Current trend in the treatment of Hodgkin's disease

The analysis of three subsequent randomized trials carried out within the frame of the European Organization for Research on Cancer (E.O.R.T.C.) enables to define a strategy for the staging and the treatment of early stages of Hodgkin's disease. Several prognostic factors were identified by multivariate analyses: 1) erythrocyte sedimentation rate, which has a greater impact on relapse-free survival than systemic symptoms but which can be combined with them; the combination of the two is a more powerful prognostic indicator than ESR alone; 2) the number of involved lymphatic areas: patients with one or two lymphatic areas involved (CS I and II2) have a better outcome than stage II patients with 3 or more areas involved (CS II3). Patients with favorable prognostic indicators are submitted to staging laparotomy because for them spleen involvement has a pejorative impact. For patients with unfavorable indicators, the spleen involvement has little prognostic significance and therefore those patients who need, anyway, an aggressive treatment do not undergo staging laparotomy. Patients with favorable prognostic indicators and negative staging laparotomy can be treated by radiotherapy alone, patients with positive laparotomy or patients with unfavorable prognostic indicators are treated by combination of multiple chemotherapy and radiotherapy.     

Evolutionary aspects of “chloroplast-like” trnN and trnH expression in higher-plant mitochondria

Two identical “chloroplast-like” tRNA^Asn genes, trnN1 and trnN2, have been identified in the potato (Solanum tuberosum) mitochondrial genome. The flanking sequences of trnN1 are unrelated to the corresponding authentic potato chloroplast regions, whilst those of trnN2 are very similar to the chloroplast sequences. The trnN1 copy is present in the mitochondrial genome of various plants whereas the second copy, trnN2, is absent from all the other plant genomes studied so far. Interestingly, both trnN copies are expressed in potato mitochondria. Sequences flanking the chloroplast-like tRNA^His gene (trnH), present as a single copy in the potato mitochondrial DNA, are unrelated to the corresponding chloroplast sequences, whereas chloroplast-derived sequences have been maintained in the vicinity of the maize chloroplast-like mitochondrial trnH gene. However, both the potato and the maize trnH are expressed in mitochondria. Received: 10 April / 1 August 1997     

Stable micro-dystrophin gene transfer using an integrating adeno-retroviral hybrid vector ameliorates the dystrophic pathology in mdx mouse muscle

The ability to transfer the dystrophin gene stably to the skeletal muscle of DMD patients is a major confounding issue in establishing an effective gene therapy for this disease. To overcome this problem, we have examined the ability of muscle fibres from mdx mice to act as in situ factories of retroviral vector production. Tibialis anterior (TA) muscles from 4-week-old mdx mice were injected with an adenoviral vector expressing LacZ within a retroviral expression cassette (AdLZIN). Retroviral vector production was induced by the inclusion of two additional adenoviral vectors expressing retroviral gag-pol (AdGagPol) and 10A1 env genes (Ad10A1). Upon introduction of infected muscles into cell culture, colonies of beta-galactosidase-expressing myotubes formed only in cultures where the muscle was injected with AdLZIN, AdGagPol and Ad10A1, but not from muscle injected with AdLZIN only. Muscles from mdx/nude mice producing retroviral vector displayed a 4.6-fold increase in beta-galactosidase-positive myofibres after 1 month, compared with contralateral muscle in the same animal injected with AdLZIN and AdGagPol only. By constructing a hybrid adeno-retroviral vector expressing a truncated micro-dystrophin construct (AdmicroDyIN), we were able to partially correct the mdx dystrophic phenotype. AdmicroDyIN-mediated expression of micro-dystrophin in mdx TA muscle restored the formation of the dystrophin-associated glycoprotein complex and significantly reduced the level of muscle degeneration over uninjected controls. By stimulating in situ production of retroviral vector expressing micro-dystrophin, we achieved 92%+/-6% transduction of myofibres in the TA muscle by 4 weeks. Strikingly, by 3 months post injection, micro-dystrophin was still expressed to high levels in nearly all the myofibres of the TA muscle. By comparison, there was a pronounced drop in the levels of micro-dystrophin expressed by muscles injected with AdmicroDyIN only. Finally, using a novel PCR approach, we detected reverse-transcribed, integrated proviral sequences in TA muscle genomic DNA by 4 weeks post injection, the levels of which were found to increase after 3 months.     

