The addition of doxycycline to fluoroquinolones for bacterial prophylaxis in autologous stem cell transplantation for multiple myeloma.

BACKGROUND: Bacterial prophylaxis with a fluoroquinolone (FQ) during autologous stem cell transplant (ASCT) is common, although not standardized among transplant centers. The addition of doxycycline (doxy) to FQ prophylaxis was previously linked to reduced neutropenic fever and bacteremia in multiple myeloma (MM) patients undergoing ASCT although several confounders were present. We compared the incidence of neutropenic fever and bacteremia between MM patients variably receiving prophylaxis with FQ alone and FQ-doxy during ASCT. METHODS: Systematic retrospective chart review of MM patients who underwent ASCT between January 2016 and December 2021. The primary objective was to determine the effect of bacterial prophylaxis on neutropenic fever and bacteremia within 30 days of ASCT. Multivariable logistic regression for neutropenic fever and univariate logistic regression for bacteremia accounted for differences in subject characteristics between groups. RESULTS: Among 341 subjects, 121 received FQ and 220 received FQ-doxy for prophylaxis. Neutropenic fever developed in 67 (55.4%) and 87 (39.5%) subjects in the FQ and FQ-doxy groups, respectively (p = .005). Bacteremia was infrequent, with 5 (4.1%) and 5 (2.3%) cases developing in the FQ and FQ-doxy groups, respectively (p = .337). Among Gram-negative bacteremia events, 7/7 Escherichia coli strains were FQ-resistant, and 5/7 were ceftriaxone-resistant. CONCLUSION: The FQ-doxy prophylaxis group had fewer cases of neutropenic fever than the FQ group, however, there was no significant difference in bacteremia. High rates of antibiotic resistance were observed. An updated randomized controlled trial investigating appropriate prophylaxis for ASCT in the context of current oncology standards and changing antimicrobial resistance rates is warranted.

Educational and occupational aspirations of adolescent and young adult cancer survivors: a qualitative analysis.

PURPOSE: Adolescent and young adult cancer survivors (AYACS) are patients diagnosed with cancer between 15 and 39 years of age. AYACS are often derailed from planned educational and occupational endeavors due to disruption from cancer treatment and its consequences. The study objective was to examine how a personal cancer diagnosis impacted AYACS' experiences related to these endeavors. METHODS: Semi-structured interviews were conducted as part of a larger study assessing psychosocial challenges among a younger AYACS subset aged 15-25 years old at the time of cancer diagnosis. Interviews were coded based on responses and were used to develop themes related to educational and occupational endeavors. RESULTS: Data were collected from 35 participants. Five themes emerged: (1) Pauses in educational attainment had a detrimental effect on educational goals for some participants, but further solidified and sculpted educational plans for others; (2) Although participants experienced challenges accomplishing educational goals, supportive school environments helped surmount these challenges; (3) Participants reflected on rethinking career aspirations, though some desired to pursue the same occupation planned before cancer diagnosis; (4) Participants experienced challenges, including physical and cognitive limitations, upon returning to work; and (5) Participants valued autonomy and normalcy through work and appreciated supportive and flexible work environments. CONCLUSIONS: AYACS prioritize professional achievement, yet encounter challenges in achieving professional goals. Our findings create a foundation for developing and testing prospective interventions to promote continuance of school and work during cancer treatment when feasible, and proactive reintegration strategies for those who paused professional goals due to cancer treatment.

Multi-dimensional analysis identifies an immune signature predicting response to decitabine treatment in elderly patients with AML.

Decitabine is a DNA-hypomethylating agent that has been widely applied for the treatment of acute myeloid leukaemia (AML) patients who are elderly or unfit for intensive therapy. Although effective, the complete response rate to decitabine is only around 30% and the overall survival remains poor. Emerging data support that regulation of DNA methylation is critical to control immune cell development, differentiation and activation. We hypothesize that defining how decitabine influences the immune responses in AML will facilitate the development of novel immune-based leukaemia therapeutics. Here, we performed phenotypic and functional immune analysis on clinical samples from AML patients receiving decitabine treatment and demonstrated a significant impact of decitabine on the immune system. T-cell expression of inhibitory molecules was upregulated and the ability of CD8 T cells to produce cytokines was decreased upon decitabine treatment. Importantly, in an unbiased comprehensive analysis, we identified a unique immune signature containing a cluster of key immune markers that clearly separate patients who achieved complete remission after decitabine from those who failed to do so. Therefore, this immune signature has a strong predictive value for clinical response. Collectively, our study suggests that immune-based analyses may predict clinical response to decitabine and provide a therapeutic strategy to improve the treatment of AML.

