Ultra-low-dose estradiol and dydrogesterone for treatment of vasomotor symptoms in Europe and China.

OBJECTIVE: Among postmenopausal women, oral, ultra-low-dose continuous combined estradiol (E0.5 mg) plus dydrogesterone (D2.5 mg) reduces vasomotor symptoms (VMS). METHODS: This study was a post hoc analysis of data from two phase 3, double-blind studies. Postmenopausal women were randomized 2:1:2 to receive E0.5 mg/D2.5 mg, E1 mg/D5 mg (not included in this analysis) or placebo for 13 weeks (European study), or randomized 1:1 to receive E0.5 mg/D2.5 mg or placebo for 12 weeks (Chinese study). Endpoints assessed in ethnicity subgroups (European and Chinese) included changes from baseline in number of hot flushes, number of moderate-to-severe hot flushes and Menopause Rating Scale (MRS) score. RESULTS: Overall, 579 women were included in the analysis (E0.5 mg/D2.5 mg, n = 288; placebo, n = 291). European and Chinese women receiving E0.5 mg/D2.5 mg experienced greater reductions from baseline in mean daily number of hot flushes and mean daily number of moderate-to-severe hot flushes at week 4, week 8 and end of treatment versus those receiving placebo. Significant improvements in the 'hot flushes, sweating' MRS item score were reported in both European and Chinese women. CONCLUSION: Oral, ultra-low-dose continuous combined 0.5 mg 17ß-estradiol and 2.5 mg dydrogesterone improved VMS compared with placebo in European and Chinese postmenopausal women, with a positive impact on health-related quality of life.

Ultra-low-dose continuous combined estradiol and dydrogesterone in postmenopausal women: A pooled safety and tolerability analysis.

Objective: To assess the safety and tolerability of ultra-low dose estradiol and dydrogesterone (E0.5 mg/D2.5 mg) among postmenopausal women. Methods: This pooled analysis of data from three clinical studies assessed the effects of continuous combined ultra-low-dose estradiol and dydrogesterone among postmenopausal women. Participants received E0.5 mg/D2.5 mg or placebo for 13 weeks (double-blind, randomized, European study), E0.5 mg/D2.5 mg or placebo for 12 weeks (double-blind, randomized, Chinese study), or E0.5 mg/D2.5 mg for 52 weeks (open-label, European study). Safety outcomes included treatment-emergent adverse events (TEAEs), treatment-emergent serious adverse events (TESAEs), treatment discontinuation due to a TEAE, and adverse events of special interest (AESIs). Results: Overall, 1027 women were included in the pooled analysis (E0.5 mg/D2.5 mg, n = 736; placebo, n = 291). Mean treatment exposure was 288.9 days in the E0.5 mg/D2.5 mg group and 86.6 days in the placebo group. The proportion of women experiencing ≥1 TEAE was similar in the E0.5 mg/D2.5 mg and placebo groups (50.1% vs 49.5%, respectively). TESAEs occurred in 12 (1.6%) women receiving E0.5 mg/D2.5 mg and 9 (3.1%) women receiving placebo. Discontinuation of study treatment was infrequent in both groups (E0.5 mg/D2.5 mg: 1.5%; placebo: 2.4%). The occurrence of breast pain was more common in the E0.5 mg/D2.5 mg group than in the placebo group (2.0% vs 0.3%) as was uterine hemorrhage (6.5% vs 2.4%). The incidence of acne, hypertrichoses and weight increased was similar between groups. Conclusions: Across three studies, ultra-low-dose estradiol plus dydrogesterone was well tolerated among postmenopausal women, with no increase in TEAEs or TESAEs compared with placebo.

A Phase III randomized controlled trial of oral dydrogesterone versus intravaginal progesterone gel for luteal phase support in in vitro fertilization (Lotus II): results from the Chinese mainland subpopulation.

Lotus II, a randomized, open-label, multicenter, international study compared the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) gel for luteal support in IVF. A prespecified subgroup analysis was performed on 239 Chinese mainland subjects from the overall study population (n = 1034), who were randomized to oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily from the day of oocyte retrieval until 12 weeks of gestation. The aim was to demonstrate non-inferiority of oral dydrogesterone to MVP gel, assessed by the presence of a fetal heartbeat at 12 weeks of gestation. In the Chinese mainland subpopulation, there was a numerical difference of 9.4% in favor of oral dydrogesterone, with ongoing pregnancy rates at 12 weeks of gestation of 61.4% and 51.9% in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 9.4%; 95% CI: -3.4 to 22.1); in the overall population, these were 38.7% and 35%, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). In both the Chinese mainland subpopulation and the overall population, dydrogesterone had similar efficacy and safety to MVP gel. With convenient oral administration, dydrogesterone has potential to transform luteal support treatment.

