Can head sway patterns differentiate between patients with Meniere's disease vs. peripheral vestibular hypofunction?

Background: Meniere's disease (MD) is defined by episodic vertigo, unilateral sensorineural hearing loss and fluctuating aural symptoms. Due to the variable clinical presentation, objective tests of MD may have significant diagnostic utility. Head kinematics derived from a head-mounted display (HMD) have demonstrated to be sensitive to vestibular dysfunction. The purpose of this pilot study was to investigate whether head sway can differentiate between patients with MD, vestibular hypofunction (VH) and healthy controls. Materials/methods: 80 adults (30 healthy controls, 32 with VH, and 18 with MD) were recruited from a tertiary vestibular clinic. All underwent a postural control assessment using the HTC Vive Pro Eye HMD that recorded head sway in the anterior-posterior (AP), medio-lateral (ML), pitch, yaw and roll direction. Participants were tested with 2 levels of visual load: a static versus oscillating star display. Each scene lasted 60 s and was repeated twice. Sway in each direction was quantified using root mean square velocity (VRMS) for the first 20 s and full 60 s of each scene. Results: Static visual: participants with VH showed significantly larger head VRMS than controls in the AP (60 s and 20 s) and pitch (20 s) directions. Dynamic visual: participants with VH showed significantly larger head VRMS than controls all directions for both the 60 and 20 s analysis. Participants with MD did not differ significantly from the control or the VH group. Conclusion: While limited in numbers, Patients with MD had a high variability in head sway in all directions, and their average head sway was between controls and those with VH. A larger sample as well as patients with worse symptoms at time of testing could elucidate whether head sway via HMD could become a viable test in this population. A similar finding between 20- and 60-s scene and the full portability of the system with an in-clinic testing setup could help these future endeavors. Head sway derived from HMD is sensitive to VH and can be clinically useful as an outcome measure to evaluate sensory integration for postural control.

Insight into postural control in unilateral sensorineural hearing loss and vestibular hypofunction.

This pilot study aimed to identify postural strategies in response to sensory perturbations (visual, auditory, somatosensory) in adults with and without sensory loss. We tested people with unilateral peripheral vestibular hypofunction (N = 12, mean age 62 range 23-78), or with Unilateral Sensorineural Hearing Loss (USNHL, N = 9, 48, 22-82), or healthy controls (N = 21, 52, 28-80). Postural sway and head kinematics parameters (Directional Path in the anterior-posterior and medio-lateral directions (sway & head); pitch, yaw and roll (head) were analyzed in response to 2 levels of auditory (none, rhythmic sounds via headphones), visual (static, dynamic) and somatosensory cues (floor, foam) within a simulated, virtual 3-wall display of stars. We found no differences with the rhythmic auditory cues. The effect of foam was magnified in the vestibular group compared with controls for anterior-posterior and medio-lateral postural sway, and all head direction except for medio-lateral. The vestibular group had significantly larger anterior-posterior and medio-lateral postural sway and head movement on the static scene compared with controls. Differences in pitch, yaw and roll emerged between vestibular and controls only with sensory perturbations. The USNHL group did not increase their postural sway and head movement with the increased visual load as much as controls did, particularly when standing on the foam. They did not increase their medio-lateral sway with the foam as much as controls did. These findings suggest that individuals with USNHL employ a compensatory strategy of conscious control of balance, the functional implications of which need to be tested in future research.

Postural and Head Control Given Different Environmental Contexts.

