Diffuse Hyperplasia Research Articles

Idiopathic Pulmonary Lymphoid Diffuse Hyperplasia

We describe a 70-year-old woman affected by diffuse pulmonary lymphoid hyperplasia (DPLH). DPLH is a rare clinical-pathological entity generally associated with connective tissue diseases, but we diagnosed our case as an idiopathic DPLH. To the best of our knowledge, this is the first case of idiopathic DPLH reported in medical literature.

Cardiothoracic manifestations of neuroendocrine tumours.

Cardiothoracic neuroendocrine tumour (NET) manifestations encompass a vast disease spectrum. Pulmonary neuroendocrine tumours represent a range of tumour grade and differentiation characteristics from pre-malignant diffuse neuroendocrine cell hyperplasia, well-differentiated, low-grade carcinoid tumours with excellent outcomes, through to high-grade small-cell lung carcinoma and large-cell neuroendocrine carcinoma with poor prognoses. Rarer thymic NETs represent a similarly wide neoplastic spectrum. Cardiac carcinoid is a paraneoplastic manifestation of the carcinoid syndrome and often the cause of mortality in NETs with hepatic metastases. Cardiothoracic NET manifestations are reviewed herein from a radiologists' perspective, discussing the diverse clinical presentations, spectrum of neoplastic and paraneoplastic manifestations, imaging features and treatment options.

右肺中葉低形成に発生したびまん性特発性神経内分泌過形成を伴った肺カルチノイドの1例

右肺中葉低形成に発生したびまん性特発性神経内分泌過形成を伴った肺カルチノイドの1例

Update of pathological diagnosis of pulmonary neuroendocrine tumor

Pulmonary neuroendocrine tumors are common in pathological practice and its pathological classification and histological grading are not exactly the same as that of those in the digestive tract and pancreas. In 2015 edition of World Health Organization classification, pulmonary neuroendocrine tumors are classified as carcinoid tumors (including typical carcinoid and atypical carcinoid), small cell lung carcinoma, large cell neuroendocrine carcinoma, and precursor lesion diffuse idiopathic neuroendocrine cell hyperplasia; each category has distinctive morphological and immunohistochemical features. The morphologic features including growth patterns and cytological appearances are keys for the diagnosis of neuroendocrine tumor, and immunohistochemical findings are also critical for its diagnosis. Furthermore, the diagnostic criteria vary for different types of specimen. In this article, we present a concise review and summary of the update of clinicopathological characterizations of pulmonary neuroendocrine tumor, with an emphasis on its diagnostic criteria and differential diagnosis.

Differentiation of Adrenal Hyperplasia From Adenoma by Use of CT Densitometry and Percentage Washout.

The purpose of this study was to quantitatively differentiate adrenal hyperplasia from adenoma with the use of adrenal CT protocols. Between January 2004 and November 2012, a total of 156 patients (69 men and 87 women; mean age, 48.9 years) underwent unenhanced CT, early contrast-enhanced CT, and delayed contrast-enhanced CT before undergoing adrenalectomy. Of these patients, 142 had 144 adenomas and 14 had nodular (n = 12) or diffuse (n = 2) hyperplasia. An ROI was placed on 144 adenomas and 27 hyperplastic nodules that were 1 cm or larger or on the four thickest areas of both adrenal glands. The number of each type of lesion and the attenuation value, absolute percentage washout (APW), and relative percentage washout (RPW) associated with hyperplasia and adenoma were compared. The reference standard was pathologic examination. A mixed model and the Fisher exact test were used for statistical analysis. On unenhanced CT, the mean (± SD) attenuation value for hyperplasia and adenoma was 18.8 ± 10.8 HU and 13.7 ± 15.6 HU, respectively (p = 0.375). When a threshold of 10 HU or lower was used, 22.6% of hyperplastic lesions (7/31) were misdiagnosed as adenomas. The mean APW associated with hyperplasia and adenoma was 73.7% ± 9.3% and 67.3% ± 26.2%, respectively (p = 0.449), whereas the mean RPW for hyperplasia and adenoma was 61.2% ± 9.2% and 59.9% ± 23.0%, respectively (p = 0.625). When an APW threshold of 60% or higher or an RPW threshold of 40% or higher was used, 100% of hyperplastic lesions (31/31) were misdiagnosed as adenoma. Three or more nodules were detected in 33.3% of patients with nodular hyperplasia (4/12) but in none of the patients with adenoma (p < 0.001). Adrenal hyperplasia cannot be quantitatively differentiated from adenoma because there is significant overlap in findings from CT densitometry and assessment of percentage washout. However, the presence of three or more nodules increases the likelihood of nodular hyperplasia.

