Final overall survival analysis for the phase II RECORD-3 study of first-line everolimus followed by sunitinib versus first-line sunitinib followed by everolimus in metastatic RCC.

BACKGROUND: RECORD-3 compared everolimus and sunitinib as first-line therapy, and the sequence of everolimus followed by sunitinib at progression compared with the opposite (standard) sequence in patients with metastatic renal cell carcinoma (mRCC). This final overall survival (OS) analysis evaluated mature data for secondary end points. PATIENTS AND METHODS: Patients received either first-line everolimus followed by second-line sunitinib at progression (n = 238) or first-line sunitinib followed by second-line everolimus (n = 233). Secondary end points were combined first- and second-line progression-free survival (PFS), OS, and safety. The impacts of neutrophil lymphocyte ratio (NLR) and baseline levels of soluble biomarkers on OS were explored. RESULTS: At final analysis, median duration of exposure was 5.6 months for everolimus and 8.3 months for sunitinib. Median combined PFS was 21.7 months [95% confidence interval (CI) 15.1-26.7] with everolimus-sunitinib and 22.2 months (95% CI 16.0-29.8) with sunitinib-everolimus [hazard ratio (HR)EVE-SUN/SUN-EVE, 1.2; 95% CI 0.9-1.6]. Median OS was 22.4 months (95% CI 18.6-33.3) for everolimus-sunitinib and 29.5 months (95% CI 22.8-33.1) for sunitinib-everolimus (HREVE-SUN/SUN-EVE, 1.1; 95% CI 0.9-1.4). The rates of grade 3 and 4 adverse events suspected to be related to second-line therapy were 47% with everolimus and 57% with sunitinib. Higher NLR and 12 soluble biomarker levels were identified as prognostic markers for poor OS with the association being largely independent of treatment sequences. CONCLUSIONS: Results of this final OS analysis support the sequence of sunitinib followed by everolimus at progression in patients with mRCC. The safety profiles of everolimus and sunitinib were consistent with those previously reported, and there were no unexpected safety signals. CLINICAL TRIALS NUMBER: ClinicalTrials.gov identifier, NCT00903175.

Phase II trial of second-line everolimus in patients with metastatic renal cell carcinoma (RECORD-4).

BACKGROUND: RECORD-1 demonstrated clinical benefit of everolimus in patients with metastatic renal cell carcinoma (mRCC) previously treated with sunitinib, sorafenib, or both; prior treatment with cytokines, bevacizumab, and chemotherapy was also permitted. RECORD-4 prospectively assessed everolimus in a purely second-line setting. METHODS: Patients with clear-cell mRCC were enrolled into one of three cohorts based on first-line therapy with sunitinib, other anti-VEGF agents, or cytokines. Patients were treated with everolimus 10 mg/day until progression (RECIST, v1.0) or intolerance. The primary end point was progression-free survival (PFS) per investigator review. Data cutoff was 1 September 2014, for the primary analysis and 26 June 2015, for the final overall survival (OS) analysis. RESULTS: Enrolled patients (N = 134) previously received sunitinib (n = 58), other anti-VEGF therapy (n = 62; sorafenib, 23; bevacizumab, 16; pazopanib, 13; tivozanib, 5; and axitinib, 3), or cytokines (n = 14). Overall median age was 59 years, and most patients were men (68%) and of favorable/intermediate MSKCC risk (52/37%). Overall median PFS was 7.8 months [95% confidence interval (CI) 5.7-11.0]; in the cohorts, it was 5.7 months (95% CI 3.7-11.3) with previous sunitinib, 7.8 months (95% CI 5.7-11.0) with other previous anti-VEGF therapy, and 12.9 months [95% CI 2.6-not estimable (NE)] with previous cytokines. Overall, 67% of patients achieved stable disease as their best objective response. At final OS analysis, total median OS was 23.8 months (95% CI 17.0-NE) and, in the cohorts, it was 23.8 months (95% CI 13.7-NE) with previous sunitinib, 17.2 months (95% CI 11.9-NE) with other previous anti-VEGF therapy, and NE (95% CI 15.9-NE) with previous cytokine-based therapy. Overall, 56% of patients experienced grade 3 or 4 adverse events (regardless of relationship to study drug). CONCLUSIONS: These results confirm the PFS benefit of second-line everolimus after first-line sunitinib or other anti-VEGF therapies. The safety profile of everolimus was consistent with previous experience. CLINICAL TRIAL NAME AND IDENTIFIER: Everolimus as Second-line Therapy in Metastatic Renal Cell Carcinoma (RECORD-4), ClinicalTrials.gov identifier, NCT01491672.

