Subsequent Course Of Disease Research Articles

Modern-day limeys: Clinical, laboratory, and radiological profile of 10 paediatric scurvy patients

ABSTRACT Scurvy is often considered a disease of the past and well described in children with neurodevelopment and autistic spectrum disease. Clinicians overlook the diagnosis of scurvy, leading to unwarranted laboratory investigations and, unfortunately, significant delays in diagnosis. This study aims to describe 10 cases of scurvy in a tertiary hospital setup with their clinical profile, comorbidities, radiological, and subsequent disease course in children presenting to the pediatric rheumatology department at Amrita Hospital, Kochi, from 2017 to 2022. Demographic, imaging, and associated comorbid conditions including neuropsychiatric abnormalities were documented. They were all reviewed in 2 weeks for improvement of symptoms. A total of 10 children (3 females) were included in this study. The disease manifested predominantly in early childhood (median age: 5.5 years). All patients had unexplained bone pain and inability to bear weight. The referral diagnosis of 8/10 patients was juvenile idiopathic arthritis. Two patients had autism as a comorbidity. Selective eating habits and food faddism were present in 2/10 children. All patients have made a full functional recovery at review. All patients had imaging findings suggestive of scurvy. Pediatricians and rheumatologists alike must consider scurvy in a child with unexplained bone pain and symptoms masquerading as primary rheumatological diseases. Selective eating habits need to be treated with timely and appropriate psychological rehabilitation and dietary education. Resolution of symptoms and radiographic features with vitamin C supplementation is the strongest evidence for scurvy.

Clinical features and outcomes in carriers of pathogenic desmoplakin variants.

Pathogenic variants in the desmoplakin (DSP) gene are associated with the development of a distinct arrhythmogenic cardiomyopathy phenotype not fully captured by either dilated cardiomyopathy (DCM), non-dilated left ventricular cardiomyopathy (NDLVC), or arrhythmogenic right ventricular cardiomyopathy (ARVC). Prior studies have described baseline DSP cardiomyopathy genetic, inflammatory, and structural characteristics. However, cohort sizes have limited full clinical characterization and identification of clinical and demographic predictors of sustained ventricular arrhythmias (VAs), heart failure (HF) hospitalizations, and transplant/death. In particular, the relevance of acute myocarditis-like episodes for subsequent disease course is largely unknown. All patients with pathogenic/likely pathogenic (P/LP) DSP variants in the worldwide DSP-ERADOS Network (26 academic institutions across nine countries) were included. The primary outcomes were the development of sustained VA and HF hospitalizations during follow-up. Fine-Gray regressions were used to test association between clinical and instrumental parameters and the development of outcomes. Eight hundred patients [40.3 ± 17.5 years, 47.5% probands, left ventricular ejection fraction (LVEF) 49.5 ± 13.9%] were included. Over 3.7 [1.4-7.1] years, 139 (17.4%, 3.9%/year) and 72 (9.0%, 1.8%/year) patients experienced sustained VA and HF episodes, respectively. A total of 32.5% of individuals did not fulfil diagnostic criteria for ARVC, DCM, or NDLVC; their VA incidence was 0.5%/year. In multivariable regression, risk features associated with the development of VA were female sex [adjusted hazard ratio (aHR) 1.547; P = .025], prior non-sustained ventricular tachycardia (aHR 1.721; P = .009), prior sustained VA (aHR 1.923; P = .006), and LVEF ≤ 50% (aHR: 1.645; P = .032), while for HF, they were the presence of T-wave inversion in 3+ electrocardiogram leads (aHR 2.036, P = .007) and LVEF ≤ 50% (aHR 3.879; P < .001). Additionally, 70 (8.8%) patients experienced a myocardial injury episode at presentation or during follow-up. These episodes were associated with an increased risk of VA and HF thereafter (HR 2.394; P < .001, and HR 5.064, P < .001, respectively). Patients with P/LP DSP variants experience high rates of sustained VA and HF hospitalizations. These patients demonstrate a distinct clinical phenotype (DSP cardiomyopathy), whose most prominent risk features associated with adverse clinical outcomes are the presence of prior non-sustained ventricular tachycardia or sustained VA, T-wave inversion in 3+ leads on electrocardiogram, LVEF ≤ 50%, and myocardial injury events.

Clinical significance of time interval between surgery and adjuvant chemotherapy in patients with gastric cancer after gastrectomy: A population-based cohort study using a nationwide claims database.

333 Background: Adjuvant chemotherapy can reduce recurrence rates by eradicating microscopic metastases which may persist after curative resection. However, the optimal time interval (TI) between the surgery and chemotherapy remains controversial. Methods: The data were obtained from the NHIS of Korea. We included patients who underwent gastrectomy for gastric cancer between 2013 and 2018. To determine the optimal cut-off point of TI, a restricted cubic spline cox regression model was established, and categorized the population into three groups based on TI: the early group (≤ 20 days), the reference group (21-34 days), and the late group (≥ 35 days) with the reference interval group having the lowest mortality and recurrence. Propensity score matching was performed for each group. The primary outcomes were disease-free survival (DFS) and overall survival (OS). Results: During the study period, 98,556 patients underwent surgery for gastric cancer. After excluding ineligible participants, 6,602 patients were included in the analysis. The median DFS and OS did not differ significantly between the early and reference groups ( p=0.7258 and p=0.6056, respectively). In comparison between the late and reference groups, the median DFS was significantly lower in the late group ( p=0.0079). 5-year DFS were 77.6% and 81.3% in the late and reference groups, respectively. Furthermore, the late group showed worse OS than the reference group ( p=0.0336). OS at 5-year were 82.1% and 85.0% in the late and reference groups, respectively. In the multivariable analysis, DFS in the late group retained inferiority (aHR 1.138, 95% CI: 1.003-1.292, p=0.045). OS showed a worse trend without significance compared to the reference group (aHR 1.138, 95% CI: 0.984-1.317, p=0.0805). Conclusions: Adjuvant chemotherapy after gastrectomy in patients with gastric cancer should be initiated within five weeks of surgery. A delay of more than five weeks may have a detrimental effect on the subsequent disease course.

