Propene Polymerization Promoted by C2-Symmetric Metallocene Catalysts: From Atactic to Isotactic Polypropene in Consequence of an Isotope Effect

We studied the polymerization of propene-2-d promoted by the prototypical isotactic-specific catalyst system rac-ethylenebis(4,5,6,7-tetrahydro-1-indenyl)ZrCl2/MAO. In this communication, we report the results of our investigation, documenting a large isotope effect on the balance between polyinsertion and epimerization and, therefore, on the stereospecificity. The mechanistic implications of such results are also discusse

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

A thermophysical study of the melting process in alkyl chain metal n-alkanoates: The thallium (I) series

The peculiar thermal behavior of the thallium(I) n-alkanoates series (consisting in several transitions between polymorphic and mesomorphic phases) in comparison with other metallic n-alkanoates series is stated. The allowance of highly accurate adiabatic heat capacity data permits a study of the CH2CH2 contributions to the lattice heat capacity curve at low temperature. Moreover, in this series an anomalous gradual enhancement of the lattice heat capacity has been interpreted from vibrational spectroscopy results as a noncooperative effect due to the internal hindered rotation of the alkyl chain (formation of gauche defects, even in the solid state). The thermodynamics of the “stepwise melting process” from the totally ordered solid at low temperature to the isotropic liquid is based on a revised lattice heat-capacity curve. This was used to evaluate the energy and entropy not only of the clear first order transitions present in the series but also of the described noncooperative effect. The CH2CH2 enthalpy and entropy contribution for this series is estimated and a comparison with the published values for other series is carried out. Moreover, the texture of the mesophases is revealed by polarized light microscopy. © 1999 American Institute of Physics.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/69602/2/JCPSA6-111-8-3590-1.pd

Molecular screening with liquid biopsy for anti-EGFR retreatment in metastatic colorectal cancer: preliminary data from the randomized phase 2 PARERE trial

Background Retreatment with anti-EGFR monoclonal antibodies is a promising strategy in patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who achieved benefit from previous anti-EGFR exposure upon exclusion of mutations in RAS/BRAF genes according to circulating tumor DNA (ctDNA) analysis by means of liquid biopsy (LB). This treatment approach is now being investigated in the randomized phase II trial PARERE (NCT04787341). We here present preliminary findings of molecular screening.Methods Patients with RAS/BRAFV600E wt mCRC according to tissue genotyping who benefited from previous anti-EGFR-based treatment (fluoropyrimidines, oxaliplatin, irinotecan, and antiangiogenics) and then experienced disease progression to EGFR targeting were eligible for screening in the PARERE trial. The next-generation sequencing (NGS) panel Oncomine (TM) was employed for ctDNA testing.Results A total of 218 patients underwent LB, and ctDNA sequencing was successful in 201 of them (92%). RAS/BRAFV600E mutations were found in 68 (34%) patients and were mainly subclonal (median variant allele fraction [VAF] for KRAS, NRAS, and BRAF mutant clones: 0.52%, 0.62%, and 0.12%, respectively; p = 0.01), with KRASQ61H being the most frequently detected (31%). Anti-EGFR-free intervals did not predict ctDNA molecular status (p = 0.12). Among the 133 patients with RAS/BRAFV600E wt tumors according to LB, 40 (30%) harbored a mutation in at least another gene potentially implied in anti-EGFR resistance, mainly with subclonal expression (median VAF, 0.56%). In detail, alterations in PIK3CA, FBXW7, GNAS, MAP2K, ERBB2, BRAF (class I and II non-BRAFV600E), SMAD, EGFR, AKT1, and CTNNB1 occurred in 13%, 8%, 7%, 3%, 2%, 2%, 1%, 1%, 1%, and 1% cases, respectively. Co-mutations were detected in 13 (33%) out of 40 patients.Conclusions This is the largest prospective cohort of mCRC patients screened with LB for anti-EGFR retreatment in a randomized study. ctDNA genotyping reveals that at least one out of three patients candidate for retreatment should be excluded from this therapy, and other potential drivers of anti-EGFR resistance are found in approximately one out of three patients with RAS/BRAFV600E wt ctDNA

Multistep tumor genetic evolution and changes in immunogenicity trigger immune-mediated disease eradication in stage IV melanoma: lessons from a single case

