International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017).

In recent years, the number of approved and investigational agents that can be safely administered for the treatment of lymphoma patients for a prolonged period of time has substantially increased. Many of these novel agents are evaluated in early-phase clinical trials in patients with a wide range of malignancies, including solid tumors and lymphoma. Furthermore, with the advances in genome sequencing, new "basket" clinical trial designs have emerged that select patients based on the presence of specific genetic alterations across different types of solid tumors and lymphoma. The standard response criteria currently in use for lymphoma are the Lugano Criteria which are based on [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography or bidimensional tumor measurements on computerized tomography scans. These differ from the RECIST criteria used in solid tumors, which use unidimensional measurements. The RECIL group hypothesized that single-dimension measurement could be used to assess response to therapy in lymphoma patients, producing results similar to the standard criteria. We tested this hypothesis by analyzing 47 828 imaging measurements from 2983 individual adult and pediatric lymphoma patients enrolled on 10 multicenter clinical trials and developed new lymphoma response criteria (RECIL 2017). We demonstrate that assessment of tumor burden in lymphoma clinical trials can use the sum of longest diameters of a maximum of three target lesions. Furthermore, we introduced a new provisional category of a minor response. We also clarified response assessment in patients receiving novel immune therapy and targeted agents that generate unique imaging situations.

Phase I combination study of trabectedin and capecitabine in patients with advanced malignancies.

BACKGROUND: To determine the maximum tolerated dose (MTD), safety and pharmacokinetics of trabectedin with capecitabine in patients with advanced malignancies. DESIGN: In this Phase I, open-label, dose-finding study, patients refractory to standard therapy received trabectedin (3-h intravenous infusion, 0.4-1.3 mg/m(2), day 1) and capecitabine (2,000 or 1,600 mg/m(2)/day orally, days 2-15) every 3 weeks. Standard "3 + 3" dose escalation was used to define the MTD. Antitumor response was assessed every two cycles; adverse events (AEs) were recorded throughout. RESULTS: Forty patients received 149 cycles of treatment (median 2; range 1-11) at nine dose levels. Gastrointestinal dose-limiting toxicities in two patients at two dose levels with capecitabine at 2,000 mg/m(2)/day prompted dose reduction to 1,600 mg/m(2)/day and initiation of new trabectedin dose escalation at 0.6 mg/m(2). The MTD was capecitabine 1,600 mg/m(2)/day + trabectedin 1.1 mg/m(2). Common grade 3-4 drug-related AEs were neutropenia (20%), nausea (18%), diarrhea (15%) and palmar-plantar erythrodysesthesia (15%). One patient with cholangiocarcinoma achieved a sustained partial response, and 18 patients maintained stable disease (six for ≥6 months). CONCLUSIONS: The combination of trabectedin and capecitabine is generally well tolerated, without pharmacokinetic interactions, and shows some activity in patients with advanced cancers.

Selected novel anticancer treatments targeting cell signaling proteins.

Empirical approaches to discovery of anticancer drugs and cancer treatment have made limited progress in the cure of cancer in the last several decades. Recent advances in technology and expanded knowledge of the molecular basis of tumorigenesis and metastasis have provided unique opportunities to design novel compounds that rationally target the abnormal molecular and biochemical signals leading to cancer. Several such novel agents have completed advanced stages in clinical development. The excellent clinical results achieved by some of these compounds are creating new paradigms in management of patients with neoplastic diseases. Clinical development of these agents also raises challenges to the traditional methods of drug evaluation and measurement of efficacy.

Effects of recombinant human tissue factor pathway inhibitor on thrombus formation and its in vivo distribution in a rat DIC model.

Tissue factor pathway inhibitor (TFPI) plays a key role in modulating tissue factor-dependent blood coagulation. This study was done to determine not only the inhibitory effects of recombinant human TFPI (rTFPI) on thrombus formation in rat models with disseminated intravascular coagulation (DIC), but also to identify the distribution of exogenous TFPI in vivo. Disseminated intravascular coagulation was induced by administering a priming dose of carrageenan 10 mg/kg body weight and was followed 24 hours later by a provocative dose of lipopolysaccharide (LPS) 500 mg/kg body weight. The rTFPI was administered intravenously at a dose of either 1 or 4 mg/kg body weight immediately after LPS treatment. Exogenous rTFPI at a dose of 4 mg/kg significantly inhibited the consumption of fibrinogen, platelets and factor VIIa (P < .05) and also reduced the number of fibrin thrombi formed in the liver, lungs, kidneys, and spleen (P < .05), whereas rTFPI at a dose of 1 mg/kg had no significant inhibitory effect on these DIC parameters. Recombinant human rTFPI activity was rapidly cleared from the plasma; however, a significant amount of the inhibitor was still present in tissues even 3 to 6 hours after intravenous administration. Exogenous TFPI was mainly identified in Kupffer cells, macrophages, and on the microvascular endothelial lining of different organs. In the kidney, rTFPI was identified on both the abluminal surface of the renal tubules and the luminal surface of the proximal convoluted tubules. No rTFPI, however, was detected in the hepatocytes. Tissue factor was mainly expressed by monocytes/macrophages. These findings suggest that TFPI plays an important role in modulating TF-dependent thrombogenesis. The elucidation of the rTFPI distribution and interactions in vivo might thus provide valuable insight into its inhibitory mechanisms as well as its therapeutic implications in DIC.

