Moderate hypofractionated helical tomotherapy for prostate cancer in a cohort of older patients: a mono-institutional report of toxicity and clinical outcomes.

PURPOSE OR OBJECTIVE: To evaluate toxicity and outcomes of moderately hypofractionated helical tomotherapy for the curative treatment of a cohort of patients aged ≥ 75 years with localized prostate cancer (PC). MATERIALS AND METHODS: From January 2013 to February 2017, 95 patients with median age 77 years (range 75-88) were treated for PC. 39% were low risk, 33% intermediate risk (IR), 28% high risk (HR). Median iPSA was 9.42 ng/ml (1.6-107). Androgen deprivation was prescribed according to NCCN recommendations. All patients received 70 Gy in 28 fractions to the prostate; 61.6 Gy were delivered to the seminal vesicles for IR; whole pelvis irradiation with a total dose of 50.4 Gy was added in the HR group. Toxicity evaluation was based on CTCAE V4.0 criteria, biochemical failure was defined following Phoenix criteria. Quality of Life was assessed with the EPIC-26 index. Overall survival and biochemical failure-free survival were analysed with Kaplan-Meier method. RESULTS: With a median follow-up of 36 months (range 24-73), acute and late toxicity were acceptable. No correlation between toxicity patterns and clinical or dosimetric parameter was registered. EPIC-26 showed a negligible difference in urinary and bowel function post-treatment that did not reach statistical significance. The 2- and 3-years OS were 93% and 87% with cancer specific survival of 97.9% and 96.2%. CONCLUSION: Moderate hypofractionated RT reported excellent outcomes in our cohort of older patients. Shorter schedules may be proposed regardless of chronological age facilitating the treatment compliance in the older population.

p85 regulatory subunit of PI3K mediates cAMP-PKA and estrogens biological effects on growth and survival.

Cyclic adenosine 3'5' monophosphate (cAMP) and protein kinase A (PKA) cooperate with phosphatidylinositol 3' kinase (PI3K) signals in the control of growth and survival. To determine the molecular mechanism(s) involved, we identified and mutagenized a specific serine (residue 83) in p85alpha(PI3K), which is phosphorylated in vivo and in vitro by PKA. Expression of p85alpha(PI3K) mutants (alanine or aspartic substitutions) significantly altered the biological responses of the cells to cAMP. cAMP protection from anoikis was reduced in cells expressing the alanine version p85alpha(PI3K). These cells did not arrest in G1 in the presence of cAMP, whereas cells expressing the aspartic mutant p85D accumulated in G1 even in the absence of cAMP. S phase was still efficiently inhibited by cAMP in cells expressing both mutants. The binding of PI3K to Ras p21 was greatly reduced in cells expressing p85A in the presence or absence of cAMP. Conversely, expression of the aspartic mutant stimulated robustly the binding of PI3K to p21 Ras in the presence of cAMP. Mutation in the Ser 83 inhibited cAMP, but not PDGF stimulation of PI3K. Conversely, the p85D aspartic mutant amplified cAMP stimulation of PI3K activity. Phosphorylation of Ser 83 by cAMP-PKA in p85alpha(PI3K) was also necessary for estrogen signaling as expression of p85A or p85D mutants inhibited or amplified, respectively, the binding of estrogen receptor to p85alpha and AKT phosphorylation induced by estrogens. The data presented indicate that: (1) phosphorylation of Ser 83 in p85alpha(PI3K) is critical for cAMP-PKA induced G1 arrest and survival in mouse 3T3 fibroblasts; (2) this site is necessary for amplification of estrogen signals by cAMP-PKA and related receptors. Finally, these data suggest a general mechanism of PI3K regulation by cAMP, operating in various cell types and under different conditions.

The p85 regulatory subunit of PI3K mediates TSH-cAMP-PKA growth and survival signals.

Phosphatidylinositol 3-kinase (PI3K) is necessary for thyroid stimulating hormone (TSH)-induced cell cycle progression. To determine the molecular mechanism linking PI3K to TSH, we have identified a serine residue in p85alpha(PI3K) phosphorylated by protein kinase A (PKA) in vitro and in vivo. Expression of an alanine mutant (p85A) abolished cyclic AMP/TSH-induced cell cycle progression and was lethal in thyroid cells (FRTL-5). The aspartic version of the p85alpha(PI3K) (p85D) inhibited apoptosis following TSH withdrawal. The p85alpha(PI3K) wild type not the p85A bound PKA regulatory subunit RIIbeta in cells stimulated with cAMP or TSH. The binding of the aspartic version of p85alpha(PI3K) to RIIbeta was independent of cAMP or TSH stimulation. Similarly, binding of PI3K to p21Ras and activation of AKT, a downstream PI3K target, were severely impaired in cells expressing the p85A mutant. Finally, we found that the catalytic activity of PI3K was stimulated by TSH in cells expressing the wild-type p85alpha(PI3K) but not in cells expressing p85A. This latter mutant did not affect the epidermal growth factor-stimulated PI3K activity. We suggest that (1) TSH-cAMP-induced PKA phosphorylates p85alpha(PI3K) at serine 83, (2) phosphorylated p85alpha(PI3K) binds RIIbeta-PKA and targets PKAII to the membrane, and (3) PI3K activity and p21Ras binding to PI3K increase and activate PI3K downstream targets. This pathway is essential for the transmission of TSH-cAMP growth signals.

