Large Granular Lymphocytic Leukemia: Clinical Features, Molecular Pathogenesis, Diagnosis and Treatment.

Large granular lymphocytic (LGL) leukemia is a lymphoproliferative disorder characterized by persistent clonal expansion of mature T- or natural killer cells in the blood via chronic antigenic stimulation. LGL leukemia is associated with specific immunophenotypic and molecular features, particularly STAT3 and STAT5 mutations and activation of the JAK-STAT3, Fas/Fas-L and NF-κB signaling pathways. Disease-related deaths are mainly due to recurrent infections linked to severe neutropenia. The current treatment is based on immunosuppressive therapies, which frequently produce unsatisfactory long-term responses, and for this reason, personalized approaches and targeted therapies are needed. Here, we discuss molecular pathogenesis, clinical presentation, associated autoimmune disorders, and the available treatment options, including emerging therapies.

Pim Kinase Inhibitors Increase Gilteritinib Cytotoxicity in FLT3-ITD Acute Myeloid Leukemia Through GSK-3ß Activation and c-Myc and Mcl-1 Proteasomal Degradation.

Acute myeloid leukemia (AML) with fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD) has poor outcomes. FLT3-ITD drives constitutive and aberrant FLT3 signaling, activating STAT5 and upregulating the downstream oncogenic serine/threonine kinase Pim-1. FLT3 inhibitors are in clinical use, but with limited and transient efficacy. We previously showed that concurrent treatment with Pim and FLT3 inhibitors increases apoptosis induction in FLT3-ITD-expressing cells through posttranslational downregulation of Mcl-1. Here we further elucidate the mechanism of action of this dual targeting strategy. Cytotoxicity, apoptosis and protein expression and turnover were measured in FLT3-ITD-expressing cell lines and AML patient blasts treated with the FLT3 inhibitor gilteritinib and/or the Pim inhibitors AZD1208 or TP-3654. Pim inhibitor and gilteritinib cotreatment increased apoptosis induction, produced synergistic cytotoxicity, downregulated c-Myc protein expression, earlier than Mcl-1, increased turnover of both proteins, which was rescued by proteasome inhibition, and increased efficacy and prolonged survival in an in vivo model. Gilteritinib and Pim inhibitor cotreatment of Ba/F3-ITD cells infected with T58A c-Myc or S159A Mcl-1 plasmids, preventing phosphorylation at these sites, did not downregulate these proteins, increase their turnover or increase apoptosis induction. Moreover, concurrent treatment with gilteritinib and Pim inhibitors dephosphorylated (activated) the serine/threonine kinase glycogen synthase kinase-3ß (GSK-3ß), and GSK-3ß inhibition prevented c-Myc and Mcl-1 downregulation and decreased apoptosis induction. The data are consistent with c-Myc T58 and Mcl-1 S159 phosphorylation by activated GSK-3ß as the mechanism of action of gilteritinib and Pim inhibitor combination treatment, further supporting GSK-3ß activation as a therapeutic strategy in FLT3-ITD AML. SIGNIFICANCE: FLT3-ITD is present in 25% of in AML, with continued poor outcomes. Combining Pim kinase inhibitors with the FDA-approved FLT3 inhibitor gilteritinib increases cytotoxicity in vitro and in vivo through activation of GSK-3ß, which phosphorylates and posttranslationally downregulates c-Myc and Mcl-1. The data support efficacy of GSK-3ß activation in FLT3-ITD AML, and also support development of a clinical trial combining the Pim inhibitor TP-3654 with gilteritinib.

Impact of KRAS and NRAS mutations on outcomes in acute myeloid leukemia.

