Entire Patient Population Research Articles

First-line osimertinib for poor performance status patients with EGFR mutation-positive non-small cell lung cancer: A prospective observational study.

The clinical outcomes of poor performance status (PS) patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) who are treated with osimertinib as a first-line treatment have not been sufficiently evaluated. This study aimed to assess the efficacy and safety of osimertinib in chemotherapy-naive and poor PS (2 or more) patients with NSCLC harboring sensitive EGFR mutations. We assessed the clinical effects of osimertinib as a first-line treatment for patients with poor PS NSCLC with an exon 19 deletion or exon 21 L858R mutation in EGFR. All patients were administered osimertinib (80mg/day) as the initial treatment. Sixteen patients (nine women and seven men) who were treated between August 2018 and July 2021 were included in this study; their median age was 78years. The overall objective response rate was 56.3%. The median progression-free survival (PFS) of the entire patient population was 10.5months and the PS score improved in 8 of 16 patients (50%). The most common adverse event was acneiform rash (42%), followed by diarrhea (36%) and paronychia (36%); none of these were of grade ≥ 3. Interstitial lung disease occurred in 2 patients (12.5%); however, no treatment-related deaths occurred. Considering the findings of this study, osimertinib appears to be an effective and safe treatment option for patients with poor PS and advanced NSCLC harboring sensitive EGFR mutations. To obtain conclusive results, further studies with larger cohorts are warranted.

145 EDITH (EMERGENCY DEPARTMENT IN THE HOME): FACTORS THAT INFLUENCE CONVEYANCE RATES TO HOSPITAL

Abstract Background The EDITH team has provided an alternative care pathway for older adults in need of emergency services. Patients are attended to by a doctor and Occupational Therapist in their own home as an alternative to an emergency department presentation. The conveyance rate for transfers to hospital is 7.2% of total patients treated by the EDITH service. It is imperative to identify this patient group and look for commonalities in same. This assists with service planning and also identifies high risk patients who may need transfer to hospital; thus ensuring patients are prioritised appropriately within the service. Methods Following an audit of a subsample (n = 230) of the entire EDITH patient population (3,137 patients), 26 patients were transferred to hospital. Analysis of the Health Care Record was completed to identify similarities in this population group and compare same with the ‘typical patient profile’. Results It was found that 38% of patients had a recent ED presentation (in the past month) and 31% had a prolonged hospital stay (> 2 weeks in past year). 57% had a documented change in functional baseline over past 2 weeks. 46% of patients were transferred to level 4 acute hospitals for medical follow up and 54% were transferred to level 3 hospitals or rehabilitation facilities for MDT input. 77% of patients had a Clinical Frailty Scale score of 6 and above (moderately frail) compared with 62% of the non-conveyance population. Presenting complaints included: falls 35%, respiratory issues 12%, pain management 12%, gastrointestinal issues 12%. Conclusion Risk factors for conveyance to hospital for EDITH patients have been identified. This knowledge can potentially be used to triage patients and ensure timely review from EDITH for this high risk patient group.

CD109 expression in tumor cells and stroma correlates with progression and prognosis in pancreatic cancer.

CD109 is a glycosylphosphatidylinositol-anchored glycoprotein, whose expression is upregulated in some types of malignant tumors. High levels of CD109 in tumor cells have been reported to correlate with poor prognosis; however, significance of CD109 stromal expression in human malignancy has not been elucidated. In this study, we investigated the tumorigenic properties of CD109 in pancreatic ductal adenocarcinoma (PDAC). Immunohistochemical analysis of 92 PDAC surgical specimens revealed that positive CD109 expression in tumor cells was significantly associated with poor prognosis (disease-free survival, p = 0.003; overall survival, p = 0.002), and was an independent prognostic factor (disease-free survival, p = 0.0173; overall survival, p = 0.0104) in PDAC. Furthermore, CD109 expression was detected in the stroma surrounding tumor cells, similar to that of α-smooth muscle actin, a histological marker of cancer-associated fibroblasts. The stromal CD109 expression significantly correlated with tumor progression in PDAC (TNM stage, p = 0.033; N factor, p = 0.024; lymphatic invasion, p = 0.028). In addition, combined assessment of CD109 in tumor cells and stroma could identify the better prognosis group of patients from the entire patient population. In MIA PaCa-2 PDAC cell line, we demonstrated the involvement of CD109 in tumor cell motility, but not in PANC-1. Taken together, CD109 not only in the tumor cells but also in the stroma is involved in the progression and prognosis of PDAC, and may serve as a useful prognostic marker in PDAC.

