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Eyre: Janssen: Honoraria; Roche: Honoraria; Gilead: Consultancy, Honoraria, Other: commercial research support; Abbvie: Honoraria. Islam:Gilead: Honoraria, Other: Conference attendance sponosrship. Nicholson:Pfizer: Other: Conference attendance sponosrship; Takeda: Other: Conference attendance sponsorship. Fegan:Gilead: Honoraria; Roche: Honoraria; Janssen: Honoraria; Abbvie: Consultancy, Other: Conference attendance sponsorship. Smith:Gilead: Employment, Equity Ownership. Cursley:Gilead: Employment. Ramroth:Gilead Sciences: Employment. Rajakumaraswamy:Gilead Sciences, Inc.: Employment.

Introduction: Marginal zone lymphoma (MZL) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) comprise approximately 7% and 2%, respectively, of non-Hodgkin's lymphomas (NHL) (Teras 2016). MZL is further subclassified as splenic MZL (sMZL), nodal MZL (nMZL), or extranodal MZL (eMZL). Standard first-line therapies for LPL/WM include rituximab plus an alkylating agent and/or proteasome inhibitor or ibrutinib (Castillo 2017), while standard first-line treatment for MZL varies by subtype (Rosand 2017). There are limited treatment options for patients who have relapsed after first-line therapy. Idelalisib, a selective oral inhibitor of PI3Kδ, demonstrated efficacy in indolent NHL (iNHL), including MZL and LPL/WM, at a median follow-up of 9.7 months (mos) in a phase 2 study (NCT01282424; 101-09; Gopal 2014). Here, we present the final, long-term results for patients with double-refractory MZL and LPL/WM from the 101-09 study.

The origin of diastereoselectivity in the addition of alkyl lithium to chiral Schiff bases has been investigated experimentally and theoretically and the formation of the major diastereomer can be explained from the energy minimized structure of the Schiff base in which the phenyl group has been found to orient in such a manner that it posed lesser steric hindrance to the incoming nucleophile as compared to the alkyl group

A continuous one-one map of the open unit disc of onto itself which is not a homeomorphism is constructed.

Radiation therapy (RT) is the standard of care for cases of superior vena cava (SVC) syndrome secondary to metastatic adenopathy. Histologies vary in radiosensitivity and response time, making alternative therapies such as chemotherapy and/or intravenous stenting preferable alternative options for certain diagnoses. Metastatic urothelial carcinoma is a particularly rare cause of SVC syndrome with only 3 cases reported in the literature. Consequently, optimal management remains challenging, particularly in cases of high tumor burden. Here we present a case of highly advanced metastatic urothelial cancer with SVC syndrome and tracheal compression. The patient started urgent RT but expired midway through her treatment course due to systemic progression of disease, requiring SVC and tracheal stenting. The authors review the literature including discussion of the few other known cases of SVC syndrome due to urothelial carcinoma and a review of this histology’s response to RT. This experience suggests, that in cases of SVC syndrome with widespread advanced disease, stenting and chemotherapy with or without RT may be the most important initial treatment plan, depending on goals of care.

Peng: Janssen: Consultancy; Evidera: Employment. Pan:Janssen: Consultancy; Evidera: Employment. Sorensen:Evidera: Employment; Janssen: Consultancy. Dorman:Janssen: Consultancy; Evidera: Employment. Xu:Janssen: Consultancy; Evidera: Employment. Sallum:Evidera: Employment; Janssen: Consultancy. Gaudig:Janssen: Employment. Sengupta:Janssen: Employment. Wildgust:Janssen Global Services: Employment. Sun:Janssen: Employment.

Peng: Janssen: Consultancy; Evidera: Employment. Pan:Janssen: Consultancy; Evidera: Employment. Sorensen:Evidera: Employment; Janssen: Consultancy. Dorman:Janssen: Consultancy; Evidera: Employment. Xu:Evidera: Employment; Janssen: Consultancy. Sallum:Evidera: Employment; Janssen: Consultancy. Gaudig:Janssen: Employment. Sengupta:Janssen: Employment. Wildgust:Janssen Global Services: Employment. Sun:Janssen: Employment.

