Small molecule antagonist of the bone morphogenetic protein type I receptors suppresses growth and expression of Id1 and Id3 in lung cancer cells expressing Oct4 or nestin.

BACKGROUND: Bone morphogenetic proteins (BMP) are embryonic morphogens that are aberrantly expressed in lung cancer. BMPs mediate cell fate decisions and self-renewal of stem cells, through transcription regulation of inhibitor of differentiation protein/DNA binding proteins (Id1-3). Inhibition of BMP signaling decreases growth and induces cell death of lung cancer cells lines by downregulating the expression of Id proteins. It is not known whether the BMP signaling cascade regulates growth and the expression of Id proteins of lung cancer cells expressing the stem cell markers Oct4 and/or nestin. METHODS: Lung cancer cells expressing Oct4 or nestin were isolated from lung cancer cell lines by stably transfecting the Oct4 promoter or nestin promoter expression vectors that induce expression of the green fluorescent protein reporter. RESULTS: Our studies suggest that lung cancer cells expressing Oct4 or nestin are different cell populations. Microarray and quantitative RT-PCR demonstrated that the expression of specific stem cell markers were different between isolated Oct4 and nestin cells. Both the Oct4 and nestin populations were more tumorigenic than controls but histologically they were quite different. The isolated Oct4 and nestin cells also responded differently to inhibition of BMP signaling. Blockade of BMP signaling with the BMP receptor antagonist DMH2 caused significant growth inhibition of both the Oct4 and nestin cell populations but only increased cell death in the nestin population. DMH2 also induced the expression of nestin in the Oct4 population but not in the nestin cells. We also show that BMP signaling is an important regulator of Id1 and Id3 in both the Oct4 and nestin cell populations. Furthermore, we show that NeuN is frequently expressed in NSCLC and provide evidence suggesting that Oct4 cells give rise to cancer cells expressing nestin and/or NeuN. CONCLUSION: These studies show that although biologically different, BMP signaling is growth promoting in cancer cells expressing Oct4 or nestin. Inhibition of BMP signaling decreases expression of Id proteins and suppresses growth of cancer cells expressing Oct4 or Nestin. Small molecule antagonists of the BMP type I receptors represent potential novel drugs to target the population of cancer cells expressing stem cell markers.

Sarcoid-Like Granulomatous Disease: Pathologic Case Series in World Trade Center Dust Exposed Rescue and Recovery Workers.

Sarcoid-like granulomatous diseases (SGD) have been previously identified in cohorts of World Trade Center (WTC) dust-exposed individuals. In the present studies, we analyzed lung and/or lymph node biopsies from patients referred to our clinic with suspected WTC dust-induced lung disease to evaluate potential pathophysiologic mechanisms. Histologic sections of lung and/or lymph node samples were analyzed for markers of injury, oxidative stress, inflammation, fibrosis, and epigenetic modifications. Out of seven patients examined, we diagnosed four with SGD and two with pulmonary fibrosis; one was diagnosed later with SGD at another medical facility. Patients with SGD were predominantly white, obese men, who were less than 50 years old and never smoked. Cytochrome b5, cytokeratin 17, heme oxygenase-1, lipocalin-2, inducible nitric oxide synthase, cyclooxygenase 2, tumor necrosis factor α, ADP-ribosylation factor-like GTPase 11, mannose receptor-1, galectin-3, transforming growth factor ß, histone-3 and methylated histone-3 were identified in lung and lymph nodes at varying levels in all samples examined. Three of the biopsy samples with granulomas displayed peri-granulomatous fibrosis. These findings are important and suggest the potential of WTC dust-induced fibrotic sarcoid. It is likely that patient demographics and/or genetic factors influence the response to WTC dust injury and that these contribute to different pathological outcomes.

Youngest reported patient presenting with an androgen producing sclerosing stromal ovarian tumor.

BACKGROUND: Sclerosing stromal tumors are extremely rare sex cord stromal tumors of the ovary, with approximately 100 cases reported since first described in 1973. These tumors present predominantly in the 2nd and 3rd decades of life, typically present with pelvic/abdominal pain and tenderness, mass, and/or abnormal menses, and with hormonal activity reported predominantly in postmenarchal females. Only 5 cases of these tumors have been reported in premenarchal girls, with age ranging from 7 months to 12 years. Only 2 demonstrated hormonal manifestations, with vaginal bleeding due to hyperestrogenism in the 7 month old, and virilization in an 11-year-old female. CASE: We report a 9-year-old female who was diagnosed with this ovarian tumor, and who presented with virilization. SUMMARY AND CONCLUSION: This report is remarkable as our patient not only was diagnosed with an ovarian tumor that is extremely rare in this age group but is the youngest reported patient with this tumor who presented with virilization.

Sox9 mediates Notch1-induced mesenchymal features in lung adenocarcinoma.

Sox9 has gained increasing importance both functionally and as a prognostic factor in cancer. We demonstrate a functional role for Sox9 in inducing a mesenchymal phenotype in lung ADC. We show that Sox9 mRNA and protein are overexpressed in lung ADC, particularly those with KRAS mutations. Sox9 expression correlated with the Notch target gene Hes1, and numerous other Notch pathway components. We observed that Sox9 is a potent inducer of lung cancer cell motility and invasion, and a negative regulator of E-cadherin, a key protein that is lost during epithelial-mesenchymal transition (EMT). Moreover, we show that Notch1 signaling directly regulates Sox9 expression through a SOX9 promoter binding site, independently of the TGF-ß pathway, and that Sox9 participates in Notch-1 induced cell motility, cell invasion, and loss of E-cadherin expression. Together, the results identify a new functional role for a Notch1-Sox9 signaling axis in lung ADC that may explain the correlation of Sox9 with tumor progression, higher tumor grade, and poor lung cancer survival. In addition to Notch and TGF-ß, Sox9 also acts downstream of NF-κB, BMP, EGFR, and Wnt/ß-catenin signaling. Thus, Sox9 could potentially act as a hub to mediate cross-talk among key oncogenic pathways in lung ADC. Targeting Sox9 expression or transcriptional activity could potentially reduce resistance to targeted therapy for lung ADC caused by pathway redundancy.