Hematopoietic transcription factor mutations: important players in inherited platelet defects.

Transcription factors (TFs) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet defects are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for defects in platelet production, morphology, and function. The hematopoietic TFs implicated in patients with impaired platelet function and number include runt-related transcription factor 1, Fli-1 proto-oncogene, E-twenty-six (ETS) transcription factor (friend leukemia integration 1), GATA-binding protein 1, growth factor independent 1B transcriptional repressor, ETS variant 6, ecotropic viral integration site 1, and homeobox A11. These TFs act in a combinatorial manner to bind sequence-specific DNA within promoter regions to regulate lineage-specific gene expression, either as activators or repressors. TF mutations induce rippling downstream effects by simultaneously altering the expression of multiple genes. Mutations involving these TFs affect diverse aspects of megakaryocyte biology, and platelet production and function, culminating in thrombocytopenia and platelet dysfunction. Some are associated with predisposition to hematologic malignancies. These TF variants may occur more frequently in patients with inherited platelet defects than generally appreciated. This review focuses on alterations in hematopoietic TFs in the pathobiology of inherited platelet defects.

Transcription Factor RUNX1 Regulates Platelet PCTP (Phosphatidylcholine Transfer Protein): Implications for Cardiovascular Events: Differential Effects of RUNX1 Variants.

BACKGROUND: PCTP (phosphatidylcholine transfer protein) regulates the intermembrane transfer of phosphatidylcholine. Higher platelet PCTP expression is associated with increased platelet responses on activation of protease-activated receptor 4 thrombin receptors noted in black subjects compared with white subjects. Little is known about the regulation of platelet PCTP. Haplodeficiency of RUNX1, a major hematopoietic transcription factor, is associated with thrombocytopenia and impaired platelet responses on activation. Platelet expression profiling of a patient with a RUNX1 loss-of-function mutation revealed a 10-fold downregulation of the PCTP gene compared with healthy controls. METHODS: We pursued the hypothesis that PCTP is regulated by RUNX1 and that PCTP expression is correlated with cardiovascular events. We studied RUNX1 binding to the PCTP promoter using DNA-protein binding studies and human erythroleukemia cells and promoter activity using luciferase reporter studies. We assessed the relationship between RUNX1 and PCTP in peripheral blood RNA and PCTP and death or myocardial infarction in 2 separate patient cohorts (587 total patients) with cardiovascular disease. RESULTS: Platelet PCTP protein in the patient was reduced by ≈50%. DNA-protein binding studies showed RUNX1 binding to consensus sites in ≈1 kB of PCTP promoter. PCTP expression was increased with RUNX1 overexpression and reduced with RUNX1 knockdown in human erythroleukemia cells, indicating that PCTP is regulated by RUNX1. Studies in 2 cohorts of patients showed that RUNX1 expression in blood correlated with PCTP gene expression; PCTP expression was higher in black compared with white subjects and was associated with future death/myocardial infarction after adjustment for age, sex, and race (odds ratio, 2.05; 95% confidence interval 1.6-2.7; P<0.0001). RUNX1 expression is known to initiate at 2 alternative promoters, a distal P1 and a proximal P2 promoter. In patient cohorts, there were differential effects of RUNX1 isoforms on PCTP expression with a negative correlation in blood between RUNX1 expressed from the P1 promoter and PCTP expression. CONCLUSIONS: PCTP is a direct transcriptional target of RUNX1. PCTP expression is associated with death/myocardial infarction in patients with cardiovascular disease. RUNX1 regulation of PCTP may play a role in the pathogenesis of platelet-mediated cardiovascular events.

