bluuebunny/crossref_metadata_2025 huggingface dataset:
Keep calm and invert on: Reducing blood recollection rates in the neonatal intensive care unit (NICU)
Authors: Ramos Paola , Streeton Abigail , Lunde Julie , Legried Michele , Karon Bradley , Baumann Nikola A
Published: November 2022

Background

Minimizing blood specimen recollection due to specimen integrity issues is a continuous quality improvement goal in the neonatal intensive care unit (NICU). Specimen integrity issues, such as clotting or hemolysis, are often the result of improper specimen collection processes and lead to blood loss requiring transfusion, additional painful procedures, and delays in patient care. Data collected from Mayo Clinic Hospital - Methodist Campus NICU at Mayo Clinic in Rochester, MN between January – July 2019 showed that clotted complete blood count (CBC) specimens accounted for one-third of rejected neonatal specimens followed by hemolyzed specimens for direct bilirubin (DBIL) testing. The aim of this project was to reduce the percent of CBC and DBIL tests canceled/specimens rejected due to specimen integrity issues in the NICU from 17% to 10% using the Plan-Do-Study-Act methodology.

Methods

A multidisciplinary quality improvement (QI) team was formed, inclusive of both NICU and laboratory representatives. Bedside direct observations (n=28) were performed by NICU nurses to help identify inconsistencies in the blood collection processes. A total of three Plan-Do-Study-Act (PDSA) cycles were conducted during the 2020-2021 time period. An assessment card was created and revised with each PDSA cycle. The card was completed by the nurse(s) present during the blood collection and initially identified the lab tests ordered, collection tubes, collection type (venipuncture, venous, capillary), number of tube inversions required, staff present during collection, any delays during collection, and whether the draw was deemed successful. Additionally, staff education videos for nursing and laboratory phlebotomy staff were created to demonstrate correct collection tube inversion technique.

Results

Direct observation identified inconsistent practices in tube inversion during specimen collection. The first PDSA cycle (n=207 collections, April 1 – July 13, 2021) introduced a verbal inversion count and utilization of the assessment card. The following cycle (n=336 collections, July 14 – October 10, 2021) implemented an educational video and modified the assessment card to include start and end time of the draw. The third cycle (n=243 collections, October 11 – November 30, 2021) used a simplified assessment card including patient label, tests ordered, tube type and inversions. The combined rejection rates for CBC and DBIL tests were 4.3%, 3.8% and 2.8% for the 1st, 2nd and 3rd PDSA cycles, respectively.

Conclusions

Our QI initiative reduced the specimen rejection rate for clotted CBC and hemolyzed DBIL specimens from 17% to 2.8% in the NICU. Interventions focused on improving tube inversion techniques and promoting collaborative relationships between phlebotomists and nursing staff. The use of educational videos and completion of assessment cards during collections were effective at reducing specimen rejection rates.
HLA-B evolutionary divergence is associated with poor outcomes after SARS-CoV-2 infection
Authors: Hernandez Patricia , Duffy Brian , Hock Karl , Farnsworth Christopher , Schindler Emily , Liu Chang
Published: November 2022

Objectives

Human leukocyte antigens (HLA) are highly diverse transmembrane proteins that present viral peptides to T cells and launch pathogen-specific immune responses. We aim to investigate the correlation between HLA evolutionary divergence (HED), a surrogate for the capacity to present different peptides, and the outcomes of SARS-CoV-2 infection in a cohort from the St. Louis Metropolitan area.

Methods

We enrolled adult patients with SARS-CoV-2 infection confirmed by RT-PCR who were hospitalized at two tertiary hospitals in St. Louis between March and July 2020. Genomic DNA was extracted from peripheral blood and genotyped by next-generation sequencing (NGS). HLA alleles were assigned based on key-exon sequences (G group) and limited to the 2-field resolution. HED was calculated by Grantham distance, which considers the difference in composition, polarity, and molecular volume between each pair of amino acids from maternal and paternal HLA. The HED score was obtained for HLA class I (HLA-A, -B, and -C) genotypes using the HLAdivR package in R. Clinical data were collected retrospectively from electronic medical records. A poor outcome was defined as an admission to the intensive care unit (ICU), a need for mechanical ventilation, or death. A favorable outcome was defined as the absence of the above poor outcomes.

Results

A total of 234 patients were enrolled in this study, 96 being females (41%). The median age and BMI were 66 years old and 28.30 kg/m2, respectively. African Americans comprised 71.4% of the cohort. Only 19 patients (8.1%) presented with no comorbidity; the rest had one or more comorbidities, with cardiovascular diseases being the most common. A total of 137 (58.5%) patients had poor outcomes from SARS-CoV-2 infection, while 97 (41.5%) patients had a favorable outcome. We detected a significant association between higher HLA-B HED and favorable outcomes, with each 1-point increase in HLA-B HED associated with 8% increased probability for the composite endpoint (OR 1.08, 95% CI=1.01-1.16, P = 0.04). The HED scores calculated for HLA-A or HLA-C were not significantly different between patients with favorable or poor outcomes. In a multivariate logistic regression analysis, increased HLA-B HED score, younger age, and no comorbidity were independently associated with favorable outcomes (P = 0.02, P = 0.01, and P = 0.05, respectively).

