Comparison of intermittent intravenous tacrolimus to continuous tacrolimus in adult allogeneic stem cell transplant recipients.

Introduction: Initial continuous intravenous (CIV) tacrolimus (0.03 mg/kg/day based on ideal body weight [IBW]) has been favored for graft versus host disease (GVHD) prevention in allogeneic stem cell transplant patients due to the consistent, steady-state degree of immunosuppression; however, this method poses many logistical challenges. We implemented intermittent (IIV) tacrolimus at a starting dose of 0.015 mg/kg IBW twice daily over 4 h. To our knowledge this is the first retrospective comparison of CIV to IIV tacrolimus. Objectives: The primary objective was to evaluate the safety of IIV tacrolimus in comparison to CIV with respect to nephrotoxicity and neurotoxicity. The secondary objectives were to compare the incidence of grade II-IV acute GVHD (aGVHD) and chronic GVHD (cGVHD) at day +180, outcomes including relapse and overall survival, cell engraftment, and reactivation of cytomegalovirus and Epstein-Barr virus. Methods: This retrospective, single-center review evaluated adults who received an allogeneic stem cell transplant patients between January 1, 2020, and December 31, 2022. Results: Fifty-one unique patients were eligible for evaluation - 28 in the IIV cohort and 23 in the CIV group. The number of patients who developed nephrotoxicity and neurotoxicity were comparable between groups with no significant differences noted. No severe neurotoxicity was identified in either population. Secondary objectives revealed no significant difference in GVHD incidence or survival outcomes. Conclusion: IIV tacrolimus is comparable to CIV in terms of safety while also maintaining similar outcomes at day +180. IIV is a safe and feasible alternative to CIV in adult allogeneic stem cell transplant recipients.

Safety and efficacy of cryopreserved platelets in bleeding patients with thrombocytopenia.

BACKGROUND: The short dating period of room temperature-stored platelets (PLTs; 5-7 days) limits their availability at far-forward combat facilities and at remote civilian sites in the United States. PLT cryopreservation in 6% DMSO and storage for up to 2 years may improve timely availability for bleeding patients. STUDY DESIGN AND METHODS: A dose escalation trial of DMSO-cryopreserved PLTs (CPPs) compared to standard liquid-stored PLTs (LSPs) was performed in bleeding patients with thrombocytopenia. Within each of four cohorts, six patients received escalating doses of CPP (0.5 unit, 1 unit, and sequential transfusions of 2 and 3 units) and one received a LSP transfusion. Patients were monitored for adverse events (AEs), coagulation markers, PLT responses, and hemostatic efficacy. RESULTS: Patients with a World Health Organization bleeding score of 2 or more received from 0.5 to 3 units of CPP (n = 24) or 1 unit of LSP (n = 4). There were no related thrombotic or other serious AEs experienced. Mild transfusion-related AEs of chills and fever (n = 1), transient increased respiratory rate (n = 1), DMSO-related skin odor (n = 2), and headache (n = 1) were observed after CPP transfusion. Among CPP recipients 14 of 24 (58%) had improved bleeding scores, including three of seven (43%) patients who had intracerebral bleeding. CPP posttransfusion PLT increments were significantly less than those of LSPs; however, days to next transfusion were the same. After transfusion, the CPP recipients had improvements in some variables of thrombin generation tests and thromboelastography. CONCLUSION: Cryopreserved PLT transfusions appear to be safe and effective when given to bleeding patients with thrombocytopenia.

CML in pregnancy: A case report using leukapheresis and literature review.

Chronic myelogenous leukemia (CML) complicating pregnancy is uncommon. Literature search demonstrates only a few case reports and some case series but large studies are lacking due to its uncommon presentation. Management of these patients is particularly challenging due to limited available options as several chemotherapy drugs could potentially lead to adverse outcomes and fetal malformations. Leukapheresis has been used in these situations; however paucity of data exists regarding the outcome and complications associated with the procedure. Using leukapheresis alone for extended period to manage CML during pregnancy is also rare. Here we report a case of CML complicating pregnancy which was successfully managed utilizing leukapheresis, followed by a review of literature addressing this controversial issue.

Unraveling the complexity of the senescence-associated secretory phenotype in adamantinomatous craniopharyngioma using multimodal machine learning analysis.

