Direct comparison of risankizumab and fumaric acid esters in systemic therapy-naïve patients with moderate-to-severe plaque psoriasis: a randomized controlled trial.

BACKGROUND: Fumaric acid esters (FAEs; Fumaderm® ) are the most frequently prescribed first-line systemic treatment for moderate-to-severe plaque psoriasis in Germany. Risankizumab (Skyrizi® ) is a humanized IgG1 monoclonal antibody that specifically binds to the p19 subunit of interleukin 23. OBJECTIVES: To compare risankizumab treatment to FAEs in patients with psoriasis. METHODS: This phase III randomized, active-controlled, open-label study with blinded assessment of efficacy was conducted in Germany. Patients were randomized (1 : 1) to subcutaneous risankizumab 150 mg (weeks 0, 4 and 16) or oral FAEs at increasing doses from 30 mg daily (week 0) up to 720 mg daily (weeks 8-24). Enrolled patients were adults naïve to and candidates for systemic therapy, with chronic moderate-to-severe plaque psoriasis. Phototherapy was not allowed within 14 days before or during the study. RESULTS: Key efficacy endpoints were met at week 24 for risankizumab (n = 60) vs. FAEs (n = 60) (P < 0·001): achievement of a ≥ 90% improvement in Psoriasis Area and Severity Index (PASI; primary endpoint 83·3% vs. 10·0%), ≥ 100% improvement in PASI (50·0% vs. 5·0%), ≥ 75% improvement in PASI (98·3% vs. 33·3%), ≥ 50% improvement in PASI (100% vs. 53·3%) and a Static Physician's Global Assessment of clear/almost clear (93·3% vs. 38·3%). The rates of gastrointestinal disorders, flushing, lymphopenia and headache were higher in the FAE group. One patient receiving risankizumab reported a serious infection (influenza, which required hospitalization). There were no malignancies, tuberculosis or opportunistic infections in either treatment arm. CONCLUSIONS: Risankizumab was found to be superior to FAEs, providing earlier and greater improvement in psoriasis outcomes that persisted with continued treatment, and more favourable safety results, which is consistent with the known safety profile. No new safety signals for risankizumab or FAEs were observed.

Patient-reported outcomes with risankizumab versus fumaric acid esters in systemic therapy-naïve patients with moderate to severe plaque psoriasis: a phase 3 clinical trial.

BACKGROUND: In a phase 3 clinical study, patients from Germany with moderate to severe psoriasis who were naïve to systemic treatment and received risankizumab had greater and more rapid disease improvements compared with those who received fumaric acid esters (FAEs). OBJECTIVE: To evaluate patient-reported outcomes (PROs) in patients treated with risankizumab compared with FAEs. METHODS: Adult patients were randomized 1:1 to receive either risankizumab 150 mg subcutaneous injections at weeks 0, 4 and 16 or FAEs (Fumaderm® ) provided according to the prescribing label. PRO secondary endpoints assessed were Psoriasis Symptom Scale (PSS), Dermatology Life Quality Index (DLQI), 36-Item Short Form Health Survey, version 2 (SF-36v2), Patient Benefit Index (PBI), Hospital Anxiety and Depression Scale (HADS), Patient Global Assessment (PtGA) and European Quality of Life 5 Dimensions 5 Level (EQ-5D-5L). PROs were assessed at weeks 0, 16 and 24. RESULTS: Sixty patients each were randomized to receive risankizumab or FAEs. A significant PSS improvement was observed with risankizumab vs. FAEs at weeks 16 and 24 for total and psoriasis-associated redness, itching and burning scores (P < 0.001). DLQI scores were significantly lower (reflecting better health-related quality of life) with risankizumab vs. FAEs, with least squares (LS) mean differences of -7.4 and -7.6 at weeks 16 and 24, respectively (both P < 0.001). Patients randomized to risankizumab also had larger improvements in SF-36 Physical and Mental Component Summary scores, HADS anxiety and depression scores, PtGA, and EQ-5D-5L index and visual analogue scale scores (all P ≤ 0.002) at weeks 16 and 24 compared with FAEs. PBI was significantly higher, indicating greater benefit, with risankizumab vs. FAEs, with an LS mean difference of 1.1 and 1.3 at weeks 16 and 24, respectively (both P < 0.001). CONCLUSIONS: Risankizumab provides significant benefits over FAEs in improving PROs across several dimensions in patients with moderate to severe psoriasis.

Sustained long-term efficacy and safety of adalimumab in paediatric patients with severe chronic plaque psoriasis from a randomized, double-blind, phase III study.