Routine second-opinion cytopathology review of thyroid fine needle aspiration biopsies reduces diagnostic thyroidectomy.

BACKGROUND: Follicular thyroid carcinoma cannot be distinguished reliably from benign follicular neoplasia by fine needle aspiration (FNA) biopsy. Given an estimated 20% risk of malignancy, many patients with indeterminate FNA biopsies require thyroidectomy for diagnosis. Some centers have shown significant discordance when a second pathologist evaluates the same FNA biopsy. We sought to determine whether routine second-opinion cytopathology reduces the need for diagnostic thyroidectomy, especially in patients with indeterminate FNA biopsies. METHODS: In all, 331 thyroid FNA biopsy specimens obtained from outside centers from 2004 to 2009 were reviewed at our institution. The FNA biopsy results were categorized into nondiagnostic (Bethesda I), benign (Bethesda II), indeterminate (follicular/Hurthle cell neoplasm, follicular/Hurthle cell lesion; Bethesda III & IV), and malignant (papillary or suspicious for papillary or other malignancy; Bethesda V and VI). Second-opinion cytology was compared with the initial opinion in 331 cases and with final operative pathology in the 250 patients who progressed to thyroidectomy. RESULTS: The average patient age was 51 with a predominant number of female (79%) participants. The overall cytology concordance for all 331 FNA biopsies was 66% (218/331). Concordance was highest at 86% (74/86) with malignant FNA biopsies. Concordance in the 129 patients with indeterminate FNA biopsies was only 37% (48/129). Indeterminate FNA biopsies were reread as nondiagnostic in 21% (27/129) of patients and as benign in 42% (54/129) of patients. Twenty-two patients with an indeterminate FNA biopsy reread as benign progressed to operative therapy for reasons other than cytology (eg, symptomatic nodule and radiation exposure/high risk) and were found to be benign in 95% (21/22) of patients on operative pathology for a 95% negative predictive value. An additional 11 patients with an indeterminate FNA reread as benign had follow-up FNA biopsies, each of which was benign. Indeterminate FNA biopsies on initial cytology had a malignancy rate of 13% (17/129) on operative pathology compared with 29% (14/48) for indeterminate FNA biopsies from second opinion. A second opinion improved FNA biopsy accuracy from 60% to 74%. Overall, second-opinion cytology of indeterminate FNA biopsies avoided diagnostic operation in 25% (32/129). CONCLUSION: Routine second opinion review of indeterminate thyroid FNA biopsies can potentially obviate the need for diagnostic thyroidectomy in 25% of patients without increases in false negatives.

Actinic conjunctivitis in children: Clinical features, relation to sun exposure, and proposed staging and treatment.

BACKGROUND: Actinic conjunctivitis is an ocular photosensitivity reaction found mainly in children in certain populations in the Andean regions of South America, Mexico, and in the southwestern United States. Its clinical features, treatment, and possible relation to duration of sun exposure have not been fully described in the ophthalmologic literature. METHODS: A 20-member ophthalmic team traveled to an Andean region of Ecuador to provide ophthalmic care to children. All children with conjunctivitis were examined. A novel 3-stage classification of actinic conjunctivitis, devised by one of the authors, was used to stage the disease. The parents of each child with actinic conjunctivitis were asked how much time the child spent outside. Histopathological evaluations were performed on children who underwent surgery. RESULTS: A total of 206 children were examined, of whom 36 had changes consistent with actinic conjunctivitis. Stage 1 disease was diagnosed in 17 children, stage 2 in 9, and stage 3 in 10 in the most severely affected eye. The amount of time the child spent outside correlated with disease severity (r = 0.77, p < 0.001). Histopathologic samples showed an intense inflammatory response with hyperplasia of the vascular endothelium, pigmentary migration, and occasional eosinophilia. CONCLUSIONS: Actinic conjunctivitis is prevalent among children of the highlands of Ecuador. Although it has an allergic component, our data suggest that the severity of the disease is significantly associated with sun exposure. The finding that the lesions are found only in the exposed conjunctiva supports the hypothesis that UV exposure is the main cause of the disease.

Unusual forms of immature sporulating Coccidioides immitis diagnosed by fine-needle aspiration biopsy.

Coccidioidomycosis is an endemic infection acquired by inhalation of the spores (arthroconidia) of the thermally dimorphic fungus, Coccidioides immitis. The arthroconidia transform into spherical cells called mature spherules in the lung. Immature spherules and other atypical forms of immature C immitis have rarely been found in vivo. We report on a case that presented unusual forms of immature sporulating C immitis in a fine-needle aspiration specimen. A 36-year-old Chinese woman, living in New Jersey for the past 10 years, presented with fever, night sweats, hemoptysis, and an abnormal chest radiograph approximately 9 months after a brief vacation trip to the Grand Canyon in Arizona. She was treated with antibiotics for 4 weeks without improvement. Subsequent chest computed tomography showed a 3-cm cavitary lesion in the right lower lobe of the lung. Fine-needle aspiration biopsy revealed diverse morphologic forms of a fungus that was confirmed by culture as immature sporulating C immitis.