High frequency of disease progression in pediatric spinal cord low-grade glioma (LGG): management strategies and results from the German LGG study group

BackgroundKnowledge on management of pediatric spinal cord low-grade glioma (LGG) is scarce.MethodsWe analyzed clinical datasets of 128 pediatric patients with spinal LGG followed within the prospective multicenter trials HIT-LGG 1996 (n = 36), SIOP-LGG 2004 (n = 56), and the subsequent LGG-Interim registry (n = 36).ResultsSpinal LGG, predominantly pilocytic astrocytomas (76%), harbored KIAA1549-BRAF fusion in 14/35 patients (40%) and FGFR1-TACC1 fusion in 3/26 patients (12%), as well as BRAFV600E mutation in 2/66 patients (3%). 10-year overall survival (OS) and event-free survival (EFS) was 93% ± 2% and 38% ± 5%, respectively. Disseminated disease (n = 16) was associated with inferior OS and EFS, while age ≥11 years and total resection were favorable factors for EFS. We observed 117 patients following total (n = 24) or subtotal/partial resection (n = 74), biopsy (n = 16), or radiologic diagnosis only (n = 3). Eleven patients were treated first with chemotherapy (n = 9) or irradiation (n = 2). Up to 20.8 years after diagnosis/initial intervention, 73/128 patients experienced one (n = 43) or up to six (n = 30) radiological/clinical disease progressions. Tumor resections were repeated in 36 patients (range, 2-6) and 47 patients required nonsurgical treatment (chemotherapy, n = 20; radiotherapy, n = 10; multiple treatment lines, n = 17). Long-term disease control for a median of 6.5 (range, 0.02-20) years was achieved in 73/77 patients following one (n = 57) or repeated (n = 16) resections, and in 35/47 patients after nonsurgical treatment.ConclusionsThe majority of patients experienced disease progression, even after years. Multiple interventions were required for more than a third, yet multimodal treatment enabled long-term disease control. Molecular testing may reveal therapeutic targets.     

Carisbamate has powerful disease-modifying effects in the lithium-pilocarpine model of temporal lobe epilepsy

Lithium-pilocarpine, a relevant model of temporal lobe epilepsy was used to test the neuroprotective and antiepileptogenic effects of carisbamate. Status epilepticus (SE) was induced in adult rats by lithium and pilocarpine. Carisbamate (30, 60, 90, and 120?mg/kg) was injected at 1 and 9?h after SE onset and continued twice daily for 6 additional days. The reference groups received diazepam instead of carisbamate. Neuroprotection was assessed during the first 24?h of SE with Fluoro-Jade B and after 14 days with thionine staining. SE severity and epileptic outcome were assessed by video, and surface and depth electroencephalographic recordings. At the two highest doses, carisbamate treatment reduced SE severity; produced strong neuroprotection of hippocampus, ventral cortices, thalamus, and amygdala; prevented mossy fiber sprouting in the dentate gyrus of the hippocampus; and delayed or suppressed the occurrence of spontaneous motor seizures. Rats with no spontaneous motor seizures displayed spike-and-wave discharges that share all the characteristics of absence seizures. In conclusion, carisbamate is able to induce strong neuroprotection and affect the nature of epileptogenic events occurring during and after lithium-pilocarpine status epilepticus, reflecting marked insult- and disease-modifying effects.     

Molecular detection and characterisation of fungal heat shock protein 60

Heat shock proteins (Hsp) are highly conserved molecules, which are both constitutively expressed and up‐regulated in response to various stress conditions. In particular, fungal Hsp60 can act as immunodominant antigens and facilitate powerful immunological properties. A possible cellular heat shock response was investigated in eight fungi (Aspergillus fumigatus, Aspergillus terreus, Penicillium chrysogenum, Cladosporium cladosporioides, Scedosporium apiospermum, Trichophyton mentagrophytes, Candida albicans and Saccharomyces cerevisiae). Fully automated RNA extraction was followed by quantitative real‐time RT‐PCR targeting fungus‐specific Hsp60 mRNA and sequencing of the amplicon. Levels of temperature‐dependent gene expression were evaluated and rates of similarity and identity were compared. While Hsp60 mRNA was constitutively expressed in all the samples tested, a temperature‐dependent induction was not shown in C. cladosporioides. In the 80‐amino acid fragment from the hypothetical protein, 66% of the amino acids were identical, 20% showed a conserved and 8% a semi‐conserved substitution. Our findings should contribute to a better understanding of host–pathogen relationship and suggest that fungal Hsp60 under temperature‐related stress conditions might act as an immunogenic trigger in orchestrating fungi‐related diseases.     

