Some new reactive polymers for the immobilization of enzymes.

From poly(vinyl alcohol) precursors, various reactive carriers for the immobilization of enzymes were synthesized. As insoluble starting polymers, the following products were used: poly(vinyl alcohol), gels crosslinked with terephthalaldehyde, hydrolyzed beads of crosslinked poly(vinyl acetate), poly(vinyl acetate-co- ethylene) tubes coated with poly(vinyl alcohol), and poly(vinyl alcohol)-containing synthetic pulp. Reactive groups introduced into these carriers or methods for their activation included the diazonium- and isothiocyanato group, and the glutardialdehyde-, BrCN, 2, 4, 6-trichloro-s-triazien, and p-benzoquinone methods. Furthermore, SH-specific reactive groups such as N-substituted maleimide groups or activated mixed disulfides with 2-thiopyridyl groups could be introduced into PVA-polymers. Enzymes like hydrolases (e.g. papain, trypsin, chymotrypsin, urease), oxidoreductases (e.g. glucose oxydase, catalase, glucose-6-phosphate dehydrogenase) as well as the example of transferase hexokinase coimmobilized with glucose-6-phosphate dehydrogenase, were immobilized by reactive poly(vinyl alcohol) carriers. The properties of the immobilized enzymes were investigated.

Simultaneous paclitaxel and radiotherapy: initial clinical experience in lung cancer and other malignancies.

This report summarizes results from a series of pilot trials using combined-modality chemoradiotherapy with paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) as a radiosensitizing agent in patients with cancers of the lung, cervix, and bladder. In a phase I study of paclitaxel/radiotherapy in patients with locally advanced non-small cell lung cancer, five paclitaxel dose levels were evaluated in conjunction with simultaneous radiation (total dose, 59.4 Gy). A minimum of five patients were treated at each dose level; paclitaxel doses ranged from 45 mg/m2 over 3 weeks (level 1) to 65 mg/m2 for 7 weeks. Of 34 enrolled patients, 25 are evaluable for toxicity and response. Side effects were generally moderate for this combined-modality therapy, although two patients at level 5 developed dose-limiting toxicities (grade 4 esophagitis and grade 3 pneumonitis). Among 25 evaluable patients, complete and partial response rates were 4% (one patient) and 64% (16 patients), respectively; eight patients had a minor response. Median survival was 6 months (range, 1 to 20 months). Therapy was well tolerated, suggesting that the combined modalities offer a practical, effective therapy for patients with non-small cell disease. A paclitaxel dose of 55 mg/m2 is recommended for further study of combined-modality chemoradiotherapy in this clinical setting. In another trial, 33 women with inoperable, locally advanced cervical cancer received carboplatin 50 mg/m2 via intravenous infusion simultaneously with external-beam radiation therapy and vaginal brachytherapy, to define the regimen's toxicity and safety. Among the 33 women, 78% achieved a complete response to therapy. The investigators next conducted a trial of paclitaxel 50 mg/m2 given weekly over 3 hours with the previous carboplatin/radiotherapy regimen in four women and documented two partial responses, one near-complete response, and one minor response, with moderate, manageable toxicity. In a final case report on a patient with recurrent bladder cancer, simultaneous radiotherapy and weekly paclitaxel 50 mg/m2 intravenously over 3 hours yielded a partial remission, prompting the investigators to plan a phase I study to confirm the regimen's efficacy and safety. Additional planned studies include a phase I trial of simultaneous chemoradiotherapy in patients with cancer of the head and neck.

