Detecting somatic mutations in genomic sequences by means of Kolmogorov-Arnold analysis.

The Kolmogorov-Arnold stochasticity parameter technique is applied for the first time to the study of cancer genome sequencing, to reveal mutations. Using data generated by next-generation sequencing technologies, we have analysed the exome sequences of brain tumour patients with matched tumour and normal blood. We show that mutations contained in sequencing data can be revealed using this technique, thus providing a new methodology for determining subsequences of given length containing mutations, i.e. its value differs from those of subsequences without mutations. A potential application for this technique involves simplifying the procedure of finding segments with mutations, speeding up genomic research and accelerating its implementation in clinical diagnostics. Moreover, the prediction of a mutation associated with a family of frequent mutations in numerous types of cancers based purely on the value of the Kolmogorov function indicates that this applied marker may recognize genomic sequences that are in extremely low abundance and can be used in revealing new types of mutations.

Phase Ib study of CP-868,596, a PDGFR inhibitor, combined with docetaxel with or without axitinib, a VEGFR inhibitor.

BACKGROUND: Tumoural interstitial hypertension, possibly modulated by platelet-derived and vascular endothelial growth factor receptors (PDGFR and VEGFR), may mediate resistance to chemotherapy. METHODS: Forty-eight patients with advanced solid tumours received oral PDGFR inhibitor CP-868,596 (60-100 mg twice daily (BID)) and docetaxel (75-100 mg m⁻²), or CP-868,596 (60 mg BID), docetaxel (75 mg m⁻²), and VEGFR inhibitor axitinib (5 mg BID). RESULTS: The CP-868,596/docetaxel was escalated as above. The CP-868,596/docetaxel/axitinib was not dose escalated because of increased incidence of mucositis-like adverse events (AEs) with concurrent neutropenia relative to that expected for docetaxel. All tested regimens were tolerable, including 100 mg BID CP-868,596 (recommended phase II dose) plus 100 mg m⁻² docetaxel (maximum approved dose). Most treatment-emergent AEs were mild-moderate and reversible, commonly including nausea, diarrhoea, vomiting, constipation, fatigue, and anaemia (CP-868,596/docetaxel), and hypertension, lethargy, diarrhoea, and fatigue (CP-868,596/docetaxel/axitnib). Pharmacokinetics were unaffected by co-administration. Twenty-one patients achieved stable disease, including all seven evaluable on CP-868,596/docetaxel/axitinib. All nine CP-868,596/docetaxel/axitinib patients received therapy for a median of six (range, 3-16) cycles. CONCLUSIONS: The CP-868,596/docetaxel was well tolerated, but increased efficacy was not observed. Addition of axitinib delivered greater benefits than expected in the number of patients achieving prolonged stable disease with a moderate increase in AEs.

Treatment with imatinib improves drug delivery and efficacy in NSCLC xenografts.

Imatinib, an inhibitor of PDGF-Rbeta and other tyrosine kinase receptors, has been shown to decrease microvessel density and interstitial fluid pressure in solid tumours, thereby improving subsequent delivery of small molecules. The purpose of this study was to test whether pretreatment with imatinib increases the efficacy of traditional chemotherapy in mice bearing non-small cell lung carcinoma xenografts, and to investigate the effects of imatinib on liposomal drug delivery. Efficacy treatment groups included (n=9-10): saline control, imatinib alone (oral gavage, 100 mg kg(-1) x 7 days), docetaxel alone (10 mg kg(-1) i.p. 2 x /week until killing), and imatinib plus docetaxel (started on day 7 of imatinib). Tumours were monitored until they reached four times the initial treatment volume (4 x V) or 28 days. A separate experiment compared tumour doxorubicin concentrations (using high performance liquid chromatography) 24 h after treatment with liposomal doxorubicin alone (6 mg kg(-1) i.v., n=9) or imatinib plus liposomal doxorubicin (n=16). Imatinib plus docetaxel resulted in significantly improved antitumour efficacy (0/10 animals reached 4 x V by 28 days) when compared to docetaxel alone (3/9 reached 4 x V, P=0.014) or imatinib alone (9/10 reached 4 x V, P=0.025). Pretreatment with imatinib also significantly increased tumour concentrations of liposomal doxorubicin. Overall, these preclinical studies emphasise the potential of imatinib as an adjunct to small molecule or liposomal chemotherapy.

Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-beta and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation.

Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent predictive factors for poor survival and poor treatment response in cancer patients. However, the relationship between IFP and tumour hypoxia has not yet been clearly established. Preclinical studies have shown that lowering IFP improves treatment response to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of phosphorylated platelet-derived growth factor receptor-beta (p-PDGFR-beta), a tyrosine kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-beta. We hypothesised that Imatinib, a specific PDGFR-beta inhibitor will, in addition to p-PDGFR-beta inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation. A549 human lung adenocarcinoma xenografts overexpressing PDGFR-beta were grown in nude mice. Tumour-bearing animals were randomised to control and treatment groups (Imatinib 50 mg kg(-1) via gavage for 4 days). Interstitial fluid pressure was measured in both groups before and after treatment. EF5, a hypoxia marker, was administered 3 h before being killed. Tumours were sectioned and stained for p-PDGFR-beta, VEGF and EF5 binding. Stained sections were viewed with a fluorescence microscope and image analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-beta, VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows that p-PDGFR-beta-overexpressing tumours can be effectively treated with Imatinib to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib treatment improves tumour oxygenation and downregulates tumour VEGF expression.

[Schimke immuno-osseous dysplasia]. / Simkeova imunsko-kostana displazija.

Schimke immuno-osseous dysplasia (OMIM *242900) is a rare autosomal recessive disorder that affects primarily the bone, the immune system, the kidneys, the skin and the vascular system. The patients have intrauterine growth retardation, short stature with short neck and trunk, peculiar clinical phenotype: triangular face, broad nasal bridge, bulbous nasal tip, small palpebral fissures, long upper lip and low hairline. The characteristic features include spondyloepiphyseal dysplasia, hyperpigmented maculae, proteinuria with progressive renal failure, lymphopenia with recurrent infections and cerebral ischaemia. We describe a girl, 5 years old, with short-trunk type of dwarfism (height 75 cm, below 3rd centile), short neck, accentuated lumbal lordosis and protruding abdomen. The patient had peculiar face with a broad, depressed nasal bridge, bulbous nasal tip, and slightly elongated upper lip. The hair was thin and sparse. Numerous pigmented spots resembling lentigines were visible on the trunk and abdomen. Radiographs showed spondyloepiphyseal dysplasia. At the age of 2 years laboratory analyses showed normal growth hormone secretion, normal thyroid function tests, normal female karyotype and no mucopolisachariduria. Since the age of 4 years, several episodes of transitory right-sided hemiparesis with spontaneous recovery, were observed. Seizures occurred at 5 years of age, when the MRI brain imaging showed multiple areas of ischaemia. She also experienced transient nephrotic syndrome, lymphopenia and low IgG accompanied by septicaemia.

Cellular and connective tissue changes in alveolar septal walls in emphysema.

Emphysema is commonly defined as enlargement of airspaces distal to terminal bronchioles accompanied by destruction of alveolar walls, but without obvious fibrosis. Morphometric techniques were used to correlate changes in components of the alveolar septa surrounding enlarged airspaces in human emphysema with the mean linear intercept (Lm) of those airspaces. Alveolar and capillary surface density decreased with increased Lm, but the ratio of these surface densities to each other remained close to normal for mild to moderate increases in Lm. This suggests that the decreased gas exchange observed in emphysema is initiated by a total loss of septa and not by selective pathological changes of the microvasculature. Increases in septal wall thickness directly correlated with increases in Lm. For the mild to moderate emphysema lesions included in this study, an increase of 100% in Lm correlated with a 130% increase in the relative volume of the alveolar septal interstitium. Significant increases occurred in both elastin (0.14 to 0.56 microm(3)/microm(2) basement membrane [BM]) and collagen (0.49 to 1. 63 microm(3)/microm(2) BM). The increase in elastin and collagen raises the possibility of a remodeling process in the connective matrix in alveolar walls. Whether or not the new connective tissue represents a disordered, nonfunctional regional response needs to be determined.