Introduction
The aim of this systematic review and meta-analysis was to evaluate the best currently available evidence from randomized controlled trials comparing pulsed electromagnetic fields (PEMF) ...or low-intensity pulsed ultrasound (LIPUS) bone growth stimulation with placebo for acute fractures.
Materials and methods
We performed a systematic literature search of the medical literature from 1980 to 2013 for randomized clinical trials concerning acute fractures in adults treated with PEMF or LIPUS. Two reviewers independently determined the strength of the included studies by assessing the risk of bias according to the criteria in the Cochrane Handbook for Systematic Reviews of Interventions.
Results
Seven hundred and thirty-seven patients from 13 trials were included. Pooled results from 13 trials reporting proportion of nonunion showed no significant difference between PEMF or LIPUS and control. With regard to time to radiological union, we found heterogeneous results that significantly favoured PEMF or LIPUS bone growth stimulation only in non-operatively treated fractures or fractures of the upper limb. Furthermore, we found significant results that suggest that the use of PEMF or LIPUS in acute diaphyseal fractures may accelerate the time to clinical union.
Conclusions
Current evidence from randomized trials is insufficient to conclude a benefit of PEMF or LIPUS bone growth stimulation in reducing the incidence of nonunions when used for treatment in acute fractures. However, our systematic review and meta-analysis suggest that PEMF or LIPUS can be beneficial in the treatment of acute fractures regarding time to radiological and clinical union. PEMF and LIPUS significantly shorten time to radiological union for acute fractures undergoing non-operative treatment and acute fractures of the upper limb. Furthermore, PEMF or LIPUS bone growth stimulation accelerates the time to clinical union for acute diaphyseal fractures.
Volatile organic compounds (VOCs) in exhaled breath have the potential to be used as biomarkers for screening and diagnosis of diseases. Clinical studies are often complicated by both modifiable and ...non-modifiable factors influencing the composition of VOCs in exhaled breath. Small laboratory animal studies contribute in obtaining fundamental insight in alterations in VOC composition in exhaled breath and thereby facilitate the design and analysis of clinical research. However, long term animal experiments are often limited by invasive breath collection methods and terminal experiments. To overcome this problem, a novel device was developed for non-invasive breath collection in mice using glass nose-only restrainers thereby omitting the need of anesthetics. C57Bl/6 J mice were used to test reproducibility and different air sampling settings for air-flow (ml min
) and time (minutes). Exhaled air was collected on desorption tubes and analysed for VOCs by gas chromatography time-of-flight mass spectrometry (GC-tof-MS). In total 27 compounds were putatively identified and used to assess the variability of the VOC measurements in the breath collections. Best reproducibility is obtained when using an air flow of 185 ml min
and a collection time of 20 min. Due to the non-invasive nature of breath collections in murine models, this device has the potential to facilitate VOC research in relation to disturbed metabolism and or disease pathways.
SummaryBackgroundTrastuzumab duocarmazine is a novel HER2-targeting antibody–drug conjugate comprised of trastuzumab covalently bound to a linker drug containing duocarmycin. Preclinical studies ...showed promising antitumour activity in various models. In this first-in-human study, we assessed the safety and activity of trastuzumab duocarmazine in patients with advanced solid tumours. MethodsWe did a phase 1 dose-escalation and dose-expansion study. The dose-escalation cohort comprised patients aged 18 years or older enrolled from three academic hospitals in Belgium, the Netherlands, and the UK with locally advanced or metastatic solid tumours with variable HER2 status who were refractory to standard cancer treatment. A separate cohort of patients were enrolled to the dose-expansion phase from 15 hospitals in Belgium, the Netherlands, Spain, and the UK. Dose-expansion cohorts included patients aged 18 years or older with breast, gastric, urothelial, or endometrial cancer with at least HER2 immunohistochemistry 1+ expression and measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST). Trastuzumab duocarmazine was administered intravenously on day 1 of each 