Oral dydrogesterone versus intravaginal micronized progesterone gel for luteal phase support in IVF: a randomized clinical trial.

STUDY QUESTION: Is oral dydrogesterone 30 mg daily non-inferior to 8% micronized vaginal progesterone (MVP) gel 90 mg daily for luteal phase support in IVF? SUMMARY ANSWER: Oral dydrogesterone demonstrated non-inferiority to MVP gel for the presence of fetal heartbeats at 12 weeks of gestation (non-inferiority margin 10%). WHAT IS KNOWN ALREADY: The standard of care for luteal phase support in IVF is the use of MVP; however, it is associated with vaginal irritation, discharge and poor patient compliance. Oral dydrogesterone may replace MVP as the standard of care if it is found to be efficacious with an acceptable safety profile. STUDY DESIGN, SIZE, DURATION: Lotus II was a randomized, open-label, multicenter, Phase III, non-inferiority study conducted at 37 IVF centers in 10 countries worldwide, from August 2015 until May 2017. In total, 1034 premenopausal women (>18 to <42 years of age) undergoing IVF were randomized 1:1 (stratified by country and age group), using an Interactive Web Response System, to receive oral dydrogesterone 30 mg or 8% MVP gel 90 mg daily. PARTICIPANTS/MATERIALS, SETTING, METHODS: Subjects received either oral dydrogesterone (n = 520) or MVP gel (n = 514) on the day of oocyte retrieval, and luteal phase support continued until 12 weeks of gestation. The primary outcome measure was the presence of fetal heartbeats at 12 weeks of gestation, as determined by transvaginal ultrasound. MAIN RESULTS AND THE ROLE OF CHANCE: Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates in the full analysis sample (FAS) at 12 weeks of gestation of 38.7% (191/494) and 35.0% (171/489) in the oral dydrogesterone and MVP gel groups, respectively (adjusted difference, 3.7%; 95% CI: -2.3 to 9.7). Live birth rates in the FAS of 34.4% (170/494) and 32.5% (159/489) were obtained for the oral dydrogesterone and MVP gel groups, respectively (adjusted difference 1.9%; 95% CI: -4.0 to 7.8). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP gel. LIMITATIONS, REASONS FOR CAUTION: The analysis of the results was powered to consider the ongoing pregnancy rate, but a primary objective of greater clinical interest may have been the live birth rate. This study was open-label as it was not technically feasible to make a placebo applicator for MVP gel, which may have increased the risk of bias for the subjective endpoints reported in this study. While the use of oral dydrogesterone in fresh-cycle IVF was investigated in this study, further research is needed to investigate its efficacy in programmed frozen-thawed cycles where corpora lutea do not exist. WIDER IMPLICATIONS OF THE FINDINGS: This study demonstrates that oral dydrogesterone is a viable alternative to MVP gel, due to its comparable efficacy and tolerability profiles. Owing to its patient-friendly oral administration route, dydrogesterone may replace MVP as the standard of care for luteal phase support in fresh-cycle IVF. STUDY FUNDING/COMPETING INTERESTS(S): This study was sponsored and supported by Abbott. G.G. has received investigator fees from Abbott during the conduct of the study. Outside of this submitted work, G.G. has received non-financial support from MSD, Ferring, Merck-Serono, IBSA, Finox, TEVA, Glycotope and Gedeon Richter, as well as personal fees from MSD, Ferring, Merck-Serono, IBSA, Finox, TEVA, Glycotope, VitroLife, NMC Healthcare, ReprodWissen, Biosilu, Gedeon Richter and ZIVA. C.B. is the President of the Belgian Society of Reproductive Medicine (unpaid) and Section Editor of Reproductive BioMedicine Online. C.B. has received grants from Ferring Pharmaceuticals, participated in an MSD sponsored trial, and has received payment from Ferring, MSD, Biomérieux, Abbott and Merck for lectures. G.S. has no conflicts of interest to be declared. A.P. is the General Secretary of the Indian Society of Assisted Reproduction (2017-2018). B.D. is President of Pune Obstetric and Gynecological Society (2017-2018). D.-Z.Y. has no conflicts of interest to be declared. Z.-J.C. has no conflicts of interest to be declared. E.K. is an employee of Abbott Laboratories GmbH, Hannover, Germany and owns shares in Abbott. C.P.-F. is an employee of Abbott GmbH & Co. KG, Wiesbaden, Germany and owns shares in Abbott. H.T.'s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, Origio, Besins, Ferring and Mithra (now Allergan); and H.T. has received consultancy fees from Finox-Gedeon Richter, Merck, Ferring, Abbott and ObsEva. TRIAL REGISTRATION NUMBER: NCT02491437 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 08 July 2015. DATE OF FIRST PATIENT'S ENROLLMENT: 17 August 2015.

