Carole Holm

Ovarian Cancer Staging: Does It Require a Gynecologic Oncologist?

Forty-seven patients with presumed Stages I-II invasive ovarian epithelial carcinoma were treated with intravenous 50 mg/m2 cis-platinum, for 2-18 cycles (median, 9), 50 mg/m2 doxorubicin for 2-14 cycles (median, 9), and/or 600 mg/m2 cyclophosphamide for 2-14 cycles (median, 6) after surgical staging by a gynecologic oncologist or a nononcologic surgeon. Mean follow-up is 6.8 years. Cumulative 5-year actuarial survival is 73 +/- 6%; 75 +/- 12% for Stage I and 71 +/- 8% for Stage II disease. When screened for poor prognosticators, only the specialty of the operating surgeon was identified (P < 0.05). Five-year actuarial survival and disease-free survival, respectively, for Stages I-II patients surgically staged by a gynecologic oncologist were 83 +/- 7% and 76 +/- 8%, compared to 59 +/- 11% (P < 0.05) and 39 +/- 11% (P < 0.03) for the group operated upon by a nononcologist.

Sequelae of lateral ovarian transposition in unirradiated cervical cancer patients

The sequelae of lateral ovarian transposition (LOT) in cervical cancer patients has been examined only in the light of the effect of pelvic radiation therapy on ovarian preservation. Preservation of ovarian function has not been examined in the absence of radiation therapy, and symptomatic ovarian cyst formation in transposed ovaries with the need for subsequent surgery has not been addressed in either radiated or unirradiated cervical cancer patients. We studied 84 premenopausal FIGO stage IA or IB cervical cancer patients treated by primary radical hysterectomy between the years 1978 and 1988. None of these patients received adjuvant radiation therapy. Fifty-nine of eight-four patients had radical hysterectomy (RH) without LOT. These patients were compared to 25 of 84 patients who had LOT in addition to RH. The incidence of symptomatic ovarian cysts, the majority requiring operative intervention, was 24% in the ovarian transposition patients as compared to 7.4% in those who had RH alone. This threefold increase in symptomatic benign ovarian cyst formation in the translocated ovary was significant (P = .048). On the other hand, LOT in these RH patients does not appear to increase the incidence of early menopause (P greater than 0.05). On follow-up of those patients who did not incur additional surgery or radiation, 4.3% became menopausal, as compared to 4.1% of those patients undergoing RH alone, with the mean ages of the two groups being comparable.

Noninvasive Analysis of the Sputum Transcriptome Discriminates Clinical Phenotypes of Asthma

RATIONALE The airway transcriptome includes genes that contribute to the pathophysiologic heterogeneity seen in individuals with asthma. OBJECTIVES We analyzed sputum gene expression for transcriptomic endotypes of asthma (TEA), gene signatures that discriminate phenotypes of disease. METHODS Gene expression in the sputum and blood of patients with asthma was measured using Affymetrix microarrays. Unsupervised clustering analysis based on pathways from the Kyoto Encyclopedia of Genes and Genomes was used to identify TEA clusters. Logistic regression analysis of matched blood samples defined an expression profile in the circulation to determine the TEA cluster assignment in a cohort of children with asthma to replicate clinical phenotypes. MEASUREMENTS AND MAIN RESULTS Three TEA clusters were identified. TEA cluster 1 had the most subjects with a history of intubation (P = 0.05), a lower prebronchodilator FEV1 (P = 0.006), a higher bronchodilator response (P = 0.03), and higher exhaled nitric oxide levels (P = 0.04) compared with the other TEA clusters. TEA cluster 2, the smallest cluster, had the most subjects that were hospitalized for asthma (P = 0.04). TEA cluster 3, the largest cluster, had normal lung function, low exhaled nitric oxide levels, and lower inhaled steroid requirements. Evaluation of TEA clusters in children confirmed that TEA clusters 1 and 2 are associated with a history of intubation (P = 5.58 × 10(-6)) and hospitalization (P = 0.01), respectively. CONCLUSIONS There are common patterns of gene expression in the sputum and blood of children and adults that are associated with near-fatal, severe, and milder asthma.

Urinary Hexane Diamine to Assess Respiratory Exposure to Hexamethylene Diisocyanate Aerosol: A Human Inhalation Study

Abstract The use of urinary hexane diamine (HDA) as a biomarker to assess human respiratory exposure to hexamethylene diisocyanate (HDI) aerosol was evaluated. Twenty-three auto body shop workers were exposed to HDI biuret aerosol for two hours using a closed exposure apparatus. HDI exposures were quantified using both a direct-reading instrument and a treated-filter method. Urine samples collected at baseline, immediately post exposure, and every four to five hours for up to 20 hours were analyzed for HDA using gas chromatography and mass spectrometry. Mean urinary HDA (μg/ g creatinine) sharply increased from the baseline value of 0.7 to 18.1 immediately post exposure and decreased rapidly to 4.7, 1.9 and 1.1, respectively, at 4,9, and 18 hours post exposure. Considerable individual variability was found. Urinary HDA can assess acute respiratory exposure to HDI aerosol, but may have limited use as a biomarker of exposure in the workplace.

