An updated review of anti-Ro52 (TRIM21) antibodies impact in connective tissue diseases clinical management.

Anti-Ro52 (or anti-TRIM21) antibodies are part of the family of anti-Ro/SSA antibodies, historically markers of Sjögren syndrome and systemic lupus erythematosus. Anti-Ro52 antibodies represent one the most frequently encountered autoantibodies in patients with connective tissue disease (primary Sjögren syndrome, systemic lupus erythematosus, systemic sclerosis and idiopathic inflammatory myopathies). Because of their lack of specificity and detection in patients with non-autoimmune disorders, the usefulness of anti-Ro52 testing in connective tissue diseases is still matter of debate among clinicians and immunologists. Autoantibodies are mainly diagnostic markers for autoimmune diseases but some of them can also be directly involved in the generation of tissue damage. Over the past decade several authors reported associations of anti-Ro52 antibodies with some clinical features - especially interstitial lung disease - and survival in patients with connective tissue diseases. There is also a growing evidence of the role of anti-Ro52 antibodies in the pathogenesis of connective tissue diseases. In this review, we comprehensively discuss the clinical associations of anti-Ro52 antibodies in the different connective tissue diseases and the recent advances on their potential role in the inflammatory response.

[A POEMS syndrome revealed by a blue toe syndrome]. / Un syndrome POEMS révélé par un syndrome des orteils bleus.

INTRODUCTION: Arterial and venous thromboses occur in almost one in five patients with POEMS syndrome and usually in macrocirculation. CASE REPORT: We report a 67-year-old male with a POEMS syndrome who presented initially with a blue toe syndrome. He complained of Raynaud's syndrome and left foot paresthesia. Physical examination showed gynecomastia, lymphadenopathies and skin lesions. Cardiovascular investigations excluded atrial fibrillation, unstable atherosclerotic lesions and vascular calcifications. Imaging studies showed diffuse osteosclerotic lesions. Monoclonal protein with lambda light chain was discovered and serum level of VEGF was increased at 2900pg/ml. CONCLUSION: This is to our knowledge the first case of thrombotic microangiopathy in POEMS syndrome without embolic cause or calciphylaxis.

Circulating cellular adhesion molecules and risk of diabetes: the Multi-Ethnic Study of Atherosclerosis (MESA).

AIMS: To test the hypothesis that soluble cellular adhesion molecules would be positively and independently associated with risk of diabetes. METHODS: Soluble levels of six cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1, E-cadherin, L-selectin and P-selectin) were measured in participants in the Multi-Ethnic Study of Atherosclerosis, a prospective cohort study. Participants were then followed for up to 10 years to ascertain incident diabetes. RESULTS: Sample sizes ranged from 826 to 2185. After adjusting for age, sex, race/ethnicity, BMI and fasting glucose or HbA1c , four cellular adhesion molecules (ICAM-1, E-selectin, VCAM-1 and E-cadherin) were positively associated with incident diabetes and there was a statistically significant trend across quartiles. Comparing the incidence of diabetes in the highest and lowest quartiles of each cellular adhesion molecule, the magnitude of association was largest for E-selectin (hazard ratio 2.49; 95% CI 1.26-4.93) and ICAM-1 (hazard ratio 1.76; 95% CI 1.22-2.55) in fully adjusted models. Tests of effect modification by racial/ethnic group and sex were not statistically significant for any of the cellular adhesion molecules (P > 0.05). CONCLUSIONS: The finding of significant associations between multiple cellular adhesion molecules and incident diabetes may lend further support to the hypothesis that microvascular endothelial dysfunction contributes to risk of diabetes.

Accuracy of self-reported tobacco use status among hematopoietic SCT patients.

Tobacco use is a risk factor for adverse outcomes among hematopoietic SCT (HSCT) patients. Accurate identification of tobacco use offers a vital opportunity to treat this risk factor. The current study compared self-reported tobacco use status with serum cotinine levels among HSCT patients at the time of pre-transplant evaluation. A total of 444 participants completed both assessments; 44 participants (9.9%) were classified as tobacco users with serum cotinine concentrations >2 ng/mL vs 29 with self-reporting. Sensitivity and specificity of self-reporting were 65.9% and 100%, respectively. Positive and negative predictive values were 100% and 96.4%, respectively. Comparing tobacco use documented in the medical record with cotinine, sensitivity and specificity were 51.2% and 99.2%, respectively. Factors associated with tobacco use were male gender, single relationship status, less education and younger age. In summary, utilization of serum cotinine assays increased detection of tobacco use cases >50% over self-reporting. Results are discussed in the context of translation to care, including clinical and ethical implications, and current tobacco use treatment guidelines. When cotinine assays are not available, self-reporting of any tobacco use in the year before HSCT should trigger brief advice and cessation or relapse prevention counseling.

