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.

Low rCBV values in glioblastoma tumor progression under chemoradiotherapy.

PURPOSE: After standard treatment for glioblastoma, perfusion MRI remains challenging for differentiating tumor progression from post-treatment changes. Our objectives were (1) to correlate rCBV values at diagnosis and at first tumor progression and (2) to analyze the relationship of rCBV values at tumor recurrence with enhancing volume, localization of tumor progression, and time elapsed since the end of radiotherapy in tumor recurrence. METHODS: Inclusion criteria were (1) age > 18 years, (2) histologically confirmed glioblastoma treated with STUPP regimen, and (3) tumor progression according to RANO criteria > 12 weeks after radiotherapy. Co-registration of segmented enhancing tumor VOIs with dynamic susceptibility contrast perfusion MRI was performed using Olea Sphere software. For tumor recurrence, we correlated rCBV values with enhancing tumor volume, with recurrence localization, and with time elapsed from the end of radiotherapy to progression. Analyses were performed with SPSS software. RESULTS: Sixty-four patients with glioblastoma were included in the study. Changes in rCBV values between diagnosis and first tumor progression were significant (p < 0.001), with a mean and median decreases of 32% and 46%, respectively. Mean rCBV values were also different (p < 0.01) when tumors progressed distally (radiation field rCBV values of 1.679 versus 3.409 distally). However, changes and, therefore, low rCBV values after radiotherapy in tumor recurrence were independent of time. CONCLUSION: Chemoradiation alters tumor perfusion and rCBV values may be decreased in the setting of tumor progression. Changes in rCBV values with respect to diagnosis, with low rCBV in tumor progression, are independent of time but related to the site of recurrence.

Phase I study of CC-90010, a reversible, oral BET inhibitor in patients with advanced solid tumors and relapsed/refractory non-Hodgkin's lymphoma.

BACKGROUND: Bromodomain and extra-terminal (BET) proteins are epigenetic readers that regulate expression of genes involved in oncogenesis. CC-90010 is a novel, oral, reversible, small-molecule BET inhibitor. PATIENTS AND METHODS: CC-90010-ST-001 (NCT03220347; 2015-004371-79) is a phase I dose-escalation and expansion study of CC-90010 in patients with advanced or unresectable solid tumors and relapsed/refractory (R/R) non-Hodgkin's lymphoma (NHL). We report results from the dose escalation phase, which explored 11 dose levels and four dosing schedules, two weekly (2 days on/5 days off; 3 days on/4 days off), one biweekly (3 days on/11 days off), and one monthly (4 days on/24 days off). The primary objectives were to determine the safety, maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D) and schedule. Secondary objectives were to evaluate signals of early antitumor activity, pharmacokinetics, and pharmacodynamics. RESULTS: This study enrolled 69 patients, 67 with solid tumors and two with diffuse large B-cell lymphoma (DLBCL). The median age was 57 years (range, 21-80) and the median number of prior regimens was four (range, 1-9). Treatment-related adverse events (TRAEs) were mostly mild and manageable; grade 3/4 TRAEs reported in more than two patients were thrombocytopenia (13%), anemia, and fatigue (4% each). Six patients had dose-limiting toxicities. MTDs were 15 mg (2 days on/5 days off), 30 mg (3 days on/11 days off), and 45 mg (4 days on/24 days off). The RP2D and schedule selected for expansion was 45 mg (4 days on/24 days off). As of 8 October 2019, one patient with grade 2 astrocytoma achieved a complete response, one patient with endometrial carcinoma had a partial response, and six patients had prolonged stable disease ≥11 months. CONCLUSIONS: CC-90010 is well tolerated, with single-agent activity in patients with heavily pretreated, advanced solid tumors.

Suspended LRSPP for the development of highly integrated active plasmonic devices.

We present a novel long-range surface plasmon polariton (LRSPP) device consisting of a suspended dielectric matrix in which an electrically active, millimeter-long metallic waveguide is embedded. We show that, by opening an air gap under the lower cladding, the influence of the substrate is suppressed and the symmetry of the thermo-optical distribution around the LRSPP waveguide is preserved over extended ranges of applied electrical current with minimal optical losses. Experimental results show that, compared to a standard nonsuspended structure, our device allows either the induction of a phase change that is three times larger, for a fixed electrical power, or, equivalently, a scaling down of the device to one-tenth of its original length, for a fixed phase change.

