M. Hallek

Early Prediction of Nonprogression in Advanced Non–Small-Cell Lung Cancer Treated With Erlotinib By Using [18F]Fluorodeoxyglucose and [18F]Fluorothymidine Positron Emission Tomography

PURPOSEnPositron emission tomography (PET) with both 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) and 3-[(18)F]fluoro-3-deoxy-L-thymidine (FLT) was evaluated with respect to the accuracy of early prediction of nonprogression following erlotinib therapy, independent from epidermal growth factor receptor (EGFR) mutational status, in patients with previously untreated advanced non-small-cell lung cancer (NSCLC).nnnPATIENTS AND METHODSnThirty-four patients with untreated stage IV NSCLC were evaluated in this phase II trial. Changes in FDG and FLT uptake after 1 (early) and 6 (late) weeks of erlotinib treatment were compared with nonprogression measured by computed tomography after 6 weeks of treatment, progression-free survival (PFS), and overall survival (OS).nnnRESULTSnChanges in FDG uptake after 1 week of therapy predicted nonprogression after 6 weeks of therapy with an area under the receiver operating characteristic curve of 0.75 (P = .02). Furthermore, patients with an early metabolic FDG response (cutoff value: 30% reduction in the peak standardized uptake value) had significantly longer PFS (hazard ratio [HR], 0.23; 95% CI, 0.09 to 0.59; P = .002) and OS (HR, 0.36; 95% CI, 0.13 to 0.96; P = .04). Early FLT response also predicted significantly longer PFS (HR, 0.31; 95% CI, 0.10 to 0.95; P = .04) but not OS and was not predictive for nonprogression after 6 weeks of therapy.nnnCONCLUSIONnEarly FDG-PET predicts PFS, OS, and nonprogression after 6 weeks of therapy with erlotinib in unselected, previously untreated patients with advanced NSCLC independent from EGFR mutational status.

Autologous blood stem cell transplantation in refractory systemic lupus erythematodes with recurrent longitudinal myelitis and cerebral infarction

Autologous hematopoietic stem cell transplantation (ASCT) has the potential to eliminate autoreactive lymphocytes and may represent a therapeutic option for patients with refractory autoimmune diseases. We describe a 19-year old woman with neuropsychiatric systemic lupus erythematodes (NPSLE) presenting with acute longitudinal myelitis and aseptic meningitis. Despite therapy with methylprednisolone and cyclophosphamide (CYC), recurrence of longitudinal myelitis and a disabling stroke-like relapse occurred. Hematopoietic stem cells were mobilized by CYC at 2 g/m2 and G-CSF. The patient was conditioned by CYC at 200 mg/kg and anti-thymocyte globulin and 3.6 = 106 CD34+ cells/kg were infused. Hematopoietic regeneration was observed on day 12 after ASCT. Currently, 18 months after ASCT, the patient is in clinical remission with no evidence for residual serological or neuroradiological activity of SLE. Although a longer follow-up will be needed to reliably assess the efficacy of ASCT in this patient, the present case demonstrates that ASCT may represent a therapeutic option for patients with severe NPSLE.

Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia

Hypoxia-induced p38 MAPK activation reduces Mcl-1 expression and facilitates sensitivity towards BH3 mimetics in chronic lymphocytic leukemia

CBP/p300 acetyltransferases regulate the expression of NKG2D ligands on tumor cells.

Tumor surveillance of natural killer (NK) cells is mediated by the cytotoxicity receptor natural-killer group 2 member D (NKG2D). Ligands for NKG2D are generally not expressed on healthy cells, but induced on the surface of malignant cells. To date, NKG2D ligand (NKG2D-L) induction was mainly described to depend on the activation of the DNA damage response, although the molecular mechanisms that regulate NKG2D-L expression remain largely unknown. Here, we show that the acetyltransferases CBP (CREB-binding protein) and p300 play a crucial role in the regulation of NKG2D-L on tumor cells. Loss of CBP/p300 decreased the basal cell surface expression of human ligands and reduced the upregulation of MICA/B and ULBP2 in response to histone deacetylase inhibitors or DNA damage. Furthermore, CBP/P300 deficiency abrogated the sensitivity of stressed cells to NK cell-mediated killing. CBP/p300 were also identified as major regulators of mouse NKG2D ligand RAE-1 in vitro and in vivo using the Eμ-Myc lymphoma model. Mechanistically, we observed an enhanced activation of the CBP/p300 binding transcription factor CREB (cAMP response element-binding protein) correlating to the NKG2D-L upregulation. Moreover, increased binding of CREB and CBP/p300 to NKG2D-L promoters and elevated histone acetylation were detectable. This study provides strong evidence for a major role of CBP and p300 in orchestrating NKG2D-L induction and consequently immunosurveillance of tumors in mice and humans. These findings might help to develop novel immunotherapeutic approaches against cancer.

