[Age-related characteristics of the efficacy of different glucocorticosteroids in the therapy of acute lymphoblastic leukemia].

AIM: To determine predictors for decision-making on a differential approach to choosing glucocorticosteroids (GCS) for children and adolescents with acute lymphoblastic leukemia (ALL). SUBJECTS AND METHODS: The analysis covered 1064 primary patients aged to 1 to 18 years with ALL who had been registered at the clinics of Russia and Belorussia in April 2002 to November 2006. Before induction therapy, the patients were randomized into a dexamethasone (DEXA) 6 mg/m2 group (n=539) and a methylprednisolone (MePRED) 60 mg/m2 one (n=525). RESULTS: The entire group showed no statistically significant differences in survival rates between the patients receiving DEXA or MePRED. However, an analysis of age groups revealed the benefits of DEXA in children younger than 14 years (the event-free survival (EFS) was 76±2 and 71±2%, respectively (p=0.048); the overall survival (OS) was 81±2 and 77±2%, respectively (p=0.046); therapy-induced mortality was 6.4% (DEXA) andl 1.1% (MePRED) (p=0.01 4); the rate of isolated extramedullary relapses was 1.5% (DEXA) and 4.4% (MePRED) (p=0.009). At the same time, EFS and OS in 14-to-18-year-old adolescents were statistically significantly higher than in those who used MePRED (EFS, 65±6 and 52±6%, respectively (p=0.087); OS, 72±6 and 61±6%, respectively; (p=0.l 7). CONCLUSION: The findings suggest that it is possible that the choice of a GCS for ALL therapy must be also based on a patient's age. There is a need for further studies of this matter in prospective randomized multicenter trials in children and adolescents.

Musculoskeletal pain: a new algorithm for differential diagnosis of a cardinal symptom in pediatrics.

Musculoskeletal pain (MSP) is a common childhood complaint associated with multiple differential diagnoses, including cancer. Considering the expanding spectrum of diagnostics, evaluat-ing a young patient with MSP is a challenge today, particularly for non-specialists in a primary care setting. Since childhood cancer is rare and most cardinal symptoms mimic rather non-serious diseases, misdiagnosis is not uncommon, but of significant prognostic relevance. To build the appropriate bridge between primary and secon-dary care for a child presenting with MSP, thereby preventing treatment delay and longterm sequelae, initial evaluation should follow a comprehensive, multidisciplinary, systematic and stepwise approach, which unites the patient's individual anamnestic, psychosocial, and clinical charac-teristics. After a systematic review of the literature, we generated multidisciplinarily quality-assured recommendations for efficient, rational and cost-effective primary care assessment of pediatric MSP. The algorithm promotes the identification and structured interpretation of the patient's individual clinical clues. It should serve the primary care physician to recognize when further intervention, rather than reassurance and follow-up, is needed using the minimum amount of testing to make an appropriate, prompt diagnosis in the clinical situation "child presenting with MSP". A German version of this algorithm has been published in the Guideline-Portal of The Association of the Scientific Medical Societies ("Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften", AWMF) in November 2013.

High reliability of scrotal ultrasonography in the management of childhood primary testicular neoplasms.

BACKGROUND: The role for testis-sparing surgery in the treatment of primary intratesticular lesions in childhood is growing. The reliability of scrotal ultrasonograpy (US) in the management of these lesions is still controversial. PATIENTS: Between 1991 and 2007, 383 children and adolescents presented with testicular abnormalities. Ultrasound results and records of patients with primary testicular neoplasms were analyzed. RESULTS: 12 of 383 patients (3.1%) had a histologically proven primary intratesticular neoplasm. Scrotal US was highly sensitive for the detection of these lesions. Patients' mean age at initial US was 6 years (9 prepubertal, 3 juvenile patients). The most frequent symptom was a painless unilateral scrotal mass (75%). Tumor markers or testosterone were elevated in 6/12 boys. Histology was intratesticular germ cell in 7, sexcord stromal tumor in 4 and capillary hemangioma in 1 patient. US correctly distinguished between benign and malignant lesions in all cases. When combined with clinical symptoms, US predicted 75% of histologies. After including hormone and tumor marker levels, a correct preoperative diagnosis was made for all boys with germ cell, and for 75% of boys with sexcord stromal tumor. CONCLUSION: Scrotal US is highly sensitive for the detection of childhood primary intratesticular tumors and, when combined with clinical data, highly reliable for differential diagnosis. It may help clinicians to decide when to opt for testis-sparing surgery.

