Phase I trial of fludarabine, bortezomib and rituximab for relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma

Based on the hypothesis that bortezomib may potentiate fludarabine activity by inhibiting DNA repair, we designed a phase I trial using this combination with rituximab in patients with relapsed and refractory indolent and mantle cell non-Hodgkin lymphoma. Twenty-four patients were enrolled. Non-Hodgkin lymphoma subtypes included 12 patients with follicular lymphoma, four with marginal zone lymphoma, three with lymphoplasmacytic lymphoma, three with mantle cell lymphoma and two with small lymphocytic/chronic lymphocytic leukaemia. Fludarabine and bortezomib were escalated in cohorts of three patients. Rituximab was added to the maximum tolerated dose of fludarabine and bortezomib and added significant dose-limiting myelosuppression. The maximum tolerated dose was fludarabine 25 mg/m² on days 1–3, bortezomib 1·3 mg/m² on days 1, 4, 8, 11, with rituximab 375 mg/m² on day 1 administered every 21 d. Clinical responses were observed in 11 patients, five of whom were refractory to their most recent treatment regimen. Six additional patients had stable disease for a median of 10 months (range 4–30+). Cumulative myelosuppression and neuropathy was observed. The combination of fludarabine, bortezomib, and rituximab appears to be an active regimen with manageable toxicity for relapsed NHL.     

Mapping the Spatiotemporal Dynamics of Calcium Signaling in Cellular Neural Networks Using Optical Flow

An optical flow gradient algorithm was applied to spontaneously forming networks of neurons and glia in culture imaged by fluorescence optical microscopy in order to map functional calcium signaling with single pixel resolution. Optical flow estimates the direction and speed of motion of objects in an image between subsequent frames in a recorded digital sequence of images (i.e., a movie). Computed vector field outputs by the algorithm were able to track the spatiotemporal dynamics of calcium signaling patterns. We begin by briefly reviewing the mathematics of the optical flow algorithm, and then describe how to solve for the displacement vectors and how to measure their reliability. We then compare computed flow vectors with manually estimated vectors for the progression of a calcium signal recorded from representative astrocyte cultures. Finally, we applied the algorithm to preparations of primary astrocytes and hippocampal neurons and to the rMC-1 Muller glial cell line in order to illustrate the capability of the algorithm for capturing different types of spatiotemporal calcium activity. We discuss the imaging requirements, parameter selection and threshold selection for reliable measurements, and offer perspectives on uses of the vector data.     

Dissection of the hyperadhesive phenotype of airway eosinophils in asthma

Asthma is characterized by appearance of eosinophils in the airway. Eosinophils purified from the airway 48 h after segmental antigen challenge are described as exhibiting greater adhesion to albumin-coated surfaces via an unidentified beta2 integrin and increased expression of alphaMbeta2 (CD11b/18) compared with purified blood eosinophils. We have investigated the determinants of this hyperadhesive phenotype. Airway eosinophils exhibited increased reactivity with the CBRM1/5 anti-alphaM activation-sensitive antibody as well as enhanced adhesion to VCAM-1 (CD106) and diverse ligands, including albumin, ICAM-1 (CD54), fibrinogen, and vitronectin. Purified blood eosinophils did not adhere to the latter diverse ligands. Enhanced adhesion of airway eosinophils was blocked by anti-alphaMbeta2. Podosomes, structures implicated in cell movement and proteolysis of matrix proteins, were larger and more common on airway eosinophils adherent to VCAM-1 when compared with blood eosinophils. Incubation of blood eosinophils with IL-5 replicated the phenotype of airway eosinophils. That is, IL-5 enhanced recognition of alphaM by CBRM1/5; stimulated alphaMbeta2-mediated adhesion to VCAM-1, albumin, ICAM-1, fibrinogen, and vitronectin; and increased podosome formation on VCAM-1. Thus, the hyperadhesion of airway eosinophils after antigen challenge is mediated by upregulated and activated alphaMbeta2.     

Upfront double high-dose chemotherapy with DICEP followed by BEAM and autologous stem cell transplantation for poor-prognosis aggressive non-Hodgkin lymphoma

A single center, prospective clinical trial was conducted evaluating 2 cycles of induction high-dose chemotherapy for adults younger than 65 years of age with aggressive non-Hodgkin lymphoma (NHL) and 2 to 3 Age-Adjusted International Prognostic Index risk factors. Patients received one cycle of standard dose cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by one cycle of dose-intensive cyclophosphamide 5.25 g/m(2), etoposide 1.05 g/m(2), cisplatin 105 mg/m(2) (DICEP), then underwent autologous blood stem cell collection, followed by one cycle of high-dose carmustine (BCNU) 300 mg/m(2), etoposide 800 mg/m(2), Ara-C 1600 mg/m(2), melphalan 140 mg/m(2) (BEAM), and autologous stem cell transplantation (ASCT) and radiotherapy to prior bulk. From June 1998 to August 2004, 55 patients aged 20 to 63 years (median 44 years) were accrued, 51 (92%) of whom had diffuse large B-cell NHL. Poor prognostic factors included stage 4 (n = 46), elevated lactate dehydrogenase (LDH; n = 47), Eastern Cooperative Oncology Group (ECOG) performance status 2 to 4 (n = 43), bulky mass more than 10 cm (n = 34), and marrow involvement (n = 16). Only one patient experienced nonrelapse mortality. With a median follow-up of 49 months, 4-year event-free survival (EFS) and overall survival (OS) rates for all 55 patients are 72% (95% confidence interval [CI] = 60%-84%) and 79% (95% CI = 69%-90%), respectively. In conclusion, CHOP-DICEP-BEAM is feasible and gave encouraging EFS and OS for patients with poor-prognosis aggressive NHL.     

