Patterns Of Disease Progression Research Articles

Time-to-Event Analysis with Unknown Time Origins via Longitudinal Biomarker Registration

In observational studies, the time origin of interest for time-to-event analysis is often unknown, such as the time of disease onset. Existing approaches to estimating the time origins are commonly built on extrapolating a parametric longitudinal model, which rely on rigid assumptions that can lead to biased inferences. In this paper, we introduce a flexible semiparametric curve registration model. It assumes the longitudinal trajectories follow a flexible common shape function with person-specific disease progression pattern characterized by a random curve registration function, which is further used to model the unknown time origin as a random start time. This random time is used as a link to jointly model the longitudinal and survival data where the unknown time origins are integrated out in the joint likelihood function, which facilitates unbiased and consistent estimation. Since the disease progression pattern naturally predicts time-to-event, we further propose a new functional survival model using the registration function as a predictor of the time-to-event. The asymptotic consistency and semiparametric efficiency of the proposed models are proved. Simulation studies and two real data applications demonstrate the effectiveness of this new approach. Supplementary materials for this article are available online.

Evaluation of Progression-Free Survival and Overall Survival of Epidermal Growth Factor Receptor-Positive Metastatic Lung Adenocarcinoma Patients Treated with Erlotinib.

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) such as erlotinib and gefitinib have shown promising efficacy and tolerability in patients with advanced NSCLC. Identifying subgroups of patients who benefit from EGFR-TKI treatment may help achieve better treatment responses. Therefore, this study was performed to evaluate the indicators of response to treatment, including progression-free survival (PFS) and overall survival (OS) of patients. Methods: The study was performed as a prospective cohort in patients referred to Hazrat Rasoul Akram Hospital in Tehran for two years (April 2019-April 2021). Erlotinib was administered to patients at 100-150 mg daily. After completion or discontinuation of erlotinib, patients were followed up every three months to evaluate clinical outcomes. Independent t-test or Man-Whitney test was used to compare quantitative variables, chi-square or Fisher exact test was used to compare qualitative variables, and correlation test was used to determine the relationship between quantitative data. Analysis of overall survival and progression-free survival was performed using the Kaplan-Meier test. Significant levels less than 0.05 were considered. Results: Thirty-two patients participated in the final analysis. Out of 32patients, 21 (65.6%) were female, and 11 (34.4%) were male. The mean age was 59.12±14.17years (32–89years). The mean PFS was 11.44±9.35months and, the OS of patients was 21.78±14.35months. Of the 32 patients, 4 (12.5%) had a history of smoking and, the rest had no history of smoking. Conclusion: Finally, according to the findings of the present study, the use of erlotinib can be considered as an effective first-line treatment option with controllable toxicity in patients with advanced or metastatic NSCLC with positive EGFR. In addition, metastatic progression asymptomatic disease has been identified as the predominant pattern of disease progression. It can be stated that smoking history can play a risk factor in reducing PFS time.

Association of disease progression pattern during third-line chemotherapy with nivolumab with poor prognosis in advanced gastric cancer: A multicenter retrospective study in Japan.

