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.

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.

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.

[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.

Evolution of operational research studies and development of a national control strategy against intestinal helminths in Pemba Island, 1988-92.

Intestinal helminthic infections in Pemba Island, United Republic of Tanzania, have been perceived as a public health problem for many decades. School surveys in 1988 and 1992 and a community survey in 1991 were carried out to assess the distribution of prevalence and the intensity of these infections and to define the most effective strategy for control. The prevalence of helminthic infections exceeded 85% in all the surveys, and intensity was moderate. These studies identified the high-risk age groups, high transmission areas for different parasites, and the most cost-effective anthelminthic drug. This work is an example of how existing health systems and simple analytical tools may be used to generate useful data which, in turn, are used to define suitable intervention strategies. As a result, the Ministry of Health of Zanzibar has developed a national plan for the integrated control of intestinal helminths. This plan envisages periodic mass treatment of school-age children with mebendazole (500 mg, single dose, every four months) for the control of morbidity due to Ascaris, Trichuris, and hookworms.

Detection of O6-butyl- and O6-(4-hydroxybutyl)guanine in urothelial and hepatic DNA of rats given the bladder carcinogen N-nitrosobutyl(4-hydroxybutyl)amine.

N-Nitrosobutyl(4-hydroxybutyl)amine (BBN) is a selective bladder carcinogen in rats. Its organ specificity may depend on several factors, including metabolic activation, DNA alkylation and repair within the target organ. Metabolic activation of BBN, which is asymmetrical, may result in butylating and 4-hydroxybutylating species. To test this view, BBN was administered as a single oral dose of 20 or 120 mg/rat or six doses of 20 mg/rat over 2 weeks. The animals given the single 120 mg dose were killed 3, 6 and 24 h after treatment. Rats given 20 mg or 6 x 20 mg BBN were killed 24 h after the last dose. DNA from liver and urothelial cells was hydrolyzed and analyzed for O6-butylguanine (O6-BuG) and O6-(4-hydroxybutyl)guanine [O6-(4-OH-Bu)G] as their pentafluorobenzyl-trimethylsilyl derivatives by high-resolution gas chromatography--negative ion chemical ionization mass spectrometry with selective ion recording after immunoaffinity extraction. Polyclonal antibodies raised against O6-(4-hydroxybutyl)-guanosine [O6-(4-OH-Bu)GR] were coupled to CNBr-activated Sepharose 4B. This was mixed with a gel coupled to antibodies raised against O6-BuG, already available in the laboratory, and the mixed gel was used for the one-step sample clean-up, enrichment and extraction of O6-(4-OH-Bu)G and O6-BuG from hydrolyzed DNA. O6-BuG in urothelial DNA of rats given a single dose of 120 mg BBN increased from 0.44 +/- 0.12 mumol/mol guanine (mean +/- SE) 3 h after treatment, to 17.9 +/- 7.23 mumol/mol guanine at 24 h. O6-(4-OH-Bu)G in the same tissue was 7.7 +/- 3.19 mumol/mol guanine 3 h after treatment and 12.2 +/- 7.01 mumol/mol guanine at 24 h. O6-BuG and O6-(4-OH-Bu)G were always lower in the liver than in urothelial cells. Twenty-four hours after a single dose of 20 mg BBN, urothelial O6-BuG was 5.41 +/- 1.73 mumol/mol guanine and did not accumulate after six doses of 20 mg/rat BBN, since it was 2.59 +/- 1.23 mumol/mol guanine 24 h after the last dose. O6-BuG in liver DNA was detectable after the single dose of 20 mg, but not after 6 x 20 mg/rat BBN. O6-(4-OH-Bu)G was not detected in either the bladder or the liver after 20 mg or after the six doses of BBN.(ABSTRACT TRUNCATED AT 400 WORDS)

[The pubococcygeus patch--a method for correction of female stress incontinence in simultaneous prolapse]. / Der Pubococcygeus-Patch--eine Methode zur Korrektur der weiblichen Stressinkontinenz bei gleichzeitig bestehendem Deszensus.

The pubococcygeus patch procedure is introduced as a vaginal method for treatment of severe stress urinary incontinence of the female in combination with a marked descensus requiring vaginal surgery. It is based on physiological conceptions of urethral closure mechanisms. The primary success rate in 47 women with severe stress-urinary incontinence was 85% after 3-6 months, and 60% in women with hypotonic urethra (< 30 cm H2O). The complication rate was low. The material used for the patch was lyodura (n = 43) and gore-tex (n = 4), the latter showing a 50% repulsion rate.

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.

[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.

[Obstetric pelvimetry using nuclear magnetic resonance tomography (MRI): clinical experiences with 150 patients]. / Geburtshilfliche Beckenmessung mittels Kernspintomographie (MRI): Klinische Erfahrungen bei 150 Patientinnen.

Between Oct. 1987 and Oct. 1991 150 patients of the Frauenklinik Freiburg were examined by MR pelvimetry (MRI), 135 of which were "ante partum", i.e. just before delivery. The indications were: earlier operative or strongly protracted delivery, clinical suspicion of disproportion between head and pelvis, or obstetrical "problem pelvis" indicated by manual pelvic examination or ultrasonic foetometry. Previous experimental measurements with a phantom and the comparison with conventional radiograms by Guthmann and Martius of 10 patients in puerperium have shown, that the mean divergence was +/- 2 mm, the maximum divergence 5 mm. The MRI method for pelvimetry "ante partum" or in childbed, proved to be a method of high accuracy and a very good option to judge the pelvic shape, whilst being well accepted by the patients. Furthermore, it allows to determine the foetal BIP (biparietal head-diameter), to judge the pelvic soft-tissue, as well as the visualisation of the birth canal, all without any exposure to radiation. MR pelvimetry is thus part of today's clinical routine. The disadvantages are still the high costs as well as the fact, that only few centres have access to MRI equipment. Nevertheless, the pelvimetry "post partum" can be safely practised radiologically due to the very low radiation exposure.

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.

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.

[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.

[Effect of stress incontinence surgery on urodynamic parameters. 2. Are various surgical methods comparable?]. / Der Einfluss von Stresstinkontinenzoperationen auf urodynamische Parameter. 2. Teil: Sind unterschiedliche Operationsmethoden vergleichbar?

This study examines the pre- and postoperative clinical data of 215 women operated on during 1983-87 at the University Hospital of Freiburg for stress incontinence. The following procedures were used: Anterior colporrhaphy (n = 27), anterior colporrhaphy in combination with a ventral levator plasty (n = 61), sling procedure with the Lyodura sling (n = 44), and a colposuspension within the total abdominal concept (n = 83). All the procedures, with the exception of anterior colporrhaphy, were followed by a decrease in maximum urethral pressure. The functional urethral length was not changed by any of the methods. Colposuspension showed a marked postoperative improvement of urethral stress profile parameters in the proximal and midurethra, the sling had a steep, unphysiological increase of pressure transmission ratio in the proximal urethra. The vaginal methods did not improve pressure transmission to the proximal section of the urethra, their effect was only measurable in the mid section. The urodynamic effects of different types of surgery were very individual, a fact which may be helpful in the selection of the surgical approach.