Transfer of minimally manipulated CMV-specific T cells from stem cell or third-party donors to treat CMV infection after allo-HSCT.

Cytomegalovirus (CMV) infection is a common, potentially life-threatening complication following allogeneic hematopoietic stem cell transplantation (allo-HSCT). We assessed prospectively the safety and efficacy of stem cell-donor- or third-party-donor-derived CMV-specific T cells for the treatment of persistent CMV infections after allo-HSCT in a phase I/IIa trial. Allo-HSCT patients with drug-refractory CMV infection and lacking virus-specific T cells were treated with a single dose of ex vivo major histocompatibility complex-Streptamer-isolated CMV epitope-specific donor T cells. Forty-four allo-HSCT patients receiving a T-cell-replete (D+ repl; n=28) or T-cell-depleted (D+ depl; n=16) graft from a CMV-seropositive donor were screened for CMV-specific T-cell immunity. Eight D+ depl recipients received adoptive T-cell therapy from their stem cell donor. CMV epitope-specific T cells were well supported and became detectable in all treated patients. Complete and partial virological response rates were 62.5% and 25%, respectively. Owing to longsome third-party donor (TPD) identification, only 8 of the 57 CMV patients transplanted from CMV-seronegative donors (D-) received antigen-specific T cells from partially human leukocyte antigen (HLA)-matched TPDs. In all but one, TPD-derived CMV-specific T cells remained undetectable. In summary, adoptive transfer correlated with functional virus-specific T-cell reconstitution in D+ depl patients. Suboptimal HLA match may counteract expansion of TPD-derived virus-specific T cells in D- patients.

The proteome pattern cGvHD_MS14 allows early and accurate prediction of chronic GvHD after allogeneic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) may be curative, but is associated with significant morbidity and mortality. Chronic graft-versus-host disease (cGvHD), characterized by inflammation and fibrosis of multiple target organs, considerably contributes to the morbidity and mortality even years after allo-HSCT. Diagnosis of cGvHD is based on clinical features and histology of biopsies. Here, we report the generation of a urinary cGvHD-specific proteome-pattern (cGvHD_MS14) established by capillary electrophoresis-mass spectrometry to predict onset and severity of cGvHD as an unbiased laboratory test. cGvHD_MS14 was evaluated on samples from 412 patients collected prospectively in four transplant centers. Sensitivity and specificity was 84 and 76% by cGvHD_MS14 classification. Sensitivity further increased to 93% by combination of cGvHD_MS14 with relevant clinical variables to a logistic regression model. cGvHD was predicted up to 55 days prior to clinical diagnosis. Acute GvHD is not recognized by cGvHD_MS14. cGvHD_MS14 consists of 14 differentially excreted peptides, six of those have been sequenced to date and are fragments from thymosin ß-4, eukaryotic translation initiation factor 4γ2, fibrinogen ß-chain or collagens. In conclusion, the cGvHD_MS14-pattern allows early, highly sensitive and specific prediction of cGvHD as an independent diagnostic criterion of clinical diagnosis potentially allowing early therapeutic intervention.

MiRNome and transcriptome aided pathway analysis in human regulatory T cells.

Owing to their manifold immune regulatory functions, regulatory T cells (Treg) have received tremendous interest as targets for therapeutic intervention of diverse immunological pathologies or cancer. Directed manipulation of Treg will only be achievable with extensive knowledge about the intrinsic programs that define their regulatory function. We simultaneously analyzed miR and mRNA transcript levels in resting and activated human Treg cells in comparison with non-regulatory conventional T cells (Tcon). Based on experimentally validated miR-target information, both transcript levels were integrated into a comprehensive pathway analysis. This strategy revealed characteristic signal transduction pathways involved in Treg biology such as T-cell receptor-, Toll-like receptor-, transforming growth factor-ß-, JAK/STAT (Janus kinase/signal transducers and activators of transcription)- and mammalian target of rapamycin signaling, and allowed for the prediction of specific pathway activities on the basis of miR and mRNA transcript levels in a probabilistic manner. These data encourage new concepts for targeted control of Treg cell effector functions.

MR imaging characteristics of osteoradionecrosis of the pelvis after radiation therapy on gynecological tumors.