258 Background: An acceleration of tumor growth during immunotherapy, (hyperprogressive disease [HPD]: defined as >2 times increase in tumor growth rates during nivolumab compared with prior chemotherapy, Champiat S, 2017) has been reported. We reviewed the prevalence and clinical outcomes of HPD in AGC patients treated with nivolumab, and reported that there were no differences either in progression-free survival (PFS) or overall survival (OS) between patients with HPD and those with PD other than HPD (Suzuki T, ASCO Gastrointestinal Cancers Symposium 2020). Then, we hypothesized that PD in unmeasurable lesion (ascites representing peritoneal metastasis) and appearance of new lesions, which are not included in definition of HPD, might have influenced the prognosis of AGC. Methods: The subjects of this retrospective study were 245 AGC patients with measurable disease who received nivolumab after failure of >2 chemotherapy regimens, and their responses were assessed at least 3 times (during prior therapy, before and after nivolumab) in 24 institutions. We explored the impact on prognosis of HPD, new lesion, increase of ascites in AGC patients receiving nivolumab 3 mg/kg or 240 mg/body intravenously every 2 weeks. We divided patients to 4 group according to new lesions at different organ/increase of ascites: Group (G) 1 (-/-), G 2 (+/-), G 3 (-/+), G 4 (+/+). Results: One hundred forty-seven patients (60%) showed PD, and their PFS and OS were 1.5 months(M) and 4.8 M, while those of 41 patients (16.7%) with HPD were 1.4 M and 5.0 M. Fifty-three patients showed appearance of new lesions at different organ and 58 patients showed increase of ascites (31 patients showed both). Survival outcomes of the 4 groups are shown in the Table. Patients with appearance of new lesions at different organ showed shorter prognosis compared with patients without it (median OS: G 2+4 vs G 1+3, 3.3 M vs 7.1 M; hazard ratio [HR], 1.8 [95% CI: 1.2–2.7]; p = 0.003). Also, patients with increase of ascites showed shorter prognosis compared to patients with stable/decrease of ascites (median OS: G 3+4 vs G 1+2, 3.0 M vs 7.8 M; HR, 2.6 [95% CI: 1.8–3.8]; p < 0.001). More of patients with increase of ascites could not receive subsequent chemotherapy after disease progression than others (G 1+2 vs G 3+4, 51.7% [46/89] vs 75.9% [44/58]; p = 0.03). Large tumor size, number of prior lines of chemotherapy, and high neutrophil-to-lymphocyte ratio at baseline were associated with G 4. Conclusions: Appearance of new lesions at different organ and increase of ascites, not HPD, were disease progression pattern associated with poor prognosis in AGC patients receiving nivolumab.[Table: see text]

Invited Session I: Artificial intelligence applications in ophthalmology and vision science: AI applications in glaucoma

Glaucoma is the second cause of blindness worldwide. Due to the complicated non-linear relationships between structural and functional assessment outcomes together with the large variabilities of disease progression patterns, accurate and reliable clinical assessment is a paramount importance for this slow but irreversible progressing disease. Recent advances in medical applications of artificial intelligence, especially deep learning (DL) approaches, have opened up unprecedented possibilities in computer aided clinical care. I will discuss a variety of DL studies on our large longitudinal glaucoma cohort data in collaborating IBM Watson Research Team. The topics include: 1) estimation of visual field parameters out of raw 3D optical coherence tomography (OCT) image data using a feature agnostic data driven approach, 2) forecasting functional measurements out of clinically available demographic information augmented by OCT feature analysis, 3) generating future 2D biomarker color mapping on OCT image data, and 4) identifying novel biomarkers and exploration of structure-function relationships using a group class activation mapping technique.

ThreadStates: State-based Visual Analysis of Disease Progression

A growing number of longitudinal cohort studies are generating data with extensive patient observations across multiple timepoints. Such data offers promising opportunities to better understand the progression of diseases. However, these observations are usually treated as general events in existing visual analysis tools. As a result, their capabilities in modeling disease progression are not fully utilized. To fill this gap, we designed and implemented ThreadStates, an interactive visual analytics tool for the exploration of longitudinal patient cohort data. The focus of ThreadStates is to identify the states of disease progression by learning from observation data in a human-in-the-loop manner. We propose a novel Glyph Matrix design and combine it with a scatter plot to enable seamless identification, observation, and refinement of states. The disease progression patterns are then revealed in terms of state transitions using Sankey-based visualizations. We employ sequence clustering techniques to find patient groups with distinctive progression patterns, and to reveal the association between disease progression and patient-level features. The design and development were driven by a requirement analysis and iteratively refined based on feedback from domain experts over the course of a 10-month design study. Case studies and expert interviews demonstrate that ThreadStates can successively summarize disease states, reveal disease progression, and compare patient groups.

Disease control and failure patterns of unresectable hepatocellular carcinoma following transarterial radioembolization with yttrium-90 microspheres and with/without sorafenib.