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in development for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery. Two large, phase III, randomized controlled trials compared rivaroxaban with subcutaneous (sc) enoxaparin following total knee replacement (TKR). In the recently published RECORD3 trial, rivaroxaban, 10 mg once daily (od), showed superior efficacy to an enoxaparin regimen of 40 mg od. However, enoxaparin 30 mg twice daily (bid) is the more widely used regimen in North America for VTE prophylaxis following TKR. The RECORD4 trial compared rivaroxaban 10 mg od versus enoxaparin 30 mg bid (both for 12 ± 2 days), for prevention of VTE following TKA. In the modified intent to treat population, the primary outcome (deep vein thrombosis [DVT], pulmonary embolism [PE], and all-cause mortality) occurred in 6.9% of rivaroxaban patients and 10.1% of enoxaparin patients (RRR 32%; p<0.012). Symptomatic VTE was observed in 0.7% of rivaroxaban patients and 1.2% of enoxaparin patients, although this difference was not statistically significant. There was no difference in major bleeding between rivaroxaban and enoxaparin. This analysis was designed to show the impact of the efficacy improvement with rivaroxaban and of oral vs. subcutaneous administration on US healthcare costs from a payer’s perspective. Methods: The impact of rivaroxaban was assessed using the efficacy data from RECORD4, and the reduced administration cost associated with oral therapy. The treatment cost of symptomatic VTE and major bleeding were taken from published managed care data in the US. For costing purposes, the duration of hospitalization for TKR (4 days) was obtained from a published US orthopaedic registry. It was assumed that asymptomatic events had no impact on healthcare costs, and conservatively assumed that nurses spend three minutes per day administering enoxaparin and training patients to self-inject for outpatient use while patients are in the hospital. This is likely to be an underestimate in light of other studies and clinical experience of VTE post TKR in the US clinical practice, so a sensitivity analysis included incremental costs associated with home nurse visits to administer sc injections. The duration of prophylaxis was assumed to be for 14 days. As rivaroxaban is not yet approved and available in the US, the analysis assumed similar drug acquisition costs to enoxaparin 40 mg, which is less expensive than enoxaparin 30mg bid. Results: The total cost associated with healthcare resource use in the US for the duration of treatment was $469 per patient with enoxaparin 30 mg bid injection and $307 with oral rivaroxaban 10 mg od. This implies a saving of $162 per patient. This improvement was driven primarily by the reduced drug acquisition relative to enoxaparin 30 mg bid, and monitoring costs. In addition, published data suggest home nurse visits during post-hospital prophylaxis period cost an average of $100 for enoxaparin; suggesting that potential savings with rivaroxaban could rise to $262 per patient. This analysis excludes any treatment benefits from a reduction in symptomatic events or the impact of post-thrombotic syndrome. However, pooled data from all phase III rivaroxaban trials (RECORD1, 2, 3, 4) vs. enoxaparin showed a significant reduction in symptomatic VTE and death until day 12±2 (P<0.001). Estimated US costs for the treatment for symptomatic VTE range from $9,805 to $14,146 per event. Given the reduced incidence of symptomatic events with rivaroxaban, there may be even further savings in healthcare costs associated with rivaroxaban. Conclusions: The improved efficacy of rivaroxaban over enoxaparin 30 mg BID for VTE prevention after TKR and reduced administration and acquisition costs are expected to result in savings to healthcare resources. With more than 300,000 US patients having TKR annually, these potential cost savings are significant.

