Extensive phytocannabinoid profiles of seized cannabis and cannabis-based medicines - Identification of potential distinguishing markers.

As the frequency of cannabis-based therapy increases, the ability to distinguish intake of cannabis-based medicines from recreational cannabis use becomes desirable. Minor cannabinoids have been suggested to indicate recreational cannabis use in biological matrices but are unreliable when presumably also present in directly plantderived medicines. Thus, for therapeutics such as medical cannabis, Sativex® and Dronabinol, a more thorough investigation of cannabinoid profiles is required to identify possible distinguishing markers. In this study, 16 phytocannabinoids were quantified in samples of seized and medical cannabis, Sativex® and Dronabinol from two different manufacturers, using a validated LC-MS/MS method. Analytes included delta-9- tetrahydrocannabinol, tetrahydocannabinolic acid A, cannabidiol, cannabidiolic acid, cannabigerol, cannabigerolic acid, cannabinol, cannabinolic acid, cannabichromene, cannabichromenic acid, cannabicyclol, cannabicyclolic acid, tetrahydrocannabivarin, tetrahydrocannabivarinic acid, cannabidivarin and cannabidivarinic acid. Resultant cannabinoid profiles were compared, and markers were suggested. Characteristics of Sativex® included a specific cannabidiol/tetrahydrocannabinol ratio and presence of cannabichromene, while acidic cannabinoids, cannabigerol and cannabinol occurred in only low amounts. As expected, the predominant ingredient in Dronabinol was tetrahydrocannabinol, but minor cannabinoids were quantified as well. Medical marihuana and seized cannabis were compared separately in a principal component analysis. Several medical marihuana varieties were found to significantly differ from seized cannabis, mostly regarding contents of tetrahydocannabinolic acid A and tetrahydrocannabivarinic acid and cannabidiolic and cannabidivarinic acid respectively.

Simultaneous quantification of 18 different phytocannabinoids in serum using a highly sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method.

The potential therapeutic effects of various phytocannabinoids and the availability of multiple cannabis-based medicines make it desirable to have an analytical method that simultaneously quantifies a wide range of cannabinoids in blood, beyond delta-9-tetrahydrocannabinol and its metabolites. A liquid chromatography tandem mass spectrometry (LC-MS/MS) method for quantification of 18 phytocannabinoids and cannabinoid metabolites in serum was developed and validated. The method enables simultaneous detection of delta-9-tetrahydrocannabinol, cannabidiol, cannabinol, cannabigerol, cannabichromene, cannabicyclol, tetrahydrocannabivarin and cannabidivarin and their acidic precursors tetrahydocannabinolic acid A, cannabidiolic acid, cannabinolic acid, cannabigerolic acid, cannabichromenic acid, cannabicyclolic acid, tetrahydrocannabivarinic acid and cannabidivarinic acid as well as the delta-9-tetrahydrocannabinol metabolites 11-hydroxy-tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol. Limits of detection ranged from 0.0004 to 1 ng/mL and limits of quantification ranged from 0.004 to 2 ng/mL. Calibration curves of all analytes were linear over the whole calibration range. Recovery rates of 52 to 86% were obtained for all analytes except for cannabicyclol (49%), 11-nor-9-carboxy-tetrahydrocannabinol (46%), cannabichromenic acid (44%) and cannabidivarinic acid (36%). Acceptable bias and precision data were demonstrated for all analytes. The method was successfully applied to 55 forensic serum samples, obtained from the Institute of Legal Medicine Mainz.

High dose methotrexate treatment in childhood ALL: pilot study on the impact of the MTHFR 677C>T and 1298A>C polymorphisms on MTX-related toxicity.