BACKGROUND: Adalimumab (ADA) (Humira® , AbbVie Inc., U.S.A.) is approved by the European Medicines Agency for children aged ≥ 4 years with severe plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy and safety of ADA in children with severe plaque psoriasis. METHODS: Results are presented from the 52-week long-term extension (LTE) of the randomized, double-blind, double-dummy, phase III trial, in children with severe plaque psoriasis (results from prior periods have been published). Patients aged ≥ 4 and < 18 years were randomized 1 : 1 : 1 to ADA 0·8 mg kg-1 (40 mg maximum) or 0·4 mg kg-1 (20 mg maximum) every other week or to methotrexate (MTX) 0·1-0·4 mg kg-1 (25 mg maximum) weekly. The 16-week initial treatment (IT) period was followed by a 36-week withdrawal period and a 16-week retreatment period. Patients could enter the LTE at prespecified time points to receive ADA 0·8 mg kg-1 (blinded or open label) or ADA 0·4 mg kg-1 (blinded), or to remain off treatment. Efficacy is reported for patient groups according to doses received in the IT and LTE periods. RESULTS: Of the 114 patients randomized in the IT period, 108 entered the LTE (n = 36 in each group); 93 received ADA 0·8 mg kg-1 . Efficacy (≥ 75% improvement from baseline in Psoriasis Area and Severity Index) was maintained or improved from entry to the end of the LTE: MTX(IT)/ADA 0·8(LTE) 31-86% of patients; ADA 0·4(IT)/0·4 or 0·8(LTE) 28-47%; ADA 0·8(IT)/0·8(LTE) 50-72%. No serious infections occurred in the LTE. CONCLUSIONS: After 52 weeks of long-term ADA treatment in children aged 4-18 years with severe plaque psoriasis, disease severity was reduced and maintained or further improved, as demonstrated by efficacy outcomes. No new safety risks were identified. What's already known about this topic? The results from the first three periods of this phase III trial in children aged 4-18 years with severe plaque psoriasis suggest that adalimumab is a safe and efficacious treatment option in this population. What does this study add? This is the first study to evaluate long-term treatment of adalimumab in children with severe psoriasis, and the first to evaluate switching from methotrexate to adalimumab in this population.

Adalimumab for the treatment of moderate to severe psoriasis: subanalysis of effects on scalp and nails in the BELIEVE study.

BACKGROUND/OBJECTIVE: This post hoc analysis examined the effects of adalimumab in patients with scalp and/or nail psoriasis from BELIEVE (a randomized, controlled, multicentre phase 3 safety and efficacy trial). METHODS: Efficacy was assessed in the pooled treatment group (adalimumab with or without calcipotriol plus betamethasone dipropionate) by Psoriasis Area and Severity Index (75% improvement; PASI 75), Psoriasis Scalp Severity Index (PSSI), Nail Psoriasis Severity Index (NAPSI), Dermatology Life Quality Index (DLQI) and a visual analog scale (VAS) for pain. RESULTS: Of the 730 enrolled patients, 663 (91.3%), 457 (63.1%) and 433 (60.1%) had psoriasis of the scalp, nails, or both, respectively. Similar proportions of patients with (68.2%) and without (63.5%) scalp involvement achieved a PASI 75 response at week 16 [adjusted odds ratio (OR), 1.34; P = 0.320]. PASI 75 response rates were lower in patients with nail psoriasis compared with patients without nail psoriasis at week 8 (53.0% vs. 62.9%; OR, 0.68; P = 0.019) and week 16 (65.0% vs. 73.0%; OR, 0.70; P = 0.052). PASI 75 response rates were 66.1% in patients with scalp and nail involvement and 70.8% in patients without both scalp and nail involvement at week 16 (OR, 0.87; P = 0.423). Patients in all scalp and nail subgroups reported improvements in DLQI and VAS pain scores throughout the study. Patients with scalp psoriasis exhibited large improvements in scalp symptoms demonstrated by a median (mean ± SD) decrease from baseline PSSI at week 16 of 100% (77.2 ± 96.9%). Patients with nail psoriasis improved, demonstrated by a median (mean ± SD) decrease from baseline NAPSI at week 16 of 39.5% (9.4 ± 164.5%). CONCLUSION: Our results indicate that adalimumab improves overall psoriasis and scalp and nail symptoms in this patient population with scalp psoriasis and/or nail involvement. In addition, similar PASI 75 response rates are achieved in patients with and without scalp involvement, whereas patients with nail involvement demonstrate a moderate (perhaps delayed) PASI 75 response rate.

