Anti-drug antibodies of IL-23 inhibitors for psoriasis: a systematic review.

Anti-drug antibodies (ADAs) can form with certain biological medications, but their clinical significance is not fully understood. ADA formation in psoriasis patients treated with IL-23 inhibitors was evaluated, looking at the incidence of ADAs, impact on clinical outcomes and association with adverse events. A systematic search of PubMed, Cochrane and Embase databases yielded 318 articles, which were manually reviewed. A total of 19 articles met the eligibility criteria. The incidence of ADAs with the IL-23 inhibitors was as follows: 4.1-14.7% with guselkumab, 141-31% with risankizumab and 6.51-18% with tildrakizumab. The incidence of neutralizing antibodies ranged from 01-0.6% with guselkumab, 21-16% with risankizumab and 2.5 to 3.2% with tildrakizumab. There was no evidence of reduced efficacy of psoriasis treatment with ADA presence alone. However, some studies found a reduction in clinical response with high ADA titres or with the presence of neutralizing antibodies. A few studies reported that patients with ADAs to guselkumab and risankizumab had a higher incidence of injection site reactions (ISRs). There do not appear to be other adverse events associated with ADAs with IL-23 inhibitors. Testing for presence of ADAs alone in this patient group does not appear to be predictive of treatment response. Clinically, it may be more productive to test for neutralizing antibodies or ADA titre values, although further investigation is required to show a definitive correlation.

Watson for Oncology and breast cancer treatment recommendations: agreement with an expert multidisciplinary tumor board.

Background: Breast cancer oncologists are challenged to personalize care with rapidly changing scientific evidence, drug approvals, and treatment guidelines. Artificial intelligence (AI) clinical decision-support systems (CDSSs) have the potential to help address this challenge. We report here the results of examining the level of agreement (concordance) between treatment recommendations made by the AI CDSS Watson for Oncology (WFO) and a multidisciplinary tumor board for breast cancer. Patients and methods: Treatment recommendations were provided for 638 breast cancers between 2014 and 2016 at the Manipal Comprehensive Cancer Center, Bengaluru, India. WFO provided treatment recommendations for the identical cases in 2016. A blinded second review was carried out by the center's tumor board in 2016 for all cases in which there was not agreement, to account for treatments and guidelines not available before 2016. Treatment recommendations were considered concordant if the tumor board recommendations were designated 'recommended' or 'for consideration' by WFO. Results: Treatment concordance between WFO and the multidisciplinary tumor board occurred in 93% of breast cancer cases. Subgroup analysis found that patients with stage I or IV disease were less likely to be concordant than patients with stage II or III disease. Increasing age was found to have a major impact on concordance. Concordance declined significantly (P ≤ 0.02; P < 0.001) in all age groups compared with patients <45 years of age, except for the age group 55-64 years. Receptor status was not found to affect concordance. Conclusion: Treatment recommendations made by WFO and the tumor board were highly concordant for breast cancer cases examined. Breast cancer stage and patient age had significant influence on concordance, while receptor status alone did not. This study demonstrates that the AI clinical decision-support system WFO may be a helpful tool for breast cancer treatment decision making, especially at centers where expert breast cancer resources are limited.

Diffusion tensor imaging of the hippocampus predicts the risk of dementia; the RUN DMC study.

INTRODUCTION: Cerebral small vessel disease is one of the most important risk factors for dementia, and has been related to hippocampal atrophy, which is among the first observed changes on conventional MRI in patients with dementia. However, these volumetric changes might be preceded by loss of microstructural integrity of the hippocampus for which conventional MRI is not sensitive enough. Therefore, we investigated the relation between the hippocampal diffusion parameters and the risk of incident dementia, using diffusion tensor imaging, independent of hippocampal volume. METHODS: The RUNDMC study is a prospective study among 503 elderly with small vessel disease, without dementia, with 5 years follow-up in 2012 (99.6% response-rate). Cox regression analysis was performed to calculate hazard ratios for dementia, of fractional anisotropy and mean diffusivity within the hippocampus, adjusted for demographics, hippocampal volume, and white matter. This was repeated in participants without evident hippocampal volume loss, because in these participants the visible damage might not yet have already started, whereas damage might have started on a microstructural level. RESULTS: 43 participants developed dementia (8.6%), resulting in a 5.5-year cumulative risk of 11.1% (95%CI 7.7-14.6). Higher mean diffusivity was associated with an increased 5-year risk of dementia. In the subgroup of participants with the upper half hippocampal volume, higher hippocampal mean diffusivity, more than doubled the 5-year risk of dementia. CONCLUSION: This is the first prospective study showing a relation between a higher baseline hippocampal mean diffusivity and the risk of incident dementia in elderly with small vessel disease at 5-year follow-up, independent of hippocampal volume and white matter volume.

