The usefulness of pharmacokinetic parameters for glioma grading has been reported based on the perfusion data from parts of entire-tumor volumes. However, the perfusion values may not reflect the ...entire-tumor characteristics. Our aim was to investigate the feasibility of glioma grading by using histogram analyses of pharmacokinetic parameters including the volume transfer constant, extravascular extracellular space volume per unit volume of tissue, and blood plasma volume per unit volume of tissue from T1-weighted dynamic contrast-enhanced perfusion MR imaging.
Twenty-eight patients (14 men, 14 women; mean age, 49.75 years; age range, 25-72 years) with histopathologically confirmed gliomas (World Health Organization grade II, n = 7; grade III, n = 8; grade IV, n = 13) were examined before surgery or biopsy with conventional MR imaging and T1-weighted dynamic contrast-enhanced perfusion MR imaging at 3T. Volume transfer constant, extravascular extracellular space volume per unit volume of tissue, and blood plasma volume per unit volume of tissue were calculated from the entire-tumor volume. Histogram analyses from these parameters were correlated with glioma grades. The parameters with the best percentile from cumulative histograms were identified by analysis of the area under the curve of the receiver operating characteristic analysis and were compared by using multivariable stepwise logistic regression analysis for distinguishing high- from low-grade gliomas.
All parametric values increased with increasing glioma grade. There were significant differences among the 3 grades in all parameters (P < .01). For the differentiation of high- and low-grade gliomas, the highest area under the curve values were found at the 98th percentile of the volume transfer constant (area under the curve, 0.912; cutoff value, 0.277), the 90th percentile of extravascular extracellular space volume per unit volume of tissue (area under the curve, 0.939; cutoff value, 19.70), and the 84th percentile of blood plasma volume per unit volume of tissue (area under the curve, 0.769; cutoff value, 11.71). The 98th percentile volume transfer constant value was the only variable that could be used to independently differentiate high- and low-grade gliomas in multivariable stepwise logistic regression analysis.
Histogram analysis of pharmacokinetic parameters from whole-tumor volume data can be a useful method for glioma grading. The 98th percentile value of the volume transfer constant was the most significant measure.
International Consensus on drug allergy Demoly, P.; Adkinson, N. F.; Brockow, K. ...
Allergy,
April 2014, Volume:
69, Issue:
4
Journal Article, Conference Proceeding
Peer reviewed
Open access
When drug reactions resembling allergy occur, they are called drug hypersensitivity reactions (DHRs) before showing the evidence of either drug‐specific antibodies or T cells. DHRs may be allergic or ...nonallergic in nature, with drug allergies being immunologically mediated DHRs. These reactions are typically unpredictable. They can be life‐threatening, may require or prolong hospitalization, and may necessitate changes in subsequent therapy. Both underdiagnosis (due to under‐reporting) and overdiagnosis (due to an overuse of the term ‘allergy’) are common. A definitive diagnosis of such reactions is required in order to institute adequate treatment options and proper preventive measures. Misclassification based solely on the DHR history without further testing may affect treatment options, result in adverse consequences, and lead to the use of more‐expensive or less‐effective drugs, in contrast to patients who had undergone a complete drug allergy workup. Several guidelines and/or consensus documents on general or specific drug class‐induced DHRs are available to support the medical decision process. The use of standardized systematic approaches for the diagnosis and management of DHRs carries the potential to improve outcomes and should thus be disseminated and implemented. Consequently, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the European Academy of Allergy and Clinical Immunology (EAACI), the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), and the World Allergy Organization (WAO), has decided to issue an International CONsensus (ICON) on drug allergy. The purpose of this document is to highlight the key messages that are common to many of the existing guidelines, while critically reviewing and commenting on any differences and deficiencies of evidence, thus providing a comprehensive reference document for the diagnosis and management of DHRs.
