Addition of rituximab to fludarabine and cyclophosphamide in patients with chronic lymphocytic leukaemia: a randomised, open-label, phase 3 trial.

BACKGROUND: On the basis of promising results that were reported in several phase 2 trials, we investigated whether the addition of the monoclonal antibody rituximab to first-line chemotherapy with fludarabine and cyclophosphamide would improve the outcome of patients with chronic lymphocytic leukaemia. METHODS: Treatment-naive, physically fit patients (aged 30-81 years) with CD20-positive chronic lymphocytic leukaemia were randomly assigned in a one-to-one ratio to receive six courses of intravenous fludarabine (25 mg/m(2) per day) and cyclophosphamide (250 mg/m(2) per day) for the first 3 days of each 28-day treatment course with or without rituximab (375 mg/m(2) on day 0 of first course, and 500 mg/m(2) on day 1 of second to sixth courses) in 190 centres in 11 countries. Investigators and patients were not masked to the computer-generated treatment assignment. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00281918. FINDINGS: 408 patients were assigned to fludarabine, cyclophosphamide, and rituximab (chemoimmunotherapy group) and 409 to fludarabine and cyclophosphamide (chemotherapy group); all patients were analysed. At 3 years after randomisation, 65% of patients in the chemoimmunotherapy group were free of progression compared with 45% in the chemotherapy group (hazard ratio 0·56 [95% CI 0·46-0·69], p<0·0001); 87% were alive versus 83%, respectively (0·67 [0·48-0·92]; p=0·01). Chemoimmunotherapy was more frequently associated with grade 3 and 4 neutropenia (136 [34%] of 404 vs 83 [21%] of 396; p<0·0001) and leucocytopenia (97 [24%] vs 48 [12%]; p<0·0001). Other side-effects, including severe infections, were not increased. There were eight (2%) treatment-related deaths in the chemoimmunotherapy group compared with ten (3%) in the chemotherapy group. INTERPRETATION: Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab improves progression-free survival and overall survival in patients with chronic lymphocytic leukaemia. Moreover, the results suggest that the choice of a specific first-line treatment changes the natural course of chronic lymphocytic leukaemia. FUNDING: F Hoffmann-La Roche.

Richter transformation in chronic lymphocytic leukemia (CLL)-a pooled analysis of German CLL Study Group (GCLLSG) front line treatment trials.

Richter transformation (RT) is defined as development of aggressive lymphoma in patients (pts) with CLL. The incidence rates of RT among pts with CLL range from 2 to 10%. The aim of this analysis is to report the frequency, characteristics and outcomes of pts with RT enrolled in trials of the GCLLSG. A total of 2975 pts with advanced CLL were reviewed for incidence of RT. Clinical, laboratory, and genetic data were pooled. Time-to-event data, starting from time of CLL diagnosis, of first-line therapy or of RT diagnosis, were analyzed by Kaplan-Meier methodology. One hundred and three pts developed RT (3%): 95 pts diffuse large B-cell lymphoma (92%) and eight pts Hodgkin lymphoma (8%). Median observation time was 53 months (interquartile range 38.1-69.5). Median OS from initial CLL diagnosis for pts without RT was 167 months vs 71 months for pts with RT (HR 2.64, CI 2.09-3.33). Median OS after diagnosis of RT was 9 months. Forty-seven pts (46%) received CHOP-like regimens for RT treatment. Three pts subsequently underwent allogeneic and two pts autologous stem cell transplantation. Our findings show that within a large cohort of GCLLSG trial participants, 3% of the pts developed RT after receiving first-line chemo- or chemoimmunotherapy. This dataset confirms the ongoing poor prognosis and high mortality associated with RT.

Macrocerebellum in Achondroplasia: A Further CNS Manifestation of FGFR3 Mutations?

