Quality of life of patients with locally advanced head and neck cancer treated with induction chemotherapy followed by cisplatin-containing chemoradiotherapy in the Dutch CONDOR study: a randomized controlled trial.

PURPOSE: The CONDOR study showed that docetaxel/cisplatin/5-fluorouracil (TPF) followed by conventional radiotherapy with cisplatin 100 mg/m2 on days 1, 22, and 43 (cis100 + RT; n = 27)) versus accelerated radiotherapy with cisplatin weekly 40 mg/m2 (cis40 + ART; n = 29) in locally advanced head and neck cancer (LAHNC) patients was not feasible. Here, we report the analysis of health-related quality of life (HRQOL) of the patients entered in this study. METHODS: HRQOL was assessed at baseline, after two TPF, before start of chemoradiotherapy, and 1, 4, 8, 12, and 24 months after completion of chemoradiotherapy using the EORTC-QLQ-C30 and QLQ-H&N35 in 62 patients. RESULTS: Compliance with the QOL questionnaires was 94% (59/62) at baseline and 61% (30/49) at 12 months, respectively. HRQOL decreased after TPF and further decreased during chemoradiohteray in both arms equally. Pain and swallowing dysfunction improved significantly during TPF but deteriorated below baseline levels during chemoradiotherapy, cis40 + ART > cis100 + RT (p < 0.05). HRQOL and symptoms restored to baseline within 12 months in both arms and remained at that level until 24 months. CONCLUSIONS: After TPF, cis40 + ART had a larger negative impact on symptoms than cis100 + RT, probably due to the ART. HRQOL and symptoms restored to baseline levels within 12 months after end of treatment in both arms, which is an important perspective for patients during the phase of most serious acute side effects of treatment. TRIAL REGISTRATION: NCT00774319.

A Markov Decision Model to Guide Treatment of Recurrent Colonic Diverticulitis.

BACKGROUND & AIMS: Although colonic diverticulitis is a common disorder, there is no clear treatment strategy for patients with recurrent episodes of diverticulitis. We investigated whether colonic resection or conservative or medical treatments have the greatest effects on quality-adjusted life-years (QALYs). METHODS: A Markov model simulating patients with 2 episodes of non-surgically treated diverticulitis was used to simulate all relevant outcomes of each treatment strategy. A 1-year cycle length with 10-year follow-up period was used to allow for chance of recurrent diverticulitis. Primary outcome was QALYs gained from each strategy. Factors considered were morbidity, mortality, chance of colostomy formation, risk of recurrence, and persistence of abdominal pain. The probabilities of clinical events were determined by using the best available published data. RESULTS: A strategy in which colonic resection was performed after 2 episodes of diverticulitis was associated with the lowest quality-adjusted survival (a gain of 8.66 QALYs) and highest chance of stoma formation (1.1%) but the lowest chance of a mild (3.5%) or severe (1.1%) recurrence. The strategies of colonic resection or conservative or medical treatment after the third episode of diverticulitis were comparable in terms of quality-adjusted survival, providing 8.78, 8.76, and 8.74 QALYs, respectively. Probabilistic sensitivity analysis did not change these results. Persistent abdominal complaints were lowest in the medical treatment strategy. CONCLUSIONS: Elective surgery after 2 episodes of diverticulitis should be questioned in terms of QALYs. After the third episode of diverticulitis, surgical or conservative or medical treatments provide similar QALYs, but rates of abdominal symptoms are lower with the medical treatment strategy. This Markov decision model has limitations when the individual patient and physician face a complex decision weighing early and long-term risks and benefits of elective surgery or conservative management.

Toward an evidence-based step-up approach in diagnosing diverticulitis.

