The severity of Puumala hantavirus induced nephropathia epidemica can be better evaluated using plasma interleukin-6 than C-reactive protein determinations

<p>Abstract</p> <p>Background</p> <p>Nephropathia epidemica (NE) is a Scandinavian type of hemorrhagic fever with renal syndrome caused by Puumala hantavirus. The clinical course of the disease varies greatly in severity. The aim of the present study was to evaluate whether plasma C-reactive protein (CRP) and interleukin (IL)-6 levels associate with the severity of NE.</p> <p>Methods</p> <p>A prospectively collected cohort of 118 consecutive hospital-treated patients with acute serologically confirmed NE was examined. Plasma IL-6, CRP, and creatinine, as well as blood cell count and daily urinary protein excretion were measured on three consecutive days after admission. Plasma IL-6 and CRP levels higher than the median were considered high.</p> <p>Results</p> <p>We found that high IL-6 associated with most variables reflecting the severity of the disease. When compared to patients with low IL-6, patients with high IL-6 had higher maximum blood leukocyte count (11.9 <it>vs </it>9.0 × 10⁹/l, <it>P </it>= 0.001) and urinary protein excretion (2.51 <it>vs </it>1.68 g/day, <it>P </it>= 0.017), as well as a lower minimum blood platelet count (55 <it>vs </it>80 × 10⁹/l, <it>P </it>< 0.001), hematocrit (0.34 <it>vs </it>0.38, <it>P </it>= 0.001), and urinary output (1040 <it>vs </it>2180 ml/day, <it>P </it>< 0.001). They also stayed longer in hospital than patients with low IL-6 (8 <it>vs </it>6 days, <it>P </it>< 0.001). In contrast, high CRP did not associate with severe disease.</p> <p>Conclusions</p> <p>High plasma IL-6 concentrations associate with a clinically severe acute Puumala hantavirus infection, whereas high plasma CRP as such does not reflect the severity of the disease.</p

Evidence of Disseminated Intravascular Coagulation in a Hemorrhagic Fever with Renal Syndrome—Scoring Models and Severe Illness

Background: Viral hemorrhagic fevers (VHF) are considered to be a serious threat to public health worldwide with up to 100 million cases annually. The general hypothesis is that disseminated intravascular coagulation (DIC) is an important part of the pathogenesis. The study objectives were to study the variability of DIC in consecutive patients with acute hemorrhagic fever with renal syndrome (HFRS), and to evaluate if different established DIC-scores can be used as a prognostic marker for a more severe illness. Method and Findings: In a prospective study 2006–2008, data from 106 patients with confirmed HFRS were analyzed and scored for the presence of DIC according to six different templates based on criteria from the International Society on Thrombosis and Haemostasis (ISTH). The DIC-scoring templates with a fibrinogen/CRP-ratio were most predictive, with predictions for moderate/severe illness (p,0.01) and bleeding of moderate/major importance (p,0.05). With these templates, 18.9–28.3 % of the patients were diagnosed with DIC. Conclusions: DIC was found in about one fourth of the patients and correlated with a more severe disease. This supports that DIC is an important part of the pathogenesis in HFRS. ISTH-scores including fibrinogen/CRP-ratio outperform models without. The high negative predictive value could be a valuable tool for the clinician. We also believe that our findings coul

Chemotactic and Inflammatory Responses in the Liver and Brain Are Associated with Pathogenesis of Rift Valley Fever Virus Infection in the Mouse

Rift Valley fever virus (RVFV) is a major human and animal pathogen associated with severe disease including hemorrhagic fever or encephalitis. RVFV is endemic to parts of Africa and the Arabian Peninsula, but there is significant concern regarding its introduction into non-endemic regions and the potentially devastating effect to livestock populations with concurrent infections of humans. To date, there is little detailed data directly comparing the host response to infection with wild-type or vaccine strains of RVFV and correlation with viral pathogenesis. Here we characterized clinical and systemic immune responses to infection with wild-type strain ZH501 or IND vaccine strain MP-12 in the C57BL/6 mouse. Animals infected with live-attenuated MP-12 survived productive viral infection with little evidence of clinical disease and minimal cytokine response in evaluated tissues. In contrast, ZH501 infection was lethal, caused depletion of lymphocytes and platelets and elicited a strong, systemic cytokine response which correlated with high virus titers and significant tissue pathology. Lymphopenia and platelet depletion were indicators of disease onset with indications of lymphocyte recovery correlating with increases in G-CSF production. RVFV is hepatotropic and in these studies significant clinical and histological data supported these findings; however, significant evidence of a pro-inflammatory response in the liver was not apparent. Rather, viral infection resulted in a chemokine response indicating infiltration of immunoreactive cells, such as neutrophils, which was supported by histological data. In brains of ZH501 infected mice, a significant chemokine and pro-inflammatory cytokine response was evident, but with little pathology indicating meningoencephalitis. These data suggest that RVFV pathogenesis in mice is associated with a loss of liver function due to liver necrosis and hepatitis yet the long-term course of disease for those that might survive the initial hepatitis is neurologic in nature which is supported by observations of human disease and the BALB/c mouse model

Abstract CT129: Phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in NSCLC involving the CNS