Microstructural integrity of the cingulum is related to verbal memory performance in elderly with cerebral small vessel disease: the RUN DMC study.

BACKGROUND: Cerebral small vessel disease (SVD) is related to verbal memory failures. It is suggested that early white matter damage, is located, among others, in the (posterior) cingulum at an early stage in neurodegeneration. Changes in the microstructural integrity of the cingulum assessed with diffusion tensor imaging (DTI), beyond detection with conventional MRI, may precede macrostructural changes and be related to verbal memory failures. OBJECTIVE: To investigate the relation between cingular microstructural integrity and verbal memory performance in 503 non-demented elderly with cerebral SVD. METHODS: The RUN DMC study is a prospective cohort study in elderly (50-85 years) with cerebral SVD. All participants underwent T1 MPRAGE, FLAIR and DTI scanning and the Rey Auditory Verbal Learning Test. Mean diffusivity (MD) and fractional anisotropy (FA) were assessed in six different cingular regions of interests (ROIs). Linear regression analysis was used to assess the relation between verbal memory performance and cingular DTI parameters, with appropriate adjustments. Furthermore a TBSS analysis of the whole brain was performed to investigate the specificity of our findings. RESULTS: Both our ROI-based and TBSS analysis showed that FA was positively related to immediate memory, delayed recall, delayed recognition and overall verbal memory performance of the cingulum, independent of confounders. A similar distribution was seen for the inverse association with MD and verbal memory performance with TBSS analysis. No significant relations were found with psychomotor speed, visuospatial memory and MMSE. When stratified on hippocampal integrity, the MD and FA values of the cingular ROIs differed significantly between participants with a good and poor hippocampal integrity. CONCLUSION: Microstructural integrity of the cingulum, assessed by DTI, is specifically related to verbal memory performance, in elderly with SVD. Furthermore we found that when the integrity of the hippocampus is disrupted, the cingulum integrity is impaired as well.

Phase I study of panobinostat in combination with bevacizumab for recurrent high-grade glioma.

Bevacizumab is frequently used to treat patients with recurrent high-grade glioma (HGG), but responses are generally not durable. Panobinostat is a histone deacetylase inhibitor with anti-neoplastic and anti-angiogenic effects and may work synergistically with VEGF inhibitors. We performed a phase I study to evaluate the safety and tolerability of the combination of orally administered panobinostat with bevacizumab in patients with recurrent HGG. Patients with recurrent HGG were treated on a 3 + 3 trial design. Patients received bevacizumab 10 mg/kg every other week in combination with oral panobinostat. The starting dose of panobinostat was 20 mg three times per week, weekly (cohort 1). Due to concerns for thrombocytopenia with the weekly dosing regimen, the protocol was amended to examine an every other week regimen. Cohort 2 received panobinostat 20 mg three times per week, every other week, and cohort 3 received 30 mg three times per week, every other week. Dose-limiting toxicity during the first 30 days was used to determine the maximum-tolerated dose. Twelve patients (median age 50, median KPS 90) with recurrent HGG were enrolled. One dose-limiting toxicity (DLT) (Grade 3 thrombocytopenia) was observed in cohort 1. No DLTs were observed in cohorts 2 and 3. The following grade 3 toxicities were seen in one patient each: thrombocytopenia, hypophosphatemia, esophageal hemorrhage, and deep venous thrombosis. There were no grade 4 or 5 toxicities. There were three patients with partial responses and seven with stable disease. The recommended doses for further study are oral panobinostat 30 mg three times per week, every other week, in combination with bevacizumab 10 mg/kg every other week. A phase II clinical trial in recurrent HGG is underway.

