Perfusion-metabolism coupling in recurrent gliomas: a prospective validation study with 13N-ammonia and 18F-fluorodeoxyglucose PET/CT

Introduction

We assessed the validity of “perfusion-metabolism coupling” hypothesis in recurrent glioma with ¹³N-ammonia (¹³N-NH₃) PET/CT and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) PET/CT.

Methods

Fifty-six consecutive patients (age, 38.8?±?12.1 years; 62.5 % males) with histologically proven and previously treated glioma presenting with clinical suspicion of recurrence were prospectively enrolled and evaluated with ¹³N-NH₃ PET/CT and ¹⁸F-FDG PET/CT. PET/CT images were evaluated both qualitatively and semiquantitatively. Tumor to white matter uptake ratio (T/W) and tumor to gray matter uptake ratio (T/G) were calculated and analyzed for both the modalities. A combination of clinico-radiological follow-up, repeated imaging, and biopsy (when available) were considered as the reference standard.

Results

Based on the reference standard, 27/56 patients had recurrence. ¹³N-NH₃ PET/CT and ¹⁸F-FDG PET/CT were concordant in 55/56 patients. Overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of ¹³N-NH₃PET/CT were 77.8, 86.2, 84.0, 80.7, and 82.1 %, respectively, and for ¹⁸F-FDG PET/CT were 77.8, 89.7, 87.5, 81.2, and 83.9 %, respectively. There was excellent agreement between results of ¹³N-NH₃ PET/CT and ¹⁸F-FDG PET/CT (??=?0.964; P?13N-NH₃ PET/CT and ¹⁸F-FDG PET/CT were not significantly different between high-grade and low-grade glioma (P?=?1.000). A strong positive correlation was noted between the uptake ratios derived on the two modalities (ρ?=?0.866, P?ρ?=?0.918, P?Conclusion A combination of ¹³N-NH₃ PET/CT and ¹⁸F-FDG PET/CT demonstrates that perfusion and metabolism are coupled in recurrent gliomas. These tracers target two different but interrelated aspects of the same pathologic process and can be used as surrogates for each other.     

Dosage regimens of intranasal aerosolized surfactant on otitis media with effusion in an animal model.

OBJECTIVE: To determine optimal dosage regimens of intranasal metered dose aerosolized surfactant with and without other medications in the treatment of otitis media with effusion (OME). STUDY DESIGN: Resolution of experimental OME in gerbils was determined based on otomicroscopy and tympanometry. Experimental intranasal drugs were: surfactant, surfactant with betamethasone, surfactant with phenylephrine, and a normal saline solution placebo. Medications were administered once or twice daily via a metered dose inhaler. RESULTS: For twice-daily dosing, mean days to OME resolution were 8.5 for the aerosolized surfactant, 6.3 for the surfactant with betamethasone, 18.7 for the surfactant with phenylephrine, and 16 each for control and placebo. Resolution with the once-daily dosage was longer for all conditions. Results were comparable using tympanometry. CONCLUSION: OME resolved faster than the natural course when treated with intranasal surfactant with and without steroids. Twice-daily dosing was statistically superior. SIGNIFICANCE: This study reiterates the effectiveness of OME treatment with an aerosolized synthetic surfactant with and without steroids and establishes a superior twice-daily dosage schedule.     

Intranasal phenylephrine-surfactant treatment is not beneficial in otitis media with effusion

