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ATOS is a prospective observational study evaluating the outcome of patients receiving anti-human T-lymphocyte immunoglobulin (ATLG) in unrelated donor transplantation. Primary endpoint was severe GvHD and relapse-free survival (SGRFS). GvHD prophylaxis consisted of ATLG and CSA/ MTX or MMF. Outcome was compared to the ATLG arm of our prospective randomized phase III multicenter trial trial (RCT) [1, 2]. 165 patients, median age 54 (18; 77) years, with haematological malignancies with early (45.5%), intermediate (17.6%), and advanced (37.0%) disease were included. ATLG dose differed between centers according to local practise (median total ATLG dose of 46 (IQR 32-60, range 15-91) mg/kg). Median follow-up was 70 months. Estimated probabilities at 5 years follow up were for SGRFS 0.27, OS 0.52, DFS 0.43, NRM 0.23, relapse 0.34, acute GvhD °III/IV 0.13, severe chronic GvHD 0.27. OS rates differed dependent on disease status. An effect of the given ATLG dose could not be separated from potential center effects. Despite higher age and more advanced disease in ATOS, outcome was similar to the ATLG arm of our RCT. This long-term, multicenter, experience in routine clinical practice confirms the GvHD-protective effect of ATLG without compromising relapse and non-relapse mortality rates.Clinical Trial Registry: German clinical trials register DRKS00004581., (© 2024. The Author(s).)

One of the pre-requisites for forensic DNA analysis is the fact that all nucleated cells of a person carry the same genetic information. However, this is not the case for individuals who have received an allogeneic hematopoietic stem cell or bone marrow transplantation, as all new cells formed by the bone marrow no longer show the genetic information of the recipient but that of the donor, while all other cells still carry the original information before transplantation. Thus, STR typing of a blood sample after successful transplantation yields a DNA profile that differs from the recipient's original profile and corresponds to the donor genotype instead. Evidence from a routine case suggests that transplanted individuals may show donor alleles in skin swabs, as well. In order to examine this issue more closely, various skin swabs from 28 patients who have received an allogeneic hematopoietic stem cell transplantation were examined in this study. Swabs from the right and left palm, the back of the hand, one of the two upper arms, and the neck were collected from each person. Ninety-one of the 140 resulting swabs delivered useful results. All of those samples showed mixtures of recipient and donor DNA with different mixture ratios and the proportions of donor and recipient alleles revealed inter- and intra-individual differences. Those results were discussed with respect to graft versus host disease., (© 2022. The Author(s).)

We retrospectively compared the incidence of virus infections and outcome in the context of immune reconstitution in two different HLA-haploidentical transplantation (haplo-HSCT) settings. The first was a combined T-cell-replete and T-cell-deplete approach using antithymocyte globulin (ATG) prior to transplantation in patients with hematological diseases (cTCR/TCD group, 28 patients; median age 31 years). The second was a T-cell-replete (TCR) approach using high-dose posttransplantation cyclophosphamide (TCR/PTCY group, 27 patients; median age 43 years). The incidence of herpesvirus infection was markedly lower in the TCR/PTCY (22 %) than in the cTCR/TCD group (93 %). Recovery of CD4+ T cells on day +100 was faster in the TCR/PTCY group. CMV reactivation was 30 % in the TCR/PTCY compared to 57 % in the cTCR/TCD group, and control with antiviral treatment was superior after TCR/PTCY transplantation (100 vs 50 % cTCR/TCD). Twenty-five percent of the patients in the cTCR/TCD group but no patient in the TCR/PTCY group developed PTLD. While 1-year OS was not different (TCR/PTCY 59 % vs cTCR/TCD 39 %; p = 0.28), virus infection-related mortality (VIRM) was significantly lower after TCR/PTCY transplantation (1-year VIRM, 0 % TCR/PTCY vs 29 % cTCR/TCD; p = 0.009). On day +100, predictors of better OS were lymphocytes >300/μl, CD3+ T cells >200/μl, and CD4+ T cells >150/μl, whereas the application of steroids >1 mg/kg was correlated with worse outcome. Our results suggest that by presumably preserving antiviral immunity and allowing fast immune recovery of CD4+ T cells, the TCR approach using posttransplantation cyclophosphamide is well suited to handle the important issue of herpesvirus infection after haplo-HSCT.

