Royalty Payments Research Articles

Identification of Potent BH3-Mimetic Combinations Targeting Pro-Survival Pathways in Human B-Cell Acute Lymphoblastic Leukemia

▪BackgroundPrecursor-B acute lymphoblastic leukemia (B-ALL) is an aggressive hematological malignancy. Relapsed disease has a poor prognosis, despite improved outcomes with tyrosine kinase inhibitors for Ph+ cases and immunotherapeutic approaches, such as blinotumomab and CAR-T cells. Targeting cell survival with novel small molecule BH3-mimetic inhibitors of BCL-2 (e.g. Souers et al Nat Med 2013, Roberts et al, NEJM 2016 and Casara et al, Oncotarget 2018), BCL-XL (Lessene et al, Nat Chem Biol, 2013) or MCL1 (Kotschy et al, Nature 2016) is an emerging therapeutic option. BCL-2 is reported to have a pro-survival role in BCR-ABL1, JAK2 fusion, ETV6-RUNX1 and MLL-r driven ALL (Brown et al., Journal Biological Chemistry 2017). BH3-mimetics targeting BCL-2 and BCL-XL has efficacy in paediatric ALL xenografts (Khaw et al., Blood 2016), while ruxolitinib combined with ABT-737 is synergistic in JAK2-mutant pre-B-ALL (Waibel et al., Cell Reports 2013). We now report that combined targeting of BCL-2 and MCL1 has broad pre-clinical efficacy in adult B-ALL samples with Ph+, Ph- and Ph-like characteristics.MethodsS55746 and S63845 were obtained from Servier/Novartis, A1331852 from Guillaume Lessene (WEHI), venetoclax, daunorubicin, dexamethasone (DXM) and tyrosine kinase inhibitors (TKIs) from Selleckchem. Bliss synergy scores were determined using a checkerboard approach to evaluate combinations (previously described Bliss, Ann Appl Biol 1939). Primary ALL cells were obtained from 14 patients (4 Ph+ and 10 Ph-) providing informed consent. Ex vivo cell viability (sytox blue exclusion) at 48h was determined over a 5-log dilution range (1nM-10uM) using drugs alone or in equimolar combinations. For in vivo studies, adult B-ALL patient derived xenografts were performed in NSG; NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice.ResultsDual BH3-mimetic targeting of BCL-2 and MCL1 was strongly synergistic (Bliss sum >1000) in SUPB15 (Ph+ BCR-ABL1), BV173 (lymphoid blast crisis BCR-ABL1), MUTZ5 (Ph-like) and MHHCALL4 (Ph-like) B-ALL cell lines. This was more effective than single BH3-mimetic combinations with DXM or TKIs (dasatinib or ruxolitinib) (Fig. A, B). In B-ALL patient samples, combined BCL-2 and MCL1 targeting lowered the LC50 by 10-1000 fold (to LC50<10nM) in 4/4 Ph+ ALL cases and 8/10 Ph- cases. Similarly, combined MCL1 and BCL-XL targeting demonstrated synergy in 3/4 Ph+ cases and 7/10 Ph- cases (to LC50<10nM), confirming remarkable anti-leukemic activity compared to BH3-mimetics alone or chemotherapy (daunorubicin) (Fig. C). BH3-mimetic combination therapy (S55746/S63845) compared favourably in Ph+ ALL cases to S55746 (figure D) or S63845 (Figure E) in combination with dasatinib. Preliminary data using patient-derived xenografts in NSG mice revealed in vivo efficacy of combined S55746 and S63845 therapy against 3 adult B-ALL cases (1 Ph+ and 2 Ph-). Reduction of established ALL in the bone marrow was observed in mice receiving combined S55746/S63845 after one week of treatment (p=<0.05) (Fig. F-H).ConclusionsDual BH3-mimetic targeting of BCL-2 and MCL1 induces synergistic killing of human B-ALL cell lines and primary ALL samples in vitro and rapid cytoreduction in vivo. Simultaneous inhibition of BCL-2 and MCL1 represents a novel and effective approach for targeting Ph+, Ph- and Ph-like B-ALL without need for additional DNA-damaging chemotherapy or kinase inhibition. Our results support the translational investigation of dual BH3-mimetic targeting of BCL-2 and MCL1 in the clinic.Figure legend: BLISS synergy scores for A. Ph+ and B. Ph-like ALL cell lines for drug combinations targeting BCL-2, MCL1, BCR-ABL, JAK1/2 and DXM. C. LC50 activity in primary ALL after 48hr of treatment with BH3 mimetics and combinations targeting BCL-2, MCL1, BCL-XL, compared to daunorubicin (LC50< 10nM red; ~ 100nM yellow; >1uM green). D. Comparison of BH3-mimetics targeting D.BCL-2 or E. MCL1 in combination with dasatinib in Ph+ vs Ph- primary B-ALL samples. Activity expressed as LC50 activity after 48h, with median values shown. Irradiated NSG mice were transplanted with 106 primary B-ALL cells. Engraftment of F. Ph+ and G-H. Ph- B-ALL cells was confirmed at 10 weeks by detection of hCD45 in PB. Mice were then treated with i) vehicle (d1-5), ii) S55746 100mg/kg days 1-5 by gavage, iii) S63845 25 mg/kg IV on days 2 and 4 or iv) S55746+S63845. Mice were euthanized on day 8 and hCD45+ from flushed femurs quantified. DisclosuresChanrion:Servier: Employment. Maragno:servier: Employment. Kraus-Berthier:servier: Employment. Lessene:servier: Research Funding. Roberts:Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax. Geneste:servier: Employment. Wei:Pfizer: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Research Funding; Amgen: Honoraria, Other: Advisory committee, Research Funding; Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau.

