Nasopharyngeal carcinoma (NPC) is a rare disease in children with good prognosis and high cure rate. Nevertheless, certain patients have an unfavorable prognosis due to development of refractory NPC that is unresponsive to any therapeutic strategies. The current study studies a case of a 17 years-old female with non-keratinizing NPC type IIb (T2N0M0), who passed away as a consequence of resistance to chemo-, radio- and β-interferon therapy, and to an allogenic stem cell transplantation. In order to identify factors that lead to treatment failure and fatal outcome, immunohistochemical analyses of different tumor biomarkers and hierarchical cluster analysis were performed and compared with those of eight other patients with NPC who experienced complete remission following conventional therapy. Hierarchical cluster analysis of the immunohistochemical results clearly demonstrated that staining for immunological factors (CD4, CD8 and CD56) distinguished this patient from the others. To further investigate a potential role of the immune system, lymphocytic infiltration was assessed in tumor tissue by evaluation of hematoxylin and eosin-stained tumor sections. Indeed, no tumor infiltrating lymphocytes (TILs) were observed in this NPC case, while 7 out of 8 of the other NPC samples contained variable TIL amounts. The view that immunodeficiency of the patient may be a factor in the fatal outcome of treatment is supported by the fact that this patient with NPC was not positive for Epstein-Barr virus markers and also infected by several other viruses and fungi (herpes simplex virus, human herpes virus 6, Varicella zoster virus, and Candida). In conclusion, the investigation of rare NPC cases with poor prognosis may provide an improved understanding of the molecular mechanisms involved in refractory tumors and identification of novel potential therapeutic targets for NPC in the future.

Therapies targeting p53 mostly concentrate on (re)activation of the p53 protein, to further induce apoptosis in cancer cells. In the present investigations, the focus was on the identification of small molecules that block the DNA-binding domain of p53 and thus inhibit its function. Using high-throughput in silico screening of approximately 300,000 compounds, we identified eight putatively interacting with the DNA-binding domain of p53. Subsequently, HCT116 p53 wild-type (p53(+/+)) and knockout (p53(-/-)) cells were irradiated with 16 Gy and treated with these compounds. Among the eight compounds, NSC 23175 offered the best protection against γ-irradiation-mediated injury. Microarray-based mRNA expression profiling revealed many downstream p53-dependent genes in irradiated and NSC 23175-treated p53(+/+) cells. Using a luciferase reporter assay, we showed that NSC 23175 suppressed p53 binding to the promoter of EGR1, a p53-regulated gene. The fact that NSC 23175 protected p53(+/+) cells implicates a putative protective effect of the compound during radiotherapy of p53-mutated tumors. The role of NSC 23175 as protecting agent, in reducing radiotherapy-related side-effects merits future investigation.

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.

Determining interacting cellular partners of drugs by chemical proteomic techniques is complex and tedious. Most approaches rely on activity-based probe profiling and compound-centric chemical proteomics. The anti-malarial artemisinin also exerts profound anti-cancer activity, but the mechanisms of action are incompletely understood. In the present investigation, we present a novel approach to identify artemisinin-interacting target proteins. Our approach overcomes usual problems in traditional fishing procedures, because the drug was attached to a surface without further chemical modification. The proteins identified effect among others, cell cycle arrest, apoptosis, inhibition of angiogenesis, disruption of cell migration, and modulation of nuclear receptor responsiveness. Furthermore, a bioinformatic approach confirmed experimentally identified proteins and suggested a large number of other interacting proteins. Theoretically predicted interaction partners may serve as a starting point to complete the whole set of proteins binding artemisinin.

BACKGROUND: The authors report preliminary results from a prospective multicenter study (Nasopharyngeal Carcinoma [NPC] 2003 German Society of Pediatric Oncology and Hematology/German Children's Oncology Group [NPC-2003-GPOH/DCOG]). METHODS: From 2003 to 2010, 45 patients (ages 8-20 years), including 1 patient with stage II NPC and 44 patients with stage III/IV NPC, were recruited to the study. The patient with stage II disease received radiotherapy (59.4 grays [Gy]). The patients with stage III/IV disease received 3 courses of neoadjuvant chemotherapy with cisplatin, 5-fluorouracil, and folinic acid. The cumulative irradiation dose was 54 Gy in 5 patients, who achieved complete remission after neoadjuvant chemotherapy, and 59.4 Gy in the remaining 40 patients. All patients received concomitant cisplatin during the first week and last week of irradiation. After irradiation, all patients received interferon beta for 6 months. Tumor response was evaluated by magnetic resonance imaging studies and positron emission tomography scans. RESULTS: After the completion of treatment, 43 of 45 patients were in complete remission. In 2 patients, only a partial response was achieved, followed by distant metastases (1 patient) or local progression and distant metastases (1 patient), 6 months and 10 months after diagnosis, respectively. Another patient developed a solitary pelvic bone metastasis 21 months after diagnosis. After a median follow-up of 30 months (range, 6-95 months), the event-free survival rate was 92.4%, and the overall survival was 97.1%. Acute toxicity consisted mainly of leucopenia, mucositis, and nausea; and late toxicity consisted of hearing loss and hypothyroidism. CONCLUSIONS: Combined therapy with neoadjuvant chemotherapy, radiochemotherapy, and interferon beta was well tolerated and resulted in a very good outcome that was superior to the outcomes of published results from all other pediatric NPC study groups. Cancer 2012. (c) 2012 American Cancer Society.

