Stable Progressive Disease Research Articles

N-acetylcysteine – a drug for basic and symptomatic therapy of chronic bronchitis/chronic obstructive pulmonary disease

Prevention and successful treatment of the disease exacerbations are crucial for patients with chronic bronchitis (CB) and chronic obstructive pulmonary disease (COPD). At present, a sufficient number of efforts are being made to improve both prevention of exacerbations in patients with stable disease progression and treatment of the exacerbations. According to international and domestic recommendations, mucolytic drugs are among the key therapies for both bronchitis phenotype of COPD and chronic bronchitis, the main clinical manifestation of which is a long-term productive cough. The aim of the review is to analyze modern literature data that reflect the role of N-acetylcysteine (NAC) in prevention of exacerbations during the stable course and treatment of exacerbations of chronic bronchitis and COPD.

Phenotypic spectrum of iron-sulfur cluster assembly gene IBA57 mutations: c.286 T > C identified as a hotspot mutation in Chinese patients with a stable natural history.

Mutations in IBA57 disrupt iron-sulfur clusters maturation, causing a rare mitochondrial disease. Clinical manifestations vary from neonatal lethality to childhood-onset spastic paraparesis, yet the ethnic heterogeneity and natural history remain unclear, necessitating further exploration. This study aimed to delineate the genotype-phenotype correlation of IBA57 mutations by analyzing diverse clinical presentations. We report 11 Chinese patients and include literature-reported cases, totaling 61 patients enrolled for analysis. Clinical, neuroimaging, genetic, and disease progression information were collected. Among these, 46 presented as multiple mitochondrial dysfunctions syndrome 3 (MMDS3), with 58.7% originating from Chinese population. Based on disease course, we propose three clinical subtypes: neonatal, infant and childhood subtypes. Neonatal cases universally displayed hypotonia and respiratory distress at presentation, deceased within three months. Most infancy and childhood cases exhibited developmental regression and impaired motor function. Cavitating leukoencephalopathy was a typical neuroimaging finding in MMDS3 patients. The c.286 T > C mutation was reported in 85.2% of Chinese patients. A significantly lower mortality rate was observed compared to the non-Chinese group (P = 0.002), with a survival rate exceeding 90% at 5 years, indicating a relatively stable disease progression. Fifteen cases from three families manifested the spastic paraplegia 74 phenotype, demonstrating normal development before onset, with common clinical manifestations including spastic paraplegia (14/15), visual impairment (10/13), and peripheral neuropathy (9/13). In conclusion, this study indicates a hotspot mutation in Chinese and analyses the disease progression with different clinical subtypes.

Periodontal ageing and its management via pharmacological glucose modulation

Periodontal disease (PD), a widespread non-communicable disease, affects over 90% of the global population with no known cure. Current management strategies focus on stabilization of disease progression, which is successfully achieved to a limited extent. Yet the never-ending battle of bacteria and the gingiva involves a complex interplay between genetic, microbial and environmental factors, demanding innovative approaches to improve prevention and stabilisation of this disease. Glucose is the body's source of energy and research has shown that dysregulation of the glucose metabolism impacts PD establishment and progression, as well as impact development of systemic non communicable diseases. Metformin, a drug known for its efficacy in diabetes treatment via controlling glucose metabolism, also demonstrated cardioprotective effects, increased longevity, and anti-inflammatory properties. Metformin has been used in gel format in clinical trials for PD non-surgical treatment, however, its systemic use in normoglycemic individuals with PD is less explored. A recent study presented compelling evidence of Metformin's preventive potential, impacting PD and markers of systemic health involved in metabolic health liked to improvement of lifespan. Therefore, this review discusses the aspects of ageing as a concept in the periodontium and the potential benefits of modulating glucose metabolism through Metformin to prevent PD, indirectly preventing systemic conditions involved in multi-morbidity, addressing a critical gap in current management. It also examines the choice between implementation of behaviour change and/or medication as strategy to add to current oral hygiene strategies. Finally, it discusses the ethical implications of prescribing systemic medication in dentistry.