Enhanced expression of tissue factor activity in the atherosclerotic aortas of cholesterol-fed rabbits.

Tissue factor (TF) is an initiation cofactor of the extrinsic pathway of coagulation. Although the overexpression of TF antigen and mRNA have been previously demonstrated in atherosclerotic lesions using both immunohistochemical and in situ hybridization techniques, it still remains unclear as to whether TF activity is overexpressed in atherosclerotic plaque in vivo. In thoracic aortas obtained from cholesterol-fed rabbits for 10-20 weeks, the TF-mediated activation of factor X was quantitatively assessed on the intimal surface of the aortas ex vivo using a chromogenic substrate S-2222 and the findings were then compared with the immunohistochemical distribution of TF antigen. Non-atherosclerotic intimas showed only a weak amount of TF activity, while the adventitia contained a significantly high amount of activity. In the atherosclerotic intimas where TF antigen was overexpressed by foamy and non-foamy macrophages and smooth muscle cells but not by endothelial cells, TF activity was apparently enhanced to a level similar to that in the adventitia. Scanning electron microscopy revealed a perturbation of the intimal surface of the atherosclerotic aorta. These findings suggest that TF activity is apparently enhanced in subendothelial atherosclerotic lesions and, therefore, endothelial denudation, which results in the exposure of active TF to flowing blood, leads to thrombosis and its sequelae in atherosclerotic lesions.

Procoagulant properties of atherosclerotic aortas.

TF protein was overexpressed by macrophages and smooth muscle cells and deposited in the extracellular matrix of atheroclerotic intimas. TF activity was also enhanced in the atherosclerotic intima, probably resulting in either thrombus formation or intimal fibrin deposition after the exposure of flowing blood and imbibed fibrinogen to TF in atherosclerotic lesions. These findings further support the hypothesis that the coagulation and fibrinolysis systems can play an essential role in the initiation and progression of atherosclerosis, and the clinical implications of this phenomenon may thus contribute to future investigations in the prevention and treatment of atherosclerotic diseases.

Expression of tissue factor and interleukin-1 beta in a novel rabbit model of disseminated intravascular coagulation induced by carrageenan and lipopolysaccharide.

Thrombus formation and the sequential expression of tissue factor (TF), interleukin-1 beta (IL-1 beta) and interleukin-1 receptor antagonist (IL-1 ra) in several organs were examined immunohistochemically and morphometrically in a novel model of disseminated intravascular coagulation (DIC) developed by modifying the generalized Shwartzman reaction (GSR) in rabbits. The new model [carrageenan (CA)-lipopolysaccharide (LPS)] was induced by the administration of a priming dose of intraperitoneal CA, 10 mg/kg, followed 24 h later by a provocative dose of LPS 25 micrograms/kg, while GSR was induced by the intravenous injection of two doses of LPS 25 micrograms/kg. CA was detected predominantly within macrophages in the spleen and liver. Fibrin thrombi were formed as early as 1 h after the second LPS treatment in all examined organs reaching a peak at 3-9 h and their prevalence was higher in the CA-LPS group (p < 0.05). The sequential expressions of TF and IL-1 beta correlated well with each other in both groups reaching a peak at 3-9 h with the CA-LPS group showing a more pronounced expression than the GSR group. Macrophages in the liver, spleen and lungs, and Bowman's epithelial cells expressed both proteins, while IL-1 beta was also expressed by endothelial and epithelial cells. IL-1 ra was expressed by the same cells expressing IL-1 beta, however, its expression continued to increase gradually over 24 h. The mortality rate was lower (p < 0.05) and neutrophilic sequestration less prominent in the CA-LPS group than in the GSR group. These findings indicate that CA efficiently replaced the priming LPS treatment and the consequently enhanced production of IL-1 beta may have resulted in the upregulation of TF expression leading to the high level of thrombi in this new model which may provide a tool for further studies on the role of cytokines in DIC.