Largest comparison between onset and relapses of acquired thrombotic thrombocytopenic purpura reveals severe neurological involvement and worse analytic parameters at debut.

It has been proposed that the onset of Acquired Thrombotic Thrombocytopenic Purpura (iTTP) is more severe than subsequent relapses; however, existing studies have limitations. We conducted a retrospective observational study to compare analytical and clinical severity of onset and relapse aTTP cases between 2012 and 2023. A total of 370 episodes of aTTP were analyzed, comprising 272 at initial diagnosis and 98 relapses. At onset, analytical parameters indicative of severity (low hemoglobin, low platelet count, and increased LDH) were significantly worse; patients had severe neurological symptoms (p<0.001) and ≥ 3 points in the TMA mortality score (p<0.001). In conclusion, the onset of aTTP is associated with worse analytical parameters and severe neurological involvement.

Hb Nivaria: A New Hemoglobin Variant with a Shortened α-Globin Chain [α139(HC1)Lys→Stop; HBA1: c.418A>T].

We report a novel hemoglobin (Hb) variant found in a Spanish individual from Santa Cruz de Tenerife, the Canary Islands in Spain. The proband was a 39-year-old male. High performance liquid chromatography (HPLC) displayed an unknown peak (19.3%) at a retention time of 1.3 min. eluting before Hb A0. Capillary zone electrophoresis (CZE) showed an abnormal peak (20.0%) in zone 12. Direct DNA sequencing of the α-globin genes revealed heterozygosity for a nonsense mutation at codon 139 (AAA>TAA), causing a lysine to stop codon substitution [α139(HC1)Lys→Stop; HBA1: c.418A>T]. We decided to name the variant Hb Nivaria (Tenerife) for the place of birth and residence of the proband.

Pembrolizumab Plus Gemcitabine in the Subset of Triple-Negative Advanced Breast Cancer Patients in the GEICAM/2015-04 (PANGEA-Breast) Study.

The PANGEA-Breast trial evaluated a new chemo-immunotherapeutic combination that would synergistically induce long-term clinical benefit in HER2-negative advanced breast cancer patients. Treatment consisted of 21-day cycles of 200 mg of pembrolizumab (day 1) plus gemcitabine (days 1 and 8). The primary objective was the objective response rate (ORR). The tumor infiltrating lymphocytes (TILs) density and PD-L1 expression in tumor, and the myeloid-derived suppressor cells (MDSCs) level in peripheral blood, were analyzed to explore associations with treatment efficacy. Considering a two-stage Simon's design, the study recruitment was stopped after its first stage as statistical assumptions were not met. A subset of 21 triple-negative breast cancer (TNBC) patients was enrolled. Their median age was 49 years; 15 patients had visceral involvement, and 16 had ≤3 metastatic locations. Treatment discontinuation due to progressive disease (PD) was reported in 16 patients. ORR was 15% (95% CI 3.2-37.9). Four patients were on treatment >6 months before PD. Grade ≥3 treatment-related adverse events were observed in 8 patients, where neutropenia was the most common. No association was found between TILs density, PD-L1 expression or MDSCs levels and treatment efficacy. ORR in TNBC patients also did not meet the assumptions, but 20% were on treatment >6 months.

Sulfonated Polysulfone/TiO2(B) Nanowires Composite Membranes as Polymer Electrolytes in Fuel Cells.

New proton conducting membranes based on sulfonated polysulfone (sPSU) reinforced with TiO2(B) nanowires (1, 2, 5 and 10 wt.%) were synthesized and characterized. TiO2(B) nanowires were synthesized by means of a hydrothermal method by mixing TiO2 precursor in aqueous solution of NaOH as solvent. The presence of the TiO2(B) nanowires into the polymer were confirmed by means of Field Emission Scanning Electron Microscopy, Fourier transform infrared and X-ray diffraction. The thermal study showed an increase of almost 20 °C in the maximum temperature of sPSU backbone decomposition due to the presence of 10 wt.% TiO2(B) nanowires. Water uptake also is improved with the presence of hydrophilic TiO2(B) nanowires. Proton conductivity of sPSU with 10 wt.% TiO2(B) nanowires was 21 mS cm-1 (at 85 °C and 100% RH). Under these experimental conditions the power density was 350 mW cm-2 similar to the value obtained for Nafion 117. Considering all these obtained results, the composite membrane doped with 10 wt.% TiO2(B) nanowires is a promising candidate as proton exchange electrolyte in fuel cells (PEMFCs), especially those operating at high temperatures.

Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study.

BACKGROUND: An important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in preclinical models. METHODS: We conducted a phase II trial combining dasatinib 100 mg once daily with trastuzumab 2 mg/kg and paclitaxel 80 mg/m2 weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies. RESULTS: From June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1-49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3-92), clinical benefit rate 82.8% (95% CI 64.2-94.2). Median time to progression 23.9 months (95% CI 14.9-not reached [NR]), median progression-free survival 23.9 months (95% CI 10.3-NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes. CONCLUSIONS: Dasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%. TRIAL REGISTRATION: NCT01306942, EudraCT 2010-023304-27.

A phase Ib study of sonidegib (LDE225), an oral small molecule inhibitor of smoothened or Hedgehog pathway, in combination with docetaxel in triple negative advanced breast cancer patients: GEICAM/2012-12 (EDALINE) study.

Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m2) in advanced TNBC patients. The primary objective was to ascertain the combination's maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard "3 + 3" design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m2 given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29-155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov: NCT02027376.