Cancer by Sfakianakis Alexandros

Τρίτη 22 Νοεμβρίου 2016

Developing New, Rational Therapies for Recalcitrant Small Cell Lung Cancer

The Recalcitrant Cancer Research Congressional Act of 2012 (H.R.733) directs the National Cancer Institute (NCI) to utilize resources for research and treatment of recalcitrant cancers having five-year relative survival rates of less than 20% that have not seen substantial progress in diagnosis or treatment. The initial focus will be on pancreatic carcinoma and small cell cancer of the lung (SCLC). SCLC is strongly associated with tobacco exposure and is characterized by rapid growth, early metastasis, and a five-year survival rate of less than 7%. The basic therapeutic approach for SCLC has remained unchanged for three decades, and no effective targeted therapies exist to date ( <a href="#djw119-B1" class="reflinks">1</a> , <a href="#djw119-B2" class="reflinks">2</a> ). SCLC is a poster child for recalcitrant cancers as documented in subsequent NCI responses and workshop proceedings ( <a href="#djw119-B3" class="reflinks">3</a> , <a href="#djw119-B4" class="reflinks">4</a> ). 

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Small Cell Lung Cancer Screen of Oncology Drugs, Investigational Agents, and Gene and microRNA Expression

<div class="boxTitle">Abstract</div>Background: Small cell lung carcinoma (SCLC) is an aggressive, recalcitrant cancer, often metastatic at diagnosis and unresponsive to chemotherapy upon recurrence, thus it is challenging to treat. Methods: Sixty-three human SCLC lines and three NSCLC lines were screened for response to 103 US Food and Drug Administration–approved oncology agents and 423 investigational agents. The investigational agents library was a diverse set of small molecules that included multiple compounds targeting the same molecular entity. The compounds were screened in triplicate at nine concentrations with a 96-hour exposure time using an ATP Lite endpoint. Gene expression was assessed by exon array, and microRNA expression was derived by direct digital detection. Activity across the SCLC lines was associated with molecular characteristics using pair-wise Pearson correlations. Results: Results are presented for inhibitors of targets: BCL2, PARP1, mTOR, IGF1R, KSP/Eg5, PLK-1, AURK, and FGFR1. A relational map identified compounds with similar patterns of response. Unsupervised microRNA clustering resulted in three distinct SCLC subgroups. Associating drug response with micro-RNA expression indicated that lines most sensitive to etoposide and topotecan expressed high miR-200c-3p and low miR-140-5p and miR-9-5p. The BCL-2/BCL-X L inhibitors produced similar response patterns. Sensitivity to ABT-737 correlated with higher ASCL1 and BCL2. Several classes of compounds targeting nuclear proteins regulating mitosis produced a response pattern distinct from the etoposide response pattern. Conclusions: Agents targeting nuclear kinases appear to be effective in SCLC lines. Confirmation of SCLC line findings in xenografts is needed. The drug and compound response, gene expression, and microRNA expression data are publicly available at <a href="http://ift.tt/1VuBmFB">http://ift.tt/2giavg4; . 

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De Novo vs Nevus-Associated Melanomas: Differences in Associations With Prognostic Indicators and Survival

<div class="boxTitle">Abstract</div>Background: Although 20% to 30% of melanomas are histopathologically 'nevus associated,' the majority of melanomas arise de novo, ie, in clinically normal skin with no associated nevus. We examined whether these forms of melanoma differed in their associations with clinical and histopathologic features and patient survival. Methods: We analyzed two prospective cohorts from our institution with protocol-driven follow-up information (NYU1, n = 1024; NYU2, n = 1125). We used univariate and multivariable analyses to examine associations between de novo vs nevus-associated melanoma classification and age, anatomic site, tumor thickness, tumor ulceration, mitotic index, histological subtype, clinical stage, and survival. We tested the associations identified in NYU1 using NYU2 as a replication cohort. All tests of statistical significance were two-sided. Results: In NYU1, de novo melanomas were associated with tumor thickness greater than 1.0 mm (odds ratio [OR] = 1.96, 95% confidence interval [CI] = 1.43 to 2.70, P < .001), ulceration (OR = 1.65, 95% CI = 1.10 to 2.54, P = .02), nodular subtype (OR = 3.26, 95% CI = 1.70 to 7.11, P = .001), greater than stage I (OR = 2.35, 95% CI = 1.65 to 3.40, P < .001), older age (OR = 1.64, 95% CI = 1.18 to 2.30, P = .004), and shorter overall survival (HR = 1.63, 95% CI = 1.22 to 2.18, P < .001). In NYU2, de novo melanoma was again statistically significantly associated with thickness greater than 1.0 mm (OR = 2.24, 95% CI = 1.72 to 2.93, P < .001), ulceration (OR = 2.88, 95% CI = 1.95 to 4.37, P < .001), nodular subtype (OR = 2.41, 95% CI = 1.75 to 3.37, P < .001), greater than stage I (OR = 2.42, 95% CI = 1.80 to 3.29, P < .001), older age (OR = 1.68, 95% CI = 1.31 to 2.17, P < .001), and shorter overall survival (HR = 2.52, 95% CI = 1.78 to 3.56, P < .001). In multivariable analysis, de novo classification was an independent, poor prognostic indicator in NYU2 (HR = 1.70, 95% CI = 1.19 to 2.44, P = .004). Male patients had a statistically significantly worse survival than female patients if their melanoma was de novo (NYU1, P < .001; NYU2, P < .001); unexpectedly, there was no sex difference in survival among patients with nevus-associated tumors. Conclusions: These data suggest that de novo melanomas are more aggressive than nevus-associated melanomas. This classification scheme may also provide a useful framework for investigations into sex differences in melanoma outcomes. 

