Search

The phase III study was designed to compare event-free survival (EFS) after treosulfan-based conditioning with a widely applied reduced-intensity conditioning (RIC) busulfan regimen in older or comorbid patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) undergoing allogeneic hematopoietic cell transplantation (HCT). A previously reported confirmatory interim analysis of the randomized clinical study including 476 patients demonstrated statistically significant noninferiority for treosulfan with clinically meaningful improvement in EFS. Here, the final study results and pre-specified subgroup analyses of all 570 randomized patients with completed longer-term follow-up are presented. Patients presenting HCT-specific comorbidity index >2 or aged >= 50 years were randomly assigned (1:1) to intravenous (IV) fludarabine with either treosulfan (30 g/m(2) IV) or busulfan (6.4 mg/kg IV) after stratification by disease risk group, donor type, and participating institution. The primary endpoint was EFS with disease recurrence, graft failure, or death from any cause as events. EFS of patients (median age 60 years) was superior after treosulfan compared to RIC busulfan: 36-months-EFS rate 59.5% (95% CI, 52.2-66.1) vs. 49.7% (95% CI, 43.3-55.7) with a hazard ratio (HR) of 0.64 (95% CI, 0.49-0.84), p = 0.0006. Likewise, overall survival (OS) with treosulfan was superior compared to busulfan: 36-month-OS rate 66.8% vs. 56.3%; HR 0.64 (95% CI, 0.48-0.87), p = 0.0037. Post hoc analyses revealed that these differences were consistent with the confirmatory interim analysis, and thereby the treosulfan regimen appears particularly suitable for older AML and MDS patients.

IntroductionUnderstanding prognosis, especially long-term outcome, in advanced nonsmall cell lung cancer (NSCLC) is crucial to inform patients, guide treatment and plan supportive and palliative care.MethodsPrognostic factors influencing overall survival (OS) and progression-free survival (PFS) in 2082 patients with wild-type (WT)-NSCLC (629 M1a, 249 M1b, 1204 M1c) are reported. Patients were included in the prospective German CRISP registry recruiting in >150 centres. Analysis for pre-therapeutic factors was based on results from Cox proportional hazard models.ResultsCurrent M-descriptors of the Union for International Cancer Control-8 staging system were validated: M1a and M1b patients had significantly longer median time to events compared to M1c (OS/PFS 16.4/7.2 months, 17.8/6.7 months and 10.9/5.4 months, respectively). OS and PFS were influenced by number and location of metastatic organ systems. M1c and four or more metastatic organs involved had shorter OS and PFS than M1c with one to three organs (OS hazard ratio (HR) 1.69, pConclusionIn this large observational dataset, we further defined factors for outcome in WT-NSCLC, including increased number of involved metastatic organ systems and liver metastases, as those with overall poorer prognosis and reduced survival chance.

Supplemental material, sj-docx-2-pmj-10.1177_02692163221099114 for COVID-19: Challenges and solutions for the provision of care to seriously ill and dying people and their relatives during SARS-CoV-2 pandemic – perspectives of pandemic response team members: A qualitative study on the basis of expert interviews (part of PallPan) by Isabell Klinger, Maria Heckel, Sophie Shahda, Ursula Kriesen, Carolin Schneider, Sandra Kurkowski, Christian Junghanss and Christoph Ostgathe in Palliative Medicine

Supplemental material, sj-doc-1-ict-10.1177_15347354221143064 for Association Between Cancer-Related Fatigue and Falls in Patients With Myeloproliferative Neoplasms: Results of a Multicenter Cross-Sectional Survey From the East German Study Group for Hematology and Oncology (OSHO #97) by Sabine Felser, Martin Gube, Julia Gruen, Philipp Ie Coutre, Susann Schulze, Lars-Olof Muegge, Christian Junghanss and Sabina Ulbricht in Integrative Cancer Therapies

