Treatment of patients with BRAFV600E-mutated metastatic colorectal cancer after progression to encorafenib and cetuximab: data from a real-world nationwide dataset.

BACKGROUND: Targeted therapy (TT) with encorafenib and cetuximab is the current standard for patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) who received one or more prior systemic treatments. However, the median progression-free survival (mPFS) is ∼4 months, and little is known about the possibility of administering subsequent therapies, their efficacy, and clinicopathological determinants of outcome. METHODS: A real-world dataset including patients with BRAFV600E-mutated mCRC treated with TT at 21 Italian centers was retrospectively interrogated. We assessed treatments after progression, attrition rates, and outcomes. RESULTS: Of the 179 patients included, 85 (47%), 32 (18%), and 7 (4%) received one, two, or three lines of treatment after TT, respectively. Those receiving TT in the second line were more likely to receive at least one subsequent therapy (53%), as compared with those treated with TT in the third line or beyond (30%; P < 0.0001), and achieved longer postprogression survival (PPS), also in a multivariate model (P = 0.0001). Among 62 patients with proficient mismatch repair/microsatellite stable (pMMR/MSS) tumors receiving one or more lines of treatment after second-line TT, combinatory chemotherapy ± anti-vascular endothelial growth factor (anti-VEGF) was associated with longer PFS and PPS as compared with trifluridine-tipiracil or regorafenib (mPFS: 2.6 versus 2.0 months, P = 0.07; PPS: 6.5 versus 4.4 months, P = 0.04). CONCLUSIONS: Our real-world data suggest that TT should be initiated as soon as possible after the failure of first-line treatment in BRAFV600E-mutated mCRC. Among patients with pMMR/MSS tumors, combinatory chemotherapy ± anti-VEGF appears the preferred treatment choice after TT failure.

Magnetic Janssen effect.

A pile of grains, even when at rest in a silo, can display fascinating properties. One of the most celebrated is the Janssen effect, named after the pioneering engineer who explained the pressure saturation at the bottom of a container filled with corn. This surprising behavior arises because of frictional interactions between the grains through a disordered network of contacts, and the vessel lateral walls, which partially support the weight of the column, decreasing its apparent mass. Here, we demonstrate control over frictional interactions using ferromagnetic grains and an external magnetic field. We show that the anisotropic pairwise interactions between magnetized grains result in a radial force along the walls, whose amplitude and direction is fully determined by the applied magnetic field. Such magnetic Janssen effect allows for the fine tuning of the granular column apparent mass. Our findings pave the way towards the design of functional jammed materials in confined geometries, via a further control of both their static and dynamic properties.

Bending to Kinetic Energy Transfer in Adhesive Peel Front Microinstability.

We report an extensive experimental study of a detachment front dynamics instability, appearing at microscopic scales during the peeling of adhesive tapes. The amplitude of this instability scales with its period as A_{mss}∝T_{mss}^{1/3}, with a prefactor evolving slightly with the peel angle θ, and increasing systematically with the bending modulus B of the tape backing. Establishing a local energy budget of the detachment process during one period of this microinstability, our theoretical model shows that the elastic bending energy stored in the portion of tape to be peeled is converted into kinetic energy, providing a quantitative description of the experimental scaling law.

Avalanches and extreme value statistics in interfacial crackling dynamics.

We study the avalanche and extreme statistics of the global velocity of a crack front, propagating slowly along a weak heterogeneous interface of a transparent polymethyl methacrylate block. The different loading conditions used (imposed constant velocity or creep relaxation) lead to a broad range of average crack front velocities. Our high-resolution and large dataset allows one to characterize in detail the observed intermittent crackling dynamics. We specifically measure the size S, the duration D, as well as the maximum amplitude [Formula: see text] of the global avalanches, defined as bursts in the interfacial crack global velocity time series. Those quantities characterizing the crackling dynamics follow robust power-law distributions, with scaling exponents in agreement with the values predicted and obtained in numerical simulations of the critical depinning of a long-range elastic string, slowly driven in a random medium. Nevertheless, our experimental results also set the limit of such model which cannot reproduce the power-law distribution of the maximum amplitudes of avalanches of a given duration reminiscent of the underlying fat-tail statistics of the local crack front velocities.This article is part of the theme issue 'Statistical physics of fracture and earthquakes'.

Monitoring biodiversity in libraries: a pilot study and perspectives for indoor air quality.

