Review: Recent advances in the understanding of the pathophysiology of neuromyelitis optica spectrum disorder.

Neuromyelitis optica is an autoimmune inflammatory disorder of the central nervous system that preferentially targets the spinal cord and optic nerve. Following the discovery of circulating antibodies against the astrocytic aquaporin 4 (AQP4) water channel protein, recent studies have expanded our knowledge of the unique complexities of the pathogenesis of neuromyelitis optica and its relationship with the immune response. This review describes and summarizes the recent advances in our understanding of the molecular mechanisms underlying neuromyelitis optica disease pathology and examines their potential as therapeutic targets. Additionally, we update the most recent research by proposing major unanswered questions regarding how peripheral AQP4 antibodies are produced and their entry into the central nervous system, the causes of AQP4-IgG-seronegative disease, why peripheral AQP4-expressing organs are spared from damage, and the impact of this disease on pregnancy.

The modified Memorial Symptom Assessment Scale Short Form: a modified response format and rational scoring rules.

PURPOSE: The Memorial Symptom Assessment Scale Short Form (MSAS-SF) is a widely used symptom assessment instrument. Patients who self-complete the MSAS-SF have difficulty following the two-part response format, resulting in incorrectly completed responses. We describe modifications to the response format to improve useability, and rational scoring rules for incorrectly completed items. METHODS: The modified MSAS-SF was completed by 311 women in our Peer and Nurse support Trial to Assist women in Gynaecological Oncology; the PeNTAGOn study. Descriptive statistics were used to summarise completion of the modified MSAS-SF, and provide symptom statistics before and after applying the rational scoring rules. Spearman's correlations with the Functional Assessment for Cancer Therapy-General (FACT-G) and Hospital Anxiety and Depression Scale (HADS) were assessed. RESULTS: Correct completion of the modified MSAS-SF items ranged from 91.5 to 98.7%. The rational scoring rules increased the percentage of useable responses on average 4% across all symptoms. MSAS-SF item statistics were similar with and without the scoring rules. The pattern of correlations with FACT-G and HADS was compatible with prior research. CONCLUSION: The modified MSAS-SF was useable for self-completion and responses demonstrated validity. The rational scoring rules can minimise loss of data from incorrectly completed responses. Further investigation is recommended.

Self-organizing actin patterns shape membrane architecture but not cell mechanics.

Cell-free studies have demonstrated how collective action of actin-associated proteins can organize actin filaments into dynamic patterns, such as vortices, asters and stars. Using complementary microscopic techniques, we here show evidence of such self-organization of the actin cortex in living HeLa cells. During cell adhesion, an active multistage process naturally leads to pattern transitions from actin vortices over stars into asters. This process is primarily driven by Arp2/3 complex nucleation, but not by myosin motors, which is in contrast to what has been theoretically predicted and observed in vitro. Concomitant measurements of mechanics and plasma membrane fluidity demonstrate that changes in actin patterning alter membrane architecture but occur functionally independent of macroscopic cortex elasticity. Consequently, tuning the activity of the Arp2/3 complex to alter filament assembly may thus be a mechanism allowing cells to adjust their membrane architecture without affecting their macroscopic mechanical properties.

Employment outcomes among survivors of common cancers: the Symptom Outcomes and Practice Patterns (SOAPP) study.

