Treatment of adolescents and young adults (AYA) with cancer in a multidisciplinary setting: on the way to a highly specialized AYA unit.

Further survival improvements of adolescents and young adults (AYA) with cancer are clearly affected by biological characteristics of the malignancies and age-specific needs. Multidisciplinary teams drawing expertice from both pediatric and adult cancer teams as well as clinical trials are required to meet the age specific needs of AYA patients with cancer. In 2011, the first AYA unit was established at the University Hospital Halle (Saale), where patients with newly-diagnosed cancer aged 15-25 are treated interdisciplinary by pediatric and adult oncologists. The enrollment into pediatric or adult clinical trials is controlled by age 18. Over the last 2 years, 19 AYA with cancer have been treated at the unit; and, in turn patients and their relatives reflected a high satisfaction with the offered novel health care approach. In the scope of the future Comprehensive Cancer Center at the University Hospital Halle (Saale), a complete ward is planned for all admitted AYA up to 25 years with cancer. The patients will be treated by a tumor-specialized multidisciplinary team of adult or pediatric oncologists and oncological surgeons. Therefore, we intend to establish a special teaching curriculum for physicians, nurses and psychosocial health care staff. Rather than age, cancer biology of a malignancy, surveillance data of late side effects as well as the age-specific needs of AYA patients will be crucial for best treatment options.

Molecular mechanisms of hyperthermia- and cisplatin-induced cytotoxicity in T cell leukemia.

BACKGROUND: The prognosis of early and very early relapse in acute lymphoblastic leukemia of childhood is still very poor unless a hematopoietic stem cell transplant is performed if a second remission can be achieved by induction chemotherapy. Therefore an intensification of chemotherapy is required. MATERIALS AND METHODS: In the present study the molecular mechanisms of cisplatin- and/or hyperthermia-mediated cytotoxicity in CEM cells, a human T leukemia cell line, were investigated. RESULTS: Both hyperthermia and cisplatin induced the activation of the effector caspases-3 and -6. However, caspase activation followed different time kinetics. While hyperthermia exerted maximum caspase activation immediately after application, cisplatin activated caspase-3 and -6 after 24 hours. At both time-points significant caspase-3 and -6 activation was observed when the cells were stimulated by a combination of heat and cisplatin. The application of z-VAD-fmk, a general caspase inhibitor, showed that hyperthermia mediated cytotoxicity mainly via caspase-dependent mechanisms, while cisplatin induced both caspase-dependent and -independent cytotoxicity. Time kinetic experiments revealed that hyperthermia induced cell death immediately after the heating pulse. In contrast, cisplatin-induced cell death had its maximum between 6 hours and 12 hours after the heating pulse. The combined application of heat and cisplatin induced two peaks of cytotoxicity, one immediately after the heating pulse and the other between 6 hours and 12 hours. CONCLUSION: Hyperthermia and cisplatin induced cell death in T leukemic cells by different molecular mechanisms, which might explain the enhanced cisplatin-induced cytotoxicity by hyperthermia.

Mechanisms of hyperthermia- and 4-hydroperoxy-ifosfamide-induced cytotoxicity in T cell leukemia.

The prognosis of patients with early ALL (acute lymphoblastic leukaemia) relapse is poor with conventional chemotherapy alone. Thus, intensified chemotherapy strategies are required. The application of hyperthermia enhances the efficacy of certain antineoplastic drugs such as ifosfamide. In this study, the effects and molecular mechanisms of ifosfamide (4hydroperoxy-ifosfamide = 4OOH-IFA)- and/or hyperthermia-induced cell death are investigated in CEM cells. Hyperthermia enhanced the efficacy of 4OOH-IFA in a subaddictive manner. Analysis of caspase activation revealed an early hyperthermia-induced stimulation of caspase-3 and -6 directly after the heating pulse, while maximum activation following stimulation with 4OOH-IFA was obtained after 24 hours of culture. The combination of 4OOH-IFA and hyperthermia mediated an overaddictive caspase stimulation directly following the heating phase. At this time also an overaddictive cytotoxic effect was noticed, being mainly responsible for the enhancing effects of hyperthermia on 4OOH-IFA cytotoxicity. In conclusion, hyperthermia enhanced the cytotoxic effect of 4OOH-IFA on CEM cells by stimulation of an early 4OOH-IFA effect. Thus, thermochemotherapy might be considered as an intensifying treatment option in relapsed T cell leukemias.

