The role of allogeneic hematopoietic cell transplantation for chronic lymphocytic leukemia: A review

Although the use of allogeneic hematopoietic cell transplantation (HCT) for chronic lymphocytic leukemia (CLL) has declined with the development of novel targeted agents, it continues to play an important role for eligible patients with high-risk or heavily pretreated CLL who lack other treatment options. CLL is susceptible to a potent graft-versus-leukemia (GVL) effect which produces long-lasting remissions in 30-50% of transplanted patients. While allogeneic HCT is associated with significant risks of graft-versus-host disease (GVHD), infection, and non-relapse mortality (NRM), improvements in patient and donor selection, reduced intensity conditioning (RIC), GVHD prophylaxis, and supportive care have rendered this an increasingly safe and effective procedure in the current era. In this review, we discuss recent advances in allogeneic HCT for CLL, with a focus on the optimal evidence-based strategies to maximize benefit and minimize toxicity of this potentially curative cellular therapy

Utility of tris(4-bromopyridyl) europium complexes as versatile intermediates in the divergent synthesis of emissive chiral probes

The synthetic utility of europium complexes with three coordinated 4-bromopyridyl groups for chromophore elaboration has been assessed in palladium-catalysed Sonogashira coupling reactions, and in copper(I) mediated click reactions of the triazide derivative, generated in situ. The crystal structure of the Eu complex of a p-OMe-phenyl substituted triazole at 100 K is reported in which the pendant triazole sensitising moieties interdigitate in the solid-state lattice. The triazole complex can be separated into Δ and Λ enantiomers by chiral HPLC but is weakly emissive in methanol (ε 5.5 mM−1 cm−1; λexc 320 nm; ϕ 0.2%), contrasting with a set of four alkynyl–aryl derivatives which are one thousand times brighter and absorb strongly with broad absorption maxima in the range 332 to 360 nm. An enantiopure europium complex gives an intense CPL signal in solution that is the strongest yet reported

Support infrastructure available to Canadian residents completing post-graduate global health electives: current state and future directions

Background: Global health electives offer medical trainees the opportunity to broaden their clinical horizons. Canadian universities have been encouraged by regulatory bodies to offer institutional support to medical students going abroad; however, the extent to which such support is available to residents has not been extensively studied.Methods: We conducted a survey study of Canadian universities examining the institutional support available to post-graduate medical trainees before, during, and after global health electives.Results: Responses were received from 8 of 17 (47%) Canadian institutions. Results show that trainees are being sent to diverse locations around the world with more support than recommended by post-graduate regulatory bodies. However, we found that the content of the support infrastructure varies amongst universities and that certain components—pre-departure training, best practices, risk management, and post-return debriefing—could be more thoroughly addressed.Conclusion: Canadian universities are encouraged to continue to send their trainees on global health electives. To address the gaps in infrastructure reported in this study, the authors suggest the development of comprehensive standardized guidelines by post-graduate regulatory/advocacy bodies to better ensure patient and participant safety. We also encourage the centralization of infrastructure management to the universities’ global health departments to aid in resource management. 

Measurable residual disease monitoring provides insufficient lead-time to prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia

Core-binding factor acute myeloid leukemia is characterized by t(8;21) or inv(16) and the fusion proteins RUNX1-RUNX1T1 and CBFB-MYH11. International guidelines recommend monitoring for measurable residual disease every 3 months for 2 years after treatment. However, it is unknown if serial molecular monitoring can predict and prevent morphologic relapse. We conducted a retrospective single-center study of 114 patients in complete remission who underwent molecular monitoring with RT-qPCR of RUNX1-RUNX1T1 or CBFB-MYH11 transcripts every 3 months. Morphologic relapse was defined as re-emergence of >5% blasts and molecular relapse as ≥1 log increase in transcript level between 2 samples. Over a median follow-up time of 3.7 years (range 0.2-14.3), remission persisted in 71 (62.3%) patients but 43 (37.7%) developed molecular or morphologic relapse. Patients who achieved <3 log reduction in RUNX1-RUNX1T1 or CBFB-MYH11 transcripts at end of chemotherapy had a significantly higher risk of relapse compared to patients who achieved ≥3 log reduction (61.1% vs. 33.7%, p=0.004). The majority of relapses (74.4%, n=32) were not predicted by molecular monitoring and occurred rapidly with <100 days from molecular to morphologic relapse. Molecular monitoring enabled the detection of impending relapse and permitted pre-emptive intervention prior to morphologic relapse in only 11 (25.6%) patients. The current practice of molecular monitoring every 3 months provided insufficient lead-time to identify molecular relapses and prevent morphologic relapse in the majority of patients with core-binding factor acute myeloid leukemia treated at our institution. Further research is necessary to determine the optimal monitoring strategies for these patients

