Genetic polymorphisms as predictive biomarker of survival in patients with gastrointestinal stromal tumors treated with sunitinib.

This study aimed to identify single-nucleotide polymorphisms (SNPs) that are associated with outcome to treatment with sunitinib in patients with advanced gastrointestinal stromal tumors (GIST). Forty-nine SNPS involved in the pharmacokinetic and pharmacodynamic pathway of sunitinib were associated with progression-free survival (PFS) and overall survival (OS) in 127 patients with advanced GIST who have been treated with sunitinib. PFS was significantly longer in carriers of the TT genotype in POR rs1056878 (hazards ratio (HR) 4.310, 95% confidence interval (CI):1.457-12.746, P=0.008). The presence of the T-allele in SLCO1B3 rs4149117 (HR 2.024, 95% CI:1.013-4.044, P=0.046), the CCC-CCC alleles in SLC22A5 haplotype (HR 2.603, 95% CI: 1.216-5.573, P=0.014), and the GC-GC alleles in the IL4 R haplotype (HR 7.131, 95% CI:1.518-33.496, P=0.013) were predictive for OS. This shows that polymorphisms in the pharmacokinetic and pharmacodynamic pathways of sunitinib are associated with survival in GIST. This may help to identify patients that benefit more from treatment with sunitinib.

[Focal lesions in whole-body MRI in multiple myeloma : Quantification of tumor mass and correlation with disease-related parameters and prognosis]. / Fokale Läsionen in der Ganzkörper-MRT beim multiplen Myelom : Quantifizierung der Tumorlast und Korrelation mit krankheitstypischen Parametern und Prognose.

BACKGROUND AND OBJECTIVES: In this study, we evaluated methods of quantification of tumor mass in whole-body MRI (wb-MRI) in multiple myeloma and correlated these with disease-related parameters in serum and bone marrow. MATERIALS AND METHODS: We retrospectively evaluated wb-MRIs of 52 patients with focal infiltration pattern and a total of 700 focal lesions (subsequently called lesions). We determined the longest diameter (LD), the segmented volume (SV), and the morphology (spherical or non-spherical). We correlated total number/volume of the lesions with clinical parameters and prognosis and furthermore LD with SV. After that we analyzed the agreement of SV and estimated volume (EV) using the volume formula of a sphere based on LD. RESULTS: Results showed no significant correlations of total number/volume with prognosis or clinical parameters. The latter were situated predominantly in the normal range. Furthermore, 10% of lesions were spherical. SV and LD correlated significantly in single lesions and on patient level. SV was in lesions <6 cm3 systematically larger and in lesions ≥6 cm3 smaller than EV. In 95%, we found in small lesions a deviation of EV versus SV from +0.9 cm3 to -4.6 cm3 and in large lesions from +160 cm3 to -111 cm3 (EV-SV). CONCLUSIONS: Quantification of tumor mass in the focal infiltration pattern is performed more accurately by volumetry than LD due to the predominant existence of non-spherical lesions. The patient cohort with clinical parameters predominantly in the normal range is distributed to ISS stage I and partly pretreated, a fact that makes interpretation of absent correlations more difficult. Consider also a variation in activitiy of lesions and a diffuse infiltration not detectable by MRI.

Radiation Dose Reduction in Digital Plain Radiography of the Knee after Total Knee Arthroplasty.

PURPOSE: To reduce radiation exposure of frequently performed radiographs of the knee in follow-up of total-knee arthroplasty ensuring accurate assessment by using objective quality control criteria. MATERIALS AND METHODS: In this prospective randomized study 278 radiographs of the knee in follow-up of total-knee arthroplasty were performed with standard and 37% reduced radiation dose. The evaluation of the plain-radiographs was conducted using the following criteria: bone-implant interface, implant-surface character, implant-implant discrimination and periarticular heterotopic ossification. Two radiologists evaluated these criteria using a score ranging from 1 (definitely assessable) to 4 (not assessable). If a single criterion had been evaluated with a score ≥ 3 or more than 2 criteria with ≥ 2 points, the radiograph was score das "not assessable". The study was designed as non-inferiority-trial. RESULTS: 100% of examined radiographs were scored as assessable, hence no statistical inferiority between the examinations with standard and reduced dose could be observed. Singular assessment of the defined criteria was likewise dose-independent. CONCLUSION: Plain-radiography of the knee following total-knee arthroplasty can be performed with 63% of standard dose without loss of diagnostic validity. KEY POINTS: Due to the non-inferiority of digital radiographs of the knee joint after total-knee arthroplasty done with 37% reduced image receiver dose we recommend the tested speed class of SC 800 as a new reference value for digital radiographs with this indication.

