Dupilumab Drug Survival and Associated Predictors in Patients With Moderate to Severe Atopic Dermatitis: Long-term Results From the Daily Practice BioDay Registry.

Importance: Long-term data on dupilumab drug survival in patients with atopic dermatitis (AD) are scarce. Furthermore, little is known about the factors associated with drug survival of dupilumab in AD. Objective: To describe the drug survival of dupilumab in patients with AD and to identify associated predictors. Design, Setting, and Participants: This cohort study was based on data from the multicenter prospective daily practice BioDay registry, in which 4 university and 10 nonuniversity hospitals in the Netherlands participated. Analysis included patients (age ≥18 years) participating in the BioDay registry with a follow-up of at least 4 weeks. The first patient treated with dupilumab was recorded in the BioDay registry in October 2017; data lock took place in December 2020, and data analysis was performed from October 2017 to December 2020. Main Outcomes and Measures: Drug survival was analyzed by Kaplan-Meier survival curves and associated characteristics by using univariate and multivariate Cox regression analysis. Results: A total of 715 adult patients with AD (mean [SD] age, 41.8 [16.0] years; 418 [58.5%] were male) were included with a 1-year, 2-year, and 3-year overall dupilumab drug survival of 90.3%, 85.9%, and 78.6%, respectively. Characteristics associated with shorter drug survival owing to ineffectiveness were the use of immunosuppressant drugs at baseline (hazard ratio [HR], 2.64; 95% CI, 1.10-6.37) and being a nonresponder at 4 weeks (HR, 8.68; 95% CI, 2.97-25.35). Characteristics associated with shorter drug survival owing to adverse effects were the use of immunosuppressant drugs at baseline (HR, 2.69; 95% CI, 1.32-5.48), age 65 years or older (HR, 2.94; 95% CI, 1.10-7.87), and Investigator Global Assessment score of very severe AD (HR, 3.51; 95% CI, 1.20-10.28). Conclusions and Relevance: This cohort study demonstrated a good overall 1-year, 2-year, and 3-year dupilumab drug survival. Patients using immunosuppressive therapy at baseline and those with an absence of treatment effect at week 4 tended to discontinue treatment owing to ineffectiveness more frequently. Using immunosuppressant drugs at baseline, older age, and Investigator Global Assessment score of very severe AD were characteristics associated with an increased risk for discontinuation owing to adverse effects. These data provide more insight and new perspectives regarding dupilumab treatment in AD and can contribute to the optimization of patient outcomes.

Assessment of selected B cells populations in the workers of X-ray departments.

OBJECTIVES: Workers of X-ray departments are occupationally exposed to long-term low levels of ionizing radiation (LLIR), which may affect their humoral immunity. The aim of the study was to assess the influence of LLIR on the number and proportion of B cells (CD19+), B1 cells (CD5+CD19+) and memory B cells (CD27+CD19+) in peripheral blood of such workers. MATERIALS AND METHODS: In the study group of 47 X-ray departments workers and the control group consisting of 38 persons, the number and percentage of CD19+, CD5+CD19+, CD27+CD19+ cells as well as CD5+CD19+/CD19+ and CD27+CD19+/CD19+ cell ratios were assessed using flow cytometry. Additionally, the study group was divided into 2 groups by the length of employment below and over 15 years and analysis adjusted for age and smoking habit was performed. RESULTS: The total number of CD19+ cells showed significant increase in the group of workers in comparison with the persons from the control group, whereas the percentage of CD5+CD19+ cells as well as CD27+CD19+/CD19+ and CD5+CD19+/CD19+ cell ratios were lower. Percentage, number of CD5+CD19+ cells and CD5+CD19+/CD19+ cell ratio were significantly lower in the workers with length of employment longer than 15 years in comparison with those employed below 15 years. Moreover, we found positive associations between the number of CD19+ cells and employment as well as smoking habit, whereas the number of CD5+CD19+ cells was positively associated with cigarette smoking alone. Percentage of CD5+CD19+ cells as well as CD5+CD19+/CD19+ and CD27+CD19+/CD19+ cell ratios were negatively correlated with employment. CONCLUSIONS: The study suggests association between the suppressive influence of low level ionizing radiation on circulating in peripheral blood, especially of B1 cells as well as of memory B cells, in workers of X-ray units, which is adverse in relation to microbiological threat.

Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand?

AIM: Since the introduction of chemotherapy, survival in localised high-grade osteosarcoma has improved considerably. However, there is still no worldwide consensus on a standard chemotherapy approach. In this systematic review evidence for effectiveness of each single drug and the role of response guided salvage treatment of adjuvant chemotherapy are addressed, whereas in a meta-analysis the number of drugs in current protocols is considered. METHODS: A systematic literature search for clinical studies in localised high-grade osteosarcoma was undertaken, including both randomised and non-randomised trials. Historical clinical studies from the pre-chemotherapy era were included for comparison purposes. RESULTS: Nine historical studies showed a long-term survival of 16% after only local treatment. Fifty single agent phase II studies showed high response rates for adriamycin (A, 43%), ifosfamide (Ifo, 33%), methotrexate (M, 32%), cisplatin (P, 26%) but only 4% for etposide (E). In 19 neo-adjuvant studies the mean 5-year event free survival (EFS) was 48% for 2-drug regimens and 58% for ⩾3 drug regimens, with a 5-year overall survival (OAS) of 62% and 70%, respectively. Meta-analysis showed that ⩾3 drug regimens including methotrexate plus adriamycin plus cisplatin (plus ifosfamide) (MAP(Ifo)) had significant better outcome (EFS: HR=0.701 (95% confidence interval [95% CI]: 0.615-0.799); OAS: HR=0.792 (95% CI: 0.677-0.926) than 2-drug regimens, but there was no significant difference between MAP and MAPIfo (or plus etoposide). Salvage of poor responders by changing drugs, or intensifying treatment postoperatively has not proven to be useful in this analysis. CONCLUSION: Meta-analysis in patients with localised high-grade osteosarcoma shows that 3-drug regimens, for example MAP are the most efficacious drug regimens.

Radiofrequency ablation of spinal osteoid osteoma: clinical outcome.

STUDY DESIGN: A prospective study on 24 patients with spinal osteoid osteoma treated with radiofrequency ablation (RFA). OBJECTIVE: To determine if and when computed tomography (CT)-guided RFA is a safe and effective treatment for spinal osteoid osteomas. SUMMARY OF BACKGROUND DATA: Surgery has been considered the standard treatment for spinal osteoid osteomas. Surgery may cause spinal instability, infection, and nervous injury. We evaluated CT-guided RFA as an alternative treatment. METHODS: A total of 28 RFA procedures in 24 patients with spinal osteoid osteoma were performed, using a 5-mm noncooled electrode. Clinical symptoms and spinal deformity were evaluated before and after the procedure. Unsuccessful treatment was defined as the presence of residual or recurrent symptoms. The mean follow-up was 72 months (range: 9-142 months). RESULTS: Nineteen (79%) patients were successfully treated after 1 RFA, and all except one after repeat RFA. One patient with nerve root compression needed further surgery. No complications were observed. Spinal deformity persisted in 3 of 7 patients after successful RFA. CONCLUSION: CT-guided RFA is a safe and effective treatment for spinal osteoid osteoma. Surgery should be reserved for lesions causing nerve root compression.

The healing pattern of osteoid osteomas on computed tomography and magnetic resonance imaging after thermocoagulation.