BACKGROUND: Cellular senescence can have positive and negative effects on the body, including aiding in damage repair and facilitating tumor growth. Adamantinomatous craniopharyngioma (ACP), the most common pediatric sellar/suprasellar brain tumor, poses significant treatment challenges. Recent studies suggest that senescent cells in ACP tumors may contribute to tumor growth and invasion by releasing a senesecence-associated secretory phenotype. However, a detailed analysis of these characteristics has yet to be completed. METHODS: We analyzed primary tissue samples from ACP patients using single-cell, single-nuclei, and spatial RNA sequencing. We performed various analyses, including gene expression clustering, inferred senescence cells from gene expression, and conducted cytokine signaling inference. We utilized LASSO to select essential gene expression pathways associated with senescence. Finally, we validated our findings through immunostaining. RESULTS: We observed significant diversity in gene expression and tissue structure. Key factors such as NFKB, RELA, and SP1 are essential in regulating gene expression, while senescence markers are present throughout the tissue. SPP1 is the most significant cytokine signaling network among ACP cells, while the Wnt signaling pathway predominantly occurs between epithelial and glial cells. Our research has identified links between senescence-associated features and pathways, such as PI3K/Akt/mTOR, MYC, FZD, and Hedgehog, with increased P53 expression associated with senescence in these cells. CONCLUSIONS: A complex interplay between cellular senescence, cytokine signaling, and gene expression pathways underlies ACP development. Further research is crucial to understand how these elements interact to create novel therapeutic approaches for patients with ACP.

Characteristics of patients with hematologic malignancies without seroconversion post-COVID-19 third vaccine dosing.

Objectives: The objective of this study is to explore the characteristics of the subset of patients with hematologic malignancies (HMs) who had little to no change in SARS-CoV-2 spike antibody index value levels after a third mRNA vaccine dose (3V) and to compare the cohort of patients who did and did not seroconvert post-3V to get a better understanding of the demographics and potential drivers of serostatus. Study design: This retrospective cohort study analyzed SARS-CoV-2 spike IgG antibody index values pre and post the 3V data on 625 patients diagnosed with HM across a large Midwestern United States healthcare system between 31 October 2019 and 31 January 2022. Methods: To assess the association between individual characteristics and seroconversion status, patients were placed into two groups based on IgG antibody status pre and post the 3V dose, (-/+) and (-/-). Odds ratios were used as measures of association for all categorical variables. Logistic regressions were used to measure the association between HM condition and seroconversion. Results: HM diagnosis was significantly associated with seroconversion status (P = 0.0003) with patients non-Hodgkin lymphoma six times the odds of not seroconverting compared with multiple myeloma patients (P = 0.0010). Among the participants who were seronegative prior to 3V, 149 (55.6%) seroconverted after the 3V dose and 119 (44.4%) did not. Conclusion: This study focuses on an important subset of patients with HM who are not seroconverting after the COVID mRNA 3V. This gain in scientific knowledge is needed for clinicians to target and counsel these vulnerable patients.

Real-World Third COVID-19 Vaccine Dosing and Antibody Response in Patients With Hematologic Malignancies.

Purpose: This study sought to describe the changes in immune response to a third dose of either Pfizer's or Moderna's COVID-19 mRNA vaccine (3V) among patients with hematologic malignancies, as well as associated characteristics. Methods: This retrospective cohort study analyzed pre-3V and post-3V data on 493 patients diagnosed with hematologic malignancies across a large Midwestern health system between August 28, 2021, and November 1, 2021. For antibody testing, S1 spike antigen of the SARS-CoV-2 virus titer was used to determine serostatus. Results: Among 493 participants, 274 (55.6%) were seropositive both pre- and post-3V (+/+) while 115 (23.3%) seroconverted to positive from prior negative following the third dose (-/+). The remaining 104 (21.1%) were seronegative both before and after 3V (-/-). No participant was seropositive pre-3V and seronegative post-3V (+/-). Results showed a statistically significant increase in the proportion of seropositivity after receiving a third COVID-19 vaccine (P<0.00001). Response to 3V was significantly associated with the 3V vaccine type (P=0.0006), previous COVID-19 infection (P=0.0453), and malignancy diagnosis (P<0.0001). Likelihood of seroconversion (-/+) after 3V was higher in the group of patients with multiple myeloma or related disorders compared to patients with lymphoid leukemias (odds ratio: 8.22, 95% CI: 2.12-31.79; P=0.0008). Conclusions: A third COVID-19 vaccination is effective in producing measurable seroconversion in many patients with hematologic malignancies. Oncologists should actively encourage all their patients, especially those with multiple myeloma, to receive a 3V, given the high likelihood of seroconversion.

Cerebral Venous Sinus Thrombosis Associated With Coronavirus Disease 2019: Case Report and Review of the Literature.