The prognostic significance of RAS mutations in AML is poorly understood. In this ambispective cohort study of 239 newly-diagnosed AML patients at the University of Maryland, we assessed the median overall survival (mOS) and median event-free survival (mEFS) in RAS wild-type (WT) AML (n = 196), KRAS-mutated AML (n = 11), NRAS-mutated AML (n = 25), and KRAS/NRAS-mutated AML (n = 7). We used propensity score to adjust outcomes. NRAS-mutated AML had a similar response rate to first-line treatment and mOS compared to RAS-WT AML (57 vs. 54%, p = 0.8, 22.7 vs. 14.6 months, p = 0.7). The mOS of KRAS-mutated AML was shorter compared to RAS-WT AML (p = 0.049) and NRAS-mutated AML (p = 0.02). KRAS-mutated AML treated with anthracycline-based first-line regimens had a lower relative mortality compared to treatment with hypomethylating agents with venetoclax (HR <0.01, p = 0.04) and without venetoclax (HR <0.01, p = 0.04). This study demonstrates that KRAS but not NRAS mutations are associated with worse outcomes in AML.NOVELTY STATEMENTWhat is the new aspect of your work? The clinical significance of RAS mutations remains poorly defined and prior studies have yielded conflicting results. We used causal inferential methods, propensity score modeling, to determine the impact of KRAS and NRAS mutation on survival in newly diagnosed AML patients, independent of other risk factors. Moreover, we analyzed the outcomes of KRAS and NRAS-mutated AML patients receiving first-line therapy with hypomethylating agents and other non-anthracycline-based regimens. We provided a detailed description of RAS-mutated AML, including co-occurring mutations and cytogenetic abnormalities.What is the central finding of your work? KRAS mutations but not NRAS mutations in AML are directly linked to worse outcomes even after controlling for differences in AML type, co-occurring cytogenetic changes, treatment regimens, and comorbidities. KRAS-mutated AML has a higher relative mortality when treated with a hypomethylating agent-based first-line induction regimen compared to treatment with an anthracycline-based regimen.What is (or could be) the specific clinical relevance of your work? Our findings can help refine our genetic profiles of AML, improve prognostic models, and better stratify treatment regimens.

Hospital Admissions Secondary to Diseases of the Blood, Blood-Forming Organs, and Immune System in England and Wales.

Background Non-malignant hematologic and immune disorders-related hospitalization trends are unstudied despite their importance from a public health standpoint. Therefore, this study aimed to define the hospitalization trends of the International Statistical Classification of Diseases-10 (ICD-10) category diseases of the blood and blood-forming organs and certain disorders involving the immune mechanism (B&ID). Methods We conducted an ecologic study to analyze hospital admission data obtained from England's Hospital Episode Statistics database and Wales' Patient Episode Database. Hospital admissions data for non-malignant hematologic disorders and immune disorders were extracted for the period from April 1999 to March 2019. We used the Poisson model to assess trends in hospital admissions. Results The total annual B&ID-related hospital admission (RHA) rate for all categories increased by 137.9% between 1999 and 2019 (p<0.01). Females accounted for 54% of all B&ID-RHA. Around 37% of B&ID-RHA were seen in the age group of 15-59 years and 29% in the age group of 75 years and above. The most common causes of B&ID-RHA were aplastic and other anemias and other bone marrow failure syndromes, ICD-10 category (33%) and nutritional anemias category (28%). Certain disorders involving the immune mechanism category accounted for the least number of B&ID-RHA (8.4%). The highest increase in B&ID-RHA was seen in the nutritional anemias category (3.86 fold), followed by certain disorders involving the immune mechanism (1.28 fold). Iron deficiency anemia accounted for 95.1% of all hospitalizations secondary to nutritional anemias. Around half of all, hemolytic anemia category hospitalizations were secondary to the sickle cell anemia subcategory. Conclusions Hospital admissions trends in non-malignant hematologic and immune disorders changed dynamically among age groups and gender in England and Wales over the last two decades. Understanding these changes has important implications for public health planning.

A Focus on Intermediate-Risk Acute Myeloid Leukemia: Sub-Classification Updates and Therapeutic Challenges.

