Search

Broader genetic screening has led to the growing recognition of the role of germline variants associated with adult bone marrow failure (BMF) and myeloid neoplasia (MN) not exclusively in children and young adults. In this study, we applied a germline variant panel to 3008 adult BMF and MN cases to assess the importance of germline genetics and its impact on disease phenotype and prognosis. In our cohort, up to 9.7% of BMF and 5.3% of MN cases carried germline variants. Our cohort also included heterozygous carriers of recessive traits, suggesting they contribute to the risk of BMF and MN. By gene category, variants of Fanconi anemia gene family represented the highest-frequency category for both BMF and MN cases, found in 4.9% and 1.7% cases, respectively. In addition, about 1.4% of BMF and 0.19% of MN cases harbored multiple germline variants affecting often functionally related genes as compound heterozygous. The burden of germline variants in BMF and MN was clearly associated with acquisition of monosomy 7. While BMF cases carrying germline variants showed similar overall survival as compared to the wild-type (WT) cases, MN cases with germline variants experienced a significantly shorter overall survival as compared to WT cases.

The V-domain Ig suppressor of T-cell activation (VISTA) has been recognized as a critical negative regulator of antitumor immune response and is gaining growing interest as a potential pharmacological target in immunotherapy. This molecule is highly expressed in hematopoietic stem cells and myeloid compartment, and it has been found upmodulated in acute myeloid leukemia (AML). However, VISTA-associated immune features are relatively unexplored in myeloid malignancies. Herein, we aimed to explore whether this immune checkpoint regulator could play a role in the generation of an immune escape environment in AML patients. We characterized VISTA mRNA expression levels in leukemia cell lines and in large publicly available cohorts of specimens from bone marrow of healthy individuals and AML patients at diagnosis by deploying bulk and single-cell RNA sequencing. We also defined the correlations with leukemia-associated burden using results of whole-exome sequencing of AML samples at disease onset. We showed that VISTA expression linearly increased across the myeloid differentiation tree in normal hematopoiesis. Accordingly, its transcript was highly enriched in AML cell lines as well as in AML patients at diagnosis presenting with myelomonocytic and monocytic differentiation. A strong correlation was seen with NPM1 mutations regardless of the presence of FLT3 lesions. Furthermore, VISTA expression levels at baseline correlated with disease recurrence in patients with normal karyotype and NPM1 mutations, a subgroup traditionally considered as favorable according to current diagnostic schemes. Indeed, when compared to patients with long-term remission (>5 years after standard chemotherapy regimens), cases relapsing within 2 years from diagnosis had increased VISTA expression in both leukemia and T cells. Our results suggest a rationale for developing VISTA-targeted therapeutic strategies to treat molecularly defined subgroups of AML patients to prevent disease recurrence and treatment resistance.

Background Immune thrombocytopenia (ITP) is an acquired disease characterized by thrombocytopenia secondary to autoantibodies against platelets. Here, we report the clinical characteristics of coronavirus disease 2019 (COVID‐19)‐induced ITP cases. Study Design and Methods We retrospectively reviewed 3255 COVID‐19 patients. COVID‐19‐induced ITP was diagnosed after excluding possible common causes. Bleeding severity was assessed based on the modified World Health Organization (WHO) bleeding severity score. Results We identified 11 (0.34%) patients with COVID‐19‐induced ITP. Of all patients, 63.6% were males and the median age was 63 years. The median time from COVID‐19 diagnosis to the onset of ITP was 10 days. Bleeding observed in 63.6% of the patients. Clinically significant bleeding (WHO Grade 3) occurred in single patient who required blood transfusion. Standard treatment with glucocorticoids and intravenous immunoglobulin (IVIG) was effective in achieving excellent response in most cases. Of all patients, complete response and response to treatment were achieved in 45.5% and 27.3% patients, respectively. The median time to ITP recovery was 4 days. Eltrombopag was used in three patients who relapsed. Four patients required mechanical ventilation, and none of them survived secondary to hypoxic respiratory failure. Conclusion ITP secondary to COVID‐19 usually presents after the first week of symptoms beginning. Most of our patients had WHO Grade 1–2 bleeding scores. Standard treatment with glucocorticoids and IVIG is effective in achieving an excellent response. The safety of eltrombopag is not very well established in COVID‐19 patients, and additional studies are needed for a better safety profile.