Probing complex dynamics with spatiotemporal coherence-gated DLS.

We discuss the specific features of fiber-based implementations of optical sensing techniques based on spatiotemporal coherence-gated dynamic light scattering (DLS). This sensing approach has a number of unique capabilities such as an effective isolation of single scattering, a large sensitivity, and high collection efficiency, and it can also operate over a wide range of optical regimes while providing means for proper ensemble averaging. We review a number of applications in which these specific characteristics permit recovering information beyond the capabilities of traditional light-scattering-based techniques.

The rheumatic disease-associated FAM167A-BLK locus encodes DIORA-1, a novel disordered protein expressed highly in bronchial epithelium and alveolar macrophages.

Triggering of autoimmunity that leads to rheumatic disease has been suggested to depend upon gene-environment interactions occurring in epithelial barriers and associated immune cells. Genetic studies have identified associations of the FAM167A-BLK locus with rheumatoid arthritis, systemic lupus erythematosus (SLE) and Sjögren's syndrome. While BLK (B lymphocyte kinase) has a well-established role in B cells, family with sequence similarity to 167 member A (FAM167A) and its gene family remain uncharacterized. To begin to understand the role of FAM167A in rheumatic disease pathogenesis, we explored this gene family and cloned and investigated the gene products. Expression of quantitative trait locus analysis was performed in immune cells. FAM167A and FAM167B were cloned from human peripheral blood mononuclear cells (PBMC). Gene conservation and protein properties were analysed by online tools, mRNA expression measured in mouse organs by quantitative polymerase chain reaction (qPCR) and protein expression investigated in human tissues by immunohistochemistry. We found that autoimmune risk genotypes within the FAM167A-BLK locus lead to increased expression of FAM167A. The FAM167 gene family includes two members, FAM167A and FAM167B, which are not homologous to any other annotated gene but are evolutionarily conserved. The encoded proteins, which we denote 'disordered autoimmunity' (DIORA)-1 and DIORA-2, respectively, are characterized by a high content of intrinsic disorder. Notably, DIORA-1 has its highest expression in the lung, detectable in both bronchial epithelium and alveolar macrophages with an endosomal localization pattern. In summary, the FAM167A gene is associated with several rheumatic diseases and encodes a novel disordered protein, DIORA-1, which is expressed highly in the lung, consistent with a potential role in disease pathogenesis.

Diminished CXCR5 expression in peripheral blood of patients with Sjögren's syndrome may relate to both genotype and salivary gland homing.

Genetic investigations of Sjögren's syndrome (SS) have identified a susceptibility locus at p23.3 of chromosome 11, which contains the CXCR5 gene. C-X-C motif chemokine receptor 5 (CXCR5) is a chemokine receptor expressed on B and T cell subsets, and binds the chemotactic ligand C-X-C motif chemokine ligand 13 (CXCL13). In this study we aimed to link the genetic association with functional effects and explore the CXCR5/CXCL13 axis in SS. Expression quantitative trait loci analysis of the 11q23.3 locus was performed using B cell mRNA expression data from genotyped individuals. Lymphocyte surface markers were assessed by flow cytometry, and CXCL13 levels by a proximity extension assay. CXCR5+ and CXCL13+ cells in minor salivary glands were detected using immunohistochemistry. Our results demonstrated that SS-associated genetic polymorphisms affected the expression of CXCR5 (P < 0·01). Notably, a decreased percentage of CXCR5+ cells, with lower CXCR5 expression, was observed for most circulating B and T cell subsets in SS patients, reaching statistical significance in CD19+ CD27+ immunoglobulin (Ig)D+ marginal zone (P < 0·001), CD19+ CD27+ IgD- memory (P < 0·05) and CD27-IgD double-negative (P < 0·01) B cells and CD4+ CXCR3- CCR6+ Th17 cells (P < 0·05). CXCL13 levels were increased in patient plasma (P < 0·001), and immunohistochemical staining revealed expression of CXCL13 and higher numbers of CXCR5+ cells (P < 0·0001) within focal infiltrates and interstitially in salivary glands of SS patients. In conclusion, we link a genetic susceptibility allele for SS to a functional phenotype in terms of decreased CXCR5 expression. The decrease of CXCR5+ cells in circulation was also related to homing of B and T cells to the autoimmune target organ. Therapeutic drugs targeting the CXCR5/CXCL13 axis may be useful in SS.

