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Biomedical subjects

E J Mark

Publications and source records attributed to E J Mark.

At least 19 recordsLinked to original sources
PubMed2003

Accelerated usual interstitial pneumonitis, anti-DNA antibodies and hypocomplementemia.

A healthy 60-year-old patient presented with progressive dyspnoea. Clinical, radiographic and pathological features of interstitial lung disease were found and an open lung biopsy established the diagnosis of usual interstitial pneumonitis (UIP) (idiopathic pulmonary fibrosis). Despite treatment, the patient died 4 months later in respiratory failure. Although the patient had no extra-thoracic involvement at autopsy, his illness was associated with a very high titre of anti-double-stranded DNA antibodies, hypocomplementemia, hypergammaglobulinaemia and lymphoid hyperplasia. These features and a literature review, suggest immune-mediated lung damage in a subset of patients with UIP.

Antibodies, Antinuclear↗
PubMed2003

Histopathology of coronary in-stent restenosis following gamma brachytherapy.

The histopathology of in-stent restenosis (ISR) following gamma brachytherapy is described. Such histology has not been reported previously. An 82 year old man presented with recurrent ISR three months after gamma brachytherapy to an area of ISR within a native circumflex vessel. The recurrent ISR was treated with directional coronary atherectomy; the histopathology of this directional coronary atherectomy specimen is discussed. These histopathological examinations showed abundant extracellular matrix material. Surprisingly, there was a relatively small cellular (myofibroblastic) component, with an absence of endothelial cells and little evidence of active proliferation. ISR after gamma brachytherapy may be a pathologically distinct entity.

Aged↗
PubMed2002

Cerebral vasoconstriction and stroke after use of serotonergic drugs.

Serotonin (5-hydroxytryptamine) is a potent vasoconstrictor amine. The authors report three patients who developed thunderclap headache, reversible cerebral arterial vasoconstriction, and ischemic strokes (i.e., the Call-Fleming syndrome). The only cause for vasoconstriction was recent exposure to serotonergic drugs in all patients, and to pseudoephedrine in one patient. These cases, and the literature, suggest that the use of serotonin-enhancing drugs can precipitate a cerebrovascular syndrome due to reversible, multifocal arterial narrowing.

Adult↗
PubMed2001

Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses.

We have generated a molecular taxonomy of lung carcinoma, the leading cause of cancer death in the United States and worldwide. Using oligonucleotide microarrays, we analyzed mRNA expression levels corresponding to 12,600 transcript sequences in 186 lung tumor samples, including 139 adenocarcinomas resected from the lung. Hierarchical and probabilistic clustering of expression data defined distinct subclasses of lung adenocarcinoma. Among these were tumors with high relative expression of neuroendocrine genes and of type II pneumocyte genes, respectively. Retrospective analysis revealed a less favorable outcome for the adenocarcinomas with neuroendocrine gene expression. The diagnostic potential of expression profiling is emphasized by its ability to discriminate primary lung adenocarcinomas from metastases of extra-pulmonary origin. These results suggest that integration of expression profile data with clinical parameters could aid in diagnosis of lung cancer patients.

Adenocarcinoma↗
PubMed2001

p16(INK4a) and histology-specific methylation of CpG islands by exposure to tobacco smoke in non-small cell lung cancer.