Structure, kinetics, and function of human and rhesus plasma prekallikreins are similar.

To determine if rhesus monkeys (Macaca mulatta) could serve as a model for studying the role of the contact system in the pathophysiology of human infections, we compared structural, kinetic, and functional characteristics of plasma prekallikrein and its activation products in rhesus and humans. Three prekallikrein variants (85-, 89- and 93-kDa) were revealed in rhesus plasma as compared with the two variants (85- and 88-kDa) in human plasma by immunoblotting with the monoclonal antibody MAb 13G11. The prekallikrein concentration in rhesus plasma was 1.5-fold that in human plasma as determined by computerized immunoblot analyses (CIBA) and amidolytic activity. The electrophoretic mobility of prekallikrein from plasma of both species increased after deglycosylation. Inhibition of prekallikrein activation by MAb 13G11 was 55% (rhesus plasma) and 76% (human plasma), with similar inhibition curves. Immunoblots of activated rhesus plasma showed prekallikrein, complexes of kallikrein with C1 inhibitor, alpha 2-macroglobulin and approximately 60-kDa inhibitor(s) (viz. antithrombin III), and 45-kDa fragments, like those in activated human plasma. Concentrations and molecular masses of factor XII and high molecular weight kininogen were similar in rhesus and human plasma. The activated partial thromboplastin time (APTT) and prothrombin time were 20.1 +/- 1.6 and 9.7 +/- 0.3 s for rhesus and 32.0 +/- 5.6 and 12 +/- 0.5 s for human plasma. Human and rhesus APTTs were similar when prekallikrein concentrations in human and rhesus plasma became alike by adding human purified prekallikrein.(ABSTRACT TRUNCATED AT 250 WORDS)

False assignment of familial antithrombin III deficiency with the von Kaulla assay.

As a serum assay, the von Kaulla assay for antithrombin III has been criticized on the grounds that consumption of antithrombin III during in vitro blood clotting may lead to falsely low assay values. Use of the assay to screen a Utah pedigree for familial antithrombin III deficiency lends support to this criticism. In all, the assay was performed on 150 persons. Low values on the assay were corroborated by performing an alternative coagulation assay, an amidolytic assay, and an immunoassay. While all persons with historic evidence for a diagnosis of familial antithrombin III deficiency had low assay values, eight of 23 persons with low values had normal values on the other assays.

Mechanisms of disease in hemorrhagic fever with renal syndrome.

Hemorrhagic fever with renal syndrome (HFRS) is a dramatic illness characterized by fever, and variable degrees of circulatory failure, hemorrhage, and renal insufficiency. Hantaviruses are the cause of this syndrome. In its severe form, it is associated with significant mortality. Vascular dysfunction is the key physiologic derangement in this disorder. There is a growing body of evidence that suggests that immune mechanisms account for this derangement.

Mefloquine failure in a case of falciparum malaria induced with a multidrug-resistant isolate in a non-immune subject.

In a volunteer with infection induced by injection of the mefloquine-sensitive, multidrug-resistant Vietnam Smith isolate of P. falciparum, parasitemia recurred following treatment with the candidate antimalarial drug enpiroline. Parasitemia also recurred after subsequent treatment with mefloquine and again after retreatment with the same drug. All recurrences were at the RI level. Parasite drug sensitivities determined by a semi-automated isotope microdilution method after the second and third recurrences revealed a progressive decrease in sensitivity to all arylaminoalcohols tested (halofantrine, enpiroline, and mefloquine). Decreased sensitivity persisted after 30 days of isolate culture. The parallel changes in parasite sensitivity to the synthetic arylaminoalcohols argue for development of drugs which are chemically dissimilar.

Malaria transmitted to humans by mosquitoes infected from cultured Plasmodium falciparum.

Malaria was transmitted to six normal human volunteers by mosquitoes infected from cultured gametocytes of Plasmodium falciparum. This method, which offers advantages over other methods of infecting volunteers, will be useful for evaluating the efficacy of human malaria vaccines.

