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Lanuti, Michael

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Lanuti, Michael

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Author's Publications: search.filters.isAuthorOfPublication.578620fc-79b5-46c7-a161-936a71da4ab5

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    Mouse Model of Carbon Tetrachloride Induced Liver Fibrosis: Histopathological Changes and Expression of CD133 and Epidermal Growth Factor
    (BioMed Central, 2010) Fujii, Tsutomu; Fuchs, Bryan; Yamada, Suguru; Lauwers, Gregory Y.; Kulu, Yakup; Goodwin, Jonathan M; Lanuti, Michael; Tanabe, Kenneth
    Background: In the setting of chronic liver injury in humans, epidermal growth factor (EGF) and EGF receptor (EGFR) are up-regulated and have been proposed to have vital roles in both liver regeneration and development of hepatocellular carcinoma (HCC). Chronic liver injury also leads to hepatic stellate cell (HSC) differentiation and a novel subpopulation of HSCs which express CD133 and exhibit properties of progenitor cells has been described in rats. The carbon tetrachloride (CCl4)-induced mouse model has been historically relied upon to study liver injury and regeneration. We exposed mice to CCl4 to assess whether EGF and CD133+ HSCs are up-regulated in chronically injured liver. Methods: CCl4 in olive oil was administered to strain A/J mice three times per week by oral gavage. Results: Multiple well-differentiated HCCs were found in all livers after 15 weeks of CCl4 treatment. Notably, HCCs developed within the setting of fibrosis and not cirrhosis. CD133 was dramatically up-regulated after CCl4 treatment, and increased expression of desmin and glial fibrillary acidic protein, representative markers of HSCs, was also observed. EGF expression significantly decreased, contrary to observations in humans, whereas the expression of amphiregulin, another EGFR ligand, was significantly increased. Conclusions: Species-specific differences exist with respect to the histopathological and molecular pathogenesis of chronic liver disease. CCl4-induced chronic liver injury in A/J mice has important differences compared to human cirrhosis leading to HCC.
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    Epidermal Growth Factor Gene Functional Polymorphism and the Risk of Hepatocellular Carcinoma in Patients With Cirrhosis
    (American Medical Association (AMA), 2008) Tanabe, Kenneth; Lemoine, Antoinette; Finkelstein, Dianne; Kawasaki, Hiroshi; Fujii, Tsutomu; Chung, Raymond; Lauwers, Gregory Y.; Kulu, Yakup; Muzikansky, Alona; Kuruppu, Darshini; Lanuti, Michael; Goodwin, Jonathan M.; Azoulay, Daniel; Fuchs, Bryan
    Context: Overexpression of epidermal growth factor (EGF) in the liver induces transformation to hepatocellular carcinoma in animal models. Polymorphisms in the EGF gene modulate EGF levels. Objective: To assess the relationship among human EGF gene single-nucleotide polymorphism, EGF expression, and risk of hepatocellular carcinoma. Design, Setting, and Participants: Molecular mechanisms linking the 61*G allele polymorphism to EGF expression were examined in human hepatocellular carcinoma cell lines and human liver tissue. A case-control study involving 207 patients with cirrhosis was conducted at the Massachusetts General Hospital (1999-2006) and a validation case-control study involving 121 patients with cirrhosis was conducted at Hôpital Paul Brousse (1993-2006). Restriction fragment-length polymorphism was used to determine the EGF gene polymorphism genotype. Logistic regression analysis was used to assess the association between the EGF polymorphism and hepatocellular carcinoma risk. Main Outcome Measures: Mechanisms by which the EGF gene polymorphism modulates EGF levels and associations among EGF gene polymorphism, EGF levels, and hepatocellular carcinoma. Results: Transcripts from the EGF 61*G allele exhibited more than a 2-fold longer half-life than those from the 61*A allele, and EGF secretion was 2.3-fold higher in G/G hepatocellular carcinoma cell lines than A/A cell lines. Serum EGF levels were 1.8-fold higher in G/G patients than A/A patients, and liver EGF levels were 2.4-fold higher in G/G patients than A/A patients. Among the 207 patients with cirrhosis in the Massachusetts study population, 59 also had hepatocellular carcinoma. Analysis of the distribution of allelic frequencies revealed that there was a 4-fold odds of hepatocellular carcinoma in G/G patients compared with A/A patients in the Massachusetts study population (odds ratio, 4.0; 95% confidence interval [CI], 1.6-9.6; P = .002). Logistic regression analysis demonstrated that the number of copies of G was significantly associated with hepatocellular carcinoma after adjusting for age, sex, race, etiology, and severity of cirrhosis (G/G or A/G vs A/A; hazard ratio, 3.49; 95% CI, 1.29-9.44; P = .01). The significant association was validated in the French patients with alcoholic cirrhosis and hepatocellular carcinoma. Conclusion: The EGF gene polymorphism genotype is associated with risk for development of hepatocellular carcinoma in liver cirrhosis through modulation of EGF levels.
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    Clinicopathologic and Longitudinal Imaging Features of Lung Cancer Associated with Cystic Airspaces: A Systematic Review and Meta-Analysis
    (2021-02) Mendoza, Dexter; Heeger, Allen; Mino-Kenudson, Mari; Lanuti, Michael; Shepard, Jo-Anne; Sequist, Lecia; Digumarthy, Subba
    Background: Lung cancer with cystic airspaces (LC-CAS) is an uncommon presentation of primary lung malignancy. Due to their rarity and atypical appearance, there can be delays in diagnosis and treatment. Evidence acquisition: We searched for published papers on the clinicopathologic and imaging features of LC-CAS and included studies based on predefined criteria. We extracted the clinicopathologic characteristics of the patients with LC-CAS and computed tomography (CT) imaging features of LC-CAS and performed pooled analysis for reported continuous and categorical data. Evidence synthesis: The analysis included 8 original research studies with combined 341 patients with LC-CAS (weighted mean age: 61.8 years; range: 30-87 years). Majority had stage I disease (134/217, 61.8%). The most common histologies were adenocarcinoma (289/328, 88.1%) and squamous cell carcinoma (30/328, 9.1%). The cysts in LC-CAS commonly had non-uniform (104/114; 91.2%) and thick (83/222; 37.4%) walls, had irregular margins (53/142; 37.3%), and were multilocular (99/272; 36.4%). Most LC-CAS had a nodule or soft tissue component (210/328; 64.0%). Over time, most LC-CAS had development or enlargement of the solid component (61/89, 68.5%), approximately half (43/89, 48.3%) had interval wall thickening, and a minority evolved into completely solid masses or nodules (11/89, 12.4%). The cystic component can increase (36/89, 40.4%), decrease (28/89, 31.5), or remain stable (24/89, 27.0%) in size. Conclusion: Lung cancer should be suspected in cystic lung lesions with associated wall thickening or nodularity, and the index of suspicion should be further raised if wall thickening increases or nodule develops. The cystic component in LC-CAS may enlarge, remain stable, or decrease in size over time; stability or decreased size of the cyst should not be taken as a sign of benignity. These lesions can be indolent and close and long-term follow up with imaging should be considered if these lesions are not biopsied or resected.