Thymidine phosphorylase is angiogenic and promotes tumor growth.

Platelet-derived endothelial cell growth factor was previously identified as the sole angiogenic activity present in platelets; it is now known to be thymidine phosphorylase (TP). The effect of TP on [methyl-3H]thymidine uptake does not arise from de novo DNA synthesis and the molecule is not a growth factor. Despite this, TP is strongly angiogenic in a rat sponge and freeze-injured skin graft model. Neutralizing antibodies and site-directed mutagenesis confirmed that the enzyme activity of TP is a condition for its angiogenic activity. The level of TP was found to be elevated in human breast tumors compared to normal breast tissue (P < 0.001). Overexpression of TP in MCF-7 breast carcinoma cells had no effect on growth in vitro but markedly enhanced tumor growth in vivo. These data and the correlation of expression in tumors with malignancy identify TP as a target for antitumor strategies.     

Infection and extramural delivery with use of digoxin as a feticidal agent

BackgroundMany abortion providers use digoxin to induce fetal demise prior to dilation and evacuation (D&;E). Our primary objective was to examine the frequency of infection and extramural delivery following digoxin use.Study DesignWe conducted a retrospective single-cohort study. Inclusion criteria were all women between 18 and 24 weeks of estimated gestational age who received digoxin in preparation for D&;E at our outpatient facility. We queried two electronic databases to collect data on the frequency of extramural delivery and the rate of perioperative infection.ResultsFrom January 1, 2000, to December 31, 2008, 4906 abortions were performed between 18 and 24 weeks of estimated gestation with digoxin injection administered as feticidal agent 1 day prior to D&;E. Extramural delivery frequency was 0.30%, and infection frequency was 0.04%. There were no significant differences in the frequency of extramural deliveries across procedure year (p=.2), estimated gestational age (p=.3), race/ethnicity (p=.2) or maternal age (p=.3).ConclusionRates of extramural delivery and infection are acceptably low following digoxin use prior to scheduled D&;E.     

Peripheral T-cell lymphoma associated with hemophagocytic syndrome

Nine patients with an acute disease characterized by high fever, loss of weight, prominent hepatosplenomegaly, slight or no lymphadenopathy, abnormal liver function tests, and profound pancytopenia are reported. In all cases, the disease presented in the absence of any pre-existing disease or immunosuppressive therapy. In seven of the nine patients, survival was very short (mean = 7 weeks). Two patients are still alive: one had a relapse 24 months after the initial diagnosis, while the other is in complete remission. The main pathological feature was the infiltration of the marrow, spleen and liver by neoplastic T cells, accompanied by an exuberant hyperplasia of benign-looking, hemophagocytizing histiocytes. The term "peripheral T-cell lymphoma with hemophagocytic syndrome" is proposed for this condition. Retrospective analysis of stored paraffin material (1949 to 1965) from the Radcliffe Infirmary files suggests that at least some of the cases designated as "histiocytic medullary reticulosis" by Scott and Robb-Smith were examples of the syndrome herein described.     

The plasma cell associated antigen detectable by antibody VS38 is the p63 rough endoplasmic reticulum protein.

AIMS: To characterise the 64 kDa intracellular antigen present on normal and neoplastic plasma cells detected by monoclonal antibody VS38 and by another antibody, MC186, of similar reactivity. METHODS: The VS38 monoclonal antibody was used to screen a bacterially expressed peripheral blood cDNA library, and the immunocytochemical staining of the two antibodies was compared with those raised specifically to the protein identified as the VS38 antigen. RESULTS: A partial cDNA encoding the VS38 antigen was cloned and shown to be identical to the human p63 gene. p63 is a non-glycated, reversibly palmitoylated type II transmembrane protein which is found in rough endoplasmic reticulum. Antibody MC186 also recognised this protein and both VS38 and MC186 together with two antibodies raised to p63 gave identical immunostaining patterns. CONCLUSIONS: The VS38 antigen was identified as the rough endoplasmic reticulum protein p63. While it is not exclusively expressed on plasma cells, the presence of p63 distinguishes plasma cells from other lymphoid cells because of their high secretory activity.     

The influence of high dose hydroxyurea on the incorporation of 5-iodo-2-deoxyuridine (IUdR) by human bone marrow and tumour cells in vivo.

Resistance to cytotoxics precludes the successful treatment of many solid tumours. Inhibition of DNA synthesis in normal tissues with antimetabolites such as hydroxyurea (HU) may be a useful means of improving the selective uptake of toxic thymidine analogues by the relatively resistant tumour cells. HU also inhibits DNA repair by the critical depletion of intracellular deoxyribonucleotides. Twenty-five patients with various malignancies received 5-iodo-2-deoxyuridine (IUdR) 100 mg m-2 as a 20 min i.v. infusion and the uptake of IUdR was determined 1 h later immunocytochemically. Of these patients, 14 received IUdR 23 h from the start of a continuous i.v. infusion of HU (36 g over 36 h). Uptake of IUdR was equally suppressed in bone marrow and tumour aspirates, 0.1% (+/- 0.2%) of marrow precursor cells and 0.5% (+/- 0.4%) of tumour cells respectively, in patients who received HU compared to the uptake of IUdR in 11 patients who were not given HU 6.8% (+/- 1.1%) and 12.2% (+/- 1.8%) respectively. Mean HU plasma concentrations at the time of IUdR administration was 1.7 +/- 0.2 mM. The growth fraction of tumour cells (using Ki67 labelling) was not changed after treatment with HU. It is concluded that (1) since DNA synthesis is effectively inhibited by HU in tumour cells, differential uptake of radiolabelled IUdR by those cells will not be feasible using the current schedule of HU administration, (2) HU may be used as an inhibitor of DNA repair in vivo since the degree of inhibition correlates with that required to inhibit repair experimentally and that (3) Ki67 labelling index is not useful in studying cell kinetics in patients treated with HU.     