Evaluation of the antimalarial activity of the phenanthrenemethanol halofantrine (WR 171,669).

Halofantrine (WR 171,669) was administered to 27 nonimmune subjects infected with the multi-drug resistant Vietnam Smith strain of Plasmodium falciparum. It was also administered to three other subjects, one infected with the Cambodian Buchanan strain of P. falciparum, and two with blood-induced infection with the Chesson strain of P. vivax. It cured infections with all three parasites. Against the highly chloroquine-resistant Smith strain, it was curative in single day treatment regimens. The drug was well tolerated and produced rapid clearance of parasitemia in every case.

Studies of the coagulation system in arenaviral hemorrhagic fever: experimental infection of strain 13 guinea pigs with Pichinde virus.

Significant coagulation abnormalities were associated with experimental infection of strain 13 guinea pigs with Pichinde virus, an arenavirus related to the virulent human pathogens Junin, Machupo, and Lassa viruses. Infected animals developed decreased activity of multiple coagulation factors, decreased antithrombin III levels, high levels of fibrin-fibrinogen degradation products, impaired platelet function, and thrombocytopenia. Testing for the presence of a coagulation inhibitor revealed a pattern consistent with factor deficiency. Fibrin thrombi were not found at necropsy. The findings of high fibrin-fibrinogen degradation product levels and decreased antithrombin III levels, in association with decreased activity of multiple coagulation factors and thrombocytopenia, suggest that intravascular coagulation is a feature of this experimental infection. The demonstration of abnormal platelet function is also significant, as this could contribute to defective hemostasis despite the moderate thrombocytopenia which usually occurs in arenaviral disease.

Safety and immunogenicity of a Plasmodium vivax sporozoite vaccine.

A recombinant DNA Plasmodium vivax sporozoite vaccine containing the repeating region of the Salvador I strain circumsporozoite (CS) protein was produced in Escherichia coli. This vaccine was tested in 13 naive volunteers at doses of 10-1,000 micrograms. No serious adverse reactions were noted. None of 4 volunteers receiving the 10 micrograms dose developed antibodies measurable by ELISA. Six of 9 volunteers in the other dose groups developed measurable antibodies: 5 of 5 volunteers receiving 100 micrograms and 1 of 4 receiving 1,000 micrograms. Antibody responses measured by immunofluorescence assays paralleled those seen by ELISA. None of the volunteers developed antisera that inhibited sporozoite invasion of human hepatoma cells in vitro. Lack of a classical anamnestic response and lack of a typical dose response to increasing amounts of antigen suggests the possible presence of an immunosuppressive epitope in the repetitive region of the CS protein.

Evaluation of the 4-pyridinemethanol WR 180,409 (enpiroline) in the treatment of induced Plasmodium falciparum infections in healthy, non-immune subjects.

WR 180,409 (enpiroline) was administered to 22 non-immune subjects infected with the multi-drug resistant Vietnam Smith isolate of Plasmodium falciparum. It was curative in single day treatment regimens with a minimum curative dose of approximately 10 mg/kg body weight. At this dose level it was well tolerated and produced rapid clearance of parasitemia in every case.

Platelet dysfunction contributes to the haemostatic defect in haemorrhagic fever with renal syndrome.

To characterize further the nature of haemostatic impairment in haemorrhagic fever with renal syndrome, we assessed platelet function in 9 patients in whom the diagnosis was serologically confirmed. Defective platelet aggregation was demonstrated in every patient. An abnormality of the granule release reaction was demonstrated in all of 7 patients tested. Gel-filtered platelets from a normal subject showed normal aggregation in plasma from a patient with impaired aggregation, which is evidence for an intrinsic platelet defect, and against the presence of a circulating inhibitor in this patient.

Changes in populations of immune effector cells during the course of haemorrhagic fever with renal syndrome.

To characterize the immune response in haemorrhagic fever with renal syndrome, serial changes in immune effector cells were measured in 14 patients. Significant findings included initial elevations of all major leucocyte populations, increases in suppressor T cells and B cells, decreases in helper/suppressor cell ratios, and a dramatic increase in activated T cells. These changes were most marked in severely ill patients. Changes reverted to normal over approximately one week.

Hemorrhagic fever virus-induced changes in hemostasis and vascular biology.

