Mind-body-medicine in oncology-from patient needs to tailored programs and interventions: a cross-sectional study.

Introduction: National and international guidelines recommend early integration of evidence-based multimodal interventions and programs, especially with a focus on relaxation techniques and other Mind-Body-based methods to maintain the quality of life of oncology patients, improve treatment tolerability, and promote healthy lifestyle behaviors. Consequently, we aim to understand what drives patients and how they navigate integrative medicine to best advise them. This study aimed to detect possible topics of particular interest to patients and identify the patient groups that could benefit most from further programs. Furthermore, we aimed to investigate if patients are open-minded toward integrative oncology concepts and learn about their motivational level to maintain or change behavior. Methods: Between August 2019 and October 2020 we surveyed patients undergoing oncological therapy in a university oncological outpatient center using a custom-developed questionnaire based on established Mind-Body Medicine concepts. Results: We included 294 patients with various cancers. More than half reported problems sleeping through (61%) and 42% felt stressed frequently, invariably rating this as detrimental to their health. Moreover, a slight majority (52%) felt physically limited due to their disease and only 30% performed defined exercise programs. Women were significantly more likely to feel stressed and reported with alarming frequency that they often feel "everything was up to them." The 40-65-year-olds reported significantly less restful sleep, more stress and were more dissatisfied with their situation. However, this group already used natural remedies most frequently and was most often motivated to use relaxation techniques in the next 6 months. The lower the perceived individual energy level (EL), the less frequently patients did sport, the more frequently they felt their disease impaired their activity, mostly feeling stressed and tense. We also found significant associations between negative emotions/thoughts and the variables "sleep," "use of relaxation techniques," "personal stress perception," and "successful lifestyle modification." Conclusion: Mind-Body programs that focus on patient's individual resources, with tools to explore impairing patterns of self-perception and cognitive biases, can be a valuable resource for oncology patients and should therefore be part of an integrative medical treatment concept.

Sorafenib or placebo in patients with newly diagnosed acute myeloid leukaemia: long-term follow-up of the randomized controlled SORAML trial.

Early results of the randomized placebo-controlled SORAML trial showed that, in patients with newly diagnosed acute myeloid leukaemia (AML), sorafenib led to a significant improvement in event-free (EFS) and relapse-free survival (RFS). In order to describe second-line treatments and their implications on overall survival (OS), we performed a study after a median follow-up time of 78 months. Newly diagnosed fit AML patients aged ≤60 years received sorafenib (n = 134) or placebo (n = 133) in addition to standard chemotherapy and as maintenance treatment. The 5-year EFS was 41 versus 27% (HR 0.68; p = 0.011) and 5-year RFS was 53 versus 36% (HR 0.64; p = 0.035). Allogeneic stem cell transplantation (allo SCT) was performed in 88% of the relapsed patients. Four years after salvage allo SCT, the cumulative incidence of relapse was 54 versus 35%, and OS was 32 versus 50%. The 5-year OS from randomization in all study patients was 61 versus 53% (HR 0.82; p = 0.282). In conclusion, the addition of sorafenib to chemotherapy led to a significant prolongation of EFS and RFS. Although the OS benefit did not reach statistical significance, these results confirm the antileukaemic activity of sorafenib.

Dihydropyrimidine Dehydrogenase Testing prior to Treatment with 5-Fluorouracil, Capecitabine, and Tegafur: A Consensus Paper.

BACKGROUND: 5-Fluorouracil (FU) is one of the most commonly used cytostatic drugs in the systemic treatment of cancer. Treatment with FU may cause severe or life-threatening side effects and the treatment-related mortality rate is 0.2-1.0%. SUMMARY: Among other risk factors associated with increased toxicity, a genetic deficiency in dihydropyrimidine dehydrogenase (DPD), an enzyme responsible for the metabolism of FU, is well known. This is due to variants in the DPD gene (DPYD). Up to 9% of European patients carry a DPD gene variant that decreases enzyme activity, and DPD is completely lacking in approximately 0.5% of patients. Here we describe the clinical and genetic background and summarize recommendations for the genetic testing and tailoring of treatment with 5-FU derivatives. The statement was developed as a consensus statement organized by the German Society for Hematology and Medical Oncology in cooperation with 13 medical associations from Austria, Germany, and Switzerland. Key Messages: (i) Patients should be tested for the 4 most common genetic DPYD variants before treatment with drugs containing FU. (ii) Testing forms the basis for a differentiated, risk-adapted algorithm with recommendations for treatment with FU-containing drugs. (iii) Testing may optionally be supplemented by therapeutic drug monitoring.