Methotrexate (MTX) is commonly administered in high doses for treatment of childhood acute lymphoblastic leukemia (ALL). The aim of this analysis was to study the influence of 2 common MTHFR polymorphisms (MTHFR 677C>T and 1298 A>C) on MTX toxicity in children with ALL.Retrospective analysis of 129 MTX courses in 34 pediatric patients with ALL.677C>T variants (CT or TT) were found in 19 (14 heterozygous, 5 homozygous) and 1298A>C variants (AC or CC) in 20 (16 heterozygous, 4 homozygous) patients. The MTHFR 677C>T wild type was associated with an increased frequency of grade III and IV leukopenia (60% vs. 31%, p<0.05) compared to the variants. The rate of severe infections (21% vs. 0%, p<0.05) and grade III-IV anemia (26% vs. 5%, p<0.05) was increased in carriers of the MTHFR 677C>T wild type compared to patients with the TT variant. Grade III-IV anemia was more frequent in patients with the MTHFR 1298A>C CC variant compared to the wild type (56% vs. 21%, p<0.05). The differences were not significant in a patient-based analysis.MTX related toxicity might be influenced by the MTHFR 677C>T or the MTHFR 1298A>C polymorphisms. Differences in MTX toxicity are only partially explainable by these 2 polymorphisms.

Leukapheresis and exchange transfusion in children with acute leukemia and hyperleukocytosis. A single center experience.

BACKGROUND: The risk of severe complications or death during the initial period of acute leukemia was markedly decreased due to the progress in pediatric oncology and use of simple measures like hyperhydration, forced diuresis, treatment of hyperuricemia, correction of electrolyte and coagulation disturbances and the careful use of antileukemic drugs. The incidence of leukostasis and tumor lysis syndrome depends on absolute initial white blood cell counts and the underlying type of leukemia. Leukapheresis or exchange transfusion may improve the prognosis of high risk patients. METHODS: Records of all pediatric patients who were newly diagnosed with acute leukemia between 1 / 1998 und 12 / 2008 were retrospectively reviewed for presence of hyperleukocytosis(white blood cell count > 100 GPT / l) at diagnosis and subsequent leukapheresis or exchange transfusion in regards to the clinical outcome. RESULTS: At diagnosis 11 (14 % ) of 77 children with acute leukemia (7 acute lymphoblastic leukemia / ALL; 4 acute myeloblastic leukemia /AML) had hyperleukocytosis. 4 patients (2 ALL, 2 AML) received exchange transfusion and 2 others (1 ALL, 1 AML) underwent leukapheresis. Marked cytoreduction was achieved in all patients within 24 h after therapy initiation. There were no procedure-related adverse events. Symptoms due to hyperleukocytosis markedly improved after cytoreduction. CONCLUSION: Leukapheresis or exchange transfusion together with conservative management and specific oncological therapy may contribute to rapid leukocyte reduction with acceptable risk. The exact impact of leukapheresis or exchange transfusion on short and long term outcome in pediatric patients with acute leukemia and initial hyperleukocytosis has to be evaluated in future multicentre studies or by the formation of clinical registries.

Calculation of the persistence length of a flexible polymer chain with short-range self-repulsion.

For a self-repelling polymer chain consisting of n segments we calculate the persistence length L (j,n), defined as the projection of the end-to-end vector on the direction of the j-th segment. This quantity shows some pronounced variation along the chain. Using the renormalization group and epsilon-expansion we establish the scaling form and calculate the scaling function to order epsilon 2. Asymptotically, the simple result L (j,n) approximately const [j(n-j)/n]2nu-1 emerges for dimension d = 3. Also away from the excluded-volume limit L (j,n) is found to behave very similar to the swelling factor of a chain of length j (n-j)/n. We carry through simulations which are found to be in good accord with our analytical results. For d = 2 both our and previous simulations as well as theoretical arguments suggest the existence of logarithmic anomalies.

[Compartment syndrome of the triceps brachii muscle after intramedullary nailing]. / Kompartmentsyndrom des M. triceps brachii nach Marknagelung.

We report a case of a humerus fracture with rare acute compartment syndrome of the triceps muscle after intramedullary nailing. Clinical (neurological) symptoms and measuring of the subfascial pressure of both triceps lead to early diagnosis. After immediate dermatofasciotomy we obtained full recovery of the radial nerve function.

2-(fluorine-18)fluoro-2-deoxy-D-glucose positron emission tomography in the detection and staging of malignant lymphoma. A bicenter trial.