Efficacy of adalimumab across subgroups of patients with moderate-to-severe chronic plaque psoriasis of the hands and/or feet: post hoc analysis of REACH.

BACKGROUND: The Randomized Controlled Evaluation of Adalimumab in Treatment of Chronic Plaque Psoriasis of the Hands and Feet (REACH) trial demonstrated that adalimumab was efficacious and well-tolerated for the treatment of hand and/or foot psoriasis through 28 weeks. OBJECTIVE: To evaluate the effects of patient baseline characteristics on efficacy of adalimumab treatment of hand and/or foot psoriasis. METHODS: Patients with moderate-to-severe chronic plaque psoriasis of the hands and/or feet were randomized 2 : 1 to adalimumab or placebo during the 16 week, double-blind period of REACH. Primary endpoint was percentage of patients achieving Physician's Global Assessment of the hands and/or feet of clear/almost clear at week 16. Post hoc analyses evaluated effects of baseline patient characteristics on the primary endpoint. Patients with nail psoriasis at baseline were assessed for association of Nail Psoriasis Severity Index (NAPSI) 50 response with efficacy outcomes at week 16. RESULTS: Seventy-two patients (49 adalimumab : 23 placebo) were analysed. Greater percentages of adalimumab-treated patients achieved the primary endpoint vs. placebo across all subgroups. Among 31 patients with nail psoriasis, a greater percentage of adalimumab-treated patients achieved NAPSI 50 (56.5%) vs. placebo (12.5%) at week 16. In adalimumab-treated patients, greater percentages of NAPSI 50 Responders vs. Non-responders achieved the primary endpoint, and had greater improvements in erythema, scaling, induration and fissuring, Dermatology Life Quality Index, and pain scores. CONCLUSIONS: Adalimumab was efficacious in treating chronic plaque psoriasis of the hands and/or feet over 16 weeks, regardless of baseline characteristics. Marked improvement in nail psoriasis among adalimumab-treated patients correlated with significant improvements in skin disease and patient-reported outcomes.

Relationship between methotrexate dosing and clinical response in patients with moderate to severe psoriasis: subanalysis of the CHAMPION study.

BACKGROUND: CHAMPION was a phase III trial that compared adalimumab with methotrexate and placebo for chronic plaque psoriasis. OBJECTIVES: To determine the relationship between methotrexate dosing and improvement in psoriasis for patients in CHAMPION. METHODS: Methotrexate-treated patients in CHAMPION received step-up dosing to 15 mg per week during the first 8 weeks. At week 8, PASI 50 responders (early responders, ER) were to continue with 15 mg weekly for the next 8 weeks; PASI 50 nonresponders were to receive 20 mg weekly for the next 4 weeks, followed by 20 mg weekly if they achieved ≥ PASI 50 at week 12 (late responders, LR), or 25 mg weekly if not (late nonresponders, LN). Outcomes were assessed post hoc for patients in these groups who completed CHAMPION. RESULTS: One hundred and three methotrexate-treated patients were analysed: 40 ER, 22 LR and 41 LN. Week 16 mean percentage improvement from baseline in Psoriasis Area and Severity Index was greatest in the ER group, nearly as good in LR, and poor in LN; PASI 75/90/100 response rates were 70%/32%/18%, 41%/9%/5% and 5%/0%/0%, respectively. Among patients with a PASI 75 response at week 16, 72% were in the ER group (comprising 27% of patients overall) and 23% were in the LR group. CONCLUSIONS: Nearly all week 16 PASI 75 responders in CHAMPION achieved a PASI 50 response at week 8 or 12, with maximum methotrexate dosages of 15 or 20 mg per week, respectively. Week 12 may be an appropriate time to discontinue methotrexate treatment in patients who are not achieving good responses.

Efficacy and safety of adalimumab in patients with psoriasis previously treated with anti-tumour necrosis factor agents: subanalysis of BELIEVE.

