Precision of T2 TSE MRI-CT-image fusions based on gold fiducials and repetitive T2 TSE MRI-MRI-fusions for adaptive IGRT of prostate cancer by using phantom and patient data.

INTRODUCTION: To increase precision of radiation treatment (RT) delivery in prostate cancer, MRI-based RT as well as the use of fiducials like gold markers (GMs) have shown promising results. Their combined use is currently under investigation in clinical trials. Here, we aimed to evaluate a workflow of image registration based on GMs between CT and MRI as well as weekly MRI-MRI adaption based on T2 TSE sequence. MATERIAL AND METHODS: A gel-phantom with two inserted GMs was scanned with CT and three different MR-scanners of 1.5 and 3 T (T2 TSE and T1 VIBE-Dixon, isotropic, voxel size 2 × 2 × 2 mm). After image fusion, deviations for fiducial and gel match were measured and artifacts were evaluated. Additionally, CT-MRI-match deviations and MRI-MRI-match deviations of 10 Patients from the M-basePro study using GMs were assessed. RESULTS: GMs were visible in all imaging modalities. The outer gel contours were matched with <1 mm deviation, contour volumes varied between 0 and 1%. The deviations of the GMs were less than 2 mm in any direction of MRI/CT. Shifts of peripherally or centrally located GMs were randomly distributed. The average MRI-CT-match precision of 10 patients with GMs was 1.9 mm (range 1.1-3.1 mm). CONCLUSIONS: Match inaccuracies for GMs between reference CT and voxel-isotropic T2-TSE sequences are small. Spatial deviations of CT- and MR-contoured fiducials were less than 2 mm, i.e., below SLT of the applied modalities. In patients, the average CT-MRI-match precision for GMs was 1.9 mm supporting their use in MR-guided high precision RT.

First report of robot-assisted transperineal fusion versus off-target biopsy in patients undergoing repeat prostate biopsy.

PURPOSE: To clarify the value of targeted versus off-target biopsies in men with a suspicion of prostate cancer (PC) and a visible lesion in multi-parametric magnetic resonance imaging (mpMRI) using transperineal robot-assisted biopsy. METHODS: Fifty-five consecutive men with one non-palpable suspicious lesion in mpMRI after negative 12-core transrectal ultrasound-guided biopsy were enrolled in 2014-2015. Lesions were scored using the Prostate Imaging Reporting and Data System. A robot-assisted system was utilized to collect four robot-assisted targeted transperineal biopsy cores (RA-TB) within the lesion using mpMRI-TRUS elastic fusion. Untargeted transperineal 14-core biopsy was performed only outside the lesion (RA-UB). Histological grade was compared in biopsies and available prostatectomy specimens. RESULTS: Overall, 34 of 55 patients (62%) were diagnosed with PC based on biopsy. 85% of cancers were clinically significant PC (csPC) defined as GS ≥ 7. 85% of biopsy-proven cancers were detected with RA-TB alone. RA-UB identified only one additional patient with csPC and lead to upgrading in five biopsy cases (14.7%). Pathological evaluation of 14 prostatectomy specimens showed upgrading in 2 patients (14.3%), while all other patients were correctly classified by RA-TB without need of additional RA-UB. Mean procedure duration was 43 (±6) min, and only minor complications according to Clavien-Dindo were recorded during 30-day follow-up. CONCLUSIONS: This is the first report of transperineal robot-assisted elastic mpMRI-TRUS fusion biopsy. RA-TB of positive MR lesions enabled reliable detection of csPC, while RA-UB in MRI-negative regions is of minor importance.

Diagnostic accuracy of contemporary multidetector computed tomography (MDCT) for the detection of lumbar disc herniation.

