X-linked ocular albinism (OA1), Nettleship-Falls type, is characterized by decreased ocular pigmentation, foveal hypoplasia, nystagmus, photodysphoria, and reduced visual acuity. Affected males ...usually demonstrate melanin macroglobules on skin biopsy. We now report results of deletion and mutation screening of the full-length
OA1 gene in 29 unrelated North American and Australian X-linked ocular albinism (OA) probands, including five with additional, nonocular phenotypic abnormalities (
Schnur et al. 1994). We detected 13 intragenic gene deletions, including 3 of exon 1, 2 of exon 2, 2 of exon 4, and 6 others, which span exons 2–8. Eight new missense mutations were identified, which cluster within exons 1, 2, 3, and 6 in conserved and/or putative transmembrane domains of the protein. There was also a splice acceptor–site mutation, a nonsense mutation, a single base deletion, and a previously reported 17-bp exon 1 deletion. All patients with nonocular phenotypic abnormalities had detectable mutations. In summary, 26 (∼90%) of 29 probands had detectable alterations of
OA1, thus confirming that
OA1 is the major locus for X-linked OA.
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9057
Background: The incidence of CAM use among patients with cancer is higher when compared to the general population. However, there are few studies examining CAM use in NHL ...survivors, and limited data are available regarding beliefs in CAM. This study was conducted to examine the prevalence of CAM use in NHL, define CAM beliefs among NHL survivors, and explore differences between patients with indolent and aggressive lymphoma. Methods: Newly diagnosed lymphoma patients were prospectively enrolled within 9 months of diagnosis in the University of Iowa/Mayo Clinic SPORE Molecular Epidemiology Resource from 2002-2008. NHL patients who completed the 3-year post diagnosis questionnaire, which includes questions regarding CAM use and beliefs, were included in this study. Chi-squared tests and Wilcoxon rank-sum tests were used to assess the association of CAM use with prognostic and demographic factors. Results: 719 patients were included with a median age of 63 years (range 22-92). 53% were male. Overall, 636 (89%) reported ever using CAM. 78% of patients used vitamins and 54% alternative therapies (chiropractic (36%) and massage therapy (24%)). Among CAM users, 141 (22%) believe CAM can assist the body to heal, 123 (19%) believe CAM can relieve cancer symptoms, 115 (18%) believe CAM use gives a feeling of control, 106 (17%) believe CAM can boost immunity, 24 (4%) believe CAM can cure cancer, and 35 (6%) believe CAM can prevent the spread of cancer. Female gender was associated with increased overall CAM use (p<0.0001) as well as use of vitamins (p<0.0001), herbal supplements (p=0.006) and alternative therapy (p=0.0002) specifically for cancer. Older age was also associated with increased vitamin use (p=0.005) and decreased herbal supplements use (p=0.008). There was no significant difference in overall CAM use between those with follicular lymphoma grades I-II (n=195, 91%) and non-relapsed diffuse large B-cell lymphoma (n=151, 87%), although massage therapy was utilized more often by FL survivors (29% versus 18%, p=0.005). Conclusions: CAM modalities are used by the majority of NHL survivors (89%). The assessment of CAM use and education regarding potential harms is imperative for the NHL survivor.
We evaluated inpatient asthma management practices in 10 Florida hospitals. We wanted to learn about care protocols, instrumental resources, and use of evidence-based guidelines. We sought to ...recommend strategies for improving care based on gaps identified by this study. We developed a survey that included detailed questions on care strategies and resources. Guidelines from the National Heart, Lung, and Blood Institute (NHLBI) in the Expert Panel Report 3 (EPR-3) for the Diagnosis and Management of Asthma were a primary focus. Hospitals were given the option of completing their surveys by phone or email. Data were analyzed via content coding of completed surveys. Most participating hospitals had robust protocols and resources in place for inpatient asthma management, and continually reassessed these resources for quality improvement. Overall, inpatient care practices at these hospitals adhered strongly to national guidelines for asthma management. Inpatient asthma care practices at surveyed Florida hospitals are largely robust, evidence-based, and constantly improving. Our findings suggest not only that hospitals in Florida are deeply committed to effective asthma management, but also that they have active interest in collaborating with one another to further improve care.
Background:
Lenalidomide plus rituximab (R2) has established efficacy and a tolerable safety profile in patients with previously untreated and relapsed/refractory (R/R) indolent NHL. This includes ...patients with marginal zone lymphoma (MZL) who are generally treated in a similar manner to follicular lymphoma (FL).
Aims:
Primary results for the AUGMENT study in R/R FL grade 1–3a and MZL showed significantly improved progression‐free survival (PFS) for R2 over R/placebo in the overall population and in the subgroup analyses, with the exception of the MZL subgroup. Given the small sample size for MZL patients, post hoc analyses of baseline characteristics and univariate/multivariate analyses of PFS were conducted to examine possible explanations for these results.
