Rolf Mertens

Visceral Leishmaniasis in a German Child Who Had Never Entered a Known Endemic Area: Case Report and Review of the Literature

We describe a case of visceral leishmaniasis in a 15-month-old German child. Diagnosis was significantly delayed because the patient had no history of travel to known endemic areas. Congenital or blood transfusion-associated leishmaniasis was ruled out. Possible modes of transmission (including a potential new autochthonous focus of the disease in central Europe) are discussed.

Effect of intraarterial versus intravenous cisplatin in addition to systemic doxorubicin, high-dose methotrexate, and ifosfamide on histologic tumor response in osteosarcoma (study COSS-86)

In osteosarcoma, intraarterial (IA) administration of systemic treatment has been advocated to improve local tumor response preparing for, or even obviating, definitive surgery. Because data from the literature did not unequivocally support the local superiority of IA infusion, a comparative study was started in 1986. Preoperative chemotherapy consisted of 45 mg/m2 of doxorubicin on days 1 and 2; 12 g/m2 of high‐dose methotrexate on days 15 and 22; and 3 g/m2 of ifosfamide on days 29, 30, 50, and 51 followed on days 31 and 52 by intravenous (IV) versus IA tourniquet infusion of cisplatin (DDP). A strict randomization of patients was not feasible. A balanced distribution of risk factors was strived for by stratifying and allocating the appropriate patients centrally. The infusion time was prolonged from 1 to 5 hours in the IV group, and the DDP dose was reduced from 150 to 120 mg/m2 in both arms when intolerable ototoxicity became apparent. A multivariate analysis was performed to exclude a bias on the response rates from risk factor distribution and from modifications of DDP infusion time and dosage. The overall fraction of histologic good responders (> 90% necrosis) was not found to be different after IA versus IV treatment (34/50 [68%] vs. 41/59 [69%]). Intraarterial instead of IV use of DDP within an aggressive systemic treatment does not seem to improve the local tumor response.

Treatment of nasopharyngeal carcinoma in children and adolescents: definitive results of a multicenter study (NPC-91-GPOH).

Preliminary results of combined neoadjuvant chemotherapy, radiotherapy, and postradiation interferon beta (IFN‐β) in children and adolescents with nasopharyngeal carcinoma, especially in high‐risk patients, have been promising.

Molecular interaction of artemisinin with translationally controlled tumor protein (TCTP) of Plasmodium falciparum

Malaria causes millions of death cases per year. Since Plasmodium falciparum rapidly develops drug resistance, it is of high importance to investigate potential drug targets which may lead to novel rational therapy approaches. Here we report on the interaction of translationally controlled tumor protein of P. falciparum (PfTCTP) with the anti-malarial drug artemisinin. Furthermore, we investigated the crystal structure of PfTCTP. Using mass spectrometry, bioinformatic approaches and surface plasmon resonance spectroscopy, we identified novel binding sites of artemisinin which are in direct neighborhood to amino acids 19-46, 108-134 and 140-163. The regions covered by these residues are known to be functionally important for TCTP function. We conclude that interaction of artemisinin with TCTP may be at least in part explain the antimalarial activity of artemisinin.

Acute leukemia with chromosome translocation (4; 11): 7 new patients and analysis of 71 cases

SummaryClinical and laboratory features of seven patients with acute leukemia associated with the (4; 11) chromosome translocation are presented. Leukemic blasts of these patients showed lymphoid morphology in 6 (although 1 was treated for monoblastic leukemia 3 years earlier) and monocytoid morphology in 1, were positive for TdT and HD 37 (CD 19) in 6 patients, whereas weak expression of CALLA was seen in only 1 patient and T-lineage-associated antigens in none. Leukemic blasts from four patients showed the simultaneous expression of B-lymphoid and myeloid antigens, suggesting leukemogenesis in a very early multipotent progenitor cell. In 2 patients an isochromosome of the long arm of No. 7 chromosome was found in the leukemic karyotypes in addition to t (4; 11) (q21; q23); in one instance present at diagnosis, in the other one occurring at relapse. In one other patient leukemia karyotype also demonstrated trisomy 8. Leukemic cells of three patients were investigated by molecular genetics and demonstrated immunoglobulin gene rearrangements for the Ig heavy chain sequences but not for the light chain constant regions and T cell receptor sequences. All patients were treated by intensive chemotherapy. Four of the 7 patients are in continuous complete remission. The longest event-free survival time (over 2 1/2 years) was seen in one patient who had also DOWN-syndrome. Including these 7 patients a clinical analysis of 71 patients with t (4; 11) acute leukemia was made, emphasizing the following characteristics at diagnosis: female sex (62%), age under 2 years (49%), leukocyte count over 100×109/1 (61%), splenomegaly (80%), CNS-disease (11%). Survival of over 2 years was reported in less than 15% of the patients. It remains to be seen if risk-adapted treatment can alter the course of this early B-precursor acute leukemia with hitherto very bad prognosis.