OBJECTIVES: To evaluate the diagnostic accuracy of multidetector CT (MDCT) for detection of lumbar disc herniation with MRI as standard of reference. METHODS: Patients with low back pain underwent indicated MDCT (128-row MDCT, helical pitch), 60 patients with iterative reconstruction (IR) and 67 patients with filtered back projection (FBP). Lumbar spine MRI (1.5 T) was performed within 1 month. Signal-to-noise ratios (SNR) of cerebrospinal fluid (CSF), annulus fibrosus (AF) and the spinal cord (SC) were determined for all modalities. Two readers independently rated image quality (IQ), diagnostic confidence and accuracy in the diagnosis of lumbar disc herniation using MRI as standard of reference. Inter-reader correlation was assessed with weighted κ. RESULTS: Sensitivity, specificity, precision and accuracy of MDCT for disc protrusion were 98.8%, 96.5%, 97.1%, 97.8% (disc level), 97.7%, 92.9%, 98.6%, 96.9% (patient level). SNR of IR was significantly higher than FBP. IQ was significantly better in IR owing to visually reduced noise and improved delineation of the discs. κ (>0.90) was excellent for both algorithms. CONCLUSION: MDCT of the lumbar spine yields high diagnostic accuracy for detection of lumbar disc herniation. IR improves image quality so that the provided diagnostic accuracy is principally equivalent to MRI. KEY POINTS: • MDCT is an accurate alternative to MRI in disc herniation diagnosis. • By IR enhanced image quality improves MDCT diagnostic confidence similar to MRI. • Advances in CT technology contribute to improved diagnostic performance in lumbar spine imaging.

Prostate cancer gene 3 (PCA3) is of additional predictive value in patients with PI-RADS grade III (intermediate) lesions in the MR-guided re-biopsy setting for prostate cancer.

PURPOSE: Multiparametric magnetic resonance imaging (mpMRI) improves diagnostic accuracy in re-biopsies of men with prostate cancer (PC) suspicion, but predictive value is limited despite the use of the new Prostate Imaging Reporting and Data System (PI-RADS). Prognostic value of the PC-specific biomarker prostate cancer gene 3 (PCA3) added to the PI-RADS score was evaluated. METHODS: The study was a retrospective analysis of the institutional database for men with MR-guided biopsy (MR-GB) for suspicious lesion in mpMRI and who had an additional pre-MR-GB PCA3 testing for ongoing PC suspicion. All men had ≥ 1 negative ultrasound GB. Lesions were retrospectively scored by PI-RADS in three MRI sequences (T2w, DCE, and DWI). PCA3 was analyzed with cutoffs of 25 and 35. The prognostic value of mpMRI and PCA3 and the additional value of both were explored. RESULTS: Tumor detection rate (49 men, mean PSA 10 ng/ml, lesion size 40 mm(2)) was 45 % (22/49 patients). In the subgroup of PI-RADS IV°, 17/17 patients had PC; in PI-RADS III° (intermediate) 5/15 had PC, and all 5 had a PCA3 > 35. PCA3 > 35 had no additional prognostic value in the whole cohort. Out of the 10/15 PC negative patients (PI-RADS III°), PCA3 was < 35 in 6. The inclusion of PCA3 value in PI-RADS III° patients improved predictive accuracy to 91.8 %. CONCLUSION: MpMRI and subsequent grading to PI-RADS significantly improves PC detection in the re-biopsy setting. The diagnostic uncertainty in the PI-RADS intermediate group can be ameliorated by the addition of PCA3 cutoff of 35 to avoid potential unnecessary biopsies.

Topographic deformation patterns of knee cartilage after exercises with high knee flexion: an in vivo 3D MRI study using voxel-based analysis at 3T.

OBJECTIVES: To implement a novel voxel-based technique to identify statistically significant local cartilage deformation and analyze in-vivo topographic knee cartilage deformation patterns using a voxel-based thickness map approach for high-flexion postures. METHODS: Sagittal 3T 3D-T1w-FLASH-WE-sequences of 10 healthy knees were acquired before and immediately after loading (kneeling/squatting/heel sitting/knee bends). After cartilage segmentation, 3D-reconstruction and 3D-registration, colour-coded deformation maps were generated by voxel-based subtraction of loaded from unloaded datasets to visualize cartilage thickness changes in all knee compartments. RESULTS: Compression areas were found bifocal at the peripheral medial/caudolateral patella, both posterior femoral condyles and both anterior/central tibiae. Local cartilage thickening were found adjacent to the compression areas. Significant local strain ranged from +13 to -15 %. Changes were most pronounced after squatting, least after knee bends. Shape and location of deformation areas varied slightly with the loading paradigm, but followed a similar pattern consistent between different individuals. CONCLUSIONS: Voxel-based deformation maps identify individual in-vivo load-specific and posture-associated strain distribution in the articular cartilage. The data facilitate understanding individual knee loading properties and contribute to improve biomechanical 3 models. They lay a base to investigate the relationship between cartilage degeneration patterns in common osteoarthritis and areas at risk of cartilage wear due to mechanical loading in work-related activities. KEY POINTS: • 3D MRI helps differentiate true knee-cartilage deformation from random measurement error • 3D MRI maps depict in vivo topographic distribution of cartilage deformation after loading • 3D MRI maps depict in vivo intensity of cartilage deformation after loading • Locating cartilage contact areas might aid differentiating common and work-related osteoarthritis.

