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.

Serum Biglycan as a Diagnostic Marker for Non-Alcoholic Steatohepatitis and Liver Fibrosis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) has risen in prevalence substantially through the years. Although course and progression of the disease are variable, fibrosis is the most important factor. We intended to explore utility of serum biglycan (BGN) in NASH and its capacity in anticipating liver fibrosis. METHODS: Serum tests of consecutive patients with biopsy-confirmed NASH and age, gender-matched healthy volunteers were utilized to evaluate serum BGN levels using ELISA kits. The correlation between BGN and histopathological highlights of NASH was examined. While patients with fibrosis scores < 2 were assembled in mild and scores of (≥ 2) were in significant fibrosis groups. Univariate/multivariate regression analyses were performed to assess the independent predictive variables of liver fibrosis. Receiver operating characteristics (ROC) were applied to locate the best cutoff values of BGN for NASH and fibrosis. RESULTS: Seventy patients with NASH and 70 controls were recruited in the study. BGN levels were lower in NASH patients contrasted with controls 137.70 ± 33.12 pg/mL vs. 259.61 ± 187.34 pg/mL, respectively, and p < 0.001. In correlation, serum BGN was related to liver fibrosis and inflammation. The comparison between mild and significant fibrosis groups regarding BGN was as follows 155.92 ± 49.97 pg/mL vs. 390.07 ± 214.746 pg/mL, respectively, (p < 0.001). In multivariate analyses, BGN was an independent predictive factor of significant fibrosis (OR, 1.030; 95% CI: 1.011 - 1.048; p < 0.001). ROC analysis revealed that BGN was statistically significant in determination of significant fibrosis (AUROC, 0.955; 95% CI, 0.877 - 0.990; p < 0.001). Best cutoff value was 189.58 pg/mL with the best sensitivity (93.55%) and specificity (87.18%). CONCLUSIONS: Serum BGN may be a new non-invasive indicative marker for the presence of NASH, significant fibrosis, and a treatment goal in the disease process.

Hepatocellular adenomas in the Turkish population: reclassification according to updated World Health Organization criteria.

AIMS: Hepatocellular adenoma (HCA) is an uncommon liver neoplasm, and studies of HCA subtypes have been primarily limited to France, the USA, and Japan. The aim of this study was to describe the clinicopathological features of HCA subtypes in Turkey. METHODS AND RESULTS: The resection specimens of 59 cases diagnosed as 'hepatocellular adenoma' collected from 15 institutions were reviewed to confirm the diagnosis and to classify them according to the current World Health Organization 2019 classification. Immunostaining for glutamine synthetase, liver fatty acid-binding protein, C-reactive protein, ß-catenin and reticulin was performed. Of the 59 cases, 48 (81%) were diagnosed as HCA. We identified 24 (50%) hepatocyte nuclear factor 1α (HNF1α)-inactivated HCAs, five (10%) inflammatory HCAs, 15 (32%) ß-catenin-activated HCAs, three (6%) ß-catenin-activated inflammatory HCAs, and one (2%) unclassified HCA. HCA patients were predominantly female (female/male ratio of 5:1); they had a median age of 34 years and a median tumour diameter of 60 mm. In the ß-catenin-activated HCA group, nine cases (19%) showed cytoarchitectural atypia, and were also referred to as atypical hepatocellular neoplasms. In the ß-catenin-activated HCA group, three cases (6%) showed focal areas supportive of transition to HCA. The original diagnosis of HCA was changed to well-differentiated hepatocellular carcinoma in nine cases and to focal nodular hyperplasia in two cases. CONCLUSION: In our series, the major HCA subtype was HNF1α-inactivated HCA. We found a low incidence of inflammatory-type HCA. Our data also showed that ß-catenin-activated hepatocellular neoplasms, including cases with atypical histology, constituted a relatively high proportion of the cases. These findings are in contrast to those of most other studies of HCA subtypes.

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.

Is there any relationship between Helicobacter pylori infection and human epidermal growth factor receptor 2 expression in gastric cancer?