Retrospective study of dasatinib for recurrent glioblastoma after bevacizumab failure.

There is no effective treatment for recurrent glioblastoma (GBM) after bevacizumab failure. Putative mechanisms of resistance to bevacizumab include increased pericyte coverage, mediated partly by platelet-derived growth factor receptor (PDGFR) signaling, and an infiltrative tumor growth pattern potentially dependent on SRC. We explored the efficacy of dasatinib, a SRC, BCR-ABL, c-KIT, EPHA2, and PDGFRß inhibitor, in patients with recurrent GBM after bevacizumab failure. Adult patients with histologically confirmed GBM who failed bevacizumab therapy were treated with dasatinib 70-100 mg twice daily in combination with bevacizumab (n = 14), until tumor progression or unacceptable toxicity. Fourteen patients were treated. Median age was 55 years (range 32-66) and median KPS was 80 (range 50-90). All patients (100%) had glioblastomas. The median number of prior regimens was 4 (range from 2 to 6). Of the thirteen evaluable patients, none had a complete or partial response. Only one patient had stable disease after an 8 week interval. Median progression-free survival (PFS) was 28 days (95% confidence interval [CI] 26-35 days). Six month progression-free survival (PFS6) was 0%. Median overall survival (OS) was 78 days (95% CI 41-137 days). Treatment was moderately well-tolerated, although one patient sustained a grade 4 intracerebral hemorrhage. Dasatinib in conjunction with bevacizumab does not appear to have activity in patients with recurrent, heavily pretreated GBM.

White matter changes and gait decline in cerebral small vessel disease.

The relation between progression of cerebral small vessel disease (SVD) and gait decline is uncertain, and diffusion tensor imaging (DTI) studies on gait decline are lacking. We therefore investigated the longitudinal associations between (micro) structural brain changes and gait decline in SVD using DTI. 275 participants were included from the Radboud University Nijmegen Diffusion tensor and Magnetic resonance imaging Cohort (RUN DMC), a prospective cohort of participants with cerebral small vessel disease aged 50-85 years. Gait (using GAITRite) and magnetic resonance imaging measures were assessed during baseline (2006-2007) and follow-up (2011 - 2012). Linear regression analysis was used to investigate the association between changes in conventional magnetic resonance and diffusion tensor imaging measures and gait decline. Tract-based spatial statistics analysis was used to investigate region-specific associations between changes in white matter integrity and gait decline. 56.2% were male, mean age was 62.9 years (SD8.2), mean follow-up duration was 5.4 years (SD0.2) and mean gait speed decline was 0.2 m/s (SD0.2). Stride length decline was associated with white matter atrophy (ß = 0.16, p = 0.007), and increase in mean white matter radial diffusivity and mean diffusivity, and decrease in mean fractional anisotropy (respectively, ß = - 0.14, p = 0.009; ß = - 0.12, p = 0.018; ß = 0.10, p = 0.049), independent of age, sex, height, follow-up duration and baseline stride length. Tract-based spatial statistics analysis showed significant associations between stride length decline and fractional anisotropy decrease and mean diffusivity increase (primarily explained by radial diffusivity increase) in multiple white matter tracts, with the strongest associations found in the corpus callosum and corona radiata, independent of traditional small vessel disease markers. White matter atrophy and loss of white matter integrity are associated with gait decline in older adults with small vessel disease after 5 years of follow-up. These findings suggest that progression of SVD might play an important role in gait decline.

Diagnostic accuracy of the clapping test in Parkinsonian disorders.

BACKGROUND: To determine the diagnostic value of the clapping test, which has been proposed as a reliable measure to differentiate between progressive supranuclear palsy (where performance is impaired) and Parkinson's disease (where performance should be normal). METHODS: Our study group included a large cohort of consecutive outpatients including 44 patients with Parkinson's disease, 48 patients with various forms of atypical parkinsonism and 149 control subjects. All subjects performed the clapping test according to a standardized protocol. RESULTS: Clapping test performance was normal in all control subjects, and impaired in 63% of the patients with atypical parkinsonism. Unexpectedly, we also found an impaired clapping test in 29% of the patients with Parkinson's disease. CONCLUSION: Although the proportion with an abnormal clapping test was significantly higher in atypical parkinsonism, the clapping test did not discriminate well between Parkinson's disease and atypical parkinsonism.