Cardiac surgery in older patients: hospital outcomes during a 15-year period from a complete national series.

OBJECTIVESThe objective was to review national trends in activity and hospital outcomes in older patients having cardiac surgery over a 15-year time period.METHODSData were collected prospectively and uploaded to the National Institute for Cardiovascular Outcomes Research electronically. Data were validated, cleaned and processed using reproducible algorithms. Mortality was death in hospital after index operation.RESULTSA total of 227 442 cardiac procedures were recorded in patients aged ≥70 years of which 46 354 were in those aged ≥80 years. Overall patients aged ≥70 years represented 43% of all adult cardiac surgery in the most recent study year. The annual proportion of surgery in patients ≥80 years increased from 4.1% to 10.8% between the first and last study years. There has been a significant linear increase in octogenarian valve [β 67.44, 95% confidence interval (CI) 55.04 to 79.83, P < 0.001] and coronary artery bypass graft surgery (β 32.53, 95% CI 6.16 to 58.90, P = 0.020) patients. In-hospital mortality reduced significantly for patients aged 70–79 years (β −0.17, 95% CI −0.20 to −0.13, P < 0.001) and all patients aged ≥80 (β −0.37, 95% CI −0.45 to −0.30, P < 0.001). The median length of hospital stay was 7 days for 70–79 and 9 days for ≥80 group, compared with 7 days for the whole cohort <70 years.CONCLUSIONSThis study represents the largest complete validated national dataset of cardiac surgery in the entire population of older patients. Octogenarians represent 11% of adult patients having cardiac surgery by the end of the study period, a three-fold increase from the start. In-hospital mortality in patients aged ≥80 years halved during study period to only 4% despite high logistic EuroSCORE of 15%. Cardiac surgery in octogenarians places a higher demand on resources, however, with an increased postoperative length of stay.

Subgroup Analysis: Efficacy and Safety of Panobinostat in Combination with SC Bortezomib and Oral Dexamethasone in Multiple Myeloma Patients with Lenalidomide-Refractory Disease

Subgroup Analysis: Efficacy and Safety of Panobinostat in Combination with SC Bortezomib and Oral Dexamethasone in Multiple Myeloma Patients with Lenalidomide-Refractory Disease

Epidemiologic and Clinical Patterns of Lymphoma in Qatar 2013-2017: A Population-Based Cohort Study

Background:Lymphoma: either most common non-Hodgkin (NHL) or less common Hodgkin (HL), are well-known hematological malignancies. With advancement in treatment modalities, the survival in both lymphomas especially the “poor prognosis” non-Hodgkin lymphoma has evolved in the last decades. Hence, patient's outcome may be diverse and quite complicated; with some need extended time for observation, and others having multiple chemotherapy treatments. In this review, we will focus on the clinic-epidemiological patterns of various malignant lymphoma subtypes in Qatar in recent years (2013-2017)Objective:The primary aim is to investigate and compare the overall survival (OS) for both types of lymphoma; HL and NHL at 1, 3 and 5-years of follow up in adult lymphoma patients in Qatar between January 2013 - December 2017. Other objectives include comparing between the most frequent histological varieties, clinical and epidemiological characteristics of HL and NHL lymphoma in Qatar. The secondary objectives included clinical characteristics, treatments used, treatment response, disease-free survival and overall survival.Methods:A retrospective, descriptive study of consecutive cases was carried out at NCCCR, Qatar between 2013-2017. Inclusion criteria included: ≥ 18 years of age, male or female, any clinical stage at diagnosis, who had received any chemotherapy regimen, with a known outcome. Descriptive statistics was performed for all variables, and survival was assessed using Kaplan-Meier curves. Data was abstracted by Qatar National Cancer Registry and the 2008 World Health Organization (WHO) classification of hematopoietic and lymphoid tumors is used as reference for disease staging and pathological classification. We used STATA version 13.0 (StataCorp., College Station, TX) for exploratory data analysis and descriptive statistics.Results:During the period 2013-2017, 414 men and women were diagnosed with lymphoma in the state of Qatar. The median age at diagnosis being 49 years (interquartile range IQR 36-95 years; p<0.001)) for all lymphoma patients combined. Males were more likely to develop both lymphoma types; HL and NHL than females; accounting for 2/3 of cases in each, yet statistically insignificant (74% and 70%, p=0.45). Based on subtypes, mature B-cell neoplasms (61 cases, 60%) were the most common among 13 identifiable NHL-B subtypes. Majority of HL cases belonged to Lymphocyte rich subtype (54 cases, 49%). With a median follow up of 17.3 months, the 1-year, 3-year and 5-year OS for the entire population of lymphoma patients were 99%, 82% and 64% (Figure 12). When stratified by major subtypes; HL and NHL, some trends became evident at 3-years follow-up (94% versus 82%). The 5-year OS were 67% and 60%, respectively. Throughout the study period, the OS in HL group were higher than NHL (p<0.001), yet median OS was not reached.Conclusions:Diffuse large B-cell lymphoma constitutes the most frequent subtype for all lymphomas in Qatar. Overall, the survival was generally better for HL than NHL 67% and 60% respectively. Survival can be slightly deflated than other countries or regions especially HL, this is in part due to higher immigration rate in the country, so changes in survival over time (especially for longer periods) need to be examined alongside trends in incidence rates to interpret improvement in cancer control policies implemented. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