Indoor Air Quality (IAQ) in libraries is influenced by the presence of specific factors which can impact on both paper storage as well as people health. Microclimatic conditions induce and support a biodiversity pattern involving environmental and anthropic microorganisms. We used a multidisciplinary monitoring model to characterize microflora biodiversity by Next Generation Sequencing (NGS). Biodiversity indexes were adapted to evaluate anthropic vs environmental pollution by combining Shannon mean index (H), species representativeness (EH), human/environmental pollution ratio (SA) to better characterize the NGS output and acquire synthetic information on Indoor Air Microbial Biodiversity (IAMB). Results indicate a frequently low microbial load (IGCM/m3 < 1000) characterized by different species (n = 102), including several cellulose metabolizing bacteria. Workers and visitors appeared a relevant source of microbial contamination. Air biodiversity assayed by NGS seems a promising marker for studying IAQ.

Path (un)predictability of two interacting cracks in polycarbonate sheets using Digital Image Correlation.

Crack propagation is tracked here with Digital Image Correlation analysis in the test case of two cracks propagating in opposite directions in polycarbonate, a material with high ductility and a large Fracture Process Zone (FPZ). Depending on the initial distances between the two crack tips, one may observe different complex crack paths with in particular a regime where the two cracks repel each other prior to being attracted. We show by strain field analysis how this can be understood according to the principle of local symmetry: the propagation is to the direction where the local shear - mode KII in fracture mechanics language - is zero. Thus the interactions exhibited by the cracks arise from symmetry, from the initial geometry, and from the material properties which induce the FPZ. This complexity makes any long-range prediction of the path(s) impossible.

Development of molecularly imprinted polymeric nanofibers by electrospinning and applications to pesticide adsorption.

Novel polystyrene-based molecularly imprinted polymer nanofibers were synthesized through the electrospinning technique. The molecularly imprinted polymers were prepared using a non-covalent approach and atrazine as template. For comparison, nonimprinted polymer nanofibers were also synthesized. The morphology of the synthesized nanofibers was characterized using scanning electron microscopy. The adsorption of pesticides, atrazine, atrazine desisopropyl, atraton, carboxin, linuron, and chlorpyrifos was studied under equilibrium (batch) conditions. To describe the adsorption capability of the synthesized polymers, Langmuir and Freundlich models were used. The Freundlich model provided a better mathematical approximation of the sorption characteristic for polymers nanofibers. To evaluate the adsorption capacity in the presence of interferents experiments on river water samples spiked with a mixture of six pesticides were also performed. The results obtained for the highest concentration levels investigated, show a greater amount of pesticide adsorbed on molecularly imprinted polymers and non-imprinted polymers compared to those obtained using commercial stationary phases used as reference.

Flake size-dependent cyto and genotoxic evaluation of graphene oxide on in vitro A549, CaCo2 and vero cell lines.

This study was carried out by varying both graphene oxide (GO) concentration (10 μg/mL, 50 μg/mL, 100 μg/mL) and flakes sizes of 1320 nm and 130 nm. Characterization by scanning electron microscopy and Raman spectroscopy demonstrate that the area of GO flakes varies of one order of magnitude but their chemical structure remains unmodified. A 24-h cytotoxicity test showed, for A549, a loss in the viability, while the test exhibits overall a positive increase in the viability for CaCo2 and Vero. A 24-h comet assay shows a marked GO genotoxicity: for micrometer-sized GO flakes the genotoxicity is in positive correlation with the concentration, while for nanometer-sized GO flakes there was a high degree of genotoxicity at the lowest concentration tested.

High frequency monitoring reveals aftershocks in subcritical crack growth.

By combining direct imaging and acoustic emission measurements, the subcritical propagation of a crack in a heterogeneous material is analyzed. Both methods show that the fracture proceeds through a succession of discrete events. However, the macroscopic opening of the fracture captured by the images results from the accumulation of more-elementary events detected by the acoustics. When the acoustic energy is cumulated over large time scales corresponding to the image acquisition rate, a similar statistics is recovered. High frequency acoustic monitoring reveals aftershocks responsible for a time scale dependent exponent of the power law energy distributions. On the contrary, direct imaging, which is unable to resolve these aftershocks, delivers a misleading exponent value.

Idiopathic and mild subclinical hypothyroidism in childhood: clinical management.