Virtual reality allows for testing of multisensory integration for balance using portable Head Mounted Displays (HMDs). HMDs provide head kinematics data while showing a moving scene when participants are not. Are HMDs useful to investigate postural control? We used an HMD to investigate postural sway and head kinematics changes in response to auditory and visual perturbations and whether this response varies by context. We tested 25 healthy adults, and a small sample of people with diverse monaural hearing (n = 7), or unilateral vestibular dysfunction (n = 7). Participants stood naturally on a stable force-plate and looked at 2 environments via the Oculus Rift (abstract "stars;" busy "street") with 3 visual and auditory levels (static, "low," "high"). We quantified medio-lateral (ML) and anterior-posterior (AP) postural sway path from the center-of-pressure data and ML, AP, pitch, yaw and roll head path from the headset. We found no difference between the different combinations of "low" and "high" visuals and sounds. We then combined all perturbations data into "dynamic" and compared it to the static level. The increase in path between "static" and "dynamic" was significantly larger in the city environment for: Postural sway ML, Head ML, AP, pitch and roll. The majority of the vestibular group moved more than controls, particularly around the head, when the scenes, especially the city, were dynamic. Several patients with monaural hearing performed similar to controls whereas others, particularly older participants, performed worse. In conclusion, responses to sensory perturbations are magnified around the head. Significant differences in performance between environments support the importance of context in sensory integration. Future studies should further investigate the sensitivity of head kinematics to diagnose vestibular disorders and the implications of aging with hearing loss to postural control. Balance assessment and rehabilitation should be conducted in different environmental contexts.

Control Mechanisms of Static and Dynamic Balance in Adults With and Without Vestibular Dysfunction in Oculus Virtual Environments.

BACKGROUND: Deficits in sensory integration and fear of falling in complex environments contribute to decreased participation of adults with vestibular disorders. With recent advances in virtual reality technology, head-mounted displays are affordable and allow manipulation of the environment to test postural responses to visual changes. OBJECTIVES: To develop an assessment of static and dynamic balance with the Oculus Rift and (1) to assess test-retest reliability of each scene in adults with and without vestibular hypofunction; (2) to describe changes in directional path and sample entropy in response to changes in visuals and surface and compare between groups; and (3) to evaluate the relation between balance performance and self-reported disability and balance confidence. DESIGN: Test-retest, blocked-randomized experimental design. SETTING: Research laboratory. PARTICIPANTS: Twenty-five adults with vestibular hypofunction and 16 age- and sex-matched adults. METHODS: Participants stood on the floor or stability trainers while wearing the Oculus Rift. For 3 moving "stars" scenes, they stood naturally. For a "park" scene, they were asked to avoid a virtual ball. The protocol was repeated 1-4 weeks later. OUTCOME: Anteroposterior and mediolateral center-of-pressure directional path and sample entropy were derived from a force plate. RESULTS: We observed good to excellent reliability in the 2 groups, with most intraclass correlations above 0.8 and only 2 at approximately 0.4. The vestibular group had higher directional path for the stars scenes and lower directional path for the park scene compared with controls, with large variability in the 2 groups. Sample entropy decreased with more challenging environments. In the vestibular group, less balance confidence strongly correlated with more sway for the stars scenes and less sway for the park scene. CONCLUSION: Virtual reality paradigms can shed light on the control mechanism of static and dynamic postural control. Clinical utility and implementation of our portable Oculus Rift assessment should be further studied. LEVEL OF EVIDENCE: II.

Consolidative Radioimmunotherapy After Chemoimmunotherapy in Patients With Histologic Transformation of Indolent Non-Hodgkin Lymphoma.

INTRODUCTION: Histologic transformation (HT) of indolent non-Hodgkin lymphomas is an event that results in considerable morbidity and mortality. The introduction of chemoimmunotherapy regimens has resulted in an improvement in the management of this disease, and consolidation of responses with autologous stem cell transplantation appears efficacious. Many patients are not eligible for high-dose therapy, however. Radioimmunotherapy (RIT) has demonstrated single-agent efficacy in HT and can be used safely as consolidation after chemoimmunotherapy. For these reasons, RIT consolidation after chemoimmunotherapy induction has been our standard treatment approach at the University of Rochester for patients with HT who were ineligible for autologous stem cell transplantation. PATIENTS AND METHODS: A retrospective cohort study was performed to describe the clinical outcomes of these patients. Twenty-one patients were identified who received RIT consolidation. The Kaplan-Meier method was used to estimate the distributions of overall survival and progression-free survival. Comparisons were made between patients with pathologic HT and the combination of clinical HT and composite lymphoma using the log-rank test to compare survival curves. RESULTS: The median overall survival of the cohort was 84 months, and progression-free survival was 38 months. The major toxicity was myelosuppression, and 2 deaths were attributed to therapy. One case of therapy-related acute myeloid leukemia was noted. CONCLUSION: In a population of patients ineligible for high-dose therapy with autologous stem cell support, consolidation of response to chemoimmunotherapy with RIT was well tolerated and should be considered in patients with disease responsive to induction therapy.

