Advanced CT imaging features reflect distinct tissue immune profiles and exhibit high prognostic impact on NSCLC

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Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): A randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progressionfree survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials

Distinct HR expression patterns significantly affect the clinical behavior of metastatic HER2+ breast cancer and degree of benefit from novel anti-HER2 agents in the real world setting

We analyzed data from 738 HER2\u2010positive metastatic breast cancer (mbc) patients treated with pertuzumab\u2010based regimens and/or T\u2010DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression free survival at first\u2010line (mPFS1) was 12 months. Pertuzumab as first\u2010line conferred longer mPFS1 compared to other first\u2010line treatments (16 vs 9 months, p=0.0001), regardless of IHC subtype. Median PFS in second\u2010line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T\u2010DM1 compared to other agents (7 vs 6 months, p=0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs) (p=0.17), while a trend emerged for tumors with one HR (p=0.05). Conversely, PFS2 gain was significant in HRs\u2010negative tumors (p=0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T\u2010DM1 in second\u2010line following pertuzumab were significantly lower compared to pertuzumab\u2010na\uefve patients(p=0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p=0.02 and p=0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment\u2010related outcomes of HER2\u2010positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor (ER) pathways in HER2\u2010positive (mbc) patients

A retrospective multicentric observational study of trastuzumab emtansine in HER2 positive metastatic breast cancer: a real- world experience

We addressed trastuzumab emtansine (T-DM1) e cacy in HER2+ metastatic breast cancer patients treated in real-world practice, and its activity in pertuzumab- pretreated patients. We conducted a retrospective, observational study involving 23 cancer centres, and 250 patients. Survival data were analyzed by Kaplan Meier curves and log rank test. Factors testing signi cant in univariate analysis were tested in multivariate models. Median follow-up was 15 months and median T-DM1 treatment-length 4 months. Response rate was 41.6%, clinical bene t 60.9%. Median progression-free and median overall survival were 6 and 20 months, respectively. Overall, no di erences emerged by pertuzumab pretreatment, with median progression-free and median overall survival of 4 and 17 months in pertuzumab- pretreated (p=0.13), and 6 and 22 months in pertuzumab-naïve patients (p=0.27). Patients who received second-line T-DM1 had median progression-free and median overall survival of 3 and 12 months (p=0.0001) if pertuzumab-pretreated, and 8 and 26 months if pertuzumab-naïve (p=0.06). In contrast, in third-line and beyond, median progression-free and median overall survival were 16 and 18 months in pertuzumab- pretreated (p=0.05) and 6 and 17 months in pertuzumab-naïve patients (p=0.30). In multivariate analysis, lower ECOG performance status was associated with progression-free survival bene t (p<0.0001), while overall survival was positively a ected by lower ECOG PS (p<0.0001), absence of brain metastases (p 0.05), and clinical bene t (p<0.0001). Our results are comparable with those from randomized trials. Further studies are warranted to con rm and interpret our data on apparently lower T-DM1 e cacy when given as second-line treatment after pertuzumab, and on the optimal sequence order

Off-label long acting injectable antipsychotics in real-world clinical practice: a cross-sectional analysis of prescriptive patterns from the STAR Network DEPOT study

Introduction Information on the off-label use of Long-Acting Injectable (LAI) antipsychotics in the real world is lacking. In this study, we aimed to identify the sociodemographic and clinical features of patients treated with on- vs off-label LAIs and predictors of off-label First- or Second-Generation Antipsychotic (FGA vs. SGA) LAI choice in everyday clinical practice. Method In a naturalistic national cohort of 449 patients who initiated LAI treatment in the STAR Network Depot Study, two groups were identified based on off- or on-label prescriptions. A multivariate logistic regression analysis was used to test several clinically relevant variables and identify those associated with the choice of FGA vs SGA prescription in the off-label group. Results SGA LAIs were more commonly prescribed in everyday practice, without significant differences in their on- and off-label use. Approximately 1 in 4 patients received an off-label prescription. In the off-label group, the most frequent diagnoses were bipolar disorder (67.5%) or any personality disorder (23.7%). FGA vs SGA LAI choice was significantly associated with BPRS thought disorder (OR = 1.22, CI95% 1.04 to 1.43, p = 0.015) and hostility/suspiciousness (OR = 0.83, CI95% 0.71 to 0.97, p = 0.017) dimensions. The likelihood of receiving an SGA LAI grew steadily with the increase of the BPRS thought disturbance score. Conversely, a preference towards prescribing an FGA was observed with higher scores at the BPRS hostility/suspiciousness subscale. Conclusion Our study is the first to identify predictors of FGA vs SGA choice in patients treated with off-label LAI antipsychotics. Demographic characteristics, i.e. age, sex, and substance/alcohol use co-morbidities did not appear to influence the choice towards FGAs or SGAs. Despite a lack of evidence, clinicians tend to favour FGA over SGA LAIs in bipolar or personality disorder patients with relevant hostility. Further research is needed to evaluate treatment adherence and clinical effectiveness of these prescriptive patterns

