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Objective Despite the very good prognosis of endometrial cancer, a number of patients with localized disease relapse following surgery. Therefore, various adjuvant therapeutic approaches have been studied. The objective of this review is to evaluate the efficacy and safety of neoadjuvant and adjuvant therapies in patients with resectable endometrial cancer and to develop evidence-based recommendations. Methods A review of the scientific literature published between January 1990 and June 2012 was performed. The search was limited to published phase III clinical trials and meta-analyses evaluating the efficacy of neoadjuvant or adjuvant therapies in patients with endometrial carcinoma or carcinosarcoma. A total of 23 studies and five meta-analyses were identified. Results The selected literature showed that in patients with a low risk of recurrence, post-surgical observation is safe and recommended in most cases. There are several therapeutic modalities available for treatment of endometrial cancers with higher risk of recurrence, including vaginal brachytherapy, external beam radiotherapy, chemotherapy, or a combination of these. Conclusions Considering the evidence available to date, the CEPO recommends the following: 1)post-surgical observation for most patients with a low recurrence risk; 2)adjuvant vaginal brachytherapy for patients with an intermediate recurrence risk; 3)adjuvant pelvic radiotherapy with or without vaginal brachytherapy for patients with a high recurrence risk; addition of adjuvant chemotherapy may be considered as an option for selected patients (excellent functional status, no significant co-morbidities, poor prognostic factors); 4)adjuvant chemotherapy and pelvic radiotherapy with or without brachytherapy and para-aortic irradiation for patients with advanced disease; 5)hormonal therapy is not recommended in the adjuvant setting.

Compound heterozygotes for β-thalassemia and high oxygen affinity hemoglobin (Hb) have been documented, but experience in the management of such rare cases is minimal. Although hydroxyurea (HU) has never been used in a heterozygote with high oxygen affinity Hb and β-thalassemia, we hypothesized that it would decrease erythrocytosis through a lowered production of abnormal cells and increase of P 50 by induction of fetal hemoglobin (HbF). We present the case of a patient with compound high oxygen affinity Hb mutation with β-thalassemia. PCR analysis revealed combined Hb Regina and IVS1-110 G/A mutations. Treatment with HU caused a decrease in Ht (61.1% to 38.6%) and erythrocyte volume (74.87 mUkg to 40.65 mUkg), as well as an increase in P 50 (6 mmHg to 10 mmHg ) and HbF level (3.6% to 29.8%) at 12-month follow-up. Effects of HU on 2,3 DPG and HbNO levels did not appear to be predictable. Corroboration with other cases is needed to establish solid evidence on the clinical efficacy of HU in this population.

Big endothelin-1 (ET-1) injected systemically in vivo induces a long-lasting pressor response, in contrast to its active metabolite ET-I, which alters in a biphasic fashion the mean arterial pressure (MAP) of the anesthetized rabbit. In this study we investigated the effect of selective ET A or ET B receptor blockade on the pressor response and increase in plasma prostacyclin (PGI 2 ) levels (determined by RIA) induced by big ET-I in the anesthetized rabbit. Pretreatment (5 min) of the rabbit with the ET B receptor antagonist BQ-788 (0.25 mg/kg) potentiated the ET-1 (1 nmol/kg) and, interestingly, big ET-1 (0.5 nmol/kg) induced pressor responses. The selective ET A receptor antagonist BQ-123 (1 mg/kg) significantly reduced the big ET-1 (0.5 and 3 nmol/kg) pressor responses. Big ET-I (3 nmol/kg) injected i.v. induced an increase in plasma PGI2 levels in contrast to intra-arterial (i.a.) administration. This increase was prevented by BQ-123 (1 mg/kg) but not by BQ-788 (0.25 nmol/kg). Furthermore, in the presence of BQ-788, i.a. administration of big ET-1 (3 nmol/kg) induced a significant release of PGI 2 . These results show that vasodilator ET B receptors may be activated after conversion of big ET-1 to its active metabolite. Furthermore, after pulmonary conversion of big ET-1, ET A receptors may be responsible for the release of vasodilator and anti-aggregatory prostacyclin, which modulates the big ET-l-induced responses in the rabbit.

