Recombinant human anti-transforming growth factor beta1 antibody therapy in systemic sclerosis: a multicenter, randomized, placebo-controlled phase I/II trial of CAT-192

OBJECTIVE: To evaluate CAT-192, a recombinant human antibody that neutralizes transforming growth factor beta1 (TGFbeta1), in the treatment of early-stage diffuse cutaneous systemic sclerosis (dcSSc). METHODS: Patients with SSc duration of <18 months were randomly assigned to the placebo group or to 1 of 3 CAT-192 treatment groups: 10 mg/kg, 5 mg/kg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT-192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ-based disease, serum levels of soluble interleukin-2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFbeta1 and TGFbeta2. RESULTS: Forty-five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT-192 and 3 deaths in the group receiving 5 mg/kg of CAT-192. There were more adverse events and more serious adverse events in patients receiving CAT-192 than in those receiving placebo, although these events were not more frequent in the high-dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT-192. Improvement in the MRSS correlated with the disease duration (r = -0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027). CONCLUSION: We report the first evaluation of a systemically administered and repeatedly dosed anti-TGFbeta1 drug. In this pilot study, CAT-192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed.     

Attenuation of human neck muscle activity following repeated imposed trunk-forward linear acceleration

It has been suggested that, after a passive linear acceleration of a seated subject which resembles a small, rear-end car impact, sensory information from proprioceptive, vestibular, and visual systems elicit stabilizing neck muscular responses. These neck muscular responses are presumably reflex based and are modified with the magnitude of the perturbation. A key issue that remains is to determine whether the neck and head postural responses can be modulated by a previous experience of the acceleration and not only by the magnitude of the acceleration. This question is of interest because, contrary to cadaver studies, one could expect that humans apprehending a rapid trunk acceleration would adopt a bracing behavior to minimize head movements. The aim of the present experiment was to verify whether neck-muscle activities can be modulated when prior knowledge about whole-body acceleration onset, direction, and magnitude are unknown compared with when only acceleration onset is unknown. Nine seated subjects were submitted to 11 imposed, forward linear accelerations (1.1g). For the first trial, subjects were completely unaware of the platform acceleration characteristics (onset, direction, amplitude, and acceleration magnitude). For the subsequent ten trials, subjects knew they would be submitted to a forward linear acceleration, but the onset of the acceleration was unknown. Head kinematics and EMG responses of the neck muscles to the first perturbation were similar for all subjects (6.2° head extension, EMG activity starting from 55 to 72 ms after platform onset). Following the first trial, however, all subjects showed a decreased neck EMG activity. Moreover, subjects responded in one of two ways across trials: one group of subjects (n=5) maintained a constant head angular position and velocity, whereas the other group (n=4) showed an increased head angular position (up to 12.6°) and velocity. This suggests that the first perturbation trial revealed a completely reactive response. After this initial trial, the responses observed may present a mixture of feedforward and feedback control. It is likely that whiplash injuries occur under conditions resembling those observed for the first trial only. If this is the case, the behavior for the following trials cannot be representative of injury mechanisms occurring in whiplash-like motion. Altogether, our results strongly suggest that, following repeated trunk linear accelerations of a constant magnitude, the nervous system prefers to minimize muscle stress instead of adopting a bracing strategy. Electronic Publication     

Splenic metastases in a large unselected autopsy series

We analyzed the files of all autopsies performed at the Institute of Pathology of the Philipps-University Marburg between 1980 and 1999 with respect to the presence of splenic metastasis. The total number of autopsies within the study period was 8,563. In 1,898 cases, a solid malignant tumor (1,774 carcinomas, 36 sarcomas, 27 malignant melanomas) was diagnosed. Metastasis to the spleen occurred in 57 cases (3.0%). Compared to the whole study population, patients with splenic metastasis were significantly younger (59 years vs. 67 years, p<0.05) and had significantly more metastastic sites (median: 6 vs. median:1, p<0.05). This underlines the assumption that splenic metastasis is associated with a worse prognosis. Lung cancer, cutaneous malignant melanoma, and breast cancer were the most frequent primary tumors, accounting for 24.6%, 15.8%, and 12.3% of all spleen metastases, respectively. Patients with testicular germ cell tumors (patients: 9, spleen metastasis: 4), malignant melanoma (patients: 27, spleen metastasis: 9, 33%), and small cell lung cancer (patients: 106, spleen metastasis: 8, 7.5%) had the highest frequency of splenic involvement. Most (n=48) metastases were detected macroscopically, the remaining ones were micrometastases (n=2), small tumor cell clusters, and single tumor cells within sinusoids (n=7). The present study underlines the importance of spleen metastasis as an indicator of poor prognosis. There are, however, various aspects as to the detection and morphology of spleen metastasism, which merit further scrutiny.     