A Prospective Observational Study of Osimertinib for Chemo-Naive Elderly Patients with EGFR Mutation-Positive Non-Small Cell Lung Cancer.

BackgroundThe clinical outcomes of elderly patients with EGFR-mutated non-small cell lung cancer (NSCLC) who are treated with osimertinib have not been sufficiently evaluated. This study aimed to assess the efficacy and safety of osimertinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations.Patients and MethodsWe assessed the clinical effects of osimertinib as a first-line treatment for elderly NSCLC patients (≥75 years of age) with an exon 19 deletion or exon 21 L858R mutation in EGFR. All patients were administered 80 mg/day osimertinib as initial treatment.ResultsForty-three patients (24 women and 19 men) with adenocarcinoma who were treated between August 2018 and July 2021 were included in this study; their median age was 79 years (range, 75–90 years). The overall objective response rate was 60.5%. The median progression-free survival (PFS) and time to treatment failure (TTF) of the entire patient population were 22.1 months and 14.6 months, respectively. The most common adverse event was rash acneiform (42%), followed by diarrhea (33%) and paronychia (28%); none of these were grades ≥3. Interstitial lung disease developed in 8 patients (18.6%); however, no treatment-related deaths occurred. Multivariate analysis identified performance status and disease stage as predictors of PFS and TTF.ConclusionConsidering the findings of this study and despite an observed discordance between PFS and TTF, osimertinib appears to be an effective and safe treatment option in elderly patients with advanced NSCLC harboring sensitive EGFR mutations. To obtain conclusive results, further studies in a larger elderly population are warranted.

Diabetes Prevention in a U.S. Healthcare System: A Portrait of Missed Opportunities

Type 2 diabetes is a widespread, preventable illness. The U.S. Preventive Services Task Force (USPSTF) has screening guidelines for diabetes prevention. The aim is to establish the extent to which U.S. Preventive Services Task Force's guidelines for prediabetes screening, diagnosis, and treatment are followed in a large health system and to identify missed opportunities for diabetes prevention. A comprehensive analysis of the electronic health records for the entire patient population of a large health center between August 1, 2019 and October 31, 2020 was analyzed, focusing on 21,448 patients eligible for prediabetes screening according to USPSTF recommendations. Compliance with U.S. Preventive Services Task Force recommendations for screening, diagnosis, and treatment was assessed. Of the 21,448 patients identified as eligible for prediabetes screening, 13,465 (62.8%) were screened in accordance with the USPSTF recommendations. Of those patients screened, 3,430 met the requirements for a prediabetes diagnosis. Only 185 (5.4%) of patients who screened positive for prediabetes received a formal diagnosis of prediabetes, and no patients who received a diagnosis received appropriate treatment for their prediabetes. Women were more likely than men to be screened (p<0.001), and non-Hispanic Whites were less likely than non-Hispanic Blacks and Hispanics to be formally diagnosed even after screening positive (p<0.001). Although a majority of eligible patients receive appropriate screening for prediabetes, diagnosis and treatment of patients who screen positive for prediabetes is not common practice. Future research and policy may benefit from a focus on classifying diabetes prevention as a quality metric and incentivizing behaviors consistent with diabetes prevention.

Optimal access route for pontine cavernous malformation resection with preservation of abducens and facial nerve function.