BACKGROUND: Few large clinical studies have evaluated whether switching tumour necrosis factor antagonists (anti-TNFs) is likely to improve psoriasis in patients with prior anti-TNF treatment. OBJECTIVE: The aim of this subanalysis of the BELIEVE study was to assess the efficacy and safety of adalimumab for psoriasis in patients with and without previous anti-TNF treatment. METHODS: The BELIEVE study enrolled patients with moderate to severe psoriasis and prior failure, intolerance or contraindication to ≥2 systemic therapies. In this 16-week, double-blind, randomized, controlled trial, patients received adalimumab (80 mg, week 0; 40 mg every other week, weeks 1-15) with either topical vehicle or topical calcipotriol/betamethasone dipropionate (C/B) applied once daily for 4 weeks, then as needed. The primary endpoint was ≥75% improvement from baseline in Psoriasis Area and Severity Index score (PASI 75) at week 16. This post hoc subanalysis evaluated the safety and efficacy of adalimumab, with and without topical therapy, in BELIEVE patients who had prior exposure to anti-TNFs. RESULTS: Of 730 patients enrolled, 282 (38.6%) had prior anti-TNFs and 448 (61.4%) were anti-TNF-naïve. Combining topical vehicle and topical C/B study populations, 61.7% of patients with prior anti-TNFs achieved PASI 75 at week 16, compared with 71.7% of anti-TNF-naïve patients (P=0.095). Adalimumab resulted in clinically meaningful improvement regardless of which prior anti-TNF agent had been used, the number of prior anti-TNFs tried, or reasons for discontinuation of prior anti-TNF therapy. Adverse event incidences were similar between patients with and without prior anti-TNF therapy. CONCLUSION: Adalimumab was effective and well-tolerated in patients with psoriasis previously treated with anti-TNF therapy.

A phase IIIb, multicentre, randomized, double-blind, vehicle-controlled study of the efficacy and safety of adalimumab with and without calcipotriol/betamethasone topical treatment in patients with moderate to severe psoriasis: the BELIEVE study.

BACKGROUND: Data are lacking on the use of topical therapies in combination with tumour necrosis factor blockers for the treatment of psoriasis. OBJECTIVES: To assess the efficacy and safety of adalimumab (ADA) with topical calcipotriol/betamethasone (C/B) in patients with psoriasis resembling those treated in routine clinical practice. METHODS: A 16-week, randomized, vehicle-controlled trial was conducted in patients with moderate to severe psoriasis and previous failure, intolerance or contraindications to two or more systemic treatments. All patients received ADA (80 mg, week 0; 40 mg every other week, weeks 1-15) in addition to either topical C/B or drug-free vehicle applied once daily for 4 weeks, and as needed thereafter. The primary endpoint was 75% improvement from baseline in Psoriasis Area and Severity Index (PASI 75) at week 16. RESULTS: A total of 730 patients received either ADA + C/B (n = 366) or ADA + vehicle (n = 364). PASI 75 response was initially higher with the combination therapy [14.8% for ADA + C/B vs. 5.8% for ADA + vehicle at week 2 (P < 0.001); and 40.7% vs. 32.4%, respectively, at week 4 (P = 0.021)]. After week 4, the trend was towards a higher response with ADA monotherapy, with no statistical difference in the PASI 75 response at week 16 (64.8% for ADA + C/B vs. 70.9% for ADA monotherapy, P = 0.086). Safety findings were consistent with previous ADA trials. CONCLUSIONS: ADA + C/B resulted in more rapid and higher efficacy within the first 4 weeks; thereafter, the trend was towards a higher response with ADA monotherapy. There was no statistical difference in the PASI 75 response at week 16. Both treatment regimens were well tolerated.

Surgical management of subfoveal choroidal neovascular membranes in age-related macular degeneration by macular relocation: experiences of an early-stopped randomised clinical trial (MARAN Study).

RATIONALE: The MARAN (Macular Relocation in Age-related Neovascular disease) trial was planned to assess the effectiveness of full macular relocation (MR) in patients with neovascular age-related macular degeneration (AMD). DESIGN: Randomised, prospective, controlled clinical trial. METHODS: Patients suffering from visual loss because of AMD were randomised to either surgery or a control group receiving standard treatment (observation or photodynamic therapy (PDT)). The primary end point was the change of visual acuity (VA) (ETDRS) 52 weeks after randomisation compared with initial VA, and secondary end points included reading performance, contrast sensitivity, stability of fixation, eye-specific quality of life, and the absolute number of letters read correctly at 52 weeks compared with initial examination. RESULTS: Owing to early determination, only 28 patients were included in the study. The study did not show a difference between the two groups with respect to the final visual result or any of the secondary outcomes measured. The study was limited by the low recruitment that was, at least in part, attributed to the inherent risks for those patients randomised to the surgical arm of the study as well as to the emerging new treatments for AMD. CONCLUSION: The results of the MARAN trial failed to recruit a sufficient number of patients and a superiority of surgery over observation or PDT in patients with exudative AMD was not shown. There was a trend that the reading function was superior after surgery. In the light of the new pharmacological treatments, surgical options such as MR will be an option for only selected cases.