Paclitaxel and simultaneous radiation in locally advanced stage IIIA/B non-small cell lung cancer: a clinical phase I study.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most active single agents for the treatment of non-small cell lung cancer, with response rates of 21% to 24%. We present a phase I study with paclitaxel and simultaneous radiation in previously untreated, locally advanced, inoperable, stage IIIA/B non-small cell lung cancer. The aims of the study were to determine the maximum tolerated dose, define the safety and toxicity, and obtain preliminary data about the activity of the combined modality. Patients received a fixed dose of radiotherapy (1.8 Gy/d, 5 days a week for 6.5 weeks, for a total dose of 59.4 Gy) and concomitant chemotherapy with paclitaxel 45 mg/m2 days 1, 8, and 15 in level 1; days 1, 8, 15, 22, and 29 in level 2; and days 1, 8, 15, 22, 29, 36, and 43 in level 3. The paclitaxel dosage was increased to 55 mg/m2 on days 1, 8, 15, 22, 29, 36, and 43 in level 4. Paclitaxel was administered as a 3-hour continuous intravenous infusion. Dexamethasone, clemastine, and ranitidine were given for hypersensitivity prophylaxis. Twenty-two patients (18 men and four women) entered the study; their median age was 66.5 years (age range, 38 to 74 years). Disease stage was IIIA in six of 22 patients and stage IIIB in 16. Six patients were treated at level 1, five at level 2, five at level 3, and six at level 4. There were 18 patients evaluable for toxicity and response. Side effects generally were moderate during the treatment period. One patient withdrew by request after the first course, one patient died of tumor bleeding after five courses, one patient died of progressive disease (lymphangiosis carcinomatosa of both lungs) after the sixth course, and one patient is too early for evaluation. Among the 18 patients evaluable for response, there were one complete and 10 partial remissions; seven patients reached a minor response. It is concluded that the therapy was well tolerated in these patients. Importantly, no severe adverse events were observed that could be associated with paclitaxel or radiotherapy. This combined modality appears to be a practicable and effective treatment of non-small cell lung cancer. The maximum tolerated dose has not yet been reached, and dose escalation is planned.

Simultaneous radiochemotherapy with paclitaxel in non-small cell lung cancer: a clinical phase I study.

Paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) is one of the most active single agents available for the treatment of non-small cell lung cancer (NSCLC), with reported response rates of 21% to 24%. Its observed radiosensitizing effect is attributed to its interruption of cell development at the G2/M phase of the cell cycle, when cells are most sensitive to the killing effects of ionizing radiation. This phase I study of paclitaxel and simultaneous radiation therapy in patients with previously untreated, locally advanced inoperable stage IIIA/B NSCLC was designed to determine the maximum tolerated paclitaxel dose, to define the safety and toxicity of this combined modality, and to obtain preliminary data on its activity. Patients received a fixed dose of radiotherapy (1.8 Gy/d, 5 days a week, in shrinking-field technique, for a total dose of 59.4 Gy) and concomitant chemotherapy with a 3-hour infusion of paclitaxel once weekly on day 1, initially at a dose of 45 mg/m2, for 3 weeks. This dose remained constant during study levels 1 to 3, with the number of weeks of treatment increasing to 5 and 7 at levels 2 and 3, respectively. At dose level 4, the paclitaxel dose was increased to 55 mg/m2 over 7 weeks. Of 22 NSCLC patients who entered the study, 18 are evaluable for toxicity and response. Responses included one complete and 10 partial remissions; the other seven patients had minimal improvement. The therapy was well tolerated; no severe adverse events were associated with paclitaxel or radiotherapy. This combined modality appears to be a practicable and effective treatment for NSCLC. The maximum tolerated paclitaxel dose has not yet been reached, and dose escalation is planned.

Carboplatin and radiotherapy in the treatment of head and neck cancer: six years' experience.

Between 1987 and 1991, 103 patients with advanced head and neck carcinoma were treated with radiochemotherapy plus carboplatin. Tumors were located in the oral cavity in 33 patients, the oropharynx in eight, and the hypopharynx in seven. Four patients had a tumor of the epipharynx and three, tumor of the larynx. In 48 patients tumor involvement included two or more compartments. Radiotherapy was performed with cobalt-60 rays or 8-MeV photons in a fractionation of 5 x 2 Gy/wk to a dose of 50 Gy. Carboplatin 60 to 70 mg/m2/d was administered days 1 through 5 and 29 through 33. For inoperable patients radiotherapy was continued to a dose of 70 to 74 Gy. To date, 103 patients have entered the study and 100 have completed treatment; three patients died during the treatment period. Actuarial 1- and 2-year survival rates are 77% and 53%, respectively, for all patients; comparable figures for patients with interposed surgery are 93% and 69%, and for the patients treated with radiotherapy alone, 71% and 47%. In a pilot study conducted between 1990 and 1991, 15 patients with advanced head and neck carcinomas underwent hyperfractionated accelerated radiotherapy (2 x 1.6 Gy/d 5 days per week; total dose, 64 to 67.2 Gy) and simultaneous intravenous carboplatin (60 mg/m2, days 1 through 5 and 29 through 33). Eleven patients had T4 and four had T3 tumors. At the end of the treatment period, 12 patients had achieved a complete tumor remission and all others attained a partial tumor involution. Although acute side effects were more pronounced compared with conventional irradiation, this treatment regimen is feasible and the initial complete remission rate of 80% is encouraging. As a result of the encouraging results achieved with hyperfractionated accelerated radiotherapy, we initiated a multicenter randomized study in November 1991. Patients with advanced head and neck carcinomas are either randomized for conventional radiotherapy plus carboplatin or hyperfractionated accelerated irradiation plus carboplatin. As of July 1994, 178 patients have been entered in the study. Results will be evaluated after the study is completed.