Incorporation of simian virus 5 fusion protein into murine leukemia virus particles and its effect on the co-incorporation of retroviral envelope glycoproteins

We describe the generation of murine leukemia virus (MLV) virus particles carrying the paramyxovirus fusion protein F from simian virus 5 (SV5-F). This glycoprotein was expressed in cells providing Moloney MLV (MoMLV) Gag and Pol proteins and a lacZ retroviral vector. SV5-F was correctly expressed, processed, and efficiently incorporated into retroviral particles. SV5-F-bearing retroviruses were not infectious although a weak binding to primate and rodent cells could be detected and SV5-F could mediate cell to cell fusion. We then co-expressed the SV5-F glycoprotein in retroviral particles with chimeric and wild-type MoMLV envelope glycoproteins. Our results show that F strongly inhibited infection via the retroviral envelopes although the mechanism of inhibition was different depending on the retroviral envelope used.     

Treatment of non-Hodgkin's lymphomas in adults, stages III and IV with favorable histology : abstention or therapeutic aggressiveness?

Within the inhomogeneous group of non Hodgkin's lymphomas, the natural history of lymphomas with favorable histologies, stages III and IV is uncommon; survival can be long, but the relapse rate is high, and finally the ten-year survival rate is poor. In order to improve these results, various proposals have been made. Presently, two main attitudes can be defined. The first one is based on data showing a better survival rate when a complete remission has been obtained; consequently, a very aggressive treatment scheme (for example an association of chemotherapy--including Adriamycin--and total body irradiation) is proposed. The second attitude is based on favorable results obtained by a "deferred treatment", the patients being treated only when the disease is symptomatic. Actually, the review of the literature shows that these two attitudes are complementary rather than antagonistic. For a young adult patient, essentially if histology is more "intermediate" than really "favorable" and if the patient presents with bulky tumoral masses, aggressive treatment must be proposed, because it is the only attitude able to achieve complete remission and therefore able to provide chances of long term survival. For an older patient, essentially with a very favorable histology and without any symptoms such an aggressive therapy appears too risky. "Light" treatments and occasionally "deferred treatment" can be proposed in these cases.     

Myocardial perfusion damage after mediastinal irradiation for Hodgkin's disease: a thallium-201 single photon emission tomography study

Conflicting data have been reported on the incidence of myocardial abnormalities after mediastinal irradiation for Hodgkin's disease. We studied myocardial perfusion in 31 clinically asymptomatic patients (13 male, 18 female, mean age 35 years) 7 years (range 3–11 years) after mantle field radiotherapy. Thallium-201 tomoscintigraphic data were obtained after exercise, 4 h later and at rest (8–15 days later). Images were analysed visually and quantitatively (sectorial quantification of ²⁰¹T1 uptake on the bull's eye images of the short-axis slices) compared with those of 35 subjects with a low likelihood of coronary artery disease. Twenty-five tomographic data sets were available. Images were visually abnormal in 21 patients (84%) showing an heterogeneous ²⁰¹Tl uptake. In 68%, the sectorial ²⁰¹Tl uptake was lower than the mean ²⁰¹Tl uptake value minus 2 standard deviations measured in subjects with a low likelihood of coronary artery disease. Significant redistribution (quantitatively assessed 10%) was present in 10 patients (40%). In most of the patients, the location and the shape of the defect(s) could not be anatomically related to an epicardial coronary vessel disease. These results indicate that after mediastinal irradiation the ²⁰¹Tl myocardial uptake is frequently abnormal. The observed patterns suggest a disease of the small coronary vessels and/or the existence of a myocardial fibrosis rather than epicardial coronary artery disease.     