OBJECTIVE: To compare the healing pattern of osteoid osteomas on computed tomography (CT) and magnetic resonance imaging (MRI) after successful and unsuccessful thermocoagulation. MATERIALS AND METHODS: Eighty-six patients were examined by CT and 18 patients by dynamic gadolinium-enhanced MRI before and after thermocoagulation for osteoid osteoma. Thermocoagulation was successful in 73% (63/86) and unsuccessful in 27% (23/86) of patients followed by CT. Thermocoagulation was successful in 72% (13/18) of patients followed by MRI. After treatment, the healing of the nidus on CT was evaluated using different healing patterns (complete ossification, minimal nidus rest, decreased size, unchanged size or thermonecrosis). On MRI the presence of reactive changes (joint effusion, "oedema-like" changes of bone marrow and soft tissue oedema) and the delay time (between arterial and nidus enhancement) were assessed and compared before and after thermocoagulation. RESULTS: Complete ossification or a minimal nidus rest was observed on CT in 58% (16/28) of treatment successes (with > 12 months follow-up), but not in treatment failures. "Oedema-like" changes of bone marrow and/or soft tissue oedema were seen on MR in all patients before thermocoagulation and in all treatment failures. However, residual "oedema-like" changes of bone marrow were also found in 69% (9/13) of treatment successes. An increased delay time was observed in 62% (8/13) of treatment successes and in 1/5 of treatment failures. CONCLUSION: Complete, or almost complete, ossification of the treated nidus on CT correlated with successful treatment. Absence of this ossification pattern, however, did not correlate with treatment failure. CT could not be used to identify the activity of the nidus following treatment. The value of MR parameters to assess residual activity of the nidus was limited in this study.

Osteoid osteoma: factors for increased risk of unsuccessful thermal coagulation.

PURPOSE: To retrospectively identify risk factors that may impede a favorable clinical outcome after thermocoagulation for osteoid osteoma. MATERIALS AND METHODS: Informed consent (permission for the procedure and permission to use patient data for analysis) was obtained from all patients who met study criteria, and institutional review board did not require approval. Analysis included age, sex, size and location of osteoid osteoma, presence of calcified nidus, number of needle positions used for coagulation, coagulation time, accuracy of needle position, learning curve of radiologist, and previous treatment in 95 consecutive patients with osteoid osteoma treated with thermocoagulation. With chi(2) analysis, Fisher exact test, or unpaired Student t test and logistic regression analysis, 23 unsuccessfully treated patients were compared with 72 successfully (pain-free) treated patients. RESULTS: Parameters associated with decreased risk for treatment failure were advanced age (mean age, 24 years in treatment success group vs 20 years in treatment failure group) and increased number of needle positions during thermocoagulation. Estimated odds ratios were, respectively, 0.93 (95% confidence interval: 0.88, 0.99) and 0.10 (95% confidence interval: 0.02, 0.41). Patients with a lesion of 10 mm or larger seemed at risk for treatment failure (odds ratio = 2.68), but the 95% confidence interval of 0.84 to 8.52 included the 1.00 value. Needle position was inaccurate in nine of 23 patients with treatment failure; only one needle position was used in eight of these nine patients. Lesion location, calcification, sex, coagulation time, radiologist's learning curve, and previous treatment were not risk factors. CONCLUSION: Multiple needle positions reduce the risk of treatment failure in all patients and should especially, but not exclusively, be used in large (> or =10-mm) lesions or lesions that are difficult to engage to reduce the risk for unsuccessful treatment.

Osteoid osteoma: clinical results with thermocoagulation.

PURPOSE: To determine the clinical results in an unselected group of consecutive patients with osteoid osteoma treated with thermocoagulation. MATERIALS AND METHODS: In 97 consecutive patients with clinical and/or radiologic evidence of osteoid osteoma at any location, the clinical symptoms were assessed before and after thermocoagulation with computed tomographic guidance. A good response was defined as disappearance of symptoms that were manifested at presentation and attributed to osteoid osteoma. Clinical assessment was performed prior to discharge; within 2 weeks after the procedure; and at 3, 6, 12, and 24 months follow-up. After 24 months, a postal questionnaire was used for assessment. RESULTS: The mean clinical follow-up after the only or the last thermocoagulation session was 41 months (range, 5-81 months). Response was good after one session of thermocoagulation in 74 (76%) of 97 patients, and the 95% CI was 68% to 85%. Patients with persistent symptoms did well after repeated thermocoagulation (good response in 10 of 12 patients), but results of repeated thermocoagulation were poor in patients with recurrent symptoms (good response in five of 10). The overall success rate after one or two thermocoagulation procedures combined was 92% (89 of 97 patients), and the 95% CI was 86% to 97%. Complications were observed in two patients. CONCLUSION: Percutaneous thermocoagulation is a safe and effective method for treatment of osteoid osteoma at any location. Repeated thermocoagulation is successful in patients with persistent symptoms.