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor submitted to US FDA for approval for the prevention of venous thromboembolism (VTE) after major orthopaedic surgery and is also in development for prevention and treatment of thromboembolic disorders. A recently published Phase III trial, RECORD1, compared rivaroxaban 10 mg once daily (od) with subcutaneous (sc) enoxaparin 40 mg od as VTE prophylaxis over 35 days in patients following total hip replacement (THR). The primary outcome (deep vein thrombosis, pulmonary embolism, and all-cause mortality) occurred in 1.1% of rivaroxaban patients and in 3.7% of enoxaparin patients (RRR 70%; p<0.001). The recently published RECORD2 compared 35 days’ rivaroxaban prophylaxis (10 mg od) with a short-term,10–14 day enoxaparin regimen (40 mg od) followed by placebo. The primary outcome occurred in 2.0% of the rivaroxaban group and 9.3% of the enoxaparin + placebo group (RRR 79%; p<0.001). The two drugs had similar safety profiles. This analysis compares the cost-effectiveness of 5 weeks’ prophylaxis with rivaroxaban in patients undergoing THR from US payer’s perspective. Methods: Three Economic decision models were developed based on the efficacy and safety parameters from individual RECORD1 and RECORD2 trials as well as combined RECORD1and 2 results, due to different treatment durations with enoxaparin (35 days in RECORD1 and 14 days in RECORD 2) vs. 35 days’ rivaroxaban. The models followed patients for up to 1 year post THA. The clinical efficacy (deep vein thrombosis [DVT], pulmonary embolism [PE], and symptomatic VTE events) and safety profiles of both drugs during the period of prophylaxis were obtained from the published RECORD1 and 2 trials, while the incidence of VTE up to 90 days following surgery was extrapolated based on epidemiological data (Quinlan et al., 2007). The incidence of recurrent VTE and post-thrombotic syndrome beyond this period was based on clinical data (Prandoni et al., 1997). The treatment costs for symptomatic VTE and major bleeding were taken from published sources in the US. For costing purposes, the duration of hospitalization for THA was obtained from a published US orthopaedic registry (3 days). It was also conservatively assumed that no incremental nurse time or home visit costs were associated with sc enoxaparin injection. Since rivaroxaban is not yet approved in the US, the economic model assumed similar drug acquisition costs to enoxaparin 40mg od. Results: Using rivaroxaban for 35 days appears to be a cost-effective and, in some instances, a cost-saving option compared with enoxaparin. The 1-year economic model based on RECORD2 (vs. 14 days’ enoxaparin) showed that 35 days’ rivaroxaban was associated with an incremental cost per symptomatic event avoided of $5,945. The analysis based on RECORD1 with a 35-day duration with both drugs showed that rivaroxaban resulted in an $82 cost saving, and a reduction of 6 symptomatic events per 1000 patients undergoing THR. Similarly, the –combined analysis based on RECORD 1and 2 showed a $19 cost saving and a reduction of 14 symptomatic events per 1000 patients favoring rivaroxaban. This improvement was driven primarily by the reduced costs of hospitalization for symptomatic events. Sensitivity analyses including the costs associated with home nurse time or training patients to self-administer enoxaparin showed potential for more cost-savings if patients receive oral rivaroxaban. Conclusions: Despite the clinical benefits of extended prophylaxis for up to 5 weeks with enoxaparin, and its recommendations in the guidelines, its use is limited in current US clinical practice, potentially due to inconvenience and high cost. Oral rivaroxaban given for 5 weeks has the potential to be cost effective, based on its superior efficacy over enoxaparin in patients undergoing THR. With more than 150,000 US patients having hip replacement annually, the benefits of using rivaroxaban could be significant.