Molecular Patterns of Response and Outcome in the Chemotherapy and Venetoclax in Elderly AML Trial (CAVEAT study)

▪Background: Venetoclax (VEN) is a potent small molecule BH3-mimetic drug that selectively targets the prosurvival protein BCL-2 and has an emerging role for treatment in Acute Myeloid Leukaemia (AML). This ongoing Phase 1b study aims to evaluate the optimal dose, safety and efficacy of VEN in combination with modified intensive chemotherapy in fit, elderly patients with AML who have not received prior induction chemotherapy. Here we present updated data including molecular correlates of response and treatment outcomes.Methods:Eligibility: Patients were enrolled with AML (excluding APL), age ≥65 years (≥60 years if monosomal karyotype), ECOG 0-1 and adequate organ function. Prior HMA/LDAC was permitted after a 14-day washout. Treatment: 1) Dose escalation cohorts comprised VEN 50mg (Cohort A), 100mg (B), 200mg (C), 400mg (D) or 600mg (E); 2) a 7-day VEN pre-phase incorporating dose ramp-up to minimise tumour lysis risk followed by a 7-day overlap with chemotherapy (day -6 to +7); 3) attenuated induction chemotherapy with cytarabine 100mg/m2/day IVI d1-5 staggered with idarubicin 12mg/m2 IV d2-3. For patients in remission, 4 cycles of consolidation were administered, comprising 14 days of VEN (day -7 to +7) with bolus cytarabine (100mg/m2/day IV d+1-2) and idarubicin (12mg/m2 IV d+1) followed by 7 cycles of VEN monotherapy maintenance; planned to commence q28d. Antifungal azoles were avoided during VEN exposure. The first patient was enrolled 17JUL2016. Molecular studies- Next generation sequencing using a 54-gene TruSight myeloid panel was performed on baseline bone marrow samples. FLT3-ITD testing was performed by capillary electrophoresis. RT-qPCR was used to detect minimal residual disease (MRD) in NPM1-mutated cases (assay sensitivity: 10-5-10-6).Results: The data cut-off date was 13JUL2018. 44 patients were enrolled with 3 patients still in the induction cycle. Median age was 72 years (range 63-80 years; 23% ≥75 years), 66% of patients were male, 41% had secondary AML and 38% prior hypomethylating agent (HMA) exposure. Main grade ≥3 non-haematological adverse events during induction were febrile neutropenia (56%), sepsis (32%), rapid atrial fibrillation (15%), diarrhoea (12%), nausea (10%) and localised infection (10%). No clinical TLS was observed. One hematologic dose-limiting toxicity was reported in cohort E (VEN 600mg), but a maximum tolerated dose has not been reached. We observed progressive delay in platelet count recovery as patients proceeded with each cycle of therapy (median time to platelets ≥50x109/L was 25d in induction, 37d in consolidation 1 and 57d in consolidation 4). Treatment-related mortality was 7% in induction. 18/38 (47%) had ≥30% relative reduction in bone marrow (BM) blasts after 7 days of pre-phase VEN monotherapy, with no correlation between VEN dosage and the degree of BM blast reduction.Overall CR/CRi rate was 71%. CR/CRi was achieved in 95% of patients with de novo AML (vs 42% in secondary/therapy-related AML). Response rates were 88% in intermediate vs 46% in adverse cytogenetic risk AML. Responses in patients with prior HMA therapy were 43% and 84% for previously untreated patients. Molecular data were available for 41 patients. 98% had ≥1 mutation detected. (Figure 1) Responses in response-evaluable patients were most common in NPM1 mutant AML (100%; n=7), followed by RUNX1 (90%; n=11), RAS (90%; n=10) and IDH (89%; n=9). Lowest responses were observed in TP53 mutant AML (33%; n=9). NPM1 MRD assessment was performed on 6 patients, of which 5 (83%) achieved NPM1 MRD negativity. (Figure 2) Updated response, response duration and survival data will be presented, along with molecular characteristics of relapse.Conclusion: To date, VEN up to 600mg in combination with 5+2 induction chemotherapy is tolerable in fit elderly patients with AML. Initial response rates >80% were observed in de novo AML, as well as NPM1, RUNX1, RAS and IDH mutant AML, whereas responses were lower in patients with prior HMA exposure, adverse karyotype, secondary and TP53 mutant AML. Molecular determinants of relapse require further study. [Display omitted] DisclosuresWei:Servier: Consultancy, Honoraria, Other: Advisory committee, Research Funding; Amgen: Honoraria, Other: Advisory committee, Research Funding; Novartis: Honoraria, Other: Advisory committee, Research Funding, Speakers Bureau; Pfizer: Honoraria, Other: Advisory committee; Celgene: Honoraria, Other: Advisory committee, Research Funding; Abbvie: Honoraria, Other: Advisory board, Research Funding, Speakers Bureau. Fong:Celgene: Other: Advisory board; Novartis: Other: Advisory board; Amgen: Research Funding; Pfizer: Other: Speaker fees. Reynolds:Novartis: Equity Ownership, Other: former employee of Novartis AG and holds stock in the company. . Roberts:Janssen: Research Funding; AbbVie: Research Funding; Genentech: Research Funding; Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax.

