IntroductionMajor progress has been achieved in the past decade in understanding the biology of B-cell chronic lymphocytic leukemia (CLL), leading to new therapeutic concepts and a trend toward improved survival. However, the disease remains incurable, and many patients develop drug resistance. [1][2][3] Despite the long lifespan of CLL cells in vivo, these cells undergo rapid and spontaneous apoptosis in vitro but can be rescued by marrow stromal cells, [4][5][6] nurse-like cells, 7 and follicular dendritic cells. 8 There are also indications that the stromal cells mediate resistance to chemotherapy in CLL cells. 9 This point to the dependence of CLL cells on antiapoptotic stimuli that could be provided in vivo by marrow microenvironment 10,11 and may have a major effect on disease progression and response or resistance to therapy.Bone marrow microenvironment is a complex structure that comprises accessory cells (stromal cells, adipocytes, reticulum cells, endothelial cells, follicular dendritic cells, T cells, and macrophages), matrix proteins, and soluble factors, including growth factors and cytokines. 11,12 Bone marrow stromal cells (BMSCs) represent a major component of the marrow microenvironment. They originate from the mesenchymal stem cells and have hematopoietic supportive properties. They also produce matrix proteins, express integrin ligands, and release several cytokines and growth factors that are involved in the generation and maturation of normal and leukemic B cells. [11][12][13] Therefore, BMSCs could provide a suitable milieu for the development and survival of CLL cells. However, the antiapoptotic cascades and the molecular events that are activated upon the interaction between CLL cells and BMSCs are not fully identified.Several stimuli that are endogenously produced in the microenvironment were shown to activate the antiapoptotic phosphatidylinositol 3-kinase (PI3-K)/Akt pathway. These include cytokines and growth factors, 14 adhesion molecules and matrix proteins, 15 and involve receptors that are expressed on the surface of CLL cells, including the B-cell receptor, CD19, and CD5. [16][17][18] This strongly suggests that the PI3-K/Akt pathway might play a central role in the interaction between CLL cells and the bone marrow microenvironment. The PI3-K/Akt cascade contributes to the regulation of many cellular processes, including motility, proliferation, apoptosis, and tumorigenesis. 14,19 Class I of PI3-K family is the best characterized and comprises p110␣, p110␤, p110␥, and The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked ''advertisement'' in accordance with 18 USC section 1734. For personal use only. on May 11, 2018. by guest www.bloodjournal.org From p110␦ isotypes. 14,19 The first generation of pan-PI3-K inhibitors (LY294002 and wortmannin) provided substantial information on the molecular mechanism of action and ...

The development of multidrug resistance (MDR) is a major problem during cancer treatment. Drug efflux via ATP-binding cassette (ABC) transporters is the main mechanism responsible for resistance to chemotherapeutics. We have recently observed that statins enhance susceptibility to doxorubicin-induced apoptosis in human rhabdomyosarcoma cells, which is now also observed in human SH-SY5Y neuroblastoma cells. We have therefore investigated the ABC transporter activity to confirm a possible inhibition by statins in SH-SY5Y cells. Indeed, simvastatin directly inhibited dye transport at equimolar concentrations of the ABC transporter inhibitor, verapamil. Making use of the fluorescence behavior of doxorubicin the accumulation of anthracycline was monitored in real-time confocal microscopy. The intracellular doxorubicin accumulation was immediately enhanced by statins in SH-SY5Y cells and also in a MYCN-amplified neuroblastoma cell line STA-NB-10. The heavily glycosylated P-glycoprotein (ABCB1, P-gp) transporter appeared as a 180-and 140-kDa species. Atorvastatin and simvastatin reduced the 180-kDa form of P-gp, but not verapamil. Thereby the fully glycosylated species is shifted to the core glycosylated species (140 kDa), which was only seen at statin exposure times longer than 24 hr. The functional importance of glycosylation of the transporter was highlighted by exogenous application of N-glycosidase F, which was sufficient to enhance doxorubicin accumulation. Hence, these novel findings of statins' dual impact on P-gp have clinical implications. The enhanced intracellular accumulation of chemotherapeutics or other ABC transporter substrates in the presence of statins may represent a novel concept to overcome MDR in cancer therapy and improve drug safety.Neuroblastoma is the most common solid tumor in early childhood. About 55% of patients older than 1 year already have metastases at the time of diagnosis and therefore have a poor survival rate despite intensive therapy. 1 In $20% of the neuroblastoma a MYCN oncogene amplification occurs, which is the most unfavorable prognostic factor. 2,3 The MYCN amplification is the best established clinical and biological marker, which allows determination of the prognosis of the tumor, with numerous reports confirming the association with rapid tumor progression, advanced clinical stage and poor outcome. 3,4 Studies have shown that the expression of the multidrug resistance-associated protein 1 (MRP1, ABCC1) in neuroblastoma also correlates with poor clinical outcome and prognosis. 5,6 Recently, a prospective study has provided further evidence that high levels of MRP1 expression are strongly associated with MYCN oncogene amplification and predictive of poor outcome. 7 ATP-binding cassette (ABC) transporters, also termed multidrug resistance (MDR) proteins, play an important role in the efflux of many drugs. 8,9 Moreover, these ABC transporters are overexpressed in a wide range of tumors, for example, colon, kidney, adrenocortical or hepatocellular carcinomas, and thereby conf...