Low Serum Vitamin D Levels Are Associated With Inferior Survival in Follicular Lymphoma: A Prospective Evaluation in SWOG and LYSA Studies.

PURPOSE: Recent literature reports a potential association between high vitamin D and improved lymphoma prognosis. We evaluated the impact of pretreatment vitamin D on follicular lymphoma (FL) outcome. PATIENTS AND METHODS: SWOG participants were previously untreated patients with FL enrolled onto SWOG clinical trials (S9800, S9911, or S0016) involving CHOP chemotherapy plus an anti-CD20 antibody (rituximab or iodine-131 tositumomab) between 1998 and 2008. Participants included in our second independent cohort were also previously untreated patients with FL enrolled onto the Lymphoma Study Association (LYSA) PRIMA trial of rituximab plus chemotherapy (randomly assigned to rituximab maintenance v observation) between 2004 and 2007. Using the gold-standard liquid chromatography-tandem mass spectrometry method, 25-hydroxyvitamin D was measured in stored baseline serum samples. The primary end point was progression-free survival (PFS). RESULTS: After a median follow-up of 5.4 years, the adjusted PFS and overall survival hazard ratios for the SWOG cohort were 1.97 (95% CI, 1.10 to 3.53) and 4.16 (95% CI, 1.66 to 10.44), respectively, for those who were vitamin D deficient (< 20 ng/mL; 15% of cohort). After a median follow-up of 6.6 years, the adjusted PFS and overall survival hazard ratios for the LYSA cohort were 1.50 (95% CI, 0.93 to 2.42) and 1.92 (95% CI, 0.72 to 5.13), respectively, for those who were vitamin D deficient (< 10 ng/mL; 25% of cohort). CONCLUSION: Although statistical significance was not reached in the LYSA cohort, the consistent estimates of association between low vitamin D levels and FL outcomes in two independent cohorts suggests that serum vitamin D might be the first potentially modifiable factor to be associated with FL survival. Further investigation is needed to determine the effects of vitamin D supplementation in this clinical setting.

Rationale and Design of the International Lymphoma Epidemiology Consortium (InterLymph) Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: Non-Hodgkin lymphoma (NHL), the most common hematologic malignancy, consists of numerous subtypes. The etiology of NHL is incompletely understood, and increasing evidence suggests that risk factors may vary by NHL subtype. However, small numbers of cases have made investigation of subtype-specific risks challenging. The International Lymphoma Epidemiology Consortium therefore undertook the NHL Subtypes Project, an international collaborative effort to investigate the etiologies of NHL subtypes. This article describes in detail the project rationale and design. METHODS: We pooled individual-level data from 20 case-control studies (17471 NHL cases, 23096 controls) from North America, Europe, and Australia. Centralized data harmonization and analysis ensured standardized definitions and approaches, with rigorous quality control. RESULTS: The pooled study population included 11 specified NHL subtypes with more than 100 cases: diffuse large B-cell lymphoma (N = 4667), follicular lymphoma (N = 3530), chronic lymphocytic leukemia/small lymphocytic lymphoma (N = 2440), marginal zone lymphoma (N = 1052), peripheral T-cell lymphoma (N = 584), mantle cell lymphoma (N = 557), lymphoplasmacytic lymphoma/Waldenström macroglobulinemia (N = 374), mycosis fungoides/Sézary syndrome (N = 324), Burkitt/Burkitt-like lymphoma/leukemia (N = 295), hairy cell leukemia (N = 154), and acute lymphoblastic leukemia/lymphoma (N = 152). Associations with medical history, family history, lifestyle factors, and occupation for each of these 11 subtypes are presented in separate articles in this issue, with a final article quantitatively comparing risk factor patterns among subtypes. CONCLUSIONS: The International Lymphoma Epidemiology Consortium NHL Subtypes Project provides the largest and most comprehensive investigation of potential risk factors for a broad range of common and rare NHL subtypes to date. The analyses contribute to our understanding of the multifactorial nature of NHL subtype etiologies, motivate hypothesis-driven prospective investigations, provide clues for prevention, and exemplify the benefits of international consortial collaboration in cancer epidemiology.