INTRODUCTION: Risk factors for employment difficulties after cancer diagnosis are incompletely understood, and interventions to improve post-cancer employment remain few. New targets for intervention are needed. METHODS: We assessed a cohort of 530 nonmetastatic cancer patients (aged ≤ 65 years, >6 months from diagnosis, off chemo- or radiotherapy) from the observational multi-site Symptom Outcomes and Practice Patterns study. Participants reported employment change, current employment, and symptoms. Groups were based on employment at survey (working full- or part-time versus not working) and whether there had been a change due to illness (yes versus no). The predictive power of symptom interference with work was evaluated for employment group (working stably versus no longer working). Race/ethnicity, gender, cancer type, therapy, and time since diagnosis were also assessed. Association between employment group and specific symptoms was examined. RESULTS: The cohort was largely non-Hispanic white (76 %), female (85 %), and diagnosed with breast cancer (75 %); 24 % reported a change in employment. On multivariable analysis, participants with at least moderate symptom interference were more likely to report no longer working than their less effected counterparts (odds ratio (OR) = 8.0, 95 % CI, 4.2-15.4), as were minority participants compared with their non-Hispanic white counterparts (OR = 3.2, 95 % CI, 1.8-5.6). Results from the multiple regression model indicated the combination of fatigue (OR = 2.3, 95 % CI, 1.1-4.7), distress (OR = 3.9, 95 % CI, 1.7-9.0), and dry mouth (OR = 2.6, 95 % CI, 1.1-6.2) together with race/ethnicity and time since diagnosis adequately accounted for employment group. CONCLUSIONS: Our findings support the hypothesis that residual symptom burden is related to post-cancer employment: Residual symptoms may be targets for intervention to improve work outcomes among cancer survivors. IMPLICATIONS FOR CANCER SURVIVORS: This analysis examines whether increased symptom burden is associated with a change to not working following a cancer diagnosis. We also examined individual symptoms to assess which symptoms were most strongly associated with not working after a cancer diagnosis. Our hope is that we will be able to use this information to both screen survivors post-active treatment as well as target high-risk symptoms for further and more aggressive intervention, in an attempt to improve post-cancer work outcomes.

A retrospective analysis of cardiovascular morbidity in metastatic hormone-refractory prostate cancer patients on high doses of the selective COX-2 inhibitor celecoxib.

This data were previously presented in February 2007 at the American Society of Clinical Oncology's Prostate Cancer Symposium in Orlando, FL, USA. COX-2 inhibition has shown promise in treating prostate cancer, but concerns exist regarding the risk profile associated with this class of drugs. This study analyzes the cardiovascular and cerebral vascular morbidity associated with high doses of the COX-2 inhibitor, celecoxib, in patients with metastatic hormone-refractory prostate cancer (mHRPC). We retrospectively reviewed 67 patients with mHRPC who were treated at our institution between 1999 and 2005. All charts were reviewed for cardiac risk factors and the clinical course whilst on therapy and post-treatment was analyzed. This study included 34 patients who were on protocols that involved celecoxib 400 mg b.i.d.. Treatment ranged from 21 to 355 days, with a median of 118.5 days. There were three myocardial infarctions (MIs)--two in the study group and one in the control group. One patient had a MI while on treatment, but he had a significant cardiac disease history. There were also two cerebral vascular accidents (CVAs) in each group, although none in any patient who was on-study. Although this is a small study, these findings, in the context of other published data, suggest that some patients with advanced malignancies may still benefit from therapies involving COX-2 inhibitors without clinically significant increase in risk for MI or CVA.

Eukaryotic expression: developments for structural proteomics.

The production of sufficient quantities of protein is an essential prelude to a structure determination, but for many viral and human proteins this cannot be achieved using prokaryotic expression systems. Groups in the Structural Proteomics In Europe (SPINE) consortium have developed and implemented high-throughput (HTP) methodologies for cloning, expression screening and protein production in eukaryotic systems. Studies focused on three systems: yeast (Pichia pastoris and Saccharomyces cerevisiae), baculovirus-infected insect cells and transient expression in mammalian cells. Suitable vectors for HTP cloning are described and results from their use in expression screening and protein-production pipelines are reported. Strategies for co-expression, selenomethionine labelling (in all three eukaryotic systems) and control of glycosylation (for secreted proteins in mammalian cells) are assessed.

Substance p-fibronectin-cytokine interactions in myeloproliferative disorders with bone marrow fibrosis.

Bone marrow (BM) fibrosis could occur secondarily to several clinical disorders: hematological and nonhematological. Clinical presentation of fibrosis could occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome and myeloma. The pathophysiology underlying BM fibrosis remains unclear despite intensive study, with a corresponding lack of specific therapy. This review discusses new insights in the role of substance P, cytokines and fibronectin in the development of BM fibrosis. Substance P is a neuropeptide that possesses pleiotropic properties, e.g. neurotransmission and immune/hematopoietic modulation and is linked to BM fibrosis. Cytokines and growth factors, in particular those associated with fibrogenic properties, e.g. TGF-beta, IL-1 and platelet-derived growth factor, are linked to BM fibrosis. Extracellular matrix proteins are increased in patients with BM fibrosis. Fibronectin in the sera of patients with BM fibrosis is complexed to substance P. Fibronectin appears to protect substance P from degradation by endogenous peptidases. This review describes the preliminary findings on the colocalization of substance P and fibronectin in the BM of patients with fibrosis. These data are reviewed in the context of published reports with particular focus on the relevant cytokines. A more detailed understanding of intra- and intercellular mechanisms in BM fibrosis may lead to effective therapy.