Interleukin-6 receptor blockade enhances CD39+ regulatory T cell development in rheumatoid arthritis and in experimental arthritis.

OBJECTIVE: The rationale for blocking interleukin-6 (IL-6) in rheumatoid arthritis (RA) lies chiefly in the proinflammatory effect of this cytokine. Few studies have evaluated the consequences of anti-IL-6 receptor (IL-6R) antibody treatment on Treg cells. This study was undertaken to elucidate the mechanism of action of anti-IL-6R antibody treatment by studying the effects on Treg cells in an experimental arthritis model and in patients with RA. METHODS: Mice with collagen-induced arthritis (CIA) were treated with a mouse anti-IL-6R antibody (MR16-1), and changes in Treg, Th1, and Th17 cells were assessed at key time points during the course of the disease. Peripheral blood from 15 RA patients was collected on day 0 and after 3 months of tocilizumab treatment for flow cytometry analysis of Th17 and Treg cells. RESULTS: In MR16-1-treated mice, Th17 cell frequencies were unchanged, whereas Treg cell frequencies were increased. The Treg cell phenotype showed marked changes, with an increase in the frequency of CD39+ Treg cells in the lymph nodes and spleen. Interestingly, similar CD39+ Treg cell expansion was observed in RA patients who were tocilizumab responders at 3 months, with no change in Th17 cell frequency. Moreover, fluorescence-activated cell-sorted CD39+ Treg cells from responder RA patients were functionally able to suppress the proliferation of conventional T cells. CONCLUSION: In both CIA and RA, the frequency of functionally suppressive CD39+ Treg cells is increased as a result of anti-IL-6R treatment, whereas Th17 cells are unaffected. The modification of Treg cell frequency and phenotype may be one of the mechanisms involved in the therapeutic effect of IL-6 blockade in RA.

Phase II study of neoadjuvant therapy with docetaxel, cisplatin, panitumumab, and radiation therapy followed by surgery in patients with locally advanced adenocarcinoma of the distal esophagus (ACOSOG Z4051).

BACKGROUND: Preoperative chemoradiotherapy (CRT) improves outcomes in patients with locally advanced but resectable adenocarcinoma of the esophagus. ACOSOG Z4051 evaluated CRT with docetaxel, cisplatin, and panitumumab (DCP) in this patient group with a primary end point of a pathologic complete response (pCR) ≥35%. PATIENTS AND METHODS: From 15 January 2009 to 22 July 2011, 70 patients with locally advanced but resectable distal esophageal adenocarcinoma were enrolled. Patients received docetaxel (40 mg/m(2)), cisplatin (40 mg/m(2)), and panitumumab (6 mg/kg) on weeks 1, 3, 5, 7, and 9 with RT (5040 cGy, 180 cGy/day × 28 days) beginning week 5. Resection was planned after completing CRT. PCR was defined as no viable residual tumor cells. Secondary objectives included near-pCR (≤10% viable cancer cells), toxicity, and overall and disease-free survival. Adverse events were graded using the CTCAE Version 3.0. RESULTS: Five of 70 patients were ineligible. Of 65 eligible patients (59 M; median age 61), 11 did not undergo surgery, leaving 54 assessable. PCR rate was 33.3% and near-pCR was 20.4%. Secenty-three percent of patients completed DCP (n = 70) and 92% completed RT. 48.5% had toxicity ≥grade 4. Lymphopenia (43%) was most common. Operative mortality was 3.7%. Adult respiratory distress syndrome was encountered in two patients (3.7%). At median follow-up of 26.3 months, median overall survival was 19.4 months and 3-year overall survival was 38.6% (95% confidence interval 24.5% to 60.8%). CONCLUSIONS: Neoadjuvant CRT with DCP is active (pCR + near-pCR = 53.7%) but toxicity is significant. Further evaluation of this regimen in an unselected population is not recommended. CLINICALTRIALSGOV IDENTIFIER: NCT00757172.

The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice.

