Efficacy of Corticosteroid Therapy for HTLV-1-Associated Myelopathy: A Randomized Controlled Trial (HAMLET-P)

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)

Clinical and Molecular Heterogeneity in Patients with Innate Resistance to Anti-PD-1 +/− Anti-CTLA-4 Immunotherapy in Metastatic Melanoma Reveals Distinct Therapeutic Targets

While immune checkpoint inhibitors targeting the CTLA-4 and PD-1 receptors have significantly improved outcomes of many patients with metastatic melanoma, there remains a group of patients who demonstrate no benefit. In this study, we sought to characterise patients who do not respond to anti-PD-1-based therapies based on their clinical, genetic and immune profiles. Forty patients with metastatic melanoma who did not respond to anti-PD-1 +/− anti-CTLA-4 treatment were identified. Targeted RNA sequencing (n = 37) was performed on pretreatment formalin-fixed paraffin-embedded (FFPE) melanoma specimens. Patients clustered into two groups based on the expression profiles of 26 differentially expressed genes: an immune gene rich group (n = 17) expressing genes associated with immune and T cell signalling, and a second group (n = 20) expressing genes associated with metabolism, signal transduction and neuronal signalling. Multiplex immunohistochemistry validated significantly higher densities of tumour-infiltrating lymphocytes (TILs) and macrophages in the immune gene-rich group. This TIL-high subset of patients also demonstrated higher expression of alternative immune-regulatory drug targets compared to the TIL-low group. Patients were also subdivided into rapid progressors and other progressors (cut-off 2 mo progression-free survival), with significantly lower TILs (p = 0.04) and CD68+ macrophages (p = 0.0091) in the rapid progressors. Furthermore, a trend towards a higher tumour burden was observed in rapid progressors (p = 0.06). These data highlight the need for a personalised and multilayer (clinical and molecular) approach for identifying the most appropriate treatments for anti-PD-1 resistant patients and provides insight into how individual treatment strategies can be achieved.

Progression of Aortic Stenosis and Long-term Follow-Up in Women

Data on the rate of progression of aortic stenosis (AS) in women are limited. We retrospectively studied 95 female patients (age 75 ± 13 yrs) with aortic valve area (AVA) <2.0 cm2 (mild AS 1.5-1.9 cm2, moderate AS 1.0-1.4 cm2, severe AS <1.0 cm2). All patients underwent serial transthoracic echocardiography. We determined annual AVA decrease (rate of AS progression) by 3 approaches, each of which was applied to the entire cohort: 1) as a single group; 2) in the 3 subgroups of mild, moderate and severe AS; and 3) in the rapid and slower progressors. Study endpoints were aortic valve replacement (AVR) and all-cause mortality. The mean duration of follow-up was 4.5 ± 2.9 years. Mean rate of reduction in AVA for the total study group was 0.14 ± 0.16 cm2/yr and was directly related to presence of hypertension and baseline AVA, and inversely related to follow-up duration (all p<0.05). The annualized decrease in AVA for each of the subgroups of mild, moderate and severe AS at baseline was 0.21±0.31 cm2, 0.13±0.11 cm2, 0.11±0.09 cm2, respectively (p<0.0001). Rapid progression of AS (decrease in AVA ≥0.20 cm2/yr) occurred in 21% of patients (n=20) and was associated with baseline hypertension (p=0.03) and inversely related to follow-up duration (p=0.0007). Rapid progressors had shorter follow-up than slower progressors (20 vs. 42 mos, p=0.002). Event-free survival with end-points of death (n=65) or surgical/transcatheter AVR (n=24) at 1, 3, and 5 years, respectively, was 93%, 66% and 40% for mild AS; 96%, 72% and 48% for moderate AS; and 93%, 38% and 24% for severe AS. Thus, event-free survival at 5 years in patients with baseline severe AS was approximately half that of patients with AS of mild or moderate severity. In addition, event-free survival at 1 year in slower progressors was 92% and in rapid progressors was 70%.

