Exploring management and outcomes of elderly patients with glioblastoma using data from two randomised trials (GEINO1401/EX-TEM).

PURPOSE: The impact of age on optimal management of glioblastoma remains unclear. A recent combined analysis of two randomised trials, GEINO14-01 and EX-TEM, found no benefit from extending post-radiation temozolomide in newly diagnosed glioblastoma. Here, we explore the impact of age. METHODS: Relevant intergroup statistics were used to identify differences in tumour, treatment and outcome characteristics based on age with elderly patients (EP) defined as age 65 years and over. Survival was estimated using the Kaplan Meier method. RESULTS: Of the combined 205 patients, 57 (28%) were EP. Of these, 95% were ECOG 0-1 and 65% underwent macroscopic resection compared with 97% and 61% of younger patients (YP) respectively. There were numerically less MGMT-methylated (56% vs. 63%, p = 0.4) and IDH-mutated (4% vs. 13%, p = 0.1) tumours in EP vs. YP. Following surgery, EP were more likely to receive short course chemoradiation (17.5% vs. 6%, p = 0.017). At recurrence, EP tended to receive or best supportive care (28.3% vs. 15.4%, p = 0.09) or non-surgical options (96.2% vs. 84.6%, p = 0.06), but were less likely to receive bevacizumab (23.1% vs. 49.5%, p < 0.01). Median PFS was similar at 9.3months in EP and 8.5months in YP, with similar median OS at 20months. CONCLUSION: In this trial population of predominantly fit EP, survival was similar to YP despite a proportion receiving less aggressive therapy at diagnosis and recurrence. Advancing age does not appear to be an adverse prognostic factor for glioblastoma when patients are fit for treatment, and a less aggressive approach in selected patients may not compromise outcomes.

A combined analysis of two prospective randomised studies exploring the impact of extended post-radiation temozolomide on survival outcomes in newly diagnosed glioblastoma.

PURPOSE: The optimal duration of post-radiation temozolomide in newly diagnosed glioblastoma remains unclear, with no published phase III randomised trials. Standard-of-care stipulates 6 months. However, in routine care, it is often extended to 12 months, despite lacking robust supporting data. METHODS: GEINO14-01 (Spain) and EX-TEM (Australia) studies enrolled glioblastoma patients without progression at the end of 6 months post-radiation temozolomide. Participants were randomised 1:1 to six additional months of temozolomide or observation. Primary endpoint was 6-month progression free survival from date of randomisation (6mPFS). Secondary endpoints included overall survival (OS) and toxicity. 204 patients were required to detect an improvement in 6mPFS from 50 to 60% (80% power). Neither study recruited sufficient patients. We performed a combined analysis of individual patient data. RESULTS: 205 patients were recruited: 159 in GEINO14-01 (2014-2018) and 46 in EX-TEM (2019-2022). Median follow-up was 20.0 and 14.5 months. Baseline characteristics were balanced. There was no significant improvement in 6mPFS (57.2% vs 64.0%, OR0.75, p = 0.4), nor across any subgroups, including MGMT methylated; PFS (HR0.92, p = 0.59, median 7.8 vs 9.7 months); or OS (HR1.03, p = 0.87, median 20.1 vs 19.4 months). During treatment extension, 64% experienced any grade adverse event, mainly fatigue and gastrointestinal (both 54%). Only a minority required treatment changes: 4.5% dose delay, 7.5% dose reduction, 1.5% temozolomide discontinuation. CONCLUSION: For glioblastoma patients, extending post-radiation temozolomide from 6 to 12 months is well tolerated but does not improve 6mPFS. We could not identify any subset that benefitted from extended treatment. Six months should remain standard-of-care.

Development and validation of a minimally invasive and image-guided tape stripping method to sample atopic skin in children.