Shaher M Samrah,1 Abdel-Hameed Al-Mistarehi,2 Tariq Kewan,3 Sohaib M Al-Khatib,4 Ali M Ibnian,1 Randa S Samrah,5 Basheer Y Khassawneh1 1Department of Internal Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan; 2Department of Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan; 3Department of Internal Medicine, Cleveland Clinic, Cleveland, OH, USA; 4Department of Pathology and Laboratory Medicine, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan; 5Faculty of Medicine, Jordan University of Science and Technology, Irbid, JordanCorrespondence: Shaher M SamrahFaculty of Medicine, Jordan University of Science and Technology, P.O.Box: 630001, Irbid, 22110, JordanEmail samrah@just.edu.joAbdel-Hameed Al-MistarehiDepartment of Public Health and Family Medicine, Faculty of Medicine, Jordan University of Science and Technology, P.O.Box: 630001, Irbid, 22110, JordanEmail awalmistarehi18@med.just.edu.joBackground: Coronavirus disease 2019 (COVID-19) viral course and behavior remain unpredictable. This study describes incubation time and viral clearance of COVID-19 hospitalized cases in Northern Jordan.Methods: All COVID-19 confirmed cases hospitalized from March 15 to June 09, 2020, were included. Nasopharyngeal swabs were collected, and COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) was performed every two days in all cases. The viral cure was defined when two negative RT-PCR tests were obtained ≥ 24 hours apart. Viral clearance time (VCT) reflects the time from the first positive nasopharyngeal swab to the first of two consecutive negative tests.Results: In this cohort, a total of 157 patients were included. Most cases resulted from two major outbreaks. The median incubation period was 6 days (IQR, 3– 10) and ranged from 1 to 17 days. The median VCT was 13 days (IQR, 7– 2) and ranged from 1 to 40 days. Symptomatic presentation and abnormal chest radiograph were predictors for a prolonged VCT (p=0.015 and p=0.014, respectively). The median time of resolution of symptoms was 7 days (IQR, 3– 10 days). Most symptomatic cases (91.7%) remained RT-PCR positive for up to 20 days after symptoms resolution, with a median of 13.5 days. VCT significantly correlated with the incubation period (p=0.013).Conclusion: Viral cure lagged for as long as 20 days after resolution of symptoms. Continuing with social-distancing, frequent hand hygiene, and wearing facial mask remains essential and is recommended even after clinical resolution of symptoms.Keywords: viral clearance, viral shedding, incubation period, COVID-19, coronavirus, pandemic, CDC

Background We undertook this study to evaluate the association between hyperglycemia and outcomes in patients with coronavirus disease 2019 (COVID‐19) admitted to the intensive care unit (ICU). Methods We conducted a multicenter retrospective study involving all adults with COVID‐19 admitted to the ICU between March and May 2020. Patients were divided into normoglycemic (average blood glucose, Highlights Hyperglycemia has been reported in almost half of the patients infected with coronavirus disease 2019.In critically ill patients, hyperglycemia is associated with increased morbidity and mortality, irrespective of preexisting diabetes.In our study, patients with blood glucose ≥140 mg/dL and admitted to the intensive care unit were found to have the worst outcomes in terms of mortality, mechanical ventilation need, and intensive care unit length of stay.Further studies are needed to clarify if outcomes significantly improve with tighter glucose targets.

Objective In this study, we aimed to explore the relationship between five selected proinflammatory and immune-mediated genes (TNF rs1800629G>A, rs361525G>A, rs1799964T>C, LTA rs1800683G>A, rs909253A>G, TNFAIP8 rs1042541C>T, LEPR rs1327118G>C, and LEP rs2167270G>A) and the risk and overall survival of DLBCL patients within the Jordanian Arab population. Methods One hundred twenty-five patients (125) diagnosed with DLBCL at the King Abdullah University Hospital (KAUH) between 2013 and 2018 and 238 healthy cancer-free control subjects with similar geographic and ethnic backgrounds to the patients were included in the study. Genomic DNA was extracted from the formalin-fixed paraffin-embedded tissues of the subjects and from peripheral blood samples of the controls. The Sequenom MassARRAY® sequencer system (iPLEX GOLD) was used. The analyses included assessments of population variability and survival. Results Our study showed significant differences in the distribution of the studied polymorphisms of DLBCL between the patients and controls for TNF rs1800629G>A, LTA rs909253 G>A and LEP rs2167270 G>A. TNF rs1800629G>A (p = 0.01), in which the G allele harbors a higher risk of DLBCL (GG and GA genotypes when compared with AA genotype) (p = 0.044). The LTA rs909253 A>G polymorphism is associated with a higher risk of DLBCL in the allelic model (p = .004). LEP rs2167270 G>A polymorphism is associated with a decreased risk of DLBCL in the recessive mode models (p = .03). Subjects with the dominant model for TNF-a rs1799964 (TT genotype in comparison with the combined TT/TC genotype) and patients with the homozygous genotype (GG) of rs361525 have better overall survival rates. Conclusion Our results confirmed the diversity and the heterogeneity of the disease. Although the study has a limitation because of its relatively small size, it clearly emphasizes the significance of ancestry and genetic composition as the determinants of DLBCL risk and behavior. .