Recent Advance in Disease Modifying Therapies for Spinal Muscular Atrophy

Abstract Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease characterized by progressive weakness and atrophy of skeletal muscles. With homozygous survival motor neuron 1 (SMN1) gene mutation, all SMA patients have at least one copy of the SMN2 gene, which provides an opportunity for drug targeting to enhance SMN expression. Current three disease modifying drugs, including nusinersen, onasemnogene abeparvovec, and risdiplam, have demonstrated impressive effectiveness in SMA treatment. Nusinersen is an antisense oligonucleotide targeting SMN2 pre-messenger RNA (mRNA) to modify alternative splicing and is effective in SMA children and adults, administrating via intermittent intrathecal injection. Onasemnogene abeparvovec is an adeno-associated viral vector carrying human SMN1 gene, featuring intravenous injection once in a lifetime for SMA patients less than 2 years of the age. Risdiplam is a small molecule also targeting SMN2 pre-mRNA and is effective in SMA children and adults with administration via oral intake once per day. Patients with SMA should receive these disease modifying therapies as soon as possible to not only stabilize disease progression, but potentially obtain neurological improvement. The development in these therapies has benefited patients with SMA and will potentially provide insight in future drug discovery for other neurodegenerative diseases.

Comprehensive Evaluation of Sporadic Late-Onset Cerebellar Ataxias: Clinical Presentation, Diagnostic Challenges, and Treatment Outcomes.

Sporadic late-onset cerebellar ataxias (SLOCA) present a diagnostic challenge due to their heterogeneous etiologies and complex clinical manifestations. This retrospective study aimed to conduct a comprehensive evaluation of six male patients diagnosed with SLOCA, with a mean age of 55 years and an average symptom onset at 47 years. All patients presented with gait and balance disturbances, with additional sensory abnormalities observed in two cases. Neurological examinations revealed varied cerebellar syndromes, including static and static-kinetic presentations, accompanied by peripheral neurogenic syndromes in some instances. Brain MRI findings showed cerebellar atrophy, predominantly involving the vermis, in a subset of patients. Biochemical and serological investigations yielded mostly unremarkable results, although two patients exhibited significant vitamin E deficiency and anti-Hu antibodies (anti-neuronal nuclear antibody type 1). Electromyography confirmed sensory axonal neuropathy in those with peripheral neurogenic syndromes. Treatment with TOCO 500 mg (Vitamin E) was administered to four patients, with follow-up indicating stable disease progression in two cases. This study underscores the complexity of SLOCA and the need for a multidisciplinary approach to diagnosis and management. Further research is warranted to elucidate the underlying mechanisms and improve clinical outcomes for affected individuals.

Predictive analytics support for complex chronic medical conditions: An experience-based co-design study of physician managers’ needs and preferences

PurposeThe literature suggests predictive technology applications in health care would benefit from physician and manager input during design and development. The aim was to explore the needs and preferences of physician managers regarding the role of predictive analytics in decision support for patients with the highly complex yet common combination of multiple chronic conditions of cardiovascular (Heart) and kidney (Nephrology) diseases and diabetes (HND). MethodsThis qualitative study employed an experience-based co-design model comprised of three data gathering phases: 1. Patient mapping through non-participant observations informed by process mining of electronic health records data, 2. Semi-structured experience-based interviews, and 3. A co-design workshop. Data collection was conducted with physician managers working at or collaborating with the HND center, Danderyd University Hospital (DSAB), in Stockholm, Sweden. HND center is an integrated practice unit offering comprehensive person-centered multidisciplinary care to stabilize disease progression, reduce visits, and develop treatment strategies that enables a transition to primary care. ResultsInterview and workshop data described a complex challenge due to the interaction of underlying pathophysiologies and the subsequent need for multiple care givers that hindered care continuity. The HND center partly met this challenge by coordinating care through multiple interprofessional and interdisciplinary shared decision-making interfaces. The large patient datasets were difficult to operationalize in daily practice due to data entry and retrieval issues. Predictive analytics was seen as a potentially effective approach to support decision-making, calculate risks, and improve resource utilization, especially in the context of complex chronic care, and the HND center a good place for pilot testing and development. Simplicity of visual interfaces, a better understanding of the algorithms by the health care professionals, and the need to address professional concerns, were identified as key factors to increase adoption and facilitate implementation. ConclusionsThe HND center serves as a comprehensive integrated practice unit that integrates different medical disciplinary perspectives in a person-centered care process to address the needs of patients with multiple complex comorbidities. Therefore, piloting predictive technologies at the same time with a high potential for improving care represents an extreme, demanding, and complex case. The study findings show that health care professionals’ involvement in the design of predictive technologies right from the outset can facilitate the implementation and adoption of such technologies, as well as enhance their predictive effectiveness and performance. Simplicity in the design of predictive technologies and better understanding of the concept and interpretation of the algorithms may result in implementation of predictive technologies in health care. Institutional efforts are needed to enhance collaboration among the health care professionals and IT professionals for effective development, implementation, and adoption of predictive analytics in health care.