Acute myeloid leukemia (AML) represents a heterogeneous group of hematopoietic neoplasms deriving from the abnormal proliferation of myeloid progenitors in the bone marrow. Patients with AML may have highly variable outcomes, which are generally dictated by individual clinical and genomic characteristics. As such, the European LeukemiaNet 2017 and 2022 guidelines categorize newly diagnosed AML into favorable-, intermediate-, and adverse-risk groups, based on their molecular and cytogenetic profiles. Nevertheless, the intermediate-risk category remains poorly defined, as many patients fall into this group as a result of their exclusion from the other two. Moreover, further genomic data with potential prognostic and therapeutic influences continue to emerge, though they are yet to be integrated into the diagnostic and prognostic models of AML. This review highlights the latest therapeutic advances and challenges that warrant refining the prognostic classification of intermediate-risk AML.

Patterns of treatment and their outcomes in primary breast lymphoma; a comprehensive population-based analysis.

BACKGROUND: Primary breast lymphoma (PBL) is managed differently among centers, using surgery, systemic therapy and/or radiation. With data derived from the National Cancer Database (NCDB), we aim to describe treatments utilized in the United States, estimate the overall survival (OS) of different therapeutic modalities and determine the role of systemic therapy in patients with PBL. METHODS: We conducted a retrospective cohort study using de-identified data from the NCDB. The NCDB provided records of 4616 patients diagnosed with PBL between 2004 and 2015. We excluded patients diagnosed with HIV, with no survival data, not treated in the reporting facility, without histologic confirmation, with stage III/ IV disease and for whom surgery, radiation, or systemic therapy was contraindicated. Both propensity score weighting and Cox models were used to obtain adjusted estimates. Based on histopathology, PBL was classified into indolent (I-PBL) and aggressive (A-PBL). RESULTS: In a sample size of 2063 PBL patients, the median age was 67 years (interquartile range (IQR): 57-78), and 97% were females. In 1027 patients with I-PBL, the median follow-up was 66 months (95% confidence interval (CI): 32.6-107.2) and 60% of patients had extranodal marginal zone subtype. Systemic therapy did not improve adjusted-OS (median: 154 vs. 143 months, P = 0.36) (Hazard ratio (HR): 0.86, 95% CI: 0.60-1.25, P = 0.42). The treatment arms associated with the highest adjusted 5-year OS were as follows: radiation (85%), surgery (79%), systemic & radiation (87%) and radiation & surgery (87%) (P = 0.9). In 1036 patients with A-PBL, the median follow-up was 67.4 months (95% CI: 35.9-105), and 87% of patients had diffuse large B-cell subtype. Patients with A-PBL who received systemic therapy had an improved adjusted-OS (median: 115 vs. 72 months, P < 0.01) (HR: 0.45, 95% CI: 0.38-0.53, P < 0.001). The treatment arms associated with the highest adjusted 5-year OS were: systemic (69%), systemic & radiation (77%), systemic & radiation & surgery (79%) and systemic & surgery (79%) (P = 0.4). CONCLUSIONS: Systemic therapy used as first-line treatment is essential in A-PBL. Local therapy in the I-PBL using surgery and/or radiation is effective in long-term disease control. There is significant variation in front-line treatment modalities utilized in PBL across the US, many associated with similar outcomes.

Trends in Hospital Admissions Due to Neoplasms in England and Wales between 1999 and 2019: An Ecological Study.

Objectives: This study aimed to investigate the trends in neoplasm-related hospital admissions (NRHA) in England and Wales between 1999 and 2019. Methods: This is an ecological study using publicly available data taken from the two main medical databases in England and Wales; the Hospital Episode Statistics database in England and the Patient Episode Database in Wales. Hospital admissions data were collected for the period between April 1999 and March 2019. Results: A total of 35,704,781 NRHA were reported during the study period. Females contributed to 50.8% of NRHA. The NRHA rate among males increased by 50.0% [from 26.62 (95% CI 26.55−26.68) in 1999 to 39.93 (95% CI 39.86−40.00) in 2019 per 1000 persons, trend test, p < 0.001]. The NRHA rate among females increased by 44.1% [from 27.25 (95% CI 27.18−27.31) in 1999 to 39.25 (95% CI 39.18−39.32) in 2019 per 1000 persons, trend test, p < 0.001]. Overall, the rate of NRHA rose by 46.2% [from 26.93 (95% CI 26.89−26.98) in 1999 to 39.39 (95% CI 39.34−39.44) in 2019 per 1000 persons, trend test, p < 0.001]. Conclusion: Hospital admission rates due to neoplasms increased between 1999 and 2019. Our study demonstrates a variation in NRHA influenced by age and gender. Further observational studies are needed to identify other factors associated with increased hospital admissions among patients with different types of neoplasms.