Efficacy and safety results from the randomized controlled comparative study of adalimumab vs. methotrexate vs. placebo in patients with psoriasis (CHAMPION).

BACKGROUND: Biologic therapies such as adalimumab, a tumour necrosis factor antagonist, are safe and effective in the treatment of moderate to severe chronic plaque psoriasis. OBJECTIVES: To compare a biologic agent with methotrexate, a traditional systemic agent, to define clearly the role of biologics in psoriasis. METHODS: Patients with moderate to severe plaque psoriasis were randomized to adalimumab (80 mg subcutaneously at week 0, then 40 mg every other week, n=108), methotrexate (7.5 mg orally, increased as needed and as tolerated to 25 mg weekly; n=110) or placebo (n=53) for 16 weeks. The primary efficacy endpoint was the proportion of patients achieving at least a 75% improvement in the Psoriasis Area and Severity Index (PASI 75) after 16 weeks. Safety was assessed at all visits through week 16. RESULTS: After 16 weeks, 79.6% of adalimumab-treated patients achieved PASI 75, compared with 35.5% for methotrexate (P<0.001 vs. adalimumab) and 18.9% for placebo (P<0.001 vs. adalimumab). Statistically significantly more adalimumab-treated patients (16.7%) than methotrexate-treated patients (7.3%) or placebo-treated patients (1.9%) achieved complete clearance of disease. The response to adalimumab was rapid, with a 57% improvement in mean PASI observed at week 4. Adverse events were similar across treatment groups. Adverse events leading to study discontinuation were greatest in the methotrexate group, primarily because of hepatic-related adverse events. CONCLUSIONS: After 16 weeks, adalimumab demonstrated significantly superior efficacy and more rapid improvements in psoriasis compared with either methotrexate or placebo.

Effectiveness of adalimumab for rheumatoid arthritis in patients with a history of TNF-antagonist therapy in clinical practice.

OBJECTIVE: To evaluate the effectiveness and safety of adalimumab in patients with rheumatoid arthritis (RA) who previously discontinued tumour necrosis factor (TNF) antagonists for any reason in clinical practice. METHODS: ReAct (Research in Active Rheumatoid Arthritis) was a large, open-label trial that enrolled adults with active RA who had previously been treated with traditional disease-modifying anti-rheumatic drugs or biological response modifiers. Patients self-administered adalimumab 40 mg subcutaneously every other week for 12 weeks and were allowed to enter an optional long-term extension phase. Measures of adalimumab effectiveness included American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) response criteria, Disease Activity Score 28 (DAS28) and the Health Assessment Questionnaire Disability Index (HAQ DI). RESULTS: Of 6610 patients, 899 had a history of etanercept and/or infliximab therapy; these patients experienced substantial clinical benefit from adalimumab treatment. At week 12, 60% of patients had an ACR20 and 33% had an ACR50 response; 76% had a moderate and 23% had a good EULAR response. In addition, 12% achieved a DAS28 < 2.6, indicating clinical remission, and 13% achieved a HAQ DI score <0.5. The allergic adverse event rate, regardless of relationship to adalimumab, was 6.5/100-patient-years (PYs) in previously TNF-antagonist-exposed patients and 4.3/100-PYs in TNF-antagonist-naive patients. A multiple regression analysis indicated no statistically significantly increased risk of serious infections in patients who received prior TNF antagonists compared with TNF-antagonist-naive patients. CONCLUSION: In typical clinical practice, adalimumab was effective and well-tolerated in patients with RA previously treated with etanercept and/or infliximab.

Final report of the early vs. late infantile strabismus surgery study (ELISSS), a controlled, prospective, multicenter study.

