Association of SULT1A1 Arg²¹³His polymorphism with male breast cancer risk: results from a multicenter study in Italy.

Male breast cancer (MBC) is rare and poorly understood. Like female breast cancer (FBC), MBCs are highly sensitive to hormonal changes, and hyperestrogenism, specifically, represents a major risk factor for MBC. MBC is considered similar to late-onset, post-menopausal estrogen/progesteron receptors positive FBC (ER+/PR+). Sulfotransferase 1A1 (SULT1A1) is an enzyme involved in the metabolism of estrogens. Recently, SULT1A1 common functional polymorphism Arg(213)His (638G>A) variant has been found to be associated with increased breast cancer (BC) risk, particularly in post-menopausal women. For this reason, we decided to explore whether SULT1A1 Arg(213)His could exert an effect on MBC development. The primary aim of this study was to evaluate the influence of the SULT1A1 Arg(213)His polymorphism on MBC risk. The secondary aim was to investigate possible associations with relevant clinical-pathologic features of MBC. A total of 394 MBC cases and 786 healthy male controls were genotyped for SULT1A1 Arg(213)His polymorphism by PCR-RFLP and high-resolution melting analysis. All MBC cases were characterized for relevant clinical-pathologic features. A significant difference in the distribution of SULT1A1 Arg(213)His genotypes was found between MBC cases and controls (P < 0.0001). The analysis of genotype-specific risk showed a significant increased MBC risk in individuals with G/A (OR 1.97, 95% CI 1.50-2.59; P < 0.0001) and A/A (OR 3.09, 95% CI 1.83-5.23; P < 0.0001) genotypes in comparison to wild-type genotype, under co-dominant model. A significant association between SULT1A1 risk genotypes and HER2 status emerged. Results indicate that SULT1A1 Arg(213)His may act as a low-penetrance risk allele for developing MBC and could be associated with a specific tumor subtype associated with HER2 overexpression.

Changes in autonomic regulation and ventricular repolarization induced by subclinical hyperthyroidism.

UNLABELLED: The aim of the present study was to evaluate the effect of subclinical hyperthyroidism (SHT) on cardiovascular autonomic function and ventricular repolarization. METHODS: Thirty subjects (25 females; mean age 49.6 ± 9.8 years) with SHT, as judged by reduced TSH serum levels and normal free T4 and T3 serum levels, and 30 age and sex-matched control subjects underwent standard 12-lead ECG, and 24h ambulatory ECG monitoring. The dispersion of the QT interval, an index of inhomogeneity of repolarization, and the heart rate variability (HRV), a measure of cardiac autonomic modulation, were studied. RESULTS: Patients with SHT showed higher QT dispersion (p<0.001) and lower HRV measures (0.01>p<0.001) than controls. In SHT patients, QT dispersion was inversely related to HRV (r=-0.47, p<0.01). CONCLUSION: The results of the present study demonstrated that SHT is associated with a sympathovagal imbalance, characterized by increased sympathetic activity in the presence of diminished vagal tone, and with an increased inhomogeneity of ventricular recovery times. The assessment of HRV and QT dispersion in patients with SHT may represent a useful tool in monitoring the cardiovascular risk of this condition.

Thyroid hormones and the cardiovascular system: pathophysiology and interventions.

Thyroid dysfunction, however mild, can significantly affect the cardiovascular (CV) system. The effects of thyroid hormones may be viewed as genomic and non-genomic, with the former occurring over a longer time scale and both affecting structural and functional proteins in CV tissue. As the interplay between thyroid function and the CV system becomes elucidated, particularly in the context of a system biology approach, the heart failure phenotype is better understood. Symptomatology is related to disturbance in inotropic and chronotropic function. Moreover, biochemical changes reflected by thyroid function testing with the non-thyroidal illness syndrome can prognosticate and guide therapy in heart failure. In addition, empiric treatment with thyroid hormone analogues or T3 represent emergent and highly controversial interventions.

Phase II trial of weekly intravenous gemcitabine administration with interferon and interleukin-2 immunotherapy for metastatic renal cell cancer.

