Lymphoma for the acute physician: diagnostic challenges and initial treatment decisions.

Prompt diagnosis of lymphoma facilitates early treatment and improves outcomes for patients. For non-haemato-oncologists, it is important to have an understanding of how lymphoma can present and the initial work-up. This review is intended to provide clinicians with background to aid clinical decisional making at presentation and when managing treatment related complications. There will be particular emphasis on emergency presentations (tumour lysis syndrome, management of patients with a mediastinal mass, infections in lymphoma patients) and novel treatment options which have unique toxicities often requiring multi-specialty expertise.

Upfront lower dose lenalidomide is less toxic and does not compromise efficacy for vulnerable patients with relapsed refractory multiple myeloma: final analysis of the phase II RevLite study.

The combination of lenalidomide and dexamethasone is an established treatment for patients with multiple myeloma (MM). Increasingly, treatment attenuation is advocated for frail/elderly patients to minimize toxicity even though there have been no prospective studies to demonstrate whether lenalidomide dose attenuation impacts on response and survival outcome. This prospective multicentre phase II study assessed the efficacy and tolerability of lower dose lenalidomide (15 mg) and dexamethasone (20 mg) in 149 eligible patients with relapsed/refractory MM aged over 59 years and/or with renal impairment. The overall response rate was 71% (complete response 15%). Median (range) progression-free survival (PFS) and overall survival (OS) were 8·9 (6·9-11·5) and 30·5 (20·0-36·2) months, respectively. Upon formal statistical comparison of these endpoints to that of a matched cohort of patients from the pivotal phase III MM009/MM010 studies who received standard-dose lenalidomide (25 mg) and high-dose dexamethasone (40 mg) no difference was seen in PFS (P = 0·34) and OS (P = 0·21). Importantly, grade 3-4 toxicities were reduced with low-dose lenalidomide, mainly lower neutropenia (29% vs. 41%), infections (23% vs. 31%) and venous thromboembolism (3% vs. 13%). This study supports a strategy of lenalidomide dose reduction at the outset for at-risk patients, and prospectively confirms that such an approach reduces adverse events while not compromising patient response or survival outcomes.

Personality, health, and brain integrity: the Lothian birth cohort study 1936.

OBJECTIVE: To explore associations between the 5-factor model (FFM; neuroticism, extraversion, openness/intellect, agreeableness, and conscientiousness), personality traits, and measures of whole-brain integrity in a large sample of older people, and to test whether these associations are mediated by health-related behaviors. METHOD: Participants from the Lothian Birth Cohort 1936 completed the International Personality Item Pool measure, a 5-factor public-domain personality measure (http://ipip.ori.org), and underwent a structural magnetic resonance brain scan at the mean age of 73 years, yielding 3 measures of whole brain integrity: average white matter fractional anisotropy (FA), brain-tissue loss, and white matter hyperintensities (N = 529 to 565). Correlational and mediation analyses were used to test the potential mediating effects of health-related behaviors on the associations between personality and integrity. RESULTS: Lower conscientiousness was consistently associated with brain-tissue loss (ß = -0.11, p < 0.01), lower FA (ß = 0.16, p < 0.001) and white matter hyperintensities (ß = -0.10, p < 0.05). Smoking, alcohol consumption, diet, physical activity, body mass index and a composite health-behavior variable displayed significant associations with measures of brain integrity (range of r = 0.10 to 0.25). The direct effects of conscientiousness on brain integrity were mediated to some degree by health behaviors, with the proportions of explained direct effects ranging from 0.1% to 13.7%. CONCLUSION: Conscientiousness was associated with all 3 measures of brain integrity, which we tentatively interpret as the effects of personality on brain aging. Small proportions of the direct effects were mediated by individual health behaviors. RESULTS provide initial indications that lifetime stable personality traits may influence brain health in later life through health-promoting behaviors.

Incidental findings on brain MR imaging in older community-dwelling subjects are common but serious medical consequences are rare: a cohort study.

OBJECTIVES: Incidental findings in neuroimaging occur in 3% of volunteers. Most data come from young subjects. Data on their occurrence in older subjects and their medical, lifestyle and financial consequences are lacking. We determined the prevalence and medical consequences of incidental findings found in community-dwelling older subjects on brain magnetic resonance imaging. DESIGN: Prospective cohort observational study. SETTING: Single centre study with input from secondary care. PARTICIPANTS: Lothian Birth Cohort 1936, a study of cognitive ageing. MAIN OUTCOME MEASURES: Incidental findings identified by two consultant neuroradiologists on structural brain magnetic resonance imaging at age 73 years; resulting medical referrals and interventions. PRIMARY AND SECONDARY OUTCOME MEASURES: PREVALENCE OF INCIDENTAL FINDINGS BY INDIVIDUAL CATEGORIES: neoplasms, cysts, vascular lesions, developmental, ear, nose or throat anomalies, by intra- and extracranial location; visual rating of white matter hyperintensities and brain atrophy. RESULTS: There were 281 incidental findings in 223 (32%) of 700 subjects, including 14 intra- or extracranial neoplasms (2%), 15 intracranial vascular anomalies (2%), and 137 infarcts or haemorrhages (20%). Additionally, 153 had moderate/severe deep white matter hyperintensities (22%) and 176 had cerebral atrophy at, or above, the upper limit of normal (25%) compared with a normative population template. The incidental findings were unrelated to white matter hyperintensities or atrophy; about a third of subjects had both incidental findings and moderate or severe WMH and a quarter had incidental findings and atrophy. The incidental findings resulted in one urgent and nine non-urgent referrals for further medical assessment, but ultimately in no new treatments. CONCLUSIONS: In community-dwelling older subjects, incidental findings, including white matter hyperintensities and atrophy, were common. However, many findings were not of medical importance and, in this age group, most did not result in further assessment and none in change of treatment.