The p16(INK4a) protein inhibits cyclin-dependent kinase 4, a key regulator of progression through the G(1) phase of the cell cycle. Methylation of CpG islands in the promoter region is an important avenue for inactivation of p16. The mechanism of methylation of the p16 promoter region, however, has not been elucidated. Recent reports investigating p16 methylation in non-small cell lung cancer (NSCLC) suggest that carcinogens in tobacco smoke induce the DNA methylation process. We investigated the association between methylation of the p16 promoter region and exposure to tobacco smoke in 185 primary NSCLCS: We also studied the relationship of p16 methylation with mutation of the K-ras and p53 genes, as well as with methylation at the DAP-kinase and p14(ARF) loci. Finally, we evaluated the prognostic significance of p16 methylation in NSCLC. The prevalence of p16 methylation was greater in squamous cell carcinoma (41%) compared with adenocarcinoma (22%; P = 0.03; Fisher's exact test). Methylation of p16 was significantly associated with pack-years smoked (P = 0.007; Wilcoxon rank sum test), duration of smoking (P = 0.0009; Wilcoxon rank sum test), and negatively with the time since quitting smoking (P = 0.03; Wilcoxon rank sum test). No methylation of the nearby p14(ARF) locus was detected, and methylation of the DAP-kinase locus was not associated with either p16 methylation or with exposure to tobacco smoke. In patients with stage 1 adenocarcinoma, p16 methylation was an independent risk factor predicting significantly shorter postsurgery survival (P = 0.03), controlling for the significant effects of other factors, including K-ras mutation. These findings suggest that methylation of CpG islands in tobacco-associated cancers occurs in a gene- and tissue-specific manner and is induced directly or indirectly by exposure to tobacco smoke in NSCLC.

Aged↗
PubMed2001

Promoter methylation of DAP-kinase: association with advanced stage in non-small cell lung cancer.

Death associated protein (DAP)-kinase is a 16 kDa calmodulin-dependent serine/threonine kinase that carries a death domain at its C-terminus. DAP-kinase functions as a positive mediator of apoptosis that is induced by interferon-gamma. Recent studies suggest that DAP-kinase is involved in tumor metastasis and that it can be inactivated by methylation of CpG islands in the promoter region of the gene in some human tumors. However, little is known about the factors that are associated with the occurrence of DAP-kinase promoter methylation. We investigated both the possible associations of tobacco carcinogen and asbestos exposure with DAP-kinase promoter methylation, and the demographic and clinical factors associated with DAP-kinase promoter methylation in non-small cell lung cancer (NSCLC). One hundred and eighty-five patients diagnosed with NSCLC undergoing surgical resection from June, 1992 through December, 1996 at Massachusetts General Hospital participated in this study. Methylation-Specific PCR (MSP), performed using fresh-frozen tissue, was used to determine the methylation status of the promoter region of the DAP-kinase gene. Forty-seven (25%) of 185 tumors showed DAP-kinase promoter methylation. There was a significant association between methylation and an advanced pathologic stage (P=0.003, Fisher's exact test). Methylation of the DAP-kinase promoter was also associated with an increase in tumor size (P=0.009, Fisher's exact test) and lymph node involvement (P=0.04). No association was found between promoter methylation of DAP-kinase and k-ras or p53 mutation. In addition there was no association with a history of exposure to tobacco or asbestos. Controlling for age, sex, and histology, the odds ratios describing the association of DAP-kinase hypermethylation with stage were 2.70 (1.13--6.45), 3.11 (1.37--7.08) and 7.77 (1.21--50.03) in stages II, III and IV, respectively. Stage I cases with DAP-kinase promoter methylation had worse overall survival, but with the small sample size and limited follow-up this did not reach statistical significance. Our findings suggest that methylation of the promoter region of the DAP-kinase gene is not associated with exposure to tobacco or asbestos. However, they strongly suggest that DAP-kinase may be important in the progression of non-small cell lung cancer from early to late stage disease.

Adult↗
PubMed2001

Tobacco smoke-induced DNA damage and an early age of smoking initiation induce chromosome loss at 3p21 in lung cancer.