Background: Antimicrobial stewardship activities are essential to improve prudent antimicrobial use. The aim of the present study was to evaluate changes in antimicrobial prescriptions in cats after the introduction of prudent use guidelines promoted by an online antimicrobial stewardship tool (AntibioticScout.ch) in Switzerland. Data from 792 cats presented to two university hospitals and 14 private practices in 2018 were included and compared to 776 cases from 2016. Cats were diagnosed with acute upper respiratory tract disease (aURTD), feline lower urinary tract disease (FLUTD) and abscesses. Clinical history, diagnostic work-up and antimicrobial prescriptions (class, dosage, duration) were assessed. Type and proportions [95% confidence intervals] of antimicrobial prescriptions were compared between the two evaluation periods and a mixed effects logistic regression model was applied to evaluate compliance with Swiss prudent use guidelines. Results: From 2016 to 2018, the proportion of antimicrobial prescription in all included cases decreased from 75.0% [71.8-78.0] to 66.7% [63.3-69.9]; this decrease was most pronounced for treatments at university hospitals (67.1% [59.5-74.0] to 49.3% [40.9-57.8]) and for cats with FLUTD (60.1% [54.6-65.4] to 48.8% [43.2-54.4]). Use of 3rd generation cephalosporins in private practices declined from 30.7% [26.5-35.1] to 22.1% [18.4-26.2], while overall use of non-potentiated aminopenicillins increased from 19.6% [16.4-23.0] to 27.8% [24.1-31.9]. In cases where antimicrobial therapy was indicated, compliance with guidelines did not increase (33.3% [26.6-40.6] to 33.5% [27.2-40.2]), neither at universities nor in private practices. On the other hand, antimicrobial treatment was more often withheld in cases with no indication for antimicrobial therapy (35.6% [30.1-41.4] to 54.0% [47.6-60.4]); this was found for private practices (26.7% [20.8-33.4] to 46.0% [38.4-53.7]) and for aURTD cases (35.0% [26.5-44.2] to 55.4% [44.7-65.8]).

The risk of potential drug-drug interactions (PDI) is poorly studied in oncology. We included 105 patients with advanced non-small-cell lung cancer (NSCLC), 100 patients with advanced breast cancer (BC) and 100 patients of the palliative care unit (PCU) receiving systemic palliative treatment between 2010 and 2015. All patients suffered from advanced incurable cancer and received basic palliative care. PDI were assessed using the hospINDEX of all drugs approved in Switzerland in combination with a specific drug interaction software. Primary study objective was to assess the prognostic impact of PDI per patient cohort using Kaplan-Meier statistics. The median number of comedications was 5 (range 0-15). Major-risk PDI were detected in 74 patients (24.3%). The number of comedications was significantly associated with PDI (p < 0.0001). Major-risk PDI increased from 14% in patients with < 4 comedications to 24% in patients with 4-7 comedications, 40% with 8-11 comedications and 67% in patients with > 11 comedications. Median overall survival (OS) was 8.6 months in NSCLC, 33 months in BC and 1.2 months in PCU patients. PDI were significantly associated with inferior OS in BC (HR = 1.32, 95% CI 1.01-1.74, p = 0.049), but not in NSCLC (HR = 1.11, 95% CI 0.84-1.47, p = 0.45) or PCU (HR = 1.12, 95% CI 0.86-1.45, p = 0.41). PDI remained significantly associated with OS in BC (HR = 1.32, p = 0.049) in the adjusted model. In conclusion, PDI are frequent in patients with advanced cancer and increased caution with polypharmacy is warranted when treating such patients.