Personal and Shared Tumor-Antigen Prioritization in Diffuse Large B Cell Lymphoma Patients Undergoing CD19 CAR T Cell Treatment

Backgroun d: Durable response to Axi-cel CD19 CAR T cell therapy is associated with activation and clonotypic expansion of the host T cell repertoire (Cheloni et al Blood, ASH, 2022). The characterization of the tumor microenvironment (TME) and the identification of tumor antigens associated with therapeutic efficacy is a critical area of investigation. Aim: We sought to determine the association between the host immune activation in response to tumor-associated and tumor-specific antigens and the clinical response to CAR-T cell treatment in diffuse large B cell lymphoma patients. Methods: RNAseq was performed on FFPE lymphoma samples collected before CAR T cell infusion (N=16). Patients were divided into 3 distinct cohorts: stable progressive disease at 1 month post-CAR T (non-responders, n=2), disease relapse within 6 months post-CAR T (relapsed, n=3), and on-going response lasting greater than 1 year (long-term responders, n=11). For neoantigens, mutations were retrieved following the GATK best practices for RNAseq data and annotated with Variant Effect Predictor (VEP). Tumor-specific antigens and tumor-associated antigens were detected by prioritizing 9-11mer amino acid sequences, preferentially presented by class I molecules, observed solely or primarily in tumor samples, respectively, as compared to a pool of healthy controls derived from 250 RNAseq samples, corresponding to 29 tissues (GTEx Portal). Antigen prioritization was performed following weighted scoring considering RNA expression, translation potential, peptide-MHC binding affinity, predicted immunogenicity, physicochemical properties, and clonality, in the case of neoantigens. Using deconvolution methods and canonical marker expression, we characterized the major immune cell types within the TME. Results: Higher cell proportions of lymphocytes and innate immune cells, including NK, and activated dendritic cells were observed in long-term responders, suggesting that a higher infiltration of these cell types in the tumor bed is associated with a better response to CAR T cell therapy. Notably, a positive correlation between the mutational burden and the a/b clonotypic expansion of peripheral blood cytotoxic T cell populations, detected from single-cell immunoprofiling (Cheloni et al Blood, ASH, 2022) was observed in eight long-term responders, consistent with prior studies highlighting the significance of neoantigens in eliciting robust and durable immune response against cancer cells. A high occurrence of neoantigens originating from the Titin ( TTN) gene in two long-term responders with the highest mutational burden was observed, and from ACTB and ACTG1, mutated genes associated with lymphoid cancers. A substantial enrichment of shared tumor antigens originating from retroelements was observed in long-term responders, suggesting the presence of common epitopes that drive an antigen-specific response. Conclusion: These findings shed light on the potential immunogenicity of specific neoantigens and shared antigens derived from repetitive elements, which could serve as promising targets for immunotherapeutic strategies in lymphoma patients. Understanding the tumor immune landscape and antigenic features associated with long-term response to CAR T cell therapy may pave the way for the development of personalized and effective combinatorial treatments for lymphoid cancers.

Predictive significance of circulating tumor DNA against patients with T790M-positive EGFR-mutant NSCLC receiving osimertinib

Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. The prognostic usefulness of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Therefore, the present study evaluated ctDNA during osimertinib administration as a second-line or more setting to identify the relationship between EGFR mutation levels and outcomes in patients with advanced non-small cell lung cancer (NSCLC). Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were registered. Plasma samples were collected at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed by digital polymerase chain reaction. The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib than at pretreatment, and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. No statistically significant difference was observed in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD. The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

Clinical effectiveness of screening for age-related macular degeneration: A systematic review

Introduction Age-related macular degeneration (AMD) is an eye disease that occurs in patients over 50 years old. Early diagnosis enables timely treatment to stabilize disease progression. However, the fact that the disease is asymptomatic in its early stages can delay treatment until it progresses. As such, screening in specific contexts can be an early detection tool to reduce the clinical and social impact of the disease. Objective Assess the effectiveness of screening methods for early detection of AMD in adults aged 50 years or older. Methods A systematic review of comparative observational studies on AMD screening methods in those aged 50 years or older, compared with no screening or any other strategy. A literature search was conducted in the MEDLINE (via PubMed), Embase, Cochrane Library and Lilacs database. Results A total of 5,290 studies were identified, three of which met the inclusion criteria and were selected for the systematic review. A total of 8,733 individuals (16,780 eyes) were included in the analysis. The screening methods assessed were based on optical coherence tomography (OCT) compared with color fundus photography, and OCT and telemedicine testing compared to a standard eye exam. Conclusion The systematized data are limited and only suggest satisfactory performance in early screening of the population at risk of developing AMD. OCT and the telemedicine technique showed promising results in AMD screening. However, methodological problems were identified in the studies selected and the level of evidence was considered low.