PURPOSE: Helicobacter pylori(HP) is a significant causative agent of gastric cancer (GC). However, the underlying mechanisms involved in its pathogenesis and association with oncoproteins are unclear. The aim of the present study was to evaluate the relationship between HP infection and human epidermal growth factor receptor 2 (HER2) expression in GC patients. MATERIALS AND METHODS: Surgery (173) or endoscopic biopsy (35) specimen of 208 patients diagnosed with GC was evaluated for the presence of HER2 and HP. HER2 expression was assessed by fluorescence in situ hybridization (FISH) method, whereas HP status was evaluated histologically. Giemsa stain was used to identify HP status, in case HP could not be recognized in routine H and E-stained sections despite careful examination. RESULTS: The median age was 63 years (27-91), and most patients were male (male/female: 149/59). Of all the 208 patients, HP was positive in 87 (41.8%) and negative in 121 (58.2%) patients. FISH positivity for HER2 was observed in 41 (19.7%) patients, whereas FISH negativity was observed in 167 (80.3%) patients. According to the Chi-square test, patient distribution was 21 in HER2-positive HP-negative group, 20 in HER2-positive HP-positive group, 100 in HER2-negative HP-negative group, and 67 in HER2-negative HP-positive group. No correlation was found between HP and HER2 status (P = 0.314). HP positivity had significant effect on median overall survival (27.4 vs. 12.9 months, P = 0.046). CONCLUSIONS: Our results suggest that there is no relationship between HP infection and HER2 status in patients with GC.

Structural Characteristics in the γ Chain Variants Associated with Fibrinogen Storage Disease Suggest the Underlying Pathogenic Mechanism.

Particular fibrinogen γ chain mutations occurring in the γ-module induce changes that hamper γ-γ dimerization and provoke intracellular aggregation of the mutant fibrinogen, defective export and plasma deficiency. The hepatic storage predisposes to the development of liver disease. This condition has been termed hereditary hypofibrinogenemia with hepatic storage (HHHS). So far, seven of such mutations in the fibrinogen γ chain have been detected. We are reporting on an additional mutation occurring in a 3.5-year-old Turkish child undergoing a needle liver biopsy because of the concomitance of transaminase elevation of unknown origin and low plasma fibrinogen level. The liver biopsy showed an intra-hepatocytic storage of fibrinogen. The molecular analysis of the three fibrinogen genes revealed a mutation (Fibrinogen Trabzon Thr371Ile) at exon 9 of the γ chain in the child and his father, while the mother and the brother were normal. Fibrinogen Trabzon represents a new fibrinogen γ chain mutation fulfilling the criteria for HHHS. Its occurrence in a Turkish child confirms that HHHS can present in early childhood and provides relevant epidemiological information on the worldwide distribution of the fibrinogen γ chain mutations causing this disease. By analyzing fibrinogen crystal structures and calculating the folding free energy change (ΔΔG) to infer how the variants can affect the conformation and function, we propose a mechanism for the intracellular aggregation of Fibrinogen Trabzon and other γ-module mutations causing HHHS.

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.

The effect of Helicobacter pylori eradication on functional dyspepsia in Turkish children.

BACKGROUND: The aim of this study was to evaluate the effect of Helicobacter pylori (H. pylori) eradication on dyspepsia symptom scores in children with functional dyspepsia (FD). MATERIALS AND METHODS: One hundred and fifty functional dyspeptic children (ages 8-18 years, mean: 13.3 ± 2.84 years; 30% male) were enrolled to this prospective study. Upper gastrointestinal endoscopy was performed on all patients, and the samples from the gastric antrum and corpus were obtained for the existence of H. pylori. 13 Carbon-urea breath test was performed to evaluate the eradication therapy's efficacy. The symptoms were assessed at first visit and at the 8th week and 16th week. RESULTS: Forty-nine (33%) children were in the H. pylori-positive group, and 101 (67%) children were in the H. pylori-negative group. Dyspepsia symptom scores improved at 8th week in both groups (P < .05). Helicobacter pylori was eradicated in 30 patients (61%), while in the H. pylori-eradicated group, all dyspepsia symptoms' scores decreased, and in the H. pylori-uneradicated group, only three symptoms' scores decreased. Symptom scores were lower in H. pylori-eradicated group than H. pylori-uneradicated group. CONCLUSIONS: Although the tests used for the diagnosis of H. pylori in functional dyspeptic patients increased the cost of health care, the dyspepsia symptom scores decreased with the eradication therapy in a high prevalence community. The findings may differ in low prevalence communities where the diagnostic tests for H. pylori infection are not recommended in children in the absence of alarm signs or symptoms.

Sevoflurane exerts brain-protective effects against sepsis-associated encephalopathy and memory impairment through caspase 3/9 and Bax/Bcl signaling pathway in a rat model of sepsis.

