Evaluating the use of plerixafor in stem cell mobilisation – an economic analysis of the PHANTASTIC trial

Plerixafor is an effective haematopoietic stem cell mobilising agent in candidates for autologous transplantation, including patients with myeloma and lymphoma. Here we compare 98 plerixafor recipients in the PHANTASTIC trial with 151 historic controls mobilised by conventional chemotherapy (each with granulocyte colony‐stimulating factor, G‐CSF). Seventy (71.4%) plerixafor‐mobilised patients achieved the composite primary endpoint of ≥4 × 10⁶ CD34+ cells kg^?1 in ≤2 aphereses and no clinically significant neutropenia, compared to 48 (31.8%) historic controls (P < 0.001), and this significant advantage was maintained in scenario analyses testing components of this composite endpoint. A patient‐level cost analysis was undertaken for 249 patients, which included the cost of remobilising patients where initial mobilisation had failed. Combined mean treatment cost for plerixafor mobilised patients was £12,679 compared with £11,694 for historical controls. However, plerixafor produces an average saving of £3,828 per lymphoma patient but average cost increase by £5,245 per myeloma patient. The present data demonstrate cost‐effectiveness for plerixafor as a first line mobilisation agent, certainly for lymphoma patients, where substantial resource savings and achievement of the primary endpoint are likely. J. Clin. Apheresis 31:434–442, 2016. © 2015 Wiley Periodicals, Inc.     

Celiac disease diagnosed in the elderly

BACKGROUND AND AIMS: In the past 20 years, a growing proportion of new cases of celiac disease (CD) are diagnosed in adults and in patients with extraintestinal manifestations. Our understanding of the extremely wide spectra of manifestations and the profound effects on elderly patients is improving. Nevertheless, CD is still underdiagnosed in elderly patients. In this study, we describe a case series of CD patients diagnosed after the age of 60. METHODS: A retrospective chart review was preformed in cases of CD diagnosed after the age of 60. Patients were included if they had positive serology and histologic findings compatible with CD. Eligible patients were reinterviewed, and demographic, clinical, and laboratory information were recorded. RESULTS: During the study period, 7 patients with CD diagnosed after the age of 60 were identified. The most common presenting findings were weight loss, iron deficiency anemia, and diarrhea. Two patients suffered from severe early osteoperosis and 2 additional patients had elevated liver function tests. Neurologic manifestation was suspected in 3 cases. Two female patients presented with cognitive decline that was attributed to Alzheimer dementia but ameliorated after the initiation of gluten-free diet. The third patient had peripheral neuropathy that completely resolved after the initiation of gluten-free diet. Median lag in diagnosis was 8 years. Diet treatment led to complete resolution of symptoms in most cases and a significant weight gain (median 7.75 kg, range 5 to 11). One patient developed a fatal intestinal T-cell lymphoma. CONCLUSIONS: In this case series, we have described several cases of CD in patients over the age of 60 with a varied spectrum of manifestations. We have also found a significant lag in diagnosis and treatment. We believe that it is important to promote the identification of CD as a possible culprit in varied clinical conditions in the elderly population.     

Chronic beta-adrenoceptor blockade and human atrial cell electrophysiology: evidence of pharmacological remodelling

OBJECTIVE: Chronic beta-adrenoceptor antagonist (beta-blocker) treatment reduces the incidence of reversion to AF in patients, possibly via an adaptive myocardial response. However, the underlying electrophysiological mechanisms are presently unclear. We aimed to investigate electrophysiological changes in human atrial cells associated with chronic treatment with beta-blockers and other cardiovascular-acting drugs. METHODS: Myocytes were isolated enzymatically from the right atrial appendage of 40 consenting patients who were in sinus rhythm. The cellular action potential duration (APD), effective refractory period (ERP), L-type Ca(2+) current (I(CaL)), transient (I(TO)) and sustained (I(KSUS)) outward K(+) currents, and input resistance (R(i)) were recorded using the whole cell patch clamp. Drug treatments and clinical characteristics were compared with electrophysiological measurements using simple and multiple regression analyses. P<0.05 was taken as statistically significant. RESULTS: In atrial cells from patients treated chronically with beta-blockers, the APD(90) and ERP (75 beats/min stimulation) were significantly longer, at 213+/-11 and 233+/-11 ms, respectively (n=15 patients), than in cells from non-beta-blocked patients, at 176+/-12 and 184+/-12 ms (n=11). These cells also displayed a significantly reduced action potential phase 1 velocity (22+/-3 vs. 34+/-3 V/s). Chronic beta-blockade was also associated with a significant reduction in the heart rate (58+/-3 vs. 69+/-5 beats/min) and in the density of I(TO) (8.7+/-1.3 vs. 13.7+/-2.1 pA/pF), an increase in the R(i) (214+/-24 vs. 132+/-14 MOmega), but no significant change in I(CaL) or I(KSUS). The I(TO) blocker 4-aminopyridine largely mimicked the changes in phase 1 and ERP associated with chronic beta-blockade, in cells from non-beta-blocked patients. Chronic treatment of patients with calcium channel blockers or angiotensin converting enzyme inhibitors (n=11-13 patients) was not associated with any significant changes in atrial cell electrophysiology. CONCLUSION: The observed atrial cellular electrophysiological changes associated with chronic beta-blockade are consistent with a long-term adaptive response, a type of 'pharmacological remodelling', and provide mechanistic evidence supportive of the anti-arrhythmic actions of beta-blockade.     

Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells

Central memory CD8+ T cells (T(CM)) and effector memory CD8+ T cells (T(EM)) are found in humans and mice; however, their relative contributions to host immunity have only recently been examined in vivo. Further, the ability of T(CM) to treat an established tumor or infection has yet to be evaluated. To address the therapeutic potential of different tumor-reactive CD8+ T cell memory subsets, we used an established model for the in vitro generation of T(CM) and T(EM) by using IL-15 and IL-2, respectively. Adoptively transferred T(CM) exhibited a potent in vivo recall response when combined with tumor-antigen vaccination and exogenous IL-2, leading to the eradication of large established tumors. By contrast, T(EM) were far less effective on a per-cell basis. Microarray analysis revealed that the signature of highly in vivo effective antitumor T cells included the overexpression of genes responsible for trafficking to secondary lymphoid tissues. This gene expression profile correctly predicted the in vitro and in vivo lymphoid-homing attributes of tumor-reactive T cells. Furthermore, we found that homing to secondary lymphoid tissue is required for optimal tumor treatment. Our findings indicated that highly in vivo effective antitumor T cells were those that initially targeted secondary lymphoid tissue, rather than tumor sites, as had previously been postulated. Thus, tumor-reactive CD8+ T cell populations with the phenotypic and functional attributes of T(CM) may be superior to T(EM)/effector T cells for adoptive immunotherapies using concomitant tumor-antigen vaccination.     

Coronary artery stenting for acute closure complicating primary angioplasty for acute myocardial infarction

We report a case of progressive right coronary artery dissection complicating direct angioplasty for an acute inferior myocardial infarct, with successful bail-out stenting of the affected vessel.