[Functional magnetic resonance imaging of the kidneys]. / Funktionelle Magnetresonanztomographie der Nieren.

Interest in functional renal magnetic resonance imaging (MRI) has significantly increased in recent years. This review article provides an overview of the most important functional imaging techniques and their potential clinical applications for assessment of native and transplanted kidneys, with special emphasis on the clarification of renal tumors.

[Diagnostic accuracy of dual energy CT angiography in patients with diabetes mellitus]. / Diagnostische Genauigkeit der Dual-energy-CT-Angiographie bei Patienten mit Diabetes mellitus.

OBJECTIVES: Peripheral arterial disease (PAD) represents a major and highly prevalent complication in patients with diabetes mellitus. The diagnostic, non-invasive work-up by computed tomography angiography (CTA) is limited in the presence of extensive calcification. The aim of the study was to determine the diagnostic accuracy of dual energy CTA (DE-CTA) for the detection and characterization of PAD in patients with diabetes mellitus. MATERIAL AND METHODS: In this study 30 diabetic patients with suspected or known PAD were retrospectively included in the analysis. All subjects underwent DE-CTA (Somatom Definition Flash, Siemens Healthcare, Erlangen, Germany) prior to invasive angiography, which served as the reference standard. Blinded analysis included assessment of the presence and degree of peripheral stenosis on curved multiplanar reformatting (MPR) and maximum intensity projections (MIP). Conventional measures of diagnostic accuracy were derived. RESULTS: Among the 30 subjects included in the analysis (83% male, mean age 70.0 ± 10.5 years, 83% diabetes type 2), the prevalence of critical stenosis in 331 evaluated vessel segments was high (30%). Dual energy CT identified critical stenoses with a high sensitivity and good specificity using curved MPR (100% and 93.1%, respectively) and MIP images (99% and 91.8%, respectively). In stratified analysis, the diagnostic accuracy was higher for stenosis pertaining to the pelvic and thigh vessels as compared with the lower extremities (curved MPR accuracy 97.1% vs. 99.2 vs. 90.9%; respectively, p < 0.001). CONCLUSION: The use of DE-CTA allows reliable detection and characterization of peripheral arterial stenosis in patients with diabetes mellitus with higher accuracy in vessels in the pelvic and thigh regions compared with the vessels in the lower legs.

CT perfusion technique for assessment of early kidney allograft dysfunction: preliminary results.

OBJECTIVES: To assess the benefit of quantitative computed tomography (CT) perfusion for differentiating acute tubular necrosis (ATN) and acute rejection (AR) in kidney allografts. METHODS: Twenty-two patients with acute kidney allograft dysfunction caused by either AR (n = 6) or ATN (n = 16) were retrospectively included in the study. All patients initially underwent a multiphase CT angiography (CTA) protocol (12 phases, one phase every 3.5 s) covering the whole graft to exclude acute postoperative complications. Multiphase CT dataset and dedicated software were used to calculate renal blood flow. Renal biopsy or clinical course of disease served as the standard of reference. Mean effective radiation dose and mean amount of contrast media were calculated. RESULTS: Renal blood flow values were significantly lower (P = 0.001) in allografts undergoing AR (48.3 ± 21 ml/100 ml/min) compared with those with ATN (77.5 ± 21 ml/100 ml/min). No significant difference (P = 0.71) was observed regarding creatinine level with 5.65 ± 3.1 mg/dl in AR and 5.3 ± 1.9 mg/dl in ATN. The mean effective radiation dose of the CT perfusion protocol was 13.6 ± 5.2 mSv; the mean amount of contrast media applied was 34.5 ± 5.1 ml. All examinations were performed without complications. CONCLUSION: CT perfusion of kidney allografts may help to differentiate between ATN and rejection. KEY POINTS: • Quantitative CT perfusion of renal transplants is feasible. • CT perfusion could help to non-invasively differentiate AR from ATN. • CT perfusion might make some renal biopsies unnecessary.

[Automated breast volume scanner (ABVS) : a new approach for breast imaging]. / Automated-breast-volume-Scanner (ABVS) : Eine neue Methode zur Mammadiagnostik.