BACKGROUND: Molecular skin profiling techniques, typically performed on skin samples taken by punch biopsy, have enhanced the understanding of the pathophysiology of atopic dermatitis (AD), thereby enabling the development of novel targeted therapeutics. However, punch biopsies are not always feasible or desirable, and novel minimally invasive methods such as skin tape stripping have been developed. AIM: To develop, optimize and validate a novel tape stripping method guided by noninvasive in vivo skin imaging to sample atopic skin in children. METHODS: Skin tape stripping-based procedures were compared and optimized using data from 30 healthy controls (HCs: 5 adults, 25 children) and 39 atopic children. Evaluations were guided by high-resolution photography, reflectance confocal microscopy, optical coherence tomography and transepidermal water loss measurements. We assessed and compared adverse events (AEs), the time needed to perform the sampling and the cDNA levels obtained from the tapes. RESULTS: Tape stripping methods based on previously described protocols resulted in erosions in all participants and required a median time of 65 min to perform (range 60-70 min), but provided good cDNA yield. Shorter durations appeared less invasive but provided lower cDNA yield. The final optimized tape stripping protocol, using 11 tapes of 22 mm in diameter, each applied twice for 5 s with 90° rotation, did not produce significant AEs, was completed within a median time of 7 min (range 5-15 min) and provided good cDNA yield both in HCs and atopic children. CONCLUSION: Our minimally invasive method is safe and reliable, and provides reproducible acquisition of cDNA in atopic children. In addition, it enables rapid sample collection, a crucial factor in clinical practice.

Non-invasive clinical and microscopic evaluation of the response to treatment with clobetasol cream vs. calcipotriol/betamethasone dipropionate foam in mild to moderate plaque psoriasis: an investigator-initiated, phase IV, unicentric, open, randomized clinical trial.

BACKGROUND: Treatment response for psoriasis is typically evaluated using clinical scores. However, patients can relapse after clinical clearance, suggesting persistent inflammation. Dermoscopy, reflectance confocal microscopy (RCM) and optical coherence tomography (OCT) can non-invasively improve treatment response assessment. OBJECTIVES: To compare the clinical and non-invasive microscopic features in a psoriatic target lesion treated with clobetasol cream or calcipotriol/betamethasone dipropionate foam (Cal/BD foam). METHODS: Prospective, unicentric, open, randomized clinical trial comparing clinical data [total clinical score (TCS)] and microscopic data (dermoscopy, RCM and OCT) in psoriasis patients treated with clobetasol or Cal/BD foam. RESULTS: We included 36 adult patients (22 men). At week 4, more patients treated with Cal/BD foam achieved TCS ≤1 than with clobetasol (63.2% vs. 18.8%, P = 0.016). Treatment satisfaction was higher with Cal/BD foam (P < 0.03). Microscopically, Cal/BD foam induced more reduction in epidermal thickness at week 4 (P < 0.049). Dilated horizontal blood vessels were more common with clobetasol than with Cal/BD foam at week 8 (69.2% vs. 31.2%, P = 0.159). If epidermal hyperplasia was noted at baseline, the response was poorer with clobetasol (P = 0.029). LIMITATIONS: Small sample size, open study, imaging sampling bias. CONCLUSION: Cal/BD foam is more effective than clobetasol, has better patient satisfaction and induces greater reduction in the hyperkeratosis/acanthosis, regardless of baseline epidermal hyperplasia.

A Be-type star with a black-hole companion.

Stellar-mass black holes have all been discovered through X-ray emission, which arises from the accretion of gas from their binary companions (this gas is either stripped from low-mass stars or supplied as winds from massive ones). Binary evolution models also predict the existence of black holes accreting from the equatorial envelope of rapidly spinning Be-type stars (stars of the Be type are hot blue irregular variables showing characteristic spectral emission lines of hydrogen). Of the approximately 80 Be X-ray binaries known in the Galaxy, however, only pulsating neutron stars have been found as companions. A black hole was formally allowed as a solution for the companion to the Be star MWC 656 (ref. 5; also known as HD 215227), although that conclusion was based on a single radial velocity curve of the Be star, a mistaken spectral classification and rough estimates of the inclination angle. Here we report observations of an accretion disk line mirroring the orbit of MWC 656. This, together with an improved radial velocity curve of the Be star through fitting sharp Fe II profiles from the equatorial disk, and a refined Be classification (to that of a B1.5-B2 III star), indicates that a black hole of 3.8 to 6.9 solar masses orbits MWC 656, the candidate counterpart of the γ-ray source AGL J2241+4454 (refs 5, 6). The black hole is X-ray quiescent and fed by a radiatively inefficient accretion flow giving a luminosity less than 1.6 × 10(-7) times the Eddington luminosity. This implies that Be binaries with black-hole companions are difficult to detect in conventional X-ray surveys.

BRAF mutation is not associated with an increased risk of recurrence in patients undergoing resection of colorectal liver metastases.

