Evaluation Of Antibody Response To Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination In Patients With Lymphoid And Solid Organ Malignancies

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the current COVID-19 pandemic. There is emerging evidence regarding suboptimal response to vaccination against COVID-19 in patients with hematologic and solid organ malignancies. We conducted a single-center prospective study assessing seroconversion in response to vaccination against COVID-19 in 53 patients with chronic lymphocytic leukemia (CLL), non-Hodgkin’s lymphoma (NHL), multiple myeloma (MM), and solid organ malignancies. A quantitative immunoassay of IgG antibodies to SARS-CoV-2 Spike (S) protein was measured prior to vaccination and at 2 weeks after completion of two-dose vaccination series. A fourfold increase in antibody titers was considered positive seroconversion. Through a predesigned survey, patients also self-reported side effects from each dose of vaccination. Seroconversion on vaccination was seen in 6/12 (50%) patients with CLL, 7/11 (63.6%) patients with NHL, 9/10 (90%) patients with MM, and 17/20 (85%) patients with solid organ malignancy. Only 6 of the 14 (42.8%) patients currently on or with previous history of rituximab use seroconverted. Injection site soreness was the most reported side effect. The only severe side effect occurred in a patient with solid organ malignancy who developed Parsonage-Turner syndrome. Patients with CLL and NHL appear less likely to respond to vaccination against COVID-19 in contrast to patients with MM or solid organ malignancies. Previous treatment with rituximab is a possible risk factor for suboptimal response to vaccination. These data highlight the importance of continuing risk mitigation strategies against COVID-19 in individuals with hematologic malignancy, particularly those with CLL or on treatment with rituximab

When age is truly only a number: late diagnosis of von Willebrand disease type 2B in a 61-year-old woman

von Willebrand disease (VWD) type 2B is a rare bleeding disorder, presenting with moderate-to-severe lifelong bleeding. We present the case of a 61-year-old woman who was misdiagnosed as immune thrombocytopenic purpura during her three pregnancies resulting in a delayed diagnosis of VWD type 2B. This genetically confirmed diagnosis resulted in testing and the establishment of the diagnosis in her otherwise asymptomatic adult son as well. VWD may not be diagnosed till beyond mid adulthood in women with thrombocytopenia previously attributed to pregnancy and should be considered as a differential in female patients developing thrombocytopenia less than 100 × 10/μl with an increased bleeding assessment tool score

Interventions to improve resident reporting of patient safety events: a quality improvement initiative

Background: Patient safety events (PSE) are opportunities to improve patient care but physicians rarely report them. In a previous study, residents identified knowledge regarding what constitutes a PSE, perceived lack of time, complexity of the reporting process, lack of feedback, and perceived failure to resolve the issue despite reporting to be barriers limiting their PSE reporting. The residency programs and system patient safety and quality improvement departments created targeted interventions to address identified barriers. Objective: Assess effectiveness of targeted interventions on improving PSE reporting rates amongst residents. Methods: As part of a multi-residency patient safety project, interventions were created to focus on the removal of barriers to reporting PSE identified previously. Post-interventions, an identical cross-sectional survey of the residents at the same two community teaching hospitals was conducted from Sept to Dec 2018 through an online questionnaire tool. Results: 78 out of 149 residents (52.3%) completed the survey. We found a significant improvement in the number of residents who endorsed reporting a PSE in the past 1 year (51.2% vs 23.5%, p = 0.001), as well as during the course of their training (52.6% vs 26.5%, P = 0.001). There was also a significant decrease in the number of residents who were unsure of how to report a PSE (p = 0.031) as well as those who viewed medical error as a sign of incompetence (p = 0.036). Conclusion: Our study demonstrates that simplifying the PSE reporting process, improving knowledge and acceptance of patient safety/quality improvement principles and promotion of a just culture improves resident PSE reporting

Evaluation of Antibody Response to Severe Acute Respiratory Syndrome Coronavirus 2 (Sars-Cov-2) Immunizations in Patients with B-Cell Malignancies

