Partially successful treatment of a patient with chronic lymphocytic leukemia and Hodgkin's disease: case report and literature review

Chronic lymphocytic leukemia (CLL) is rarely associated with Hodgkin's disease (HD). We report a case of nodular sclerosis HD in a patient previously diagnosed with CLL. Reed-Sternberg cells were CD15(+) and CD30(+). He was treated with dose-escalated CHOP and at relapse, mitoxantrone, vinblastine, and CCNU (MVC) with partial response to the former and complete response to the latter, although the patient died 15 months later. Data from 88 other similar cases published in the English language were analyzed. Based on the histological and clinical features at the time of transformation, these patients were divided into distinct categories for analysis. Prognosis was found to be poorer in patients with continued active CLL when compared with those with CLL in remission at the time of transformation to HD. It is suggested that these two presentations may derive from different pathogenic mechanisms.     

The Impact of Consumer-Directed Health Plans and Patient Socioeconomic Status on Physician Recommendations for Colorectal Cancer Screening

Background  Consumer-directed health plans are increasingly common, yet little is known about their impact on physician decision-making and preventive service use. Objective  To determine how patients’ deductible levels and socioeconomic status may affect primary care physicians’ recommendations for colorectal cancer screening. Design, Setting, and Participants  Screening recommendations were elicited using hypothetical vignettes from a national sample of 1,500 primary care physicians. Physicians were randomized to one of four vignettes describing a patient with either low or high socioeconomic status (SES) and either low- or high-deductible plan. Bivariate and multivariate analyses were used to examine how recommendations varied as a function of SES and deductible. Outcome Measures  Rates of recommendation for home fecal occult blood testing, sigmoidoscopy, colonoscopy, and inappropriate screening, defined as no screening or office-based fecal occult blood testing. Results  A total of 528 (49%) eligible physicians responded. Overall, 7.2% of physicians recommended inappropriate screening; 3.2% of patients with high SES in low-deductible plans received inappropriate screening recommendations and 11.4% of patients with low SES in high-deductible plans for an adjusted odds ratio of 0.22 (0.05–0.89). The odds of a colonoscopy recommendation were over ten times higher (AOR 11.46, 5.26–24.94) for patients with high SES in low-deductible plans compared to patients with low SES in high-deductible plans. Funds in medical savings accounts eliminated differences in inappropriate screening recommendations. Conclusions  Patient SES and deductible-level affect physician recommendations for preventive care. Coverage of preventive services and funds in medical savings accounts may help to mitigate the impact of high-deductibles and SES on inappropriate recommendations. Craig Evan Pollack and Giridhar Mallya: The authors contributed equally to this publication.     

Cell transplantation after oxidative hepatic preconditioning with radiation and ischemia-reperfusion leads to extensive liver repopulation

The inability of transplanted cells to proliferate in the normal liver hampers cell therapy. We considered that oxidative hepatic DNA damage would impair the survival of native cells and promote proliferation in transplanted cells. Dipeptidyl peptidase-deficient F344 rats were preconditioned with whole liver radiation and warm ischemia-reperfusion followed by intrasplenic transplantation of syngeneic F344 rat hepatocytes. The preconditioning was well tolerated, although serum aminotransferase levels rose transiently and hepatic injury was observed histologically, along with decreased catalase activity and 8-hydroxy adducts of guanine, indicating oxidative DNA damage. Transplanted cells did not proliferate in the liver over 3 months in control animals and animals preconditioned with ischemia-reperfusion alone. Animals treated with radiation alone showed some transplanted cell proliferation. In contrast, the liver of animals preconditioned with radiation plus ischemia-reperfusion was replaced virtually completely over 3 months. Transplanted cells integrated in the liver parenchyma and liver architecture were preserved normally. These findings offer a paradigm for repopulating the liver with transplanted cells. Progressive loss of cells experiencing oxidative DNA damage after radiation and ischemia-reperfusion injury could be of significance for epithelial renewal in additional organs.     

