Comparative effects of cocaine and cocaethylene on alveolar epithelial type II cells.

Abuse of cocaine (COC) and alcohol have been among the leading causes of non-prescription drug-related deaths in the USA and are known to cause acute and chronic lung diseases. The co-abuse of COC and alcohol results in the production of an active metabolite, cocaethylene (CE). The effects of COC and its metabolites on the respiratory system have been scarcely studied. This study was aimed at comparing the toxic effects of eqimolar concentration (1 mM) of COC and CE on alveolar epithelial type II cells. This was performed by measuring cell growth, viability, clonogenic activity, cell cycle and reactive oxygen species (ROS) generation. The treatment of CE and COC resulted in a significant inhibition of cell proliferation with the formation of an average of three colonies which measured about 1.74×10(-15) m each and 25 colonies each of about 5.73×10(-15) m, respectively, while untreated cells yielded 31 colonies of 8.75×10(-15) m (p<0.05). The treatments of CE and COC resulted in the reduction of the growth fraction of alveolar epithelial type II cells without significant decrease in viability. In addition, there was an approximately twofold increase in ROS generation as compared to the controls (p<0.05). Therefore, CE-induced inhibition of cellular proliferation may contribute to the pathogenesis of diffuse alveolar damage in co-abusers of COC and alcohol.

Fortilin reduces apoptosis in macrophages and promotes atherosclerosis.

Atherosclerosis, a deadly disease insufficiently addressed by cholesterol-lowering drugs, needs new therapeutic strategies. Fortilin, a 172-amino acid multifunctional polypeptide, binds p53 and blocks its transcriptional activation of Bax, thereby exerting potent antiapoptotic activity. Although fortilin-overexpressing mice reportedly exhibit hypertension and accelerated atherosclerosis, it remains unknown if fortilin, not hypertension, facilitates atherosclerosis. Our objective was to test the hypothesis that fortilin in and of itself facilitates atherosclerosis by protecting macrophages against apoptosis. We generated fortilin-deficient (fortilin(+/-)) mice and wild-type counterparts (fortilin(+/+)) on a LDL receptor (Ldlr)(-/-) apolipoprotein B mRNA editing enzyme, catalytic polypeptide 1 (Apobec1)(-/-) hypercholesterolemic genetic background, incubated them for 10 mo on a normal chow diet, and assessed the degree and extent of atherosclerosis. Despite similar blood pressure and lipid profiles, fortilin(+/-) mice exhibited significantly less atherosclerosis in their aortae than their fortilin(+/+) littermate controls. Quantitative immunostaining and flow cytometry analyses showed that the atherosclerotic lesions of fortilin(+/-) mice contained fewer macrophages than those of fortilin(+/+) mice. In addition, there were more apoptotic cells in the intima of fortilin(+/-) mice than in the intima of fortilin(+/+) mice. Furthermore, peritoneal macrophages from fortilin(+/-) mice expressed more Bax and underwent increased apoptosis, both at the baseline level and in response to oxidized LDL. Finally, hypercholesterolemic sera from Ldlr(-/-)Apobec1(-/-) mice induced fortilin in peritoneal macrophages more robustly than sera from control mice. In conclusion, fortilin, induced in the proatherosclerotic microenvironment in macrophages, protects macrophages against Bax-induced apoptosis, allows them to propagate, and accelerates atherosclerosis. Anti-fortilin therapy thus may represent a promising next generation antiatherosclerotic therapeutic strategy.

Lymph node involvement in immunohistochemistry-based molecular classifications of breast cancer.