Abstract 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

Paediatric cancer patients often experience fear and pain from the disease but also in connection with the necessary diagnostic and therapeutic procedures. The treatment of pain is a priority for all patients, especially for critically ill children because of their vulnerability and limited understanding. The experience of pain is always subjective and depends on the age, the pain experience and the environment.In contrast to adults, it is often difficult to detect character of pain, pain intensity and pain localization in very young patients. Diagnostic and therapeutic procedures are performed in analgosedation for a given drug scheme by a pediatrician experienced in intensive care.In addition, a local anesthetic for an access system/lumbar punctures in the form of EMLA® patch is to be carried out. A rapid and effective treatment of pain and appropriate analgesia can prevent patients from being traumatized.For severe pain, malignancy- or chemotherapy-induced (eg. mucositis WHO grade 3 and 4) initial use of strong opiates is recommended instead of climbing the WHO ladder. For strong opiates, there is no maximum dose, as long as a dose increase leads to clinically observable increase in analgesia, without severe side effects. Patient-controlled analgesia with morphine as continuous subcutaneous or intravenous infusions and the possibility of a bolus injection is suited for children aged 6 years. A measurement of O2-saturation is essential during this infusion. Prophylactic approaches also must be used consistently in regard to the acute side effect of opiate treatment. Good experience, we have also made a non-drug therapy, e.g. personnel/physical affection, cuddling, massage, etc.The choice of analgesia depends on the nature and cause of pain. In neuropathic pain or phantom pain coanalgetics should be used to effectively treat pain in young patients. Different analgesic treatment approaches of the appropriate indications and adverse effects are presented. A particular challenge for the pediatrician is the sufficient and adequate pain therapy in palliative care.

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.

A common side effect of chemotherapy is reversible or nonreversible nephrotoxicity. SDS polyacrylamide gel electrophoresis combined with laser densitometry was evaluated as a suitable method to analyze pathologic urine proteins. A total of 52 pediatric patients were followed during and 63 patients were followed after therapy. During therapy renal damage was recorded in 43% of the leukemia patients, in 56% of nephroblastoma patients, and 75% of patients with other tumors. Three or more months after therapy pathologic patterns were seen in 25% of acute lymphoblastic leukemia patients, in 35% of patients with nephroblastoma, and in 62% of other patients. Patients with persistent complete tubular proteinuria and mixed glomerular/tubular proteinuria were found to have a high risk for irreversible renal damage and should be controlled periodically. This method permits a rapid and reliable analysis of urine proteins and is suitable for follow-up tests of renal function during and after chemotherapy.

Although most cases of alveolar rhabdomyosarcoma (RMS) are characterized by the chromosomal translocation t(2;13)(q35;q14), several cases have been reported with a variant t(1;13)(p36;q14). We present the clinical, morphological and cytogenetic features of an alveolar RMS in a 4-year-old boy. Chromosomal analysis revealed a hypertriploid to hypotetraploid karyotype with a t(1;13)(p36;q14) in all tumor cells. It appears that alveolar RMS with t(1;13) occurs in younger children and displays a higher incidence to upper and lower extremity than tumors with t(2;13).

BACKGROUND. The increasing use of chemotherapy has improved the prognosis of patients with nasopharyngeal carcinoma (NPC), and the authors demonstrated the beneficial effect of adjuvant interferon (IFN)-beta in a previous pilot study of children with advanced stage NPC. The current multi-institutional, cooperative GPOH (Gesellschaft fur Padiatrische Onkologie und Hamatologie) study NPC-91 was begun in 1992 to determine the efficacy of preradiation chemotherapy, radiotherapy, and adjuvant IFN-beta in the treatment of advanced stage NPC. METHODS. Of a total of 22 patients, 21 had American Joint Committee on Cancer Stage III or TV disease, and 1 had Stage II disease. The median age was 12 years (range, 8-16 years). Twenty of 22 received 3 courses of preradiation chemotherapy consisting of methotrexate 120 mg/m(2) on Day 1, cisplatin 100 mg/m(2) on Day 1, and 5-fluorouracil 1000 mg/m(2) for five days as well as 6 doses of leucovorin 25 mg/m(2) every six hours beginning on Day 2. The Stage II patient received no chemotherapy, and chemotherapy was terminated for another during the first course. AU patients had radiation therapy, stratified by stage. The cumulative dose to the primary sites was 59.4 gray (Gy), with single doses of 1.8 Gy. A total of 45 Gy was delivered to the neck area. Finally, all patients were treated with recombinant IFN-beta (10(5) U per kg of body weight) 3 times a week for 6 months. RESULTS. The response rate was 91%. These patients stayed in first remission during a median follow-up of 32 months. With the exception of one reversible cardiotoxicity, moderate chemotherapy-related toxicity was observed. CONCLUSIONS. In this study, patients with advanced stage NPC had a good prognosis with treatment consisting of neoadjuvant cisplatin and 5-fluorouracil, radiotherapy, and adjuvant IFN-beta. It is particularly noteworthy that distant metastases did not develop. (C) 1997 American Cancer Society.

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-negative 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.

We report on a newborn with disseminated neuroblastoma, intracerebral metastasis, localized in the right choroid plexus could be visualized by sonography and computed tomography. Despite low dose chemotherapy with adriamycin and cyclophosphamide skin and plexus metastasis showed marked progression. Therefore multiagent chemotherapy (NBL-82-Study) was initiated and further investigations revealed complete regression of the intra- and extracranial metastases and the leftsided adrenal tumor as well. Two years after the end of therapy, the patient is in good condition without signs of relapse. This case report underlines the importance of cranial sonography or computed tomography in disseminated neuroblastoma of young infants in order to detect or exclude intracranial metastases.