Multimode interference dynamic light scattering.

When dealing with dynamic scattering systems, being able to collect strong signals while maintaining a high signal-to-noise ratio (SNR) is critical. It is well known that a spatially coherent measurement provides the largest SNR, while a partially coherent one provides better means for proper spatial averaging. In this Letter, we present a robust implementation of a fiber-based, single-mode, common-path interferometer assisted by multimode interference. We show that light can be efficiently collected from larger coherent regions while keeping a high SNR that is comparable to that of a pure single-mode arrangement. Additionally, our implementation allows having both a stable local oscillator encoding information on the fiber-medium interface and a linear dependence on scattering density. These two attributes, in turn, permit accessing the effective optical properties of the dynamic complex system.

Stress homogenization effect in multicore fiber optic bending sensors.

In this work we study the particular case of an optical fiber subjected to compression-bending load, the most common loading configuration for testing fiber optic bending sensors. Our analysis is based on the foundations of column theory and reveals a progressive stress homogenization across the optical fiber with increasing bending. This effect is general to any optical fiber subjected to this load configuration and it is of particular interest for structures with multiple cores since the state of stress experienced by each core can significantly differ even for a condition of constant load. The approach outlined here captures relevant features observed in experiments with multicore fiber optic bending sensors. Also, this approach can be incorporated into coupled-mode theory for assessing the performance of spectrally operated fiber sensors based on multicore coupled structures under realistic conditions commonly encountered in the experiments and without the need of performing computationally expensive simulations. The progressive stress homogenization, as well as the regime of homogeneous stress dominated by the bending contribution, is experimentally demonstrated using a multicore optical fiber with three coupled cores. Our observations are similar to those reported in recent experiments using other multicore fibers with different number of cores.

Intracranial stents in the endovascular treatment of acute ischemic stroke. / Uso del stent intracraneal en el tratamiento endovascular en agudo del ictus.

OBJECTIVE: To evaluate the efficacy and safety of intracranial stenting as a rescue therapy after failed mechanical thrombectomy in patients with acute ischemic stroke. MATERIAL AND METHODS: We retrospectively studied 42 patients treated with intracranial stenting after failed mechanical thrombectomy between December 2008 and January 2016. We compared outcomes before and after the incorporation of stentrievers. We assessed the degree of recanalization in the carotid and basilar territories (modified TIMI score), prognostic factors, and outcome (modified Rankin Score at 3 months). Safety was evaluated in function of the appearance of symptomatic intracranial hemorrhage (SICH). RESULTS: Median NIHSS was 17 in patients with carotid territory strokes and 26 in those with vertebrobasilar territory strokes. Median time from onset of symptoms to treatment was 225minutes in carotid territory strokes and 390minutes in vertebrobasilar territory strokes. A total of 10 patients underwent intravenous fibrinolytic therapy before treatment with stentrievers. Two patients developed SICH; both had undergone intravenous fibrinolytic therapy (p=0.0523). Recanalization was effective in 30 (71.4%) in the entire series: in 7 (50%) of 14 patients treated before the incorporation of stentrievers and in 23 (82.1%) of 28 treated after the incorporation of stentrievers (p=0.0666). Outcome at 3 months was good in 2 (14.3%) patients in the earlier group and in 14 (50%) patients in the later group (p=0.042). We found significant associations between recanalization and outcome (p=0.0415) and between shorter time to treatment and outcome (p=0.002). Outcome was good in 14 (48.3%) of the 29 patients with carotid territory strokes and in 2 (15.4%) of the 13 patients with vertebrobasilar territory strokes (p=0.078). CONCLUSIONS: Intracranial stenting is the rescue treatment when the usual treatment fails. Stentrievers must be used to eliminate the clot burden before stenting. In our study, antiplatelet treatment did not seem to increase the risk of SICH except in patients with prior intravenous fibrinolytic treatment.

In situ characterization of structural dynamics in swelling hydrogels.