BACKGROUND: Prognosis and treatment options differ for each molecular subtype of breast cancer, but risk of regional lymph node (LN) metastasis for each subtype has not been well studied. Since LN status is the most important predictor for prognosis, the aim of this study is to investigate the propensity for LN metastasis in each of the five breast cancer molecular subtypes. METHODS: Under an institutional review board-approved protocol, we retrospectively reviewed the charts of all pathologically confirmed breast cancer cases from January 2004 to June 2012. Five subtypes were defined as luminal A (hormone receptor positive, Ki-67 low), luminal B (hormone receptor positive, Ki-67 high), luminal human epidermal growth factor receptor 2 (HER2), HER2-enriched (hormone receptor negative), and triple negative (TN). RESULTS: A total of 375 patients with complete data were classified by subtype: 95 (25.3%) luminal A, 120 (32%) luminal B, 69 (18.4%) luminal HER2, 26 (6.9%) HER2-enriched, and 65 (17.3%) TN. On univariate analysis, age (<50), higher tumor grade, HER2+ status, tumor size, and molecular subtype were significant for LN positivity. Molecular subtype correlated strongly with tumor size (χ(2); P = 0.0004); therefore, multivariable logistic regression did not identify molecular subtype as an independent variable to predict LN positivity. CONCLUSIONS: Luminal A tumors have the lowest risk of LN metastasis, whereas luminal HER2 subtype has the highest risk of LN metastasis. Immunohistochemical-based molecular classification can be readily performed and knowledge of the factors that affect LN status may help with treatment decisions.

Significance of Ki-67 and p53 immunoexpression in the differential diagnosis of oral necrotizing sialometaplasia and squamous cell carcinoma.

Necrotizing sialometaplasia (NS) is a benign condition that usually involves the hard palate and can be mistaken for invasive squamous cell carcinoma (SCC). In this study, we have demonstrated that p53 and Ki-67 staining may assist in the differential diagnosis of NS from SCC. Thirteen cases of NS and 20 cases of oral cavity SCC were randomly selected from our surgical pathology archive from 1992 to 2009. Each case was additionally stained with Ki-67, p53, BCL-2, p16, and epidermal growth factor receptor (EGFR) antibodies. All 13 cases of NS were negatively stained for BCL-2, EGFR, and Ki-67. Three cases (23%) showed weak and focal positive nuclear staining for p53. Two cases (15%) showed positive staining for p16. In 16 well-differentiated SCC cases, p53 was positive in 12 cases (75%); BCL-2, p16, EGFR were positive in 3 cases (18%); and Ki-67 was positive in all cases (100%). In 4 moderately differentiated SCC cases, p53 expression was positive in all cases. Two tumors (50%) had a positive expression of BCL-2. Three cases (75%) had a positive p16 staining, and 1 (25%) had a positive EGFR staining. All cases were positive with high nuclear staining greater than 35% of cells for Ki-67. Ki-67 and p53 showed more intense staining and increased in moderately differentiated SCC comparing with well-differentiated SCC and NS. BCL-2, EGFR, and p16 had the same pattern of staining with the same extent in NS and SCCs. The diagnosis of NS may be difficult and may be supplemented via immunohistochemistry by demonstrating focal or absent p53, low to absent Ki-67 (<10% of cells). Although Ki-67 and p53 staining are generally more intense and are increased in malignancy, these findings may be helpful adjuncts in the differential diagnosis of NS from SCC in appropriate clinical setting.

Mycobacterium haemophilum and Histoplasma capsulatum coinfection in a renal transplant patient.

We report the case of a 22-year-old man who presented with a Mycobacterium haemophilum and Histoplasma capsulatum coinfection occurring 21 years after a living-donor-related renal transplant.

The immunohistochemical profile of atypical eosinophilic syncytial changes vs serous carcinoma.

Endometrial epithelial cytoplasmic change (EECC) is an adaptive cytoplasmic change commonly seen in the endometrium. Previously considered "metaplasia," EECC is now the preferred term because it offers a descriptive designation without implying a specific mechanism of development. There are 5 types of EECC: squamous, ciliated cell, eosinophilic, mucinous, and secretory (clear cell and hobmail cell) changes. Eosinophilic syncytial change (ESC) is a similar but unrelated degenerative change seen in endometrial breakdown. Some cases of ESC show atypical cytologic features that may resemble endometrial adenocarcinoma. Thirteen endometrial biopsy and curettage specimens with atypical ESCs (AESCs) were compared against 10 hysterectomy specimens with endometrial serous carcinoma. Clinical information and immunohistochemical staining profiles for markers phosphatase and tensin homologue deleted on chromosome 10 (PTEN), p53, and Ki-67 were evaluated in each case. All 13 cases of AESC (100%) showed moderate-to-strong staining for PTEN, whereas PTEN expression was absent in all endometrial serous carcinomas (P < .001). Seven cases of AESC (54%) showed focal, weak positivity for p53, whereas all cases of serous carcinoma (100%) showed strong staining (P < .001). The Ki-67 index was low (3%-15%) and found in only 3 cases in AESC (32%) but was high (60%-90%) in all cases of endometrial serous carcinoma (100%) (P < .001). Atypical ESC and serous carcinoma share several morphological features on hematoxylin and eosin-stained sections that may complicate accurate diagnosis. The PTEN, p53, and Ki-67 staining profile can effectively distinguish between AESC and malignancy in difficult cases, providing an invaluable tool for a challenging diagnostic dilemma.

