Mutation-based, short-term "neoadjuvant" treatment allows resectability in stage IVB and C anaplastic thyroid cancer.

INTRODUCTION: Few available data indicate that a mutation-based "neoadjuvant" therapy in advanced anaplastic thyroid carcinoma (ATC) might convert an initially unresectable primary tumor to resectable and optimize local tumor control. We evaluated a preoperative short-term "neoadjuvant" therapy with a BRAF-directed therapy or, in case of BRAF non-mutated tumors, an mKI/checkpoint inhibitor combination in three patients with ATC stage IVB and C. METHODS: In the context of preoperative diagnostics, immunohistochemistry (IHC) assessment and genetic analysis was started as soon as possible. The antiangiogenetic therapy with lenvatinib was immediately after diagnosis of ATC started as bridging therapy. In case of a BRAF-mutated ATC, a combination therapy of dabrafenib and trametinib, in case of BRAF-wildtype ATC a combination of pembrolizumab and lenvatinib was given for 4 weeks. If re-staging has shown a significant therapy response due to a decrease in size of > 50%, surgical resection was reconsidered. A primary tumor resection was performed first. As a second step, limited distant metastasis have been resected approximately 4 weeks after thyroid surgery. After postoperative recovery, the targeted systemic therapy was continued. PATIENTS: Two patients presented with BRAF-wildtype ATC stage IVC, one with BRAF-mutated ATC stage IVB. All patients were evaluated by surgery, nuclear medicine and oncology upon diagnosis of ATC. RESULTS: In all three cases, the "neoadjuvant" therapy induced a dramatic response and led to local resectability in primarily non-resectable ATC stage IVB or C. We have chosen for the first time a short-term "neoadjuvant" treatment period to reduce the risk of bleeding and/or fistula due to potential rapid tumor shrinkage. The results of surgery after only short-term "neoadjuvant" therapy showed two R0 und one R1 resections. Postoperative histopathological findings confirmed an extent of tumor necrosis or regressive fibrotic tissue between 60 and > 95% in our patients. CONCLUSIONS: A short-term mutation-based "neoadjuvant" therapy can achieve local resectability in initially unresectable ATC stage IVB or C. A neoadjuvant treatment period of about 4 weeks seems to show similar response as a treatment duration of at least 3 months.

Budget impact of the Oncotype DX® test compared to other gene expression tests in patients with early breast cancer in Germany.

PURPOSE: Gene expression tests can inform decisions on whether to recommend chemotherapy for patients with HR+, HER2- early breast cancer. The goal of this analysis was to compare treatment costs by an expanded budget impact model of reimbursed gene expression tests in Germany. METHODS: A cost comparison was constructed as an expanded budget impact model to calculate average total costs per patient covered by public health insurance. Based on the strong clinical evidence from the prospective randomized controlled trial TAILORx including more than 10,000 patients with HR+ and node negative breast cancer, the assumption was made that the Oncotype DX® test accurately predicts chemotherapy benefit and clinical outcomes. For the further reimbursed tests (EndoPredict®, MammaPrint®, Prosigna®), results from comparative studies - aligned with prognosis studies - as analyzed in IQWiG Rapid Report D19-01 were applied. RESULTS: The use of the Oncotype DX test led to estimated average savings per patient of 2,500 € vs. EndoPredict, 1,936 € vs. MammaPrint, and 649 € vs. Prosigna. Savings were achieved by reduction of unnecessary chemotherapy use, a consequence of false-positive test results (EndoPredict 73%, MammaPrint 42%, Prosigna 20%). False-negative test results (EndoPredict 5%, MammaPrint 22%, Prosigna 49%) reduced necessary chemotherapies, which initially results in cost savings, but may lead to increased long-term costs associated with management of progressive disease. CONCLUSION: The results from this model suggest that the use of the Oncotype DX test reduces the cost of health care in Germany making it the most cost effective test compared to the further tests.

CD11c+ dendritic cells mediate antigen-specific suppression in extracorporeal photopheresis.