3-week cycle. In the dose-escalation phase, trastuzumab duocarmazine was given at doses of 0·3 mg/kg to 2·4 mg/kg (3 + 3 design) until disease progression or unacceptable toxicity. The primary endpoint of the dose-escalation phase was to assess safety and ascertain the recommended phase 2 dose, which would be the dose used in the dose-expansion phase. The primary endpoint of the dose-expansion phase was the proportion of patients achieving an objective response (complete response or partial response), as assessed by the investigator using RECIST version 1.1. This ongoing study is registered with ClinicalTrials.gov, number NCT02277717, and is fully recruited. FindingsBetween Oct 30, 2014, and April 2, 2018, 39 patients were enrolled and treated in the dose-escalation phase and 146 patients were enrolled and treated in the dose-expansion phase. One dose-limiting toxic effect (death from pneumonitis) occurred at the highest administered dose (2·4 mg/kg) in the dose-escalation phase. One further death occurred in the dose-escalation phase (1·5 mg/kg cohort) due to disease progression, which was attributed to general physical health decline. Grade 3–4 treatment-related adverse events reported more than once in the dose-escalation phase were keratitis (n=3) and fatigue (n=2). Based on all available data, the recommended phase 2 dose was set at 1·2 mg/kg. In the dose-expansion phase, treatment-related serious adverse events were reported in 16 (11%) of 146 patients, most commonly infusion-related reactions (two 1%) and dyspnoea (two 1%). The most common treatment-related adverse events (grades 1–4) were fatigue (48 33% of 146 patients), conjunctivitis (45 31%), and dry eye (45 31%). Most patients (104 71% of 146) had at least one ocular adverse event, with grade 3 events reported in ten (7%) of 146 patients. No patients died from treatment-related adverse events and four patients died due to disease progression, which were attributed to hepatic failure (n=1), upper gastrointestinal haemorrhage (n=1), neurological decompensation (n=1), and renal failure (n=1). In the breast cancer dose-expansion cohorts, 16 (33%, 95% CI 20·4–48·4) of 48 assessable patients with HER2-positive breast cancer achieved an objective response (all partial responses) according to RECIST. Nine (28%, 95% CI 13·8–46·8) of 32 patients with HER2-low, hormone receptor-positive breast cancer and six (40%, 16·3–67·6) of 15 patients with HER2-low, hormone receptor-negative breast cancer achieved an objective response (all partial responses). Partial responses were also observed in one (6%, 95% CI 0·2–30·2) of 16 patients with gastric cancer, four (25%, 7·3–52·4) of 16 patients with urothelial cancer, and five (39%, 13·9–68·4) of 13 patients with endometrial cancer. InterpretationTrastuzumab duocarmazine shows notable clinical activity in heavily pretreated patients with HER2-expressing metastatic cancer, including HER2-positive trastuzumab emtansine-resistant and HER2-low breast cancer, with a manageable safety profile. Further investigation of trastuzumab duocarmazine for HER2-positive breast cancer is ongoing and trials for HER2-low breast cancer and other HER2-expressing cancers are in preparation. FundingSynthon Biopharmaceuticals.
Summary
Background
Drug survival is a marker for treatment success. To date, no analyses relating dermatological quality‐of‐life measures to drug survival have been published.
Objectives
(i) To ...describe 1‐year drug survival for adalimumab, etanercept and ustekinumab in a daily practice psoriasis cohort, and (ii) to introduce the concept of ‘happy’ drug survival, defined as Dermatology Life Quality Index (DLQI) ≤ 5 combined with being ‘on drug’ at a specific time point.
Methods
Data were extracted from a prospective registry. Drug survival was analysed using Kaplan–Meier estimates. ‘Happy’ drug survival was calculated, with data split into ‘happy’ (DLQI ≤ 5) vs. ‘unhappy’ (DLQI > 5) at baseline and months 3, 6, 9 and 12.
Results
249 treatment episodes were included (101 adalimumab, 82 etanercept, 66 ustekinumab). The 1‐year drug survival rates for ustekinumab, adalimumab and etanercept were 85%, 74% and 68%, respectively. Ustekinumab showed a better confounder‐corrected drug survival vs. etanercept hazard ratio (HR) 3·8, P = 0·02 and a trend towards better survival vs. adalimumab (HR 2·3, P = 0·1). At baseline, the majority (n = 115, 73%) was considered ‘unhappy’ and a minority ‘happy’ (n = 42, 27%) (ratio ‘happy’:‘unhappy’ was 1 : 2.7). The percentage of treatment episodes with ‘happy’ on‐drug patients increased to 79% after 1 year.