Methods:
The phase III AUGMENT study randomized patients 1:1 to R2 (lenalidomide PO 20 mg/day (d), d1–21/28 X12 cycles plus rituximab IV 375 mg/m2 weekly in cycle 1 and d1 of cycles 2–5) or rituximab‐placebo (R/placebo; same dosing schedule). PFS by 2007 IWG (without PET) was the primary endpoint. Post hoc Cox regression models were used for univariate analysis of one risk factor and multivariate analyses including treatment arm and significant risk factors (P < 0.05) from the univariate analyses.
Results:
A total of 63/358 (18%) MZL patients were part of the overall study population, including n = 14/16 MALT, n = 9/6 splenic, and n = 8/10 nodal MZL subtypes for respective R2 and R/placebo arms. Numerical differences between treatment arms for baseline demographics and disease characteristics for MZL patients favoring the R/placebo arm were: fewer R2 patients had an ECOG score of 0 (55% R2 vs 72% R/placebo), and more R2 (vs R/placebo) patients were older (≥65 y: 68% vs 59%; ≥70 y: 42% vs 38%), were refractory to the last prior regimen (13% vs 3%), had Ann Arbor stage IV disease at enrollment (65% vs 41%), high‐risk MALT‐IPI score (50% vs 19%), elevated LDH (29% vs 19%), B symptoms (13% vs 3%), and high tumor burden per GELF criteria (65% vs 56%). The most common grade 3/4 AEs for MZL patients receiving R2 vs R/placebo, respectively, were neutropenia (47% vs 16%), pneumonia (3% vs 13%), and leukopenia (10% vs 0). A total of 5 deaths occurred in the R2 arm (most associated with progression of disease; 2 deaths occurred early at 3 and 13 days after randomization one prior to receiving R2 and one 2 days after treatment initiation) and 2 in the R/placebo arm. Despite worse prognostic features, best response was improved with R2 (vs R/placebo) with ORR = 65% vs 44% (P = 0.13) and CR = 29% vs 13% (P = 0.13), although neither were statistically significant. Improved response rates did not translate into a survival advantage for R2. Median PFS for MZL patients was 20.2 mo R2 vs 25.2 mo R/placebo (HR = 1.00; 95% CI, 0.47–2.13; P = 1.0). Univariate analyses showed that several baseline factors were prognostic for MZL patients (P < 0.05): Ann Arbor stage IV, elevated LDH, and unfit for chemotherapy (Table). Multivariate analyses adjusting for the imbalance in these 3 significant prognostic factors showed an adjusted PFS HR of 0.51 (95% CI, 0.20–1.28) favoring the R2 arm, similar to the PFS HR in the overall population (HR = 0.46; 95% CI, 0.34–0.63). The univariate and multivariate analyses suggested that the imbalance in baseline prognostic factors impacted PFS results for MZL patients.
Summary/Conclusion:
Overall, these findings suggest that the PFS results in MZL patients were negatively impacted by the imbalance in baseline prognostic factors and more aggressive disease in the R2 over the R/placebo arm.
Single agent therapy with the novel agent lenalidomide has shown efficacy in relapsed lymphomas, through anti-proliferative and immunomodulatory mechanisms, and may have a synergistic effect with ...rituximab. There is limited data on the efficacy and safety of lenalidomide in multidrug combinations in treatment naïve patients. We designed a phase II single arm trial of untreated low grade NHL patients with lenalidomide, rituximab, cyclophosphamide, and dexamethasone (LR-CD) to evaluate tumor response, toxicity (adverse events) and survival1. Initial analysis showed promising results in patients with lymphoplasmacytic lymphoma (WM), and the cohort was expanded for analysis. Lenalidomide has previously been studied with rituximab in this population but significant toxicity, mainly anemia (8/16 (50%) grade 2 and 1/16 (6%) grade 3), caused cessation of study enrollment2. We report here results of the Waldenström's macroglobulinemia cohort.
Eligibility: 18 years of age, untreated indolent NHL, ECOG PS ≤2, nodes ≥ 2cm by MRI or CT or IgM ≥ 400mg/dL, ANC >1400 mm³, platelet count ≥ 100,000/mm³, creatinine ≤ 2mg/dL. Treatment consisted of IV rituximab 375mg/m2 on day 1, oral lenalidomide 20mg days 1-21, cyclophosphamide 250mg/m2 days 1, 8, 15, and dexamethasone 40mg days 1, 8,15, 22, on a 28 day cycle. All patients received aspirin 325 mg daily. Treatment continued 2 cycles beyond best response up to a maximum of 12 cycles. Toxicity was assessed using NCI CTCAE v3.0.