Conclusion

Our study shows a significant correlation between lower HLA-B HED scores and poor outcomes after SARS-CoV-2 infection. This finding suggests that maximizing the presentation of diverse SARS-CoV-2 peptides by HLA-B alleles may improve the clearance of SARS-CoV-2. Further studies are warranted to understand the functional and mechanistic implications of this finding.
Evaluation of Bio-Rad D100 for HbA1c testing of dried blood spot samples
Authors: Wei Ruhan , Kroner Grace , Reineks Edmunds
Published: November 2022

Hemoglobin A1c (HbA1c) testing is critical for diabetes diagnosis and monitoring. Although many studies have demonstrated the feasibility of measuring HbA1c from dried blood spots (DBS) using immunoassays, enzymatic assays, and certain high-performance liquid chromatography (HPLC) assays, there is limited evidence supporting the use of the Bio-Rad D100 HPLC method. We evaluated the feasibility of testing HbA1c from DBS using Bio-Rad D100 to support the assessment of glycemic control for the growing field of telehealth.

Deidentified residual EDTA whole blood samples were processed, and HbA1c was measured on the Bio-Rad D100 on day zero. Concurrently, DBS were prepared for each sample by spotting 50 µL of blood onto a Whatman® 903 filter paper. The samples were dried overnight and stored at room temperature for two days. On day 2, a DBS disc with a diameter of 3.2 mm was eluted with 4.5 mL of Bio-Rad diluent for 20 minutes. The supernatants of the DBS samples were then processed on the platform. HbA1c values from the DBS samples were compared to the EDTA whole blood results.

Compared to the EDTA samples, the HbA1c concentrations of the corresponding DBS samples were elevated, especially for samples with original results less than 7.0%. Furthermore, the chromatograms of the DBS samples were significantly altered; we observed baseline elevation and the appearance of unknown minor peaks. This issue was investigated. First, blank DBS samples were created by directly spotting filter paper with diluent or adding diluent into an empty EDTA tube and then spotting the filter paper with the mixture of diluent and EDTA. The blank DBS samples were tested, and the lack of peaks suggested that the interference was not from the diluent, EDTA, or the filter paper. DBS samples were also prepared with sodium heparin whole blood, finger-stick capillary blood, and multiple brands of filter papers and tested using a different HPLC method. However, the interference was still present in those samples, indicating the interference is most likely due to the time-dependent degradation of the samples themselves. Of note, the alternate HPLC method showed less chromatogram alteration. To prevent possible adduct formation, DBS samples were eluted in the presence of various concentrations of cysteine (Jeppsson et al. 1986). However, the pretreatment did not eliminate the chromatogram changes. Finally, a multiple regression model was created using the results of day two A1c, A0, and F peaks, and a correction factor was generated. The corrected HbA1c concentrations were well within +/-6% of the initial HbA1c concentrations. In conclusion, the Bio-Rad D100 HPLC method appears particularly susceptible to stability changes in DBS samples, and further analysis is needed before employing a correction factor.
Incidence of Heparin Induced Thrombocytopenia (HIT) in patients with severe COVID-19
Authors: Barouqa Mohammad , Arackal Anita , Reyes-Gil Morayma
Published: November 2022

Introduction

To prevent and treat thrombotic complications in patients hospitalized with severe COVID-19 infection, anticoagulation treatments primarily with heparin and low molecular weight heparin have been recommended. Heparin-induced thrombocytopenia (HIT) is a rare but conceivably fatal reaction to heparin that is characterized by a sudden drop in platelet count accompanied by new onset of thrombosis 4-10 days after heparin exposure. The purpose of this retrospective study was to investigate the prevalence of thrombocytopenia and HIT in hospitalized COVID-19 patients, as well as their association with mortality.

Methods

3,672 plasma samples were collected from patients admitted to the first wave of COVID-19 in our institution at New York City (March to May 2020). All patients admitted with a platelet count of less than 150 k/ul were assigned to the thrombocytopenic group. In addition, two groups with similar demographics and normal platelet counts were randomly selected based on discharge outcome: alive vs. deceased (n= 88 per group). PF4 IgG Elisa and heparin neutralization were carried out in accordance with the manufacturer's instructions. A positive HIT result required an optical density (OD) greater than 0.4 and heparin neutralization greater than 50%. Statistical analysis was done in R studio (V.1.4.1717) to analyze demographics (age, gender, ethnicity), initial laboratory data, anticoagulation on admission, and thrombosis.

Results

Only 86 of the 3,672 (2.3%) patients admitted had thrombocytopenia. Only 1 of the 86 patients tested positive for HIT (1.1% ). 4 cases of the non-survivors (4.5%) tested positive for HIT compared to none of the survivors in the two groups with normal platelet counts. One of these 4 cases had a history of thrombosis (DVT). Interestingly, the PF4 Elisa ODs in non-survivors were significantly higher than in survivors (0.09 vs. 0.06, p-value< 0.001). Although the platelet count did not differ significantly between the two groups, the mean platelet volume (MPV) on admission and its maximum peak during hospitalization were significantly higher in non-survivors than in survivors.