Unusually long survival time after resection and irradiation of a brain metastasis from osteosarcoma

Cerebral metastases of osteosarcomas are rare. The cases published up to now have manifested only a short relapse-free period of survival. Intracranial filia generation must be anticipated if metastasis formation takes place in the lung.We report here on a young patient who underwent operation for an intraparenchymal cerebral metastasis 76 months after amputation of the left leg due to an osteosarcoma chondroblasticum, and who is, at present, healthy, 13 months after resection. This unusually long survival time is attributed to the good neurological status before craniotomy, early diagnosis, and the improvement of the cytostatic therapy (COSS-80-scheme).

CT-guided percutaneous large-bore biopsies in benign and malignant pediatric lesions

Thirty-nine consecutive pediatric patients underwent large-bore biopsies of 41 lesions under computed tomography (CT) guidance; general anesthesia was not required. Adequate material was obtained in all patients. There were no false-netative or false-positive results. Typing accuracy was 100% in malignant disease and 92% in benign lesions. No significant complications occurred. Percutaneous large-bore biopsy is a safe, reliable, and time-saving method that obviates the need for open surgery and general anesthesia in the diagnosis of primarily non-resectable lesions, or lesions that do not require resection. Another major advantage over open surgery in malignant disease is the absence of delay in starting urgently needed chemotherapy.

Abstract 1993: Fishing for artemisinin-interacting proteins from human nasopharyngeal cancer cells

Determining cellular target molecules of drugs by chemical proteomic techniques is complex and tedious. Most approaches rely on activity-based probe profiling and compound-centric chemical proteomics. The antimalarial artemisinin also exerts profound anti-cancer activity, but the mechanisms of action are incompletely understood. In the present study, we have identified artemisinin-interacting target proteins from human nasopharyngeal carcinoma cell line CNE1. Thereby, our approach overcomes usual problems in traditional fishing procedures, because the drug was attached to a polystyrene surface without further chemical modification. Using mass spectrometry we have identified 20 proteins which effect cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. One protein out of the twenty was further investigated in vitro for direct ligand binding. Furthermore, a blind-docking based approach confirmed experimentally identified proteins and suggested further interacting proteins. Theoretically predicted interaction partners may serve as a starting point to complete the whole set of proteins binding artemisinin. In our investigations, we have comprised artemisinins role in cancer treatment in a greater shape through a systematic biological strategy and thus, are able to show novel insights into its mode of action. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1993. doi:1538-7445.AM2012-1993

Femurkopfnekrose als Komplikation der ALL-Therapie bei Kindern und Jugendlichen

Akute Leukämien sind die häufigsten malignen Erkrankungen des Kindesalters: ca. 4 von 100.000 Kindern bis zum vollendeten 14. Lebensjahr erkranken jährlich neu, dies entspricht etwa 600 Neumanifestationen pro Jahr in Deutschland und ca. 2000 pro Jahr in den USA [16, 31]. Ein Drittel aller malignen Erkrankungen im Kindesalter sind akute Leukämien: 80–85% davon akute lymphoblastische Leukämien (AML).Mit Hilfe moderner Therapieverfahren, v. a. der kombinierten zytostatischen Therapie, konnte die Prognose der Erkrankung im Laufe der letzten Jahrzehnte erheblich verbessert werden. Die rezidivfreie Überlebensrate nach 5 Jahren liegt in Deutschland derzeit bei 70–75% [16]. In Anbetracht dieser ausgezeichneten Prognose gewinnt die Frage nach der Lebensqualität nach überstandener Erkrankung an Bedeutung.Die Autoren möchten anhand der hier dargestellten Kasuistiken auf eine mögliche Folge der ALL-Therapie hinweisen, und zwar auf die im pädiatrischen Krankengut v.a. bei jugendlichen Patienten zu beobachtende Hüftkopfnekrose, deren Auftreten nicht selten mit einer dauerhaften Behinderung des betroffenen Patienten einhergeht.