Addition of sorafenib versus placebo to standard therapy in patients aged 60 years or younger with newly diagnosed acute myeloid leukaemia (SORAML): a multicentre, phase 2, randomised controlled trial.

BACKGROUND: Preclinical data and results from non-randomised trials suggest that the multikinase inhibitor sorafenib might be an effective drug for the treatment of acute myeloid leukaemia. We investigated the efficacy and tolerability of sorafenib versus placebo in addition to standard chemotherapy in patients with acute myeloid leukaemia aged 60 years or younger. METHODS: This randomised, double-blind, placebo-controlled, phase 2 trial was done at 25 sites in Germany. We enrolled patients aged 18-60 years with newly diagnosed, previously untreated acute myeloid leukaemia who had a WHO clinical performance score 0-2, adequate renal and liver function, no cardiac comorbidities, and no recent trauma or operation. Patients were randomly assigned (1:1) to receive two cycles of induction therapy with daunorubicin (60 mg/m(2) on days 3-5) plus cytarabine (100 mg/m(2) on days 1-7), followed by three cycles of high-dose cytarabine consolidation therapy (3 g/m(2) twice daily on days 1, 3, and 5) plus either sorafenib (400 mg twice daily) or placebo on days 10-19 of induction cycles 1 and 2, from day 8 of each consolidation, and as maintenance for 12 months. Allogeneic stem-cell transplantation was scheduled for all intermediate-risk patients with a sibling donor and for all high-risk patients with a matched donor in first remission. Computer-generated randomisation was done in blocks. The primary endpoint was event-free survival, with an event defined as either primary treatment failure or relapse or death, assessed in all randomised patients who received at least one dose of study treatment. We report the final analysis. This trial is registered with ClinicalTrials.gov, number NCT00893373, and the EU Clinical Trials Register (2008-004968-40). FINDINGS: Between March 27, 2009, and Nov 28, 2011, 276 patients were enrolled and randomised, of whom nine did not receive study medication. 267 patients were included in the primary analysis (placebo, n=133; sorafenib, n=134). With a median follow-up of 36 months (IQR 35·5-38·1), median event-free survival was 9 months (95% CI 4-15) in the placebo group versus 21 months (9-32) in the sorafenib group, corresponding to a 3-year event-free survival of 22% (95% CI 13-32) in the placebo group versus 40% (29-51) in the sorafenib group (hazard ratio [HR] 0·64, 95% CI; 0·45-0·91; p=0·013). The most common grade 3-4 adverse events in both groups were fever (71 [53%] in the placebo group vs 73 [54%] in the sorafenib group), infections (55 [41%] vs 46 [34%]), pneumonia (21 [16%] vs 20 [14%]), and pain (13 [10%] vs 15 [11%]). Grade 3 or worse adverse events that were significantly more common in the sorafenib group than the placebo group were fever (relative risk [RR] 1·54, 95% CI 1·04-2·28), diarrhoea (RR 7·89, 2·94-25·2), bleeding (RR 3·75, 1·5-10·0), cardiac events (RR 3·46, 1·15-11·8), hand-foot-skin reaction (only in sorafenib group), and rash (RR 4·06, 1·25-15·7). INTERPRETATION: In patients with acute myeloid leukaemia aged 60 years or younger, the addition of sorafenib to standard chemotherapy has antileukaemic efficacy but also increased toxicity. Our findings suggest that kinase inhibitors could be a useful addition to curative treatment for acute myeloid leukaemia. Overall survival after long-term follow-up and strategies to reduce toxicity are needed to determine the future role of sorafenib in treatment of this disease. FUNDING: Bayer HealthCare.

Systematic Nutritional Support in Allogeneic Hematopoietic Stem Cell Transplant Recipients.

Allogeneic hematopoietic stem cell transplantation (HSCT) has become an established treatment modality for various hematological diseases. However, in allogeneic HSCT, patients often suffer from severe gastrointestinal complications caused by the conditioning regimen and acute/chronic graft-versus-host disease, which requires support by multidisciplinary nutritional support teams (NST). In addition, pretransplantation nutritional status can affect the clinical outcome after allogeneic HSCT. Therefore, it is important to refer the patient to a NST when becoming aware of nutritional problems before allogeneic HSCT. It is also important to follow nutritional status over the long term, as patients often suffer from various nutritional problems, such as malnutrition and metabolic syndrome, even late after allogeneic HSCT. In summary, NST can contribute to the improvement of nutritional status and possibly prognosis at every stage before and after allogeneic HSCT. Here, we aim to give a comprehensive overview of current understanding about nutritional support in allogeneic HSCT and try to provoke a constructive discussion to stimulate further investigation.

