Early detection of biochemically occult autonomous thyroid nodules.

OBJECTIVE: Autonomously functioning thyroid areas may be associated with subclinical or overt hyperthyroidism, but may exist even in the presence of normal TSH. This study was aimed at comparing the rate of autonomously functioning areas and their cardiac sequelae in patients with nodular goitre studied with the usual and a novel approach. DESIGN AND METHODS: In total 490 adult outpatients with thyroid nodular goitre, living in a mild iodine-deficient area, were selected in our referral centre for thyroid diseases from 2009 to 2014 on the basis of a suspicion of thyroid functional autonomy. They were divided in three groups according to a non-conventional approach (excessive response to thyroxine treatment: group 1) or conventional approach (low/normal TSH with clinical suspicion or low TSH: groups 2 and 3). All patients of the study with the suspicion of thyroid functional autonomy underwent thyroid scan with radioactive iodine (I131) uptake (RAIU). RESULTS: The percentage of confirmed thyroid functional autonomy was 319/490, being significantly higher in group 3 than in groups 1 and 2 (81.5 vs 64.7 vs 52.6%; chi-square P < 0.0001). However, the diagnosis with non-conventional approach was made at a significant earlier age (P < 0.0001). Cardiac arrhythmias as well as atrial fibrillation were similarly detected by conventional and non-conventional approaches (chi-square test: P = 0.2537; P = 0.8425). CONCLUSIONS: The hyper-responsiveness to thyroxine treatment should induce the suspicion of thyroid functional autonomy at an early stage, allowing to detect autonomous functioning areas in apparently euthyroid patients.

Individually-tailored thyroxine requirement in the same patients before and after thyroidectomy: a longitudinal study.

OBJECTIVE: Thyroxine (T4) requirement after total thyroidectomy for differentiated thyroid carcinoma (DTC) is a debated issue. As most of the studies in the area have been retrospective and/or performed with heterogeneous therapeutic approaches, we designed our study to determine T4 requirement in the same patients and treatment settings, before and after total thyroidectomy. DESIGN, PATIENTS AND METHODS: This was a longitudinal study including 23 goitrous patients treated with T4 in an individually tailored fashion. All patients exhibited a stable TSH (median TSH = 0.28 mU/l) at a stable T4 dose for at least 1 year before surgery (median T4 dose = 1.50 µg/kg per day). The patients underwent total thyroidectomy based on cancer suspicion or compressive symptoms. Eventually diagnosed as having DTC (pT1b-pT2N0) and following surgical and radiometabolic treatment, they were treated with the same pre-surgical doses of T4. RESULTS: Three months after surgery,using the same pre-surgical dose, median TSH increased up to 5.38 mU/l (P<0.0001) and so the T4 dose had to be increased (median T4 dose = 1.95 µg/kg per day; +30%; P < 0.0001). Once divided by patients' age, we observed that, after thyroidectomy and maintaining the same pre-surgical dose, serum TSH significantly increased both in younger and in older patients (median TSH = 4.57 and 6.11 mU/l respectively). Serum TSH was restored to the pre-surgical level by increasing the dose up to 1.95 and 1.77 µg/kg per day (+25 and +21%) respectively. CONCLUSIONS: Following the same treatment regimen, a thyroidectomized patient requires one-third higher therapeutic T4 dose than before surgery. Despite this increase, the dose of T4 needed in our patients remains significantly lower than that previously described in athyreotic patients.

[Effects of dose of erythropoiesis stimulating agents on cardiovascular outcomes, quality of life and costs of haemodialysis. the clinical evaluation of the DOSe of erythropoietins (C.E. DOSE) Trial]. / Effetti della dose degli agenti stimolanti l'eritropoiesi su esiti cardio-cerebrovascolari, qualità di vita e costi in emodialisi.

BACKGROUND: Anaemia is a risk factor for death, adverse cardiovascular outcomes and poor quality of life in patients with chronic kidney disease (CKD). Erythropoietin Stimulating Agents (ESA) are the most used treatment option. In observational studies, higher haemoglobin (Hb) levels (around 11-13 g/dL) are associated with improved survival and quality of life compared to Hb levels around 9-10 g/dL. Randomized studies found that targeting higher Hb levels with ESA causes an increased risk of death, mainly due to adverse cardiovascular outcomes. It is possible that this is mediated by ESA dose rather than haemoglobin concentration, although this hypothesis has never been formally tested. METHODS: We present the protocol of the Clinical Evaluation of the Dose of Erythropoietins (C.E. DOSE) trial, which will assess the benefits and harms of a high versus a low ESA dose therapeutic strategy for the management of anaemia of end stage kidney disease (ESKD). This is a randomized, prospective open label blinded end-point (PROBE) design trial due to enroll 900 haemodialysis patients. Patients will be randomized 1:1 to 4000 UI/week i. v. versus 18000 UI/week i. v. of epoetin alfa, beta or any other epoetin in equivalent doses. The primary outcome of the trial is a composite of cardiovascular events. In addition, quality of life and costs of these two strategies will be assessed. The study has been approved and funded by the Italian Agency of Drugs (Agenzia Italiana del Farmaco (AIFA)) within the 2006 funding plan for independent research on drugs (registered at www.clinicaltrials.gov (NCT00827021)).

