[Perioperative handling of anticoagulation]. / Perioperativer Umgang mit Antikoagulation.

A growing number of patients in Germany receive a long-term prophylactic anticoagulation with phenprocoumone or one of the novel direct oral anticoagulants (NOAC), such as dabigatran, rivaroxaban or apixaban. The most common indication for an oral anticoagulant therapy is atrial fibrillation (approximately 75%) where the anticoagulant therapy can reduce the risk for an embolic event, particularly stroke by 60%. Operations carried out during such a therapy can result in major bleeding complications. On the other hand, suspending anticoagulant therapy can lead to an increased risk of thromboembolisms. Thus, the preoperative assessment should address the bleeding risk of the planned operation, the individual risk of thromboembolism, as well as other factors, such as patient age and renal function. If the individual assessment shows a substantial risk of perioperative bleeding when anticoagulant treatment is continued and a substantial risk of thromboembolism if the treatment is suspended, then a perioperative bridging, for example with low molecular weight heparin, is necessary. Perioperative bridging also leads to an increased risk of perioperative bleeding. Thus, undifferentiated bridging for all patients with atrial fibrillation with anticoagulant treatment is not recommended. Instead, the indications for a perioperative bridging should be decided according to individual risk profiles.

[Perioperative handling of immunosuppressive therapy]. / Perioperativer Umgang mit immunsuppressiver Therapie.

Every year 16 million operations are performed in Germany. Many patients have an autoimmune disorder, for example rheumatoid arthritis, psoriasis or chronic inflammatory bowel disease, which requires treatment. Immunosuppressants are widely applied. Physicians must make a risk-adapted decision whether the immunosuppressant medication can be continued perioperatively or if certain drugs must be paused and if so, with what risks. The handling of immunosuppressants during the perioperative period is very relevant as many patients, for example with rheumatoid arthritis are in need of a hip or knee replacement or patients with inflammatory bowel disease need an operation due to the chronic illness. The interruption of an immunosuppressant therapy should be discussed in an interdisciplinary board according to the underlying disease, because the continuation of immunosuppressants perioperatively can lead to an increased rate of complications, especially wound healing disorders. If a patient is on a glucocorticoid therapy the following must be considered: during the perioperative period the body has an increased demand for glucocorticoids due to the stress reaction. If glucocorticoids are administered in a dosage of more than 7.5 mg/day equivalent of prednisolone this stress reaction is inhibited. Thus, in these cases a perioperative substitution with hydrocortisone is recommended.

[Perioperative handling of antidiabetic drugs]. / Perioperativer Umgang mit Antidiabetika.

Diabetes mellitus is the most frequent metabolic disorder in the western world with a prevalence of 3% in adults under 65 years of age and 14.3% in adults over 65 years of age. Due to the increasing age of our population, the number of patients taking oral antidiabetic drugs has increased. Thus, operating physicians must make a risk-adapted decision whether the medication can be continued perioperatively or if certain drugs must be paused, and if so, with what risks. Operative interventions can lead to a number of metabolic shifts, which change the normal glucose metabolism. Hyperglycemia in the perioperative period is a risk factor for postoperative sepsis, dysfunction of the endothelium, cerebral ischemia and poor wound healing. Due to perioperative fasting oral antidiabetic medication can lead to severe hypoglycemia if taken during this period. This leads to an increased morbidity and mortality in the perioperative period and extends the duration of stay in the intensive care unit (ICU) as well as the overall hospital stay. Oral antidiabetic medication should be paused on the day of the operation and restarted in line with the gradual postoperative return to solid food. Especially metformin, the most commonly used medication in the treatment of type 2 diabetes, should be paused perioperatively due to the severe side effect of lactate acidosis.

[The use of tumor therapeutics in the perioperative period]. / Perioperativer Umgang mit antitumoralen Medikamenten.