Magrolimab, Rituximab and Acalabrutinib for Relapsed/Refractory (R/R) Diffuse Large B-Cell Lymphoma (DLBCL): Results from the Phase 1 PRISM Trial

Background: R/R DLBCL patients (pts) who fail multiple lines of treatment or are ineligible for novel treatments, including CAR T-cell therapy, have poor clinical outcomes. The combination of the anti-CD47 monoclonal antibody (mAb) magrolimab and rituximab enhances macrophage-mediated antibody-dependent cellular phagocytosis in DLBCL (Advani et al. NEJM 2019). We hypothesized that the Bruton's tyrosine kinase inhibitor acalabrutinib would further enhance clinical activity in R/R DLBCL. We present the final analysis of Arm 3 of the Phase 1 PRISM platform study of acalabrutinib with magrolimab and rituximab in all molecular subtypes of R/R DLBCL (NCT03527147). Methods:Adults with DLBCL and ECOG PS ≤2 who had failed ≥1 line of prior chemoimmunotherapy or were ineligible for high-dose chemotherapy with stem-cell rescue and/or CAR T-cell therapy were eligible. Pts with prior CAR T-cell therapy were excluded from the dose-limiting toxicity (DLT) evaluable pts. Pts received magrolimab 1 mg/kg IV priming dose on cycle 1 day 1 (C1D1) of a 28-day cycle, then 30 mg/kg IV on D8, D15, and D22, on D1, D8, D15, and D22 of C2, and on D1 and D15 thereafter. Rituximab 375 mg/m2 was given on D8, D15, and D22 of C1, D1 of C2-6 and every other cycle from C8 onwards. Acalabrutinib was given continuously at 100 mg twice daily. Combination treatment was given until disease progression or for a maximum of 2 years. DLTs were evaluated from first treatment administration until the end of C1. The primary objective was safety of the combination regimen. Secondary objectives included response rate, pharmacokinetics (PK), and immunogenicity. Exploratory analyses included baseline tumor samples, baseline and longitudinal immunophenotyping of peripheral blood, and cytokine and mutation analysis of plasma samples. Results:By 31 March 2021, 7 pts with DLBCL (including 3 with transformed disease) were enrolled. Median age was 72 years (51-84). Pts had received a median of 4 prior regimens (range 1-6). Three (42.9%) pts were refractory to their most recent regimen. No DLTs were observed in 6 DLT-evaluable pts. Five pts discontinued treatment due to progressive disease (PD), 1 due to an adverse event (AE), and 1 due to study termination. Grade ≥3 AEs regardless of causality reported in ≥10% of pts included anemia (42.9%), thrombocytopenia (28.6%), bilirubin elevation (14.3%), vomiting (14.3%), and ALT elevation (14.3%). Two pts experienced serious AEs (1 pneumonitis, 1 septic shock). Overall, the safety profile was consistent with magrolimab monotherapy studies. No treatment-related deaths were reported. Two (28.6%) pts had an objective response per Response Evaluation Criteria in Lymphoma (RECIL) 2017; both were complete responses (CR). At a median follow-up of 8.3 months, response durations for these pts were 0.03 and 7.36 months. One CR pt had a non-germinal center B-cell (GCB) DLBCL; the other was unknown. Of the 2 PD pts, 1 had non-GCB DLBCL with a BN2/A53 genetic subtype and 1 had GCB DLBCL with an EZB/A53 genetic subtype. Fluctuations in cell-free DNA (cfDNA) and cytokines tended to correlate with response by imaging. Both PD pts had higher plasma cfDNA concentrations than other pts (1 pt at screening, C1D1, and C1D8 and the other at C1D15, C2D1, and end of treatment). CR pts had lower mutational burden and lower variant allele frequencies than PD pts at screening and longitudinally. The allele frequencies of copy number alterations in tissue samples at screening were also higher in stable disease and PD pts. PD pts had higher baseline levels of ICAM1, IL-10, IL-15, IL-6, MCP-1, MIP1a, MIP1b, TNF-b, VEGF-A, and VEGF-D than non-PD pts. PK data were consistent with monotherapy results and no antibodies to magrolimab were detected. Conclusions:Acalabrutinib combined with magrolimab and rituximab was safe and tolerable in pts with advanced R/R DLBCL and no prior exposure to CAR T-cell therapy. The safety profile of the combination was consistent with the known safety profiles of the individual agents. However, due to the lack of obvious clinical synergy of the triplet over acalabrutinib monotherapy or the combination of magrolimab and rituximab, the study was stopped prematurely. Conclusions from cfDNA and cytokine analyses are limited by small pt numbers, but such analyses should be included in future studies of targeted combinations because mounting evidence suggests they tend to correlate with response.