Impact of FLT3-ITD Insertion Length on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study.

The prognostic significance of the length of internal tandem duplication (ITD) insertions in mutant FLT3 genes in acute myeloid leukemia (AML) is controversial. We conducted a retrospective study to evaluate the correlation between the ITD base-pair (bp) insertion length and clinical outcomes. The mutational status of the FLT3 gene was evaluated in 402 of 467 consecutive AML patients treated at the University of Maryland Greenebaum Comprehensive Cancer Center between 2013 and 2020; 77 had FLT3-ITD mutations. Patients were divided into three cohorts based on bp insertion length (<30 (0−33rd percentile), 30−53 (34th−66th percentile),and >53 (>66th percentile)). The median overall survival (OS) of patients was 16.5 months (confidence interval (CI) 7.3-NA), 18.5 months (CI 7.3-NA), and 21.9 months (CI 19.1-NA) (p = 0.03) for the <30, 30−53, and >53 bp insertion length cohorts, respectively. The adjusted median event-free survival (EFS) for the ITD insertion lengths >30, 30−53, and >53 bp was 11.1 months (CI 2.8−16.5), 5.2 months (CI 2.9−12.6), and 9.1 months (CI 5.4-NA) (p = 0.5), respectively. Complete remission (CR) rates were 64% (<30 inserted bp), 55% (30−53 inserted bp), and 79% (>53 inserted bp) (p = 0.23). For patients treated with gilteritinib and midostaurin, the unadjusted median OS was not statistically significantly different between cohorts.

Consolidative Autologous Stem Cell Transplantation Versus Whole Brain Radiation in PCNSL; a Nationwide Analysis.

BACKGROUND: The best consolidation strategy after induction chemotherapy in Primary CNS Lymphoma (PCNSL) remains controversial. Our objective is to estimate the overall survival (OS) for autologous stem cell transplantation (ASCT) versus whole brain radiation (WBRT) in the consolidation setting. We also sought to evaluate the factors affecting treatment selection METHODS: We identified 1620 patients with PCNSL who received chemotherapy followed by either ASCT or WBRT between 2004 and 2015 from the National Cancer Database. A propensity score weighting methodology was used to compare survival outcomes. Factors affecting treatment selection were investigated using a logistic regression model. Annual percentage change (APC) was calculated to assess the trend of ASCT use. RESULTS: Only 12.2% of patients received ASCT, and this proportion rose steadily between 2004 and 2015, with APC of +23%. Treatment selection was affected by age, type of area, distance from the treating facility, and level of education. With a median follow-up of 68.4 months, adjusted-median OS was 91.4 months and not reached for WBRT and ASCT groups, respectively (P < .001). 5-year OS was 74.4% in the ASCT group versus 58.7% in the WBRT group (HR 0.40, 95% CI 0.27-0.60, P -value < .01). CONCLUSION: Socioeconomic factors affect the selection of consolidative treatment in patients with PCNSL which can alter outcomes. Frequency of consolidative ASCT is increasing for patients with PCNSL. This is the first and largest cohort study, to our knowledge, to show an OS advantage in favor of ASCT. This OS benefit needs to be confirmed in a randomized controlled fashion.

Outcomes of Newly Diagnosed Acute Myeloid Leukemia Patients Treated With Hypomethylating Agents With or Without Venetoclax: A Propensity Score-Adjusted Cohort Study.