Adrenomedullary Hyperplasia in a Patient with Poorly Controlled Hypertension and Neurofibromatosis Type 1: A Case Report

A 73-year-old male with a known diagnosis of neurofibromatosis type 1 (or Von Recklinghausen’s disease) was referred to the authors’ unit because of suspected pheochromocytoma. He had poorly controlled hypertension with elevated metanephrine levels and incomplete cortisol suppression at 1 mg overnight dexamethasone test. Adrenal CT showed bilateral adrenal hyperplasia and a nodule suspected of being a pheochromocytoma, while 123I-MIBG SPECTCT showed intense hyperfixation in the left adrenal gland. Left transperitoneal Laparoscopic adrenalectomy was performed and the histologic diagnosis was diffuse and nodular adrenal medullary hyperplasia. We believe that medullary adrenal Hyperplasia is, among the causes of secondary hypertension, a separate entity and should be considered as a possible diagnosis in all patients with poorly controlled hypertension and radiological findings not typical of adenoma.

Tumeurs neuroendocrines pulmonaires et lésions prénéoplasiques

In the recently published 2015 World Health Organization (WHO) classification of tumors of the lungs, all neuroendocrine tumors of the lungs are presented for the first time in one single chapter. In this classification, high-grade small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC) are differentiated from intermediate grade atypical carcinoids (AC) and low-grade typical carcinoids as well as from preinvasive lesion diffuse neuroendocrine hyperplasia DIPNECH. In the 2004 WHO classification, SCLC and carcinoids each had a separate chapter and LCNEC was listed in the chapter on large cell carcinoma of the lungs. The new WHO classification also gives some recommendations for the diagnosis on small biopsies. This review describes morphological, immunohistochemical, and genomic characteristic of these tumors according to the new classification.

Histological Lesions and Cellular Response in the Skin of Alpine Chamois (Rupicapra r. rupicapra) Spontaneously Affected by Sarcoptic Mange

Population dynamics of chamois (genus Rupicapra, subfamily Caprinae) can be influenced by infectious diseases epizootics, of which sarcoptic mange is probably the most severe in the Alpine chamois (Rupicapra rupicapra rupicapra). In this study, skin lesions and cellular inflammatory infiltrates were characterized in 44 Alpine chamois affected by sarcoptic mange. Dermal cellular responses were evaluated in comparison with chamois affected by trombiculosis and controls. In both sarcoptic mange and trombiculosis, a significantly increase of eosinophils, mast cells, T and B lymphocytes, and macrophages was detected. Moreover, in sarcoptic mange significant higher numbers of T lymphocytes and macrophages compared to trombiculosis were observed. Lesions in sarcoptic mange were classified in three grades, according to crusts thickness, correlated with mite counts. Grade 3 represented the most severe form with crust thickness more than 3.5 mm, high number of mites, and severe parakeratosis with diffuse bacteria. Evidence of immediate and delayed hypersensitivity was detected in all three forms associated with diffuse severe epidermal hyperplasia. In grade 3, a significant increase of B lymphocytes was evident compared to grades 1 and 2, while eosinophil counts were significantly higher than in grade 1, but lower than in grade 2 lesions. An involvement of nonprotective Th2 immune response could in part account for severe lesions of grade 3.