The automated breast ultrasound technique has been known for a long time but did not play an important role in diagnostics due to its inferior sensitivity for small solid lesions with low frequency transducers and its uncomfortable examination technique with the patients in a supine position and the breast immersed in water. The automated breast volume scanner (AVBS) is a high-end ultrasound scanner which employs frequencies of 5-14 MHz and consists of a flexible arm with the transducer at the end, a touchscreen and a 3D workstation. The scan is performed with the patient in the prone position. Depending on the breast size, various presettings are available from which the examiner may select the most appropriate. AVBS has various major advantages, such as being independent from the experience of the operator as well as supplying consistent and reproducible results. Additionally, for the first time it became possible to obtain coronal images of the complete breast, which greatly assists the planning of surgical interventions. In this article the ABVS technique will be described and results will be illustrated by means of clinical examples.

[Late gadolinium enhancement in the diagnostics of ischemic heart disease: technical principles, contrast optimization and clinical application]. / Late-Gadolinium-Enhancement in der Diagnostik der koronaren Herzerkrankung : Technische Grundlagen, Kontrastoptimierung und klinische Anwendung.

BACKGROUND: The purpose of the study was to explore a "dark blood" technique and to compare it with a standard inversion recovery gradient echo (IR GRE) sequence in the visualization of myocardial infarction. PATIENTS AND METHODS: A total of 9 patients were examined with standard IR GRE and a "dark blood" sequence 15 mins after contrast medium application (0.2 mmol/kg body weight gadobenate dimeglumine). Contrast-to-noise ratios (CNR) were calculated for each sequence. RESULTS: The CNR(inf-lvc) was significantly higher in the "dark blood" technique compared to the IR GRE sequence, while the CNR(inf-myo) was significantly lower. CONCLUSIONS: Small subendocardial infarctions may be easier to detect with the "dark blood" technique. However, the standard IR GRE sequence is superior in the demarcation of infarctions in relation to the myocardium and cannot be replaced by the "dark blood" technique.

Local topological analysis of densitometer-generated scan images of the proximal femur for differentiation between patients with hip fracture and age-matched controls.

SUMMARY: We evaluate densitometer-generated scan images of the proximal femur with respect to topological properties of bone mineral distribution patterns in selected regions of interest. In a population of 100 post-menopausal women, the method has a highly discriminative potential with a performance superior to standard densitometry. Results vary with anatomical location within the proximal femur. INTRODUCTION: The objectives of the study were to evaluate densitometer-generated scan images of the proximal femur with respect to topological properties of bone mineral distribution patterns in selected regions of interest, to test the ability for differentiation between post-menopausal women hip fracture and controls, and to compare results with standard bone densitometry. MATERIALS AND METHODS: We used dual-energy X-ray absorptiometry (DXA) to measure the femoral bone mineral density (BMD) of 100 post-menopausal women (73.4 +/- 12.2), 50 of whom had a recent hip fracture. Local bone mineral distribution in the scanner-generated images was analyzed in the standard DXA-regions of interest (ROIs; femoral neck, the shaft, the trochanteric area; and the total hip) using an optimized, local topological parameter MF2D. Performance of topological analysis and BMD was tested by receiver-operator characteristic and discriminant analysis. RESULTS: Area under the curve (AUC) for correct differentiation between patients with and without fractures by BMD in the different ROIs ranged from 0.64 to 0.71; AUC of regional density-pattern analysis varied between 0.79 and 0.84. Using multivariate statistical models, between 71% and 84% of patients were correctly identified as fracture/non-fracture cases by regional topological analysis, whereas BMD reached levels from 58% to 68%. CONCLUSION: Our analysis indicates that identification of patients with hip fracture by regional evaluation of density patterns varies with anatomical location within the proximal femur. In our study population, performance of the novel parameter was superior to densitometry.

MR-based semi-automated quantification of renal functional parameters with a two-compartment model--an interobserver analysis.