The short arm of chromosome 3 is thought to harbor a novel oncogenic locus that is important in the genesis of lung cancer. The region at 3p21 is believed to contain a distinct locus that is sensitive to loss from the action of tobacco smoke carcinogens and has been reported to be specifically targeted for deletion in lung cancer. To investigate whether 3p21 alteration in lung cancer is associated with carcinogen exposure, PCR-based analysis was performed to detect loss of heterozygosity (LOH) on chromosome 3 at 3p21 in non-small cell lung carcinoma (NSCLC). We also measured instability at the BAT-26 locus, because the mismatch DNA repair gene, hMLH1, is found at 3p21. LOH at 3p21 was analyzed for association with the clinical features of NSCLC, p53 mutation status, polynuclear aromatic hydrocarbon-DNA adduct levels (measured using 32P-postlabeling) and carcinogen exposure information including cigarette smoking and asbestos exposure. Of 219 lung cancers, 150 cases (68.5%) were informative at the D3S1478 locus, and 44.2% of squamous cell carcinoma cases and 30.2% of adenocarcinoma cases showed 3p21 LOH. None of the cancers showed BAT-26 instability. The prevalence of 3p21 LOH was higher in both current and former smokers compared with never smokers and was higher in p53 mutated cases. Among squamous cell carcinoma cases, there was a strong association of increased 3p21 LOH with increasing polynuclear aromatic hydrocarbon-DNA adducts levels (P = 0.03), as well as an increased prevalence LOH with earlier age of smoking initiation (P = 0.02). Our results confirm that 3p21 LOH is strongly associated with measures of biologically effective dose of exposure to tobacco carcinogens. Our results also suggest that alterations of hMLH1 are not related to any of the reported associations, because there was no evidence of microsatellite instability. Finally, LOH in 3p21 may be an early molecular event in NSCLC, because it is significantly associated with a tendency to start smoking at a young age.

Adenocarcinoma↗
PubMed2000

Lipid-rich diffuse malignant mesothelioma: a case report.

An 80-year old man presented with shortness of breath and was found to have a large right pleural effusion. Cytology of the pleural fluid showed atypical papillary clusters of epithelioid cells. Multiple white-yellow nodules studding the pleural surfaces were seen at thoracoscopy, and biopsies showed solid and papillary clusters of large epithelioid cells with abundant cytoplasm filled with clear vacuoles. Special stains and electron microscopic findings indicated that the tumor was a diffuse malignant mesothelioma with numerous intracytoplasmic lipid vacuoles. Fat stain may be useful at time of frozen section for a pleural-based tumor with vacuolated cells, and the presence of lipid vacuoles in a pleural-based tumor does not exclude diffuse malignant mesothelioma.

Aged↗
PubMed2000

Polymorphisms in the DNA repair genes XRCC1 and ERCC2 and biomarkers of DNA damage in human blood mononuclear cells.

Polymorphisms in several DNA repair genes have recently been identified, but little is known about their phenotypic significance. To determine whether variation in DNA repair genes is related to host DNA damage, we studied the association between polymorphisms in XRCC1 (codon 399) and ERCC2 (codon 751) and two markers of DNA damage, sister chromatid exchange (SCE) frequencies (n = 76) and polyphenol DNA adducts (n = 61). SCE frequencies were determined using a modified fluorescence-Giemsa method and polyphenol DNA adducts were determined using a P1-enhanced (32)P-post-labeling procedure. XRCC1 and ERCC2 genotypes were identified using PCR-RFLP. Mean SCE frequencies among current smokers who were homozygous carriers of the 399Gln allele in XRCC1 were greater than those in 399Arg/Arg current smokers. We also observed a possible gene-dosage effect for XRCC1 399Gln and detectable DNA adducts, and significantly more adducts among older subjects who were carriers of the 399Gln allele than in younger subjects with the 399Arg/Arg genotype. The polymorphism in ERCC2 was unrelated to SCE frequency or DNA adduct level. Our results suggest that carriers of the polymorphic XRCC1 399Gln allele may be at greater risk for tobacco- and age-related DNA damage.

Aged↗
PubMed2000

Mycobacterium abscessus infection in cystic fibrosis. Colonization or infection?

We present a case of a patient with cystic fibrosis who was thought to be colonized with Mycobacterium abscessus for 13 yr prior to developing clinically apparent mycobacterial infection. However, histologic evidence indicated that invasive mycobacterial disease was present from the onset. While accepting that chronic endobronchial colonization with atypical mycobacteria may occur in patients with cystic fibrosis, the repeated isolation of mycobacteria from the sputum of these patients should alert the clinician to the possibility of indolent disease. Early consideration of treatment for this infection should occur in any patient with cystic fibrosis in whom there is an unexplained deterioration in lung function. The recent introduction of high dose ibuprofen raises concerns about its possible contribution to the progression of the infection.