BACKGROUND: The lack of pathognomonic findings and the chance of complicated disease have resulted in the widespread use of additional imaging to diagnose acute colonic diverticulitis (ACD). The added value of additional imaging in the diagnostic workup of patients suspected of ACD is not well defined. AIMS: The aim of this study was to systematically review the literature of the accuracy of the clinical evaluation and diagnostic modalities for patients with suspected ACD, to come to an evidence-based approach to diagnose ACD. METHODS: A systematic review and meta-analysis of studies that reported diagnostic accuracy of the clinical diagnosis and diagnostic modalities in patients with suspected diverticulitis were performed. Study quality was assessed with the STARD checklist. True-positive, true-negative, false-positive, and false-negative findings were extracted and pooled estimates of sensitivity and specificity per diagnostic test were calculated, if applicable. RESULTS: The overall quality of the studies reporting the diagnostic accuracy of the clinical diagnosis, contrast enema and magnetic resonance imaging (MRI) were moderate to poor and not suitable for meta-analysis. Sensitivity of the clinical diagnosis varied between 64% and 68%. Ultrasound (US) and computed tomography (CT) studies were eligible for meta-analysis. Summary sensitivity estimates for US were 90% (95% CI: 76-98%) versus 95% (95% CI: 91-97%) for CT (p = 0.86). Summary specificity estimates for US were 90% (95% CI: 86-94%) versus 96% (95% CI: 90-100%) for CT (p = 0.04). Sensitivity for MRI was 98% and specificity varied between 70% and 78%. Sensitivity of contrast enema studies varied between 80% and 83%. CONCLUSION: In two-thirds of the patients, the diagnosis of ACD can be made based on clinical evaluation alone. In one-third of the patients, additional imaging is a necessity to establish the diagnosis. US and CT are comparable in diagnosing diverticulitis and superior to other modalities. CT has the advantage of higher specificity and the ability to identify alternative diagnoses. The role of MRI is not yet clear in diagnosing ACD. Contrast enema is considered an obsolete imaging technique to diagnose ACD based on lower sensitivity and specificity than US and CT. A step-up approach with CT performed after an inconclusive or negative US, seems a logical and safe approach for patients suspected of ACD.

Effectiveness of heparin solution versus normal saline in maintaining patency of intravenous locks in neonates: a double blind randomized controlled study.

AIM: The aim of this study was to evaluate the effect of heparin versus saline as flush solution for maintaining patency in peripheral intravenous locks in neonates and to investigate whether other variables influence the longevity of intravenous locks. BACKGROUND: Heparin is usually used as a regular flush solution to prevent occlusion of peripheral intravenous locks in neonates. There is no clear recommendation using heparin or saline flushing peripheral intravenous locks in neonates. The disadvantage of heparin cannot be ignored, especially in this patient group. METHODS: In a double blind prospective randomized study, neonates (gestational age >27 weeks) with intravenous locks were randomly assigned to receive heparin or saline as a flush solution in a 21-month period (2002-2004). The main outcome was the duration of patency. RESULTS: Eighty-eight neonates were included. No statistically significant difference was found in patency of peripheral intravenous locks flushed with 0.7 mL heparin (10 units/mL) (N = 42, median 56 hours) or 0.7 mL saline (N = 46, median 61 hours). When the analysis was confined to removed locks because of non-elective events, no statistically significant difference was found in duration of patency (P = 0.27). CONCLUSION: As no difference in patency could be established, using saline as a flush solution is preferable to heparin in peripheral intravenous locks in neonates, given the greater likelihood of complications associated with heparin. Although these data are more than 5 years old, the relevance of the outcome is still important for the clinical practice because of the potential adverse effects of heparin in these vulnerable infants.

Correlation of Morphology and Function of Flecks Using Short-Wave Fundus Autofluorescence and Microperimetry in Patients With Stargardt Disease.

Purpose: The purpose of this study was to evaluate the functional relevance of longitudinal changes in hyperautofluorescent areas and flecks in Stargardt disease (STGD1) using short-wavelength autofluorescence (SW-AF) imaging. Methods: In this prospective, longitudinal study, 31 patients with STGD1 (56 eyes) underwent microperimetry (MP) and SW-AF imaging twice in 3 to 5 years. A total of 760 MP test points were included in the statistical analysis based on stable fixation and accurate alignment of SW-AF and MP. Autofluorescence intensity was qualitatively assessed in all MP test points. Small circumscriptive hyperautofluorescent lesions were defined as flecks. Longitudinal imaging characteristics observed on SW-AF were classified into the following categories: appearing, disappearing, and stable flecks, stable hyperautofluorescent, and stable background autofluorescence. The relationship between SW-AF intensity changes and MP changes was analyzed using a linear mixed model corrected for baseline sensitivity. Results: Retinal sensitivity declined most in locations without change in SW-AF intensity. Functional decline per year was significantly larger in flecks that disappeared (-0.72 ± 1.30 dB) compared to flecks that appeared (-0.34 ± 0.65 dB), if baseline sensitivity was high (≥10 dB; P < 0.01). The correlation between the change observed on SW-AF and the sensitivity change significantly depended on the sensitivity at baseline (P = 0.000). Conclusions: Qualitative longitudinal assessment of SW-AF poorly reflected the retinal sensitivity loss observed over the course of 3 to 5 years. Translational Relevance: When aiming to assess treatment effect on lesion level, a multimodal end point including MP focused on hyperautofluorescent lesions appears essential but needs further studies on optimizing MP grids, eye-tracking systems, and alignment software.

Affective symptoms and apathy in myotonic dystrophy type 1 a systematic review and meta-analysis.