Time interval between surgery and adjuvant chemotherapy in patients with gastric cancer after gastrectomy: a population-based cohort study using a nationwide claim database.

Adjuvant chemotherapy can reduce recurrence rates by eradicating microscopic metastases which may persist after curative resection. However, the optimal time interval (TI) between the surgery and chemotherapy remains controversial. This study investigated the optimal TI between surgery and chemotherapy. A population-based cohort study using a nationwide claims database. The data were obtained from the Korean National Health Insurance Service (NHIS) of Korea. We included patients who underwent gastrectomy between 2013 and 2018. To determine the optimal cutoff point of TI, a restricted cubic spline Cox regression model was established, and categorized the population into three groups based on TI: the early (⩽20 days), the late (⩾35 days), and the reference group (21-34 days), and with the reference group having the lowest mortality and recurrence. Propensity score matching was performed for each group. The primary outcomes were disease-free survival (DFS) and overall survival (OS). After excluding ineligible participants, 6602 patients were included. The median DFS and OS did not differ significantly between the early and reference groups (p = 0.7258 and p = 0.6056, respectively). In comparison between the late and reference groups, it was significantly lower in the late group (p = 0.0079). Five-year DFS rates were 77.6% and 81.3% in the late and reference groups, respectively. The late group showed worse OS than the reference group (p = 0.0336). Five-year OS rates were 82.1% and 85.0% in the late and reference groups, respectively. In the multivariable analysis, DFS in the late group retained inferiority [adjusted hazard ratio (aHR): 1.138, 95% confidence interval (CI): 1.003-1.292, p = 0.045]. OS showed a worse trend without significance compared to the reference group (aHR: 1.138, 95% CI: 0.984-1.317, p = 0.0805). Adjuvant chemotherapy after gastrectomy in patients with gastric cancer should be initiated within 5 weeks of surgery. A delay of more than 5 weeks may have a detrimental effect on the subsequent disease course.

Gut microbiome dynamics and associations with mortality in critically ill patients

BackgroundCritical illness and care within the intensive care unit (ICU) leads to profound changes in the composition of the gut microbiome. The impact of such changes on the patients and their subsequent disease course remains uncertain. We hypothesized that specific changes in the gut microbiome would be more harmful than others, leading to increased mortality in critically ill patients.MethodsThis was a prospective cohort study of critically ill adults in the ICU. We obtained rectal swabs from 52 patients and assessed the composition the gut microbiome using 16 S rRNA gene sequencing. We followed patients throughout their ICU course and evaluated their mortality rate at 28 days following admission to the ICU. We used selbal, a machine learning method, to identify the balance of microbial taxa most closely associated with 28-day mortality.ResultsWe found that a proportional ratio of four taxa could be used to distinguish patients with a higher risk of mortality from patients with a lower risk of mortality (p = .02). We named this binarized ratio our microbiome mortality index (MMI). Patients with a high MMI had a higher 28-day mortality compared to those with a low MMI (hazard ratio, 2.2, 95% confidence interval 1.1–4.3), and remained significant after adjustment for other ICU mortality predictors, including the presence of the acute respiratory distress syndrome (ARDS) and the Acute Physiology and Chronic Health Evaluation (APACHE II) score (hazard ratio, 2.5, 95% confidence interval 1.4–4.7). High mortality was driven by taxa from the Anaerococcus (genus) and Enterobacteriaceae (family), while lower mortality was driven by Parasutterella and Campylobacter (genera).ConclusionsDysbiosis in the gut of critically ill patients is an independent risk factor for increased mortality at 28 days after adjustment for clinically significant confounders. Gut dysbiosis may represent a potential therapeutic target for future ICU interventions.

Genetic variation of the HIV-1 subtype C transmitted/founder viruses long terminal repeat elements and the impact on transcription activation potential and clinical disease outcomes.

A genetic bottleneck is a hallmark of HIV-1 transmission such that only very few viral strains, termed transmitted/founder (T/F) variants establish infection in a newly infected host. Phenotypic characteristics of these variants may determine the subsequent course of disease. The HIV-1 5' long terminal repeat (LTR) promoter drives viral gene transcription and is genetically identical to the 3' LTR. We hypothesized that HIV-1 subtype C (HIV-1C) T/F virus LTR genetic variation is a determinant of transcriptional activation potential and clinical disease outcome. The 3'LTR was amplified from plasma samples of 41 study participants acutely infected with HIV-1C (Fiebig stages I and V/VI). Paired longitudinal samples were also available at one year post-infection for 31 of the 41 participants. 3' LTR amplicons were cloned into a pGL3-basic luciferase expression vector, and transfected alone or together with Transactivator of transcription (tat) into Jurkat cells in the absence or presence of cell activators (TNF-α, PMA, Prostratin and SAHA). Inter-patient T/F LTR sequence diversity was 5.7% (Renge: 2-12) with subsequent intrahost viral evolution observed in 48.4% of the participants analyzed at 12 months post-infection. T/F LTR variants exhibited differential basal transcriptional activity, with significantly higher Tat-mediated transcriptional activity compared to basal (p<0.001). Basal and Tat-mediated T/F LTR transcriptional activity showed significant positive correlation with contemporaneous viral loads and negative correlation with CD4 T cell counts (p<0.05) during acute infection respectively. Furthermore, Tat-mediated T/F LTR transcriptional activity significanly correlated positively with viral load set point and viral load; and negatively with CD4 T cell counts at one year post infection (all p<0.05). Lastly, PMA, Prostratin, TNF-α and SAHA cell stimulation resulted in enhanced yet heterologous transcriptional activation of different T/F LTR variants. Our data suggest that T/F LTR variants may influence viral transcriptional activity, disease outcomes and sensitivity to cell activation, with potential implications for therapeutic interventions.