Incidence and relevance of QTc-interval prolongation caused by tyrosine kinase inhibitors.

BACKGROUND: Tyrosine kinase inhibitors (TKIs) are associated with prolongation of the QTc interval on the electrocardiogram (ECG). The QTc-interval prolongation increases the risk of life-threatening arrhythmias. However, studies evaluating the effects of TKIs on QTc intervals are limited and only consist of small patient numbers. METHODS: In this multicentre trial in four centres in the Netherlands and Italy we screened all patients who were treated with any TKI. To evaluate the effects of TKIs on the QTc interval, we investigated ECGs before and during treatment with erlotinib, gefitinib, imatinib, lapatinib, pazopanib, sorafenib, sunitinib, or vemurafenib. RESULTS: A total of 363 patients were eligible for the analyses. At baseline measurement, QTc intervals were significantly longer in females than in males (QTcfemales=404 ms vs QTcmales=399 ms, P=0.027). A statistically significant increase was observed for the individual TKIs sunitinib, vemurafenib, sorafenib, imatinib, and erlotinib, after the start of treatment (median ΔQTc ranging from +7 to +24 ms, P<0.004). The CTCAE grade for QTc intervals significantly increased after start of treatment (P=0.0003). Especially patients who are treated with vemurafenib are at increased risk of developing a QTc of ⩾470 ms, a threshold associated with an increased risk for arrhythmias. CONCLUSIONS: These observations show that most TKIs significantly increase the QTc interval. Particularly in vemurafenib-treated patients, the incidence of patients at risk for arrhythmias is increased. Therefore, especially in case of combined risk factors, ECG monitoring in patients treated with TKIs is strongly recommended.

Modern Radiological Postoperative Diagnostics of the Hip Joint in Children and Adults.

UNLABELLED: The assessment of bone healing and loosening of endoprosthesis material was long the primary indication for postoperative projection radiography and CT imaging of the hip joint following trauma and endoprosthesis implantation. With the increasing number of joint-preserving surgery, e. g. of surgical hip luxation and hip arthroscopy for the treatment of femoroacetabular impingement (FAI), high-resolution imaging of intra-articular pathologies before and after surgery has become increasingly important. In this review article, diagnostic imaging of the hip joint is presented following common trauma surgery and orthopedic surgery interventions. The imaging modalities of projection radiography, CT and MRI including direct MR-arthrography are discussed with regard to their diagnostic capability in the postoperative assessment of the hip joint. Among others topics, imaging is discussed following hip arthroplasty, following surgical hip luxation and arthroscopic interventions for the treatment of FAI, as well as following core decompression for avascular necrosis of the femoral head. Moreover, orthopedic interventions of the hip joint in children and adolescents are presented and the dedicated reporting of postoperative imaging is outlined. KEY POINTS: • Consolidation of osteotomies and position of implants should be assessed in postoperative imaging. • MRI is useful for confirming correct articulation after treatment of congenital hip dislocation. • Radiologically assessable complications after total hip replacement are inlay wear, loosening, dislocation, periarticular ossifications and infection. • MRI can detect and classify pseudotumours in cases of metal-metal pairing after total hip replacement.

[Clinical or radiological diagnosis of impingement]. / Klinische oder radiologische Diagnose des Impingements.