Partielle Milzembolisation bei Kindern mit Hypersplenismus unterschiedlicher Genese

ZusammenfassungFragestellung: Die Splenektomie stellt lebenslang ein erhöhtes Risiko dar, an einer Postsplenektomiesepsis zu erkranken. Das Risiko bis zu 10% ist bei Patienten, die im Alter von weniger als 5 Jahren splenektomiert wurden, besonders hoch. Als Alternative zu den chirurgischen Verfahren Splenektomie und Hemisplenektomie bei Patienten mit Hypersplenismus wird die partielle Milzembolisation vorgestellt. Methode: Bei 4 Kleinkindern im Alter von 13–84 Monaten (Median 43 Monate) mit Hyperspleniesyndrom unterschiedlicher Genese wurde eine selektive Milzembolisation erfolgreich durchgeführt. Die partielle Embolisation erfolgte durch eine Verabreichung von 150–250 µm großen Ivalonpartikeln nach selektiver Katheterisierung der Milzarterienäste 2. Ordnung, wodurch ein peripherer Verschluß einzelner Milzsegmente gelang. Schmerzkrisen und infektiologische Komplikationen konnten in der Postembolisationsphase durch eine konsequente analgetische Behandlung mit einer mehrtägigen Morphindauertropfinfusion und Antibiotikagaben (Tobramycin und Ampicillin) vermieden werden. Bei einem Patienten traten unmittelbar nach der Embolisation eine kurzzeitige Ileussymptomatik und eine Fieberepisode auf. Alle Patienten konnten nach 5–10 Tagen entlassen werden. Ergebnisse: Wenige Tage nach der Embolisation stiegen Hämoglobin, Leukozyten und Thrombozyten bei allen Patienten an. Weitere Erythrozyten- bzw. Thrombozytentransfusionen waren nicht mehr erforderlich. Ein Patient mit unklarem Dysmorphiesyndrom, Gedeihstörung, nicht klassifizierbaren Immundefekt, Karnitinmangel und Verdacht auf eine Lymphohistiozytose wies in der Nachbeobachtungszeit stabile Blutwerte (Leukozyten >5×103/µl und Hämoglobin >10 g/dl) auf. Der Patient starb 26 Monate nach der Embolisation an einer therapierefraktären Pneumonie und Sepsis mit Verbrauchskoagulopathie bei einer seit 8 Monaten bekannten Atelektase der rechten Lunge. Die übrigen 3 Patienten befinden sich in einem guten Allgemeinzustand mit einer mittleren Beobachtungszeit von 32 Monaten. Schwere Infektionen wurden nicht mehr beobachtet. Ein erneutes Hyperspleniesyndrom wurde bisher bei keinem Patienten beobachtet. Schlußfolgerung: Eine partielle Milzembolisation stellt beim dauerhaft transfusionspflichtigen Hyperspleniesyndrom im Kindesalter eine risikoarme, unter konsequenter Analgesie wenig schmerzhafte Alternative zur Hemi- bzw. Splenektomie dar.SummaryProblem: Splenectomy in young patients leads to a high rate of overwelming postsplenectomy infection. In addition, the immunologic competence of young children does not evolve as usual, resulting in an increased risk for certain bacterial infections. Here we present partial splenic embolisation for hyperplenism as an alternative to surgical splenectomy. Method, patients: In 4 children (age 13 to 84 month, median 43 months) with severe hypersplenism of various origin a selective splenic embolisation was performed suc-cessfully. By selective catheterisation low-molecular-weight particles were injected into splenic arteries. This partial embolisation led to a segmental occlusion of peripheral splenic areas. After the procedure the patients received morphine infusions as analgesic and an antibiotic treatment with ampicillin and tobramycin, so that either attacks of pain nor infections occured One patient developed brief ileus symptoms and fever directly after embolisation. The patients were discharged after 5 to 10 days. Results: Hematologic parameters improved within a few days in all patients, thus transfusions were no longer necessary. One pa- tient with an unidentified syndrome with dysmorphia died of pneumonia and septicemia 26 months after embolisation. At this time he had developed histological signs of lymphohistiocytosis as underlying disease. Three patients are in a good condition now with markedly reduced susceptibility to infection after a mean observation period of 30 months. A relapse of hypersplenism was not seen under regular follow-up, hemato-logic parameters remained normal or improved in one patient. Conclusion: In our opinion partial splenic embolisation in children with hyperplenism requiring frequent transfusions is an alternative to splenectomy, being less invasive and with fewer risks.