Subclinical hypothyroidism (SH) is a common clinical problem in children and adolescents, for which there are many controversial issues regarding natural course and management. Aim of this review is to report on the state of the art regarding these controversial points of idiopathic SH in pediatric age. We included in our search only full-length articles on natural history and treatment of SH in children with no associated diseases or genetic syndromes, thus identifying only 13 papers that were suitable for our analysis. According to the results of these retrospective or longitudinal studies a persistently mild TSH elevation (between 5 and 10 mIU/L) in SH children with no underlying disease is unable to affect growth and bone maturation or body mass index (two studies) or cognitive function (one study). Moreover, the risk of a deterioration over time of thyroid function in the untreated cases with mild and idiophatic SH is only 12% (one study). Progression odds increase with increasing baseline TSH, with goiter presence and with positive anti-thyroid antibodies (two studies in children). Although no broad consensus exists on whether children with mild SH require L-T4 therapy, nevertheless, on the basis of the results of the majority of included studies, it can be concluded that L-T4 treatment is not indicated when TSH is repeatedly between 5 and 10 mIU/L and an underlying disease has been excluded. By contrast, treatment is suitable in the cases with TSH>10 mIU/L and/or an underlying disease.

Cross-sectional and prospective study of the effects of GH therapy on metabolic panel in children with GH deficiency.

BACKGROUND: Numerous studies have shown that GH, in addition to promoting linear growth, exerts a key role in many metabolic processes. However, there are only few studies aiming at evaluating the metabolic panel of children with GH deficiency (GHD). The aims of the study were: to verify the presence of metabolic alterations in GHD children in comparison with age-matched controls and to check the possible effects of two year GH therapy on the metabolic parameters in GHD. STUDY DESIGN: cross-sectional and prospective; one center experience POPULATION AND METHODS: We enrolled 32 pediatric GHD patients (group A) and 33 sex- and age-matched healthy controls (group B). Baseline serum assays (lipid, insulin, glucose) were performed in both groups. GHD children underwent replacement therapy with GH. The same assays were repeated after 12 and 24 months of GH treatment. RESULTS: No differences, in basal assays were found between the two groups. In group A, after initiation of GH, there was a significant increase of basal insulin and HOMA- insulin resistance (IR) index (p <0.001). In children with severe GHD (peak GH <3 ng / ml), after beginning of GH therapy a significant improvement in the lipid profile was found (p < 0.05). CONCLUSIONS: a) At the time of diagnosis GHD children had a metabolic picture that was not different from non- GHD group; b) in children with severe GHD, the metabolic profile showed a trend towards at improvement after the initiation of replacement therapy with GH, with beneficial effects in terms of total cholesterol, LDL cholesterol and cardiovascular risk indices; c) GHD patients with unfavorable metabolic profile (high BMI and hypercholestorolemia) need a monitoring of glucose metabolism by periodical evaluations of insulin and HOMA - IR.

Evans Syndrome: A case report.

We describe a case of a 14-years old caucasian female affected by autoimmune hemolytic anemia and thrombocytopenia successfully treated with intravenous immunoglobulin and steroids. Nevertheless, neutropenia occurred during follow-up period. Positivity of direct antiglobulin test and sieric anti-neutrophil antibodies suggested the diagnosis of Evans syndrome trilineage.

[Klinefelter syndrome: clinical and auxological features of 14 patients diagnosed in childhood]. / La sindrome di Klinefelter: aspetti anamnestici, clinici ed auxologici di una casistica diagnosticata in età pediatrica.

UNLABELLED: Klinefelter syndrome (KS) is the most frequent chromosomal aneuploidy with a prevalence of 1:500 men but it often remains a largely undiagnosed condition and only 10% of cases are identified in childhood and adolescence. We report the anamnestic, clinical and auxological findings of 14 KS patients diagnosed in paediatric age. 3/14 patients (21%) with KS were diagnosed in prenatal age by amniocentesis, 1 patient was diagnosed at birth due to genital ambiguity and the remaining 10/14 (71.4%) were diagnosed at a chronological age younger than 15 years old for a clinical picture characterized by a peculiar cognitive and behavioral pattern or genital anomalies and abnormalities of pubertal development. The classical karyotype 47 XXY was present in 10/14 subjects (72%), a mosaic form (46 XY/47 XXY) was present in 2/14 (14%) and a complex aneuploidy (48 XXYY and 48 XXXY)was present in the remaining 2/14 (14%) patients. All KS patients diagnosed in childhood and adolescence (10/14 =71.4 %) showed a stature taller than the respective target height and also the predicted final height (calculated from a chronological age older than 7 years old) and the reached final height were significantly taller than target height. CONCLUSION: according to our retrospective data we can assert that KS in paediatric age is characterized by a stature taller than target

Sound and light from fractures in scintillators.

Prompted by intriguing events observed in certain particle-physics searches for rare events, we study light and acoustic emission simultaneously in some inorganic scintillators subject to mechanical stress. We observe mechanoluminescence in Bi4Ge3O12, CdWO4, and ZnWO4, in various mechanical configurations at room temperature and ambient pressure. We analyze the temporal and amplitude correlations between the light emission and the acoustic emission during fracture. A novel application of the precise energy calibration of Bi4Ge3O12 provided by radioactive sources allows us to deduce that the fraction of elastic energy converted to light is at least 3×10(-5).

