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1.  Oral Epithelium as a Surrogate Tissue for Assessing Smoking-Induced Molecular Alterations in Lungs 
Both the lungs and oral cavity are exposed to tobacco carcinogens in smokers. We hypothesized that the oral epithelium undergoes molecular alterations similar to those in lungs and therefore may be used as a surrogate tissue to assess tobacco-induced molecular alterations.
Promoter methylation of p16 and FHIT genes was analyzed with methylation-specific PCR in 1,774 oral and bronchial brush specimens (baseline and 3 months after intervention) from 127 smokers enrolled in a prospective randomized placebo-controlled chemoprevention trial. The association between methylation patterns in oral tissues and bronchial methylation indices (methylated sites/total sites per subject) was analyzed blindly.
At baseline, promoter methylation was observed in 23%, 17%, and 35% of the bronchial tissues for p16, FHIT, and either of the two genes, respectively, which were comparable to the 19%, 15%, and 31% observed in the oral tissues. Among the 125 individuals with available data from both oral and bronchial tissues, strong correlations were observed between tissues from the two sites (P<0.0001 for both p16 and FHIT). Among the 39 individuals with oral tissue methylation in either of the two genes, the mean bronchial methylation index was 0.53 (± 0.29) compared with only 0.27 (± 0.26) for the 86 subjects without oral tissue methylation (P<0.0001). Similar correlations were also observed in samples obtained at 3 months after chemopreventive intervention.
The oral epithelium may be used as a surrogate tissue to assess tobacco-induced molecular damage in lungs, which has an important implication in conducting biomarker-based lung cancer prevention trials.
PMCID: PMC4183362  PMID: 19138934
2.  A Case of Comorbid Myxoma and Chronic Lymphocytic Leukemia: Not Just a Coincidence? 
Background. It is unclear why cardiac myxomas develop. We describe a case of comorbid myxoma and chronic lymphocytic leukemia (CLL) to offer insights into the tumor's pathophysiology. Case. A 56-year-old female with recurrent venous thromboembolism developed embolic stroke. Transesophageal echocardiogram showed a 1.7 × 1 cm sessile left atrial mass at the interatrial septum. Histopathology revealed myxoma with a B cell lymphocytic infiltrate suggestive of a low grade lymphoproliferative disorder. Bone marrow biopsy and flow cytometry of blood and the cardiac infiltrate supported the diagnosis of atypical CLL. She was followed clinically in the absence of symptoms, organ infiltration, or cytopenia. After eighteen months, she developed cervical and axillary lymphadenopathy. Biopsy confirmed B cell CLL/small lymphocytic lymphoma. She elected to undergo chemotherapy with fludarabine, cyclophosphamide, and rituximab, with clinical remission. Conclusions. The coexistence of two neoplastic processes may be coincidental, but the cumulative likelihood is estimated at 0.002 per billion people per year. A shared pathogenic mechanism is more likely. Possibilities include chronic inflammation, vascular endothelial growth factor A, shared genetic mutations, changes in posttranslational regulation, or alterations in other cellular signaling pathways. Additional studies could expand our current understanding of the molecular biology of both myxomas and CLL.
PMCID: PMC4020543  PMID: 24868472
3.  Patterns of Relapse and Progression in Multiple Myeloma Patients after Autologous Stem Cell Transplantation: Implications for Patients’ Monitoring After Transplantation 
Bone marrow transplantation  2012;48(3):419-424.
