Role of proton-coupled folate transporter in pemetrexed resistance of mesothelioma: clinical evidence and new pharmacological tools.

BACKGROUND: Thymidylate synthase (TS) has a predictive role in pemetrexed treatment of mesothelioma; however, additional chemoresistance mechanisms are poorly understood. Here, we explored the role of the reduced-folate carrier (RFC/SLC19A1) and proton-coupled folate transporter (PCFT/SLC46A1) in antifolate resistance in mesothelioma. PATIENTS AND METHODS: PCFT, RFC and TS RNA and PCFT protein levels were determined by quantitative RT-PCR of frozen tissues and immunohistochemistry of tissue-microarrays, respectively, in two cohorts of pemetrexed-treated patients. Data were analyzed by t-test, Fisher's/log-rank test and Cox proportional models. The contribution of PCFT expression and PCFT-promoter methylation to pemetrexed activity were evaluated in mesothelioma cells and spheroids, through 5-aza-2'-deoxycytidine-mediated demethylation and siRNA-knockdown. RESULTS: Pemetrexed-treated patients with low PCFT had significantly lower rates of disease control, and shorter overall survival (OS), in both the test (N = 73, 11.3 versus 20.1 months, P = 0.01) and validation (N = 51, 12.6 versus 30.3 months, P = 0.02) cohorts. Multivariate analysis confirmed PCFT-independent prognostic role. Low-PCFT protein levels were also associated with shorter OS. Patients with both low-PCFT and high-TS levels had the worst prognosis (OS, 5.5 months), whereas associations were neither found for RFC nor in pemetrexed-untreated patients. PCFT silencing reduced pemetrexed sensitivity, whereas 5-aza-2'-deoxycytidine overcame resistance. CONCLUSIONS: These findings identify for the first time PCFT as a novel mesothelioma prognostic biomarker, prompting prospective trials for its validation. Moreover, preclinical data suggest that targeting PCFT-promoter methylation might eradicate pemetrexed-resistant cells characterized by low-PCFT expression.

Effects of hospital policies and practices on initiation and duration of breastfeeding.

BACKGROUND: The aim of this study was to verify if hospital policies and practices, independently of main maternal sociodemographic determinants, influence initiation and duration of breastfeeding. METHODS: The study was carried out at the Immunization Centre of Messina where all infants born in the four maternity wards of Messina are vaccinated, using a structured questionnaire, constructed in conformity with the methodology suggested by the WHO. RESULTS: Data analysis, performed by non-parametric and multivariate analysis of variance and by Kaplan-Meier curves, showed that the highest probability rate (P < 0.001) of initiation and duration of breastfeeding, independently of maternal age, parity, education levels, smoke and work was found in infants born in a University Hospital, characterized by earlier times of first suckling, longer hospital stay and higher rate of exclusive breastfeeding at discharge. CONCLUSION: Our data emphasize the role and responsibility of hospital policies and practices in the promotion, and in the duration of breastfeeding.

[Comparison between pre- and postnatal echographic screening of malformative uropathies]. / Confronto tra lo screening ecografico pre- e postnatale delle uropatie malformative.

AIM: The aim of this study has been to compare the validity of postnatal echographic screening in respect of prenatal echography in early diagnosis of malformative uropathies (MU). METHODS: In 6578 infants, who have been submitted to fetal echography, and to a postnatal screening of MU in our Neonatal Service of Echography (University of Messina), we have compared the diagnostic agreement of prenatal with postnatal echography. RESULTS: Our comparison demonstrates that, in respect of postnatal screening, only 35.71% of pyelectasies and 73.17% of hydronephrosis have been diagnosed by fetal echography, and, in particular, only 18.75% of no-dilated MU. CONCLUSIONS: These data confirm that, in our country, the postnatal screening of MU has still significance and suggest that, before excluding this screening, it is necessary to verify everywhere the validity of fetal echography.

Plasma leptin, insulin, and neuropeptide Y concentrations in infants.

Changes in plasma leptin, insulin, and neuropeptide Y (NPY) concentrations were determined by radioimmunological methods in healthy infants. Compared with umbilical concentrations, on the 4th day of life plasma leptin and insulin were significantly decreased, and NPY was significantly increased. No correlation was observed between leptin, insulin, and NPY.

Significance of selective carotid angiography during complete cardiac catheterization in patients candidates to combined aortic valve and carotid surgery.

