Recent investigations demonstrate that bacille Calmette-Guerin (BCG), a potent inducer of Th1 response, infection prior to allergen sensitization inhibits Th2 immune responses to the allergen. ...However, it is not clear whether BCG infection in allergen-presensitized rats switches off Th2 response and prevents allergic asthmatic reaction to the subsequent allergen exposure. In this study we investigate whether BCG infection in ovalbumin (OVA)-presensitized Sprague-Dawley rats suppresses airway hyperresponsiveness and eosinophilic inflammation induced by OVA and Th2 cytokine production. BCG infection in OVA-presensitized rats significantly inhibited not only the sensitivity of airway smooth muscle to electrical field stimulation and acetylcholine but also absolute eosinophil counts in bronchoalveolar lavage fluid. As a correlate, interleukin-4 (IL-4) production significantly decreased and interferon-gamma (IFN-gamma) slightly increased, resulting in a markedly decreased ratio of IL-4-IFN-gamma in OVA-presensitized rats with BCG infection. These results indicate that BCG infection in pre-sensitized rats suppresses allergic asthmatic reaction and Th2 immune response. It is possible from these findings that BCG vaccine may be used as an immunomodulating agent for the sensitized host with preestablished Th2 memory.
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Background: In non-clear cell renal cell carcinoma (ncRCC), the efficacy of VEGF tyrosine kinase inhibitor (TKI) is controversial. In the while, a mTOR inhibitor, temsirolimus ...showed a promising efficacy in ncRCC patients in ARCC trial. Hence, we investigated the role of everolimus in ncRCC with this phase II trial. Methods: ncRCC patients received everolimus 10 mg once daily until disease progression or unacceptable toxicity. We included patients who had received VEGF TKI previously, while excluded patients who received previous mTOR inhibitor. The primary end point was progression free survival (PFS). Results: A total of 49 patients were enrolled from 5 centers. Their median age was 57 years (range 24-75 years) and male to female ratio was 37:12. Histology of the patients included papillary (n=29), chromophobe (n=8), collecting duct (n=2), sarcomatoid (n=4), and unclassifiable (n=6) RCC. Twenty-three patients had been treated with VEGF-TKI prior to the study enrollment. Among 49 patients, 46 patients underwent radiologic response assessment after everolimus treatment. Partial response was observed in 5 patients (10.2%) and stable disease in 25 patients (51.0%). Diseases of 16 patients (32.7%) progressed despite of everolimus administration. Histology of 5 patients who showed objective response to everolimus included chromophobe carcinoma (n=2), papillary carcinoma (n=2) and unclassifiable carcinoma (n=1). During the study period, 34 patients experienced PFS events and median PFS was 5.2 months. Patients with chromophobe histology showed longer PFS than patients with the other histologies (median PFS 18.8 months vs. 3.5 months, p=0.027). Estimated median PFS were not significantly different between patients VEGF-TKI treatment and patients without previous VEGF-TKI treatment (median PFS 7.1 vs. 3.7 months, p=0.110). Toxicity profiles were commensurable with previous reports. Conclusions: Everolimus shows considerable efficacy in ncRCC. Patients with chromophobe histology might earn benefit from everolimus treatment especially. Previous treatment with VEGF-TKI seems not to significantly influence outcome of everolimus therapy in these patients. (ClinicalTrials.gov number, NCT00830895)
This study evaluated the effects of somatic mutations and single nucleotide polymorphisms (SNPs) on disease progression and tried to verify the two-hit theory in cancer pathogenesis. To address this ...issue, SNP analysis was performed using the UCSC hg19 program in 10 acute myeloid leukemia patients (samples, G1 to G10), and somatic mutations were identified in the same tumor sample using SomaticSniper and VarScan2. SNPs in KRAS were detected in 4 out of 10 different individuals, and those of DNMT3A were detected in 5 of the same patient cohort. In 2 patients, both KRAS and DNMT3A were detected simultaneously. A somatic mutation in IDH2 was detected in these 2 patients. One of the patients had an additional mutation in FLT3, while the other patient had an NPM1 mutation. The patient with an FLT3 mutation relapsed shortly after attaining remission, while the other patient with the NPM1 mutation did not suffer a relapse. Our results indicate that SNPs with additional somatic mutations affect the prognosis of AML.