Autologous stem cell transplantation (ASCT) is widely used in first-line treatment of multiple myeloma (MM). However, most patients eventually have relapse or progression of disease (R/POD). While precise knowledge of R/POD patterns would be important to generate evidence-based surveillance recommendations after ASCT, such data is limited in the literature, especially after introduction of the free light chain assay (FLCA). This retrospective study examined the patterns of R/POD after first-line ASCT in 273 patients, using established criteria. At time of R/POD, only 2% of patients had no associated serologic evidence of R/POD. Eighty five percent had asymptomatic R/POD first detected by serologic testing, while 15% had symptomatic R/POD with aggressive disease, early R/POD, and short survival, with poor cytogenetics and younger age identified as risk factors. While occult skeletal lesions were found in 40% of asymptomatic patients tested following serologic R/POD, yearly skeletal surveys and urine testing were poor at heralding R/POD. We found a consistent association between paraprotein types at diagnosis and R/POD allowing informed recommendations for appropriate serologic monitoring and propose a new needed criterion using FLCA for patients relapsing by FLC only. Our findings provide important evidence-based recommendations that strengthen current monitoring guidelines after first-line ASCT in MM.
PMCID: PMC3594539  PMID: 22890289
Multiple Myeloma; Autologous Transplantation; Relapse; Free Light Chain Assay
4.  Frequent expression of MAGE1 tumor antigens in bronchial epithelium of smokers without lung cancer 
Melanoma antigens (MAGE) are frequently expressed in lung cancer and are promising targets of anticancer immunotherapy. Our preliminary data suggested that MAGE may be expressed during early lung carcinogenesis, raising the possibility of targeting MAGE as a lung cancer prevention strategy. The purpose of this study was to investigate MAGE activation patterns in the airways of chronic smokers without lung cancer. MAGE-A1, -A3 and -B2 gene expression was determined in bronchial brush cells from chronic former smokers without lung cancer by reverse transcription-PCR (RT-PCR). The results were correlated with clinical parameters. The 123 subjects had a median age of 57 years, a median of 40 pack-years smoking history, and had quit smoking for at least one year prior to enrollment. Among the subjects, 31 (25%), 38 (31%), and 46 (37%) had detectable MAGE-A1, -A3 and -B2 expression, respectively, in their bronchial brush samples. Expression of MAGE-A1 and -B2 positively correlated with pack-years smoking history (P=0.03 and 0.03, respectively). The frequency of expression did not decrease despite a prolonged smoking cessation period. In conclusion, MAGE-A1, -A3 and -B2 genes are frequently expressed in the bronchial epithelial cells of chronic smokers without lung cancer, suggesting that chronic exposure to cigarette smoke activates these genes even before the malignant transformation of bronchial cells in susceptible individuals. Once activated, the expression persists despite long-term smoking cessation. These data support the targeting of MAGE as a novel lung cancer prevention strategy.
PMCID: PMC3440643  PMID: 22977481
melanoma antigens; airway; smokers; lung cancer; prevention
5.  Heterotransplant mouse model cohorts of human malignancies: A novel platform for Systematic Preclinical Efficacy Evaluation of Drugs (SPEED) 
Advances in molecular biology demonstrate that cancer is heterogeneous disease necessitating a personalized management approach. This is introducing a paradigm shift in clinical trial designs where molecular characterization of cancers is assuming importance equal to (or even more than) the traditional histologic diagnosis as the eligibility criterion for randomized clinical trials of new therapies. Recommendations have been made to gather the molecular information from clinical phase II trials distinguishing responding from non responding tumors for subsequent planning of large scale phase III trials. However by the time we reach phase II level, more than a billion dollars apart from years of research have been invested. It would be therefore prudent to conceptualize laboratory based platforms to obtain the proof of concept as early as possible, even before embarking upon the pivotal clinical trials. In this regard, we hereby propose and detail a novel preclinical platform incorporating the existing mouse models to address the issue of tumor heterogeneity in a systematic manner through creation of a setting similar to phase II trials in human patients. By providing critical information about a drug's efficacy and the molecular determinants of response early on, this platform would potentially provide a solid foundation to build avant-garde clinical trials integrating recent advances in molecular medicine.
PMCID: PMC2776291  PMID: 19966934
Cancer; heterotransplant; animal model; therapeutics; drug development

Results 1-5 (5)