Objective We compared the effects of sevoflurane and isoflurane on systemic inflammation, sepsis-associated encephalopathy, and memory impairment in a rat sepsis model of cecal ligation and puncture (CLP)-induced polymicrobial peritonitis. Methods Twenty-four rats were assigned to sham, CLP, CLP + sevoflurane, and CLP + isoflurane groups. At 72 hours after CLP, the rats underwent behavior tests. Serum cytokines were evaluated. Brain tissue samples were collected for determination of glutathione peroxidase (GPX), superoxide dismutase (SOD), and catalase; the wet/dry weight ratio; myeloperoxidase (MPO) and malondialdehyde (MDA); apoptotic gene release; and histologic examinations. Results The MPO level, wet/dry weight ratio, and histopathology scores were lower and the Bcl2a1 and Bcl2l2 expressions were upregulated in both the CLP + sevoflurane and CLP + isoflurane groups compared with the CLP group. The interleukin-6, interleukin-1ß, MDA, and caspase 3, 8, and 9 levels were lower; the GPX, SOD, Bax, Bcl2, and Bclx levels were higher; and non-associative and aversive memory were improved in the CLP + sevoflurane group compared with the CLP + isoflurane group. Conclusion Sevoflurane decreased apoptosis and oxidative injury and improved memory in this experimental rat model of CLP. Sevoflurane sedation may protect against brain injury and memory impairment in septic patients.

Pazopanib-Induced Hepatotoxicity in an Experimental Rat Model.

Pazopanib is an effective treatment for advanced renal cell carcinoma and soft tissue sarcoma. Besides classical adverse events of this drug class, hepatotoxicity has been described as a frequent side effect. The aim of the present study was to evaluate the effect of pazopanib on the liver in an experimental rat model. Sixteen Wistar albino rats were divided into 3 groups: experimental toxicity was induced with pazopanib (10 mg/kg) administered for 28 days (group 2) or 56 days (group 3) orally by gavage. Group 1 (control group) received only distilled water. Rats in groups 2 and 3 were sacrificed after the collection of blood and tissue samples on the 28th and 56th days, respectively. We found significant differences in bilirubin, alkaline phosphatase, lactate dehydrogenase, glucose, triglyceride, very-low-density lipoprotein, and iron values (p < 0.050 for all) but none in any other parameter (p > 0.050). All rats in the control group had normal histological features; however, none of the rats in groups 2 and 3 showed normal histology. In group 2, we observed mild sinusoidal dilatation, congestion, enlarged Kupffer cells, accumulation of yellow-brown-black pigment in the Kupffer cells and the accumulation of hemosiderin with Prussian blue reaction in the hepatocytes. In group 3, the findings mentioned above were more prominent, and besides these findings focal acinar transformation and macrovesicular steatosis were also observed. In group 3, mild inflammation within the portal areas was observed consisting of lymphocytes, neutrophils, and eosinophils. This study is the first that reports the biochemical and histopathological evaluation of pazopanib-related hepatic toxicity.

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.

Determination of certain bacterial groups in gut microbiota and endotoxin levels in patients with nonalcoholic steatohepatitis.

BACKGROUND/AIMS: In recent years, the role of the gut microbiota has emerged in several diseases. Herein we aimed to determine the fecal microbiota, endotoxin levels, and inflammation markers in patients with nonalcoholic steatohepatitis (NASH) and healthy controls. MATERIALS AND METHODS: A total of 46 NASH patients and 38 healthy controls were included. NASH patients were diagnosed according to the steatosis, activity, and fibrosis score/fatty liver inhibition of progression algorithm. 16S rRNA gene-targeted specific primers were used for quantification of certain bacterial groups, and a plasmid library was constructed and sequenced in order to determine dominant Lactobacillus and Bifidobacterium members in patients and controls. RESULTS: Significantly decreased Akkermansia muciniphila and increased Enterobacteriaceae levels were determined in patients compared to healthy controls even after adjusting for the body mass index (BMI) and age. Patients with ≥F2 fibrosis had significantly higher Enterobacteriaceae levels compared to F0-F1 fibrosis. Serum endotoxin and high-sensitivity C-reactive protein levels were significantly higher in patients group. According to the sequencing results, L. reuteri, which was one of the dominant Lactobacillus species in the patient group, could not be detected in healthy controls. Bifidobacterium infantis was found in the patients' feces but not in the controls. CONCLUSION: We demonstrated a BMI and age-independent association between the presence of NASH and levels of A. muciniphila and Enterobacteriaceae as well as increased endotoxin levels. L. reuteri was abundant in the patient group, suggesting that dominant Lactobacillus species should be considered before probiotic treatments.