Video-assisted thoracoscopic sympathectomy-splanchnicectomy for pancreatic cancer pain.

Patients with unresectable pancreatic cancer often suffer severe pain. Various techniques are available for pain control. We present a patient with pancreatic cancer who underwent unilateral video-assisted thoracoscopic sympathectomy-splanchnicectomy and had complete pain relief. This minimally invasive procedure offers promise in carefully selected patients with severe pain from pancreatic cancer and other conditions which are not amenable to conventional interventions.

Mimicry between neurokinin-1 and fibronectin may explain the transport and stability of increased substance P immunoreactivity in patients with bone marrow fibrosis.

Bone marrow (BM) fibrosis may occur in myeloproliferative diseases, lymphoma, myelodysplastic syndrome, myeloma, and infectious diseases. In this study, the role of substance P (SP), a peptide with pleiotropic functions, was examined. Some of its functions-angiogenesis, fibroblast proliferation, and stimulation of BM progenitors-are amenable to inducing BM fibrosis. Indeed, a significant increase was found in SP-immunoreactivity (SP-IR) in the sera of patients with BM fibrosis (n = 44) compared with the sera of patients with hematologic disorders and no histologic evidence of fibrosis (n = 46) (140 +/-12 vs 18 +/-3; P <.01). Immunoprecipitation of sera SP indicated that this peptide exists in the form of a complex with other molecule(s). It was, therefore, hypothesized that SP might be complexed with NK-1, its natural receptor, or with a molecule homologous to NK-1. To address this, 3 cDNA libraries were screened that were constructed from pooled BM stroma or mononuclear cells with an NK-1 cDNA probe. A partial clone (clone 1) was retrieved that was 97% homologous to the ED-A region of fibronectin (FN). Furthermore, sequence analyses indicated that clone 1 shared significant homology with exon 5 of NK-1. Immunoprecipitation and Western blot analysis indicated co-migration of SP and FN in 27 of 31 patients with BM fibrosis. Computer-assisted molecular modeling suggested that similar secondary structural features between FN and NK-1 and the relative electrostatic charge might explain a complex formed between FN (negative) and SP (positive). This study suggests that SP may be implicated in the pathophysiology of myelofibrosis, though its role would have to be substantiated in future research. (Blood. 2001;97:3025-3031)

The role of physical proximity in nosocomial diarrhea.

To examine physical proximity as a risk factor for the nosocomial acquisition of Clostridium difficile-associated diarrhea (CDAD) and of antibiotic-associated diarrhea (AAD), we assessed a retrospective cohort of 2859 patients admitted to a community hospital from 1 March 1987 through 31 August 1987. Of these patients, 68 had nosocomial CDAD and 54 had nosocomial AAD. In multivariate analysis, physical proximity to a patient with CDAD (relative risk [RR], 1.86; 95% confidence interval [CI], 1.06-3.28), exposure to clindamycin (RR, 4.22; 95% CI, 2.11-8.45), and the number of antibiotics taken (RR, 1.49; 95% CI, 1.23-1.81) were significant. For patients with nosocomial AAD, exposure to a roommate with AAD (RR, 3.94; 95% CI, 1. 27-12.24), a stay in an intensive care unit or cardiac care unit (RR, 1.93; 95% CI, 1.05-3.53), and the number of antibiotics taken (RR, 2.01; 95% CI, 1.67-2.40) were significant risk factors. Physical proximity may be an independent risk factor for acquisition of nosocomial CDAD and AAD.

The memorial symptom assessment scale short form (MSAS-SF).