Abstract Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed a Phase I study [AACR #1185, 2013] and is being evaluated in a Phase II trial in patients with primary brain cancers and with melanoma, breast, and lung cancers with metastases to brain. The aims are to assess clinical response when DM-CHOC-PEN is administered I.V. at MTD and to monitor duration of responses and safety (IND 68,876). We report here the responses and toxicities seen in patients with NSCLC involving the CNS. Patients &amp; Methods: In Phase I, DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to patients with advanced cancer; cohorts received escalating doses from 39 - 111 mg/m2. The Phase II dose schedule is 2-tiered: 85.8 mg/m2 for patients with liver involvement and 98.7 mg/m2 for patients with normal livers. Results: Fifty two (52) patients have been treated to date - 26 in Phase I (cancer patients with or without CNS involvement) and 26 in Phase II (with CNS involvement). The drug was well tolerated; the most common adverse effects were fatigue (17%), reversible liver dysfunction (9%) and nausea (11%). No neuro/psychological, hematological, cardiac or renal toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-111 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively. Both DM-CHOC-PEN and DM-PEN were detected 3 to 15 days after administration associated (up to 50%) with rbcs. DM-CHOC-PEN was also detected in CNS tumor tissue obtained surgically from five (5) patients - concentrations of 75-210 ng/g, 22 days to 9 mos. post treatments at doses of 39 or 98.7 mg/m2 of drug. To date, 16 patients with lung cancer (11 with NSCLC involving the CNS) have been treated. Seven of the 11 patients with NSCLC involving the CNS (incl. 6 with cerebellar disease) have responded with CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 6+ - 21+ mos. Conclusion: DM-CHOC-PEN is safe at these dose levels and has produced objective responses with manageable toxicities in NSCLC involving the CNS. Complete data on patient responses and observed toxicities will be presented. We propose a 2-stage mechanism for drug entry into the CNS and into NSCLC cells via reversible binding with RBCs and then L-glutamine transport into cells. Supported by NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Roy S. Weiner, T Mahmood, C Gordon, ML Ware, LR Morgan, TM Cosgriff, AH Rodgers, G Bastian, R Kawauchi, M Matrana, J-J Zou. Phase II clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in NSCLC involving the CNS. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT129.</jats:p

Abstract CT052: Clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in cancers involving the CNS

Abstract Background: 4-Demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) is a poly-chlorinated pyridine cholesteryl carbonate with a MOA via bis-alkylation of DNA @ N7-guanine and N4-cytosine that has completed Phase I and II trials (the latter on subjects with CNS involvement) [AACR #1185, 2013; AACR #CT 129]. The primary aim was to assess clinical response and secondary aims to monitor toxicities/safety and verify the MTDs for IV administered DM-CHOC-PEN that derived in Phase I study (IND 68,876). We report here the responses and toxicities seen in all the subjects treated. Subjects &amp; Methods: In Phase I, DM-CHOC-PEN was administered as a 3-hr IV infusion once every 21 days to subjects with advanced cancer; cohorts received escalating doses from 39 - 111 mg/m2. The Phase II dose schedule was 2-tiered: 85.8 mg/m2 for subjects with liver involvement and 98.7 mg/m2 for subjects with normal livers. Results: Fifty two (52) subjects have been treated to date - 25 in Phase I (cancer subjects with or without CNS involvement) and 27 in Phase II (with CNS involvement). The common tumor types treated were primary brain cancers and melanoma, breast, and lung cancers involving the CNS. The drug was well tolerated; the most common adverse effects were fatigue (17%), reversible liver dysfunction (9%) and nausea (11%). No neuro/psychological, hematological, cardiac or renal toxicities were observed. PK modeling revealed that AUCs were parallel for all dose levels (39-111 mg/m2). The Cmax for DM-CHOC-PEN and DM-PEN (4-demethylpenclomedine, a metabolite) were 3 and 24 hours, respectively. Both DM-CHOC-PEN and DM-PEN were detected 3 to 15 days after administration associated (up to 50%) with rbcs. Of interest, young adults (&amp;lt;40 y/o) demonstrated significant increases in Cmax and AUC vs. older subjects, supporting the need for trials in adolescents and young adults. DM-CHOC-PEN was also detected in CNS tumor tissue obtained surgically from five (5) subjects - in concentrations of 75-210 ng/g, 22 days to 9 mos. post treatments at doses of 39 or 98.7 mg/m2 of drug. To date, 16 subjects with lung cancer (11 with NSCLC involving the CNS) have been treated. Seven of the 11 subjects with NSCLC involving the CNS (incl. 6 with cerebellar disease) have responded with CR/PR (RECIST 1.1) and improved OS/QOL/PFS (Kaplan-Meier) lasting 8+ - 32+ mos. Conclusion: DM-CHOC-PEN is safe at these dose levels and has produced objective responses with manageable toxicities in subjects with cancer involving the CNS. Complete data on subject responses and observed toxicities will be presented. We propose a 3-stage mechanism for drug entry into the CNS and into NSCLC cells via reversible binding with RBCs and then associated with L-glutamine transport into cells. Supported by NCI/SBIR grants - R43/44CA132257 and NIH NIGMS 1 U54 GM104940 - the latter funds the Louisiana Clinical and Translational Science Center. Citation Format: Roy S. Weiner, Lee Roy Morgan, T Mahmood, R. Kawauchi, C. Gordon, ML Ware, M. Matrana, TM Cosgriff, AH Rodgers, G. Bastian, M. Bhandari, J-J Zou. Clinical trial results for 4-demethyl-4-cholesteryloxycarbonylpenclomedine (DM-CHOC-PEN) in cancers involving the CNS [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT052. doi:10.1158/1538-7445.AM2017-CT052</jats:p