CLINICAL/METHODICAL ISSUE: Shoulder impingement syndrome is a clinically common entity involving trapping of tendons or bursa with typical clinical findings. STANDARD RADIOLOGICAL METHODS: Important radiological procedures are ultrasound, magnetic resonance imaging (MRI) and MR arthrography. Projection radiography and computed tomography (CT) are ideal to identify bony changes and CT arthrography also serves as an alternative method in cases of contraindications for MRI. These modalities support the clinically suspected diagnosis of impingement syndrome and may identify its cause in primary diagnosis. In addition, effects of impingement are determined by imaging. Therapy decisions are based on a synopsis of radiological and clinical findings. PERFORMANCE: The sensitivity and specificity of these imaging modalities with regard to the diagnostics of a clinically evident impingement syndrome are given in this review article. PRACTICAL RECOMMENDATIONS: Orthopedic and trauma surgeons express the suspicion of an impingement syndrome based on patient history and physical examination and radiologists confirm structural changes and damage of intra-articular structures using dedicated imaging techniques.

Pharmacokinetically guided sunitinib dosing: a feasibility study in patients with advanced solid tumours.

BACKGROUND: Plasma exposure of sunitinib shows large inter-individual variation. Therefore, a pharmacokinetic (PK) study was performed to determine safety and feasibility of sunitinib dosing based on PK levels. METHODS: Patients were treated with sunitinib 37.5 mg once daily. At days 15 and 29 of treatment, plasma trough levels of sunitinib and N-desethyl sunitinib were measured. If the total trough level (TTL) was <50 ng ml(-1) and the patient did not show any grade ⩾3 toxicity, the daily sunitinib dose was increased by 12.5 mg. If the patient suffered from grade ⩾3 toxicity, the sunitinib dose was lowered by 12.5 mg. RESULTS: Twenty-nine out of 43 patients were evaluable for PK assessments. Grade ⩾3 adverse events were experienced in seven patients (24%) at the starting dose and in nine patients (31%) after dose escalation. TTLs were below target in 15 patients (52%) at the starting dose. Of these, five patients (17%) reached target TTL after dose escalation without additional toxicity. CONCLUSIONS: In a third of the patients that were below target TTL at standard dose, the sunitinib dose could be increased without additional toxicities. This could be the basis for future studies and the implementation of a PK-guided dosing strategy in clinical practice.

Association analysis of genetic polymorphisms in genes related to sunitinib pharmacokinetics, specifically clearance of sunitinib and SU12662.

Interpatient variability in the pharmacokinetics (PK) of sunitinib is high. Single nucleotide polymorphisms (SNPs) in PK candidate genes have been associated with the efficacy and toxicity of sunitinib, but whether these SNPs truly affect the PK of sunitinib remains to be elucidated. This multicenter study involving 114 patients investigated whether these SNPs and haplotypes in genes encoding metabolizing enzymes or efflux transporters are associated with the clearance of sunitinib and its active metabolite SU12662. SNPs were tested as covariates in a population PK model. From univariate analysis, we found that the SNPs in CYP3A4, CYP3A5, and ABCB1 were associated with the clearance of both sunitinib and SU12662. In multivariate analysis, CYP3A4*22 was found to be eliminated last with an effect size of -22.5% on clearance. Observed effect sizes are below the interindividual variability in clearance and are therefore too limited to directly guide individual dosing of sunitinib.

[Modern digital plain-radiography of the whole spine in scoliosis patients--dose reduction and quality criteria]. / Moderne digitale Radiografie der Ganzwirbelsäule bei Skoliose - Dosisreduktion und Qualitätskriterien.

PURPOSE: To reduce the radiation exposure of plain radiographs of the entire spine depending on specific indications, since these are frequently performed examinations of children and young adults with scoliosis and to determine objective quality control criteria to ensure accurate assessment. MATERIALS AND METHODS: In this prospective randomized study 323 patients underwent plain-radiography of the entire spine with standard and 50 % reduced dose. In an experimental pilot-study this target-dose was determined using an Alderson-Phantom. The evaluation of the experimental radiographs, as well as, the randomized plain-radiographs was conducted using the following criteria: endplates (Cobb-angle), spinal process and pedicel (rotation), lateral margin of the vertebral body (lateral alignment), identification of C7 / S1 (perpendicular). Two radiologists evaluated these criteria using a score ranging from 1 (definitely assessable) to 4 (not assessable). If one single criteria was evaluated with a score of 3 or more points or more than 2 criteria with 2 points, the radiograph was scored as "not assessable". The statistical analysis was conducted as a non-inferiority-trial. RESULTS: Seven (2.4 %) of the 290 examined x-rays were scored as not assessable. There was no statistic inferiority between the examinations with standard or reduced dose, while singular assessment of the defined criteria was likewise dose-independent. CONCLUSION: Plain-radiography of the total spine in patients with scoliosis can be performed with a dose reduction of 50% without a loss of validity. The obtained quality control criteria were clinically applicable.

