Rapid-fractionation preoperative chemoradiation, pancreaticoduodenectomy, and intraoperative radiation therapy for resectable pancreatic adenocarcinoma

PURPOSE: To evaluate the toxicities, radiographic and pathologic responses, and event-free outcomes with combined modality treatment that involves preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and electron-beam intraoperative radiation therapy (EB-IORT) for patients with resectable pancreatic adenocarcinoma. PATIENTS AND METHODS: Patients with radiographically resectable localized adenocarcinoma of the pancreatic head were entered onto a preoperative protocol that consisted of a 2-week course of fluorouracil (5-FU) 300 mg/m2 daily 5 days per week and concomitant rapid-fractionation radiation 30 Gy, 3 Gy daily 5 days per week. Radiographic restaging was performed 4 weeks after chemoradiation, and patients with localized disease underwent pancreaticoduodenectomy with EB-IORT 10 to 15 Gy. RESULTS: Thirty-five patients were entered onto the study and completed chemoradiation, 34 (97%) as outpatients. Three patients (9%) experienced grade 3 nausea and vomiting; no other grade 3 or 4 toxicities were observed. Of the 27 patients taken to surgery, 20 patients (74%) underwent pancreaticoduodenectomy with EB-IORT. All patients had a less than grade III pathologic response to preoperative chemoradiation. At a median follow-up of 37 months, the 3-year survival rate in patients who underwent combined modality therapy was 23%. CONCLUSION: Combined modality treatment with preoperative rapid-fractionation chemoradiation, pancreaticoduodenectomy, and EB-IORT is associated with minimal toxicity and excellent locoregional control. This represents one approach to maximize the proportion of patients who receive all components of combined modality therapy and avoids the toxicity of pancreaticoduodenectomy in patients found to have metastatic disease at the time of restaging.     

Laboratory abnormalities in thrombotic thrombocytopenic purpura. Canadian Apheresis Group

Thrombotic thrombocytopenic purpura is an uncommon disorder that requires prompt recognition and intervention to prevent death. To date, information regarding the classic laboratory abnormalities in the disease has been derived from small numbers of patients whose laboratory tests have been done at many different sites. We report the laboratory findings in 135 patients who presented with thrombotic thrombocytopenic purpura to 17 Canadian centres. 50 men and 85 women had a mean platelet count of 25.3+/-19.4x10(9)/l. The initial platelet count correlated with mortality; 32% of patients with a platelet count of 20x10(9)/l or less died compared with 18% of patients with a platelet count >20x10(9)/l (P=0.058). The platelet-associated IgG was elevated in 88% at presentation whereas the indirect platelet suspension immunofluorescence test was positive in only 18%, 93% of the sera showed reactivity against platelets following protein blotting. All sera tested also showed reactivity against endothelial cells. Immune complexes were seen in all patients, whereas the platelet aggregating factor was detected in 59%. Although the von Willebrand factor was elevated in the majority of patients at entry, the multimer pattern was variable and showed no predictive pattern. Renal dysfunction was common (18%).     

Transduction of full-length TAT fusion proteins into mammalian cells: TAT-p27Kip1 induces cell migration

Human procathepsin L has been expressed in E. coli in the form of inclusion bodies. The recombinant protein was isolated, refolded and processed at pH 5.5 by the addition of dextran sulfate which increased the overall yield of cathepsin L almost 10-fold. After the auto-activation of the 38 kDa procathepsin L at least three processing sites were determined by N-terminal amino acid sequencing. After replacing the Ala205 residue by glutamic acid, cathepsin B-like specificity was introduced into cathepsin L. This mutation resulted in a 15-fold increased activity toward the substrate Z-Arg-Arg-AMC and in a 29-fold decreased activity toward Z-Phe-Arg-AMC. Residue 205 is thereby confirmed experimentally to be critical for the specificity of cathepsins B and L.     