BACKGROUND: BRAF mutation is associated with a poor prognosis in patients with metastatic colorectal cancer. For patients with resectable colorectal liver metastases (CRLMs), the prognostic impact of BRAF mutation is unknown and the benefit of surgery debated. This nationwide intergroup (ACHBT, FRENCH, AGEO) study aimed to evaluate the oncological outcome of patients undergoing liver resection for BRAF-mutated CRLMs. METHODS: The study included patients who underwent resection for BRAF-mutated CRLMs in 24 centres between 2012 and 2016. A case-matched comparison was made with 183 patients who underwent resection of CRLMs with wild-type BRAF during the same interval. RESULTS: Sixty-six patients who underwent resection for BRAF-mutated CRLMs in 24 centres were compared with 183 patients with wild-type BRAF. The 1- and 3-year disease-free survival (DFS) rates were 46 and 19 per cent for the BRAF-mutated group, and 55·4 and 27·8 per cent for the group with wild-type BRAF (P = 0·430). In multivariable analysis, BRAF mutation was not associated with worse DFS (hazard ratio 1·16, 95 per cent c.i. 0·72 to 1·85; P = 0·547). The 1- and 3-year overall survival rates after surgery were 94 and 54 per cent respectively among patients with BRAF mutation, and 95·8 and 82·9 per cent in those with wild-type BRAF (P = 0·004). Median survival after disease progression was 23·0 (95 per cent c.i. 11·0 to 35·0) months among patients with mutated BRAF and 44·3 (35·9 to 52·6) months in those with wild-type BRAF (P = 0·050). Multisite disease progression was more common in the BRAF-mutated group (48 versus 29·8 per cent; P = 0·034). CONCLUSION: These results support surgical treatment for resectable BRAF-mutated CRLM, as BRAF mutation by itself does not increase the risk of relapse after resection. BRAF mutation is associated with worse survival in patients whose disease relapses after resection of CRLM, as for non-metastatic colorectal cancer.

The relationship between frailty and polypharmacy in older people: A systematic review.

AIMS: Frailty is a complex geriatric syndrome resulting in decreased physiological reserves. Frailty and polypharmacy are common in older adults and the focus of extensive studies, although little is known about the impact they may have on each other. This is the first systematic review analysing the available evidence on the relationship between frailty and polypharmacy in older adults. METHODS: Systematic review of quantitative studies. A comprehensive literature search for publications in English or Spanish was performed on MEDLINE, CINAHL, the Cochrane Database and PsycINFO in September 2017 without applying restrictions on the date of publication. Studies reporting any relationship between frailty and polypharmacy in older adults were considered. RESULTS: A total of 25 publications were included, all of them observational studies. Evaluation of Fried's frailty criteria was the most common approach, followed by the Edmonton Frail Scale and FRAIL scale. Sixteen of 18 cross-sectional analyses and five of seven longitudinal analyses demonstrated a significant association between an increased number of medications and frailty. The causal relationship is unclear and appears to be bidirectional. Our analysis of published data suggests that polypharmacy could be a major contributor to the development of frailty. CONCLUSIONS: A reduction of polypharmacy could be a cautious strategy to prevent and manage frailty. Further research is needed to confirm the possible benefits of reducing polypharmacy in the development, reversion or delay of frailty.

Accurate determination of energy requirements in hospitalised patients with parenteral nutrition.

BACKGROUND: The prescription of parenteral nutrition (PN) in hospitalised patients requires an estimation of the energy requirements. Most studies employing prediction equations (PEs) to estimate energy requirements have focused on critically ill patients. The present study aimed to evaluate several PEs of the resting energy expenditure (REE) to identify the most accurate equation for estimating the REE required for PN. METHODS: This cross-sectional and descriptive study included patients hospitalised with medical or surgical diagnoses, making them candidates for PN. Epidemiological data, the reason for hospital admission, nutritional screening results, characteristics of the PN administered and REE by indirect calorimetry (IC) were recorded and, subsequently, PEs were calculated. RESULTS: In total, 116 patients were recruited with a mean (SD) age of 56.7 (13.8) years and body mass index of 21.3 (4.25) kg m-2 . The diagnosis was medical in 52% of patients and surgical in 48%. The mean (SD) REEs of patients, according to IC, were: 6.11 (1.18) MJ [1461 (281) kcal]; and according to PEs: Mifflin, 5.07 (1.05) MJ [1212 (252) kcal]; Owen, 5.43 (0.72) MJ [1298 (172) kcal]; Harris-Benedict, 5.38 (0.85) MJ [1285 (204) kcal]; Ireton-Jones, 6.20 (1.69) MJ [1481 (403) kcal]; and short equation, 6.12 (0.92) MJ [1464 (220) kcal]. A comparison of the results obtained for the REE by IC and with PEs indicated that the short equation had less bias than the other equations, with an accuracy of 54% CONCLUSIONS: In hospitalised patients who receive PN, determination of the REE should ideally be made by IC. PEs are acceptable but not exact and so their estimation could overfeed or underfeed the patient.