Nodular mucinosis of the breast in a supernumerary nipple: case report and review of the literature.

Nodular mucinosis is an extraordinary stromal lesion of the breast. The usual clinical presentation is that of an oozing, slow-growing, soft, non-tender, lobulated mass in the subareolar region. Histologically, it is a non-encapsulated myxoid/mucinous lesion with a sparse infiltrate of spindle cells within a collagenized stroma. The histogenesis of nodular mucinosis is undetermined but the pattern of staining of the spindle cells suggests it might be of myofibroblastic origin. We herein report for the first time in the English literature a case of nodular mucinosis occurring in a supernumerary nipple. We also discuss the main differential diagnoses and review the literature of previously published cases of this entity.

Idiopathic bronchiolitis with features of diffuse panbronchiolitis in an African-American patient with hepatitis C virus infection.

Diffuse panbronchiolitis (DPB) is an idiopathic inflammatory process involving respiratory bronchioles, largely restricted to Japanese people and associated with HLA Bw54. We report a case of idiopathic bronchiolitis with DPB features in an African American with hepatitis C virus infection, correlated with postmortem anatomic findings. The 53-year-old patient presented with shortness of breath and productive cough. Examination revealed hypercapnic respiratory failure. Lung computed tomography showed diffuse centrilobular nodules and branching linear opacities, whereas lung biopsy demonstrated diffuse peribronchiolar fibrosis and chronic inflammation with bronchiolectasis. He died 37 days postadmission. Autopsy revealed numerous bronchiolocentric nodules with bronchiolectasis and sheets of foamy macrophages in alveolar septa and spaces. This is a rare example of idiopathic bronchiolitis with features of DPB in an hepatitis C virus-infected African-American patient. Hepatitis C virus infection is known to be associated with extrahepatic pulmonary manifestations, and DPB may be one of these. Early diagnosis will allow appropriate treatment and may slow the disease progression.

Immunohistochemical characterization of subtypes of male breast carcinoma.

INTRODUCTION: Male breast cancer accounts for around 1% of all breast cancer cases but the incidence has risen in recent years. This study aimed to classify the molecular subtypes of male breast cancers based on the expression profile of immunomarkers and to evaluate their association with clinicopathological features and expression patterns of epidermal growth factor receptor (EGFR) and nuclear factor kappaB (NF-kappaB). METHODS: A total of 42 cases of male breast carcinoma were examined retrospectively using immunostains for estrogen receptor (ER), progesterone receptor (PR), cytokeratin 5/6 (CK5/6), EGFR, and NF-kappaB. Human epidermal growth factor receptor 2 (HER2) expression was evaluated by immunostaining and confirmed by fluorescent in situ hybridization (FISH). RESULTS: The luminal A subtype was the most common subtype in male breast cancer (83%, 35/42), which was followed by the luminal B subtype (17%, 7/42). Basal-like and HER2+/ER- subtypes were not identified in this group. All carcinomas expressed ER and 67% of them were PR+. High nuclear grades were more common in the luminal B subtype (71%, 5/7) than in the luminal A subtype (34%, 12/35). The luminal B subtype carcinomas expressed EGFR (42%, 3/7) and NF-kappaB (57%, 4/7) more frequently than the luminal A subtype did (17%, 6/35 and 37%, 13/35, respectively). CONCLUSIONS: In our study group, luminal A and B subtypes were the major subtypes of male breast carcinoma. The immunophenotypical features of male breast cancer differ from those of its female counterpart. Luminal B subtype tended to have high nuclear grade and more frequent expression of EGFR and NF-kappaB.

Infratentorial angioleiomyoma: a new location for a rare neoplastic entity.