Increased interleukin-4-positive lymphocytes in patients with Hashimoto's thyroiditis and concurrent non-endocrine autoimmune disorders.

A prevalent T helper type 1 (Th1) subset of lymphocytes has been described in Hashimoto's thyroiditis (HT), but whether a similar polarization may characterize HT when associated with non-endocrine autoimmune disorders (NEAD) is not known. The aim of the present study was to analyse the intracellular Th1 and Th2 distinctive cytokines in patients with isolated HT or associated with non-endocrine autoimmune disorders. Intracellular cytokine expression was assessed in peripheral blood lymphocytes (PBL) of 68 out-patients (females = 55; males = 13; median age = 6 years) with HT : 33 had isolated HT and 35 had a concurrent NEAD. The percentage of interferon (IFN)-γ and interleukin (IL)-2 Th1- and IL-4 Th2-positive cells was measured by flow cytometric analysis. We found an increased percentage of IL-2-positive cells in all patients, without differences between patients with isolated HT or associated with NEAD. IFN-γ(+) cells were also increased in both groups, but the median percentage of those with isolated HT was lower than in patients with HT+NEAD (19·0 versus 29·9%; P = 0·0082). An increased number of IL-4-positive cells was observed in three of 33 (9·1%) patients with isolated HT and in 25 of 35 patients with NEAD [71%; P < 0·0001; relative risk (RR) = 3·18]. The median values of IL-4(+) cells (HT = 5·0% versus HT + NEAD = 16·8%) confirmed this large difference (P < 0·0001). A clear-cut increase of IL-4(+) lymphocytes characterizes patients with autoimmune thyroiditis who have associated non-endocrine autoimmune disorders. These findings may represent an initial tool to detect patients with autoimmune thyroiditis in which additional non-endocrine autoimmune disorders may be awaited.

The presence of non-segmental vitiligo modifies intracellular cytokine subsets in patients with chronic lymphocytic thyroiditis.

Chronic lymphocytic thyroiditis and vitiligo often occur in association and seem to be characterized by a prevalent Th1-driven autoimmune process. The aim of this study is to analyze selected intracellular Τh1 and Th2 cytokines in patients with Hashimoto?s thyroiditis when associated with non-segmental vitiligo. We analyzed intracellular interleukin-2, interferon-gamma (Τh1) and interleukin-4 (Th2), in peripheral blood lymphocytes of 23 patients with isolated Hashimoto?s thyroiditis (group A) and of 11 patients with Hashimoto?s thyroiditis associated with non-segmental vitiligo (group B). Peripheral blood lymphocytes were stimulated and incubated with specific monoclonal antibodies. Intracellular cytokines were assayed by flow cytometric analysis. Interleukin-2 and interferon-gamma positive cells were increased in almost all patients but the median values were similar in patients with isolated Hashimoto?s thyroiditis and in those with concurrent vitiligo. In contrast, the number of patients with increased interleukin-4 positive cells was higher in patients with thyroiditis and vitiligo (9/11) than in those with isolated thyroiditis (2/23; p<0.0001). The median values of IL-4 positive cells in the two groups confirmed this difference (A: 5.8 percent, vs B: 20.6 percent; p=0.0011). Increased interleukin-4 positive lymphocytes characterize Hashimoto?s thyroiditis when associated with non-segmental vitiligo, suggesting a modified balance from highly prevalent Th1 to mixed Th1/Th2 subset.

Effect of mesalazine on mucosal immune biomarkers in irritable bowel syndrome: a randomized controlled proof-of-concept study.