BACKGROUND: The optimal age for surgery for infantile esotropia is controversial. Proponents of early surgery believe that further loss of binocular vision can be prevented by early surgery, a minority believes that binocular vision can even be restored by early surgery. The ELISSS compared early with late surgery in a prospective, controlled, non-randomized, multicenter trial. METHODS: Fifty-eight clinics recruited children aged 6-18 months for the study. Each clinic operated all eligible children either 'early', i.e. at age 6-24 months, or 'late', i.e. at age 32-60 months. At baseline the angle of strabismus, refraction, degree of amblyopia and limitation of abduction were assessed. Intermediate examinations took place every six months. Children were evaluated at age six in the presence of independent observers. Primary endpoints were (i) level of binocular vision, (ii) manifest angle of strabismus at distance and (iii) remaining amblyopia. Secondary endpoints were number of operations, vertical strabismus, angle at near and the influence of surgical technique. RESULTS: A total of 231 children were recruited for early and 301 for late surgery. Age at entry examination was 11.1 months (SD 3.7 months) in the early group and 10.9 (SD 3.7) months in the late group. Refraction, amblyopia and limitation of abduction were distributed equally in the early and late groups, but the angle of strabismus was slightly larger in the early group. Dropout-rates were 26.0% in the early and 22.3% in the late group. At age six, 13.5% of the early vs. 3.9% of the late group recognized the Titmus Housefly; 3.0% of the early and 3.9% of the late group had stereopsis beyond Titmus Housefly. No significant difference was found for angle of strabismus. 35.1% of the early group and 34.8% of the late group did not have an angle between 0 degrees and 10 degrees , the thresholds set for re-operation. For ratio of the visual acuities (remaining amblyopia) there was a small but significant advantage for the early group. There was hardly any correlation between the baseline parameters and the primary endpoints. Children scheduled for early surgery had first been operated at 20 (SD 8.4) months, but 8.2% had not been operated at age six. Children scheduled for late surgery had been operated at 49.1 (SD 12.7) months, but 20.1% had not been operated at age six. The number of operations per child was 1.18 (SD 0.67) in the early and 0.99 (SD 0.64) in the late group. Age at recruitment, age that strabismus reportedly had started and refraction at entry examination were similar among operated and non-operated children. Only the angle of strabismus at entry predicted, to some extent, whether a child had been operated at age six. DISCUSSION: Children operated early had better gross stereopsis at age six as compared to children operated late. They had been operated more frequently, however, and a substantial number of children in both groups had not been operated at all.

Micrometastatic bone marrow cells at diagnosis have no impact on survival of primary breast cancer patients with extensive axillary lymph node involvement treated with stem cell-supported high-dose chemotherapy.

BACKGROUND: To determine the impact of micrometastatic bone marrow cells (MMC) on survival in high-risk primary breast cancer (HRPBC) patients treated with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). PATIENTS AND METHODS: Ninety-one HRPBC patients (73 patients with > or =10 involved axillary lymph nodes (ALN), 18 premenopausal women with > or =4 involved ALN) received one cycle (eight patients) or two cycles of HDCT and ASCT. Bone marrow aspiration was performed before systemic treatment to search for MMC using a cocktail of four monoclonal epithelial-specific antibodies (5D3, HEA125, BM7 and BM8). The influence of MMC and other prognostic factors on disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) was analysed. RESULTS: In 23 of 91 patients (25%) we detected a median of three MMC (range, 1-43) among 10(6) mononuclear cells. With a median follow-up of 62 months (range, 10-117), the detection of MMC was not associated with DFS (P=0.929), DDFS (P=0.664) or OS (P=0.642). In multivariate analysis the strongest predictor was nodal ratio for DFS (P=0.012) and expression of p53 for OS (P <0.001). CONCLUSION: The detection of MMC at diagnosis has no impact on survival in HRPBC patients treated with HDCT and ASCT.

Diagnostic occlusion test in cases of unilateral strabismus sursoadductorius.

PURPOSE: To investigate the diagnostic occlusion test (OT) according to Marlow in strabismus sursoadductorius (StS; also known as 'unilateral superior oblique palsy') and its implications for surgical treatment. METHODS: In 67 cases of StS, angles of strabismus were measured before and after patching the affected eye for three days. Horizontal, vertical and torsional deviations were measured in front of the tangent screen of Harms in nine directions of gaze. RESULTS: After OT, most cases of StS showed the following distribution of vertical deviation (VD) on horizontal versions: setting the VD in 30 degrees adduction to 100%, VD in primary position (PP) was 50%, VD in abduction 14%, excyclotropia in PP about 40% of the amount of VD. Those StS-cases showing the same distribution of VD on horizontal versions before and after OT were called 'typical' ones (27% of the patients). However, 73% of the patients showed a different distribution before OT: 68% VD in PP, 36% VD in abduction, excyclotropia of 20% in PP. After OT these cases converted to the normal pattern described above: VD in PP was 53 % and VD in 30 degrees abduction was 19%, excyclotropia in PP was 36%. CONCLUSION: In 'typical' StS-cases, OT is not necessary. 'Atypical' cases, however, can be converted into 'typical' ones: they get more incomitant VD on horizontal versions and greater excyclotropia in PP. As VD in adduction remains almost the same in both groups after OT, surgery can be based on the angle in adduction. In individual 'atypical' patients the amount of oblique muscle surgery has to be modified after OT.

