Predictive value of 1q21 gain in multiple myeloma is strongly dependent on concurrent cytogenetic abnormalities and first-line treatment

Improved therapies in multiple myeloma (MM) have forced a constant risk stratification update, first Durie-Salmon, then international scoring systems (ISS), next revised-ISS (RISS) including high-risk cytogenetic abnormalities (HRCAs) such as del(17p) and t(4;14), and now R2-ISS including 1q21 gain has been proposed. Predictive value of 1q21 gain by itself or in concurrence with other cytogenetic abnormalities is evaluated in 737 real-world plasma cell neoplasm (PCN) patients under current therapies. Ten-year progression-free survival (10y-PFS) rates for patients with 2, 3 and >3 copies of 1q21 were 72.2%, 42.5% and 43.4% (P<1.1×10^-17). Cox regression analysis confirmed that 1q21 gain was an independent prognostic factor for PFS (HR=1.804, P<0.0001, Harrell C-statistic =0.7779±0.01495) but not for OS (P=0.131). Gain of 1q21 was strongly associated with hypodiploidy (38.8% vs. 7.0%, P=1.3×10^-22), hyperdiploidy (44.1% vs. 16.4%, P=1.6×10^-13), HRCAs (12.6% vs. 3.5%, 1.8×10^-5), IGH breaks (12.3% vs. 2.1%, P=2.1×10^-7) and del(13q) (8.0% vs. 4.0%, P=0.031). In our series, 1q21 gain by itself did not improve RISS predictive capacity in patients either eligible or ineligible for autologous stem cell transplantation (ASCT). However, compared with patients with other 1q21 gains: concurrence with hyperdiploidy improved the prognosis of ASCT-eligible patients from 62.5% to 96.0% 10-year overall-survival (10y-OS, P<0.002); concurrence with hypodiploidy improved the prognosis of ASCT-ineligible patients from 35.7% to 71.0% (P=0.013); and concurrence with del(13q) worsened the prognosis of ASCT-ineligible patients from 12.5% to 53.4% (P=0.035). Gain of 1q21 should be patient-wisely evaluated, irrespective of the RISS, considering its concurrence with other cytogenetic abnormalities and eligibility for ASCT.     

Lipoinjection augmentation of the soft palate for velopharyngeal stress incompetence.

OBJECTIVES/HYPOTHESIS: Velopharyngeal stress incompetence in professional musicians is an uncommon but potentially career-ending problem. Pharyngeal flaps, V-Y palatal pushback procedures, Teflon or collagen injection of the posterior pharyngeal wall, and speech therapy have all been used to address this problem. The ideal procedure for this subset of patients with velopharyngeal incompetence (VPI) with high-pressure, mild VPI would be one that combines low morbidity and an expedient recovery for the busy musician. We describe an approach of endoscopically assisted autologous lipoinjection of the soft palate. STUDY DESIGN: A retrospective review of our experience treating high-pressure stress VPI in two professional musicians. METHODS: Literature review and retrospective chart review. RESULTS: Two musicians underwent autologous lipoinjection of the soft palate for stress VPI. Patients resumed full play within 2 weeks of the operation with no serious complications. There has been no recurrence of the VPI after 18 and 12 months of follow-up, respectively. CONCLUSIONS: Velopharyngeal stress incompetence in musicians is an uncommon disorder. Velopharyngeal incompetence in these patients may not present as in a typical manner with hypernasality but may go undiagnosed for years mistakenly rationalized as a declining performance ability rather than a curable structural problem. The performance demands of professional musicians necessitate a timely solution to their VPI. More precise and limited contouring of palatal bulk can be achieved through the lipoinjection technique than compared with traditional palatal V-Y pushback or a standard pharyngeal flap. Lipoinjection of the palate can be performed as an outpatient procedure with only minor discomfort and an expedient recovery for the career musician.     