Improved upper limb function in non-ambulant children with SMA type 2 and 3 during nusinersen treatment: a prospective 3-years SMArtCARE registry study

BackgroundThe development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months.MethodsSMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM).ResultsData from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score.ConclusionOur results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity.

Nusinersen (Spinraza)


 CADTH recommends that Spinraza should not be reimbursed by public drug plans for the treatment of patients with type II and type III 5q spinal muscular atrophy (SMA) regardless of ambulatory status if initiated in patients older than 18 years of age.
 No randomized clinical trials evaluating the efficacy or safety of Spinraza in treatment-naïve adult patients with type II or type III SMA have been conducted.
 Evidence from 4 observational studies generally suggested that treatment with Spinraza may improve or maintain physical abilities; however, due to the limitations of these studies, it was not possible to conclude that the improvement or maintenance in physical function including movement or strength were a result of Spinraza.
 There is a need for treatments in adult patients with type II and type III SMA that stabilize disease progression, including the avoidance of using machines to help breathing, improve strength in the upper limbs, and improve health-related quality of life (HRQoL). However, the evidence reviewed did not show that Spinraza would meet any of these needs.

Conservative Iron Chelation for Neuroferritinopathy.

Neuroferritinopathy is a rare inherited neurodegenerative disease with brain iron accumulation characterized by brain iron overload resulting in progressive movement disorders. No treatment is currently available. We assessed conservative iron chelation with deferiprone at 30 mg/kg/day on the disease progression with controlled periods of discontinuation. Four patients with confirmed molecular diagnosis of neuroferritinopathy were given deferiprone at different stages of disease progression and with clinical and biological monitoring to control benefit and risk. The four patients showed slight to high improvement. In one case, we managed to stabilize disease progression for more than 11 years. In another case, we were able to reverse symptoms after a few months of treatment. The earliest the treatment was started, the most efficient it was on disease progression. Conservative iron chelation should be further assessed in neuroferritinopathy. © 2022 International Parkinson and Movement Disorder Society.

A Comparative Study of Ranibizumab and Aflibercept for Neovascular Age-Related Macular Degeneration: 12-Month Outcomes of Polish Therapeutic Program in Non-Tertiary Institution.

IntroductionThis single-center study aimed to compare the 12-month treatment outcomes of ranibizumab with that of aflibercept in routine clinical practice.MethodsCohort of patients diagnosed with treatment-naïve neovascular age-related macular degeneration (AMD), treated using either ranibizumab (n = 33 eyes) or aflibercept (n = 44 eyes) monotherapy over a 12-month follow-up period was analyzed. Anonymous data were extracted from the electronic database dedicated to the drug program.ResultsIn the ranibizumab group, there were no statistically significant changes in best-corrected visual acuity (BCVA) (Early Treatment Diabetic Retinopathy Study [ETDRS] letters) and central retina thickness (CRT) (µm), between baseline (67.9 ± 8.6 & 384.9 ± 97.9) and at 12 months (67.9 ± 12.1 & 398.9 ± 127.1; P = 0.372 & P = 0.884, respectively). In the aflibercept, there was an improvement in BCVA and reduction in CRT between baseline (64.2 ± 8.1 & 414.3 ± 97.8) and at 12 months (70.7 ± 7.4 & 342.3 ± 71.6; P < 0.001 & P < 0.001, respectively). There was no difference in BCVA between the two groups at either diagnosis (P = 0.101) or 12 months (P = 0.917). Mean number of injections in the ranibizumab group was significantly lower (4.9 ± 1.5) than in the aflibercept group (6.7 ± 1; P < 0.001).Conclusions One initial injection of ranibizumab and then pro re nata (PRN) regimen resulted in stabilization of disease progression. Drug selection and treatment scheme could influence twelve-months outcomes. In the aflibercept group, three initial monthly injections and then every two months provided both significant BCVA improvement and CRT reduction at 12 months of treatment.

Sustained Complete Response after Biological Downstaging in Patients with Hepatocellular Carcinoma: XXL-Like Prioritization for Liver Transplantation or "Wait and See" Strategy?