Background Multiple vaccines have been granted emergency use authorization by the Food and Drug Administration against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Of the currently available vaccines, none have been systematically studied for efficacy or toxicity in patients with immunodeficiency or with immunosuppressed states, such as B cell malignancy. The purpose of the study was to evaluate the immune response to currently available vaccines against COVID-19 in patients with hematologic and solid organ malignancies. Methods This prospective study enrolled 53 patients; 12 with CLL, 10 with multiple myeloma (MM), 11 with non-Hodgkin's lymphoma (NHL) and 21 with a solid organ malignancy. Using a quantitative assay, IgG antibodies to SARS-CoV-2 Spike (S) protein, and nucleocapsid (N) protein by enzyme immunoassay were measured at baseline prior to vaccination and at 2 weeks after completion of vaccination. A fourfold increase in IgG was considered a positive response to vaccination. Through a predesigned survey, patients also self-reported side effects from each dose of vaccination. Results Seroconversion with vaccination was seen in 9/10 (90%) patients with MM, 5/12 (41.7%) patients with CLL, 6/11 (54.1%) patients with NHL, and 17/21 (80.9%) patients with solid organ malignancy. Per univariate analysis, CLL (OR 0.23, 95% CI 0.05-0.88; p= 0.033) was associated with lower odds of seroconversion while NHL (OR 0.48, 95% CI 0.12-1.8; p =0.291), MM (OR 5.33, 95% CI 0.61-46.08; p= 0.128) and solid organ malignancy (OR 2.90, 95% CI 0.79-10.64; p= 0.107) were not. Among patients with hematological malignancies, 5/13 (38.3%) patients treated with rituximab and 2/7 (28.5%) patients on immunoglobulin replacement (IgR) therapy responded to vaccination. This corresponded to reduced odds of seroconversion, 0.18 (95% CI 0.047-0.69; p = 0.013) in patients treated with rituximab and 0.14 (95% CI 0.024-0.826; p=0.030) in patients on IgR. Among patients with solid organ malignancies, treatment with chemotherapy (OR 2.05, 95% CI 0.48-8.61; p=0.320), immunotherapy (OR 4.57, 95% CI 0.52-39.9; p=0.169) or endocrine therapy (OR 1.0) did not lower odds of seroconversion with vaccination. Multivariate analysis revealed patients who received rituximab were less likely to respond to vaccination as compared to patients not previously treated with rituximab (OR 0.22, 95% CI 0.05-0.955; p=0.044). Injection site soreness was the most commonly reported side effect. The only severe side effect occurred in a patient with solid organ malignancy who developed Parsonage Turner syndrome. Conclusion Our study, to the best of our knowledge, is the first study comparing pre and post vaccination IgG titers against the SARS-CoV-2 S protein. Majority of patients with MM and solid organ malignancies, including those receiving active treatment, responded adequately to immunization. Patients with CLL appear less likely to respond to vaccination against COVID-19 as compared to patients with NHL, MM or solid organ malignancies. Previous treatment with rituximab was the most significant risk factor for suboptimal response to vaccination, regardless of underlying hematologic malignancy. These data highlight the importance of continuing risk mitigation strategies against COVID-19 in individuals with hematologic malignancy, particularly those with CLL or on treatment with rituximab. Future research is needed to investigate approaches to provide protective IgG against SARS-CoV-2 in this at-risk population. [Figure: see text] DISCLOSURES: Mustafa:  Genentech: Speakers Bureau; GalaxoSmithKline: Speakers Bureau; CSL Behring: Speakers Bureau; Regeneron: Speakers Bureau; AstraZeneca: Speakers Bureau. Walsh:  Janssen: Research Funding; Merck: Research Funding; Pfizer: Research Funding. Jamshed:  Takeda: Honoraria

Downregulation of S100 calcium binding protein A9 in esophageal squamous cell carcinoma