A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization.

STUDY QUESTION: Is oral dydrogesterone 30 mg daily (10 mg three times daily [TID]) non-inferior to micronized vaginal progesterone (MVP) 600 mg daily (200 mg TID) for luteal support in in vitro fertilization (IVF), assessed by the presence of fetal heartbeats determined by transvaginal ultrasound at 12 weeks of gestation? SUMMARY ANSWER: Non-inferiority of oral dydrogesterone versus MVP was demonstrated at 12 weeks of gestation, with a difference in pregnancy rate and an associated confidence interval (CI) that were both within the non-inferiority margin. WHAT IS KNOWN ALREADY: MVP is routinely used in most clinics for luteal support in IVF, but it is associated with side effects, such as vaginal irritation and discharge, as well as poor patient acceptance. Dydrogesterone may be an alternative treatment due to its patient-friendly oral administration. STUDY DESIGN, SIZE, DURATION: Lotus I was an international Phase III randomized controlled trial, performed across 38 sites, from August 2013 to March 2016. Subjects were premenopausal women (>18 to <42 years of age; body mass index (BMI) ≥18 to ≤30 kg/m2) with a documented history of infertility who were planning to undergo IVF. A centralized electronic system was used for randomization, and the study investigators, sponsor's study team, and subjects remained blinded throughout the study. PARTICIPANTS/MATERIALS, SETTING, METHODS: In total, 1031 subjects were randomized to receive either oral dydrogesterone (n = 520) or MVP (n = 511). Luteal support was started on the day of oocyte retrieval and continued until 12 weeks of gestation (Week 10), if a positive pregnancy test was obtained at 2 weeks after embryo transfer. MAIN RESULTS AND THE ROLE OF CHANCE: In the full analysis set (FAS), 497 and 477 subjects in the oral dydrogesterone and MVP groups, respectively, had an embryo transfer. Non-inferiority of oral dydrogesterone was demonstrated, with pregnancy rates at 12 weeks of gestation of 37.6% and 33.1% in the oral dydrogesterone and MVP treatment groups, respectively (difference 4.7%; 95% CI: -1.2-10.6%). Live birth rates of 34.6% (172 mothers with 213 newborns) and 29.8% (142 mothers with 158 newborns) were obtained in the dydrogesterone and MVP groups, respectively (difference 4.9%; 95% CI: -0.8-10.7%). Oral dydrogesterone was well tolerated and had a similar safety profile to MVP. LIMITATIONS, REASONS FOR CAUTION: The analysis of the results was powered to consider the clinical pregnancy rate, but the live birth rate may be of greater clinical interest. Conclusions relating to the differences between treatments in live birth rate, observed in this study, should therefore be made with caution. WIDER IMPLICATIONS OF THE FINDINGS: Oral dydrogesterone may replace MVP as the standard of care for luteal phase support in IVF, owing to the oral route being more patient-friendly than intravaginal administration, as well as it being a well tolerated and efficacious treatment. STUDY FUNDING/COMPETING INTEREST(S): Sponsored and supported by Abbott Established Pharmaceuticals Division. H.T.'s institution has received grants from Merck, MSD, Goodlife, Cook, Roche, Besins, Ferring and Mithra (now Allergan) and H.T. has received consultancy fees from Finox, Ferring, Abbott, ObsEva and Ovascience. G.S. has nothing to disclose. E.K. is an employee of Abbott GmbH. G.G. has received investigator fees from Abbott during the conduct of the study; outside of this submitted work, G.G. has received personal fees and non-financial support from MSD, Ferring, Merck-Serono, Finox, TEVA, Glycotope, as well as personal fees from VitroLife, NMC Healthcare LLC, ReprodWissen LLC and ZIVA LLC. TRIAL REGISTRATION NUMBER: NCT01850030 (clinicaltrials.gov). TRIAL REGISTRATION DATE: 19 April 2013. DATE OF FIRST PATIENT'S ENROLLMENT: 23 August 2013.

Dydrogesterone metabolism in human liver by aldo-keto reductases and cytochrome P450 enzymes.

