Overview on the use of recombinant human thyrotropin in thyroid cancer of follicular cell origin

Stimulation by recombinant human thyroid-stimulating hormone (rhTSH) has gained wide acceptance as an alternative to thyroid hormone withdrawal in the management of patients with differentiated thyroid cancer. RhTSH has the advantage to avoid both the clinical consequences of hypothyroidism, with a positive impact on quality of life and work productivity, and the risk of cancer growth due to the long-lasting endogenous thyrotropin stimulation. RhTSH is a heterodimeric glycoprotein produced by recombinant DNA technology that has the ability to stimulate thyroglobulin production and radioiodine uptake by thyroid cells. RhTSH is now widely used in the follow-up of thyroid cancer patients in order to improve sensitivity of thyroglobulin (Tg) measurement as well as in preparation of (131)I diagnostic whole-body scan. Although initially approved only for diagnostic purposes, rhTSH has been now approved both in Europe and in the United States for remnant ablation in low-risk patients. As far as residual or metastatic cancer treatment, rhTSH has been initially used on a compassionate need basis for elderly and frailer patients and for patients in whom the withdrawal of thyroid hormone was medically contraindicated. Nowadays, there is a trend for widening the use of rhTSH in therapy, in order to avoid hypothyroidism and the concern about the effect of prolonged endogenous thyroid-stimulating hormone stimulation on cancerous cells. Unfortunately, the studies which address the efficacy of rhTSH in cancer treatment are still scarce and the opportunity of its clinical application remains controversial. In addition, rhTSH has been shown to improve the accuracy of [(18)F]-2-fluoro-deoxy-D-glucose positron emission tomography to detect non-functioning thyroid cancer. Although all studies agree on that rhTSH is much better tolerated from the clinical point of view than thyroid hormone withdrawal, there is some controversy about its comparative ability to raise Tg levels and concentrate radioiodine in cancerous thyroid cells. The aim of this paper is to review the performances of rhTSH as compared to hypothyroidism, considering Tg stimulation and diagnostic whole-body scan sensitivity during follow-up, and its effectiveness for normal remnant ablation and for therapy of metastatic disease.     

Detection of somatic mosaicism and classification of Fanconi anemia patients by analysis of the FA/BRCA pathway

Fanconi anemia (FA) is characterized by congenital abnormalities, bone marrow failure, chromosome fragility, and cancer susceptibility. Eight FA-associated genes have been identified so far, the products of which function in the FA/BRCA pathway. A key event in the pathway is the monoubiquitination of the FANCD2 protein, which depends on a multiprotein FA core complex. In a number of patients, spontaneous genetic reversion can correct FA mutations, leading to somatic mosaicism. We analyzed the FA/BRCA pathway in 53 FA patients by FANCD2 immunoblots and chromosome breakage tests. Strikingly, FANCD2 monoubiquitination was detected in peripheral blood lymphocytes (PBLs) in 8 (15%) patients. FA reversion was further shown in these patients by comparison of primary fibro-blasts and PBLs. Reversion was associated with higher blood counts and clinical stability or improvement. Once constitutional FANCD2 patterns were determined, patients could be classified based on the level of FA/BRCA pathway disruption, as "FA core" (upstream inactivation; n = 47, 89%), FA-D2 (n = 4, 8%), and an unidentified downstream group (n = 2, 4%). FA-D2 and unidentified group patients were therefore relatively common, and they had more severe congenital phenotypes. These results show that specific analysis of the FA/BRCA pathway, combined with clinical and chromosome breakage data, allows a comprehensive characterization of FA patients.     

Feasibility and technical problems of sentinel node analysis in melanoma

BACKGROUND: Development of the sentinel lymph node (SLN) biopsy the last 10 years has changed surgical approach of solid tumor treatment and particularly of melanoma. The aim of our study was to analyze in our hospital, the feasibility of the SLN biopsy technique in order to define a better prognostic classification of melanomas. PATIENTS AND METHODS: Between July 1999 and October 2003, 97 patients were included in this study in our center. Criteria for inclusion were cutaneo-mucosal melanoma of Breslow >or=1,5 mm, and/or Clarck >or=IV, and/or ulceration, and/or signs of regression, before any surgical margins. RESULTS: Lymphoscintigraphy (LS) identified at least 1 SLN in 94 cases/97 (97%), thus permitting intraoperative SLN mapping and sentinel node biopsy of at least 1 lymph node in 88 cases/94 (94%). Failure of the SLN procedure was noted in 9 cases: in 3 cases, no lymph node was individualized by LS, in 1 patient, intraoperative SLN mapping failed to find the previously identified SLN and in 5 cases, a SLN was identified by LS and intraoperative mapping but could not be removed because of its deep location and difficulty of dissection. In 17 patients, removal of one or two "non sentinel lymph node(s)" was (were) made by the surgeon because of its (their) suspected aspect (black or large). Among the 88 patients who had dissection of at least 1 SLN, a micrometastasis was detected by standard histological evaluation and/or immunohistochemical stains in 14 cases (16%) and into a "non SLN" in 2 cases (2,3%). The median follow up of patients was 16 months (1- 48 months). Among the 14 patients with positive SLN, 6 (43%) relapsed. The other eight were in complete remission of their melanoma with a mean follow up of 11,44 months . Among the 74 patients with negative SLN, 7 (9,5%) developed a recurrence. Among the 9 patients in whom any sentinel lymph node have been removed, 3 had a relapse (one in transit than on lymph nodes, and two on lymph nodes). CONCLUSION: Our results are in accordance with the literature, and confirm the feasibility of SLN mapping and of SLN histological analysis in our center. We described in this study technical problems we encountered. Our study also show the prognostic value of this technique. However, advantage in global survey of sentinel node dissection and regional lymph node dissection in cases of micrometastases has still to be demonstrated.     

Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say never again

Assessment of the host immune status is becoming a key issue in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the long-term follow-up of these patients, severe post-transplant infections, relapse or secondary malignancies may be directly related to persistent immune defects. In allo-HSCT, T-cell differentiation of donor progenitors within the recipient thymus is required to generate naive recent T-cell emigrants (RTE). These cells account for a durable T-cell reconstitution, generating a diverse T-cell receptor (TCR) repertoire and robust response to infections. It is now possible to quantify the production of RTE by measuring thymic T-cell receptor excision circles or 'TREC' which are small circular DNA produced during the recombination of the genomic segments encoding the TCR alpha chain. Here we discuss the role of thymic function in allo-HSCT. The pre-transplant recipient thymic function correlates with clinical outcome in terms of survival and occurrence of severe infections. Post-transplant, TREC analysis showed that the thymus is a sensitive target to the allogeneic acute graft-versus-host disease (GvHD) reaction but is also prone to recovery in young adult patients. In all, thymus is a key player for the quality of immune reconstitution and clinical outcome after allo-HSCT. Thymic tissue is plastic and it is a future challenge to halt or reverse thymic GVHD therapeutically by acting at the level of T-cell progenitors generation, thymic homing and/or epithelial thymic tissue preservation.     

Hematopoietic growth factor expression and ATRA sensitivity in acute promyelocytic blast cells

Acute promyelocytic leukemia (APL) is a homogeneous subgroup of acute myeloid leukemias (AMLs) characterized by the presence of the t(15,17) translocation and the resulting promyelocytic myeloid leukemia/retinoic acid receptor alpha (PML/RAR alpha) fusion proteins. To date APL is the only AML that is sufficiently sensitive to all-trans retinoic acid's (ATRA) differentiating effect. In vivo ATRA alone achieves complete remission in most APL patients. However, failure or partial responses are observed and the molecular basis of the absence of ATRA response in these patients has not been determined. To gain insights in the cell growth and differentiation of APL cells, expression of hematopoietic growth factors (HGF) shown to be produced by leukemic cells (interleukin-1 beta [IL-1 beta], IL-6, tumor necrosis factor alpha (TNF alpha), granulocyte colony-stimulating factor [G-CSF], granulocyte- macrophage colony-stimulating factor [GM-CSF], and IL-3) was studied in 16 APL samples. Twelve APL cases expressed IL-1 beta, IL-6, and TNF alpha, but not G-CSF, GM-CSF, and IL-3. These cases achieved complete remission with ATRA therapy. The four remaining patients (either TNF alpha negative or G-CSF, GM-CSF or IL-3 positive) did not achieve complete remission with ATRA. In all cases, in vivo response to ATRA therapy was correlated to the in vitro differentiation effect of all- trans retinoic acid 10(-6) mol/L. Thus, ATRA differentiation induction was strongly correlated to the HGF expression (P < .0001). These results suggest that the presence or absence of HGF's expression by APL cells may contribute to the therapeutic effect of ATRA in this disease.     

Early-onset ankylosing spondylitis is associated with a functional MICA polymorphism

Major histocompatibility complex (MHC) class I chain-related A (MICA) molecules deliver activating signals through the NKG2D receptor expressed on the surface of natural killer (NK), CD8alphabeta and gammadelta T cells, and the MICA gene is polymorphic. The recently described MICA amino acid substitution at position 129 (MICA-129) seems to affect its binding to NKG2D. We investigated whether this dimorphism (MICA-129met [methionine] and MICA-129val [valine]) is associated with susceptibility to ankylosing spondylitis (AS) in a cohort of Algerian patients stratified according to their HLAB27 status and the age of onset of the disease. DNA from 129 patients and 76 healthy individuals were analyzed to determine the HLA-B generic type as well as MICA-129 polymorphism. Statistical analysis revealed: (1) a weaker association between AS and HLA-B27 in Algerians than in that reported for European patients (63% versus 80-90%), suggesting a possible influence of other genetic/environmental determinants in the studied population and (2) an association between MICA-129 met/met genotype and juvenile AS (p = 0.02) independent of HLA-B27 status. These data suggest a potential role for a functionally relevant MICA gene polymorphism in autoimmune/inflammatory disease susceptibility.