Conclusions
Ustekinumab showed a better overall drug survival than etanercept, and a trend towards a better overall drug survival than adalimumab. After 1 year, patients reported to be ‘happy’ in 79% of episodes and ‘unhappy’ in 21%. We introduced the new concept of ‘happy’ drug survival because the proportion of on‐drug patients with good quality of life is an important indicator for treatment success.
What's already known about this topic?
The Dermatology Life Quality Index is a validated score for dermatology‐specific quality‐of‐life measurements.
Drug survival studies of biologics for psoriasis show varying results and differ in study design and population.
To date, studies including drug survival rates for ustekinumab are scarce.
What does this study add?
The introduction of a concept named ‘happy’ drug survival, which combines drug survival rates with dermatology‐specific quality‐of‐life measures to evaluate treatments for psoriasis.
Analysis of ‘happy’ drug survival showed that the proportion of ‘on‐drug’ biologic users with a good quality of life increased from 27% to 79% after 1 year of treatment.
Ustekinumab showed a better overall drug survival vs. etanercept and a trend towards a better survival vs. adalimumab.
Background: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates gene expression in critical pathways involved in tumor growth and metastases. In this report, we investigated ...whether the level of HIF-1α is increased during carcinogenesis in breast tissue and is associated with other tumor biomarkers. Methods: Paraffin-embedded clinical specimens from five pathologic stages of breast tumorigenesis and from normal breast tissue were used. HIF-1α protein and the biomarkers vascular endothelial growth factor (VEGF), HER-2/neu, p53, Ki-67, and estrogen receptor (ER) were identified immunohistochemically, and microvessel density (a measure of angiogenesis) was determined. Associations among levels of HIF-1α and these biomarkers were tested statistically. All statistical tests are two-sided. Results: The frequency of HIF-1α-positive cells in a specimen increased with the specimen's pathologic stage (P<.001, χ2 test for trend) as follows: normal breast tissue (0 specimens with ≥1% HIF-1α-positive cells in 10 specimens tested), ductal hyperplastic lesions (0 in 10), well-differentiated ductal carcinomas in situ (DCIS) (11 in 20), well-differentiated invasive breast cancers (12 in 20), poorly differentiated DCIS (17 in 20), and poorly differentiated invasive carcinomas (20 in 20). Increased levels of HIF-1α were statistically significantly associated with high proliferation and increased expression of VEGF and ER proteins. In DCIS lesions, increased levels of HIF-1α were statistically significantly associated with increased microvessel density. HIF-1α showed a borderline association with HER-2/neu but no association with p53. Conclusions: The level of HIF-1α increases as the pathologic stage increases and is higher in poorly differentiated lesions than in the corresponding type of well-differentiated lesions. Increased levels of HIF-1α are associated with increased proliferation and increased expression of ER and VEGF. Thus, increased levels of HIF-1α are potentially associated with more aggressive tumors.
Summary
Background
It is important to assess which patients with psoriasis are more likely to achieve high clinical responses on biologics.
Objectives
To assess the number of treatment episodes (TEs) ...that achieve a 100% improvement in Psoriasis Area and Severity Index (PASI 100), PASI 90 or PASI ≤ 5 at week 24 of biological treatment, and which baseline patient characteristics predict treatment response.
Methods
Data from patients with psoriasis treated with adalimumab, etanercept, infliximab or ustekinumab were extracted from a prospective cohort. TEs with high clinical responses were described. Uni‐ and multivariate regression analyses were performed with the generalized estimating equation method to elucidate which baseline patient characteristics were predictors for PASI 90 and PASI ≤ 5 at week 24.