Acupuncture compared to placebo-acupuncture for postoperative nausea and vomiting prophylaxis: a randomised placebo-controlled patient and observer blind trial.

This randomised, placebo-controlled, patient and observer blinded trial was conducted to determine whether acupuncture at the acupuncture point P6 is effective in preventing postoperative nausea and vomiting (PONV) compared to placebo acupuncture. Female patients (n = 220) scheduled for gynaecological or breast surgery were randomly assigned to two groups receiving either acupuncture (n = 109) or placebo acupuncture (n = 111). Each group was stratified for type of surgery and included two subgroups receiving intervention either before or after induction of anaesthesia. The incidence of PONV and/or antiemetic rescue medication within 24 h after surgery was the main outcome measure which showed no statistically significant difference between groups (43.7% acupuncture, 50.9% placebo, p = 0.27). The differences were more pronounced for patients having gynaecological surgery (48.9% acupuncture, 67.6% placebo, p = 0.07) than for those having breast surgery (38.7% acupuncture, 40.3% placebo, p = 0.86). The secondary outcome, vomiting, was significantly reduced by acupuncture from 39.6% to 24.8% (p = 0.03). Subgroup analysis showed no difference between applications of acupuncture before compared to after induction of anaesthesia.

[Incidence and extent of postoperative macular edema following vitreoretinal surgery with and without combined cataract operation]. / Inzidenz und Ausprägung von postoperativem Makulaödem nach Makulaforamenoperation mit und ohne kombinierte Kataraktoperation.

PURPOSE: In the majority of patients with full-thickness macular hole, closure can be achieved with vitreoretinal surgery techniques. However, postoperative function is variable and the prognostic determinants for visual acuity are incompletely understood. We evaluated the incidence and extent of macular edema after macular foramen surgery with and without combined cataract-surgery. METHODS: Between October 1997 and March 2001 macular foramen surgery was performed in 125 eyes from 116 patients. Fluorescein angiograms with sufficient quality were obtained from 59 eyes using a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph, HRA, Heidelberg Engineering, Heidelberg) and were evaluated by two independent observers. RESULTS: Angiographic macular edema was noted on average 4.2 months after the operation in 47 out of 59 (79.7%) eyes. The incidence of macular edema was 87% in eyes after a combined cataract operation compared to 66.7 % in eyes with no simultaneous operation ( p=0.735). Mean postoperative visual acuity was 0.4 (min 0.1-max 1.2) with no significant difference between eyes with (4.1 lines) and without macular edema (3.5 lines) with regard to visual improvement from baseline. CONCLUSIONS: The results indicate a high incidence of macular edema in eyes after macular hole surgery with subsequent anatomical success. Apparently, the presence of macular edema is not associated with short term visual impairment. Furthermore it seems that a combined cataract operation compared to a consecutive procedure is not associated with disadvantages regarding the functional outcome.

Digital analysis of choroidal neovascularisation in consecutive fluorescein angiograms for use in longitudinal clinical trials.

BACKGROUND/AIMS: To document the natural history and to assess the efficacy of interventional therapies in neovascular age related macular degeneration (AMD), an accurate and reproducible method is required for analysis of consecutive fluorescence angiograms. The development and evaluation of an image analysis software for this purpose is described here. It allows for the quantitative analysis of changes in CNV and/or leakage area over time. METHODS: In digitised angiograms, a mouse driven arrow was used to delineate the CNV border. The ratio of the CNV area to the square of the distance between two vessels was automatically calculated by pixel count to compensate for variation in image sizes at different examination times. These results were directly transferred and stored in a database. To assess reproducibility, CNV areas in 20 patients with occult and 20 patients with classic CNV were determined independently by two readers. RESULTS: There was only marginal variability between observers with this method: the mean deviation was 0.01 pixels for classic CNV (95% CI -0.17 to +0.15, SD 0.35) and 0.55 pixels for occult CNV (95% CI -1.06 to -0.04, SD 1.14). CONCLUSIONS: This practical PC based method allows for quantification of angiographic features such as CNV size in early frames and area of leakage in late frames. Limitations include non-readily defined borders in angiograms of poor image quality or indistinct borders of the hyperfluorescent areas of interest. The software is applicable to future clinical trials where the analysis of neovascular complex changes is required, for example, following therapeutic intervention.

Prognostic value of Doppler echocardiographic mitral inflow patterns: implications for risk stratification in patients with chronic congestive heart failure.