[Radiological diagnostics of spinal tumors. Part 2: special diagnostics of intradural tumors and tumor-like lesions]. / Radiologische Diagnostik spinaler Tumoren. Teil 2: Spezielle Diagnostik intraduraler Tumoren und tumorähnlicher Läsionen.

Intradural tumors are classified into extramedullary and intramedullary localization. A distinct attribution to one of these compartments is essential for finding the appropriate diagnosis. In the radiological evaluation of intradural tumors magnetic resonance imaging (MRI) is the most important method and in contrast to osseous spinal tumors, radiography and computed tomography are of minor importance. According to the globally established WHO grading system, tumors of the central nervous system are histopathologically classified into four grades. Through grades I to IV malignancy and proliferative activity increase. Prognosis is inversely correlated to the WHO grade. Intradural tumors are generally treated by neurosurgeons. Besides neurological symptoms intradural tumors often cause spinal malpositioning. Thus knowledge of the most frequent intradural tumors and their characteristic magnetic resonance findings are important in the orthopedic practice.

[Radiological diagnostics of spinal tumors. Part 1: general tumor diagnostics and special diagnostics of extradural tumors]. / Radiologische Diagnostik spinaler Tumoren. Teil 1: Allgemeine Tumordiagnostik und spezielle Diagnostik extraduraler Tumoren.

Radiological investigation of spinal tumors includes identification of the suspect lesions as well as their relation to surrounding critical structures, such as nerve roots and the myelon. With the use of computed tomography (CT) the delineation of bone and with magnetic resonance tomography the assessment of bone marrow and soft tissue are possible with high-spatial resolution and multi-planar reconstructions. The consolidation of clinical information, distribution pattern and morphology of the lesion itself results in the final radiological evaluation. Because of low invasiveness and complications, CT-guided biopsy is a common tool in cases of suspected lesions. With the help of multi-planar reconstructions even difficult approaches are possible without impairment of critical structures. This review article discusses typical imaging characteristics of common tumors originating from the vertebral column after a section on basic and general aspects of tumor diagnostics.

[Soft tissue swelling of the sternoclavicular joint]. / Weichteilschwellung des Sternoklavikulargelenks.

A 73-year-old woman presented with a swelling of the right sternoclavicular joint the size of a hens egg which had persisted for 2 years. After a corticosteroid injection 8 months previously the swelling was asymptomatic. The magnetic resonance imaging (MRI) scan showed synovialitis of the sternoclavicular joint with edema of the adjacent bone. The constellation is indicative of Tietze syndrome, an inflammation of costochondral junctions of the ribs or chondrosternal joints. The treatment is usually directed at pain relief and benign conditions are often self-limiting.

[Postoperatively increased oxygen demand and hemoptysis after extubation]. / Postoperativ erhöhter Sauerstoffbedarf und Hämoptysen nach Extubation.

A 22-year-old man on postoperative day 1 after open reduction with internal fixation of a distal fibula fracture presented with hemoptysis and increased oxygen demand. X-ray and contrast-enhanced computed tomography revealed bilateral patchy opacities and mediastinal emphysema. After bronchoscopy and bronchoalveolar lavage, a diagnosis of alveolar hemorrhage was made. The medical history revealed regular abuse of marihuana and cocaine.

[Imaging in the emergency room]. / Bildgebung im Schockraum.

