Patients with chemotherapy-induced granulocytopenia for neoplastic diseases and those receiving cyclosporin A plus corticosteroids for prevention and treatment of organ transplant rejection are two immunologically distinct patient populations with high risks for development of invasive pulmonary aspergillosis. In order to compare the pathogenesis of aspergillosis in these two high-risk populations and to further characterize the role of cyclosporin A in development of pulmonary aspergillosis, we studied the patterns of infection and inflammation in two clinically applicable rabbit models of invasive pulmonary aspergillosis. There were striking differences in the patterns of infection and inflammation of invasive pulmonary aspergillosis according to the type of underlying immune defect. Among rabbits challenged with the same intratracheal inoculum, there was a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% survival in rabbits immunosuppressed with cyclosporin A plus methylprednisolone (CsA+MP). Lesions of pulmonary aspergillosis in granulocytopenic rabbits consisted predominantly of coagulative necrosis, intraalveolar hemorrhage, and scant mononuclear inflammatory infiltrate. By comparison, pulmonary foci in rabbits immunosuppressed by CsA+MP consisted mainly of neutrophilic and monocytic infiltrates, inflammatory necrosis, and scant intraalveolar hemorrhage. There was extensive infiltration by hyphae with angioinvasion in granulocytopenic rabbits, whereas conidia in various stages of germination predominated in CsA+MP treated animals in which there was a paucity of hyphae or angioinvasion. Extrapulmonary disease predominated in granulocytopenic rabbits. Methylprednisolone was the major immunosuppressive drug in rabbits treated with CsA+MP. Cyclosporin A alone did not increase the progression of pulmonary aspergillosis and did so only when used chronically with methylprednisolone.

We characterized 27 episodes of fungemia in 22 children infected with the human immunodeficiency virus (HIV). Fungemia in these patients presented as a community-acquired infection in the setting of outpatient total parenteral nutrition or intravenous antibiotic therapy through a chronically indwelling central venous catheter (CVC). Fungemia developed only in patients with CVCs (P < .001). Non-albicans Candida species, Torulopsis glabrata, Rhodotorula rubra, and Bipolaris spicifera constituted 52% of all causes. Fungemia was detected early, within a median of 2.4 days after the onset of new fever, which permitted prompt administration of amphotericin B (mean dosage, 0.7 mg/[kg.day]; median duration, 19 days). CVCs were removed in 23 (85%) of the episodes. We conclude that fungemia in HIV-infected children often presents as a community-acquired infection, is frequently due to newly emerging opportunistic fungi, and can be managed, with a high level of success (95% survival with no posttherapeutic sequelae), by early diagnosis, prompt initiation of amphotericin B therapy, and removal of the CVC.

Itraconazole and amphotericin B were compared by using a newly developed model of invasive pulmonary aspergillosis in rabbits immunosuppressed with methylprednisolone and cyclosporin A (CsA). Both itraconazole at 40 mg/kg (given orally) and amphotericin B at 1 mg/kg (given intravenously) had in vivo antifungal activity in comparison with controls. At these dosages, amphotericin B was more effective than itraconazole in reducing the tissue burden (loglo CFU per gram) of Aspergillus fumigatus (P < 0.05) and the number of pulmonary lesions (P < 0.01). However, there was considerable variation in the near-peak concentrations of itraconazole in plasma (median, 4.15 ,ug/ml; range, <0.5 to 16.8 ,g/ml) and a strong inverse correlation between concentrations of itraconazole in plasma and the tissue burden ofA.fumigatus. An inhibitory sigmoid maximum-effect model predicted a significant pharmacodynamic relationship (r = 0.87, P < 0.001) between itraconazole concentrations in plasma and antifungal activity as a function of the tissue burden ofA.fumigatus.This model demonstrated that levels in plasma of greater than 6 ,ug/ml were associated with a significantly greater antifungal effect. Levels in plasma of less than 6 ,g/ml were associated with a rapid decline in the antifungal effect. Itraconazole, in comparison with amphotericin B, caused a twofold elevation of CsA levels (P < 0.01) but was less nephrotoxic (P < 0.01). This study of experimental pulmonary aspergillosis demonstrated that amphotericin B at 1 mg/kg/day was more active but more nephrotoxic than itraconazole at 40 mg/kg/day, that itraconazole increased concentrations of CsA in plasma, and that the antifungal activity of itraconazole strongly correlated with concentrations in plasma in an inhibitory sigmoid maximum-effect model. These findings further indicate the importance of monitoring concentrations of itraconazole in plasma as a guide to increasing dosage, improving bioavailability, and optimizing antifungal efficacy in the treatment of invasive pulmonary aspergillosis.

