Kidney failure is an important outcome for patients, clinicians, researchers, healthcare systems, payers, and regulators. However, no harmonized international consensus definitions of kidney failure ...and key surrogates of progression to kidney failure exist specifically for clinical trials. The International Society of Nephrology convened an international multi-stakeholder meeting to develop consensus on this topic. A core group, experienced in design, conduct, and outcome adjudication of clinical trials, developed a database of 64 randomized trials and the 163 included definitions relevant to kidney failure. Using an iterative process, a set of proposed consensus definitions were developed and subsequently vetted by the larger multi-stakeholder group of 83 participants representing 18 different countries. The consensus of the meeting participants was that clinical trial kidney failure outcomes should be comprised of a composite that includes receipt of a kidney transplant, initiation of maintenance dialysis, and death from kidney failure; it may also include outcomes based solely on laboratory measurements of glomerular filtration rate: a sustained low glomerular filtration rate and a sustained percent decline in glomerular filtration rate. Discussion included important considerations, such as (i) recognition of existing nomenclature for kidney failure; (ii) applicability across resource settings; (iii) ease of understanding for all stakeholders; and (iv) avoidance of inappropriate complexity so that the definitions can be used across ranges of populations and trial methodologies. The final definitions reflect the consensus for use in clinical trials.
Abstract only
Background:
Intracranial haemorrhage (ICH) is associated with significant long-term morbidity, high healthcare costs and mortality. There is a paucity of accurate national incidence ...rate data on ICH, fatal ICH and ICH sub-types in patients on FXai anticoagulants (e.g. rivaroxaban and apixaban).
Aim:
To describe patient characteristics and incidence of ICH following the initial use of FXai in an ongoing multi-country study.
Methods:
A retrospective observational cohort analysis of electronic health records from new users of FXai in the UK and Canada. Individuals with FXai prescriptions for a therapeutic indication such as venous thromboembolism, atrial fibrillation (AF), and/or non-mechanical cardiac-valve replacement, were included. Demographic and clinical data were summarised using descriptive statistics, and incidence rates for ICH events were reported per 100 person-years with 95% confidence intervals. Subgroups have been analysed.
Results:
In the UK and Canada, there were a total of 383,433 new users of FXai; average age 69 years, 54% male, average BMI 29 kg/m
2
and 88% of patients used an oral FXai. The most common indication was AF (73%). 1650 and 438 ICH events were reported in the UK and Canada, with 1-year incidence rates of 0.56 and 0.72 per 100 person-years, 27% and 26% were fatal (Table), respectively. Event rates remain elevated in the years following FXai initiation.
Conclusions:
Findings indicate incidence rates of ICH in patients treated with FXai were consistent over time, approximately 0.64 per 100 person-years or 1:160 patients per year throughout the course of treatment. Case fatality rates are high, around 27%, remaining elevated in the years following FXai initiation.
Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive ...antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.
Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb ...targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002.
Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints.
Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28-0.76;
= 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23-0.83;
= 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03-0.48;
= 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34-0.99;
= 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25-0.97;
= 0.041). Toxicity was not different between arms.
Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.
Purpose Uterine serous carcinoma is a rare, aggressive variant of endometrial cancer. Trastuzumab is a humanized monoclonal antibody that targets human epidermal growth factor receptor 2 (HER2)/neu, ...a receptor overexpressed in 30% of uterine serous carcinoma. This multicenter, randomized phase II trial compared carboplatin-paclitaxel with and without trastuzumab in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu. Methods Eligible patients had primary stage III or IV or recurrent HER2/neu-positive disease. Participants were randomly assigned to receive carboplatin-paclitaxel (control arm) for six cycles with or without intravenous trastuzumab (experimental arm) until progression or unacceptable toxicity. The primary end point was progression-free survival, which was assessed for differences between treatment arms via one-sided log-rank tests. Results From August 2011 to March 2017, 61 patients were randomly assigned. Forty progression-free survival-related events occurred among 58 evaluable participants. Among all patients, median progression-free survival was 8.0 months (control) versus 12.6 months (experimental; P = .005; hazard ratio HR, 0.44; 90% CI, 0.26 to 0.76). Similarly, median progression-free survival was 9.3 (control) versus 17.9 (experimental) months among 41 patients with stage III or IV disease undergoing primary treatment ( P = .013; HR, 0.40; 90% CI, 0.20 to 0.80) and 6.0 (control) versus 9.2 months (experimental), respectively, among 17 patients with recurrent disease ( P = .003; HR, 0.14; 90% CI, 0.04 to 0.53). Toxicity was not different between treatment arms, and no unexpected safety signals emerged. Conclusion Addition of trastuzumab to carboplatin-paclitaxel was well tolerated and increased progression-free survival. These encouraging results deserve further investigation to determine their impact on overall survival in patients with advanced or recurrent uterine serous carcinoma who overexpress HER2/neu.