[Turner-like syndrome: a case report]. / Sembrava fosse una sindrome di Turner: descrizione di un caso clinico.

A prepubescent 11 year-old girl came to our attention for short stature. Auxological evaluation showed peculiar phenotype. In order to exclude Turner syndrome standard karyotype was performed with normal result. Because of anemia and selective deficiency of the erythroid lineage further investigations were performed and a diagnosis of Blackfan-Diamond anemia was made.

The relationship between TORCH complex false positivity and obstetric outcome in patients with antiphospholipid syndrome.

OBJECTIVE: The presence of TORCH IgM positivity is not a specific indicator of primary infection; the assessment of IgG avidity index has been shown to be useful in identifying or excluding primary infection in pregnant women with no pre-gestational TORCH serology. TORCH is an acronym for Toxoplasmosis, Others (HBV, syphilis, Varicella-Zoster virus, Epstein Barr virus, Coxsackie virus and Parvovirus), Rubella, Cytomegalovirus (CMV) and Herpes Simplex. PATIENTS AND METHODS: Data from 54 pregnancies in women with antiphospholipid syndrome (APS) were assessed in comparison with data from 222 healthy pregnant women as controls. Each woman in both groups was systematically screened for TORCH IgG and IgM during pre-conceptional evaluation and/or at the beginning of pregnancy. The assessment of IgG avidity was also evaluated in order to identify primary infection or false positivity. RESULTS: A significant increase of CMV IgM false positivity in APS in comparison with controls was detected. A worse pregnancy outcome was observed among APS patients having CMV IgM false positivity in comparison with APS patients without false positivity; in particular a statistically significant lower neonatal birth weight and a lower neonatal birth weight percentile were observed. CONCLUSION: Our data suggest that the presence of CMV IgM false positivity could represent a novel prognostic factor for poor pregnancy outcome in APS patients.

Complementemia and obstetric outcome in pregnancy with antiphospholipid syndrome.

OBJECTIVE: To investigate the predictive value of serum C3 and C4 complement component levels in relation to pregnancy outcome in patients with antiphospholipid syndrome (APS). MATERIALS AND METHODS: A prospective study of 47 pregnancies associated with APS was performed. Pregnancy outcome was analyzed in terms of: fetal loss, preterm delivery (≤34 gestational weeks), fetal intrauterine growth restriction (IUGR), birth weight <2500 g and preeclampsia. Week at delivery, neonatal birth weight and neonatal birth weight percentile were also investigated. Hypocomplementemia, positivity for anti-dsDNA and triple positivity for antiphospholipid antibodies (aPL) were related to pregnancy outcome. RESULTS: Forty-three pregnancies ended in live births with a fetal loss rate of 8.5%. Fetal death, preterm delivery and birth weight <2500 g were associated with hypocomplementemia (p = 0.019, p = 0.0002, p < 0.0001 respectively). Lower neonatal birth weight, lower neonatal birth weight percentile and lower week at delivery were associated with hypocomplementemia (p < 0.0001, p = 0.0003, p < 0.0001 respectively) and with triple aPL positivity (p = 0.008, p = 0.014, p = 0.03 respectively). A poor pregnancy outcome was confirmed among primary APS (PAPS) pregnancies with hypocomplementemia. Multivariate analysis confirmed that hypocomplementemia was an independent predictor of lower neonatal birth weight (p = 0.0001) and lower week at delivery (p = 0.002). CONCLUSION: Hypocomplementemia could be considered a novel prognostic factor for pregnancy outcome in APS patients.

Transient global amnesia as the first symptom of primary antiphospholipid syndrome: a case report.

We describe the case of a 45-year-old woman who had drawn our attention for some recent episodes of transient global amnesia that, upon further examination, resulted from ischemic events caused by multiple arterial thrombosis (bilateral internal carotid occlusion, significant stenosis of the right external carotid, mild stenosis of the right vertebral artery, right anterior cerebral artery occlusion and severe stenosis of the anterior descending coronary artery) due to primary antiphospholipid syndrome. Revascularisation of either carotid was not attempted. A percutaneous intervention in the anterior descending coronary artery stenosis was performed successfully. Due to severe arterial thrombosis, the patient was discharged with only duplex antiplatelet treatment and subcutaneous anticoagulant therapy, since immunotherapy is not indicated in primary APS. The occurrence of transient global amnesia should raise the suspicion of APS.