The aim of this study was to analyze the differences between posterolateral and posteromedial approaches to pontine cavernous malformations (PCMs) in order to verify the hypothesis that a posterolateral approach is more favorable with regard to preservation of abducens and facial nerve function. The authors conducted a retrospective analysis of 135 consecutive patients who underwent microsurgical resection of a PCM. The vascular lesions were first classified in a blinded fashion into 4 categories according to the possible or only reasonable surgical access route. In a second step, the lesions were assessed according to which approach was performed and different patient groups and subgroups were determined. In a third step, the modified Rankin Scale score and the rates of permanent postoperative abducens and facial nerve palsies were assessed. The largest group in this series comprised 77 patients. Their pontine lesion was eligible for resection from either a posterolateral or posteromedial approach, in contrast to the remaining 3 patient groups in which the lesion location already had dictated a specific surgical approach. Fifty-four of these 77 individuals underwent surgery via a posterolateral approach and 23 via a posteromedial approach. When comparing these 2 patient subgroups, there was a statistically significant difference between postoperative rates of permanent abducens (3.7% vs 21.7%) and facial (1.9% vs 21.7%) nerve palsies. In the entire patient population, the abducens and facial nerve deficit rates were 5.9% and 5.2%, respectively, and the modified Rankin Scale score significantly decreased from 1.6 ± 1.1 preoperatively to 1.0 ± 1.1 at follow-up. The authors' results suggest favoring a posterolateral over a posteromedial access route to PCMs in patients in whom a lesion is encountered that can be removed via either surgical approach. In the present series, the authors have found such a constellation in 57% of all patients. This retrospective analysis confirms their hypothesis in a large patient cohort. Additionally, the authors demonstrated that 4 types of PCMs can be distinguished by preoperatively evaluating whether only one reasonable or two alternative surgical approaches are available to access a specific lesion. The rates of postoperative sixth and seventh nerve palsies in this series are substantially lower than those in the majority of other published reports.

Evaluation of nonaccidental trauma in infants presenting with skull fractures: a retrospective review.

Nonaccidental trauma (NAT) is one of the leading causes of serious injury and death among young children in the United States, with a high proportion of head injury. Numerous studies have demonstrated the safety of discharge of infants with isolated skull fractures (ISFs); however, these same studies have noted that those infants with suspected abuse should not be immediately discharged. The authors aimed to create a standardized protocol for evaluation of infants presenting with skull fractures to our regional level I pediatric trauma center to best identify children at risk. A protocol for evaluation of NAT was developed by our pediatric trauma committee, which consists of evaluation by neurosurgery, pediatric surgery, and ophthalmology, as well as the pediatric child protection team. Social work evaluations and a skeletal survey were also utilized. Patients presenting over a 2-year period, inclusive of all infants younger than 12 months at the time of presentation, were assessed. Factors at presentation, protocol compliance, and the results of the workup were evaluated to determine how to optimize identification of children at risk. A total of 45 infants with a mean age at presentation of 5.05 months (SD 3.14 months) were included. The most common stated mechanism of injury was a fall (75.6%), followed by an unknown mechanism (22.2%). The most common presenting symptoms were swelling over the fracture site (25 patients, 55.6%), followed by vomiting (5 patients, 11.1%). For the entire population of patients with skull fractures, there was suspicion of NAT in 24 patients (53.3% of the cohort). Among the 30 patients with ISFs, there was suspicion of NAT in 13 patients (43.3% of the subgroup). Infants presenting with skull fractures with intracranial findings and ISFs had a substantial rate of concern for the possibility of nonaccidental skull fracture. Although prior studies have demonstrated the relative safety of discharging infants with ISFs, it is critical to establish an appropriate standardized protocol to evaluate for infants at risk of abusive head trauma.

Quality of life and emotional vulnerability in a national cohort of adolescents living with Fontan circulation.

To investigate quality of life and mental health after Fontan completion, we aimed to characterise outcomes in a representative group of adolescent patients. The study was part of the pre-transition clinical work-up in adolescents with Fontan-type palliation of univentricular CHD. The programme covers the entire paediatric Fontan patient population in Norway. Our cross-sectional study included 42 adolescents with Fontan circulation aged 15-18. We recruited a control group of 29 healthy peers. Quality of life was measured by the Pediatric Quality of Life Inventory Questionnaire, while mental health was assessed with the Strength and Difficulties Questionnaire. Fontan patients scored lower than healthy controls on the Pediatric Quality of Life Inventory total (p = 0.004), the physical (p < 0.001) and social (p = 0.001) functioning subscale, and the Strength and Difficulties Questionnaire subscale of emotional symptoms (p = 0.035). Compared to two of the healthy teens (7%), seven patients (16%) in the Fontan group scored as having impaired mental health (p = 0.224). The female/male ratio for individuals with impaired health was 7:2 (p = 0.003). Compared to healthy controls, adolescents after Fontan-type palliation in Norway have good health-related quality of life and mental health, despite having slightly lower score than healthy individuals, mainly in physical domains and school functioning. Compared to healthy controls and healthy teenagers, these adolescents have somewhat more emotional problems, and compared to male patients, female patients more often have impaired mental health.