Complete pathological remission of locally advanced, unresectable pancreatic cancer (LAPC) after intensified neoadjuvant chemotherapy.

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) has an extremely poor prognosis. Results of neoadjuvant (radio-)chemotherapy approaches aiming at achieving resectability are currently not satisfactory. CASE REPORT: We report the case of a 67-year-old woman with histologically confirmed pancreas carcinoma that was not resectable on first surgical exploration who achieved a well-documented complete pathological remission (pCR). The carcinoma became resectable after consecutive neoadjuvant treatment with nanoparticle albumin-bound (nab)-paclitaxel/gemcitabine and FOLFIRINOX chemotherapy regimens. CONCLUSION: This is the first reported LAPC case in which neoadjuvant chemotherapy alone has been shown to lead to demonstrated pCR. CA19-9 levels, but not imaging criteria, were useful for response prediction and timing of the Whipple's procedure. The findings in this case suggest possible conceptual changes in the treatment approach for LAPC, and indicate that the new effective chemotherapy regimens should be integrated into clinical trials for LAPC.

Combining dasatinib with dexamethasone long-term leads to maintenance of antiviral and antileukemia specific cytotoxic T cell responses in vitro.

Maintaining graft versus leukemia (GvL) and antivirus responses of cytotoxic T cells (CTLs) while suppressing graft-versus-host disease (GvHD) remains a challenge after allogeneic bone marrow transplantation. Clinical observations indicate that combining glucocorticoids with multi-tyrosine-kinase inhibitors could be a successful therapeutic approach. We and others have shown that the BCR-ABL/SRC kinase inhibitor dasatinib may enhance or suppress T cells in vitro. In this report, we evaluated combination effects of dasatinib and dexamethasone on CD3⁺ and virus-specific CD8⁺ T cells directly ex vivo and on antigen-specific leukemia-reactive and alloreactive CD8⁺ T cell clones. Functional outcomes assessed included cytokine production (IL-2, IFN-γ, TNF-α), degranulation (CD107a/b), activation (CD69 upregulation), proliferation, apoptosis and necrosis induction, and signal transduction. Overall, helper CD4⁺ T cells were more sensitive to inhibitory effects of the drug combination than cytotoxic CD8⁺ T cells and were more naive than memory T cell subsets. Of note, synergistic inhibitory effects occurred in different memory but not in naive T cell subsets. The drug combination inhibited virus-specific CD8⁺ T cell proliferation, but left cytokine production and degranulation unaltered, which may be due to the viral memory subset composition. Dasatinib rather hampered IFN-γ secretion and cytotoxic activity of human leukocyte antigen (HLA)-reactive CTLs, whereas effector functions of leukemia-reactive CTLs were maintained or enhanced when applied long term. Our data suggest that dasatinib might modulate GvL- differently than GvHD-promoting CTLs and provide a rationale to explore the drug combination further to treat GvHD while preserving GvL and antiviral CTL responses.

Integrin-linked kinase is dispensable for multiple myeloma cell survival.

We investigated the utility of integrin-linked kinase (ILK) as a target for therapeutic intervention in multiple myeloma (MM). ILK (over-)expression was assessed in primary samples and MM cell lines, and the molecular and physiological consequences of siRNA-mediated ILK ablation were compared to treatment with the small molecule inhibitor QLT0267. Whereas ILK expression was ubiquitous, overexpression was only rarely observed in patient biopsies. ILK knockdown had no effect on the viability or survival pathway activity pattern of MM cells. Conversely, QLT0267 induced cell death in MM cell lines and most primary tumor samples via the intrinsic apoptotic pathway. Although this effect was largely tumor cell-specific it is unlikely to have been mediated via ILK. We conclude that ILK does not play a prominent role in the promotion or sustenance of established MM.

Enhancement of natural killer cell effector functions against selected lymphoma and leukemia cell lines by dasatinib.