PURPOSE: Since metastatic renal cell carcinoma has a poor prognosis and treatment strategies, including hormone therapy, chemotherapy and immunotherapy, have little impact on the quality of life and global survival statistics, new interest has recently focused on the combination of immuno-chemotherapy using pyrimidine analogues, such as gemcitabine. MATERIALS AND METHODS: In a phase II study 16 patients with metastatic renal cell carcinoma were treated with 1,000 mg./m. gemcitabine intravenously on days 1, 8, 15 and 28 for 6 months, 3 MU (1 MU = 1 x 10(6) IU) interferon (IFN)-alpha intramuscularly 3 times a week and 4.5 million IU interleukin (IL)-2 subcutaneously daily for 5 days a week for 2 consecutive weeks every month for 6 months. Responding and nonprogressing cases were maintained on immunotherapy consisting of IFN-alpha and IL-2 for further 6 months. RESULTS: In 15 evaluable patients overall response rate (1 complete response plus 3 partial response) was 28% while stable disease was achieved in 7 (47%). Median survival duration was 20 months (range, 9 to 26+) and median time to tumor progression was 14 months (6 to 26+). The complete response lasted 24+ months and partial response lasted 16 months. The regimen was well tolerated with only 1 case of neutropenia (WHO grade 3), while anorexia, fatigue and flu-like symptoms were the most common toxicity problems but were never greater than grade 2. CONCLUSIONS: Despite the small sample size, this study demonstrates that gemcitabine combined with standard doses of IFN-alpha and low doses of IL-2 is effective treatment for metastatic renal cell carcinoma. This biotherapy was well tolerated and resulted in an optimum objective response and relatively long-term survival.

Weekly gemcitabine plus Epirubicin as effective chemotherapy for advanced pancreatic cancer: a multicenter phase II study.

The current role of chemotherapy in pancreatic carcinoma is limited, and progress in the treatment of this disease represents a significant challenge to medical oncology. The most promising drug under study is gemcitabine, a relatively new antimetabolite that represents an attractive candidate for combination chemotherapy because of its excellent side-effect profile and the absence of overlapping toxicities with other chemotherapeutic agents. Combined administration of gemcitabine and anthracyclines could result in the induction of DNA breaks that are not easily repaired by the cell's machinery, thus enhancing the apoptotic signals triggered by these lesions. Forty-four patients with locally advanced and/or metastatic pancreatic adenocarcinoma were enrolled in this multicenter study. Patients received Epirubicin 20 mg m(-2) for 3 weeks followed by 1 week of rest (1 cycle) and gemcitabine 1000 mg m(-2) after Epirubicin on the same day. All were assessable for toxicity and response, 11 patients responded to treatment with one complete response and 10 partial responses, for an overall response rate of 25%. Median survival was 10.9 months (range, 2-26 months). Therapy was well tolerated, with a low incidence of haematologic grade >2 toxicity. A total of 12 of 27 (44.4%) eligible patients attained a clinical benefit response. Our findings suggest that the gemcitabine-epirubicin schedule is active and well tolerated in patients with advanced pancreatic cancer.

Gemcitabine plus Epi-doxorubicin as first-line chemotherapy for bladder cancer in advanced or metastatic stage: a phase II.

Combination chemotherapy with newer, more active drugs in patients with advanced and/or metastatic bladder cancer might show improved response rate and survival. Gemcitabine (GEM) and Epidoxorubicin (EPI) have demonstrated activity in this disease. In addition, experimental studies in vitro have shown that the two agents have additive-synergistic effects when used in combination. Our prior phase I dose-finding study in previously untreated patients with advanced or metastatic bladder cancer defined recommended doses for further trials of GEM 1000 mg/m2 and EPI 25 mg/m2 on days 1, 8 and 15 every 28 days. A phase II trial at this dose level was initiated in previously untreated patients to assess efficacy and toxicity. Eligible patients had measurable disease; Karnofsky performance status (PS) of > 40; no prior chemotherapy; and adequate bone marrow reserve, cardiac, hepatic and renal function. Thirty- one patients (22 males, 9 females) with median age of 64 (range 44-75) and median PS of 80 were accrued, and all were eligible. Twelve patients had T4N1-2 M0, 8 had lymph node only metastases, while 11 had visceral metastases (liver, bone, lung). A total of 181 cycles was administered (range 3-7 per patient). Major toxicities (WHO grade > or = 3) were: neutropenia in 5 patients, thrombocytopenia in 2 patients, and anemia in 2 patients. Three patients had febrile neutropenic episodes and only 3 patients required dose reduction. Grade 1-2 non-hematological toxicities included nausea/vomiting, stomatitis and alopecia. No cardiac toxicity was observed. Of the 30 response evaluable patients, 17 (57%) demonstrated a major response (3 complete and 14 partial) (95% CI: 39%-75%), 7 had stable disease (23%) and 6 progressed (20%). These preliminary results confirm the phase I observation that the combination of GEM--EPI is highly active in the treatment of advanced and metastatic bladder cancer with a favourable toxicity profile.

