Continuous versus intermittent tamoxifen versus intermittent/alternated tamoxifen and medroxyprogesterone acetate as first line endocrine treatment in advanced breast cancer: an EORTC phase III study (10863)

BackgroundContinuous ligand depletion of endocrine responsive tumours may enhance resistance to therapy. Intermittent treatment with tamoxifen (T) was considered to mimic (incomplete) ligand depletion and reintroduction. Furthermore it was postulated that alternating tamoxifen with a non-cross resistant endocrine modality could (further) postpone hormone resistance.Patients and methodsPostmenopausal patients with advanced breast cancer who did not progress after 4 months of first line T therapy were randomised to continue T (40 mg daily) or to 2 monthly intermittent T or intermittent/alternated T and medroxyprogesterone acetate (MPA, 300 mg daily). At progression during break or during MPA, T should be reintroduced. Endpoints of the study were progression free survival (PFS), time to resistance to tamoxifen and overall survival (OS).ResultsOf 593 registered patients, 276 were randomised. After 8 years follow-up the median PFS for continuous T, intermittent T and intermittent/alternated T and MPA was 11.0 (8.1–15.2), 8.0 (6.2–12.4) and 10.8 (7.1–16.7) months, respectively (NS). Resistance to tamoxifen was established only in 84%, 70% and 55% of patients in the three treatment arms, respectively. The median times from randomisation to resistance to tamoxifen were 12.5 (9.1–21.1), 13.2 (8.8–19.8) and 24.0 (16.9-60.9) months, respectively (p < 0.001), without translation in differences in survival times.ConclusionIntermittent T or intermittent/alternated T and MPA had no impact on PFS or OS as compared with classical continuous T in patients with advanced breast cancer.Intermittent/alternated T and MPA resulted in prolonged time to resistance to T, but this might partly be due to bias by omittance of the proof of tamoxifen resistance in a high proportion of the patients in this treatment arm.     

Regression of intracardiac heparin-induced thrombosis after aortic root surgery

Heparin-induced thrombocytopenia and thrombosis syndrome (type II) is associated with thromboembolic complications and a mortality rate up to 30%. We describe a patient who developed intracardiac and aortic Dacron prosthesis heparin-induced thrombosis after aortic root conservative surgery. Successive transoesophageal echocardiographies demonstrated a progressive regression of intracardiac thrombosis with oral anticoagulation by warfarin and antiplatelet therapy combining aspirin and clopidogrel.     

Supplemental private health insurance and depressive symptoms in older married couples

Stress process theory is applied to examine lack of supplemental private health insurance as a risk factor for depressive symptomatology among older married couples covered by Medicare. Dyadic data from 130 African-American couples and 1,429 White couples in the 1993 Asset and Health Dynamics Among the Oldest-Old Survey were analyzed using hierarchical generalized linear modeling. Lack of supplemental insurance is operationalized at the household level in terms of neither spouse covered, one spouse covered, or both spouses covered. Controlling for covariates at both individual and couple levels, supplemental insurance has significant impact on depression, but the pattern differs by race. White couples report the highest depression when neither spouse is covered by private health insurance; African-American couples report the highest depression when only one spouse is covered. Results suggest lack of supplemental private health insurance coverage is a stressor that significantly affects depressive symptoms.     

EORTC cutaneous lymphoma task force. European Organisation for Research and Treatment of Cancer

The Cutaneous Lymphoma Task Force has represented the European Organisation for Research and Treatment of Cancer (EORTC) over the last two decades and has received worldwide acceptance and the highest respect. The group has been able to bring together the world's experts in this field to try to solve the basic problems associated with primary lymphomas of the skin and to create a productive scientific research basis. The definition and the classification of the disease per se has been a major controversial problem and the development of an EORTC classification for primary cutaneous lymphoma has been one of the main goals of the group. The purpose of this paper is to highlight and to provide a historical perspective regarding the contribution of the EORTC Cutaneous Lymphoma Group to the development of consensus guidelines for securing uniform diagnosis, classification and management of the heterogeneous group of primary cutaneous lymphomas. Some future perspectives and strategies of the group are also presented.     