Disease-modifying therapy usage in patients with multiple sclerosis in France: A 6-year population-based study

BackgroundMost data regarding the use of disease-modifying therapies (DMTs) in multiple sclerosis (MS) comes from clinical series or regional databases that have a risk of recruitment bias. French health administrative data offers the significant advantage of being extensive in regards to both MS population coverage and DMT prescriptions. ObjectivesTo describe patterns of DMTs usage at the level of the entire French population of MS patients from 2010 to 2015. MethodsMS patients were identified during a 6-year study period via the French national health data system (covering 97% of the general population) and characteristics of patients who received at least one treatment were compared to those that never received treatment over the indicated period. A state sequence analysis was performed to study in a longitudinal way MS patients who started DMTs in 2010 and then to classify them into groups of similar therapeutic patterns. DMTs were categorized into first-line, second-line and off-label use, and included untreated periods for at least six months. Groups that were obtained were described and compared using a multinomial logistic regression. ResultsA total of 112,415 patients with MS were identified, of whom 54.0% received at least one DMT over the 6 years. The probability of being treated significantly decreased with age. Comorbidities and physical limitations appeared to be more frequent in not treated patients than in treated patients. Significant differences were also found between the two groups regarding the use of healthcare services (hospitalizations and visits to general practitioner, neurologist and nurse). Based on the 6-year therapeutic sequences, a four-cluster typology was obtained on the 4,474 patients who started a DMT in 2010. The first group which consisted of more than half of the patients (57.0%) mainly used first-line DMTs. The second group (13.1%) represented patients with second-line DMTs whereas the third group (7.3%) was comprised of off-label users and the last group (22.6%) was composed of MS patients who received no or minimal treatments. Classification into one of these groups was associated with patient's age, long-term disease status, pregnancy occurrence, estimated level of disability, levels of care (visits to a neurologist, nurse and/or physiotherapist and hospital/rehabilitation stays) and occurrence of death. ConclusionsThe exhaustive population-based dataset from the French national health data system gave the opportunity to provide a detailed description regarding the use of DMTs for MS at national level. The innovative method of state sequence analysis allowed obtaining four homogeneous groups of patients among thousands of longitudinal therapeutic sequences. The predominant place of first-line treatments was confirmed even if the type of first-line treatments has probably changed since 2015.

Abstract 2701: Molecular profiling to assess the immune response to neoadjuvant SABR in early breast cancer

Abstract Radiation therapy is used successfully in the treatment of breast cancer. Stereotactic radiation therapy (SBRT) is well established in the treatment of lung cancer, brain metastases and various other metastatic sites. Localized radiotherapy can promote dendritic cells maturations and activation and enhances phagocytosis of cells by antigen-presenting cells (APCs) increased presentation of tumor-associated antigenic peptides, and T cells being primed from naïve towards memory phenotypes In this study we evaluated the ability to implement a three fraction SBRT regimen for low-risk primary carcinoma of the breast prior to lumpectomy and profiled the immune microenvironment using NanoString's GeoMx Digital Spatial Profiling (DSP) platform and we performed NanoString gene expression profiling using the Human v.1.1 PanCancer immune profiling panel. NanoString's DSP platform was used to analyze 25 patient samples from the SIGNAL 2.0 clinical trial. For analysis, region of interest were selected comparing the tumor microenvironment (TME, CD45+ve) and tumor (pan cytokeratin) in pre and post treated FFPE slides. A panel of 60-antibodies were analyzed in each region. For gene expression profiling total RNA was extracted from the frozen tissue and the human V.1.1 PanCancer Immune Profiling Panel was used. We observed notable differences in the immune microenvironment gene expression patterns in samples pre- and post-treatment. We identified a total of 175 differentially expressed genes (DEGs) using a 5% adjusted p-value across the entire patient population regardless of which radiation arm. Pathway analysis identified genes associated with activation of immune response, signaling by interleukins and adaptive immune response were significantly changed in the post treatment samples. Deconvolution of the immune cell mRNA gene expression data demonstrated that there were significant changes in the cellular composition after radiotherapy. There were significant increase in expression levels of macrophages, dendritic cells, neutrophils and CD8 T cells post radiation treatment. In conclusion we have demonstrated through proteomic and transcriptomic profiling, SBRT elicits an immune response with increases in the innate response. Citation Format: Melanie Spears, Vida Talebian, Linda Liao, Megan Hopkins, Kalan Lynn, Michael Lock, Anat Kornecki, John M. Bartlett, Muriel Brackstone. Molecular profiling to assess the immune response to neoadjuvant SABR in early breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2701.