Introduction Among the Jordanian population, brain tumors are the tenth most common type of cancers in both males and females, comprising 2.8% of all newly diagnosed neoplasms. Diffuse gliomas are the most prevalent and the most aggressive primary brain tumors in adults. The incidence of diffuse gliomas varies among different populations; this variation is partially linked to genetic polymorphisms. The purpose of the study is to examine the association between (BRCA1 rs799917G>A, rs1799966T>C, EXO1 rs1047840G>A, EME1 rs12450550T>C, ERCC2 rs13181T>G, rs1799793C>T, and XRCC1 rs1799782G>A) DNA repair gene polymorphisms and glioblastoma multiforme (GBM) susceptibility, and survival in the Jordanian Arab population. Methods Eighty-four patients diagnosed with glioblastoma multiforme at the King Abdullah University Hospital (KAUH) between 2013 and 2018 and 225 healthy cancer-free control subjects with similar geographic and ethnic backgrounds to the patients were included in the study. Genomic DNA was extracted from the formalin-fixed paraffin-embedded tissues of the subjects. The Sequenom MassARRAY® sequencer system (iPLEX GOLD) was used. The analyses included assessments of population variability and survival. Results This study is the first to address the relationship between BRCA1 rs1799966 and rs799917 SNP, and the risk of GBM among the Arab Jordanian population. The findings of the study show that BRCA1 rs799917 is associated with decreased risk of GBM in the recessive model (AA vs G/G-A/G: OR, 0.46, 95% CI, 0.26-0.82, p=0.01) and the same SNP is associated with increased risk of GBM in the overdominant model (AG vs G/G-A/A: OR, 1.72, 95% CI, 1.02-2.89, p=0.04).

Background Acute cholecystitis is an emergency condition. If not promptly diagnosed and properly managed, the complication of gangrenous cholecystitis may develop, which may be a life-threatening complication. Objectives The study aims to examine various characteristics and physiological parameters in patients diagnosed with acute cholecystitis to evaluate if significant predictive factors exist for the differential diagnosis of gangrenous cholecystitis. Materials and methods This was a retrospective study included patients with acute cholecystitis diagnosis, who presented to ‘blinded for peer review’ from 1 January 2010 to 1 January 2017. Parameters evaluated included liver function tests, complete cell count, C reactive protein, erythrocyte sedimentation rate (ESR), amylase and lipase levels, as well as medical history, and presenting clinical signs. Cases were divided according to whether or not there was a histopathological diagnosis of gangrenous cholecystitis. Results A total of 186 (54.5%) female and 155 (45.5%) male cases were examined. Patients with gangrenous cholecystitis tended to be male, showed a significantly higher white cell count, higher neutrophil percentage, lower lymphocyte percentage and higher ESR compared with patients without gangrenous cholecystitis. However, serum amylase and lipase demonstrated no differential diagnostic utility Conclusion Male patients with a high ESR level, high total leucocyte count with a relative high proportion of neutrophils and a low proportion of lymphocytes were found to be at increased risk of the presence of gangrenous cholecystitis.

Background Although several studies discussed new-onset thrombocytopenia in the setting of COVID-19 infection, the course of chronic ITP in patients with COVID-19 and the propensity to relapse remains not well addressed. Methods This a retrospective study that included all adult patients with the diagnosis of chronic ITP who admitted to

