BackgroundMultiple myeloma is an incurable plasma cell malignancy that is mostly restricted to the bone marrow. Cancer-induced dysfunction of cytotoxic T cells at the tumor site may be responsible for immune evasion and therapeutical failure of immunotherapies. Therefore, enhanced knowledge about the actual status of T cells in myeloma bone marrow is urgently needed. Here, we assessed the expression of inhibitory molecules PD-1, CTLA-4, 2B4, CD160, senescence marker CD57, and CD28 on T cells of naive and treated myeloma patients in the bone marrow and peripheral blood and collected data on T cell subset distribution in both compartments. In addition, T cell function concerning proliferation and expression of T-bet, IL-2, IFNγ, and CD107a was investigated after in vitro stimulation by CD3/CD28. Finally, data was compared to healthy, age-matched donor T cells from both compartments.MethodsMulticolor flow cytometry was utilized for the analyses of surface molecules, intracellular staining of cytokines was also performed by flow cytometry, and proliferation was assessed by 3H-thymidine incorporation. Statistical analyses were performed utilizing unpaired T test and Mann-Whitney U test.ResultsWe observed enhanced T cell exhaustion and senescence especially at the tumor site. CD8+ T cells expressed several molecules associated with T cell exhaustion (PD-1, CTLA-4, 2B4, CD160) and T cell senescence (CD57, lack of CD28). This phenotype was associated with lower proliferative capacity and impaired function. Despite a high expression of the transcription factor T-bet, CD8+ T cells from the tumor site failed to produce IFNγ after CD3/CD28 in vitro restimulation and displayed a reduced ability to degranulate in response to T cell stimuli. Notably, the percentage of senescent CD57+CD28− CD8+ T cells was significantly lower in treated myeloma patients when compared to untreated patients.ConclusionsT cells from the bone marrow of myeloma patients were more severely impaired than peripheral T cells. While our data suggest that terminally differentiated cells are preferentially deleted by therapy, immune-checkpoint molecules were still present on T cells supporting the potential of checkpoint inhibitors to reactivate T cells in myeloma patients in combination therapies. However, additional avenues to restore anti-myeloma T cell responses are urgently needed.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-016-0345-3) contains supplementary material, which is available to authorized users.

We report the ten-year results for three designs of stem in 240 total hip replacements, for which subsidence had been measured on plain radiographs at regular intervals. Accurate migration patterns could be determined by the method of Einzel-BildRoentgen-Analyse-femoral component analysis (EBRA-FCA) for 158 hips (66%).Of these, 108 stems (68%) remained stable throughout, and five (3%) started to migrate after a median of 54 months. Initial migration of at least 1 mm was seen in 45 stems (29%) during the first two years, but these then became stable. We revised 17 stems for aseptic loosening, and 12 for other reasons. Revision for aseptic loosening could be predicted by EBRA-FCA with a sensitivity of 69%, a specificity of 80%, and an accuracy of 79% by the use of a threshold of subsidence of 1.5 mm during the first two years. Similar observations over a five-year period allowed the long-term outcome to be predicted with an accuracy of 91%.We discuss the importance of four different patterns of subsidence and confirm that the early measurement of migration by a reasonably accurate method can help to predict long-term outcome. Such methods should be used to evaluate new and modified designs of prosthesis. J Bone Joint Surg [Br] 1999;81-B:273-80. Received 17 February 1998; Accepted after revision 12 May 1998 The prognostic value of early migration of an acetabular cup has been demonstrated by several authors, with loosening within two years predicted with sensitivities and specificities of over 80%.

Malposition of the acetabular component is a risk factor for post-operative dislocation after total hip replacement (THR). We have investigated the influence of the orientation of the acetabular component on the probability of dislocation. Radiological anteversion and abduction of the component of 127 hips which dislocated post-operatively were measured by Einzel-Bild-Röentgen-Analysis and compared with those in a control group of 342 patients. In the control group, the mean value of anteversion was 15 degrees and of abduction 44 degrees. Patients with anterior dislocation after primary THR showed significant differences in the mean angle of anteversion (17 degrees), and abduction (48 degrees) as did patients with posterior dislocation (anteversion 11 degrees, abduction 42 degrees). After revision patients with posterior dislocation showed significant differences in anteversion (12 degrees) and abduction (40 degrees). Our results demonstrate the importance of accurate positioning of the acetabular component in order to reduce the frequency of subsequent dislocations. Radiological anteversion of 15 degrees and abduction of 45 degrees are the lowest at-risk values for dislocation.

Periacetabular osteotomy (PAO) is a well established method to treat hip dysplasia in the adult. There is, however, a lack of information on the subjective outcome of patients with complications after PAO. The purpose of this study was therefore to assess the influence of complications on the patients' post-operative wellbeing and function: 60 PAOs on 50 patients were investigated retrospectively after a mean follow-up of 7.4 years. The patients' self-reported assessment of health and function was evaluated by the Medical Outcomes Short Form-36 (SF-36) and the Western Ontario and McMaster Universities (WOMAC) questionnaires at last follow-up. Forty healthy persons served as a control group. Of the 60 interventions 13 had no complications. Minor complications occurred in 25 (41%) and in 22 (37%) at least one major complication occurred. SF-36 summary measure was 76.4 for PAO patients and 90.3 for the control group. Mean WOMAC score was 25

Several methods of measuring the migration of the femoral component after total hip replacement have been described, but they use different reference lines, and have differing accuracies, some unproven. Statistical comparison of different studies is rarely possible.We report a study of the EBRA-FCA method (femoral component analysis using Einzel-Bild-Röntgen-Analyse) to determine its accuracy using three independent assessments, including a direct comparison with the results of roentgen stereophotogrammetric analysis (RSA).The accuracy of EBRA-FCA was better than ±1.5 mm (95% percentile) with a Cronbach's coefficient alpha for interobserver reliability of 0.84; a very good result.The method had a specificity of 100% and a sensitivity of 78% compared with RSA for the detection of migration of over 1 mm. This is accurate enough to assess the stability of a prosthesis within a relatively limited period. The best reference line for downward migration is between the greater trochanter and the shoulder of the stem, as confirmed by two experimental analyses and a computer-assisted design.