Compliance With Vaccination Recommendations Among Patients With Multiple Myeloma: A Real World Experience.

Compliance With Vaccination Recommendations Among Patients With Multiple Myeloma: A Real World Experience.

Operative Management of Failed Rotator Cuff Repair With Soft Tissue Release.

BackgroundWe hypothesize that revision surgery that includes soft tissue releases for patients with residual pain and reduced range of motion following rotator cuff repair can provide pain relief and improvement of motion and function.MethodsPatients were identified via a retrospective chart over a 10-year period who had a history of previous rotator cuff repair and had revision surgery with or without a rotator cuff repair and soft tissue release. Changes in visual analog scores (VAS) pain score on a 10-point scale and shoulder motion including forward flexion and external rotation were evaluated from the preoperative visit to the postoperative visit.ResultsIn total, 73 patients underwent procedures to address their symptoms following failed rotator cuff repair. Patients that underwent soft tissue release with revision rotator cuff repair and those who underwent isolated soft tissue release had decreased postoperative VAS pain scores (absolute reduction of 3 and 1.6 points, respectively) and improved postoperative forward flexion (15.3° and 13.6° respectively). Patients that have had one previous surgery had decreased pain (absolute reduction of 3.2 points), increased forward flexion and external rotation (16.2° and 4.9°). Patients that underwent two or more previous surgeries had decreased pain (absolute reduction of 1.8 points) and increased forward flexion (12.7°). Patients who were filing a Worker’s compensation claim also had decreased pain (absolute reduction of 2.2 points) and increased forward flexion (14.9°). Overall, there was a VAS pain scores absolute reduction of 2.6 points or 49.5% when examining the entire patient population.ConclusionOperative management by performing soft tissue release with or without concurrent revision rotator cuff repair is successful for both decreasing pain as well as improving motion. This effect was noted both in patients with commercial insurance and worker’s compensation claims. Improvements of pain and motion were more significant in patients who had undergone one prior surgery compared to those who have had multiple prior procedures.

Lettuce Plants Expressing High Levels of Factor VIII Antigen in the Chloroplast for Oral Tolerance in Hemophilia a