As NK cell immunotherapy is still poorly successful, combinations with drugs enhancing NK cell activity are of major interest. NK large granular lymphocyte expansions associated with improved survival have been described under monotherapy with the Bcr-Abl/Src inhibitor dasatinib, which inhibits NK cell functions in vitro. As Src kinases play a major role in inhibitory and activating signaling pathways of NK cells, both outcomes appear plausible. To clarify these contradictory observations and potentially enable the use of dasatinib as adjuvant, we analyzed how clinically relevant doses promote NK cell effector functions. Polyclonal human NK cells were studied ex vivo. Functional outcomes assessed included conjugate formation, calcium flux, receptor regulation, cytokine production, degranulation, cytotoxicity, apoptosis induction and signal transduction. While dasatinib inhibits NK cell effector functions during functional assays, 24 hr pretreatment of NK cells followed by washout of dasatinib, led to dose-dependent enhancement of cytokine production, degranulation marker expression and cytotoxicity against selected lymphoma and leukemia cell lines. Mechanistically, this was neither due to an altered viability of NK cells nor increased NKG2D, LFA-1 or conjugate formation with target cells. Receptor proximal signaling events were inhibited. However, a slight time dependent enhancement of Vav phosphorylation was observed under certain circumstances. The shift in Vav phosphorylation level may be one major mechanism for NK cell activity enhancement induced by dasatinib. Our findings argue for a careful timing and dosing of dasatinib application during leukemia/lymphoma treatment to enhance NK cell immunotherapeutic efforts.

Preclinical anti-myeloma activity of the novel HDAC-inhibitor JNJ-26481585.

Pharmacological inhibitors of histone deacetylases (HDACs) are currently being developed and tested as anti-cancer agents and may be useful to enhance the therapeutic efficiency of established anti-myeloma treatments. This study preclinically evaluated the effects of the 'second generation' pan-HDAC inhibitor JNJ-26481585 on human multiple myeloma (MM) cells from established cell lines and primary MM samples (n=42). Molecular responses in both groups of MM cells included histone acetylation, a shift in Bcl2-family members towards proapoptotic bias, attenuation of growth and survival pathway activity and Hsp72 induction. Mcl-1 depletion and Hsp72 induction were the most reliable features observed in JNJ-26481585-treated primary MM samples. The drug alone effectively induced myeloma cell death at low nanomolar concentrations. In vitro combination of JNJ-26481585 with anti-myeloma therapeutic agents generally resulted In effects close to additivity. In view of the favourable activity of this novel HDAC-inhibitor towards primary myeloma cells further evaluation in a clinical setting is warranted.

Anti-myeloma activity of the novel 2-aminothienopyrimidine Hsp90 inhibitor NVP-BEP800.

The 90 kD heat shock protein (Hsp90) molecular chaperone sustains multiple components of oncogenic pathways and has recently emerged as a therapeutic target that is now being clinically tested in a number of malignancies. In order to address formulation issues and to deal with possible resistance mechanisms against small molecule Hsp90 inhibitors, a range of compounds based on different molecular scaffolds are now being developed. The present study preclinically tested the effects of the novel 2-aminothienopyrimidine class Hsp90 inhibitor NVP-BEP800, which is suitable for oral formulations, on multiple myeloma cells from established cell lines and on a larger cohort (n = 40) of primary myeloma samples. The drug effectively and specifically killed the majority of primary myeloma cells in coculture with bone marrow stromal cells and reliably entailed molecular consequences of Hsp90 blockade - such as survival pathway breakdown and client protein depletion - in multiple myeloma cells from cell lines as well as from patients. Collectively, the properties of this novel drug support clinical testing in multiple myeloma.

State of the art therapy in multiple myeloma and future perspectives.

Treatment for multiple myeloma (MM) has changed beyond recognition in the past decades. While until the early 1980s, MM caused a slow progressive decline in quality of life until death after about two years, today's patients can expect a 50% chance of achieving a complete remission, a median survival time of five years and a 20% chance of surviving longer than ten years. State of the art therapy comprises: evidence-based supportive care; highly effective and well tolerated chemotherapeutic regimens; and for patients qualifying for intensive high-dose conditioning, autologous haematopoietic stem cell transplantation (HSCT) is an option. Maintenance therapy has become increasingly important since a majority of patients is able to achieve a good remission after front-line therapy which is aimed to be preserved as long as possible. In addition, improved understanding of the disease biology has led to the development of novel biological treatment agents, such as thalidomide, bortezomib and others, targeted at cellular mechanisms and interactions, e.g. with the bone marrow microenvironment. These strategies are incrementally integrated into modern MM care. This review considers recent clinical advancements in anti-myeloma strategies and provides an overview of the state of the art management of MM patients.