Achondroplasia is the result of a mutation in the fibroblast growth factor receptor 3 gene (FGFR3). Appearances suggestive of macrocerebellum have not been described in this patient group. We retrospectively reviewed MR imaging studies of the brain in 23 children with achondroplasia. A constellation of imaging findings that are recognized in macrocerebellum was observed, including cerebellar hemisphere enlargement (inferior and superior extension, wrapping around the brainstem); an effaced retro- and infravermian cerebellar subarachnoid CSF space; a shortened midbrain; distortion of the tectal plate; and mass effect on the brainstem. All MR imaging studies exhibited some of these findings. Quantitative analysis confirmed an increased cerebellar volume compared with age- and sex-matched controls. We hypothesized that this may be due to direct effects of the FGFR3 mutation on cerebellar morphogenesis.

Seborrhoeic keratoses in patients with internal malignancies: a case-control study with prospective accrual of patients.

BACKGROUND: The association between the eruption of numerous seborrhoeic keratoses as a result of an underlying malignancy is controversially discussed. The aim of this case-control study with prospective accrual of patients was to determine whether a direct association exists between the number seborrhoeic keratoses and internal malignancies. METHODS: The numbers and sites of seborrhoeic keratoses were counted in 150 oncological patients and 150 matched controls. Additionally, the presence or absence of pruritus, acanthosis nigricans, and the sudden appearance of seborrhoeic keratoses were assessed. RESULTS: Seborrhoeic keratoses did not differ significantly between patients with internal malignancies and controls. Only two patients fulfilled the criteria of the Leser-Trélat sign, defined as the eruption of numerous seborrhoeic keratoses as a cutaneous marker of an underlying internal malignancy. CONCLUSION: No association was found between seborrhoeic keratoses and cancer. Furthermore, our data did not provide support to the validity of the Leser-Trélat sign in patients with internal malignancies.

Temporal Lobe Malformations in Achondroplasia: Expanding the Brain Imaging Phenotype Associated with FGFR3-Related Skeletal Dysplasias.

Thanatophoric dysplasia, achondroplasia, and hypochondroplasia belong to the fibroblast growth factor receptor 3 (FGFR3) group of genetic skeletal disorders. Temporal lobe abnormalities have been documented in thanatophoric dysplasia and hypochondroplasia, and in 1 case of achondroplasia. We retrospectively identified 13 children with achondroplasia who underwent MR imaging of the brain between 2002 and 2015. All children demonstrated a deep transverse temporal sulcus on MR imaging. Further common neuroimaging findings were incomplete hippocampal rotation (12 children), oversulcation of the mesial temporal lobe (11 children), loss of gray-white matter differentiation of the mesial temporal lobe (5 children), and a triangular shape of the temporal horn (6 children). These appearances are very similar to those described in hypochondroplasia, strengthening the association of temporal lobe malformations in FGFR3-associated skeletal dysplasias.

Vascular endothelial growth factor in patients with psoriatic arthritis.

OBJECTIVE: To determine the levels of vascular endothelial growth factor (VEGF) in patients with active psoriatic arthritis, patients with inactive psoriatic arthritis, and healthy controls. Serum VEGF levels were correlated with clinical and laboratory features in patients with active psoriasis arthritis. METHODS: Serum samples from 14 patients with active psoriatic arthritis, 14 patients with inactive psoriatic arthritis, and 9 healthy controls were investigated. VEGF levels in the serum were measured using a sensitive sandwich ELISA. RESULTS: The mean serum VEGF concentration in patients with active PA was 394.4 pg/ml (394 +/- 171.8), in patients with inactive PA 200.4 pg/ml (200.4 +/- 115.7), and in healthy subjects 214.3 pg/ml (214.3 +/- 162.1). Patients with active psoriasis arthritis had significantly higher levels of VEGF compared to patients with inactive psoriasis arthritis and healthy individuals (p > 0.001). In contrast, VEGF levels were comparable in patients with inactive psoriatic arthritis and controls (p =0.659). Furthermore, in patients with psoriatic arthritis, VEGF levels were positively correlated with ESR, HAQ, PASI and VAS. CONCLUSION: VEGF levels may be regarded as a good indicator of active psoriasis arthritis.

Enlarged parietal foramina: MR imaging features in the fetus and neonate.