Eucoleus contortus Parasitism in Captive-Bred Valley Quail Callipepla californica (Shaw, 1798): Disease and Control

After the introduction of an infected valley quail into a colony, Eucoleus contortus became a severe problem. Despite previous treatment with anthelmintics, four out of nine quails were affected and died due to disease complications. Major clinical signs were profuse oral mucous secretion, frequent swallowing movements, and whitish diarrhea. Main pathological findings included thickened and wrinkled crop walls, parasites deeply embedded in the stratified squamous epithelium, and diffuse mucosa hyperplasia. Keeping the remaining quails in a wire mesh-floored aviary under treatment with levamisole and applying management practices to the dirt floor aviaries (temporary depopulation, bedding exchange and liming) promoted the health and growth of the quail colony. Apparently, the anthelmintics given to these birds had little effect on the control of the disease. Regularly treatments decreased temporarily the egg counts, which increased again during periods (breeding season) in dirt floor aviaries, even after applying the aforementioned environmental measures. This paper highlights the importance of adopting appropriate health management practices to both prevent and control E. contortus infection in susceptible avian flocks housed in outdoor aviaries with dirt floor, often a necessary condition in bird conservation programs.

Duodenal Gastrinoma Associated with Multiple Endocrine Neoplasia Type 1 (MEN1) Detected by Esophagogastroduodenoscopy (EGD), which was buried under Ulcer

A 66-year-old Japanese male was shown to have severe ulcers with hypergastrinemia in the stomach through proximal horizontal part of the duodenum, who complained of dysphagia and vomiting. He suffered from gastric ulcer at 63, proven to have undergone parathyroidectomy for hyperparathyroidism at his 5th decade. Though had no definitely enlarged pituitary detectable by computed tomography (CT), he had slight defects in the visual field and hyperprolactinemia. A diagnosis of MEN1 was entertained. Follow up EGD revealed 5 small sessile submucosal tumors (SMTs) with a central depression or erosion in the duodenal bulb through descending part of the duodenum, which had been obscured beneath ulcers. Demonstrated in the regenerative mucosa by their biopsy were clusters of small tumor cells, which, though considered the tips of neuroendocrine (NE) tumor (NET) lying in the deeper layer, were not large enough to be proven so by immunostaining with the markers in the serial sections, and diffuse hyperplasia of synaptophysin-, chromogranin A- and gastrin-positive NE cells in Brunner glands (BGs), the preneoplastic lesion characteristic of MEN1-associated duodenal gastrinoma, supporting the diagnosis, which was firmly guaranteed by positively elevated glucagon-provoked plasma gastrin. Subtotal stomach-preserving pancreaticoduodenectomy (SSPPD) established the final diagnosis of duodenal gastrinomas graded G1 associated with MEN1, which were shown to be tightly contained in the densely conglomerated hyperplastic BGs. No metastases were detected. This is the first case in the world, in which all the three characteristics of MEN1- associated duodenal gastrinoma were demonstrated by EGD. Difficulty in endoscopically detecting the NET lies in the fact that, in addition to its smallness and deep localization, it might be buried under peptic ulcer at a certain stage of the natural history and that an attempt to biopsy it is hampered by the densely conglomerated barrier of the hyperplastic BGs in some cases.

Reevaluation and Classification of Duodenal Lesions in B6C3F1 Mice and F344 Rats from 4 Studies of Hexavalent Chromium in Drinking Water.

Thirteen-week and 2-year drinking water studies conducted by the National Toxicology Program (NTP) reported that hexavalent chromium (Cr(VI)) induced diffuse epithelial hyperplasia in the duodenum of B6C3F1 mice but not F344 rats. In the 2-year study, Cr(VI) exposure was additionally associated with duodenal adenomas and carcinomas in mice only. Subsequent 13-week Cr(VI) studies conducted by another group demonstrated non-neoplastic duodenal lesions in B6C3F1 mice similar to those of the NTP study as well as mild duodenal hyperplasia in F344 rats. Because intestinal lesions in mice are the basis for proposed safety standards for Cr(VI), and the histopathology data are relevant to the mode of action, consistency (an important Hill criterion for causality) was assessed across the aforementioned studies. Two veterinary pathologists applied uniform diagnostic criteria to the duodenal lesions in rats and mice from the 4 repeated-dose studies. Comparable non-neoplastic intestinal lesions were evident in mice and rats from all 4 studies; however, the incidence and severity of intestinal lesions were greater in mice than rats. These findings demonstrate consistency across studies and species and highlight the importance of standardized nomenclature for intestinal pathology. The differences in the severity of non-neoplastic lesions also likely contribute to the differential tumor response.

