Prolonged Temozolomide Maintenance Therapy in Newly Diagnosed Glioblastoma.

BACKGROUND: The impact of prolonging temozolomide (TMZ) maintenance beyond six cycles in newly diagnosed glioblastoma (GBM) remains a topic of discussion. We investigated the effects of prolonged TMZ maintenance on progression-free survival (PFS) and overall survival (OS). PATIENTS AND METHODS: In this retrospective single-center cohort study, we included patients with GBM who were treated with radiation therapy with concomitant and adjuvant TMZ. For analysis, patients were considered who either completed six TMZ maintenance cycles (group B), continued with TMZ therapy beyond six cycles (group C), or stopped TMZ maintenance therapy within the first six cycles (group A). Patients with progression during the first six TMZ maintenance cycles were excluded. RESULTS: Clinical data from 107 patients were included for Kaplan-Meier analyses and 102 for Cox regressions. Median PFS times were 8.1 months (95% confidence interval [CI] 6.1-12.4) in group A, 13.7 months (95% CI 10.6-17.5) in group B, and 20.9 months (95% CI 15.2-43.5) in group C. At first progression, response rates of TMZ/lomustine rechallenge were 47% in group B and 13% in group C. Median OS times were 12.7 months (95% CI 10.3-16.8) in group A, 25.2 months (95% CI 17.7-55.5) in group B, and 28.6 months (95% CI 24.4-open) in group C. Nevertheless, multivariate Cox regression for patients in group C compared with group B that accounted for imbalances of other risk factors showed no different relative risk (RR) for OS (RR 0.77, p = .46). CONCLUSION: Our data do not support a general extension of TMZ maintenance therapy beyond six cycles. The Oncologist 2017;22:570-575 IMPLICATIONS FOR PRACTICE: Radiation therapy with concomitant and adjuvant temozolomide (TMZ) maintenance therapy is still the standard of care in patients below the age of 65 years in newly diagnosed glioblastoma. However, in clinical practice, many centers continue TMZ maintenance therapy beyond six cycles. The impact of this continuation is controversial and has not yet been addressed in prospective randomized clinical trials. We compared the effect of more than six cycles of TMZ in comparison with exactly six cycles on overall survival (OS) and progression-free survival (PFS) by multivariate analysis and found a benefit in PFS but not OS. Thus, our data do not suggest prolonging TMZ maintenance therapy beyond six cycles, which should be considered in neurooncological practice.

Improved recognition of ineffective chest compressions after a brief Crew Resource Management (CRM) training: a prospective, randomised simulation study.

BACKGROUND: Chest compressions are a core element of cardio-pulmonary resuscitation. Despite periodic training, real-life chest compressions have been reported to be overly shallow and/or fast, very likely affecting patient outcomes. We investigated the effect of a brief Crew Resource Management (CRM) training program on the correction rate of improperly executed chest compressions in a simulated cardiac arrest scenario. METHODS: Final-year medical students (n = 57) were randomised to receive a 10-min computer-based CRM or a control training on ethics. Acting as team leaders, subjects performed resuscitation in a simulated cardiac arrest scenario before and after the training. Team members performed standardised overly shallow and fast chest compressions. We analysed how often the team leader recognised and corrected improper chest compressions, as well as communication and resuscitation quality. RESULTS: After the CRM training, team leaders corrected improper chest compressions (35.5%) significantly more often compared with those undergoing control training (7.7%, p = 0.03*). Consequently, four students have to be trained (number needed to treat = 3.6) for one improved chest compression scenario. Communication quality assessed by the Leader Behavior Description Questionnaire significantly increased in the intervention group by a mean of 4.5 compared with 2.0 (p = 0.01*) in the control group. CONCLUSION: A computer-based, 10-min CRM training improved the recognition of ineffective of chest compressions. Furthermore, communication quality increased. As guideline-adherent chest compressions have been linked to improved patient outcomes, our CRM training might represent a brief and affordable approach to increase chest compression quality and potentially improve patient outcomes.

Measurement of reading speed with standardized texts: a comparison of single sentences and paragraphs.