Prognosis is poor for patients with biologically aggressive Non-Hodgkin lymphoma (NHL), refractory to chemotherapy or relapsed after autologous transplantation, especially when no disease control before allogeneic transplantation is achieved. In 16 patients (median age 53, median prior regimes 5) with relapsed or refractory non-remission NHL, we analysed retrospectively the efficacy of a sequential therapy comprising clofarabine re-induction followed by a reduced-intensity conditioning with fludarabine, CY and melphalan, and T-cell-replete HLA-haploidentical transplantation. High-dose CY was utilized post-transplantation. All patients engrafted. Early response (day +30) was achieved in 94%. Treatment-related grade III-IV toxicity occurred in 56%, most commonly transient elevation of transaminases (36%), while there was a low incidence of infections (19% CMV reactivation, 19% invasive fungal infection) and GVHD (GVHD: acute III-IV: 6%; mild chronic: 25%). One-year non-relapse mortality was 19%. After a median follow-up of 21 months, estimated 1- and 2-year PFS was 56 and 50%, respectively, with 11 patients (69%) still alive after 2 years. In summary, sequential therapy is feasible and effective and provides an acceptable toxicity profile in high-risk non-remission NHL. Presumably, cytotoxic reinduction with clofarabine provides enough remission time for the graft-versus lymphoma effect of HLA-haploidentical transplantation to kick in, even in lymphomas that are otherwise chemo-refractory.

Haploidentical haematopoietic SCT (HSCT) using T-cell-replete grafts and post-transplant high-dose CY has found increasing acceptance. Our purpose was to evaluate the feasibility and outcome of this strategy as second HSCT incorporating donor change for acute leukaemia relapse after a first allogeneic transplantation. The courses of 20 consecutive adults (median age 37 years, 12 male) with AML (n=14), ALL (n=5) and acute bi-phenotypic leukaemia (n=1) were analysed retrospectively. Conditioning consisted of fludarabine, CY and either melphalan or TBI or tresosulfan+/-etoposide. Engraftment was achieved in 17 (85%), and a second remission was induced in 15 patients (75%) on day +30. The rate of grade II-IV acute GvHD was 35%, while chronic GvHD occurred in five patients. Most commonly observed grade III-IV toxicities were mucositis (30%), hyperbilirubinemia (20%), elevation of transaminases (20%) and creatinine (20%), while invasive fungal infection affected 30%. One-year non-relapse mortality (NRM) was 36%. At a median follow-up of 17 months, estimated 1-year OS was 45%, and 1-year relapse-free survival was 33%. This strategy was feasible and allowed for successful engraftment with a moderate rate of toxicity. Early outcome and NRM are at least comparable with results after a second HSCT from HLA-matched donors without donor change at HSCT2.

Loss of heterozygosity (LOH) is a common event in malignant cells. In this work we introduce a new approach to identify patients with loss of heterozygosity in the HLA region either at first diagnosis or after HLA mismatched allogeneic HSCT. Diagnosis of LOH requires a high purity of recipient target cells. FACS is time consuming and also frequently prevented by rather nonspecific or unknown immune phenotype. The approach for recipient cell enrichment is based on HLA targeted complement-dependent cytotoxicity (CDC). Relative fluorescent quantification (RFQ) analysis of HLA intron length polymorphisms then allows analysis of HLA heterozygosity. The approach is exemplified in recent clinical cases illustrating the detection of an acquired allele loss. As illustrated in one case with DPB1, distinct HLA loci in donor and patient were sufficient for both proof of donor cell removal and evaluation of allele loss in the patient's leukemic cells. Results were confirmed using HLA-B RFQ analysis and leukemia-associated aberrant immunophenotype (LAIP) based cell sort. Both results confirmed suspected loss of HLA heterozygosity. Our approach complements or substitutes for FACS-based cell enrichment; hence it may be further developed as novel routine diagnostic tool. This allows rapid recipient cell purification and testing for loss of HLA heterozygosity before and after allogeneic HSCT in easily accessible peripheral blood samples.

Purpose: Cancer in pregnancy is a rare circumstance. However, the coincidence of pregnancy and malignancy is supposed to increase due to a general tendency of postponing childbearing to older age. To date, clinical guidelines are scarce and experience regarding therapeutic management is limited to case reports., Methods: This review focuses on general diagnostic and therapeutic principles including systemic therapy for malignancies in pregnancy., Results: In part I, we report on diagnosis and therapy of gynecological tumors., Conclusion: The diagnosis of gestational cancer faces both oncologist and obstetrician to the dilemma of applying appropriate diagnostic techniques and adequate local and systemic therapy to an expectant mother without harming the fetus.

Purpose: In case of non-gynecological solid tumors and hematological malignancies diagnosed during pregnancy, individual diagnostic and treatment options must be established by an interdisciplinary team., Methods: In part II of the present review we report on diagnostic and therapeutic principles in distinct entities of solid and hematological malignancies., Results: On the basis of a review of the current literature, clinical guidelines and algorithms have been established for diagnosis and therapy of maternal cancer during pregnancy., Conclusions: The prognosis of the malignancy and the patient's informed consent must be taken into consideration when the well-being of the expectant mother is weighed against the well-being of the unborn child in case of maternal cancer during pregnancy.