1. The metabolism of dydrogesterone was investigated in human liver cytosol (HLC) and human liver microsomes (HLM). Enzymes involved in dydrogesterone metabolism were identified and their relative contributions were estimated. 2. Dydrogesterone clearance was clearly higher in HLC compared to HLM. The major active metabolite 20α-dihydrodydrogesterone (20α-DHD) was only produced in HLC. 3. The formation of 20α-DHD by cytosolic aldo-keto reductase 1C (AKR1C) was confirmed with isoenzyme-specific AKR inhibitors. 4. Using recombinantly expressed human cytochrome P450 (CYP) isoenzymes, dydrogesterone was shown to be metabolically transformed by CYP3A4 and CYP2C19. 5. A clear contribution of CYP3A4 to microsomal metabolism of dydrogesterone was demonstrated with HLM and isoenzyme-specific CYP inhibitors, and confirmed by a significant correlation between dydrogesterone clearance and CYP3A4 activity. 6. Contribution of CYP2C19 was shown to be clearly less than CYP3A4 and restricted to a small group of human individuals with very high CYP2C19 activity. Therefore, it is expected that CYP2C19 genetic variations will not affect dydrogesterone pharmacokinetics in man. 7. In conclusion, dydrogesterone metabolism in the liver is dominated primarily by cytosolic enzymes (particularly AKR1C) and secondarily by CYP3A4, with the former exclusively responsible for 20α-DHD formation.

Treatment of Chinese Patients with Hypertriglyceridemia with a Pharmaceutical-Grade Preparation of Highly Purified Omega-3 Polyunsaturated Fatty Acid Ethyl Esters: Main Results of a Randomized, Double-Blind, Controlled Trial.

INTRODUCTION: The lipid-modifying potential of omega-3 polyunsaturated fatty acids in Chinese patients is under-researched. We conducted a multicenter, randomized, placebo-controlled, double-blind, parallel-group study of twice-daily treatment with OMACOR (OM3EE), a prescription-only formulation of highly purified ethyl esters of omega-3 polyunsaturated fatty acids in Chinese adult patients (≥18 years) who had elevated baseline fasting serum triglycerides (TG). METHODS: Patients were stratified according to the severity of their hypertriglyceridemia (severe HTG, with baseline TG ≥500 and <1000 mg/dL or moderate HTG, with baseline TG >200 and <500 mg/dL) or use of statins. Patients randomized to OM3EE therapy received 2 g/day for 4 weeks, then 4 g/day for 8 weeks. The primary efficacy endpoint was the percentage change in fasting serum TG between baseline and the end of treatment in patients with severe HTG. The study was concluded after a planned interim analysis demonstrated a significant TG-lowering effect of OM3EE in that contingent (p=0.0019). RESULTS: The mean TG end-of-treatment effect of OM3EE was -29.46% (standard deviation 40.60%) in the severe HTG contingent compared with +0.26% (standard deviation 54.68%) in the placebo group. Corresponding changes were -12.12% and -23.25% in the moderate HTG and combination cohorts (vs +55.45% and +6.24% in relevant placebo groups). A dose-dependent reduction in TG was evident in all patient contingents. Safety and tolerability of OM3EE were in line with previous experience. DISCUSSION: These data indicate that OMACOR therapy at a dose of 2-4 g/day is an effective treatment for Chinese patients with raised TG levels and is well tolerated.

Dydrogesterone as an oral alternative to vaginal progesterone for IVF luteal phase support: A systematic review and individual participant data meta-analysis.

The aim of this systematic review and meta-analysis was to conduct a comprehensive assessment of the evidence on the efficacy and safety of oral dydrogesterone versus micronized vaginal progesterone (MVP) for luteal phase support. Embase and MEDLINE were searched for studies that evaluated the effect of luteal phase support with daily administration of oral dydrogesterone (20 to 40 mg) versus MVP capsules (600 to 800 mg) or gel (90 mg) on pregnancy or live birth rates in women undergoing fresh-cycle IVF (protocol registered at PROSPERO [CRD42018105949]). Individual participant data (IPD) were extracted for the primary analysis where available and aggregate data were extracted for the secondary analysis. Nine studies were eligible for inclusion; two studies had suitable IPD (full analysis sample: n = 1957). In the meta-analysis of IPD, oral dydrogesterone was associated with a significantly higher chance of ongoing pregnancy at 12 weeks of gestation (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.08 to 1.61; P = 0.0075) and live birth (OR, 1.28; 95% CI, 1.04 to 1.57; P = 0.0214) compared to MVP. A meta-analysis combining IPD and aggregate data for all nine studies also demonstrated a statistically significant difference between oral dydrogesterone and MVP (pregnancy: OR, 1.16; 95% CI, 1.01 to 1.34; P = 0.04; live birth: OR, 1.19; 95% CI, 1.03 to 1.38; P = 0.02). Safety parameters were similar between the two groups. Collectively, this study indicates that a higher pregnancy rate and live birth rate may be obtained in women receiving oral dydrogesterone versus MVP for luteal phase support.

A parametric analysis of ordinal quality-of-life data can lead to erroneous results.

