Addition of chemotherapy to nivolumab after PD-1 inhibitor failure as bridge to allogeneic stem cell transplantation in classical Hodgkin's lymphoma: report on three cases and literature review.

The poor prognosis of refractory or relapsed (R/R) classical Hodgkin's lymphoma (cHL) after autologous stem cell transplantation has improved greatly due to the introduction of brentuximab vedotin and PD-1 inhibitors. However, the duration of response achieved with these novel agents is too short. The information about the management of patients after anti-PD-1 therapy failure is very limited in cHL, although chemotherapy alone or combined with PD-1 inhibitors has shown encouraging results. We report three cases of heavily pretreated cHL, refractory to nivolumab monotherapy, successfully rescued with the addition of chemotherapy to nivolumab, as a bridge to allogeneic stem cell transplantation (allo-SCT). All three patients presented poor clinical features such as three to four previous lines including brentuximab vedotin and autologous stem cell transplantation, refractoriness to the last line of therapy previous to nivolumab, and rapid disease progression. Notwithstanding these characteristics and nivolumab failure, they achieved a complete response after the addition of chemotherapy, were consolidated with allo-SCT, and still remain in complete response. There are few studies concerning the combination of PD-1 inhibitors and chemotherapy after nivolumab failure, including one retrospective study and one phase II trial with nivolumab plus bendamustine. Therefore, only few patients are consolidated with allo-SCT. However, there are several ongoing trials investigating new combinations of chemotherapy and PD-1 inhibitors in R/R cHL, as well as in first line. All these data suggest that anti-PD-1 therapy may reprogram the immune system, activating and inhibiting effector and immunosuppressive cells, respectively, leading to overtake of chemorefractoriness. Allo-SCT can increase the immune-related events of patients treated with anti-PD-1 previously, consistent on acute graft-versus-host disease, sinusoidal obstruction syndrome, and noninfectious febrile syndrome. In conclusion, the combination of PD-1 inhibitor and chemotherapy may be a feasible therapy after anti-PD-1 treatment failure as a bridge to allo-SCT.

Directing self-assembly in solution towards improved cooperativity in Fe(iii) complexes with amphiphilic tridentate ligands.

An amphiphilic iron(iii) complex with a tridentate Schiff-base ligand was prepared by condensation of a hexadecyloxy functionalised salycylaldehyde with a diamine followed by complexation with FeCl2 and anion methathesis with NaClO4. The complex shows spin crossover both in the solid state and solution. However in solution self-assembly and consequently aggregation of individual molecules form concentration dependent particles with sizes of 300 nm for higher concentrations, or 5 nm for lower concentrations. Aggregate formation was confirmed by NANO-flex 180° DLS Size, scan-rate dependent cyclic voltammetry and scanning electron microscopy. Molecular simulations were used to investigate the self-assembly of the complex in solution, including the role of residual water molecules. The simulations showed the self-assembly of reverse micelle-like structures when a small water cluster is inserted in solution, whereas no large aggregates formed in dehydrated environments. The perchlorate anions were found near the metal centres, stabilizing the aggregates around the water pool. Simulations of pre-assembled structures further showed the lack of stability of large aggregates in the absence of water. The larger aggregates promoted efficient communication between the iron(iii) centres and the compound displayed spin crossover in solution at around 220 K with a 10 K hysteresis window, as measured by NMR and SQUID magnetometry.

Selecting the spin crossover profile with controlled crystallization of mononuclear Fe(iii) polymorphs.

Two polymorphic species of the [Fe(5-Br-salEen)2]ClO4 compound were obtained, each of them being selectively recovered after evaporation of the solvent at a controlled rate. While polymorph 1a is formed during slow evaporation, fast evaporation favors polymorph 1b. The importance of the evaporation rate was recognized after detailed studies of the reaction temperature, solvent evaporation rate and crystallization temperature effects. The complex in the new polymorphic form 1a showed an abrupt spin crossover at 172 K with a small 1 K hysteresis window and over a narrow 10 K range. 57Fe Mössbauer spectroscopy and differential scanning calorimetry, complemented by X-ray studies for both the high-spin and low-spin forms, were used to further characterize the new polymorphic phase 1a. Both polymorphs are based on the same Fe(iii) complex cation hydrogen bonded to the perchlorate anion. These units are loosely bound in the crystals via weak interactions. In the new polymorph 1a, the hydrogen bonds are stronger, while the weak hydrogen and halogen bonds, as well as π-π stacking, create a cooperative network, not present in 1b, responsible for the spin transition profile.

Oxidation of 5-Chloromethylfurfural (CMF) to 2,5-Diformylfuran (DFF).