Ex vivo generation of cytokine-induced killer cells (CD3+ CD56+) from post-stem cell transplant pediatric patients against autologous-Epstein-Barr virus-transformed lymphoblastoid cell lines

EBV-PTLDs affect as high as 20% of SCT recipients especially those with T-cell depleted grafts while high mortality rates were also noted. Adoptive allogeneic and autologous CTLs have a therapeutic potential in this setting. However, the process of expansion of these cells is tedious and time consuming in both allogeneic and autologous CTL generation. For the allogeneic SCT, another major obstacle is unavailability of donors especially in an unrelated SCT setting. The aim of the present study was therefore to investigate the efficacy of autologous CIK cells (CD3+ CD56+) against autologous EBV-LCLs from post-SCT pediatric patients. We could demonstrate that CIK cells can be generated within two wk and did show the significant cytotoxicity against autologous EBV-LCLs. CIK cells may provide a potent tool for use in post-transplantation adoptive immunotherapy.     

High-dose therapy and autologous transplantation for lymphoma: The Peter MacCallum Cancer Institute experience

Abstract
Background: High-dose therapy (HDT) with autologous bone marrow or blood cell transplantation for the treatment of lymphoma commenced at Peter MacCallum Cancer Institute in 1986.
Aim: To examine the patient characteristics and outcomes of patients with non-Hodgkin's lymphoma (NHL) and Hodgkin's disease (HD) treated with HDT and autologous transplantation at our Institute in the first 10 years of the service (1986–95).
Methods: A retrospective analysis was performed examining patient characteristics, prior chemotherapy regimens, pretransplant disease status, HDT regimen, source of stem cells, time for haematopoietic recovery, complications of transplantation, response rates, overall survival (OS) and progression-free survival (PFS).
Results: Sixty-seven patients with NHL were treated with an estimated 5-year OS rate of 44% (95% confidence interval (CI) 32–56%) and PFS rate of 34% (95% CI 21–44%). Factors independently predictive of an unfavourable PFS on multivariate analyses were presence of constitutional symptoms at transplant ( P < 0.002) and chemotherapy-resistant disease at transplant ( P = 0.02). Twenty-three patients with HD were treated with a 5-year predicted OS rate of 74% (95% CI 56–92%) and PFS rate of 57% (95% CI 36–77%). There was no difference in PFS for HD patients who relapsed either within 12 months of completion of front-line therapy or after this time ( P = 0.5). The transplant-related mortality for the entire cohort was 17%, with a progressive decrease over time.
Conclusion: HDT with autologous transplanta- tion achieves durable PFS and OS in patients with lymphoma. Improved patient selection, therapy modifications according to prognostic factors and ongoing improvements in supportive care should improve outcomes further. (Intern Med J 2001; 31: 279–289)     

A prospective study of risk-adapted therapy for large cell non-Hodgkin's lymphoma with VACOP-B followed by high-dose CBV and autologous progenitor cell transplantation for high-risk patients in remission

Several centres reported a favourable outcome after high-dose chemotherapy with autologous progenitor cell transplantation in selected patients with high-risk large cell non-Hodgkin's lymphoma in first remission. Based on these observations, we wanted to prospectively determine the outcome of a risk-adapted therapy for patients with large cell lymphoma. Patients aged 60 years or less received 12 weeks of VACOP-B chemotherapy. For high-risk patients in remission this was immediately followed by high-dose chemotherapy with cyclophosphamide, carmustine and etoposide and autologous progenitor cell transplantation. High-risk criteria were defined before the establishment of the International Index and included large cell lymphoma stage III or IV or mediastinal large lymphoma with sclerosis stage II or higher, and the presence of bulky tumours and/or an elevated LDH. 89 patients fulfilled the clinical selection criteria and were entered onto this multicentre study. 82 patients were evaluable after confirmation of large cell histology by pathology review. Of these, 51 were considered to be in the low-risk group and 31 in the high-risk group. The 3-year event-free survival for all patients was 68%. The 3-year event-free survival was 76% for the low-risk and 55% for the high-risk group (P = 0.061). Only 22/31 high-risk patients were able to receive the high-dose chemotherapy in first remission as intended. In conclusion, although our study demonstrated that a risk-adapted therapy for large cell lymphoma could be safely administered, the potential impact on outcome of the strategy chosen here is likely to be small.     