Extracorporeal photopheresis (ECP) represents one of the most widespread and effective cell therapies for graft-versus-host disease and other T cell-mediated disorders. However, the key factors affecting the therapeutic efficacy of ECP remain unclear. We hypothesized that therapeutic effects are mediated by ECP-treated antigen-presenting dendritic cells (DC). To test this hypothesis, we used the experimental model of contact hypersensitivity (CHS). The ECP's therapeutic activity improved when the total cell dose of the ECP-treated cells was increased. We used different haptens during sensitization to demonstrate that the anti-inflammatory activity of ECP is antigen-specific. This confirmed the hypothesis that professional antigen-presenting cells are involved in the mode of action. Also, the ECP's therapeutic activity was abrogated by the depletion of CD11c+ DC, which represents fewer than 1% of all the ECP-exposed cells. Finally, we confirm the critical importance of CD11c+ DC for ECP activity by showing that only a few purified CD11c+ DC are sufficient to mediate its therapeutic effect. The finding that ECP-treated, physiological antigen-presenting DC alone mediate antigen-specific modulation of a pathological immune response may result in better-targeted interventions when treating patients.

Ultrasmall Moment Incommensurate Spin Density Wave Order Masking a Ferromagnetic Quantum Critical Point in NbFe_{2}.

In the metallic magnet Nb_{1-y}Fe_{2+y}, the low temperature threshold of ferromagnetism can be investigated by varying the Fe excess y within a narrow homogeneity range. We use elastic neutron scattering to track the evolution of magnetic order from Fe-rich, ferromagnetic Nb_{0.981}Fe_{2.019} to approximately stoichiometric NbFe_{2}, in which we can, for the first time, characterize a long-wavelength spin density wave state burying a ferromagnetic quantum critical point. The associated ordering wave vector q_{SDW}=(0,0,l_{SDW}) is found to depend significantly on y and T, staying finite but decreasing as the ferromagnetic state is approached. The phase diagram follows a two-order-parameter Landau theory, for which all of the coefficients can now be determined. Our findings suggest that the emergence of spin density wave order cannot be attributed to band structure effects alone. They indicate a common microscopic origin of both types of magnetic order and provide strong constraints on related theoretical scenarios based on, e.g., quantum order by disorder.

[Rare diseases recognizable from blood smears]. / Seltene Erkrankungen am Blutbild erkennen.

The examination of peripheral blood smears is not only essential for the differential diagnostics of hematological diseases but can also provide important indications for general internal diseases, infections, hereditary diseases and poisoning. By the systematic analysis of a blood smear for alterations to thrombocytes, erythrocytes and leukocytes, a blood smear investigation can make a decisive contribution to the formulation of a diagnosis. In this way evidence of rare diseases can also be gained when taking the corresponding clinical findings into consideration.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

This corrects the article DOI: 10.1038/leu.2017.9.

The influence of transcranial alternating current stimulation (tACS) on fluid intelligence: An fMRI study.

The past decades have witnessed a huge interest in uncovering the neural bases of intelligence (e.g., Stelmack, & Houlihan, 1995; Stelmack, Knott, & Beauchamp, 2003). This study investigated the influence of transcranial alternating current stimulation (tACS) on fluid intelligence performance and corresponding brain activation. Previous findings showed that left parietal theta tACS leads to a transient increase in fluid reasoning performance. In an attempt to extend and replicate these findings, we combined theta tACS with fMRI. In a double-blind sham-controlled experiment, N = 20 participants worked on two intelligence tasks (matrices and paper folding) after theta tACS was applied to the left parietal cortex. Stimulation-induced brain activation changes were recorded during task processing using fMRI. Results showed that theta tACS significantly increased fluid intelligence performance when working on difficult items in the matrices test; no effect was observed for the visuo-spatial paper folding test. Whole-brain analyses showed that left parietal brain stimulation was accompanied by lower activation in task-irrelevant brain areas. Complemental ROI analyses revealed a tendency towards lower activation in the left inferior parietal cortex. These findings corroborate the functional role of left parietal theta activity in fluid reasoning and are in line with the neural efficiency hypothesis.

Long-term survival of sorafenib-treated FLT3-ITD-positive acute myeloid leukaemia patients relapsing after allogeneic stem cell transplantation.