Conclusions

We only found HIT positive cases among non-survivors, implying that HIT is associated with COVID severity. The incidence of HIT in severe COVID-19 patients appears to be higher than the pre-COVID-19 historical rates of HIT in hospitalized patients (<1%). Although thrombocytopenia is relatively uncommon in COVID-19 patients, the MPV was significantly higher in non-survivors, suggesting that platelet activation and destruction may explain the higher rate of HIT in COVID-19.
On-Cell Stability for Therapeutic Drug Monitoring
Authors: Nelson Heather , Pearson Lauren , Rudolf Joseph , Doyle Kelly
Published: November 2022

Introduction

A common problem in many clinical laboratories and outpatient clinics is processing specimens rapidly to comply with specimen stability criteria. Labs receive thousands of samples a day and may face challenges with staffing, equipment malfunction, or workflow, which can prevent immediate processing of samples. Currently, for therapeutic drug monitoring, the lab is required to centrifuge specimens and remove the serum/plasma from cells within 2-hours (CLSI-GP44-A4). Many of these drugs are monitored in the outpatient setting, which may require longer transportation times to get specimens from the collection location to the laboratory. This creates challenges for the lab in processing samples within 2-hours and may result in unnecessary rejection of otherwise acceptable specimens. Not all clinical sites have the staffing or space to process the specimens on site. Our objective was to determine if the on-cell stability of therapeutic drugs can be extended to beyond two hours.

Methods

We performed spiking studies to determine the on-cell stability of phenytoin in whole blood that was collected from healthy donors in barrier-free red top tubes. Phenytoin was spiked into the whole blood at a final concentration of about 10 (therapeutic) or 40 (toxic) µg/mL. The spiked whole blood samples were mixed by inverting six times and then were left at ambient temperature for 30 minutes, 2-, 4-, 6-, or 12-hours, after which they were centrifuged, and the serum was removed for analysis of total phenytoin concentration on the Abbott Architect and free and total phenytoin on the Beckman AU (n=3 per time point and concentration). In vivo studies are ongoing for an extended list of therapeutic drugs, in which two extra red top tubes are collected from patients being monitored for phenytoin, valproic acid, digoxin, vancomycin, lithium, or carbamazepine therapy. The two study tubes are kept at ambient temperature for 6- or 12-hours after collection before being centrifuged and separated from cells. The 6- and 12-hour drug concentrations were compared to the patient’s standard of care tube that was processed within 2-hours, after clotting for 30 minutes.

Results

Spiking studies demonstrated phenytoin was stable on cells for at least 12-hours at both 10 and 40 µg/mL. The percent total phenytoin remaining at 12-hours relative to the 30-minute control was 104 ± 2% at 10 µg/mL and 99 ± 16% at 40 µg/mL. Furthermore, the fraction of free phenytoin did not change over the 12 hours (10 µg/mL: 8 ± 1% free; 40 µg/mL: 10 ± 1% free). Our preliminary in vivo studies have shown no change in vancomycin or lithium concentration in samples processed 6- and 12-hours post-collection.

Conclusion

We have demonstrated that phenytoin, vancomycin, and lithium collected in red-top tubes are stable on cells at ambient temperature for at least 12-hours.
The Pandemic as a Catalyst for Digital Pathology Adoption as an LDT
Authors: Smith Geoffrey , Raiff Ross , Badve Sunil , Krasinskas Alyssa , Roback John
Published: November 2022

Whole-slide images (WSI) are the basis for the application of artificial intelligence/machine learning and other informatics methods to histological diagnosis and will further blur the line separating anatomic and clinical pathology. FDA classified WSI systems for primary diagnosis as class III (highest risk) medical devices until 2017. This discouraged anatomic pathology laboratories at risk-averse domestic institutions like mine from investing in these digital pathology (DP) platforms. In 2017, FDA downgraded WSI to class II (moderate risk) when they de-novo approved a system marketed by Philips. We were not interested in that system at my institution, but the downgrade caused us to reset our perception of the risk of validating a RUO system for primary diagnosis. Cost remained a barrier. In April 2020, FDA issued temporary guidance stating they would not enforce premarket approval of WSI systems to facilitate pathologists working remotely during the SARS-CoV-2 pandemic. The guidance included a statement that “laboratories and hospitals consider performing a validation study.” In January 2021, FDA proposed making the temporary non-enforcement guidance permanent. So, in a little more than three years, WSI for primary diagnosis had gone from class III to exempted from pre-market approval! This nicely aligned the approval framework for WSI with the approval framework for our conventional optical microscopes, which are statutorily exempted from approval, and further reset our perception of risk. In April 2021, FDA withdrew the proposal to make non-enforcement permanent, but the temporary non-enforcement guidance is still in effect at the time of writing. Amid all this FDA activity, the College of American Pathologists updated and reissued their consensus guidelines for validating WSI systems for diagnostic purposes in March 2021. The narrative mentions the FDA’s recent approval of a few WSI systems and anticipates more, but the expert panel recommendations do not include any related to the approval status of systems. The reissue of this document reminded us that, as clinical laboratorians, we are capable of safely validating WSI as a laboratory-developed test and are supported in doing so by consensus guidelines from one of our leading professional organizations. In early 2021 we committed to funding a DP initiative to make WSI part of our routine histological process for 10% of our anatomic pathology cases. The initial capital investment is $1.5M. When realized, the microscope slides for designated pathology services will be transported directly from the cover slipper to a slide scanner and electronically distributed to pathologists using a clinical-grade image management system that we share with our radiology department. We made the decision to fund this in the context of the regulatory (decreased perception of risk), sociological (demand for remote telepathology), and technological (availability of scalable WSI systems) changes that occurred during the pandemic.
Levels and in-unit stability of 11-nor-9-carboxy-9-tetrahydrocannabinol (9-carboxy-THC) in donor platelets and whole blood: is enough present to have an impact on recipients?
Authors: Potterveld Susan , Annen Kyle , DomBourian Melkon , Pasko Bryce , Helander Louise
Published: November 2022

Objective

The safety of the United States donor blood supply has been questioned in the context of recreational marijuana legalization in Colorado and other states nationwide. It is unclear whether cannabis use by donors presents a danger to recipients, either through direct toxicity or socioeconomic ramifications. Our objectives are to both determine if the active metabolite of tetrahydrocannabinol (THC), 11-nor-9-carboxy-9-tetrahydrocannabinol (9-carboxy-THC), is present in donated units in a dosage high enough to impact the recipient and to assess for in-unit metabolism or degradation.