Inhibitor formation is a serious complication in factor VIII (FVIII) replacement therapy for the X-linked bleeding disorder hemophilia A and occurs in 20-30% of patients. No prophylactic tolerance protocols exist. In previous proof-of-principle work, we demonstrated oral tolerance induction to FVIII in hemophilia A mice using frozen tobacco leaf cells expressing the heavy chain (HC) and C2 domain of human B domain-deleted (BDD) FVIII (Blood 124:1659-68, 2014). This approach is based on expression of heterologous proteins in the chloroplasts of green leaves and natural bioencapsulation provided by plant cell wall, so that the antigen is protected until its release in the small intestine. The antigens are expressed as fusions with the transmucosal carrier CTB proteins for effective targeting of the gut epithelium and translocation to the immune system. However, significant hurdles toward clinical feasibility remained that we now successfully addressed. Until now, methods to express large human proteins in chloroplasts of edible crop plants did not exist. Building on our recently established gene transfer technology for lettuce chloroplasts and identification of powerful posttranscriptional regulatory elements, we focused on the development of chloroplast genomics tools (e.g. bioinformatics tools for codon optimization and assays that identify sites of ribosome stalling), which ultimately allowed us to express high levels of FVIII antigen in edible crop plants that are suitable for clinical application. Remarkably, codon-optimization improved expression of FVIII heavy chain (HC) and light chain (LC) by15- to 42-fold. Hence, the entire BDD-FVIII sequence can be orally delivered, thereby covering the entire patient population regardless of individual CD4+ T cell epitope usage. A clinical grade manufacturing process is in place, and lyophilization of leaf cells generates material that is stable at ambient temperature for at least 2 years. Testing in hemophilia A mice showed effectiveness of low FVIII antigen doses upon delivery of lyophilized lettuce cells. Repeated oral gavage (twice/week for 2 months) of a mixture of CTB-HC and CTB-C2 suppressed subsequent inhibitor formation against intravenous FVIII (1IU, once/ week for 4 weeks) in hemophilia A mice as well as the original tobacco material, using very low doses of 0.15-0.5 ug/antigen/mouse. When using CTB-HC/CTB-LC combination, a dose of 1.5 ug was most optimal and suppressed inhibitor titers by ~1 log (avg. 4.7 BU/ml vs 44 BU/ml in controls; 50% of tolerized mice had 0-3 BU/ml, while 86% of controls developed 6-126 BU/ml, n=12-14, P <0.05). Translational oral tolerance studies in humans would benefit from cellular biomarkers. Our prior studies showed induction of two subsets of Treg that suppress antibody formation against FVIII, namely CD4+CD25+FoxP3+ Treg and LAP+CD4+CD25-FoxP3- Treg. The latter stain positive on the cell surface for LAP (latency-associated peptide) because of overexpression of TGF-b. Although we found increases in the frequencies of LAP+CD4+CD25-FoxP3- Treg in peripheral blood, a statistical significance was not always observed when compared to the blood of control mice that received intravenous FVIII but not oral tolerance. However, we found significant and consistent increases in the frequencies of circulating LAP-expressing CD4+CD25+FoxP3+ Treg in tolerized mice, suggesting that LAP may be a suitable cellular biomarker for plant-based oral tolerance induction. In conclusion, clinical candidates for oral tolerance to FVIII are now available in form of lettuce plants expressing immunogenic domains or the entire antigen. DisclosuresHerzog:Novo Nordisk: Research Funding; Applied Genetic Technologies Corporation: Consultancy; Spark Therapeutics: Patents & Royalties. Daniell:Novo Nordisk: Research Funding.

CORR Insights®: Is There an Association Between Bundled Payments and "Cherry Picking" and "Lemon Dropping" in Orthopaedic Surgery? A Systematic Review.

CORR Insights®: Is There an Association Between Bundled Payments and "Cherry Picking" and "Lemon Dropping" in Orthopaedic Surgery? A Systematic Review.

Telemedicine-based early rule out and followup ECG algorithm for COVID-19 patients

Funding AcknowledgementsType of funding sources: None.BackgroundDrugs with the potential to prolong QT are used in the treatment of coronavirus 19 (COVID-19) pneumonia. We have developed a telemedicine-based corrected QT (QTc) follow-up algorithm that allows early rule out for follow up.AimsIn this study, we investigated the availability and safety of the algorithm.Study designRetrospective cohortMethodsConsecutive patients; administered hydroxychloroquine (HCQ) for COVID-19 pneumonia were enrolled into digital ECG recording program which includes QTc follow-up algorithm.ResultsPatients were classified into three groups as those, excluded promptly from the QTc follow-up based on two consecutive ECG findings (early rule out, n = 92) and those, for whom the follow-up was continued (n = 12) and usual care group (n = 68). Of note, 237 ECG tracings were performed in our algorithm population contrary to standard practice of daily recommended ECG monitoring which could have yielded 975 ECG tracings along with accompanied risks of exposure. This way; we ended in 738 (75.7%) fewer ECG tracings. Sustained ventricular arrhythmia or sudden cardiac death was not observed in the entire patient population.ConclusionsIt is safe to rely on telemedicine-based early rule out algorithm in COVID-19 patients, receiving hydroxychloroquine treatment. This algorithm abolished the need for further ECG in majority of patients without increased risk during follow up. These algorithms can significantly reduce the healthcare worker exposures by eliminating the need for ECG follow-up promptly. Figure. Covid-19 Follow up Algorithm

Research of the epidemiology on cancer of the trachea, bronchi, lungs as important components in the development of effective directions for increasing the effectiveness of pharmaceutical support for cancer patients