Sixteen patients with lymphoplasmacytic lymphoma, with monoclonal IgM present at baseline, have enrolled at Mayo Clinic with 15 evaluated for toxicity and response (1 withdrew before treatment). Four patients are still receiving treatment. Patient characteristics: median age 69 (47-83), 87% male, 100% Caucasian, median IgM 4480 (1740-7890). At baseline 4/15 (27%) patients had grade 2 anemia and 2/15 (13%) had grade 3. Median number of cycles administered was 8, and 73% completed the study per protocol. Overall best response rate was 80%, 1 patient with CR and 11 with PR. The most common grade 3 or 4 adverse events were neutropenia (13% grade 3 and 33% grade 4), anemia (27% grade 3, 13% grade 4), and leukopenia (grade 3, 13%, grade 4, 20%). Six patients had grade 3 or higher nonhematologic toxicity. At a median follow up of 17 months (0.9-38.3), 11 patients had not progressed and 4 progressed. The median PFS is 24.9 months, and the OS at 2 years is 86%. One death secondary to relapsed disease occurred 7.7 months after completing 12 cycles of treatment.
LR-CD can be safely administered in newly diagnosed symptomatic Waldenström's macroglobulinemia. The main toxicities are anemia and neutropenia, with more anemia (≥gr3 40% vs. 14%) than seen in other low grade histologies treated with LR-CD1. A prior study of lenalidomide and rituximab in WM was stopped due to the development of anemia suggesting that lenalidomide was not a safe or efficacious drug in this disease. However, while we did see anemia develop during therapy with LR-CD, 6/15 patients had grade≥2 anemia at baseline. Compared to historical results this highly active regimen deserves study in a randomized trial.
1 Blood (ASH Annual Meeting Abstracts), Nov 2012; 120: 2741
2 Clin Cancer Res 2009; 355 15(1) January 1, 2009
This trial is sponsored by Celgene
Off Label Use: lenalidomide is not approved for treatment of waldenstrom macroglobulinemia. Nowakowski:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stewart:Onyx: Consultancy, Research Funding; Millenium: Honoraria, Research Funding; Celgene: Honoraria; BMS: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Fonseca:millennium: Consultancy; amgen: Consultancy; Binding site: Consultancy; onyx: Consultancy; medtronic: Consultancy; Genzyme: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; lilly: Consultancy; Onyx: Research Funding; cylene: Research Funding. Tiedemann:Celgene: Honoraria; Janssen: Honoraria. Reeder:Celgene: Research Funding; Novartis: Research Funding; Millenium: Research Funding.
Congenital hypomyelinating neuropathy (CHN; MIM# 605253) is a severe neuropathy with early infancy onset inherited as an autosomal dominant or recessive trait. Sural nerve biopsy shows a ...characteristic picture of nonmyelinated and poorly myelinated axons with basal lamina onion bulbs and lack of myelin breakdown products. Several mutations in the MTMR2, PMP22, EGR2, and MPZ genes have been found in patients with CHN. The authors describe the clinical and morphologic features of a patient with CHN and the identification of a novel Thr124Lys mutation in the MPZ gene.
Synaptic disturbances may play a key role in the pathophysiology of schizophrenia. This study was designed to further investigate possible synaptic alterations in the brains of chronic schizophrenic ...patients. Chromogranin B was applied as a marker for large dense core vesicles and synapsin I as a protein associated with the synaptic vesicle membrane. The distribution and density of chromogranin B-and synapsin I-like immunoreactivity in subregions of the hippocampus was compared between controls (
n=16) and patients with schizophrenia (
n=17).
The overall distribution of hippocampal chromogranin B- and synapsin I-like immunoreactivity was similar in controls and in schizophrenic patients with the highest densities in the terminal field of mossy fibers and in the inner molecular layer of the dentate gyrus. In schizophrenic hippocampi, a significant reduction in the density of chromogranin B-like immunoreactivity was found in the CA4 and CA3 but not in the CA1 area of the dentate gyrus based on computerized image analysis. The loss of immunoreactivity was localized to mossy fibers and terminals surrounding hilar interneurons. Double-labelling immunohistochemistry revealed that synapsin I was co-expressed with chromogranin B in these neuronal structures and was also significantly reduced in schizophrenic hippocampi.
The present study demonstrates an area-specific reduction of chromogranin B which is paralleled by a decrease of synapsin I. The loss of presynaptic proteins involved in distinct steps of exocytosis may cause complex synaptic disturbances in specific hippocampal subregions resulting in an imbalanced neurotransmitter availability in schizophrenic patients.