BACKGROUND: Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD)-positive acute myeloid leukaemia (AML) relapsing after allogeneic stem cell transplantation (allo-SCT) has a dismal prognosis with limited therapeutic options. FLT3-ITD kinase inhibition is a reasonable but palliative experimental treatment alternative in this situation. Information on long-term outcome is not available. METHODS: We performed a long-term follow-up analysis of a previously reported cohort of 29 FLT3-ITD-positive AML patients, which were treated in relapse after allo-SCT with sorafenib monotherapy. FINDINGS: With a median follow-up of 7.5 years, 6 of 29 patients (21%) are still alive. Excluding one patient who received a second allo-SCT, five patients (17%) achieved sustained complete remissions with sorafenib. Four of these patients are in treatment-free remission for a median of 4.4 years. INTERPRETATION: Sorafenib may enable cure of a proportion of very poor risk FLT3-ITD-positive AML relapsing after allo-SCT.

Assessment of imatinib as first-line treatment of chronic myeloid leukemia: 10-year survival results of the randomized CML study IV and impact of non-CML determinants.

Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400 mg/day (n=400) could be optimized by doubling the dose (n=420), adding interferon (IFN) (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival was 80% and 10-year relative survival was 92%. Survival between IM400 mg and any experimental arm was not different. In a multivariate analysis, risk group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs other) influenced survival significantly, but not any form of treatment optimization. Patients reaching the molecular response milestones at 3, 6 and 12 months had a significant survival advantage. For responders, monotherapy with IM400 mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease, more life-time can currently be gained by carefully addressing non-CML determinants of survival.

Amb a 1 isoforms: Unequal siblings with distinct immunological features.

BACKGROUND: Ragweed pollen represents a major allergy risk factor. Ragweed extracts contain five different isoforms of the major allergen Amb a 1. However, the immunological characteristics of Amb a 1 isoforms are not fully investigated. Here, we compared the physicochemical and immunological properties of three most important Amb a 1 isoforms. METHODS: After purification, the isoforms were physicochemically characterized, tested for antibody binding and induction of human T-cell proliferative responses. Their immunological properties were further evaluated in vitro and in vivo in a mouse model. RESULTS: Amb a 1 isoforms exhibited distinct patterns of IgE binding and immunogenicity. Compared to Amb a 1.02 or 03 isoforms, Amb a 1.01 showed higher IgE-binding activity. Isoforms 01 and 03 were the most potent stimulators of patients' T cells. In a mouse model of immunization, Amb a 1.01 induced higher levels of IgG and IgE antibodies when compared to isoforms 02 and 03. Interestingly, ragweed-sensitized patients also displayed an IgG response to Amb a 1 isoforms. However, unlike therapy-induced antibodies, sensitization-induced IgG did not show IgE-blocking activity. CONCLUSION: The present study showed that naturally occurring isoforms of Amb a 1 possess different immunogenic and sensitizing properties. These findings should be considered when selecting sequences for molecule-based diagnosis and therapy for ragweed allergy. Due to its high IgE-binding activity, isoform Amb a 1.01 should be included in diagnostic tests. In contrast, due to their limited B- and T-cell cross-reactivity patterns, a combination of different isoforms might be a more attractive strategy for ragweed immunotherapy.

[Choosing wisely recommendations in hematology and oncology]. / Klug-entscheiden-Empfehlungen in der Hämatologie und Onkologie.

Many new diagnostic and therapeutic options have been introduced in the field of hematology and medical oncology during recent years. Rational treatment recommendations are thus of even greater importance. Five presumably underused measures are recommended (positive recommendations), primarily pertaining to supportive therapy, but also concerning the selective use of molecular diagnostics. Recommendations to avoid unnecessary procedures (negative recommendations) involve a possible excessive use of anticancer therapy and imaging, and insufficiently selective use of growth factors, antiemetics, and targeted therapies.

High-dose thiotepa-based chemotherapy with autologous stem cell support in elderly patients with primary central nervous system lymphoma: a European retrospective study.

