Pharmacological properties of fluphenazine-mustard, an irreversible calmodulin antagonist

We describe an improved synthesis and properties of fluphenazine-mustard, a potent phenothiazine having an alkylating chlorethylamine chain in its structure. The drug possesses anticalmodulin activity equivalent to the parent compound, but unlike fluphenazine dihydrochloride, the mustard derivative irreversibly antagonizes the ability of calmodulin to activate cyclic nucleotide phosphodiesterase. This property is partially calcium-dependent and can be overcome by coincubation with excess fluphenazine dihydrochloride. The compound irreversibly inactivated calmodulin when incubated with intact cells and caused single-stranded breakage of DNA. Fluphenazine-mustard possesses potent antiproliferative and cytotoxic properties against malignant cell lines that are likely to be mediated through both of these actions.     

Isolated Castleman disease of the neck: MR findings.

Castleman disease in an 11-year-old girl appeared as a neck mass that grew despite antibiotic treatment. MR showed a well-defined solid mass, isointense with muscle on short-repetition-time/short-echo-time images, with a stellate area of central hypointensity on long-repetition-time/long-echo-time images, that did not enhance with gadolinium.     

Overexpression/amplification of HER-2/neu is uncommon in hepatocellular carcinoma

BACKGROUND： Hepatocellular carcinoma （HCC） is one of the most prevalent fatal cancers in the world. Despite advances in early diagnosis and improvements in surgical techniques, the survival of patients with HCC even after resection is poor because of the high incidence of recurrences. Therefore, the identification of prognostic factors may be helpful in the development of new treatment protocols. AIMS： To investigate HER-2/neu status in HCC by immunohistochemistry （IHC） and fluorescence in situ hybridisation （FISH）, and to explore the possibility of using trastuzumab in the treatment of HCC. METH ODS： Eight hundred and sixty eight surgical samples from patients with primary HCC were examined for their HER-2/neu status. IHC for HER-2/neu was performed with the HercepTest kit; FISH analysis was performed with the PathVysion HER-2 DNA probe kit. The correlations between HER-2/neu overexpression and clinicopathological characteristics were analysed statistically. RESULTS： HER-2/neu overexpression was detected in 21 （2.42%） of the 868 primary HCCs. Only one specimen showed HER-2/neu gene amplification by FISH. No significant associations were found between HER-2/neu overexpression and the clinicopathological parameters. CONCLUSIONS： There is a low frequency of HER-2/neu overexpression/amplification in HCC. There appears to be no role for HER-2/neu as a prognostic marker and no benefit of anti-HER-2/neu trastuzumab treatment in patients with HCC.     

Role of protein kinase C in the modulation of multidrug resistance: expression of the atypical gamma isoform of protein kinase C does not confer increased resistance to doxorubicin.

Cross-resistance to anticancer drugs, termed multidrug resistance (MDR), is functionally associated with the expression of a plasma membrane, energy-dependent, drug efflux pump termed P-glycoprotein (PGP), the product of the mdr1 gene. We have shown previously that MCF-7 breast carcinoma cells transfected with the human mdr1 gene (BC-19 cells) exhibit greater MDR when stably transfected with protein kinase C alpha (PKC alpha). We now demonstrate that transfection of BC-19 cells with the gamma isoform of PKC (BC-19/PKC gamma cells), which is not normally present in BC-19 cells, does not confer increased resistance to doxorubicin, despite a 19-fold increase in PKC activity. All of the increased PKC activity is accounted for by PKC gamma and it is rapidly down-regulated by phorbol dibutyrate, within 15 min of treatment. Endogenous PKC alpha and PKC epsilon activities are not affected by phorbol dibutyrate. The cytotoxicity of doxorubicin was similar in BC-19/neo or BC-19/PKC gamma cells after either 2-hr or continuous drug exposure, and co-treatment with phorbol dibutyrate increased resistance to doxorubicin 4-fold in both cell lines. Phosphorylation of PGP was similar in both cell lines and drug accumulation was not affected by overexpression of PKC gamma. These results demonstrate that transfection of PGP-expressing cells with an atypical isoform of PKC does not confer increased MDR, and they suggest that the regulation of PGP is phenotype specific with respect to the isoform of PKC.     

Diastematomyelia presenting as progressive weakness in an adult after spinal fusion for adolescent idiopathic scoliosis.

BACKGROUND CONTEXT: Diastematomyelia is uncommon and rarely presents in adulthood. This report draws attention to the fact that patients who underwent spinal fusion for deformity before the widespread use of computed tomography (CT) and magnetic resonance imaging (MRI) may have unrecognized spinal cord abnormalities. This should be considered if revision surgery is contemplated. PURPOSE: This case report focuses on the late presentation of lower-extremity weakness in a 44-year-old woman with a split cord malformation (diplomyelia), diastematomyelia and tethered cord syndrome. STUDY DESIGN/SETTING: METHODS: The patient underwent instrumented posterior spinal fusion with a Harrington rod as a child for progressive thoracolumbar scoliosis. As an adult, she developed paraparesis after a traumatic event.The patient underwent decompressive laminectomy, subtotal resection of the old fusion mass and resection of the osseous septum. Postoperatively, an anterior spinal fluid leak in the lower thoracic region required repeated fascial grafting, resection of a pseudomeningocele and reverse left latissimus dorsi flap transfer. The leak was controlled, and the patient had near complete resolution of her paraparesis 1 year after her surgery. RESULTS: The case described herein is unusual in that patients with diplomyelia and diastematomyelia rarely are symptomatic in adulthood. However, trauma may precipitate the onset of neurologic symptoms. This patient underwent spinal surgeries to address deformity, pain and progressive lower-extremity weakness. Preoperative CT and MRI studies showed a split cord malformation and diastematomyelia at L1-L2 with spinal stenosis and tethering of both hemicords. CONCLUSIONS: Progressive weakness without any previous neurologic deficit or neurocutaneous stigmas of an underlying spinal cord abnormality may develop in the adult with unrecognized diastemotomyelia. This case demonstrates that a thorough preoperative workup of patients with complex spinal deformities is imperative.     

Adrenal magnetic resonance imaging in addison’s disease

Magnetic resonance imaging of the adrenal glands was performed in 9 patients with Addison’s disease to evaluate the role of magnetic resonance (MR) in this entity. All patients had bilateral adrenal masses demonstrated by computed tomography (CT); etiologies included adrenal hemorrhage (2 patients), granulomatous disease (1 patient), adrenal lymphoma (3 patients), and adrenal metastases (3 patients). Spin-echo axial images were obtained at repetition times (TR) 0.5, 2.0 s and TE 28, 56 ms, using a Diasonics superconducting magnet operating at 0.35 T. In the patients with lymphoma, metastases, and granulomatous disease, the adrenal masses appeared hypointense or isointense with liver on the T₁-weighted images (TR 0.5 s, TE 28 ms). In cases of adrenal hemorrhage, areas of hyperintensity were seen on TR 0.5, TE 56 ms sequences, due to shortening of T₁ values. In both groups of patients the masses were hyperintense on T₂ weighted sequences. Mean calculated T₁ of the hemorrhagic glands was 449 ms, compared with a mean of 782 ms for mestastases and lymphoma. While MR is not capable of distinguishing between acute inflammatory and metastatic disases of the adrenal glands, it may be equally efficacious as CT in suggesting the diagnosis of adrenal hemorrhage in patients with Addison’s disease.