In this case report, we describe a 29 year-old male patient with a history of chronic cannabis abuse presenting with recurrent vomiting, intense nausea and abdominal pain. Abstinence from cannabis resolved both vomiting and abdominal pain. We conclude that in case of chronic cannabis abuse, patients presenting with severe and chronic nausea, vomiting, accompanied by abdominal pain and compulsive behaviour (hot bathing), in the absence of other obvious causes, the diagnosis of cannabinoid-induced hyperemesis syndrome should be considered., (© Georg Thieme Verlag KG Stuttgart · New York.)

Myeloid leukemic cells can differentiate into leukemia-derived dendritic cells (DC(leu)), presenting known/unknown leukemic-antigens. Induced anti-leukemic T-cell-responses are variable. To further elicit DC/DC(leu)-induced T-cell-response-patterns we performed (functional)flow-cytometry/fluorolysis-assays before/after mixed lymphocyte cultures (MLC) of matched (allogeneic) donor-T-cells (n=6), T-cells prepared at relapse after stem cell transplantation (n=4) or (autologous) patients'-T-cells (n=7) with blast-containing-mononuclear-cells ('MNC') or DC(leu)-containing DC ('DC'). Compared to 'MNC' 'DC' were better mediators of anti-leukaemic T-cell-activity, although not in every case effective. We could define cut-off proportions of mature DC, DC(leu), proliferating, CD4(+), CD8(+) and non-naive T-cells after 'MNC'- or 'DC'-stimulation, that were predictive for an anti-leukemic-activity of stimulated T-cells as well as a response to immunotherapy. Interestingly especially ratios >1 of CD4:CD8 or CD45RO:CD45RA T-cells were predictive for anti-leukemic function after DC-stimulation. In summary the composition and quality of DC and T-cells after a MLC-stimulating-phase is predictive for a successful ex-vivo and in-vivo anti-leukemic response, especially with respect to proportions of proliferating, CD4(+) and CD45RO(+) T-cells. Successful cytotoxicity and the development of a T-cell-memory after 'DC'-stimulation could be predictive for the clinical course of the disease and may pave the way to develop adoptive immunotherapy, especially for patients at relapse after SCT., (Copyright © 2010 Elsevier Inc. All rights reserved.)

We discuss the case of a 32 year-old male with severe microcytic anemia (hemoglobin 2,9 g/dl) and megaloblastic changes in the bone marrow. The patient reported of substantial dietary weight loss. The family history was positive for beta-thalassemia. Previous blood work showed iron deficiency with mild anemia. Further work-up verified beta-thalassemia minor and revealed severely decreased vitamin B12 levels with positive anti intrinsic-factor antibodies, pathognomonic for autoimmune pernicious anemia. The paradoxon therefore dissolved as a pernicious anemia with megaloblastic changes with microcytic erythrocytes due to beta-thalassemia.

Plesiomonas shigelloides is known to cause mild to cholera-like diarrhea in most infected persons. In immunocompromised patients extra-intestinal manifestations have been described. We report the first case of pneumonia caused by P. shigelloides in a 76-year-old woman who had undergone a curative gastrectomy and esophageal-jejunostomy due to a low differentiated adenocarcinoma of the stomach (pT2, pN1 pMx, G3, R0, Lauren: intestinal type). The patient was admitted in hospital with clinical signs of pulmonary infection. CT-scan revealed a cavernous lesion in the right upper pulmonary lobe. Bronchial lavage showed a granulocytic inflammation 105CFU/ml P. shigelloides. Although antibiotic treatment led to a decrease of inflammation parameters and decrease of the pulmonary infiltrate the patient died due to development of torsades de pointes tachycardia leading to ventricular fibrillation and hypoxic brain damage.

Recently it was shown that myeloid leukemic cells can be induced to differentiate into leukemia-derived dendritic cells (DCleu), regaining the stimulatory capacity of professional DCs while presenting the leukemic antigen repertoire. But so far, the induced antileukemic T-cell responses have varied in specificity and efficacy, or have even mediated opposite effects. In an attempt to further characterize the DC/DCleu induced T-cell response pattern, immunoscope spectratyping, a novel and powerful tool to detect T-cell receptor (TCR) rearrangements was used in combination with functional flow cytometry and non-radioactive fluorolysis assays. Human leucocyte antigen (HLA) matched donor T-cells were repeatedly stimulated, either with leukemic blasts (French-American-British, FAB M4eo) or the corresponding blast-derived DCs. Functional comparison revealed no significant difference in their T-cell stimulatory capacity, while the DC/DCleu fraction favored T-cells with a higher lytic activity, comprising a higher proportion of T-memory CD45R0+ cells. Stimulation with blasts and DC/DCleu induced a similar TCR restriction pattern, while stimulation with DC/DCleu favored the CD4 T-cell subset and seemed to cause a higher grade of restriction. In conclusion, a combined strategy using spectratyping with functional tests might not only provide useful information about the specificity and efficacy of the induced T-cell response, but also pave the way to gain effective T-cell clones for therapeutic use.