BACKGROUNDImpressive survival outcome of our previous study in unresectable hepatocellular carcinoma (HCC) patients undergoing yttrium-90 glass microspheres transarterial radioembolization (TARE) with/without sorafenib according to individuals’ disease burden, i.e., intrahepatic tumor load (IHT) and adverse disease features (ADFs) might partly be confounded by other treatments and underlying hepatic function. Therefore, a dedicated study focusing on treatment response and assessment of failure patterns might be a way to improve treatment outcome in addition to patient selection based on the disease burden.AIMTo assess the tumor response, disease control and patterns of disease progression following TARE with/without sorafenib in unresectable HCC patients.METHODSThis retrospective study was conducted in successful TARE procedures with available pre- and post-treatment imaging studies (n = 169). Three treatment subgroups were (1) TARE only (TARE_alone) for IHT ≤ 50% without ADFs, i.e., macrovascular invasion, extrahepatic disease (EHD) and infiltrative/ill-defined HCC (n = 63); (2) TARE with sorafenib (TARE_sorafenib) for IHT > 50% and/or presence of ADFs (n = 81); and (3) TARE only for patients who could not receive sorafenib due to contraindication or intolerance (TARE_no_sorafenib) (n = 25). Objective response rate (ORR; consisted of complete response (CR) and partial response (PR)), disease control rate (DCR; consisted of CR, PR and stable disease) and failure patterns of treated, intrahepatic and extrahepatic sites were assessed using the modified response evaluation criteria in solid tumors. Time to progression (TTP) was calculated from TARE to the first radiologic progression at any site using Kaplan-Meier method. Identification of prognostic factors for TTP using the univariate Kaplan-Meier method and multivariate Cox proportional hazard model were performed in major population subgroups, TARE_alone and TARE_sorafenib.RESULTSThe median radiologic follow-up time was 4.4 mo (range 0.5-48.8). In treated area, ORR was highest in TARE_sorafenib (53.1%), followed by TARE_alone (41.3%) and TARE_no_sorafenib (16%). In intrahepatic area, DCR remained highest in TARE_sorafenib (84%), followed by TARE_alone (79.4%) and TARE_no_sorafenib (44%). The overall DCR was highest in TARE_alone (79.4%), followed by TARE_sorafenib (71.6%) and TARE_no_sorafenib (40%). Dominant failure patterns were intrahepatic for both TARE_alone (44.5%) and TARE_sorafenib (38.4%). Extrahepatic progression was more common in TARE_sorafenib (32%) and TARE_no_sorafenib (40%) than in TARE_alone (12.7%). TTP was longest in TARE_alone (8.6 mo; 95%CI: 3.4-13.8), followed by TARE_sorafenib (5.1 mo; 95%CI: 4.0-6.2) and TARE_no_sorafenib (2.7 mo; 95%CI: 2.2-3.1). Pre-existing EHD (HR: 0.37, 95%CI: 0.24-0.56, P < 0.001) was a sole prognostic factor for TTP in TARE_sorafenib with no prognostic factor for TTP in TARE_alone.CONCLUSIONTARE with/without sorafenib according to individuals’ disease burden provided DCR approximately 70% with intrahepatic progression as dominant failure pattern. Extrahepatic progression was more common in procedures with initially high disease burden.

Claims-Based Network Analysis of Disease Progressions in Complex and Non-Complex Older Adults

Older adults are the fastest growing subset of complex patients with high medical, behavioral, and social needs. Understanding differences in disease progression patterns between complex and non-complex older adults is critical for understanding disease risk and tailoring patient-centered interventions. We identified complex patients as those having frequent medical encounters and multiple chronic conditions within the first year of the study period and non-complex patients as the converse. This study compares the disease progression patterns of (a) complex and (b) non-complex older adults by creating disease progression networks (DPN) from claims data of 762,362 patients (mean age = 73) from 2016 to 2020. We characterized the network size and density between the complex patient DPN (C-DPN) and non-complex patient DPN (NC-DPN), and compared disease progression incidence, time-to-progression, and age- and gender-related risk. Results show that the C-DPN was denser and had a wider range of values for risk of progression compared to the NC-DPN. This implies more varied disease progression patterns occurring in the complex adults. We were also able to compare (median) time-to-progressions of diseases relative to each subpopulation and found variation in disease progression time. Furthermore, k-means clustering on the network allowed us to identify highly connected diseases involved in many disease pathways that are prevalent among older adults. (e.g., lipoprotein disorders, hypertension, major depressive disorder). Our results suggest that DPNs can be used to identify important conditions and time-points for tailoring care to the complex and non-complex older adults.