BACKGROUND: The authors undertook a prospective evaluation of the clinical value of 2-fluoro [18-]-2-deoxyglucose positron emission tomography (FDG-PET) in the detection and staging of malignant lymphoma compared with computed tomography (CT) and bone marrow biopsy (BMB). METHODS: Fifty-two consecutive patients with untreated malignant lymphoma were evaluated prospectively in a bicenter study. FDG-PET, CT, and BMB were performed for investigating lymph node/extranodal manifestations and bone marrow infiltration. Thirty-three percnt of the discrepant results were verified by biopsy, magnetic resonance imaging, or clinical follow-up (range, 4-24 month). RESULTS: Altogether, 1297 anatomic regions (lymph nodes, organs, and bone marrow) were evaluated. FDG-PET and CT scans were compared by receiver operating characteristic (ROC) curve analysis. The area under the ROC curve were as follows: lymph nodes, 0.996 (PET) and 0.916 (CT); extranodal, 0.999 (PET) and 0.916 (CT); supradiaphragmatic, 0.996 (PET) and 0.905 (CT); and infradiaphragmatic, 0.999 (PET) and 0.952 (CT). In these analyses, FDG-PET was significantly superior to CT (P < 0.05), except in infradiaphragmatic regions, in which the two methods produced equivalent results. In detecting bone marrow infiltration, FDG-PET was superior to CT and was equivalent to BMB. In 4 of 52 patients (8%), FDG-PET led to an upstaging and a change of therapy. CONCLUSIONS: Noninvasive FDG-PET is very accurate in the staging of malignant lymphoma. Compared with standard staging modalities (CT and BMB), PET was significantly superior and led to changes in the therapy regimen for 8% of patients.

Early detection and accurate description of extent of metastatic bone disease in breast cancer with fluoride ion and positron emission tomography.

PURPOSE: Previous studies have shown that bone metastases are revealed by magnetic resonance imaging (MRI) or bone marrow scintigraphy several months before they are visible by conventional bone scintigraphy (BS). We present a new approach for detecting bone metastases in patients with breast cancer. We compared findings obtained with fluoride ion (F-18) and positron emission tomography (PET) with those obtained with conventional BS. PATIENTS AND METHODS: Thirty-four breast cancer patients were prospectively examined using F-18-PET and conventional BS. F-18-PET and BS were performed within 3 weeks of each other. Metastatic bone disease was previously known to be present in six patients and was suspected (bone pain or increasing levels of tumor markers, Ca(2+), alkaline phosphatase) in 28 patients. Both imaging modalities were compared by patient-by-patient analysis and lesion-by-lesion analysis, using a five-point scale for receiver operating characteristic (ROC) curve analysis. A panel of reference methods was used, including MRI (28 patients), planar x-ray (17 patients), and spiral computed tomography (four patients). RESULTS: With F-18-PET, 64 bone metastases were detected in 17 patients. Only 29 metastases were detected in 11 patients with BS. As a result of F-18-PET imaging, clinical management was changed in four patients (11.7%). For F-18-PET, the area under the ROC curve was 0.99 on a lesion basis (for BS, it was 0.74; P <.05) and 1.00 on a patient basis (for BS, it was 0.82; P <.05). CONCLUSION: F-18-PET demonstrates a very early bone reaction when small bone marrow metastases are present, allowing accurate detection of breast cancer bone metastases. This accurate detection has a significant effect on clinical management, compared with the effect on management brought about by detection with conventional BS.

Positron emission tomography with 18-fluorodeoxyglucose in the staging and follow-up of lymphoma in the chest.

The purpose of this retrospective study was to evaluate the accuracy of positron emission tomography (PET) using 18-F-fluorodeoxyglucose (FDG) in predicting lymphomatous involvement in the hilar and mediastinal regions in the staging and follow-up of patients with malignant lymphoma. One hundred forty-seven thoracic PET studies in 89 consecutive lymphoma patients were reviewed. Static FDG-PET imaging was performed following application of 270 MBq FDG (mean). Results of FDG-PET were compared with the findings of computed tomography (CT) in all patients and clinical follow-up examination. Eighty-nine of 147 (60%) PET studies showed no FDG uptake in the hilar or mediastinal regions, while 58 (40%) studies did detect FDG uptake in these regions. In 52 of 58 abnormal studies (90%), lymphomatous involvement of the hilar and/or mediastinal regions seen by CT was present. In the remaining six abnormal PET studies (10%), FDG uptake was considered as false-positive because of missing lesions on corresponding CT scans. In four patients false-positive FDG uptake was observed before treatment, in two patients after completion of therapy. In these two patients FDG uptake after therapy was caused by thymus hyperplasia. The remaining four cases before treatment remained unresolved. Sensitivity of FDG-PET was 96%, specificity 94%, positive predictive value 90%, and negative predictive value 98%, respectively. The present study suggests that FDG-PET has potential value in predicting lymphomatous involvement in the hilar and mediastinal regions. FDG-PET may obviate invasive diagnostic procedures in patients with lymphoma.