Architecture of the SARS-CoV-2-specific T cell repertoire.

The T cell response plays an indispensable role in the early control and successful clearance of SARS-CoV-2 infection. However, several important questions remain about the role of cellular immunity in COVID-19, including the shape and composition of disease-specific T cell repertoires across convalescent patients and vaccinated individuals, and how pre-existing T cell responses to other pathogens-in particular, common cold coronaviruses-impact susceptibility to SARS-CoV-2 infection and the subsequent course of disease. This review focuses on how the repertoire of T cell receptors (TCR) is shaped by natural infection and vaccination over time. We also summarize current knowledge regarding cross-reactive T cell responses and their protective role, and examine the implications of TCR repertoire diversity and cross-reactivity with regard to the design of vaccines that confer broader protection against SARS-CoV-2 variants.

Two-Year Outcomes After Variable Duration of Drug Cessation in Patients With Maculopathy Associated With Pentosan Polysulfate Use

Prior retrospective studies have provided limited evidence on disease progression following drug cessation in patients with maculopathy associated with pentosan polysulfate (PPS). To evaluate the 2-year evolution of maculopathy associated with PPS use after drug cessation. This cohort study prospectively evaluated the natural history of patients with maculopathy associated with PPS use. Participants seen at the Emory Eye Center were enrolled between December 1, 2018, and December 1, 2019, and data were collected through November 30, 2021. The main outcomes were changes in visual function and structure. Visual function was assessed annually with refraction and Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), mesopic microperimetry, and dark adaptometry. Structural outcomes included presence and extent of complete retinal pigment epithelium and outer retinal atrophy (cRORA), macular central subfield thickness (CST), and subfoveal choroidal thickness (SFCT). Of the 12 participants (23 eyes), 11 (91.7%) were female (1 [8.3%] male), 11 (91.7%) were White (1 [8.3%] Black), and median (IQR) age at enrollment was 58 (47-64) years. Median (IQR) time from PPS discontinuation to initial visit was 0.6 (0.4-1.9) years. Median baseline ETDRS BCVA letter score was 83 (Snellen equivalent, 20/20) (IQR, 80-86.5 [20/25-20/20]), with a median 2-year change of -3 (IQR, -6 to -0.5; P = .08). Four eyes (17.4%) had a letter score decline of 15 or more, all associated with progressive cRORA. Median change in microperimetry average threshold was -3.5 dB (IQR, -4.1 to -2.5 dB; P = .001), and percent reduced threshold was 32.5% (IQR, 20.3%-52.8%; P = .004). Nine eyes (39%) had macular cRORA at baseline, with a median linearized growth rate of 0.23 mm/y (IQR, 0.22-0.25 mm/y). Two eyes (8.7%) without atrophy at baseline developed new-onset cRORA. Median baseline CST was 284 μm (IQR, 253-291 μm), with a median 2-year change of -5 μm (IQR, -13 to 0.5 μm; P = .0497). Median 2-year change in SFCT was 1 μm (IQR, -18 to 16 μm; P = .91). The findings of this cohort study suggest that functional and structural deficits continue to progress in PPS-associated maculopathy even after drug cessation. Additional study is needed to determine whether these findings can be generalized to other patients with PPS-associated maculopathy and whether longer follow-up could determine subsequent disease course.

Nipah Virus Aerosol Challenge of Three Distinct Particle Sizes in Nonhuman Primates.

Aerosol and inhalational studies of high-consequence pathogens allow researchers to study the disease course and effects of biologicals transmitted through aerosol in a laboratory-controlled environment. Inhalational studies involving Nipah virus with small (1-3μm), intermediate (6-8μm), and large particles (10-14μm) were explored in African green nonhuman primates to determine if the subsequent disease course more closely recapitulated what is observed in Nipah virus human disease. The aerosol procedures outlined describe the different equipment/techniques used to generate the three particle sizes and control the site of particle deposition within this animal model.