BACKGROUND: IPF is a common form of interstitial lung disease for which there is no effective therapy and usually results in death. Two previous contradictory studies showed anticoagulant therapy  to be associated with both improved and worsened survival, respectively. OBJECTIVE: The objective of this retrospective cohort study was to evaluate the effect of anticoagulant therapy on the survival and disease progression of patients with idiopathic pulmonary fibrosis (IPF) in real clinical practice. METHODS: We compared the clinical characteristics, time to disease progression, incidence of acute exacerbation, and survival of 25 (20%) IPF patients receiving anticoagulant therapy to the remaining 97 IPF patients not receiving anticoagulant therapy. In addition we conducted a sensitivity analysis using as comparator a group of 25 patients matched by age, sex, functional impairment, cardiac comorbidities and pulmonary hypertension. RESULTS: Patients on anticoagulant therapy had a worse 1- and 3-year survival (84% and 53% versus 89% and 64% in the non-anticoagulant group, respectively), a difference that persisted after adjusting for age and comorbidities (hazard ratio 3.1 - 95% confidence interval, 1.4 to 7.0; p=0.006) and after comparison with the matched group (adjusted HR=4.8, 95% CI: 1.8-12.8; p=0.002). IPF patients on anticoagulant therapy had a shorter interval to disease progression ( 0.7 years versus 1.6 years, adjusted HR 2.2 -95% CI, 0.96 to 5.1; p=0.063) confirmed also in the analysis with matched subgroups (HR=2.7 (95% CI: 1.2-6.5); p=0.023). The incidence of acute exacerbations did not differ in the two groups (22% versus 23%). Two patients (8%) experienced anticoagulant treatment related complications and included an episode of hemorrhagic shock. CONCLUSION: In this retrospective study patients treated with anticoagulants had a worse survival and a shorter interval to disease progression. This support the recent finding that warfarin worsen the respiratory status and survival of IPF patients.

Preventing progression to first-episode psychosis in early initial prodromal states.

BACKGROUND: Young people with self-experienced cognitive thought and perception deficits (basic symptoms) may present with an early initial prodromal state (EIPS) of psychosis in which most of the disability and neurobiological deficits of schizophrenia have not yet occurred. AIMS: To investigate the effects of an integrated psychological intervention (IPI), combining individual cognitive-behavioural therapy, group skills training, cognitive remediation and multifamily psychoeducation, on the prevention of psychosis in the EIPS. METHOD: A randomised controlled, multicentre, parallel group trial of 12 months of IPI v. supportive counselling (trial registration number: NCT00204087). Primary outcome was progression to psychosis at 12- and 24-month follow-up. RESULTS: A total of 128 help-seeking out-patients in an EIPS were randomised. Integrated psychological intervention was superior to supportive counselling in preventing progression to psychosis at 12-month follow-up (3.2% v. 16.9%; P = 0.008) and at 24-month follow-up (6.3% v. 20.0%; P = 0.019). CONCLUSIONS: Integrated psychological intervention appears effective in delaying the onset of psychosis over a 24-month time period in people in an EIPS.

Transformation of low grade glioma and correlation with outcome: an NCCTG database analysis.

Glioblastomas (GBM) may originate de novo (primary), or following transformation from a lower grade glioma (secondary), and it has been postulated that these tumors may have different biological behaviors. We performed a correlative analysis involving 204 patients with glioma treated prospectively on NCCTG clinical trials. Central pathology review of tumor tissues taken at the time of initial diagnosis and at recurrence were performed in all patients. Tumors progressed from low (WHO grade 2) to high (grade 3-4) at recurrence in 45% low grade oligodendroglioma patients, in 70% with low grade oligoastrocytoma, and 74% with low grade astrocytoma (P = 0.031). Median overall survival (OS) from initial diagnosis varied by histology: oligodendroglioma, 8.8 years; (95% CI 5.7-10.2); oligoastrocytoma, 4.4 years (95% CI 3.5-5.6); astrocytoma grade 2 3.1 years (astrocytoma grade 2-4, 2.1 years) (95% CI 1.7-2.5, P < 0.001). Mean time to recurrence (TTR) also varied between patients with de novo GBM, those secondary GBM, and those that remained non-GBM at recurrence (1.1 ± 1.1 vs. 2.9 ± 1.8 vs. 4.0 ± 2.9 years, respectively, P < 0.001). Median OS from time of recurrence also varied between these three categories (0.7 years, 95% CI: 0.5-1.1 vs. 0.6 years, CI: 0.5-1.0 vs. 1.4 years, 95% CI: 1.1-2.0, respectively) (P < 0.001). At time of relapse, transformation to higher grade is frequent in low grade pure and mixed astrocytomas, but is observed in less than half of those with low grade oligodendroglioma. From time of recurrence, OS was not significantly different for those with primary versus secondary GBM, and it may thus be reasonable include patients with secondary GBM in clinical therapeutic trials for recurrent disease.