Adult↗
PubMed2000

Bronchocentric granulomatosis with mucus impaction due to bronchogenic carcinoma. An association with clinical relevance.

OBJECTIVE: To describe an unexpected inflammatory process associated with malignancy in the lung and to postulate a new mode of pathogenesis. DESIGN: Retrospective review of surgical pathologic findings. SETTING: Academic hospital pathology department. PATIENTS: Four patients, 2 men and 2 women, ranging in age from 45 to 74 years, each of whom had a solitary mass on chest radiographs. INTERVENTIONS: Pulmonary lobectomy. MAIN OUTCOME MEASURE: Histopathologic identification of bronchocentric granulomatosis. RESULTS: Accompanying a bronchogenic carcinoma in each case was a necrotizing chronic granulomatous reaction centered around bronchioles that were plugged with mucus, necrotic detritus from the tumor, lipid, or a combination of these substances. Eosinophils were present in small numbers in one case. The pathologic findings characterize bronchocentric granulomatosis. CONCLUSIONS: The presence of bronchocentric granulomatosis in the biopsy of a mass does not exclude the presence of an accompanying bronchogenic carcinoma associated with obstruction of bronchioles. Bronchocentric granulomatosis in some cases may represent an immunologic response to tumor detritus or lipid, as well as to mucus impaction.

Adenocarcinoma↗
PubMed1999

Implications and prognostic value of K-ras mutation for early-stage lung cancer in women.

BACKGROUND: Because there is no clear consensus as to the predictive value of K-ras gene mutation for survival in patients with lung cancer, we examined the occurrence of K-ras mutations in a large, prospective case series of non-small-cell lung cancer (NSCLC). Our goals were to define the patient characteristics associated with K-ras mutation and to determine whether mutation of this gene might be a biomarker of patient prognosis. METHODS: Consecutive, newly diagnosed patients with lung cancer treated with potentially curative resection over a 4-year period were recruited for study. The mutation status of K-ras codon 12 in each patient's tumor DNA was determined by means of polymerase chain reaction-restriction fragment length polymorphism analysis of archived pathology specimens. Analyses were restricted to adenocarcinoma. RESULTS: There was a statistically significant association between female sex and K-ras mutation after adjustment for carcinogen exposures (odds ratio = 3.3; 95% confidence interval [CI] = 1.3-7.9); mutations were found only in smokers. Comparison of Kaplan-Meier curves indicated a strong association between K-ras mutation and decreased patient survival (two-sided P =.009); analysis stratified by pathologic staging groups revealed that this association was statistically significant only for stage I tumors (two-sided P =.002). Cox proportional hazards modeling indicated that K-ras codon 12 mutation was a statistically significant predictor of patient survival, after adjustment for the effects of age, sex, and stage (risk ratio = 1.8; 95% CI = 1.1-3.1). CONCLUSIONS: After adjustment for environmental exposures, non-small-cell lung tumors in women appear to be more likely than those in men to harbor K-ras mutations, suggesting a possible role of estrogen exposure in either the initiation or the selection of K-ras mutant clones in adenocarcinoma. In addition, our data suggest that K-ras codon 12 mutation is a marker of aggressive NSCLC, as evidenced by its association with decreased patient survival, particularly for early-stage disease.

Adenocarcinoma↗
PubMed1999

k-ras mutation and occupational asbestos exposure in lung adenocarcinoma: asbestos-related cancer without asbestosis.