MO447: Glomerular Transcriptomics in IGA Nephropathy Differentiates Between Disease Progression and Stability in Low-Risk Patients After Prolonged Follow-Up

Abstract BACKGROUND AND AIMS IgA nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. We have previously shown that patients with assumed benign IgAN can develop progressive kidney failure, including end-stage kidney disease, after a sufficiently long follow-up period [1]. In the reported patient cohort [1], histological, clinical and laboratory findings at the time of diagnosis were unable to predict a subsequent stable or progressive disease course. Thus, we hypothesized that glomerular transcriptomics from the diagnostic kidney biopsy could help make this distinction. METHOD We included all progressive patients (n = 27) and patients with the stable or remitting disease (non-progressors, n = 42) from our previously reported cohort of adult patients with biopsy-proven and assumed benign IgAN (n = 192). Progression was defined as a ≥ 50% decline in eGFR from the diagnostic kidney biopsy, performed between 1988 and 1999 until follow-up examination [1]. The median follow-up time was 22 years. Glomerular cross-sections were obtained through laser-capture microdissection from archival kidney biopsy sections for RNA extraction and sequencing, using NovaSeq 6000 (Illumina, USA) at Functional Genomics Centre Zurich, Switzerland. Samples yielding insufficient sequencing quality were excluded, leaving n = 8 progressors and n = 9 non-progressors for analysis, using limma [2] and edgeR [3] in R Bioconductor. RESULTS In the first round of analysis, we identified 1818 differentially expressed genes (P ≤ 0.05, absolute fold change ≥ 2), of which 1562 genes were overrepresented in progressors and 256 genes were overrepresented in non-progressors. Principal component analysis and hierarchical cluster analysis revealed a separation between the two study groups, indicating that underlying transcriptomic differences are present many years prior to the overt manifestation of disease progression. Interestingly, in progressors, the nuclear factor-kappa B complex, linked to IgAN pathogenesis [4], was the most overabundant transcription factor and Fc Fragment of IgA Receptor (FCAR) was the most overrepresented differentially abundant mRNA. Ingenuity Pathway Analysis (Qiagen, USA) suggested an overrepresentation of the phagosome formation pathway (P = 3.09E-08, Z-score = 8.43), indicating phagosome activation in progressors, possibly a response to the observed FCAR overexpression. To identify potential markers for disease progression, we used an unsupervised K Nearest Neighbour analysis of 1818 differentially expressed genes, allowing combinations of ≤ 10 genes. A two-component classifier (APOL5 and ZXDC) performed best, classifying 15/17 samples correctly (sensitivity 75%, specificity 100%, accuracy 88.24%) on average 21 years prior to a manifested decrease in eGFR. Further refinements of the statistical analyses and confirmation studies are planned to substantiate our initial findings. CONCLUSION Glomerular mRNA sequencing performed at the time of diagnosis of assumed benign IgAN can differentiate between subsequent stable and progressive disease courses in the distant future. In our cohort, combining APOL5 and ZXDC can predict subsequent disease course with 88.24% accuracy already 21 years prior to the discovery of progression with conventional means.

PET-Based Staging Is Cost-Effective in Early-Stage Follicular Lymphoma.

The objective was to assess the cost-effectiveness of staging PET/CT in early-stage follicular lymphoma (FL) from the Canadian health-care system perspective. Methods: The study population was FL patients staged as early-stage using conventional CT imaging and planned for curative-intent radiation therapy (RT). A decision analytic model simulated the management after adding staging PET/CT versus using staging CT alone. In the no-PET/CT strategy, all patients proceeded to curative-intent RT as planned. In the PET/CT strategy, PET/CT information could result in an increased RT volume, switching to a noncurative approach, or no change in RT treatment as planned. The subsequent disease course was described using a state-transition cohort model over a 30-y time horizon. Diagnostic characteristics, probabilities, utilities, and costs were derived from the literature. Baseline analysis was performed using quality-adjusted life years (QALYs), costs (2019 Canadian dollars), and the incremental cost-effectiveness ratio. Deterministic sensitivity analyses were conducted, evaluating net monetary benefit at a willingness-to-pay threshold of $100,000/QALY. Probabilistic sensitivity analysis using 10,000 simulations was performed. Costs and QALYs were discounted at a rate of 1.5%. Results: In the reference case scenario, staging PET/CT was the dominant strategy, resulting in an average lifetime cost saving of $3,165 and a gain of 0.32 QALYs. In deterministic sensitivity analyses, the PET/CT strategy remained the preferred strategy for all scenarios supported by available data. In probabilistic sensitivity analysis, the PET/CT strategy was strongly dominant in 77% of simulations (i.e., reduced cost and increased QALYs) and was cost-effective in 89% of simulations (i.e., either saved costs or had an incremental cost-effectiveness ratio below $100,000/QALY). Conclusion: Our analysis showed that the use of PET/CT to stage early-stage FL patients reduces cost and improves QALYs. Patients with early-stage FL should undergo PET/CT before curative-intent RT.

Endoscopic Prediction of Crohn's Disease Postoperative Recurrence.