Categorisation of myopia progression by change in refractive error and axial elongation and their impact on benefit of myopia control using orthokeratology

Aims To compare the value of pre-treatment axial elongation (AE) and changes in refractive sphere (M change) for predicting the success in orthokeratology (ortho-k), in order to better identify suitable candidates for myopia control. Methods This study further analysed the data of 66 subjects receiving 7-month ortho-k treatment, following a 7-month observation period, during which single-vision spectacles were worn. Rate of myopia progression was determined by AE and M change and subjects categorised as slow, moderate, or rapid progressors based on these changes. Outcomes of myopia control, based on the AE reduction after ortho-k, were classified as ‘ineffectual’, ‘clinically insignificant’, or ‘beneficial’. Results Of the 20 subjects, initially categorised as slow by AE and, of whom 95% were similarly categorised by M change, none benefitted from ortho-k. In contrast, of the 22 subjects with moderate AE, 77% and 23% displaying slow and moderate M change, respectively, the majority (73%) benefitted from ortho-k lens wear. The 24 subjects with rapid AE were poorly identified by M change, with only 21% correctly categorised. The vast majority of rapid progressors showed significant benefit after ortho-k. Conclusion Progression of AE is a good indicator of subsequent success of ortho-k treatment. Delaying commencement of therapy is prudent for children with slow progression as results indicate that they would be unlikely to benefit from this intervention. As change in refractive error frequently underestimates rapid progression of AE, its value for identifying appropriate candidates for myopia control is poor.

Changes in Motor Unit Number Estimate and Forced Vital Capacity as Predictors of ALS Progression

Background: An independent measure of lower motor neuron function that can be monitored over time is essential to evaluating the effect of drugs or stem cell transplantation and to determining prognosis in amyotrophic lateral sclerosis (ALS). Longitudinal changes in forced vital capacity-percent of predicted (FVC%) and motor unit number estimate (MUNE) may identify patient groups with more rapid disease progression. Objective: We attempted to define cutoff values for 3-month changes in FVC% and MUNE that identify ALS patients with rapidly progressive disease defined as survival of 30 months or less from symptom onset. Design: Cohort study. Subjects: We report data from 26 ALS patients, 10 patients reported previously and 16 patients not reported previously, except for the reproducibility of their MUNE data. Results: Of the 26 patients, 7 had rapid progression. Either a 40% decrease in statistical MUNE or a 20% decrease in FVC% over 3 months identified 6 of 7 rapid progressors (Sensitivity=86% 95% confidence interval [CI] 42.1% - 99.6%). Of the 19 patients without rapid progression, 18 met neither the FVC or MUNE criterion (Specificity = 94.7% CI 95% 74.0% - 99.9%). In a proportional hazards model, 3 month change in both FVC and MUNE were significantly predictive of decreased survival. Conclusion: We suggest the use of a three-month change in MUNE or FVC% as a secondary enrollment criterion in therapeutic trials or to identify a subgroup of rapid progressors that may respond differently to treatments.

Predictive factors of rapid linear renal progression and mortality in patients with chronic kidney disease

Background Risk factors predictive of rapid linear chronic kidney disease (CKD) progression and its associations with end-stage renal disease (ESRD) and mortality requires further exploration, particularly as patients with linear eGFR trajectory represent a clear paradigm for understanding true CKD progression. Methods A linear regression slope was applied to all outpatient estimated glomerular filtration rate (eGFR) values for patients in the Salford Kidney Study who had ≥2years follow-up, ≥4 eGFR values and baseline CKD stages 3a-4. An eGFR slope (ΔeGFR) of ≤-4ml/min/1.73m2/yr defined rapid progressors, whereas -0.5 to +0.5ml/min/1.73m2/yr defined stable patients. Binary logistic regression was utilised to explore variables associated with rapid progression and Cox proportional hazards model to determine predictors for mortality prior to ESRD. Results There were 157 rapid progressors (median ΔeGFR -5.93ml/min/1.73m2/yr) and 179 stable patients (median ΔeGFR -0.03ml/min/1.73m2/yr). Over 5 years, rapid progressors had an annual rate of mortality or ESRD of 47 per 100 patients compared with 6 per 100 stable patients. Factors associated with rapid progression included younger age, female gender, higher diastolic pressure, higher total cholesterol:high density lipoprotein ratio, lower albumin, lower haemoglobin and a urine protein:creatinine ratio of >50g/mol. The latter three factors were also predictive of mortality prior to ESRD, along with older age, smoking, peripheral vascular disease and heart failure. Conclusions There is a heterogenous interplay of risk factors associated with rapid linear CKD progression and mortality in patients with CKD. Furthermore, rapid progressors have high rates of adverse outcomes and require close specialist monitoring.