The impact of smoking on outcomes among patients undergoing hematopoietic SCT for the treatment of acute leukemia.

A paucity of research exists examining the potential impact of tobacco use on cancer treatment outcomes, especially among patients treated with hematopoietic SCT (HSCT). A retrospective cohort study design was used to examine the impact of smoking on duration of hospitalization and overall survival among 148 consecutive patients undergoing HSCT for treatment of acute leukemia from 1999 to 2005. Of the 148 patients, 15% reported current smoking, 30% former smoking, and 55% never used tobacco. Patients were followed for a median 3.5 years (interquartile range=2.1-5.5). Compared to no history of smoking, current smoking was associated with worse pre-HSCT pulmonary function tests (P<0.02 in each case), more days hospitalization (46.2 days versus 25.7 days, P=0.025), and poorer overall survival (hazard ratio (HR)=1.88; 95% CI 1.09-3.25). Results were similar after multivariate adjustment, although the association with overall survival attenuated slightly (HR=1.75; 95% CI 1.00-3.06). Current smoking appears to adversely affect the number of days hospitalized post HSCT and overall survival. Translational research focused on interventions to promote tobacco cessation may lead to improved HSCT outcomes.

Multicenter phase II trial of adjuvant therapy for resected pancreatic cancer using cisplatin, 5-fluorouracil, and interferon-alfa-2b-based chemoradiation: ACOSOG Trial Z05031.

BACKGROUND: The American College of Surgeons Oncology Group sought to confirm the efficacy of a novel interferon-based chemoradiation regimen in a multicenter phase II trial. PATIENTS AND METHODS: Patients with resected (R0/R1) adenocarcinoma of the pancreatic head were treated with adjuvant interferon-alfa-2b (3 million units s.c. on days 1, 3, and 5 of each week for 5.5 weeks), cisplatin (30 mg/m(2) i.v. weekly for 6 weeks), and continuous infusion 5-fluorouracil (5-FU; 175 mg·m(2)/day for 38 days) concurrently with external-beam radiation (50.4 Gy). Chemoradiation was followed by two 6-week courses of continuous infusion 5-FU (200 mg·m(2)/day). The primary study end point was 18-month overall survival from protocol enrollment (OS18); an OS18 ≥65% was considered a positive study outcome. RESULTS: Eighty-nine patients were enrolled. Eighty-four patients were assessable for toxicity. The all-cause grade ≥3 toxicity rate was 95% (80 patients) during therapy. No long-term toxicity or toxicity-related deaths were noted. At 36-month median follow-up, the OS18 was 69% [95% confidence interval (CI) 60% to 80%]; the median disease-free survival and overall survival were 14.1 months (95% CI 11.0-20.1 months) and 25.4 months (95% CI 23.4-34.1 months), respectively. CONCLUSIONS: Notwithstanding promising multi-institutional efficacy results, further development of this regimen will require additional modifications to mitigate toxic effects.

Antineuronal antibodies in sporadic late-onset cerebellar ataxia.

Sporadic late-onset cerebellar ataxia of unknown cause is considered a neurodegenerative disorder whose underlying mechanisms are still unknown. To identify antineuronal autoantibodies, immunohistochemical and immunoblotting techniques were performed in 67 patients with sporadic cerebellar degeneration of unknown cause. Elevated P/Q-type voltage-gated calcium channel (VGCC)-specific antibodies were found in eight patients (11.9%). There was no hint of a paraneoplastic disorder in any of the patients. The present findings suggest an autoimmune contribution to the pathophysiology of a subgroup of sporadic late-onset cerebellar ataxia.

Haemosiderin-laden macrophages in the bronchoalveolar lavage fluid of patients with diffuse alveolar damage.

Quantification of haemosiderin-laden macrophages in bronchoalveolar lavage fluid (BALF) has been used to diagnose diffuse alveolar haemorrhage (DAH) but has not been assessed in patients with diffuse alveolar damage (DAD). The present study analysed BALF obtained from 21 patients with DAD diagnosed by surgical lung biopsy. The median age of 21 patients with DAD was 68 yrs (range 18-79 yrs); 14 (67%) were male and 12 (57%) were immunocompromised. The median proportion of haemosiderin-laden macrophages in BALF was 5% (range 0-90%), but was >or=20% in seven (33%) patients, fulfilling the commonly used BALF criterion for DAH. There was a trend toward a positive correlation between the percentage of haemosiderin-laden macrophages in BALF and parenchymal haemorrhage assessed semiquantitatively by histopathological analysis. Patients with >or=20% haemosiderin-laden macrophages in BALF showed a significantly increased mortality rate (p = 0.047) compared to those with <20%. In patients with an acute onset of diffuse lung infiltrates and respiratory distress, >or=20% haemosiderin-laden macrophages in BALF can occur with DAD, and is not necessarily diagnostic of DAH. The finding of >or=20% haemosiderin-laden macrophages in BALF is associated with a worse prognosis in patients with DAD.