Surgical aspects and outcome of delayed tethered cord release.

Out of a total of 550 children followed up at our spina bifida center, we report on 81 patients who were reoperated upon for secondary tethered cord syndrome between 1993 and 2000. In four cases with preceding severe progressive scoliosis, untethering was followed by surgical correction and stabilization of curvatures. In 77 patients, the indication for surgery was based on late progressive neurological deterioration. The current clinical relevance of competing etiologic factors such as symptomatic Chiari malformation, hydromyelia, and shunt dysfunction, requiring different clinical management, had been previously carefully excluded. The children underwent magnetic resonance imaging (MRI) or myelo-computed tomography (m-CT) to identify the morphologic extent of tethering and any associated spinal malformations such as dermoid tumors (19 cases) or diastematomyelia (9 cases). Surgery became faster and safer through bilateral dural incision, undercutting arachnoid adhesions along the tethered area, although this procedure increased the need for dural grafting. Complete release of the conus medullaris and cauda equina was achieved in a total of 75 cases (93 %) including those who had undergone prophylactic surgery. A mean follow-up of 4.8 years in 77 patients operated upon for late progressive neurological deterioration confirmed stabilization of presenting symptoms in 65 cases (84 %) with 20 of them (26 %) even showing significant improvement. In 12 patients (16 %), including all cases of incomplete untethering (n = 4), there was further deterioration.

Expression of p33ING1 mRNA and chemosensitivity in brain tumor cells.

BACKGROUND: Mutations and down-regulation of tumor suppressor genes can contribute to both tumorigenesis and chemotherapy resistance. The tumor suppressor p33ING1 has growth-inhibitory and pro-apoptotic effects recruiting p53 and it plays a role in DNA repair through interaction with PCNA. We questioned whether p33ING1 mRNA expression correlates with the chemosensitivity of brain tumor cells. MATERIALS AND METHODS: Various malignant brain tumor cell lines were examined for their sensitivity to cisplatin, doxorubicin, etoposide and the antimitotic agents vincristine and paclitaxel by MTT-cytotoxicity assays. p33ING1 mRNA expression was determined by RT-PCR. RESULTS: We found that, unlike other tumor types, ING1 levels were higher in glioma cell lines than in normal control cells. Medulloblastoma cells revealed the lowest ING1 expression of the lines tested. Comparing all cell lines, p33ING1 gene expression significantly (p = 0.028) correlated with resistance to vincristine (r2 = 0.87). CONCLUSION: Our results suggest that p33ING1 mRNA levels may be used to predict the chemosensitivity of brain tumor cells to vincristine.

Overcoming cisplatin resistance: design of novel hydrophobic platinum compounds.

BACKGROUND: The anticancer activity of cisplatin derives from its ability to crosslink DNA. Cisplatin-resistance is partially caused by enhanced nucleotide excision repair (NER). Major 1,2-intrastrand crosslinks can create a hydrophobic notch at the damage site, which can be specifically bound by damage-recognition proteins, thus shielded from NER-activity. We aimed at preventing resistance by enhancing this mechanism using more hydrophobic platinum compounds. METHODS: We synthesized three platinum analogs with increased hydrophobic characteristics. Performing MTT-assays, the efficacy of cisplatin and the novel agents was compared in a fibroblast and eight brain tumour cell lines. RESULTS: Among the novel compounds, the most hydrophobic molecule, methylpyridineplatinum, was most cytotoxic (LC50 = 5.84 x 10(-5) M), followed by methylpyrazineplatinum, the second most hydrophobic (LC50 = 1.79 x 10(-4) M), and pyridineplatinum (LC50 = 2.76 x 10(-4) M). Overall, cisplatin revealed highest cytotoxicity (LC50 = 8.77 x 10(-6) M). CONCLUSIONS: Comparison of the novel compounds supports the hypothesis that increased hydrophobicity contributes to higher antitumour-activity. Other advantageous characteristics of cisplatin might relate to its remaining highest efficacy.