What clinicians are asking pathologists when dealing with lung neuroendocrine neoplasms?

Lung neuroendocrine tumors (NET) are currently classified in resection specimens according to four histological categories, namely typical carcinoid (TC), atypical carcinoid (AC), large-cell neuroendocrine carcinoma (LCNEC) and small cell carcinoma (SCC). Diagnostic criteria have remained unchanged in the 2015 WHO classification, which has ratified the wide acceptance and popularity of such terminology in the pathologists׳ and clinicians׳ community. A unifying umbrella of NE morphology and differentiation has been recognized in lung NET, which has pushed to enter an unique box of invasive tumors along with diffuse idiopathic pulmonary NE cell hyperplasia (DIPNECH) as a pre-invasive lesion with a potential toward the development of carcinoids. However, uncertainties remain in the terminology of lung NET upon small samples, where Ki-67 antigen could play some role to avoid misdiagnosing carcinoids as high-grade NE tumors. Epidemiologic, clinical and genetic traits support a biological three-tier over a pathology four-tier model, according to which TC are low malignancy tumors, AC intermediate malignancy tumors and LCNEC/SCC high malignancy tumors with no significant differences in survival among them. Inconsistencies in diagnostic reproducibility, troubles in the therapy of AC and LCNEC, and limitations to histology within the same tumor category argue in favor of a global re-thinking of lung NET where a grading system could play a role. This review outlines three main key questions in the field of lung NET: (A) unbiased diagnoses, (B) the role of Ki-67 and tumor grading, and (C) management of predictive markers. Answers are still inconclusive, thus additional research is required to improve our understanding on lung NET.

Diffuse Neuroendocrine Hyperplasia with Obliterative Bronchiolitis and Usual Interstitial Pneumonia: An Unusual “Headcheese Pattern” with Nodules

A 74-year-old non-smoker female presented to our attention with a history of dyspnea and cough. CT scan revealed multiple areas of patchy ground glass attenuation associated to a diffuse mosaic oligoemia. Scattered bilateral subcentimetric pulmonary nodules were also present. Patient underwent a surgical lung biopsy. Specimens showed features of diffuse neuroendocrine hyperplasia, microhoneycombing, fibroblast foci. A final diagnosis of diffuse neuroendocrine hyperplasia with obliterative bronchiolitis and UIP was rendered.

Pathology of Struma Ovarii: A Report of 96 Cases.

Thyroid tissue is a relatively frequent component of mature teratoma and can occur in 5-20 % of cases. Struma ovarii is defined as ovarian goiter which comprises either entirely or predominantly thyroid tissue (>50 %). This also includes cases of mature teratoma with less than 50 % thyroid tissue but harboring thyroid-associated malignancy. A total of 118 patients with mature teratoma containing thyroid tissue were identified at our institution (1989 to 2014). Ninety-six cases were diagnosed struma ovarii, including 10 cases of papillary thyroid carcinoma, 1 case of highly differentiated follicular carcinoma of ovarian origin (HDFCO), 5 cases of strumal carcinoid, and 80 cases of struma ovarii (53 cases of thyroid-only struma ovarii). Six cases had diffuse adenomatous hyperplasia, and seven cases had focal adenomatous hyperplasia. There was no recurrence on follow-up except one of the papillary thyroid carcinomas. Concurrent primary ovarian lesions included: serous cystadenoma--3, mucinous cystadenoma--4, Brenner tumor--3, thecoma--2, ovarian fibroma--1, and focal hilus cell hyperplasia--4 cases. In this series, papillary thyroid carcinoma and strumal carcinoid were the most common well-differentiated neoplasm/malignancies arising in struma ovarii; these demonstrate a minimal or no aggressive clinical behavior.