Acute Normovolemic Hemodilution does not Reduce Antithrombin Concentration for Cardiac Surgery

BACKGROUND: Acute normovolemic hemodilution (ANH) is used to reduce allogeneic blood transfusion with cardiac surgery. This procedure involves pre-operatively removing and storing a volume of whole blood and replacing the volume with crystalloid. The stored blood is then available for transfusion, if required. Hemodilution associated with ANH may reduce the effectiveness of heparin anticoagulation due to dilution of antithrombin. The aim of this study was to determine if antithrombin concentrations are reduced in patients who undergo one unit of ANH during cardiac surgery. METHODS: Patients scheduled for cardiac surgery (n = 71) were grouped according to whether they did or did not undergo ANH pre-operatively. Antithrombin concentrations were measured before and after ANH. This study had 80% power to detect a difference in reduction of antithrombin concentration of 6% between groups following ANH with an alpha error of <0.05. The effect of one unit ANH was expected to cause a difference of 12% or greater. RESULTS: No significant difference in the concentration of antithrombin between ANH patients and those that did not have ANH, nor was there a difference in the decrease in antithrombin between groups. CONCLUSIONS: The results indicate that one unit of ANH does not significantly reduce the concentration of antithrombin prior to cardiac surgery. Thus patients who undergo one unit of ANH are not at increased risk due to dilution of antithrombin.     

Advances in mesenchymal stromal cell therapy in the management of Crohn’s disease

Introduction: The aim of therapy in Crohn’s disease (CD) is induction and maintenance of remission, promotion of mucosal healing and restoration of quality of life. Even the best treatment regimes, including combinations of biologics and immunomodulators lack durable efficacy and have well documented side effects. Accordingly, there is an unmet need for novel therapies. Mesenchymal stromal cells (MSCs) are a subset of non-hematopoietic stem cells that home to sites of inflammation where they exert potent immunomodulatory effects and contribute to tissue repair. Their utility is being explored in several inflammatory and immune mediated disorders including CD, where they have demonstrated favourable safety, feasibility and efficacy profiles.

Areas covered: This review highlights current knowledge on MSC therapy and critically evaluates their safety, efficacy and potential mechanisms of action in CD.

Expert commentary: Building on positive early phase clinical trials and a recent phase 3 trial in perianal CD, there is considerable optimism for the possibility of MSCs changing the treatment landscape in complicated CD. Although important questions remain unanswered, including the safety and durability of MSC therapy, optimal adjunctive therapies and their sourcing and manufacturing, it is anticipated that MSCs are likely to enter mainstream treatment algorithms in the near future.     

Recombinant human erythropoietin in autologous blood donors: a dose-finding study

A dose-finding study of recombinant human erythropoietin (rhEPO) was performed in 60 autologous donors who donated 2 units of blood prior to orthopaedic or vascular surgery. The correction of phlebotomy-induced anaemia was studied in four groups of 15 patients who received 500 U/kg, 250 U/kg, 125 U/kg or no (controls) rhEPO subcutaneously twice per week during a 3-week period. Haemoglobin concentration in the 500 U/kg, 250 U/kg and 125 U/kg group and in the controls reached respectively 99·2, 98·8, 91·9 and 87·1% of pre-phlebotomy value. Flow cytometric analysis of reticulocytes showed a steady increase of reticulocyte count as the dose increased. Maximal levels of high fluorescence reticulocytes which represent early changes of erythropoiesis were reached after 7 d and decreased thereafter in each group. Serum ferritin decreased significantly to approximately 50% of baseline values in all groups; no differences in the decrease of serum ferritin were observed between the patients who received rhEPO and the controls. No severe adverse events were observed.
This study demonstrates a dose-related effect of rhEPO on erythropoiesis in autologous donors during the first 2 weeks. No further increase of reticulocytes was observed despite continued rhEPO therapy, which may be due to the inability of the mononuclear phagocytic system to release additional iron. To restore pre-phlebotomy haemoglobin concentration, a dose of 250 U/kg rhEPO was sufficient.