The presence and severity of endoscopic recurrence after Crohn's disease intestinal resection predicts subsequent disease course. The Rutgeerts postoperative endoscopic recurrence score is unvalidated but has proven prognostically useful in many clinical studies. This study aimed to investigate the association between specific early endoscopic findings and subsequent disease course. In the setting of a randomized controlled trial (the POCER study), 85 patients underwent colonoscopy at 6 and 18 months after intestinal resection. Patients received 3 months of metronidazole, and high-risk patients received a thiopurine (or adalimumab if they were thiopurine intolerant). For endoscopic recurrence (Rutgeerts score ≥i2) at 6 months, patients stepped up to a thiopurine, fortnightly adalimumab with thiopurine, or weekly adalimumab. Central readers confirmed Rutgeerts, Simple Endoscopic Score for Crohn's Disease, Crohn's Disease Endoscopic Index of Severity scores, and 5 newly tested endoscopic parameters: anastomotic ulcer depth (superficial vs deep), number of ulcers (0, ≤2, >2), ulcer size (1-5 mm, ≥6 mm), circumferential extent of ulceration (<25%, ≥25%), and the presence or absence of stenosis. The POCER index, based on the 6-month postoperative findings, was then developed in relation to predicting the endoscopic outcome at 18 months. Of the 5 parameters, the combination of ulcer depth and circumference at the anastomosis at 6 months was associated with endoscopic recurrence at 18 months (odds ratio [OR], 1.6; 95% confidence interval [CI], 1.03-2.50; P = 0.035) with an area under the receiver operating characteristic curve of 0.62 (95% CI, 0.5-0.75). The combination of these 2 parameters formed the basis of the POCER index (range, 0-4 with 0 denoting no ulcers and 4 denoting deep ulceration with >25% circumferential involvement). The new index had a strong correlation with the Rutgeerts score measured at the same time points: Spearmans' r = .80 at 6 months and r = .77 at 18 months (P < 0.001 at both time points). A POCER index of ≥2 and a Rutgeerts score of ≥i2 both had a sensitivity of 0.41 for recurrence; however, the POCER index had a higher specificity (0.8 and 0.67, respectively). The POCER index at 6 months was associated with endoscopic recurrence at 18 months (OR, 1.5; 95% CI, 1.2-2.0; P = 0.002; area under the receiver operating characteristic curve of 0.70; 95% CI, 0.57-0.82), but the Rutgeerts score was not (OR, 1.2; 95% CI, 0.8-1.8; P = 0.402). The POCER postoperative index comprises 2 key endoscopic factors related to the anastomosis that are associated with subsequent disease progression. A higher score, comprising the adverse prognostic factors of deep or circumferentially extensive anastomotic ulceration, may help identify patients who require more intensive therapy.

Predictors of Hyperviscosity Syndrome (HVS) in Waldenström Macroglobulinemia (WM)

Abstract Background Up to 30% of patients (pts) with WM can develop HVS, although serum viscosity (sV) level associated with hyperviscosity-related symptoms in individual pts with WM varies (symptomatic threshold). Also, monoclonal IgMs exhibit a wide range of intrinsic viscosity values with differing individual properties. A recent study proposed that serum IgM level (sIgM) level >6000 mg/dL at diagnosis be considered a new criterion for initiating therapy in otherwise asymptomatic (smoldering) WM to pre-empt the development of HVS.(Gustine et al., BJH 2017) However, the study did not consider patients' sV as information on this parameter was unavailable. We therefore 1) evaluated the predictors of HVS including sV in WM, and 2) assessed the potential value of incorporating the sIgM level at diagnosis into the Consensus criteria for initiating therapy in WM. (Kyle et al., Semin Oncol. 2003) Methods All pts seen at Mayo Clinic, Rochester, between January 1, 01/01/1996 and 06/30/ 2017, in whom a definitive diagnosis of WM was made, were included. HVS was identified by the presence of ≥1 symptoms characteristic of HVS (Stone et al., Blood 2012) that could not otherwise be attributed to another cause. Receiver Operating Characteristic (ROC) curve analysis was used to identify cut-off for continuous variables. Multivariate analysis (MVA) using Cox proportional hazard method was performed to identify independent predictive factors for HVS. Based on this, sV and sIgM at diagnosis of WM were used to formulate a score to predict the cumulative probability of developing HVS in pts who did not present with HVS at diagnosis of WM. sV of 2.2-4.0 cp and sIgM >4,600 mg/dl at diagnosis of WM were given 1 point each and sV >4cp at diagnosis was given 2 points based on hazard ratios (HR) on MVA, allowing for a minimum additive score of 0 and maximum of 3. Kaplan -Meier method was utilized for all time-to-event analyses. Results Of 687 pts, HVS was observed in 93 (13.5%) pts, either at the time of diagnosis of WM (n=48) or subsequently during the disease course. The baseline characteristics, presenting symptoms and laboratory parameters of pts with and without HVS, are outlined in Table 1. Optimal cut-offs from ROC curve analysis for sV and sIgM were 2.2 cp and 4600 mg/dL, respectively for predicting the development of HVS. After excluding the pts who developed HVS at diagnosis, a MVA showed that sIgM >4600mg/dL [HR 3.1 (1.3-8.9); p 2.2 cp [HR 7.6 (3.2-20.5 p 4 cp and sIgM >4600 mg/dL (score 3), with 36% cumulative probability of developing HVS at 6 months (Figure 1). Of 520 pts in whom sIgM levels at diagnosis were available, 107 (21%) had a sIgM level >6000 mg/dL. Of these, 83 (78%) pts had one or more indications at diagnosis or instituting systemic therapy per the 2003 Consensus criteria [Hb 6000 mg/dl at diagnosis were otherwise asymptomatic (smoldering WM), not requiring therapy at diagnosis. The median sV for this cohort was 1.6 cp (1.0-4.0 cp) and no pts had sV >4 cp. Of these 24 pts, none developed HVS subsequently, and median time to frontline treatment was 9 years (95% CI 3.6-12.3 years). The median follow-up for the entire cohort was 9.6 years (95% CI: 8.9-10.6) with no difference in the OS in pts with HVS [median OS 9.6 years (95% CI: 6.2-12.3)] versus pts without HVS [median OS 9.7 years (95% CI: 8.8-10.7), p=0.67]. Conclusion A vast majority of patients with baseline sIgM >6000 mg/dL already have an indication for commencement of therapy based on the 2003 Consensus guidelines. The probability of developing HVS in otherwise asymptomatic patients with sIgM level >6000 mg/dl alone at diagnosis remains low if sV is not taken into account, and high sIgM levels alone at diagnosis may not merit preemptive therapy. A simple scoring system based on sVand sIgM level can reliably predict for the development of HVS in pts who do not present with HVS at diagnosis. Regardless, the overall outcome of pts with WM is unaffected by the development of HVS. Download : Download high-res image (224KB) Download : Download full-size image Disclosures Kumar: Celgene, Millennium/Takeda, Onyx, AbbVie, Janssen, Sanofi, Novartis, Amgen, Genentech, Merck, Oncopeptides, Roche, Skyline Diagnostics: Research Funding; Celgene, Millennium, BMS, Onyx, Janssen, Noxxon, AbbVie, Amgen, Merck, Oncopeptides, Skyline Diagnostics, Takeda: Consultancy; Skyline: Honoraria. Gertz: Celgene, Novartis, Smith-Kline, Prothena, Ionis, Amgen: Honoraria; Millennium: Consultancy, Honoraria. Witzig: Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta: Research Funding; Kura: Research Funding. Dingli: Karyopharm Therapeutics: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Alexion Pharmaceuticals: Consultancy. Dispenzieri: Celgene, Millenium, Pfizer, Janssen: Research Funding. Ansell: Affimed: Research Funding; Bristol-Myers Squibb: Research Funding; Merck: Research Funding; Seattle Genetics: Research Funding; Celldex: Research Funding. Kapoor: Takeda, Celgene and Amgen: Research Funding.