BACKGROUND: Otitis media is the most common reason for non-well-child visits to the primary care physician. Various treatments are in use to try to ameliorate the pain arising from Eustachian tube (ET) dysfunction. One such treatment is topical phenylephrine spray, despite clinical evidence disputing its use. Previous research by this laboratory has demonstrated the beneficial effect of topical surfactant treatment in reducing ET opening pressure, allowing the tube to open. This study is designed to test the effectiveness of topical phenylephrine, delivered with surfactant, in reducing days of effusion in OME, in an animal model. METHODS: OME was generated by injecting Klebsiella pneumoniae lipopolysaccharide into the right bullae of 28 gerbils. After frank OME resulted, the animals were divided into four groups. Group 1 received no treatment or propellant spray alone (placebo). Group 2 received intranasal surfactant spray once daily. Group 3 received intranasal surfactant-phenylephrine spray once daily. Group 4 received intranasal surfactant-phenylephrine spray twice daily. All animals were evaluated on a daily basis by both otomicroscopy and tympanometry, and treatment was ceased when the ear returned to normal appearance. Evaluations were continued for a total of 30 days. Chi-squared analysis with significance set at .05 was performed. RESULTS: In the untreated and placebo groups, middle ear effusion resolved at 16.25 days by otomicroscopy and 28.26 days by tympanometry. In Group 2 (surfactant alone), effusion resolved at 10.57 days and 15.71 days, respectively. In Group 3 (surfactant-phenylephrine once daily), effusion resolved at 15.67 days and 28.33 days. In Group 4 (surfactant-phenylephrine twice daily), effusion resolved at 18.67 days and 28.33 days. These results were statistically significant. CONCLUSIONS: Intranasal phenylephrine-surfactant treatment is shown to be at least ineffective, and possibly detrimental, in the resolution of OME, in this animal model. The hypothesis is that surfactant potentiates the drying effect of phenylephrine at the ET by allowing it to get to the ET more easily; in addition, the drying effect of phenylephrine prevents full surfactant action. We believe that these results can be extrapolated to humans and that phenylephrine should be avoided in these cases.     

A Novel Approach to Testing for Average Bioequivalence Based on Modeling the Within-Period Dependence Structure

Bioequivalence trials are commonly conducted to assess therapeutic equivalence between a generic and an innovator brand formulations. In such trials, drug concentrations are obtained repeatedly over time and are summarized using a metric such as the area under the concentration vs. time curve (AUC) for each subject. The usual practice is to then conduct two one-sided tests using these areas to evaluate for average bioequivalence. A major disadvantage of this approach is the loss of information encountered when ignoring the correlation structure between repeated measurements in the computation of areas. In this article, we propose a general linear model approach that incorporates the within-subject covariance structure for making inferences on mean areas. The model-based method can be seen to arise naturally from the reparameterization of the AUC as a linear combination of outcome means. We investigate and compare the inferential properties of our proposed method with the traditional two one-sided tests approach using Monte Carlo simulation studies. We also examine the properties of the method in the event of missing data. Simulations show that the proposed approach is a cost-effective, viable alternative to the traditional method with superior inferential properties. Inferential advantages are particularly apparent in the presence of missing data. To illustrate our approach, a real working example from an asthma study is utilized.     

Isolated cardiac metastasis in a patient with neuroendocrine carcinoma of pancreas discovered on 68Ga-DOTANOC PET/CT

We present an interesting image that demonstrates utility of ⁶⁸Ga-DOTANOC PET/CT for demonstrating rare metastatic sites of neuroendocrime tumor.     

ClCATRlCAL GASTRIC STENOSIS CAUSED BY CORROSIVE INGESTION

Sixteen patients with gastric cicatrization due to ingestion of corrosive agents were treated over a 7 year period at Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) Hospital, Pondicheny. Fifteen patients developed gastric outlet obstruction due to ingestion of corrosives, while another had midgas-tric stenosis due to formalin intake. An asSociated oesophageal stricture was present in 62.5% of the cases. Partial gastrectomy was found to be the most satisfactory procedure and carried out in 60% of the cases. Pyloroplasty done in one patient was found inadequate within 1 year of surgery. Gastrojejunostomy carried out in two patients was asSociated with prolonged hospitalization due to malfunction of the anastomotic site.     

Cicatrical gastric stenosis caused by corrosive ingestion

Sixteen patients with gastric cicatrization due to ingestion of corrosive agents were treated over a 7 year period at Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) Hospital, Pondicherry. Fifteen patients developed gastric outlet obstruction due to ingestion of corrosives, while another had midgastric stenosis due to formalin intake. An associated oesophageal stricture was present in 62.5% of the cases. Partial gastrectomy was found to be the most satisfactory procedure and carried out in 60% of the cases. Pyloroplasty done in one patient was found inadequate within 1 year of surgery. Gastrojejunostomy carried out in two patients was associated with prolonged hospitalization due to malfunction of the anastomotic site.     