Long-Term Follow-up of Patients with Mantle Cell Lymphoma Treated with Venetoclax Monotherapy

Introduction: Venetoclax is a selective, oral inhibitor of BCL2, a key regulator of the intrinsic apoptotic pathway. The dose-escalation phase 1 study of venetoclax in patients with relapsed/refractory non-Hodgkin lymphoma (NHL) enrolled 106 patients from June 2011, and the overall response rate across the entire NHL cohort was 44%. The highest response rate (75%) was seen in the 28 patients with mantle cell lymphoma (MCL) (Davids et al., J Clin Oncol. 2017). Here, we report longer-term outcomes for those patients, now with a median of 27 months (range: 0.2 - 59) follow up.Methods: Venetoclax was administered in dose cohorts ranging from a maximum dose of 300-1200 mg and continued until progressive disease (PD) or unacceptable toxicity; intra-patient dose escalation was allowed. Adverse events (AEs) were assessed by NCI-CTCAE v4.0 and responses were assessed using 2007 Cheson IWG response criteria, utilizing CT scans beginning at week 6. The data cut off for this analysis was June 4th, 2018.Results: For the 28 patients with MCL, the median age was 72 years (range: 35 - 85). They had received a median of 3 (range: 1 - 7) prior treatments; 5 patients received prior PI3K inhibitor (but no prior ibrutinib). The median time from the preceding treatment to start of venetoclax was 13 months (range: 2 - 148). The median dose of venetoclax was 400 mg/day; 25/28 received at least 400mg/day. Median time on study drug was 11 months (range: 0.2 - 59). Three patients have been on therapy for over 4 years.The overall response rate was 75%, with 6 (21%) patients achieving complete remission (CR) and 15 (54%) partial response (PR). The median duration of response was 16 months (95% CI: 4, 30) and median progression free survival was 11 months (95% CI: 5, 21) for all patients (Figure). The 2 year PFS estimate was 30% (95% CI: 14%, 47%) for all patients, 83% (95% CI: 27%, 97%) for patients who achieved CR and 14% (95% CI: 2%, 37%) for patients who achieved PR. One patient who achieved PR proceeded to allogeneic stem cell transplant and remained disease free at the last protocol defined follow-up (24 months after coming off study). Three patients developed progressive disease after receiving venetoclax for more than two years of therapy (time to progression: 31, 33, and 33 months). Two patients with CR continue on study without evidence of progression, currently at 47 and 59 months of venetoclax monotherapy.The most common (≥25% of patients with MCL) all grade treatment emergent AEs were nausea (57%), diarrhea (50%), fatigue (39%), constipation (29%) and upper respiratory infection (25%). The most common (≥10% of patients with MCL) grade 3/4 AEs were neutropenia (14%), anemia (14%), pneumonia (11%), and thrombocytopenia (11%). Biochemical tumor lysis syndrome (TLS), without accompanying clinical features, was reported in one patient considered high risk for TLS. Specific interventions were not required, and the patient continued on study drug.Conclusions: Venetoclax monotherapy leads to durable remission in a meaningful proportion of patients with pretreated MCL. Further studies in MCL are currently investigating potential biomarkers for durable response to venetoclax combination regimens, including a Phase 3 randomized study with ibrutinib (SYMPATICO, NCT03112174). [Display omitted] DisclosuresDavids:Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Merck: Consultancy; AbbVie, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Verastem: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy; MEI Pharma: Consultancy, Research Funding; Gilead: Membership on an entity's Board of Directors or advisory committees; Surface Oncology: Research Funding. Roberts:Walter and Eliza Hall: Employment, Patents & Royalties: Employee of Walter and Eliza Hall Institute of Medical Research which receives milestone and royalty payments related to venetoclax; AbbVie: Research Funding; Genentech: Research Funding; Janssen: Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Humphrey:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Alter:AbbVie, Inc: Employment, Equity Ownership. Masud:AbbVie, Inc: Employment, Equity Ownership. Buss:Abbvie, Inc: Employment, Equity Ownership. Verdugo:AbbVie, Inc: Employment, Equity Ownership. Seymour:Janssen: Honoraria, Research Funding; Celgene: Consultancy; Genentech Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Research Funding.

1587. Analysis of Breakthrough Blood Stream Infections in Left Ventricular Assist Device Recipients Managed With Chronic Antimicrobial Suppressive Therapy

BackgroundLeft ventricular assist devices (LVAD)-associated infections are associated with fivefold higher 1-year mortality. Published literature is insufficient to inform clinicians regarding optimal management of bloodstream infection (BSI) in patients LVAD recipients. In particular, it is unclear which episodes of BSI may result in occult hematogenous seeding of the device surfaces, and therefore should be managed with chronic suppressive therapy (CAS). We aim to describe BSI, CAS, and breakthrough BSI in our LVAD population.MethodsWe retrospectively reviewed 332 episodes of all LVAD infections at Mayo Clinic from 2007 to 2015. We categorized BSI as LVAD related/associated and LVAD nonrelated as defined by established criteria in the cardiac device literature. Our primary outcome was to describe breakthrough BSI in LVAD related and nonrelated infections in patients receiving CAS and those who were not.ResultsWe identified 68 episodes of bacteremia in our LVAD population. Of these, 55 were proven BSI (see Fig 1). In our study cohort, 45/55 (82%) were male and median patient age was 62 years. A majority of LVAD implants were destination therapy 34/55 (62%) and 35/55(64%) had a central line in place at the time of BSI. Twenty patients had non-VAD-related BSI and nine of these (9/20, 45%) patients were placed on CAS with two of these (2/9, 22%) had subsequent breakthrough BSI, whereas 11/20 (55%) were not placed on CAS with no breakthrough infections seen (Figure 1).ConclusionOur preliminary data suggest that routine use of CAS for non-VAD-related BSI is not necessary as only a minority go on to have breakthrough BSI. Limiting unnecessary use of antibiotics will have significant implications for stewardship and preventing emergence of resistance. Disclosures L. M. Baddour, UpToDate: Collaborator, Royalty payment. M. R. Sohail, TyRx Inc: Investigator, Research support; Medtronic Inc: Investigator, Research support; Medtronic Inc: Consultant, Speaker honorarium; Spectranetics: Consultant, Speaker honorarium; Boston Scientific Corp: Consultant, Speaker honorarium.

