Consolidation of first remission using radioimmunotherapy with yttrium-90-ibritumomab-tiuxetan in adult patients with Burkitt lymphoma

The addition of anti-CD20 antibodies to high intensity polychemotherapy regimens has improved response and survival rates in newly diagnosed patients with Burkitt lymphoma (BL). However, the role of additional anti-CD20 directed radioimmunotherapy for consolidation of first remission (CR1) has not been reported so far in BL patients receiving rituximab during first-line treatment. We compared five BL patients receiving Y-90-IT radioimmunotherapy consolidation in CR1 to 22 consecutive BL patients without consolidation. We observed that Y-90-IT treatment was associated with clinically relevant myelosuppression. After a median follow-up of 50 months, none of the patients with Y-90-IT treatment relapsed, and no patient died. In contrast, one patient (4.5%) in the non-Y-90-IT group relapsed (50 months-PFS 95.5%; p = 0.6336), and one patient died (50 months-OS 95.5%; p = 0.6171). In conclusion, our data suggest that survival rates are excellent and equal in rituximab pretreated BL patients with or without Y-90-IT consolidation in first remission.

Induction of apoptosis and enhancement of chemosensitivity in human prostate cancer LNCaP cells using bispecific antisense oligonucleotide targeting Bcl-2 and Bcl-xL genes

OBJECTIVE: To determine whether a specifically designed bispecific (Bcl-2/Bcl-xL) antisense oligonucleotide (ASO) induces apoptosis and enhances chemosensitivity in human prostate cancer LNCaP cells, as Bcl-2 and Bcl-xL are both anti-apoptotic genes associated with treatment resistance and tumour progression in many malignancies, including prostate cancer. MATERIALS AND METHODS: Inhibition of Bcl-2 and Bcl-xL expression by the bispecific ASO was evaluated using real-time reverse transcription-polymerase chain reaction and Western blotting, while growth inhibition and induction of apoptosis were analysed by a crystal violet assay, flow cytometry and Western blotting of apoptosis-relevant proteins. The effect of combined treatment with bispecific ASO and chemotherapy or small-interference RNA (siRNA) targeting the clusterin gene was also investigated. RESULTS: Bispecific ASO reduced Bcl-2 and Bcl-xL expression in LNCaP cells in a dose-dependent manner. There was cell growth inhibition, increases in the sub-G0-G1 fraction, and cleavage of caspase-3 and poly(ADP-Ribose) polymerase proteins in LNCaP cells after bispecific ASO treatment. Interestingly, Bcl-2/Bcl-xL bispecific ASO treatment also resulted in the down-regulation of Mcl-1 and up-regulation of Bax. The sensitivity of LNCaP cells to mitoxantrone, docetaxel or paclitaxel was significantly increased, reducing the 50% inhibitory concentration by 45%, 80% or 90%, respectively. Furthermore, the apoptotic induction by Bcl-2/Bcl-xL bispecific ASO was synergistically enhanced by siRNA-mediated inhibition of clusterin, a cytoprotective chaperone that interacts with and inhibits activated Bax. CONCLUSIONS: These findings support the concept of the targeted suppression of Bcl-2 anti-apoptotic family members using multitarget inhibition strategies for prostate cancer, through the effective induction of apoptosis.

Novel pressure-to-cornea index in glaucoma

BACKGROUND: Several conversion tables and formulas have been suggested to correct applanation intraocular pressure (IOP) for central corneal thickness (CCT). CCT is also thought to represent an independent glaucoma risk factor. In an attempt to integrate IOP and CCT into a unified risk factor and avoid uncertain correction for tonometric inaccuracy, a new pressure-to-cornea index (PCI) is proposed. METHODS: PCI (IOP/CCT(3)) was defined as the ratio between untreated IOP and CCT(3) in mm (ultrasound pachymetry). PCI distribution in 220 normal controls, 53 patients with normal-tension glaucoma (NTG), 76 with ocular hypertension (OHT), and 89 with primary open-angle glaucoma (POAG) was investigated. PCI's ability to discriminate between glaucoma (NTG+POAG) and non-glaucoma (controls+OHT) was compared with that of three published formulae for correcting IOP for CCT. Receiver operating characteristic (ROC) curves were built. RESULTS: Mean PCI values were: Controls 92.0 (SD 24.8), NTG 129.1 (SD 25.8), OHT 134.0 (SD 26.5), POAG 173.6 (SD 40.9). To minimise IOP bias, eyes within the same 2 mm Hg range between 16 and 29 mm Hg (16-17, 18-19, etc) were separately compared: control and NTG eyes as well as OHT and POAG eyes differed significantly. PCI demonstrated a larger area under the ROC curve (AUC) and significantly higher sensitivity at fixed 80% and 90% specificities compared with each of the correction formulas; optimum PCI cut-off value 133.8. CONCLUSIONS: A PCI range of 120-140 is proposed as the upper limit of "normality", 120 being the cut-off value for eyes with untreated pressures or=22 mm Hg. PCI may reflect individual susceptibility to a given IOP level, and thus represent a glaucoma risk factor. Longitudinal studies are needed to prove its prognostic value.