OBJECTIVE: Measurements from health-related quality-of-life (HRQoL) studies, although usually of an ordered categorical nature, are typically treated as continuous variables, allowing the calculation of mean values and the administration of parametric statistics, such as t-tests. We investigated whether parametric, compared to nonparametric, analyses of ordered categorical data may lead to different conclusions. STUDY DESIGN AND SETTING: HRQoL data were obtained from patients with a diagnosis of asthma (n=192) and chronic obstructive pulmonary disease (COPD; n=88) at two time points. The impact of the group factor (asthma vs. COPD) and the time factor (t1 vs. t2) on HRQoL was analyzed with a metric approach (repeated measures ANOVA) and two ordinal approaches (each with a nonparametric repeated measures ANOVA). RESULTS: Using the metric approach, a significant effect of "group" (P=0.0061) and "time" (P=0.0049) on HRQoL was found. The first ordinal approach (ranked total score) still showed a significant effect for "group" (P=0.0033) with a worse HRQoL for patients suffering from COPD. In the second approach (ranks for each HRQoL item and summed ranks), there were no significant effects. CONCLUSION: Applying simple parametric methods to ordered categorical HRQoL scores led to different results from those obtained with nonparametric methods. In these cases, an ordinal approach will prevent inappropriate conclusions.

Protein adsorption during LDL-apheresis: proteomic analysis.

BACKGROUND: The aim of our study was to investigate the clearance of functional proteins by different low-density lipoprotein-apheresis (LDL-A) methods with the help of proteomic analyses. METHODS: Proteins were eluated from the different LDL-A columns and investigated with 2D electrophoresis combined with mass spectrometry methods. In parallel, we quantified the plasma protein loss from patients treated with double-filtration plasmapheresis (DFPP; n = 9), direct adsorption of lipoproteins (DALI; n = 5) or heparin-induced extracorporeal LDL precipitation (HELP; n = 7) with routine laboratory methods and western blots. RESULTS: Proteomic analyses of the column-bound proteins revealed a column-type-dependent loss with the highest number of protein spots in DALI-treated patients (1001 +/- 36), followed by HELP (881 +/- 25) and DFPP (535 +/- 20). More than 70 functional proteins were identified. These proteins are involved in the coagulation pathway (e.g. kininogen1) and have adhesive (e.g. fibronectin), rheological (e.g. fibrinogen) and immunological/inflammatory properties (e.g. complement components). Quantification with western blot analyses demonstrated a significant depletion (P < 0.01) of these proteins comparing serum samples before and after the column with a systemic lowering in patients' serum. CONCLUSIONS: These data reveal strong interaction between column and serum proteins during LDL-A. The clearance of proteins with adhesive, rheological, and inflammatory characteristics may have beneficial effects on microcirculation and reduce chronic inflammation but may also concomitantly induce side effects such as an increased bleeding risk.

Effect of bleaching on subsurface micro-hardness of composite and a polyacid modified composite.

OBJECTIVE: To investigate the influence of different bleaching techniques on subsurface physical properties of composite and polyacid modified composite tested via determination of micro-hardness. METHODS: Specimens of Tetric Flow, Tetric EvoCeram and Compoglass were light cured (2.5mm thickness) and stored in artificial saliva for 2 weeks (n=12/group). The samples were only removed for application of the following bleaching agents in a humid atmosphere: Either Vivastyle (1h/d), Whitestrips (30min/d), sodium-perborate-water mixture (once for 72h), Simply White (1h/d), or Opalescence XtraBoost (1st and 5th day for 15min) were applied on the surfaces of the samples. Untreated specimens served as negative controls, samples treated with ethyl alcohol for 1h acted as positive controls. After the bleaching period, samples were cross-sectioned and the micro-hardness (Knoop) of different subsurface levels (0.1mm-2.0mm) was determined. RESULTS: All bleaching techniques significantly reduced the Knoop-hardness of the restoratives compared to untreated controls. Thereby, bleaching significantly affected not only superficial but also the deep layers of the specimens: in superficial layers (0.1mm, 0.2mm) lowest micro-hardness values amounted to 69.5% and 76.3% of the respective untreated controls (Compoglass/Vivastyle). In deeper subsurface levels, the lowest hardness was observed with Opalescence/Tetric EvoCeram (0.3mm: 78.3%; 0.4mm: 80%; 0.5mm: 80.5%; 1.0mm: 84.2%; 2.0mm: 84.4%). SIGNIFICANCE: Bleaching with the tested bleaching agents softens the adhesive restorative materials examined. Due to the fact that subsurface layers are also affected, polishing of the surface may not suffice for re-establishing the physical properties of the surface of the fillings.

Long-term follow-up after transoral laser microsurgery and adjuvant radiotherapy for advanced recurrent squamous cell carcinoma of the head and neck.

