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.

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.

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.

Depressive Symptoms and Amygdala Volume in Elderly with Cerebral Small Vessel Disease: The RUN DMC Study.

Introduction. Late onset depressive symptoms (LODSs) frequently occur in elderly with cerebral small vessel disease (SVD). SVD cannot fully explain LODS; a contributing factor could be amygdala volume. We investigated the relation between amygdala volume and LODS, independent of SVD in 503 participants with symptomatic cerebral SVD. Methods. Patients underwent FLAIR and T1 scanning. Depressive symptoms were assessed with structured questionnaires; amygdala and WML were manually segmented. The relation between amygdala volume and LODS/EODS was investigated and adjusted for age, sex, intracranial volume, and SVD. Results. Patients with LODS had a significantly lower left amygdala volume than those without (P = 0.02), independent of SVD. Each decrease of total amygdala volume (by mL) was related to an increased risk of LODS (OR = 1.77; 95% CI 1.02-3.08; P = 0.04). Conclusion. Lower left amygdala volume is associated with LODS, independent of SVD. This may suggest differential mechanisms, in which individuals with a small amygdala might be vulnerable to develop LODS.

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.

Subjective cognitive failures and hippocampal volume in elderly with white matter lesions.

BACKGROUND: Subjective cognitive failures (SCF) and subjective memory failures (SMF) have been reported to be an early predictor of Alzheimer disease (AD) and have been attributed to white matter lesions (WML). Since AD is characterized by hippocampal degeneration, it is surprising that its relation with hippocampal atrophy has been investigated only sparsely. Previous studies on this are rare, limited in sample size, and did not adjust for WML. OBJECTIVE: To determine the relation between SCF and hippocampal volume in strata of objective cognitive performance among elderly without dementia with incidental WML. METHODS: The Radboud University Nijmegen Diffusion tensor and MRI Cohort study is a prospective cohort study among 503 subjects with WML aged between 50 and 85 years. All subjects underwent FLAIR and T1 MRI scanning. The amount of SCF and SMF was rated by the Cognitive Failure Questionnaire. Cognitive function was assessed by a cognitive screening battery. Volumetric measures of hippocampus and WML were manually performed. We assessed the relation between hippocampal volume and SCF and SMF adjusted for age, sex, education, depression, intracranial volume, and WML volume. RESULTS: Subjects with SCF and SMF had lower hippocampal volumes than those without (p = 0.01 and p = 0.02). This was most noteworthy in subjects with good objective cognitive performance (p(trend) = 0.007 and p(trend) = 0.03), and not in those with poor objective cognitive performance. CONCLUSION: Subjective cognitive failures (SCF) are associated with lower hippocampal volume, even in subjects without objective cognitive impairment and independent of white matter lesions. SCF has a radiologic detectable pathologic-anatomic substrate.

Bevacizumab for recurrent malignant gliomas: efficacy, toxicity, and patterns of recurrence.

BACKGROUND: Bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor, may have activity in recurrent malignant gliomas. At recurrence some patients appear to develop nonenhancing infiltrating disease rather than enhancing tumor. METHODS: We retrospectively reviewed 55 consecutive patients with recurrent malignant gliomas who received bevacizumab and chemotherapy to determine efficacy, toxicity, and patterns of recurrence. Using a blinded, standardized imaging review and quantitative volumetric analysis, the recurrence patterns of patients treated with bevacizumab were compared to recurrence patterns of 19 patients treated with chemotherapy alone. RESULTS: A total of 2.3% of patients had a complete response, 31.8% partial response, 29.5% minimal response, and 29.5% had stable disease. Median time to radiographic progression was 19.3 weeks. Six-month progression-free survival (PFS) was 42% for patients with glioblastoma and 32% for patients with anaplastic glioma. In 23 patients who progressed on their initial therapy, bevacizumab was continued and the concurrent chemotherapy agent changed. In no case did the change produce a radiographic response, but two patients had prolonged PFS of 20 and 31 weeks. Recurrence pattern analysis identified a significant increase in the volume of infiltrative tumor relative to enhancing tumor in bevacizumab responders. CONCLUSIONS: Combination therapy with bevacizumab and chemotherapy is well-tolerated and active against recurrent malignant gliomas. At recurrence, continuing bevacizumab and changing the chemotherapy agent provided long-term disease control only in a small subset of patients. Bevacizumab may alter the recurrence pattern of malignant gliomas by suppressing enhancing tumor recurrence more effectively than it suppresses nonenhancing, infiltrative tumor growth.

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.

Dose evaluation for long-term magnesium treatment in aneurysmal subarachnoid haemorrhage.

BACKGROUND: Magnesium is a neuroprotective agent that might prevent or reverse delayed cerebral ischaemia after aneurysmal subarachnoid haemorrhage (SAH). We are presently running a randomized, placebo-controlled, double blind trial with magnesium sulphate (64 mmol/day intravenously). We studied whether this treatment regime resulted in our target serum magnesium levels of 1.0-2.0 mmol/L. METHODS: Magnesium sulphate was administered intravenously as soon as possible after admission and continued until 14 days after occlusion of the aneurysm. Serum magnesium measurements were done at baseline and at least every 2 days during administration of trial medication. For comparison we used the serum magnesium levels of the placebo-treated patients. RESULTS: Magnesium therapy was begun in 94 patients. The mean magnesium level in the treatment period was 1.47 +/- 0.32 mmol/L. In 81 patients serum magnesium stayed within target levels during the entire treatment period. One patient had a serum magnesium level below 1.0 mmol/L (0.91 mmol/L) in a single measurement and 10 patients had serum magnesium levels above 2.0 mmol/L at one or more measurements. In six patients magnesium therapy was discontinued: in three because of nausea, headache, or both in combination with serum magnesium levels above 2.0 mmol/L and in the other three because of hypotension, phlebitis and renal failure. CONCLUSIONS: With an intravenous dosage schedule of 64 mmol magnesium sulphate a day, serum magnesium levels of 1.0-2.0 mmol/L can easily be maintained without severe side effects for an extended period in a vast majority of patients with SAH.