1143-P: ZnT8 Autoantibody Positivity Does Not Predict Pediatric Diabetes Presentation or Subsequent Clinical Course

Introduction: Type 1 diabetes specific autoantibodies are glutamic acid decarboxylase (GAD65), protein tyrosine phosphatase-like islet antigen 2 (IA2), insulin (IAA), and Zinc transporter 8 protein (ZnT8). The aim of our study was to determine if the presence of ZnT8 antibodies(Ab) was predictive of clinical presentation at diagnosis or subsequent disease course. Methods: Between January 2003 and May 2019, 105 patients aged ≤ 21 years with a clinical diagnosis of T1DM had at least 1 diabetes autoantibody measured. For subjects who had less than 4 autoantibodies analyzed initially, residual serum sample was retrieved, and remaining autoantibodies were analyzed. Retrospective chart review was completed. At diagnosis, we evaluated BMI z-score, HbA1c, and the presence and severity of DKA. Complications recorded post diagnosis included episodes of DKA, diagnosis of autoimmune (AI) disease, and the presence of vascular complications. Results: Of the 105 patients, 71 were ZnT8(+) (68%). When comparing ZnT8Ab(+) to (-) patients at diagnosis, there was no difference in age (p=0.94), BMI z-score (p=0.83) or presence of DKA (p=0.26). There was no difference in duration of follow up between ZnT8 Ab (+) and (-) groups (p=0.54). Over follow-up, (0.05-15.7 years), there was no difference in rates of DKA episodes (p=0.71). There were no macrovascular complications recorded and no difference in microvascular complications between the 2 groups (p=0.14). There were more AI conditions in the ZnT8Ab(+) group, 77% compared to 23% in ZnT8Ab(-), but this did not reach statistical significance (p=0.12). Conclusions: Our study, unlike others, suggests that the presence of ZnT8 Ab does not result in a difference in disease course at presentation. This study adds to the literature as it has follow up on patients. Over up to 15 years of follow-up, there is no difference in complications between those with and without ZnT8 Ab’s. This study should be validated with larger numbers and longer follow up. Disclosure A. R. Dahl: None. S. Jenkins: None. J. Zbacnik: None. J. Foster: None. S. Pittock: None.

Computing infection distributions and longitudinal evolution patterns in lung CT images

BackgroundSpatial and temporal lung infection distributions of coronavirus disease 2019 (COVID-19) and their changes could reveal important patterns to better understand the disease and its time course. This paper presents a pipeline to analyze statistically these patterns by automatically segmenting the infection regions and registering them onto a common template.MethodsA VB-Net is designed to automatically segment infection regions in CT images. After training and validating the model, we segmented all the CT images in the study. The segmentation results are then warped onto a pre-defined template CT image using deformable registration based on lung fields. Then, the spatial distributions of infection regions and those during the course of the disease are calculated at the voxel level. Visualization and quantitative comparison can be performed between different groups. We compared the distribution maps between COVID-19 and community acquired pneumonia (CAP), between severe and critical COVID-19, and across the time course of the disease.ResultsFor the performance of infection segmentation, comparing the segmentation results with manually annotated ground-truth, the average Dice is 91.6% ± 10.0%, which is close to the inter-rater difference between two radiologists (the Dice is 96.1% ± 3.5%). The distribution map of infection regions shows that high probability regions are in the peripheral subpleural (up to 35.1% in probability). COVID-19 GGO lesions are more widely spread than consolidations, and the latter are located more peripherally. Onset images of severe COVID-19 (inpatients) show similar lesion distributions but with smaller areas of significant difference in the right lower lobe compared to critical COVID-19 (intensive care unit patients). About the disease course, critical COVID-19 patients showed four subsequent patterns (progression, absorption, enlargement, and further absorption) in our collected dataset, with remarkable concurrent HU patterns for GGO and consolidations.ConclusionsBy segmenting the infection regions with a VB-Net and registering all the CT images and the segmentation results onto a template, spatial distribution patterns of infections can be computed automatically. The algorithm provides an effective tool to visualize and quantify the spatial patterns of lung infection diseases and their changes during the disease course. Our results demonstrate different patterns between COVID-19 and CAP, between severe and critical COVID-19, as well as four subsequent disease course patterns of the severe COVID-19 patients studied, with remarkable concurrent HU patterns for GGO and consolidations.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio in Adult-Onset Still Disease, their Relationship with Baseline Disease Activity and Subsequent Disease Course: A Single-Center Retrospective Cohort Study