Numerous volatile organic compounds (VOCs) exist in Earth's atmosphere, most of which originate from biogenic emissions. Despite VOCs' critical role in tropospheric chemistry, studies for evaluating ...their atmosphere-ecosystem exchange (emission and deposition) have been limited to a few dominant compounds owing to a lack of appropriate measurement techniques. Using a high—mass resolution proton transfer reaction—time of flight—mass spectrometer and an absolute value eddy-covariance method, we directly measured 186 organic ions with net deposition, and 494 that have bidirectional flux. This observation of active atmosphere-ecosystem exchange of the vast majority of detected VOCs poses a challenge to current emission, air quality, and global climate models, which do not account for this extremely large range of compounds. This observation also provides new insight for understanding the atmospheric VOC budget.
Abstract Purpose Combined hepatocellular carcinoma (HCC) and cholangiocellular carcinoma (CCC) is a rare pair of intrahepatic malignancies. Differential diagnosis among combined HCC-CCC, HCC, or CCC ...can be difficult; thus malignancies other than ordinary HCC are occasionally encountered unexpectedly in explanted liver specimens. The present study analyzed the long-term outcomes of liver transplantation (OLT) among patients with HCC-CCC. Methods Between January 1999 and December 2009, we performed 2137 adult OLT at our institution including 15 cases of pathologically confirmed HCC-CCC, who all underwent OLT with a pretransplant diagnosis of HCC. We reviewed retrospectively the medical records of these 15 patients. Results Their mean age was 58.9 ± 7.2 years. The median preoperative alpha-fetoprotein level was 32.6 ng/mL. Fourteen patients underwent living donor and one deceased donor OLT. The Milan criteria were met in 12 cases. A single tumor was identified in 8 and multiple lesions in 7 patients. The maximal tumor diameter was 2.9 ± 1.7 cm. Seven patients experienced tumor recurrences: including 6 within the first 12 months. All of the patients who experienced recurrences died at a median 4 months after that diagnosis. The overall patient survival rates were 66.7% at 1 year and 60.0% at 3 and 5 years. Disease-free patient survival rates were 60.0% at 1 year and 53.3% at 3 and 5 years. Conclusions Patients with combined HCC-CCC showed a high rate of early recurrences, particularly within the first year.
Multicentre study.
To define the clinical characteristics of patients with tuberculosis (TB) destroyed lung due to past TB.
We reviewed patients with TB-destroyed lung between May 2005 and June 2011.
...A total of 595 patients from 21 hospitals were enrolled. The mean age was 65.63 ± 0.47 (mean ± standard error); 60.5% were male. The mean number of lobes involved was 2.59 ± 0.05. Pleural thickening was observed in 54.1% of the patients. Mean forced vital capacity (FVC), forced expiratory volume in 1 s (FEV(1)), FEV(1)/FVC, bronchodilator response and number of exacerbations per year were respectively 2.06 ± 0.03 l (61.26% ± 0.79), 1.16 ± 0.02 l (49.05% ± 0.84), 58.03% ± 0.70, 5.70% ± 0.34, and 0.40 ± 0.04. The number of lobes involved was significantly correlated with FVC and FEV(1), and with the number of exacerbations per year. Use of long-acting muscarinic antagonists or long-acting beta-2 agonists plus inhaled corticosteroids resulted in bronchodilatory effects. Multivariable regression analysis showed that age, initial FEV(1) (%) and number of exacerbations during follow-up were independent factors affecting change in FEV(1).
Decreased lung function with exacerbation, and progressive decline of FEV(1) were observed in patients with TB-destroyed lung.
Patients who have residual invasive carcinoma after the receipt of neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer have poor prognoses. The benefit ...of adjuvant chemotherapy in these patients remains unclear.
We randomly assigned 910 patients with HER2-negative residual invasive breast cancer after neoadjuvant chemotherapy (containing anthracycline, taxane, or both) to receive standard postsurgical treatment either with capecitabine or without (control). The primary end point was disease-free survival. Secondary end points included overall survival.