Chronic NSAID use and long-term decline of renal function in a prospective rheumatoid arthritis cohort study

OBJECTIVES Non-steroidal anti-inflammatory drugs (NSAIDs) may cause kidney damage. This study assessed the impact of prolonged NSAID exposure on renal function in a large rheumatoid arthritis (RA) patient cohort. METHODS Renal function was prospectively followed between 1996 and 2007 in 4101 RA patients with multilevel mixed models for longitudinal data over a mean period of 3.2 years. Among the 2739 'NSAID users' were 1290 patients treated with cyclooxygenase type 2 selective NSAIDs, while 1362 subjects were 'NSAID naive'. Primary outcome was the estimated glomerular filtration rate according to the Cockroft-Gault formula (eGFRCG), and secondary the Modification of Diet in Renal Disease and Chronic Kidney Disease Epidemiology Collaboration formula equations and serum creatinine concentrations. In sensitivity analyses, NSAID dosing effects were compared for patients with NSAID registration in ≤/>50%, ≤/>80% or ≤/>90% of assessments. FINDINGS In patients with baseline eGFRCG >30 mL/min, eGFRCG evolved without significant differences over time between 'NSAID users' (mean change in eGFRCG -0.87 mL/min/year, 95% CI -1.15 to -0.59) and 'NSAID naive' (-0.67 mL/min/year, 95% CI -1.26 to -0.09, p=0.63). In a multivariate Cox regression analysis adjusted for significant confounders age, sex, body mass index, arterial hypertension, heart disease and for other insignificant factors, NSAIDs were an independent predictor for accelerated renal function decline only in patients with advanced baseline renal impairment (eGFRCG <30 mL/min). Analyses with secondary outcomes and sensitivity analyses confirmed these results. CONCLUSIONS NSAIDs had no negative impact on renal function estimates but in patients with advanced renal impairment.

Diagnosis and management of developmental dysplasia of the hip from triradiate closure through young adulthood

Abstract The current treatment of painful hip dysplasia in the mature skeleton is based on acetabular reorientation. Reorientation procedures attempt to optimize the anatomic position of the hyaline cartilage of the femoral head and acetabulum in regard to mechanical loading. Because the Bernese periacetabular osteotomy is a versatile technique for acetabular reorientation, it is helpful to understand the approach and be familiar with the criteria for an optimal surgical correction. The femoral side bears stigmata of hip dysplasia that may require surgical correction. Improvement of the head-neck offset to avoid femoroacetabular impingement has become routine in many hips treated with periacetabular osteotomy. In addition, intertrochanteric osteotomies can help improve joint congruency and normalize the femoral neck orientation. Other new surgical techniques allow trimming or reducing a severely deformed head, performing a relative neck lengthening, and trimming or distalizing the greater trochanter.  An increasing number of studies have reported good long-term results after acetabular reorientation procedures, with expected joint preservation rates ranging from 80% to 90% at the 10-year follow-up and 60% to 70% at the 20-year follow-up. An ideal candidate is younger than 30 years, with no preoperative signs of osteoarthritis. Predicted joint preservation in these patients is approximately 90% at the 20-year follow-up. Recent evidence indicates that additional correction of an aspheric head may further improve results.

Cohort study of somatostatin-based radiopeptide therapy with [(90)Y-DOTA]-TOC versus [(90)Y-DOTA]-TOC plus [(177)Lu-DOTA]-TOC in neuroendocrine cancers

Radiopeptide therapy is commonly performed with a single radioisotope. We aimed to compare the effectiveness of somatostatin-based radiopeptide therapy with a single versus a combination of radioisotopes.