Supplemental material, sj-docx-1-pmj-10.1177_02692163221099114 for COVID-19: Challenges and solutions for the provision of care to seriously ill and dying people and their relatives during SARS-CoV-2 pandemic – perspectives of pandemic response team members: A qualitative study on the basis of expert interviews (part of PallPan) by Isabell Klinger, Maria Heckel, Sophie Shahda, Ursula Kriesen, Carolin Schneider, Sandra Kurkowski, Christian Junghanss and Christoph Ostgathe in Palliative Medicine

Supplemental material, sj-docx-1-pmj-10.1177_02692163221099114 for COVID-19: Challenges and solutions for the provision of care to seriously ill and dying people and their relatives during SARS-CoV-2 pandemic – perspectives of pandemic response team members: A qualitative study on the basis of expert interviews (part of PallPan) by Isabell Klinger, Maria Heckel, Sophie Shahda, Ursula Kriesen, Carolin Schneider, Sandra Kurkowski, Christian Junghanss and Christoph Ostgathe in Palliative Medicine

Tumors arising in the context of Lynch Syndrome or constitutional mismatch repair deficiency are hypermutated and have a good response towards immune-checkpoint inhibitors (ICIs), including α-PD-L1 antibodies. However, in most cases, resistance mechanisms evolve. To improve outcomes and prevent resistance development, combination approaches are warranted. Herein, we applied a combined regimen with an α-PD-L1 antibody and gemcitabine in a preclinical tumor model to activate endogenous antitumor immune responses. Mlh1−/− mice with established gastrointestinal tumors received the α-PD-L1 antibody (clone 6E11, 2.5 mg/kg bw, i.v., q2wx3) and gemcitabine (100 mg/kg bw, i.p., q4wx3) in mono- or combination therapy. Survival and tumor growth were recorded. Immunological changes in the blood were routinely examined via multi-color flow cytometry and complemented by ex vivo frameshift mutation analysis to identify alterations in Mlh1−/−-tumor-associated target genes. The combined therapy of α-PD-L1 and gemcitabine prolonged median overall survival of Mlh1−/− mice from four weeks in the untreated control group to 12 weeks, accompanied by therapy-induced tumor growth inhibition, as measured by [18F]-FDG PET/CT. Plasma cytokine levels of IL13, TNFα, and MIP1β were increased and also higher than in mice receiving either monotherapy. Circulating splenic and intratumoral myeloid-derived suppressor cells (MDSCs), as well as M2 macrophages, were markedly reduced. Besides, residual tumor specimens from combi-treated mice had increased numbers of infiltrating cytotoxic T-cells. Frameshift mutations in APC, Tmem60, and Casc3 were no longer detectable upon treatment, likely because of the successful eradication of single mutated cell clones. By contrast, novel mutations appeared. Collectively, we herein confirm the safe application of combined chemo-immunotherapy by long-term tumor growth control to prevent the development of resistance mechanisms.

Background The tumor suppressor protein phosphatase and tensin homolog (PTEN) is a key regulator of the PI3K/AKT pathway which is frequently altered in a variety of tumors including a subset of acute B-lymphoblastic leukemias (B-ALL). While PTEN mutations and deletions are rare in B-ALL, promoter hypermethylation and posttranslational modifications are the main pathways of PTEN inactivation. Casein Kinase II (CK2) is often upregulated in B-ALL and phosphorylates both PTEN and DNA methyltransferase 3A, resulting in increased PI3K/AKT signaling and offering a potential mechanism for further regulation of tumor-related pathways. Methods Here, we evaluated the effects of CK2 inhibitor CX-4945 alone and in combination with hypomethylating agent decitabine on B-ALL proliferation and PI3K/AKT pathway activation. We further investigated if CX-4945 intensified decitabine-induced hypomethylation and identified aberrantly methylated biological processes after CK2 inhibition. In vivo tumor cell proliferation in cell line and patient derived xenografts was assessed by longitudinal full body bioluminescence imaging and peripheral blood flow cytometry of NSG mice. Results CX-4945 incubation resulted in CK2 inhibition and PI3K pathway downregulation thereby inducing apoptosis and anti-proliferative effects. CX-4945 further affected methylation patterns of tumor-related transcription factors and regulators of cellular metabolism. No overlap with decitabine-affected genes or processes was detected. Decitabine alone revealed only modest anti-proliferative effects on B-ALL cell lines, however, if combined with CX-4945 a synergistic inhibition was observed. In vivo assessment of CX-4945 in B-ALL cell line xenografts resulted in delayed proliferation of B-ALL cells. Combination with DEC further decelerated B-ALL expansion significantly and decreased infiltration in bone marrow and spleen. Effects in patient-derived xenografts all harboring a t(4;11) translocation were heterogeneous. Conclusions We herein demonstrate the anti-leukemic potential of CX-4945 in synergy with decitabine in vitro as well as in vivo identifying CK2 as a potentially targetable kinase in B-ALL. Electronic supplementary material The online version of this article (10.1186/s12885-019-5411-0) contains supplementary material, which is available to authorized users.