AIM: Association of aortic valve stenosis (AVS) with carotid artery disease (CD) constitutes a high risk clinical setting for combined surgery. Carotid angiography is still considered the gold standard for carotid artery imaging, but its use is confined in cases of dubious or inconclusive sonographic examination. Despite the widespread use of ultrasonography, selective angiography may be practical in patients undergoing complete routine cardiac catheterization for AVS due to characteristic abnormalities in flow velocity pattern due to aortic valve stenosis. The present retrospective study aims to estimate the feasibility and role of carotid angiography during complete routine cardiac catheterization in the assessment of CD associated with AVS in patients candidates for combined surgery, in whom Doppler ultrasonography was inconclusive. METHODS: In agreement with cardiac and vascular surgeons, patients aged >60 years, presence of risk factors, and inconclusive Doppler ultrasonographic examination underwent selective carotid artery angiography during complete cardiac catheterization. The angiographic and clinical records of these patients were reviewed. RESULTS: Sixty patients (male/female 28/32, mean age 64.5+/-10.6 years) underwent carotid angiography during left and right catheterization. Optimal visualization of carotid trunk anatomy and morphology was achieved in all patients. Forty-one patients (68.3%) had no carotid artery atherosclerotic involvement, whereas 4 (6.6%) had low grade CD. Fifteen patients (8.3%, male/female: 7/8, mean age 70+/-10.4 years) were diagnosed with critical stenosis of one (14 patients) or both (1 patients) internal carotid arteries. The mean lesion degree was 77.1+/-2.1%. Culprit plaques, bifurcation lesion and occlusion have been discovered in 6.6%, 20%, and 26.6% of patients, respectively. Two arterial spasms (3.3%), and no intrahospital complications were observed. CONCLUSION: In highly selected patients with combined CD and AVS and inconclusive Doppler ultrasonographic examination, selective carotid angiography during heart catheterization is safe, acceptably time-consuming and it may give an optimal anatomical picture of CD.

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.

[Severe aortic valve stenosis and coronary disease in the elderly. Epidemiology and hemodynamic features]. / Stenosi aortica serrata e malattia coronarica nell'anziano. Epidemiologia e caratteristiche emodinamiche.

BACKGROUND: Aortic valve replacement is an effective and safe intervention in the elderly, but to-day the prevalence of coronary artery disease in the elderly has still to be clarified. Aim of this paper is to analyze in a retrospective study the epidemiology and the hemodynamic relation of the association of severe aortic valve stenosis with coronary artery disease in patients over 75 years. METHODS: In a retrospective study of 12.000 cardiac catheterization procedures, patients with severe aortic valve stenosis were selected: the patients over 75 years (30 patients) were screened for presence/absence of coronary lesion forming two groups: correlations with anatomic and hemodynamic variables were made. RESULTS: 36.6% (11 patients) of the over-75 had significative coronary lesions; the coronary arteries involved were the anterior descendent coronary artery and the right coronary artery; no significative differences were found as to risk factors between the two groups except hypertension; the greater number of calcifications and mitral and aortic regurgitation was found in patients with coronary disease; the values of ejection fraction and cardiac index were significantly smaller in patients with coronary disease. CONCLUSIONS: In patients over 75 the severe aortic valve stenosis is frequently associated with coronary disease and the association is greater than in younger persons; some particular features confirm the elderly patients as a class at particular risk in which coronary angiography and combined bypass graft and valve replacement are of primary importance for the outcomes.

Rarities in the catheterization Lab. A strange type of single coronary artery.

The single coronary artery, a rare but well described coronary artery anomaly, is considered potentially dangerous. A case of a 71-year old woman, suffering from a moderate arterial hypertension and frequent episodes of atypical chest pain is described. The woman was found to have a strange type of single coronary with hypoplastic circumflex coronary artery, difficulty classifiable as a Lipton R-II A single coronary artery. The anatomical features and classification criteria of the case are also described.

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.

Incidence of dehydration and hypernatremia in exclusively breast-fed infants.

OBJECTIVES: To verify in exclusively breast-fed, term infants the incidence of hypernatremic dehydration and identify possible maternal and/or infant factors that interfere with successful breast-feeding. STUDY DESIGN: We prospectively included all healthy breast-fed neonates referred to our Neonatology Unit between October 1999 and March 2000. All neonates with a weight loss > or = 10% of birth weight had a breast-feeding test and a determination of serum sodium, urea, and base excess. Student t test and chi-square test were used for statistical analysis of the data. RESULTS: Of 686 neonates, 53 (7.7%) had a weight loss > or = 10% of the birth weight, and 19 also had hypernatremia. These 53 neonates had a significantly higher incidence of caesarean delivery and lower maternal education than neonates with a weight loss < 10%. CONCLUSION: Our prospective study demonstrates that a weight loss > or = 10% during the first days of life is frequent. Daily weight evaluation, careful breast-feeding assessment, and early routine postpartum follow-up are effective methods to prevent hypernatremic dehydration and promote breast-feeding.