Lumbosacral magnetic root stimulation in lumbar plexopathy

We report a 76-yr-old man with left femoral nerve distribution weakness resulting from a nontraumatic retroperitoneal hematoma associated with coumadin anticoagulation. Although electric root stimulation was relatively contraindicated, magnetic lumbosacral root stimulation identified a proximal conduction block allowing more extensive assessment of the nerve damage. To our knowledge, this is the first report of magnetic root stimulation in assessment of lumbosacral plexus dysfunction in retroperitoneal hematoma.     

Standardising Reported Outcomes of Surgery for Intermittent Exotropia – A Systematic Literature Review

Background: Intermittent exotropia (IXT) is one of the most common strabismus entities worldwide, but it remains poorly understood. Investigators differ regarding which parameters should be used to characterize IXT and to evaluate interventions. Surgery is an established treatment option but problems can arise when comparing surgical effectiveness if there is a wide range of different outcome measures that can be used. This study aimed to assess the extent of standardization of reported outcomes in studies of surgery for IXT.

Methods: With institutional R&D committee approval, we conducted, according to a predefined protocol, a systematic literature review of outcomes of surgery for IXT published in the last 10 years. The databases used were Medline and EMBASE. Two analysts independently performed the searches. The separate lists were then compared and collated to maximize our return rate for included papers and allow evaluation of our strategies.

Results: Fifty-six studies met our inclusion criteria. Thirty-two were retrospective and twenty-four prospective. Outcome measures varied widely between studies and variously included ocular alignment, stereopsis, visual acuity, re-operation rate, and postoperative drift. Even for ocular alignment, there was no agreed definition of postoperative success. Time frames for assessing outcomes ranged from two months to two years after surgery.

Conclusions: The lack of harmony in outcome reporting for studies of surgery for IXT is counterproductive. We suggest 4 core outcomes for all future studies, which have already been incorporated into two current randomized trials: alignment, near stereoacuity, control score, and quality of life score.     

Development of an Arabic version of the National Eye Institute Visual Function Questionnaire as a tool to study eye diseases patients in Egypt

AIM:To develop and test an Arabic version of the National Eye Institute Visual Function Questionnaire-25 (NEI-VFQ-25).METHODS:NEI-VFQ-25 was translated into Arabic according to WHO translation guidelines. We enrolled adult consenting patients with bilateral chronic eye diseases who presented to 14 hospitals across Egypt from October to December 2012, and documented their clinical findings. Psychometric properties were then tested using STATA.RESULTS:We recruited 379 patients, whose mean age was (54.5±15)y. Of 46.2% were males, 227 had cataract, 31 had glaucoma, 23 had retinal detachment, 37 had diabetic retinopathy, and 61 had miscellaneous visual defects. Non-response rate and the floor and ceiling numbers of the Arabic version (ARB-VFQ-25) were calculated. Internal consistency was high in all subscales (except general health), with Cronbach-α ranging from 0.702-0.911. Test-retest reliability was high (intraclass correlation coefficient 0.79).CONCLUSION:ARB-VFQ-25 is a reliable and valid tool for assessing visual functions of Arabic speaking patients. However, some questions had high non-response rates and should be substituted by available alternatives. Our results support the importance of including self-reported visual functions as part of routine ophthalmologic examination.     

Bilateral non-union of high tibial osteotomies treated by total knee arthroplasty: a case report

Non-union following high tibial osteotomy (HTO) is very uncommon. We present a case of bilateral non-union of HTOs with end-stage knee arthritis treated with staged, bilateral, posterior stabilized knee replacements. A 77-year-old female presented to our clinic with complaints of debilitating knee pain. She used a frame to get about in her home, she was unable to get up stairs, and she rarely went outside. Simple radiographs revealed bilateral non-unions of her osteotomies, subluxation of the tibial plateauxs and severe knee osteoarthritis. At the time of surgery, the non-unions were found to be fibrous stable. We took a minimal tibial plateaux resection and used long stem tibial stems with offset couplers to bypass the non-unions. At minimum 1 year follow-up, she was walking pain free with full knee range of motion. We found that primary total knee replacement (TKR) using tibial stems and without treating the tibial non-union gave satisfactory results.