Expert consensus guidelines: Intravenous iron uses, formulations, administration, and management of reactions.

Intravenous iron has become an essential component for the treatment of iron deficiency and iron deficiency anemia. Individuals administering Intravenous iron should have knowledge in intravenous iron administration, including a pre-infusion assessment to evaluate infusion reaction risks, pre- and post-infusion monitoring, identification of and management of infusion reactions, accurate documentation of these reactions, laboratory monitoring and recognition and management of treatment-emergent hypophosphatemia. This comprehensive consensus provides step-by-step guidance and tools for practitioners to promote safe delivery of intravenous iron, recognition, and management of infusion reactions and treatment-emergent hypophosphatemia.

Trainees' perspectives on sickle cell education: a qualitative needs assessment.

BACKGROUND: Sickle cell disease (SCD) exemplifies many of the social, racial, and healthcare equity issues in the United States. Despite its high morbidity, mortality, and cost of care, SCD has not been prioritized in research and clinical teaching, resulting in under-trained clinicians and a poor evidence base for managing complications of the disease. This study aimed to perform a needs assessment, examining the perspectives of medical trainees pursuing hematology/oncology subspecialty training regarding SCD-focused education and clinical care. METHOD: Inductive, iterative thematic analysis was used to explore qualitative interviews of subspecialty hematology-oncology trainees' attitudes and preferences for education on the management of patients with SCD. Fifteen trainees from six programs in the United States participated in 4 focus groups between April and May 2023. RESULTS: Thematic analysis resulted in 3 themes: 1. Discomfort caring for patients with SCD. 2. Challenges managing complications of SCD, and 3. Desire for SCD specific education. Patient care challenges included the complexity of managing SCD complications, limited evidence to guide practice, and healthcare bias. Skill-building challenges included lack of longitudinal exposure, access to expert clinicians, and didactics. CONCLUSIONS: Variations in exposure, limited formal didactics, and a lack of national standardization for SCD education during training contributes to trainees' discomfort and challenges in managing SCD, which in turn, contribute to decreased interest in entering the SCD workforce. The findings underscore the need for ACGME competency amendments, dedicated SCD rotations, and standardized didactics to address the gaps in SCD education.

Lipid Receptor GPR31 (G-Protein-Coupled Receptor 31) Regulates Platelet Reactivity and Thrombosis Without Affecting Hemostasis.

OBJECTIVE: 12-LOX (12-lipoxygenase) produces a number of bioactive lipids including 12(S)-HETE that are involved in inflammation and platelet reactivity. The GPR31 (G-protein-coupled receptor 31) is the proposed receptor of 12(S)-HETE; however, it is not known whether the 12(S)-HETE-GPR31 signaling axis serves to enhance or inhibit platelet activity. Approach and Results: Using pepducin technology and biochemical approaches, we provide evidence that 12(S)-HETE-GPR31 signals through Gi to enhance PAR (protease-activated receptor)-4-mediated platelet activation and arterial thrombosis using both human platelets and mouse carotid artery injury models. 12(S)-HETE suppressed AC (adenylyl cyclase) activity through GPR31 and resulted in Rap1 (Ras-related protein 1) and p38 activation and low but detectable calcium flux but did not induce platelet aggregation. A GPR31 third intracellular (i3) loop-derived pepducin, GPR310 (G-protein-coupled receptor 310), significantly inhibited platelet aggregation in response to thrombin, collagen, and PAR4 agonist, AYPGKF, in human and mouse platelets but relative sparing of PAR1 agonist SFLLRN in human platelets. GPR310 treatment gave a highly significant 80% protection (P=0.0018) against ferric chloride-induced carotid artery injury in mice by extending occlusion time, without any effect on tail bleeding. PAR4-mediated dense granule secretion and calcium flux were both attenuated by GPR310. Consistent with these results, GPR310 inhibited 12(S)-HETE-mediated and PAR4-mediated Rap1-GTP and RASA3 translocation to the plasma membrane and attenuated PAR4-Akt and ERK activation. GPR310 caused a right shift in thrombin-mediated human platelet aggregation, comparable to the effects of inhibition of the Gi-coupled P2Y12 receptor. Co-immunoprecipitation studies revealed that GPR31 and PAR4 form a heterodimeric complex in recombinant systems. CONCLUSIONS: The 12-LOX product 12(S)-HETE stimulates GPR31-Gi-signaling pathways, which enhance thrombin-PAR4 platelet activation and arterial thrombosis in human platelets and mouse models. Suppression of this bioactive lipid pathway, as exemplified by a GPR31 pepducin antagonist, may provide beneficial protective effects against platelet aggregation and arterial thrombosis with minimal effect on hemostasis.