Randomized trial of adjuvant chemotherapy versus control after curative resection for gastric cancer: 5-year follow-up.

Adjuvant chemotherapy of gastric cancer after curative resection is still subject to discussion. In this study 137 patients with gastric adenocarcinoma, all with positive nodes, were randomized after curative resection so that 69 received epidoxorubicin (EPI), leucovorin (LV) and 5-fluorouracil (5-FU) on days 1-3 every 3 weeks for 7 months, whereas the remaining 68 did not. After a follow-up period of 5 years, 21 of the 69 treated patients (30%) and nine controls (13%) were still alive; median survival time was 18 months for the controls and 31 months for the patients treated with adjuvant chemotherapy (P< 0.01).

Insulin resistance and hyperinsulinemia: No independent relation to left ventricular mass in humans.

BACKGROUND: Hyperinsulinemia and insulin resistance may contribute to the development of cardiac hypertrophy. In humans, however, the evidence is inconclusive. METHODS AND RESULTS: We studied 50 nondiabetic subjects covering a wide range of age (20 to 65 years), body mass index (BMI, 19 to 40 kg x m(-2)), and mean blood pressure (72 to 132 mm Hg). Plasma insulin concentrations and secretory rates were measured at baseline and during an oral glucose tolerance test; insulin sensitivity was measured by the insulin clamp technique. Left ventricular mass (LVM) (by 2D M-mode echocardiography) was distributed normally and was higher in obese (BMI >/=27 kg x m(-2), n=16) or hypertensive patients (blood pressure >140/90 mm Hg, n=21) (50+/-8 and 55+/-10 g x m(-2.7), respectively) than in 13 nonobese, normotensive subjects (40+/-8 g x m(-2.7), P:=0.0004). In a multivariate model adjusting for sex, age, BMI, and blood pressure, neither insulin concentrations (fasting or postglucose) nor insulin sensitivity or secretory rates were significant correlates of LVM. Systolic blood pressure (P:=0.003) and BMI (P:=0.01) were the only independent correlates of LVM. From the regression, the impact of hypertension (as a systolic pressure of 180 versus 140 mm Hg=+20%) was twice as large as that of obesity (as a BMI of 35 versus 25 kg x m(-2)=+11%), the two factors being additive. CONCLUSIONS: When adequate account is taken of body mass and blood pressure, insulin, as concentration, secretion, or action, is not an independent determinant of LVM in nondiabetic subjects.

Melatonin as biological response modifier in cancer patients.

The neuroendocrine system modulates the immune response through neuropeptides and neurohormones, findings which point to the existence of a neuro-endocrine-immune system regulatory axis. At the same time, there is growing evidence that the pineal gland has anti-neoplastic properties, which include the action of its principal hormone, melatonin (MLT), on the immune system through the release of cytokines by activated T-cells and monocytes. The present study was carried out on 31 patients (19 males and 12 females, age range 46-73 years) with advanced solid tumors (7 gastric, 9 enteric, 8 renal, 5 bladder, 2 prostate) who either failed to respond to chemotherapy and radiotherapy or showed insignificant responses and were therefore shifted to MLT therapy (10 mg/die orally for 3 months). We obtained blood samples just before the start of MLT administration and after 30 days of therapy. Plasma was collected in EDTA tubes on ice, immediately centrifuged at 4 degrees C and stored frozen at -80 degrees C; samples were measured by immunoradiometric assays (Medgenix-Fleurus, Belgium) for tumor necrosis factor alpha (TNF), interleukin-1, 2 and 6 (IL-1, IL-2, IL-6) and interferon gamma (IFN). We used Student's paired t-test to compare each patient's cytokine circulating levels before and after MLT administration and found a significant differences (p < 0.05). After 3 months of therapy, none of our patients displayed adverse reactions to MLT or had to discontinue treatment. Nineteen patients (61%) showed disease progression. The other 12 (39%), however, achieved disease stabilization with no further growth of either the primary tumor or of secondaries; moreover, they experienced an improvement in their general well-being, in terms of Tchekmedyian's criteria, associated with a significative decrease of IL-6 circulating levels. These findings are consistent with the hypothesis that MLT modulates immune function in cancer patients by activating the cytokine system which exerts growth-inhibitory properties over a wide range of tumor cell types. Furthermore, by stimulating the cytotoxic activity of macrophages and monocytes, MLT plays a critical role in host defence against the progression of neoplasia.