The association between retinal vessel morphology and retinal nerve fiber layer thickness in an elderly population.

BACKGROUND AND OBJECTIVE: To investigate the relationship between retinal vessel morphology (branching coefficient, bifurcation angle, and fractal analysis) and retinal nerve fiber layer (RNFL) thickness in an elderly population. PATIENTS AND METHODS: One hundred and one participants from the Lothian Birth Cohort 1936 (population of people all born in 1936) were studied. RNFL thickness measurements (using optical coherence tomography [OCT]) and digital retinal photographs were collected. The retinal images were analyzed using custom-designed software called the Vascular Assessment and Measurement Platform for Images of the Retina. RESULTS: Greater deviation from the optimal arteriolar branching coefficient was associated with greater RNFL thickness (r = 0.249, P = .028). There was no significant association between RNFL thickness and the other retinal vessel morphology parameters. CONCLUSION: RNFL thickness increased significantly with suboptimality of arteriole branching coefficient. These findings cannot be explained by our current understanding of OCT. OCT-based biomarker metrics require further study to better define retinal neurovascular imaging and anatomy.

Heavy-chain amyloidosis in TGFBI-negative and gelsolin-negative atypical lattice corneal dystrophy.

PURPOSE: An atypical case of late-onset lattice corneal dystrophy is described in a 61-year-old man without a family history of eye disease. Mutational analysis of the TGFBI gene excluded any pathogenic sequence variants. However, 2 years later, renal impairment and nephrotic syndrome were diagnosed, resulting in a diagnosis of systemic heavy-chain amyloidosis. METHODS: Slit-lamp examination, corneal photography, and in vivo confocal microscopy were performed. General systemic evaluation included blood and urine assessment, bone marrow and renal biopsies, and cardiologic evaluation. A DNA sample underwent initial mutational analysis of TGFBI and, subsequently, gelsolin. The renal biopsy sample was subject to direct protein sequencing by mass spectrometry. RESULTS: A bilateral, atypical, fine, midperipheral lattice corneal dystrophy with minor central subepithelial scarring was clinically characterized. Subsequently, abnormal renal functions with proteinuria, IgG lambda paraproteinemia, extensive deposition of amyloid in renal glomeruli, and increased plasma cells in bone marrow were identified. No pathogenic sequence mutations were identified in TGFBI or the gelsolin genes. Direct protein sequencing by mass spectrometry showed amyloid to be heavy-chain deposition rather than the more usual light-chain deposition. CONCLUSIONS: Atypical midperipheral lattice corneal dystrophy presenting with adult onset and negative family history should arouse suspicion for an association with paraproteinemias or amyloidosis. Exclusion of TGFBI mutations should alert the clinician to the possibility of potentially life-threatening conditions, with referral for careful systemic evaluation.

PROTHROMBINEX(®)-VF (PTX-VF) usage for reversal of coagulopathy: prospective evaluation of thrombogenic risk.

INTRODUCTION: Prothrombin complex concentrates (PCCs) are used for the urgent reversal of oral vitamin K antagonists in patients with life-threatening bleeding or prior to urgent procedures/surgery. PCCs offer rapid and complete reversal without the disadvantages of volume overload and adverse reactions seen with fresh frozen plasma (FFP). There is concern about the risk of thrombosis associated with the use PCCs; data on this is limited at present. OBJECTIVES: To determine the incidence of objectively confirmed arterial or venous thromboembolism within 30 days following the administration of PROTHROMBINEX®-VF (PTX-VF) to acutely reverse a prolonged INR. MATERIALS/METHODS: A prospective observational study was conducted at two teaching hospitals in Auckland, NZ. All patients who received PTX-VF for the acute reversal of prolonged INR were eligible. Baseline patient demographics and reasons for PTX-VF administration were recorded. Patients were reviewed at days 7 and 30, to confirm/exclude thromboembolism or adverse events. RESULTS: 173 patients were enrolled from August 2008 to March 2009. The most frequent indication for reversal was acute bleeding. At 30 days 4.6% (8/173) patients had a definite/probable thrombotic event, and 16.7% had died either due to the presenting bleed (intracranial haemorrhage) or a complication of their presenting complaint (e.g. sepsis, renal failure). CONCLUSIONS: Acute reversal of anticoagulant therapy with PTX-VF is associated with a significant rate of thromboembolism (4.6%) within 30 days. These events can be explained by ongoing cessation of anticoagulant therapy in patients with ongoing risk factors for arterial or venous thrombosis, rather than directly attributable to PTX-VF therapy.