Value of whole breast magnetic resonance elastography added to MRI for lesion characterization

The purpose of this work was to assess the diagnostic value of magnetic resonance elastography (MRE) in addition to MRI to differentiate malignant from benign breast tumors, and the feasibility of performing MRE on the whole breast. MRE quantified biomechanical properties within the entire breast (50 slices) using an 11 min acquisition protocol at an isotropic image acquisition resolution of 2 × 2 × 2 mm³. Fifty patients were included. Finally, 43 patients (median age 52) with a suspect breast lesion detected by mammography and/or ultrasound were examined by MRI and MRE at 1.5 T. The viscoelastic parameters, i.e. elasticity (G_d), viscosity (G_l), the magnitude of the complex shear modulus , and the phase angle , were measured via MRE and correlated with MRI Breast Imaging—Reporting and Data System (BI‐RADS) score, histological type, and histological grade. Stroma component and angiogenesis were also correlated with viscoelastic properties. In the 43 lesions, G_d decreased and y increased with the MRI BI‐RADS score (p_Gd = 0.02, p_y = 0.002), whereas (G_l) and y were increased in malignant lesions (p_Gl = 0.045, p_y = 0.0004). The area under the curve increased from 0.84 for MRI BI‐RADS alone to 0.92 with the MRI BI‐RADS and y (AUC increase +0.08; 95% CI (?0.003; 0.16)). Lesion characterization using the y parameter increased the diagnostic accuracy. The phase angle y was found to have a significant role (p = 0.01) in predicting malignancy independently of the MRI BI‐RADS. Interestingly, histological analysis showed no correlation between viscoelastic parameters and percentage and type of stroma, CD34 quantification of vessels, or histological grade. The combination of MRE and MRI improves the diagnostic accuracy for breast lesions in the studied cohort. In particular, the phase angle y was found to have a significant role in predicting malignancy in addition to BI‐RADS.     

Wilms' Tumor 1 Gene Expression Using a Standardized European LeukemiaNet-Certified Assay Compared to Other Methods for Detection of Minimal Residual Disease in Myelodysplastic Syndrome and Acute Myelogenous Leukemia after Allogeneic Blood Stem Cell Transplantation

Overexpression of the Wilms' tumor 1 (WT1) gene is informative in many patients with acute myelogenous leukemia (AML) and myelodysplastic syndromes (MDS) and is measurable in peripheral blood (PB). Despite these advantages, WT1 has not broadly been established as a marker for minimal residual disease (MRD) monitoring after allogeneic hematopoietic stem cell transplantation (allo-HSCT) due to limited patient numbers, differing sample sources, and nonstandardized in-house methods. To estimate the value of WT1 as an MRD marker, we serially quantified PB WT1 expression using a standardized European LeukemiaNet-certified assay in 59 patients with AML and MDS after allo-HSCT. We compared its performance with routine methods such as chimerism, XY-fluorescence in situ hybridization (FISH), disease-specific cytogenetic, and molecular analyses, which were accessible in 100%, 34%, 68%, and 37%, respectively. Twenty-four patients (41%) relapsed within a median of 126 days after allo-HSCT, and 20 of them showed at least 1 elevated WT1 value above the validated cutoff. The other 35 patients (59%) remained in complete remission, and only 1 patient had a transient increase in WT1 expression. This reflects a sensitivity of 83% and a specificity of 97% for WT1 and appears to be favorable compared with the sensitivities and specificities observed for chimerism (33% and 91%), XY-FISH (67% and 73%), cytogenetic (33% and 77%), and molecular (78% and 85%) analyses. Further supporting its predictive impact, elevated WT1 expression prompted an earlier BM biopsy and consecutively the diagnosis of relapse in 62% of patients. The results of this real-life experience imply that PB WT1 expression is measurable by a standardized assay and predicts imminent relapse after allo-HSCT with high sensitivity and specificity in most patients with AML and MDS.     