Introduction: Adult-onset Still Disease (AoSD) is a rare systemic polygenic nonfamilial autoinflammatory disease of unknown aetiology. The long-term course of the disease can be categorised in three different definitions including self-limited course, intermittent course or chronic course. Recently, Neutrophil-to-Lymphocyte Ratio (NLR) and Platelet-to-Lymphocyte Ratio (PLR) were investigated in various rheumatic diseases as an informative markers in evaluating severity of inflammation and disease activity. Aim: To explore association between baseline NLR, PLR, disease activity score and subsequent disease course in patients with AoSD. Materials and Methods: This retrospective cohort study enrolled 61 patients with AoSD and 61 age-matched patients with Fibromyalgia Syndrome (FMS). Pouchot score was specifically used in AoSD patients to assess disease activity based on symptoms, physical examination findings and laboratory results from April 2020 to July 2020. Patients with AoSD were subgrouped into three groups: self-limited; intermittent; and chronic course. The association of NLR and PLR with disease activity score was analysed between groups by using independent samples t-test, Mann-Whitney U test and Kruskal Wallis Variance Analysis. Differences between categorical variables were analysed using chi-square test. A p≤0.05 was considered statistically significant. Results: The mean follow-up of the 61 patients with AoSD was 74 months (range, 14-169). Eighteen patients (29.5%) had a self-limited disease course, nine (14.8%) an intermittent disease course and thirty four (55.7%) a chronic disease course. AoSD patients had significantly higher serum NLR, PLR and lower Mean Platelet Volume (MPV) values than FMS patients {6.68 (1.67-19.7), 1.83 (1.1-4) p=0.0001; 187 (82.9-549), 114 (72-246) p=0.0001; 8.3 (6.4-11.3), 9.3 (7.7-11.7) p=0.0001, respectively}. NLR, PLR and Pouchot score were similar among AoSD subgroups, which were grouped according to disease pattern. The majority of patients in the self-limited and chronic course groups had higher baseline Pouchot score without statistical significance. The NLR and C-Reactive Protein (CRP) were significantly higher in AoSD patients with active disease than inactive disease {7.02 (1.8-19.7), 4.17 (1.67-14.8) p=0.06; 13 (1.9-29.5), 9 (1.6-20.9) p=0.046, respectively)}. Conclusion: High NLR and elevated CRP levels are related to active disease in AoSD patients. Although NLR, PLR and Pouchot score were similar among subgroups, patients with a chronic course or self-limited course had higher NLR values and more active disease at diagnosis compared with patients with an intermittent course.

Does inflammatory bowel disease have different characteristics according to stage of adolescence?

Background:There is a lack of data about demographic and treatment characteristics of adolescent patients with inflammatory bowel disease (IBD). The aim of this retrospective, epidemiological study was to evaluate characteristics and therapeutic features of Hungarian adolescents with IBD.Methods:We analysed the social security databases of the National Health Insurance Fund. Adolescent patients with IBD for whom data from 2009 to 2016 were observable in the database were enrolled. Patients aged 14 to 17 years and 18 to 21 years were defined as middle and late adolescent patients.Results:The incidences of IBD were 20.12 per 100,000 middle adolescent patients and 29.72 per 100,000 late adolescent patients. Admission to gastroenterology department was higher in both groups compared with admissions to surgery department. Mesalazine was used by a high proportion of Crohn’s disease and ulcerative colitis patients. Rates of corticosteroid use were similar in both groups, with a tendency to decrease over time. The need for biologic agents was higher in the middle adolescent patients. The proportion of patients in the middle adolescent group who received anti-TNF therapy showed an increasing tendency.Conclusion:Our data suggest differences in the treatment strategies of gastroenterologists for these age groups. The greater need of anti-TNF therapy among the middle adolescent group indicates that adolescent patients before the transition to adult care may have a more severe disease phenotype. We expect that a strategy of early, effective treatment will significantly ameliorate the subsequent disease course, which is manifested in adult care.

Hemispheric infiltrative grade II gliomas in adults: association of residual tumour volume and extent of tumour resection with malignant transformation.

Evaluation of the impact of surgical treatment on malignant transformation (MT) of adult supratentorial infiltrative grade II gliomas (G2G) in a series of chemotherapy and radiotherapy-naïve patients. Despite G2G are slow-growing tumours, they typically undergo MT with a subsequent fatal disease course. An extensive resection alone likely changes their biological behaviour and defers MT; however, this impact is not unequivocally confirmed. Thirty-eight chemotherapy and radiotherapy-naïve adult patients operated from 2005 till 2014 for a G2G were investigated. Based on postoperative magnetic resonance imaging (MRI) and/or positron emission tomography follow-up (FU) scans, the patients were classified as "transformers" (15 patients in whom MT occurred during the FU-period) and "non-transformers" (23 patients). The follow-up period of "non-transformers" was longer (p <0.0001). After adjustment for known risk factors - age, male sex, astrocytoma histology, preoperative tumour volume, preoperative contrast enhancement and positive isocitrate dehydrogenase 1 gene mutation status - a larger log postoperative tumour volume (p=0.031) and a smaller extent of resection (p=0.0086) were associated with a shorter MT-free survival. In our series, less extensive resections were associated with a shorter time to MT. Our data support an adoption of techniques enabling extensive G2G resections, such as intraoperative imaging and awake resections, into everyday routine (Tab. 1, Fig. 2, Ref. 40).