There is a deficiency of real-world data on the impact of combining venetoclax (VEN) with hypomethylating agents (HMAs) in newly diagnosed acute myeloid leukemia (AML) patients. We conducted a single-center, propensity-adjusted retrospective cohort study to compare composite complete remission (CCR) rates, median overall survival (m-OS) and median event-free survival (m-EFS). A total of 170 adult AML patients were treated with first-line azacitidine (AZA) or decitabine (DEC) +/- VEN. Median age was 71 years and 99 (58%) were male. Median follow-up in HMA and HMA-VEN groups was 79 and 21 months. Treatments included AZA alone (n=35, 21%), DEC alone (n=84, 49%), AZA-VEN (n=24, 14%) and DEC-VEN (n=27, 16%). VEN improved CCR rates to HMAs overall (52% vs. 27%, P<0.05) and to AZA (54% vs. 10%, P<0.05), but not to DEC (43% vs. 32%, P=0.35); it did not improve OS, and only improved EFS for AZA (10.5 vs. 3.8 months, P<0.05). CCR rates were lower with AZA than with DEC (13% vs. 33%, P<0.05), but OS and EFS were not different statistically. CCR rates did not differ for AZA-VEN vs. DEC-VEN (CCR: 58% vs. 52%, P=0.66), but OS and EFS were longer for AZA-VEN (m-OS: 12.3 vs. 2.2 months, P<0.05; m-EFS: 9.2 vs. 2.1 months, P<0.05). Our analysis showed that combining VEN with AZA in newly diagnosed AML patients improved outcomes, but combining VEN with DEC did not. AZA-VEN was associated with improved outcomes compared to DEC-VEN. Further studies are needed to test the benefit of combining VEN with DEC.

Impact of IDH1 c.315C>T SNP on Outcomes in Acute Myeloid Leukemia: A Propensity Score-Adjusted Cohort Study.

Acute myeloid leukemia (AML) is the common type of acute leukemia in adults. Definitive prognostic significance of variants of unknown significance lacks for many commonly mutated genes, including the isocitrate dehydrogenase 1 (IDH1) synonymous single nucleotide polymorphism (SNP) variant c.315C>T. In this retrospective cohort study of 248 AML patients at the University of Maryland Greenebaum Comprehensive Cancer Center, we show that the IDH1 c.315C>T SNP, previously reported to be associated with poor prognosis by other studies with conflicting data, does not confer worse prognosis, with a median overall survival (OS) of 17.1 months compared to 15.1 months for patients without this SNP (P=0.57). The lack of negative effect on prognosis by IDH1 SNP c.315C>T is consistent with the absence of amino acid alteration (p.Gly105Gly).

The Trend of Combined Modality Treatment and its Outcomes in Elderly Patients With Primary CNS Lymphoma: A 12-year Population-based Analysis Using Propensity Score.

BACKGROUND/AIM: The addition of radiation to chemotherapy in elderly patients with primary central nervous system lymphoma (PCNSL) remains controversial. This aim of this study was to assess the trend of combined modality treatment (CMT) and compare its survival with chemotherapy alone and radiation alone in non-HIV patients. PATIENTS AND METHODS: We identified 6,537 patients who received single treatment modality, CMT, or no treatment at all between 2004 and 2015 from the National Cancer Database. Factors affecting treatment selection were investigated using a logistic regression model. Annual percentage change (APC) was calculated to assess the trend of CMT use. A propensity score weighting methodology was used to compare survival outcomes. RESULTS: Only 12.8% of patients received CMT, and this proportion steadily declined between 2004 (17.7%) and 2015 (8.7%), with an APC of -6.0% (95%CI=-8.0 - -4.0, p-value <0.001) during the 12 years. Apart from classical prognostic factors (age and comorbidities), treatment selection was significantly influenced by sex, facility type, degree of urbanization, and type of insurance. CMT had improved survival [median overall survival 19.5 months (95%CI=15.7-22.8)] compared with single-modality treatment. This effect was more prominent in the first year. CONCLUSION: Socioeconomic factors affect the selection of treatment in elderly patients with PCNSL. CMT is falling out of favor in this patient population due to the risks of neurotoxicity. Further work should focus on developing strategies that minimize toxicity and access disparities without compromising survival.