BACKGROUND: Intestinal immune infiltration contributes to symptoms in patients with irritable bowel syndrome (IBS). AIM: To assesses the effect of mesalazine (mesalamine) on mucosal immune cells in patients with IBS, through a pilot study. METHODS: A randomized, double-blind, placebo-controlled trial in 20 patients with IBS in tertiary care setting. Patients were randomized to receive placebo or 800 mg mesalazine three times daily for 8 weeks. The primary endpoint was a significant reduction in total colonic immune cells on biopsies obtained at the end of treatment compared to baseline. Secondary endpoints included effects on subsets of immune cells, inflammatory mediators and symptom severity. Intention-to-treat analysis was performed. RESULTS: Mesalazine markedly reduced immune cells as compared with placebo (P = 0.0082); this effect was ascribed to a marked inhibition of mast cells (P = 0.0014). Mesalazine significantly increased general well-being (P = 0.038), but had no significant effects on abdominal pain (P = 0.084), bloating (P = 0.177) or bowel habits. No serious drug-related adverse events were reported during the study. CONCLUSIONS: Mesalazine is an effective and safe approach to reduce mast cell infiltration and may improve general well-being in patients with IBS. These results support the hypothesis that immune mechanisms represent potential therapeutic targets in IBS.

[Patient satisfaction in hemodialysis: a pilot cross-sectional analysis and a review]. / Valutazione del grado di soddisfazione da trattamento nel paziente in emodialisi: metologia di ricerca, strumenti, limiti e studio pilota trasversale.

BACKGROUND: Assessment of patient satisfaction is not performed routinely in many healthcare institutions. In this review, we discuss methodological aspects of assessment of patient satisfaction in hemodialysis. We also present a pilot study conducted in the Gambro Healthcare Italy dialysis clinics network. METHODS: Patient satisfaction was assessed in a network of hemodialysis units by using an internally validated Italian translation of the Choices for Healthy Outcomes in Caring for ESRD (CHOICE) questionnaire. A cross-sectional analytic study design was used and data analysed with univariate and multivariate hierarchical logistic regression to explore correlates of the risk of being unsatisfied with dialysis treatment. Covariates which were considered include a series of over 20 clinical, demographic, organizational and structural aspects. In addition, unexplained inter-centre residual variability due to 'case-mix' was explored and plotted. RESULTS: Seventeen dialysis units participated in this cross-sectional analysis and 758/1001 (75.7%) provided answers to the questionnaires. There was a statistically significant association on multivariate hierarchical analysis between the risk of being unsatisfied with dialysis treatment and interdialysis body weight gain (unit of increase: 1 kg, p=0.004). On the contrary, the risk of unsatisfaction with dialysis treatment was significantly lower in patients with higher dry weight (unit of increase: 1 kg, p=0.002). Our multivariate hierarchical analysis identified some residual variability between dialysis units (n=6 outliers) which may not be explained by any of over 20 potential confounding covariates which were explored. CONCLUSIONS: Assessment of ''customer satisfaction'' is standard practice in private for profit product companies in general but needs to be increasingly recognized as a standard in both public and private providers of healthcare services. Social research methods, which are used for this type of analysis, need to be fine tuned and actively implemented in order to better understand how we may influence the quality of service we provide to our patients and the level at which they rate it.

Failure of imaging techniques in revealing breast cancer progression.

This study focuses on a case of a 67-year-old woman with occult breast cancer involving the axillary lymph nodes. The instrumental examinations employed, positron emission tomography included, were not useful in diagnosing the disease. When the patient was surgically treated micro-invasive breast cancer was diagnosed. This peculiar malignant pathology is a matter of discussion especially because it is hardly diagnosable. Because of such diagnostic difficulties it may happen that micro-invasive carcinoma progression can easily mislead routine diagnostic screenings performed on women over 50.

Increased serum inhibin B levels in postmenopausal women with altered thyroid function.

Hyper- and hypothyroidism have significant effects on the female reproductive system. However, little in the way of data is available on the relationship between ovarian paracrine control and thyroid function. This study was aimed at characterising the serum levels of inhibin B in relation to altered thyroid function. Serum inhibin B and FSH levels were measured in 91 women (51 regularly cycling and 40 postmenopausal). The mean serum concentration of inhibin B in euthyroid cycling women (0.025 +/- 0.018 microg/l) was similar to that observed in hyper- and hypothyroid patients (0.022 +/- 0.015 and 0.018 +/- 0.014 microg/l, respectively, p=ns). Inhibin B levels were obviously reduced (-72%) in euthyroid postmenopausal women. In contrast, in hyper- and hypothyroid postmenopausal women, inhibin B levels remained substantially at the premenopausal level. So far, serum inhibin B appeared to be significantly increased in both hyperthyroid patients (0.025 +/- 0.014 microg/l; p<0.0001) and in hypothyroid patients (0.016 +/- 0.006 microg/l; p=0.0006). Altered thyroid function did not affect FSH levels at fertile age. However, a significant decrease of FSH levels was observed in hyper- and hypothyroid (-52% and -43%, respectively) postmenopausal women. Nevertheless, these FSH levels remained in the postmenopausal range. These results indicate that an altered thyroid function affects serum inhibin B levels in postmenopausal women.