Simple SummaryThe XXL trial has recently shown that biological downstaging is an effective strategy to also allow liver transplantation into patients with more advanced hepatocellular carcinoma without alternative curative options. Some potential limits of the XXL downstaging protocol are (a) the rather high downstaging failure rate (i.e., 32%), and (b) the additional prioritization of transplantation for patients with a potential good prognosis without transplant, i.e., those obtaining a complete response to downstaging. In this study, we showed that, using aggressive surgical downstaging, it is possible to considerably decrease the downstaging failure rate. Moreover, we showed that it is possible to avoid an immediate prioritization of transplantation for patients with a sustained complete response to downstaging by applying a “wait and see” policy. This policy seems to spare a relevant number of organs without worsening patient outcome.The XXL trial represents the first prospective validation of “biological downstaging” in liver transplantation (LT) for hepatocellular carcinoma. The aim of this study was to compare the Padua downstaging protocol to the XXL protocol in terms of downstaging failure rates and patient outcome. A total of 191 patients undergoing aggressive surgical downstaging and potentially eligible for LT from 2012 to 2018 at our center were retrospectively selected according to XXL trial criteria. Unlike the XXL trial, patients with a complete response to downstaging did not receive any prioritization for LT. Downstaging failure was defined as stable progressive disease or post-treatment mortality. The statistical method of “matching-adjusted indirect comparison” was used to match the study group to the XXL population. Downstaging failure rate was considerably lower in the study group than in the XXL trial (12% vs. 32%, d value = |0.683|). The survival curves of our LT group (n = 68) overlapped with those of the LT-XXL group (p = 0.846). Survival curves of non-LT candidates with a sustained complete response (n = 64) were similar to those of transplanted patients (p = 0.281). Our study represents a validation of the current Padua and Italian policies of denying rapid prioritization to patients with complete response to downstaging. Such a policy seems to spare organs without worsening patient outcome.

Allogeneic hematopoietic stem cell transplantation in patients with childhood cerebral adrenoleukodystrophy: A single-center experience "Better prognosis in earlier stage".

ALD is a rare X-linked peroxisomal metabolic disorder with many distinct phenotypes of disease that emerge on a wide scale from adrenal insufficiency to fatal cALD which progresses to a vegetative state within a few years. Currently, HSCT is the only treatment method known to stabilize disease progression in patients with cALD. In this study, we aim to report our HSCT experience in patients with cALD and the factors that determine the success of HSCT, as a single-center experience. The study cohort involves 23 boys with cALD and three patients with ALD trait and new-onset abnormal behavior who underwent allogeneic HSCT between January 2012 and September 2019 in our transplantation center. Loes scoring, NFS, scale and MFD were performed for evaluating the severity of the cerebral disease. The study cohort was divided into two groups according to baseline NFS and Loes score: early-stage (NFS≤1 and Loes score <9) and advanced stage (NFS>1 or Loes score ≥9). The pretransplant stage of disease impacted both OS and MFD-free survival. The estimated OS and MFD-free survival at 3years in patients with advanced disease were 46.1% (95% CI 19.0-73.2) and 23.1% (95% CI 0.2-46.0), respectively, and all patients with the early disease were alive (p: .004) and MFD-free (p<.001) at 3years. This study demonstrated that early HSCT is vital in patients with cALD. The early-stage disease had a significant survival advantage and free from disease progression after HSCT.

THORACOSCOPIC SURGICAL STAPLING AND ENDOBRONCHIAL VALVE PLACEMENT FOR LUNG VOLUME REDUCTION WITH INCOMPLETE LOBAR FISSURES: INITIAL EXPERIENCE