STMO-3 Mid- to long-term outcome of supratotal resection of IDH1 wild-type glioblastoma based on 11C-methionine PET: a retrospective, single-center study

PurposeMid- to long-term outcome in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection both of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-Met positron emission tomography (Met-PET), are not clarified.MethodsA retrospective, single-center review was performed in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was completely resected. Only patients who were operated on until November 2019 were included for evaluation of mid- to long-term outcome. Following resection, all patients underwent standard radiotherapy and temozolomide treatment, and were followed for progression-free survival (PFS) and overall survival (OS).ResultsAmong the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median PFS in the GTR and SupTR groups was 8.8 months (95% confidence interval [CI], 5.2–14.9) and 27.8 months (95% CI, 6.0-not estimable) respectively (p=0.08 by log-rank test). Median OS was 17.7 months (95% CI, 14.2–35.1) in GTR and not reached (95% CI, 30.5-not estimable) in SupTR, respectively; this difference was statistically significant (p=0.03 by log-rank test). No postoperative neurocognitive impairment was observed in SupTR patients.ConclusionCompared to GTR alone, SupTR strategy with aggressive resection of both CE tumors and Met uptake area in GBM patients under awake craniotomy with functional preservation results in a survival benefit associated with better local control.

Disease Progression and Mutation Pattern in a Large Cohort of LGMD R1/LGMD 2A Patients from India.

Calpainopathy is caused by mutations in the CAPN3 . There is only one clinical and genetic study of CAPN3 from India and none from South India. A total of 72 (male[M]:female [F] = 34:38) genetically confirmed probands from 72 independent families are included in this study. Consanguinity was present in 54.2%. The mean age of onset and duration of symptoms are 13.5 ± 6.4 and 6.3 ± 4.7 years, respectively. Positive family history occurred in 23.3%. The predominant initial symptoms were proximal lower limb weakness (52.1%) and toe walking (20.5%). At presentation, 97.2% had hip girdle weakness, 69.4% had scapular winging, and 58.3% had contractures. Follow-up was available in 76.4%, and 92.7% were ambulant at a mean age of 23.7 ± 7.6 years and duration of 4.5 years, remaining 7.3% became wheelchair-bound at 25.5 ± 5.7 years of age (mean duration = 13.5 ± 4.6), 4.1% were aged more than 40 years (duration range = 5–20). The majority remained ambulant 10 years after disease onset. Next-generation sequencing (NGS) detected 47 unique CAPN3 variants in 72 patients, out of which 19 are novel. Missense variants were most common occurring in 59.7% (homozygous = 29; Compound heterozygous = 14). In the remaining 29 patients (40.3%), at least one suspected loss of function variant was present. Common recurrent variants were c.2051–1G > T and c.2338G > C in 9.7%, c.1343G > A, c.802–9G > A, and c.1319G > A in 6.9% and c.1963delC in 5.5% of population. Large deletions were observed in 4.2%. Exon 10 mutations accounted for 12 patients (16.7%). Our study highlights the efficiency of NGS technology in screening and molecular diagnosis of limb-girdle muscular dystrophy with recessive form (LGMDR1) patients in India.

The Natural History of Lower Risk MDS: Factors Predicting Progression to High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Very Low and Low Risk MDS According to the R-IPSS Criteria

The Natural History of Lower Risk MDS: Factors Predicting Progression to High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Very Low and Low Risk MDS According to the R-IPSS Criteria

Eight-Color Flow Cytometry Phenotypic Markers and Disease Progression in Monoclonal Gammopathy of Unknown Significance