Geographical variation in attitudes towards smoking: findings from the COMMIT communities

This paper examines the links between attitudes towards cigarette smoking and the social environments of communities involved in the U.S. National Cancer Institute's Community Intervention Trial for Smoking Cessation (COMMIT). Our objective is to identify sources of social-geographic variation in smoking attitudes and norms which can hinder or enhance public health efforts to reduce tobacco use. The analysis had two stages: (1) place (measured as region and community) was identified as an important main effect accounting for individual variation in smoking attitudes independent of smoking status and personal characteristics; (2) case studies of COMMIT sites in North Carolina, Iowa, Washington, New Jersey and New Mexico were conducted to reveal features of the local milieux which could account for variations in smoking attitudes. Some of the place characteristics that we suggest are linked to local attitudes include economic reliance on the tobacco industry, libertarian political orientations, socio-economic conditions, legislative context and ethnic composition. Given the effects of regional and community attributes on individual attitudes towards smoking, we conclude that public health efforts to control smoking should continue to be targeted beyond individual smokers to the broader social environment.     

The dynamics of the dominant alpha-rhythm frequency in the perception and reproduction of time intervals

In contrast to cytotoxic agents inducing rapid cell death, biological agents such as hormones, vitamins (e.g., retinoids), cytokines, and antireceptor antibodies act slowly and may alter ratios between cell growth and programmed cell death (apoptosis). We showed previously that anti-interleukin 6 (IL-6) and antitransferrin (Tf) receptor antibodies inhibited in vitro growth and induced death of myeloma cells. Retinoids also inhibit in vitro growth of human cancer cells and decrease IL-6 receptor display and autosecretion by some myeloma cells. Retinoids may also antagonize in vitro growth-promoting effects of iron and transferrin. To develop a novel strategy for treating myeloma, we examined antiproliferative and cytotoxic effects of retinoids in combination with anti-Tf or anti-IL-6 receptor antibodies. Myeloma cell lines were cultured with retinoids with or without anti-growth factor receptor monoclonal antibodies. Both all-trans retinoic acid (ATRA) and 13-cis-retinoic acid showed variable, dose-dependent inhibition of myeloma cell line growth. ATRA also induced significant down-regulation of myeloma IL-6 receptors and inhibited IL-6 autosecretion by myeloma cells. Antiproliferative effects of ATRA were increased by coculture with anti-Tf but not anti-IL-6 receptor antibodies. Colony-forming assays showed that antiproliferative effects of anti-Tf receptor antibodies were largely reversible, but 1 microM ATRA was cytotoxic to myeloma cells. To assess apoptosis, a flow cytometry assay detecting DNA damage was used. Using previously studied cell line models, flow cytometry detected programmed cell death induced by transforming growth factor beta1 in leukemia cells and by anti-growth factor receptor antibody treatment of IL-6-dependent myeloma cells, treatments which caused only modest increases in the percentage of cells undergoing morphological apoptosis and increased internucleosomal DNA degradation. Flow cytometry analysis of ATRA and anti-Tf antibody-treated myeloma cells also showed evidence for apoptosis induced by ATRA, but not with anti-Tf receptor antibodies. These changes were apparent several days before detection of internucleosomal DNA degradation on agarose gels in 8226 cells but were not detected at any time in U266 cells, which underwent cell death but showed no DNA damage using flow cytometry or degradation on agarose gels. Retinoids merit further study as possible maintenance or chemoprevention therapies for clonal plasma cell disorders and for treating paraneoplastic disorders such as Castleman's disease. Flow cytometry rapidly detects apoptosis induced by biological agents and may be useful for in vitro screening of novel biological therapies.     

Characterization of the ocular antiallergic and antihistaminic effects of olopatadine (AL-4943A), a novel drug for treating ocular allergic diseases