Fluorescence changes in human gamma-globulin induced by free-radical activity.

Low-intensity ultraviolet irradiation was used to generate free-radical activity in lipid-free human gamma-globulin. The changes were monitored by fluorescence spectroscopy and gel filtration chromatography. The pattern and the effect of thiol compounds, free-radical scavengers and antioxidants point to a free-radical-mediated process. Initial energy uptake was probably in the region of aromatic amino acid residues, followed by complex intramolecular rearrangements. Irradiation led to the formation of molecular species and complexes whose fluorescence characteristics were different from those of native gamma-globulin and indistinguishable from those observed in inflammatory exudates.

Ten-year follow-up of subjects with impaired glucose tolerance: prevention of diabetes by tolbutamide and diet regulation.

In a diabetes detection survey carried out between 1962 and 1965, 2477 (1.1%) of 228,883 subjects had Clinistix-positive glucosuria after a carbohydrate-rich luncheon meal. Of these 2477, 578 displayed impaired tolerance to oral glucose without having manifest diabetes. From this group, 267 men were divided into five groups and subjected to the following treatments and controls: (a) diet regulation and 0.5 g tolbutamide t.i.d. (N = 49), annual oral glucose tolerance test (OGTT); (b) diet regulation and one placebo tablet t.i.d. (N = 48), annual OGTT; (c) diet regulation only (N = 50), annual OGTT; (d) no treatment (N = 61), annual OGTT; and (e) no treatment, OGTT at follow-up (N = 59 at follow-up). In addition, a control group was included comprised of men with normal OGTT (N = 52). At follow-up, 29% of those without diet regulation and medication (group e: N = 59) had developed diabetes. Of those on diet regulation, but without active medication (group b plus group c, N = 98), 13% had diabetes. No individual maintaining tolbutamide and diet regulation (N = 23) had progressed to diabetes. In this group, 80% of those later examined (N = 11) had serum tolbutamide concentrations in the therapeutic range. No individual with initially normal OGTT developed diabetes or impaired OGTT. The findings suggest that normal oral glucose tolerance signifies little risk of progress to impaired glucose tolerance and manifest diabetes, whereas impaired glucose tolerance is associated with a high risk of progression to diabetes. In addition, it seems possible that treatment with diet regulation, in combination with tolbutamide, may prevent or postpone progression from impaired glucose tolerance to manifest diabetes.

[Alzheimer's disease and treatment of vascular risk factors]. / De ziekte van Alzheimer en behandeling van vasculaire risicofactoren.

There is increasing evidence that vascular risk factors including hypertension, high cholesterol, hyperhomocysteinaemia and diabetes mellitus are connected to the risk of Alzheimer's disease (AD). The risk of AD may be reduced by the treatment of hypertension prior to onset of cognitive impairment. One small randomised clinical trial has provided some evidence of beneficial effects on cognition of cholesterol-lowering drugs such as the statins in patients with AD. Treatment of hypertension, hyperhomocysteinaemia and diabetes mellitus with the aim of halting the progression of cognitive decline in AD is still under study and results are awaited. For the time being findings from the trials carried out thus far should be interpreted with care due to methodological shortcomings, both in study design and execution. In order to investigate the role of vascular risk factors both in the aetiology and treatment of AD, large prospective randomised trials with long-term follow-up of AD patients who have been diagnosed using revised uniform diagnostic criteria that take the heterogeneity of the disease into account, are necessary.

Nutrient intake and health status of vegans. Chemical analyses of diets using the duplicate portion sampling technique.