Low utility of the H-Score and HLH-2004 criteria to identify patients with secondary hemophagocytic lymphohistiocytosis after CAR-T cell therapy for relapsed/refractory diffuse large B-Cell lymphoma.

Secondary hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immune dysregulation disorder. Use of chimeric antigen receptor T-cell therapy (CAR-T) is associated with cytokine release syndrome (CRS), Immune Effector Cell Associated Neurotoxicity Syndrome (ICANS) and secondary HLH. However, application of HLH scoring systems (H-score, HLH-2004 criteria) are not validated in this setting. We analyzed the utility of applying the H-score and the HLH-2004 criteria to identify patients with possible HLH post-CAR-T for Relapsed/Refractory Diffuse Large B-cell Lymphoma. Only two of four patients with post CAR-T HLH met five or more of the diagnostic criteria for HLH by HLH 2004 criteria. In contrast all four post CAR-T HLH patients had a high H-score (>169); however, an additional ten patients that did not have HLH also had a high H-score. Thus, in this patient population, both scoring systems were demonstrated to have low prognostic significance in differentiating between high grade CRS and HLH.

Musculoskeletal System and Connective Tissue Related Hospital Admission in England and Wales Between 1999 and 2019: An Ecologic Study.

Background There is a lack of data describing inpatient hospitalization trends for musculoskeletal and connective tissue diseases in the United Kingdom. Aim We aim to provide a comprehensive analysis of the trends of musculoskeletal and connective tissue disease related hospitalizations between 1999 and 2019 in England and Wales. Method We conducted an ecologic study. The data were obtained from the Hospital Episode Statistics database in England and the Patient Episode Database in Wales between 1999 and 2019. We used ICD-10 (International Classification of Diseases, 10th Revision) codes M00-M99 to identify hospital admissions. Results The total annual hospital admission rate increased from 1,303.63 (95% CI: 1,300.55-1,306.71) in 1999 to 2,479.09 (95% CI: 2,475.14-2,483.04) in 2019 per 100,000 persons (p<0.01). The ICD-10 categories other joint disorders, osteoarthritis, and other dorsopathies accounted for 19.6%, 19.6%, and 18.6% of hospitalizations, respectively. Advanced age groups experienced a larger increase in hospitalization rates (128.6% in the age group of 75 years and above vs. 45.9% in the age group below 15 years). Females contributed to 57.7% of hospitalizations and experienced a larger increase in hospitalization rate compared to males (103.8% vs. 73.8%). Conclusion Between 1999 and 2009, the hospitalization rate for musculoskeletal and connective tissue diseases has steadily increased in England and Wales. However, the rate has plateaued or declined in many of musculoskeletal and connective tissue diseases between 2010 and 2019. Due to the chronicity of these diseases, their significant morbidity, and significant long-term disability, national interventions are needed to mitigate the effects of the increased cost of treatment.

Hospital admission trends due to respiratory diseases in England and Wales between 1999 and 2019: an ecologic study.

BACKGROUND: Identifying trends of hospital admissions for respiratory diseases is crucial for public health and research to guide future clinical improvements for better outcomes. This study aims to define the trends of respiratory disease-related hospital admissions (RRHA) in England and Wales between 1999 and 2019. METHODS: An ecological study was conducted using hospital admission data taken from the Hospital Episode Statistics database in England and the Patient Episode Database for Wales. Hospital admissions data for respiratory diseases were extracted for the period between April 1999 and March 2019. The trend in hospital admissions was assessed using a Poisson model. RESULTS: Hospital admission rate increased by 104.7% [from 1535.05 (95% CI 1531.71-1538.38) in 1999 to 3142.83 (95% CI 3138.39-3147.26) in 2019 per 100,000 persons, trend test, p < 0.01]. The most common causes were influenza and pneumonia, chronic lower respiratory diseases, other acute lower respiratory infections, which accounted for 26.6%, 26.4%, and 14.9%, respectively. The age group 75 years and above accounted for 34.1% of the total number of hospital admissions. Males contributed to 50.5% of the total number of hospital admissions. Hospital admission rate in females increased by 119.8% [from 1442.18 (95% CI 1437.66-1446.70) in 1999 to 3169.38 (95% CI 3163.11-3175.64) in 2019 per 100,000 persons, trend test, p < 0.001]. Hospital admission rate increased by 92.9% in males [from 1633.25 (95% CI 1628.32-1638.17) in 1999 to 3149.78 (95% CI 3143.46-3156.09) in 2019 per 100,000 persons, trend test, p < 0.001]. CONCLUSION: During the study period, hospital admissions rate due to respiratory diseases increased sharply. The rates of hospital admissions were higher among males for the vast majority of respiratory diseases. Further observational studies are warranted to identify risk factors for these hospital admissions and to offer relevant interventions to mitigate the risk.