Results
In total, 454 TEs were extracted (159 adalimumab; 193 etanercept; 19 infliximab; 83 ustekinumab) from 326 patients. At week 24, in 3%, 15% and 59% of TEs, respectively, PASI 100, PASI 90 and PASI ≤ 5 was reached. In TEs without a PASI 100 or PASI 90 response, PASI ≤ 5 was still achieved in 58% and 52%, respectively. Baseline PASI ≥ 10 was a strong predictor for achieving PASI 90; baseline PASI < 10 and a lower baseline body mass index (BMI) were significant predictors for PASI ≤ 5 at week 24.
Conclusions
A limited number of patients achieved PASI 100 or PASI 90 at 24 weeks of biological treatment. Including an absolute PASI score in the assessment of psoriasis severity is important. Baseline BMI was an important, modifiable predictor for a high response.
What's already known about this topic?
A high clinical response in patients with psoriasis is shifting towards a 90% improvement compared with baseline Psoriasis Area and Severity Index (PASI 90).
To date, no studies have assessed which patients with psoriasis are more likely to achieve a high clinical response at week 24 of biological treatment.
What does this study add?
We focused on high responders, defined as achieving PASI 100, PASI 90 or PASI ≤ 5.
Frequency of reaching high clinical responses at 24 weeks of biological treatment was assessed, as were predictors that could identify patients with the ability to respond well to biological treatment.
In only a limited number of treatment episodes are PASI 90 (15%) or PASI 100 (3%) achieved.
Lower baseline body mass index is a predictor for achieving PASI ≤ 5.
Linked Comment: Zheng. Br J Dermatol 2017; 176:576.
Summary
Background
The efficacy of etanercept and ustekinumab in psoriasis has been compared in one randomized controlled trial. Comparison of the long‐term effectiveness of biologics in ...daily‐practice psoriasis treatment is currently lacking.
Objectives
To compare the effectiveness between the three widely used outpatient biologics adalimumab, etanercept and ustekinumab in daily‐practice psoriasis treatment and to correct for confounders.
Methods
Data were extracted from the prospective, multicentre BioCAPTURE registry. Multilevel linear regression analyses (MLRAs) and generalized estimating equation (GEE) analyses were performed on the course of mean Psoriasis Area and Severity Index (PASI) and PASI 75 (≥ 75% reduction vs. baseline). Both models were corrected for confounders. Subgroup analyses for biological dose were performed.
Results
We included 356 patients with 513 treatment episodes: 178 adalimumab, 245 etanercept and 90 ustekinumab. MLRA showed a similar effectiveness between adalimumab, etanercept and ustekinumab after 1 year, but the highest effectiveness for ustekinumab during 5 years of treatment (P = 0·047; ustekinumab vs. etanercept, P = 0·019). GEE analysis revealed a higher chance of attaining PASI 75 with adalimumab and ustekinumab than with etanercept at 1 year of treatment. A higher than label dose was more often used in patients treated with etanercept (adalimumab, etanercept and ustekinumab: respectively 31·5%, 55·1% and 17% after 1 year, P < 0·001; 39·3%, 71·4% and 24% after 5 years, P < 0·001).
Conclusions
Compared with etanercept, ustekinumab had the highest effectiveness during 5 years of treatment. Patients receiving adalimumab and ustekinumab more often reached PASI 75 than those on etanercept at 1 year of treatment. Dose escalation was more frequent in etanercept and adalimumab than in ustekinumab.
What's already known about this topic?
Randomized controlled clinical trials (RCTs) have shown that biologics are effective in treating selected patients with psoriasis.
RCTs comparing ustekinumab with adalimumab or etanercept with adalimumab have not been performed.
Patients from RCTs differ from patients in daily practice, and this might influence the effectiveness of biologics in the clinic.
What does this study add?
This prospective daily‐practice study compared the 1‐ and 5‐year effectiveness of adalimumab, etanercept and ustekinumab in psoriasis, corrected for confounders.
We showed a significantly higher confounder‐corrected Psoriasis Area and Severity Index (PASI) decrease for ustekinumab vs. etanercept over 5 years.
At 1 year of treatment, patients treated with adalimumab and ustekinumab had a higher chance of attaining PASI 75 than patients on etanercept after correction for confounders.
Etanercept was the agent most often prescribed in high doses in daily practice.