OBJECTIVES: This prospective study tested whether transmitral flow patterns add incremental value to peak oxygen consumption (VO2) in determining the prognosis of patients with chronic congestive heart failure (CHF) and systolic dysfunction. BACKGROUND: Peak VO2 is an objective marker of functional capacity and is routinely used as a criterion to identify heart transplant candidates. Diastolic dysfunction limits functional capacity, but its prognostic importance relative to that of peak VO2 is unknown. METHODS: Peak VO2 and mitral inflow velocities were prospectively measured in 311 consecutive patients (mean age 54 years, 84% male) with impaired left ventricular function (ejection fraction <40%; 88 patients with ischemic and 223 with dilated cardiomyopathy) who were evaluated for heart transplant candidacy. RESULTS: During a mean follow-up period of 512 +/- 314 days, 65 patients died and 43 patients underwent heart transplantation. Diastolic filling patterns, peak VO2 and left ventricular end-diastolic diameters were independent predictors of cardiac mortality. In patients with peak VO2 < or = 14 ml/min per kg body weight, the outcome was markedly poorer in the presence of restrictive filling patterns as compared with their absence (two-year survival rate 52% vs. 80%). Similarly, despite peak VO2 levels >14 ml/min per kg, the outcome was less favorable in the presence of restrictive filling patterns (two-year survival rate 80% vs. 94%). A risk-stratification model based on the identified independent noninvasive predictors separated groups into those with high (93%), intermediate (65%) and low (39%) two-year survival rates. CONCLUSIONS: Transmitral flow patterns add incremental value to peak VO2 in determining the prognosis of patients with CHF and impaired systolic function.

Intention-to-treat: methods for dealing with missing values in clinical trials of progressively deteriorating diseases.

Since it came up in the 1960s, the principle of intention-to-treat (ITT) has become widely accepted for the analysis of controlled clinical trials. In this context the question of how to perform such an analysis in the presence of missing information about the main endpoint is of major importance. Uncritical use of several ad hoc strategies for dealing with missing values is common in the practice of clinical trials. On the other hand, little is known about possible dangers and problems of applying these strategies. We therefore performed a detailed investigation of different methods for dealing with missing values in order to develop recommendations for their practical use. A simulation study was performed investigating possible consequences on type I error and power of applying different methods for dealing with missing values. The simulations were based on a clinical trial of osteoporosis, a progressively deteriorating disease. The strategies examined can be roughly classified into numerical imputation strategies (last observation carried forward, mean and regression based methods) and non-parametric strategies (rank and dichotomization based methods). Different drop-out mechanisms and different types of progression of disease are considered. The type I error increases drastically for the different strategies, especially if the courses of disease vary between treatment groups. The loss in power can be substantial. There is no strategy which is adequate for all different combinations of drop-out mechanisms, drop-out rates and courses of disease over time. For drop-out rates less than 20 per cent and similar courses of disease in the treatment groups, missing values might be replaced by the mean of the other group, or counted as treatment failures after dichotomization of the endpoint. For larger drop-out rates or less similar courses of disease, no adequate recommendations can be given. Because of the drastic consequences of increasing drop-out rates, it has to be a primary goal in clinical trials to keep missing values to a minimum. Unobserved information cannot be reliably regained by any methodological resources. As there are no strategies for universal use, reasons for the choice of a certain method have to be provided when designing and analysing clinical trials.

Nonconvulsive status epilepticus--a possible cause of mental retardation in patients with Lennox-Gastaut syndrome.

Lennox-Gastaut syndrome (LGS) is one of the most severe types of childhood epilepsy. It is usually resistant to treatment and associated with mental retardation. To delineate the risk factors associated with the outcome of LGS, we evaluated, in a retrospective and multicentre study, the course of the disease, EEG tracings, and intellectual function in 101 patients. Inclusion criteria were the presence of tonic seizures as well as slow spike and wave complexes in the EEG. The average documented observation period was 16 years (range 4-31 years). Overall, the intellectual and neurological outcome was poor. At the last follow-up, 38% of the patients could not speak, 21% were unable to walk and only 4% were free of seizures. Four independent risk factors for severe mental retardation were identified by multivariate analysis. These were in a decreasing order of importance: nonconvulsive status epilepticus (NCSE), odds ratio (OR) 25.2, a previous diagnosis of West syndrome (OR 11.6), a symptomatic etiology of epilepsy (OR 9.5), and an early age at onset of epilepsy (OR 4.7). The results highlight the association between NCSE and the severity of mental retardation in patients with LGS; this association appears to be independent of symptomatic etiology. Our data provide an indirect evidence that, at least in some of the patients, NCSE is not only a concomitant feature, but also a cause of severe mental retardation.