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P &lt; .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Magnetic structure and magnetocalorics of GdPO4

Under the terms of the Creative Commons Attribution License 3.0 (CC-BY).The magnetic ordering structure of GdPO4 is determined at T=60 mK by the diffraction of hot neutrons with wavelength λ=0.4696 Å. It corresponds to a noncollinear antiferromagnetic arrangement of the Gd moments with propagation vector k=(1/2,0,1/2). This arrangement is found to minimize the dipole-dipole interaction and the crystal-field anisotropy energy, the magnetic superexchange being much smaller. The intensity of the magnetic reflections decreases with increasing temperature and vanishes at T≈0.8 K, in agreement with the magnetic ordering temperature TN=0.77 K, as reported in previous works based on heat capacity and magnetic susceptibility measurements. The magnetocaloric parameters have been determined from heat capacity data at constant applied fields up to 7 T, as well as from isothermal magnetization data. The magnetocaloric effect, for a field change ΔB=0-7T, reaches -ΔST=375.8mJ/cm3K-1 at T=2.1 K, largely exceeding the maximum values reported to date for Gd-based magnetic refrigerants.We acknowledge the Spanish MINECO for funding this research through Grant Nos. MAT2012-38318-C03-01 and MAT2013-44063-R. Research at the Oak Ridge National Laboratory for one author (L.A.B.) was sponsored by the U.S. Department of Energy, Basic Energy Sciences, Materials Sciences and Engineering Division.Peer Reviewe

Estructura magnetica del fuerte magnetocalórico GdPO4 a 60 mK

Resumen del trabajo presentado a la "VII Reunión de la Sociedad Española de Técnicas Neutrónicas" celebrada en Pamplona del22 al 25 de junio de 2014.El GdPO4 presenta, en el rango de temperaturas del helio líquido, un excepcionalmente fuerte efecto magnetocalórico, que excede en un 50% al del siguiente compuesto conocido hasta la fecha, en cualquier rango de temperatura. eso se debe a una conjunción de factores favorables como son: a) Alta densidad de moemnto magnético, b) Bajísima anisotropía del Gd, c) Muy pequeño canje debido a los electrones 4f y al enlace fuertemente iónico, que evita el solapamiento de funciones de onda, y d) una estructura cristalina frustrante, tanto para las interacciones de canje como para la interacción dipolar. Como resultado se ordena sólo a Tn=0.77K y presente todo su poder magneto calórico en el rango de temperaturas del helio líquido lo que lo hace ideal para la tecnología de refrigeración por desmagnetización adiabática, superando por mucho al compuesto más utilizado, granate de gadolinio y galio (GGG). Es bien sabido que el Gd es muy absorvente de los neutrones térmicos, por tanto se ha estudiado la estructura magnética en monocristal a 60 mK, mediante en un experimento realizado en el ILL, instrumento D9, con neutrones calientes de λ=0.5 ºA y criostato de dilución 3He/4He. Para ello es necesaria la geometría de >normal beam> en que todo criostato puede girar alrededor de la vertical mientras el detetctor bidimensional, se mueve en horizontal, con un pequeño movimineto posible en vertical. La estructura cristalina es tipo monazita: monoclínica P21/n, con Z=4 átomos magnéticos por celda unidad. La estructura magnética resulta ser antiferromagnética, no colineal, en 4 subredes, con μ=6.9 μB, k=(1/2, 0, 1/2) y en un modo que hemos dado en llamar CxAyCz siguiendo convenciones similares a las de Bertaut. Un cálculo de las energías (energía magnética total por partícula Et/kB=-2.0K, de capacidad calorífica, Et se ha definido como nula para el sistema desordenado) de interacción muestra que esta estructura ocurre por competición de la interacción dipolar (la más fuerte, de Rd/kB=-1.5K, con respecto al sistema desordenado), la anisotropía (EA/kB=-0.40K) y el canje (EA/kB=-0.12K), que muy débil.Trabajo financiado a través del proyecto del Ministerio de Economía y Competitividad (MINECO)(MAT2012-38318-C03-01).Peer Reviewe