PURPOSE: To assess the interobserver agreement in a semi-automated quantification approach of MR-renal perfusion and filtration parameters with a two-compartment model analysis. MATERIALS AND METHODS: Twelve consecutive patients underwent renal perfusion measurements after intravenous injection of 7 ml Gd-BOPTA at 4 ml/s at 3.0 T. Two independent observers placed two regions of interest (ROI) manually on the axial slice, one in the abdominal aorta to determine the arterial input function (AIF), and one at the tissue-air interface for retrospective triggering. The data were fitted on a pixel-by-pixel basis to the two-compartment model, producing maps of the perfusion parameters FP (plasma flow), TP (plasma mean transit time) and of the tubular filtration parameters FT (tubular flow) and TT (tubular mean transit time). A cortical ROI was segmented by selecting those pixels with plasma volume VP>10 ml/100 ml, and the model fit was repeated on a ROI basis to produce the cortical averages. RESULTS: The average values (observer 1/observer 2) were FP (226.2/187.3 ml/100 ml/min), TP (9.0/9.1s), FT (23.5/20.8 ml/100 ml/min), TT (142.1/140.0 s). The correlation coefficients between both observers were 0.90 (FP), 0.80 (TP), 0.80 (FT), 0.78 (TT). Correlations of all values were significant (p<0.05). A paired t-test yielded significant differences for FP (p=0.004). DISCUSSION/CONCLUSION: The data demonstrate a significant systematic difference for the parameter FP, while TP seems to be most stable. Further decrease of the residual variability of all parameters seems desirable to improve the robustness of the method for clinical routine.

[TKI 2.0 - changes in the medical treatment of renal cell carcinoma]. / TKI 2.0 ­ Wandel in der medikamentösen Therapie des Nierenzellkarzinoms.

Only for renal cell carcinoma (RCC) in a local stage curative treatment option by surgical resection exists. For metastatic disease the 5­year survival rate decreases radically. A factor that contributes to this is the low sensibility to radiation and chemotherapeutics. Since the approval of the tyrosine kinase inhibitors in 2006 effective drugs for the treatment of mRCC is available. The specific inhibition of the vascular-endothelial-growth (VEGF)-receptor and the "mammalian Target of Rapamycin" (mTOR) leads to a prolongation of the progression-free survival as well as the overall survival rate. For a long time, the current target therapy with TKI appeared to be exhausted, but since recently research has gone a step further. Thus, Cabozantinib and Lenvatinib in the combination with Everolimus have been approved for second-line therapy in mRCC. For the first time a clinical study demonstrated positive results for an adjuvant treatment with sunitinib in patients with a high-risk RCC. Furthermore, in april 2016 the immune checkpoint inhibitor Nivolumab was approved for second-line therapy in mRCC in Germany. The following report examines briefly the current therapeutic recommendations, new findings and drug approvals and ongoing clinical trials.

GPI-anchored TIMP-1 treatment renders renal cell carcinoma sensitive to FAS-meditated killing.

The resistance of tumours to immune-mediated lysis has been linked to the biology of matrix metalloproteinases (MMPs), and specifically to the cell surface expression of MMPs by the tumour cell. The endogenous tissue inhibitors of metalloproteinases (TIMPs) exhibit diverse physiological/biological functions including the moderation of tumour growth, metastasis and apoptosis. These biologic activities are mediated in part by the stoichiometry of TIMP/MMP/cell surface protein interactions. A glycosylphosphatidylinositol (GPI) anchor was fused to TIMP-1 to focus defined concentrations of this inhibitory protein on the surface of three renal cell carcinoma (RCC) cell lines (RCC-26, RCC-53 and A498) independently of cell surface protein-protein interactions. Exogenously added TIMP-1-GPI efficiently inserted into the RCC cell membrane and dramatically altered the association of MMPs with the cell surface. TIMP-1-GPI treatment inhibited RCC proliferation and rendered the normally FAS-resistant RCC cells sensitive to FAS-induced apoptosis but did not alter perforin-mediated lysis by cytotoxic effector cells. The increased sensitivity to FAS-mediated apoptosis correlated with an alteration in the balance of pro- and antiapoptotic BCL-2-family proteins. By interfering with the proliferative capacity and inducing sensitivity to immune effector mechanisms GPI-anchored TIMP-1 may represent a more effective version of the TIMP-1 protein for therapeutic strategies.

Experimental characterization of the biaxial mechanical properties of porcine gastric tissue.

Health problems related to the stomach are among the most important sources of morbidity in industrialized countries. There is evidence that mechanics may play an important role in various such pathologies. However, so far experimental data characterizing the mechanical properties of gastric tissue remain scarce, which significantly limits our understanding of the mechanics of the stomach. To help close this gap, we performed biaxial mechanical tests of porcine gastric tissue patches. Our experiments reveal a considerable anisotropy and different mechanical properties in the three major regions of the stomach (fundus, corpus, antrum). Moreover, they demonstrate that the mechanical properties of the gastric wall and the physiological function of the different regions of the stomach are closely related. This finding suggests that further examination of the mechanics of the gastric wall may indeed be a promising avenue of research towards a better understanding of the organic causes of frequent health problems related to the stomach.