Pain and pain management in newborn infants: a survey of physicians and nurses

BACKGROUND: Despite an increased awareness among clinicians regarding pain and pain management for infants undergoing surgery, pain associated with procedures performed outside the operating room may not be adequately managed. PURPOSE: To examine the beliefs and self-described behavior of physicians and nurses regarding the management of procedural pain in newborn infants. METHODS: A survey was distributed to 467 clinicians (nurses and physicians) working in 11 level II and 4 level III nurseries in a large metropolitan area. Respondents were asked to rate the painfulness of 12 common bedside nursery procedures and how often pharmacologic and nonpharmacologic (comfort) measures are currently used and should be used for those procedures. Demographic data were also collected. RESULTS: Surveys were completed by 374 clinicians (80% response rate). Physicians and nurses believe infants feel as much pain as adults and that 9 of the 12 listed procedures are moderately to very painful. Neither pharmacologic nor comfort measures are believed to be used frequently, even for the most painful procedures. Physicians and nurses believe both pharmacologic and comfort measures should be used more frequently, but nurses believe comfort measures should be used more frequently than do physicians. Beliefs about infant pain and procedural pain were related to pain management preferences. Physicians' but not nurses' ratings were associated with significant personal pain. CONCLUSIONS: Despite their beliefs that infants experience significant procedure-related pain, clinicians believe pain management for infants remains below optimal levels. Barriers to more consistent and effective pain management need to be identified and surmounted.     

Bacterial and mammalian DNA alkyltransferases sensitize Escherichia coli to the lethal and mutagenic effects of dibromoalkanes

Here we confirm and extend our previous studies demonstrating that the mutagenic potency of 1,2-dibromoethane (DBE) and dibromomethane (DBM) is markedly enhanced (not prevented) in bacteria expressing the O6- alkylguanine-DNA alkyltransferase (ATase) encoded by the Escherichia coli ogt gene. We demonstrate that, in close parallel with mutagenesis, the Ogt ATase sensitizes the bacteria to the lethal effects of these carcinogens, suggesting that one or more of the potentially mutagenic lesions induced by DBE and DBM in the presence of Ogt has additional lethal capacity. We further demonstrate that the sensitization to both lethality and mutagenesis by DBE and DBM is a property shared by other DNA alkyltransferases. This objective was accomplished by quantifying the induction of mutations and lethal events in ogt- ada- E. coli expressing an exogenous bacterial or mammalian ATase from a multicopy plasmid. Mammalian recombinant ATases enhanced the lethal and mutagenic actions of DBE and suppressed the lack of sensitivity of the vector- transformed bacteria to DBM. In most cases the order of effectiveness of the ATases ranked: murine > human > Ogt > rat. Further comparisons included the full-length Ada ATase from E. coli and a truncated Ada version (T-ada) that retains the O6-methylguanine binding domain of the protein. The full-length Ada ATase was effective in enhancing the lethality but not the mutagenicity induced by DBE and DBM. The T-ada ATase provided less sensitization than Ada to lethality by DBE, but of the three bacterial ATases T-ada yielded the highest sensitization to mutagenesis by this compound. T-ada and Ada ATases were in general less effective than the mammalian versions, with the exception of the rat recombinant ATase. The effectiveness of the different mammalian and bacterial ATases in promoting the deleterious actions of dibromoalkanes was compared with the effectiveness of these proteins in suppressing the lethal and mutagenic effects induced by N-nitroso-N-methylurea. The ability to sensitize E. coli to the lethal and mutagenic effects of DBE and DBM seems restricted to DNA alkyltransferase, since overexpression of thioredoxin (Trx) or glutaredoxin (Grx1) in ogt- ada- cells showed no effect, in spite of the reported potential of bioactive dihaloethane- derived species to alkylate Trx.