Rate-dependence of antiarrhythmic and proarrhythmic properties of class I and class III antiarrhythmic drugs.

Rate or frequency-dependence is a characteristic property of antiarrhythmic drugs belonging to the Vaughan William classes I and III. The rate-dependence of class I drugs (i.e., increasing blockade of fast Na(+)-channels with faster rates) results from periodical drug binding to Na(+)-channel sites which are preferably available in the activated and/or inactivated channel states (use-dependence). With respect to their binding and unbinding kinetics, class I drugs can be subdivided into three groups (group 1-group 3) which differ in their block-frequency relations as well as in their onset kinetics of channel blockade. These properties can serve as predictors of the anti- and proarrhythmic potential of class I drugs. Class III drugs (blockers of potassium channels) are mostly characterized by reverse rate-dependence (loss of class III action at faster rates). However, this property cannot be attributed to reverse use-dependence, i.e., binding to channels in the rested state. It is more likely due to different rate-dependent contributions of the two components of the delayed rectifier potassium current to repolarization, when the rapidly activating, the rectifying component IKr is specifically blocked by class III drugs, while the slowly activating component IKs remains unchanged. In spite of their reverse rate-dependence, class III drugs exert an antifibrillatory effect when fibrillation is induced by frequent stimulation. This can be attributed to the slow time course of the decline (offset kinetics) of the class III effect accompanying a sudden increase in frequency. Proarrhythmic effects of class III drugs result from the delay in repolarization that may favor the development of early afterdepolarizations. The proarrhythmic potential of class III drugs is species dependent and is favored if the contribution of IKr to the repolarization phase of the action potential is comparatively large.

[Cataract surgery in narrow pupil and postoperative fibrin reaction, especially after sphincterectomy]. / Kataraktchirurgie bei enger Pupille und postoperative Fibrinreaktion, insbesondere nach Sphinkterektomie.

BACKGROUND: Since increased intraoperative iris irritation can lead to increased postoperative inflammation, we are interested in postoperative reactions to several varied surgical procedures. We performed pupil stretching, iridotomy with iris suture, and partial sphincterectomy. MATERIALS AND METHODS: From January 1995 to January 1996, 100 patients (103 eyes) with narrow pupils underwent cataract surgery. In 13 eyes a iridotomy and iris suture were performed, in 28 eyes a partial sphincterectomy. In 62 eyes there was no surgical intervention after pupil stretching. Postoperative examinations were carried out in the early postoperative phase (up to 5 days postoperative) as well as 4 weeks after surgery. Fibrin reaction was classified according to 3 grades, (1) faint fibrinous threads, (II) fibrinous net, and (III) membranous fibrin exsudation. RESULTS: In the group without additional surgery there was a fibrinous reaction of grade I and II in 11 eyes. This complication occurred after iridotomy and iris suture in four cases and after sphincterectomy in four cases. While the intensity of fibrinous reaction was comparable in the first two groups, the fibrinous reaction after sphincterectomy was more intensive in one eye (grade III). However, response to intensive local antiphlogistic therapy was good. Frequency of fibrinous reaction in the three groups was statistically not significant. It should be pointed out that there was a partial restoration of pupil movements through sphincterectomy: mean pupil diameter was 4 mm, and 2.5 mm under exposure to light. Three patients had no pupillary reaction at all. CONCLUSIONS: Partial sphincterectomy facilities intraoperative manipulations of cataract surgery. Postoperative inflammatory reaction is rare and was very responsive to medical treatment. The reconstruction of pupillary movement is part of full visual function and, last but not least a round pupil is aesthetically more desirable.

Postoperative astigmatism and relative strength of tunnel incisions: a prospective clinical trial.