In order to reduce mortality in severely injured patients, a rapid radiologic diagnosis is essential. Sonography plays a role only as a focused assessment with sonography for trauma (FAST) to clarify free intraperitoneal fluid immediately on admittance. Today, whole-body multislice helical computed tomography (CT) has become increasingly important as a diagnostic tool. Based on the results of the CT scan, patients can be referred for laparotomy or safely classified for "wait and see" treatment. Although the reduction in injury-related mortality would outweigh the risk of radiation dose, the indiscriminate use of CT for patients with minor injuries is not justified and must be avoided.

[Symptomatic bilateral soft tissue tumor of the breast wall]. / Symptomatischer bilateraler Weichteiltumor der Brustwand.

A 54-year-old woman presented with progressive swelling of the right scapula as well as motion-dependent pain. The medical history revealed a polyglandular autoimmune syndrome and lumbar disc degeneration. The magnetic resonance imaging (MRI) scan showed a bilateral well-defined muscle isointense space-occupying lesion situated between the scapula, rib cage and thoracic muscles with homogeneous contrast enhancement. The constellation is indicative of a elastofibroma dorsi, a rare mesenchymal tumor often appearing bilaterally.

Elevated expression of SerpinA1 and SerpinA3 in HLA-positive cervical carcinoma.

In cervical cancer, an important mechanism by which tumour cells escape immune surveillance is loss of HLA class I, enabling tumours to evade recognition and lysis by cytotoxic T lymphocytes. Some tumours, however, escape from immune surveillance without accumulating defects in antigen presentation. We hypothesized that tumours with no or partial loss of HLA class I develop alternative mechanisms to prevent immune elimination. To investigate this hypothesis, genome-wide expression profiling using Illumina arrays was performed on cervical squamous cell carcinomas showing overall loss of HLA class I, partial, and normal HLA class I protein expression. Statistical analyses revealed no significant differences in gene expression between tumours with partial (n = 11) and normal HLA class I expression (n = 10). Comparison of tumours with normal/partial HLA class I expression (n = 21) with those with overall loss of HLA class I expression (n = 11) identified 150 differentially expressed genes. Most of these genes were involved in the defence response (n = 27) and, in particular, inflammatory and acute phase responses. Especially SerpinA1 and SerpinA3 were found to be up-regulated in HLA-positive tumours (3.6- and 8.2-fold, respectively), and this was confirmed by real-time PCR and immunohistochemistry. In a group of 117 tumours, high SerpinA1 and SerpinA3 expression in association with normal/partial HLA expression correlated significantly with poor overall survival (p = 0.035 and p = 0.05, respectively). Thus, HLA-positive tumours are characterized by higher expression of genes associated with an inflammatory profile. In addition, expression of the acute phase proteins SerpinA1 and SerpinA3 in HLA-positive tumours is associated with worse prognosis.

FLT3 ligand gene expression and protein production in human colorectal cancer cell lines and clinical tumor specimens.

Dendritic cells (DC) are professional antigen presenting cells (APC) whose proliferation and functional differentiation can be induced by hematopoietic growth factors including GM-CSF and FLT3 ligand (FL). Colorectal cancers are known to be infiltrated by dendritic cells (DC) and neoplastic cells have been shown to produce GM-CSF. In this work we investigated FLT3 ligand (FL) gene expression and protein production in human colorectal cancer cell lines and clinical tumor specimens. Using reverse transcription polymerase chain reaction (RT-PCR), 6 out of 6 established tumor lines were found to express to variable extents FL gene. In 1 of them, SW480, FL immunoreactivity could be observed by taking advantage of specific antibodies. In contrast, soluble FL could not be detected in any culture supernatant. FLT3 receptor (FR) gene was not expressed and exogenous addition to the cultures of recombinant FL (rFL) did not affect the proliferation of the tumor lines. FL gene expression was investigated using a densitometry-assisted, semiquantitative RT-PCR in clinical tumor specimens. Specific FL gene transcripts were amplified from 12 of 12 surgical samples. In these cases, FL gene expression of significantly lower intensity was also detected in healthy mucosa sampled in the vicinity (2 cm) or at a distance (10 cm) from neoplastic outgrowth. Immunohistochemical studies identified FL-positive cancer cells in 5 of 5 cases tested. No positivity was detected in healthy mucosa epithelia at a distance from the tumor or in stromal cells. FL content in preoperative sera from colorectal cancer patients (n = 13) did not exceed the levels detected in healthy donors (

GM-CSF gene expression and protein production in human colorectal cancer cell lines and clinical tumor specimens.