A new twist on an ‘old’ ligand:a [Mn₁₆] double square wheel and a [Mn₁₀] contorted wheel

Ligand design remains key to the synthesis of coordination compounds possessing specific topologies, nuclearities and symmetries that direct targeted physical properties. N,O-chelates based on ethanolamine have been particularly prolific in constructing a variety of paramagnetic 3d transition metal complexes with fascinating magnetic properties. Here, we show that combining three ethanolamine moieties within the same organic framework in the form of the pro-ligand 1,3,5-tri(2-hydroxyethyl)-1,3,5-triazacyclohexane (LH3) leads to the formation of two highly unusual Mn wheels. Reaction of Mn(NO3)2·6H2O with LH3 in basic methanolic solutions leads to the formation of [MnIII12MnII4(μ3-O)6(μ-OH)4(μ3-OMe)2(μ-OMe)2(L)4(LH)2(H2O)10](NO3)6(OH)2 (1) and [MnIII10(μ3-O)4(μ-OH)4(μ-OMe)4(L)4(H2O)4](NO3)2 (2), the only difference in the synthesis being the ratio of metal:ligand employed. The structure of the former describes two offset [MnIII6MnII2] square wheels, linked through a common centre, and the latter a single [MnIII10] wheel twisted at its centre, such that the top half is orientated perpendicular to the bottom half. In both cases the L3−/LH2− ligands dictate the orientation of the Jahn-Teller axes of the MnIII ions which lie perpendicular to the triazacyclohexane plane. Direct current magnetic susceptibility and magnetisation data reveal the presence of competing exchange interactions in 1 and strong antiferromagnetic interactions in 2. Given the simplicity of the reactions employed and the paucity of previous work, the formation of these two compounds suggests that LH3 will prove to be a profitable ligand for the synthesis of a multitude of novel 3d transition metal complexes.CJM and TGT thank the Hellenic Foundation for Research and Innovation (H.F.R.I.) under the “First Call for H.F.R.I. Research Projects to support Faculty members and Researchers and the procurement of high-cost research equipment grant” (Project Number: 400). EKB thanks the EPSRC for financial support under grant reference numbers EP/I03255X/1 and EP/I031421/1. GL and ME thank the Ministerio de Ciencia e Innovación (RTI2018-094909-J-I00) and CSIC (PIE 201960E002).Peer reviewe

Magnetic and entanglement properties of molecular Cr2nCu2 heterometallic spin rings

We investigate the low-temperature magnetic and entanglement properties of a series of molecular Cr2nCu2 heterometallic spin rings (withn=4,5,6). These are cyclic spin systems, consisting of two Cu2+(s=1/2) ions, coupled by two antiferromagnetic segments of nCr3+(s=3/2) ions. Thermodynamic measurements (magnetization, susceptibility, and specific heat) allow us to determine the total spin of the ground state and to estimate the spin-Hamiltonian parameters related to magnetic anisotropy. X-ray spectroscopies (XAS and XMCD) are used to probe the local magnetization of the Cr and Cu ions, and provide results that are consistent with the bulk magnetization data. We finally investigate the relation between heterometallicity and entanglement in these prototypical spin systems. In particular, we focus on the spatial modulation of entanglement induced by the Cu defect spins and on the long-distance entanglement between them induced by the two Cr chains