A Comparative Study of Real-Time and Static Ultrasonography Diagnoses for the Incidental Detection of Diffuse Thyroid Disease

The aim of this study was to compare the diagnostic accuracy of real-time and static ultrasonography (US) for the incidental detection of diffuse thyroid disease (DTD). In 118 consecutive patients, a single radiologist performed real-time US before thyroidectomy. For static US, the same radiologist retrospectively investigated the sonographic findings on a picture-archiving and communication system after 3 months. The diagnostic categories of both real-time and static US diagnoses were determined based on the number of abnormal findings, and the diagnostic indices were calculated by a receiver operating characteristic (ROC) curve analysis using the histopathologic results as the reference standard. Histopathologic results included normal thyroid (n = 77), Hashimoto thyroiditis (n = 11), non-Hashimoto lymphocytic thyroiditis (n = 29), and diffuse hyperplasia (n = 1). Normal thyroid and DTD showed significant differences in echogenicity, echotexture, glandular margin, and vascularity on both real-time and static US. There was a positive correlation between US categories and histopathologic results in both real-time and static US. The highest diagnostic indices were obtained when the cutoff criteria of real-time and static US diagnoses were chosen as indeterminate and suspicious for DTD, respectively. The ROC curve analysis showed that real-time US was superior to static US in diagnostic accuracy. Both real-time and static US may be helpful for the detection of incidental DTD, but real-time US is superior to static US for detecting incidental DTD.

Abstract 4580: Expression of γH2AX as a biomarker of genotoxic carcinogen in the urinary bladder of rats

Abstract Background: Bladder cancer is the seventh most common cancer in males worldwide. Recent studies have demonstrated that DNA double-strand breaks are recognized to be a serious injury leading to genome instability and cancer development. The rapid phosphorylation of histone H2AX at Serine 139, to become γH2AX, occurs in response to DNA double-strand breaks. Roles of γH2AX in carcinogenesis are still unclear, and there are few reports on the association with bladder cancer. We have previously demonstrated that γH2AX expression is induced in urinary bladders of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN)-treated rat (Toyoda et al., J Toxicol Pathol, 26: 215-221, 2013). To evaluate the value of γH2AX as a biomarker for carcinogenicity and genotoxicity to the urinary bladder, we performed an immunohistochemical analysis of γH2AX expression in chemical-treated rats. Methods: Six-week-old male F344 rats were treated with 0.05% BBN, 1.8% 2-nitroanisole (2-NA), 2% 2,2-bis (bromomethyl)-1,3-propanediol (BMP), 0.1% phenethyl isothiocyanate (PEITC), 3% melamine, or 3% uracil in either drinking water (BBN) or diet (other chemicals) for 4 weeks. Animals were sacrificed at 4 or 6 weeks of the experiment, and immunohistochemistry for γH2AX in urinary bladders was performed. Results: At week 4, γH2AX expression in the urothelium were significantly increased in BBN and 2-NA groups compared with the controls. γH2AX expression ratio (positive cells/1000 cells) in BBN, 2-NA and control groups were 76±21, 111±37 and 0.8±0.6, respectively. γH2AX was recognized as dot-like foci in nuclei of epithelial cells, and the positive cells were mainly located near the basal layer of the mucosa. In BMP and PEITC groups, γH2AX expression was mainly observed in umbrella cells and intermediate cells, respectively. In melamine and uracil groups, there were diffuse urothelial hyperplasia and focal expression of γH2AX especially in the basal layer. The expression ratios of γH2AX in BMP, PEITC, melamine and uracil groups were 8.3±6.6, 26±9.0, 16±11 and 11±11, respectively. Two weeks after withdrawal of administration, although the expression ratio of γH2AX was markedly reduced in all groups, it remained high in BBN (17±1.9) and 2-NA (19±3.4) groups compared with the controls (0.6±0.9). Discussion and conclusion: BBN and 2-NA, genotoxic bladder carcinogens, induced more extensive γH2AX expression in the urothelium than other non-genotoxic (melamine and uracil) or non-carcinogenic chemicals (BMP and PEITC), and γH2AX-positive cells remained in relatively large numbers even 2 weeks after withdrawal of its administration. In addition, ratio of basal cells, intermediate cells and umbrella cells in γH2AX-positive cells showed similar patterns in BBN/2-NA and melamine/uracil groups. These data indicate that γH2AX has potential as a biomarker for early detection of genotoxic carcinogen in the urinary bladder. Citation Format: Takeshi Toyoda, Young-Man Cho, Jun-ichi Akagi, Yasuko Mizuta, Kumiko Ogawa. Expression of γH2AX as a biomarker of genotoxic carcinogen in the urinary bladder of rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4580. doi:10.1158/1538-7445.AM2015-4580