Viral hemorrhagic fever (VHF) denotes a virus-induced acute febrile, hemorrhagic disease reported from wide areas of the world. Hemorrhagic fever (HF) viruses are encapsulated, single-stranded RNA viruses that are associated with insect or rodent vectors whose interaction with humans defines the mode of disease transmission. There are 14 HF viruses, which belong to four viral families: Arenaviridae, Bunyaviridae, Filoviridae and Flaviviridae. This review presents, in order, the following aspects of VHF: (1) epidemiology, (2) anomalies of platelets and coagulation factors, (3) vasculopathy, (4) animal models of VHFs, (5) pathogenic mechanisms, and (6) treatment and future studies. HF viruses produce the manifestations of VHFs either by direct effects on cellular functions or by activation of immune and inflammatory pathways. In Lassa fever, Rift Valley fever and Crimean-Congo HF, the main feature of fatal illness appears to be impaired/delayed cellular immunity, which leads to unchecked viremia. However, in HF with renal syndrome and dengue HF, the immune response plays an active role in disease pathogenesis. The interplay of hemostasis, immune response, and inflammation is very complex. Molecular biologic techniques and the use of animal models have helped to unravel some of these interactions.

Long-term survival in Wiskott-Aldrich syndrome: case report and literature review.

The case reported concerns a 29-year-old man who was seen because of clinical and laboratory features consistent with Wiskott-Aldrich Syndrome. While an infant he underwent splenectomy for thrombocytopenia. Evaluation revealed small platelets, abnormal immunoglobulin levels, impaired delayed hypersensitivity, and mildly reduced neutrophil chemotaxis. His response to vaccination with polyvalent pneumococcal vaccine was subnormal. Possible factors accounting for his long-term survival are discussed.

Epidemic hemorrhagic fever. The mechanism of coagulation and fibrinolysis.

To understand the mechanism of hemorrhage, coagulation and fibrinolysis in epidemic hemorrhagic fever (EHF), thrombin time (TT), prothrombin time (PT), fibrinogen (FIG), the platelet count (PLAT), plasminogen (PLG), antithrombin-III (AT-III), fibrin-fibrinogen degraded products (FDP) and platelet functions of aggregation and release were studied dynamically with advanced methods in 134 EHF patients. TT and PT were prolonged, FIG, AT-III and PLG were decreased and FDP was increased. Besides, the decrease of PLAT, the platelet functions of aggregation and release were below the normal level. The results showed that the balance of blood coagulation and fibrinolysis was lost from the early stage of the disease.

Early analysis of viremia and clinical tests in patients with epidemic hemorrhagic fever.

We analysed the early viremia and clinical tests in 82 patients with epidemic hemorrhagic fever (EHF). The results showed that the changes in viremia and clinical tests are related to the severity of the disease and prognosis. Higher concentrations of the virus in infected patients might cause a more unfavourable prognosis and more abnormalities in clinical tests. CK-MB, SGOT, SGPT, serum creatinine and urea nitrogen contents increased markedly, while serum total protein, albumin and calcium contents decreased markedly, indicating that the heart, liver and kidney in EHF patients were severely damaged. Markedly increased WBC and monocytes showed that the patients were seriously infected. Platelet count, antithrombin-III and plasminogen decreased markedly, demonstrating that there were marked changes in the coagulation-anticoagulation and fibrinolytic system of the EHF patients. Changes in RBC, Hb and HCT contents indicated that the blood in the EHF patients had a higher concentration. This study gives further evidence that EHFV plays an important role in the pathogenesis of EHF.

Interruption study of viremia of patients with hemorrhagic fever with renal syndrome in the febrile phase.

Kinetic changes of viremia were observed in 287 cases of hemorrhagic fever with renal syndrome (HFRS) in whom ribavirin was administered with double blind random control studied by means of virus isolation, indirect immunofluorescence assay and enzyme-linked immunosorbent assay. The positive rate of viremia was 79.7% (Sp = 3%) and positive rate of HERS IgM was 85% (Sp = 3.1%) before treatment. Viremia could be interrupted by ribavirin as in the ribavirin treated group, the viremia positive rate decreased, duration of viremia was shortened, viral antigen products, virus titer and HFRS IgG antibody level were reduced as compared with the control group. This showed that viremia was very frequent in patients in the febrile phase and ribavirin is an effective antiviral drug in HFRS during the febrile phase. Dosage and course of treatment of this drug are discussed.