Effect of recombinant human granulocyte colony stimulating factor (R-metHuG-CSF) as an adjunct to large-field radiotherapy: a phase I study.

PURPOSE: To test the feasibility of recombinant human granulocyte colony stimulating factor application during large-field radiotherapy. METHODS AND MATERIALS: Fifteen patients with clinically and histologically proven malignancy who received large-field radiotherapy entered this study. Administration of recombinant granulocyte colony stimulating factor (G-CSF) at a dose of 300 microgram subcutaneously was started on Friday and was continued on Saturday and Sunday after the first radiotherapy treatment, which began on the Monday before. In this way four courses of G-CSF were applied every Friday, Saturday, and Sunday during the radiotherapy period. Absolute neutrophil cell (ANC) and blood counts were monitored twice a week and compared to a second group of 15 patients who received large-field radiotherapy without G-CSF. Before and at the end of every cycle of G-CSF, ANC, blood counts, and biochemistry were measured. We compared the myelotoxicity of the patients treated with G-CSF with 15 patients without G-CSF treated at the same period with large-field radiotherapy, in match pair technique. RESULTS: G-CSF increased the ANC throughout the period of irradiation, and the treatment time needed for competing radiotherapy was shorter in the group who received G-CSF. Fourteen of 15 patients who received G-CSF treatment completed large-field radiotherapy without pause. Only 1 of 15 patients not receiving G-CSF was able to receive radiation treatment on schedule. Patients receiving G-CSF completed treatment with the mantle-field technique in 24 days and those with the abdominal bath technique in 26.5 days. Conversely, patients treated without G-CSF completed treatment with the mantle-field technique in 30.5 days and those with the abdominal bath technique in 36 days. The most frequent side effect was musculoskeletal pain. CONCLUSION: The prophylactic application of G-CSF during large-field radiotherapy before the onset of neutropenia was feasible in this schedule. Whether or not this shortening of treatment duration will translate into an improvement in efficacy is not clear.

New interstitial HDR brachytherapy technique for prostate cancer: CT based 3D planning after transrectal implantation.

We have developed a new interstitial HDR brachytherapy technique for the treatment of prostate cancer using CT based 3D planning after transrectal implantation of four non-parallel needles. CT based needle reconstruction, target definition, evaluation and documentation, including DVHs and 3D imaging, is a feasible, safe and well tolerated treatment concept.

Correcting organ motion artifacts in x-ray CT systems based on tracking of motion phase by the spatial overlap correlator. II. Experimental study.

This paper presents the experimental part of an investigation on tracking and eliminating organ motion artifacts in x-ray CT cardiac applications with emphasis on imaging coronary calcification. The system methodology consists of a software implementation of the spatial overlap correlator (SSOC) concept in x-ray CT scanners to track the net amplitude and phase of organ motion during the CT data acquisition process. A coherent sinogram synthesis (CSS) method is then used to identify the repeated phases of a periodic organ motion from the information provided by the SSOC process and hence synthesize a new sinogram with no motion effects. Since the SSOC scheme is capable of tracking cardiac motion, it identifies also the projection points associated with minimum amplitude cardiac motion effects. These points are used to identify a 180 degrees plus the fan angle sinogram for image reconstruction. This leads to a retrospective gating (RG) scheme that is based on the output of the SSOC process. Performance comparison of the proposed methodology with the retrospective ECG gating using real data sets with phantoms and human patients provides a performance assessment of the merits of the proposed methods. Real results demonstrate that the new methodology eliminates the requirement for ECG gating. Moreover, the CSS and the new RG methods do not require breath holding and they can be implemented in x-ray CT scanners to image coronary calcification and the heart's ventricles.

Clinical relevance of tumor ploidy and micronucleus formation for oral cavity cancer.