Reversible increase of serum activin A levels in women with Graves' disease.

The aim of this study was to analyze the serum levels of activin A in hyperthyroid patients with Graves' disease. Serum activin A and FSH levels were measured in a total of 93 females (64 regularly cycling and 29 post-menopausal). Of these, 20 were hyperthyroid patients with Graves disease, 33 were euthyroid goitrous patients (20 had autoimmune thyroiditis AT and 13 only had goiter) representing the internal control group and 40 were healthy subjects representing the external control group. Serum levels of activin A were higher in goitrous patients with AT than in control subjects (p=0.0388). Activin A levels were almost doubled in the cycling and in post-menopausal hyperthyroid women (0.91+/-0.21 vs 0.43+/-0.07 microg/l; p<0.0001 and 0.92+/-0.22 vs 0.48+/-0.24 microg/l; p=0.0001, respectively). In 10 cycling hyperthyroid patients, studied even after methimazole treatment, that increase was substantially reversed, once euthyroidism was attained (p=0.002). These findings indicate that thyroid function and autoimmune processes significantly affect serum levels of activin A in patients with Graves' disease.

In vitro models of a three-drug regimen (epirubicin, cisplatin and fluorouracil) for the treatment of colorectal cancer.

The activity of epirubicin, cisplatin and 5-fluorouracil (5-FU), as single agents or in combination (ECF), was investigated in three human colon cancer cell lines by two different assays (cell-counting assay and sulforhodamine B assay) in vitro. 5-FU was tested with both short and continuous exposure. Particular interest was focused on the results obtained in the HCT8-FU cell line, a subline with experimentally induced resistance to 5-FU. The positive modulation of both cisplatin and epirubicin cytotoxicity by 5-FU makes the ECF regimen an attractive protocol for combination therapy in colorectal cancer.

Epirubicin, cisplatin and continuous-infusion 5-fluorouracil (ECF regimen) in the treatment of advanced colorectal cancer.

Thirty-one patients with advanced colorectal cancer were treated with a regimen of epirubicin, cisplatin and continuous-infusion (c.i.) 5-fluorouracil (5-FU) (ECF regimen). Twenty-seven patients were evaluable for response rate (RR), progression-free survival (PFS) and overall survival (OS). In this study, the ECF chemotherapy yielded a 51% RR with a PFS of more than 8 months, an OS of more than 11 months and tolerable toxicity. In spite of the perplexity concerning the use of anthracyclines in colorectal cancer, the ECF regimen seems to be a possible treatment even for this malignancy. Controlled studies with ECF versus standard treatments and versus 5-FU alone in c.i. are necessary.

Age-related prevalence of platelet-associated immunoglobulins G in nonthrombocytopenic patients with autoimmune thyroid disease and autoimmune polyglandular syndrome.

OBJECTIVE: The prevalence of platelet-associated IgG (paIgG) in nonthrombocytopenic patients with autoimmune thyroid disease (AITD) alone or associated with autoimmune polyglandular syndrome (APS) has been studied. SUBJECTS: A total of 164 individuals were enrolled in this study: 81 patients with AITD alone, 33 patients with APS, and 50 healthy controls. RESULTS: The presence of paIgG was recorded in 41 of 81 patients with AITD (51%) as compared with 2 of 50 control subjects (4%, p < 0.0001). The prevalence of paIgG in patients with APS was higher even when compared with patients with AITD alone (25/33, 76%; p = 0.02). The presence of paIgG was not related to the functional thyroid parameters. The prevalence of paIgG was higher in the older than in the younger patients (75 vs. 47%, p = 0.0037). CONCLUSIONS: The results indicate that the prevalence of paIgG in patients with AITD is higher than previously thought, namely in elderly patients and in patients with APS, and not related to the thyroid function.

Atrophic body gastritis in patients with autoimmune thyroid disease: an underdiagnosed association.