Lymphocytic hypophysitis simulating a pituitary adenoma in a nonpregnant woman.

Lymphocytic adenohypophysitis can cause pituitary expansion and hypopituitarism closely mimicking the features of a pituitary adenoma. In contrast to pituitary adenoma, lymphocytic adenohypophysitis occurs almost exclusively in young women in relation to pregnancy. We report a case of a 43-year-old nonpregnant nullipara who exhibited an intrasellar mass with diffuse homogeneous contrast enhancement on magnetic resonance imaging scanning. Serum hormone analyses revealed secondary hypoadrenalism, hypothyroidism, and hypogonadism. The patient underwent surgery for a presumed nonsecreting pituitary adenoma. Histopathological examination showed extensive infiltration of the anterior pituitary gland by chronic inflammatory cells. The immunohistochemical pattern of the inflammatory cells indicated the chronic and putatively autoimmune nature of the disease.

Effects of octreotide on morphology of pituitary adenomas in acromegaly.

We studied the effects of the long-acting somatostatin analogue octreotide (SMS 201-995, Sandoz, Basel, Switzerland) on the morphology of pituitary adenomas in acromegaly. Of the 29 adenomas examined by light microscopy, 16 had been treated pre-operatively with octreotide. The treated adenomas were compared with the untreated adenomas. 14 adenomas were also studied by electron microscopy. In 23 cases we performed in-situ-hybridization for GH-mRNA. Under light microscopy, we found a decrease in amyloid deposits and a higher amount of cell necroses and fibroses after treatment, mainly in the tumors with shrinkage. Tumor shrinkage was diagnosed when the maximal diameter of the adenoma decreased for at least 1/3 during octreotide treatment in NMR examination. Immunohistochemical examinations showed that treated adenomas, especially those with tumor shrinkage, possessed more GH immunoreactive cells, and after in-situ-hybridization we found a higher content of GH-mRNA. On the ultrastructural level, rough endoplasmic reticulum appeared to be increased in treated adenomas. The increase of GH-mRNA and of rough endoplasmic reticulum suggests the likelihood of an increased secretory activity due to a rebound effect after short-term pre-operative omission of octreotide. Other findings are discussed.

Detection of growth hormone, prolactin and human beta-chorionic gonadotropin mRNA in growth hormone-secreting pituitary adenomas and in prolactin-secreting pituitary adenomas by in situ hybridization using a non-isotopic detection method.

A non-isotopic in situ hybridization method with digoxigenin-labelled probes was used to examine growth hormone (GH), prolactin (PRL) and human beta-chorionic gonadotropin (beta-hCG(LH)) gene expression in 63 pituitary tumours in acromegaly and 20 adenomas in hyperprolactinaemia. hCG and LH were detected simultaneously because of the extensive homology (more than 90%) of their mRNA sequences (1). A comparison with former results obtained with 35S-labelled probes shows the value of the easier and faster non-isotopic method. Additionally, immunohistochemical data are included to give even more evidence for the synthesis of the respective hormones by the tumour cells. In all 63 adenomas in acromegaly, GH mRNA was revealed in 59 PRL mRNA and in 36 beta-hCG(LH) mRNA. A positive immunostaining for GH was found in all, for PRL in 40, and for beta-hCG(LH) in 34 adenomas. The comparison of the two in situ hybridization methods revealed no differences concerning GH mRNA detection, but not all tumours positive after non-isotopic PRL and beta-hCG(LH) mRNA detection showed signals with the radioactive method. Referring to the 20 PRL-secreting adenomas, PRL gene expression was demonstrable in all, GH mRNA in 12, and beta-hCG(LH) mRNA in 2 cases. Comparing the positive results of immunohistochemistry with those of in situ hybridization, correspondence was found in 19 cases for PRL, in 5 cases for GH and in no case for beta-hCG(LH).