Melatonin's growth-inhibitory effect on hepatoma AH 130 in the rat.

We tested the effects of daily melatonin treatment on the growth of the ascites hepatoma in rats, determining survival time, cell number and cell cycle phases at various stages of tumor development. Melatonin inhibited cellular proliferation, doubled mean life-time and increased survival. Thymidine incorporation in hepatoma cells from treated rats decreased significantly without changes in the apoptotic index. Flow cytometric analysis showed that melatonin slowed cell cycle progression by increasing the number of cells in phase G0G1. Thus, similar to in vitro models, melatonin's oncostatic action in vivo appears to be directed to specific cell cycle mechanisms, which remain to be elucidated.

Adjuvant chemotherapy after gastric resection in node-positive cancer patients: a multicentre randomised study.

After curative resection for gastric adenocarcinoma, 103 patients, all with positive nodes, were randomised so that 48 received adjuvant chemotherapy of epidoxorubicin (EPI) 75 mg m-2 on day 1, leucovorin (LV) 200 mg m-2 on days 1-3 and 5-fluorouracil (5-FU) 450 mg m-2 on days 1-3, every 21 days for 7 months, whereas the remaining 55 did not. During the first year of observation, 21 control patients (38%) and five treated patients had recurrences. After a follow-up period of 36 months, 12 of the treated patients (25%) and only seven controls (13%) were still alive. At that point, the median survival was 13.6 months for the 55 untreated patients and 20.4 months for the 48 treated patients, a significant difference. We found a survival advantage for patients treated with the EPI-LV-5-FU regimen and a consistent delay in the appearance of recurrent or metastatic cancer. Acute toxicity was mild and treatment was well accepted by all patients. There was no long-term toxicity or any cardiac toxicity. We conclude that this particular chemotherapy, administered shortly after gastric resection, improves survival rate in node-positive gastric cancer patients, even although final assessment of this particular adjuvant approach must await completion of the trial.

[Effects of rehabilitation on cardiovascular autonomic function in ischemic cardiopathy]. / Effetti della riabilitazione sulla funzione autonomica cardiovascolare nella cardiopatia ischemica.

METHODS: Twenty patients with uncomplicated myocardial infarction randomized in two groups (group 1 and 2) of ten patients were investigated. Only group 1 trained four months according to a protocol of rehabilitation, whereas patients of group 2 followed their usual activity (control group). The autonomic cardiovascular function was estimated by Ewing's tests, that evaluate the variations of heart rate and blood pressure during deep breathing. RESULTS: Our data showed an increase of parasympathetic tone in group 1 (Valsalva ratio 1.55 +/- 0.28 vs 1.36 +/- 0.28, p < 0.01; variation in heart rate during deep breathing 17.3 +/- 4.6 vs 13.3 +/- 4.2). The sympathetic activity tests showed no significant difference after training. On the other hand, group 2 showed no significant difference in sympathetic and parasympathetic activity. CONCLUSIONS: In patients with uncomplicated myocardial infarction physical training increases the parasympathetic activity; as shown in the literature, such an increase can have clinical and prognostic importance, since improves cardiac performance and reduces the risk of sudden death from arrhythmic events.

[The ultrasonic characterization of myocardial hypertrophy: new prospects]. / Caratterizzazione ultrasonica della ipertrofia miocardica: nuove prospettive.