Survival of malignant pleural mesothelioma cases in the Tuscan Mesothelioma Register, 1988-2000: a population-based study.

This study analyses survival of Tuscan residents (Italy, 3.5 million population) diagnosed by histological examination with malignant pleural mesothelioma (MPM) during the period 1988-2000, and recorded in the Tuscan Malignant Mesothelioma Register. The aim was to establish the prognostic role of demographic, diagnostic and asbestos exposure variables. During 1988-2000, 381 MPM cases were recorded (318 men; 63 women). Vital status was ascertained up to 31 December 2002. No cases were lost to follow-up. Median survival of certain MPM was 324 days (11 months; 95% CI 297-366); 45.7% (95% CI 40.6-50.6%) survived more than 1 year; 24.2% (95% CI 20.0-28.5%) more than 2 years. In univariate and multivariate analyses survival was associated with histological subtype (epithelioid subtype had the longest survival). Gender, age, period of diagnosis, hospital of diagnosis and asbestos exposure did not show significant effects. Therapeutic information was available for patients of the period 1997-2000. There was no significant difference in survival between treated versus untreated patients. In conclusion, no advance in prognosis at the population level in the most recent period can be suggested on the basis of the data available to the Tuscan Malignant Mesothelioma Register.

The early growth response gene EGR-1 behaves as a suppressor gene that is down-regulated independent of ARF/Mdm2 but not p53 alterations in fresh human gliomas.

PURPOSE: EGR-1 is an immediate early gene with diverse functions that include the suppression of growth. EGR-1 is down-regulated many cancer cell types, suggesting a tumor suppressor role, and may critically involve the p53 pathway. The aim of this work was to measure the expression of EGR-1 and the p16/INK4a/ARF-Mdm2-p53 pathway status in fresh human gliomas. EXPERIMENTAL DESIGN: Thirty-one human gliomas with different grades of malignancy were investigated for Egr-1 mRNA and the protein expression, frequency, and spectrum of p53 gene mutations, mdm2 gene amplification, and p16/INK4a/ARF allele loss. RESULTS: The amplification of Mdm2 and the deletion of the p16/INK4a gene was found in 3 and 5 cases, respectively, whereas mutations of p53, including two novel mutations, were observed in 10 other cases. The three types of changes occurred strictly mutually exclusively, emphasizing that these genes operate in a common pathway critical to glioma progression. EGR-1 mRNA was significantly down-regulated in astrocytomas (14.7 +/- 5.1%) and in glioblastomas (33.6 +/- 10.0%) versus normal brain. Overall, EGR-1 mRNA was strongly suppressed (average, 15.2 +/- 13.9%) in 27 of 31 cases (87%), independent of changes in p16/INK4a/ARF and Mdm2; whereas 4 of 31 cases with residual EGR-1 expression as well as the highest EGR-1 variance segregated with p53 mutations. Immunohistochemical analyses confirmed the suppression of EGR-1 protein. CONCLUSIONS: These results indicate that EGR-1 is commonly suppressed in gliomas independent of p16/INK4a/ARF and Mdm2 and that suppression is less crucial in tumors bearing p53 mutations, and these results implicate an EGR-1 growth regulatory mechanism as a target of inactivation during tumor progression.

The perception of AIDS in the Bété and Baoulé of the Ivory Coast.

The purpose of this study was to gain a better understanding of the socio-cultural aspects of transmissible diseases, in particular AIDS perceptions, among the two major Ivorian ethnic groups, the Bété and Baoulé, in order to implement more suitable educational programmes. The methods used consist of structured interviews to obtain quantitative findings on knowledge and practices, and 'focus groups' and semi-structured interviews with key-informants for the collection of qualitative data. Interpretations according to traditional ways of thinking are widespread among both the Bété and Baoulé. Urinating where an AIDS patient has urinated and sorcery attacks are considered possible ways of transmitting AIDS according to traditional categories of pure-impure and supernatural powers intervention. Educational level is the factor which most influences a person's knowledge of AIDS and prevention methods through western categories. Education as well as a better knowledge of the disease appear to be associated with an attitude that favours isolating the patient. The content of health education messages on AIDS, in the rural environment, cannot be separated from the Bétés or Baoulés conceptions of transmissible diseases.

