Myeloablative intensified conditioning regimen with in vivo T-cell depletion (ATG) followed by allografting in patients with advanced multiple myeloma. A phase I/II study of the German Study-group Multiple Myeloma (DSMM)

We investigated toxicity and efficacy of in vivo T-cell depletion with anti-thymocyte globulin (ATG) as part of an intensified myeloablative conditioning regimen followed by allogeneic stem cell transplantation in patients with advanced multiple myeloma. The conditioning regimen consisted of modified total body irradiation, busulfan and cyclophosphamide (n=15) or in the case of prior dose-limiting radiotherapy of busulfan and cyclophosphamide (n=3). The median age was 44 years (range, 29-53) and the median time from diagnosis to transplant was 12 months (range, 6-144). Grade II-IV acute graft-versus-host disease (GvHD) occurred in six patients (35%). Severe grade III/IV GvHD developed in one patient (6%). Three patients died of therapy-related causes (17%). A complete remission (CR) with negative immunofixation after allogeneic transplantation was seen in eight of the evaluable patients (53%). After a median follow-up of 41 months (range, 8-84), the estimated overall survival at 6 years for all patients is 77% (CI 95%: 58-96%). The estimated progression-free survival at 6 years for all patients is 31% (CI 95%: 2-59%) and 46% (CI 95%: 9-83%) for patients with CR. In vivo T-cell depletion with ATG resulted in a low rate of severe GvHD with low treatment-related mortality, and a substantial number of long-term survivors.     

Variation in hospital mortality after pancreatoduodenectomy is related to failure to rescue rather than major complications: a nationwide audit

Background

In the mandatory nationwide Dutch Pancreatic Cancer Audit, rates of major complications and Failure to Rescue (FTR) after pancreatoduodenectomy between low- and high-mortality hospitals are compared, and independent predictors for FTR investigated.

Respiratory virology and microbiology in intensive care units: a prospective cohort study

Our aim was to determine the frequency of 12 common respiratory viruses in patients admitted to intensive care units with respiratory symptoms, evaluate the clinical characteristics and to compare the results to routine microbiological diagnostics. Throat swabs from 122 intensive care‐patients >18 years with acute respiratory symptoms were collected upon admission and analysed with multiplex real‐time polymerase chain reaction, for 12 community respiratory viruses. Blood and respiratory tract specimens were analysed for bacteria and fungi upon clinicians' request. Clinical and paraclinical data were collected. Viruses were detected in 19 (16%) of the 122 study patients. Five virus‐positive patients (26%) had possible clinically relevant bacteria or fungi co‐detected. Patients with exacerbation in COPD were associated with a viral infection (p = 0.02). Other comorbidities, clinical and paraclinical parameters, and death were independent of a viral infection or co‐detection of bacteria/fungi. In conclusion, respiratory viruses were frequently detected in the patients. The investigated clinical and paraclinical parameters were not different in viral infections compared to other agents, thus respiratory viruses likely have similar impact on the clinical course as other agents. In 25% of the virus‐positive patients, polymicrobial aetiology was identified. Comprehensive and sensitive diagnostic methods should be emphasized to enhance respiratory diagnostics.     

Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program

Human leukocyte antigen (HLA)-identical sibling bone marrow transplantation is an effective treatment for Wiskott-Aldrich syndrome. However, most children with this disease lack such donors and many patients receive transplants from alternative donors. This study compared outcomes of HLA-identical sibling, other related donor, and unrelated donor transplantation for Wiskott-Aldrich syndrome. The outcome of 170 transplantations for Wiskott-Aldrich syndrome, from 1968 to 1996, reported to the International Bone Marrow Transplant Registry and/or National Marrow Donor Program were assessed. Fifty-five were from HLA-identical sibling donors, 48 from other relatives, and 67 from unrelated donors. Multivariate proportional hazards regression was used to compare outcome by donor type and identify other prognostic factors. Most transplant recipients were younger than 5 years (79%), had a pretransplantation performance score greater than or equal to 90% (63%), received pretransplantation preparative regimens without radiation (82%), and had non-T-cell-depleted grafts (77%). Eighty percent received their transplant after 1986. The 5-year probability of survival (95% confidence interval) for all subjects was 70% (63%-77%). Probabilities differed by donor type: 87% (74%-93%) with HLA-identical sibling donors, 52% (37%-65%) with other related donors, and 71% (58%-80%) with unrelated donors (P =.0006). Multivariate analysis indicated significantly lower survival using related donors other than HLA-identical siblings (P =.0004) or unrelated donors in boys older than 5 years (P =.0001), compared to HLA-identical sibling transplants. Boys receiving an unrelated donor transplant before age 5 had survivals similar to those receiving HLA-identical sibling transplants. The best transplantation outcomes in Wiskott-Aldrich syndrome are achieved with HLA-identical sibling donors. Equivalent survivals are possible with unrelated donors in young children.     

