Stem cell transplantation in patients with severe congenital neutropenia without evidence of leukemic transformation

Severe congenital neutropenia (CN) (Kostmann syndrome) is a hematologic disorder characterized by a maturation arrest of myelopoiesis at the promyelocyte/myelocyte stage of development. This arrest results in severe neutropenia leading to absolute neutrophil counts (ANC) below 0.2 x 10(9)/L associated with severe bacterial infections from early infancy. Data on over 300 patients with CN collected by the Severe Chronic Neutropenia International Registry (SCNIR) beginning in 1994 indicate that more than 90% of these patients respond to recombinant human granulocyte-colony stimulating factor (r-HuG-CSF) treatment with an ANC greater than 1. 0 x 10(9)/L. For patients who are refractory to r-HuG-CSF treatment and continue to have severe and often life-threatening bacterial infections, hematopoietic stem cell transplantation is the only currently available treatment. We report on a total of 11 patients with CN reported to the SCNIR who underwent transplantation for reasons other than malignant transformation between 1976 and 1998. Of these patients, 8 were nonresponders or showed only partial response to r-HuG-CSF treatment with ongoing infections. Results from these patients suggest that transplantation of stem cells from an HLA-identical sibling is beneficial for patients refractory to r-HuG-CSF. (Blood. 2000;95:1195-1198)     

A comparison of granulopoiesis in culture from blood and marrow cells of nonleukemic individuals and patients with acute leukemia.

The objective of this study was to compare the concentration of committed granulopoietic progenitor cells (CFU-C) in marrow and blood. For individuals without leukemia, a highly significant correlation was observed between the concentration of CFU-C obtained from the two sites. However, CFU-C in blood had a slower sedimentation velocity than that reported for marrow and were found not to be in the DNA synthetic phase of the cycle using the tritiated thymidine suicide tehcnique. In patients with acute leukemia, no correlation was observed between concentrations of CFU-C in marrow and peripheral blood, regardless of whether the patients were newly diagnosed, in remission, or in relapse. We concluded that studies of the peripheral blood do not yield the same information in respect to granulopoietic progenitor cells as do studies of the marrow.     

Spontaneously acquired fistula from the right coronary artery to the right ventricular cavity.

A 47 year old man developed a fistula from the right ventricular branch of the right coronary artery to the right ventricular cavity in association with distal occlusion of the main trunk of the right coronary artery. There was no clinical or electrocardiographic evidence of acute myocardial infarction.     

Quality control of multidrug resistance assays in adult acute leukemia: correlation between assays for P-glycoprotein expression and activity

We have compared multiple assays for the P-glycoprotein (Pgp/MDR1) phenotype in fresh and thawed adult acute leukemia to validate and quantitate measures for the expression and function of Pgp. The results are related to the Pgp-expressing KB8 and KB8-5 call lines. The most sensitive assay was the measurement of modulation of the rhodamine 123 (R123) fluorescence by 2 micromol/L PSC833, followed by the modulation of the probe calcein-AM. We also found a good intralaboratory and interlaboratory correlation between the values of the R123/PSC833 assay for fresh as well as thawed samples. In addition, the affects of PSC833 on 3H-daunorubicin (DNR) accumulation, DNR fluorescence, and 3H- vincristine accumulation were very similar. The correlation between the DNR/PSC833 and R123/PSC833 test was r = .86 (N = 51). The modulation of drug accumulation by 8 micromol/L verapamil was the some as the PSC833 effect for DNR (117%, N = 21), but was higher for vincristine in every single case (161% v 121%, N = 22; P< .001), indicating additional verapamil effects, not related to Pgp. The correlation of the staining of viable cells for Pgp with the monoclonal antibody MRK16 was r = .77 (N = 52) for the R123/PSC833 functional test and r = .84 (N = 50) for the DNR/PSC833 test. From these results it could be calculated that a maximal increase of the mean DNR accumulation of about 50% can be achieved by blocking Pgp pump activity with PSC833 in leukemic blast samples with the highest mean Pgp expression. Subpopulations of blast calls with higher Pgp activity are likely to be present. Their relevance has to be studied further. The methods outlined here allow the reliable, quantitative monitoring of the Pgp/MDR1 phenotype in leukemias in multicentered, clinical Pgp modulation studies.     