Enlarged parietal foramina are believed to be benign and familial and due to a variable degree of defective intramembranous ossification of the parietal bones. We report 2 patients with this condition in whom fetal and neonatal MR imaging studies illustrate the antenatal and perinatal evolution of this condition and the associated persistence of a falcine sinus. We discuss its relationship to the spectrum of cephalocoeles.

Effect of first-line treatment on second primary malignancies and Richter's transformation in patients with CLL.

This study aimed to assess the frequency of and the contributing factors for second primary malignancies (SPMs) and Richter's transformations (RTs) following first-line treatment of chronic lymphocytic leukemia within four phase II/III trials of the GCLLSG evaluating fludarabine (F) vs F+cyclophosphamide (FC), chlorambucil vs F, FC without or with rituximab, and bendamustine+R (BR). Among 1458 patients, 239 (16.4%) experienced either an SPM (N=191) or a RT (N=75). Solid tumors (N=115; 43.2% of all second neoplasias) appeared most frequently, followed by RTs (N=75; 28.2%). Patients showed a 1.23-fold increased risk of solid tumors in comparison to the age-matched general population from the German cancer registry. Age>65 (hazard ratio (HR) 2.1; P<0.001), male sex (HR 1.7; P=0.01), co-morbidities (HR 1.6; P=0.01) and number of subsequent treatments⩾1 (HR 12.1; P<0.001) showed an independent adverse prognostic impact on SPM-free survival. Serum thymidine kinase>10 U/l at trial enrollment (HR 3.9; P=0.02), non-response to first-line treatment (HR 3.6; P<0.001) and number of subsequent treatments⩾1 (HR 30.2; P<0.001) were independently associated with increased risk for RT.

Age-related pituitary volumes in prepubertal children with normal endocrine function: volumetric magnetic resonance data.

BACKGROUND: Evaluation of the size of the pituitary gland on magnetic resonance imaging (MRI) may be difficult, considering the wide variation in normal gland morphology. Given the paucity of age-related biometric data, our purpose was to obtain standard normal reference values for pituitary volumes in prepubertal children using three-dimensional MRI data. METHODS: Children under the age of 10 yr undergoing brain MRI for seizures or idiopathic developmental delay and who had no endocrine abnormality were recruited prospectively over 2 yr. All MRI studies included a three-dimensional sequence. Only subjects with normal studies were included. One hundred thirty-nine children were eligible (mean age, 5.2 yr). Direct pituitary volumes were measured from contiguous 1-mm thick reconstructed coronal and sagittal images. Estimated pituitary volumes were calculated using pituitary height, width, and length. RESULTS: Volumes obtained from reconstructions in either plane were essentially identical. There was a linear increase in log-transformed pituitary volume with age, but relatively weak correlations with height or body mass index. There was no gender difference and only weak correlations between pituitary height and pituitary volume and between estimated pituitary volume calculation and measured pituitary volume. We provide age-related reference ranges for pituitary volumes in graphical and tabular forms.

Overcorrected radial keratotomy treated with posterior chamber phakic intraocular lens and laser thermal keratoplasty.

PURPOSE: Modern refractive surgery is effective in a large majority of cases in achieving a good first time result. Some attempts at correction, however, are less successful and require subsequent revision. METHODS: A case of secondary hyperopic astigmatism (+0.75 +1.50 x 45 degrees) is reported in a patient who had undergone radial keratotomy for myopia of -6.00 +0.75 x 90 degrees, 8 years previously. Preoperative uncorrected visual acuity was 20/120 improving to 20/20 with correction. Further refractive procedures were performed including arcuate keratotomy, posterior chamber phakic intraocular lens implantation and laser thermal keratoplasty to improve the uncorrected visual result. RESULTS: Final uncorrected visual acuity was 20/40, spectacle-corrected visual acuity was 20/20 with a manifest refraction of +0.50 +1.00 x 40 degrees. CONCLUSIONS: This case demonstrates how the consecutive application of several procedures can successfully refine an initially unsatisfactory refractive result. The potential for reduced predictability and additional complications with each procedure should not be forgotten.

Periorbital necrobiosis lipoidica.

Necrobiosis lipoidica is a granulomatous skin condition typically occurring on the legs. A patient with this condition presented with gross bilateral induration of the eyelids sufficient to close both eyes.

