High-dose chemotherapy with autologous PBSC transplantation for poor prognosis germ cell tumors: a retrospective monocenter analysis of 44 cases.

Germ cell cancer (GCC) is curable in metastatic stages. The International Germ Cell Cancer Collaborative Group (IGCCCG) reports a poor prognosis subgroup with a 5-year survival of 48%. High-dose chemotherapy with PBSC transplantation (HD-PBSCT) in these patients showed promising results in phase II, but failed to show significant advantage in randomized trials. We report our monocenter series of all poor and selected intermediate prognosis germ cell tumor patients treated with multiple-course HD-PBSCT and secondary surgery of remaining tissue. We performed a retrospective analysis of our complete series of 44 patients (40 poor prognosis and 4 intermediate prognosis) treated by HD-PBSCT as part of first-line therapy from 1999 to 2010. The CR rate after up to four cycles of HD-PBSCT and radical resection of residual manifestations was 73%. The 3-year survival rate was 79.5% (median follow-up of 51.5 months; range: 7-143 months). Disease-related death rate was 16%. HD-PBSCT-related death did not occur. One patient died postsurgery. Multiple courses of HD-PBSCT with radical secondary surgery is safe and effective in poor prognosis metastatic GCC. Despite disappointing phase III studies it is of high interest to further study this field.

Dose-escalated CHOEP for the treatment of young patients with aggressive non-Hodgkin's lymphoma: I. A randomized dose escalation and feasibility study with bi- and tri-weekly regimens.

BACKGROUND: To determine the maximum tolerated dose of a bi- and tri-weekly combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone plus etoposide (CHOEP) regimen without stem-cell support. PATIENTS AND METHODS: Randomized phase I/II multicenter four-level (cyclophosphamide: 1000-1200-1400-1600 mg/m2; doxorubicin: 55-60-65-70 mg/m2; etoposide: 375-450-525-600 mg/m2) dose escalation study with CHOEP-14 and CHOEP-21 in young patients (18-60 years) with newly diagnosed aggressive non-Hodgkin's lymphoma. Dose-limiting toxicity was defined as thrombocytopenia <80,000/mm3 and leukocytopenia <2500/mm3 on days 16 (CHOEP-14) and 23 (CHOEP-21) or prolonged (>4 days) leukocytopenia (<1000/mm3) or thrombocytopenia (<20,000/mm3). RESULTS: One hundred and thirty-nine patients (high-CHOEP-14: 47, high-CHOEP-21: 92) were randomly allocated to the study. Maximal tolerated dose was level 2 for CHOEP-14 and level 4 for CHOEP-21. With a less favorable profile of patients in CHOEP-14, 4-year event-free survival was 47.9% after high-CHOEP-14 and 66.2% after high-CHOEP-21, 4-year overall survival 62.1% after high-CHOEP-14 and 73.4% after high-CHOEP-21, respectively. CONCLUSION: Significant dose escalations of CHOEP are possible with granulocyte colony-stimulating factor support, with different chemotherapy models favoring the maximally escalated bi- or tri-weekly regimen, respectively. Because a higher total dose can be achieved with six cycles of the tri-weekly compared with the biweekly regimen, CHOEP-21 at dose escalation level 3 was chosen for a nationwide randomized comparison with baseline CHOEP-21 in a subsequent phase III trial.

Circulating angiopoietin-2 is a strong prognostic factor in acute myeloid leukemia.