Environmental carcinogen exposure is requisite for the development of nearly all lung cancer, and it is well known that asbestos exposure interacts synergistically with tobacco smoke to induce lung cancer. However, the precise molecular lesions induced by asbestos are unknown. Furthermore, it is also unknown whether asbestos carcinogenesis proceeds in a fashion independent of or dependent upon the induction of fibrosis in workers with high asbestos exposures. Previous studies have suggested that asbestos is associated with the presence of a k-ras mutation in adenocarcinoma of the lung. We aimed to test whether occupational asbestos exposure was associated with k-ras codon 12 mutations in lung adenocarcinoma tumors and to determine whether this was conditional on the presence of asbestosis. All newly diagnosed, resectable lung cancer patients receiving treatment at the Massachusetts General Hospital between November 1992 and December 1996 were eligible to participate. Because k-ras mutation is very strongly associated with adenocarcinoma, and men were more likely to be occupationally exposed to asbestos, the study was restricted to males with this histological diagnosis. There were 84 male patients with available questionnaire-derived work history data and paraffin-embedded tumor tissue for determination of k-ras mutation status. Chest radiographic evaluation was done for all of the patients who reported occupational exposure to asbestos. The prevalence of k-ras mutation was higher among those with a history of occupational asbestos exposure (crude odds ratio, 4.8; 95% confidence interval, 1.5-15.4) compared to those without asbestos exposure, and this association remained after adjustment for age and pack-years smoked (adjusted odds ratio, 6.9; 95% confidence interval, 1.7-28.6). An index score that weights both the dates of exposure and the estimated intensity of exposure indicated that those with k-ras mutations had significantly greater asbestos exposures than those without mutations (P < 0.01). Analysis of the descriptive components of exposure indicated that the duration of exposure was not associated with k-ras mutation, but that the time since initial exposure was significantly associated with mutation status. The association of k-ras mutation and reported asbestos exposure was not dependent on the presence of radiographic evidence of asbestos-related disease. These data suggest that asbestos exposure increases the likelihood of mutation at k-ras codon 12 and that this process occurs independently of the induction of interstitial fibrosis.

Adenocarcinoma↗
PubMed1999

Carcinogen exposure, p53 alteration, and K-ras mutation in synchronous multiple primary lung carcinoma.

BACKGROUND: Synchronous multiple primary lung tumors (SMPLT) have been estimated to occur in 1% of lung carcinoma patients. Criteria for SMPLT diagnosis include different cancer histologies, location in different lobes of the lung, or genetic discordance. Patients with SMPLT have a poor clinical prognosis with decreased 5-year disease survival, despite diagnosis at an early stage. Field cancerization (the induction of somatic mutation in large clones of epithelial cells after carcinogen exposure) has been proposed to be an integral process involved in the development of SMPLT. Host factors also may contribute to the development of SMPLT. METHODS: The authors investigated the occurrence of p53 and K-ras alterations in tumors from SMPLT patients and also studied the association between carcinogen exposure and polymorphic metabolic traits in SMPLT patients, comparing these patients with individuals with one primarily lung tumor. RESULTS: In a case-control study of lung carcinoma susceptibility, 6 patients were identified whose 33 multiple tumors met the criteria of SMPLT. The incidence was 3.6% (16 of 451 patients), which was higher than many previously published series. Among the multiple tumors, 73% (24 of 33 tumors) were adenocarcinomas. Patients with SMPLT smoked more (73.0 pack-years vs. 56.2 pack-years; P = 0.07) and longer (45.8 years vs. 37.0 years; P < 0.03) than patients with only 1 tumor. For those patients who stopped smoking, patients with SMPLT had stopped smoking more recently than those with a single primary tumor (3.4 years vs. 7.3 years; P = 0.08). A total of 39% of SMPLT tumors (13 of 33 tumors) had detectable p53 alterations; 36% had genetic changes in p53 measured by polymerase chain reaction-single strand conformation polymorphism, and 33% showed positive immunostaining for p53 protein. This was comparable to the occurrence of p53 mutations and immunostaining in single tumor cases (30%). Age, gender, family history of cancer, and the prevalence of polymorphic metabolic traits previously associated with lung carcinoma susceptibility did not differ among SMPLT patients compared with patients with a single tumor. CONCLUSIONS: The patients with SMPLT had significantly more tobacco exposure, and their tumors apparently had independently arising p53 and K-ras mutations, suggesting that field cancerization may be important in lung carcinogenesis.

Adenocarcinoma↗
PubMed1999

Early age at smoking initiation and tobacco carcinogen DNA damage in the lung.