Durable remissions are observed in 10%-20% of treated patients with advanced metastatic melanoma but the factors associated with long-term complete clinical responses are largely unknown. Here, we report the molecular characteristics of tumor evolution during disease progression along a 9-year clinical course in a patient with advanced disseminated melanoma who received different treatments, including trametinib, ipilimumab, radiation, vemurafenib, surgical tumor debulking and a second ipilimumab course, ultimately achieving complete long-term disease remission. Longitudinal analyses of therapies-resistant metastatic tumors revealed the effects of different treatments on tumor's microenvironment and immunogenicity, ultimately creating a milieu favorable to immunotherapy response. Monitoring of the temporal dynamics of T cells by analysis of the T cell receptor (TCR) repertoire in the tumor and peripheral blood during disease evolution indicated that T-cell clones with common TCR rearrangements, present at low levels at baseline, were maintained and expanded after immunotherapy, and that TCR diversity increased. Analysis of genetic, molecular, and cellular components of the tumor depicted a multistep process in which treatment with kinase inhibitors strongly conditioned the immune microenvironment creating an inflamed milieu converting cold into hot tumors, while ipilimumab impacted and increased the TCR repertoire, a requirement for tumor rejection. Since the optimal sequencing of treatment with antibodies targeting immune checkpoints and kinase inhibitors for advanced melanoma is still clinically debated, this case indicates that immunotherapy success is possible even after progression on targeted therapy

Negative hyperselection of patients with RAS and BRAF wild-type metastatic colorectal cancer who received panitumumab-based maintenance therapy

PURPOSE We assessed the prognostic/predictive role of primary tumor sidedness and uncommon alterations of anti\u2013epidermal growth factor receptor (EGFR) primary resistance (primary resistance in RAS and BRAF wild-type metastatic colorectal cancer patients treated with anti-EGFR monoclonal antibodies [PRESSING] panel) in patients with RAS/BRAF wild-type (wt) metastatic colorectal cancer (mCRC) who were randomly assigned to panitumumab plus fluorouracil, leucovorin, and oxaliplatin (FOLFOX-4) induction followed by maintenance with panitumumab with or without fluorouracil (FU) plus leucovorin (LV); Valentino trial (ClinicalTrials.gov identifier: NCT02476045). PATIENTS AND METHODS This prespecified retrospective analysis included 199 evaluable patients with RAS/ BRAF wt. The PRESSING panel included the following: immunohistochemistry (IHC) and in situ hybridization for HER2/MET amplification, IHC with or without RNA sequencing for ALK/ROS1/NTRKs/RET fusions, next-generation sequencing for HER2/PIK3CAex.20/PTEN/AKT1 and RAS mutations with low mutant allele fraction, and multiplex polymerase chain reaction for microsatellite instability. PRESSING status (any positive biomarker v all negative) and sidedness were correlated with overall response rate (ORR), progression-free survival (PFS), and overall survival (OS) in the study population and by treatment arm. RESULTS Overall, left- and right-sided tumors were 85.4% and 14.6%, respectively, and PRESSING-negative and -positive tumors were 75.4% and 24.6%, respectively. At a median follow-up of 26 months, inferior outcomes were consistently observed in right- versus left-sided tumors for ORR (55.2% v 74.1%; P = .037), PFS (8.4 v 11.5 months; P = .026), and OS (2-year rate: 50.2% v 65.1%; P = .062). Similar results were observed in the PRESSING-positive versus PRESSING-negative subgroup for ORR (59.2% v 75.3%; P = .030), PFS (7.7 v 12.1 months; P, .001), and OS (2-year rate: 48.1% v 68.1%; P = .021). The PFS benefit of FU plus LV added to panitumumab maintenance, reported in the study, was independent from sidedness and PRESSING status (interaction for PFS P = .293 and .127, respectively). However, outcomes were extremely poor in patients who received single-agent panitumumab and had right-sided tumors (median PFS, 7.7 months; 2-year OS, 38.5%) or PRESSING-positive tumors (median PFS, 7.4 months; 2-year OS, 47.0%). CONCLUSION The combined assessment of sidedness and molecular alterations of anti-EGFR primary resistance identified a consistent proportion of patients with RAS/BRAF\u2013wt mCRC who had inferior benefit from initial anti-EGFR\u2013based regimens, particularly after maintenance with single-agent anti-EGFRs