

Pathologic basis of pyogenic, nonpyogenic, and other spondylitis and discitis.

Pyogenic spondylitis and discitis are usually seen following a recent infection or surgery. A septic embolus causes an infarcted area within the bone. Pyogenic spondylitis is characterized by edema, vascular leakage, and supportive inflammatory reaction characterized with polymorphonuclear leukocytes. In tuberculosis of the spine, active lesions are characterized by formation of epithelioid granulomas with central caseating necrosis. Mycobacterium tuberculosis can be shown by histochemical stains for acid-fast bacteria or by immunochemistry. In brucella spondylitis, microgranulomatous proliferation composed of histiocytes containing numerous bacilli without caseating necrosis is characteristic. Brucella melitensis can be shown on histochemical Gram stain.