AIMS AND BACKGROUND: To study the clinical relevance of tumor ploidy and micronucleus formation as prognostic factors. METHODS AND STUDY DESIGN: Twenty-eight patients with squamous cell carcinoma of the oral cavity were treated with primary radiochemotherapy consisting of irradiation up to 70 Gy in combination with cisplatin. Cell cycle distribution, micronucleus formation and ploidy were evaluated by flow cytometry of biopsies taken before treatment and after irradiation to 10 Gy (5x2 Gy). Sexteen out of 28 patients relapsed after a minimum follow-up period of two years. RESULTS: Flow cytometry of the recurrence biopsy showed hyperpentaploid (5c exceeding) cells in 13/16 (81%) of the relapsed patients. In 7 patients the hyperploid clone was not present in the flow cytometry of the primary tumors. Ploidy could retrospectively be determined also by image cytometry in archival tumor material of the pretreatment specimens. Patients with a level below 100 5c cells per 10,000 cell nuclei were shown to have a significantly better prognosis than patients with more than 100 hyperpentaploid tumor cells. The micronucleus formation was 2-5 times higher in tumors showing a good response to treatment than in carcinomas relapsing within two years. CONCLUSIONS: The 5c-exceeding ratio measured by image cytometry and micronucleus formation proved to be good prognostic parameters for the clinical outcome of patients with locally advanced head and neck carcinomas.

International migration under incomplete information.

"We present a model for deriving optimal sequential migration decisions under incomplete information. As a main characteristic of the model, the decision maker can rationally learn about pecuniary and non-pecuniary net return on migration in different countries by migrating into these countries. Furthermore it is shown that the optimal migration policy can be characterized by a 'simple' procedure, called 'Gittins-index policy'. In the context of our sequential migration model we find more satisfying explanations for some relevant empirical observations (e.g. remigration) than...would be possible within the traditional deterministic approach." (SUMMARY IN FRE AND GER)

Temporary vs. permanent migration: a decision theoretical approach.

"The decision problem of the guest worker as a target saver is considered. He plans to accumulate capital in the host country for investment in the home country after return migration. As the worker is supposed to be incompletely informed about the economic variables in the host country he might prolong his stay unexpectedly provided the economic conditions in the host country are unfavourable. Explicit conditions for the economic variables are given such that temporary migration turns into permanent migration."

A temporary equilibrium model for international migration.

"This paper is concerned with the existence of temporary equilibria of migration with an overlapping generation structure and analyzes some of its properties. In the first part of the paper sufficient conditions for the existence of a temporary equilibrium of migration (in a given period) are given. In the second part some interesting properties of migration equilibria are analyzed. In particular the effects of differing degrees of information of the individuals on migration equilibria are investigated. Furthermore, it is shown that incomplete information alone suffices to induce migration flows even between countries that can be regarded as 'identical' from an economic point of view."

Development of the glycosylphosphatitylinositol-anchoring defect characteristic for paroxysmal nocturnal hemoglobinuria in patients with aplastic anemia.

The introduction of immunosuppressive therapy for treatment of aplastic anemia has led to a considerable improvement in the prognosis of this disease. However, long-term follow-up of these patients showed a high incidence of "late" hematologic complications such as myelodysplasia and paroxysmal nocturnal hemoglobinuria (PNH). The detection of the glycosylphosphatitylinositol (GPI)-anchoring defect on peripheral blood cells of patients with aplastic anemia is now available as a new tool for early specific detection of PNH and is more sensitive than the Ham-test. Granulocytes appear to be the first cells affected in 11 patients with a GPI-anchoring defect of 29 suffering from aplastic anemia investigated in the present study. The later involvement of erythrocytes and a positive Ham test was observed in 1 patient. From our data it can be concluded that the rate of PNH resulting from aplastic anemia might be higher than reported in the literature when the Ham test alone was used for follow-up. Furthermore, our results suggest the clinical response to immunosuppressive therapy appears to be worse in the group developing the GPI-anchoring defect than in the group without this deficiency.

[Chronic coronary artery occlusion--age, morphology and chance of reopening. An attempt to define indications]. / Chronische Koronararterienverschlüsse--Alter, Morphologie und Chance der Wiedereröffnung. Versuch einer Abgrenzung von Indikationen.

In chronic coronary occlusions the rate of successful reopening seems to be improved with the help of new techniques; the chance of success can be judged by the age of occlusion. Frequently this age cannot be fixed exactly. The purpose of the study was therefore to find out, whether the chance of reopening can be judged by morphology. 60 patients in whom the occlusions could not be passed with a conventional wire were treated with the ROTACS system. Cine angios were reviewed carefully, morphological details in at least two projections were evaluated in graphic representations and correlated with the acute success rate and the estimated age of occlusion. Morphological parameters associated with a higher rate of success (type A) were: 1) a clearcut proximal stump with 2) no sidebranches at the site of occlusion, 3) no bridging collaterals and 4) only a slight filling of the distal vessel. Parameters with a low success rate (type B) were: 1) no proximal stump, 2) sidebranches at the site of occlusion, 3) bridging collaterals and 4) a very good distal filling. 48/60 (80%) of occlusions could be classified in type A or type B. The success rate was 17/21 (81%) (type A) versus 5/27 (18.5%) (type B) (p < 0.0002). The estimated age of type B occlusions was significantly higher than in type A: median 8 versus median 4 months (p < 0.002). It is concluded that the rate of success in reopening chronic coronary occlusions can be judged in the majority of patients using morphological parameters.