Staphylococcus-Associated Glomerulonephritis Mimicking Henoch-Schönlein Purpura and Cryoglobulinemic Vasculitis in a Patient With an Epidural Abscess: A Case Report and Brief Review of the Literature

Rationale: Staphylococcus-associated glomerulonephritis (SAGN) is a rare immune complex–mediated glomerulonephritis associated with active Staphylococcus infection. We report a case illustrating the importance of clinical history and kidney biopsy findings in establishing the correct diagnosis. Presenting concerns of the patient: We report the case of a 64-year-old man with alcohol-associated cirrhosis, type 2 diabetes mellitus, and hypertension who presented to hospital with lower back and abdominal pain, rectal bleeding, a purpuric lower extremity rash, and oliguric acute kidney injury with microscopic hematuria and nephrotic-range proteinuria. Diagnoses: Skin biopsy revealed IgA leukocytoclastic vasculitis. Serum cryoglobulins were positive and there was hypocomplementemia with a low C3 level. Magnetic resonance imaging of the lumbar spine revealed septic discitis and epidural abscesses caused by a recent Staphylococcus aureus bacteremia. Kidney biopsy showed IgA-dominant and C3-dominant proliferative glomerulonephritis with subepithelial humps in keeping with SAGN. Interventions: Urgent hemodialysis was initiated along with a prolonged course of intravenous cefazolin. Outcomes: Remarkably, the patient demonstrated a complete recovery of renal function after 2 months of dialysis dependence and successful treatment of the epidural abscesses. Lessons learned: This case shows that SAGN can closely mimic the clinical, laboratory, and histological presentation of Henoch-Schönlein Purpura or cryoglobulinemic vasculitis. Clinical history and kidney biopsy, particularly electron microscopic analysis, are essential to establishing the correct diagnosis to avoid the unnecessary and potentially harmful administration of immunosuppression. Despite the typically poor prognosis of SAGN, this case report illustrates that full renal recovery remains possible with supportive care and eradication of the underlying infection

Induced circularly polarized luminescence arising from anion or protein binding to racemic emissive lanthanide complexes

A circularly polarized luminescence (CPL) spectrometer has been built and used to study the binding interaction of lactate and four different proteins with racemic EuIII and TbIII complexes in aqueous solution. Lactate binding gives rise to strong induced CPL spectra, and the observed emission dissymmetry factors vary linearly with enantiomeric composition. Particularly strong induced TbIII CPL also characterizes the binding interaction of alpha-1-acid glycoprotein with a dissociation constant, Kd, of 2.5 μM

High-Dose Methotrexate as CNS Prophylaxis in High-Risk Aggressive B-Cell Lymphoma

PURPOSE CNS progression or relapse is an uncommon but devastating complication of aggressive B-cell lymphoma. There is no consensus regarding the optimal approach to CNS prophylaxis. This study was designed to determine whether high-dose methotrexate (HD-MTX) is effective at preventing CNS progression in patients at high risk of this complication. PATIENTS AND METHODS Patients age 18-80 years with aggressive B-cell lymphoma and high risk of CNS progression, treated with curative-intent anti–CD20-based chemoimmunotherapy, were included in this international, retrospective, observational study. Cause-specific hazard ratios (HRs) and cumulative risks of CNS progression were calculated according to use of HD-MTX, with time to CNS progression calculated from diagnosis for all patients (all-pts) and from completion of frontline systemic lymphoma induction therapy, for patients in complete response at completion of chemoimmunotherapy (CR-pts). RESULTS Two thousand four hundred eighteen all-pts (HD-MTX; n = 425) and 1,616 CR-pts (HD-MTX; n = 356) were included. CNS International Prognostic Index was 4-6 in 83.4% all-pts. Patients treated with HD-MTX had a lower risk of CNS progression (adjusted HR, 0.59 [95% CI, 0.38 to 0.90]; P = .014), but significance was not retained when confined to CR-pts (adjusted HR, 0.74 [95% CI, 0.42 to 1.30]; P = .29), with 5-year adjusted risk difference of 1.6% (95% CI, –1.5 to 4.4; all-pts) and 1.4% (95% CI, –1.5 to 4.1; CR-pts). Subgroups were underpowered to draw definitive conclusions regarding the efficacy of HD-MTX in individual high-risk clinical scenarios; however, there was no clear reduction in CNS progression risk with HD-MTX in any high-risk subgroup. CONCLUSION In this large study, high-risk patients receiving HD-MTX had a 7.2% 2-year risk of CNS progression, consistent with the progression risk in previously reported high-risk cohorts. Use of HD-MTX was not associated with a clinically meaningful reduction in risk of CNS progression