Widely tunable mid-infrared generation via frequency conversion in semiconductor waveguides.

Phase matching in a multilayer AlGaAs waveguide is used to generate mid-IR (7.5-8.5 µm) light through difference frequency generation (DFG) between a 1550 nm pump and 1950 nm signal. This represents the longest wavelength generated through DFG in a 2D waveguide mode in a semiconductor waveguide. It was produced with an efficiency of 1.2×10(-4) %/W in a 1 mm long sample. The process is shown to be tunable across >2 µm through appropriate tuning of the input pump and signal wavelengths and/or waveguide geometry, and is therefore a viable platform for monolithic, tunable, mid-IR sources.

Aphid feeding behavior in relation to potato virus Y (PVY) acquisition.

Potato virus Y (PVY) is transmitted by aphids in a nonpersistent manner and aphid species differ in their ability to transmit PVY. During host selection, aphids will land and probe on nonhost plant species and this behavior is an important component of the epidemiology of many aphid-transmitted viruses. In this study, we hypothesized that host selection behavior varies between aphid species and the host or nonhost status of the plant and this behavior will modulate their ability to acquire PVY. Three potato colonizers, Myzus persicae (Sulzer), Macrosiphum euphorbiae (Thomas), and Aphis nasturtii (Kaltenbach) and three casual visitors to potato fields, Myzus cerasi (F.), Rhopalosiphum padi (L.), and Sitobion avenae (F.) were evaluated using two acquisition assays. In one assay, the normal host selection and feeding behavior of aphid species were eliminated using an artificial diet while the other considered the normal host selection and feeding behavior of aphid species on potato plants. PVY acquisition rates of aphid species widely differed between the two assays indicating the impact of host selection and feeding behavior on PVY acquisition. This behavior varied greatly between potato colonizers and noncolonizers. We recommend that laboratory evaluations of PVY vector efficiency consider the normal host selection and feeding behavior of aphid species on potatoes.

A new approach for the identification of aphid vectors (Hemiptera: Aphididae) of potato virus Y.

Potato virus Y (PVY) is one of the most economically important viruses affecting potato crops worldwide. PVY can be transmitted from potato to potato by several aphid species, most of which do not colonize the potato crop. New methods including preservation of viral RNA on stylets of aphids collected from yellow pan trap samples, polymerase chain reaction detection of PVY from the stylets of one aphid, and aphid identification using DNA barcoding were used to identify possible PVY vectors from field samples. In total, 65 aphid taxa were identified from the samples that tested positive for PVY. Among those, 45 taxa had never been evaluated for their ability to transmit PVY, and 7 were previously labeled as nonvectors. These results demonstrated that the list of PVY vectors is likely longer than previously reported and that most (if not all) species of aphids could be considered as potential vectors. This premise has important implications in the management of PVY in seed potato production.

Wavelength scaling of high harmonic generation efficiency.

Using longer wavelength laser drivers for high harmonic generation is desirable because the highest extreme ultraviolet frequency scales as the square of the wavelength. Recent numerical studies predict that high harmonic efficiency falls dramatically with increasing wavelength, with a very unfavorable lambda(-(5-6)) scaling. We performed an experimental study of the high harmonic yield over a wavelength range of 800-1850 nm. A thin gas jet was employed to minimize phase matching effects, and the laser intensity and focal spot size were kept constant as the wavelength was changed. Ion yield was simultaneously measured so that the total number of emitting atoms was known. We found that the scaling at constant laser intensity is lambda(-6.3+/-1.1) in Xe and lambda(-6.5+/-1.1) in Kr over the wavelength range of 800-1850 nm, somewhat worse than the theoretical predictions.

Behavior of bird cherry-oat aphid and green peach aphid in relation to potato virus Y transmission.