Abstract
Purpose: EML4-ALK fusions occur in approximately 5% of non-small cell lung carcinoma and define a subpopulation of lung cancer patients highly responsive to ALK kinase inhibitors. Current ...methodologies for detecting presence of ALK rearrangements are labor-intensive, costly, and not ideally suited for screening large number of patient samples. To allow for a sensitive, facile, and inexpensive methodology to detect EML4-ALK fusions, we developed a direct transcript profiling to detect common variants of EML4-ALK fusions. Experimental Design: Using a single multiplex assay, we simultaneously interrogated presence of EML4-ALK transcripts and ALK 3′ over-expression in 8 ALK-positive and 22 ALK-negative NSCLC samples previously tested by fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC). For controls, we also tested ALK-positive cancer cells lines NCI-H3122 and NCI-H2228, and an ALK-negative cell line A549. Purified RNA from formalin-fixed paraffin-embedded (FFPE) tissue sections was hybridized in duplicates to a biotinylated capture probe and a color-coded reporter probe designed to hybridize to sequences spanning EML4-ALK junction. In addition, multiple probes were created to hybridize within 5′ and 3′ regions of ALK transcript to detect discordant levels between the breakpoint, indicative of fusion event. Purified hybridization complexes are immobilized and aligned on a cartridge where a microscope CCD camera images and counts the molecular color-coded tags attached to reporter probes. The number of reporter counts corresponds to the number of transcripts being interrogated. Results: With this assay, we obtained 100% concordance in EML4-ALK fusion calls to results generated by FISH and IHC analyses. Similar findings were obtained for control cancer cell lines. The assay is highly reproducible and sensitive, detecting ALK-fusion transcripts even in samples with low tumor content. Using the combined strategy of fusion detection and ALK 5′ and 3′ transcript quantification, we were able to validate the status of one patient negative for ALK rearrangement by FISH but positive for ALK protein expression by IHC. Conclusions: We have developed a novel and sensitive methodology to screen for common EML4-ALK fusions in NSCLC. The assay is inexpensive, easy to perform, high-throughput and compatible with FFPE tissue samples. This is a promising technology highly suitable for screening large numbers of tumor samples without the need for cDNA synthesis and PCR amplification.
Citation Format: {Authors}. {Abstract title} abstract. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4553. doi:1538-7445.AM2012-4553
Local reaction to allergen-specific immunotherapy (SIT) usually appears within 30 minutes, but cases with exercise-induced urticaria at the SIT site 2-3 weeks after the last allergen injection have ...been reported. A 28-year-old man was treated with house dust mite-SIT for 5 years, due to asthma when he was an 11-year-old boy. On a treadmill exercise test for 50 minutes, erythema, swelling, and pruritus occurred at the SIT site, which lasted for one hour. There was no evidence of complement activation, and the skin biopsy specimens showed no apparent difference between the lesion and normal sites in the distribution of inflammatory cells and in mast cell degranulation. However, the morphine, but not the histamine, skin test responses were increased after the exercise. There must be a remaining long-term sequela of the SIT, including an increased releasability of mast cells, even after more than 10 years.
Systemic steroids are highly effective for patients with moderate-to-severe asthma exacerbations. Steroid-induced psychosis is known to be one of the adverse effects of steroid therapy, although ...infrequent. However, there is no reliable method of predicting steroid psychosis. We experienced the case of a 40-year-old asthmatic man who had previously taken steroids without any psychological side effect, but became acutely delirious after receiving some doses of steroids, higher than the previous doses, under a condition of emotional stress. The mean dose of prednisolone administered was 82 mg/day (1.37 mg/kg/day) for 10 days but the patient had taken two courses of steroids (0.82 mg/kg/day and 0.5 mg/kg/day, respectively) for asthma exacerbations without any psychiatric episodes during the previous year. At this time, the patient was under a condition of emotional stress related to family reasons. The asthmatic exacerbation of this case may be precipitated from sudden emotional stress and the following treatment with a high dose of steroida should be used cautiously due to the possibility of psychotic side reactions.
Airway hyperresponsiveness (AHR) to direct stimuli, such as methacholine (MCh), is observed not only in asthma but other diseases. AHR to indirect stimuli is suggested to be more specific for asthma. ...The purpose of this study was to determine whether asthmatic airway inflammation is more closely related to AHR to hypertonic saline (HS), an indirect stimulus, than to MCh.
