[Show abstract][Hide abstract] ABSTRACT: Background:
It has been previously demonstrated in several cancer models, that Dronabinol (THC) may have anti-tumor activity - however, controversial data exists for acute leukemia. We have anecdotal evidence that THC may have contributed to disease control in a patient with acute undifferentiated leukemia.
To test this hypothesis, we evaluated the antileukemic efficacy of THC in several leukemia cell lines and native leukemia blasts cultured ex vivo. Expression analysis for the CB1/2 receptors was performed by Western immunoblotting and flow cytometry. CB-receptor antagonists as well as a CRISPR double nickase knockdown approach were used to evaluate for receptor specificity of the observed proapoptotic effects.
Meaningful antiproliferative as well as proapoptotic effects were demonstrated in a subset of cases - with a preference of leukemia cells from the lymphatic lineage or acute myeloid leukemia cells expressing lymphatic markers. Induction of apoptosis was mediated via CB1 as well as CB2, and expression of CB receptors was a prerequisite for therapy response in our models. Importantly, we demonstrate that antileukemic concentrations are achievable in vivo.
Our study provides rigorous data to support clinical evaluation of THC as a low-toxic therapy option in a well defined subset of acute leukemia patients.
[Show abstract][Hide abstract] ABSTRACT: Background:
Rare sites of metastases, atypical symptoms and paraneoplastic syndromes are often neglected or misinterpreted, especially when they represent early symptoms of an underlying malignant disease. Hence, an interdisciplinary approach to these patients is essential to avoid tumor progression and metastatic spread in order to provide curative treatment options to the patients. We here report the case of a young woman presenting with visual loss which led to diagnosis of a thymic carcinoma.
A 28-year old white woman presented with subacute loss of vision in the last trimester of her first pregnancy which was first interpreted as an exacerbation of a pre-existing dermatomyositis and treated with steroids. After failure of steroid therapy choroidal metastases from an undifferentiated thymic carcinoma were diagnosed. This also shed a new light on the dermatomyositis the patient had been suffering from for seven years possibly representing a paraneoplastic syndrome from the tumor. Despite aggressive chemotherapy, the patient died from progressive disease eight years after first onset of dermatomyositis and 14 months after initial diagnosis of the thymic carcinoma.
Choroidal metastases from a thymic carcinoma have never been reported before but should be included into the differential diagnosis of choroidal masses.
[Show abstract][Hide abstract] ABSTRACT: Renal cell carcinoma (RCC) is an immunogenic tumor for which immunotherapeutic approaches could be associated with clinically relevant responses. It was recently shown, that induction of T-cell responses against multiple tumor-associated antigen (TAA) epitopes results in prolonged overall survival in RCC patients. In 2003–2005 we performed a phase I/II trial testing an mRNA-based vaccine formulation consisting of a mixture of in vitro transcribed RNA coding for six different TAAs (MUC1, CEA, Her2/neu, telomerase, survivin, MAGE-A1) in 30 metastatic RCC (mRCC) patients. In the first 14 patients vaccinations were applied i.d. on days 0, 14, 28, and 42. In the consecutive 16 patients an intensified protocol consisting of i.d. injections (daily on days 0–3, 7–10, 28, and 42) was used. After the respective induction periods, patients in both cohorts were vaccinated monthly until tumor progression. At survival update performed in July 2015 one of the 30 patients was still alive. One patient was lost to follow-up. Median survival of 24.5 months (all patients) and 89 months (favorable risk patients) exceeded predicted survival according to MSKCC risk score. Impressively, long-term survivors displayed immunological responses to the applied antigens while vice versa no patient without detectable immune response had survived more than 33 months. The current survival update shows a clear correlation between survival and immunological responses to TAAs encoded by the naked mRNA vaccine. This is one of the first vaccination studies and the only RNA trial that reports on safety and efficacy after a follow-up of more than ten years.