Laparoscopic splenectomy and the treatment outcomes for idiopathic thrombocytopaenic purpura at North Shore Hospital.

AIM: Firstly, the demographics of laparoscopic splenectomy cases at North Shore Hospital (Takapuna, Auckland, New Zealand), the outcomes of operative technique, and perioperative complications by a single surgeon were reviewed. Secondly, analysis was performed on patients with idiopathic thrombocytopaenic purpura (ITP) with regard to platelet response and detection of preoperative predictors. METHODS: Laparoscopic splenectomy patients from 1998 to 2007 were reviewed with respect to demographics, operation and their complications. ITP outcomes, analysed separately, were categorised as complete remission for postsplenectomy platelet counts greater than 150 x 10(9)/L, partial remission as 30 - 149 x 10(9)/L and refractory as platelet counts less than 30 x 10(9)/L. The relationships between preoperative steroid, immunoglobulin transfusion and operative outcomes were analysed. RESULTS: 29 (67%) out of 43 laparoscopic splenectomies were for ITP. For ITP cases, 19 (65%) achieved complete remission and six (21%) partial remission at 3-month follow-up. Follow-up detected that two cases in each group had relapses after 3 months. Explorative data analysis suggested that a lack of preoperative transfusion may predict an approximately 80% chance of complete remission postsplenectomy. There was one conversion to an open splenectomy and no mortality with minimal complications. CONCLUSION: Cumulatively, in 86% of cases, laparoscopic splenectomy created a significant increase in platelet counts at 3-month postoperatively without any long-term morbidity. Although not strongly demonstrated, preoperative immunoglobulin transfusion may be correlated with remission.

AKT signaling within the ventral tegmental area regulates cellular and behavioral responses to stressful stimuli.

BACKGROUND: The neurobiological mechanisms by which only a minority of stress-exposed individuals develop psychiatric diseases remain largely unknown. Recent evidence suggests that dopaminergic neurons of the ventral tegmental area (VTA) play a key role in the manifestation of stress vulnerability. METHODS: Using a social defeat paradigm, we segregated susceptible mice (socially avoidant) from unsusceptible mice (socially interactive) and examined VTA punches for changes in neurotrophic signaling. Employing a series of viral vectors, we sought to causally implicate these neurotrophic changes in the development of avoidance behavior. RESULTS: Susceptibility to social defeat was associated with a significant reduction in levels of active/phosphorylated AKT (thymoma viral proto-oncogene) within the VTA, whereas chronic antidepressant treatment (in mice and humans) increased active AKT levels. This defeat-induced reduction in AKT activation in susceptible mice was both necessary and sufficient to recapitulate depressive behaviors associated with susceptibility. Pharmacologic reductions in AKT activity also significantly raised the firing frequency of VTA dopamine neurons, an important electrophysiologic hallmark of the susceptible phenotype. CONCLUSIONS: These studies highlight a crucial role for decreases in VTA AKT signaling as a key mediator of the maladaptive cellular and behavioral response to chronic stress.

Polycythaemia vera presenting as ST-elevation myocardial infarction.

A case of ST-elevation myocardial infarction as the first presentation of polycythaemia vera is described. The discussion summarises the evidence for the safety and efficacy of contemporary ST-elevation treatment strategies in the setting of polycythaemia vera.

Ovarian steroid hormones modulate circadian rhythms of neuroendocrine dopaminergic neuronal activity.

Dopamine (DA) is the primary inhibitor of prolactin (PRL) secretion. Three populations of neuroendocrine dopaminergic neurons (NDNs) designated tuberoinfundibular (TIDA), tuberohypophyseal (THDA) and periventricular hypophyseal DAergic (PHDA) neurons regulate PRL secretion. Given that ovarian steroids modulate both DA release and PRL secretion independently, we characterized the role of steroid hormones in coupling rhythmic NDN activity and PRL secretion. OVX rats under a standard 12:12 L:D cycle (L:D), constant dark (DD), or a 6-h phase-delayed L:D cycle (pdL:D) were treated with Estradiol-17beta (E) or E and Progesterone (E+P). NDN activity, defined by DA:DOPAC ratio in nerve terminals, was determined by HPLC-EC. E or E+P stimulated PRL surges in L:D that persisted under DD. In TIDA neurons, E or E+P treatment reduced the amount of DA released under L:D and DD and advanced the rhythm of DA turnover. E and E+P treatment reduced THDA and PHDA neuron activity under L:D, but did not affect these rhythms under DD. Circadian rhythms of PRL, corticosterone and DA turnover in NDN terminals from steroid treated rats entrained to a pdL:D cycle within 7 days. Therefore, ovarian steroids differentially adjust the timing and magnitude of NDN activity to facilitate coupling of DA release and PRL secretion.