Iron Overload in the Liver of 2 Children: Nonalcoholic Steatohepatitis and Juvenile Hemochromatosis.

BACKGROUND: Iron overload disorders are hereditary hemochromatosis and secondary etiologies other than hereditary hemochromatosis. We describe 2 boys presenting with iron overload. Juvenile hemochromatosis and nonalcoholic steatohepatitis (NASH) related iron overload are the genetic and secondary causes, respectively. OBSERVATIONS: Both patients benefited from phlebotomy even if they had different etiologies. CONCLUSIONS: In childhood, the diagnosis of iron overload syndromes is crucial because they do not confront us with obvious symptoms and findings. Early initiation of a phlebotomy program can prevent mortality. NASH might lead to iron overload and iron overload might aggravate the clinical course of NASH.

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.

Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension.

UNLABELLED: Despite advances in the diagnosis and management of idiopathic noncirrhotic portal hypertension, its pathogenesis remains elusive. Insight may be gained from study of early-onset familial idiopathic noncirrhotic portal hypertension, in which Mendelian mutations may account for disease. We performed exome sequencing of eight subjects from six kindreds with onset of portal hypertension of indeterminate etiology during infancy or childhood. Three subjects from two consanguineous families shared the identical rare homozygous p.N46S mutation in DGUOK, a deoxyguanosine kinase required for mitochondrial DNA replication; haplotype sharing demonstrated that the mutation in the two families was inherited from a remote common ancestor. All three affected subjects had stable portal hypertension with noncirrhotic liver disease for 6-16 years of follow-up. This mutation impairs adenosine triphosphate binding and reduces catalytic activity. Loss-of-function mutations in DGUOK have previously been implicated in cirrhosis and liver failure but not in isolated portal hypertension. Interestingly, treatment of patients with human immunodeficiency viral infection with the nucleoside analogue didanosine is known to cause portal hypertension in a subset of patients and lowers deoxyguanosine kinase levels in vitro; the current findings implicate these effects on deoxyguanosine kinase in the causal mechanism. CONCLUSION: Our findings provide new insight into the mechanisms mediating inherited and acquired noncirrhotic portal hypertension, expand the phenotypic spectrum of DGUOK deficiency, and provide a new genetic test for a specific cause of idiopathic noncirrhotic portal hypertension. (Hepatology 2016;63:1977-1986).

Liver metastases from adenocarcinomas of unknown primary site: management and prognosis in 68 consecutive patients.

BACKGROUND: In this retrospective study, we aimed to evaluate the clinicopathological characteristics of the patients presenting with liver metastases from unknown primary site besides survival rates, treatment outcomes, and prognostic factors. METHODS: In all, 68 patients followed-up at our center with adenocarcinoma of unknown primary (ACUP) metastatic to the liver between 2005 and 2013 were enrolled. All of the liver metastases were proven by liver biopsy and all yielded diagnosis of adenocarcinoma. RESULTS: Median age was 61 years (29-90) and most of the patients were male (male/female: 43/25). The liver was the only metastatic site in 2 (3%) patients whilst 66 patients (97%) had extrahepatic metastases. The most common extrahepatic metastatic sites were lymph nodes (89.7%), lungs (32.4%), bones (25%), peritoneum (11.8%), brain (4.4%), and adrenal glands (2.9%). Of all 68 patients, 39 (57.4%) were treated with chemotherapy. Median overall survival (OS) was significantly higher in ACUP patients treated with chemotherapy [12.5 months (95% CI 8.3-16.7) vs. 4 months (95% CI 1.2-6.8), (p = 0.026), respectively]. In multivariate analysis, ECOG (Eastern Cooperative Oncology Group) performance status (p = 0.009), chemotherapy (p = 0.024), serum albumin (p = 0.012), and serum CA 19-9 level (p = 0.026) at initial diagnosis were identified as independent prognostic factors influencing survival for the patients with liver metastases from ACUP. CONCLUSION: Patients with liver metastases from ACUP have poor prognosis and chemotherapy improves survival. Decreased serum albumin level, increased CA 19-9 level and poor performance status are independent poor prognostic factors.

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.