Respond to this article
Linked Comment: Ormerod. Br J Dermatol 2017; 176:856–857
Summary
Background
Predictors for successful treatment are important for personalized medicine. Predictors for drug survival of biologics in psoriasis have been assessed, but not split for different ...biologics or for the reason of discontinuation.
Objectives
To compare long‐term drug survival between the outpatient biologics adalimumab, etanercept and ustekinumab in patients with psoriasis, and to elucidate predictors for overall survival and drug discontinuation due to ineffectiveness and side‐effects for each biologic separately.
Methods
Ten years of data were extracted from the prospective, multicentre, long‐term BioCAPTURE registry. Kaplan–Meier survival analyses and confounder‐corrected multivariate Cox regression analysis for drug survival (MCR‐DS) were performed to compare drug survival between biologics. To elucidate the predictors for different reasons of discontinuation for each biologic, univariate Cox regression analyses and multivariate Cox regression analyses for predictors (MCR‐P) with backward selection were performed.
Results
In total, 526 treatment episodes – 186 adalimumab, 238 etanercept and 102 ustekinumab – were included covering 1333 treatment years. MCR‐DS showed a significantly higher overall survival for ustekinumab compared with adalimumab and etanercept. MCR‐P showed that higher body mass index (BMI) was a predictor for discontinuation due to ineffectiveness for etanercept and ustekinumab and that female sex was a predictor for discontinuation due to side‐effects for adalimumab, etanercept and ustekinumab.
Conclusions
Ustekinumab has the highest confounder‐corrected long‐term drug survival in psoriasis treatment, compared with adalimumab and etanercept. Higher BMI is a predictor for discontinuation due to ineffectiveness in etanercept and ustekinumab, and female sex is a consistent predictor for discontinuation due to side‐effects in all three outpatient biologics.
What's already known about this topic?
Drug survival of biologics for psoriasis has been analysed, but few publications used prospective multicentre daily‐practice data.
These studies found that ustekinumab had the highest confounder‐corrected overall drug survival, but they did not split survival analysis for the different biologics or for different reasons of discontinuation.
Different predictors for overall drug survival were found in prospective and retrospective studies.
What does this study add?
This study reports on a longer period of drug survival than previous studies.
Ustekinumab has a higher confounder‐corrected drug survival and higher survival for discontinuation due to ineffectiveness and side‐effects than adalimumab and etanercept.
Higher body mass index (BMI) predicts discontinuation due to ineffectiveness in etanercept and ustekinumab, and female sex is a consistent predictor for discontinuation due to side‐effects in all three biologics.
Linked Comment: Egeberg. Br J Dermatol 2016; 175:247–248
Plain language summary available online
The best practice for the organization of follow-up care in oncology is under debate, due to growing numbers of cancer survivors. Understanding survivors' preferences for follow-up care is elementary ...for designing patient-centred care. Based on data from prostate cancer and melanoma survivors, this study aims to identify: 1) preferences for follow-up care providers, for instance the medical specialist, the oncology nurse or the general practitioner; 2) characteristics associated with these preferences and 3) the preferred care provider to discuss cancer-related problems.
Survivors diagnosed with prostate cancer (N = 535) and melanoma (N = 232) between 2007 and 2013 as registered in The Netherlands Cancer Registry returned a questionnaire (response rate was 71% and 69%, respectively). A latent class cluster model analysis was used to define preferences and a multinomial logistic regression analysis was used to identify survivor-related characteristics associated with these preferences.
Of all survivors, 29% reported no preference, 40% reported a preference for the medical specialist, 20% reported a preference for both the medical specialist and the general practitioner and 11% reported a preference for both the medical specialist and the oncology nurse. Survivors who were older, lower/intermediate educated and women were more likely to have a preference for the medical specialist. Lower educated survivors were less likely to have a preference for both the medical specialist and the general practitioner. Overall, survivors prefer to discuss diet, physical fitness and fatigue with the general practitioner, and hereditary and recurrence with the medical specialist. Only a small minority favored to discuss cancer-related problems with the oncology nurse.
Survivors reported different preferences for follow-up care providers based on age, education level, gender and satisfaction with the general practitioner, showing a need for tailored follow-up care in oncology. The results indicate an urgency to educate patients about transitions in follow-up care.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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