Our first clinical experience with radiosynoviorthesis by means of 166Ho-holmium-boro-macroaggregates

BACKGROUND: In this paper, we evaluate the therapeutic and adverse effects of the application of 166-holmium-boro-macroaggregates (HMBA) in radiosynovectomy (RSO) of the knees. We assessed the efficacy and safety of 166Ho-HBMA in a prospective clinical trial in patients suffering from chronic synovitis. MATERIAL AND METHODS: An effective component of radiopharmaceutical 166Ho-boro-macroaggregates is radionuclide 166Ho which has both β-emission and γ-emission. The physical half-life time of 166Ho is 26.8 hours. After application of the radiopharmaceutical into a joint cavity, the effect of β-emission causes radiation necrosis of pathologically changed (inflamed) synovial membrane. From 15th April 2005, we have started RSO of knees by means of new radiopharmaceutical 166Ho-boro-macroaggregates in patients with gonarthrosis, rheumatoid arthritis, chronic synovitis, psoriatic arthritis, gout arthropathy. Seventeen intra-articular injections were performed in fifteen patients receiving a mean activity of 972 MBq (range: 904-1057 MBq) 166Ho-HMBA. The patients were hospitalized for three days. Side effects were evaluated during hospital stay and after 6-8 weeks. Static scintigraphy of knee joints and measurements of blood radioactivity were performed. Therapeutic effects were evaluated after 6-8 weeks. RESULTS: In 2 hours and 2 days after application, we proved, by means of knee and inguinal scintigraphy, only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes in four patients. In treated patients, no serious adverse effects occurred. Nine patients were without complaints; 4 patients had slight knee exsudation and 2 patients had great exsudation. Therapeutic effects after 6-8 weeks were as follows: 2 patients were without pain, 9 with lower pain, 3 with the same pain and 1 patient with increased pain. Joint motion was improved in 7 patients, remained the same in 7 patients and was impaired in 1 patient. Analgesics consumption was lower in 5 patients, the same in 9 patients and greater in 1 patient. Knee exsudation was absent in 2 patients, lower in 4 patients, the same in 6 patients and greater in 3 patients. CONCLUSIONS: We proved only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes. Six patients had early slight or great radiation synovitis. The possible cause could be rather high applicated activity. One can take into consideration its reduction. Therapeutic effects can be precisely evaluated after a longer time interval than was possible for us (6-8 weeks after RSO). 166Ho-boro-macroaggregates can extend the scale of clinically used radiopharmaceuticals for RSO. This paper is presented in the scope of the first stage of clinical evaluation of synovectomy application of holmium-boro-macroaggregates

Increased Urinary Nitrate Excretion in Inflammatory Bowel Disease

Peer Reviewe

Aurora kinase A drives the evolution of resistance to third-generation EGFR inhibitors in lung cancer.

Although targeted therapies often elicit profound initial patient responses, these effects are transient due to residual disease leading to acquired resistance. How tumors transition between drug responsiveness, tolerance and resistance, especially in the absence of preexisting subclones, remains unclear. In epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma cells, we demonstrate that residual disease and acquired resistance in response to EGFR inhibitors requires Aurora kinase A (AURKA) activity. Nongenetic resistance through the activation of AURKA by its coactivator TPX2 emerges in response to chronic EGFR inhibition where it mitigates drug-induced apoptosis. Aurora kinase inhibitors suppress this adaptive survival program, increasing the magnitude and duration of EGFR inhibitor response in preclinical models. Treatment-induced activation of AURKA is associated with resistance to EGFR inhibitors in vitro, in vivo and in most individuals with EGFR-mutant lung adenocarcinoma. These findings delineate a molecular path whereby drug resistance emerges from drug-tolerant cells and unveils a synthetic lethal strategy for enhancing responses to EGFR inhibitors by suppressing AURKA-driven residual disease and acquired resistance

Phase I/II Study of Refametinib (BAY 86-9766) in Combination with Gemcitabine in Advanced Pancreatic cancer

Background Activating KRAS mutations are reported in up to 90% of pancreatic cancers. Refametinib potently inhibits MEK1/2, part of the MAPK signaling pathway. This phase I/II study evaluated the safety and efficacy of refametinib plus gemcitabine in patients with advanced pancreatic cancer. Methods Phase I comprised dose escalation, followed by phase II expansion. Refametinib and gemcitabine plasma levels were analyzed for pharmacokinetics. KRAS mutational status was determined from circulating tumor DNA. Results Ninety patients overall received treatment. The maximum tolerated dose was refametinib 50 mg twice daily plus standard gemcitabine (1000 mg/m2 weekly). The combination was well tolerated, with no pharmacokinetic interaction. Treatment-emergent toxicities included thrombocytopenia, fatigue, anemia, and edema. The objective response rate was 23% and the disease control rate was 73%. Overall response rate, disease control rate, progression-free survival, and overall survival were higher in patients without detectable KRAS mutations (48% vs. 28%, 81% vs. 69%, 8.8 vs. 5.3 months, and 18.2 vs. 6.6 months, respectively). Conclusion Refametinib plus gemcitabine was well tolerated, with a promising objective response rate, and had an acceptable safety profile and no pharmacokinetic interaction. There was a trend towards improved outcomes in patients without detectable KRAS mutations that deserves future investigation

The transcription factor Sox5 modulates Sox10 function during melanocyte development