Parathyroid adenoma imaging-preoperative localization

ABSTRACT Primary hyperparathyroidism (PHPT) is a frequent endocrine disorder that can only be cured by a surgical procedure that is parathyroidectomy. The main causes are usually solitary benign adenoma (80-85%), diffuse or nodular hyperplasia (10-15%), or parathyroid carcinoma (&lt;1%). Out of the known localization techniques, ultrasonography, nuclear scintigraphy and computer tomography (CT scan) are most commonly used [1]. The aim of this study is to evaluate the sensibility of ultrasonography by comparison to scintigraphy and CT scan for the preoperative localization of parathyroid adenoma in patients with biochemically confirmed primary hyperparathyroidism. Localization studies were correlated with intraoperative findings, histopathological outcomes. In a retrospective study we analyzed 60 patients out of 245 patients who had undergone parathyroidectomy for PHPT between 2012-2013 in the Surgery Department of the National Institute of Endocrinology, Bucharest. Preoperative evaluation included imaging explorations (ultrasonography, scintigraphy and cervical CT scan) and therapeutic success was confirmed by histopathological result and the evolution of hormonal and biochemical tests. Intraoperative exploration revealed a single adenoma in 59 patients and one double adenoma. Thyroid disease was associated in 27 (45%) patients

Role of Sphingosine-1-Phosphate in Transplant Vasculopathy Evoked by Anti-HLA Antibody

Transplant vasculopathy (TV) represents the main cause of late graft failure and limits the long-term success of organ transplantation. Cellular and humoral immune responses contribute to the pathogenesis of the concentric and diffuse intimal hyperplasia of arteries of the grafted organ. We recently reported that the mitogenic signaling, evoked in human vascular smooth muscle cells (hmSMC) by the anti-HLA class I monoclonal antibody W6/32, implicates neutral sphingomyelinase-2, suggesting a role for sphingolipids in intimal hyperplasia of TV. Here, we investigated whether the mitogenic sphingolipid, sphingosine-1-phosphate (S1P), is involved in intimal hyperplasia elicited by W6/32. Studies were done on cultured hmSMC and on an in vivo model of TV, consisting of human mesenteric arteries grafted into SCID/beige mice, injected weekly with W6/32. hmSMC migration and DNA synthesis elicited by W6/32 were inhibited by the sphingosine kinase-1 (SK1) inhibitor dimethylsphingosine, the anti-S1P antibody Sphingomab and the S1PR1/R3 inhibitor VPC23019. W6/32 stimulated SK1 activity, while siRNA silencing SK1, S1PR1 and S1PR3 inhibited hmSMC migration. In vivo, Sphingomab significantly reduced the intimal thickening induced by W6/32. These data emphasize the role of S1P in intimal hyperplasia elicited by the humoral immune response, and open perspectives for preventing TV with S1P inhibitors.

Evaluating the Radiation From Accidental Exposure During a Nondestructive Testing Event.