Hospital Admissions Due to Ischemic Heart Diseases and Prescriptions of Cardiovascular Diseases Medications in England and Wales in the Past Two Decades.

OBJECTIVES: The aim of this study was to explore the trend of ischemic heart disease (IHD) admission and the prescriptions of IHD medications in England and Wales. METHODS: A secular trends study was conducted during the period of 1999 to 2019. We extracted hospital admission data for patients from all age groups from the Hospital Episode Statistics database in England and the Patient Episode Database for Wales. Prescriptions of IHD medications were extracted from the Prescription Cost Analysis database from 2004 to 2019. The chi-squared test was used to assess the difference between the admission rates and the difference between IHD medication prescription rates. The trends in IHD-related hospital admission and IHD-related medication prescription were assessed using a Poisson model. The correlation between hospital admissions for IHD and its IHD medication-related prescriptions was assessed using the Pearson correlation coefficient. RESULTS: Our study detected a significant increase in the rate of cardiovascular disease (CVD) medication prescriptions in England and Wales, representing a rise in the CVD medications prescription rate of 41.8% (from 539,334.95 (95% CI = 539,286.30-539,383.59) in 2004 to 764,584.55 (95% CI = 764,545.55-764,623.56) in 2019 prescriptions per 100,000 persons), with a mean increase of 2.8% per year during the past 15 years. This increase was connected with a reduction in the IHD hospital admission rate by 15.4% (from 838.50 (95% CI = 836.05-840.94) in 2004 to 709.78 (95% CI = 707.65-711.92) in 2019 per 100,000 persons, trend test, p < 0.01), with a mean decrease of 1.02% per year during the past 15 years and by 5% (from 747.43 (95% CI = 745.09-749.77) in 1999 to 709.78 (95% CI = 707.65-711.92) in 2019 per 100,000 persons, trend test, p < 0.01) with a mean decrease of 0.25% per year during the past two decades in England and Wales. CONCLUSION: The rate of hospitalisation due to IHD has decreased in England and Wales during the past two decades. Hospitalisation due to IHD was strongly and negatively correlated with the increase in the rates of dispensing of IHD-related medications. Other factors contributing to this decline could be the increase in controlling IHD risk factors during the past few years. Future studies exploring other risk factors that are associated with IHD hospitalisation are warranted.

Hospitalization and Post-hospitalization Outcomes Among Teaching Internal Medicine, Employed Hospitalist, and Locum Tenens Hospitalist Services in a Tertiary Center: a Prospective Cohort Study.