BACKGROUND: The Memorial Symptom Assessment Scale Short Form (MSAS-SF), an abbreviated version of the Memorial Symptom Assessment Scale, measures each of 32 symptoms with respect to distress or frequency alone. A physical symptom subscale (PHYS), psychologic symptom subscale (PSYCH), and global distress index (GDI) can be derived from the Short Form. We validated the MSAS-SF in a population of cancer patients. METHODS: Two hundred ninety-nine cancer patients examined at the Section of Hematology/Oncology completed the MSAS-SF and the Functional Assessment Cancer Therapy (FACT-G). The Karnofsky performance status (KPS), extent of disease (EOD), and demographic data were assessed. The Cronbach alpha coefficient was used to assess internal reliability. MSAS-SF subscales were assessed against subscales of the FACT-G, the KPS, and EOD to determine criterion validity. Test-retest analysis was performed at 1 day and at 1 week. RESULTS: The Cronbach alpha coefficients for the MSAS-SF subscales ranged from 0.76 to 0.87. The MSAS-SF subscales showed convergent validity with FACT subscales. Correlation coefficients were -0.74 (P < 0.001) for the PHYS and FACT-G physical well-being subscales, -0.68 (P < 0.001) for the PSYCH and FACT emotional well-being subscales, and -0.70 (P < 0.001) for GDI and FACT summary of quality-of-life subscales. The MSAS-SF subscales demonstrated convergent validity with performance status, inpatient status, and extent of disease. The test-retest correlation coefficients for the MSAS-SF subscales ranged from 0.86 to 0.94 at 1 day and from 0.40 to 0.84 for the 1 week group. CONCLUSIONS: The MSAS-SF is a valid and easy to use instrument for symptom assessment.

Validation of the Edmonton Symptom Assessment Scale.

BACKGROUND: The Edmonton Symptom Assessment Scale (ESAS) is a nine-item patient-rated symptom visual analogue scale developed for use in assessing the symptoms of patients receiving palliative care. The purpose of this study was to validate the ESAS in a different population of patients. METHODS: In this prospective study, 240 patients with a diagnosis of cancer completed the ESAS, the Memorial Symptom Assessment Scale (MSAS), and the Functional Assessment Cancer Therapy (FACT) survey, and also had their Karnofsky performance status (KPS) assessed. An additional 42 patients participated in a test-retest study. RESULTS: The ESAS "distress" score correlated most closely with physical symptom subscales in the FACT and the MSAS and with KPS. The ESAS individual item and summary scores showed good internal consistency and correlated appropriately with corresponding measures from the FACT and MSAS instruments. Individual items between the instruments correlated well. Pain ratings in the ESAS, MSAS, and FACT correlated best with the "worst-pain" item of the Brief Pain Inventory (BPI). Test-retest evaluation showed very good correlation at 2 days and a somewhat smaller but significant correlation at 1 week. A 30-mm visual analogue scale cutoff point did not uniformly distinguish severity of symptoms for different symptoms. CONCLUSIONS: For this population, the ESAS was a valid instrument; test-retest validity was better at 2 days than at 1 week. The ESAS "distress" score tends to reflect physical well-being. The use of a 30-mm cutoff point on visual analogue scales to identify severe symptoms may not always apply to symptoms other than pain.

Symptom and quality of life survey of medical oncology patients at a veterans affairs medical center: a role for symptom assessment.

BACKGROUND: The current study was conducted to assess symptom prevalence and symptom intensity and their relation to quality of life in medical oncology patients at a Veterans Affairs medical center. METHODS: Consecutive inpatients and outpatients were asked to complete the Functional Assessment Cancer Therapy (FACT-G), Memorial Symptom Assessment Scale (MSAS), and the Brief Pain Inventory. Symptoms then were analyzed by their relation to Karnofsky performance status (KPS) and quality of life. RESULTS: Two hundred forty patients participated. The median number of symptoms was 8 per patient (range, 0-30 symptoms). The 5 most prevalent symptoms were lack of energy (62%), pain (59%), dry mouth (54%), shortness of breath (50%), and difficulty sleeping (45%). Patients with moderate intensity pain had a median number of 11 symptoms and patients with moderate intensity lack of energy had a median number of 13 symptoms. The number of intense symptoms increased as the KPS decreased (P < 0.001). Patients with moderately intense pain or fatigue also were more likely to experience nausea, dyspnea, and lack of appetite. The number of symptoms rated as present on the MSAS was found to correlate significantly with the FACT-G Sum Quality of Life score. CONCLUSIONS: Intense symptoms were highly prevalent in this population. The presence of pain, lack of energy, or poor performance status should lead to comprehensive symptom assessment. Patients free of disease nevertheless still may experience intense symptoms. The number of symptoms present may be a helpful guide to quality of life. Routine comprehensive symptom assessment may identify a significant fraction of patients who urgently require intensive symptom palliation.