1085. Enterococcal Cardiac Implantable Electronic Device (CIED) Infections: Clinical Features and Outcomes

BackgroundUnlike enterococcal native and prosthetic valve infective endocarditis (IE), enterococcal CIED infections are not well described.MethodsData from the Multicenter Electrophysiologic Device Infection Collaboration (MEDIC), a prospective, observational, multinational cohort study of CIED infections, were used to provide a descriptive analysis of adult patients with CIED infections due to enterococcal species.ResultsOf 433 patients, 21 (4.8%) were diagnosed with enterococcal CIED infection. Specific data on enterococcal species and antimicrobial susceptibilities were not recorded. The mean age was 70.8 years. No patient had previous CIED infection. Twelve patients (57%) had permanent pacemakers, 5 (24%) had implantable cardioverter defibrillators, and 4 (19%) had biventricular devices. Among the 21 infections, 3 (14%) were categorized as CIED-related bloodstream infections and 18 (86%) as IE; no patient had isolated pocket infection. Of the IE cases, four were valvular IE, eight were lead IE, and six were both. Fourteen cases of IE (78%) were definite by the modified Duke criteria. Median time from last device procedure to infection was 510 days (range 37–2,952 days). The most common presenting symptom was fever (48%); five patients (24%) exhibited local signs of pocket infection. All 21 patients underwent TEE with vegetations demonstrated in 17 (81%). Blood cultures grew enterococci from all patients. The most common antimicrobial regimen was a penicillin plus aminoglycoside (38%); two patients (9.5%) received ampicillin + ceftriaxone. Antibiotics were given for a median of 43 days. Only 14 patients (67%) had complete device removal; the seven patients retaining their device were judged to be at high risk for extraction. There was one death during the index hospital stay with four additional patients dying over the 6 months after therapy (overall mortality 24%); two of the seven patients retaining their CIED died.ConclusionEnterococci caused 4.8% of all CIED infections in our cohort. Most infections appeared to be hematogenous in origin with late onset. IE was the most common infectious syndrome. A penicillin plus aminoglycoside, given for 6 weeks, was the most frequent therapy. Only 67% of patients underwent device removal. At 6 months follow-up, no relapses had occurred but overall mortality was 24%.Disclosures J. E. Peacock Jr., Pfizer, Inc.: Shareholder, Owns common stock in Pfizer which was inherited and held in a trust. M. R. Sohail, TyRx Inc.: Investigator, Research support. Medtronic Inc.: Investigator, Research support. Medtronic Inc.: Consultant, Speaker honorarium. Spectranetics: Consultant, Speaker honorarium. Boston Scientific Corp: Consultant, Speaker honorarium. L. M. Baddour, UpToDate: Collaborator, Royalty payment. J. M. Miro, Abbvie: Consultant and Grant Investigator, Consulting honoraria and Research grant. Bristol-Myers Squibb: Consultant and Grant Investigator, Consulting honoraria and Research grant. Genentech: Consultant and Grant Investigator, Consulting honoraria and Research grant. Medtronic: Consultant and Grant Investigator, Consulting honoraria and Research grant. Novartis: Consultant and Grant Investigator, Consulting honoraria and Research grant. Gilead Sciences: Consultant and Grant Investigator, Consulting honoraria and Research grant. Pfizer: Consultant and Grant Investigator, Consulting honoraria and Research grant. ViiV Healthcare: Consultant and Grant Investigator, Consulting honoraria and Research grant. A. J. Greenspon, Medtronic: Consultant, Speaker honorarium. Boston Scientific: Consultant, Speaker honorarium. St. Jude: Consultant, Speaker honorarium. R. G. Carrillo, St. Jude Medical Group: Speaker’s Bureau, Research support. Spectranetics: Consultant, Speaker honorarium. Sorin Group: Speaker’s Bureau, None. Boston Scientific Corp: Speaker’s Bureau, None. D. Z. Uslan, Medtronic: Investigator, Research support. Boston Scientific: Consultant, Speaker honorarium.

Association of Compensation From the Surgical and Medical Device Industry to Physicians and Self-declared Conflict of Interest

Surgical and medical device manufacturers have a cooperative relationship with clinicians. When evaluating published works, one should assess the integrity and academic credentials of the authors, who serve as putative experts. A relationship with a relevant manufacturer may increase the potential risk for bias in relevant studies. To characterize the association of industrial payments by device manufacturers, self-declared conflict of interest (COI), and relevance of publications among physicians receiving the highest compensation. This population-based bibliometric analysis identified 10 surgical and medical device manufacturing companies and the 10 physicians receiving the highest compensation from each company using the 2015 Open Payments Database (OPD) general payments data. For each of the 100 physicians, the total amount of general payments, number of payments, institution type, and academic rank were recorded. Royalty or license payments were excluded. A search of PubMed identified articles published by each physician from January 1 through December 31, 2016, and their associated COI declaration. Scopus was used to identify bibliometric data reported as the h index (number of papers by a researcher with at least h citations each). Discrepancy between self-declared COI and industry payments. The 100 physicians included in the sample population (88% men) were paid a total of $12 446 969, with a median payment of $95 993. Fifty physicians (50.0%) were faculty at academic institutions. The mean (SD) h index was 18 (18; range, 0-75) for the authors. In 2016, 412 articles were published by these physicians, with a mean (SD) of 4 (6) publications (range, 0-25) and median of 1 (36 physicians had no publications). Of these articles, 225 (54.6%) were relevant to the general payments received by the authors. Only in 84 of the 225 relevant publications (37.3%) was the potential COI declared by the authors. A high level of inconsistency was found between self-declared COI and the OPD among the physicians receiving the highest industry payments. Therefore, a policy of full disclosure for all publications, regardless of relevance, is proposed. No statistically significant association was demonstrated between academic rank or productivity and industrial payments.