Background: Impaired B-cell receptor (BCR) function has been associated with the progress of several B-cell malignancies. The spleen tyrosine kinase (SYK) represents a potential therapeutic target in a subset of B-cell neoplasias. In precursor B-acute lymphoblastic leukemia (B-ALL), the pathogenic role and therapeutic potential of SYK is still controversially discussed. We evaluate the application of the SYK inhibitor entospletinib (Ento) in pre- and pro-B-ALL cell lines, characterizing the biologic and molecular effects. Methods: SYK expression was characterized in pre-B-ALL (NALM-6) and pro-B-ALL cell lines (SEM and RS4, 11). The cell lines were exposed to different Ento concentrations and the cell biological response analyzed by proliferation, metabolic activity, apoptosis induction, cell-cycle distribution and morphology. BCR pathway gene expression and protein modulations were further characterized. Results: Ento significantly induced anti-proliferative and pro-apoptotic effects in NALM-6 and SEM, while barely affecting RS4, 11. Targeted RNAseq revealed pronounced gene expression modulation only in NALM-6, while Western Blot analyses demonstrated that vital downstream effector proteins, such as pAKT, pERK, pGSK3&beta, p53 and BCL-6, were affected by Ento exposure in the inhibitor-sensitive cell lines. Conclusion: Different acting modes of Ento, independent of pre-BCR dependency, were characterized, unexpected in SEM. Accordingly, SYK classifies as a potential target structure in a subset of pro-B-ALLs.

The isoquinolinamine FX-9 is a novel potential chemotherapeutic agent showing antiproliferative effects against hematologic and prostate cancer cell lines such as B- and T-acute lymphoblastic leukemia and prostate cancer (PC) of different species. Interestingly, FX-9 shows no hemolytic activity and low toxicity in benign adherent cells. The detailed FX-9 molecular mode of action is currently not fully understood. But application on neoplastic cells induces pro-apoptotic and antimitotic effects. Canine prostate cancer (cPC) represents a unique spontaneous occurring animal model for human androgen-independent PC. Human androgen-independent PC as well as cPC are currently not satisfactorily treatable with chemotherapeutic protocols. Accordingly, the evaluation of novel agent combinations bears significant potential for identifying novel treatment strategies. In this study, we combined FX-9 with the currently approved therapeutic agents doxorubicin, carboplatin, the demethylating substance azacitidine as well as further potentially antitumorigenic agents such as dichloroacetic acid (DCA) in order to evaluate the respective synergistic potential. The combinations with 1-5 μM FX-9 were evaluated regarding the effect after 72 hours on cell viability, cell count and apoptotic/necrotic cells in two human prostate cancer cell lines (LNCaP, PC-3) and a canine prostate cancer cell line (Adcarc1258) representing androgen-dependent and -independent PC/cPC forms. FX-9 in combination with azacitidine decreases cell viability and increases cell death with positive Bliss values. Furthermore, this decreases the cell count with neutral Bliss values on PC-3. Carboplatin in combination with FX-9 reduces cell viability with a neutral Bliss value and increases cell death on LNCaP with calculated positive Bliss values. DCA or doxorubicin in combination with FX-9 do not show synergistic or additive effects on the cell viability. Based on these results, azacitidine or carboplatin in combination with FX-9 offers synergistic/additive efficacy against prostate adenocarcinoma cell lines in vitro. The beneficial effects of both combinations are worth further investigation.