In vitro metabolism of bladder carcinogenic nitrosamines by rat liver and urothelial cells.

In order to establish the importance of the target organ in the activation of bladder carcinogens, we compared rat liver and urothelial cell alpha-hydroxylation activities using as substrates N-nitrosobutyl(4-hydroxybutyl)amine and its metabolite N-nitrosobutyl(3-carboxypropyl)amine, two potent urinary bladder carcinogens in animals. Previous studies have shown that the production of molecular nitrogen can serve as an indicator of nitrosamine alpha-hydroxylation. The use of doubly 15N-labelled nitrosamines and the gas chromatography-mass spectrometric detection of 15N2 formed gives a measurement of the extent of this metabolic step. Various amounts of 15N-labelled substrates were incubated for 60 min at 37 degrees C with rat liver S9 preparations or urothelial cell homogenates in the presence of a NADPH generating system. Both enzyme sources metabolized 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine and N-nitrosobutyl(3-carboxypropyl)amine through the alpha-hydroxylation pathway. Using hepatic S9 fractions, 15N2 production from 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine increased from 1.69 +/- 0.02 nmol/h per mg protein (mean +/- S.E.) to 5.78 +/- 0.5 with substrate concentrations ranging between 0.55 and 5.55 mM. 15N2 produced by urothelial cell homogenates was about 40-50% that of the liver S9. 15N-labelled N-nitrosobutyl(3-carboxypropyl)amine was also metabolized through the alpha-hydroxylation pathway both by hepatic S9 and urothelial cell homogenates, though to a lesser extent. 15N2 production was about 10-times less than from 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine, but again urothelial cell 15N2 production was about 40-50% that of the liver. Treatment with phenobarbital resulted in a 2.7-fold increase in the 15N2 produced from 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine by hepatic S9. No effect was observed with urothelial cell homogenates. Acetone treatment had no effect on 15N2 production from 15N-labelled N-nitrosobutyl(4-hydroxybutyl)amine by hepatic S9, but raised 15N2 production by urothelial cell homogenates 1.8 times. Although the liver has a greater capacity than the bladder for activating the 15N-labelled nitrosamines studied, the target organ can metabolize bladder carcinogens, thus increasing the possibility of a local toxic effect. Moreover, the distribution of P-450 isozymes might be different in the bladder and this could affect the metabolism of nitrosamines reportedly formed in the human bladder in some pathological conditions.

[Acromegalic cardiopathy: a morphofunctional study with color-Doppler echocardiography]. / Cardiopatia acromegalica: studio morfo-funzionale con ecocardiografia color-Doppler.

We used color-Doppler echocardiography in an investigation of cardiac morphology and function to verify the cardiac anatomic and functional changes in acromegalic patients with or without hypertension and hyperlipemic states. Fifteen patients with growth hormone-secreting pituitary adenoma (mean age: 47.9 years) and 15 healthy control subjects were studied. We measured serum growth hormone (GH), somatomedin-C, cholesterol, triglyceride levels and carried out echocardiographic studies of the following cardiac morpho-functional parameters: left ventricular diameter, volume, mass and wall systolic stress. Serum GH and somatomedin-C levels were significantly higher in acromegalic patients than in controls (p < 0.001 and p < 0.001 respectively). Echocardiography evidenced increased left ventricular mass (60% of the acromegalic patients; p < 0.05) and increased wall systolic stress (53.3%; p < 0.05). Color-Doppler analysis evidenced abnormal diastolic function in 8 acromegalic patients (p < 0.001). We thus conclude that the most characteristic feature of acromegalic heart disease is left ventricular involvement, diastolic dysfunction, increased left ventricular mass or wall systolic stress. The pathogenesis is most probably multifactorial: essential hypertension, associated with slow and progressive evolution of heart disease, appears to be a determining factor.

[Diphosphonates in the treatment of osteoporosis and in the prevention of associated fractures]. / I bifosfonati nel trattamento dell'osteoporosi e nella prevenzione delle fratture correlate.

Diphosphonates are capable to increase vertebral bone mineral mass in postmenopausal osteoporosis. Because the risk of fractures is related to the reduction of bone mass, the positive effect of diphosphonates most probably produced a decrease in fracture rate. At present these drugs represent a rational option for the treatment of postmenopausal osteoporosis.

Iodopropyl-branched polysiloxane gel electrolytes with improved ionic conductivity upon cross-linking.

We here report the implementation of poly[(3-N-methylimidazoliumpropyl)methylsiloxane-co-dimethylsiloxane]iodides as suitable polymeric hosts for a novel class of in situ cross-linkable iodine/iodide-based gel-electrolytes for dye-sensitized solar cells. The polymers are first partially quaternized and then subjected to a thermal cross-linking which allows the formation of a 3D polymeric network which is accompanied by a dramatic enhancement of the ionic conductivity.

