Role of chemotherapy and the receptor tyrosine kinases KIT, PDGFRalpha, PDGFRbeta, and Met in large-cell neuroendocrine carcinoma of the lung.

PURPOSE: Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a relatively uncommon, high-grade neuroendocrine tumor sharing several features with small-cell lung carcinoma (SCLC) but currently considered as a variant of non-SCLC and accordingly treated with poor results. Little is known about the optimal therapy of LCNEC and the possible therapeutic molecular targets. PATIENTS AND METHODS: We reviewed 83 patients with pure pulmonary LCNEC to investigate their clinicopathologic features, therapeutic strategy, and immunohistochemical expression and the mutational status of the receptor tyrosine kinases (RTKs) KIT, PDGFRalpha, PDGFRbeta, and Met. RESULTS: LCNEC histology predicted a dismal outcome (overall median survival, 17 months) even in stage I patients (5-year survival rate, 33%). LCNEC strongly expressed RTKs (KIT in 62.7% of patients, PDGFRalpha in 60.2%, PDGFRbeta in 81.9%, and Met in 47%), but no mutations were detected in the exons encoding for the relevant juxtamembrane domains. Tumor stage and size (> or = 3 cm) and Met expression were significantly correlated with survival. At univariate and multivariate analysis, SCLC-based chemotherapy (platinum-etoposide) was the most important variable correlating with survival, both in the adjuvant and metastatic settings (P < .0001). CONCLUSION: Pulmonary LCNEC represents an aggressive tumor requiring multimodal treatment even for resectable stage I disease, and LCNEC seems to respond to adjuvant platinum-etoposide-based chemotherapy. Patients who received this therapy had the best survival rate. Despite our failure in finding mutational events in the tested RTKs, the strong expression of KIT, PDGFRalpha, PDGFRbeta, and Met in tumor cells suggests an important role of these RTKs in LCNEC, and these RTKs seem to be attractive therapeutic targets.     

Practical and analytical aspects of using friend controls in case-control studies: experience from a case-control study of childhood cancer

We report empirical data on the use of friend controls, specifically response rates, case-control concordance and analytical approaches. The data derive from a North American multi-institutional study of childhood cancer that was conducted in 2002-07 and that focused on paternal exposures. Case parents nominated friends as potential controls; up to three controls participated per case. For 137 (69%) of the 199 case families, at least one control parent participated. Of 374 potential controls contacted, 247 (66%) participated. Case fathers with controls were markedly more likely to be non-Hispanic White, college graduates and non-smokers compared with case fathers without controls. Odds ratios adjusted for demographic characteristics were generally similar but occasionally differed between analyses that included only members of matched sets and those that included all participants, i.e., controls and cases with and without controls. For demographic characteristics, simulations demonstrated that the observed concordance of cases and controls within matched sets exceeded that expected under random ascertainment, indicating probable overmatching. However, the observed concordance of smoking and other exposures was similar to the expectation under random ascertainment, suggesting little overmatching on exposures. Although not ideal, friend controls were convenient, had a reasonably high response rate and provided controls closely matched on race/ethnicity, education and age.     

Betamethasone, progesterone and RU-486 (mifepristone) exert similar effects on connexin expression in trophoblast-derived HTR-8/SVneo cells

Connexins (Cx) are membrane proteins able to influence cell trophoblast responses, such as proliferation, differentiation, migration and invasiveness. Likewise, glucocorticoids are also known to modulate many factors involved in implantation, including trophoblast gap-junction intercellular communication, although their influence on pregnancy is controversial. In order to investigate the effects of betamethasone, a synthetic glucocorticoid, on Cx and glucocorticoid receptor (GR) expression and localisation, as well as on cell proliferation, the extravillous trophoblast-derived HTR-8/SVneo cell line was used as a model. The results, confirmed by means of immunofluorescence, demonstrate that betamethasone selectively modifies GR and Cx expression, enhancing the GRα isoform without affecting GRβ, and inhibiting Cx40 expression whilst increasing that of Cx43 and Cx45. Furthermore, betamethasone was shown to exert an inhibitory action on cell proliferation. In this model the abortion drug RU-486 (mifepristone), reported to be a GR antagonist, did not counteract this effect of betamethasone. On the contrary, it induced responses similar to those of the hormone. Knowing that RU-486 is also a potent progesterone-receptor antagonist, the effect of progesterone alone and in combination with the drug on Cx expression and cell proliferation was then tested. Progesterone showed the same effect as betamethasone on Cx expression, but it did not affect proliferation. Based on these results, neither the abortion effects of RU-486 nor the protective action of betamethasone and progesterone are exerted by modulation of Cx. RU-486 did not antagonise the progesterone effect, suggesting that its abortive action does not involve alteration of trophoblast Cx expression.     

Administration of GnRH antagonists in case of elevated progesterone at initiation of the cycle: a prospective cohort study

In patients with elevated progesterone levels at the beginning of an ART (assisted reproductive technology) treatment cycle, the outcome of controlled ovarian stimulation (COS) may be inappropriate. A prospective cohort study was conducted to investigate whether the administration of a GnRH antagonist prior to the start of COS in these patients could lead to a similar pregnancy rate than in case of normal progesterone. Four hundred eighty-four patients were included in this study between February 2009 and July 2009. COS was initiated on day 2 of the cycle when estradiol (E(2)) and progesterone (P) serum levels were normal (E(2) ≤ 80 pg/ml, P ≤ 1.5 ng/ml; 'normal P group'). When serum progesterone was > 1.5 ng/ml on day 2 of the cycle ('high P group'), stimulation was not initiated, instead a GnRH antagonist was administered at a dosage of 0.25 mg during three consecutive days. In both study groups, efficient ovarian stimulation ensued and pregnancy rates did not diverge significantly. The results of the study led us to conclude that administration of a GnRH antagonist normalizes progesterone levels in those cases with isolated elevated serum progesterone levels at the start of the ART treatment cycle, and that this pretreatment is compatible with adequate ovarian stimulation and results in acceptable pregnancy rates.