Hereditary Cancer Syndromes—A Primer on Diagnosis and Management,Part 2: Gastrointestinal Cancer Syndromes

Hereditary causes due to mutations and defects in certain genes account for roughly 5% to 10% of all colorectal cancers. These inherited syndromes have been associated with a 60% to 100% lifetime risk for development of colorectal cancer, depending on the genetic syndrome, and many also carry an increased risk for multiple extracolonic malignancies. In this second part of a review series on hereditary cancer syndromes, the focus will be to provide guidance on the features and management of the most commonly encountered hereditary colorectal cancers and polyposis conditions including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis, and hamartomatous polyposis.     

Neuroimaging and neurophysiology of periodic lateralized epileptiform discharges: observations and hypotheses

PURPOSE: We assessed neuroimaging lesion type and distribution in patients with periodic lateralized epileptiform discharges (PLEDs), with a view to identifying electrographic differences between PLEDs associated with differing lesion locations. Our observations led us to consider a conceptual synthesis between PLEDs and periodic complexes (PCs). METHODS: Retrospective review of acute neuroimaging results (CT/MRI) on patients identified to have EEG PLEDs, for the period 1999-2003 (n=106). Blinded classification of original EEG recordings. RESULTS: Neuroimaging abnormalities were classified as acute or chronic cortical, or acute or chronic subcortical. Seven out of 106 scans were classified nonlesional. Overall approximately 70% of scans had cortical abnormalities, whether acute or chronic; approximately 23% had subcortical abnormalities. "Cortical" PLEDs were significantly longer in duration (p<0.05) and more variable in morphology (p<0.01) than "subcortical" PLEDs. CONCLUSIONS: Structural brain disease commonly, but not invariably, underlies PLEDs; lesion type is spatiotemporally variable. Cortical and subcortical PLEDs have distinct EEG signatures. There is evidence that these may relate to mechanisms for other pathological large-scale oscillatory brain synchronies (e.g., PCs).     

Bismuth-norfloxacin complex: synthesis, physicochemical and antimicrobial evaluation

Norfloxacin is a fluoroquinolone antibacterial agent which is active against various Gram-positive as well as Gram-negative microorganisms. Presence of metal ions considerably alters the activity of fluoroquinolones against potentially susceptible bacteria. As bismuth is known to possess a good antibacterial activity, bismuth complex of norfloxacin was prepared by reacting bismuth citrate with aqueous solution of norfloxacin. The structure of the bismuth-norfloxacin complex (BNC) was confirmed by spectral, chemical and elemental analysis. Antimicrobial studies were carried out using agar diffusion method against Escherichia coli (ATCC 25922), Klebsiella pneumoniae (NTCC 10320), Staphylococcus aureus (ATCC 29213), Bacillus pumilis (NTCC 8241) and Staphylococcus epidermidis (ATCC 12228). The results showed significant increase (p<0.05, Tukeys test) in antibacterial activity of BNC as compared with norfloxacin and physical mixture of norfloxacin and bismuth citrate. This increase in activity is being considered due to increased bioavailability of the metal drug complex. Thus, the use of the BNC may be preferable over norfloxacin alone.     

Synthesis and Anti‐HIV‐1 Integrase Activitiy of Cyano Pyrimidinones

A series of 2‐phenethyl/benzylthio‐6‐oxo‐4‐phenyl‐1,6‐dihydropyrimidine‐5‐carbonitrile were synthesized and tested against recombinant HIV‐1 integrase in an enzyme assay. 2‐(Phenethylthio)‐4‐(4‐chlorophenyl)‐6‐oxo‐1,6‐dihydropyrimidine‐5‐carbonitrile 4m and 2‐(phenethylthio)‐4‐(3‐chlorophenyl)‐6‐oxo‐1,6‐dihydropyrimidine‐5‐carbonitrile 4o showed significant inhibition against integrase in the assay (strand transfer: IC₅₀ values of 16 and 17 μM, respectively).     