Efficacy of pazopanib and sunitinib in advanced axial chordoma: a single reference centre case series

Background

Chordomas are rare malignant tumours of the axial skeleton and skull base supposed to arise from cellular remnants of the notochord. These tumours have the potential to metastasize (30–40 %), usually in the later course of the disease. However, the greatest morbidity is usually a result of loco-regional recurrence with infiltration and destruction of surrounding bone and soft tissue. Patients with unresectable or metastatic chordoma are faced with a poor prognosis since cytotoxic chemotherapy or other systemic therapies have not proven their efficacy yet. However, several molecularly targeted drugs have been proposed as potentially beneficial, including tyrosine kinase inhibitors (TKIs) directed at vascular endothelial growth factor receptor (VEGFR), like pazopanib and sunitinib.

Case presentation

Five patients with unresectable or metastatic chordoma were treated with VEGFR inhibitors pazopanib or sunitinib in the Leiden University Medical Centre (LUMC) between 2008 and 2015. Two out of four patients treated with pazopanib derived clinical benefit and disease remained stable for respectively 14 and 15 months. The one patient treated with sunitinib achieved a partial response according to RECIST 1.1 which lasted for a total of 27 months. No serious adverse events were observed.

Conclusion

These results on the use of pazopanib and sunitinib in chordoma are promising, with an objective response on sunitinib and a median progression free interval of 8.5 months (range 3–15 months), comparable to that of imatinib, in the pazopanib subgroup. However further research is needed to assess the definite role of VEGFR inhibitors in chordoma.

     

The prognostic significance of tumour cell detection in the peripheral blood versus the bone marrow in 733 early-stage breast cancer patients

Introduction  

The detection of circulating tumour cells (CTCs) in the peripheral blood and disseminated tumour cells (DTCs) in the bone marrow are promising prognostic tools for risk stratification in early breast cancer. There is, however, a need for further validation of these techniques in larger patient cohorts with adequate follow-up periods.     

Small molecule inhibitors of peptidoglycan synthesis targeting the lipid II precursor

Bacterial peptidoglycan glycosyltransferases (GTs) of family 51 catalyze the polymerization of the lipid II precursor into linear peptidoglycan strands. This activity is essential to bacteria and represents a validated target for the development of new antibacterials. Application of structure-based virtual screening to the National Cancer Institute library using eHits program and the structure of the glycosyltransferase domain of the Staphylococcus aureus penicillin-binding protein 2 resulted in the identification of two small molecules analogues 5, a 2-[1-[(2-chlorophenyl)methyl]-2-methyl-5-methylsulfanylindol-3-yl]ethanamine and 5b, a 2-[1-[(3,4-dichlorophenyl)methyl]-2-methyl-5-methylsulfanylindol-3-yl]ethanamine that exhibit antibacterial activity against several Gram-positive bacteria but were less active on Gram-negative bacteria. The two compounds inhibit the activity of five GTs in the micromolar range. Investigation of the mechanism of action shows that the compounds specifically target peptidoglycan synthesis. Unexpectedly, despite the fact that the compounds were predicted to bind to the GT active site, compound 5b was found to interact with the lipid II substrate via the pyrophosphate motif. In addition, this compound showed a negatively charged phospholipid-dependent membrane depolarization and disruption activity. These small molecules are promising leads for the development of more active and specific compounds to target the essential GT step in cell wall synthesis.     