PURPOSE: The aim of this study was to evaluate the efficacy of adjuvant radiotherapy after transoral laser microsurgery for advanced recurrent head-and-neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Between 1988 and 2000, 37 patients with advanced local recurrences (23 local and 14 locoregional recurrences) of HNSCC without distant metastases were treated in curative intent with organ-preserving transoral laser microsurgery and adjuvant radiotherapy (before 1994 split-course radiotherapy with carboplatinum, after 1994 conventional radiotherapy). Initial therapy of the primary (8.1% oral cavity, 35.1% oropharynx, 13.5% hypopharynx, and 43.3% larynx) before relapse was organ-preserving transoral laser microsurgery without any adjuvant therapy. RESULTS: After a median follow-up of 124 months, the 5-year overall survival rate was 21.3%, the loco-regional control rate 48.3%, respectively. In multivariate analysis, stage of original primary tumor (Stage I/II vs. Stage III/IV), and patient age (<58 years vs. >or=58 years) showed statistically significant impact on prognosis. In laryngeal cancer, larynx preservation rate after treatment for recurrent tumor was 50% during follow-up. CONCLUSION: Our data show that organ-preserving transoral laser microsurgery followed by adjuvant radiotherapy is a curative option for patients who have advanced recurrence after transoral laser surgery and is an alternative to radical treatment.

Assessment of molecular events in squamous and non-squamous cell lung carcinoma.

Although considerable knowledge exists on the tumor biology of lung cancer, there is still a need to assess molecular events for the clinical management of the disease. We studied the pattern of chromosomal imbalances in 45 non-small cell lung carcinomas (NSCLC) by comparative genomic hybridization (CGH) and correlated the results with clinicopathological features including immunohistochemical (IHC) expression of the epidermal growth factor receptor (EGFR). Twenty-one tumors were squamous cell carcinomas (SCC) and 24 non-squamous cell lung carcinomas (NSCC) comprising 9 adenocarcinomas (ADC), 9 large cell carcinomas (LCC), 4 sarcomatoid carcinomas and 2 adenosquamous carcinomas. The mean number of individual imbalances was 7.1 for SCC (mean gains, 3.8; mean losses, 3.4) and 6.4 for NSCC (mean gains, 4.5; mean losses, 1.9). Several individual imbalances correlated significantly with increasing number of imbalances, that were +1q, -3p, +3q, -5q, -8p, +8q, +7p, +12p, and +14q. Altogether, the most frequent imbalances were +3q (49%), +5p (49%), -5q (36%), +8q (29%), -8p (24%), -3p (22%), +7p (22%), +12p (22%), +14q (20%), +18p (20%), +1q (18%), and +7q (18%). Among these, +3q and +18p correlated significantly with SCC, and +5p and +14q with NSCC. Remarkably, overlapping imbalances included +3q26, +7p11 in SCC and +1q21, +3q24, +12p11, and +14q12 in NSCC. EGFR expression was higher in SCC than in NSCC and correlated with +3q in the entire series. In addition, +12p correlated significantly with disease progress with the exception of nodal involvement in NSCC as well as with disease progress, regardless of nodal involvement, in the entire series. In conclusion, the present study contributes to the molecular biological characterization of NSCLC histological subtypes and through evaluation of molecular events to the recently emergent focus on novel markers for lung cancer treatment.

Changes of microvascular perfusion during acute ureteral obstruction in the rat kidney - the influence of gastrin releasing peptide.

INTRODUCTION: Peritubular renal microcirculation has not been directly visualized in acute ureteral obstruction. Therefore, we used epiilluminescence intravital microscopy and an animal model for the assessment of microvascular perfusion. MATERIALS AND METHODS: In group 1 (n = 5) the left kidney of Wistar rats was exteriorized and placed on a heatable stage for microcirculatory analysis. FITC-dextran was injected for plasma staining. Microcirculatory stability of the model was assessed by a repeated intravital microscopy at baseline, 60, and 120 minutes. In detail, the functional peritubular vessel density (FVD, total vessel length per area in cm/cm(2)), the red blood cell velocities and diameters in/of arterioles and peritubular capillaries and the perfusion index were measured. In group 2 (n = 7) the left ureter was obstructed after baseline microscopy. In a third group (n = 6) the influence of the antidiuretic and vasoconstrictive peptide gastrin releasing peptide on peritubular microcirculation of the obstructed kidney was measured. RESULTS: Repeated intravital microscopy did not induce major microcirculatory disturbances in group 1. Acute ureteral obstruction significantly decreased the index of peritubular perfusion. Moreover, FVD was found decreased at 120 minutes after a small rise at 60 minutes. Whereas blood cell velocities were not changed, arteriolar diameters were decreased after 120 minutes. GRP infusion lowered intrapelvic pressures at 60 and at 120 minutes. The transient increase of FVD (group 2) was not observed. The calculated peritubular flow remained nearly constant compared to a decrease in group 2. Histological assessment did not reveal any microscopy induced renal damage nor any differences between the groups. CONCLUSIONS: (1) The model is stable for a time period of at least 120 minutes and allows for the direct visualization of the renal peritubular vessels. (2) Peritubular microcirculation shows a significant deterioration during ureteral obstruction. (3) Infusion of GRP may be beneficial for the microcirculation of the acutely obstructed kidney.