INTRODUCTION: Coronavirus disease 2019 (COVID-19) is associated with significant risk of acute thrombosis. We present a case report of a patient with cerebral venous sinus thrombosis (CVST) associated with COVID-19 and performed a literature review of CVST associated with COVID-19 cases. CASE REPORT: A 38-year-old woman was admitted with severe headache and acute altered mental status a week after confirmed diagnosis of COVID-19. Magnetic resonance imaging brain showed diffuse venous sinus thrombosis involving the superficial and deep veins, and diffuse edema of bilateral thalami, basal ganglia and hippocampi because of venous infarction. Her neurological exam improved with anticoagulation (AC) and was subsequently discharged home. We identified 43 patients presenting with CVST associated with COVID-19 infection. 56% were male with mean age of 51.8±18.2 years old. The mean time of CVST diagnosis was 15.6±23.7 days after onset of COVID-19 symptoms. Most patients (87%) had thrombosis of multiple dural sinuses and parenchymal changes (79%). Almost 40% had deep cerebral venous system thrombosis. Laboratory findings revealed elevated mean D-dimer level (7.14/mL±12.23 mg/L) and mean fibrinogen level (4.71±1.93 g/L). Less than half of patients had prior thrombotic risk factors. Seventeen patients (52%) had good outcomes (mRS <=2). The mortality rate was 39% (13 patients). CONCLUSION: CVST should be in the differential diagnosis when patients present with acute neurological symptoms in this COVID pandemic. The mortality rate of CVST associated with COVID-19 can be very high, therefore, early diagnosis and prompt treatment are crucial to the outcomes of these patients.

Blocking UBE2N abrogates oncogenic immune signaling in acute myeloid leukemia.

Dysregulation of innate immune signaling pathways is implicated in various hematologic malignancies. However, these pathways have not been systematically examined in acute myeloid leukemia (AML). We report that AML hematopoietic stem and progenitor cells (HSPCs) exhibit a high frequency of dysregulated innate immune-related and inflammatory pathways, referred to as oncogenic immune signaling states. Through gene expression analyses and functional studies in human AML cell lines and patient-derived samples, we found that the ubiquitin-conjugating enzyme UBE2N is required for leukemic cell function in vitro and in vivo by maintaining oncogenic immune signaling states. It is known that the enzyme function of UBE2N can be inhibited by interfering with thioester formation between ubiquitin and the active site. We performed in silico structure-based and cellular-based screens and identified two related small-molecule inhibitors UC-764864/65 that targeted UBE2N at its active site. Using these small-molecule inhibitors as chemical probes, we further revealed the therapeutic efficacy of interfering with UBE2N function. This resulted in the blocking of ubiquitination of innate immune- and inflammatory-related substrates in human AML cell lines. Inhibition of UBE2N function disrupted oncogenic immune signaling by promoting cell death of leukemic HSPCs while sparing normal HSPCs in vitro. Moreover, baseline oncogenic immune signaling states in leukemic cells derived from discrete subsets of patients with AML exhibited a selective dependency on UBE2N function in vitro and in vivo. Our study reveals that interfering with UBE2N abrogates leukemic HSPC function and underscores the dependency of AML cells on UBE2N-dependent oncogenic immune signaling states.

Ocular Adnexal Lymphoma Presenting with Visual Loss.

CONTEXT: Elderly patients with visual loss often have age-related macular degeneration, diabetic retinopathy, glaucoma, and cataract as common causes of visual loss. Other less common etiologies should be considered, especially in those presenting with systemic associations. CASE REPORT: The patient discussed in our review is an 80-year-old female, with a history of diabetic retinopathy and macular degeneration who presented with a sudden deterioration of vision. While this was initially attributed to diabetic retinopathy, she was eventually noted to have a salmon patch lesion in her conjunctiva, diagnosed on biopsy to be a diffuse large B-cell lymphoma. CONCLUSION: Because of the significant rate of disseminated disease among patients with lymphomas in the orbit that carries a worse prognosis, early diagnosis is essential to promote better overall survival of these patients. We describe here a patient diagnosed with conjunctival lymphoma associated with pronounced visual loss and review the literature on this subject.

Augmented and standard Berlin-Frankfurt-Munster chemotherapy for treatment of adult acute lymphoblastic leukemia.

The augmented Berlin-Frankfurt-Munster (aBFM) regimen has demonstrated improved outcomes in children with acute lymphomblastic leukemia (ALL), but efficacy in adults is unknown. In this retrospective study, we evaluated clinical outcomes in 29 adult ALL patients (aged 19-70) treated with standard BFM (sBFM) or dose-intensive aBFM. Patients were stratified into risk groups based on age, cytogenetic abnormalities, peripheral leukocytosis and response to induction chemotherapy. Inter-mediate risk patients less than 50 years old and all high-risk patients were assigned to aBFM. Complete remission after induction therapy was achieved in 93% of patients. Fifteen patients completed a full course of BFM chemotherapy, with seven discontinuing because of relapse, three because of toxicity, two because of transplantation and two toxic deaths. Five-year event-free survival (EFS) was 45% (95% CI 30-67%), with 39% and 50% rates of EFS observed in the aBFM and sBFM subgroups at 5 years, respectively. Overall survival at 5 years was 62% (95% CI 46-82%), with 61% and 62% in the aBFM and sBFM subgroups alive at 5 years, respectively. Two toxic deaths were observed, and infections and neuropathy were the most common toxicities. sBFM and aBFM have efficacy and toxicity comparable with other adult ALL regimens.