[Preventive long-term intravenous immunoglobulin infusion in children with acute lymphatic leukemia. I. Anticomplementary activity of gamma globulin preparations is a function of the preparation and IgG concentration prior to infusions]. / Prophylaktische Langzeit-i.v.-Immunglobulin-Infusion bei Kindern mit akuter lymphatischer Leukämie. I. Die antikomplementäre Aktivität der Gammaglobulinpräparate ist eine Funktion des Präparates und der IgG-Konzentration prae infusionem.

The influence of intravenous gammaglobulin infusions (ivGG) on hemolytic complement function and the concentration of serum C3 and its split product C3dg was studied in 20 children with acute lymphocytic leukemia (ALL) undergoing ivGG prophylaxis. IvGG was infused once monthly over a period of 20 months using two different preparations commercially available. Serum and EDTA-plasma were collected before initiation of ivGG therapy (time 1), after 10 and 20 months (time 2 and 3), before and immediately after the infusions. IvGG was infused in connection with chemotherapy (according to the CoAll 82 protocol). 16 of 60 sera collected prior to infusions contained less than 700 mg/dl IgG. Mean IgG concentrations could be raised to 198 mg/dl (time 1), 219 mg/dl (time 2), and 213 mg/dl (time 3), respectively. -CH 50 prior to infusions was below normal in 15 of 59 sera, afterwards in 25 of 59 sera. AP 50 before (after) infusions was decreased in 29 of 59 (36 of 60) sera, C3 in 18 of 60 (24 of 60) sera. C3dg was slightly elevated in one EDTA-plasma prior to ivGG infusions and in 5 of the plasmas following infusions. IvGG infusions resulted in a significant loss of hemolytic activity of serum complement (p less than 0.01, F-test). The effect was more profound if IgG concentrations before infusions were less than 700 mg/dl, but this was true for only one of the two used ivGG preparations. The long term follow up over two years showed no significant changes of complement functions (F-test), indicating complete recovery of complement function from short term anticomplementary effects.

[Significance of immune complexes in children with severe hemophilia A in substitution treatment with factor VIII concentrates]. / Bedeutung von Immunkomplexen bei Kindern mit schwerer Hämophilie A unter Substitutionsbehandlung mit Faktor VIII-Konzentration.

Sera and EDTA-Plasma of patients with severe Haemophilia A were analysed for immune complexes and the hemolytic activity of complement in relation to Factor VIII replacement, in order to confirm or possibly exclude a relationship to allergic reactions. Immune complexes were isolated by PEG precipitation and quantitated. In addition a solid phase ELISA assay was used to detect complement-binding complexes. Total hemolytic complement activity of the classical and the alternate pathway was measured in addition to the C3 splitproduct C3d. The results obtained from 12 patients with severe Haemophilia A showed slightly increased immune complex titers, no changes of the immune complex levels during Factor VIII replacement and no alteration of the complement system following the infusions. One patient developed an allergic reaction without evidence of complement activation.

Anaphylaxis to L-asparaginase during treatment for acute lymphoblastic leukemia in children--evidence of a complement-mediated mechanism.

L-Asparaginase (l-Asp) is widely used as an effective drug against childhood and adult acute lymphoblastic leukemia (ALL). However, it is immunogenic in humans and may lead to hypersensitivity reactions. The immunological basis of these reactions is not clear. Since the presence of l-Asp specific IgG-antibodies seems to correlate better with clinical reactions than IgE-antibodies and IgG-antibodies are known to be able to fix and activate the complement system, we speculated that the mechanism of anaphylaxis may be complement- rather than IgE-mediated. We analyzed 24 children with ALL (age 2-15 yr) for changes in the complement system during l-Asp infusions. Chemotherapy was administered according to the CoALL 82 protocol which is derived from the CoALL 80 protocol recently published. The formation of specific antibodies of IgM and IgG classes against l-Asp was monitored by a solid phase ELISA. The immunological responsiveness of individual patients varied over a wide range but both types of antibodies were induced. Anaphylactic reactions were observed on eight occasions in eight children. The infusions in the remaining 16 patients were tolerated without clinical reactions. Significant activation of complement was demonstrated in seven of eight reaction occasions and in none of the occasions without reactions. The most important complement activation parameter monitored was the C3 split product C3d measured in EDTA-plasma. We conclude that anaphylaxis to l-Asp in patients with ALL can be explained in most instances on the basis of complement activation induced by the formation of immune complexes of l-Asp and specific antibodies of IgM and IgG classes.