Characterizing the structural morphology and the local viscoelastic properties of soft complex systems raises significant challenges. Here we introduce a dynamic light scattering method capable of in situ, continuous monitoring of structural changes in evolving systems such as swelling gels. We show that the inherently non-stationary dynamics of embedded probes can be followed using partially coherent radiation, which effectively isolates only single scattering contributions even during the dramatic changes in the scattering regime. Using a simple and robust experimental setup, we demonstrate the ability to continuously monitor the structural dynamics of chitosan hydrogels formed by the Ag(+) ion-triggered gelation during their long-term swelling process. We demonstrate that both the local viscoelastic properties of the suspending medium and an effective cage size experienced by diffusing probe particles loaded into the hydrogel can be recovered and used to describe the structural dynamics of hydrogels with different levels of cross-linking. This characterization capability is critical for defining and controlling the hydrogel performance in different biomedical applications.

[Vertebrobasilar recanalization techniques before the placement of stent-retrievers: reopening is not synonymous with good outcome]. / Técnicas de recanalización vertebrobasilar antes de la introducción de las endoprótesis recuperadoras: la reapertura no es sinónimo de buena evolución.

OBJECTIVES: To evaluate the recanalization rate and clinical outcome three months after endovascular treatment for vertebrobasilar occlusion before the placement of stentrievers. MATERIAL AND METHODS: We reviewed all cases of basilar thrombosis treated with endovascular techniques at our center. We reviewed the clinical outcomes with the main objective of determining the recanalization rate and the secondary objective of evaluating the outcome using the modified Rankin scale (mRS) three months after treatment. We assessed clinical and angiographic variables and correlated them with outcome and complications. RESULTS: We reviewed a total of 27 consecutive patients (mean age, 58.1±15.5 y; median National Institutes of Health Stroke Scale (NIHSS), 21, interquartile range, 18-29; median Glasgow coma score (GCS) 7, interquartile range, 4-9.5). The mean time between the onset of symptoms and endovascular treatment was 26.3±41.7hours. Complete or partial recanalization was achieved in 23 (85.1%) patients. Three months after treatment, 16 (59.2%) had died and 6 (22.2%) had good outcome (mRS ≤ 2). CONCLUSION: Endovascular treatment achieved a high rate of recanalization of occlusions of the basilar artery. Nevertheless, a high percentage of the patients did not have a good outcome. New materials might improve the prognosis in these patients.

Recovery of spermatogenesis after androgenic anabolic steroids abuse in men. A systematic review of the literature.

OBJECTIVE: This systematic review aims to evaluate the optimal treatment for male infertility resulting from Anabolic Androgenic Steroids (AAS) abuse. METHODS: A systematic review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies that compared different protocols for the recovery of spermatogenesis in patients after AAS use were included. RESULTS: 13 studies investigating different protocols to restore spermatogenesis in patients with AAS abuse met the inclusion criteria. The available agents that showed restoration of spermatogenesis include injectable gonadotropins, selective estrogen receptor modulators, and aromatase inhibitors, but their use is still poorly described in the literature. CONCLUSIONS: Clinicians need to be aware of the detrimental effects of AAS on spermatogenesis. AAS-associated infertility may be reversible, but sperm production may take over a year to normalize. Both conservative and aggressive treatment can boost spermatogenesis with positive results. Further understanding of male reproductive endocrinology and high-quality data on the field of restoration of spermatogenesis after AAS abuse are warranted.

In-fiber directional coupler for high-sensitivity curvature measurement.

A curvature fiber optic sensor using a two-core fiber (TCF) is proposed and demonstrated. The TCF is designed to operate as a directional coupler with one core located exactly at the center of the fiber and the other off-axis, but close to the center of the fiber. This design allows straightforward splicing of the TCF to single mode fibers (SMF), and alignment of the off-axis core is not strictly required for optimum operation. The sensor is fabricated by simply splicing a 5 cm long section of TCF between two SMF sections, which provides a sinusoidal spectral response. When the fiber is bent, the coupling parameters are modified due to stress-optic and effective length effects, effectively blue-shifting the sinusoidal spectral response of the sensor and allowing for the measurement of curvature. The sensor exhibits linear response and a sensitivity of -137.87 nm/m(-1) for curvature ranging from 0 to 0.27 m(-1), making it suitable to measure small curvatures with high sensitivity.

Determinants of self-monitoring of blood glucose in patients with Type 1 diabetes: a multi-centre study in Brazil.