Sensitivity in detecting osseous lesions depends on anatomic localization: planar bone scintigraphy versus 18F PET.

UNLABELLED: Radionuclide bone scanning (RNB) is considered to be the most practical screening technique for assessing the entire skeleton for skeletal metastases. However, RNB has been shown to be of lower sensitivity than MRI and CT in detecting osteolytic metastases. A prospective study was designed to evaluate the accuracy of planar RNB versus tomographic bone imaging with 18F-labeled NaF and PET (18F PET) in detecting osteolytic and osteoblastic metastases and its dependency on their anatomic localization. METHODS: Forty-four patients with known prostate, lung or thyroid carcinoma were examined with both planar RNB and 18F PET. A panel of reference methods including MRI of the spine, 1311 scintigraphy, conventional radiography and spiral CT was used as the gold standard. RNB and 18F PET were compared by a lesion-by-lesion analysis using a five-point score for receiver operating characteristic (ROC) curve analysis. RESULTS: 18F PET showed 96 metastases (67 of prostate carcinoma and 29 of lung or thyroid cancer), whereas RNB revealed 46 metastases (33 of prostate carcinoma and 13 of lung or thyroid cancer). All lesions found with RNB were also detected with 18F PET. Compared with 18F PET and the reference methods, RNB had a sensitivity of 82.8% in detecting malignant and benign osseous lesions in the skull, thorax and extremities and a sensitivity of 40% in the spine and pelvis. The area under the ROC curve was 0.99 for 18F PET and 0.64 for RNB. CONCLUSION: 18F PET is more sensitive than RNB in detecting osseous lesions. With RNB, sensitivity in detecting osseous metastases is highly dependent on anatomic localization of these lesions, whereas detection rates of osteoblastic and osteolytic metastases are similar. Higher detection rates and more accurate differentiation between benign and malignant lesions with 18F PET suggest the use of 18F PET when possible.

[F-18-FDG PET for primary diagnosis differential diagnosis of pleural processes]. / F-18-FDG-PET zur Primärdiagnostik und Dignitätsbeurteilung pleuraler Prozesse.

PURPOSE: Positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) has been shown to be accurate for differentiating benign from malignant pulmonary lesions. Therefore, we evaluated the capability of FDG-PET in the characterisation of pleural lesions. PATIENTS AND METHODS: PET was performed in thirteen patients with pleural or intrapulmonal tumors (three with additional pleural effusion) and in three patients with aetiologically unclear pleural effusion demonstrated by CT. In all cases the diagnosis was confirmed histologically. The PET-imaging was carried out in fasted patients 50 minutes after injection of 400-670 MBq F-18-FDG without attenuation correction. RESULTS: Twelve patients were found to have pleural or pulmonal malignomas (9 pleural mesotheliomas, 3 bronchogenic adenocarcinoma with carcinomatous pleurisy). Four patients had benign pleural changes (1 fibroma, 1 tuberculous pleurisy, 1 pleural fibrosis, 1 empyema). With FDG-PET, all 12 pleural or intrapulmonal malignomas had high FDG-uptake and were classified correctly. Due to very low or virtually deficient FDG-uptake, four histologically benign lesions were correctly interpreted as nonmalignant. CONCLUSION: These preliminary results suggest that FDG-PET is accurate in detecting malignant pleural tumors.

Whole-body 2-[18F]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) for accurate staging of Hodgkin's disease.