2,5-Diformylfuran (DFF) is an important biorenewable building block, namely for the manufacture of new polymers that may replace existing materials derived from limited fossil fuel resources. The current reported methods for the preparation of DFF are mainly derived from the oxidation of 5-hydroxymethylfurfural (HMF) and, to a lesser extent, directly from fructose. 5-Chloromethylfurfural (CMF) has been considered an alternative to HMF as an intermediate building block due to its advantages regarding stability, polarity, and availability from glucose and cellulose. The only reported method for the transformation of CMF to DFF is restricted to the use of DMSO as the solvent and oxidant. We envisioned that the transformation could be performed using more attractive conditions. To that end, we explored the oxidation of CMF to DFF by screening several oxidants such as H2O2, oxone, and pyridine N-oxide (PNO); different heating methods, namely thermal and microwave irradiation (MWI); and also flow conditions. The combination of PNO (4 equiv.) and Cu(OTf)2 (0.5 equiv.) in acetonitrile was identified as the best system, which lead to the formation of DFF in 54% yield under MWI for 5 min at 160 °C. Consequently, a range of different heterogeneous copper catalysts were tested, which allowed for catalyst reuse. Similar results were also observed under flow conditions using copper immobilized on silica under thermal heating at 160 °C for a residence time of 2.7 min. Finally, HMF and 5,5'-oxybis(5-methylene-2-furaldehyde) (OBMF) were the only byproducts identified under the reaction conditions studied.

Hb A1c Determination by Capillary Electrophoresis is an Efficient Method for Detecting ß-Thalassemias and Hemoglobin Variants.

Glycated hemoglobin (Hb A1c) determination by multicapillary zone electrophoresis (MZE) can additionally be used to detect Hb A2, Hb F and most common hemoglobin (Hb) variants. We assessed the effectiveness of this method for detecting ß-thalassemia (ß-thal), δß-thalassemia (δß-thal) and most common Hb variants. Moreover, Hb F/Hb A2 is evaluated as an index for discriminating between ß- and δß-thal traits. The theoretical ß-thalassemia major (ß-TM) birth rate in our healthcare area is calculated and contrasted with real data. A MZE technique was used for Hb A1c measurements in 27,724 patients. Previous criteria for carrier detection were established and subsequently confirmed by molecular biology techniques. Positive predictive value (PPV) was 100.0%. The prevalence of ß-thal trait (including δß-thal) was 0.34%. The most prevalent mutations (estimated per 100,000 population) were HBB: c.118C > T (57.7%), HBB: c.93-21G>A (50.5%), HBB: c.92 + 1G > A (43.3%), HBB: c.92 + 6T > C (32.5%) and HBB: c.20delA (18.0%) for ß-thalassemias, and Hb S (HBB: c.20A > T) (32.5%) and Hb J-Baltimore (HBB:c.3880T>A) (28.9%) for Hb variants. We found a paradoxical result between the theoretical ß-TM birth rate and real data. We calculated an optimal Hb F/Hb A2 index cutoff of 0.71 for discriminating between ß- and δß-thal traits. This method is highly cost-effective for detecting ß-thalassemias and common Hb variants. Prevalence results match previous data for the Spanish population. Heterogeneity of mutations in Spain has markedly increased as a consequence of migration. The Hb F/Hb A2 index cutoff could be used to predict δß-thal trait.

Integrating clinical features and genetic lesions in the risk assessment of patients with chronic myelomonocytic leukemia.

Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm with variable clinical course. To predict the clinical outcome, we previously developed a CMML-specific prognostic scoring system (CPSS) based on clinical parameters and cytogenetics. In this work, we tested the hypothesis that accounting for gene mutations would further improve risk stratification of CMML patients. We therefore sequenced 38 genes to explore the role of somatic mutations in disease phenotype and clinical outcome. Overall, 199 of 214 (93%) CMML patients carried at least 1 somatic mutation. Stepwise linear regression models showed that these mutations accounted for 15% to 24% of variability of clinical phenotype. Based on multivariable Cox regression analyses, cytogenetic abnormalities and mutations in RUNX1, NRAS, SETBP1, and ASXL1 were independently associated with overall survival (OS). Using these parameters, we defined a genetic score that identified 4 categories with significantly different OS and cumulative incidence of leukemic evolution. In multivariable analyses, genetic score, red blood cell transfusion dependency, white blood cell count, and marrow blasts retained independent prognostic value. These parameters were included into a clinical/molecular CPSS (CPSS-Mol) model that identified 4 risk groups with markedly different median OS (from >144 to 18 months, hazard ratio [HR] = 2.69) and cumulative incidence of leukemic evolution (from 0% to 48% at 4 years, HR = 3.84) (P < .001). The CPSS-Mol fully retained its ability to risk stratify in an independent validation cohort of 260 CMML patients. In conclusion, integrating conventional parameters and gene mutations significantly improves risk stratification of CMML patients, providing a robust basis for clinical decision-making and a reliable tool for clinical trials.

Dynamic spin interchange in a tridentate Fe(iii) Schiff-base compound.

The thermosalient effect is still a rare and poorly understood phenomenon, where crystals suddenly jump, bend, twist or explode upon undergoing a thermally activated phase transition. The synthesis and characterisation of the new spin transition Fe(iii) compound [Fe(5-Br-salEen)2][ClO4] (salEen = N-ethyl-N-(2-aminoethyl)salicylaldiminate) is described and its thermosalient behaviour reported. It is the first example of a thermosalient effect with a spin transition and magnetic, calorimetric, diffraction, microscopy and computational studies are used to characterise these effects. Both thermosalient effect and spin transition occur around 320 K upon heating and are accompanied by an anisotropic unit cell change with conservation of crystal symmetry that causes a large enough stress of the crystal lattice to induce crystal explosion. This stress can ultimately be traced back to a diffusionless and distortive structural perturbation resulting in a coupled spin transition-thermosalient effect.