Medical history, lifestyle, family history, and occupational risk factors for follicular lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

BACKGROUND: Follicular lymphoma (FL) has been linked with cigarette smoking and, inconsistently, with other risk factors. METHODS: We assessed associations of medical, hormonal, family history, lifestyle, and occupational factors with FL risk in 3530 cases and 22639 controls from 19 case-control studies in the InterLymph consortium. Age-, race/ethnicity-, sex- and study-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression. RESULTS: Most risk factors that were evaluated showed no association, except for a few modest or sex-specific relationships. FL risk was increased in persons: with a first-degree relative with non-Hodgkin lymphoma (OR = 1.99; 95% CI = 1.55 to 2.54); with greater body mass index as a young adult (OR = 1.15; 95% CI = 1.04 to 1.27 per 5 kg/m(2) increase); who worked as spray painters (OR = 2.66; 95% CI = 1.36 to 5.24); and among women with Sjögren syndrome (OR = 3.37; 95% CI = 1.23 to 9.19). Lower FL risks were observed in persons: with asthma, hay fever, and food allergy (ORs = 0.79-0.85); blood transfusions (OR = 0.78; 95% CI = 0.68 to 0.89); high recreational sun exposure (OR = 0.74; 95% CI = 0.65 to 0.86, fourth vs first quartile); who worked as bakers or millers (OR = 0.51; 95% CI = 0.28 to 0.93) or university/higher education teachers (OR = 0.58; 95% CI = 0.41 to 0.83). Elevated risks specific to women included current and longer duration of cigarette use, whereas reduced risks included current alcohol use, hay fever, and food allergies. Other factors, including other autoimmune diseases, eczema, hepatitis C virus seropositivity, hormonal drugs, hair dye use, sun exposure, and farming, were not associated with FL risk. CONCLUSIONS: The few relationships observed provide clues suggesting a multifactorial etiology of FL but are limited in the extent to which they explain FL occurrence.

Vestibular rehabilitation following mild traumatic brain injury.

INTRODUCTION: Vertigo, dizziness, and imbalance are a symptom complex that is commonly found following concussion. Early metabolic changes following concussion may lead to worsening of the injury and symptoms in individuals not properly managed from the outset. When symptoms do not recover spontaneously, skilled vestibular rehabilitation can be an effective modality in an attempt to normalize the individual's vestibular responses. PURPOSE: The purpose of this review is to appraise the current and accepted methods available to the skilled clinician in quantifying and treating vestibular dysfunction following concussion. Incidence and prognostic indicators will be reviewed along with common barriers to recovery. SUMMARY: Vestibular Rehabilitation following concussion utilizes similar tools and techniques employed when treating those solely with peripheral pathology. The clinician must not only have a solid understanding of when and why certain exercises are required, but also be willing to accept that less exercise may be indicated in this population. As injury to the system following mild traumatic brain injury can include both peripheral and central structures, the duration of therapy and the time to recovery may be prolonged. Co-morbidities including cognitive and behavioral issues, visual-perceptual dysfunction, metabolic dysfunction, and autonomic dysfunction may hamper the effectiveness of the traditional Vestibular Rehabilitation approach. As successful treatment does not occur in a vacuum, working closely with other disciplines well versed in treating these co-morbid issues will help the individual to obtain optimal recovery. CONCLUSION: Vestibular Rehabilitation is an effective modality for managing dizziness, vertigo, and imbalance following concussion. Careful consideration of the acuity of the injury, along with effective management of co-morbid conditions will optimize the result.