Potato virus Y is transmitted to potato in a nonpersistent manner by many aphid species, some of which do not colonize this crop. The behavior of bird cherry-oat aphid, Rhopalosiphum padi (L.) on potato, Solanum tuberosum L., a plant species that is not colonized by this aphid, was described and compared with that of the potato-colonizing green peach aphid, Myzuspersicae (Sulzer). A higher proportion of winged morph of R. padi than M. persicae left the plant, but aphids that stayed in contact with the plant took the same mean time to initiate the first probe and it lasted the same mean time compared with M. persicae. Electronic penetration graph technique was used to study the probing behavior of the aphids during Potato virus Y (family Potyviridae, genus Potyvirus, PVY) transmission tests. Transmission rate decreased from 29 to 8% when the acquisition time increased from 5 min of continuous probing to 1 h with M. persicae, but it remained low (2 and 1%) with R. padi. Most of the difference in transmission rate between acquisition time with M. persicae and between aphid species was related to the change in the time and behavior taking place between the last cell puncture of the acquisition phase to the first cell puncture of the inoculation phase. Results presented here clearly demonstrated the importance of host plant selection and probing behavior in the transmission of nonpersistent plant viruses. They also stress the need to consider the behavior of the aphid in the design of laboratory tests of virus vector efficacy.

Effect of itopride on gastric emptying in longstanding diabetes mellitus.

Delayed gastric emptying (GE) occurs in 30-50% of patients with longstanding type 1 or 2 diabetes, and represents a major cause of morbidity. Current therapeutic options are limited. We aimed at evaluating the effects of itopride on GE in patients with longstanding diabetes. Twenty-five patients (20 type 1, 5 type 2; 10 males, 15 females; mean age 45.2 +/- 2.7 years; body mass index 27.5 +/- 0.9 kg m(-2); duration of diabetes 20.2 +/- 2.4 years) were enrolled in a double-blind, placebo-controlled, randomized, crossover trial. Subjects received both itopride (200 mg) and placebo t.i.d. for 7 days, with a washout of 7-14 days. GE (scintigraphy), blood glucose (glucometer) and upper gastrointestinal (GI) symptoms (questionnaire) were measured following each treatment period. The test meal comprised 100 g ground beef (99mTc-sulphur colloid) and 150 mL of 10% dextrose [67Ga-ethylenediaminetetraacetic acid (EDTA)]. There was a slight trend for itopride to accelerate both solid (P = 0.09) and liquid (P = 0.09) GE. With itopride treatment, the emptying of both solids and liquids tended to be more accelerated, as the emptying with placebo was slower (solids: r = 0.39, P = 0.057; liquids: r = 0.44, P < 0.03). Twelve (48%) patients had delayed solid and/or liquid GE on placebo and in this group, itopride modestly accelerated liquid (P < 0.05), but not solid (P = 0.39), emptying. Itopride had no effect on mean blood glucose during the GE measurement (placebo: 9.8 +/- 0.6 mmol L(-1) vs itopride: 9.6 +/-0.6 mmol L(-1)), or GI symptoms (placebo: 1.4 +/- 0.4 vs itopride: 1.8 +/- 0.5). Itopride, in a dose of 200 mg t.i.d. for 7 days, tends to accelerate GE of liquids and solids in longstanding diabetes. The magnitude of this effect appears to be modest and possibly dependent on the rate of GE without itopride.

Itopride in functional dyspepsia: results of two phase III multicentre, randomised, double-blind, placebo-controlled trials.

BACKGROUND: Functional dyspepsia (FD) is a common disorder but there is currently little efficacious drug therapy. Itopride, a prokinetic approved in several countries, showed promising efficacy in FD in a phase IIb trial. The aim of this study was to test the efficacy and safety of this drug in FD. METHODS: Two similar placebo-controlled clinical trials were conducted (International and North America). Males and females, 18-65 years old, with a diagnosis of FD (Rome II) and the absence (by upper endoscopy) of any relevant structural disease were recruited. All were negative for Helicobacter pylori and, if present, heartburn could not exceed one episode per week. Following screening, patients were randomised to itopride 100 mg three times daily or identical placebo. The co-primary end points were: (1) global patient assessment (GPA) of efficacy; and (2) Leeds Dyspepsia Questionnaire (LDQ). Symptoms were evaluated at weeks 2, 4 and 8. Secondary measures of efficacy included Nepean Dyspepsia Index (NDI) quality of life. RESULTS: The GPA responder rates at week 8 on itopride versus placebo were similar in both trials (45.2% vs 45.6% and 37.8 vs 35.4%, respectively; p = NS). A significant benefit of itopride over placebo was observed for the LDQ responders in the International (62% vs 52.7%, p = 0.04) but not the North American trial (46.9% vs 44.8%). The safety and tolerability profile were comparable with placebo, with the exception of prolactin elevations, which occurred more frequently on itopride (18/579) than placebo (1/591). CONCLUSION: In this population with FD, itopride did not show a difference in symptom response from placebo.

