Antitumor vaccination of patients with glioblastoma multiforme: a pilot study to assess feasibility, safety, and clinical benefit.

PURPOSE: Prognosis of patients with glioblastoma is poor. Therefore, in glioblastoma patients, we analyzed whether antitumor vaccination with a virus-modified autologous tumor cell vaccine is feasible and safe. Also, we determined the influence on progression-free survival and overall survival and on vaccination-induced antitumor reactivity. PATIENTS AND METHODS: In a nonrandomized study, 23 patients were vaccinated and compared with nonvaccinated controls (n = 87). Vaccine was prepared from patient's tumor cell cultures by infection of the cells with Newcastle Disease Virus, followed by gamma-irradiation, and applied up to eight times. Antitumor immune reactivity was determined in skin, blood, and relapsed tumor by delayed-type hypersensitivity skin reaction, ELISPOT assay, and immunohistochemistry, respectively. RESULTS: Establishment of tumor cell cultures was successful in approximately 90% of patients. After vaccination, we observed no severe side effects. The median progression-free survival of vaccinated patients was 40 weeks (v 26 weeks in controls; log-rank test, P = .024), and the median overall survival of vaccinated patients was 100 weeks (v 49 weeks in controls; log-rank test, P < .001). Forty-five percent of the controls survived 1 year, 11% survived 2 years, and there were no long-term survivors (> or = 3 years). Ninety-one percent of vaccinated patients survived 1 year, 39% survived 2 years, and 4% were long-term survivors. In the vaccinated group, immune monitoring revealed significant increases of delayed-type hypersensitivity reactivity, numbers of tumor-reactive memory T cells, and numbers of CD8(+) tumor-infiltrating T-lymphocytes in secondary tumors. CONCLUSION: Postoperative vaccination with virus-modified autologous tumor cells seems to be feasible and safe and to improve the prognosis of patients with glioblastomas. This could be substantiated by the observed antitumor immune response.     

The International Prognostic Scoring System (IPSS) for childhood myelodysplastic syndrome (MDS) and juvenile myelomonocytic leukemia (JMML).

The International Prognostic Scoring System (IPSS) for myelodysplastic syndrome (MDS) is based upon weighted data on bone marrow (BM) blast percentage, cytopenia, and cytogenetics, separating patients into four prognostic groups. We analyzed the value of the IPSS in 142 children with de novo MDS and 166 children with juvenile myelomonocytic leukemia (JMML) enrolled in retro- and prospective studies of the European Working Group on childhood MDS (EWOG-MDS). Survivals in MDS and JMML were analyzed separately. Among the criteria considered by the IPSS score, only BM blasts <5% and platelets >100 x 10(9)/l were significantly associated with a superior survival in MDS. In JMML, better survival was associated with platelets >40 x 10(9)/l, but not with any other IPSS factors including cytogenetics. In conclusion, the IPSS is of limited value in both pediatric MDS and JMML. The results reflect the differences between myelodysplastic and myeloproliferative diseases in children and adults.     

Cystatin C: efficacy as screening test for reduced glomerular filtration rate

Serum cystatin C, a cysteine proteinase inhibitor, has been proposed as a marker of glomerular filtration rate (GFR). Serum cystatin C, serum creatinine and creatinine clearance were measured in 226 patients with various nephropathies, covering the entire range of renal function, to evaluate the efficacy of cystatin C as a screening test to detect reduced creatinine clearance in comparison to creatinine. Subgroups of 53 patients with glomerular and 26 patients with tubular impairment were compared to assess whether cystatin C performed differently in either glomerular or tubular impairment. Cystatin C detected reduced creatinine clearance with higher sensitivity (97 vs. 83%), and higher negative predictive value (96 vs. 87%) compared to creatinine. In parallel, 95% sensitivity of cystatin C as derived from receiver-operating characteristic plot was significantly higher (p < 0.05). In the subgroups with glomerular or tubular impairment, cystatin C and creatinine did not significantly differ with regard to efficacy. Serum cystatin C is as efficacious as serum creatinine to detect reduced GFR as measured by creatinine clearance. The efficacy of cystatin C as a screening test may even be superior compared to creatinine. In addition, the efficacy of cystatin C is independent of either glomerular or tubular impairment.     

Halm-Zielke-Instrumentation als primärstabile Weiterentwicklung der Zielke-VDS bei idiopathischen Skoliosen