[Show abstract][Hide abstract] ABSTRACT: The transcription factor SOX2 is a key regulator of pluripotency in embryonic stem cells and plays important roles in early organogenesis. Recently, SOX2 expression was documented in various cancers and suggested as a cancer stem cell (CSC) marker. Here we identify the Ser/Thr-kinase AKT as an upstream regulator of SOX2 protein turnover in breast carcinoma (BC). SOX2 and pAKT are co-expressed and co-regulated in breast CSCs and depletion of either reduces clonogenicity. Ectopic SOX2 expression restores clonogenicity and in vivo tumorigenicity of AKT-inhibited cells, suggesting that SOX2 acts as a functional downstream AKT target. Mechanistically, we show that AKT physically interacts with the SOX2 protein to modulate its subcellular distribution. AKT kinase inhibition results in enhanced cytoplasmic retention of SOX2, presumably via impaired nuclear import, and in successive cytoplasmic proteasomal degradation of the protein. In line, blockade of either nuclear transport or proteasomal degradation rescues SOX2 expression in AKT-inhibited BC cells. Finally, AKT inhibitors efficiently suppress the growth of SOX2-expressing putative cancer stem cells, whereas conventional chemotherapeutics select for this population. Together, our results suggest the AKT/SOX2 molecular axis as a regulator of BC clonogenicity and AKT inhibitors as promising drugs for the treatment of SOX2-positive BC.
[Show abstract][Hide abstract] ABSTRACT: Limited therapeutic options are available after relapse of acute leukaemia following first reduced intensity conditioning haematopoietic stem cell transplantation (RIC1). A retrospective study on European Society for Blood and Marrow Transplantation (EBMT) registry data was performed on 234 adult patients with acute leukaemia who received a second RIC transplantation (RIC2) from 2000 to 2012 as a salvage treatment for relapse following RIC1. At the time of RIC2, 167 patients (71.4%) had relapsed or refractory disease, 49 (20.9%) were in second CR and 18 (7.7%) in third or higher CR. With a median follow-up of 21 (1.5-79) months after RIC2, 51 patients are still alive. At 2 years, the cumulative incidence of non-relapse mortality (NRM), relapse incidence (RI), leukaemia-free survival (LFS) and overall survival (OS) were 22.4% (95% confidence interval (CI): 17-28.4), 63.9% (56.7-70.1), 14.6% (8.8-18.5) and 20.5% (14.9-26.1), respectively. In patients with acute myelogenous, biphenotypic and undifferentiated leukaemia (representing 89.8% of all patients), duration of remission following RIC1 >225 days, presence of CR at RIC2, patient's Karnofsky performance status >80 at RIC2 and non-myeloablative conditioning were found to be the strongest predictors of patients' favourable outcome.Bone Marrow Transplantation advance online publication, 5 October 2015; doi:10.1038/bmt.2015.221.
No preview · Article · Oct 2015 · Bone marrow transplantation
[Show abstract][Hide abstract] ABSTRACT: We report a retrospective single-center analysis of 112 consecutive patients that underwent allogeneic hematopoietic cell transplantation (HCT) after reduced-intensity conditioning (RIC) with fludarabine (FLU) and busulfan (BU) for the treatment of acute myeloid leukemia (AML), myelodysplastic syndrome (MDS) and myeloproliferative syndrome (MPS) from 2005 to 2014. Three-year event-free survival (EFS) and overall survival (OS) were 46 and 58 %, respectively. Patients ≥60 years of age showed a similar outcome compared to younger patients (3-year OS 55 vs. 61 %, p = 0.96; 3-year EFS 46 vs. 46 %, p = 0.82). Cumulative incidence of non-relapse mortality (NRM) at 3 years adjusted for relapse as competing risk was 25 % for patients aged <60 years and 15 % for older patients (p = 0.15). Infusions of higher CD34(+) blood stem cell doses were associated with a significantly better outcome in the elderly subgroup (3-year OS 82 vs. 39 %, p = 0.007). Moreover, complete donor chimerism at day +100 was associated with a significantly improved survival (3-year OS 69 vs. 23 %, p = 0.003). In conclusion, our data suggest that RIC with FLU/BU enables long-term disease-free survival even in an elderly patient population. Age has no negative impact on the outcome of allogeneic HCT, and decision for transplant should be based on disease risk and performance status rather than age alone.