Structural brain alterations in subjects at high-risk of psychosis: a voxel-based morphometric study.

Forty Untreated high-risk (HR) individuals for psychosis and 75 healthy control subjects (HC) matched for age, gender, handedness and educational level were investigated by structural MRI. HR subjects were recruited at the Early Detection and Intervention Centre for Mental Crises (FETZ) of the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Germany. Measurements of gray matter volumes were performed by voxel-based morphometry using SPM5. The sample of HR subjects showed GM volume reductions in frontal, lateral temporal and medial temporal regions compared to the healthy control group. These regions are compatible with structural findings in the clinically apparent disease of schizophrenia.

[Port stapling for simplified port implantation in laparoscopic adjustable gastric banding]. / Port-Stapling zur Erleichterung der Portimplantation bei der laparoskopischen Magenbandoperation.

BACKGROUND: The purpose of this study was to evaluate the applicability of a port stapling device to simplify and improve port implantation in laparoscopic adjustable gastric banding (LAGB). METHODS: From November 2005 to September 2006, a prospective study was conducted on 23 consecutive patients who underwent LAGB with Swedish adjustable gastric banding. Patients were randomized to either conventional titanium-port implantation or port stapling using the "Velocity" device. RESULTS: No differences in age, body weight, body mass index, fascia depth or incision length were reported between the groups. Port implantation time was significantly less using port stapling (90+/-24 s) compared to conventional port implantation (521+/-138 s). Port related complaints postoperatively and at follow-up were equal in both groups. CONCLUSIONS: Port stapling is an excellent tool to facilitate port implantation, particularly in massively obese patients with a thick abdominal wall.

[Changes in the public's social distance toward individuals with schizophrenia in six German cities. Results of representative pre- and postinterventional telephone surveys from 2001 to 2004]. / Veränderungen in der sozialen Distanz der Bevölkerung gegenüber schizophren Erkrankten in 6 deutschen Grossstädten. Ergebnisse einer repräsentativen Telefonbefragung 2001 und 2004.

BACKGROUND: In several German cities various programmes and initiatives have been conducted during recent years aimed at reducing the stigma attached to mental illness, especially schizophrenia. So far only single interventions in specific target groups have been evaluated but not their effectiveness in the general population. METHODS: Two representative telephone surveys with repeated measurements were conducted in six German cities (n 7,225/4,622). Social distance towards people with schizophrenia and knowledge of antistigma projects were assessed. RESULTS: Between 2001 and 2004 the social distance toward persons with schizophrenia decreased in the general population. Persons familiar with antistigma projects or who lived in cities with such projects showed lower social distance. CONCLUSIONS: For the first time evidence has been found that antistigma interventions are successful in reducing the stigma attached to schizophrenia in the general population.

[Guideline for therapy of malignant thyroid tumours: pleading for an actualization]. / Leitlinie zur Therapie maligner Schilddrüsentumoren: Plädoyer für eine Aktualisierung.

Total (or near total) thyroidectomy (TE) followed by radioiodine ((131)I) ablation (RIA) of residual thyroid tissue is considered to be the ideal treatment for differentiated thyroid carcinoma. However, the actual guideline of the DGN (German Society of Nuclear Medicine) recommends for the so-called papillary micro-carcinoma of the thyroid (PMC) no further therapeutic strategy (no complete TE, no (131)I-ablation of the remaining lobe). PMC has been defined as papillary carcinoma measuring 1 cm (T1) in maximal diameter according to the World Health Organization classification system for thyroid tumours (1988). The new WHO-classification (starting in 2003) defines the T1-tumour measuring 2 cm in maximal diameter. The authors demand a new, modern guideline, following the new WHO classification. This includes, that despite the overall excellent prognosis for patients with PMC, the treatment of patients with T1-tumours of the new WHO-classification (including the "old" PMC) should be no different from the treatment of patients with conventional papillary thyroid carcinoma, i.e. complete surgery (TE and central lymph node dissection) followed by RIA of residual thyroid tissue. The authors argue that it is not appropriate to consider the tumour size as the single most important key factor for therapy and prognosis. Even small tumours may have poor prognostic factors, such as lymph node metastasis, multifocality or molecular characteristics (expression of oncogenes).