Endovascular Management of Venous Thromboembolic Disease in the Oncologic Patient Population.

PURPOSE OF REVIEW: Venous thromboembolic disease causes significant mortality and morbidity in the oncologic patient population. Recently, minimally invasive endovascular technologies have been developed as an adjunct to antithrombotic therapy for the management of DVT and PE. The current and potential roles for endovascular treatment of cancer-associated venous thromboembolism (VTE) will be reviewed in this article. RECENT FINDINGS: The recent NCCN guidelines recommend endovascular therapy in patients eligible for therapeutic anticoagulation who present with life-, organ-, or limb-threatening thrombosis. However, symptomatic non-life-threatening VTE can negatively affect QOL and physical function, both of which have prognostic implications in the cancer population. Endovascular therapies have been shown to improve physical function and QOL in prospective trials performed in a non-oncologic patient population as well as small retrospective studies in the cancer population. In addition to treating life- and limb-threatening thrombosis, endovascular therapy for VTE can improve QOL and physical function in comparison to anticoagulation alone. Prospective trials are warranted to assess the benefit of endovascular therapy for quality of life-years, performance status, and overall survival in the oncologic patient population.

Acute and chronic pain management in patients with sickle cell disease in the modern era: a comprehensive review.

Sickle cell disease (SCD) is the most common inherited red blood cell (RBC) disorder worldwide, resulting in chronic hemolytic anemia, vaso-occlusion, tissue hypoxia, and ultimately end organ damage. The hallmark of the disease is manifested by vaso-occlusive crisis (VOC) resulting in acute on chronic pain, and the most common cause for presentation to the emergency department and hospital admission. The management of pain for patients with SCD in the U.S. has historically been socially and politically complex with most patients experiencing pain on a daily basis but not seeking immediate medical attention. The pathophysiology of acute and chronic pain in SCD is multifactorial and complex. Here, we describe factors contributing to acute and chronic pain in SCD and management strategies.

Nonchemotherapy Treatment of Immunoglobulin Light Chain Amyloidosis.

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare, life-threatening disease characterized by the deposition of misfolded proteins in vital organs such as the heart, the lungs, the kidneys, the peripheral nervous system, and the gastrointestinal tract. This causes a direct toxic effect, eventually leading to organ failure. The underlying B-cell lymphoproliferative disorder is almost always a clonal plasma cell disorder, most often a small plasma cell clone of <10%. Current therapy is directed toward elimination of the plasma cell clone with the goal of preventing further organ damage and reversal of the existing organ damage. Autologous stem cell transplantation has been shown to be a very effective treatment in patients with AL amyloidosis, although it cannot be widely applied as patients are often frail at presentation, making them ineligible for transplantation. Treatment with cyclophosphamide, bortezomib, and dexamethasone has emerged as the standard of care for the treatment of AL amyloidosis. Novel anti-plasma cell therapies, such as second generation proteasome inhibitors, immunomodulators, monoclonal antibodies targeting a surface protein on the plasma cell (daratumumab, elotuzumab), and the small molecular inhibitor venetoclax, have continued to emerge and are being evaluated in combination with the standard of care. However, there is still a need for therapies that directly target the amyloid fibrils and reverse organ damage. In this review, we will discuss current and emerging nonchemotherapy treatments of AL amyloidosis, including antifibril directed therapies under current investigation.

IV iron formulations and use in adults.

Intravenous iron has become a major component of the therapeutic armamentarium for iron deficiency and iron deficiency anemia. The earliest formulations were associated with unacceptable toxicity. Newer formulations, with complex carbohydrate cores that bind elemental iron more tightly, allow the administration of full therapeutic doses in 15 to 60 minutes. Nonetheless, a folklore of danger, fueled by earlier formulations no longer available, continues to foment caution. Complement-mediated minor infusion reactions, referred to as complement activation-related pseudo-allergy, resolve without therapy. Inappropriate intervention with vasopressors and H1 blockers converts these minor reactions into hemodynamically significant adverse events. Four new formulations, low-molecular-weight iron dextran, ferumoxytol, ferric carboxymaltose, and ferric derisomaltose, all approved for the treatment of iron deficiency in a host of conditions, are now widely used with an excellent safety profile. Herein, the administration, safety, indications, and management of infusion reactions are discussed. Treatment-emergent hypophosphatemia, a newly recognized side effect for some formulations, is also reviewed. Based on the preponderance of published evidence, intravenous iron should be moved up-front for the treatment of iron deficiency and iron deficiency anemia in those conditions in which oral iron is suboptimal.