A strict vegetarian diet [vegan diet (VD)] was investigated. Six middle-aged vegans (three men and three women) collected copies of 24-h diets using the duplicate portion sampling technique. By chemical analyses, the nutrient composition was determined in detail and compared with corresponding figures of a normal mixed Swedish diet. In the VD 30% of the energy originated from fat compared with 40% in normal Swedish mixed diet (MD). Linoleic acid was the dominant fatty acid (60% of total fat in VD versus 8% in MD). The VD contained 24 g protein/1000 kcal compared to 30 g/1000 kcal in MD, but the intake of essential amino acids by the vegans exceeded the recommendations. Dietary fiber was about 5 times higher in the vegan diet (29 versus 6 g/1000 kcal) and sucrose similar to MD (18 versus 21 g/1000 kcal). Among the inorganic nutrients the concentration of calcium (351 versus 391 mg/1000 kcal) and sodium (53 versus 49 mmol/1000 kcal) were similar in both types of diets but the amount of potassium (56 versus 30 mmol/1000 kcal, magnesium (300 versus 110 mg/1000 kcal), iron (9 versus 6.5 mg/1000 kcal), zinc (6.5 versus 4.7 mg/1000 kcal), and copper (2 versus 0.7 mg/1000 kcal) were nearly doubled. Iodine (39 versus 156 micrograms/1000 kcal and selenium (5 versus 17 micrograms/1000 kcal) were much lower in the VD, selenium even being undetectable in several 24-h diets. The VD was rich in folic acid (301 versus 90 micrograms/1000 kcal in MD) but the intake of vitamin B12 was only 0.3 to 0.4 microgram/day (MD: 3 to 4 micrograms/day). No clinical signs of nutritional deficiency were observed in the vegans. Serum protein levels of the vegans as well as their serum lipoproteins were near the lower range of the reference group. In addition, none of the vegans was overweight and their blood pressures were low for their age.

Role of host antibody in the chemotherapeutic action of praziquantel against Schistosoma mansoni: identification of target antigens.

We have demonstrated previously in a mouse model that effective chemotherapy against Schistosoma mansoni with praziquantel (PZQ) is dependent upon an intact host antibody response. In the same study, it was found that worms recovered from PZQ-treated animals display surface-bound antibodies. In order to identify the target antigens of the antibodies involved in the synergy between PZQ and the immune response, monoclonal antibodies (mAbs) and polyclonal antisera recognizing different tegumental components were tested by indirect immunofluorescence (IF) assay for their ability to bind in vitro to the surface of 6-week-old schistosomes perfused from nude (athymic) mice 1 h after PZQ treatment. Nude mice were used as hosts because worms from these animals were found to lack bound anti-schistosome antibodies. Only 5 of the 21 antibodies tested reacted with drug-treated worms. This indicated that the damage caused by PZQ to the schistosome tegument is restricted to specific tegumental components. Of the positive reactions, one group of antibodies gave IF patterns different from, whereas the other group gave IF reactions similar to those seen with worms perfused from immunologically intact mice. Antibodies against a schistosome esterase and alkaline phosphatase produced reaction patterns in the former category. In contrast, two out of three monoclonal antibodies recognizing different epitopes on a 200-kDa glycoprotein abundant in worm tubercles gave IF patterns very similar to those observed on schistosomes from drug-treated, intact mice. The biological significance of these reactions was confirmed by demonstrating that transfer of one of the positive monoclonal antibodies to 6-week-infected, B cell-depleted (mu-suppressed) mice reconstitutes the efficacy of PZQ treatment to normal levels. The above results suggest that the antibodies involved in the mechanism of action of PZQ react with a limited set of antigens. Furthermore, they implicate the 200-kDa tubercle protein as a major target of this response in naturally infected hosts.

Analysis of antibody reactivity in the sera of 42 patients with paraproteinaemia.

The clinical expression of disease in patients with conditions in which autoimmunity is thought to contribute to the pathogenesis of disease is the result of an unfortunate combination of predisposing and environmental factors. The presence of autoantibodies showing a variety of antigen specificities in sera from many of these patients has been closely correlated with particular spectra of organ involvement or tissue destruction. Their precise role in the disease process is as yet unclear. Sera from patients with paraproteinaemia also often contain autoantibodies to a variety of cell components, although symptoms of autoimmune disease are rarely found in this group of individuals. In this study of 42 sera from patients with paraproteinaemia we have confirmed the presence of autoantibodies in 33% (13/42) of samples. Amongst the autoantibodies detected were those to human neutrophils (3), U1RNP (8) and cardiolipin (4). In five sera, the immunoglobulin class of autoantibody did not correlate with that of the monoclonal band. This study extends previous reports of the repertoire of autoantibodies present in sera from patients with paraproteinaemia.