Hyperlipidemia and Primary Prevention of Stroke: Does Risk Factor Identification and Reduction Really Work?

Stroke is one of the leading causes of death. Hyperlipidemia is a major risk factor for stroke. The United States Preventive Service Task Force defines lipid screening guidelines. Treatment options of hyperlipidemia include lifestyle modifications and medical management. Statins have been shown to decrease lipids and exert a pleiotropic effect on intracranial vasculature and inflammatory modulators, leading to neuroprotection. Lower low-density lipoprotein and higher high-density lipoprotein levels are associated with decreased risk of stroke. Despite screening guidelines and evidence of the efficacy of statins, there are numerous barriers to maintaining adequate control of lipids.     

Multiple pathways inhibit NHEJ at telomeres

The nonhomologous end-joining (NHEJ) repair pathway is inhibited at telomeres, preventing chromosome fusion. In budding yeast Saccharomyces cerevisiae, the Rap1 protein directly binds the telomere sequences and is required for NHEJ inhibition. Here we show that the Rap1 C-terminal domain establishes two parallel inhibitory pathways through the proteins Rif2 and Sir4. In addition, the central domain of Rap1 inhibits NHEJ independently of Rif2 and Sir4. Thus, Rap1 establishes several independent pathways to prevent telomere fusions. We discuss a possible mechanism that would explain Rif2 multifunctionality at telomeres and the recent evolutionary origin of Rif2 from an origin recognition complex (ORC) subunit.     

Exploring the effectiveness of a specialized therapy programme for burnout using subjective report and biomarkers of stress

The increasing prevalence of stress-related disorders such as burnout urges the need for specialized treatment approaches. Programmes combining psychotherapy and regenerative interventions emerge to be the most successful. However, evaluated therapy programmes are scarce and usually involve subjective symptom quantification without consideration of physiologic parameters. The aim of the present exploratory, single-group study was the multimodal investigation of the effectiveness of a specialized holistic therapy programme by assessing symptoms and biological markers of chronic stress. Seventy-one in-patients (39 men/32 women; age 46.8 ± 9.9 years) of a specialized burnout ward with the additional diagnosis of burnout (Z73.0) in conjunction with a main diagnosis of depressive disorder (F32 or F33) according to the International Classification of Diseases (ICD)-10 were included in the study. In addition to symptomatology, the stress-responsive biomarkers heart rate variability (HRV) and serum brain-derived neurotrophic factor (BDNF) were measured in patients at admittance to and discharge from the burnout ward applying a 6-week specialized treatment programme. At discharge, patients showed a significant reduction of symptom burden and a significant increase in serum BDNF, while HRV remained unchanged. The findings implicate that the therapy programme may have beneficial effects on symptomatology and neuroplasticity of patients with burnout. As therapy was often supplemented by psychopharmacological treatment, a relevant influence of antidepressant medication especially on BDNF has to be considered.     

Oral and cervical HPV infection in HIV-positive and HIV-negative women attending a sexual health clinic in São Paulo,Brazil

Objective

To investigate the prevalence of HPV infections in the oral and cervical mucosa of HIV-positive and HIV-negative women attending a sexual health clinic.

Methods

One-hundred HIV-positive women and 100 HIV-negative women were recruited from a sexual health clinic in São Paulo, Brazil. All participants were given an oral and cervical examination. Cytologic samples were evaluated via HPV DNA test.

Results

In oral samples, HPV DNA was observed in 11 women from the HIV-positive group and 2 from the HIV-negative group. High-risk HPV subtypes were prevalent in both groups and no difference between groups was detected. HPV DNA was detected in cervical scrapings from 41 HIV-positive women and 45 HIV-negative women (P = 0.67). No participants showed oral lesions, whereas 15 HIV-positive and 17 HIV-negative women presented with macroscopic genital lesions.

Conclusion

HPV is detected more often in cervical scrapings than in oral samples. However, HPV oral shedding is more frequent in HIV-positive than in HIV-negative individuals. Concurrence of infection (high and low risk) was not observed in oral and cervical mucosa.