A double-blind comparative study of clozapine and risperidone in the management of severe chronic schizophrenia.

OBJECTIVE: This prospective, double-blind, multicenter, parallel-group study compared the efficacy and safety of therapeutic doses of clozapine and risperidone in patients with severe chronic schizophrenia and poor previous treatment response. METHOD: Male or female patients aged 18-65 years who met DSM-IV criteria for schizophrenia and study requirements for poor previous treatment response (N=273) were randomly assigned to double-blind treatment with either clozapine or risperidone administered over 12 weeks in increasing increments. The primary efficacy measures were the magnitude of improvement in Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impression (CGI) scores. Adverse events were recorded throughout the study. RESULTS: The magnitude of improvement in mean BPRS and CGI scores from baseline to end of the study was significantly greater in the clozapine group than in the risperidone group. Statistically significant differences in favor of clozapine were also seen for most of the secondary efficacy measures (Positive and Negative Syndrome Scale, Calgary Depression Scale, Psychotic Depression Scale, and Psychotic Anxiety Scale). The adverse event profile was similar for both treatment groups, with a lower risk of extrapyramidal symptoms in the clozapine group. CONCLUSIONS: Clozapine showed superior efficacy over risperidone in this patient population. Both treatments were equally well tolerated as demonstrated through their adverse event profiles, although as expected clozapine was associated with a lower risk of extrapyramidal symptoms than risperidone.

Family response to difficult hospitalizations: the phenomenon of 'working through'.

This paper describes the process and outcomes of a project to learn about qualitative research methods. A small study of family participation in decision-making was conducted with 7 family members who were interviewed after an inter-unit patient transfer. The data analysis used strategies derived from grounded theory, family life-cycle framework and storytelling. The interviews indicated respondents' concerns about the patient, their efforts to balance their lives during a time of disarray and their sorting through crises in their lives ('working through'). 'Working through' discourse has identifiable features, including: linking the past, present and future; refrains; rhetorical questions; and self-talk. Clinicians should encourage the 'working through' process by family during the hospitalization of a family member.

A rapid reversed phase high performance liquid chromatographic method for the determination of docetaxel (Taxotere) in human plasma using a column switching technique.

A rapid, simple and sensitive isocratic high performance liquid chromatography (HPLC) method was developed to measure the concentration of docetaxel in plasma samples with UV detection at 227 nm. The method uses a column switching technique with an Ultrasphere C18 column (75 x 4.6 mm ID, 3 mu, Altex, USA) as clean-up column and a CSC-nucleosil C8 column (150 x 4.6 mm ID, 5 mu, CSC, Montreal, Canada) as the analytical column. The mobile phase consisted of Phosphate buffer (30 mM, pH = 3)-acetonitrile (47:53, v/v) with the flow rates of 1.1 and 1.3 ml min-1 for clean-up and analytical columns, respectively. Paclitaxel was used as an internal standard. The plasma samples were extracted using a solid phase extraction method with Ammonium acetate (30 mM, pH = 5)-acetonitrile (50:50, v/v) as final eluent. The extraction method showed a recovery of 92% for docetaxel. In this system, the retention times of docetaxel and Paclitaxel were 7.2 and 8.5 min, respectively. The detection limit of docetaxel in plasma is 2.5 ng ml-1. This analytical method has a very good reproducibility (7.2% between-day variability at a concentration of 10 ng ml-1). It is applicable in clinical and pharmacokinetic studies.

Topographic organization of medial pulvinar connections with the prefrontal cortex in the rhesus monkey.