Expression of neutral endopeptidase (NEP/CD10) on pancreatic tumor cell lines, pancreatitis and pancreatic tumor tissues

Neutral endopeptidase (NEP/CD10) is a cell surface zinc metalloprotease cleaving peptide bounds on the amino terminus of hydrophobic amino acids and inactivating multiple physiologically active peptides. Loss or decrease in NEP/CD10 expression have been reported in many types of malignancies, but the role of NEP/CD10 in pancreatic carcinoma has not yet been identified. Using real-time RT-PCR, flow cytometry as well as immunohistochemistry, NEP/CD10 expression was quantified in both pancreatic carcinoma cell lines and in tumor specimens obtained from patients with primary pancreatic carcinomas. Three out of 8 pancreatic carcinoma cell lines exhibit heterogeneous NEP/CD10 expression levels: PATU-8988T expressed the highest NEP/CD10 levels, whereas HUP-T4 and HUP-T3 cells showed a moderate to low NEP/CD10 expression. NEP/CD10 immunoreactivity was found in 6 of 24 pancreatic ductal adenocarcinomas, but also in 3 of 6 tissues of patients with chronic pancreatitis. NEP/CD10 expression in pancreatic tumor lesions and cell lines was not associated with tumor grading and staging. Treatment of PATU-8988T cells with the histone deacetylase inhibitors sodium butyrate and valproic acid induced an increase of NEP/CD10 expression. This was accompanied by a reduced cell proliferation rate of PATU-8988T cells, which was increased by the addition of the enzyme activity inhibitors phosphoramidon and thiorphan. Thus, NEP/CD10 is differentially expressed in pancreatic tumors and might be involved in the proliferative activity of pancreatic cancer cells. However, further studies are needed to provide more detailed information of the role of NEP/CD10 under physiological and pathophysiological conditions of the pancreas.     

Conserved mutation of Epstein-Barr virus-encoded BamHI-A Rightward Frame-1 (BARF1) gene in Indonesian nasopharyngeal carcinoma

Background  

BamHI-A rightward frame-1 (BARF1) is a carcinoma-specific Epstein-Barr virus (EBV) encoded oncogene. Here we describe the BARF1 sequence diversity in nasopharyngeal carcinoma (NPC), other EBV-related diseases and Indonesian healthy EBV carriers in relation to EBV genotype, viral load and serology markers. Nasopharyngeal brushings from 56 NPC cases, blood or tissue from 15 other EBV-related disorders, spontaneous B cell lines (LCL) from 5 Indonesian healthy individuals and several prototype EBV isolates were analysed by PCR-direct sequencing.     

Head and Neck Cancer in the Elderly: A Retrospective Study over 10 Years (1999 - 2008)

Introduction

Treatment of elderly patients is in many ways different from that for younger ones. The aim of the present study was to identify the particular characteristics and needs of elderly patients suffering from head and neck cancer. From these patterns, considerations for this special group can be deduced.

Patients and Material

The subjects for this study consisted of 376 patients suffering from head and neck cancer that were treated between 1999 and 2008, 99 (26.3.%) of whom were older than 70 years and were evaluated retrospectively concerning smoking/alcohol abuse, ASA status, kind of malignant neoplasm, localization and treatment.

Results

The male-female ratio was 53:46, and mean age, 79 years (71 - 98). Out of 95 patients with a squamous cell carcinoma, 4 patients had a verrucous form. Out of 99 patients, 26 had a maxillary carcinoma and 12 patients had experienced previous non-head-and-neck cancer. An ASA score of 2 or 3 was found in 86 of the patients.

Conclusion

The group of patients with head and neck cancer who were older than 70 years was characterized by a higher portion of female patients, a higher number of maxillary carcinomas, and a higher prevalence of previous second cancer.Making decisions in cancer therapy for elderly patients is challenging. Patients suffering from operable head and neck cancer should be treated with curative intent and with regard to quality of life if a careful assessment of comorbidities is performed preoperatively.

     

Avemar, a nontoxic fermented wheat germ extract, induces apoptosis and inhibits ribonucleotide reductase in human HL-60 promyelocytic leukemia cells

Avemar (MSC) is a nontoxic fermented wheat germ extract demonstrated to significantly improve the survival rate in patients suffering from various malignancies. We investigated its effects in human HL-60 promyelocytic leukemia cells. After 24, 48, and 72 h of incubation, Avemar inhibited the growth of HL-60 cells with IC₅₀ values of 400, 190, and 160 μg/ml, respectively. Incubation with MSC caused dose-dependent induction of apoptosis in up to 85% of tumor cells. In addition, Avemar attenuated the progression from G2–M to G0–G1 phase of the cell cycle and was also found to significantly reduce the in situ activity of ribonucleotide reductase, the key enzyme of de novo DNA synthesis. We conclude that Avemar exerts a number of beneficial effects which could support conventional chemotherapy of human malignancies.