Abstract Endothelin-1 (0.25 nmol/kg, injected into the left cardiac ventricle) induces a protracted increase of mean arterial pressure that is significantly reduced by the selective ET A receptor antagonist BQ-123 (1 and 10 mg/kg) in the anesthetized rabbit. The sole administration of the selective ET B antagonist BQ-788 (0.25 mg/kg) induces a pressor response abolished by BQ-123 (1 mg/kg). Concomitant to the increase in mean arterial pressure, BQ-788 induces a significant increase in plasma levels of endothelin-1 and its precursor big endothelin-1. The nitric oxide synthase inhibitor N ω -nitro- l -arginine methyl ester (L-NAME; 10 mg/kg) also increases arterial blood pressure, and the response is reduced dose-dependently by BQ-123 (1 and 10 mg/kg). In addition, the administration of BQ-788 in the presence of L-NAME induced a further increase in arterial blood pressure. The duration of the pressor response to L-NAME is also significantly reduced by an endothelin-converting enzyme inhibitor, phosphoramidon (10 mg/kg). Finally, L-NAME induces an increase in plasma levels of big endothelin-1 but not endothelin-1. Our results illustrate that blockade of either nitric oxide synthase or ET B receptors triggers a raise in plasma levels of endothelin-1 or its precursor. These later moieties are suggested to be significantly involved, through the activation of ET A receptors, in the pressor effects of L-NAME and BQ-788 in the anesthetized rabbit.

Introduction: A 38-year-old causasian male with hepatomegaly, splenomegaly and erythrocytosis (Ht 69.2%, Hb 217 g/L, MCV 76fl, normal WBC and platelets counts) presented with flank pain found to be a renal artery thrombosis. He had a history of increased Ht since birth without bone marrow (BM), cardiac, pulmonary, renal or cerebral anomalies and for which a diagnosis of a high oxygen affinity hemoglobinopathy was made. The disease had previously been uncomplicated without therapy. Initial evaluation in our center revealed a normal BM morphology, a normal karyotype and an abnormal Hb HPLC (elevated HbF (4.9%) and an abnormal Hb eluting after normal HbA1). The red cell mass was increased at 74.9 ml/kg (normal = 26.5 ml/kg). The oxygen (O2) P50 saturation determined from the Hb-O2 dissociation curve using an Hemox-Analyser was markedly decreased at 6 mmHg (normal = 27 mmHg). α and β globins (gb) HPLC demonstrated normal α, but 100% abnormal β-gb. A diagnosis of a double heterozygote for β-gb gene was established: an allele with mutation causing high affinity for O2 and an allele causing β-thalassemia (thal) minor. Anticoagulation and serial phlebotomies did not improve the erythrocytosis. Therapy with hydroxyurea (HU) was therefore proposed to the patient. Objectives: To determine the β-gb genotype and to evaluate the effect of HU therapy at maximally tolerated dose (MTD) on induction of HbF and its effect on Ht, P50, red cell mass, 2,3-DPG and total HbNO concentrations. Methods and results: Sequencing of the β-gb locus was done by RT-PCR amplified mRNA and by PCR amplified DNA, using primers spanning almost the entire gene (−450 to 601 bp, excluding a small portion of IVS2). Two mutations were identified: Leu96→Val (339C→G) in exon 2, producing Hb Regina, a high O2 affinity hemoglobin variant, and IVS1-110 G/A, a frequent mutation causing β-thal minor. Therapy with HU was initiated at 7 mg/kg/day. Dose was increased to MTD resulting in a dose of 25 mg/kg/day. Table 1 summarizes variations in relevant parameters while on HU therapy. Conclusion: HU rapidly induced HgF and improved measured parameters in this patient with a high O2 affinity Hb/β-thal minor. HU’s effect in this case did not seem to be strictly related to its anti-proliferation properties. Induction of HbF and subsequent increase in P50 probably reduced Epo production (data pending) and erythropoiesis. Modifications in other mediators of O2 release were also modified by HU. The changes in HbNO are not totally consistant with the rest of the data, being increased at 3 months but decreased at 6 months. While on HU therapy, the patient did not present any new complications (thrombotic or other) and clinically reported an improved exercise tolerance. Further evaluation will focus on epigenetic factors affecting HbF expression and correlation of NO level with plasma L-arginine concentration. | Time | HU dose (mg/kg) | Ht (%) | HbF (%) | P50 (mm/Hg) | 2,3-DPG (umol/g Hb) | Total HbNO (nM) | Red cell mass (ml/kg) | |:----------------------------------------:| --------------- | ------ | ------- | ----------- | ------------------- | --------------- | --------------------- | | NA: not available, TBD: to be determined | | Baseline | | 61.1 | 3.6 | 6 | 21.3 | 242.7 | 74.9 | | 3 months | 21 | 69.4 | 9.1 | 6 | 19.0 | 694.3 | NA | | 6 months | 25 | 56.9 | 15.1 | 9 | 21.4 | 105.8 | NA | | 8 months | 25 | 46.7 | 25.4 | TBD | TBD | TBD | 51.7