The association between early life and adult body mass index and physical activity with risk of non-Hodgkin lymphoma: impact of gender.

PURPOSE: To evaluate the association of body mass index (BMI) and physical activity (PA) during adulthood and at the age of 18 years with risk of non-Hodgkin lymphoma (NHL). METHODS: We enrolled 950 newly diagnosed NHL patients and 1146 frequency-matched clinic-based controls. Height, weight, and PA (recent adult and at the age of 18 years) were self-reported. Odds ratios (ORs), 95% confidence intervals, and tests for trend were estimated using unconditional logistic regression adjusted for age, gender, and residence. RESULTS: BMI at the age of 18 years was associated with an increased NHL risk (OR, 1.38 for highest vs. lowest quartile; p-trend = .0012), which on stratified analysis was specific to females (OR, 1.90; p-trend = .00025). There was no association of adult BMI with NHL risk. Higher PA in adulthood (OR, 1.03; p-trend = .85) or at the age of 18 years (OR, 0.88; 95% confidence interval, 0.72-1.07) was not associated with risk, but there was an inverse association for adult PA that was specific to females (OR, 0.71; p-trend = .039). Only BMI at the age of 18 years remained significantly associated with NHL risk when modeled together with PA in adulthood or at the age of 18 years. There was little evidence for heterogeneity in these results for the common NHL subtypes. CONCLUSIONS: Early adult BMI may be of greatest relevance to NHL risk, particularly in females.

Early life sun exposure, vitamin D-related gene variants, and risk of non-Hodgkin lymphoma.

PURPOSE: It has been hypothesized that vitamin D mediates the inverse relationship between sun exposure and non-Hodgkin lymphoma (NHL) risk reported in several recent studies. We evaluated the association of self-reported sun exposure at ages <13, 13-21, 22-40, and 41+ years and 19 single nucleotide polymorphisms (SNPs) from 4 candidate genes relevant to vitamin D metabolism (RXR, VDR , CYP24A1, CYP27B1) with NHL risk. METHODS: This analysis included 1,009 newly diagnosed NHL cases and 1,233 frequency-matched controls from an ongoing clinic-based study. Odds ratios (OR), 95 % confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression. RESULTS: There was a significant decrease in NHL risk with increased sun exposure at ages 13-21 years (OR(≥15 vs. ≤3 h/week) = 0.68; 95 % CI, 0.43-1.08; p(trend) = 0.0025), which attenuated for older ages at exposure. We observed significant main effect associations for 3 SNPs in VDR and 1 SNP in CYP24A1: rs886441 (OR(per-allele) = 0.82; 95 % CI, 0.70-0.96; p = 0.016), rs3819545 (OR(per-allele) = 1.24; 95 % CI, 1.10-1.40; p = 0.00043), and rs2239186 (OR(per-allele) = 1.22; 95 % CI, 1.05-1.41; p = 0.0095) for VDR and rs2762939 (OR(per-allele) = 0.85; 95 % CI, 0.75-0.98; p = 0.023) for CYP24A1. Moreover, the effect of sun exposure at age 13-21 years on overall NHL risk appears to be modified by germline variation in VDR (rs4516035; p(interaction) = 0.0066). Exploratory analysis indicated potential heterogeneity of these associations by NHL subtype. CONCLUSION: These results suggest that germline genetic variation in VDR, and therefore the vitamin D pathway, may mediate an association between early life sun exposure and NHL risk.

Involved field radiation therapy following high dose chemotherapy and autologous stem cell transplant benefits local control and survival in refractory or recurrent Hodgkin lymphoma.