Angiogenesis plays an important role in solid tumors and hematologic malignancies. The angiopoietins act as essential regulators in this process. We investigated the impact of circulating angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2) and soluble Tie2 (sTie2) on overall survival in patients with acute myeloid leukemia (AML). Ang-1, Ang-2 and sTie2 were measured in plasma samples from 68 AML patients and 11 controls using enzyme-linked immunosorbent assay. Circulating levels of Ang-2 and sTie2 (median (range): 1098.0 (361.4-4147.6) pg/ml and 3.40 (1.21-10.00) ng/ml, respectively) were significantly elevated in AML patients as compared to controls (307.9 (199.7-1225.0) pg/ml and 2.88 (1.71-3.29) ng/ml; P<0.001 and P=0.014). In a univariate Cox proportional hazards model, higher levels of Ang-2 and sTie2 were predictive of poor survival. In multivariate analyses, Ang-2 and cytogenetics proved to be independent prognostic factors, with a relative risk of 4.07 (95% confidence interval (CI) 1.88-8.81) and 2.70 (95% CI 1.25-5.81), respectively. The 3-year survival rate for AML patients with Ang-2 levels>/=1495.6 pg/ml was only 14.7% compared to 64.7% for those with Ang-2 levels<1495.6 pg/ml. These data provide evidence that circulating Ang-2 represents an independent prognostic factor in AML and may be used as a prognostic tool in the risk-adapted management of AML.

[Cardiorespiratory effects of heliox using a model of upper airway obstruction]. / Kardiorespiratorische Effekte von Heliox an einem Modell der oberen Atemwegsobstruktion.

Heliox is a mixture of Oxygen and Helium. The low density of Helium allows this mixture to flow in a laminar pattern where oxygen, nitrogen or air flow would be turbulent. Therefore the force necessary to move a volume of gas (e.g. Heliox) is greatly reduced in comparison to a turbulent gas flow. In a respiratory loading experiment we investigated the effects which Heliox exerts on hemodynamic as well respiratory variables. 10 volunteers were breathing spontaneously and through three different endotracheal (ET-) tubes (ID 4.0, 4.5, 5.0 mm). The subjects were switched from room air to Heliox and differences in the variables heart rate (HR), blood pressure (BP), stroke volume (SV), stroke index (SI), peripheral vascular resistance (TPRI) and left ventricular work index (LVWI) were measured. Furthermore the (PhAng) between abdomen and thorax was detected using respiratory inductance plethysmography (n=2) and the sense of dyspnoe under the different conditions was assessed by the use of a dyspnea score (DS). The means of BP, SV, SI, TPRI and LVWI did not significantly differ between the resting and the different loading conditions irrespective of the gas that was used. The variability of hemodynamic measures was significant larger during loaded vs. unloaded breathing. Heliox could significantly reduce this degree of variability. In two subjects Heliox could also significantly reduce the PhAng as well as DS. Heliox showed effects on hemodynamic as well as respiratory and subjective variables. These effects can be interpreted as a reduction of the extent of pressure variations in the intrapleural space leading to less impact on hemodynamic variables while breathing Heliox vs. room air in a resistive loading experiment. In the future the combined measurement of hemodynmic variables as well as non-invasive assessment of respiration might shed new light on cardio-respiratory interaction and effects of Heliox during airway obstruction.

Combination chemotherapy with gemcitabine plus oxaliplatin in patients with intensively pretreated or refractory germ cell cancer: a study of the German Testicular Cancer Study Group.