Introduction: Flow cytometric immunophenotyping is considered an indispensable tool for the diagnosis, classification, and monitoring of plasma cell disorders. Herein, we seek to study the clinical significance of expression of phenotype markers in monoclonal gammopathy of unknown significance (MGUS).Methods: We identified a cohort of patients with a diagnosis of MGUS from the institutional myeloma database. Bone marrow (BM) aspirate assessment was performed using 8-color immunophenotypic next-generation flow cytometric (NGF) analysis with a minimum sensitivity of 10 -5 cells at the time of diagnosis or first visit to our institution. BM aspirate samples were immunophenotyped on a FACSCanto II flow cytometer using antibodies (BD) to delineate normal and abnormal plasma cells [CD138 (V-500), CD38 (FITC), CD19 (PE-Cy7), CD45 (V-450), CD27 (PercpCy5.5), CD81 (APC-H-7), CD56 (APC) and CD20 (PE)]. The sensitivity or the Limit of Detection (LOD) for this assay was validated to 20 cells in 2 ×10 6 events (0.001%), and the reproducibility or Lower Limit of Quantitation (LLOQ) is 50 cells in 2 ×10 6 events. Clinical and laboratory variables were also collected. Based on previously published data, expression (CD19, CD45, CD81), and lack of expression (CD56, CD27, CD20) of the above-mentioned surface antigens were analyzed. Additional variables such as IgA isotype, size of M-protein (≥15 g/L), and abnormal free light chain ratio(abnFLR) (defined as <0.1 or >10) were included in regression fitting models.Results: A total of 157 patients with MGUS were included in this analysis. The median age at diagnosis was 60 years (range 24- 84), 84 (53 %) patients were female and 25 (16%) were African American. Overall, IgG Kappa (75/148, 50%) was the most common isotype. Fluorescent-in-situ hybridization (FISH) data were available in 35 patients with t (4:14) and t (14;16) seen in 3 patients each. At a median follow-up of 18.15 years (quantiles 11.35, 33.62), 28 patients experienced disease progression (25 to MM, 2 to Waldenstrom macroglobulinemia, and 1 Smoldering myeloma). The median progression-free survival of this cohort was 17.3 years. Among these, occurrences of the bone lesion (8/28; 28.6%) were the most common pattern of disease progression to MM. This analysis showed lower odds of progression with the expression of CD27 (OR-0.39, 95% CI 0.15-0.99) (figure 1A). Disease progression was more common in patients with an abnormal plasma cell clone size ≥ of 3.1% at diagnosis (60% vs. 12.5%, p=0.0005). An abnormal plasma cell clone of ≥3.1% at diagnosis, was associated with increased odds of progression (OR-10.79, 95% CI 4.02-28.98) and a shorter PFS (12.5 years versus NR, p=0.01) (figure 1B). Serum M-spike ≥1.5 g/dL (OR-3.54;95% 1.30-9.62) and abnFLR (OR-2.30, 95% CI 1.00-5.32) were also associated with a higher odds of progression. However, in this population, the presence of IgA isotype did not increase the odds of MGUS progression. In a stepwise regression model, serum M-spike≥1.5 g/dL, abnFLR, and the lack of expression of CD27 were associated with the risk of disease progression.Conclusion: In addition to previously published risk factors, our cohort shows that the expression of CD27 antigen by eight-color flow cytometry confers a lower risk of disease progression of MGUS. This is consistent with our previous report that CD27 is progressively down-regulated in the transition from normal plasma cells (NPC) to MGUS to MM (Zhan et al, Blood 2006). Furthermore, we show that size of the myeloma clone (≥ 3.1% ) is a possible surrogate marker for disease progression in MGUS.Figure 1: 1A shows forest plot of odds ratios for flow cytometry markers, IgA isotype, size of M protein, abnFLR and plasma cell clone size. 1B shows the Kaplan Meier estimates of PFS for patients stratifies by plasma cell clone size. [Display omitted] DisclosuresMohan: Medical College of Wisconsin: Current Employment. Atrash: GSK: Research Funding; AMGEN: Research Funding; Jansen: Research Funding, Speakers Bureau.

Afatinib treatment in a large real-world cohort of nonsmall cell lung cancer patients with common and uncommon epidermal growth factor receptor mutation.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between EGFR mutation subtypes in a large afatinib-treated cohort in which 516 EGFR-mutated NSCLC patients receiving afatinib as front-line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF /dT790MLAF ), non-T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type-I and the rest as type-II uncommon mutation. Four hundred and sixty-one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression-free survival (PFS) (2.6 and 4.1months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4months; P=3 × 10-8 ). Type-I uncommon mutation was an independent predictor of PFS (HR 4.46 [95% CI, 2.60-7.64]; P < .001) and OS (HR 2.56 [95% CI, 1.37-4.75]; P=.003). EGFR L858R patients demonstrated a significantly higher CNS progression (cause-specific HR, 3.16; 95% CI 1.24-8.08; P=.016), and type-I uncommon mutation patients exhibited a significantly higher systemic progression (cause-specific HR, 4.95; 95% CI 2.30-10.60; P=4.3 × 10-5 ). Tendencies of higher CNS and lower systemic progression were observed in type-II uncommon mutation patients. A PFS ≥ 12 months (OR 2.38 [95% CI, 1.18-4.89]; P=.016) and uncommon EGFR mutation (OR 0.08 [95% CI, 0.01-0.48]; P=.021) were independent predictors of secondary T790M. Afatinib-treated NSCLC patients presented an EGFR genotype-specific pattern of disease progression and outcome.