Gemcitabine in combination with the oral epidermal growth factor receptor tyrosine kinase inhibitor erlotinib is a new treatment option for patients with advanced pancreatic cancer. The nonhematological side effects of this regimen mainly include diarrhea and skin rash. For each of these drugs, gemcitabine and erlotinib, lung toxicities have been described previously. In this report, we present the first case of a nonlung cancer patient experiencing not only acne-like skin toxicity, but subsequently also severe interstitial lung disease during therapy with gemcitabine and erlotinib. Both therapeutic agents were suspected as a possible cause of this adverse event. An interaction between gemcitabine and erlotinib might have also contributed to the pathogenesis of this pulmonary toxicity. Treatment with high-dose steroids was, however, very effective in our patient and a complete recovery appeared within a few days. Thus, pulmonary side effects should be regarded carefully in pancreatic cancer patients receiving palliative therapy with gemcitabine and erlotinib.

In comparison with CD4+ regulatory T cells, the generation and function of immunomodulatory CD8+T cells is less well defined. Here we describe the existence of regulatory anti-Kb-specific CD8+ T cells that are rendered tolerant during neonatal life via antigen contact exclusively on keratinocytes. These regulatory T cells maintain tolerance during adulthood as they prevent Kb-specific graft rejection by naïve CD8+ T cells. Third-party immune responses remain unaffected. Up-regulation of TGF-beta1 and granzyme B in the regulatory CD8+ T cell population suggests the involvement of these molecules in common suppressive pathways shared with CD4+ regulatory T cells. In summary, CD8+ regulatory T cells can be induced extrathymically through antigen contact on neonatally accessible parenchymal cells and maintain tolerance throughout adult life.

Context/objective: Approximately 15% of thyroid cancer patients develop subsequent metastases. The clinical course of patients with metastatic thyroid carcinoma is highly variable. We hypothesized that the metabolic activity of metastatic lesions, as defined by retention of 2-[(18)F]fluoro-2-deoxyglucose (FDG), would correlate with prognosis., Design/patients: The initial FDG-positron emission tomography (PET) scans from 400 thyroid cancer patients were retrospectively reviewed and compared with overall survival (median follow-up, 7.9 yr). We examined the prognostic value of clinical information such as gender, age, serum thyroglobulin, American Joint Committee on Cancer (AJCC) stage, histology, radioiodine avidity, FDG-PET positivity, number of FDG-avid lesions, and the glycolytic rate of the most active lesion., Results: Age, initial stage, histology, thyroglobulin, radioiodine uptake, and PET outcomes all correlated with survival by univariate analysis. However, only age and PET results continued to be strong predictors of survival under multivariate analysis. The initial American Joint Committee on Cancer stage was not a significant predictor of survival by multivariate analysis. There were significant inverse relationships between survival and both the glycolytic rate of the most active lesion and the number of FDG-avid lesions., Conclusions: FDG-PET scanning is a simple, expensive, but powerful means to restage thyroid cancer patients who develop subsequent metastases, assigning them to groups that are either at low (FDG negative) or high (FDG positive) risk of cancer-associated mortality. We propose that the aggressiveness of therapy for metastases should match the FDG-PET status.

T lymphocytes with self-destructive capacity are often found in healthy individuals, indicating efficient control mechanisms that prevent chronic autoimmune diseases. Since naive T lymphocytes do not circulate through extralymphoid tissues the concept has emerged that peripheral T cells ignore tissue-specific antigens unless they are presented by professional antigen-presenting cells in the lymphoid compartments. However, this view pays attention only to experiments performed in adult animals. This report reviews the evidence that tissues of neonatal mice, in contrast to adults, exhibit high accessibility for naive T cells, thereby allowing the direct contact with tissue-specific self-antigens on parenchymal cells during neonatal life and tolerance induction to such self-antigens. In mouse bone marrow chimeras generated at different ages, recent thymic emigrants were tolerized to a major histocompatibility class I antigen expressed on keratinocytes only during a neonatal period and not during adulthood. Blockade of T-cell migration neonatally prevented tolerance induction. The neonatally induced tolerance is maintained during adulthood, apparently by a dominant regulatory mechanism. Thus, parenchymal cells and T-cell migration in the neonate contribute to the control of autoreactive T cells.