Time-dependent changes in biochemical bone markers and serum cholesterol in ovariectomized rats: Effects of raloxifene HCl, tamoxifen, estrogen, and alendronate

Bone loss associated with postmenopausal osteoporosis can be reduced by treatment with antiresorptive agents such as estrogen or bisphosphonates. Whereas bisphosphonates primarily affect bone loss, estrogens have an advantage of also lowering serum cholesterol levels, although they have a detrimental effect in the uterus. Recently, raloxifene HCl, a selective estrogen receptor modulator (SERM), has been shown to decrease both bone loss and cholesterol levels without the negative uterine effects. These antiresorptive agents reduce bone turnover, which can be evaluated by measuring bone turnover markers. To compare the effects of estrogen, two SERMs (raloxifene HCl and tamoxifen), and alendronate, a bisphosphonate that inhibits bone loss by an estrogen-independent pathway, on metabolic bone markers and cholesterol levels, rats were ovariectomized 2 weeks prior to 3 weeks of daily oral treatment with raloxifene HCl (3 mg/kg), ethynyl estradiol (0.1 mg/kg), tamoxifen (3 mg/kg), or alendronate (3 mg/kg). Raloxifene HCl, tamoxifen, and ethynyl estradiol reduced serum cholesterol to levels below control values within 4 days after initiation of treatment, whereas alendronate had no effect. After 3 weeks of treatment, serum cholesterol values in ethynyl estradiol treated animals, although still below the control value, had risen 6.4-fold; raloxifene HCl and tamoxifen values rose by only 1.4–1.5-fold. Therefore, compared with estrogen, SERMs may have a longer-term suppressive effect on serum cholesterol. At 4 days of treatment, ovariectomized rats had a 1.4-fold increase in serum osteocalcin level compared with controls. Ethynyl estradiol lowered this level within 1 week of treatment by 18%, with a more pronounced reduction of 34% at 3 weeks. In contrast, raloxifene HCl, tamoxifen, or alendronate had very little effect after the first week (6% to 13% reduction), although there was an 18% to 25% reduction by 3 weeks. Urinary pyridinoline levels, elevated 1.4-fold in the ovariectomized rat compared with controls 2 weeks after surgery, were reduced to control values after 2 weeks of treatment with raloxifene HCl, ethynyl estradiol, tamoxifen, or alendronate. These data support the concept that estrogen, raloxifene HCI, tamoxifen, and alendronate inhibit bone loss in the ovariectomized animal by reducing bone resorption. The results also indicate that for treatment of postmenopausal osteoporosis, raloxifene HCl may have an advantage over the other antiresorptives studied in having both non-uterotrophic and hypocholesterolemic effects in addition to its ability to inhibit bone resorption.     

Hematopoietic factor-induced synthesis of von Willebrand factor by the Dami human megakaryoblastic cell line and by normal human megakaryocytes

Identification of hemopoietic factors and the molecular mechanisms by which they regulate the various stages of megakaryocyte development and platelet protein expression has been hampered by the lack of a purified, self-renewing, and responsive biological assay system. Previously, the human megakaryocytic Dami cell line has been shown to differentiate in response to phorbol ester by increasing the expression of platelet membrane glycoproteins Ib, IIb/IIIa, and the platelet protein, von Willebrand Factor (vWF). In this report, we demonstrate that this cell line is a suitable model for investigating the effects of specific cytokines and hemopoietic factors on the terminal differentiation of megakaryocytes as measured by the stimulated biosynthesis of vWF in serum-free culture. Although a low concentration (10 U/ml) of purified recombinant interleukin 3 (IL-3) had no effect, a higher concentration (100 U/ml) stimulated a three- to four fold increase in vWF synthesis. Purified thrombopoiesis-stimulating factor (TSF) alone induced a two- to threefold increase, and when used in combination with 10 U/ml IL-3, TSF induced a synergistic five- to sixfold increase in vWF synthesis. Recombinant erythropoietin (EPO) and human interleukin 6 (IL-6) each induced a twofold increase in vWF, and each acted additively with 10 U/ml IL-3. IL-3 and TSF stimulated similar increases in vWF expression by human megakaryocytes contained in nonadherent bone marrow preparations. These results demonstrate the usefulness of the Dami cell line as a serum-free culture system in which to study the direct effects of purified humoral factors on megakaryocyte and platelet protein synthesis during megakaryocyte maturation.     

Calcification of ulnar nerve in a patient with tuberculoid leprosy--a case report

A case of Tuberculoid Leprosy who showed Evidence of Calcification of Right Ulnar Nerve at Elbow on Radiological Examination is reported.