The development of esophageal squamous cell carcinoma (ESCC) is poorly understood and the major regulatory molecules involved in the process of tumorigenesis have not yet been identified. We had previously employed a quantitative proteomic approach to identify differentially expressed proteins in ESCC tumors. A total of 238 differentially expressed proteins were identified in that study including S100 calcium binding protein A9 (S100A9) as one of the major downregulated proteins. In the present study, we carried out immunohistochemical validation of S100A9 in a large cohort of ESCC patients to determine the expression and subcellular localization of S100A9 in tumors and adjacent normal esophageal epithelia. Downregulation of S100A9 was observed in 67% (n=192) of 288 different ESCC tumors, with the most dramatic downregulation observed in the poorly differentiated tumors (99/111). Expression of S100A9 was restricted to the prickle and functional layers of normal esophageal mucosa and localized predominantly in the cytoplasm and nucleus whereas virtually no expression was observed in the tumor and stromal cells. This suggests the important role that S100A9 plays in maintaining the differentiated state of epithelium and suggests that its downregulation may be associated with increased susceptibility to tumor formation

Rapid Characterization of Candidate Biomarkers for Pancreatic Cancer Using Cell Microarrays (CMAs)

Tissue microarrays have become a valuable tool for high-throughput analysis using immunohistochemical labeling. However, the large majority of biochemical studies are carried out in cell lines to further characterize candidate biomarkers or therapeutic targets with subsequent studies in animals or using primary tissues. Thus, cell line-based microarrays could be a useful screening tool in some situations. Here, we constructed a cell microarray (CMA) containing a panel of 40 pancreatic cancer cell lines available from American Type Culture Collection in addition to those locally available at Johns Hopkins. As proof of principle, we performed immunocytochemical labeling of an epithelial cell adhesion molecule (Ep-CAM), a molecule generally expressed in the epithelium, on this pancreatic cancer CMA. In addition, selected molecules that have been previously shown to be differentially expressed in pancreatic cancer in the literature were validated. For example, we observed strong labeling of CA19-9 antigen, a prognostic and predictive marker for pancreatic cancer. We also carried out a bioinformatics analysis of a literature curated catalog of pancreatic cancer biomarkers developed previously by our group and identified two candidate biomarkers, HLA class I and transmembrane protease, serine 4 (TMPRSS4), and examined their expression in the cell lines represented on the pancreatic cancer CMAs. Our results demonstrate the utility of CMAs as a useful resource for rapid screening of molecules of interest and suggest that CMAs can become a universal standard platform in cancer research

Rapid Characterization of Candidate Biomarkers for Pancreatic Cancer Using Cell Microarrays (CMAs)

Tissue microarrays have become a valuable tool for high-throughput analysis using immunohistochemical labeling. However, the large majority of biochemical studies are carried out in cell lines to further characterize candidate biomarkers or therapeutic targets with subsequent studies in animals or using primary tissues. Thus, cell line-based microarrays could be a useful screening tool in some situations. Here, we constructed a cell microarray (CMA) containing a panel of 40 pancreatic cancer cell lines available from American Type Culture Collection in addition to those locally available at Johns Hopkins. As proof of principle, we performed immunocytochemical labeling of an epithelial cell adhesion molecule (Ep-CAM), a molecule generally expressed in the epithelium, on this pancreatic cancer CMA. In addition, selected molecules that have been previously shown to be differentially expressed in pancreatic cancer in the literature were validated. For example, we observed strong labeling of CA19-9 antigen, a prognostic and predictive marker for pancreatic cancer. We also carried out a bioinformatics analysis of a literature curated catalog of pancreatic cancer biomarkers developed previously by our group and identified two candidate biomarkers, HLA class I and transmembrane protease, serine 4 (TMPRSS4), and examined their expression in the cell lines represented on the pancreatic cancer CMAs. Our results demonstrate the utility of CMAs as a useful resource for rapid screening of molecules of interest and suggest that CMAs can become a universal standard platform in cancer research