Rural Landowners, Energy Leasing, and Patterns of Risk and Inequality in the Shale Gas Industry

AbstractLandowners who lease property for shale gas development (i.e., “fracking”) face the possibility of procedural disenfranchisement and risk. They also stand to benefit financially from bonus and royalty payments. This article evaluates the frequency with which these experiences occur and how they vary between landowners. Using a mixed‐methods approach, we combine surveys and interviews with northeastern Pennsylvania landowners with a content analysis of energy lease documents. We find that landowners generally experience relatively infrequent environmental harm, receive substantial financial benefits, and leverage their property rights to secure better lease conditions. However, our findings also demonstrate that procedural disenfranchisement does occur, environmental risks are infrequent but real, and outcomes tend to vary by firm‐specific rather than sociostructural factors. Accordingly, the advantages conferred by private property are not a panacea for the alleviation of risk and inequality in energy development. These findings inject considerable nuance into ongoing discussions of risk, inequality, and shale gas development: Rather than perceiving themselves as victims, landowners tend to see themselves as beneficiaries of industry activity, an experience structured directly by their ownership of property and mineral rights.

Wednesday, September 26, 2018 7:35 AM–9:00 AM ePosters: P66. Patient perceptions of surgeon-industry relationships

BACKGROUND CONTEXT The prevalence of orthopedic surgeon-industry relationships and other physician-industry relationships led to the establishment of a national database of physician-industry interaction (the open-payments database, OPD) as part of the Physician Payments Sunshine Act (PPSA). While the transparency afforded by the PPSA is laudable, it raises questions about how these disclosures might impact patient-perceptions of their surgeon. PURPOSE To determine patient awareness of the OPD, patient awareness of their surgeon's industry relationships, how these relationships affect patient perceptions of their surgeon and which relationships caused the greatest concern to patients. STUDY DESIGN/SETTING Cross sectional study. PATIENT SAMPLE Two hundred patients. OUTCOME MEASURES Patient perceptions of surgeon-industry relationships. METHODS A 10-question survey was administered to patients prior to their first clinical evaluation with a spine surgeon. Two questions asked about patient awareness of their surgeon's industry relationships and their awareness of the OPD. One question evaluated the importance of surgeon-industry relationships to patients when choosing a provider. Six questions assessed patient perception of specific types of surgeon-industry relationships. The last survey question asked each patient to rank specific types of surgeon-industry relationships (1 = most concerning to 6 = least or not concerning). Descriptive statistics are reported. The distribution of patient-perceptions was compared using a Friedman's Two-Way Analysis of Variance by Ranks test. Distributions across awareness were compared using a Kruskal-Wallis Test. RESULTS A total of 200 patients completed the survey and were included in this analysis. The average age of patients surveyed was 48years (range: 16–89 years) with 45.0% (n=90) male patients. Most patients surveyed were Caucasian (80.5%) and had private health insurance (88.0%). A majority of patients were unaware of their physicians’ relationships with industry (89.2%) and the existence of the OPD (91.2%). Most patients (54.4%) considered surgeon-industry relationships an important, very important or most important part of choosing their physician. There were significant differences in how industry relationships affected patient perceptions. Research funding had the most positive impact on perception (47.8% very positive). Physician ownership share or stock ownership was most likely to negatively impact perception of surgeons (23.4% somewhat negative) while 73.1% of patients still reported that physician ownership had no effect or a positive impact on their perception of their surgeon. Awareness of the OPD or physician relationships did not have a significant impact on patient perception. Amongst all relationships, financial ownership was reported to be most concerning (2.92±1.99) followed by royalty payments (3.29±1.77) and consulting (3.61±1.46). Research, funding, industry sponsored dinners and speaking engagements were all scored similarly. CONCLUSIONS Our results suggest that most patients consider surgeon-industry relationships an important factor in choosing their doctor. Additionally, patients generally report a more positive view of surgeons who have active relationships with industry. These results emphasize the value of disclosure for surgeons; it provides transparency and improves their standing amongst a majority of their patients.

UTILIZATION OF ECONOMIC RIGHTS IN MUSIC AND SONG WORKS AS A PILLAR OF CREATIVE ECONOMY

The work of songs and music is one of several types of artistic works that is protected by the Act of Copyright. Copyright is regulated through Act No. 28 of 2014 About Copyright (Undang-Undang Hak Cipta or UUHC). Creators and Copyright holders have an exclusive right in the form of economic rights and moral rights. Economic rights can be acquired through the payment of royalty. According to the Act of Copyright, the National Collective Management Institution (Lembaga Manajemen Kolektif Nasional or LMKN) is the institution appointed to collect royalties from creators and/or holders of related rights. LMKN is a non-profit legal entity which has been given an authority by Copyright holders and/or holders of related rights to manage the economic rights in legally collecting and distributing royalties. In order to acquire their share in the royalty, each of the creators, Copyright holders, or the holders of related rights has to become a member of LMKN, and in return said LMKN got the authority to collect royalties from users of said artistic works. Royalty is a form of payment or rewards given to creators and/or Copyrights holders over the utilization of economic rights or related rights of a creation or a product. In Indonesia, there are a lot of LMKNs, in which the function is to collect royalties, including collecting exclusive rights of the holders of related rights.&#x0D; The resulting performance of Collective Management Institutions (Lembaga Manajemen Kolektif or LMK) has not reached its optimum capability for both creators and holders of related rights. The resulting advice of this paper is for the government to create a strict payment system and a method which can also be accessed digitally by the creators.