Abstract 2836
Monoclonal antibodies (mAb) are an effective but non-curative treatment of CLL. Although the mechanisms of action of mAb in vivo are not fully defined, complement dependent cytotoxicity ...(CDC) appears to play an important role. We have previously shown that addition of ofatumumab (OFA) significantly increases alemtuzumab (ALM) CDC in vitro and identified a subpopulation of CLL cells that are intrinsically resistant to activated complement. We propose that resistance to CDC could be an important cause of mAb treatment failure in CLL patients. To test the hypothesis that CLL cells treated in vivo with OFA would be resistant to subsequent OFA retreatment in vitro, we studied CLL cells and serum from 10 previously untreated patients with progressive CLL treated with pentostatin, cyclophosphamide, and ofatumumab (PCO).
Patients received 300 mg of OFA followed by 2 mg/m2 of pentostatin and 600 mg/m2 of cyclophosphamide on day 1 of therapy. Samples were taken prior to treatment (S1), immediately after the OFA infusion and prior to chemotherapy (S2), and post-chemotherapy before the second dose of OFA on day 2 (S3). Mononuclear blood cells isolated from EDTA anticoagulated blood by Ficoll-Paque centrifugation were purified to achieve a concentration of > 90% CLL. CDC was assayed at a concentration of 2 × 106/ml CLL cells with 10 mg/ml of ALM (Genzyme), OFA (G.S.K.) or rituximab (RTX)(Genentech) in AIM V medium (Invitrogen, CA) and 10% normal human serum (10%NHS)(Sigma, MO) as a source of complement for 1 hour at 37°C. Absolute viable cell counts were measured by flow cytometry using counting beads (Trucount, BD, CA) and propidium iodide staining (Sigma, MO) with a FACSCalibur (BD, CA) and CellQuest Pro software (BD, CA). Percent CDC was calculated relative to counts for CLL cells treated with only 10%NHS. Binding of mAb and C3b to CLL cells was measured by flow cytometry with mouse anti-human Fc antibody FITC-HB43 and anti-C3b antibody FITC-7C12. C5 deficient serum (C5-serum)(Sigma, MO) was used to examine mAb and C3b binding without CDC. Results were expressed as delta mean fluorescent intensity (dMFI) relative to cells treated without mAb in 10%NHS or C5-serum as appropriate. Complement (CH50) was measured based on lysis of opsonized sheep red cells using standard methods. OFA concentrations in serum samples were determined by measuring the level of binding to Daudi cells compared to standards as previously described.
S1 CLL cells were significantly more susceptible to in vitro OFA CDC (median 30%) than S2 and S3 cells (both 0%, p=0.002)(Fig. 1). In contrast, high levels of CDC (median 86 – 88%) were induced in vitro by ALM in all these samples and prior in vivo exposure to OFA did not affect susceptibility to ALM CDC in vitro (p>0.1). CLL cells from S2&S3 had low levels of OFA binding both prior to and post in vitro exposure to OFA (median dMFI 2 and 3 respectively) which was significantly less than OFA binding for S1 (median dMFI 38 p=0.002) likely reflecting in vivo trogocytosis of bound OFA and CD20, as previously described for RTX. In vitro ALM binding was higher than OFA (median dMFI>150) in all specimens. C3b binding was low in S2&S3 both before and after in vitro OFA exposure (median dMFI 3 and 4 respectively) with significantly higher levels in S1 (median dMFI 94, p=0.002). C3b binding was higher in all CLL cells treated with ALM (median dMFI>358). OFA treatment resulted in marked decreases in serum complement levels in S2 (median 86%, range 65–98%) and S3 (median 78% range 61–88%) compared to S1. The median serum OFA concentration was 18.5 μg/ml (range 7.3–50.4) in S2 and 19.8 μg/ml (range 0–32.3) in S3.
Circulating CLL cells from patients treated with OFA are resistant to in vitro OFA CDC primarily because of low levels of expression of CD20. The reduction in complement titers could limit in vivo CDC but we found no evidence that low levels of OFA were important. Cells surviving OFA in vivo do retain sensitivity to ALM CDC. Our data support the previous description of trogocytosis in CLL patients treated with RTX and suggest that lower doses of these mAb, that promote far lower levels of trogocytosis, could be more effective in sustaining CDC. In addition, our study provides pre-clinical data to support a clinical trial of combination therapy with OFA and ALM for CLL.
This study was supported by funding from GlaxoSmithKline and the University of Iowa/Mayo Clinic Lymphoma SPORE (CA097274). Display omitted
Taylor:Genmab: Consultancy; Glaxo Smith Kline: Research Funding. Zent:GlaxoSmithKline: Research Funding; Genentech: Research Funding; Genzyme: Research Funding.
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