[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.

Urinary retinol binding protein in Indo-Asian patients with idiopathic interstitial nephritis.

BACKGROUND: Idiopathic interstitial nephritis (IIN) is common in the UK Indo-Asian population. Lack of systemic involvement and unremarkable urinalysis on stick testing suggest that it may underlie some cases of end-stage renal failure of undetermined cause. If IIN is diagnosed early, prompt initiation of treatment can improve long-term outcome. AIMS: To investigate whether urinary retinol binding protein (RBP) is elevated more commonly than urinary albumin in IIN, and might be useful in the early detection of renal disease in Indo-Asian patients. DESIGN: Preliminary observational study METHODS: We measured urinary RBP and urinary albumin in 19 Indo-Asian patients in whom a renal biopsy had shown IIN, 10 of whom had already been treated with corticosteroids at the time of specimen collection. A further 28 Indo-Asian patients with glomerular disease, and six with normal light-microscopic renal biopsy, were assessed in parallel. RESULTS: Urinary RBP/creatinine ratio (RCR) was elevated in all 19 cases of IIN, compared to 12/19 in whom the albumin/creatinine ratio (ACR) was elevated. Elevated urinary RBP was thus significantly more common than albuminuria in this group (p<0.01). Twelve of the 19 cases also satisfied the criteria for tubular proteinuria. RCR was elevated to >30 times the upper limit of normal in 7/9 who had not previously received corticosteroids, of whom four had normal ACR; none had ACR >5 times the upper limit of normal. DISCUSSION: These data suggest that measurement of urinary RBP should be explored as an adjunct to albuminuria, if screening for renal disease in the Indo-Asian population is contemplated.

Glomerular protein sieving and implications for renal failure in Fanconi syndrome.

BACKGROUND: Glomerular sieving coefficients (GSCs) of proteins have been measured extensively in animals but not humans. We have studied the proteinuria of Fanconi syndrome, a "knock-out" of renal tubular protein reabsorption, to estimate GSCs and detect potential contributors to development of renal failure. METHODS: Immunoassay of proteins and polypeptides in serum and urine of patients with early Dent's disease (mean GFR = 83 mL/min, range 60 to 101, N = 5), Lowe's syndrome (N = 3), and ADIF (N = 2) were used. RESULTS: Twenty-one proteins, ranging in mass from insulin (5.1 kD) and parathyroid hormone (PTH; 9.4 kD) to transferrin (78 kD) and intact IgG (160 kD), were present in Fanconi urine at> 6 to 1000-fold normal. A simple model assuming complete "knock-out" of the reuptake of each protein filtered normally by the glomerulus was applied to protein excretion by Dent's patients. GSCs were estimated for 12 plasma proteins, including albumin (7.7 +/- 0.9 x 10-5) and IgG (4.2 +/- 0.28 x 10-5; mean +/- SEM). We calculated the albumin concentration in normal glomerular filtrate to be 3.5 +/- 0.41 mg/L (53 +/- 6.4 nmol/L), consistent with studies in rat and dog. CONCLUSIONS: To our knowledge, this study provides the first estimates of human in vivo GSCs. Our model explains why tubular proteinuria of Fanconi syndrome includes proteins of mass of albumin and above as well as low-molecular-weight proteins, and further characterizes the endocytic pathway(s) believed defective in these syndromes. High urinary concentrations of potentially bioactive hormones such as PTH, insulin, IGF-1 and the chemokine monocyte chemoattractant protein-1 (MCP-1), were found; their presence in tubular fluid may contribute to the hypercalciuria, interstitial fibrosis, and the progressive renal failure of Fanconi syndromes.

Evidence for the role of megalin in renal uptake of transthyretin.

The kidney is a major organ for uptake of the thyroid hormone thyroxine (T(4)) and its conversion to the active form, triiodothyronine. In the plasma, one of the T(4) carriers is transthyretin (TTR). In the present study we observed that TTR, the transporter of both T(4) and retinol-binding protein, binds to megalin, the multiligand receptor expressed on the luminal surface of various epithelia including the renal proximal tubules. In the kidney, megalin plays an important role in tubular uptake of macromolecules filtered through the glomerulus. To evaluate the importance of megalin for renal uptake of TTR, we performed binding/uptake assays using immortalized rat yolk sac cells with high expression levels of megalin. Radiolabeled TTR, free as well as in complex with thyroxine or retinol-binding protein, was rapidly taken up by the cells, and the uptake was strongly inhibited by a polyclonal megalin antibody and by the receptor-associated protein, a chaperone-like protein inhibiting ligand binding to megalin. In cell culture, different TTR mutations presented different levels of cell association and degradation, suggesting that the structure of TTR is important for megalin recognition. Both the apo form and the T(4)-bound form were taken up by the cells. Analysis of urine from patients with Dent's disease, a renal tubular disorder that alters receptor-mediated endocytic reabsorption of proteins, identified TTR as an abundant excreted protein. Furthermore, analysis of kidney sections of megalin-deficient mice revealed no immunohistochemical TTR labeling in intracellular vesicles in the proximal tubule cells when compared with wild type control littermates. Taken together, the present data indicate that TTR represents a novel megalin ligand of importance in the thyroid hormone homeostasis.