Characterisation of asthma subgroups associated with circulating YKL-40 levels

The chitinase-like protein YKL-40 mediates airway inflammation and serum levels are associated with asthma severity. However, asthma phenotypes associated with YKL-40 levels have not been precisely defined. We conducted an unsupervised cluster analysis of asthma patients treated at the Yale Center for Asthma and Airways Disease (n=156) to identify subgroups according to YKL-40 level. The resulting YKL-40 clusters were cross-validated in cohorts from the Severe Asthma Research Programme (n=167) and the New York University/Bellevue Asthma Repository (n=341). A sputum transcriptome analysis revealed molecular pathways associated with YKL-40 subgroups. Four YKL-40 clusters (C1–C4) were identified. C3 and C4 had high serum YKL-40 levels compared with C1 and C2. C3 was associated with earlier onset and longer duration of disease, severe airflow obstruction, and near-fatal asthma exacerbations. C4 had the highest serum YKL-40 levels, adult onset and less airflow obstruction, but frequent exacerbations. An airway transcriptome analysis in C3 and C4 showed activation of non-type 2 inflammatory pathways. Elevated serum YKL-40 levels were associated with two distinct clinical asthma phenotypes: one with irreversible airway obstruction and another with severe exacerbations. The YKL-40 clusters are potentially useful for identification of individuals with severe or exacerbation-prone asthma. Asthma with high serum YKL-40 levels is associated with severe lung function impairment and severe exacerbations http://ow.ly/wyly30elajo

Sputum Gene Expression of IL-13 Receptor α2 Chain Correlates with Airflow Obstruction and Helper T-Cell Type 2 Inflammation in Asthma

BACKGROUND BRP-39/YKL-40 is a chitinase-like protein that plays a critical role in IL-13-induced inflammation. It correlates positively with asthma severity and airway remodeling ( 1 ) via binding to IL-13 receptor α2 chain (IL-13Rα2). Because the relationship of IL-13Rα2 to human asthma has never been evaluated previously, we sought to determine the relationship between IL-13Rα2, YKL-40, and asthma. METHODS We evaluated 112 patients (69% women) with a mean age of 46.7 years. Subjects completed an asthma phenotyping protocol that included analysis of sputum gene expression by Affymetrix 1.0 ST gene array (Affymetrix, Santa Clara, CA) and YKL-40 protein levels. MEASUREMENTS AND MAIN RESULTS IL-13Rα2 gene expression was readily detectable in the sputum and correlated negatively with prebronchodilator (BD) FEV1 (rs = -0.282, P < 0.01), post-BD FEV1 (rs = -0.268, P < 0.01), pre-BD FEV1/FVC ratio (rs = -0.228, P < 0.05), and post-BD FEV1/FVC ratio (rs = -0.242, P < 0.01). IL-13Rα2 gene expression correlated positively with gene expression of IL-13 (rs = 0.484, P < 0.001), IL-5 (rs = 0.237, P < 0.05), and IL-8 (rs = 0.218, P < 0.05). Regression analysis showed that the post-BD FEV1/FVC ratio is significantly associated with IL-13Rα2 expression and CHI3L1 expression in sputum after controlling for IL-4, IL-5, IL-13, and transforming growth factor-β1 gene expression (all P < 0.01). Sputum YKL-40 gene expression positively correlated with IL-8 expression (rs = 0.357, P < 0.001) and negatively correlated with pre- and post-BD FEV1/FVC ratios (rs = -0.299, P < 0.001 and rs = -0.305, P < 0.01, respectively). Sputum and serum YKL-40 protein levels were not associated with IL-13Rα2 expression. CONCLUSIONS This analysis demonstrates that IL-13Rα2 is associated with reduced lung function, helper T-cell type 2 gene expression, and airflow obstruction in the airway of individuals with asthma, which might in turn be driven by airway remodeling. Future studies will be required to define the proinflammatory and remodeling effects of this receptor that up to now has been considered solely a modulator of IL-13-induced inflammation.

Vitamin A Chemoprevention of Lung Cancer

This article describes an ongoing short-term biomarker study of Vitamin A in subjects at high risk for lung cancer. Workers exposed to asbestos and cigarettes have a markedly increased risk of developing lung cancer and parenchymal fibrosis. Epidemiologic and experimental studies have shown that dietary vitamin A has significant anticancer and immunomodulatory effects (1-6). However, whether intervention with supplemental vitamin A can reduce the mortality or morbidity from either disease and the mechanisms involved remains unclear. Airway metaplasia on bronchial biopsy and inflammation on bronchoalveolar lavage (BAL) are considered potential markers for the development of lung cancer and parenchymal fibrosis respectively. Our prior clinical studies (see below) have shown an high incidence of both of these lesions in asbestos-exposed subjects, findings consistent with the idea that the processes of inflammation and carcinogenesis are linked. We have hypothesized that 1) the vitamin A intervention may reduce both bronchial metaplasia and lung inflammation, 2) the mechanism of this effect may be through modulation of relevant pulmonary cytokines, growth factors, and/or oncogenes, and 3) local lung vitamin A status may be a key modifiable host determinant or biomarker of susceptibility. We are performing a double-blind placebo controlled 6 month trial of combination 0-carotene and retinol in 50 subjects at high risk for both lung cancer and parenchymal fibrosis to address these hypotheses. This study should provide valuable data on whether vitamin A can modify potential early markers of lung cancer and fibrosis, the mechanisms involved, and the role of local vitamin A. The findings may lead to effective preventive strategies for lung cancer.