The extensive use of ultrasound imaging in cardiology has greatly contributed to expand both its diagnostic possibilities and its utility in the interpretation of physiopathologic mechanisms. Conventional echocardiography is the more specific technique for the diagnosis of myocardial hypertrophy which, in turn, is one of the most important cardiovascular risk factors. The improvement of ultrasound technology may expand the possibility of noninvasive characterization of left ventricular hypertrophy by adding to the already known information about left ventricular mass and function, and that relative to the degree of hypertrophy-related fibrosis. In the present paper the authors reviewed the knowledge about biological and hemodynamic factors which contribute to the development and regression of myocardial hypertrophy. The possible role of new ultrasonic technology in the tissue characterization of myocardial hypertrophy is also discussed.

[Cardiovascular effects of amitriptyline in therapeutic dosages. Echocardiographic study]. / Effetti cardiovascolari dell'amitriptilina a dosaggi terapeutici. Studio ecocardiografico.

The authors studied the cardiovascular effects of amitriptyline at therapeutic plasma concentrations in 15 depressed patients (6 M. 9 F.) without cardiovascular disease both before treatment and after six months of therapy. The cardiovascular effects were evaluated by means of electrocardiographic and 2D-echocardiographic examinations in basal conditions and after hand-grip stress test. The effects of isometric hand-grip exercise (IHG) on left ventricular size and performance were studied non invasively in all patients at rest and after 3 min. of IHG at 30% of maximum contraction. Left ventricular internal diameter was measured at end-diastole and end-systole on LV echograms, and blood pressure was measured by sphygmomanometer. Our data confirmed the depressant effect of amitriptyline even on healthy myocardium, an effect that becomes manifest only at handgrip stress with a significant reduction of ejection fraction (form 70.6 to 66.4%; p < 0.001), while ECG and arterial blood pressure did not change throughout the study. This goes to show that treatment with tricyclic antidepressants always has a latent depressant effect on myocardial contractility that becomes clinically evident under stress, as well as in subjects with heart disease and in the elderly. Hence the need to monitor left ventricular function, as well as ECG and blood pressure, and to exercise great caution in prescribing tricyclic antidepressants to subjects with a history of myocardial failure.

Dilation of venous vessels at the splenic hilum in normal sized spleens as an indication of pathologic splenic involvement: preliminary results.

Twelve hundred patients without liver or heart disease, having a normal sized spleen without focal lesions, were examined by ultrasonography to measure the inner diameter of the splenic vein in relation to possible current or recent recovery from pathologic processes. SVD was measured at the hilum of the spleen with the patients supine. Ten of the patients in whom dilation of the SVD was found, together with a group of healthy controls (25), were subsequently studied with a duplex Doppler analysis to measure the venous outflow from the spleen. The results showed 1,175 spleens (98%) with SVD at the hilum of < 8 mm and 25 spleens (2%) with SVD of > 8 mm. Twenty-three of 25 patients (92%) with enlarged SVD had recent histories of hematopoietic or infectious diseases. Ten of 23 patients with enlarged SVD were studied further with a Doppler analysis. They demonstrated a rapid splenic blood flow with maximum flow velocities ranging from 14 to 27 cm/sec and high outflow volumes (from 430 to 1,227 ml/min, averaging 786 ml/min +/- 266), both significantly increased in comparison with controls (outflow volume from 200 to 355 ml/min, averaging 274 +/- 40; P < 0.0001). We conclude that dilation of the SVD accompanied by an increased intrasplenic blood flow volume without splenic enlargement would indicate a state of increased perfusion of splenic tissue associated with an immune response, reflecting reaction of the spleen to disease.

[The pancreas in diabetes mellitus. The echographic aspects]. / Il pancreas nel diabete mellito. Aspetti ecografici.