BACKGROUND: There are no prospective studies comparing hospitalization and post-hospitalization outcomes between teaching internal medicine services and non-teaching hospitalists, and no prospective studies comparing these outcomes between locum and employed hospitalists. OBJECTIVE: To compare the length of stay, hospital costs readmission rate, and mortality rate in patients treated by teaching internal medicine services vs. hospitalists and among patients treated by locum vs. employed hospitalists. DESIGN: Prospective cohort study. Propensity score was used to obtain weighted estimates. SETTING: Referral center. PATIENTS: All patients 18 years and older admitted to internal medicine services. INTERVENTION: Treatment by teaching internal medicine services vs. hospitalists. Treatment by locum hospitalists vs. employed hospitalists. MAIN MEASURES: Primary outcome was adjusted length of stay and secondary outcomes included hospital cost, inpatient mortality, 30-day all-cause readmission, and 30-day mortality. KEY RESULTS: A total of 1273 patients were admitted in the study period. The mean patient age was 61 ± 19 years, and the sample was 52% females. Teaching internal medicine physicians admitted 526 patients and non-teaching hospitalists admitted 747 patients. Being seen exclusively by teaching internal medicine physicians comports with a shorter adjusted hospital stay by 0.6 days (95% CI - 1.07 to - 0.22, P = .003) compared to non-teaching hospitalists. Adjusted length of stay was 1 day shorter in patients seen exclusively by locums compared to patients seen exclusively by employed services (95% CI - 1.6 to - 0.43, P < .001) with an adjusted average hospital cost saving of 1339 dollars (95% CI - 2037 to - 642, P < .001). There was no statistically significant difference in other outcomes. CONCLUSIONS: Teaching internal medicine services care was associated with a shorter stay but not with increased costs, readmission, or mortality compared to non-teaching services. In contrary to the "expected," patients treated by locums had shorter stays and decreased hospital costs but no increase in readmissions or mortality.

Spontaneous subdural hematoma in a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia with normal platelet count after dasatinib treatment.

Dasatinib, which is an inhibitor of BCR-ABL and SRC family tyrosine kinases, is used for the treatment of patients with Philadelphia chromosome (Ph) positive leukemia, especially for those who develop resistance or who are intolerant to imatinib. The most common adverse effects attributed to its use are: myelosuppression, nausea, diarrhea, and peripheral edema. Hemorrhage, which could be gastrointestinal, genitourinary or central nervous system, is a less frequent adverse effect. In this case, we report a patient affected by precursor B-cell acute lymphoblastic leukemia (ALL) positive for the Ph chromosome translocation treated with the tyrosine kinase inhibitor (TKI) dasatinib. During the treatment with dasatinib the patient developed subdural hematoma (SDH). She did not have any head trauma, thrombocytopenia, coagulopathy or meningeal involvement, making dasatinib-induced platelet dysfunction the most likely cause of SDH.

The prevalence of isolated growth hormone deficiency among children of short stature in Jordan and its relationship with consanguinity.

OBJECTIVE: The prevalence of isolated growth hormone deficiency (IGHD) among short-statured children in Jordan, where consanguineous marriage (CM) is common, is unknown. No studies have investigated the relationship between degrees of consanguinity and IGHD. This study aimed to determine the prevalence of IGHD among short-statured children referred to a university hospital in Jordan and its relationship with different degrees of consanguinity. DESIGN: We conducted a 24-month cross-sectional observational trial at an outpatient tertiary care center in Amman, Jordan. PATIENTS: We obtained detailed family histories, medical evaluations and laboratory tests for 94 short-statured children (50 boys and 44 girls aged 6-16 years). MEASUREMENTS: Complete and partial GHD were defined as peak GH responses of 5 and 7 µg/l (15 and 21 mIU/l) [IRMA/DiaSorin®], respectively, in both exercise and insulin tolerance tests. RESULTS: GHD was diagnosed in 69·1% of the short children, including 86% (43/50) of the children of consanguineous parents (83·3%, 93·8% and 81·8% of children of first cousins, first cousins once removed and second cousins, respectively) and 50% (20/44) of the children of nonconsanguineous parents (P = 0·039, 0·002 and 0·013, respectively). However, there was no statistically significant difference in the prevalence of small pituitary MRI between GH-deficient children of consanguineous parents and those of nonconsanguineous parents (28·6% vs 13·6%, P = 0·3). CONCLUSIONS: The prevalence of IGHD among referred short children in Jordan was exceptionally high and significantly higher in the children of CM. In countries where CM is common, preconception counselling and rigorous surveillance for GHD in short children may be indicated.