No preview · Article · Sep 2015 · Annals of Hematology
[Show abstract][Hide abstract] ABSTRACT: Major route additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukaemia (CML) indicate an increased risk of progression and shorter survival. Since major route ACA are almost always unbalanced, it is unclear whether other unbalanced ACA at diagnosis also confer an unfavourable prognosis. On the basis of 1348 Philadelphia chromosome-positive chronic phase patients of the randomized CML study IV, we examined the impact of unbalanced minor route ACA at diagnosis versus major route ACA on prognosis. At diagnosis, 1175 patients (87.2 %) had a translocation t(9;22)(q34;q11) and 74 (5.5 %) a variant translocation t(v;22) only, while a loss of the Y chromosome (-Y) was present in addition in 44 (3.3 %), balanced or unbalanced minor route ACA each in 17 (1.3 %) and major route ACA in 21 (1.6 %) cases. Patients with unbalanced minor route ACA had no significantly different cumulative incidences of complete cytogenetic remission or major molecular remission and no significantly different progression-free survival (PFS) or overall survival (OS) than patients with t(9;22), t(v;22), -Y and balanced minor route karyotypes. In contrast, patients with major route ACA had a shorter OS and PFS than all other groups (all pairwise comparisons to each of the other groups: p ≤ 0.015). Five-year survival probabilities were for t(9;22) 91.4 % (95 % CI 89.5-93.1), t(v; 22) 87 % (77.2-94.3), -Y 89.0 % (76.7-97.0), balanced 100 %, unbalanced minor route 92.3 % (72.4-100) and major route 52.2 % (28.2-75.5). We conclude that only major route, but not balanced or unbalanced minor route ACA at diagnosis, has a negative impact on prognosis of CML.
No preview · Article · Sep 2015 · Annals of Hematology
[Show abstract][Hide abstract] ABSTRACT: Insufficient production of leukocytes, thrombocytes and erythrocytes after allogeneic peripheral blood stem cell transplantation (PBSCT) represents a life-threatening complication.
In 20 adult patients with poor graft function (PGF defined as transfusion-dependent platelet counts <20,000/µl, or leukocytes <1500/µl, or transfusion-dependent anemia) and variable causes of PGF after allogeneic PBSCT, immunomagnetically selected CD34(+) stem cell boosts (SCB) from matched unrelated (n = 8), mismatched unrelated (n = 11) or haploidentical (n = 1) donors were applied without prior conditioning.
Patients received a median of 4.6 × 10(6) CD34(+) cells per kilogram bodyweight (1.9-9.1 × 10(6)) and low T cell numbers (median 0.2 × 10(4), range 0.04-0.6 × 10(4)). All patients showed responses in at least one hematopoietic lineage. Engraftment for platelets, leukocytes and hemoglobin was 88, 88 and 100 % after a median of 14, 13 and 18 days, respectively. With regard to the complete cohort, 90 % (n = 18) showed an increase in platelets (median 76,500/µl, range -7000 to 223,000/µl), 95 % (n = 19) had an increase in leukocytes (median 3110/µl, range 150-13,740/µl) and 90 % (n = 18) improved with regard to hemoglobin (median 1.9 g/dl, range -0.9 to 5.1 g/dl). Due to effective T cell depletion, only one patient developed graft versus host disease (GvHD, grade III) after SCB. Patients were followed for a median of 7.5 months (1-74 months) with 11 patients being alive and disease free with normalized peripheral blood counts at the end of follow-up.
CD34(+)-selected SCB are safe and effective and can durably improve PGF even in patients receiving grafts from unrelated matched or mismatched donors with low incidence of GvHD.