Safety of antitumour necrosis factor treatments in chronic rheumatic diseases: therapy discontinuations related to side effects.

WHAT IS KNOWN AND OBJECTIVE: The appearance of antitumor necrosis factor drugs (ATDs) has been a major advance in the management of these patients. However, due to the immunosuppressive effect of these therapies, side effects that require treatment discontinuations can appear. The purpose of this study was to evaluate the frequency of ATD discontinuation due to adverse drug effects (ADEs) and the influence of different factors such as diagnosis, ATD prescribed and concomitant disease-modifying antirheumatic drugs (DMARDs). METHODS: Observational study from a prospective cohort conducted in a tertiary hospital (1350 beds) in Spain. Data were obtained from the database of the Rheumatology Outpatient Unit of the hospital and patients' clinical files. Included patients had a diagnosis of RA or peripheral or axial SpA (ankylosing spondylitis, psoriatic SpA, non-radiographic SpA, SpA associated with inflammatory bowel disease or reactive arthritis) treated between November 2000 and March 2014 with infliximab (IFX), etanercept (ETN) or adalimumab (ADA). RESULTS AND DISCUSSION: Study cohort included 531 rheumatic patients (282 patients with RA, 53·1%, and 249 patients with SpA, 46·9%). ATDs were discontinued in 62 cases (11·7%) because of ADEs, mainly inmunogenicity and infections (mainly due to infusion reactions, 58·1%, and infections, 19·3%). ATD discontinuation was higher in the group of RA patients compared with SpA (44/282 (15·6%) in RA vs. 18/249 (7·23%) in SpA). The appearance of ADEs that led to drop out was more frequent in patients under IFX therapy (45 (18·6%) with IFX vs. 12 (7·59%) with ETN and 5 (3·81%) with ADA). We observed a significantly increased risk of ADEs when patients received IFX than when ETN or ADA were used (P < 0·001); 444 patients (83·6%) received DMARDs in combination with ATDs. The risk of ATD withdrawal was significantly higher in patients treated with leflunomide as compared to those who do not (OR = 1·984, P < 0·05). WHAT IS NEW AND CONCLUSION: Discontinuation of ATD due to ADEs is relatively frequent and it depends on the diagnosis and ATD administered. The risk of treatment discontinuation is higher in patients diagnosed with RA vs. SpA or treated with IFX (rather than with ETN or ADA). The addition of DMARDs to ATDs increased the frequency of treatment discontinuation, up to three concomitant medications. Leflunomide in combination with an ATD significantly increased the probability of treatment discontinuation due to adverse reactions.

Acute effects of simultaneous electromyostimulation and vibration on leg blood flow in spinal cord injury.

STUDY DESIGN: Randomized crossover. OBJECTIVES: To analyze the acute effects of isolated and simultaneous application of whole-body vibration (WBV) and electromyostimulation (ES) on popliteal artery blood velocity (BV) and skin temperature (ST) of the calf in subjects with spinal cord injury (SCI). SETTING: Valladolid, Spain. METHODS: Ten subjects with SCI were assessed in five different sessions. After a familiarization session, four interventions were applied in random order; WBV, ES, simultaneous WBV and ES (WBV+ES), and 30 s of WBV followed by 30 s of ES (WBV30/ES30). Each intervention consisted of 10 sets × 1 min ON+1 min OFF. Subjects were seated on their own wheelchairs with their feet on the vibration platform (10 Hz, 5 mm peak-to-peak), and ES was applied on the gastrocnemius muscle of both legs (8 Hz, 400 µs). RESULTS: The simultaneous application (WBV+ES) produced the greatest increase in mean BV (MBV; 36% and 42%, respectively) and peak BV (PBV; 30% and 36%, respectively) during the intervention. This intervention produced the greatest mean increases in MBV (21%) and PBV (19%) during the recovery period. Last, this intervention produced the highest increase in ST during the intervention (2.1 °C). CONCLUSION: The simultaneous application of WBV+ES seems to produce a greater increase in MBV and PBV of the popliteal artery and ST of the calf than the isolated (WBV or ES) or consecutive application of both stimuli (WBV30/ES30). This study provides an efficient therapeutic methodology to improve peripheral arterial properties, which is pivotal in SCI patient's rehabilitation.