Olopatadine (AL-4943A; KW-4679) [(Z)-11-[3-(dimethylamino)propylidene]-6, 11-dihydrodibenz[b,e]oxepine-2-acetic acid hydrochloride] is an antiallergic/antihistaminic drug under development for topical ocular use. The effects of the compound on release of proinflammatory mediators (histamine, tryptase and prostaglandin D2) from monodispersed human conjunctival mast cells were assessed. Histamine receptor subtype binding affinities and functional potencies were determined with ligand binding and phosphoinositide turnover assays, respectively. Olopatadine inhibited the release of histamine, tryptase and prostaglandin D2, in a concentration-dependent manner (IC50 = 559 microM). Evaluation of the interaction of olopatadine with histamine receptors revealed a relatively high affinity for the H1 receptor (Ki = 31.6 nM, pKi = 7.5 +/- 0.1, n = 7) but lower affinities for H2 receptors (Ki = 100 microM, pKi = 4.0 +/- 0.19, n = 7) and H3 receptors (Ki = 79.4 microM, pKi = 4.1 +/- 0.16, n = 7). The H1 selectivity of olopatadine was superior to that of other ocularly used antihistamines studied, such as ketotifen, levocabastine, antazoline and pheniramine. The profiling of olopatadine in 42 nonhistamine receptor binding assays revealed that olopatadine interacts with only two nonhistamine receptor/uptake sites to any significant degree (pIC50 < or = 5-6). Olopatadine inhibited histamine-induced phosphoinositide turnover in human conjunctival epithelial cells (IC50 = 10 nM, pIC50 = 8.0, n = 4) and in other human ocular cells (IC50 = 15.8-31.6 nM, pIC50 = 7.5-7.8) and exhibited apparent noncompetitive antagonist properties in these cells, with an estimated dissociation constant (Kb) of 19.9 nM (pKb = 7.7, n = 6). This combination of mast cell mediator release inhibition and selective H1 receptor antagonism suggests that olopatadine may be particularly useful in the treatment of ocular allergic diseases. Indeed, olopatadine has recently shown clinical efficacy in an allergic conjunctivitis model in human subjects.     

In utero diagnosis of intrapericardial teratoma: a case for in utero open fetal surgery

We present a case of intrapericardial teratoma diagnosed by ultrasound at 26 weeks of gestation presenting as a large tumour mass and rapid development of hydrops fetalis. The fetus died in utero one day before scheduled open fetal surgery.     

Anthracycline doses in patients with liver dysfunction: do UK oncologists follow current recommendations?

The question of whether UK oncologists follow current anthracycline dose modifications when treating patients with liver dysfunction was addressed through a questionnaire. Oncologists were asked the dose of doxorubicin or epirubicin they would prescribe for a woman with breast cancer and liver metastases who had one of four different patterns of abnormal liver chemistry. In each case, the median dose of anthracycline that would have been prescribed was close to that currently recommended. There was, however, wide variation in the dose that oncologists said they would prescribe, some avoiding an anthracycline altogether, whereas others would give full-dose treatment. Medical oncologists would prescribe a significantly lower dose of anthracycline than clinical oncologists for a patient with the most severely disturbed liver tests. Overall, medical oncologists were also significantly more likely to prescribe epirubicin. These results show the need for new, widely accepted anthracycline dose modifications for patients with liver dysfunction.     

NAD+-dependent glyceraldehyde-3-phosphate dehydrogenase from Thermoproteus tenax. The first identified archaeal member of the aldehyde dehydrogenase superfamily is a glycolytic enzyme with unusual regulatory properties

The hyperthermophilic archaeum Thermoproteus tenax possesses two glyceraldehyde-3-phosphate dehydrogenases differing in cosubstrate specificity and phosphate dependence of the catalyzed reaction. NAD+-dependent glyceraldehyde-3-phosphate dehydrogenase catalyzes the phosphate-independent irreversible oxidation of D-glyceraldehyde 3-phosphate to 3-phosphoglycerate. The coding gene was cloned, sequenced, and expressed in Escherichia coli. Sequence comparisons showed no similarity to phosphorylating glyceraldehyde-3-phosphate dehydrogenases but revealed a relationship to aldehyde dehydrogenases, with the highest similarity to the subgroup of nonphosphorylating glyceraldehyde-3-phosphate dehydrogenases. The activity of the enzyme is affected by a series of metabolites. All effectors tested influence the affinity of the enzyme for its cosubstrate NAD+. Whereas NADP(H), NADH, and ATP reduce the affinity for the cosubstrate, AMP, ADP, glucose 1-phosphate, and fructose 6-phosphate increase the affinity for NAD+. Additionally, most of the effectors investigated induce cooperativity of NAD+ binding. The irreversible catabolic oxidation of glyceraldehyde 3-phosphate, the control of the enzyme by energy charge of the cell, and the regulation by intermediates of glycolysis and glucan degradation identify the NAD+-dependent glyceraldehyde-3-phosphate dehydrogenase as an integral constituent of glycolysis in T. tenax. Its regulatory properties substitute for those lacking in the reversible nonregulated pyrophosphate-dependent phosphofructokinase in this variant of the Embden-Meyerhof-Parnas pathway.