BACKGROUND: DNA adducts formed as a consequence of exposure to tobacco smoke may be involved in carcinogenesis, and their presence may indicate a high risk of lung cancer. To determine whether DNA adducts can be used as a "dosimeter" for cancer risk, we measured the adduct levels in nontumorous lung tissue and blood mononuclear cells from patients with lung cancer, and we collected data from the patients on their history of smoking. METHODS: We used the 32P-postlabeling assay to measure aromatic hydrophobic DNA adducts in nontumorous lung tissue from 143 patients and in blood mononuclear cells from 54 of these patients. From the smoking histories, we identified exposure variables associated with increased DNA adduct levels by use of multivariate analyses with negative binomial regression models. RESULTS/ CONCLUSIONS: We found statistically significant interactions for variables of current and former smoking and for other smoking variables (e.g., pack-years [number of packs smoked per day x years of smoking] or years smoked), indicating that the impact of smoking variables on DNA adduct levels may be different in current and former smokers. Consequently, our analyses indicate that models for current and former smokers should be considered separately. In current smokers, recent smoking intensity (cigarettes smoked per day) was the most important variable. In former smokers, age at smoking initiation was inversely associated with DNA adduct levels. A highly statistically significant correlation (r=.77 [Spearman's correlation]; two sided P<.001) was observed between DNA adduct levels in blood mononuclear cells and lung tissue. IMPLICATIONS: Our results in former smokers suggest that smoking during adolescence may produce physiologic changes that lead to increased DNA adduct persistence or that young smokers may be markedly susceptible to DNA adduct formation and have higher adduct burdens after they quit smoking than those who started smoking later in life.

Age Factors↗
PubMed1999

Bronchoalveolar carcinoma: clinical, radiologic, and pathologic factors and survival.

BACKGROUND: The principal feature of bronchoalveolar carcinoma is that it spreads along airways or aerogenously with multifocality, but many issues are unresolved. METHODS: We studied 119 patients with pathologically confirmed bronchoalveolar carcinoma. Symptoms, smoking status, radiologic findings, the size of tumor, operative procedures, and complications were reviewed. We studied the pathologic features: presence or absence of aerogenous spread, patterns of growth, cell type, nuclear grade, mitosis, rate of bronchoalveolar carcinoma in adenocarcinoma, and lymphocyte infiltration. The correlation among clinical, radiologic, and pathologic findings was examined, and the factors affecting survival were analyzed. RESULTS: Symptomatic patients had more infiltrative radiographic features, and asymptomatic patients tended to have more mass-like features (P <.0001). Tumors with radiographically infiltrating lesions tended to have mucinous histologic features (P =.006). Tumors with mass lesions by radiograph tended to have nonmucinous and sclerosing histologic features (P =.003). Aerogenous spread was seen in 94% of specimens. The presence of a variety of cell types suggested multiple clonal origin. The overall survival in those patients undergoing resection was 69.1% at 5 years and 56.5% at 10 years. The significant factors affecting survival were radiologic presence of a mass or infiltrate, pathologic findings of the presence of sclerosis, association with a scar, the rate of bronchoalveolar carcinoma in adenocarcinoma, lymphocyte infiltration grade, nodal involvement, and status of complete resection. Mitosis or nuclear grade of tumor cells did not correlate with survival. CONCLUSIONS: Bronchoalveolar carcinoma showed good overall survival with appropriate surgical procedures. Certain radiologic or pathologic findings correlated with survival. These findings may enhance the ability to predict long-term survival.

Adenocarcinoma, Bronchiolo-Alveolar↗
PubMed1999

Infantile disseminated visceral giant cell arteritis presenting as sudden infant death.

The rare clinicopathological entity 'disseminated visceral giant cell arteritis' (DVGCA) was first described in 1978. It is characterized by widespread small-vessel giant cell angitis and extravascular granulomas. A normal and healthy 7-month-old boy who presented unexpectedly with sudden infant death syndrome (SIDS) is reported. Histological examination at autopsy revealed giant cell angitis of the aorta, common carotid, coronary, pulmonary, celiac, mesenteric and common iliac arteries. There were also granulomas in the tracheal wall and liver. To our knowledge, this is the first documented case of DVGCA occurring in an infant younger than 12 months of age. A review of the literature on DVGCA is presented in this report, and the differential diagnosis is discussed.

Arteries↗