[Repeat cesarean section--an analysis of 2,024 cesarean sections]. / Die Resectio--eine Analyse an 2024 Schnittentbindungen.

Based on the data of 2024 Caesarean sections which had been performed at our hospital during 1970-1981 indications, maternal complications and foetal outcome in 385 cases of repeat cesarean deliveries were analysed. In spite of the increasing overall Caesarean section rate, the rate of repeat section remained constant during the observed period. Repeat Caesarean section was more often performed because of maternal than of foetal reasons. Compared to primary Caesarean section, maternal and foetal prognosis proved to be more favourable in repeated procedures. This should be considered in deciding whether repeat Caesarean section should be resorted to or whether normal delivery should be attempted.

[The course of labor in very young and older pregnant patients]. / Geburtsverlauf bei sehr jungen und älteren Gebärenden.

The course of pregnancy and delivery and the fetal outcome were analyzed in 23 women aged less than 16 years and 151 women aged 42 years or more. Most of the adolescent mothers were delivered spontaneously without any major problems. In patients aged 42 years and more there was a higher rate of pregnancy complications due to predisposing risks and a high incidence of prolonged labour, correlated to an increased frequency of operative deliveries and in general more active obstetrical management. Fetal outcome was good in both groups. The results demonstrate the necessity of intensive prenatal care in both groups. Whereas in young gravidae spontaneous delivery can be expected in most cases, the women with advanced maternal age do need an active obstetrical management including all the abilities of modern perinatal medicine. Intensive antenatal and perinatal care provided, the prognosis for mother and child can be estimated as good in both groups.

[Steroid hormone receptors in ovarian carcinomas and their clinical significance]. / Steroidhormon-Rezeptoren beim Ovarialkarzinom und ihre klinische Bedeutung.

Concentrations of estrogen (ER) and progesterone receptors (PR) were determined in 197 malignant tumors of the ovary. The frequency of receptors was the same as in breast cancer (ER 64%, PR 49%). In non-epithelial ovarian carcinomas steroid receptors were found only in granulosa cell tumors. PR was found less often in metastases than in primary tumors and after chemotherapy. Premenopausal tumors were more often PR-positive than postmenopausal carcinomas (71% versus 52%). ER were always constant. PR-negative tumors seemed to respond better to chemotherapy than positive tumors. Patients with PR-negative ovarian carcinomas seem to have a better prognosis than patients with PR-positive cancer. The clinical stage or the histological grade of the tumors did not correlate to the receptor status.

Oestrogen and progesterone receptors in the involuting rat uterus.

The concentrations of cytoplasmic oestrogen and progesterone receptors were measured in rat myometrium during the post partum involution of the uterus. The concentration of the oestrogen receptor declined within 24 h post partum to about 20% of the value at delivery. A slight rise in the concentration occurred during the subsequent 24 h. The concentration of the progesterone receptor remained nearly constant the first day after delivery. Thereafter it decreased just as the concentration of the oestrogen receptor had fallen one day before. The results suggest that the post partum levels of oestrogen and progesterone receptors are regulated by the same mechanisms as those known for the non-pregnant state.

[Cesarean section in multiple pregnancy especially with triplets and quadruplets--preparation and execution]. / "Die Schnittentbindung bei Mehrlingen vor allem bei Drillingen und Vierlingen"--Vorbereitung und Durchführung.

The frequency of multiple pregnancies has increased in perinatal centers during the last years. The result is a rise in perinatal risk. Because of prematurity and abnormal presentations and positions, cesarean section rate is high in this group. This paper discusses the intra- and perioperative problems that may occur in cesarean section of multiple pregnancies, advices are given for perioperative management. In the discussion of surgical techniques, the amnion preserving incision according to Hillemanns is described as a reliable procedure, especially in multiple pregnancies combined with prematurity.

Evidence for Raynaud's syndrome among haemodialyzed patients: influence of flunarizine treatment.

A bloodless study with a Photoplethysmographic test of the limb's blood circulation among haemodialyzed patients with arteriovenous fistula and the influence of Flunarizine treatment was performed. All patients showed a blood reduction flux on the hand with fistulas in front of the controlateral limb. Three patients affected by Raynaud Syndrome were identified. The Flunarizine treatment did not show significative blood flux variations among among those patients with low Photopletysmographic index (P.I.) in the limb with arteriovenous fistula, while a significative increase of P.I. was registered in the limb of the patients affected by Raynaud Syndrome. Concluding, the Photopletysmographic test is useful to follow the limb's blood circulation of haemodialyzed with arterio-venous fistula, being it bloodless, sure and repeteable test to follow the influence of vasoactive therapy.