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Endogenous Estrogens, Estrogen Metabolites, and Breast Cancer Risk in Postmenopausal Chinese Women

<div class="boxTitle">Abstract</div>Background: The role of estrogen metabolism in determining breast cancer risk and differences in breast cancer rates between high-incidence and low-incidence nations is poorly understood. Methods: We measured urinary concentrations of estradiol and estrone (parent estrogens) and 13 estrogen metabolites formed by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring in a nested case-control study of 399 postmenopausal invasive breast cancer case participants and 399 matched control participants from the population-based Shanghai Women's Health Study cohort. Odds ratios (ORs) and 95% confidence intervals (CIs) of breast cancer by quartiles of metabolic pathway groups, pathway ratios, and individual estrogens/estrogen metabolites were estimated by multivariable conditional logistic regression. Urinary estrogen/estrogen metabolite measures were compared with those of postmenopausal non-hormone-using Asian Americans, a population with three-fold higher breast cancer incidence rates. All statistical tests were two-sided. Results: Urinary concentrations of parent estrogens were strongly associated with breast cancer risk (OR Q4vsQ1 = 1.94, 95% CI = 1.21 to 3.12, Ptrend = .01). Of the pathway ratios, the 2-pathway:total estrogens/estrogen metabolites and 2-pathway:parent estrogens were inversely associated with risk (OR Q4vsQ1 = 0.57, 95% CI = 0.35 to 0.91, Ptrend = .03, and OR Q4vsQ1 = 0.61, 95% CI = 0.37 to 0.99, Ptrend = .04, respectively). After adjusting for parent estrogens, these associations remained clearly inverse but lost statistical significance (OR Q4vsQ1 = 0.65, 95% CI = 0.39 to 1.06, Ptrend = .12 and OR Q4vsQ1 = 0.76, 95% CI = 0.44 to 1.32, Ptrend = .28). The urinary concentration of all estrogens/estrogen metabolites combined in Asian American women was triple that in Shanghai women. Conclusions: Lower urinary parent estrogen concentrations and more extensive 2-hydroxylation were each associated with reduced postmenopausal breast cancer risk in a low-risk nation. Markedly higher total estrogen/estrogen metabolite concentrations in postmenopausal United States women (Asian Americans) than in Shanghai women may partly explain higher breast cancer rates in the United States. 

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Congenital Hypothyroidism: An Unusual Combination of Biochemical Abnormalities

A forty-five-day-old female infant presented with prolonged jaundice with clinical features suggestive of congenital hypothyroidism (CHT). On investigations, the infant was noted to have indirect hyperbilirubinemia (13.8 mg/dl) with increased levels of AST (298 IU/dl) and ALT (174 IU/dl) in the serum. The child had low levels of free T3 (500 microIU/ml) in the serum. The combination of indirect hyperbilirubinemia and raised levels of hepatic transaminases has not been reported in babies with CHT. Following institution of oral thyroxin therapy, the serum bilirubin levels ameliorated (2.9 mg/dl) considerably by 15 days of therapy and the serum levels of AST (40 IU/dl) and ALT (20 IU/dl) got normalized. The case demonstrates that raised levels of hepatic transaminases can occur in infants with CHT and these can resolve just with thyroxin therapy, obviating the need for extensive investigative laboratory work-up.

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Dilated Cardiomyopathy Induced by Chronic Starvation and Selenium Deficiency

Protein energy malnutrition (PEM) has been rarely documented as a cause of cardiovascular abnormalities, including dilated cardiomyopathy. Selenium is responsible for antioxidant defense mechanisms in cardiomyocytes, and its deficiency in the setting of PEM and disease related malnutrition (DRM) may lead to exacerbation of the dilated cardiomyopathy. We report a rare case of a fourteen-year-old boy who presented with symptoms of congestive heart failure due to DRM and PEM (secondary to chronic starvation) along with severe selenium deficiency. An initial echocardiogram showed severely depressed systolic function consistent with dilated cardiomyopathy. Aggressive nutritional support and replacement of selenium and congestive heart failure medications that included diuretics and ACE inhibitors with the addition of carvedilol led to normalization of the cardiac function within four weeks. He continues to have significant weight gain and is currently completely asymptomatic from a cardiovascular standpoint.

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Validation of questionnaire on the Spiritual Needs Assessment for Patients (SNAP) questionnaire in Brazilian Portuguese

Diego de Araujo Toloi, Deise Uema, Felipe Matsushita, Paulo Antonio da Silva Andrade, Tiago Pugliese Branco, Fabiana Tomie Becker de Carvalho Chino, Raquel Bezerra Guerra, Túlio Eduardo Flesch Pfiffer, Toshio Chiba, Rodrigo Santa Cruz Guindalini, Daniel P Sulmasy and Rachel P Riechelmann

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