The medial nucleus of the pulvinar complex (PM) has widespread connections with association cortex. We investigated the connections of the PM with the prefrontal cortex (PFC) in macaque monkeys, with tracers placed into the PM and the PFC, respectively. Injections of wheat germ agglutinin-horseradish peroxidase (WGA-HRP) placed into the PM resulted in widespread anterograde terminal labeling in layers III and IV, and retrograde cellular labeling in layer VI of the PFC. Injections of tracers centered on the central/lateral PM resulted in labeling of dorsolateral and orbital regions, whereas injections centered on caudal, medial PM resulted in labeling of dorsomedial and medial PFC. Since injections of the PM included neighboring thalamic nuclei, retrograde tracers were placed into distinct cytoarchitectonic regions of the PFC and retrogradely labeled cells in the posterior thalamus were charted. The results of this series of tracer injections confirmed the results of thalamic injections. Injections placed into areas 8a, 12 (lateral and orbital), 45, 46 and 11, retrogradely labeled neurons in the central/lateral PM, while tracer injections placed into areas 9, 12 (lateral), 10 and 24, labeled medial PM. The connections of the PM with temporal, parietal, insular, and cingulate cortices were also examined. The central/lateral PM has reciprocal connections with posterior parietal areas 7a, 7ip, and 7b, insular cortex, caudal superior temporal sulcus (STS), caudal superior temporal gyrus (STG), and posterior cingulate, whereas medial PM is connected mainly with the anterior STS and STG, as well as the cingulate cortex and the amygdala. These connectional studies suggest that the central/ lateral and medial PM have divergent connections which may be the substrate for distinct functional circuits.

Effects of long-term use of high-dose inhaled steroids on bone density and calcium metabolism.

BACKGROUND: Inhaled steroids are the mainstay in the antiinflammatory treatment of asthma. In the last few years, these agents have been used in increasing doses. Because high doses of inhaled steroids can reduce serum osteocalcin levels, there are concerns regarding their long-term effects on bone metabolism. METHODS: We examined the effects of doses of 800 micrograms/day or greater of beclomethasone or budesonide for more than 18 months in 37 asthmatic subjects (group A), matched to a control group of 37 asthmatic subjects using little or no inhaled steroids (< 500 micrograms, group B). All had a clinical evaluation, measurements of expiratory flows, and determination of serum creatinine, calcium, phosphate, gamma-glutamyl transpeptidase, alkaline phosphatase, cortisol, and osteocalcin levels. A 2-hour urinary sample was obtained for creatinine, calcium, phosphate, hydroxyproline, and cortisol measurements. Bone density was assessed at the lumbar spine level and at the hip with a Hologic-QDR-2000 osteodensitometer (Hologic, Boston, Mass.). RESULTS: The mean (+/- SD) daily dose of inhaled steroids over the last 2 years was 1140 +/- 353 micrograms in group A (mean duration of use of > 800 micrograms/day, 34.2 +/- 13.0 months) and 89 +/- 98 micrograms for group B (mean duration of use of < 500 micrograms/day, 15.7 +/- 18.8 months). The number of oral steroid treatments (< 15 days) during the last 2 years was small in the two groups, 0.92 +/- 1.27 in group A and 0.05 +/- 0.23 in group B (p > 0.05). The only differences between our two groups in terms of serum or urinary parameters were for mean osteocalcin level, which was lower in group A (2.16 +/- 1.09 ng/ml) than in group B (2.70 +/- 0.98 ng/ml) (p = 0.029), and in mean urinary phosphorous level, which was higher in group A (1.44 +/- 0.76 mmol/2 hr) than in group B (1.26 +/- 0.89 mmol/2 hr (p = 0.034). Mean urinary hydroxyproline levels were 15.51 +/- 6.98 mumol/2 hr in group A and 13.53 +/- 7.13 mumol/2 hr in group B (p > 0.05). Mean mineral bone densities of the lumbar spine and hip were similar in the two groups with values of 0.923 +/- 0.136 gm/cm2 and 0.719 +/- 0.147 gm/cm2 in group A and 0.933 +/- 0.154 gm/cm2 and 0.694 +/- 0.095 gm/cm2 in group B (p > 0.05). The T and Z scores for lumbar spine were -1.32 +/- 1.22 and -0.85 +/- 1.02 in group A and -1.19 +/- 1.33 and -0.72 +/- 1.08 in group B (p > 0.05). There was no correlation between the duration or dose of steroid use and bone density or osteocalcin. Although the serum osteocalcin level was lower in the group of subjects using high-dose inhaled steroids, suggesting an osteoblastic depression, bone density was not significantly different compared with the control group. CONCLUSIONS: This study shows that although the serum osteocalcin level was lower and the urinary phosphorus level was higher in subjects using high-dose inhaled steroids for a mean of 34 months, compared with a control group, no significant difference in bone density or other markers of bone metabolism was found between the two groups.