Shape-restricted estimation and spatial clustering of COVID-19 infection rate curves

The study of regional COVID-19 daily reported cases is used to understand pattern of spread and disease progression over time. These data are challenging to model due to noise that is present, which arises from failures in reporting, false positive tests, etc., and the spatial dependence between regions. In this work, we extend a recently developed Bayesian modeling framework for inference of functional data to jointly estimate and cluster daily reported cases data from US states, while accounting for spatial dependence between US states. Shape-restriction allows us to directly infer the number of extrema of a smooth infection rate curve that underlies noisy data. Other parameters in the model account for the relative timing of extrema, and the magnitude and severity of infection rates. We incorporate mobility behavior of each US state’s population into an informative prior model to account for the spatial dependence between US states. Our model corroborates past work that shows that different US states have indeed experienced COVID-19 differently, but that there are regional patterns within the US. The modeling results can be used to assess severity of infection in individual US states and trends of neighboring US states to aid pandemic planning. Retrospectively, this model can be used to see which factors (governmental, behavioral, etc.) are associated with the varying shapes of infection rate curves, which is left as future work.

Proximity to Brainstem at Recurrence is Associated with Decreased Survival in IDH Wild-Type Glioblastoma

Recent autopsy data from patients with glioblastoma (GBM) has demonstrated that pronounced brainstem infiltration is now a common pattern of disease progression near the end of life. The present study evaluated the association of disease proximity to the brainstem on imaging, both at diagnosis and at recurrence, with overall survival (OS).140 patients with IDH wild-type GBM treated definitively with resection and adjuvant chemoradiation at a single institution from 2013-2019 were retrospectively analyzed. Disease proximity to brainstem was calculated from measurements made on T1 post-contrast MRI brain obtained at diagnosis postoperatively and at recurrence. Tumor volume was approximated by the resection cavity plus adjacent extrinsic enhancement, measured during target delineation at time of treatment delivery. The Kaplan-Meier method was used to estimate OS, and multivariable analysis was performed using the Cox proportional hazards model. Logistic regression was used to assess the effect of tumor volume on brainstem involvement, and the relationship between tumor volume and proximity to brainstem was assessed by the Spearman correlation.Median distance of disease to brainstem was 22.4 mm (range 0-54) at diagnosis, with 2.1% (n = 3) having brainstem involvement. At 56-month median follow-up, 87% of patients had recurrence; 2-year OS was 38.6%. Median distance of disease to brainstem was 20.8 mm (range 0-63) at recurrence, with 5.7% (n = 8) having brainstem involvement at recurrence. Controlling for resection status, MGMT methylation, and Karnofsky performance status, there was no noted association of brainstem invasion (P = .60) or proximity at diagnosis (P = .14) with OS. However, at recurrence, distance from the brainstem was significantly associated with improved OS when measured continuously (HR: .97, 95% CI: .95-.99, P = 0.001) and when compared by group (20-40 mm vs. ≤20 mm: HR .59, 95% CI: .35-.99, P = 0.05; > 40 mm vs. ≤20 mm: HR .16, 95% CI: 0.05-.55, P = 0.003). While volume of tumor at diagnosis was not found to be independently associated with brainstem involvement (P = .99) or OS (P = .90) at recurrence, tumor volume at diagnosis was found to be significantly associated with disease proximity to brainstem at the time of recurrence (P = 0.037), with larger volume disease more likely to recur close to the brainstem.GBM proximity to the brainstem at diagnosis was not found to be prognostic, whereas disease proximity to the brainstem at recurrence was associated with worse OS. Tumor volume at diagnosis was found to be associated with disease proximity at recurrence, with higher volume disease at diagnosis associated with greater proximity to the brainstem at recurrence. These findings may have ramifications for upfront and salvage radiation treatment design.A. Bajaj: None. E.T. Benishay: None. I.B. Helenowski: None. R. Savoor: None. M.R. Drumm: None. N. Rammohan: None. S. Sachdev: None. C.M. Horbinski: None. T. Kruser: Employee; Northwestern Memorial Hospital. Honoraria; Elsevier, OncLive. Speaker's Bureau; AstraZeneca. Advisory Board; AstraZeneca.

