Intratumor genetic heterogeneity and head and neck cancer relapse.

BACKGROUND: Head and neck squamous cell carcinomas are treated by surgery, radiotherapy (RT), chemoradiotherapy (CRT) or combinations thereof, but locoregional recurrences (LRs) occur in 30-40% of treated patients. We have previously shown that in approximately half of the LRs after CRT, cancer driver mutations are not shared with the index tumor. AIM: To investigate two possible explanations for these genetically unrelated relapses, treatment-induced genetic changes and intratumor genetic heterogeneity. METHODS: To investigate treatment-induced clonal DNA changes, we compared copy number alterations (CNAs) and mutations between primary and recurrent xenografted tumors after treatment with (C)RT. Intratumor genetic heterogeneity was studied by multi-region sequencing on DNA from 31 biopsies of 11 surgically treated tumors. RESULTS: Induction of clonal DNA changes by (C)RT was not observed in the xenograft models. Multi-region sequencing demonstrated variations in CNA profiles between paired biopsies of individual tumors, with copy number heterogeneity scores varying from 0.027 to 0.333. In total, 32 cancer driver mutations could be identified and were shared in all biopsies of each tumor. Remarkably, multi-clonal mutations in these same cancer driver genes were observed in 6 of 11 tumors. Genetically distinct heterogeneous cell cultures could also be established from single tumors, with different biomarker profiles and drug sensitivities. CONCLUSION: Intratumor genetic heterogeneity at the level of the cancer driver mutations might explain the discordant mutational profiles in LRs after CRT, while there are no indications in xenograft models that these changes are induced by CRT.

[Identification of differentiated dysplasia improves prediction of oral leukoplakia at increased risk of malignant progression]. / Onderkenning van gedifferentieerde dysplasie voor het voorspellen van de kans op maligne ontaarding van orale leukoplakie.

Oral leukoplakia is the most common potentially malignant disorder of the oral mucosa with a rate of malignant transformation into oral squamous cell carcinoma of 1-2% annually. The presence or absence of dysplasia as defined by the WHO is an important histological marker for malignant transformation risk assessment, but is not sufficiently accurate for patient stratification. We investigated whether identifying differentiated dysplasia contributes to oral leukoplakia malignant transformation risk assessment. We investigated whether classic or differentiated dysplasia were present in 84 oral leukoplakias. In 25 of these patients a squamous cell carcinoma developed during follow-up. Risk of malignant progression of oral leukoplakia increased from 3.3 (HR, p = 0.002) when only classic dysplasia was considered to 7.4 (HR, p = 0.001) when both classic and differentiated dysplasia were combined. This study demonstrates that identifying differentiated dysplasia as a separate type of dysplasia is important for the prognosis and stratification of patients with oral leukoplakia.

Architecture of European plastic surgery.

The architecture of European Plastic Surgery was published in 1996 [Nicolai JPA, Scuderi N. Plastic surgical Europe in an organogram. Eur J Plast Surg 1996; 19: 253-256.] It is the objective of this paper to update information of that article. Continuing medical education (CME), science, training, examination, quality assurance and relations with the European Commission and Parliament all are aspects covered by the organisations to be discussed.

High pressure liquid chromatographic analysis of the serum concentration of cefuroxime after an intravenous bolus injection of cefuroxime in patients with a coronary artery bypass grafting.

A simple reversed-phase high pressure liquid chromatographic method was developed for the determination of cefuroxime in the serum of patients undergoing coronary artery bypass grafting. The serum was cleaned up with a 3.3% solution of perchloric acid in water. Cefalexine was used as an internal standard. Detection was made by a UV multi-wavelength detector. The optimum wavelength for cefuroxime is 275 nm. The absolute recovery of this method was 90.9%; the limit of quantification was 0.7 mg/l. This analytical method was used in a study to investigate the cefuroxime serum concentration--time curves in 26 patients undergoing coronary artery bypass grafting. It was found that one single dose is sufficient to obtain effective serum concentrations.

[Results of conservative treatment of transverse fracture of the distal tibia and fibula in children]. / Resultate nach konservativ behandelten distalen queren Unterschenkelfrakturen beim Kind.

66 children who were admitted to the Surgical Department of the University Children's Hospital in Zurich because of transverse fracture of the distal tibia and fibula were followed up. They were treated conservatively by reduction followed by immobilization in a plaster of Paris cast reaching to the upper thigh; the foot was placed in the equinus position. Perfect axial reposition should be aimed at. If this cannot be achieved, a varus deformity of up to 6 degrees, a valgus deformity of up to 10 degrees and antecurvation of up to 10 degrees are permissible, as this malposition usually cures itself in time. If the malformation exceeds the limits described above, operative reduction and fixation should be carried out in children over 12 years of age. All children with malposition must be followed up for a long time to observe whether the malposition will gradually disappear and to ascertain whether static difficulties will occur and may have to be corrected by osteotomy.