PURPOSE: To describe MR imaging characteristics of osteoradionecrosis (ORN) of the pelvis as a result of radiation therapy (RT) on gynecological tumors. MATERIAL AND METHODS: Radiography, computed tomography (CT) and magnetic resonance imaging (MRI) were performed on 9 women (mean age 67.5 years) with gynecological tumors to identify ORN. T1- and T2-weighted sequences and contrast-enhanced t1-weighted sequences with and without fat saturation were used. The patients began developing pain after the completion of RT indicating a possible ORN a which time MRI was performed. MR images were correlated with the results of clinical examinations. RESULTS: Depending on the time elapsed after RT, ORN presented with different signal intensities. The acquired images suggested that signal changes in T2-weighted images as well as the different enhancement behaviour of ORN could be dependent on the time elapsed after RT. Visualisation of the affected regions was best achieved with fat-saturated T1-weighted sequences. CT showed increased density in the affected regions corresponding to osteosclerosis. In all cases the sacroiliac joint was affected, some times bilaterally. CONCLUSION: MRI is helpful in detecting and characterizing ORN. Changes in signal intensity, based on histopathological tissue changes could make a chronological classification possible.

[Role of radiotherapy in the treatment of multiple myeloma]. / Wertigkeit der Radiotherapie in der Behandlung des multiplen Myeloms.

BACKGROUND: Chemotherapy is the treatment of choice in multiple myeloma; but there are no curative options. Therefore, the treatment rationale is characterized by reduction of symptoms and inhibition of complications. Regarding reduction of pain, treatment of (impending) fractures, and spinal cord compression radiation is an important part of palliative treatment. In our retrospective study we report the effect of radiotherapy on reduction of pain, recalcification and the reduction of neurological symptoms and evaluate factors which have an impact on therapeutic outcome. PATIENTS AND METHODS: From 1, Jan 1988 to 31, Dec 1998, 42 patients (19 women, 23 men; range of ages 46 to 85 years, median age 64.9 years) with 71 target volumes were irradiated (median dose 36 Gy, 2 to 3 Gy 5 times/week) because of symptomatic disease (67/71: osseous pain, 45/71: fractures/impending fractures, 13/71: spinal cord compression) (Tables 1 and 2). The median time from diagnosis to the first course of radiotherapy was 11.9 months (0.3 to 90 months). At the time of first irradiation, 5 and 37 patients were in tumor Stage II and III (Salmon/Durie), respectively. The median value of the Karnofsky performance was 70% (40 to 90%). RESULTS: During follow-up (at least 6 months) in 85% of target volumes complete and partial pain relief (measured by patients' perception and the use of analgetic medication) was achieved; recurrences were seen in 8.8%. In 26/56 (46.4%) lesions evaluable a recalcification was seen whereas 17.9% showed progressive disease (comparison of radiographs before and after radiation). In 22.3% of all lesions initially with impending fracture (4/18) radiotherapy failed because of fracture after treatment (Tables 3 and 4). Simultaneous chemotherapy and a Karnofsky performance > or = 70 had a significant impact on a positive response to treatment, respectively. Spinal cord compression symptoms were reduced in 7/13 (53.8%) of patients (scaled due to the classification by Findlay 1987). The median survival from diagnosis for the entire group was 34.9 months (7.5 to 119.3 months), after irradiation 13.1 months (0.2 to 105.3 months) (Figure 1). CONCLUSION: When adequately indicated radiotherapy has shown to be an effective palliative treatment. Taking under consideration that the results are retrospective we suppose that in multiple myeloma the local response to radiation is supported by a favorable performance status and simultaneous chemotherapy. Irradiation treatment does not change prognosis regarding overall survival.

[Prognostic factors and the effect of radiotherapy in the treatment of differentiated thyroid carcinomas]. / Prognostische Faktoren und Einfluss der Strahlentherapie bei Behandlung differenzierter Schilddrüsenkarzinome.

PURPOSE: In the treatment of differentiated thyroid carcinomas the indication for adjuvant radiotherapy is discussed contradictory. The following study analyzes the long-term survival rates of patients with follicular and papillar thyroid carcinomas after percutaneous radiotherapy. PATIENTS AND METHOD: Records of 178 patients with differentiated thyroid carcinomas (132 female, median age 46 years; 46 male, median age 47 years) were evaluated. Following thyroid-resection and radioiodine therapy external beam irradiation was performed with a telecobalt device and high energy electrons (mean reference dose 54.7 Gy). Hundred and twenty patients (67.4%) had a histologically confirmed papillary carcinoma, 58 (32.6%) patients had follicular carcinoma. In the group with papillary carcinoma 57 patients (47.5%) were classified as stage I, 11 patients (9.2%) as stage II, 48 patients (40.0%) as stage III, 4 patients (3.3%) as stage IV, respectively, in the group with follicular carcinoma 21 patients (36.2%) were classified as stage I, 4 patients (6.9%) as stage II, 28 patients (48.3%) as stage III and 5 patients (8.6%) as stage IV. Survival, recurrence rate and prognostic factors were analyzed.