In this retrospective multicentre study, we investigated the outcomes of elderly primary central nervous system lymphoma (PCNSL) patients (⩾65 years) who underwent high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) at 11 centres between 2003 and 2016. End points included remission, progression-free survival (PFS), overall survival (OS) and treatment-related mortality. We identified 52 patients (median age 68.5 years, median Karnofsky Performance Status before HDT-ASCT 80%) who all underwent thiotepa-based HDT-ASCT. Fifteen patients (28.8%) received HDT-ASCT as first-line treatment and 37 (71.2%) received it as second or subsequent line. Remission status before HDT-ASCT was: CR 34.6%, PR 51.9%, stable disease 3.8% and progressive disease 9.6%. Following completion of HDT-ASCT, 36 patients (69.2%) achieved CR (21.2% first-line setting and 48.1% second or subsequent line setting) and 9 (17.3%) PR (5.8% first-line setting and 11.5% second or subsequent line setting). With a median follow-up of 22 months after HDT-ASCT, median PFS and OS were reached after 51.1 and 122.3 months, respectively. The 2-year PFS and OS rates were 62.0% and 70.8%, respectively. We observed two HDT-ASCT-associated deaths (3.8%). In selected elderly PCNSL patients, HDT-ASCT, using thiotepa-based conditioning regimes, is feasible and effective. Further prospective and comparative studies are warranted to further evaluate the role of HDT-ASCT in elderly PCNSL patients.

[Immunotherapy of cancer with checkpoint inhibitors : Not only in malignant melanoma]. / Immuntherapie von Tumorerkrankungen mit Checkpoint-Inhibitoren : Nicht nur beim malignen Melanom.

The newest weapon in cancer therapy is checkpoint inhibition, which is the result of basic immunology research. The success of this therapy is based on the fact that upon light microscopy, many solid tumors harbor lymphocytic cells infiltrating the tumor (TILs), and in many solid tumors, the presence of these TILs are prognostic. Ipilimumab was the first monoclonal antibody developed against a target present on T cells after becoming activated, CTLA-4. In malignant melanoma, ipilimumab showed its beneficial effect as compared to a placebo peptide. However, the therapy with this antibody harbors significant toxicity. Meanwhile, other targets such as PD-1, also expressed on (late) activated T cells, were identified, and therapies with antibodies inhibiting PD-1/PD-L1 are less toxic. Although these antibodies show response only in a minority of patients, the benefit seems durable in some of these patients. In solid tumors such as melanoma or non-small cell lung cancer (NSCLC), treatment with PD-1 inhibitors has resulted in a significant prolongation of survival, even in first-line treatment. As these drugs have been approved in many indications, it is important to know the drugs and side effects. Resistance towards these drugs are caused by low expression of the natural ligand, PD-L1, in the tumor tissue, as well as acquired loss of signal transduction of interferon-related genes such as JAK1 or JAK2, respectively. Also new in cancer therapy are bispecific T cell engager monoclonal antibodies (BiTEs) such as blinatumomab, and autologous chimeric antigen receptor-modified T cells (CAR-Ts). The later have proven their efficacy mainly in hematological neoplasias such as precursor-B-ALL. The dramatic costs of all these new drugs will have an enormous impact on the health care systems in the near future.

Expression of the CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML.

It is unknown, why only a minority of chronic myeloid leukemia (CML) patients sustains treatment free remission (TFR) after discontinuation of tyrosine kinase inhibitor (TKI) therapy in deep molecular remission (MR). Here we studied, whether expression of the T-cell inhibitory receptor (CTLA-4)-ligand CD86 (B7.2) on plasmacytoid dendritic cells (pDC) affects relapse risk after TKI cessation. CML patients in MR displayed significantly higher CD86+pDC frequencies than normal donors (P<0.0024), whereas TFR patients had consistently low CD86+pDC (n=12). This suggested that low CD86+pDC might be predictive of TFR. Indeed, in a prospective analysis of 122 patients discontinuing their TKI within the EURO-SKI trial, the one-year relapse-free survival (RFS) was 30.1% (95% CI 15.6-47.9) for patients with >95 CD86+pDC per 105 lymphocytes, but 70.0% (95% CI 59.3-78.3) for patients with <95 CD86+pDC (hazard ratio (HR) 3.4, 95%-CI: 1.9-6.0; P<0.0001). Moreover, only patients with <95 CD86+pDC derived a significant benefit from longer (>8 years) TKI exposure before discontinuation (HR 0.3, 95% CI 0.1-0.8; P=0.0263). High CD86+pDC counts significantly correlated with leukemia-specific CD8+ T-cell exhaustion (Spearman correlation: 0.74, 95%-CI: 0.21-0.92; P=0.0098). Our data demonstrate that CML patients with high CD86+pDC counts have a higher risk of relapse after TKI discontinuation.