[Coronary artery anomalies and coronary disease: is there a relationship?]. / Anomalie coronariche e coronaropatia: esiste una relazione?

BACKGROUND: It has been suggested that in coronary anomalies the turbulence of the flow might develop atherosclerosis, but this theory remains controversial. The relationship between coronary anomalies and coronary artery disease have been studied. METHODS: Twenty-five patients [15 males, 10 females (mean age 75+/-1.4 years)] with coronary anomalies at coronary angiography were enrolled in a prospective study. Thirteen patients out of 25 (group 1) had critical coronary artery disease (>50% of reduction in luminal diameter). The anomalous vessels passing intramyocardial or between aorta and pulmonary veins were excluded. Twelve patients out of 25 had no sign of atherosclerosis (group 2). At clinical and instrumental follow-up (54+/-8.4 months) the number of cardiovascular events (acute myocardial infarct, unstable angina, silent ischemia, bypass or PTCA interventions, cardiovascular death) was evaluated in the two groups. RESULTS: Age and ejection fraction value were no statistically different in the two groups. Risk factors were significantly (p<0.04) higher in group 1 (smoke, hypertension, hypercholesterolemia, diabetes). The patients number with cardiovascular events was significantly higher in group 1(11 patients vs 2) confirming the independence of the two phenomena. No correlation was found between presence of risk factors and presence of events. A correlation (r=0.70) was found only between previous coronary artery disease and number of events. CONCLUSIONS: No relationship between coronary anomalies and coronary artery disease seems to be confirmed. The real relevance of flow turbulence in the development of atherosclerosis in coronary anomalies needs to be still confirmed.

Incidence of meconium aspiration syndrome in term meconium-stained babies managed at birth with selective tracheal intubation.

The delivery room management of infants born through meconium stained amniotic fluid (MSAF) remains controversial. The aim of this prospective study was to evaluate maternal and neonatal characteristics of MSAF infants and the incidence of meconium aspiration syndrome (MAS) in routine delivery room management which reserved selective intubation for depressed/asphyxiated babies. Between October 1993 and September 1997, a consecutive sample of 3745 full-term infants was analyzed. Of these, 361 were MSAF infants. No significant difference in maternal age, parity, gestational age, sex, low 1 and 5 minute Apgar scores, metabolic acidemia, or need for endotracheal intubation was found between MSAF and non-MSAF infants. Only one of the MSAF infants (0.28%), who needed intubation, developed MAS. Identification of postterm pregnancy and prenatal asphyxia is the best prevention of MAS.

[Diabetes and pregnancy. Maternal risk factors and neonatal morbidity]. / Diabete e gravidanza. Fattori di rischio materni e morbilità neonatale.

BACKGROUND: To verify in our population the incidence of infants of mother with insulin dependent diabetes mellitus (IDDM) or gestational diabetes (GD) and to evaluate the maternal characteristics influencing neonatal outcome. METHODS: The study was retrospectively performed on 6179 infants born between 1995 and 1998 at the Obstetric Clinic of the University of Messina and referred the Division of Neonatology. The following groups have been selected: group A (offsprings of IDDM mothers), group B (offsprings of DG mothers), group C and group D, controls, (2 infants of the same sex and gestational age born before and after the infants of group A and group B, respectively). The parameters analyzed were: diabetic familiarity, age, weight and body mass index (BMI) of the mothers, delivery, gestational age, weight at birth, neonatal outcome. RESULTS: The infants of IDDM mothers were 3% and the infants of GD mothers were 0.8%. Group A and group B present a significantly higher incidence of: diabetic familiarity, cesarean section, macrosomia, hypoglycemia, hypocalcemia, hyperbilirubinemia. The GD mothers had weight and BMI higher than IDDM mothers. The infant weight did not correlate with maternal weight and BMI. CONCLUSIONS: These data suggest that in our population GD is underestimated, metabolic control in pregnancy is insufficient, obstetric practices are too invasive, neonatal outcome is verosimely correlated only to metabolic control.

[Health status of neonates born to immigrants at the University Polyclinic of Messina in 1993-1998. A case-control study]. / Stato di salute dei neonati figli di immigrati nati presso il Policlinico Universitario di Messina negli anni 1993-1998. Studio-caso-controllo.