BACKGROUND: Atrophic body gastritis (ABG) has never been histologically characterized in patients with autoimmune thyroid disease (AITD), and its prevalence may be substantially different from that previously assessed based on only indirect evidence. OBJECTIVE: To detect and characterize the presence of ABG in patients with AITD. METHODS: Sixty-two patients with AITD (5 men and 57 women), aged between 21 and 74 years, have been screened for the presence of ABG by assaying serum gastrin levels. Patients with hypergastrinemia underwent gastroscopy followed by the histological examination of multiple biopsy specimens. The diagnosis of ABG was based on hypergastrinemia and pentagastrin-resistent achlorhydria, confirmed by histological examination. RESULTS: Twenty-two (35%) of 62 patients had hypergastrinemia (mean +/- SEM gastrin level, 1070+/-288 pmol/L). The diagnosis of ABG has been histologically confirmed in all 22 patients, and the score of atrophy was moderate to severe. In group A (patients aged 20-40 years; n = 21), 6 patients (29%) had ABG, compared with 11 patients (37%) in group B (patients aged 41-60 years; n = 30) and 5 patients (45%) in group C (patients aged 61-80 years; n = 11). Antiparietal cell antibodies were detected in only 68% (15/22) of patients with ABG. Anemia was observed in 82% (18/ 22) of patients with AITD and ABG but only in 22% (9/40) of patients without ABG (P<.0001). CONCLUSIONS: In the patients with AITD studied, about one third had ABG, which was diagnosed also in young patients; the measurement of gastrin levels represented the most reliable tool in the diagnosis of ABG; and the presence of anemia, even microcytic, was suggestive of undiagnosed ABG.

Stress proteins in fungal diseases.

Heat shock proteins (hsps) are ubiquitous families of proteins, found in all organisms studied so far. They are highly conserved across the species barrier and serve fundamental functions in cell physiology. The term 'heat shock' was adopted because of the early observation of the heat-inducible nature of these proteins, although, as it is now realized that they can be induced by a variety of stressful stimuli, it is probably more appropriate to call them 'stress proteins'. The nomenclature of many hsps, for example hsp90, hsp70 and hsp60, reflects the approximate molecular mass of hsps within each of these families. For many bacterial and parasitic infections, hsps were first recognized as immunodominant antigens on immunoblots of extracts from the organism probed with immune sera, or in T-cell proliferation assays. They have now been identified in a range of fungal pathogens, again often linked to an immune response. In this symposium, we review the association of hsps with humoral immunity to candidosis and aspergillosis, cellular immunity to histoplasmosis, and the identification of hsp70 in another dimorphic fungus, Paracoccidioides brasiliensis. Finally, the crucial role of the membrane in setting the temperature of the heat shock response in yeasts is discussed.

High-dose chemotherapy with bone marrow transplantation for advanced colorectal cancer.

A chemotherapy regimen based on high doses of BCNU and mitomycin C with autologous bone marrow transplantation was used in 18 patients with advanced colorectal carcinoma. Haematological toxicity was manageable, with a short nadir for white blood cells and platelets. The response rate was 33%, with a prevalence in peritoneal lesions compared to liver or lung metastases. Extra-haematological toxicity appeared in 16% of cases: a case of veno-occlusive disease of the liver and two cases of lung impairment are discussed. Although the response rate obtained with the regimen was satisfactory, the more extensive use of high-dose chemotherapy followed by autologous bone marrow transplantation requires the identification of less toxic protocols.

Comparative in vitro and in vivo study of a nitroxyl derivative of 5-fluorouracil (magnizil) on human gastrointestinal tumors.

AIMS AND BACKGROUND: There is much interest in nitroxyl derivatives of cytotoxic agents. We evaluated the potential activity of magnizil, a derivative of 5-fluorouracil, on human gastrointestinal tumors in 3 different in vitro and in vivo experimental models. METHODS: The activities of magnizil and 5-fluorouracil were comparatively determined in vitro on the HT29 cell line by a clonogenic assay and on tumor clinical specimens by an antimetabolic assay. The activity of both the drugs against human tumors was also assessed in mice with the subrenal capsule assay. RESULTS: A similar cytotoxic activity was found for magnizil and 5-fluorouracil on the HT29 cell line. As regards human tumors, a lower activity was observed for the nitroxyl derivative than for 5-fluorouracil, with response rates of 25% and 50%, respectively, at comparable concentrations. Moreover, among the tumors transplanted in the subrenal capsule of mice, two were sensitive to magnizil and 3 to 5-fluorouracil. CONCLUSIONS: Even though experimental results on human tumors indicate a somewhat lower activity for magnizil than the parent compound, its low toxicity and the possibility to clinically use high doses suggest the opportunity to further investigate the potential of this new anticancer agent on larger series of colorectal cancers in experimental systems.