Granulocyte-macrophage colony stimulating factor (GM-CSF) gene expression and protein production were investigated in colorectal cancer cell lines and surgical specimens. In 6 of 6 established tumor lines, expression of the GM-CSF gene was observed by reverse transcription polymerase chain reaction (RT-PCR). Furthermore, for 2 of the lines, the cytokine was detectable in > or = 100 pg/ml amounts in culture supernatants by enzyme-linked immunosorbent assay tests. Addition of recombinant GM-CSF at doses ranging between 30 pg and 30 ng/ml did not appear to affect the proliferation of colorectal cancer cell lines as measured by 3H-thymidine incorporation. GM-CSF gene expression was then examined in surgical specimens by a densitometry-assisted, semiquantitative RT-PCR technique. In the 10 samples analyzed, significantly higher expression was detectable in tumors, as compared with autologous healthy mucosa sampled in the vicinity (2 cm) or at distance (10 cm) from the neoplastic focus. Immunohistochemistry studies performed on 13 specimens led to the identification of intracytoplasmic GM-CSF in tumor cells in 9 samples. In 6 of these, positivity of stromal fibroblasts and lymphocytes adjacent to the tumor was also observed. In contrast, intracellular GM-CSF was only detectable in 2 cases in untransformed epithelial cells, close to the neoplasm, but never in healthy mucosa at distance from the tumor. Infiltration by dendritic cells (DC) was also investigated. In 5 of 8 colorectal cancers tested, DC aggregates accounted for more than 10% of stromal cells. Lower numbers were detectable in healthy mucosa. However, DC infiltration could not be correlated with the presence of GM-CSF-positive neoplastic cells in the tumor specimens. Remarkably, cultured DC were unable to exert significant cytotoxic activity against colorectal cancer cells in vitro.

C-type lectin-like receptors in peptide-specific HLA class I-restricted cytotoxic T lymphocytes: differential expression and modulation of effector functions in clones sharing identical TCR structure and epitope specificity.

C-type lectin-like inhibitory receptors are heterodimers consisting of CD94 and NKG2-A-B molecules expressed on NK cells and on a subset of activated T lymphocytes. Their inhibitory effects on NK cytotoxicity and on the NK-like activity of T cell clones have been demonstrated, but no data are currently available on antigen-specific class I-restricted cytotoxic T lymphocytes (CTL). We have generated a panel of HLA-A2.1-restricted CTL clones directed against a nonapeptide derived from a melanoma-associated antigen, dopachrome tautomerase (TRP-2). All clones were CD8+ and TCR alphabeta+. About half of them expressed a CD94bright phenotype, whereas the remaining were CD94dim. Only the CD94bright CTL expressed the NKG2-A-B gene, consistent with the expression of a C-type, lectin-like, inhibitory CD94/NKG2-A-B heterodimer. Both CD94bright and CD94dim clones appeared to require similar amounts of synthetic epitope sensitizing target cells. Addition of anti-CD94 mAb resulted in a significant increase of specific killing by CD94bright, but not by CD94dim clones in the presence of suboptimal concentrations of peptide, whereas, when optimal amounts were used, the mAb did not induce a significant modulation of the cytotoxicity. Antigen-induced inward [Ca2+]i fluxes were unaffected, but an enhancement of TCR down-modulation could be observed in the presence of anti-CD94 mAb at high concentration of antigenic peptide. The analysis of the TCR-Vbeta repertoire of the CTL clones by RT-PCR and immunofluorescence revealed that all clones regardless of CD94 phenotype shared Vbeta22 expression. Most importantly, sequence analysis showed that they all expressed identical Vbeta22 TCR rearranged with Jbeta2.1 and Cbeta2. Taken together, these data indicate that different expression of functionally active lectin-like inhibitory receptors can be detected in CTL clones sharing identical TCR sequence and peptide specificity.