The result of the prespecified interim analysis met the primary end point, so this trial was terminated early. The final analysis showed that disease-free survival was longer in the capecitabine group than in the control group (74.1% vs. 67.6% of the patients were alive and free from recurrence or second cancer at 5 years; hazard ratio for recurrence, second cancer, or death, 0.70; 95% confidence interval CI, 0.53 to 0.92; P=0.01). Overall survival was longer in the capecitabine group than in the control group (89.2% vs. 83.6% of the patients were alive at 5 years; hazard ratio for death, 0.59; 95% CI, 0.39 to 0.90; P=0.01). Among patients with triple-negative disease, the rate of disease-free survival was 69.8% in the capecitabine group versus 56.1% in the control group (hazard ratio for recurrence, second cancer, or death, 0.58; 95% CI, 0.39 to 0.87), and the overall survival rate was 78.8% versus 70.3% (hazard ratio for death, 0.52; 95% CI, 0.30 to 0.90). The hand-foot syndrome, the most common adverse reaction to capecitabine, occurred in 73.4% of the patients in the capecitabine group.
After standard neoadjuvant chemotherapy containing anthracycline, taxane, or both, the addition of adjuvant capecitabine therapy was safe and effective in prolonging disease-free survival and overall survival among patients with HER2-negative breast cancer who had residual invasive disease on pathological testing. (Funded by the Advanced Clinical Research Organization and the Japan Breast Cancer Research Group; CREATE-X UMIN Clinical Trials Registry number, UMIN000000843 .).
Purpose
This multi-center, randomized, phase III study was conducted to demonstrate the non-inferiority of DA-3031 compared with daily filgrastim in patients during the first cycle of chemotherapy ...for breast cancer in terms of the duration of severe neutropenia (DSN).
Methods
Seventy-four patients with breast cancer who were receiving combination chemotherapy with docetaxel, doxorubicin, and cyclophosphamide (TAC) were enrolled. All participants were randomized to receive either daily subcutaneous injections of filgrastim 100 μg/m
2
/day for up to 10 days or a single subcutaneous injection of DA-3031 at fixed doses of 6 mg on day 2 of each chemotherapy cycle.
Results
The mean duration of grade 4 (G4) neutropenia in cycle 1 was 2.08 ± 0.85 days for the filgrastim group and 2.28 ± 1.14 days for the DA-3031 group. The difference between groups was 0.2 ± 1.10 days (95 % confidence interval (CI) = −0.26, 0.66), which supported non-inferiority. No statistically significant differences were observed in nadir absolute neutrophil count (ANC) (154.34/mm
3
and 161.75/mm
3
for the filgrastim and DA-3031 groups, respectively;
P
= 0.8414) or in time to ANC recovery (10.03 ± 0.75 and 9.83 ± 1.56 days in the filgrastim and DA-3031 groups, respectively;
P
= 0.0611) during cycle 1. Serious AEs occurred in six (15.8 %) patients receiving filgrastim and in ten (27.8 %) patients receiving DA-3031; however, none was determined to be related to the study drug.
Conclusions
DA-3031 and daily filgrastim are similar in regard to DSN and safety in breast cancer patients receiving TAC chemotherapy.
BACKGROUND AND PURPOSE
Ginsenosides are the main constituents for the pharmacological effects of Panax ginseng. Such effects of ginsenosides including cardioprotective and anti‐platelet activities ...have shown stability and bioavailability limitations. However, information on the anti‐platelet activity of ginsenoside‐Rp1 (G‐Rp1), a stable derivative of ginsenoside‐Rg3, is scarce. We examined the ability of G‐Rp1 to modulate agonist‐induced platelet activation.
EXPERIMENTAL APPROACH
G‐Rp1 in vitro and ex vivo effects on agonist‐induced platelet‐aggregation, granule‐secretion, Ca2+i mobilization, integrin‐αIIbβ3 activation were examined. Vasodilator‐stimulated phosphoprotein (VASP) and MAPK expressions and levels of tyrosine phosphorylation of the glycoprotein VI (GPVI) signalling pathway components were also studied. G‐Rp1 effects on arteriovenous shunt thrombus formation in rats or tail bleeding time and ex vivo coagulation time in mice were determined.