UTILIZATION OF ECONOMIC RIGHTS IN MUSIC AND SONG WORKS AS A PILLAR OF CREATIVE ECONOMY

The work of songs and music is one of several types of artistic works that is protected by the Act of Copyright. Copyright is regulated through Act No. 28 of 2014 About Copyright (Undang-Undang Hak Cipta or UUHC). Creators and Copyright holders have an exclusive right in the form of economic rights and moral rights. Economic rights can be acquired through the payment of royalty. According to the Act of Copyright, the National Collective Management Institution (Lembaga Manajemen Kolektif Nasional or LMKN) is the institution appointed to collect royalties from creators and/or holders of related rights. LMKN is a non-profit legal entity which has been given an authority by Copyright holders and/or holders of related rights to manage the economic rights in legally collecting and distributing royalties. In order to acquire their share in the royalty, each of the creators, Copyright holders, or the holders of related rights has to become a member of LMKN, and in return said LMKN got the authority to collect royalties from users of said artistic works. Royalty is a form of payment or rewards given to creators and/or Copyrights holders over the utilization of economic rights or related rights of a creation or a product. In Indonesia, there are a lot of LMKNs, in which the function is to collect royalties, including collecting exclusive rights of the holders of related rights.&#x0D; The resulting performance of Collective Management Institutions (Lembaga Manajemen Kolektif or LMK) has not reached its optimum capability for both creators and holders of related rights. The resulting advice of this paper is for the government to create a strict payment system and a method which can also be accessed digitally by the creators.

ROYALTY OF INDONESIAN SONGS COPYRIGHTS AT YAYASAN KARYA CIPTA INDONESIA ISSUED BY LAW NUMBER 19 OF 2002 ON COPYRIGHTS

This article aims at describing the role of Yayasan Karya Cipta Indonesia (YKCI) in copyright protection in Indonesia and the mechanism of royalty payment on Indonesian songs to the YKCI. The approach used in this study is normative approach as this study is conducted on secondary, primary, and tertiary legal materials, such as books, legal journals, and expert (secondary data) research results; its main legislation is Law no. 19 of 2002 on Copyright (primary data); English and Indonesia dictionaries and tertiary law which is the result of library research, supported by legal materials in the form of documents from field research results. From the collected legal materials, analysis in the method of the qualitative descriptive was conducted. The results indicated that YKCI's role as an administrator body in copyright protection is to collect royalties from parties that use songs or music commercially and help dispute resolution between creators, users or record producers of songs or music creations. Furthermore, the mechanism of royalty payments to YKCI shall be initiated by the authorization of YKCI by the creator or the copyright holder of the song, so on the basis of such power of attorney, YKCI exercises the collection or withdrawal of royalties by a percentage mechanism from the dealer's selling price through a permit saving per song at a rate for recording into a cassette, CD, VCD, and other media. Law Number 19 of 2002 on Copyright should be accompanied by the willingness and ability of the apparatus in enforcing it so that what to be achieved with the Act can be obtained. In addition, it is recommended that the government immediately issue provisions on the roles, duties and functions of the Copyright Council as well as the organic rules that explain the authority of YKCI which may be the appointment of the Director-General of Intellectual Property Rights (IPR) as endorsement of a collective society in order to attract royalties. The government also needs to make a standard contract of licensing agreement between the Copyright of Songs and Music in the event of announcement. In addition, YKCI also needs to be open including to the power of attorney (Creator of the song) so that the Creator can know the frequency of their song announcement and the large royalty that must be obtained.

The failure of eco-forestry as a small-scale native forest management model in Papua New Guinea

Deforestation and forest degradation are problems common to many tropical countries, including Papua New Guinea (PNG). These problems are often a result of the environmentally unsustainable logging practices of industrial logging companies. Beginning in the 1990s, six organizations attempted to mitigate the deforestation and forest degradation occurring in PNG by facilitating small-scale native forest management by Indigenous forest landowners. All six organizations utilized an ‘eco-forestry’ approach, involving selective harvesting of timber combined with the milling of timber by Indigenous forest landowners using portable sawmills. The lumber produced was sold into local and international markets as sustainable certified under Forest Stewardship Council (FSC) principles. The use of portable sawmills was also intended to provide the landowners with a greater financial return compared to the timber royalty payments they could receive from logging companies. This study used a literature review and interviews with key informants from the eco-forestry organizations and the PNG Forest Authority to assess the effectiveness of variants of the portable sawmilling model. We found that each of the six organizations were unsuccessful in developing a financially viable model for small-scale native forest management by Indigenous forest landowners in PNG. All the Indigenous landowners were unable to continue their portable sawmill operations once the donor funding of the eco-forestry organizations ceased. In addition, the operators of portable sawmills struggled to produce lumber that met the quality and quantity demands of buyers, who ultimately ceased purchasing the lumber. Furthermore, the Indigenous landowners struggled to adhere to the FSC principles, resulting in a loss of FSC certification. The study identifies a need for a new small-scale native forest management model in PNG. We recommend that future research involve collaboration with private sector businesses and professionally trained operators to inform the development of a small-scale forest management model which is financially profitable while also adhering to the principles of eco-forestry.