PURPOSE: To investigate the influence of incision depth and site on wound strength and postoperative astigmatism. SETTING: Virchow Memorial Hospital Eye Clinic, Berlin, Germany. METHODS: In this prospective, randomized study, 180 patients with a 7.0 mm tunnel incision depth of 300 and 500 microns; limbal incision and scleral incision; temporal scleral incision and scleral incision at the 12 o'clock position; temporal limbal incision and limbal incision at the 12 o'clock position. Postoperative astigmatism was measured by keratometry and videokeratoscopy 1 day, 1 and 4 weeks, and 8 months postoperatively. Wound strength was measured with an ophthalmodynamometer on the first postoperative day and after 1 week at the site with the least mechanical stability adjacent and posterior to the primary incision. RESULTS: The temporal incision, which was performed 1.0 mm behind the surgical limbus, led to induced astigmatism of 0.65 diopters (D) +/- 0.23 (SD) after 8 months. When incision was at the 12 o'clock position, the induced astigmatism was 0.97 +/- 0.41 D. Induced astigmatism was highest following a limbal incision in the 12 o'clock position (1.33 +/- 0.63 D). This effect was less pronounced with a temporal incision. Incision depth did not significantly influence induced astigmatism. An incision depth of 500 microns led to induced astigmatism of 0.94 +/- 0.50 D; a depth of 300 microns led to induced astigmatism of 0.78 +/- 0.64 D. After 1 week, wound strength was highest with temporal scleral incisions (38.6 +/- 2.1 kPa by ophthalmodynamometer) and lowest with limbal incisions in the 12 o'clock position (30.8 +/- 7.7 kPa). CONCLUSIONS: Incisions site significantly influenced mechanical wound strength and induced astigmatism; incision depth influenced neither. In general, incisions in the 12 o'clock position induced more astigmatism than temporal incisions.

[3 1/2 years experiences with ECCE with tunnel incision]. / Dreieinhalb Jahre Erfahrung bei ECCE mit Tunnelschnitt.

Since January 1992 planned extracapsular cataract extraction (ECCE) is performed routinely with the no-stitch technique at our clinic. To minimize surgically induced astigmatism further, modified wound constructions for planned ECCE with on 1.1-mm tunnel width were evaluated. The follow-up time was up to 3 years postoperatively. For 250 eyes wound closure was performed prospectively either sutureless (n = 70), with a single perpendicular suture (n = 100) or cross sutures (n = 40) at the 12 o'clock position or sutureless in the temporal position (n = 40). The complication rate was 4% (filtering bleb, iris prolapse or transient hypotonia). There were no wound ruptures, but once endophthalmitis was observed. Late mean astigmatism after up to 3 years follow-up for vertical incision was 2.05 +/- 1.16 D (1.01 +/- 0.96 D preoperatively) for sutureless wound closure, 1.63 +/- 1.08 D (0.86 +/- 0.95 D) for perpendicular and 1.76 +/- 0.88 D (0.73 +/- 0.55 D) for cross-sutures. A temporal incision resulted in 0.78 +/- 0.52 D (1.0 +/- 0.69 D) of astigmatism and was only performed on eyes with against the rule astigmatism preoperatively. Surgically induced astigmatism was stabilized early. For with the rule astigmatism preoperatively, a 12 o'clock incision with a perpendicular single suture is recommended and for against the rule astigmatism, a temporal incision.

[Incidence of recurrence after primary pterygium excision, phototherapeutic keratectomy with the ArF:Excimer laser and local mitomycin C administration]. / Die Rezidivhäufigkeit nach primärer Pterygiumexzision, phototherapeutischer Keratektomie (PTK) mit dem ArF:Excimerlaser und lokaler Mitomycin-C-Applikation.

BACKGROUND: In this clinical trial the recurrence-rate after primary pterygium-excision, phototherapeutic keratectomy with the ArF:excimerlaser and local application of mitomycin C should be estimated. MATERIAL AND METHODS: Forty eyes of 38 patients underwent primary pterygium-excision using a bare-sclera technique. All patients underwent phototherapeutic keratectomy (PTK) with the ArF:excimerlaser of the wound region. Postoperative all patients were treated with mitomycin C 0.02% twice daily for four days and for 4-6 weeks with a combination of gentamycin and dexametason eye drops triple a day. Minimum follow-up was 24 month (median 41 month). RESULTS: Two eyes developed a recurrence after 12 and 28 month respectively. The overall recurrence rate was 5% (corneal recurrence 2.5%). One patient developed a minute granuloma in the area of the excision. There were no other complications during the follow-up. CONCLUSIONS: The excision of pterygium using the bare-sclera technique, phototherapeutic keratektomy und local application of mitomycin C 0.02% eye drops is a safe method with a low recurrence-rate. All recurrences occured after more than one year postoperatively.