Angioleiomyomas are benign neoplasms most often located in the subcutaneous tissue of middle-aged individuals and usually confined to the subcuticular and deep dermal layers of the lower extremities. An intracranial site for this tumor is exceedingly rare, with very few reports documenting locations in the neuraxis. To the authors' knowledge the present case represents the first reported instance of an infratentorial angioleiomyoma. The authors conducted a review of selected English-language papers published since 1960 describing well-documented cases of intracranial vascular leiomyomas, with detailed information on the clinical presentation, radiology, pathology, and particulars of surgical management in each case.

Clinico- pathologic presentation of hypersensitivity pneumonitis in Egyptian patients: a multidisciplinary study.

BACKGROUND: Hypersensitivity pneumonitis (HP) is a common diffuse parenchymal lung disease in Egypt which can be difficult to recognize due to the dynamic symptoms & associated environmental factors. METHODS: Forty-three Egyptian patients were enrolled in this study, presenting with dyspnea and cough, predominant ground-glass opacity (GGO) in high-resolution computed tomography (HRCT) where lung biopsy was needed to establish the diagnosis. RESULTS: The age range was 15 to 60 years. Females represented 90.7% (39 patients) while 9.3% (4 patients) of our patients were males. History of contact with birds was detected in 9 (20.9%) patients. Most of our patients (60.5%) didn't have exposure history, and only 8 patients (18.6%) were living in geographic areas in Egypt that are known for the exposure to environmental etiologic factors (cane sugar exhaust fumes). The most common HRCT pattern was GGO with mosaic parenchyma in 18 patients (41.86%), followed by GGO with centrilobular nodules in 9 patients (20.93%), then isolated diffuse GGO in 5 patients (11.62%), GGO with traction bronchiectasis in 4 patients (9.3%), GGO with consolidation in 3 patients (6.97%), GGO with reticulations in 2 patients (4.65%), and GGO with cysts in 2 patients (4.65%). The most common histologic finding was isolated multinucleated giant cells in 38 patients (88.3%) commonly found in airspaces (24 patients) and less commonly in the interstitium (14 patients), followed by interstitial pneumonia and cellular bronchiolitis in 36 patients (83.7% each), interstitial ill-formed non-necrotizing granulomas in 12 patients (27.9%), fibrosis in 10 patients (23.2%), and organizing pneumonia pattern in 4 patients (9.3%). CONCLUSION: The diagnosis of HP presenting with predominant GGO pattern in HRCT requires a close interaction among clinicians, radiologists, and pathologists. Some environmental and household factors may be underestimated as etiologic factors. Further environmental and genetic studies are needed especially in patients with negative exposure history.

Mimicks of pancreatic malignancy in patients with chronic pancreatitis: correlation of computed tomography imaging features with histopathologic findings.

Differentiation of chronic pancreatitis and pancreatic carcinoma can be a clinical and radiologic dilemma. Several patients with chronic pancreatitis can undergo unnecessary major abdominal surgery for benign lesions. This pictorial review illustrates the computed tomographic findings and histopathologic features of lesions mimicking pancreatic neoplasm in patients with chronic pancreatitis. Several benign lesions can simulate pancreatic malignancy in patients with chronic pancreatitis. Knowledge of the computed tomographic appearance of these benign entities is important to prevent unnecessary surgeries.

Concurrent Nontuberculous Mycobacteria Infection and High-Grade Anterior Mediastinal Extraskeletal Osteosarcoma (ESOS): Is There a Connection?

BACKGROUND Extraskeletal osteosarcomas (ESOS) of the mediastinum are extremely rare and may present with concurrent nontuberculous mycobacteria infection. CASE REPORT We present the second documented case of high-grade anterior mediastinal extraskeletal osteosarcoma in a 59-year-old man with a history of treated, latent tuberculosis (TB). Sputum samples grew Mycoplasma avium complex and Mycobacterium fortuitum. Imaging showed a right-sided 7.6 cm mass with compression of the main bronchus. Subsequent biopsy with vimentin staining established the diagnosis of ESOS. Due to the patient's rapidly declining performance status, he was not deemed a candidate for surgery or chemotherapy. He subsequently expired within one month of presentation. CONCLUSIONS We present a unique case of high-grade anterior mediastinum ESOS and a review of the literature regarding all documented cases of ESOS to date. We suggest there is a possible link between mediastinal masses and nontuberculous mycobacteria infection.