Pembrolizumab with R-CHOP in previously untreated diffuse large B-cell lymphoma: potential for biomarker driven therapy

Tumor programmed death-ligand 1 (PD-L1) expression in diffuse large B-cell lymphoma (DLBCL) is associated with inferior outcomes. The first-line immunologically-replete setting may be an opportune time for PD-1 inhibition. We evaluated pembrolizumab in combination with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in untreated patients with DLBCL. Eligible patients were age 18 or older, had adequate organ function, and had DLBCL requiring full-course therapy. Patients received pembrolizumab 200 mg/cycle with R-CHOP, primarily to assess toxicity. Response assessment utilized standard criteria, and PD-L1 staining was performed at a validated central laboratory. Among 30 patients, toxicity was comparable to standard R-CHOP but with two grade ≥3 immune related adverse events (rash, pneumonitis). The overall and complete response rate was 90% and 77%. With 25·5 months of median follow-up, 2-year progression-free survival (PFS) is 83%. PD-L1 expression was associated with non-GCB subtype, and improved PFS and survival. Pembrolizumab can safely be added to R-CHOP, and is associated with a high CR rate and 2-year PFS. Improved PFS with PR-CHOP in PD-L1 expressing tumors contradicts historical data in R-CHOP treated patients, supporting evaluation of PD-L1 as a biomarker to identify DLBCL patients who may benefit from this first-line strategy.     

Autologous retro-pubic urethral sling: a novel,quick, intra-operative technique to improve continence after robotic-assisted radical prostatectomy

After radical prostatectomy, many men may suffer from urinary incontinence, which can have detrimental effects on quality of life. We describe a novel technique using an autologous retro-pubic urethral sling placed at the time of robotic-assisted laparoscopic prostatectomy (RALP) and evaluate its impact on post-operative urinary continence. During 2011, 153 men who underwent sling placement at the time of RALP at a high-volume academic institution were compared to 78 men who did not undergo sling placement. The primary outcomes were time to one and no pads per day. The association between these outcomes and placement of a sling was assessed using Cox proportional hazards regression. Median follow-up was 26 weeks in those who had slings and 32.5 weeks in those who did not. Clinical and pathological characteristics were similar between the groups, with the exception that sling patients were older (p < 0.01) and underwent less nerve sparing (p < 0.01). Multivariate analysis showed that sling placement did not appear to have an effect on time to one (p = 0.24) or no pads per day (p = 0.20). Although the association between sling placement and early return of urinary continence did not reach statistical significance, there was a selection bias against the sling, since it was placed in men who were expected to have more difficulty regaining their continence. A randomized trial is needed to assess the true benefit of sling placement on urinary continence.     

ACEP Guidelines on Acute Nontraumatic Headache Diagnosis and Management in the Emergency Department,Commentary on Behalf of the Refractory,Inpatient, Emergency Care Section of the American Headache Society

The American College of Emergency Physicians (ACEP) published guidelines in July 2019 on the diagnosis and management of acute nontraumatic headaches in the emergency department, focusing predominantly on the diagnosis of subarachnoid hemorrhage and the role of imaging and lumbar puncture in diagnosis. The ACEP Clinical Policies document is intended to aide Emergency Physicians in their approach to patients presenting with acute headache and to improve the accuracy of diagnosis, while promoting safe patient care practices. The Clinical Policies document also highlights the need for future research into best practices to distinguish primary from secondary headaches and the efficacy and safety of current treatment options for acute headaches. The following commentary on these guidelines is intended to support and expand on these guidelines from the Headache specialists’ perspective, written on behalf of the Refractory, Inpatient, Emergency Care section of the American Headache Society (AHS). The commentary have been reviewed and approved by Board of Directors of the AHS.