Converting Royalty Payment Structures for Patent Licenses

Basic economic techniques equip a damages expert with a reliable means of converting a royalty payment with one structure to a royalty of equivalent value under a different structure. I show that one can use reliable methodologies to convert royalty payments across structures both in cases where the parties have executed a one-way license — that is, a license in which the parties determine the conditions for the licensee’s use of the patent holder’s patents — and in cases where the parties have executed a cross license, which grants each party the right to use the counterparty’s patents. When the license uses a simple royalty structure, converting the royalty payment across different structures is also relatively simple. For example, information about the patent-practicing product’s projected price might suffice to convert a per-unit royalty fee to a derived royalty rate. However, when the license in question is a cross license or complex license, converting royalty payments to a derived royalty rate might be more burdensome, as it might require the estimation of additional parameters, such as relative portfolio strength. Nevertheless, with sufficient data, existing economic methodologies offer a reliable basis for estimating and comparing the derived royalty rates of different licenses. Courts can supplement the derived royalty rate with adjustments to account for a company’s bargaining power or market risk implicit in the different royalty structures.

Here’s a Brilliant Idea: Free Vending Machine Stories for Kids

Dear Readers,The New York Times recently published a fascinating article about a cylindrical kiosk that spits out short stories on strips of paper of varying length determined by your preferred reading time (one, three, or five minutes). The Short Story Dispenser was conceived and created by a French start-up publisher called Short Édition whose aim is “to adapt literature to the modern world by combining short literature, the community and technology.” Short Édition has more information on its website for anyone wanting to learn how the dispenser can “bring literature to unexpected places”. I was delighted to learn that the stories are offered free of charge and the publisher has already collected more than 100,000 submissions. The good news is that authors receive royalty payments each time their work is accessed via the dispenser. The machines have an attractive design and they have already been installed in over 150 international locations, including airports, cafes, hospitals, universities, and libraries. In fact, I was thrilled to discover that my local airport installed a dispenser last January to provide passengers with access to short stories written by local writers. According to the Times article, the dispenser is available for $9,200 (US) plus an additional content fee of $190 per month. The publisher offers a variety of literary genres, so owners of dispensers can easily tailor their content offerings to different audiences. It would therefore be straightforward to offer free stories specifically for young readers. I sincerely hope that the dispenser continues to proliferate in locations where young people gather, such as libraries and schools. Perhaps this article will inspire some of you to advocate for a dispenser in your community. And perhaps others will consider writing receipt-sized stories for children that could be made available by Short Édition. Whatever you do, let’s take a moment to celebrate a new and innovative way of sharing stories with children and readers of all ages.Happy reading!Robert DesmaraisManaging Editor

The Implications of Petroleum Conflict in the Context of the Federal Government and the Kelantan State Government Relations

Malaysia is one of those countries that rely on petroleum-based revenues as one of its main sources of national income. The majority of its oil fields are found in the coasts of Kelantan, Terengganu, Sabah and Sarawak. Upon the discovery of these, Malaysia had incorporated a national petroleum company named “Petronas” on 17th August 1974 to manage all related matters to exploration and exploitation of petroleum in the country. Subsequently, on 1st October 1974, the Parliament had passed Petroleum Development Act 1974 that, inter alia, gives the power and right for exploration and exploitation of petroleum to Petronas and to pay 5% of oil royalty to the petroleum-producing states. However, due to ideological differences between the federal government and the state government of Kelantan, this lucrative natural source has found itself at the center of conflict between the two. The study analyzes the implication of such a petroleum-based conflict against the federal-state relations within a context of a democratic Malaysia. In order to so, as far as oil royalty payment arrangement is concerned, the concept of federalism was applied as a tool of analysis to evaluate the extent of the effectiveness of the relations between the federal government and the state government of Kelantan. Pursuant to that, the discussion of this study revolves around qualitative data approach based on documents related to the oil royalty agreement between the federal government and state government of Kelantan. The analysis has indicated that Malaysia, as a federalist country, has failed to put into practice the true concept of federalism. One of the major reasons behind this was conflicting political interests. The impacts of such could be seen from the distinctive way the federal government treated the state governments, in this case Kelantan, whose state government was formed by the opposition political party. The Malaysian federal government's extensive power and the different constitutional interpretation also contributes to the conflict especially in the context of the federal legislative policies that often being perceived as discriminating against the state government.

A stochastic techno-economic assessment of seabed mining of polymetallic nodules in the Clarion Clipperton Fracture Zone

Polymetallic nodules found in the Clarion Clipperton Fracture Zone in the NE Pacific contain more nickel, manganese and cobalt than all terrestrial reserves combined. Following the 1982 Law of the Sea Convention and its 1994 Implementing Agreement, the resources of the international seabed beyond the limits of national jurisdiction will be developed for the benefit of mankind by attracting investment and technology, whilst demanding that necessary measures be taken to ensure effective protection of the marine environment. To date, no single commercial seabed mining activity has taken place in international waters, and the development of balanced and stimulating exploitation regulation is needed, based on accurate economic analysis. This paper presents the first detailed, vertically integrated, stochastic techno-economic assessment from a contractor's perspective, and contributes to the development of the world's first exploitation regulations. The economic performance measured by the internal rate of return was compared using deterministic and probabilistic commodity price forecasting models. Different levels of a financial payment regime, comprising of a royalty payment and a payment to internalize environmental costs, were considered. When real growth was included, the internal rate of return remains above the hurdle rate when a transitional, total-cost, financial payment regime is below 2 per cent during the initial period and below 4 per cent for the remaining tenure period. Following a 10-year moving average of commodity prices, including real growth, a 77.51 per cent probability was calculated of achieving a hurdle rate of 18 per cent.