Heat-labile Escherichia coli toxin enhances the induction of allergen-specific IgG antibodies in epicutaneous patch vaccination.

Epicutaneous allergen-specific immunotherapy (EPIT) is proposed as an alternative route for allergen-specific immunotherapy (AIT). The induction of allergen-specific blocking IgG antibodies represents an important mechanism underlying AIT, but has not been investigated for EPIT. Here, we compared the induction of allergen-specific blocking IgG in outbred guinea pigs which had been immunized with recombinant birch pollen allergen Bet v 1 using patch delivery system (PDS) with or without heat-labile toxin (LT) from Escherichia coli or subcutaneously with aluminum hydroxide (Alum)-adsorbed rBet v 1. Only subcutaneous immunization with Alum-adsorbed rBet v 1 and epicutaneous administration of rBet v 1 with PDS in combination with LT from E. coli induced allergen-specific IgG antibodies blocking allergic patients' IgE, but not immunization with rBet v 1 via PDS alone. Our results suggest that patch vaccination with rBet v 1 in combination with LT may be a promising strategy for allergen-specific immunotherapy against birch pollen allergy.

Ultra-high vacuum compatible induction-heated rod casting furnace.

We report the design of a radio-frequency induction-heated rod casting furnace that permits the preparation of polycrystalline ingots of intermetallic compounds under ultra-high vacuum compatible conditions. The central part of the system is a bespoke water-cooled Hukin crucible supporting a casting mold. Depending on the choice of the mold, typical rods have a diameter between 6 mm and 10 mm and a length up to 90 mm, suitable for single-crystal growth by means of float-zoning. The setup is all-metal sealed and may be baked out. We find that the resulting ultra-high vacuum represents an important precondition for processing compounds with high vapor pressures under a high-purity argon atmosphere up to 3 bars. Using the rod casting furnace, we succeeded to prepare large high-quality single crystals of two half-Heusler compounds, namely, the itinerant antiferromagnet CuMnSb and the half-metallic ferromagnet NiMnSb.

[Economic Short-Term Cost Model for Stereotactic Radiotherapy of Neovascular AMD]. / Ökonomisches Kostenmodell zur Radiotherapie der neovaskulären AMD.

OBJECTIVES: Stereotactic radiation therapy (Oraya, OT) is available as a second line therapy for patients who, despite intensive anti-VEGF therapy for neovascular AMD, do not show an improvement in CNV. As OT is expensive (5,308 €), the short term economics for starting this therapy were investigated. METHODS: A short-term cost model was set up in MS Excel with a two year time horizon. On the basis of the data of the randomised, controlled INTREPID pivotal trial and current treatment practice in Germany, the costs were compared of conventional anti-VEGF therapy, with or without a single OT treatment. Patients with an active lesion after initial anti-VEGF therapy and a maximum lesion diameter ≤ 4 mm were included. Modeled cost components/aspects were direct savings from injection number, control follow-up examinations and aids, as well as anti-VEGF switches. Costs for Germany were employed and a univariate sensitivity analysis was performed to address the existing uncertainty. RESULTS: For the patients with a maximum AMD lesion diameter ≤ 4 mm and a macula volume > 7.4 mm(3), the INTREPID trial showed a mean reduction of 3.68 intravitreal injections for 16 Gy radiation versus sham over a time period of 2 years. These 3.68 IVM result in ~ 4,500 € direct cost savings. Moreover, due to the higher response rate with 16 Gy radiation, the number of follow-up visits and aids can be reduced, which results in savings between 207 € and 1,224 € over 2 years. After radiation, fewer anti-VEGF switches for low or non-responders are expected, which is modeled to result in ~ 1.7 fewer injections over 2 years. Due to overall fewer injections, fewer endophthalmitis cases would be expected. However, endophthalmitis and microvascular abnormalities, which can be observed in a few cases, are associated with low or non-quantifiable costs in this cost-cost comparison model. In summary, cost reductions of between 6,400 and 8,500 € are predicted in the model over two years, which have to be compared to the costs of a single application of OT. CONCLUSIONS: The short-term economic analysis shows that anti-VEGF therapy combined with OT results in savings above the costs for OT itself over a 2 year time horizon. Overall, the approach gives potential cost reductions, if the appropriate indication is followed.