Objectives BNT‐162b2, mRNA‐1273, and Ad26.COV2.S vaccines data regarding adverse events (AEs) are scarce. In this report, we aimed to describe fatal and non‐fatal possible AEs after COVID‐19 vaccine administration. Methods An observational multicenter study investigating the causes of emergency department visits and hospital admissions within 10 days of COVID‐19 vaccination. Patients who received first or second doses of COVID‐19 vaccines and presented to the emergency department (ED), as well as those admitted to the hospitals or intensive care units (ICUs) were included. Causes of ED, hospital, and ICU admissions and discharges were collected based on the International Classification of Diseases, Tenth Revision (ICD‐10) coding system. Results Between December 2020 and March 2021, 1842 patients visited the ED within 10 days of COVID‐19 vaccine administration. The mean age was 70.3 years. Overall, 1221 patients presented after the first dose of the vaccine and 653 after the second dose. Trauma (14.9%), hypertensive emergency/urgency (7.8%), generalized pain and arthralgia (5.7%), and chest pain (4.4%) were the most common causes of presentation to the ED. Of all ED presentations, mortality rate was at 2.2% (41 patients) with a median follow‐up time of 68.0 days, versus 2.6% in unvaccinated ED patients. Postvaccination acute hypoxemic respiratory failure (46.3%), septic shock (24.4%), and cardiogenic shock (12.2%) were the most common causes of death. Conclusion Although reported AEs are not necessarily caused by the vaccination, this study provides further information about possible AEs after COVID‐19 immunization, especially those requiring hospital admission. This study also supports prior data that serious AEs post vaccination are much lower than primary COVID‐19 infections. Further studies are needed to investigate causalities between vaccines and reported AEs across all age groups.

Background Cancer-associated thrombosis (CAT) is a major cause of mortality in cancer patients. Immune checkpoint inhibitors (ICIs) have been associated with multiple side effects including CAT. The aim of this study is to investigate risk factors and prognostic impact associated with CAT events during ICIs treatment. Methods This is a multi-center retrospective study that included stage IV cancer patients treated with ICIs. Results We identified 552 cancer patients treated with ICIs. During follow-up time, 58 (10.5%) patients developed 67 venous thromboembolism (VTE) events while on ICIs. Anticoagulation use at the time of ICIs treatment start was associated with significantly higher VTE incidence rate (IRR: 2.23). No significant difference in VTE IRR was observed depending on response to ICIs treatment, aspirin use, or Khorana VTE risk score. Melanoma as primary cancer, Khorana score, ECOG status, and anemia at baseline were able to predict mortality. Conclusions The incidence of CAT in stage-IV cancer patients treated with ICIs was higher in our study compared to previous reports. Control group of patients who did not receive ICIs is needed for better identification of CAT risk factors. Khorana score was a good predictor of mortality but not CAT risk and needs to be further validated in a homogenous group of patients.

Background: Considering the rapid spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the clinical implications of gastrointestinal (GI) and hepatic manifestations of coronavirus disease 2019 (COVID-19) in the U.S. population require analysis. Methods: We retrospectively reviewed all adult patients with COVID-19 admitted to our facility. Patients were divided into two groups based on the presence of GI symptoms and transaminitis at presentation. Univariable analysis was performed to assess the differences between study groups. Kruskal-Wallis and Pearson's chi-square tests were used to compare the median of continuous and categorical variables, respectively. Multivariate logistic regression analysis was performed to identify predictors of mechanical ventilation, cytokine release syndrome (CRS), and mortality after adjusting for baseline variables. Results: A total of 84 patients were analyzed. After adjusting for baseline comorbidities, presence of GI symptoms (aOR, adjusted odds ratio 4.2, 95% CI, 1.17-15.60, p=0.03) and transaminitis on admission (aOR 5.69, 95% CI, 1.47-21.99, p=0.01) were associated with CRS. Transaminitis on admission and elevated total bilirubin during hospitalization were associated with an increased need for mechanical ventilation (aOR 6.17, 95% CI, 1.49-25.44, p=0.02 and aOR 7.29, 95% CI, 1.73-30.75, p=0.007, respectively). An elevated aspartate aminotransferase (AST) on admission (aOR 13.41, 95% CI, 1.08-165.69, p=0.04) and elevated total bilirubin during hospitalization (aOR 82.68, 95% CI, 1.67-4074.8, p=0.02) were independently associated with an increased risk of mortality in COVID-19 patients. Conclusion: COVID-19 patients with transaminitis on admission had a higher risk of requiring mechanical ventilation and developing CRS. Patients with elevated AST on admission and elevated total bilirubin had higher mortality. Patients with GI symptoms did not have worse outcomes.

Thrombocytopenia 2 (THC2) is an autosomal dominant disorder characterized by ankyrin repeat domain 26 mutation and moderate thrombocytopenia. THC2 exposes patients to a low risk of bleeding and an increased likelihood of myelodysplastic syndrome/acute myeloid leukemia. Germline evaluation for a genetic disorder should be considered when a patient presents with isolated thrombocytopenia and associated dysmegakaryopoiesis. In this case report, we present a male patient who presented with isolated thrombocytopenia but was ultimately confirmed to have an inherited THC2 thrombocytopenia/myelodysplastic syndrome. Given the rarity of the disease, no clear guidelines on how to follow THC2 patients over the long term have been established. We recommend a monthly complete blood count and clinical visits every 3 months at a minimum.