Inherited thrombocytopenias: the beat goes on.

In this issue of Blood, Bottega et al document mutations in ACTN1, which encodes the cytoskeletal protein α-actinin 1, in 10 of 239 consecutive probands with an inherited thrombocytopenia--making ACTN1 an important cause of familial thrombocytopenia.

Inherited platelet dysfunction and hematopoietic transcription factor mutations.

Transcription factors (TFs) are proteins that bind to specific DNA sequences and regulate expression of genes. The molecular and genetic mechanisms in most patients with inherited platelet dysfunction are unknown. There is now increasing evidence that mutations in hematopoietic TFs are an important underlying cause for the defects in platelet production, morphology, and function. The hematopoietic TFs implicated in the patients with impaired platelet function include Runt related TF 1 (RUNX1), Fli-1 proto-oncogene, ETS TF (FLI1), GATA-binding protein 1 (GATA1), and growth factor independent 1B transcriptional repressor (GFI1B). These TFs act in a combinatorial manner to bind sequence-specific DNA within a promoter region to regulate lineage-specific gene expression, either as activators or as repressors. TF mutations induce rippling downstream effects by simultaneously altering the expression of multiple genes. Mutations involving these TFs affect diverse aspects of megakaryocyte biology and platelet production and function, culminating in thrombocytopenia, platelet dysfunction, and associated clinical features. Mutations in TFs may occur more frequently in the patients with inherited platelet dysfunction than generally appreciated. This review focuses on the alterations in hematopoietic TFs in the pathobiology of inherited platelet dysfunction.

GIST treatment options after tyrosine kinase inhibitors.

OPINION STATEMENT: The management of advanced gastrointestinal stromal tumor (GIST) has been dramatically altered by the development of tyrosine kinase inhibitors. The disease, which had a median overall survival of 12 months for patients with unresectable disease, now has a median survival approaching 5 or more years. The challenge faced clinically is how to care for patients when they have progressed on all approved therapies. Clinical trials evaluating the role of novel combination therapies with investigational agents that target AKT/PI3K pathways are of interest especially given the preclinical rationale available. The addition of an mTOR inhibitor can be tried as these are available, but requires care and monitoring for additional toxicities. With improved understanding of this disease, which we thought of as one biology, personalized therapies are being studied and tested and is particularly relevant for GIST that are less responsive to the standard kinase inhibitors, such as platelet-derived growth factor alpha (PDGFRA) D842V and wild-type/succinate dehydrogenase (SDH)-deficient GIST. IGF1R inhibitors as a class are not being developed because of the lack of significant efficacy in many clinical trials and the efficacy in WT GIST has been limited; to date drugs targeting VEGFR, such as sunitinib and regorafenib, appear to be the best agents available for this group of patients. The exciting findings seen with CTLA4 and PD-1/PD-L1 antibodies in melanoma and other solid tumors is exciting, especially because there is a growing body of evidence that such approaches have biologic rationale; clinical trials evaluating these agents are awaited with interest. Last, recent work has shed light on older agents that may have a role in GIST. Moving forward to test these agents alone or in combination with TKIs offers potentially new strategies for treating advanced disease.

Focal cranial hyperostosis from meningioma: a complication from previous radiation treatment for childhood T-cell acute lymphoblastic leukemia.

Nearly 75% of childhood cancer survivors will experience an adverse late effect from previous therapy. In patients previously treated with cranial irradiation, the late effect can manifest as secondary central nervous system tumors. Presented is a case of a 20 year man with a history of T-cell lymphoblastic leukemia diagnosed at age 22 months, treated with chemotherapy and cranial irradiation. He had developed increasing prominence of the top of his head over several months. Plain radiograph showed frontal calvarium thickening with focal "hair-on-end" periosteal reaction. Magnetic resonance imaging revealed an enhancing dural-based mass with transcalvarial extension, confirmed after resection to be meningioma (World Health Organization Grade I). This case illustrates an atypical presentation of a late effect of childhood cancer treatment and highlights the need to be informed about prior treatments received and potential attendant complications.