SESSION TITLE: Fellows Obstructive Lung Disease Posters SESSION TYPE: Fellow Case Report Posters PRESENTED ON: October 18-21, 2020 INTRODUCTION: Emphysema affects more than 4 million cases diagnosed in the US. Recently, bronchial valves were approved for selected patients with complete lobar fissure and severe hyperinflation. Unfortunately, most patients have collateral ventilation (CV) and thus are not candidates for bronchoscopic lung volume reduction alone. Combined minimally invasive thoracoscopic intervention to complete lung fissure along with bronchial valves (BVs) to achieve lung volume reduction is an appealing treatment for the majority of patients with CV. Our group has recently described the use of this combined procedure in animal models, but this is the first description in clinical practice. CASE PRESENTATION: A 58-year-old woman with severe heterogeneous emphysema and hyperinflation underwent endobronchial bronchial valves placement without significant improvement in her symptoms or pulmonary function tests at her 6 months follow-up visit. Following a multidisciplinary discussion with thoracic surgery, the patient underwent major fissure completion via VATS. The patient tolerated the procedure well and was discharged from the hospital on postoperative day 3. At 1-month follow up, patient-reported progressive improvement in her dyspnea. Her chest radiography showed atelectasis of the target lobe. Her lung function test showed an improvement of 0.1L (4%) in her FEV1, a decrease of 0.5L (27%) in her RV, and an increase of 1.4mL/min/mmHg (18%) in her DLCO. Another 59-year-old woman with severe homogeneous emphysema with hyperinflation. She underwent bronchial valve placement without significant improvement in her symptoms or pulmonary function tests at 12 months follow up visit. Following a multidisciplinary discussion with thoracic surgery, the patient underwent major fissure completion via VATS along with the removal of abundant pleural adhesions. She had an air leak for 3 days that resolved and was discharged home at postoperative day 4. At one month follow up, the patient had no improvement in her dyspnea. Her chest radiography showed hyperinflation without improvement in the lung function test. DISCUSSION: As emphysema remains an irreversible disease, treatment goals are primarily aimed to slow and stabilize disease progression, relieve symptoms, and improve quality of life. The most important factor that may prevent the development of desired lung volume reduction following bronchial valve treatment is CV. We present the first 2 cases in which a thoracoscopic approach was used to complete the interlobar fissures to address CV. The refinement of the technique along with appropriate patient selection is still under progress. CONCLUSIONS: Lobar fissure completion along with bronchial valves is a promising management alternative for patients with CV. Reference #1: Majid A, Kheir F, Alape D, Chee A, Parikh M, DeVore L, et al. Combined Thoracoscopic Surgical Stapling and Endobronchial Valve Placement For Lung Volume Reduction With Incomplete Lobar Fissures: An Experimental Pilot Animal Study. J Bronchol Interv Pulmonol. 2019 Aug;1. Reference #2: Global Initiative for Chronic Obstructive Lung Disease (GOLD): Global Strategy for the Diagnosis, Management, and Prevention of COPD 2020. Reference #3: Koster D, Slebos D-J. The fissure: interlobar collateral ventilation and implications for endoscopic therapy in emphysema. Int J Chron Obstruct Pulmon Dis. 2016 Apr;765. DISCLOSURES: No relevant relationships by Sidhu Gangadharan, source=Web Response No relevant relationships by Fayez Kheir, source=Web Response Consultant relationship with Boston Scientific Please note: $1001 - $5000 by Adnan Majid, source=Web Response, value=Consulting fee Consultant relationship with olympus Please note: $5001 - $20000 by Adnan Majid, source=Web Response, value=Consulting fee Consultant relationship with pinacle biologics Please note: $1001 - $5000 by Adnan Majid, source=Web Response, value=Consulting fee Consultant relationship with cook medical Please note: $1001 - $5000 by Adnan Majid, source=Web Response, value=Consulting fee No relevant relationships by Daniel Ospina-Delgado, source=Web Response

Epidemiological &amp; Clinical Manifestation of Cirrhosis of Liver in a Tertiary Hospital

Introduction:Cirrhosis of liver is common Medical problem in our country and causing for significant morbility &amp; mortality. This study was aimed to findout actiology and clinical presentation of cirrhosis in this southern part of Bangladesh.&#x0D; Materials &amp; Methods: An observantional study was conducted in Khulna Medical College Hospital from January 2016 to June 2016. That included adult (&gt;15yrs) cirrhosis patient in medicine ward on the basis of history &amp; clinical examination.&#x0D; Results: Common age is (37-48)yrs, 80% were male patient. Male Female ratio 4:1. Anorexia &amp; dyspepsia were the most common symptom. 78% presented with ascites 34% presented with variceal bledding. Aetiology are Hepatitis B (52%), Hepatitis C (24%) &amp; idiopathic 16%.&#x0D; Conclusion: Screening for chronic liver disease should include history and physical examination, serum transaminase measurement, upper abdominal ultrasonography, and in some case, fibroscan. Management of patient with cirrhosis should be prevention &amp; early intervention to stabilize disease progression and to avoid or delay clinical decompensation and the need for liver transplantation.&#x0D; Medicine Today 2020 Vol.32(2): 100-103

Optimized management of nivolumab (Nivo) and ipilimumab (Ipi) in advanced renal cell carcinoma (RCC): A response-based phase II study (OMNIVORE).