Treatment of steroid-resistant acute graft-versus-host disease with daclizumab and etanercept

Steroid-resistant acute GVHD (aGVHD) following allogeneic hematopoietic stem cell transplantation (alloHSCT) continues to be associated with a high mortality. We report the results of a phase II study of treatment of steroid-resistant aGVHD with the IL-2 receptor antibody daclizumab combined with the TNF-receptor fusion protein etanercept. Treatment consisted of daclizumab 1 mg/kg given i.v. on days 1, 4, 8, 15, 22 and etanercept 16 mg/m(2) s.c. on days 1, 5, 9, 13, 17. A total of 21 patients (age 15-61 years) with steroid-resistant aGVHD after alloHSCT were included in the study. Donor types were HLA-matched related (n=6), HLA-matched unrelated (n=14), and HLA-mismatched unrelated (n=1). Eight patients achieved complete, and six showed partial remission of aGVHD. Seven patients did not respond. Four of 21 patients are currently alive with a median follow-up of 586 (185-1155) days. Three patients died due to relapsed malignancy. Treatment-related mortality was due to infectious complications (n=11) or organ failure due to aGVHD (n=3). In total, 12 patients developed subsequent chronic GVHD. In conclusion, the data demonstrate an acceptable response rate of the combination of daclizumab and etanercept in the treatment of steroid-resistant aGVHD. Nevertheless, long-term mortality due to infectious complications and chronic GVHD remains high.     

Kidney Function and Plasma Copeptin Levels in Healthy Kidney Donors and Autosomal Dominant Polycystic Kidney Disease Patients

Background and objectives

Plasma copeptin, a marker of arginine vasopressin, is elevated in patients with autosomal dominant polycystic kidney disease and predicts disease progression. It is unknown whether elevated copeptin levels result from decreased kidney clearance or as compensation for impaired concentrating capacity. Data from patients with autosomal dominant polycystic kidney disease and healthy kidney donors before and after donation were used, because after donation, overall GFR decreases with a functionally normal kidney.

Design, setting, participants, & measurements

Data were obtained between October of 2008 and January of 2012 from healthy kidney donors who visited the institution for routine measurements predonation and postdonation and patients with autosomal dominant polycystic kidney disease who visited the institution for kidney function measurement. Plasma copeptin levels were measured using a sandwich immunoassay, GFR was measured as ¹²⁵I-iothalamate clearance, and urine concentrating capacity was measured as urine-to-plasma ratio of urea. In patients with autosomal dominant polycystic kidney disease, total kidney volume was measured with magnetic resonance imaging.

Results

Patients with autosomal dominant polycystic kidney disease (n=122, age=40 years, men=56%) had significantly higher copeptin levels (median=6.8 pmol/L; interquartile range=3.4–15.7 pmol/L) compared with donors (n=134, age=52 years, men=49%) both predonation and postdonation (median=3.8 pmol/L; interquartile range=2.8–6.3 pmol/L; P<0.001; median=4.4 pmol/L; interquartile range=3.6–6.1 pmol/L; P<0.001). In donors, copeptin levels did not change after donation, despite a significant fall in GFR (from 105±17 to 66±10; P<0.001). Copeptin and GFR were significantly associated in patients with autosomal dominant polycystic kidney disease (β=−0.45, P<0.001) but not in donors. In patients with autosomal dominant polycystic kidney disease, GFR and total kidney volume were both associated significantly with urine-to-plasma ratio of urea (β=0.84, P<0.001; β=−0.51, P<0.001, respectively).

Conclusions

On the basis of the finding in donors that kidney clearance is not a main determinant of plasma copeptin levels, it was hypothesized that, in patients with autosomal dominant polycystic kidney disease, kidney damage and associated impaired urine concentration capacity determine copeptin levels.