Nonmyeloablative allogeneic stem cell transplantation for chronic lymphocytic leukaemia offers the possibility of disease control with minimal morbidity and mortality--a single institution experience.

Allogeneic stem cell transplantation is a treatment option for patients with poor risk CLL. We conducted a retrospective analysis of all CLL patients allografted at our institution, the University Hospital of Cologne, Germany. Data was collected on 40 patients from 2004 to 2012. The mean age was 54, and the majority were male (75xa0%). On average, the patients were diagnosed 6xa0years (range 2–12) prior to transplant with an average of 4xa0years (range 1–8) from time of first-line therapy to transplant. The remission states at the time of transplant were complete remission (CR) (nu2009=u20094), stable disease (nu2009=u200910), partial remission (nu2009=u200920) and progressive disease (nu2009=u20096). Only reduced intensity conditioning regimens were employed. The average CD34+ cell dose was 4.16u2009×u2009106/kg. Neutrophil engraftment was seen by day +17 (range 10–23) post-transplant, and 88xa0% achieved 95–100xa0% donor chimerism by day 100. Overall survival, progression-free survival and non-relapse mortality at 2xa0years post-transplant were 65, 52.5 and 27.5xa0%, respectively. A total of 51xa0% of patients were found to be minimal residual disease (MRD)-negative at 1xa0year post-transplant. Our single-centre experience confirms the valuable role of allogeneic stem cell transplantation (allo-SCT) in the treatment of poor risk CLL patients with promising long-term survival and acceptable transplant-related mortality. The advent of newer therapeutic agents should not hinder the consideration of allo-SCT for this patient cohort as it remains the only curative option for these patients.

Neutropenie und Sepsis

ZusammenfassungDas klinische Management von Infektionen während einer Neutropenie stellt eine große diagnostische und therapeutische Herausforderung dar. Die etablierten Sepsiskriterien sind nur bedingt anwendbar. Die Diagnostik wird durch eine begleitende Thrombopenie und die häufige respiratorische Insuffizienz erschwert. Fulminante Verläufe, eine Blutungsneigung und das „engraftment“ erschweren z.xa0T. die Therapie. Wichtig sind klare und gut kommunizierte Diagnostik- und Therapiealgorithmen, schnelles Handeln sowie eine enge Zusammenarbeit von Intensivmedizinern und hämatologisch bzw. onkologisch tätigen Ärzten.AbstractThe clinical management of neutropenic infections represents a great diagnostic and therapeutic challenge. Established sepsis criteria only partially reflect the neutropenic setting. Diagnostic procedures are frequently impaired by thrombocytopenia and progressive respiratory insufficiency. Increased tendency to bleed, engraftment, and fulminant progression represent major therapeutic challenges. Thus, crucial for the diagnosis and therapy of neutropenic sepsis are clear and well-communicated algorithms, rapid action, and close collaboration between oncologists and intensivists.

Diagnostisches Management von Fieber

ZusammenfassungFieber ist ein Symptom unterschiedlichster Erkrankungen. Das diagnostische Management ist von entscheidender Bedeutung. Dabei spielt die Schnittstelle zwischen niedergelassenem Arzt und Krankenhaus eine große Rolle. Bei der Erkennung von lebensbedrohlichen oder komplexen Situationen mit Fieber kommt dem Hausarzt eine besondere Bedeutung zu. Der hier vorgestellte diagnostische Algorithmus kann als Grundlage für eine rasche und zielführende Diagnostik dienen. Eine gute Kommunikation zwischen Hausarzt und Krankenhausarzt ist zwingend erforderlich.AbstractFever is axa0symptom of axa0wide range of diseases. Its diagnostic management is of crucial importance, whereby the interface between general practitioner and hospital plays an important role. The family practitioner is of particular importance in the detection of life-threatening or complex situations involving fever. The diagnostic algorithm presented here can serve as the basis for rapid and targeted diagnostics. Good communication between the doctor and the hospital doctor is mandatory.