Sixty-four consecutive adult patients with suspected asthma (45 asthma and 19 non-asthma) performed a combined bronchial challenge and sputum induction with 4.5% saline, and MCh challenge on the next day.
Both HS-PD15 and MCh-PC20 were significantly lower in asthma patients than in non-asthma patients. However, the sensitivity/specificity for asthma was 48.9%/100%, respectively, in the HS test and 82.2%/84.2%, respectively, in the MCh test. There was a significant relationship between HS-PD15 and MCh-PC20 and only 52.9% of patients with MCh-PC20 < or = 4 mg/mL showed HS-AHR, but 4 patients with HS-AHR showed MCh-PC20 > 4 mg/mL. There were significant correlations between both HS-PD15 and MCh-PC20 and FEV1, or sputum eosinophils, but FEV1 was more closely related to MCh-PC20 (r = 0.478, p < 0.01) than to HS-PD15 (r = 0.278, p < 0.05), and sputum eosinophils were more closely related to HS-PD15 (r = -0.324, p < 0.01) than to MCh-PC20 (r = -0.317, p < 0.05). Moreover, the IL-5 level (r = 0.285, p < 0.05) and IFN-gamma/IL-5 ratio (r = 0.293, p < 0.05) in sputum were significantly related to HS-PD15, but not to MCh-PC20.
HS-AHR may reflect allergic asthmatic airway inflammation more closely than MCh-AHR.
Purpose. We tried to establish clinically relevant human myeloma cell lines that can contribute to the understanding of multiple myeloma (MM). Materials and Methods. Mononuclear cells obtained from ...MM patient’s bone marrow were injected via tail vein in an NRG/SCID mouse. Fourteen weeks after the injection, tumor developed at subcutis of the mouse. The engraftment of MM cells into mouse bone marrow (BM) was also observed. We separated and cultured cells from subcutis and BM. Results. After the separation and culture of cells from subcutis and BM, we established two cell lines originating from a single patient (SNU_MM1393_BM and SNU_MM1393_SC). Karyotype of the two newly established MM cell lines showed tetraploidy which is different from the karyotype of the patient (diploidy) indicating clonal evolution. In contrast to SNU_MM1393_BM, cell proliferation of SNU_MM1393_SC was IL-6 independent. SNU_MM1393_BM and SNU_MM1393_SC showed high degree of resistance against bortezomib compared to U266 cell line. SNU_MM1393_BM had the greater lethality compared to SNU_MM1393_SC. Conclusion. Two cell lines harboring different site tropisms established from a single patient showed differences in cytokine response and lethality. Our newly established cell lines could be used as a tool to understand the biology of multiple myeloma.
Abstract The aims of the present study are two-fold: (1) to define the clinical features of hypoplastic myelodysplastic syndrome (h-MDS) in comparison with aplastic anemia (AA) and (2) to evaluate ...the prognostic roles of karyotyping and fluorescent in situ hybridization (FISH) in these hypoplastic marrow syndromes. Based on a medical record review at Seoul National University Hospital, the records of 409 patients diagnosed with either h-MDS or AA were evaluated. Of these patients, 358 had been diagnosed with AA and 51 with h-MDS (median age, 39 years). At diagnosis, 235 and 165 patients underwent karyotyping and FISH analysis, respectively. Karyotypic abnormalities and trisomy 8 and trisomy 1q FISH abnormalities were found more frequently in h-MDS patients than in AA patients. Median overall survival (OS) of h-MDS patients was shorter than that of AA patients (83 vs. 201 months, P = 0.007), with the OS of h-MDS patients falling between that of severe and very severe AA patients. Patients with h-MDS had more frequent leukemic conversion ( P < 0.001) than did AA patients. In AA patients, karyotypic abnormality was not prognostic ( P = 0.646), while in h-MDS patients, abnormalities in trisomy 1q FISH ( P = 0.002) and in 20q deletion FISH ( P = 0.005) were predictive of poor prognosis. In conclusion, the prognosis for h-MDS patients falls between that of severe and very severe AA patients. Moreover, h-MDS is frequently accompanied by karyotypic and FISH abnormalities and is prone to leukemic conversion. Trisomy 1q and 20q deletion FISH abnormalities may have important prognostic roles in patients with h-MDS.
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