PURPOSE: Long-term survival is rarely achieved in patients with cisplatin-refractory germ cell cancer (GCT). Both single-agent gemcitabine and oxaliplatin have shown activity in patients who experience relapse or are refractory to cisplatin treatment. This study investigates the activity of a gemcitabine plus oxaliplatin regimen in these patients. PATIENTS AND METHODS: Gemcitabine was administered at a dose of 1,000 mg/m(2) on days 1 and 8; oxaliplatin was administered at a dose of 130 mg/m(2) on day 1. Response was evaluated every 4 weeks. RESULTS: Thirty-five patients with a median age of 37 years (range, 21 to 54 years) were enrolled onto the study. Primary tumor localization was gonadal, retroperitoneal, or mediastinal in 30, one, and four patients, respectively. Patients had been pretreated with a median of six platinum-containing cycles (range, four to 13 cycles) and 89% of patients previously had experienced treatment failure after high-dose chemotherapy with peripheral-blood stem-cell transplantation. Sixty-three percent of patients were considered absolutely cisplatin-refractory or cisplatin-refractory. A median of two cycles (range, 1 to 6 cycles) per patient were applied. Toxicity consisted mainly of myelosuppression, with Common Toxicity Criteria grade 3 occurring in 54% of patients. Only 9% of patients developed neutropenic fever. Three patients attained a complete remission (CR), two patients attained a marker-negative partial remission, and 11 patients attained a marker-positive partial remission, resulting in an overall response rate of 46% (95% CI, 30% to 64%). All three patients with CR and one patient with a marker-negative partial remission remained disease free at 16+, 12+, 4+, and 2+ months of follow-up. Seven (44%) of these 16 responses, including one CR, occurred in cisplatin-refractory patients. CONCLUSION: Gemcitabine plus oxaliplatin demonstrates antitumor activity with acceptable toxicity in heavily pretreated patients with relapsed or cisplatin-refractory GCT, and may offer a chance of long-term survival for selected patients.

[Verapamil sensitive ventricular tachycardia with myocardial failure in a 2-year-old child]. / Verapamilsensitive ventrikuläre Tachykardie mit myokardialer Funktionseinschränkung bei einem zweijährigen Kind.

UNLABELLED: Ventricular arrhythmias can both result from and cause myocardial dysfunction. We report a case of a two-year-old girl with ventricular tachycardia showing signs of heart failure consisting with a tachycardiomyopathy. The therapy with class I and class III antiarrhythmic drugs did not improve the cardiac situation significantly. The cardiologic investigations were consistent with the verapamil-sensitive ventricular tachycardia in young adults. The treatment with verapamil led to a normal rhythm and function of the heart. CONCLUSION: Verapamil-type calcium channel blockers can also be used in children for the treatment of ventricular tachycardias if the corresponding investigations show characteristic findings.

Plant regeneration from mesophyll and suspension protoplasts of Silybum marianum.

Mesophyll protoplasts of six lines of Silybum marianum were enzymatically isolated from young leaves, embedded in sodium alginate, and cultivated in KM-medium. Division frequencies observed after ten days were strongly influenced by the protoplast density. When 5 x 10 (4)/ml protoplasts were plated, division frequencies of about 35% were obtained, with a protoplast population density of 1 x 10 (5)/ml division frequencies of about 75% resulted. Plant regeneration experiments undertaken with the protocalluses on medium containing BAP led to shoot formation in only two lines with regeneration frequencies of less than 1% in one (M 24) and up to 7% in a second line (M 2), respectively. However, when the protocalluses from line M 2 were treated with thidiazuron (TDZ) in a first culture step, and with BAP in a second step, the shoot formation frequency rose to 22%. Shoots were rooted on hormone free MS agar medium and transferred into soil where plants grew to maturity. Similar results were obtained when protoplasts of the line M 2, isolated from a suspension culture, were cultivated.

Genetic investigations on Silybum marianum and S. eburneum with respect to leaf colour, outcrossing ratio, and flavonolignan composition.

In crossing experiments between S. marianum and S. eburneum the number of fruits produced was relatively high as compared to the two parental species. All the F(1)-plants showed the variegated leaf characteristic of S. marianum, whereas after selfing the F(2)-plants had completely green and variegated leaves in a ratio of about 3:1 indicating that the leaf colour is monofactorially inherited. This proves that the two species are only variants. Using leaf colour as the genetic marker, the outcrossing rate in field experiments was studied. Since the outcrossing rate on average is only about 2%, SILYBUM is predominantly a self-pollinator. From 11 randomly selected plants, three inbred generations were produced and their silymarin composition (silibinin, silidianin, silichristin) was studied. Two types of lines could be distinguished based on the relative values of three flavonolignans: lines with approximately 70% silibinin, 30% silichristin, and traces of silidianin in all inbred generations and those with the relative contents of the compounds 30%, 57%, and 13%, respectively.