Background Tocilizumab was approved for chimeric antigen receptor T–cell therapy induced cytokine release syndrome and it may provide clinical benefit for selected COVID–19 patients. Methods In this retrospective cohort study, we analyzed hypoxic COVID–19 patients who were consecutively admitted between March 13, 2020 and April 19, 2020. Patients with lung infiltrates and elevated inflammatory markers received a single dose of tocilizumab if no contraindication was present. Systemic steroid, hydroxychloroquine, and azithromycin were concomitantly used for majority of the patients. Findings Of the 51 patients included for analysis, 28 (55%) received tocilizumab and 23 (45%) did not receive tocilizumab. Tocilizumab cohort required more invasive ventilation (68% vs. 22%) at baseline and during entire hospitalization (75% vs. 48%). The median time to clinical improvement in tocilizumab vs. no tocilizumab cohorts was 8 days (Interquartile range [IQR]: 6·25 – 9·75 days) vs. 13 days (IQR: 9·75 – 15·25 days) among patients who required mechanical ventilation at any time (Hazard ratio for clinical improvement: 1·83, 95% confidence interval [CI]: 0·57 – 5·84) and 6·5 days vs. 7 days among all patients (Hazard ratio for clinical improvement: 1·14, 95% CI: 0·55 – 2·38), respectively. The median duration of vasopressor support and invasive mechanical ventilation were 2 days (IQR: 1·75 – 4·25 days) vs. 5 days (IQR: 4 – 8 days), p = 0.039, and 7 days (IQR: 4 – 14 days) vs. 10 days (IQR: 5 – 15 days) in tocilizumab vs. no tocilizumab cohorts, p = 0.11, respectively. Similar rates of hospital–acquired infections occurred in both cohorts (18% in tocilizumab and 22% in no tocilizumab cohort). Interpretation In patients with severe COVID-19, tocilizumab was associated with significantly shorter duration of vasopressor support. Although not statistically significant, tocilizumab also resulted in shorter median time to clinical improvement and shorter duration of invasive ventilation. These findings require validation from ongoing clinical trials of Tocilizumab in COVID–19 patients.

Introduction Primary breast lymphoma (PBL) is a rare malignancy that accounts for less than 0.5% of all breast malignancies. Materials and Methods We retrospectively analyzed 36 PBL patients to report the clinical characteristics and outcomes of patients with indolent and aggressive histologic subtypes. Results Thirteen (36%) patients had aggressive and 23 (64%) had indolent PBL. Marginal zone lymphoma was the most common histologic subtype (33%). Stage IE, IIE, and IV disease were seen in 27 (75%), six (17%), and three (8%) patients, respectively. Patients with aggressive PBL more often presented with a breast lump and/or B symptoms (unexplained weight loss, fever, night sweats) (78% vs. 31%, p = 0.005). Commonly used treatment modalities for aggressive vs. indolent PBL were chemotherapy alone (23% vs. 26%, p = 0.8), chemoradiotherapy (46% vs. 9%, p = 0.009), radiotherapy alone (15% vs. 22%, p = 0.6), and observation (0% vs. 26%, p = 0.07), respectively. The five-year overall survival (OS) and progression-free survival (PFS) of PBL patients were 82% (95% CI: 67 - 100) and 63% (95% CI: 45 - 89), respectively. The five-year OS of patients with aggressive vs. indolent PBL were 92% (95% CI: 77 - 100) vs. 80% (95% CI: 63 - 100), respectively (p = 0.6). The five-year OS of patients who received > 1, 1, and 0 treatment modalities were 92% (95% CI: 77 - 100), 86% (95% CI: 63 - 100), and 53% (95% CI: 21 - 100), respectively. Conclusion In our cohort, the higher utilization of chemoradiotherapy in aggressive PBL was able to overcome the worse prognosis of these patients. At least one treatment modality should be considered in patients with indolent PBL, given that observation alone was associated with a poor prognosis.

Myocardial infarction (MI) after blunt chest trauma (BCT) is a rare but potentially life-threatening situation that should be addressed immediately in a patient who presents to the ED. Early management is directly related to favorable outcomes. Here we describe a case of ST-elevation MI after BCT.