KEY RESULT
G‐Rp1 markedly inhibited platelet aggregation induced by collagen, thrombin or ADP. While G‐Rp1 elevated cAMP levels, it dose‐dependently suppressed collagen‐induced ATP‐release, thromboxane secretion, p‐selectin expression, Ca2+i mobilization and αIIbβ3 activation and attenuated p38MAPK and ERK2 activation. Furthermore, G‐Rp1 inhibited tyrosine phosphorylation of multiple components (Fyn, Lyn, Syk, LAT, PI3K and PLCγ2) of the GPVI signalling pathway. G‐Rp1 inhibited in vivo thrombus formation and ex vivo platelet aggregation and ATP secretion without affecting tail bleeding time and coagulation time, respectively.
CONCLUSION AND IMPLICATIONS
G‐Rp1 inhibits collagen‐induced platelet activation and thrombus formation through modulation of early GPVI signalling events, and this effect involves VASP stimulation, and ERK2 and p38‐MAPK inhibition. These data suggest that G‐Rp1 may have therapeutic potential for the treatment of cardiovascular diseases involving aberrant platelet activation.
Mutation in PTEN has not yet been detected, but its function as a tumor suppressor is inactivated in many cancers. In this study we determined that, activated Notch signaling disables PTEN by ...phosphorylation and thereby contributes to gastric tumorigenesis. Notch inhibition by small interfering RNA or γ-secretase inhibitor (GSI) induced mitotic arrest and apoptosis in gastric cancer cells. Notch inhibition induced dephosphorylation in the C-terminal domain of PTEN, which led to PTEN nuclear localization. Overexpression of activated Notch1-induced phosphorylation of PTEN and reversed GSI-induced mitotic arrest. Dephosphorylated nuclear PTEN caused prometaphase arrest by interaction with the cyclin B1-CDK1 complex, resulting in their accumulation in the nucleus and subsequent apoptosis. We found a correlation between high expression levels of Notch1 and low survival rates and, similarly, between reduced nuclear PTEN expression and increasing the TNM classification of malignant tumours stages in malignant tissues from gastric cancer patients. The growth of Notch1-depleted gastric tumors was significantly retarded in xenografted mice, and in addition, PTEN deletion restored growth similar to control tumors. We also demonstrated that combination treatment with GSI and chemotherapeutic agents significantly reduced the orthotopically transplanted gastric tumors in mice without noticeable toxicity. Overall, our findings suggest that inhibition of Notch signaling can be employed as a PTEN activator, making it a potential target for gastric cancer therapy.
Summary
Background
Low‐osmolar non‐ionic radiocontrast media (RCMs) are commonly used throughout hospitals. However, the incidence of immediate adverse drug reactions (ADRs) to various low‐osmolar ...non‐ionic RCMs is not well studied. We compared the incidence of immediate ADRs among different low‐osmolar non‐ionic RCMs used in computed tomography (CT).
Methods
Severance Hospital has collected data for adverse reactions occurring in‐hospital using an internally developed system. Using this data, we reviewed 1969 immediate ADRs from 286 087 RCM‐contrasted CT examinations of 142 099 patients and compared the immediate ADRs of iobitridol, iohexol, iopamidol, and iopromide. We analysed the incidence of immediate ADRs to different RCMs, as well as the effect of single or multiple CT examinations per day.
Results
Iopromide showed the highest incidence of immediate ADRs (1.03%) and was followed by iopamidol (0.67%), iohexol (0.64%), and iobitridol (0.34%). In cases of anaphylaxis, iopromide also showed the highest incidence (0.041%), followed by iopamidol (0.023%), iohexol (0.018%), and iobitridol (0.012%). Risk of immediate ADR due to multiple CT examinations (1.19%) was significantly higher than the risk due to a single CT examination (0.63%). Risk of anaphylaxis was also higher for multiple CT examinations (0.052%) than for a single CT examination (0.020%).
Conclusions and Clinical Relevance
The incidence of immediate ADRs varied according to the low‐osmolar non‐ionic RCM used. Iopromide‐induced immediate ADRs were more frequent, while iobitridol was associated with fewer immediate ADRs than other RCMs. Multiple CT examinations per day resulted in a higher incidence of immediate ADRs and anaphylaxis than a single CT examination. Clinicians should consider these risk differences of immediate ADRs when prescribing contrasted CT examinations.
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