BACKGROUND:The prognosis for patients with colorectal cancer (CRC) depends mainly on standard clinicopathologic factors. However, patients with similar disease characteristics exhibit various outcomes, especially in stage II. Therefore, the identification of molecular prognostic markers is needed to predict patient outcomes. METHODS: The authors assessed the prognostic value of c-Kit (also called cluster of differentiation 117 [CD117] or KIT), cyclooxygenase-2 (COX-2), tumor protein 53 (p53), and Kirsten rat sarcoma viral oncogene homolog (K-ras) aberrations in 90 patients with stage II CRC using immunohistochemistry and molecular techniques. The results were correlated with standard clinicopathologic prognostic factors, overall survival (OS), and disease-free survival (DFS). RESULTS: COX2 and c-Kit overexpression was detected in 54.6% and 59.3% of patients, respectively. Overexpression of p53 was detected in 47 patients, including 29 who had mutations, and a unique mutation pattern was detected with 3 hotspots at codons 72, 245, and 273. Overexpression of ras was detected in 44 patients, including 37 who had mutations. On multivariate analysis, c-Kit overexpression, p53 codon 72 mutations, perforation, and performance status were independent prognostic factors for DFS (P ¼ .054, P ¼ .015, P < .0001, and P ¼ .043, respectively); whereas codon 12 K-ras mutation, performance status, and perforation were independent prognostic factors for OS (P ¼ .033, P ¼ .006, and P < .0001, respectively). CONCLUSIONS: The current results provide evidence for the prognostic value of c-Kit overexpression in patients with stage II CRC. The high p53 mutation rate and the unique hotspot in codon 72 have not been reported previously in CRC. This may be related to environmental or racial features that are unique to the studied population. Cancer 2010;116:4954-64.

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Background: Patients with stage II CRC have a varying survival outcome. Therefore, it is critical to identify prognostic biomarkers that can define more aggressive forms of the disease. We assessed the expression levels of five miRNAs that have been previously addressed in relation to the development and progression of solid and hematological tumors.

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Background: Despite advances in the treatment of classic Hodgkin lymphoma (CHL), current therapies fail to cure 10%-15% of patients, and a similar proportion of patients may be over treated, resulting in both short-term and long-term treatment-related complications. Current prognostic models predict the outcome of treatment with imperfect accuracy, and clinically relevant biomarkers have not been established to improve on international prognostic score. Patients and Methods: CD 68 protein and RNA expression were assessed in 81 classic Hodgkin's lymphoma patients from Egypt by immunohistochemistry and Quantitative real time PCR (Q-RTP) respectively. Then CD 68 positive and CD 68 negative cases where profiled using the SABioscience array (Qiagen). Genetic aberrations were correlated to standard prognostic factors, patients response to the treatment, progression free and overall survival (PFS, OS) rates. Results: Increased CD68 protein and RNA expression were detected in 70.3% and 53.1% of the cases, respectively. Increased CD68 protein associated significantly with old age &gt;40 (p = 0.035), advanced stage (p = 0.007), and poor response to treatment (DP/SD, p = 0.001). CD68 RNA expression significantly associated with age (p = 0.035), and poor response to treatment (DP/SD, p = 0.001). CD68+ positive patients, showed high expression of cathepsin L, IL-12, ATXN2L, CTL4A and MMP11. The 5 years OS correlated significantly with CD68, IL-12, MMP11 and CTL4A-RNA expression (p&lt; 0.001) as well as with age (p&lt;0.001) and stage (p&lt;0.001). The 5 years PFS correlated significantly with age (p = 0.003), stage (p = 0.012), CD68 protein and RNA expression (p&lt; 0.001) as well as with cathepsin L, IL-12, CTL4A and MMP11 (p&lt;0.01). CD68 protein expression significantly correlated with 2 years OS (p&lt; 0.001). Conclusions: in classic Hodgkin's lymphoma, CD68+ macrophage and aberrant expression of cathepsin L, IL-12, CTL4A and MMP11 provide sensitive biomarkers that can accurately predict patients response to treatment and survival with high accuracy. Citation Format: Abdel-Rahman N. Zekri, Abeer A. Bahnassy, Ahmad E-S El-Bastawisi, Osama Hammad, Nasr M. Ali, John E. Diks, Hend F. Yousif. Prognostic and predictive values of CD68+ macrophage and aberrant expression of cathepsin L, IL-12, CTL4A genes in classic Hodgkin's lymphoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2217. doi:10.1158/1538-7445.AM2015-2217