[Technique of Autologous Chondrocyte Implantation for Severe Radiocarpal Arthrosis: Status Quo after 24 Months]. / Technik der autologen Chondrozytenimplantation bei ausgeprägter Radiokarpalarthrose: Status quo nach 24 Monaten.

We illustrate the operative technique of autologous chondrocyte implantation (ACI) to restore a 4° cartilage damage of the radius surface in the case of a 22-year-old patient, and report on the clinical and radiological results at 6 and 24 months postoperatively.

Maternal balanced translocation leading to partial duplication of 4q and partial deletion of 1p in a son: cytogenetic and FISH studies using band-specific painting probes generated by chromosome microdissection.

A 9-month-old boy with pre- and post-natal growth retardation, microcephaly, plagiocephaly, and several minor anomalies had the initial karyotype: 46,XY,der(1)t(1;?) (p36.1;?). Further analysis showed that the der(1) was derived from an unfavorable segregation of a maternal complex chromosome rearrangement, i.e., 46,XX,der(1)t(1;?) (p36.1;?), der(4)t(4;?)(q?;?). Whole chromosome fluorescence in situ hybridization (FISH) and chromosome microdissection were used to clarify the maternal karyotype as: 46,XX,der(1)t(1;4)(4qter-->4q33::1p36.13-->1qter),der( 4)t(1;4)inv(4)(4pter-->4q31.3::1p36.33-->1p36.13::4q33 -->4q31.3::1p36.33-->1pter). Therefore, the karyotype of the boy actually was 46,XY,der(1)t(1;4) (p36.13;q33). Clinical comparison of the patient's clinical findings showed similarities to individuals with partial del(1p) and dup(4q). To our knowledge the above cytogenetic abnormalities have not been described previously. This case further demonstrates the advantages of chromosome microdissection and FISH in the identification of anomalous chromosome regions and breakpoints.

Translocation (6;9;22)(p25;q34;q11.2) identified by FISH in acute leukemia.

Fluorescence in situ hybridization (FISH) study of bone marrow cells from a patient with clinically and immunologically acute leukemia showed that an apparent t(6;22)(p25; q11.2) identified by routine banding techniques concealed a complex t(6;9;22)(p25;q34; q11.2). This observation further supports the importance of FISH in those cases where a chromosome rearrangement could not be reliably detected by conventional cytogenetic study.

Detection of PML-RAR alpha fusion transcript in Ph positive leukemia with acute promyelocytic phenotype lacking the t(15;17) cytogenetic abnormality.

A 39-year-old woman was diagnosed with acute promyelocytic leukemia (APL) with disseminated intravascular coagulation syndrome. The hematologic examination showed a morphologic, cytochemical, and immunophenotypic picture typical of an APL, with a marked leukocytosis and a mixed population of hypergranular and microgranular promyelocytes. The cytogenetic analysis showed a 46,XX,t(9;22) karyotype, without any alterations of chromosomes 15 and 17. The t(15;17) translocation was not evident in FISH experiments, while a molecular analysis revealed the presence of a PML-RAR alpha chimera.

Some observations on fluorescence in situ hybridization evaluation of chronic myelocytic leukemia.

Cosmid probes specific for the major BCR/ABL rearrangement (commercially available probes) were employed by us to evaluate 134 patients with the clinical diagnosis of chronic myelocytic leukemia (CML). The following represent our main observations: 1) No significant statistical difference regarding a false positive fusion signal was seen in the distribution pattern between the Ph negative (-) cases (110) and the normal controls (3.23 +/- 1.97 vs 2.8 +/- 1.92, respectively). 2) The mean percentage of cells with a positive fusion signal in the Ph positive (+) CML cases at presentation was 70 +/- 12.3 in bone marrow samples (12 cases) and 45 +/- 12.4 in blood samples (3 cases). 3) A significant discrepancy was seen between the interphase FISH and cytogenetics data in the monitoring of four out of eight patients post-therapy. The clinical significance of this observation needs to be clarified. 4) Three Ph(-) patients with significant leukocytosis had closely adjacent but not fused signals (20%, 16%, and 20% of cells, respectively, vs. the control: 4%). This may indicate a temporal and spatial association between chromosomes 9 and 22 prior to the BCR/ABL rearrangement (Ph chromosome formation).