Methods

We will quantify the amount of 9-carboxy-THC in platelet units donated by self-reported cannabis users through liquid chromatography with tandem mass spectrometry (LC-MS/MS) testing and correlate the assay data with donor survey responses. To gain insight into in-unit metabolite stability, we also will test whole blood units at several time points throughout storage, collected from participants who self-report taking a known oral dose of THC prior to donation.

Results

Institutional review board approval for a study evaluating marijuana at a children’s hospital presented a challenge, requiring the addition of an organizational risk review and an update to the hospital transfusion consent for approval. Thus, the projected timeline of this study has been extended. Study recruitment flyers and an email screening survey have generated interest from volunteer donors. The email survey was sent to 9,208 donors who had previously donated at least once, from which we received 372 responses (4.04% response rate). Of the respondents, 49 individuals reported daily marijuana use, 33 reported marijuana usage 4-6 times per week, 32 reported usage 1-3 times/week, 30 reported usage 1-3 times/month, 52 reported rare usage, and 167 reported never using marijuana. Overall, out of the survey respondents, over 50% reported at least some marijuana usage, and 31% reported at least weekly marijuana usage. Although this number is small, our prior study found that many were repeat donors. Research visits are currently being scheduled for interested participants.

Conclusions

This study highlights the challenges of performing marijuana research at a children’s hospital and illustrates why there is a lack of published data evaluating the effects of recreational marijuana legalization. Although completion of this project investigating this controversial topic has been delayed, persistent advocation for this area of interest is opening doors for future studies and will hopefully pave the way to fill our knowledge gaps. The results of this research study will inform decisions regarding donor eligibility and safety of the national blood supply as well as address associated socioeconomic implications.
Utilization of system-wide urine drug testing to safely confront opioid misuse.
Authors: Bava Ejas Palathingal , Arora Kanika , Totten Amanda , Copeland Jacqueline , Crow Joseph , Shah Vinay , Frank Cathrine , Sibai Nabil , Winston-Mcpherson Gabrielle
Published: November 2022

Abuse and addiction of opioids leading to overdose deaths has increased significantly in Michigan since 2014. Moreover, a recent study showed that a majority (92%) of clinicians at Henry Ford Health System (HFHS) had reported prescribing narcotics in a way that was out of their comfort zone. To tackle this menace, we needed to equip our physicians with the appropriate tools to monitor patient compliance. In 2017, our laboratory implemented a reflexive urine drug testing (UDT) strategy called the directed pain panel (DPP). This panel included testing for natural/semi-synthetic /synthetic opiates, benzodiazepines, and cocaine metabolites. In 2019, the DPP was enhanced by adding buprenorphine, fentanyl, and tramadol. It is beneficial to order the DPP as opposed to UDSC (Urine drug screen) because UDSC does not detect the synthetic narcotics methadone, fentanyl, tramadol, and buprenorphine. DPP also has better sensitivity for detection of oxycodone. The primary aim of the current study was to evaluate UDT orders for chronic pain patients and to focus our efforts on improving the lab testing available to our providers to manage patients safely and effectively. Therefore, we evaluated the utilization of our testing strategy by doing a survey among chronic pain physicians in addition to retrospectively analyzing total orders for DPP (chronic pain panel, directed, urine) and UDSC (drug screen, urine) for chronic pain patients at five locations in Michigan over a one-year period (8/2020-8/2021). We collaborated with key providers and accessed their test ordering history to assess compliance with ordering the preferred UDT panel. The DPP represented 68% of all UDTs ordered for this population, however there were still a significant number of UDSC orders (32%). When order location was evaluated, the majority of UDSC orders originated from two locations (80%). When provider ordering patterns were evaluated, most providers (65%) ordered the DPP > 50% of the time. In addition, 70% of all UDSC orders came from just two providers. This data showed that HFHS pain management clinicians favored ordering the DPP, however a small minority of ordering providers may benefit from targeted education regarding the advantages of the DPP. Hence, we educated the physicians who were ordering UDSC. They were willing to modify their practice to order DPP, instead of UDSC. This may pave the way for better patient compliance as well as reduced overdose and abuse of opioids.
Development of a generalizable UMAP-based approach for comparing clinical flow cytometry data with application to NPM1-mutated AML cohorts
Authors: van den Akker Tayler , Patel Sanjay , Simonson Paul
Published: November 2022

Introduction

AML with mutated NPM1 is associated with heterogeneous clinicopathologic features. We sought to study the association between phenotype, genetics, and clinical behavior using treatment-naïve bone marrow samples of NPM1-mutated AML. Prior phenotypic studies using flow cytometry data have primarily focused on the blast population in isolation or used less comprehensive analysis techniques, such as simple visual histogram assessment. We applied a dimensionality-reduction algorithm (UMAP) to analyze retrospective clinical flow cytometry data of tumor and non-tumor cells in an initial small cohort of NPM1-mutated samples.