The Presence of Leishmania braziliensis DNA in the Nasal Mucosa of Cutaneous Leishmaniasis Patients and the Search for Possible Clinical and Immunological Patterns of Disease Progression: A Cross Sectional Study.

Leishmania braziliensis is the most important causal agent of American tegumentary leishmaniasis (ATL), and 3 to 5% of patients develop mucosal lesions. The mechanisms related to parasite and host immune interactions and the parasite life cycle that lead to dissemination to the mucosa are poorly understood. We aimed to detect L. braziliensis DNA in the nasal mucosa of cutaneous leishmaniasis (CL) patients with early mucous dissemination and to relate those findings to specific inflammatory responses. Nasal swabs were collected from patients with the cutaneous form of ATL. L. braziliensis DNA was investigated using TaqMan-based real-time PCR. The levels of serum cytokines (IL-12, IL-6, TNF-α, IL-10, IL-1β and IL-8) were measured by a multiplex cytometric array. A Poisson regression model was used to test prevalence ratios (PRs) and multivariate interactions of clinical and laboratory characteristics. Of the 79 CL patients, 24 (30%) had L. braziliensis DNA in the nasal mucosa. In the multivariate model, parasite DNA presence in mucosa was associated with a reduction in IL-12 levels (PR = 0.440; p=0.034), increased IL-6 levels (PR = 1.001; p=0.002) and a higher number of affected body segments (PR = 1.65; p<0.001). In this study, we observed a higher rate of early dissemination to the nasal mucosa than what was previously described. We suggest that an enhanced Th1 profile characterized by higher IL-12 is important for preventing dissemination of L. braziliensis to the mucosa. Further evaluation of parasite-related interactions with the host immunological response is necessary to elucidate the dissemination mechanisms of Leishmania.

750 An Unusual Presentation of a Rare Clinical Entity – A Case Report of Spontaneous Common Bile Duct Perforation in an Adult

Abstract Spontaneous or non-traumatic perforation of the extrahepatic biliary system is a rare clinical phenomenon, with few cases reported since its first mention in medical literature by Freeland in 1882. Given the rarity, misdiagnosis is common with the diagnosis almost always made during urgent exploratory laparotomy. We describe a case of spontaneous common bile duct (CBD) perforation in an 83-year-old female with no associative underlying disease process identified. The patient presented with sudden onset abdominal pain with no identifiable trigger, with minimal past medical history. Examination was remarkable for findings of epigastric tenderness and guarding. Haematological investigation was remarkable only for hyperamylasaemia and leucocytosis. Pneumoperitoneum was ruled out and following contrast CT abdomen and pelvis a working diagnosis of mild pancreatitis was made. US Abdomen and MRCP found no evidence of cholelithiasis, with minimal biliary duct dilatation. The patient continued to deteriorate on the ward, with aspiration of new intrabdominal fluid collection raising suspicion of perforated viscus. Exploratory laparotomy revealed a 1-cm defect in the CBD with frank bile leak. A T-tube was placed in the common bile duct defect, with an abdominal robertson drain also inserted. No further bile leak was identified via Tubogram, with the patient successfully discharged following multidisciplinary rehabilitation in intensive care and the ward setting. Surgeons should seek out this uncommon diagnosis in patients with hyperamylasaemia and suspected cholelithiasis who do not conform to normal biliary/pancreatic disease progression patterns.

The Concept of α-Synuclein Strains and How Different Conformations May Explain Distinct Neurodegenerative Disorders.

In the past few years, an increasing amount of studies primarily based on experimental models have investigated the existence of distinct α-synuclein strains and their different pathological effects. This novel concept could shed light on the heterogeneous nature of α-synucleinopathies, a group of disorders that includes Parkinson's disease, dementia with Lewy bodies and multiple system atrophy, which share as their key-molecular hallmark the abnormal aggregation of α-synuclein, a process that seems pivotal in disease pathogenesis according to experimental observations. However, the etiology of α-synucleinopathies and the initial events leading to the formation of α-synuclein aggregates remains elusive. Hence, the hypothesis that structurally distinct fibrillary assemblies of α-synuclein could have a causative role in the different disease phenotypes and explain, at least to some extent, their specific neurodegenerative, disease progression, and clinical presentation patterns is very appealing. Moreover, the presence of different α-synuclein strains might represent a potential biomarker for the diagnosis of these neurodegenerative disorders. In this regard, the recent use of super resolution techniques and protein aggregation assays has offered the possibility, on the one hand, to elucidate the conformation of α-synuclein pathogenic strains and, on the other hand, to cyclically amplify to detectable levels low amounts of α-synuclein strains in blood, cerebrospinal fluid and peripheral tissue from patients. Thus, the inclusion of these techniques could facilitate the differentiation between α-synucleinopathies, even at early stages, which is crucial for successful therapeutic intervention. This mini-review summarizes the current knowledge on α-synuclein strains and discusses its possible applications and potential benefits.