The aim: to conduct epidemiological studies on cancer of the trachea, bronchi, lungs as important components in the development of effective directions for increasing the effectiveness of pharmaceutical support for cancer patients in Ukraine.&#x0D; Materials and methods. The study used data from special literature, which presents the results of research on cancer in different countries of the world and data from the National Cancer Registry from 2014-2019 by indicators of morbidity and mortality of the population of Ukraine from cancer of the trachea, bronchi and lungs, including by gender. General theoretical (historical, analytical-comparative, systemic, graphic, logical, hypothetical-deductive) and applied (mathematical-statistical, epidemiological) research methods were used.&#x0D; Results. It was found that during 2014-2018 in terms of morbidity and mortality of the population from cancer of the trachea, bronchi and lungs in Ukraine, there was a positive dynamics of decline. So, in terms of incidence rates, which are standardized by WHO in 2018, the data decreased compared to 2014 by 8.4 %, and according to the “Ukrainian standard” – by 7.0 %. Mortality rates, which were standardized by WHO, decreased in 2018 compared to 2014 by 12.1 %, and those presented according to the “Ukrainian standard” – by 11.1 %. It was proved that the average data on morbidity and mortality of male patients were 6.2 and 7.4 times higher than in the same data for female patients. The different nature of changes in morbidity and mortality rates of patients in accordance with their gender in the dynamics of years has been established. So, for the female cohort of patients, the incidence and mortality rate from cancer of the trachea, bronchi and lungs during 2014-2018 had a complex zigzag character of changes, and in 2019, compared with the data of 2014, they increased by 22.54 % and 23.6 %, respectively. In the male cohort of patients, we observed a positive trend towards a decrease in mortality during 2014-2019. So, in 2019, these indicators reached their minimum and were equal to 57.0 and 44.0 cases per 100 thousand population. According to the data of 2019, the incidence and mortality of men from cancer of the trachea, bronchi and lungs relative to the data of 2014 decreased by 21.4 % and 25.0 %, respectively. It looks encouraging that there was relatively little fluctuation during 2014-2019 epidemiological indicators, both in general for the entire population of patients and female patients.&#x0D; Conclusions. The established characteristics and trends in the formation of the onco-epidemiological profile of the country's population for trachea, bronchus and lung cancer in dynamics over the years necessitate further research, taking into account changes in the main demographic indicators development of society

D2 dissection improves disease-specific survival in advanced gastric cancer patients: 15-year follow-up results of the Italian Gastric Cancer Study Group D1 versus D2 randomised controlled trial

BackgroundThe extended lymphadenectomy (D2) was recently introduced in several guidelines as the optimal treatment for gastric cancer, based only on the 15-year follow-up results of the Dutch randomised trial, while the British Medical Research Council (MRC) study failed to demonstrate a survival benefit over the more limited D1 dissection. The Italian Gastric Cancer Study Group randomised controlled trial (RCT) was also undertaken to compare D1 versus D2 gastrectomy, and a tendency to improve survival in patients with advanced resectable disease (pT > 1N+) was documented despite negative results in the entire patient population. Now we present the 15-year follow-up results of survival and gastric cancer-related mortality. MethodsBetween June 1998 and December 2006, eligible patients with gastric cancer who signed the informed consent were randomised at 5 centres to either D1 or D2 gastrectomy. Intraoperative randomisation was implemented centrally by phone call. Primary outcome was overall survival (OS); secondary end-points were disease-specific survival, postoperative morbidity and mortality. Analyses were by intention to treat. Strict quality control measures for surgery, lymph node removal, pathology and patient follow-up were implemented and monitored. Registration number: ISRCTN11154654 (http://www.controlled-trials.com). FindingsA total of 267 eligible patients were assigned to either D1 (133 patients) or D2 (134) procedure. Median follow-up time was 16.76 years. Analyses were done both in overall patient population and in pT > 1N+. One hundred patients (38.5) were alive without recurrence. OS and disease-specific survival (DSS) were very high in both arms. In overall population, they were not different between D1 and D2 arm (51.3% vs. 46.8% and 65% vs. 67% respectively, p = 0.31 and p = 0.94). DSS was significantly higher after D2 in pT > 1N+ patients (29.4% vs. 51.4%, p = 0.035). OS and DSS were better after D1 in patients older than 70 years (p = 0.003 and p = 0.006). DSS was higher after D1 also in early stages (p = 0.01). InterpretationAfter 15-year follow up, despite no relevant difference in overall population, DSS and gastric cancer-related mortality of patients with advanced disease and lymph node metastases are improved by D2 procedure. Further data available from this trial suggest that D1 procedure should be preferably used in older patients and in early disease. As accurate detection of advanced diseases can be currently provided by adequate preoperative workup in referral centres, D2 procedure should be recommended in these cases. FundingPiedmont Regional fund for Finalized Healthy Research Project, Application 2003 for data collection.