PURPOSE: We examined the influence of text length (single sentence versus a paragraph of several sentences) on the repeatability of reading speed measurements in normal-sighted subjects. METHODS: We compared reading speeds for the German versions of the Radner charts (single sentences of 14 words each) and the International Reading Speed Texts (IReST) charts (paragraphs, on average 132 words) in 30 normal-sighted elderly subjects aged 51-81 years (mean 64.5 years ± 7.2 SD). Three texts each of both lengths were read aloud in random order. The influence of text length (single sentence or paragraph) and text sample (each single text) on reading speed was calculated by a regression model and Bland-Altman analysis. RESULTS: Mean reading speed (words per minute) showed no significant difference for single sentences (170 wpm ± 33 SD) and paragraphs (167 wpm ±31 SD). Differences in reading speeds within one type of reading material were higher between single sentences than between paragraphs. Correlation coefficients between speeds were higher for paragraphs (r = 0.96-0.98) than for single sentences (r = 0.69-0.78). Variations between reading speeds for three texts of each length were markedly lower for paragraphs than for single sentences: (median, interquartile range [IQR]): 6.7, IQR 13.9; 3.0, IQR 8.3; -2.0, IQR 9.7 versus -8.8, IQR 29.6; 15.6, IQR 29.4; 22.7, IQR 19.4, respectively. CONCLUSIONS: Since reading speeds assessed with paragraphs show lower variance among texts than those for single sentences, they are better suited for repeated measurements, especially for long-term monitoring of the course of reading performance and for assessing effects of interventions in subjects with reading disorders.

Predictive value of food sensitization and filaggrin mutations in children with eczema.

BACKGROUND: It was reported that in infants with eczema and food sensitization, the presence of a filaggrin (FLG) null mutation predicts future asthma with a specificity and positive predictive value of 100%. OBJECTIVES: We sought to evaluate the predictive value of food sensitization and food allergy, FLG haploinsufficiency, and their combination in infants with early-onset eczema for persistent eczema and childhood asthma. METHODS: The German Infant Nutritional Intervention (GINI) and Influence of Lifestyle-related Factors on the Immune System and the Development of Allergies in Childhood (LISA) birth cohorts, as well as a collection of 65 cases of early-onset eczema with and without food allergy were investigated. RESULTS: The risk for asthma was significantly increased by food sensitization (positive diagnostic likelihood ratios [PLRs] of 1.9 [95% CI, 1.1-3.4] in the GINI cohort and 5.5 [95% CI, 2.8-10.8] in the LISA cohort) and the presence of an FLG mutation (PLRs of 2.9 [95% CI, 1.2-6.6] in the GINI cohort and 2.8 [95% CI, 1.0-7.9] in the LISA cohort) with a rather high specificity (79.1% and 92.9% in the GINI cohort and 89.0% and 91.7% in the LISA cohort, respectively) but low sensitivity (40.0% and 39.3% in the GINI cohort and 31.6% and 23.5% in the LISA cohort, respectively). Likewise, the risk for persistent eczema was increased. In the clinical cases neither food allergy nor FLG mutations had a significant effect. The combination of both parameters did not improve prediction and reached positive predictive values of 52.3% (GINI cohort), 66.9% (LISA cohort), and 30.6% (clinical cases), assuming an asthma prevalence in children with early eczema of 30%. CONCLUSION: Early food sensitization and the presence of an FLG mutation in infants with early eczema increase the risk for later asthma, but the combination of the 2 factors does not represent a clinically useful approach to reliably identify children at risk.

A comprehensive analysis of the COL29A1 gene does not support a role in eczema.