AIM: The aim of this study was to determine the relationship between the daily frequency of self-monitoring of blood glucose and glycaemic control, demographic and socio-economic status in patients with Type 1 diabetes under routine clinical care in Brazil. METHODS: This was a cross-sectional, multi-centre study conducted between December 2008 and December 2010 in 28 public clinics in 20 Brazilian cities. The data were obtained from 3176 patients, aged 22 ± 11.8 years, of whom 56.3% were female and 57.4% were Caucasian. The mean time since diabetes diagnosis was 11.7 ± 8.1 years. RESULTS: The prevalence of self-monitoring of blood glucose was 88.5%. There was a significant increase in self-monitoring frequency associated with female gender, lower ages, more intensive diabetes management and higher socio-economic status. A correlation between HbA(1c) levels and the daily frequency of self-monitoring was observed (r(s) = -0.13; P = 0.001). The mean HbA1c levels were related to the daily frequency of self-monitoring (P < 0.001) without additional benefit to patients who performed self-monitoring more than four times daily (9.2, 11.2, 10.2,15.2 and 15% for one, two, three, four, five or more self-monitoring tests daily, respectively; P < 0.0001). CONCLUSIONS: The majority of our patients (88.5%) performed three or more self-monitoring tests daily, with more frequent testing reported by females, younger patients, those on intensive insulin regimens and of higher socio-economic status. No additional benefit was found in patients who performed self-monitoring more than four times daily. The diabetes care team must improve patients' education regarding self-monitoring of blood glucose and its benefits.

[Bilateral ureterocele in single collection system: a particular case]. / Ureterocele bilateral en sistema único: un caso particular.

INTRODUCTION: Ureterocele is an uncommon congenital urinary tract malformation, which consists in a cystic dilation of the vesical portion of the ureter. We present a rare case of ureterocele, reviewing the most important aspects and characteristics that make it so unusual. CASE: Seven year old male admitted for hematuria in the context of afebrile urinary tract infection, the ultrasound revealed a right hydroureteronephrosis (HUN) in a single collecting system and a voiding cystourethogram (VCUG) showed a right ureterocele. A cystoscopy demonstrated the presence of a bilateral orthotopicureterocele in a single collecting system. The patient underwent an endoscopic incision in order to drain the hydronephrotic system. After a month, while performing a check up using ultrasound, we could observe an important reduction in the right HUN, however, it also was acknowledged the presence of dilation of the left distal ureter, reason why it was decided to puncture the left ureterocele. COMMENTS: We present an unusual case: male with a bilateral orthotopicureterocele in a single collecting system and its clinical management. Its particularity is discussed.

Emerging targets for cancer treatment: S100A9/RAGE.

Developing better treatments that work for the majority of patients with brain metastasis (BM) is highly necessary. Complementarily, avoiding those therapeutic procedures that will not benefit a specific patient is also very relevant. In general, existing therapies for patients with BM could be improved in terms of molecular stratification and therapeutic efficacy. By questioning the benefit of whole brain radiotherapy as provided nowadays and the lack of biomarkers detecting radioresistance, we identified S100A9 and receptor for advanced glycation end-products (RAGE) as a liquid biopsy biomarker and a potential target for a radiosensitizer, respectively. Both of them are being clinically tested as part of the first comprehensive molecular strategy to personalized radiotherapy in BM.

Phase transitions of liposomes: when light meets heat.

Phase transitions of liposomes are normally studied by differential scanning calorimetry. A suspension of liposomes is subjected to an increase (decrease) of temperature and when heat is absorbed (released), the liposomes transit from a gel (liquid) to a liquid (gel) phase. This endothermic (exothermic) process takes place at a temperature called the melting temperatureTm, which is distinctive of the type of lipids forming the vesicles. The vesicles, though, also modify their size in the transition. Indeed, the thickness of the membranes decreases (increases) because carbon tails misalign (align). Concomitant with the modifications in the membrane thickness, the diameter (D) of the liposomes changes too. Therefore, when they are inspected by light, the scattered signal carries information from such dilatation (contraction) process. We performed careful experiments using dynamic light scattering as a function of temperature to detect the size changes of different liposomes. Gaussian fits of the derivatives of theDvsTcurves coincide within 1% with thermograms, which hints to the possibility of performing thermodynamic studies of lipid systems employing light.