Forty patients with diabetes mellitus (25 with insulin-dependent and 15 with non-insulin dependent diabetes) were studied by means of US in order to evaluate possible volumetric alterations in the pancreas and their eventual progression over time. Thirty healthy subjects were also studied as a control group. The following variables were recorded: thickness of the head, body and tail of the pancreas and area of its head. The patients were also divided into 5 groups according to the age of diabetes (< 1, > 1, > 7, > 14, > 21 years). The results showed 25 IDDM patients to exhibit significant reduction in these variables relative to controls (p < = 0.01), especially in the body (average reduction -40%) and tail (average reduction -20%) of the pancreas. NIDDM patients exhibited non-significant reductions in pancreatic size. The study of the 5 groups of IDDM patients, divided according to the duration of diabetes, revealed all pancreatic variables to reduce more than in controls within a year since diagnosis, to exhibit relative increase during the next 7 years and finally to reduce again in the following years. These results show that anatomic damage to the pancreas occurs within the first year of diabetes. Moreover, IDDM was seen to alter the normal proportions among the single anatomic structures forming the pancreas, especially relative to two anatomic ratios--i.e., head/body and tail/body pancreatic thickness. The relative values in IDDM patients were markedly higher than those in controls (p < 0.001). The patients were again divided into 5 groups according to the age of diabetes: the values of the above ratios in the course of diabetes greatly differed from those observed in controls--i.e., they increased within the first year of diabetes, were steady during the next 7 years, and returned to normal values after 21 years of diabetes, which meant the return to the normal anatomic ratios among the three parts of the pancreas.

Slow-releasing nicardipine in the treatment of Raynaud's phenomena without underlying diseases.

Calcium channel blockers have been used in the treatment of primary and secondary Raynaud's phenomenon (RP), and a beneficial effect was often recorded. The efficacy of slow-releasing nicardipine was assessed in a clinically homogeneous series of RP without underlying diseases in a randomized, double blind, cross-over and placebo controlled trial. Out of twenty-one selected patients (18 women and 3 men, mean age 46 +/- 12 yrs) eighteen completed the study and three dropped out, one for inadequate compliance and two due to headache. After a three-week period, slow-releasing nicardipine (20 mg two times daily) was significantly more useful than placebo: the number of RP episodes per week decreased (p less than 0.02), severity of discomfort and hand disability scores, evaluated after single RP attack, clearly improved (p less than 0.005 and p less than 0.02, respectively). According to clinical improvement, time of peak flow after postischemic reactive hyperaemia test was significantly reduced only after nicardipine (p less than 0.01). These results show that slow-releasing nicardipine is generally well tolerated and can provide effective improvement in RP patients without underlying diseases.

Echocardiographic contrast imaging of the human right heart: a multicenter study of the efficacy, safety, and reproducibility of intravenous SHU-454.

The contrast agent SHU-454 was intravenously injected in 103 patients during echocardiography: 37 mL/patient +/- 7 ml/patient. The quality of the contrast effect was optimal in 13, good in 51, sufficient in 30, and poor in 9 patients; reproducibility was optimal in 38, good in 46, sufficient in 17, and poor in 2 patients. Taste sensation, arm discomfort, or atypical chest pain occurred in 5 patients, premature ventricular contractions in 3. An isolated anginal attack occurred in 1 patient with frequent episodes at rest. A slight reduction in hematologic indices was attributed to hemodilution. Thus, SHU-454 produces a good and reproducible contrast effect with tolerable side effects.

[Echocardiographic parameters and systolic times in arterial hypertension in the elderly]. / Parametri ecocardiografici e tempi sistolici nell'ipertensione arteriosa dell'anziano.

In 40 subjects, 15 mean age 70.7 +/- 5.6 with systolic-diastolic hypertension, 15 mean age 75.5 +/- 6.8 years with systolic hypertension and 10 mean age 73.6 +/- 5.1 normotensive control group we have analyzed with M-mode 2D echocardiography and echophonocardiography the following parameters: diastolic--EDD--and systolic diameter--SD--of left ventricle, diastolic thickness of septum--SSD--and posterior wall--SPPD--of left ventricle, left ventricular ejection fraction--EF--(Theicholtr. formula), radius posterior wall thickness--R/SPPD--, left ventricular mass--LVM--(Devereux' formula), and systolic time intervals (Q-A2, LVET, PEP and PEP/LVET). The differences between groups are: systolic-diastolic hypertensive patients have increased EDD, SPPD and LVM, reduction of EF and increased PEP/LVET ratio in comparison with B and C groups; systolic hypertension doesn't increase EDD; SSD and PEP/LVET increase, while the EF remains within normal limits. In the healthy aged subjects SSD, SPPD and LVM are normal.