Treatment with (90)Y- and (177)Lu-DOTATOC in patients with metastatic neuroendocrine tumors

BACKGROUND: Treatment with (90)Y- or (177)Lu-DOTATOC has recently been introduced in the palliative treatment of somatostatin receptor-expressing neuroendocrine tumors (NETs). The aim of the study was to present clinical experience with (90)Y- and (177)Lu-DOTATOC therapy in the management of NET. METHODS: To prove suitability for treatment each patient underwent scanning with (111)In-DTPAOC or (68)Ga-DOTATOC positron emission tomography/computed tomography. All patients received [(90)Y-DOTATOC] as initial treatment. In case of disease relapse the treatment was repeated. To avoid side effects of repeated [(90)Y] applications, a switch to [(177)Lu-DOTATOC] was carried out. Clinical, biochemical, and radioimaging responses were documented. RESULTS: Twenty patients with metastatic nonresectable NETs (15 pancreas NETs, 2 midgut NETs, 1 gastrinoma, 1 paraganglioma, 1 NET of unknown primary origin) were included. In 8 patients the treatment was repeated more than once (mean, 3 times; range, 2-5 times). After [(90)Y] treatment moderate toxicity was observed in 8 patients. No serious adverse events were documentable. After restaging, a partial remission was found in 5 patients, stable disease in 11 patients, and tumor progression in 4 patients. CONCLUSIONS: Peptide receptor-targeted radionuclide therapy is a promising, safe, and feasible approach in the palliative therapy of patients with NET.

[Radiation exposure in (90)Y-Zevalin therapy: results of a prospective multicentre trial]

AIM of this study was the assessment of the radiation exposure from preparation and application of (90)Y-Zevalin, the measurement of the dose rate at the patient, the exposure of family members as well as the determination of the activity concentration in urine of patients. METHODS: Overall data from 31 therapeutic administrations carried out in four institutions were evaluated. During preparation and application of (90)Y-Zevalin the finger exposures of radiochemists, technicians, and physicians were measured. The dose rate of the patient was measured immediately after radioimmunotherapy. In patients treated in a nuclear medicine therapy unit, urine was collected over a two day period and the corresponding activity was determined. Family members of outpatients were asked to wear a dosimeter over a seven day period. RESULTS: During the preparation we found a maximum skin dose of 6 mSv at the average, and during application of 3 mSv, respectively. After administration of (90)Y the dose rate was 0.4 +/- 0.1 microSv/h at 2 m distance. Urine measurements yielded a cumulated 24 h excretion of 3.9 +/- 1.4% and 4.4 +/- 1.4% within 48 h, respectively, that is equivalent to 43 +/- 18 and 50 +/- 20 MBq of (90)Y, respectively. Family members received a radiation exposure of 40 +/- 14 microSv over seven days. CONCLUSION: During preparation and application of (90)Y-Zevalin appropriate radiation shielding is necessary. For family members as well as nursing staff no additional special radiation protection measures beyond those being common for other nuclear medicine procedures are necessary.

Survival after somatostatin based radiopeptide therapy with (90)Y-DOTATOC vs. (90)Y-DOTATOC plus (177)Lu-DOTATOC in metastasized gastrinoma.

We aimed to explore the effects of (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC on survival of patients with metastasized gastrinoma. Patients with progressive metastasized gastrinoma were treated with repeated cycles of (90)Y-DOTATOC or with cycles alternating between (90)Y-DOTATOC and (177)Lu-DOTATOC until tumor progression or permanent toxicity. Multivariable Cox regression analyses were used to study predictors of survival. A total of 36 patients were enrolled; 30 patients received (90)Y-DOTATOC (median activity per patient 11.8GBq; range: 6.1-62.2GBq) and 6 patients received (90)Y-DOTATOC plus (177)Lu-DOTATOC (median activity per patient: 14.8GBq; range: 7.4-14.8GBq). Response was found in 26 patients (72.2%), including morphological (n=12, 33.3%), biochemical (n=14, 38.9%) and/or clinical response (n=6, 16.2%). A total of 21 patients (58.3%) experienced hematotoxicity grade 1/2, while 1 patient (2.8%) experienced hematotoxicity grade 3; no grade 4 hematotoxicity occurred. Furthermore, 2 patients (5.6%) developed grade 4 renal toxicity; no grade 5 renal toxicity occurred. Responders had a significantly longer median survival from time of enrollment than non-responders (45.1 months, range: 37.1-53.1 months vs. 12.6 months, range: 11.0-14.2, hazard ratio: 0.12 (0.027-0.52), p=0.005). Additionally, there was a trend towards longer median survival with (90)Y-DOTATOC plus (177)Lu-DOTATOC as compared to (90)Y-DOTATOC alone (60.2 months, range: 19.8-100.6 months vs. 27.0 months, range: 4.0-50.0, hazard ratio: 0.21 (0.01-3.98), p=0.16). Response to (90)Y-DOTATOC and (90)Y-DOTATOC plus (177)Lu-DOTATOC therapy is associated with a longer survival in patients with metastasized gastrinoma. Both treatment regimens are promising tools for management of progressive gastrinoma.