Important prognostic value of standardized objective criteria of response in stage D2 prostatic carcinoma.

One hundred and eighty-six previously untreated patients with clinical stage D2 prostate cancer have been followed according to the criteria of objective response of the National Prostatic Cancer Project (NPCP). All patients received combination therapy with the antiandrogen Flutamide and the LHRH agonist (D-Trp6, des-Gly-NH2(10)]LHRH ethylamide (or surgical castration, 10 patients) as first treatment. Forty-nine patients (26.3%) achieved a complete response as best response while 56 (30.1%) and 69 (37.1%) patients had partial and stable responses, respectively, and only 12 patients (6.5%) did not respond to treatment. The median times required to achieve stable, partial and complete responses were 155, 183 and 401 days, respectively. The best response achieved has a major influence on the probability of continuing response and survival. While the 50% probability of continuing response is more than 3 years for the complete responders, it is reduced to 630 and 517 days for partial and stable responders, respectively. While the non-responders have a median life expectancy of 10.0 months, this value is increased to 30.3 and 37.8 months for the stable and partial responders, respectively. The best probability of survival is for the complete responders with a 95.9% probability of survival at 3 years. There is no significant correlation between the time required to achieve a best response (phase 1) and the duration of the response before progression occurs (phase 2) or the time between progression and death (phase 3) for any of the categories of responses. A longer period of time required to achieve a complete response is associated with a longer survival. When analysis is made, in an attempt to predict response, of the baseline characteristics of the patients before treatment, a low number of bone metastases and better performance status are associated with a greater chance of achieving a complete response while partial, stable and progression responses cannot be predicted from the baseline characteristics. The present data show the importance of standardization of the objective criteria of response to treatment in advanced prostate cancer. Thus, the patients who achieve a complete response have a much more favorable prognosis while partial and stable categories of response have a closely similar prognosis which is inferior to the complete responders. Moreover, the present data indicate that the stable category of response has an important prognostic value which is almost superimposable and not statistically different from the partial response in terms of duration of response and survival.(ABSTRACT TRUNCATED AT 400 WORDS)

Mediodorsal nucleus: areal, laminar, and tangential distribution of afferents and efferents in the frontal lobe of rhesus monkeys.