Systemic transforming growth factor-beta in patients with bone marrow fibrosis--pathophysiological implications.

Idiopathic myelofibrosis (IMF) and secondary myelofibrosis (MF) are characterized by bone marrow (BM) fibrosis, neoangiogenesis, and increased extracellular matrix (ECM) proteins. These characteristics may be partially attributed to transforming growth factor beta (TGF-beta), a cytokine produced by monocytes. In myelofibrosis, monocytes are increased and activated with concomitant up-regulation of intracytoplasmic TGF-beta. We have therefore determined systemic TGF-beta in patients with either BM fibrosis: IMF, n = 18; MF, n = 16; or without BM fibrosis: hematologic disorders with normal platelets (n = 31); high platelets (n = 9); or normal controls (n = 27). Compared with nonfibrosis sera, there was significant TGF-beta elevation in BM fibrosis sera (P < 0.0001). Most (>80%) of the TGF-beta is active and belongs to the-beta1 isoform. In situ hybridization and immunohistochemical analyses in BM biopsy sections showed a marked increase in TGF-beta1 only in patients with fibrosis. Moreover, TGF-beta protein was detected mainly in myelomonocytic-like predominant areas. To determine if another functionally similar cytokine, basic fibroblast growth factor (bFGF), may be important to BM fibrosis, we quantitated sera levels and found elevation in 57% compared with 100% elevation for TGF-beta. The data indicate that irrespective of etiology, systemic TGF-beta is elevated in patients with BM fibrosis. TGF-beta likely plays an important role in the development of BM fibrosis. The study also provides a significant parameter for early therapeutic intervention in BM fibrosis.

Quality of life and survival: the role of multidimensional symptom assessment.

BACKGROUND: Recent data from clinical trials suggest that quality-of-life (QOL) measurements may independently predict survival. The relation between survival and QOL measurements was tested among 122 inpatients and 96 outpatients with malignancies at one of four sites (colon, breast, ovary, or prostate) who participated in a cross-sectional validation study of the Memorial Symptom Assessment Scale (MSAS), a measure of the frequency of, severity of, and distress caused by physical symptoms. METHODS: The relation between MSAS summary scores and survival was evaluated in a multivariate analysis that adjusted concurrently for other important covariates, such as age, site and extent of disease, inpatient status, Karnofsky performance status (KPS), and other QOL measurements. RESULTS: In the multivariate analysis, extent of disease (P < 0.0001), inpatient status (P=0.014), higher MSAS physical symptom subscale score (P=0.004), and lower KPS score (P=0.009) independently predicted decreased survival. Other QOL measurements did not contribute significantly to the model. CONCLUSIONS: The MSAS physical symptom subscale score significantly predicts survival and adds to the prognostic information provided by KPS and extent of disease. Patients may be under-assessed regarding both the number and the severity of symptoms. Measurements of physical symptoms and related distress offer additional prognostic information concerning the survival of patients with cancer and may account for the predictive value of QOL scores.

Increased phantom limb pain as an initial symptom of spinal-neoplasia.

Phantom limb pain is a common sequela of amputation. Studies suggest that over time, there is a decrease in frequency and intensity of phantom pain. Persistently increased phantom pain has been seen in benign lesions affecting the peripheral and central nervous system. We present a 74-year-old woman who had a left above-knee amputation for leiomyosarcoma of the foot 24 years previously. She had been free of disease and ambulated independently until 1 month before hospitalization, when she noted increasing pain in her phantom foot. At the time of admission, she had developed increasing low back pain and was diagnosed with adenocarcinoma of unknown primary. Work-up confirmed involvement of the L4 vertebral body with epidural and paraspinal disease. We believe this is the first reported case of worsening phantom limb pain resulting from a spinal metastasis. We review the literature on the potential implications of increased phantom pain.

Intravenous phenytoin in the management of crescendo pelvic cancer-related pain.

Rapidly progressive pain, or "crescendo" pain, can be a difficult management problem. A cancer patient is presented who experienced crescendo neuropathic pain due to progressive pelvic disease. This patient reported significant pain relief with the administration of intravenous phenytoin. The case illustrates the type of therapeutic approach that may be considered for crescendo pain and highlights a potential role for intravenous phenytoin in the management of patients with crescendo cancer-related neuropathic pain.