P0085MAYO AND PRO-PKD SCORE CONCORDANCE FOR PROGRESSION OF RENAL FALIURE EVALUATION IN ADPKD PATIENTS

Background and Aims Autosomal dominant polycystic kidney disease (ADPKD) is a multisystemic disease characterized by the progressive development of bilateral renal cysts, resulting in enlargement of the kidney volume due to cystic formations, hypertension, haematuria, and loss of renal function. Recent advances in genomics have contributed to have a better understanding of the pathogenesis of the disease suggesting new treatment strategies to inhibit or delay cysts formation and expansion.Since 2015, the European Medicines Agency approved Vaptans as therapy to slow the growth of kidney volume and the decline in kidney function in patients defined rapid progressors. In 2016 European Renal Association-European Dialysis and Transplant Association (ERA-EDTA) Working Groups on Inherited Kidney Disorders and European Renal Best Practice (WGIKD/ ERBP) published a position statement for definition of rapid progression. These recommendations included two algorithms to assess indications for initiation of ADPKD treatment. They selected three criteria based on: 1) the relationship between TKV(total kidney volume) and the decline in renal function according CRISP study, using Mayo Clinic Score 2) eGFR slope with an average ≥2.5 mL/min/1.73 m2/ yearly loss of renal function over a period of 5 yearsor 3) the link between genetic mutation and clinical information study using Propkd score.A 5 –years follow-up is not always available to achieve the criteria for rapid progressor, therefore the use of scores in clinical practice is widespread.In this scenario both scores (MAYO and PRO-PKD) are able to define rapid progressor patients and it is possible to use them alternatively as reported in literature. The aim of this study is to evaluate the prognostic scores in a real life experience. Method All ADPKD patients in follow-up in our Nephrology Unit from January 2017 to July 2019 were included in the study. Descriptive statistics were used to summarize demographic and clinical characteristics. Therefore we classified them for TKV, genetic mutation, renal function, Mayo score and Propkd score. Rapid progression was defined as 1C-D-E Mayo and high risk PRO PKD while non rapid progressors was 1A-1B mayo and low and intermediate PRO-PKD. Kappa statistic was used to determinate the concordance between Mayo and PROPKD score. Change in renal function within patients with the same class of score where analysed using Paired Wilcoxon signed rank sum test. Results We examined75 patients, 78% between 18-50 years, equally distributed for sex. The results shown thatdisease was more frequent familiar (88 %) witha percentage of mutations of PKD1 versus PKD2 mutation (90,7%/9,3%). 31patients (41%) had a GFR between 45-89 ml/min, 52patients (69%) achieved the criteria for nephromegaly according guideline (TKV &gt; 750CC). Respectively 76% (57pt) and 21%(16pt) were defined as rapid progressors for Mayo score ad Propkd score. The slope of GFR was worse in patients defined rapid progressor in spite of non rapidprogressor according MAYO score (-2,8 ml/min vs 0,3 ml/min) as for propkd classification (-3 vs - 1,75ml/min). Only for 15 patients the results were concordant for this two scores,43 patients identified as rapid progressor for Mayo score were non rapid progressor for Propkd score, in the same way 2 patients classified for Propkd were not rapid progressor for Mayo score. K of Coen of 0,07. Conclusion High risk patients present a significant decline in renal function in the first year with both score systems, confirming results of previous studies. Currently the scores used to define rapid progressors select patients differently. Concordance between scores il low (K of Cohen 0,076). The Propkd score is more selective compared to Mayo score. NeverthelessProPKD allows to identify some rapid progressor patients excluded from the use of the Mayo score only. The combined use of scoring may however increases the ability to identify progressive patients.