BACKGROUND: Based on a recent positional cloning approach, it was claimed that the collagen 29A1 gene (COL29A1), which encodes an epidermal collagen, represents a major risk gene for eczema underlying a previously reported linkage to chromosome 3q21. However, thus far, not a single replication attempt has been published, and no definitive functional data have been provided. OBJECTIVES: We aimed to determine whether COL29A1 polymorphisms contribute to eczema susceptibility and whether COL29A1 expression is altered in eczema. METHODS: We investigated the reported association of COL29A1 variants with eczema, subtypes of eczema, and eczema-related traits in 5 independent and large study populations comprehensively phenotyped for allergic diseases: a set of 1687 German patients with eczema and 2387 population control subjects, a collection of 274 German families with eczema-diseases children, a cross-sectional population of German children (n = 3099), the Swedish population-based birth cohort Children Allergy and Milieu in Stockholm, an Epidemiologic Study (BAMSE) (n = 2033), and the European cross-sectional Prevention of Allergy-Risk Factors for Sensitization Related to Farming and Anthroposophic Lifestyle (PARSIFAL) study (n = 3113). An additional set of 19 COL29A1 coding single nucleotide polymorphisms was analyzed in BAMSE and PARSIFAL. COL29A1 expression was investigated by using in situ hybridization. RESULTS: We found no evidence for a relationship between COL29A1 polymorphisms and eczema. The equivalence test rejected the hypothesis of association even excluding small effects. In situ hybridization carried out on biopsy specimens from lesional and nonlesional skin of patients with eczema and from healthy control subjects did not show any differences in the cellular distribution pattern of COL29A1 expression at the mRNA level. CONCLUSIONS: Our results suggest that COL29A1 is unlikely to contain genetic variants that have a major effect on eczema or atopy susceptibility.

Impact of breakfast on daily energy intake--an analysis of absolute versus relative breakfast calories.

OBJECTIVE: The role of breakfast energy in total daily energy intake is a matter of debate. Acute feeding experiments demonstrated that high breakfast energy leads to greater overall intake supported by cross-sectional data of a free-living population. On the other hand, a large intraindividual analysis has indicated that a high proportion of breakfast to overall intake is associated with lower daily energy intake. To evaluate these apparently contradictory results in greater detail both ways of analysis were applied to the same data set of dietary records. METHODS: On an intraindividual basis total daily energy intake was related to the absolute values of breakfast energy intake or to the ratio of breakfast to overall intake, respectively. Food intake of 280 obese and 100 normal weight subjects was analyzed who recorded over 10 (obese) or 14 (normal weight) consecutive days, respectively. RESULTS: Increasing breakfast energy was associated with greater overall intake in normal weight and obese subjects. The increasing ratio of breakfast to total daily energy intake was associated with a significant reduction of overall intake on days where post-breakfast energy was significantly reduced. Correlational and multiple regression analysis support the concept that absolute breakfast calories have the strongest influence on daily energy intake. CONCLUSION: Reduced breakfast energy intake is associated with lower total daily intake. The influence of the ratio of breakfast to overall energy intake largely depends on the post-breakfast rather than breakfast intake pattern. Therefore, overweight and obese subjects should consider the reduction of breakfast calories as a simple option to improve their daily energy balance.

Pain in Osteochondral Lesions of the Ankle - an Investigation Based on Data from the German Cartilage Registry (KnorpelRegister DGOU).

BACKGROUND: The aim of the study was to investigate parameters influencing the preoperative pain intensity in patients with osteochondral lesions of the ankle. The evaluation covered patient-related parameters such as age, sex, body mass index (BMI), as well as defect-related parameters, such as localisation, size and stage (according to the classification of the International Cartilage Repair Society [ICRS] and the Berndt-Harty-Loomer classification). We also examined the correlation between the different surgical techniques and additional factors, such as debridement of an impingement or stabilisation of the ankle on the one hand, and the preoperative pain intensity on the other. MATERIAL AND METHODS: 259 patients with osteochondral lesions of the ankle were operated in 32 clinical centres between October 2014 and December 2016 and enrolled consecutively in the German Cartilage Registry (KnorpelRegister DGOU). 151 patients were available for analysis. The preoperative pain intensity was assessed at the time of surgery with online questionnaires, using the Numeric Rating Scale for pain (NRS). RESULTS: The median preoperative pain intensity in the complete study population (n = 151) was 3 (range 0 - 10). There was no correlation between the age and the preoperative pain intensity (ρ = - 0.06). Further, there was not detected a difference between the two genders according to the preoperative pain intensity (p = 0.31). In female patients a higher BMI correlated with a higher preoperative pain intensity (ρ = 0.16). Within the group of patients with a solitary treated talus lesion there was no difference according to the preoperative pain intensity between the different localizations of the defect (medial vs. lateral talus) (p = 0.82). Within the group of patients with a solitary treated talus or tibia lesion there was no correlation between the defective area or the lesion stage according to the ICRS classification on the one hand, and the preoperative pain intensity on the other (ρ = 0.09, and ρ = 0.04, respectively). According to the Berndt-Harty-Loomer classification a higher lesion stage (stage four and five) was associated with a higher preoperative pain intensity (ρ = 0.13). There was no difference according to the preoperative pain intensity between the group of patients that received a debridement of a bony or soft tissue impingement in addition to the cartilage therapy and the group of patients without this kind of additional therapy (p = 0.10). Further, there was no difference according to the preoperative pain intensity between the group of patients that received a stabilisation of the ankle joint in addition to the cartilage therapy and the group of patients without a stabilisation procedure (p = 0.83). CONCLUSION: Osteochondral lesions of the ankle can be associated with a moderate and in some cases high pain intensity. In female patients a higher BMI is associated with a higher pain intensity. Further, a higher lesion stage according to the Berndt-Harty-Loomer classification is associated with a higher pain intensity, which highlights the clinical relevance of this classification.