Resistance varieties and pattern of disease progress of rust (Pucciana horiana p. henn) in Chrysanthemum

Rust is a major disease in chrysanthemum, which causes degradation of flower quality and results in up to 100% yield loss. Out of all the available strategies, breeding for host-plant resistance and knowledge of the pattern of disease progression in each variety is an effective strategy to control rust disease. The disease progress figured out the level of disease severity from time to time. It would be as guidance to control the disease, especially pesticide application. Six national superior and one introduced varieties were tested for their rust resistance. The varieties were studied to know the pattern of disease progression in each variety from vegetative to generative phase. The study was conducted from August 2014 to January 2015 in the plastic house of chrysanthemum plantation at Garung sub-District, Wonosobo regency, one of the centers chrysanthemum production in Central Java. The disease intensity was measured at 30, 60, and 90 days after planting. The results relayed that based on the rate of disease progress and the average of disease intensity, it could be identified that the superior national varieties of chrysanthemum, Kusumaswasti, Marimar, and Yulimar were more resistant to rust than the four other varieties tested. The rate of disease progress and the level of disease intensity of rust by the plant age determined the resistance of the chrysanthemum varieties to rust. Moreover, the result showed that each variety had a different rate and pattern of disease progression and could be used to control rust effectively.

P51.04 Pattern of Disease Progression on Osimertinib and Subsequent Treatment in Patients with EGFR- Mutated Non-Small Cell Lung Cancer

Osimertinib is the standard of care for patients with non-small cell lung cancer (NSCLC) who progressed with acquiring T790M mutation during first or second-generation EGFR tyrosine kinase inhibitors (TKI). Little is known about dynamics of treatment failure on osimertinib and subsequent treatment patterns following progression with osimertinib in the real world.

Brain atrophy progression in Parkinson's disease is shaped by connectivity and local vulnerability.

Brain atrophy has been reported in the early stages of Parkinson’s disease, but there have been few longitudinal studies. How intrinsic properties of the brain, such as anatomical connectivity, local cell-type distribution and gene expression combine to determine the pattern of disease progression also remains unknown. One hypothesis proposes that the disease stems from prion-like propagation of misfolded alpha-synuclein via the connectome that might cause varying degrees of tissue damage based on local properties. Here, we used MRI data from the Parkinson Progression Markers Initiative to map the progression of brain atrophy over 1, 2 and 4 years compared with baseline. We derived atrophy maps for four time points using deformation-based morphometry applied to T1-weighted MRI from 120 de novo Parkinson’s disease patients, 74 of whom had imaging at all four time points (50 Men: 24 Women) and 157 healthy control participants (115 Men: 42 Women). In order to determine factors that may influence neurodegeneration, we related atrophy progression to brain structural and functional connectivity, cell-type expression and gene ontology enrichment analyses. After regressing out the expected age and sex effects associated with normal ageing, we found that atrophy significantly progressed over 2 and 4 years in the caudate, nucleus accumbens, hippocampus and posterior cortical regions. This progression was shaped by both structural and functional brain connectivity. Also, the progression of atrophy was more pronounced in regions with a higher expression of genes related to synapses and was inversely related to the prevalence of oligodendrocytes and endothelial cells. In sum, we demonstrate that the progression of atrophy in Parkinson’s disease is in line with the prion-like propagation hypothesis of alpha-synuclein and provide evidence that synapses may be especially vulnerable to synucleinopathy. In addition to identifying vulnerable brain regions, this study reveals different factors that may be implicated in the neurotoxic mechanisms leading to progression in Parkinson’s disease. All brain maps generated here are available on request.