The value of immunocytochemical methods in the differential diagnosis of anaplastic thyroid tumours

The practical usefulness of a panel of monoclonal antibodies recognising epithelial and lymphoid antigens has been evaluated on a series of 10 routinely processed thyroid tumours of uncertain origin. All 6 small cell tumours were shown to be of lymphoid origin whereas of the 4 large cell tumours two were lymphomas and two carcinomas. Two of the tumours, one large cell and one small cell, were undiagnosable due to technical reasons (crush artefact or small size of biopsy) and emphasized the value of immunohistology in this context. Clinical follow-up of all 10 cases indicated that these distinctions are of both prognostic and therapeutic value. It is concluded that immunocytochemistry using a carefully selected panel of monoclonal antibodies is a valuable and convenient means of making an objective distinction between anaplastic thyroid tumours of epithelial or lymphoid origin.     

C2028T polymorphism in exon 12 and dinucleotide repeat polymorphism in intron 13 of the HIF-1alpha gene define HIF-1alpha protein expression in non-small cell lung cancer

OBJECTIVES: In this study, we investigated whether polymorphisms of the HIF-1alpha gene may account for the patterns of HIF-1alpha protein expression in non-small cell lung carcinomas (NSCLC) and the expression of HIF-1alpha down-stream proteins. METHODS: Specific HIF-1alpha polymorphisms were assessed in a series of patients with NSCLC: (a) the C to T transition at nucleotide 1744 (position 2028 according to sequence with accession number , which gives rise to Pro/Ser variation at codon 582), (b) the G to A nucleotide substitution at point 1790 (position 2046 according to sequence with accession number , which gives rise to Ala/Thr variation at codon 588), and (c) the dinucleotide GT repeat polymorphism in intron 13. Immunohistochemistry for HIF-1alpha and down-stream proteins (VEGF, LDH-5, GLUT-1) was also performed in tumor material. RESULTS: A strong association of the P582S polymorphism and of GT repeat polymorphism higher than 14/14 with increased HIF-1alpha expression was noted. HIF-1alpha polymorphism did not relate to the expression of the HIF-1alpha downstream proteins analysed, but significant association of HIF-1alpha expression with LDH-5 was confirmed (p=0.008). CONCLUSIONS: HIF-1alpha polymorphisms may have an important impact on HIF-protein stability and, eventually, function.     

Oxalobacter formigenes: a potential tool for the treatment of primary hyperoxaluria type 1

Primary hyperoxaluria is characterized by severe urolithiasis, nephrocalcinosis, and early renal failure. As treatment options are scarce, we aimed for a new therapeutic tool using colonic degradation of endogenous oxalate by Oxalobactor formigenes. Oxalobacter was orally administered for 4 weeks as frozen paste (IxOC-2) or as enteric-coated capsules (IxOC-3). Nine patients (five with normal renal function, one after liver-kidney transplantation, and three with renal failure) completed the IxOC-2 study. Seven patients (six with normal renal function and one after liver-kidney transplantation) completed the IxOC-3 study. Urinary oxalate or plasma oxalate in renal failure was determined at baseline, weekly during treatment and for a 2-week follow-up. The patients who showed >20% reduction both at the end of weeks 3 and 4 were considered as responders. Under IxOC-2, three out of five patients with normal renal function showed a 22-48% reduction of urinary oxalate. In addition, two renal failure patients experienced a significant reduction in plasma oxalate and amelioration of clinical symptoms. Under IxOC-3 treatment, four out of six patients with normal renal function responded with a reduction of urinary oxalate ranging from 38.5 to 92%. Although all subjects under IxOC-2 and 4 patients under IxOC-3 showed detectable levels of O. formigenes in stool during treatment, fecal recovery dropped directly at follow up, indicating only transient gastrointestinal-tract colonization. The preliminary data indicate that O. formigenes is safe, leads to a significant reduction of either urinary or plasma oxalate, and is a potential new treatment option for primary hyperoxaluria.     

Diagnostic usefulness of aberrant CD22 expression in differentiating neoplastic cells of B-Cell chronic lymphoproliferative disorders from admixed benign B cells in four-color multiparameter flow cytometry

The diagnosis of B-cell chronic lymphoproliferative disorders is a great challenge when made in a background of polyclonal B cells. We studied the diagnostic usefulness of aberrant CD22 expression for differentiating neoplastic from benign B cells by 4-color flow cytometry. Of 56 cases of B-cell chronic lymphoproliferative disorders, we found that neoplastic cells showed aberrant CD22 expression in 39 (70%) of 56 cases, including chronic lymphocytic leukemia, mantle cell lymphoma, marginal zone lymphoma, hairy cell leukemia, and follicular lymphoma. In 4 cases, monoclonality was detected definitively only by evaluating the immunoglobulin light chain restriction in B cells with aberrant CD22 expression because numerous polyclonal B cells were present. Aberrant CD22 expression is a useful marker for detection of monoclonal B cells admixed with numerous benign polyclonal B cells.