In 2010 Germany had 447,300 new cases of cancer. From 2000 to 2010 the incidence of cancer increased by 21% in men and by 14% in women. The change in the age structure with an aging population is the crucial influencing factor. Various cancer types can now be treated by oral antitumor agents used as a chronic medication. Physicians must decide whether the oral antitumor agents can be continued perioperatively or if certain drugs must be paused and if so, with what risks. Oral antitumor agents are a very heterogeneous group of medication. The use of oral antitumor agents during the perioperative period has not been thoroughly examined, but most often a perioperative interruption is recommended. In general, poor wound healing is a frequent complication of this group of medication. The handling of oral antitumor agents in the perioperative period should be based on an individual decision with consideration of the desired therapy goal as well as the individual prognosis. In general, all oral antitumor agents are chronic medication and are continued until a loss of efficacy or intolerable side effects occur. A potentially curative therapy should be paused for the shortest possible time in order not to jeopardize the remission already achieved. Furthermore, generally accepted recommendations concerning the interval between chemotherapy and a planned operation have not yet been established. A rough rule of thumb could be to plan the operation after the regeneration of the blood count or at the same point in time of the next planned chemotherapy.

[The use of platelet aggregation inhibitors in the perioperative period]. / Perioperativer Umgang mit Thrombozytenaggregationshemmern.

Every year 16 million operations are performed in Germany. Many patients take platelet aggregation inhibitors as a primary or secondary prevention to reduce the risk of cardiovascular events. Especially during the perioperative period, this risk reduction is relevant due to an increased risk for cardiac events (in approximately 6.2% of operations). As a result of a presumed increased risk of bleeding, platelet aggregation inhibitors are often paused perioperatively. Thus, doctors must decide on a risk-adapted basis whether the medication can be continued perioperatively and, if so, with what risks. If acetylsalicylic acid (ASA) treatment is solely used as primary prevention it can be paused during the perioperative period, whereas ASA treatment for secondary prevention should only be paused for operations within narrow confines. When pausing ASA, a sufficient time interval should be maintained before the operation. Furthermore, the ASA withdrawal syndrome with an increased predisposition for clotting is an important phenomenon to be considered. Additionally, the perioperative handling of dual platelet aggregation inhibition needed after coronary stent implantation should be addressed. Due to an increased risk for in-stent thrombosis, dual platelet aggregation inhibition is only reluctantly paused. Emergency surgery must, if not otherwise possible, be carried out even if the dual platelet aggregation inhibition is not paused; however, if the risk for intraoperative bleeding is too high and the risk of an in-stent thrombosis is lower in comparison, P2Y12 inhibitors (e.g. clopidogrel) should be paused and the operation carried out solely with ASA therapy.

Efficacy and safety of carfilzomib regimens in multiple myeloma patients relapsing after autologous stem cell transplant: ASPIRE and ENDEAVOR outcomes.

Autologous stem cell transplantation (ASCT) is a standard treatment for eligible multiple myeloma (MM) patients, but many patients will relapse after ASCT and require subsequent therapy. The proteasome inhibitor carfilzomib is approved for relapsed or refractory MM (RRMM). In phase 3 trials, carfilzomib-based regimens (ASPIRE, carfilzomib-lenalidomide-dexamethasone; ENDEAVOR, carfilzomib-dexamethasone) demonstrated superior progression-free survival (PFS) compared with standard therapies for RRMM (ASPIRE: lenalidomide-dexamethasone; ENDEAVOR, bortezomib-dexamethasone). This subgroup analysis of ASPIRE and ENDEAVOR evaluated outcomes according to prior ASCT status. In total, 446 patients in ASPIRE and 538 in ENDEAVOR had prior ASCT. Median PFS was longer for carfilzomib-based regimens vs non-carfilzomib-based regimens for patients with prior ASCT (ASPIRE: 26.3 vs 17.8 months (hazard ratio (HR)=0.68); ENDEAVOR: not estimable vs 10.2 months (HR=0.61)), those with one prior line of therapy that included ASCT (ASPIRE: 29.7 vs 17.8 months (HR=0.70); ENDEAVOR: not estimable vs 11.2 months (HR=0.46)), and those without prior ASCT (ASPIRE: 26.4 vs 16.6 months (HR=0.76); ENDEAVOR: 17.7 vs 8.5 months (HR=0.43)). Overall response rates also favored the carfilzomib-based regimens. No new safety signals were detected. This analysis suggests that carfilzomib-based treatment may lead to improvement in PFS and response rates regardless of prior transplant status. Further evaluation is warranted.