BACKGROUND AND PURPOSE: Patients with recurrent or primary refractory Hodgkin lymphoma (HL) treated with high dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) commonly relapse post-ASCT in previous disease sites. We sought to evaluate involved field radiation therapy (IFRT) following ASCT and patterns of recurrence, overall survival (OS), and disease specific survival (DSS). METHODS AND MATERIALS: Between May 1993 and October 2003, 62 (n=66) evaluable patients with refractory/relapsed HL underwent HDT followed by ASCT. Thirty-two (52%) patients received IFRT following transplant. Survival was calculated from the day of hematopoietic stem cell infusion. RESULTS: Median follow-up was 2.3 years (range 0.03-11.56). Estimated 3-year OS (p=0.05) and DSS (p=0.08) were 69.6% and 82.1% with IFRT and 40% and 57.6% without IFRT on univariate analysis. B-symptoms were adverse on univariate (p=0.007) and multivariate (p=0.01) analysis. HL patients who received IFRT following ASCT had improved local control in areas of previously recurrent disease (p=0.03). CONCLUSION: OS and DSS showed marginal benefit at 3 years. Given the retrospective nature of our study and attendant selection bias that can be both positive and negative, a future prospective study is warranted to better understand the value of IFRT in the transplant setting.

Syk inhibition with fostamatinib leads to transitional B lymphocyte depletion.

Cell signaling initiated by the B cell receptor is critical to normal development of B lymphocytes, most notably at the transitional B cell stage. Inhibition of this signaling pathway with the syk inhibitor, fostamatinib, has produced significant efficacy in lymphoid malignancies and autoimmune conditions. Here, we demonstrate that short-term use of fostamatinib impairs B lymphocyte development at the transitional stage without affecting mature B cell populations. Additionally, IL-10 producing B cells remained relatively constant throughout the treatment period. These findings provide insight into the mechanism of action of B cell receptor inhibition in autoimmune disease. As the development of agents targeting B cell receptor signaling proceeds, monitoring for long-term consequences as well as functional evaluation of B cell subsets may further improve our understanding of this rapidly growing class of novel agents.

High-dose therapy and autologous stem cell transplant for transformed non-Hodgkin lymphoma in the rituximab era.

The impact of rituximab on the outcome of high-dose therapy and autologous stem cell transplant (HD-ASCT) for transformed non-Hodgkin lymphoma (NHL) has not been previously described. We analyzed 18 consecutive patients with indolent NHL who transformed to diffuse large B-cell lymphoma (DLBCL), received rituximab-containing therapy either before or after transformation and underwent subsequent HD-ASCT. With a median follow-up of 40 months, the 2-year progression-free survival (PFS) was 59% and the 2-year overall survival (OS) was 82%. Six patients did not receive rituximab pre-transformation. This group had a significantly better PFS at 2 years post-HD-ASCT compared to 12 patients who were exposed to rituximab pre-transformation (p = 0.03). HD-ASCT remains an effective therapeutic option for transformed NHL in the rituximab era. However, patients exposed to rituximab pre-transformation appear to have inferior HD-ASCT outcomes, and thus may benefit from novel conditioning and maintenance regimens in the setting of HD-ASCT.

Late relapses following high-dose autologous stem cell transplantation (HD-ASCT) for Hodgkin's lymphoma (HL) in the ABVD therapeutic era.

Salvage chemotherapy followed by high-dose autologous stem cell transplantation (HD-ASCT) is the standard of care for patients who have relapsed or refractory Hodgkin's lymphoma (HL). Few trials have had long-term follow-up post-HD-ASCT in the ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) era of treatment. We reviewed 95 consecutive patients who received HD-ASCT for relapsed or refractory HL following ABVD failure between 1990 and 2006 at the University of Rochester. Median follow-up for survivors was 8.2 years. All patients received HD-ASCT following upfront ABVD (or equivalent) failure. At 5 years, overall survival (OS) and event-free survival (EFS) were 54% and 37%, respectively. In total, 54 patients have died; 37 of these patients died directly of HL. Notably, there were 19 deaths >3 years post-HD-ASCT and 13 of these late deaths are directly attributable to HL. Furthermore, there were 51 documented relapses, 9 of which occurred >3 years post-HD-ASCT. In contrast to other studies, we did not observe a plateau in EFS following transplantation. Patients appear to be at continuous risk of recurrence beyond 3 years after HD-ASCT. Our results emphasize the importance of long-term follow-up for both toxicity and recurrence, and have important implications in defining success of posttransplantation maintenance strategies.