Impact of post-transplant cyclophosphamide and splenomegaly on primary graft failure and multi-lineage cytopenia after allogeneic hematopoietic cell transplantation.

Primary graft failure (PGF) and multi-lineage cytopenia (MLC) increase the risk of nonrelapse mortality in allogeneic hematopoietic cell transplants (HCT). We evaluated the impact of post-transplant cyclophosphamide (PTCy) and splenomegaly on PGF and MLC for hematological malignancies. This study included patients with PTCy (N=84) and conventional graft-vs.-host disease prophylaxis (N=199). The occurrence of splenomegaly varied widely, ranging from 17.1 % (acute myeloid leukemia) to 66.7 % (myeloproliferative neoplasms). Ten patients (N=8 in the PTCy and N=2 in the non- PTCy) developed PGF, and 44 patients developed MLC (both N=22). PTCy and severe splenomegaly (≥20 cm) were risk factors for PGF (odds ratio (OR): 10.40, p<0.01 and 6.74, p=0.01 respectively). Moreover, severe splenomegaly was a risk factor for PGF in PTCy patients (OR: 10.20, p=0.01). PTCy (hazard ratio (HR) 2.09, p=0.02), moderate (≥15, <20 cm, HR 4.36, p<0.01), and severe splenomegaly (HR 3.04, p=0.01) were independent risk factors for MLC. However, in subgroup analysis in PTCy patients, only mild splenomegaly (≥12, <15 cm, HR 4.62, p=0.01) was a risk factor for MLC. We recommend all patients be screened for splenomegaly before HCT, and PTCy is cautioned in those with splenomegaly.

CD26lowPD-1+ CD8 T cells are terminally exhausted and associated with leukemia progression in acute myeloid leukemia.

Acute myeloid leukemia (AML) is a devastating blood cancer with poor prognosis. Novel effective treatment is an urgent unmet need. Immunotherapy targeting T cell exhaustion by blocking inhibitory pathways, such as PD-1, is promising in cancer treatment. However, results from clinical studies applying PD-1 blockade to AML patients are largely disappointing. AML is highly heterogeneous. Identification of additional immune regulatory pathways and defining predictive biomarkers for treatment response are crucial to optimize the strategy. CD26 is a marker of T cell activation and involved in multiple immune processes. Here, we performed comprehensive phenotypic and functional analyses on the blood samples collected from AML patients and discovered that CD26lowPD-1+ CD8 T cells were associated with AML progression. Specifically, the percentage of this cell fraction was significantly higher in patients with newly diagnosed AML compared to that in patients achieved completed remission or healthy controls. Our subsequent studies on CD26lowPD-1+ CD8 T cells from AML patients at initial diagnosis demonstrated that this cell population highly expressed inhibitory receptors and displayed impaired cytokine production, indicating an exhaustion status. Importantly, CD26lowPD-1+ CD8 T cells carried features of terminal exhaustion, manifested by higher frequency of TEMRA differentiation, increased expression of transcription factors that are observed in terminally exhausted T cells, and high level of intracellular expression of granzyme B and perforin. Our findings suggest a prognostic and predictive value of CD26 in AML, providing pivotal information to optimize the immunotherapy for this devastating cancer.

Mast cell leukemia with novel BRAF variant and concomitant atypical KIT variant.

Mast cell leukemia (MCL) is a leukemic variant of systemic mastocytosis defined by mast cells ≥ 20% of marrow nucleated cells. Its incidence is < 1% of all systemic mastocytosis cases [1]. Clinical characteristics and treatment of the disease are not well established and overall prognosis is very poor. We report a case of de novo mast cell leukemia with novel BRAF variant, concomitant KIT exon 9 missense mutation and complex cytogenetic abnormalities. After careful review of the literature we have not found any prior reports of concomitant BRAF and KIT variants, and complex cytogenetic abnormalities in MCL. This case provides evidence that MCL can have wide spectrum of genetic abnormalities as well as accumulation of mutations in various genes including BRAF. This finding may have significant implications for the understanding of pathogenesis, diagnosis, as well as targeted therapy of MCL.