The terminal distribution of thalamic afferents in primate prefrontal cortex has never been examined in any detail. In the present study, WGA-HRP was injected into major subdivisions of the mediodorsal nucleus (MD) in the rhesus monkey in order to determine 1) The areal distribution of MD projections, 2) the layer(s) in which MD afferents terminate, 3) the tangential pattern of the MD axonal terminals, 4) the cells of origin of the reciprocal corticothalamic pathway, and 5) the degree of reciprocity between the corticothalamic and thalamocortical pathways in the different regions of the prefrontal cortex. As expected on the basis of retrograde degeneration and transport studies, injections centered in the magnocellular (MDmc) subnucleus of MD labeled cells and terminals in the ventral and medial prefrontal cortex. Injections involving ventral MDmc labeled the more lateral of these areas (Walker's areas 11 and 12); injections of the dorsal MDmc labeled the ventromedial regions (areas 13 and 14). In contrast, injections involving mainly the lateral, parvicellular (MDpc) moiety labeled cells and terminals in dorsolateral and dorsomedial areas (Walker's 46, 9, and 8B). Area 8A was labeled most prominently when injections included the multiform portion of MD (MDmf) and area 10 had connections with anterior portions of MD. A dorsal-ventral topography for MDpc exists with dorsal MDpc labeling dorsal and dorsomedial prefrontal areas and ventral MDpc labeling dorsolateral prefrontal cortex. Our findings with respect to MD are consistent with a nucleus-to-field organization of its thalamocortical projection system. Outside of the traditional boundaries of prefrontal cortex, lateral MD projections extended to the supplementary motor area (SMA) and the dorsal part of the anterior cingulate (AC) whereas the medial MD projection targeted the ventromedial cingulate cortex and spared SMA. In addition, a few labeled cells and sparse terminals were found in the inferior parietal lobule, the superior temporal sulcus, and the anterior part of the insula after injections that involved the medial part of MD. Labeled terminals were invariably confined to layer IV and adjacent deep layer III. No terminal label was ever observed in layers I, II, superficial III, V, or VI in any part of the cerebral cortex following injections confined to any part of MD.(ABSTRACT TRUNCATED AT 400 WORDS)

Benefits of combination therapy with flutamide in patients relapsing after castration.

Two hundred and nine patients with biopsy-proven stage D2 prostatic carcinoma showing disease progression after orchiectomy or treatment with DES (stilboestrol) or an LHRH agonist alone received combination therapy with the pure antiandrogen flutamide. In patients treated with DES, the oestrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide. The objective response to therapy was assessed according to the criteria of the US NPCP. Thirteen patients had a complete response to treatment, while partial and stable responses were achieved in 20 and 39 patients respectively (total objective response rate of 34.5%). The mean duration of response was 24 months. In the non-responders the median survival was 8.1 months with a 17% probability of survival at 2 years; the probabilities of survival at 2 years of the patients who showed partial and stable responses were 87 and 67% respectively. All patients who achieved a complete response are still alive. Combination therapy with Flutamide and castration (surgical or LHRH agonist) appears to be the treatment of choice for prostate cancer patients in relapse after standard endocrine therapy.

Combination therapy with flutamide and [D-Trp6]LHRH ethylamide for stage C prostatic carcinoma.

Sixty-seven previously untreated patients presenting with clinical stage C prostatic carcinoma with no evidence of distant metastases received combination therapy using the antiandrogen Flutamide and the LHRH agonist [D-Trp6]LHRH ethylamide for an average duration of treatment of 23.5 months. Only five patients have so far shown treatment failure with 91.8% of the patients still in remission at 2 years. Three patients have died from prostate cancer while three have died from other causes, 93.5% of the patients being alive at 2 years. Local control was achieved rapidly in all except one patient. Urinary obstruction and hydronephrosis were corrected in all cases. When comparing to recent data obtained after single endocrine therapy (orchiectomy or estrogens), or radiotherapy, the rate of treatment failure at 2 years is 3.5-fold lower after combination therapy (8.2%) than monotherapy (28.4%). The death rate at 2 years following start of the combination therapy is 6.5% while it is on average 22.2% (3.4-fold higher) in the studies using monotherapy (orchiectomy or estrogens) or radiotherapy. The present data suggest that treatment of prostate cancer with combination therapy before clinical evidence of dissemination of the disease permits a better response which is possibly explained, at least in part, by the lower degree of dedifferentiation and heterogeneity of the tumors.

Changes in plasma lipoproteins during various androgen suppression therapies in men with prostatic carcinoma: effects of orchiectomy, estrogen, and combination treatment with luteinizing hormone-releasing hormone agonist and flutamide.