Methods

Custom software was developed using python, FlowKit, and umap-learn to create a dictionary of the various antibody panels, detect the antibody panels that were used in each raw data (FCS) file, and determine the flow cytometer channels that should be disregarded. Subsamples from each FCS file for a given antibody panel were combined and analyzed using UMAP to create an embedding that could then be applied to all FCS files of the given antibody panel. FCS files were subsequently prepared for analysis in FlowJo, including using UMAP coordinates. The initial pilot phase included analysis of the EuroFlow AML1 panel of 11 cases, which included 3 primary refractory cases, 3 early relapsed cases, and 5 cases which achieved clinical remission without relapse. FlowJo was used to gate and examine the clusters identified by UMAP with respect to phenotypic parameters. These same UMAP gates were applied to all 11 cases for direct comparison.

Results

The blast count ranged from 50 to 88 in these cases. The blast phenotype was determined to be myeloid (n=3), monocytic (n=4), or other (CD34-/HLA-DR-)(n=4). Although standard CD45 by side scatter gating delineates four major cell types (lymphocytes, monocytes, granulocytes, blasts), gating using the UMAP algorithm with input data from eight phenotypic markers in conjunction with scattering parameters, produced at least 10 distinct UMAP clusters of variable cellular composition. Interestingly, applying those gates to side scatter (SSC-A) by CD45 histoplots revealed 5 distinct gates falling into the traditional “blast” region of the histoplot. The UMAP gates thus identified provided quantitative values for further statistical analysis.

Conclusion

We have developed a useful tool to automatically identify the antibody panels used to generate prior flow cytometry data, preprocess the data, and apply the UMAP algorithm for creating embeddings that can be applied to additional cases. Our preliminary analyses revealed significant phenotypic heterogeneity among a small cohort of NPM1-mutated cases. Ongoing work includes expansion of the cohort and number of antibody panels incorporated into the analyses to elucidate prognostic and predictive features of tumor and non-tumor populations in treatment naïve samples of NPM1-mutated AML.
A retrospective study of the eGFR differences between the 2021 CKD-EPI Equation and the MDRD equation in Black and White Patients
Authors: Chang Jeffrey , Redden David , Lima Jose , Reddy Vishnu , Cao Liyun
Published: November 2022

Objectives

In implementing the 2021 CKD-EPI without race equation in our institution, we sought to investigate the differences between the new CKD-EPI equation and the current MDRD equation to assist clinicians in transitioning to the new equation.

Methods

A retrospective study was performed in patients with eGFR<60 ml/min/1.73 m2 calculated by MDRD. Stata was used to analyze the eGFR calculated by the two equations and measure the differences according to respective categories.

Results

eGFRs calculated by the 2021 CKD-EPI without race equation were well correlated to eGFRs calculated by the MDRD. However, notable differences were observed. Compared to the MDRD, the CKD-EPI w/o race equation for Black males with a serum creatinine less than 1.5 yielded decreased eGFR results with mean negative differences of -4.49 (18-60 years old), -6.43 (60-80 years old), and -8.87 (>80 years old). For serum creatinine cohorts between 1.5 to 2.0 and greater than 2.0, the differences were -3.35, -5.46, -7.48 and -1.86, -3.40, -4.14, respectively. A similar trend was noted in Black females. For those with a serum creatinine less than 1.5, the CKD-EPI equation yielded mean negative differences that increased with advancing age: -2.56, -4.74 and -7.27. For serum creatinine between 1.5 to 2.0 and greater than 2.0, the negative differences were -2.31, -3.73 and -5.28 and -1.30, -2.06 and -2.70, respectively. Therefore, in Black patients, the mean eGFR difference between the two equations increased as age increased and serum creatinine level decreased. In contrast, the CKD-EPI equation for White males with a serum creatinine less than 1.5 yielded increased eGFR results with mean positive difference of 7.22 (18-60 years old), 4.09 (60-80 years old), and 1.26 (>80 years old). For serum creatinine cohorts between 1.5 to 2.0 and greater than 2.0, the differences were 5.15, 2.54 and 0.18 and 2.01, 0.69 and -0.15, respectively. Similarly, White females had mean positive differences of 8.09 (18-60 years old), 4.61 (60-80 years old) and 2.00 (>80 years old). For cohorts with serum creatinine between 1.5 to 2.0 and greater than 2.0, the positive differences were 4.21, 2.24, 0.51 and 2.02, 0.82, 0.10. Therefore, in White patients, the difference of eGFR between the two equations increased as age decreased and creatinine level decreased.

Conclusions

Although the 2021 CKD-EPI equation strongly correlated with the MDRD, distinct differences exist. In our study, Black males and females exhibited a negative difference of around -5.0 and -4.0, respectively. The difference in eGFR was greater in those of older age and serum creatinine less than 1.5. Meanwhile, White males and females exhibited a positive difference of around 2.5 and 2.7. The difference in eGFR was greater in those of younger age and serum creatinine less than 1.5.
Synovial Sarcoma Isn’t Supposed to To This!
Authors: Scholl A , Chen J , Cardona D
Published: November 2022

Introduction/Objective

NA.