Lymphocyte populations in joint tissues from dogs with inflammatory stifle arthritis and associated degenerative cranial cruciate ligament rupture.

OBJECTIVE: To evaluate lymphocyte populations in stifle synovium and synovial fluid of dogs with degenerative cranial cruciate ligament rupture (CCLR). STUDY DESIGN: Prospective clinical study. ANIMALS: Dogs (n=25) with stifle arthritis and CCLR, 7 dogs with arthritis associated with cartilage degeneration (osteoarthritis [OA]), and 12 healthy Beagle dogs with intact CCL. METHODS: Arthritis was graded radiographically in CCLR dogs. After collection of joint tissues, mononuclear cells were isolated and subsequently analyzed using flow cytometry for expression of CD3, CD4, CD8, and CD21. RESULTS: The proportions of CD4(+) T helper lymphocytes, CD8(+) cytotoxic T lymphocytes, and CD3(+) CD4(-) CD8(-) T lymphocytes were increased in synovium from dogs with CCLR compared with synovium from healthy Beagle dogs (P<.05). The proportion of CD3(+) CD4(-) CD8(-) T lymphocytes in synovial fluid was increased in dogs with CCLR compared with dogs with OA (P<.05). In dogs with CCLR, the proportion of CD3(+) CD4(-) CD8(-) T lymphocytes in synovial fluid was inversely correlated with radiographic arthritis (S(R) =-0.68, P<.005). CONCLUSION: Lymphocytic inflammation of stifle synovium and synovial fluid is an important feature of the CCLR arthropathy. Lymphocyte populations include T lymphocytes expressing CD4 and CD8, and CD3(+) CD4(-) CD8(-) T lymphocytes. Presence of CD3(+) CD4(-) CD8(-) T lymphocytes was associated with development of stifle synovitis. Further work is needed to fully identify the phenotype of these cells.

The combination of bendamustine, bortezomib, and rituximab for patients with relapsed/refractory indolent and mantle cell non-Hodgkin lymphoma.

Given the significant activity and tolerability of bendamustine, rituximab, and bortezomib in patients with relapsed indolent and mantle cell non-Hodgkin lymphoma, and laboratory studies suggesting synergistic activity, we conducted a multicenter phase 2 study of the bendamustine/bortezomib/rituximab combination. Patients with relapsed or refractory indolent and mantle cell lymphoma with adequate organ function were treated with bendamustine 90 mg/m² days 1 and 4; rituximab 375 mg/m² day 1, and bortezomib 1.3 mg/m² days 1, 4, 8, 11. Six 28-day cycles were planned. Thirty patients (7 with mantle cell lymphoma) were enrolled and treated. Eight patients experienced serious adverse events, including one event of grade 5 sepsis. Common nonhematologic adverse events were generally grade 1 or grade 2 and included nausea (50%), neuropathy (47%), fatigue (47%), constipation (40%), and fever (40%). Of 29 patients evaluable for efficacy, 24 (83%) achieved an objective response (including 15 with complete response). With median follow-up of 24 months, 2-year progression-free survival is 47% (95% confidence interval, 25%-69%). On the basis of these promising results, the US cooperative groups have initiated randomized trials to evaluate this regimen in follicular and mantle cell lymphoma. This trial was registered at www.clinicaltrials.gov as #NCT00547534.

Germline variation in apoptosis pathway genes and risk of non-Hodgkin's lymphoma.