First Case of Topical 5-FU Therapy for Cutaneous Metastasis in a Patient with Colon Cancer.

Cutaneous metastasis from colon cancer is rare, occurs in less than 6% of patients and its associated with poor prognosis. Most often it presents in the abdomen, inguinal or perineal regions, supraclavicular area, and less commonly on the face, neck, scalp, and prior surgical sites. We present a case of a 41-year-old female with colon cancer who developed cutaneous metastases to the scalp, and was treated with topical 5-FU and radiation therapy. Treatment options for cutaneous metastases usually include systemic therapy, topical chemotherapy, surgical excision, or radiation. Our case is probably the first report who was treated with topical 5-FU in addition to radiation therapy. This treatment modality is easy to use and we would recommend clinical trials to be conducted to further study the use of topical 5-FU.

Gastrointestinal Stromal Tumors Incidentalomas: A Case Series.

BACKGROUND: Gastrointestinal stromal tumors (GISTs) represent approximately 0.2% of all gastrointestinal tumors. GISTs can occur anywhere along the length of the gastrointestinal tract. Most common clinical manifestations of GISTs include GI bleeding, abdominal discomfort, distention and pain. Small lesions can be found incidentally during imaging studies, endoscopy, surgery and post-mortem. The progression of disease from incidentally found indolent to symptomatic disease is unknown. CASE SERIES: Here we describe a series of cases of incidentally found GIST and their management. The first patient was a 38-years old morbid obese female with an incidentally found GIST in the stomach following an elective laparoscopic vertical sleeve gastrectomy. The second patient was a 69-year-old male who underwent elective sleeve gastrectomy for his obesity and associated refractory acid reflux. On pathologic examination of the gastrectomy specimen, GIST was diagnosed in the gastric fundus. DISCUSSION: Coexistence of GIST with other malignancies is higher than previously reported and should draw attention of clinicians towards these incidental findings. Prognosis in these patients is usually determined by other malignancy and not significantly influenced by GIST. Therefore, treatment algorithms should be focused on prognostically relevant malignancy.

Enhanced potency of prasugrel on protease-activated receptors following bivalirudin treatment for PCI as compared to clopidogrel.

ACS patients undergoing percutaneous coronary intervention (PCI) when treated with bivalirudin and clopidogrel had increased frequency of early stent thrombosis. 24 patients referred for intervention with planned bivalirudin therapy, not previously treated with a P2Y12 inhibitor and not receiving heparins or αIIbß3 inhibitors were randomized to treatment with either clopidogrel (600 mg) or prasugrel (60 mg). Platelet aggregation (PA) was measured by light transmission aggregometry (LTA) of platelet-rich plasma in response to ADP, PAR1/PAR4 thrombin receptor agonists and collagen at baseline and at 1, 2, 4 and 16 h following the cessation of bivalirudin infusion. Prasugrel-mediated inhibition of PA was significantly greater than that of clopidogrel at all time points for ADP as well as PAR1. There was an unanticipated, significantly greater protection of PAR4-mediated platelet aggregation only detected with prasugrel and not observed with clopidogrel. We further examined the effect of the hyperreactive PAR4 Thr120 variant in the protease-activated receptor 4 (PAR4), single nucleotide polymorphism (SNP) rs773902 on aggregation protection. The PAR4 protective effect with prasugrel was lost in individuals carrying the PAR4 Thr120 variant, and not in Ala120 homozygote. PAR1, ADP and collagen inhibition was not significantly affected in the hyperreactive PAR4 Thr120 variant. We documented that the P2Y12 ADP receptor-mediated regulation of the strength of the high-affinity conformation of αIIbß3 as detected by PAC-1 ab, and in control of platelet adhesiveness through Rap1 GTPase protein activation. Importantly, the PAR4 Thr120 variant resulted in the increased rate and magnitude of Rap1 activation. Human platelet PAR4 mediated-activation of αIIbß3 was phospholipase C beta (PLCß)-dependent and unlike mouse platelet PI3K-independent. These data identify a PAR4-dependent inhibitory mechanism for the prasugrel-mediated platelet inhibition, not seen with clopidogrel that could explain the reduction in stent thrombosis documented in clinical trials with prasugrel.