[Monoclonal gammopathy of undetermined significance and multiple myeloma]. / Monoklonale Gammopathie unklarer Signifikanz und multiples Myelom.

In rheumatological practice monoclonal gammopathy of undetermined significance (MGUS) is a common incidental finding. Several rheumatic inflammatory diseases are known to have an elevated risk of MGUS, which can evolve into multiple myeloma or other lymphatic malignancies. The relevant definitions of disease entities are described, as well as algorithms for further diagnostic work-up and follow-up for monoclonal gammopathy, depending on the risk of progression. Therapeutic strategies against multiple myeloma are presented. Some of these therapeutic modalities could play a future role in treating plasma cell-dominated autoimmune diseases.

IKZF1 expression is a prognostic marker in newly diagnosed standard-risk multiple myeloma treated with lenalidomide and intensive chemotherapy: a study of the German Myeloma Study Group (DSMM).

Lenalidomide is an immunomodulatory compound with high clinical activity in multiple myeloma. Lenalidomide binding to the Cereblon (CRBN) E3 ubiquitin ligase results in targeted ubiquitination and degradation of the lymphoid transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) leading to growth inhibition of multiple myeloma cells. Recently, Basigin (BSG) was identified as another protein regulated by CRBN that is involved in the activity of lenalidomide. Here, we analyzed the prognostic value of IKZF1, IKZF3, CRBN and BSG mRNA expression levels in pretreatment plasma cells from 60 patients with newly diagnosed multiple myeloma uniformly treated with lenalidomide in combination with intensive chemotherapy within a clinical trial. We found that IKZF1 mRNA expression levels are significantly associated with progression-free survival (PFS). Patients in the lowest quartile (Q1) of IKZF1 expression had a superior PFS compared with patients in the remaining quartiles (Q2-Q4; 3-year PFS of 86 vs 51%, P=0.01). This translated into a significant better overall survival (100 vs 74%, P=0.03). Subgroup analysis revealed a significant impact of IKZF1, IKZF3 and BSG expression levels on PFS in cytogenetically defined standard-risk but not high-risk patients. Our data suggest a prognostic role of IKZF1, IKZF3 and BSG expression levels in lenalidomide-treated multiple myeloma.

Longitudinal analysis of 25 sequential sample-pairs using a custom multiple myeloma mutation sequencing panel (M(3)P).

Recent advances in genomic sequencing technologies now allow results from deep next-generation sequencing to be obtained within clinically meaningful timeframes, making this an attractive approach to better guide personalized treatment strategies. No multiple myeloma-specific gene panel has been established so far; we therefore designed a 47-gene-targeting gene panel, containing 39 genes known to be mutated in ≥3 % of multiple myeloma cases and eight genes in pathways therapeutically targeted in multiple myeloma (MM). We performed targeted sequencing on tumor/germline DNA of 25 MM patients in which we also had a sequential sample post treatment. Mutation analysis revealed KRAS as the most commonly mutated gene (36 % in each time point), followed by NRAS (20 and 16 %), TP53 (16 and 16 %), DIS3 (16 and 16 %), FAM46C (12 and 16 %), and SP140 (12 and 12 %). We successfully tracked clonal evolution and identified mutation acquisition and/or loss in FAM46C, FAT1, KRAS, NRAS, SPEN, PRDM1, NEB, and TP53 as well as two mutations in XBP1, a gene associated with bortezomib resistance. Thus, we present the first longitudinal analysis of a MM-specific targeted sequencing gene panel that can be used for individual tumor characterization and for tracking clonal evolution over time.

OH-stretching in synthetic hydrogen-bonded chains.