Influence of cell isolation and recording technique on the voltage dependence of the fast cardiac sodium current of the rat.

We measured macroscopic sodium currents (INa) in preparations from adult rat ventricle under four different conditions (I-IV): using the cell attached configuration of the tight-seal patch clamp technique on cells isolated with either trypsin followed by collagenase (I) or with collagenase only (II), and using the loose patch technique on cells isolated with collagenase (II) as well as on multicellular preparations not subjected to enzyme treatment (IV). The voltage dependence of the steady-state activation of INa as well as of the steady-state inactivation differed significantly among condition I and II. Moreover, the recordings were voltage shifted in comparison to the recording condition III and IV. The potentials of half maximal activation and inactivation were: [sequence data: see text] The shift of inactivation was time dependent and continued after 3-5 min after the seal formation in condition I, but not in condition II. No time dependent shift was found in III and IV. We conclude, that the voltage dependence of cardiac sodium current is shifted by gigaseal patch recording. The degree of this shift depends on the type of enzymatic isolation procedure, with trypsin causing more pronounced effects than collagenase. The cell isolation itself seems not to interfere with the voltage dependence of INa, since loose patch recordings from multicellular preparations and from single cells isolated with collagenase show no obvious differences.

[Pathophysiology of cardiac arrhythmias]. / Pathophysiologie der Herzrhythmusstörungen.

Cardiac arrhythmias are ambiguous symptoms. Intracardiac as well as extracardiac alterations may be responsible. There is little direct information from the ECG concerning their pathophysiological mechanism. Bradycardic as well as tachycardic arrhythmias can be the result of two different fundamental disturbances: alterations of impulse formation (automaticity) or alterations of impulse conduction. Either one of these, or both of them acting together, may be responsible for the arrhythmia. Tachycardias due to disturbances of impulse formation may be brought about by enhanced firing of regular pacemakers (sino-atrial node, av-node, ventricular conduction system), by abnormal automaticity occurring in ordinary atrial or ventricular myocardium, or by triggered activity due to early or delayed afterdepolarizations. Bradycardic disturbances of impulse formation are primarily concerned with sino-atrial nodal function. Bradycardic conduction disturbances mainly impair sinoatrial or atrioventricular propagation causing partial or total conduction block. Tachyarrhythmias due to disturbances of conduction are generated by re-entry of excitatory waves either along anatomically preformed pathways or around functional obstacles (refractory zones) with excitable gaps being more or less pronounced. On the cellular level, altered activities of ionic channels or transport systems play a significant part. Such changes are caused by: alterations of electrolyte composition (potassium, sodium, calcium), acidosis or alkalosis, autonomic and hormonal influences, membrane active metabolites (long-chain acylcarnitine, lysophosphatidylcholine), drugs (class I and III antiarrhythmics, cardiac glycosides) and poisons. In disturbances of conduction other aspects like geometry of pathways or cable properties (anisotropic conduction, coupling resistances between cells) are of particular significance.(ABSTRACT TRUNCATED AT 250 WORDS)

Differential analysis of frequency-dependent effects of antiarrhythmic drugs: importance of the saturation behavior of frequency-dependent sodium-channel blockade.

Frequency-dependent effects of class I antiarrhythmic drugs on Vmax reported in the literature are analyzed with respect to periodical drug binding to sodium channels. The analysis reveals that class I action can be differentiated according to the onset kinetics as well as to the saturation behavior of frequency-dependent sodium-channel blockade at increasing frequencies. As will be shown, class I drugs even of the same subclass (Ic) may differ markedly from each other with respect to the saturation behavior of frequency-dependent block. These findings may be of interest in view of the Cardiac Arrhythmia Suppression Trial (CAST) because the results found with flecainide and encainide in this study are usually extrapolated to other Ic drugs. Additionally, the influence of postrepolarization refractoriness caused by a class I drug on the action potential shortening during repetitive premature stimulation is compared with the effects of prolongation of absolute refractoriness induced by a class III drug.