Uric acid as a novel biomarker for bone-marrow function and incipient hematopoietic reconstitution after aplasia in patients with hematologic malignancies.

PURPOSE: Prolonged aplasia and graft failure (GF) represent life-threatening complications after hematopoietic cell transplantation (HCT) requiring suitable biomarkers for early detection and differentiation between GF and poor graft function (PGF). Uric acid (UA) is a strong immunological danger signal. METHODS: Laboratory results were analyzed from patients undergoing either allogeneic or autologous HCT or induction chemotherapy for acute leukemia (n = 50 per group, n = 150 total). RESULTS: During therapy, UA levels declined from normal values to hypouricemic values (all p < 0.001). Alongside hematopoietic recovery, UA serum levels returned to baseline values. During aplasia, UA levels remained low and started steadily increasing (defined as >two consecutive days, median one 2-day increase) at a median of 1 day before rising leukocytes in allogeneic HCT (p = 0.01) and together with leukocytes in autologous HCT (median one 2-day increase). During induction chemotherapy, a UA increase was also observed alongside rising leukocytes/neutrophils but also several times during aplasia (median 3 increases). Most HCT patients had no detectable leukocytes during aplasia, while some leukocytes remained detectable after induction therapy. No increase in UA levels was observed without concomitant or subsequent rise of leukocytes. CONCLUSIONS: Changes in UA serum levels can indicate incipient or remaining immunological activity after HCT or induction therapy. They may, therefore, help to differentiate between PGF and GF.

Endoscopic balloon dilatation of Crohn's-associated intestinal strictures: High patient satisfaction and long-term efficacy.

INTRODUCTION: Stricture formation is a common long-term complication of Crohn's disease. Endoscopic balloon dilatation offers a bowel-sparing treatment option, but long-term outcome and its association with patient-, stricture-, and procedure-related factors is only poorly understood. Patient satisfaction with endoscopic balloon dilatation is largely unknown. METHODS: We performed a retrospective review of all endoscopic balloon dilatation for Crohn's disease-related strictures between January 2005 and January 2013. Long-term outcome, complication rates and predictive factors were evaluated. Patient satisfaction was assessed using a questionnaire and telephone interviews. RESULTS: A total of 118 balloon dilatations were performed for 69 strictures in 46 patients. One patient was excluded from further analysis due to malignancy. Median time from diagnosis of Crohn's disease to symptomatic stricture formation was 19 years. Technical success, defined as passage of the endoscope after dilatation, was reportedly obtained in 95 of 106 procedures (89.6%). Two perforations occurred, one of which could be managed conservatively. No episodes of severe bleeding were recorded (procedure-related complication rate: 2/118; 1.7%). During a median follow-up of 4.8 years (range 0.4-8.7), 55.6% (25/45) of patients were able to avoid surgery. Of the patients, 35.6% (16/45) did not need any further intervention, 40.0% (18/45) underwent more than one dilatation, and 24.4% (11/45) were operated after the first dilatation. The percentage of patients who were satisfied with the procedure and would again opt for balloon dilation as first line therapy was 83.3% (35/42). None of the risk factors examined in this study correlated with the necessity for subsequent surgery. DISCUSSION: Endoscopic balloon dilatation is a safe and effective first line therapy for Crohn's disease-related strictures. No technical, stenosis-, or patient-related factor reliably predicted sustained dilatation success. Patient satisfaction was high.