Cardiovascular complications are a well recognized side-effect of antihormonal therapy in men with prostatic carcinoma. We studied changes in plasma lipoproteins in patients with prostate cancer during treatment with several androgen suppression therapies. Estrogen, orchiectomy, and a combination of LHRH agonist and antiandrogen (flutamide) reduced plasma testosterone concentrations (89-92%) and plasma estradiol decreased by 85%, 44%, and 54%, respectively. Estrogen induced hypertriglyceridemia and elevation of plasma HDL cholesterol, phospholipid, and apolipoprotein A-I and A-II concentrations. Low density lipoprotein (LDL) cholesterol decreased but LDL apolipoprotein B did not. These results suggest that the cardiovascular complications that occur during estrogen administration are not mediated through changes in lipoprotein profile, other than the hypertriglyceridemic effect. Orchiectomy caused hypercholesterolemia and an increase in both total and LDL apolipoprotein B, all of which are strong determinants of cardiovascular disease. The high density lipoprotein (HDL) concentration was not affected despite a reduction in plasma testosterone, perhaps due to a simultaneous decrease in estradiol. Combination therapy had no effect on plasma lipid and apolipoprotein B concentrations, but very low density lipoprotein (VLDL) apolipoprotein B decreased, and LDL apolipoprotein B increased. The HDL cholesterol and apolipoprotein A-I concentrations increased but A-II and phospholipids did not. These results suggest enhanced lipoprotein lipase activity, consistent with the reciprocal changes in VLDL and LDL apolipoprotein B levels, apolipoprotein B enrichment of LDL particles, and increase in HDL cholesterol. The higher apolipoprotein A-I to A-II ratio indicates an increase in HDL2 subfraction due to inhibition of endothelial hepatic lipase, increased secretion of apolipoprotein A-I, or both. These effects are attributed to estradiol, which decreased less than after orchiectomy, and to additional adrenal androgen inhibition by flutamide. We conclude that estradiol plays an important role in determining plasma lipoprotein concentrations in men, and androgens exert an antagonist effect. The lipoprotein profile resulting from the combination treatment is more beneficial than that resulting from orchiectomy or estrogen administration.

Combination therapy with flutamide and castration (orchiectomy or LHRH agonist): the minimal endocrine therapy in both untreated and previously treated patients with advanced prostate cancer.

One hundred fifty-four patients with clinical stage D2 prostate cancer with no previous endocrine therapy or chemotherapy received the combination therapy with the pure antiandrogen Flutamide and the LHRH agonist [D-Trp]LHRH ethylamide for an average of 22 months (3 to 49). The objective response to the treatment was assessed according to the criteria of the US NPCP. There was a 6.3-fold increase (29.2 versus 4.6%) in the percentage of patients who achieved a complete response as compared to the results achieved in 5 recent studies limited to removal (orchiectomy) or blockade (DES or Leuprolide) of testicular androgens. Only 4.5% of patients did not respond to the combination therapy as compared to an average of 18% by standard therapy. The duration of response is also significantly increased in the patients who received the combination therapy while the death rate was decreased by approximately 2-fold between 2 and 3 years of treatment. The marked (6.3-fold) improvement in the rate of complete objective responses coupled with the 4-fold decrease in the number of non responders, the increased duration of the positive responses and the 2-fold decrease in the death rate at 2 to 3 years of treatment are obtained with the combination therapy using Flutamide and castration with no or minimal secondary effects. In addition, two hundred nine patients with biopsy-proven stage D2 prostatic adenocarcinoma showing disease progression after orchiectomy, DES or an LHRH agonist used alone received the combination therapy with the pure antiandrogen Flutamide. In patients treated with DES, the estrogen was replaced by the LHRH agonist [D-Trp6]LHRH ethylamide. Objective response to therapy was also assessed according to the criteria of the US NPCP. Thirteen patients (6.2%) had a complete response to treatment while partial and stable responses were achieved in 20 (9.6%) and 39 (18.7%) patients, respectively, for a total objective response rate of 34.5%. The mean duration of response was 24 months. While, in the non responders, the median survival was 8.13 months with a 17% probability of survival at 2 years, the probability of survival of patients who showed partial and stable responses at 2 years was 87 and 67%, respectively. All patients who achieved a complete response are still alive. Considering the excellent tolerance coupled with an objective response observed in 34.5% of the patients, the combination therapy with Flutamide and castration (surgical or LHRH agonist) appears to be the treatment of choice for prostate cancer patients in relapse after standard endocrine therapy.