Halm-Zielke Instrumentation (HZI) was developed to eliminate the disadvantage of ventral derotation spondylodesis (VDS)-Zielke in terms of lack of primary stability and in order to simplify sagittal plane control. Within a prospective clinical trial started in 1993, we have studied whether HZI fulfills these demands. HZI is an anterior double-rod system with a two screw per vertebral body fixation. The longitudinal components consist of a threaded VDS rod and a solid rod, which are attached to a hinge-conducted lid plate. Twenty-nine consecutive patients with idiopathic scoliosis and curves ranging from 36 degrees to 92 degrees were treated with HZI. The follow-up period ranged from 1 to 4 years. Correction of the frontal plane within the instrumented levels averaged 71.6% and 70.5% postoperatively and at follow-up, respectively. Derotation averaged 53.7% and mean correction of the tilt of the lowest instrumented vertebra was 69.5% at final follow-up. Thoracolumbar kyphosis was present in eight patients and was always completely corrected from +18.8 degrees to 3.3 degrees on average. One implant-related complication involved a screw breakage 18 months postoperatively without adverse effects. There was no case of pseudoarthrosis. All patients were mobilized without any additional external immobilization in terms of a brace or cast, and were allowed to go swimming for physiotherapeutical purposes immediately after wound healing. This study proves that HZI is a primary stable implant to perform VDS. Implant-related disadvantages typical of VDS are eliminated. Thereby, the period of rehabilitation is shortened by many months due to avoidance of cast and brace treatment.     

Urinary stability of carboxycyclophosphamide and carboxyifosfamide, two major metabolites of the anticancer drugs cyclophosphamide and ifosfamide

Phosphorus-31 nuclear magnetic resonance spectroscopy was used to evaluate the stability of carboxycyclophosphamide (CXCP) and carboxyifosfamide (CXIF) in human urine at pH 7.0 and 5.5 at 25°, 8°, −20°, and −80 °C. At 25 °C and pH 7.0, CXCP and CXIF are relatively stable (≈10% degradation in 24 h). In contrast, they are much less stable at pH 5.5 (≈80% degradation of CXIF and ≈50% degradation of CXCP in 24 h). The rate of degradation of CXCP and CXIF was a function of the storage temperature of the urine samples but, even at −80 °C, was not negligible: ≈30% degradation for CXCP irrespective of pH and ≈40% and 50% degradation for CXIF at pH 7.0 and 5.5, respectively, after storage for 6 months. CXCP was more stable than CXIF at either pH (7.0 or 5.5) and at all storage temperatures (8°, −20°, or −80 °C) of the urine samples. CXCP and CXIF were more stable at pH 7.0 than at pH 5.5, although this difference fell with decreasing temperatures to be almost negligible at −80 °C. To ensure a true estimate of CXCP and CXIF levels, urine samples must be frozen and stored at −80 °C within a few hours of micturition. CXCP and CXIF assays should also be carried out within 2 months and 1 month of storage, respectively. Received: 13 July 1996 / Accepted: 20 January 1997     

RAS diseases in children

RAS genes encode a family of 21 kDa proteins that are an essential hub for a number of survival, proliferation, differentiation and senescence pathways. Signaling of the RAS-GTPases through the RAF-MEK-ERK pathway, the first identified mitogen-associated protein kinase (MAPK) cascade is essential in development. A group of genetic syndromes, named “RASopathies”, had been identified which are caused by heterozygosity for germline mutations in genes that encode protein components of the RAS/MAPK pathway. Several of these clinically overlapping disorders, including Noonan syndrome, Noonan-like CBL syndrome, Costello syndrome, cardio-facio-cutaneous (CFC) syndrome, neurofibromatosis type I, and Legius syndrome, predispose to cancer and abnormal myelopoiesis in infancy. This review focuses on juvenile myelomonocytic leukemia (JMML), a malignancy of early childhood characterized by initiating germline and/or somatic mutations in five genes of the RAS/MAPK pathway: PTPN11, CBL, NF-1, KRAS and NRAS. Natural courses of these five subtypes differ, although hematopoietic stem cell transplantation remains the only curative therapy option for most children with JMML. With whole-exome sequencing studies revealing few secondary lesions it will be crucial to better understand the RAS/MAPK signaling network with its crosstalks and feed-back loops to carefully design early clinical trials with novel pharmacological agents in this still puzzling leukemia.     

Orbitofrontal cortex and impulsivity in borderline personality disorder: an MRI study of baseline brain perfusion

Behavioral and neuroimaging studies in patients with borderline personality disorder (BPD) have associated orbitofrontal cortex (OFC) dysfunction with distinct symptom clusters such as impulsivity. It is unclear, however, whether abnormal patterns of OFC activity are also present during resting-state conditions and whether OFC dysfunction is specifically associated with impulsivity in BPD. This study tested the hypothesis that BPD patients would exhibit changes of OFC baseline perfusion and explored the relationship between regional cerebral blood flow and distinct BPD symptom clusters, such as impulsivity, dissociation tension and depressive symptoms. Using continuous arterial spin labeling magnetic resonance imaging at 3 Tesla, we investigated 16 women with BPD according to DSM-IV criteria and 16 healthy female control participants during resting-state conditions. Between-group comparisons were conducted using an analysis of variance (p?<?0.05 cluster corrected). Compared to controls, BPD patients exhibited decreased blood flow in the medial OFC, whereas increased blood flow was found in the left and right lateral OFC. Correlation analyses revealed a positive relationship between medial and lateral orbitofrontal blood flow and impulsivity scores, whereas measures of dissociation tension and depression did not exhibit a significant correlation with OFC perfusion. These data suggest that dysfunction of medial and lateral regions of the OFC could specifically mediate symptoms of impulsivity in BPD.