The transcription factor Sox5 has previously been shown in chicken to be expressed in early neural crest cells and neural crest-derived peripheral glia. Here, we show in mouse that Sox5 expression also continues after neural crest specification in the melanocyte lineage. Despite its continued expression, Sox5 has little impact on melanocyte development on its own as generation of melanoblasts and melanocytes is unaltered in Sox5-deficient mice. Loss of Sox5, however, partially rescued the strongly reduced melanoblast generation and marker gene expression in Sox10 heterozygous mice arguing that Sox5 functions in the melanocyte lineage by modulating Sox10 activity. This modulatory activity involved Sox5 binding and recruitment of CtBP2 and HDAC1 to the regulatory regions of melanocytic Sox10 target genes and direct inhibition of Sox10-dependent promoter activation. Both binding site competition and recruitment of corepressors thus help Sox5 to modulate the activity of Sox10 in the melanocyte lineage

Isatuximab plus atezolizumab in patients with advanced solid tumors: results from a phase I/II, open-label, multicenter study

Background: The anti-CD38 antibody isatuximab is approved for the treatment of relapsed/refractory multiple myeloma, but there are no data on its efficacy in solid tumors. This phase I/II study (NCT03637764) assessed the safety and activity of isatuximab plus atezolizumab (Isa + Atezo), an anti-programmed death-ligand 1 (PD-L1) antibody, in patients with immunotherapy-naive solid tumors: epithelial ovarian cancer (EOC), glioblastoma (GBM), hepatocellular carcinoma (HCC), and squamous cell carcinoma of the head and neck (SCCHN). Patients and methods: Phase I assessed safety, tolerability, pharmacokinetics, pharmacodynamics, and the recommended phase II dose (RP2D) of isatuximab 10 mg/kg intravenously (i.v.) every week for 3 weeks followed by once every 3 weeks + atezolizumab 1200 mg i.v. every 3 weeks. Phase II used a Simon's two-stage design to assess the overall response rate or progression-free survival rate at 6 months (GBM cohort). Interim analysis was carried out at 6 months following first dose of the last enrolled patient in each cohort. Pharmacodynamic biomarkers were tested for CD38, PD-L1, tumor-infiltrating immune cells, and FOXP3+ regulatory T cells (Tregs) in the tumor microenvironment (TME). Results: Overall, 107 patients were treated (EOC, n = 18; GBM, n = 33; HCC, n = 27; SCCHN, n = 29). In phase I, Isa + Atezo showed an acceptable safety profile, no dose-limiting toxicities were observed, and RP2D was confirmed. Most patients experienced >= 1 treatment-emergent adverse event (TEAE), with = 3. The most frequent TEAE was infusion reactions. The study did not continue to stage 2 based on prespecified targets. Tumor-infiltrating CD38+ immune cells were reduced and almost cleared after treatment. Isa + Atezo did not significantly modulate Tregs or PD-L1 expression in the TME. Conclusions: Isa + Atezo had acceptable safety and tolerability. Clinical pharmacodynamic evaluation revealed efficient target engagement of isatuximab via treatment-mediated reduction of CD38+ immune cells in the TME. Based on clinical data, CD38 inhibition does not improve responsiveness to PD-L1 blockade in these patients

Sunitinib and bevacizumab for first-line treatment of metastatic renal cell carcinoma: a systematic review and indirect comparison of clinical effectiveness

Background: Two new agents have recently been licensed for use in the treatment of metastatic renal cell carcinoma (RCC) in Europe. This paper aims to systematically review the evidence from all available randomised clinical trials of sunitinib and bevacizumab (in combination with interferon-? (IFN-?)) in the treatment of advanced metastatic RCC.Methods: Systematic literature searches were performed in six electronic databases. Bibliographies of included studies were searched for further relevant studies. Individual conference proceedings were searched using their online interfaces. Studies were selected according to the predefined criteria. All randomised clinical trials of sunitinib or bevacizumab in combination with IFN for treating advanced metastatic RCC in accordance with the European licensed indication were included. Study selection, data extraction, validation and quality assessment were performed by two reviewers with disagreements being settled by discussion. The effects of sunitinib and bevacizumab (in combination with IFN-?) on progression-free survival were compared indirectly using Bayesian Markov Chain Monte-Carlo (MCMC) sampling in Win BUGS, with IFN as a common comparator.Results: Three studies were included. Median progression-free survival was significantly prolonged with both interventions (from approximately 5 months to between 8 and 11 months) compared with IFN. Overall survival was also prolonged, compared with IFN, although the published data are not fully mature. Indirect comparison suggests that sunitinib is superior to bevacizumab plus IFN in terms of progression-free survival (hazard ratios 0.796; 95% CI 0.63–1.0; P=0.0272).Conclusion: There is evidence to suggest that treatment with sunitinib and treatment with bevacizumab plus IFN has clinically relevant and statistically significant advantages over treatment with IFN alone in patients with metastatic RCC

The relationships between seedling root screens, root growth in the field and grain yield for wheat

Background and aims We were interested to know if laboratory screens of root growth could be used to predict root performance and grain yield of wheat when grown in the field. A secondary aim of this work was to explore the relationship between root depth and grain yield. Methods We screened 637 wheat lines, composed of elite as well as a limited number of breeding lines, to identify wheat lines with contrasting young root traits with a high throughput screen. We selected groups of wheat lines based on the size of the seedling root, root diameter and growth angle. Seventy-two wheat lines were subjected to further screening with a wax-layer screen and grown in a field experiment in two successive years. Root length distributions, from field grown wheat, were determined with the core-break method. Results We were unable to find relationships between data from the laboratory root screens and root depth in the field. In the field, wheat lines with deep roots always had high grain yields, but deep roots were not essential to obtain high yields. Wheat lines with the deepest roots were also amongst those with the greatest number of shallow roots. Conclusion Laboratory root screens did not predict root depth in the field. Root diameter, for reasons that are not clear, is correlated with high grain yield