Methods/Case Report

A 35 year old male construction worker with no significant medical history presented with left posterior knee pain, weakness and numbness. Onset of symptoms coincided with an acute gout attack three months prior. Imaging revealed a 6.3 x 6.4 x 6.2 cm intraarticular, multicystic mass arising from the anterior cruciate ligament and extending posteriorly to displace the popliteal artery and vein. It was heterogenous, partially enhancing and aggressive appearing with associated bone erosion of the femoral condyle. Needle core biopsy showed a biphasic synovial sarcoma (SS), confirmed by SS18 gene rearrangement by fluorescence in situ hybridization. The patient underwent an above the knee amputation. Histologic examination of the resected tumor revealed a heterogenous histology. There were areas characteristic of a biphasic SS, hyperchromatic spindle cells, intermixed epithelial clusters and calcifications, and solid areas of round cells with necrosis and staghorn vessels, consistent with poorly differentiated SS. Additionally, a third histologic appearance with large pleomorphic tumor cells, markedly atypical mitotic figures and what appears to be matrix production was noted. These latter findings are not well described in SS but is suggestive of dedifferentiation. Next generation sequencing was performed, focused on the dedifferentiated appearing area, which confirmed the presence of SS18-SSX1 fusion. Additional findings included PDGFRA amplification and p53 mutation. We present this interesting case in order to demonstrate a previously undescribed variant of synovial sarcoma which could be a potential pitfall, especially had this been the area initially sampled in the biopsy.

Results (if a Case Study enter NA)

NA.

Conclusion

NA.
Aneurysmal Bone Cyst (ABC), A Rare Diagnosis in Oral Pathology Based on Our 15-Year Institutional Experience
Authors: Amer S , Nobee A , Kuklani R , Proca D
Published: November 2022

Introduction/Objective

Aneurysmal bone cyst (ABC) is a rare, benign bone lesion that was first described by Jaffe and Lichtenstein in 1942. Primary ABC usually affects vertebrae and metaphyseal regions of long bones, particularly femur and tibia. Only 2-3% of ABCs occur in the head and neck region, with the mandible and maxilla being the most common. It arises mostly in children and young adults, mean age 20 yo, with no gender predilection. ABC can manifest with pain, swelling, and pathological fractures. Radiographically, it appears as a metaphyseal expansile lesion that thins the cortex and has a sclerotic rim. Lesions containing “fluid-fluid” levels are best appreciated on MRI. Approximately 70% of primary ABCs have rearrangements of the USP6 gene. The most common translocation seen in primary ABCs is t(16;17) (q22;p13) leading to the fusion of the cadherin 11 gene with USP6 gene. The USP6 gene product inhibits the differentiation of osteoblasts and dysregulates bone morphogenetic protein signaling pathway.

Methods/Case Report

A retrospective chart review of all oral pathology cases referred to our institution between 1996 and 2022 was performed; three patients diagnosed with primary ABC were identified. Patient demographic data, clinical presentation, treatment, slides, and pathologic features were reviewed.

Results (if a Case Study Enter NA)

We report of three primary ABCs of the mandible and maxilla. The mean age was 39 yo (range, 26-59 years). The mandible was affected in two cases, and the maxilla involved in one. Female: Male ratio was 2:1. All lesions were primary ABC, with no other associated lesion - they showed pseudocystic structures with fibrous stroma and a variable numbers of multinucleated giant cells in relation to sinusoidal blood spaces, as well as irregular trabeculae of osteoid and reactive woven bone.

Conclusion

Primary ABC is a rare tumor in oral pathology. The importance of this study is to increase awareness of this neoplasm in the head and neck region, as well as delineate features that help differentiate ABCs from other fibro- osseous lesions of the mandible and maxilla.
Checking for CHEK2 Hereditary Mutations in Ukrainian Women: Lack of CHECK2 Variants Contribution to Breast Cancer Susceptibility
Authors: Sulaieva O , Kozakov D , Livshun S , Matvieieva A , Shabalkov R
Published: November 2022

Introduction/Objective

Although the role of homologous recombination repair (HRR) machinery in breast cancer susceptibility has been clearly established, the range and frequency of HRR gene mutations vary profoundly in different populations. Previously high incidence of CHEK2 (Checkpoint kinase 2) mutations was shown in Eastern Europe, however, there is still limited data on the rate of CHEK2 gene mutations and their clinical implications in the Ukrainian population. The aim of this study was to assess the frequency of CHEK2 mutations and investigate whether CHEK2 variants confer susceptibility to breast cancer in Ukrainian women.

Methods/Case Report

This was a retrospective case-control study performed on 320 female breast cancer patients and 146 unaffected women (control), aged 42,3±0,51 and 40,3±0,84 respectively, who underwent NGS-testing for germline mutations in multiple genes including CHEK2. Only pathogenic (PV) and likely pathogenic (LPV) variants were considered for further analysis.

Results (if a Case Study enter NA)

The frequency of CHEK2 mutations did not differ significantly between the observed groups: there were 27 (8,4%) carriers among female breast cancer patients and 15 (10,27%) carriers in unaffected women. To note, the breast cancer patients demonstrated a high rate of CHEK2 co-mutations with BRCA1 (PV, n=3) and BRCA2 (n=2, PV). Within the range of CHEK2 genetic alterations, we reported variant c.470T>C (p.Ile157Thr) found in 22 carriers (52,4%) and deletions of exons 9-10 detected in 7 women (16,7%) as most prevalent in Ukrainian population. The rates of CHEK2 c.470T>C (p.Ile157Thr) variant were comparable among the unaffected women (n=5; 3,4%) and breast cancer group (n=17; 5,3%); exon 9-10 deletions were found in 2 (1,36%) and 5 (1,56%) cases respectively. Less frequent CHEK2 mutations were detected in ≤3 cases per group. In this study we report no contribution of CHEK2 genetic alterations to breast cancer susceptibility (OR=1,24; 95%CI 0,64-2,41; p=0,521) in Ukrainian women.