Transformation of primary human hepatocytes in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common primary liver cancer. Currently, there is limited knowledge of neoplastic transformation of hepatocytes in HCC. In clinical practice, the high rate of HCC local recurrence suggests the presence of different hepatocyte populations within the liver and particularly in the tumor proximity. The present study investigated primary human hepatocyte cultures obtained from liver specimens of patients affected by cirrhosis and HCC, their proliferation and transformation. Liver samples were obtained from seven HCC cirrhotic patients and from three patients with normal liver (NL). Immediately after surgery, cell outgrowth and primary cultures were obtained from the HCC lesion, the cirrhotic tissue proximal (CP, 1-3 cm) and distal (CD, >5 cm) to the margin of the neoplastic lesion, or from NL. Cells were kept in culture for 16 weeks. Morphologic analyses were performed and proliferation rate of the different cell populations compared over time. Glypican-3, Heppar1, Arginase1 and CD-44 positivity were tested. The degree of invasiveness of cells acquiring neoplastic characteristics was studied with a transwell migration assay. We observed that HCC cells maintained their morphology and unmodified neoplastic characteristics when cultured. Cells isolated from CP, showed a progressive morphologic transformation in HCC-like cells accompanied by modification of markers expression with signs of invasiveness. Absence of HCC contamination in the CP isolates was confirmed. In CD samples some of these characteristics were present and at significantly lower levels. With the present study, we are the first to have identified and describe the existence of human hepatocytes near the cancerous lesion that can transform in HCC in vitro.

Colorectal Cancer-Associated Fibroblasts are Genotypically Distinct.

Cells in the stromal microenvironment facilitate colorectal cancer (CRC) progression and "co-evolve" with the epithelial cancer cells. Genetic and epigenetic differences between normal colorectal mucosa fibroblasts (NF) and carcinoma-associated fibroblasts (CAF) are not known. The aim of this study is to identify differentially expressed genes and promoter methylation between NF and CAF in human CRC. RNA and DNA were extracted from cultured NF and CAF from CRC resections. Genome-wide gene expression and methylation analyses were performed using the Illumina Human HT-12 v4.0 Expression and Illumina Human Methylation 27 BeadChips. Gene expression values between NF and CAF were compared and correlated with methylation patterns. Data was analyzed using Partek Genomics Suite using one-way ANOVA and p<0.05 as significant. Ingenuity iReport™ was performed to identify potential differences in biological functions and pathways between the NF and CAF. Paired methylation and gene expression analyses from 11 NF and 10 CAF colorectal samples are reported. Unsupervised analysis of differentially expressed genes using iReport™ identified "Top Diseases" as "Cancer" and "Colorectal Cancer". Previous genome wide studies have focused on the cancer cells. We have identified differentially expressed genes and differentially methylated promoter regions that are CAF-specific in CRC.

Intraductal papilloma of the breast in association with preoncogenic gene of breast cancer.

We reported a case of an African American woman who went to the hospital with palpable right breast lump with bloody nipple discharge at University of Texas Medical Branch at Galveston. The modalities of breast imagings included mammography and ultrasonography. The method used for viral identification was Linear Array HPV genotyping test. Intraductal papilloma revealed as high density tubular or rounded lobular masses with partially circumscribed, obscured margins and clustered punctate microcalcifications on mammograms. Ultrasound showed as intraductal masses with dilated ducts. The core biopsy demonstrated duct filled with papillary lesion and post excision revealed intraductal papilloma. HPV DNA types 16, 33, 58 and 71 were detected after use of Linear Array HPV genotyping test.

A t(1;9)(q10;q10) translocation with additional 6q23 and 9q22 rearrangements in a case of chondromyxoid fibroma.

Chondromyxoid fibroma (CMF) is a rare cartilaginous tumor of bone. It typically presents in the long tubular bones and to a lesser extent in the small bones of the hands and feet of young adults. To date, several cytogenetic abnormalities have been described in association with CMF. We studied a phalangeal CMF from a 13-year-old female by cytogenetic methods. We found a novel unbalanced translocation between the long arms of chromosomes 1 and 9, resulting in loss of 1p. In addition, rearrangements involving the 6q23 and 9q22 regions were also observed. To our knowledge, this is the first report in the literature describing this novel chromosomal translocation in CMF.