We study hydrogen bond dynamics in stereoselectively synthesized polyalcohols by combining linear and two-dimensional (2D) infrared spectroscopy experiments with simulations. We consider two variants of the polyalcohols: the all-syn and all-anti tetrol, which because of their different stereochemistry of the hydroxyl groups form a linear hydrogen-bonded chain that is stable for tens of picoseconds or a system where hydrogen bonds are formed and broken on a picosecond timescale, respectively. The differences in structure and hydrogen bond dynamics gives rise to significant differences in the linear spectra for the two compounds. Furthermore, we show that the stronger hydrogen bonding for the all-syn variant leads to faster fluctuations of the site frequencies than for the all-anti one, which is reflected in the higher degree of homogeneous broadening in the 2D spectra. Because of the different stereochemistry, the coupling in the all-syn molecule is stronger than for the all-anti one, which leads to a faster delocalization of a local excitation. This explains the previously observed pump-frequency independent vibrational lifetime for the all-syn variant, since the excitation loses the memory of the pump frequency before relaxation. For the all-anti form, the coupling is weak and the excitation remains in the initially excited state, maintaining the memory of the pump frequency.

Incidence, risk factors, and implemented prophylaxis of varicella zoster virus infection, including complicated varicella zoster virus and herpes simplex virus infections, in lenalidomide-treated multiple myeloma patients.

In the era of high-dose chemotherapy and novel antimyeloma agents, the survival of multiple myeloma (MM) patients has substantially improved. Adverse effects, including infections, may however arise in the era of combination antimyeloma therapies. In general, MM patients have shown a risk of varicella zoster virus (VZV) infection of 1-4 %, increasing with bortezomib treatment or transplants, but whether immunomodulatory drugs also bear a risk of VZV/complicated herpes simplex virus (HSV) (e.g., VZV-encephalitis [VZV-E], disseminated VZV-infection [d-VZV-i], or conus-cauda syndrome [CCS]) has not been elucidated. We here assessed VZV, VZV-E, d-VZV-i, and CCS in 93 lenalidomide-treated MM patients, consecutively seen and treated in our department. Patients' data were analyzed via electronic medical record retrieval within our research data warehouse as described previously. Of the 93 MM patients receiving lenalidomide, 10 showed VZV or other complicated VZV/HSV infections. These VZV patients showed defined risk factors as meticulously assessed, including suppressed lymphocyte subsets, substantial cell-mediated immune defects, and compromised humoral immune response. Due to our findings-and in line with an aciclovir prophylaxis in bortezomib and stem cell transplant protocols-we introduced a routine aciclovir prophylaxis in our lenalidomide protocols in May 2012 to minimize adverse events and to avoid discontinuation of lenalidomide treatment. Since then, we have observed no case of VZV/complicated HSV infection. Based on our data, we encourage other centers to also focus on these observations, assess viral infections, and-in those centers facilitating a research data warehouse-advocate an analogue data review as an appropriate multicenter approach.

[Multiple myeloma]. / Das multiple Myelom.

Multiple myeloma (MM) is a cancer originating from terminally differentiated B lymphocytes, the plasma cells and is classified as a B cell non-Hodgkin lymphoma. As clonal plasma cells secrete immunoglobulin molecules (lacking antigenic specificity), an "M component" can incidentally be detected. Besides intact immunoglobulin molecules, free light chains can be produced. Although there is no specific treatment for monoclonal gammopathy of undetermined significance (MGUS), which is the defined as the presence of clonal bone marrow plasma cells and low levels (serum and/or urine) of the M component, it should be followed up in affected individuals. The symptoms of MM are numerous and often nonspecific. Diagnosis includes the quantification of monoclonal proteins in serum and urine, blood count, electrolytes and renal function, imaging of the skeleton and bone marrow puncture. The cornerstone of therapy includes melphalan- or cyclophosphamide-based regimens incorporating one of the "novel drugs" (i.e. bortezomib, thalidomide, or lenalidomide).

Multiple myeloma is affected by multiple and heterogeneous somatic mutations in adhesion- and receptor tyrosine kinase signaling molecules.