Abstract Despite the significance of H 2 O 2 -metal adducts in catalysis, materials science and biotechnology, the nature of the interactions between H 2 O 2 and metal cations remains elusive and ...debatable. This is primarily due to the extremely weak coordinating ability of H 2 O 2 , which poses challenges in characterizing and understanding the specific nature of these interactions. Herein, we present an approach to obtain H 2 O 2 –metal complexes that employs neat H 2 O 2 as both solvent and ligand. SnCl 4 effectively binds H 2 O 2 , forming a SnCl 4 (H 2 O 2 ) 2 complex, as confirmed by 119 Sn and 17 O NMR spectroscopy. Crystalline adducts, SnCl 4 (H 2 O 2 ) 2 ·H 2 O 2 ·18-crown-6 and 2SnCl 4 (H 2 O 2 )(H 2 O)·18-crown-6, are isolated and characterized by X-ray diffraction, providing the complete characterization of the hydrogen bonding of H 2 O 2 ligands including geometric parameters and energy values. DFT analysis reveals the synergy between a coordinative bond of H 2 O 2 with metal cation and its hydrogen bonding with a second coordination sphere. This synergism of primary and secondary interactions might be a key to understanding H 2 O 2 reactivity in biological systems.
Grade 3 endometrioid and uterine serous carcinomas (USC) account for the vast majority of endometrial cancer deaths. The purpose of this study was to determine folic acid receptor alpha (FRα) ...expression in these biologically aggressive (type II) endometrial cancers and evaluate FRα as a targetable receptor for IMGN853 (mirvetuximab soravtansine). The expression of FRα was evaluated by immunohistochemistry (IHC) and flow cytometry in 90 endometrioid and USC samples. The
cytotoxic activity and bystander effect were studied in primary uterine cancer cell lines expressing differential levels of FRα.
antitumor efficacy of IMGN853 was evaluated in xenograft/patient-derived xenograft (PDX) models. Semiquantitative IHC analysis indicated that 41% of the USC patients overexpress FRα. Further, overexpression of FRα (i.e., 2+) was detected via flow cytometry in 22% (2/9) of primary endometrioid and in 27% (3/11) of primary USC cell lines. Increased cytotoxicity was seen with IMGN853 treatment compared with control in 2+ expressing uterine tumor cell lines. In contrast, tumor cell lines with low FRα showed no difference when exposed to IMGN853 versus control. IMGN853 induced bystander killing of FRα = 0 tumor cells. In an endometrioid xenograft model (END(K)265), harboring 2+ FRα, IMGN853 treatment showed complete resolution of tumors (
< 0.001). Treatment with IMGN853 in the USC PDX model (BIO(K)1), expressing 2+ FRα, induced twofold increase in median survival (
< 0.001). IMGN853 shows impressive antitumor activity in biologically aggressive FRα 2+ uterine cancers. These preclinical data suggest that patients with chemotherapy resistant/recurrent endometrial cancer overexpressing FRα may benefit from this treatment.
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Nanometric field-effect-transistor (FET) sensors are made on the tip of spear-shaped dual carbon nanoelectrodes derived from carbon deposition inside double-barrel nanopipettes. The easy fabrication ...route allows deposition of semiconductors or conducting polymers to comprise the transistor channel. A channel from electrodeposited poly pyrrole (PPy) exhibits high sensitivity toward pH changes. This property is exploited by immobilizing hexokinase on PPy nano-FETs to give rise to a selective ATP biosensor. Extracellular pH and ATP gradients are key biochemical constituents in the microenvironment of living cells; we monitor their real-time changes in relation to cancer cells and cardiomyocytes. The highly localized detection is possible because of the high aspect ratio and the spear-like design of the nano-FET probes. The accurately positioned nano-FET sensors can detect concentration gradients in three-dimensional space, identify biochemical properties of a single living cell, and after cell membrane penetration perform intracellular measurements.
The measurement of key molecules in individual cells with minimal disruption to the biological milieu is the next frontier in single-cell analyses. Nanoscale devices are ideal analytical tools ...because of their small size and their potential for high spatial and temporal resolution recordings. Here, we report the fabrication of disk-shaped carbon nanoelectrodes whose radius can be precisely tuned within the range 5–200 nm. The functionalization of the nanoelectrode with platinum allowed the monitoring of oxygen consumption outside and inside a brain slice. Furthermore, we show that nanoelectrodes of this type can be used to impale individual cells to perform electrochemical measurements within the cell with minimal disruption to cell function. These nanoelectrodes can be fabricated combined with scanning ion conductance microscopy probes, which should allow high resolution electrochemical mapping of species on or in living cells.
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