Neuroinflammatory response of the choroid plexus epithelium in fatal diabetic ketoacidosis

A systemic inflammatory response (SIR) occurs prior to and during the treatment of severe diabetic ketoacidosis (DKA). IL-1beta, TNF-alpha and C5b-9 are components of SIR and have been speculated to be involved in the clinical brain edema (BE) of DKA. We studied IL-1beta, TNF-alpha, C5b-9, inducible nitric oxide (iNOS), ICAM-1, IL-10 and Hsp70 expression in the brains of two patients who died as the result of clinical BE during the treatment of DKA. IL-1beta was strongly expressed in the choroid plexus epithelium (CPE) and ependyma, and to a lesser extent in the hippocampus, caudate, white matter radiation of the pons, molecular layer of the cerebellum and neurons of the cortical gray matter. TNF-alpha was expressed to a lesser extent than IL-1beta, and only in the CP. C5b-9, previously shown to be deposited on neurons and oligodendrocytes, was found on CPE and ependymal cells. iNOS and ICAM-1 had increased expression in the CPE and ependyma. Hsp70 and IL-10 were also expressed in the CPE of the case with the shorter duration of treatment. Our data demonstrate the presence of a multifaceted neuroinflammatory cytotoxic insult of the CPE, which may play a role in the pathophysiology of the fatal brain edema of DKA.     

RGC-32 and diseases: the first 20 years

The response gene to complement (RGC)-32 acts as a cell cycle regulator and mediator of TGF-β effects. However, recent studies have revealed other functions for RGC-32 in diverse processes such as cellular migration, differentiation, and fibrosis. In addition to its induction by complement activation and the C5b-9 terminal complement complex, RGC-32 expression is also stimulated by growth factors, hormones, and cytokines. RGC-32 is induced by TGF-β through Smad3 and RhoA signaling and plays an important role in cell differentiation. In particular, RGC-32 is essential for the differentiation of Th17 cells. RGC-32^−/− mice display an attenuated experimental autoimmune encephalomyelitis phenotype that is accompanied by decreased central nervous system inflammation and reductions in IL-17- and GM-CSF-producing CD4⁺ T cells. Accumulating evidence has drawn attention to the deregulated expression of RGC-32 in human cancers, atherogenesis, metabolic disorders, and autoimmune disease. Furthermore, RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases. A better understanding of the mechanism(s) by which RGC-32 contributes to the pathogenesis of all these diseases will provide new insights into its therapeutic potential.

     

Assessment of Gene Expression Profiles in Peripheral Occlusive Arterial Disease

Background

Molecular events responsible for the onset and progression of peripheral occlusive arterial disease (POAD) are incompletely understood. Gene expression profiling may point out relevant features of the disease.

Methods

Tissue samples were collected as operatory waste from a total of 36 patients with (n = 18) and without (n = 18) POAD. The tissues were histologically evaluated, and the patients with POAD were classified according to Leriche-Fontaine (LF) classification: 11% with stage IIB, 22% with stage III, and 67% with stage IV. Total RNA was isolated from all samples and hybridized onto Agilent 4×44K Oligo microarray slides. The bioinformatic analysis identified genes differentially expressed between control and pathologic tissues. Ten genes with a fold change ≥ 2 (1 with a fold change ≥ 1.8) were selected for quantitative polymerase chain reaction validation (GPC3, CFD, GDF10, ITLN1, TSPAN8, MMP28, NNMT, SERPINA5, LUM, and FDXR). C-reactive protein (CRP) was assessed with a specific assay, while nicotinamide N-methyltransferase (NNMT) was evaluated in the patient serum by enzyme-linked immunosorbent assay.

Results

A multiple regression analysis showed that the level of CRP in the serum is correlated with the POAD LF stages (r² = 0.22, P = 0.046) and that serum NNMT is higher in IV LF POAD patients (P = 0.005). The mRNA gene expression of LUM is correlated with the LF stage (r² = 0.45, P = 0.009), and the mRNA level of ITLN1 is correlated with the ankle-brachial index (r² = 0.42, P = 0.008).

Conclusions

Our analysis shows that NNMT, ITLN1, LUM, CFD, and TSPAN8 in combination with other known markers, such as CRP, could be evaluated as a panel of biomarkers of POAD.