Treatment of aplastic anemia with antilymphocyte globulin and methylprednisolone with or without cyclosporine. The German Aplastic Anemia Study Group.

BACKGROUND AND METHODS: Immunosuppression is the most effective treatment for patients with aplastic anemia, except for bone marrow transplantation. The best results are achieved with antilymphocyte globulin or cyclosporine. Patients have been treated successfully with a combination of both agents, but there has been no controlled evaluation of its efficacy. We conducted a randomized, multicenter trial in 84 patients not eligible for bone marrow transplantation, comparing treatment with antilymphocyte globulin and methylprednisolone (41 patients--the control group) with antilymphocyte globulin, methylprednisolone, and cyclosporine (43 patients--the cyclosporine group). RESULTS: At three months significantly more patients in the cyclosporine group had a complete or partial remission in response to treatment than did patients in the control group (65 percent vs. 39 percent, P less than 0.03); this difference was confirmed at six months (70 percent vs. 46 percent, P less than 0.05). The superior results of the regimen including cyclosporine were most evident in the patients with severe or very severe aplastic anemia, whose response rate at six months was 65 percent, as compared with 31 percent of such patients in the control group (P less than 0.02). Granulocyte and hemoglobin levels became normal in most patients who responded, but platelet counts continued to be subnormal in 61 percent of the patients. Ten of 52 patients with responses (3 in the cyclosporine group and 7 in the control group) relapsed 4 to 37 months after treatment. The actuarial survival of all patients at 41 months is 64 percent in the cyclosporine group and 58 percent in the control group (P = 0.16); among the patients with severe or very severe disease, survival is 80 percent and 44 percent, respectively (P = 0.077). Cyclosporine had substantial but reversible side effects. CONCLUSIONS: Immunosuppressive treatment of aplastic anemia with antilymphocyte globulin, methylprednisolone, and cyclosporine appears to be more effective than a regimen of antilymphocyte globulin and methylprednisolone without cyclosporine and may thus represent a treatment of choice for patients who are not eligible for bone marrow transplantation.

3D interstitial HDR brachytherapy combined with 3D external beam radiotherapy and androgen deprivation for prostate cancer. Preliminary results.

BACKGROUND: Evaluation of feasibility, tolerance and efficiency for a new 3D interstitial HDR brachytherapy technique combined with 3D external beam radiotherapy and androgen deprivation for prostate cancer. PATIENTS AND METHODS: Between January 1997 and August 1998 we treated 35 patients with stage cT1-3 N0 M0 prostate cancer. Thirty-two patients with a follow-up of 12 to 28 months (median: 18 months) were evaluated. After ultrasound-guided transrectal implantation of 4 non-parallel needles, CT based 3D brachytherapy treatment planning ("Offenbach system") was performed. All patients received 4 fractions brachytherapy using a fractional dose of 5 or 7 Gy. Time between each fraction was 14 days. After brachytherapy 3D external irradiation followed up to 39.6 or 45.0 Gy. All patients received androgen deprivation, starting 2 to 19 months before brachytherapy, ending 3 months after 3D external radiotherapy. RESULTS: Posttreatment PSA levels dropped to < 1.5 ng/ml in 29/32 patients (91%). In 25 patients PSA levels were < 0.5 ng/ml, in 4 patients 0.5 to 1.5 ng/ml. In 2 patients we noted biochemical relapse. Transrectal implantation was very well tolerated. Grade 3 acute urinary toxicity occurred in 1 patient. We noted no Grade 2 or higher acute gastrointestinal toxicity. One patient developed a Grade 3 late urinary toxicity. No patient showed late gastrointestinal side effects. All 140 dose-volume histograms for 3D HDR brachytherapy were analyzed. CONCLUSIONS: The new 3D HDR brachytherapy technique, combined with 3D external irradiation and androgen deprivation, is a feasible, so far well-tolerated and effective treatment in the short-time follow-up of median 18 months.