Hintergrund: In der SARS-CoV2-Pandemie fokussierten sich die Aktivitäten der medizinischen Versorgung v.a. auf die Einrichtung von Intensivbetten für akut COVID-19 Erkrankte. Trotz des in Deutschland abgeschwächteren Verlaufs verstarben über 9.000 Menschen an bzw. mit COVID-19. Zusätzlich[zum vollständigen Text gelangen Sie über die oben angegebene URL], 19. Deutscher Kongress für Versorgungsforschung (DKVF)

Introduction: Head and neck cancer patients often suffer from physical and cognitive impairments after cancer treatment. During rehabilitation, exercise therapy can improve physical function and quality of life (QoL). Surveys demonstrated patients’ preference for home training with low- to moderate-intensity. This study was conducted in order to develope a suitable home-based training program. Therefore, the feasibility and effects of a low- to moderate-intensity exercise intervention on physical functions and QoL were evaluated. Methods: Training was conducted as supervised group training and consisted of mobilization, coordination, resistance, stretching, and relaxation exercises. The intervention lasted 12 weeks with 2 training sessions per week. Feasibility, attendance rate, physical function (eg, range of motion, 6-minute walk test [6MWT]), and QoL (eg, EORTC QLQ-30) were analyzed. Results: Ten out of 12 participants completed the intervention (83%) with an average attendance rate of 83%. Participants showed significant improvements in selected physical functions. For example, head rotation increased by 11.2° (P = .042), walking distance in the 6MWT increased by an average of 43.3 m (P = .010), and the global QoL scale improved by 8.2 points (P = .059). Additionally, there were positive changes in the physical function scale (P = .008), cognitive function scale (P = .015), and social function scale (P = .031) of the EORTC QLQ-30. Conclusion: Data indicate that the exercise program was feasible and had positive effects on physical function and QoL. Future research will analyze the effects of a home-based exercise program on physical function and QoL in a large-scale study.

Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO2) are the key enzymes of tryptophan (TRP) metabolism in the kynurenine pathway (KP). Both enzymes function as indicators of immunosuppression and poor survival in cancer patients. Direct or indirect targeting of either of these substances seems thus reasonable to improve therapy options for patients. In this study, glioblastoma multiforme (GBM) as well as head and neck squamous cell carcinomas (HNSCC) were examined because of their different mechanisms of spontaneous and treatment-induced immune escape. Effects on gene expression and protein levels were examined. Accompanying assessment of TRP metabolites from treated GBM cell culture supernatants was conducted. Our results show a heterogeneous and inversely correlated expression profile of TRP-metabolizing genes among GBM and HNSCC cells, with low, but inducible IDO1 expression upon IFNγ treatment. TDO2 expression was higher in GBM cells, while genes encoding kynurenine aminotransferases were mainly confined to HNSCC cells. These data indicate that the KP is active in both entities, with however different enzymes involved in TRP catabolism. Upon treatment with Temozolomide, the standard of care for GBM patients, IDO1 was upregulated. Comparable, although less pronounced effects were seen in HNSCC upon Cetuximab and conventional drugs (i.e., 5-fluorouracil, Gemcitabine). Here, IDO1 and additional genes of the KP (KYAT1, KYAT2, and KMO) were induced. Vice versa, the novel yet experimental cyclin-dependent kinase inhibitor Dinaciclib suppressed KP in both entities. Our comprehensive data imply inhibition of the TRP catabolism by Dinaciclib, while conventional chemotherapeutics tend to activate this pathway. These data point to limitations of conventional therapy and highlight the potential of targeted therapies to interfere with the cells' metabolism more than anticipated.

Additional File 8: Figure S5. Original blots for Fig. 3b, c, S2, S3. Red boxes indicate the regions used in the respective Figures.

Additional file 1.

Additional File 1: Table S1. List of all mice recruited in the study, respective end points and analyses conducted.