Introduction: Rivaroxaban is a novel, oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders, including the prophylaxis for venous thromboembolism (VTE) after major orthopaedic surgery. In RECORD3, the first pivotal phase III study, rivaroxaban 10 mg once daily had superior efficacy to enoxaparin 40 mg once daily for the reduction of VTE following total knee arthroplasty (TKA). Mean duration of prophylaxis was 12.1 days. The primary endpoint (deep vein thrombosis [DVT], pulmonary embolism [PE], and all-cause mortality) occurred in 9.6% of the rivaroxaban group and in 18.9% of the enoxaparin group (RRR 49%; p<0.001; modified intention-to-treat), and symptomatic VTE occurred in 1.0% and 2.6%, respectively. There was no difference in major bleeding between rivaroxaban and enoxaparin. This analysis was designed to show the impact of this efficacy improvement on healthcare costs from a payer’s perspective. Preventing DVT, PE, and all-cause mortality (primary endpoint) and symptomatic VTE events have economic benefits, because fewer healthcare resources are required. Methods: The impact of rivaroxaban on healthcare resources in the US and UK were assessed using the resource utilization in the RECORD3 trial, and the reduced administration cost associated with an oral therapy. Only non-drug costs borne by the healthcare sector were included in the analysis. The cost of symptomatic VTE was taken from published sources in the US, and from the 2007 NICE Guidelines in the UK. It was assumed that asymptomatic events had no impact on healthcare costs. It was also conservatively assumed that nurses spend three minutes per day administering a subcutaneous enoxaparin dose and training patients to self-inject for out-patient use. For costing purposes, the duration of hospitalization was 5 days. In the UK, full blood counts should be taken every 3 days while receiving enoxaparin. Results: The total cost associated with healthcare resource use in the US was $290 per patient with enoxaparin and $98 with rivaroxaban (excluding rivaroxaban and enoxaparin drug costs). This implies a resource use saving of $192 per patient due to the improved health outcomes with rivaroxaban. This improvement was driven primarily by the reduced costs of hospitalization for symptomatic events. In the UK, the total cost of resource use per patient was £48 ($78) with enoxaparin and £5 ($8) with rivaroxaban. The reduced healthcare cost of £43 ($70) per patient was driven equally by reduced hospitalization and reduced monitoring. The substantial difference in cost impact is due to higher US hospitalization costs. These results exclude the impact of post-thrombotic syndrome (PTS), the estimated 5-year rate of which is 21% in asymptomatic patients and 30% in symptomatic patients. Estimated costs for PTS treatment is more than $11,000 in the USA, and £4,000 ($6472) in the UK. Given the reduced incidence of both asymptomatic and symptomatic events with rivaroxaban, there would be even further savings in healthcare costs associated with rivaroxaban, due to a reduction in PTS. Conclusions: The clinical results shown by rivaroxaban for the prevention of VTE after TKA also result in savings to healthcare costs. With more than 600,000 US patients having hip or knee arthroplasty annually, these potential cost savings are significant.

Introduction Sepsis is the main cause of morbidity and mortality in intensive care units and its early diagnosis is not straightforward. Many studies have evaluated the usefulness of various markers of infection, including C-reactive protein (CRP), which is the most accessible and widely used. CRP is of weak diagnostic value because of its low specificity; a better understanding of patterns of CRP levels associated with a particular form of infection may improve its usefulness as a sepsis marker. In the present article, we apply multilevel modeling techniques and mixed linear models to CRP-related data to assess the time course of CRP blood levels in association with clinical outcome in children with different septic conditions.Methods We performed a retrospective analysis of 99 patients with systemic inflammatory response syndrome, sepsis, or septic shock who were admitted to the Pediatric Critical Care Unit at the University Hospital, Brno. CRP blood levels were monitored for 10 days following the onset of the septic condition. The effect of different septic conditions and of the surgical or nonsurgical diagnosis on CRP blood levels was statistically analyzed using mixed linear models with a multilevel modeling approach.Results A significant effect of septic condition and diagnosis on the course of CRP levels was identified. In patients who did not progress to septic shock, CRP blood levels decreased rapidly after reaching peak values – in contrast to the values in patients with septic shock in whom CRP protein levels decreased slowly. Moreover, CRP levels in patients with a surgical diagnosis were higher than in patients with a nonsurgical condition. The magnitude of this additional elevation in surgical patients did not depend on the septic condition.Conclusion Understanding the pattern of change in levels of CRP associated with a particular condition may improve its diagnostic and prognostic value in children with sepsis.

For Abstract see ChemInform Abstract in Full Text.

For Abstract see ChemInform Abstract in Full Text.