Combined VEGF and PD-L1 blockade displays synergistic treatment effects in an autochthonous mouse model of small cell lung cancer

Small cell lung cancer (SCLC) represents the most aggressive pulmonary neoplasm and is often diagnosed at late stage with limited survival, despite combined chemotherapies. We show in an autochthonous mouse model of SCLC that combined anti-VEGF/anti-PD-L1-targeted therapy synergistically improves treatment outcome compared with anti-PD-L1 and anti-VEGF monotherapy. Mice treated with anti-PD-L1 alone relapsed after 3 weeks and were associated with a tumor-associated PD-1/TIM-3 double-positive exhausted T-cell phenotype. This exhausted T-cell phenotype upon PD-L1 blockade was abrogated by the addition of anti-VEGF-targeted treatment. We confirmed a similar TIM-3-positive T-cell phenotype in peripheral blood mononuclear cells of patients with SCLC with adaptive resistance to anti-PD-1 treatment. Mechanistically, we show that VEGFA enhances coexpression of the inhibitory receptor TIM-3 on T cells, indicating an immunosuppressive function of VEGF in patients with SCLC during anti-PD-1-targeted treatment. Our data strongly suggest that a combination of anti-VEGF and anti-PD-L1 therapies can be an effective treatment strategy in patients with SCLC.Significance: Combining VEGF and PD-L1 blockade could be of therapeutic benefit to patients with small cell lung cancer. Cancer Res; 78(15); 4270-81. ©2018 AACR.

Transplantation hämatopoetischer Stammzellen@@@Hematopoietic stem cell transplantation: Knochenmark und Blutstammzellen@@@Bone marrow and blood stem cells

ZusammenfassungDie Zahl der Stammzelltransplantationen in Deutschland nimmt seit Jahren stetig zu. Patienten mit höherem Lebensalter und umfassenden Begleiterkrankungen werden deutlich häufiger in kurativer Intention einer Transplantation unterzogen. Aufgrund neuer Strategien wie der Nabelschnurblut- oder der haploidenten Transplantation steigt die Verfügbarkeit passender Spender weiter an. Daraus resultiert auch eine stetige Zunahme an komplex und kritisch kranken Transplantatempfängern. Neue Verfahren in der Intensivmedizin, insbesondere in der Sepsistherapie und der Beatmungsmedizin, stehen für diese Patienten zur Verfügung. Die Identifikation klarer Aufnahmekriterien sowie eindeutiger Algorithmen in Bezug auf Behandlungsdauer und -umfang ist damit eine wichtige und dynamische interdisziplinäre Herausforderung, und das nicht nur für Transplanteur und Intensivmediziner.AbstractThe number of hematopoietic stem cell transplantations is continuously increasing. On the one hand reduced intensity conditioning and improved supportive therapies allow for transplantations in patients with significant comorbidities and up to their eighth decade of life. Due to this development the number of complex and critically ill patients in need of intensive care is constantly growing. Recent developments in general critical care such as sepsis bundles and non-invasive ventilation contribute to a better outcome of these patients. However, treatment algorithms that identify patients potentially benefitting from intensive care but also reduce overtreatment of moribund patients represent a central multidisciplinary challenge not only for the treating transplant physician and intensivist.The number of hematopoietic stem cell transplantations is continuously increasing. On the one hand reduced intensity conditioning and improved supportive therapies allow for transplantations in patients with significant comorbidities and up to their eighth decade of life. Due to this development the number of complex and critically ill patients in need of intensive care is constantly growing. Recent developments in general critical care such as sepsis bundles and non-invasive ventilation contribute to a better outcome of these patients. However, treatment algorithms that identify patients potentially benefitting from intensive care but also reduce overtreatment of moribund patients represent a central multidisciplinary challenge not only for the treating transplant physician and intensivist.

Intensivmedizinisches Management hämatologischer und onkologischer Patienten

Jeder sechste Patient auf deutschen Intensivstationen hat eine Tumorerkrankung. Trotzdem besteht eine große Unsicherheit hinsichtlich der Indikationsstellung, der Therapiedauer und des Umfangs der Intensivtherapie. Während in onkologischen Zentren die Aufnahme palliativer Patienten zur zeitlich limitierten Therapie häufig etabliert ist, kann andernorts die Diagnose „Krebs“ zur Verweigerung der Aufnahme auf die Intensivstation führen. Vor dem Hintergrund der zunehmenden Zahl an Menschen, die mit einer Tumorerkrankung leben, der raschen Entwicklung von Krebstherapeutika mit unerwarteten und z. T. dramatischen Nebenwirkungen sowie der Verbesserung der Prognose von Patienten mit Zwei- oder Mehrorganversagen ist die Entwicklung von Aufnahme- und Therapiealgorithmen für kritisch kranke Tumorpatienten dringend geboten.