Analysis of the microcirculation after soft tissue reconstruction of the outer ear with burns in patients with severe burn injuries.

Reconstruction of soft tissue defects of the ear with burns remains one of the most difficult tasks for the reconstructive surgeon. Although numerous reconstructive options are available, the results are often unpredictable and worse than expected. Besides full and split skin grafting, local random pattern flaps and pedicled flaps are frequently utilized to cover soft tissue defects of the outer auricle. Because of the difficulty and unpredictable nature of outer ear reconstruction after burn injury, a case-control study was conducted to determine the best reconstructive approach. The microcirculatory properties of different types of soft tissue reconstruction of the outer ear with burns in six severely burned Caucasian patients (three men and three women; mean age, 46 years (range, 22-70)) were compared to those in the healthy tissue of the outer ear using the O2C device (Oxygen to See; LEA Medizintechnik, Gießen, Germany). The results of this study revealed that the investigated microcirculation parameters such as the median values of blood flow (control group: 126 AU), relative amount of hemoglobin (control group: 59.5 AU), and tissue oxygen saturation (control group: 73%) are most similar to those of normal ear tissue when pedicled flaps based on the superficial temporal artery were used. These findings suggest that this type of reconstruction is superior for soft tissue reconstruction of the outer ear with burns in contrast to random pattern flaps and full skin grafts regarding the microcirculatory aspects. These findings may improve the knowledge on soft tissue viability and facilitate the exceptional and delicate process of planning the reconstruction of the auricle with burns.

Primary localization and tumor thickness as prognostic factors of survival in patients with mucosal melanoma.

BACKGROUND: Data on survival with mucosal melanoma and on prognostic factors of are scarce. It is still unclear if the disease course allows for mucosal melanoma to be treated as primary cutaneous melanoma or if differences in overall survival patterns require adapted therapeutic approaches. Furthermore, this investigation is the first to present 10-year survival rates for mucosal melanomas of different anatomical localizations. METHODOLOGY: 116 cases from Sep 10 1984 until Feb 15 2011 retrieved from the Comprehensive Cancer Center and of the Central Register of the German Dermatologic Society databases in Tübingen were included in our analysis. We recorded anatomical location and tumor thickness, and estimated overall survival at 2, 5 and 10 years and the mean overall survival time. Survival times were analyzed with the Kaplan-Meier method. The log-rank test was used to compare survival times by localizations and by T-stages. PRINCIPAL FINDINGS: We found a median overall survival time of 80.9 months, with an overall 2-year survival of 71.7%, 5-year survival of 55.8% and 10-year survival of 38.3%. The 10-year survival rates for patients with T1, T2, T3 or T4 stage tumors were 100.0%, 77.9%, 66.3% and 10.6% respectively. 10-year survival of patients with melanomas of the vulva was 64.5% in comparison to 22.3% of patients with non-vulva mucosal melanomas. CONCLUSION: Survival times differed significantly between patients with melanomas of the vulva compared to the rest (p = 0.0006). It also depends on T-stage at the time of diagnosis (p < 0.0001).

Genome-wide association studies on IgE regulation: are genetics of IgE also genetics of atopic disease?

PURPOSE OF REVIEW: Total IgE levels are considered a useful endophenotype for studying the genetics of atopic diseases. However, the role and significance of genetic factors influencing IgE regulation for atopic diseases as endpoints is unclear. RECENT FINDINGS: Recently, genome-wide association studies (GWASs) have been applied to atopic traits with considerable success. A total of seven published GWASs on asthma, one GWAS on eczema, and one GWAS on total IgE have reported 11 new loci. Most of these loci appear to be trait-specific. A notable exception is the Th2 cytokine cluster, where genetic variation seems to be relevant across atopic phenotypes. SUMMARY: GWASs have identified several novel asthma and eczema loci as well as novel loci for IgE levels. In this review, we evaluate the interrelation between these loci and summarize to which degree recent findings on IgE reflect genetic vulnerability for atopic disease.