Gender, Albuminuria and Chronic Kidney Disease Progression in Treated Diabetic Kidney Disease

Background: Women are reported to have a lower incidence of renal replacement therapy, despite a higher prevalence of chronic kidney disease (CKD). Aim: To analyze diabetic kidney disease (DKD) progression in men and women. Methods: Prospective cohort: n = 261, 35% women, new consecutive nephrology DKD referrals. Results: Women smoked less and better complied with the dietary phosphate and sodium restrictions. Despite a less frequent nephrology referral, women had lower baseline albuminuria. Over a 30 ± 10-month follow-up, albuminuria decreased in women and the estimated glomerular filtration rate (eGFR) loss was slower than in men. However, the percentage of rapid progressors was similar in both sexes. The best multivariate model predicting rapid progression in men (area under curve (AUC) = 0.92) and women differed. Albuminuria and fractional excretion of phosphate (FEphosphate) were part of the men multivariable model, but not of women. The AUC for the prediction of rapid progression by albuminuria was higher in men than in women, and the albuminuria cut-off points also differed. In women, there was a higher percentage of rapid progressors who had baseline physiological albuminuria. Conclusions: Female DKD differs from male DKD: albuminuria was milder and better responsive to therapy, the loss of eGFR was slower and the predictors of rapid progression differed from men: albuminuria was a better predictor in men than in women. Lifestyle factors may contribute to the differences.

Predictive Factors of Rapid Linear Renal Progression and Mortality in Patients with Chronic Kidney Disease

Background: Risk factors predictive of rapid linear chronic kidney disease (CKD) progression and its associations with end-stage renal disease (ESRD) and mortality requires further exploration, particularly as patients with linear eGFR trajectory represent a clear paradigm for understanding true CKD progression.Methods: A linear regression slope was applied to all outpatient estimated glomerular filtration rate (eGFR) values for patients in the Salford Kidney Study who had ≥ 2 years follow-up, ≥ 4 eGFR values and baseline CKD stages 3a-4. An eGFR slope (ΔeGFR) of ≤-4 ml/min/1.73 m2/yr defined rapid progressors, whereas − 0.5 to + 0.5 ml/min/1.73 m2/yr defined stable patients. Binary logistic regression was utilised to explore variables associated with rapid progression and Cox proportional hazards model to determine predictors for mortality prior to ESRD.Results: There were 157 rapid progressors (median ΔeGFR − 5.93 ml/min/1.73 m2/yr) and 179 stable patients (median ΔeGFR − 0.03 ml/min/1.73 m2/yr). Over 5 years, rapid progressors had an annual rate of mortality or ESRD of 47 per 100 patients compared with 6 per 100 stable patients. Factors associated with rapid progression included younger age, female gender, higher diastolic pressure, higher total cholesterol:high density lipoprotein ratio, lower albumin, lower haemoglobin and a urine protein:creatinine ratio of > 50 g/mol. The latter three factors were also predictive of mortality prior to ESRD, along with older age, smoking, peripheral vascular disease and heart failure.Conclusions: There is a heterogenous interplay of risk factors associated with rapid linear CKD progression and mortality in patients with CKD. Furthermore, rapid progressors have high rates of adverse outcomes and require close specialist monitoring.

EFFICACY AND SAFETY OF LOW DOSE ATROPINE 0.01% IN SLOWING OF PROGRESSION OF MYOPIA

Background: Myopia, commonly referred to as short sightedness is a form of refractive error and is a very common cause of visual disability throughout the world. Methods: Hospital based prospective study conducted on 100 patients of Myopia attending to Department of Opthalmolgy. Results: There was no significant difference in the age, gender distribution, baseline myopia progression or follow-up duration between patients who used night application compared with daytime atropine. Effectiveness was better with daytime application. Conclusion: 1% atropine eye drops were well tolerated and efficacious for the retardation of progressive myopia in Indian eyes. Effectiveness was better with daytime application. Further studies are necessary to assess the role of 1% atropine in the rapid progressors and patients poorly responding to low-dose atropine. Keywords: Myopia, Atropine, low dose.