Additional File 3: Table S2. Gene expression fold changes of genes involved in apoptotic processes.

Current therapies are insufficient for metastatic prostate cancer (PCa) in men and dogs. As human castrate-resistant PCa shares several characteristics with the canine disease, comparative evaluation of novel therapeutic agents is of considerable value for both species. Novel isoquinolinamine FX-9 exhibits antiproliferative activity in acute lymphoblastic leukemia cell lines but has not been tested yet on any solid neoplasia type. In this study, FX-9&prime, s mediated effects were characterized on two human (PC-3, LNCaP) and two canine (CT1258, 0846) PCa cell lines, as well as benign solid tissue cells. FX-9 significantly inhibited cell viability and induced apoptosis with concentrations in the low micromolar range. Mediated effects were highly comparable between the PCa cell lines of both species, but less pronounced on non-malignant chondrocytes and fibroblasts. Interestingly, FX-9 exposure also leads to the formation and survival of enlarged multinucleated cells through mitotic slippage. Based on the results, FX-9 acts as an anti-mitotic agent with reduced cytotoxic activity in benign cells. The characterization of FX-9-induced effects on PCa cells provides a basis for in vivo studies with the potential of valuable transferable findings to the benefit of men and dogs.

Table S4. List of patient derived xenograft mice used (DOCX 16 kb)

Table S2. List of primers used for LINE-1 methylation analysis. (DOCX 13 kb)

Table S1. List of antibodies used for Western blot analyses. (DOCX 14 kb)

Table S9. Influence of CX and DEC on PTEN and CK2 promoter methylation beta values and respective fold changes (FC). (DOCX 14 kb)

In dogs as well as humans, lymphoma is one of the most common hematopoietic malignancies. Furthermore, due to its characteristics, canine lymphoma is recognized as a clinically relevant in vivo model to study the corresponding human disease. Immortalized cell lines are widely used as in vitro models to evaluate novel therapeutic agents and characterize their molecular mechanisms. However, it is known that long-term cultivation leads to clonal selection, genetic instability, and loss of the initial heterogenic character, limiting the usefulness of cell lines as preclinical models. Herein, we present a systematic characterization and comparison of the transcriptomic landscape of canine primary B- and T-cell lymphomas, five lymphoid cell lines (CLBL-1, CLBL-1M, GL-1, CL-1, and OSW) and four non-neoplastic control samples. We found that lymphomas and cell lines exhibit a common “differentiation and proliferation signature”. However, our analysis also showed that, independently of the cell of origin, the transcriptional signatures of lymphomas are more similar to each other than they are to those of cell lines. In particular, we observed that not all common therapeutic targets are similarly expressed between lymphomas and lymphoid cell lines, and provide evidence that different lymphoid cell-lines should be used to model distinct aspects of lymphoma dysregulation.

BACKGROUND: This is the final report of the G-PCNSL-SG-1 trial after a median follow-up of 81.2 months. METHODS: G-PCNSL-SG-1 (www.clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00153530","term_id":"NCT00153530"}}NCT00153530) had randomised immunocompetent patients with newly diagnosed PCNSL to high-dose methotrexate (HDMTX) - based chemotherapy followed by whole-brain radiotherapy (WBRT) or chemotherapy alone. We hypothesized that the omission of WBRT from first-line treatment would not compromise overall survival (OS; primary endpoint), using a non-inferiority design with a margin of 0.9. FINDINGS: Of 551 patients who entered the study 524 fulfilled the eligibility criteria, 410 entered the post-HDMTX phase (intention-to-treat, ITT population), and 320 were treated per protocol (PP). OS with versus without WBRT was different neither in the ITT (HR 0.997, 95%CI 0.79-1.26, p = 0.98) nor in the PP population (HR 1.03, 95%CI 0.79-1.35, p = 0.82). In the ITT population CR patients experienced neither a progression-free survival (PFS) benefit from the last HDMTX-based CHT (PFS-2) (HR 0.84, 95% CI 0.60-1.19, p = 0.33) nor an OS benefit (HR 1.13, 95% CI 0.77-1.66, p = 0.53) with WBRT. In CR patients of the PP population, WBRT conferred a benefit for PFS-2 (HR 0.68, 95%CI 0.46-1.01, p = 0.057), but no OS benefit (HR 1.06, 95%CI 0.69-1.63, p = 0.78). In non-CR patients of the ITT population, a benefit of PFS-2 (HR 0.58, 95%CI 0.44-0.77, p < 0.001), but not of OS (HR 0.86, 95%CI 0.64-1.16, p = 0.32) was found with WBRT; in non-CR patients of the PP population, WBRT conferred a benefit of PFS-2 over CHT alone (HR 0.41, 95%CI 0.29-0.57, p < 0.001) and a trend for OS, too (HR 0.76, 95%CI 0.54-1.08, p = 0.12). INTERPRETATION: Despite improvement in PFS, particularly in patients without CR to HDMTX-based CHT, no significant difference in OS was found when WBRT was omitted from primary therapy in this long-term follow-up analysis. The PFS afforded by WBRT has to be balanced against its long-term toxicity.