Multiple myeloma (MM) is a largely incurable plasma cell malignancy with a poorly understood and heterogeneous clinical course. To identify potential, functionally relevant somatic mutations in MM, we performed whole-exome sequencing of five primary MM, corresponding germline DNA and six MM cell lines, and developed a bioinformatics strategy that also integrated published mutational data of 38 MM patients. Our analysis confirms that identical, recurrent mutations of single genes are infrequent in MM, but highlights that mutations cluster in important cellular pathways. Specifically, we show enrichment of mutations in adhesion molecules of MM cells, emphasizing the important role for the interaction of the MM cells with their microenvironment. We describe an increased rate of mutations in receptor tyrosine kinases (RTKs) and associated signaling effectors, for example, in EGFR, ERBB3, KRAS and MAP2K2, pointing to a role of aberrant RTK signaling in the development or progression of MM. The diversity of mutations affecting different nodes of a particular signaling network appears to be an intrinsic feature of individual MM samples, and the elucidation of intra- as well as interindividual redundancy in mutations that affect survival pathways will help to better tailor targeted therapeutic strategies to the specific needs of the MM patient.

Signalling profile and antitumour activity of the novel Hsp90 inhibitor NVP-AUY922 in multiple myeloma.

We as well as others have recently shown that Hsp90 is overexpressed in multiple myeloma (MM) and critically contributes to tumour cell survival. Pharmacologic blockade of Hsp90 has consistently been found to induce MM cell death. However, most data have been obtained with MM cell lines whereas knowledge about the molecular effects of pharmacologic Hsp90 blockade in primary tumour cells is limited. Furthermore, these investigations have so far focused on geldanamycin derivatives. We analysed the biochemical effects of a novel diarylisoxazole-based Hsp90 inhibitor (NVP-AUY922) on signalling pathways and cell death in a large set of primary MM tumour samples and in MM cell lines. Treated cells displayed the molecular signature and pharmacodynamic properties for abrogation of Hsp90 function, such as downregulation of multiple survival pathways and strong upregulation of Hsp70. NVP-AUY922 treatment efficiently induced MM cell apoptosis and revealed both sensitive and resistant subgroups. Sensitivity was not correlated with TP53 mutation or Hsp70 induction levels and stromal cells from the bone marrow microenvironment were unable to abrogate NVP-AUY922-induced apoptosis of MM cells. Thus, NVP-AUY922 may be a promising drug for treatment of MM and clinical studies are warranted.

Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma.

The incidence of venous thromboembolism (VTE) is more than 1 per thousand annually in the general population and increases further in cancer patients. The risk of VTE is higher in multiple myeloma (MM) patients who receive thalidomide or lenalidomide, especially in combination with dexamethasone or chemotherapy. Various VTE prophylaxis strategies, such as low-molecular-weight heparin (LMWH), warfarin or aspirin, have been investigated in small, uncontrolled clinical studies. This manuscript summarizes the available evidence and recommends a prophylaxis strategy according to a risk-assessment model. Individual risk factors for thrombosis associated with thalidomide/lenalidomide-based therapy include age, history of VTE, central venous catheter, comorbidities (infections, diabetes, cardiac disease), immobilization, surgery and inherited thrombophilia. Myeloma-related risk factors include diagnosis and hyperviscosity. VTE is very high in patients who receive high-dose dexamethasone, doxorubicin or multiagent chemotherapy in combination with thalidomide or lenalidomide, but not with bortezomib. The panel recommends aspirin for patients with < or = 1 risk factor for VTE. LMWH (equivalent to enoxaparin 40 mg per day) is recommended for those with two or more individual/myeloma-related risk factors. LMWH is also recommended for all patients receiving concurrent high-dose dexamethasone or doxorubicin. Full-dose warfarin targeting a therapeutic INR of 2-3 is an alternative to LMWH, although there are limited data in the literature with this strategy. In the absence of clear data from randomized studies as a foundation for recommendations, many of the following proposed strategies are the results of common sense or derive from the extrapolation of data from many studies not specifically designed to answer these questions. Further investigation is needed to define the best VTE prophylaxis.