5005 Background: Nivo + Ipi is an established first-line treatment (tx) for advanced RCC. We hypothesized that the addition of CTLA-4 blockade may not be required for all patients (pts). Furthermore, the optimal duration of Nivo maintenance in responding pts is unknown. In this phase II response-adaptive trial, we investigate the sequential addition of 2 doses of Ipi to induce response in Nivo non-responders (NR) and duration of Nivo in responding pts (NCT03203473). Methods: We enrolled pts with advanced RCC with no prior checkpoint inhibitor exposure. All pts received Nivo alone with subsequent arm allocation based on RECISTv1.1 response within 6 months (mos) of tx. Pts with a confirmed partial response (PR) or complete response (CR) within 6 months (mos) discontinued Nivo and were observed (Arm A). Arm A pts reinitiated Nivo if they developed progressive disease (PD); Ipi was added to Nivo if PD persisted or recurred. Pts with stable disease (SD) or PD after no more than 6 mos of Nivo alone received 2 doses of Ipi (Arm B). The primary endpoints were the proportion with PR/CR at 1-year (yr) after Nivo discontinuation (Arm A) and proportion of Nivo NR who convert to PR/CR after adding Ipi (Arm B). Results: 83 pts initiated tx of whom 99% had ECOG 0-1, 96% clear cell RCC, 51% tx-naïve, and 69% IMDC intermediate/poor risk. Median follow-up was 17.0 mos. 15 pts were not allocated to an arm [7 withdrew for PD, 7 withdrew for toxicity, 1 still on tx with unconfirmed PR (uPR)]. At 6 mos, induction Nivo resulted in a confirmed PR in 11% of pts (n=9/83): 12% (n=5/42) tx-naïve, 10% (4/41) prior tx, 8% (n=1/13) favorable risk, 11% (n=8/70) intermediate/poor risk (Table). 11 pts (13%: 9 PR, 1 uPR, 1 SD) were allocated to Arm A, of whom 5 (45%, 90% CI 20-73%) remained off Nivo at ≥ 1 yr. Of 57 pts (69%) allocated to Arm B, 2 pts converted to a PR (4%, 90% CI 1-11%), both of whom had prior tx and PD as best response to Nivo alone. Grade 3-4 treatment related adverse events (TrAE) occurred in 7% (n=6/83) on induction Nivo and in 23% (n=13/57) on Arm B (Nivo + Ipi). Conclusions: We cannot currently recommend a strategy of Nivo followed by response-based addition of Ipi due to the absence of CR and low PR/CR conversion rate (4%). Though a subset of pts treated with Nivo alone can maintain durable responses off tx at 1-yr, early Nivo discontinuation in the absence of toxicity cannot currently be recommended. Investigation into biomarkers to guide tx is ongoing. Clinical trial information: NCT03203473 . [Table: see text]

Fibrillary Glomerulonephritis: Clinicopathologic Features and Atypical Cases from a Multi-Institutional Cohort.

Fibrillary GN has been defined as an immune complex-mediated GN with amyloid-like fibrils larger than amyloid which are IgG positive and Congo red negative. With discovery of DNAJB9 as a highly sensitive and specific marker for fibrillary GN, the specificity of the morphologic criteria for establishing the diagnosis of fibrillary GN has come into question. We sought to (1) determine anatomic characteristics that best define fibrillary GN and (2) identify clinical and pathologic features that predict outcomes. We retrospectively reviewed kidney biopsies from patients diagnosed with fibrillary GN or suspected fibrillary GN between 1997 and 2017 (n=266, 65% female, median age 61). Approximately 11% of kidney biopsies had one or more unusual feature including monotypic deposits, Congo red positivity, or unusual fibril diameter. Fibrillary GN as a possible monoclonal gammopathy of renal significance represented <1% of cases. Immunostaining for DNAJB9 confirmed fibrillary GN in 100% of cases diagnosed as fibrillary GN and 79% of atypical cases diagnosed as possible fibrillary GN. At a median time of 24 months (interquartile range, 8-46 months) after biopsy (n=100), 53% of patients reached the combined primary outcome of ESKD or death, 18% had CKD, and 18% had partial remission. On multivariable analysis, male sex (adjusted hazard ratio [aHR], 3.82; 95% confidence interval [95% CI], 1.97 to 7.37) and eGFR were the most significant predictors of primary outcome (aHR of 8.02 if eGFR <30 ml/min per 1.73 m2 [95% CI, 1.85 to 34.75]; aHR of 6.44 if eGFR 30 to <45 ml/min per 1.73 m2 [95% CI, 1.38 to 29.99]). Immunosuppressive therapy with rituximab was significantly associated with stabilization of disease progression. Detection of DNAJB9 is a useful diagnostic tool for diagnosing atypical forms of fibrillary GN. The outcomes for fibrillary GN are poor and progression to ESKD is influenced predominantly by the degree of kidney insufficiency at the time of diagnosis and male sex. Rituximab may help preserve kidney function for select patients with fibrillary GN. This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_11_04_CJN03870319.mp3.