Seasonal pattern of the excision rate of melanoma and naevi.

Based on available information that melanocytic skin lesions presenting a junctional component are more susceptible to the influence of ultraviolet radiation, this study compares the seasonal differences between the excision rates of melanocytic skin lesions with a junctional component to those without. The histological diagnoses of 1230 patients with melanocytic skin lesions were retrospectively analysed. Depending on the histological diagnosis four groups were formed: melanomas, dysplastic naevi, common naevi (junctional and compound naevi), and dermal naevi. All dates of operations were allocated to summer or winter halves of the year. The collected data were computer analysed for statistical description. The number of excisions of melanocytic lesions with a junctional component (melanoma, dysplastic naevi, common naevi) showed an impressive seasonal variation, with a peak during the summer months, while the excision frequency of dermal naevi was approximately constant during the year. In conclusion, we suggest that ultraviolet radiation may contribute to the seasonal pattern of excision of melanoma and naevi only when a junctional component is present.

Cataract development after implantation of the Staar Collamer posterior chamber phakic lens.

Implantation of a posterior chamber phakic intraocular lens is an effective refractive procedure with a good safety record in the short-term follow-ups reported in the literature. Cataract formation is a potential complication of the procedure. Two patients developed lens opacities in 3 eyes after the procedure was performed for myopic astigmatism. The possible causes are discussed. This is not a dangerous complication as cataract extraction is easily achieved if necessary. However, it is undesirable and further research is required to assess the long-term incidence, causes, and ways to prevent its occurrence.

Technical note: identifying and aspirating hip effusions.

Ultrasound has become a routine investigation in the investigation of the painful hip in children. It has been recommended that all effusions demonstrated by sonography be drained. Based on the experience of 800 hip aspirations, the authors describe an approach to the demonstration and aspiration of hip effusions with some of the pitfalls that result in false positive and false negative diagnoses.

B mode ultrasonography--spectrum of paediatric ocular disease.

BACKGROUND: Despite having appropriate sonographic equipment available many radiologists remain unfamiliar with B mode sonography of the eye. OBJECTIVE: This article reviews the advantages and disadvantages of B mode sonography of the paediatric eye. We illustrate the spectrum of eye abnormalities occurring in paediatric practice and the sonographic appearance of clinical entities for which sonography is appropriate. MATERIALS AND METHOD: We reviewed our experience of eye sonography within a paediatric radiology department over 8 years. A total of 212 sonographic examinations were performed on 206 eyes in 103 children, aged from 3 days to 16 years (mean 4.6 years). RESULTS: Sonography was well tolerated by the children, was a very useful imaging modality and was the only diagnostic imaging modality required in 94%. Supplementary computed tomography (CT) was performed in ten of 206 eyes (5%) and magnetic resonance imaging (MR) was performed in two of 206 eyes (1%). CONCLUSIONS: B mode sonography is a very useful imaging modality for suspected ocular or orbital pathology in children and is often the appropriate first line investigation following clinical evaluation. Radiologists familiar with sonography of the eye can provide valuable support to their ophthalmology colleagues.

Serum level of VEGF-D in patients with primary lymphedema.

Recent studies have indicated that vascular endothelial growth factor-D (VEGF-D) stimulates lymphangiogenesis in humans. Furthermore, mutations of vascular endothelial growth factor receptor 3 (VEGFR-3) have been observed in families with hereditary lymphedema. The lack of stimulation of lymphangiogenesis could lead to production of even more VEGF-D to obtain stimulation of lymphangiogenesis resulting in a high serum level of VEGF-D. The aim of the present study was to compare the serum level of VEGF-D in patients with primary lymphedema with healthy controls. In a prospective study, the serum level of VEGF-D was determined by a solid phase ELISA in patients with primary lymphedema and compared with healthy controls. In the group of patients with primary lymphedema the serum level of VEGF-D was significantly higher compared with controls (p=0.0047). The increased levels of VEGF-D observed in the present study suggest that primary lymphedema may be based on defective stimulation of VEGFR-3.