Es wurden 51 Patienten mit Ileus und Subileus auf einer Palliativstation charakterisiert (2010-2015). Konservativ geführte Patienten zeigten eine kürzere stationäre Verweildauer, aber auch ein kürzeres Überleben. Die krankenhausfreien Tage waren interventionsartunabhängig. Die initial aufnehmende Einheit präjudiziert teilweise den weiteren Behandlungsweg. Die Ileusform zeigte einen signifikanten Einfluss auf das Überleben, die Grunderkrankung, der Metastasenstatus und das Alter nicht. Starke Heterogenität und relativ kleine Fallzahlen erschweren eine Verallgemeinerung.

Ein NGS Panel zur Sequenzierung der gesamten proteinkodierenden Sequenz der Gene JAK2, MPL und CALR wurde etabliert und in der Studie: „Prävalenz von JAK2-Mutationen bei Patienten mit abdominalen Venenthrombosen“ angewendet. Das NGS Panel zeigte hohe Sensitivität. Von 02/17 bis 02/19 konnten 43 Patienten in die Studie eingeschlossen werden. Die JAK2 p.V617F Mutation konnte in 16,3 % der untersuchten Proben detektiert werden. Es konnten 6 Proben mit einer Allelfrequenz unter 2 % beschrieben werden. Klinische Daten ließen kaum Unterschiede zwischen Patienten mit und ohne Aberration erkennen.

Der PI3K/Akt-Signalweg ist einer der am häufigsten mutierten und aberrant aktivierten Signalwege bei verschiedensten Tumorentitäten, inkl. den akuten Leukämien. Als zentrales Effektorprotein reguliert die Akt-Kinase u.a. Zellwachstum und Apoptose. Akt ist bei der B-ALL häufig überexprimiert bzw. aberrant aktiviert. MK-2206 ist ein pan-Akt-Inhibitor, welcher in präklinischen Studien bereits vielversprechende Effekte gezeigt hat. In der vorliegenden Arbeit konnten durch MK-2206-Inkubation anti-leukämische Effekte sowohl auf B-ALL-Zelllinien als auch auf B-ALL-Primärzellen gezeigt werden.

Key proteins such as CK2, CDK, PI3K, AKT and KRAS are often considered as promising target molecules for therapeutic intervention strategies due to their important roles in the occurrence, development and prognosis of PDAC. The aim of this doctoral thesis was to explore the different effects of the above-mentioned key protein inhibitors on various PDAC cell lines, and to explore the effect of aberrations in the target genes of the inhibitors on the efficacy of the corresponding inhibitors by applying whole-exome sequencing (WES) and RNA sequencing (RNA-seq).

In der vorliegenden Arbeit wurden die Risikofaktoren, Behandlungs- und Langzeitergebnisse von 265 Hodenkrebs-Patienten an der urologischen Klinik des Rostocker Universitätsklinikums über einen Zeitraum von 16 Jahren retrospektiv untersucht.