A population-based assessment of blood lead levels in relation to inflammation.

BACKGROUND: Some experimental and observational research suggests that inflammation may be an important mediator of lead toxicity. However, lead-induced inflammation has not been well-studied in non-occupationally exposed populations. METHODS: Using data for 9,145 individuals >or=40 years of age from the National Health and Nutrition Examination Survey 1999-2004, we assessed the association between blood lead levels (BLLs) and C-reactive protein (CRP), fibrinogen, and white blood cell (WBC) count via ordinal logistic regression. We also examined the interaction between BLL and gender in relation to the inflammatory markers. RESULTS: No evidence for an association between lead exposure and inflammatory markers was observed with odds ratios around or below the null. Although men but not women appeared to be at increased risk of lead-induced inflammation, no consistent dose-response patterns were observed across BLL quintiles. CONCLUSION: Inflammation does not appear to be an important mediator of lead toxicity.

Cranberry supplementation as a cause of major intraoperative bleeding during vascular surgery due to aspirin-like platelet inhibition.

We report severe excessive bleeding at initiation of vascular surgery in a 74-year-old woman with thoracoabdominal aortic aneurysm undergoing thoracic endovascular aortic repair. After extensive workup, bleeding cause was determined to be an aspirin-like effect from supplemental cranberry intake. After asking the patient to stop cranberry consumption, the aspirin-like effect ceased, and the patient underwent successful thoracic endovascular aortic repair. Cranberry consumption may create an aspirin-like effect that increases risk of bleeding. Providers should be aware of potential adverse effects of cranberries on platelet function and consider inquiring about supplement use in the perioperative period.

Long-term outcomes in the treatment of acquired hemophilia A: a 16-year single institution prospective cohort experience.

: Acquired hemophilia A (AHA) is a rare bleeding disorder caused by autoantibodies against coagulation factor VIII. We conducted a single institution prospective cohort study to assess treatment strategies and long-term outcomes in AHA patients and provide further evidence for effective treatment and relapse timing. A total of 25 patients diagnosed with AHA between 2001 and 2017 at Penn State Hershey Medical Center were prospectively followed. Information was collected on factor VIII activity and inhibitor titer at diagnosis, treatment regimen(s), complete remission, and relapse time. For immunosuppressive therapy (IST), 19 patients were treated initially with prednisone and cyclophosphamide, four were treated with prednisone, one with prednisone and rituximab, and one with prednisone and second-line rituximab. 13/17 (76%) evaluable patients treated with prednisone and cyclophosphamide achieved complete remission. Four patients received rituximab as second-line therapy (inhibitor titers 34, 122, 416, and 768 BU); three achieved complete remission and one died from sepsis. Both evaluable patients receiving initial prednisone alone achieved complete remission. Five relapses occurred from 17 days to 7 years; all were treated with prednisone and cyclophosphamide and achieved complete remission. IST with prednisone and cyclophosphamide is highly effective in achieving and maintaining complete remission, even for relapsed patients. Despite dual IST with prednisone and cyclophosphamide, some patients, particularly with extremely high inhibitor titers, required addition of second-line rituximab to achieve complete remission. This supports rituximab as effective salvage treatment, including for patients with inhibitor titers at least 100-200 BU. Those who experienced relapse often did so years after complete remission, signifying importance of continued monitoring and vigilance.

Management of Neuraxial Analgesia in a Parturient with Factor XIII Deficiency: A Case Report and Proposed Management Algorithm.

Factor XIII (FXIII) deficiency is a rare coagulation defect that can be associated with significant bleeding. A 28-year-old pregnant woman, with a history of hemorrhagic stroke secondary to severe congenital FXIII deficiency, presented in active labor requesting an epidural. Factor XIII levels had been monitored throughout her pregnancy and treated with intermittent factor XIII infusions to maintain factor levels above 30% of normal. After careful multidisciplinary peripartum evaluation and FXIII replacement, neuraxial analgesia was performed without complication. Neuraxial analgesia can be performed without complication in patients with FXIII deficiency if FXIII levels are carefully managed and no other coagulopathy exists.