Conclusion

The frequency of CHEK2 mutation in Ukrainian women is relatively high as compared to available data on other populations. However, we did not find any contribution of CHEK2 pathogenic/likely pathogenic variants to breast cancer susceptibility.
Primary Malignant Peripheral Nerve Sheath Tumor of the Breast: A Rare Case Report
Authors: Tahir M , Zedan M , Bellamkonda V , Wei E , dyess L
Published: November 2022

Introduction/Objective

Primary breast sarcomas are uncommon and primary mammary malignant peripheral nerve sheet tumors (MPNST) are exceptionally rare. MPNST’s are malignant variants of peripheral nerve sheath tumors. These neoplasms are often associated neurofibromatosis type I (NF-I) but can also occur sporadically. They tend to occur in the deeper soft tissues, trunk, and extremities.

Methods/Case Report

A 60-year-old female was referred to our University Hospital for evaluation of an abnormal mammogram. Patient noticed a mass in the left breast 3 months ago and mammogram showed a large solid mass located at the left superior breast. Subsequent biopsy of the left breast lesion showed high grade malignant neoplasm with differential diagnosis of malignant phyllodes tumor, primary sarcoma, and metaplastic carcinoma. The tumor was non-responsive to the initial neoadjuvant therapy. The patient underwent modified radical mastectomy. The excised tumor was well-circumscribed, tan-white, firm, measuring 9.6 x 6.1 x 4.3 cm. The neoplastic cells were positive for CD99, S-100, SOX-10, neuron specific enolase, p53, Vimentin, focally positive for neurofilament, D2-40, p63, and negative for epithelial, melanoma and other sarcoma markers. The tumor was triple negative ER, PR, HER-2, with Ki- 67 at 61%. A diagnosis of primary high grade malignant peripheral nerve sheath tumor of the breast was rendered. The patient does not have a history of NF-1. There was no lympho-vascular or perineural invasion. After the surgery, the patient followed up without complications.

Results (if a Case Study enter NA)

N/A

Conclusion

An accurate diagnosis of this rare entity is necessary because it plays a crucial role in the therapeutic options and prognosis. In our case the patient was treated with neo-adjuvant chemotherapy followed by modified radical mastectomy. The purpose of presenting this unique case is to provide awareness of the existence of this entity among pathologists and clinicians for better patient care.
Immunochemical Fecal Occult Blood Test Screening Results prior to Colorectal Cancer Diagnosis
Authors: Petersen J M , Dalal S , Jhala D
Published: November 2022

Introduction/Objective

Immunochemical fecal occult blood testing (iFOBT) is one of the options outlined by the standard of care guidelines from the U.S. Preventive Services Task Force (USPSTF) for screening for colorectal cancer in adults. The iFOBT assay is a convenient and reasonably accurate screening assay. It has been shown in the literature, through a metanalysis of iFOBT tests, that the overall sensitivity of iFOBT in the general population for detecting colorectal cancer within 2 years of follow-up across different medical settings is 0.79 (95% confidence interval 0.69-0.86). However, similar investigation in the veteran population is sparse, but would be important given the significant differences between the Veteran population and the general population including increased medical comorbidities.

Methods/Case Report

A search of all iFOBT testing performed at a regional Veteran Affairs Medical Center (VAMC) from 10/1/2018 to 6/4/2022 was performed to identify patients with both diagnosed colorectal cancer by pathology examination and iFOBT testing within 2 years prior to this diagnosis. The iFOBT result (at least one positive prior to diagnosis or always negative) prior to diagnosis with colorectal cancer was recorded once per patient. iFOBT results collected after the day the positive colorectal pathology specimen was obtained were excluded. Demographic information was also recorded. iFOBT testing was performed using the Polymedco assay product (Cortlandt Manor, NY).

Results (if a Case Study enter NA)

There were a total of 26 patients (25 males and 1 female) with diagnosed colorectal cancer. The patient age range was 37 to 88 years (average 70) with an ethnic composition of 12 of 26 (46%) African Americans, 13 of 26 (50%) Caucasian American, and 1 of 26 (4%) Native Hawaiian or other Pacific Islander American. 20 of the 26 patients (77%) of the patients had at least one positive iFOBT test result prior to their colorectal cancer diagnosis, which is within the published observation for the accepted sensitivity in the general population.

Conclusion

While there are differences between the general population and the veteran population in terms of medical comorbidities, the iFOBT test assay performed similarly to the general population in terms of sensitivity for colorectal cancer diagnosed within 2 years of the iFOBT assay and remains an important part of the standard of care for colorectal screening for both populations.
Correlating Cytologic and Histologic Features of Hepatic Epithelioid Hemangioendothelioma
Authors: Ali M , Thomas S , Zhou Z
Published: November 2022

Introduction/Objective

Epithelioid hemangioendothelioma (EHE) is a rare malignant vascular tumor composed of epithelioid and dendritic tumor cells embedded in myxoid or hyalinized stroma. It can occur in various organs and has nonspecific clinical and radiologic presentation. We report a case of EHE in the liver with correlation of cytologic and histological findings.