Synthesis, stereoselective enzymatic hydrolysis, and skin permeation of diastereomeric propranolol ester prodrugs

Four diastereomeric propranolol ester prodrugs (1S2S, 1S2R, 1R2S, 1R2R) were synthesized by treating pure R- and S-propranolol hydrochloride with pure enantiomers R- and S-phenylbutyryl chloride. A HPLC technique using alpha-1 acid glycoprotein (chiral AGP) column was developed to study the racemization of propranolol enantiomers during synthesis and hydrolysis studies. A reversed phase HPLC method was also developed to simultaneously analyze propranolol and the ester prodrug. Hydrolysis of these esters was studied in different rat tissue homogenates, i.e., liver, intestine, plasma, skin, brain, and pure plasma cholinesterases, i.e., butyryl cholinesterase (EC 3.1.1.8) and acetyl cholinesterase (EC 3.1.1.7). In vitro percutaneous permeation studies across full thickness shaved rat skin were performed using standard side-by-side diffusion cells at 37 degrees C. The disappearance of the diastereomeric ester prodrugs in rat tissue homogenates followed apparent first-order kinetics and was stereoselective. The ratio of brain to plasma hydrolytic rate constants are 27.8, 5.58, 6.07, and 2.97 for 1S2S, 1R2R, 1R2S, and 1S2R esters, respectively. Hydrolysis of all four diastereomeric ester prodrugs was faster by acetyl cholinesterase than butyryl cholinesterase and is stereoselective. The permeability coefficients [Kp x 10(3) (cm h-1)] are 1.40 +/- 0.30, 1.41 +/- 0.27, 42.20 +/- 1.24, 29.26 +/- 3.41, 16.27 +/- 3.12, 12.99 +/- 2.84 for (R)-propranolol, (S)-propranolol, 1S2S, 1R2S, 1S2R, and 1R2R ester prodrugs, respectively. The results indicate that the 1R2S diastereomeric ester prodrug of propranolol shows greatest stability in liver and intestinal tissues while it exhibits fairly rapid conversion in plasma. The results also suggest the configuration on the second chiral carbon atom to be the determinant in the rate of hydrolysis of all the diastereomeric prodrugs in all biological media examined. The Kp of all four prodrugs markedly increased compared to that of the parent drug, with 1S2S showing a 30-fold increase in skin permeability, the highest among all four prodrugs.     

Triplex DNA-binding proteins are associated with clinical outcomes revealed by proteomic measurements in patients with colorectal cancer

ABSTRACT: BACKGROUND: Tri- and tetra-nucleotide repeats in mammalian genomes can induce formation of alternative non-B DNA structures such as triplexes and guanine (G)-quadruplexes. These structures can induce mutagenesis, chromosomal translocations and genomic instability. We wanted to determine if proteins that bind triplex DNA structures are quantitatively or qualitatively different between colorectal tumor and adjacent normal tissue and if this binding activity correlates with patient clinical characteristics. METHODS: Extracts from 63 human colorectal tumor and adjacent normal tissues were examined by gel shifts (EMSA) for triplex DNA-binding proteins, which were correlated with clinicopathological tumor characteristics using the Mann-Whitney U, Spearman's rho, Kaplan-Meier and Mantel-Cox log-rank tests. Biotinylated triplex DNA and streptavidin agarose affinity binding were used to purify triplex-binding proteins in RKO cells. Western blotting and reverse-phase protein array were used to measure protein expression in tissue extracts. RESULTS: Increased triplex DNA-binding activity in tumor extracts correlated significantly with lymphatic disease, metastasis, and reduced overall survival. We identified three multifunctional splicing factors with biotinylated triplex DNA affinity: U2AF65 in cytoplasmic extracts, and PSF and p54nrb in nuclear extracts. Super-shift EMSA with anti-U2AF65 antibodies produced a shifted band of the major EMSA H3 complex, identifying U2AF65 as the protein present in the major EMSA band. U2AF65 expression correlated significantly with EMSA H3 values in all extracts and was higher in extracts from Stage III/IV vs. Stage I/II colon tumors (p = 0.024). EMSA H3 values and U2AF65 expression also correlated significantly with GSK3 beta, beta-catenin, and NF- B p65 expression, whereas p54nrb and PSF expression correlated with c-Myc, cyclin D1, and CDK4. EMSA values and expression of all three splicing factors correlated with ErbB1, mTOR, PTEN, and Stat5. Western blots confirmed that full-length and truncated beta-catenin expression correlated with U2AF65 expression in tumor extracts. CONCLUSIONS: Increased triplex DNA-binding activity in vitro correlates with lymph node disease, metastasis, and reduced overall survival in colorectal cancer, and increased U2AF65 expression is associated with total and truncated beta-catenin expression in high-stage colorectal tumors.