BACKGROUND: The t(14;18)(q32;q21) translocation is the most commonly observed chromosomal translocation in non-Hodgkin's lymphoma (NHL), resulting in constitutive Bcl-2 expression and apoptosis inhibition. In addition, germline variation in both BCL2L11 (BIM) and CASP9, known regulators of apoptosis, has recently been linked to NHL risk. We conducted a comprehensive evaluation of 36 apoptosis pathway genes with risk of NHL. METHODS: We genotyped 226 single-nucleotide polymorphisms (SNP) from 36 candidate genes in a clinic-based study of 441 newly diagnosed NHL cases and 475 frequency-matched controls. We used principal components analysis to assess gene-level associations, and logistic regression to assess SNP-level associations. MACH was used for imputation of SNPs in BCL2L11 and CASP9. RESULTS: In gene-level analyses, BCL2L11 (P = 0.0019), BCLAF1 (P = 0.0097), BAG5 (P = 0.026), and CASP9 (P = 0.0022) were associated with NHL risk after accounting for multiple testing (tail strength, 0.38; 95% confidence interval, 0.05-0.70). Two of the five BCL2L11 tagSNPs (rs6746608 and rs12613243), both genotyped BCLAF1 tagSNPs (rs797558 and rs703193), the single genotyped BAG5 tagSNP (rs7693), and three of the seven genotyped CASP9 tagSNPs (rs6685648, rs2020902, and rs2042370) were significant at P < 0.05. We successfully imputed BCL2L11 and CASP9 SNPs previously linked to NHL, and replicated all four BCL2L11 and two of three CASP9 SNPs. CONCLUSION: We replicated the association of BCL2L11 and CASP9 with NHL risk at the gene and SNP level, and identified novel associations with BCLAF1 and BAG5. IMPACT: Closer evaluation of germline variation of genes in the apoptosis pathway with risk of NHL and its subtypes is warranted.

Vitamin D insufficiency and prognosis in non-Hodgkin's lymphoma.

PURPOSE: Vitamin D insufficiency is common in the United States, with low levels linked in some studies to higher cancer incidence, including non-Hodgkin's lymphoma (NHL). Recent data also suggest that vitamin D insufficiency is related to inferior prognosis in some cancers, although there are no data for NHL. PATIENTS AND METHODS: We tested the hypothesis that circulating 25-hydroxyvitamin D [25(OH)D] levels are predictive of event-free survival (EFS) and overall survival (OS) in a prospective cohort of 983 newly diagnosed patients with NHL. 25(OH)D and 1,25-dihydroxyvitamin D [1,25(OH)(2)D] levels were measured by liquid chromatography-tandem mass spectrometry. RESULTS: Mean age at diagnosis was 62 years (range, 19 to 94 years); 44% of patients had insufficient 25(OH)D levels (< 25 ng/mL) within 120 days of diagnosis. Median follow-up was 34.8 months; 404 events and 193 deaths (168 from lymphoma) occurred. After adjusting for known prognostic factors and treatment, 25(OH)D insufficient patients with diffuse large B-cell lymphoma (DLBCL) had inferior EFS (hazard ratio [HR], 1.41; 95% CI, 0.98 to 2.04) and OS (HR, 1.99; 95% CI, 1.27 to 3.13); 25(OH)D insufficient patients with T-cell lymphoma also had inferior EFS (HR, 1.94; 95% CI, 1.04 to 3.61) and OS (HR, 2.38; 95% CI, 1.04 to 5.41). There were no associations with EFS for the other NHL subtypes. Among patients with DLBCL and T-cell lymphoma, higher 1,25(OH)(2)D levels were associated with better EFS and OS, suggesting that any putative tumor 1-α-hydroxylase activity did not explain the 25(OH)D associations. CONCLUSION: 25(OH)D insufficiency was associated with inferior EFS and OS in DLBCL and T-cell lymphoma. Whether normalizing vitamin D levels in these patients improves outcomes will require testing in future trials.