Methods/Case Report

A 68-year-old female presented for evaluation of a right hepatic lobe lesion that was noted on Imaging. MRI abdomen with contrast showed a well-circumscribed hypointense nodule with no contrast enhancement. CT-guided fine needle aspiration showed scattered atypical epithelioid cells in a background of benign hepatocytes which were positive for vascular markers (CD31 and CD34) as well as keratins and SMA. A diagnosis of atypical vascular neoplasm was rendered. A partial hepatectomy was performed a month later which showed a 3.2 cm mass with solid tan-white cut surface. Histologically, the mass was composed of epithelioid tumor cells with focal intracytoplasmic vacuoles which were partly solid and partly forming vascular-like spaces, embedded in a background of hyalinized stroma. Immunohistochemically, in addition to the vascular markers the tumor was positive for CAMTA1 confirming the presence of WWTR1-CAMTA1 gene fusion which is characteristic for epithelioid hemangioendothelioma. The patient was discharged in good condition.

Results (if a Case Study enter NA)

NA.

Conclusion

Diagnosis of EHE on FNA is challenging. It is characterized by discohesive atypical large polygonal cells with abundant dense cytoplasm in a background of benign hepatocytes. Characteristically, the tumor cells have intracytoplasmic vacuoles containing red blood cells, which resemble signet ring-like structures. Immunohistochemically, positivity for vascular markers and CAMTA1 is diagnostic.
A Rare Case of Metastatic Extragonadal Yolk Sac Tumor – A Challenging Diagnosis on Cytomorphology
Authors: Rahmanov N , Kaur N , Manucha V
Published: November 2022

Introduction/Objective

Yolk sac tumors are characterized by variable histologic patterns and broad cytologic spectrum; thereby making the distinction from a poorly differentiated adenocarcinoma in a metastatic site extremely challenging. We present cytology and histology of a metastatic extragonadal germ cell tumor with predominant solid yolk sac component.

Methods/Case Report

36-year-old male presented with bilateral supraclavicular masses (right: 6 x 7 cm, left: 3 x 4 cm). CT chest and abdomen revealed large mediastinal and hilar nodal mass (11.6 cm), right hilar mass (8.5 cm), bilateral heterogeneous adrenal masses (right: 11.4 cm, left: 3.1 cm), and an enhancing retroperitoneal implant. Differential diagnoses of lymphoma, adrenocortical carcinoma, small cell lung carcinoma, and metastatic germ cell tumor were considered. Testicular ultrasound revealed no masses. Fine needle aspiration of supraclavicular lymph nodes showed highly cellular smears comprised of tumor cells, dispersed singly and in clusters, with irregular nuclear contours, increased nuclear to cytoplasmic ratio, coarse chromatin, occasional prominent nucleoli, and vacuolated cytoplasm. Tumor cells were positive for KRT7 and TTF-1, and negative for p40 and PAX8. A diagnosis of metastatic poorly differentiated carcinoma was rendered. Subsequent excisional biopsy of the lymph node showed a metastatic tumor with tumor cells similar to those seen in cytology, appearing in solid sheets with focal papillary architecture, replacing the entire lymph node. Additional immunohistochemistry showed expression of SALL4, Glypican 3, with lack of expression for OCT3/4, AFP, hCG, and CD30, supporting the diagnosis of metastatic yolk sac tumor, solid pattern.

Results (if a Case Study enter NA)

NA.

Conclusion

Aggressive clinical presentation, broad clinical differential diagnoses, rarity of a primary mediastinal yolk sac tumor, non-diagnostic cytomorphology along with expression of divergent differentiation markers (TTF-1 in our case) makes a definitive diagnosis of metastatic extragonadal yolk sac tumor extremely challenging. High index of clinical suspicion is required for a definitive diagnosis on cytomorphology.
FNA as a Powerful Modality to Detect Granular Cell Tumor in Male Breast: A Report and Review of Literature
Authors: Mazur I , jhala N C , Lazim A
Published: November 2022

Introduction/Objective

Granular cell tumor (GCT) is a benign mesenchymal tumor of Schwannian origin. Granular cell tumor is an uncommon tumor of the breast with a prevalence of 1:1000 to 6.7:1000 of all breast tumors. Most cases are diagnosed on surgical resection. When reported that are most commonly in middle-aged premenopausal women. Diagnosis of GCT on fine needle aspiration (FNA) in male patients is, however, extremely rare. We present here an unusual case of GCT of the breast in a male patient clinically mimicking malignancy.

Methods/Case Report

A 34-year-old male patient presented with a palpable lump in the left breast. An imaging study showed a 0.6 cm hypoechoic mass with microlobulated borders and no internal vascularity suspicious for breast carcinoma (BIRAD-4). Fine needle aspiration (FNA) of the mass was performed. Rapid onsite specimen evaluation was performed and additional passes were performed to collect sample for cell block to perform ancillary studies. FNA revealed clusters of polygonal cells with abundant eosinophilic granular cytoplasm and poorly defined borders. Those cells had round to ovoid nuclei with vesicular chromatin pattern and prominent nucleoli. A differential diagnosis of GCT, apocrine metaplasia, and lesions rich in histiocytes such as granulomatous inflammation, fat necrosis and duct ectasia were considered. Immunohistochemical staining with S100 and CD68 was performed which stained granular cytoplasm in tumor cells of GCT. A review of literature from the past 5 years shows 23 cases of GCT of the breast are reported in the literature and of these only 3 (13%) are reported in males. These tumors ranged from 20-68 years with tumor size ranging from 5- 28 mm. Only 1(4%) cases were preoperatively diagnosed using FNA. No cases of GCT were preoperatively diagnosed on FNA samples from the breast.

Results (if a Case Study enter NA)

N/A.

Conclusion

We show here that a powerful relatively noninvasive and rapid modality like FNA can be effectively utilized to detect very rare benign tumor like GCT in the male breast where imaging studies suspect breast cancer.