Influence of bleaching agents and desensitizing varnishes on the water content of dentin.

This in vitro study investigated the possible dehydration of dentin caused by bleaching agents. Furthermore, it tested whether protective dentin varnishes can maintain the physiological moisture of dentin during bleaching treatment. Fifty-five standardized dentin cylinders were prepared from freshly extracted bovine incisors under constant water irrigation. Prior to bleaching, the treatment specimens were conditioned at room temperature in a hygrophor for 14 days. The samples were divided into 11 groups. The Group A specimens, which were completely dehydrated, and Group B, which was stored for 2 weeks in a hygrophor, served as controls (A, B n=5). The other samples (n=10 each group) were coated with Vivasens [VS] (C), Bilfuorid [BF] (D) and Seal&Protect [SP] (E). Five specimens from each group (C-E) were subsequently treated with an experimental bleaching gel (Exp BG) (20% carbamide peroxide [CP], glycerine-based gel): Cb, Db, Eb. The remaining specimens were bleached with Exp BG (F) only, Vivastyle (G: 16% CP, glycerine-based gel) or Vivastyle Paint On (H: 6% CP-varnish) for 7 days (n=5 each group) with bleaching time for gels: 2 hours/day, paint on: 20 minutes/day. After the respective treatments, the overall water content of each specimen was determined using the analytical method of Karl-Fischer-titration. The water content of bovine dentin (Group B, mean%+/-SD) obtained in this study amounted to 15.24+/-0.4. All bleaching products significantly reduced the water content compared to the controls (exp BG: 13.32+/-0.47, Vivastyle 13.2+/-0.27, paint on 13.72+/-0.54; p<0.05). Also, application of SP before bleaching resulted in reduced water content (14.06+/-0.12; p=0.0005). However, bleaching with exp BG following use of VS (14.99+/-0.42) or SP (13.85+/-0.26) did not result in a reduction of water content in dentin. Pretreatment with BF did not protect dentin from water loss during bleaching (12.44+/-0.38; bi p=0.0009). All glycerine-based bleaching products used in this study had a significant dehydrating effect on dentin. The application of protective varnishes prior to bleaching treatment may reduce or even prevent dentin dehydration.

Adjuvant radiotherapy after transoral laser microsurgery for advanced squamous carcinoma of the head and neck.

PURPOSE: To evaluate the efficacy of an adjuvant radiotherapy after transoral laser microsurgery for advanced squamous cell carcinoma of the head and neck and to show that a less invasive surgery with organ preservation in combination with radiotherapy is an alternative to a radical treatment. PATIENTS AND METHODS: Between 1987 and 2000, 208 patients with advanced squamous cell carcinoma of the head and neck were treated with postoperative radiotherapy after surgical CO2 laser resection. Primary sites included oral cavity, 38; oropharynx, 88; larynx, 36; hypopharynx, 46. Disease stages were as follows: Stage III, 40 patients; Stage IV, 168 patients. Before 1994, the treatment consisted of a split-course radiotherapy with carboplatinum (Treatment A). After 1994, the patients received a conventional radiotherapy (Treatment B). RESULTS: Patients had 5-year locoregional control and disease-specific survival (DSS) rates of 68% and 48%, respectively. The 5-year DSS was 70% and 44% for Stages III and IV, respectively (p = 0.00127). Patients treated with a hemoglobin level greater or equal to 13.5 g/dL before radiotherapy had a 5-year DSS of 55% as compared with 39% for patients treated with a hemoglobin level greater than 13.5 g/dL (p = 0.0054). CONCLUSION: In this series of patients with advanced head-and-neck tumors, transoral laser surgery in combination with adjuvant radiotherapy resulted in locoregional control and DSS rates similar to those reported for radical surgery followed by radiotherapy. Treatment B has clearly been superior to Treatment A. A further improvement of our treatment regimen might be expected by the combination of adjuvant radiotherapy with concomitant platinum-based chemotherapy.

Oral ultra-low dose continuous combined hormone replacement therapy with 0.5 mg 17ß-oestradiol and 2.5 mg dydrogesterone for the treatment of vasomotor symptoms: results from a double-blind, controlled study.