BACKGROUND: To gain insight into the prevalence of apathy, depression and anxiety symptoms in myotonic dystrophy type 1 (DM1) patients on the basis of a systematic review with a meta-analysis. METHODS: One author systematically searched and selected studies from Embase, Medline, PsychInfo and Web of Science (index periods up to August 2018). Data extraction and bias assessment were performed independently by two authors. We calculated (1) a weighted pooled prevalence and (2) weighted pooled standardized mean difference (Hedges' g) from studies comparing DM1 patients to healthy and/or neuromuscular disease controls separately for symptoms of depression, anxiety and apathy. RESULTS: The pooled prevalences of depression (26 studies, n = 1267 DM1 patients), anxiety (19 studies, n = 896) and apathy (5 studies, n = 428), were 18% (95%CI: 12-25), 16 (95%CI: 13-18) and 55% (95%CI: 50-60), respectively. Effect sizes (Hedges' g) for depression, anxiety and apathy in DM1 patients compared to healthy controls were 1.04 (95%-CI: 0.71 to 1.37), 0.87 (95%-CI: 0.51 to 1.24) and 1.13 (95%-CI:0.54-1.71). Effect sizes for symptoms of depression, anxiety and apathy were 0.29 (95% CI: -0.12 to 0.70), 0.45 (95%-CI: -0.31 to 1.22) and 1.12 (95%-CI: 0.32-1.93) for DM1 patients versus neuromuscular disease controls. In most analyses, statistical heterogeneity was high. CONCLUSIONS: Estimated pooled prevalences of clinically significant levels of symptoms of depression, anxiety and apathy in DM1 are 19, 17 and 55% respectively. Symptoms of depression and anxiety in DM1 may reflect reactive adjustment to progressive impairment and restricted participation similar to other chronic neuromuscular disease. The literature on the prevalence and severity of apathy, although a clinically relevant and characteristic symptom of DM1, is relatively scarce.

The cognitive profile of myotonic dystrophy type 1: A systematic review and meta-analysis.

OBJECTIVE: To examine the cognitive profile of patients with myotonic dystrophy type 1 (DM1) on the basis of a systematic review and meta-analysis of the literature. METHODS: Embase, Medline and PsycInfo were searched for studies reporting ≥1 neuropsychological test in both DM1 patients and healthy controls. Search, data extraction and risk of bias analysis were independently performed by two authors to minimize error. Neuropsychological tests were categorized into 12 cognitive domains and effect sizes (Hedges' g) were calculated for each domain and for tests administered in ≥5 studies. RESULTS: DM1 participants demonstrated a significantly worse performance compared to controls in all cognitive domains. Effect sizes ranged from -.33 (small) for verbal memory to -1.01 (large) for visuospatial perception. Except for the domains global cognition, intelligence and social cognition, wide confidence intervals (CIs) were associated with moderate to marked statistical heterogeneity that necessitates careful interpretation of results. Out of the individual tests, the Rey-Osterrieth complex figure-copy (both non-verbal memory and visuoconstruction) showed consistent impairment with acceptable heterogeneity. CONCLUSION: In DM1 patients, cognitive deficits may include a variable combination of global cognitive impairment with involvement across different domains, including social cognition, memory and visuospatial functioning. Although DM1 is a heterogeneous disorder, our study shows that meta-analysis is feasible, contributes to the understanding of brain involvement and may direct bedside testing. The protocol for this study has been registered in PROSPERO (International prospective register of systematic reviews) under ID: 42016037415.

Insight into the number of pre-malignancies and malignancies of the skin in a hospital population in the Netherlands.

BACKGROUND: Skin cancer incidence is rising, placing a burden on healthcare systems worldwide. This problem may even be more extensive than expected, since registration of (pre)malignancies of the skin is poor. OBJECTIVE: To provide insight into the numbers of (pre)malignancies in patients with actinic keratosis (AK) or basal cell carcinoma (BCC) in 2 university and 2 general hospitals. METHODS: The types and numbers of previous tumours and of tumours during a two-year follow-up were collected from 574 patients. RESULTS: Mean time between the first diagnosed (pre)malignancy and time of inclusion was 6.6 years. Overall, 60% had multiple types of (pre)malignancies. In BCC patients, 61% had multiple BCCs, in patients with squamous cell carcinoma (SCC), 40% had multiple SCCs. The combination 'BCC and SCC' occurred in 10%, 'BCC and AK' in 47%, 'SCC and AK' in 14%. CONCLUSION: High numbers of patients with multiple (pre)malignancies were found in this patient population in university and general hospitals, which may well reflect the Dutch hospital population. We conclude that skin cancer patients are more extensively affected than was expected up till now. Consequently, the management of skin cancer may be in need of adaptation in near future and the question arises whether dermatologists have the capacity for providing care for all these patients.