No preview · Article · Aug 2015 · Journal of Cancer Research and Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Tyrosine kinase inhibitors (TKI) have changed the natural course of CML. With the advent of 2nd generation TKI safety and efficacy issues have gained interest. The randomized CML - Study IV was used for a long-term evaluation of imatinib (IM)..1503 patients have received IM, 1379 IM monotherapy. After a median observation of 7.1 years 965 patients (64%) still received IM. At 10-years, progression-free survival was 82%, overall-survival 84%, 59% achieved MR(5), 72% MR(4.5), 81% MR(4), 89% MMR and 92% MR(2) (molecular equivalent to complete cytogenetic remission). All response levels were reached faster with IM800 mg except MR(5). 8-year probabilities of adverse drug reactions (ADR) were 76%, of grade 3-4 22%, of non-hematologic 73%, and of hematologic 28%. More ADR were observed with IM800 mg and IM400 mg plus interferon α (IFN). Most patients had their first ADR early with decreasing frequency later on. No new late toxicity was observed. ADR to IM are frequent, but mostly mild and manageable, also with IM 800mg and IM 400mg + IFN. The deep molecular response rates indicate that most patients are candidates for IM discontinuation. After 10 years, IM continues to be an excellent initial choice for most patients with CML.Leukemia accepted article preview online, 13 February 2015. doi:10.1038/leu.2015.36.
[Show abstract][Hide abstract] ABSTRACT: Reduced intensity conditioning regimens lead to an increasing use of allogeneic hematopoietic cell transplantation (HCT) in elderly patients. We retrospectively analyzed 151 patients aged ⩾60 receiving allogeneic HCT 2000-2012 at our center. Median age was 66 years. Kaplan-Meier estimated 3-year OS was 42% with a median follow-up of 38 months. Cumulative incidences of progression and non-relapse mortality after 3 years were 38 and 24%. OS was better in the group of patients >65 years with a Kaplan-Meier estimated OS of 50% vs 34%, P=0.060. We observed a significant influence of donor age (<50 years: 53% vs >50 years: 30%, P=0.017) and gender match (matched: 57% vs mismatched: 32%, P=0.007) on outcome. The use of a matched related donor was inferior compared with a matched or mismatched unrelated donor (19% vs 47%, P=0.015). On multivariate analysis there was an increased hazard ratio for a non-gender-matched HLA-matched-related donor (hazard ratio 3.23, 95% confidence interval 1.55-6.74, P=0.002). Age had no significant impact on OS (P=0.414). In conclusion, the data suggest that older age alone has no negative impact on the outcome of allogeneic HCT. Transplant decision should be tailored to disease risk and patient performance status rather than age.Bone Marrow Transplantation advance online publication, 19 January 2015; doi:10.1038/bmt.2014.292.
No preview · Article · Jan 2015 · Bone Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: The breakthrough development of clinically effective immune checkpoint inhibitors illustrates the potential of T-cell-based immunotherapy to effectively treat malignancies. A remaining challenge is to increase and guide the specificities of anticancer immune responses, e.g., by therapeutic vaccination or by adoptive T-cell transfer. By analyzing the landscape of naturally presented HLA class I and II ligands of primary chronic lymphocytic leukemia (CLL), we delineated a novel category of tumor-associated T-cell antigens based on their exclusive and frequent representation in the HLA ligandome of leukemic cells. These antigens were validated across different stages and mutational subtypes of CLL and found to be robustly represented in HLA ligandomes of patients undergoing standard chemo-/immunotherapy. We demonstrate specific immune recognition of these antigens exclusively in CLL patients, with the frequencies of representation in CLL ligandomes correlating with the frequencies of immune recognition by patient T cells. Moreover, retrospective survival analysis revealed survival benefits for patients displaying immune responses to these antigens. These results directly imply these nonmutant self-peptides as pathophysiologically relevant tumor antigens and encourages their implementation for cancer immunotherapy.
Full-text · Article · Dec 2014 · Proceedings of the National Academy of Sciences