The aim of the present case-control study was to verify the incidence and the state of health of the neonates born of extracommunity parents (E.C.) in the our hospital throughout the years 1993-1998. For every neonate born of E.C. we have analyzed two italian neonates born immediately before and after. The parameters analyzed were: nationality, age, and job of the parents, abortions, number of ecography carried out during pregnancy, parity, delivery, gestational age (G.A.), weight at birth, Apgar score, malformations, perinatal mortality and neonatal morbidity. Statistical analyses were performed with the T Student test and the chi-square test. Throughout the 1993-1998 years are born 9285 neonates. Of these 199 (2.4%) were E.C. The 45% of the E.C. derived from the Far East and only the 10% were nomad. The 86% of the E.C. had a job. In the E.C. group the multiparity was significantly higher than in italian group. G.A., birth weight, number of malformation, neonatal morbidity, and perinatal mortality were the same in the E.C. and in the italian neonates. Our data, in disagreement with other Authors, demonstrate that in our hospital the state of health of the E.C. and italian neonates is not different. Because in the our analysis it results that the greater number of E.C. parents had a job, it is likely that the non-observed increased of perinatal mortality and morbidity in the neonates born of E.C. depends on the social integration of E.C.

Results of leucovorin and doxifluridine oral regimen in the treatment of metastatic colorectal cancer.

We conducted a multicentric phase II study on advanced colorectal cancer to determine the efficacy and toxicity of oral treatment with leucovorin (LV) plus doxifluridine (5'DFUR), a novel fluoropyrimidine derivative with proven antitumor activity in different experimental models. Thirty-six outpatients with measurable disease entered the trial and received orally LV 20 mg in the morning and in the afternoon, and 2 h later 5'-DFUR 500 mg/m2 every 2 days for 3 months. Thirty-four evaluable patients underwent a total of 408 weeks of treatment. The response rate was 35%, with two complete remissions and 10 partial responses. The median survival of patients who responded to treatment (responders) was 17.1 months (range 4-32), which was significantly longer (p<0.001) than the 6.5 months (range 2-11) of the patients who did not respond (non-responders). Therefore, after 4-8 weeks of treatment, 14 patients (41%) had an improvement in their performance status and/or stabilization of pain. General toxicity was usually mild, myelo and gastrointestinal toxicity were moderate, and there was no evidence of relevant neurological toxicity. These results show that a home therapy with oral LV-5'DFUR is a safe and effective treatment regimen for metastatic colorectal carcinoma.

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.

[Brachial plexus paralysis: its incidence, predisposing factors and outcome]. / Paralisi del plesso brachiale: incidenza, fattori predisponenti ed esiti.

METHODS: We have studies, retrospectively, the risk factors, incidence and outcome of obstetric palsy in all infants delivered between January 1990 and December 1994 at the Obstetric and Gynecological Department and afferent to the Neonatological Division of the University of Messina. Twenty-eight of the 5556 live born full term infants (5/1000) were at birth diagnosed as having a brachial plexus paresis. Of these eight (1.6/1000) had persistent palsy. RESULTS: In about 40-50% of the infants with brachial plexus palsy the obstetric history was characterized by high birthweight, shoulder dystocia, and parity 1. The infants who recovered totally did so during the first 12 months of life. All infants had upper brachial plexus, or Erb's palsy, which is more favorable than entire brachial plexus palsy. At follow-up (15 months-5 years), all infants with persistent palsy were afflicted by varying degrees of arm function compromise. CONCLUSIONS: We stress that, in several cases, obstetric brachial plexus palsy results in life-long handicap, and that prevention, early diagnosis and therapy need to be the goals of the obstetrical and pediatric management.

[Infants born to hypertensive mothers: a clinical-epidemiological study]. / I figli di madre ipertesa: studio clinico-epidemiologico.

The aim of this prospective study was to evaluate the frequency of the hypertensive disorders of pregnancy and their effects on the newborn infants. The study was performed between January 1992 and December 1994 on the 4793 infants born at the Obstetric Divisions of the University of Messina. These 123 infants were born of hypertensive women and 4670 were control infants. Between the two groups of infants there were significant differences with regard to the incidence of nulliparity, prematurity, low Apgar scores at birth and low birth weight. The blood pressure and the haematic parameters were not different between the two groups of infants. Five of the infants born to hypertensive women were referred to the Division of Neonatal Pathology. The low frequency of infants born to hypertensive women observed by us suggests that in our population the hypertensive disorders of pregnancy are understimated. Moreover, the high incidence of preterm and LBW infants confirms that in infants born to hypertensive women the neonatal risks are consequent to fetal growth retardation.