Prolapsed valve of the foramen ovale in newborns and infants with coarctation of the aorta.

Out of 60 newborns and infants with symptomatic coarctation of the aorta, 34 had a significant left-to-right shunt at atrial level. In 20 of these 34 children, the atrial shunt had disappeared after surgical correction of the coarctation. All patients with this "reversible" shunt, thought to be secondary to an incompetent valve of the foramen ovale, were younger than 35 days at first cardiac catheterization. Left atrial pressure and left atrial volume of these patients did not differ significantly from those in a control group without atrial shunt. The conditions necessary for the development of a valve-incompetent foramen ovale include not only an increased left ventricular work load, but also a thin and pliable valve of the foramen ovale. It is only in infants younger than one month of age that the valve is thin and pliable enough to prolapse through the foramen ovale and form a channel between the two atria, which results in a left-to-right atrial shunt.

Formation of Artemisinin in Artemisia annua During One Vegetation Period*,1.

In order to investigate the possibility of isolating greater amounts of the antimalarial compound artemisinin (quinghaosu), plants of ARTEMISIA ANNUA were cultivated and analysed at different stages of development. We found the highest content just before flowering. It was also possible to correlate development of the plants with the maximum content of artemisinin. ARTEMISIA ANNUA plants cultivated from various other sources were also examine for artemisinin content. According to our results, none of these plants contained sufficient amounts of artemisinin to justify an isolation on a technical scale. Furthermore other Artemisia species were tested. We found artemisinin in only one other species. To possibly increase the amount of artemisinin during the growth period of the plant, we tested two hormone-type growth regulators on A. ANNUA strain 811. The results showed that one of them, chlormequat, was able to increase the artemisinin content by 30% over untreated plants. We also found some slight effects of the growth regulators on morphological criteria of glandular trichomes.

[Acute course of Leigh syndrome with hypertrophic cardiomyopathy in a female infant]. / Akuter Verlauf des Leigh-Syndroms mit hypertropher Kardiomyopathie bei einem weiblichen Säugling.

A female infant already as a newborn progressively developed nutritional disturbances, metabolic acidosis, muscular hypotension and other neurologic changes, and on its 20th day of life suffered from an acute cardiac and respiratory insufficiency due to pericardial effusions causing cardiac tamponade. In spite of intensive care including mechanical ventilation the child died on the 58th day of life. Cardiac changes and cranial CT-scans are demonstrated. The characteristic symptomatology as well as blood chemistry led to the tentative diagnosis of Leigh's disease. Postmortem examination confirmed this diagnosis.

[The treatment of arrhythmias in infants and children using propafenone]. / Die Behandlung von Herzrhythmusstörungen mit Propafenon bei Säuglingen und Kindern.

Antiarrhythmic treatment was required in 35 patients aged one day to 11 8/12 years (average 5 7/12 years) for one or several of the following arrhythmias: paroxysmal supraventricular tachycardia (17), ventricular extrasystole (16), ventricular tachycardia (17), ventricular extrasystole (16), ventricular tachycardia (4), junctional tachycardia (4), and atrial flutter (3). 300 mg/m2/day oral propafenone was administered in 3 to 4 divided doses. The arrhythmia in 21 of the 35 patients had been unsuccessfully treated by digoxin (6), verapamil (5), ajmalin (4), propranolol (3), spartein (1), phenytoin (1), and lidocain (1) prior to the propafenone therapy. However, the arrhythmias could be abolished or reduced in 30 patients (85.7%) by Propafenone. In 5 patients with supraventricular tachycardia (2), junctional tachycardia (2), or ventricular extrasystole (1), propafenone therapy had no effect. In two other patients propafenone led to atrioventricular conduction disturbances and had to be discontinued. Propafenone is an effective well tolerated antiarrhythmic drug without major side effects in pediatric patients.