Beta 2-glycoprotein-1 (apolipoprotein H) excretion in chronic renal tubular disorders: comparison with other protein markers of tubular malfunction.

Urinary beta 2-glycoprotein-1 was measured in 60 patients with conditions recognised as causing renal tubular impairment and compared with established markers of early tubular malfunction. Increased beta 2-glycoprotein-1 excretion was found in 49 (82%) of the subjects; raised excretion of alpha 1-microglobulin, retinol-binding protein, and beta 2-microglobulin was found in 46 (77%), 45 (75%), and 31 (52%), respectively, and increased urinary N-acetyl-beta-D-glucosaminidase activity in 32 of 54 of the subjects (59%). The increase was particularly pronounced in those with proximal tubule malfunction, although considerable variation occurred. beta 2-glycoprotein-1 was shown to be stable in urine over the physiological pH range, and it is concluded that its measurement provides a means of detecting chronic malfunction of the renal tubules that is marginally more sensitive than assays of alpha 1-microglobulin or retinol-binding protein, and more reliable than assays of beta 2-microglobulin or N-acetyl-beta-D-glucosaminidase.

Renal impairment in myeloma: negative association with isoelectric point of excreted Bence-Jones protein.

The isoelectric point (pI) of the major form of Bence-Jones protein excreted by 62 patients with myeloma and six with macroglobulinaemia was measured by combining isoelectric focusing with immunoblotting techniques. The distribution of the pI values for both kappa and lambda type proteins was bimodal, most falling in the ranges 5.0-6.0 and 7.0-7.5. Plasma creatinine and creatinine clearance and the urine excretion of alpha-1-microglobulin and beta-2-microglobulin were measured in 24 of the patients. These patients, who were free of additional factors known to have an association with the development of renal impairment, were followed up for a mean period of 16 months (range three to 28 months). It was found that renal impairment was not related to the pI of the Bence-Jones protein excreted.

Identification of antigenic Schistosoma mansoni glycoproteins during the course of infection in mice and humans.

The progression of humoral immune responses exhibited by mice during the year following exposure to Schistosoma mansoni cercariae was established by studying radioimmunoprecipitations of adult male and cercarial glycoproteins. 35S-methionine metabolically-labeled adult S. mansoni male worm glycoproteins precipitated by sera of 14 mice were identified by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The initial specific antibody response (week 5) was directed against 3 worm glycoproteins of 55,000, 52,000 and 35,000 molecular weight (Mr). As infection progressed, all major worm glycoproteins (ranging from 400,000 to 12,000 Mr) were precipitated by sera from each mouse and only minor individual variations in titer were noted in the antibody responses of the mice against these glycoproteins. Maximal immunoreactivity toward the radiolabeled glycoproteins occurred at week 20 and remained at this level through week 50. Analogous experiments with sera from acutely- and chronically-infected humans resulted in immunoprecipitation patterns almost identical to those obtained with sera from the corresponding experimentally-infected mice. The kinetics of the antibody response against 125Iodine-labeled cercarial glycoproteins was the same as that observed with worm glycoproteins.

Tegumental expression in larval and adult stages of a major schistosome structural glycoprotein.

A monoclonal antibody has been used to identify and characterize an antigenic tegumental surface membrane glycoprotein of Schistosoma mansoni. Direct binding of 125I-labeled monoclonal antibody showed that this glycoprotein was present in eggs, cercariae, and worms of both sexes. The glycoprotein had an apparent molecular weight of 180,000. Indirect and direct immunofluorescent microscopy showed that this antigen was located on the interlinked tegumental folds of both larval and adult parasites. These findings are discussed in relation to parasite development and the mechanism by which schistosomes evade the host's immune defenses.

Dent's disease; a familial proximal renal tubular syndrome with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, metabolic bone disease, progressive renal failure and a marked male predominance.

We describe a familial form of renal Fanconi syndrome characterized by hypercalciuria, low-molecular-weight proteinuria, nephrocalcinosis and slowly progressive renal failure. Males are much more severely affected than females. The patients studied included 15 males and 10 females, and five families with up to three generations involved. Studies of the two largest families described here have already shown that their disease is inherited on the X-chromosome. The series contains the two unrelated patients originally described by Dent and Friedman in 1964 as 'hypercalcuric rickets'.