Shared medical appointments improve QOL in neuromuscular patients: a randomized controlled trial.

OBJECTIVE: To systematically study the effects of shared medical appointments (SMAs) compared with individual appointments for patients with a chronic neuromuscular disorder and their partners. METHODS: In this randomized controlled trial with a follow-up of 6 months, we included patients with a chronic neuromuscular disorder and their partners. Participants were randomly allocated to an SMA or an individual outpatient appointment. The primary outcome measure was patients' health-related quality of life (QOL) (36-Item Short Form Health Survey). Secondary outcome measures included self-efficacy, social support, patient and partner satisfaction with the appointment, and time available per patient. RESULTS: Two hundred seventy-two patients and 149 partners were included. Health-related QOL showed greater improvement in patients who had attended an SMA (mean difference 2.8 points, 95% confidence interval 0.0-5.7, p = 0.05). Secondary outcomes showed small improvements in the control group for satisfaction with the appointment (p = 0.01). Neurologists spent less time per patient during the SMAs: mean 16 minutes (range 11-30) vs. 25 minutes (range 20-30) for individual appointments. CONCLUSIONS: This study provides evidence that SMAs can improve aspects of QOL of patients with a chronic neuromuscular disorder. This could result in an alternative to individual appointments and improvements in both effectiveness and efficiency. Further research to optimize SMAs and to identify critical success factors seems warranted. These data extend evidence on SMAs for neurologic patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with chronic neuromuscular disorders, SMAs improve QOL as compared with individual medical appointments.

A quantitative assessment of costimulation and phosphatase activity on microclusters in early T cell signaling.

T cell signaling is triggered through stimulation of the T cell receptor and costimulatory receptors. Receptor activation leads to the formation of membrane-proximal protein microclusters. These clusters undergo tyrosine phosphorylation and organize multiprotein complexes thereby acting as molecular signaling platforms. Little is known about how the quantity and phosphorylation levels of microclusters are affected by costimulatory signals and the activity of specific signaling proteins. We combined micrometer-sized, microcontact printed, striped patterns of different stimuli and simultaneous analysis of different cell strains with image processing protocols to address this problem. First, we validated the stimulation protocol by showing that high expression levels CD28 result in increased cell spreading. Subsequently, we addressed the role of costimulation and a specific phosphotyrosine phosphatase in cluster formation by including a SHP2 knock-down strain in our system. Distinguishing cell strains using carboxyfluorescein succinimidyl ester enabled a comparison within single samples. SHP2 exerted its effect by lowering phosphorylation levels of individual clusters while CD28 costimulation mainly increased the number of signaling clusters and cell spreading. These effects were observed for general tyrosine phosphorylation of clusters and for phosphorylated PLCγ1. Our analysis enables a clear distinction between factors determining the number of microclusters and those that act on these signaling platforms.

Mannitol as salvage treatment for Complex Regional Pain Syndrome Type I.

INTRODUCTION: Complex Regional Pain Syndrome Type I (CRPS I) is a continuation of symptoms and signs due to a pathological exaggerated reaction in an extremity of the human body after an injury or operation. Although the clinical picture of CRPS I in the majority of patients is well known, the underlying pathophysiology remains unclear. In The Netherlands, intravenous mannitol administration used as hydroxyl radical scavenger for patients who do not respond to conservative treatment of CRPS I is advocated but little evidence supports this salvage strategy. In this study the effect of mannitol as salvage medication was evaluated in a well-defined multimodal step-up treatment protocol. PATIENTS AND METHODS: A consecutive group of 68 adult patients with persistent CRPS I was analysed, who underwent a total of 100 mannitol infusions. The effect of treatment was considered per sign and per symptom according to the Veldman et al. criteria for CRPS I. RESULTS: Overall improvement of CRPS I after mannitol treatment was successful in 24% after 1 week, and in 30% after 1 month. Mannitol treatment had some effect in patients with initially warm CRPS I in contrast to patients with cold CRPS I (OR=6.30 with CI [2.37-16.75]). Also patients with CRPS I at the upper extremity had more benefit than patients with CRPS I at the lower extremity (OR=3.26 with CI [1.34-7.93]). Poor results of mannitol treatment were associated with cold CRPS I (p<0.001), chronic CRPS I (p=0.04) and multiple mannitol treatments (p=0.04). CONCLUSION: Mannitol did not significantly contribute to the overall success of treatment in patients with CRPS I. Patients, presenting with acute, warm CRPS I in the upper extremity may have some benefit.