Chronic effects of simultaneous electromyostimulation and vibration on leg blood flow in spinal cord injury.

STUDY DESIGN: Randomized two-group parallel. OBJECTIVES: The objective of this study was to analyze the adaptations on the popliteal artery (mean blood velocity (MBV), peak blood velocity (PBV), arterial resting diameter (RD) and blood flow (BF)) induced by 12 weeks of simultaneous application of whole-body vibration and electromyostimulation (WBV+ES) in patients with spinal cord injury (SCI). Secondarily, the musculoskeletal effects of this therapy on the gastrocnemius muscle thickness (MT) and femoral neck bone mineral density (BMD) were analyzed. SETTING: Valladolid, Spain. METHODS: Seventeen SCI patients (American Spinal Injury Association (ASIA) A or B) were randomly assigned to the experimental group (EG=9) or the control group (CG=8). Each subject was assessed in four different occasions: at baseline, after 6 weeks (Post-6) and 12 weeks of the treatment (Post-12) and 8 weeks after the end of the treatment (Post-20). Subjects in the EG performed 30 10-min sessions of WBV+ES during 12 weeks. RESULTS: In the EG, RD increased compared with the baseline value at Post-6 (9.5%, P<0.01), Post-12 (19.0%, P<0.001) and Post-20 (16.7%, P<0.001). Similarly, in the EG, BF increased compared with the baseline value and with CG only at Post-12 ((33.9%, P<0.01) and (72.5%, P<0.05), respectively). Similarly, WBV+ES increased the MT of the gastrocnemius. BMD of both hips remained invariable during the study. CG showed no change at any point. CONCLUSIONS: WBV+ES improved popliteal artery BF, RD and MT after 12 weeks in SCI patients. This increase in RD remained above baseline after 8 weeks. The combination of WBV and ES could be considered a promising alternative to reverse the musculoskeletal atrophy and improve peripheral vascular properties in SCI patients.

Emulsion gels as potential fat replacers delivering ß-glucan and healthy lipid content for food applications.

Oat emulsion gels and oil-free oat gels were formulated with varying proportions of oat bran/olive oil (from 12/40 to 28/0) without or with alginate or gelatin used as animal fat replacers and/or to provide ß-glucan and MUFA for meat products. Composition, technological properties (thermal stability, colour, texture, etc.) and the effects of chilled and frozen storage of samples were evaluated. Depending on the proportion, samples developed for use as animal fat replacers in meat products may endow these with properties qualifying them for nutrition and health claims. No samples showed any noticeable syneresis and all showed good thermal stability. Increasing of oat bran/olive oil increased a* and reduced b* values, while differences in L* depended on the gelling agent. Penetration force (PF) and gel strength increased when the oat bran/oil ratio increased, with the highest values in the samples containing alginate or gelatin. Thermal losses and PF generally increased during chilled and frozen storage, and no significant differences were observed in colour or pH over storage.

Tacrolimus and the risk of solid cancers after liver transplant: a dose effect relationship.

Although increased rates of solid organ cancers have been reported following liver transplantation (LT), the impact of quantitative exposure to calcineurin inhibitors (CNI) remains unclear. We have therefore probed the relationship between the development of solid organ cancers following LT and the level of CNI exposure. This prospective single-center study was conducted between 1995 and 2008 and is based on 247 tacrolimus-treated liver transplant recipients who survived at least 1 year following surgery. The incidence of cancer was recorded, and the mean blood concentration of tacrolimus (TC) was determined at 1 and 3 years following LT. The study results indicate that 43 (17.4%) patients developed de novo solid cancers. Mean TC during the first year after LT was significantly higher in patients who developed solid organ tumors (10.3 ± 2.1 vs. 7.9 ± 1.9 ng/mL, p < 0.0001). Independent risks factors in multivariate analysis were tobacco consumption before LT (OR = 5.42; 95% CI [1.93-15.2], p = 0.0014) and mean annual TC during the first year after LT (p < 0.0001; OR = 2.01; 95% CI [1.57-2.59], p < 0.0001). Similar effects were observed in 216 patients who received tacrolimus continuously for ≥3 years. It appears therefore that CNI should be used with caution after LT, and that new immunosuppressive therapies could deliver significant clinical benefits in this regard.