OBJECTIVES: Guidelines recommend using the lowest effective dose of oestrogen for the management of vasomotor symptoms in postmenopausal women. The primary aim of this double-blind, multi-centre, randomised study was to assess the efficacy of oral ultra-low dose continuous combined hormone replacement therapy with 17ß-oestradiol and dydrogesterone. STUDY DESIGN: 313 women with ≥50 moderate to severe hot flushes during the previous week were randomised to 0.5 mg 17ß-oestradiol/2.5 mg dydrogesterone (E 0.5 mg/D 2.5 mg), 1mg 17ß-oestradiol/5mg dydrogesterone (E 1mg/D 5 mg) or placebo for 13 weeks. The placebo group then switched to E 0.5 mg/D 2.5 mg for a further 39 weeks, whilst the other groups continued on the same treatment. RESULTS: After 13 weeks, the reduction in the number of moderate to severe hot flushes/day in the E 0.5 mg/D 2.5 mg group was greater than in the placebo group (-6.4 vs. -4.9, p<0.001) and comparable to that in the 1/5 mg group (-6.3). E 0.5 mg/D 2.5 mg and E 1mg/D 5 mg significantly improved the total Menopause Rating Scale score. The number of bleeding/spotting days was lower with E 0.5 mg/D 2.5 mg than with E 1 mg/D 5 mg. The overall amenorrhoea rate with E 0.5 mg/D 2.5 mg was 81%; this increased to 91% in months 10-12. CONCLUSIONS: Continuous combined 0.5 mg 17ß-oestradiol and 2.5mg dydrogesterone was effective in alleviating vasomotor symptoms and improving quality of life, and was associated with a high amenorrhoea rate and a good tolerability profile.

Common infectious agents in multiple sclerosis: a case-control study in children.

Environmental factors, in particular infections, have been linked with the risk of developing multiple sclerosis (MS). The association of Epstein-Barr virus infection with childhood onset of MS has been recently recognized. As other infections characteristically experienced during childhood have not yet been studied in larger cohorts of paediatric MS, we conducted a study on 152 German children with MS (age at onset <16 years) and matched controls in the hope of gaining evidence for their possible aetiological role in MS. Patterns of antibody responses were determined to a range of infections which, in prior studies principally on adult patients, had revealed possible associations with MS. In this study on children the serology of several infections showed associations with MS. In the exceptional case of Chlamydia pneumoniae there was a significantly higher prevalence of IgM antibody but, more typically, as in the case of influenza A, measles, parainfluenza 2, varicella/zoster viruses and particularly to the herpes simplex virus type 2 (HSV-2) lysate antigen, there were significantly higher concentrations of IgG antibody. Additional investigations, however, make it highly unlikely that a relevant number of children have experienced infections with HSV-2. In general this study supports and emphasizes a complex infectious and immunologic background of MS.

A novel ultrasonographic synovitis scoring system suitable for analyzing finger joint inflammation in rheumatoid arthritis.

OBJECTIVE: To develop an ultrasonographic (US) synovitis scoring system suitable for evaluation of finger joint inflammation in patients with active rheumatoid arthritis (RA) and to compare semiquantitative US scoring with quantitative US measurements. METHODS: US was performed at the palmar and dorsal sides of the second through fifth metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints in 10 healthy subjects and in the clinically more affected hand in 46 RA patients. Ten patients additionally underwent magnetic resonance imaging (MRI). Synovitis was measured, standardized, and scored according to a semiquantitative method. The 2 methods (semiquantitative US scoring, quantitative US) were compared and statistical cutoffs were identified using receiver operating characteristic (ROC) curve analysis. MRI results were compared with semiquantitative US scoring and quantitative US results. The optimal US scoring method from 6 joint combinations was identified (ROC curve analysis). RESULTS: Synovitis was most frequently detected in the palmar proximal area (86% of affected joints). We found no significant differences between individual PIP joints or between individual MCP joints, indicating that all fingers within each of these joint groups should be treated equally for statistical calculations, although each joint group as a whole should be treated separately. The optimal cutoff point to distinguish between "health" and "pathology" was 0.6 mm both for MCP joints (sensitivity 94%, specificity 89%) and for PIP joints (sensitivity 90%, specificity 88%). There was no significant difference between semiquantitative US scores and quantitative US measurements. The best results for joint combinations were achieved using the "sum of 4 fingers" (second through fifth MCP and PIP joints) and "sum of 3 fingers" (second through fourth MCP and PIP joints) methods. Comparison of MRI results with semiquantitative US scores revealed high concordance. CONCLUSION: US evaluation of finger joint synovitis can be considerably simplified by focusing on the palmar side and by applying semiquantitative grading instead of quantitative measurements. For evaluation of treatment efficacy based on synovitis in RA patients, we recommend using the "sum of 3 fingers" method in longitudinal trials.