Industrial radiography is a common nondestructive testing (NDT) method used in various industries. An investigation was conducted for a 1999 incident in Taiwan where two workers (Operators A and B) were accidently exposed to an unshielded Ir source while conducting industrial radiography. Operators A and B experienced acute close-range radiation exposure to a source of Ir for 3 h at a strength of 2.33 × 10 Bq. The health of mammary glands, bone marrow, thyroid glands, eyes, and genital organs of these two workers after radiation exposure was examined. Subsequently, Operator A experienced severe radiation injury, including tissue necrosis and keratinization in the fingers, chromosomal abnormalities, reduced blood cell count, diffuse hyperplasia of the thyroid gland, opaque spots in the crystalline lens, and related radiation effects. The results showed that the left index finger and thumb, eyes, and gonads of Operator A were exposed to a radiation dose of about 369-1,070, 23.1-67.4, 2.4-5.3, and 4.2-11.6 Gy, respectively. Effective dose for Operator A was estimated to range from 6.9 to 18.9 Sv. The left fingers, thumb, eyes, and gonads of Operator B were exposed to a radiation dose of 184.9-646.2, 11.8-40.7, 0.49-3.33, and 0.72-7.18 Gy, respectively, and his effective dose was between 2.5 and 11.5 Sv. This accident indicated a major flaw in the control and regulation of radiation safety for conducting NDT industrial radiography in 1999; however, similar problems still exist. Modifications of the Ionizing Radiation Protection Act in Taiwan are suggested in this study to regulate the management of NDT industries, continually educate the NDT workers in radiation safety, and enact notification provisions for medical care systems toward acute radiation exposure events.

Abstract 2282: K-RasV12 bone marrow cell reconstitution causes lung cancer in wild type mice

Abstract The potential of recruited bone-marrow-derived cells (BMDCs) to act as a source of malignancy was disputed for a long time. A role for BMDCs in tissue repair has also been proposed, since these cells are capable of homing to the lung and differentiating into multiple epithelial cell lineages so thus contributing in lung tissue repair and regeneration. We tested the ability of bone marrow cells containing an inducible oncogene to initiate lung adenocarcinoma. Since the role of the K-Ras gene in lung cancer is well known, for our experimental strategy, we used a mouse model expressing oncogenic K-RasV12 (K-Ras+/V12RERTert/ert). This model generates a specific neoplastic phenotype induced by the K-RasV12 mutation. Mice usually develop lung tumors with complete penetrance evolving from hyperplasia, through adenoma, to adenocarcinoma, when the oncogene expression is induced by 4-hydroxitamoxifen (4-OHT) administration. Following lethal irradiation, wild-type mice were transplanted with donor bone marrow cells derived from K-RasV12 mice and, once the bone marrow was reconstituted, treated with 4-OHT. Mice were monitored and sacrificed at subsequent post-induction time points (0, 3.5, 5.5, 8.5, 11, 13.5, 15, and 16 months) and lungs and peripheral blood were collected. Analysis of the H&amp;E-stained lung sections from both reconstituted K-RasV12 and control mice revealed diffuse hyperplasia, possibly due to irradiation. Epithelial lesions, adenomas and/or adenocarcinomas, were detected in 4 out of 8 K-RasV12-reconstituted animals at 3.5, 5.5, 13.5 and 15 months post oncogene induction while no lesions were detected in the control group (transplanted but not induced mice). In addition, the K-Ras implication on the origin of the tumor was confirmed by X-Gal staining of lung lesions in reconstituted mice. In our model, -geo is indeed a marker protein coexpressed along with the same K-RasV12 transcript by a bicistronic strategy. Our results suggest a direct implication of BMDCs in lung epithelial tumor development and emphasize the need of further studies to dissect the mechanisms regulating BMDCs’ recruitment to injured tissues and their role in tumor initiation and/or progression. Citation Format: Elena Belloni, Ines Martin-Padura, Elvira Gerbino, Stefania Orecchioni, Fulvia Fusar-Imperatore, Paola Marighetti, Giovanni Bertalot, Pier Giuseppe Pelicci, Francesco Bertolini. K-RasV12 bone marrow cell reconstitution causes lung cancer in wild type mice. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2282. doi:10.1158/1538-7445.AM2015-2282