BACKGROUND: Staging of Hodgkin's disease (HD) is accomplished by a variety of invasive and non-invasive modalities. This prospective study was undertaken to investigate the value of whole-body positron emission tomography (PET) with 2-[18F]-fluoro-2-deoxy-D-glucose (FDG) in defining regions involved by lymphoma compared with conventional staging methods in patients with HD. PATIENTS AND METHODS: Fourty-four newly diagnosed patients with HD underwent FDG-PET as part of their initial staging work-up. PET findings were correlated with findings of conventional staging including computed tomography, ultrasound, bone scanning, bone marrow biopsy, liver biopsy and laparotomy. When results of FDG-PET differed to those obtained by conventional methods reevaluation was performed by biopsy, if possible, or magnetic resonance imaging. RESULTS: The results of FDG-PET were compared with three hundred twenty-one conventional staging procedures performed in 44 patients. FDG-PET was positive in 38 of 44 (86%) patients at sites of documented disease. PET detected additional lesions in five cases previously not identified by conventional staging methods. In another case a nodal lesion suspect on CT was negative at FDG-PET and was settled as true negative by biopsy. As a consequence of PET findings five patients had to be upstaged and one patient had to be downstaged, resulting in changes in treatment strategy in all six cases (14%). FDG-PET failed to visualize sites of HD in four patients. In two of our patients a false positive PET result was obtained. CONCLUSIONS: Our data indicate that FDG-PET provides an imaging technique that appears to visualize involved lesions in most patients with HD and is useful in the management of these patients.

[A new method in the determination of individual delay time in bolus application in spiral CT]. / Neues Verfahren zur Bestimmung der individuellen Verzögerungszeit für die Bolusapplikation im Spiral-CT.

Helical-CT examinations, particularly CT angiography, require precise timing between the examination procedure and the individual dynamics of contrast medium distribution in the arteriovenous system of the patient. The necessary delay between contrast medium injection and onset of has usually been either estimated or determined by means of an additional helical CT examination. The present paper introduces a new technique which allows bolus analysis without an additional scan. Prior to a CT angiography with 10 patients, two techniques for bolus analysis (BA) were compared. Prior to diagnostic contrast medium enhanced examination, a native (BA I) and a dynamic (BA II) examination were performed. Ten seconds prior to the start of each examination, a 10 ml test bolus was applied with an injection flow rate of 3 ml/s. Both examinations lasted for 30 s. During BA I, increase in attenuation in the aorta was compared at different sites, during BA II consistently at the same site. Comparison of the individual peak times yielded a coefficient of correlation of r = 0.926. The median value for BA I was 18.4 +/- 5.4 s and 19.2 +/- 4.5 s for BA II. The difference between measurement of peak time was 1.2 +/- 1.16 s. This modified technique for bolus analysis during the primary native scan of the upper abdominal organs permits calculation of the required individual delay time between contrast medium application and scan start: no additional examination is required and the method can be performed with any helical CT unit.

[Magnetic resonance tomography study of ankle joint fractures. A prospective pathologic-anatomic study]. / Kernspintomographische Untersuchung von Sprunggelenkfrakturen. Eine prospektive pathologisch-anatomische Studie.

The imaging findings in 21 patients with ankle fractures were evaluated prospectively to determine the value of MRI in diagnostics of bone, cartilage, ligament and soft tissue lesions. A total of 17 female and 4 male patients aged from 25 to 60 years (mean age 50 years) underwent an MRI examination 2-14 h after trauma. Axial, sagittal and coronal T1-weighted SE and T2-weighted GE images were performed using an extremity coil. We found 2 type A (A 1.2 and A 1.3), 17 type B (3 B 1.1, 3 B 2.1 3 B 2.2, 1 B 2.3, 5 B 3.2 and 2 B 3.3) and 2 type C (C 1.1) fractures. MRI was capable of detecting bone fractures not visible in a conventional X-ray, cartilaginous damage, ligamentous injury and subtle soft tissue lesions. We conclude that the coronal and axial planes are essential for optimal visualization of the major ligaments. The injury patterns found in this examination are identical to those described by Weber. MRI appears to be a useful examination method in special cases, but it is not a suitable screening method because of the high costs and time required.