Time, pattern, and outcome of medulloblastoma relapse and their association with tumour biology at diagnosis and therapy: a multicentre cohort study

SummaryBackgroundDisease relapse occurs in around 30% of children with medulloblastoma, and is almost universally fatal. We aimed to establish whether the clinical and molecular characteristics of the disease at diagnosis are associated with the nature of relapse and subsequent disease course, and whether these associations could inform clinical management.MethodsIn this multicentre cohort study we comprehensively surveyed the clinical features of medulloblastoma relapse (time to relapse, pattern of relapse, time from relapse to death, and overall outcome) in centrally reviewed patients who relapsed following standard upfront therapies, from 16 UK Children's Cancer and Leukaemia Group institutions and four collaborating centres. We compared these relapse-associated features with clinical and molecular features at diagnosis, including established and recently described molecular features, prognostic factors, and treatment at diagnosis and relapse.Findings247 patients (175 [71%] boys and 72 [29%] girls) with medulloblastoma relapse (median year of diagnosis 2000 [IQR 1995–2006]) were included in this study. 17 patients were later excluded from further analyses because they did not meet the age and treatment criteria for inclusion. Patients who received upfront craniospinal irradiation (irradiated group; 178 [72%] patients) had a more prolonged time to relapse compared with patients who did not receive upfront craniospinal irradiation (non-irradiated group; 52 [21%] patients; p<0·0001). In the non-irradiated group, craniospinal irradiation at relapse (hazard ratio [HR] 0·27, 95% CI 0·11–0·68) and desmoplastic/nodular histology (0·23, 0·07–0·77) were associated with prolonged time to death after relapse, MYC amplification was associated with a reduced overall survival (23·52, 4·85–114·05), and re-resection at relapse was associated with longer overall survival (0·17, 0·05–0·57). In the irradiated group, patients with MBGroup3 tumours relapsed significantly more quickly than did patients with MBGroup4 tumours (median 1·34 [0·99–1·89] years vs 2·04 [1·39–3·42 years; p=0·0043). Distant disease was prevalent in patients with MBGroup3 (23 [92%] of 25 patients) and MBGroup4 (56 [90%] of 62 patients) tumour relapses. Patients with distantly-relapsed MBGroup3 and MBGroup4 displayed both nodular and diffuse patterns of disease whereas isolated nodular relapses were rare in distantly-relapsed MBSHH (1 [8%] of 12 distantly-relapsed MBSHH were nodular alone compared with 26 [34%] of 77 distantly-relapsed MBGroup3 and MBGroup4). In MBGroup3 and MBGroup4, nodular disease was associated with a prolonged survival after relapse (HR 0·42, 0·21–0·81). Investigation of second-generation MBGroup3 and MBGroup4 molecular subtypes refined our understanding of heterogeneous relapse characteristics. Subtype VIII had prolonged time to relapse and subtype II had a rapid time from relapse to death. Subtypes II, III, and VIII developed a significantly higher incidence of distant disease at relapse whereas subtypes V and VII did not (equivalent rates to diagnosis).InterpretationThis study suggests that the nature and outcome of medulloblastoma relapse are biology and therapy-dependent, providing translational opportunities for improved disease management through biology-directed disease surveillance, post-relapse prognostication, and risk-stratified selection of second-line treatment strategies.FundingCancer Research UK, Action Medical Research, The Tom Grahame Trust, The JGW Patterson Foundation, Star for Harris, The Institute of Child Health - Newcastle University - Institute of Child Health High-Risk Childhood Brain Tumour Network (co-funded by The Brain Tumour Charity, Great Ormond Street Children's Charity, and Children with Cancer UK).

Immuno-Inflammatory Characteristics in Low Severity COVID-19 Patients with Digestive Symptoms.

Aim The outbreak of Coronavirus Disease 2019 (COVID-19) has resulted in a global pandemic, with the main manifestations being of respiratory nature, including pneumonia. It is noteworthy that digestive symptoms are also observed in COVID-19 patients. In this article, we describe the immuno-inflammatory characteristics of low severity COVID-19 patients with digestive symptoms. Methods Patients with mild symptoms of COVID-19 were split into three groups based on the patients' symptoms. The first group displayed digestive symptoms only, the second group displayed respiratory symptoms only, and the last group displayed both digestive and respiratory symptoms. Patients were discharged based on negative results of rRT-PCR testing for SARS-CoV-2 from at least two sequential respiratory tract specimens collected ≥24 hours apart. Multiorgan function and immuno-inflammatory characteristics were analyzed for all of the three groups. Results Mild liver damage and activation of the immuno-inflammatory system were the most common abnormalities observed in patients with mild COVID-19 symptoms but no significant differences were found (P > 0.05). Patients with digestive symptoms were more likely to have slightly higher and later peak values of inflammatory cytokines during the subsequent course of disease (P < 0.05). In addition, a significant correlation between IL-2 and TNF level was found in the first group which included patients with digestive symptoms only (P < 0.05). Conclusions Patients with mild cases of COVID-19 only displaying digestive symptoms are a special subtype. Patients in this group were more likely to have slightly higher and delayed peak values of inflammatory cytokines during the subsequent course of the disease. Prevention and clinical management of this type should be taken into consideration.