An estimate of the average cumulative royalty yield in the world mobile phone industry: Theory, measurement and results

An influential literature argues that dispersed patent ownership may lead to royalty stacking and excessive running royalties, thus increasing the long-run marginal cost of manufacturing phones and their prices. One set of estimates claims that the royalty stack is on the order of 20–40 percent of the value of the average phone. In order to assess this claim, we estimate the average cumulative royalty yield—the sum total of patent royalty payments earned by licensors, divided by the total value of mobile phones shipped— in the world mobile phone industry between 2007 and 2016.We “follow the money” and identify, with varying accuracy, 39 potential licensors in the smartphone value chain. We find that, of these, only 29 charged royalties in 2016, running from a low of $1.6 million to a high of $7.7 billion, summing to $14.2 billion in total, which compares with $425.1 billion in mobile phone sales. The average cumulative royalty yield in 2016 was 3.3 percent or $7.20 per phone. If we restrict this only to smartphones, the result would be $9.60 per phone, roughly 3.4 percent of the average selling price. A sensitivity analysis shows that even under a very restrictive set of assumptions, the average cumulative royalty yield on a smartphone would not exceed 5.6 percent.

The contradictions of neo-extractivism and social policy: the role of raw material exports in the Brazilian political crisis

This article explores how contradictory development tendencies within Brazil’s primary sector have contributed to the country’s enduring political crisis. I show that President Rousseff, when dealing with declining royalty payments from natural resource exports and a decrease in tax revenue from imports, financed social policies in ways that her opponents branded as unconstitutional to remove her from power. After documenting the central players within the political crisis, namely those who have been under investigation in Operação Lava Jato (Operation Car Wash), I illustrate how the ongoing corruption scandals plaguing Brazil have their roots in the country’s raw material export industries.

Retraction of: Dayer et al., J Palliat Med 2016;19(5):538–541; DOI: 10.1089/jpm.2015.0230

Journal of Palliative MedicineVol. 21, No. 2 Retraction NoticeFree AccessRetraction of: Dayer et al., J Palliat Med 2016;19(5):538–541; DOI: 10.1089/jpm.2015.0230This article retracts the following:A Palliative Care Clinic's Experience with Medication Adherence to Neuropathic Pain MedicationsPublished Online:1 Feb 2018https://doi.org/10.1089/jpm.2015.0230.retractAboutSectionsPDF/EPUB Permissions & CitationsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail The Brief Report article entitled, “Adherence to Adjuvant Neuropathic Pain Medications in a Palliative Care Clinic,” by Lindsey Dayer, Sarah Harrington, and Bradley Martin in the May 2016 issue of Journal of Palliative Medicine (JPM), [19(5): 538 – 541; DOI: 10.1089/jpm.2015.0230] requires a retraction due to a legal dispute regarding the eight-item Morisky Medication Adherence Scale (MMAS-8) which was adapted for use in the article.Dr. Dayer's article appropriately cited the original article in which the MMAS-8 scale appeared, and the original MMAS-8 article notes that the development of the scale was supported with federal funds. However, after publication of her article, Dr. Dayer was notified by Dr. Morisky's legal counsel that Dr. Morisky asserted a copyright interest in the MMAS-8 scale, and that its reuse required both a substantial royalty payment and the licensed use of an electronic grading system developed by Dr. Morisky. Dr. Dayer and her institution dispute the validity and reasonableness of Dr. Morisky's demands in light of the National Institutes of Health's Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources, 64 Fed. Reg. 72,090 (Dec. 23, 1999). As a result of Dr. Morisky's demands, Dr. Dayer contacted the Editor of JPM and requested that the scale be removed from her published paper. The Editor agreed.It is important to note that the retraction of Dr. Dayer's article is not the result of any misconduct on her part or that of her team. The retraction serves to remove the published version of the article that contains the MMAS-8 scale, and replace it with a revised version that does not contain the tool or any references to it. The elimination of the scale does not alter the conclusions of the study.Journal of Palliative Medicine is committed to the highest standards of peer review and the community it serves.FiguresReferencesRelatedDetailsRelated articlesA Palliative Care Clinic's Experience with Medication Adherence to Neuropathic Pain Medications1 Feb 2018Journal of Palliative Medicine Volume 21Issue 2Feb 2018 InformationCopyright 2018, Mary Ann Liebert, Inc.To cite this article:Retraction of: Dayer et al., J Palliat Med 2016;19(5):538–541; DOI: 10.1089/jpm.2015.0230.Journal of Palliative Medicine.Feb 2018.273-273.http://doi.org/10.1089/jpm.2015.0230.retractPublished in Volume: 21 Issue 2: February 1, 2018PDF download

INFLUENCE OF INTERNATIONALIZATION OF TAX LAW ON RUSSIAN TAX LAW ENFORCEMENT IN THE AREA OF CORPORATE TAXATION

Subject. The influence of internationalization of tax law on Russian tax law enforcement in the area of corporate taxation is considered in the article.The purpose of the paper is to analyze influence of internationalization of tax law on Russian tax law enforcement in the area of corporate taxation.Methodology. The author uses methods of theoretical analysis, particularly the theory of integrative legal consciousness, as well as legal methods, including formal legal method and methods of comparative law.Results, scope of application. The development of Russian tax legislation is influenced by acts of international organizations, primarily the Action Plan aimed at combating base erosion and profit shifting (BEPS).Trends of regulation of corporate taxation in relationships with participation of a foreign element are considered in the article. The main issues of realization of norms in the area of corporate direct taxation are brought into light, and namely, taxation of royalties, intra-group expenses, thin capitalization rules and transfer pricing. Tax agreements concluded by the Russian Federation do not contain special rules aimed at combating abuses (in contrast, for example, from European anti-avoidance rules).In recent years Russian tax law introduced institutions that had been established and applied in the tax law of foreign countries. These processes are moving forward and are characterized by frequent changes of legislation, which indicates that the concept of deoffshorization and implementation of the BEPS plan is not always elaborated at the stage of adoption of bills.Conclusions. The author comes to the conclusion that the most relevant and most controversial issues are taxation of payment of royalties, debt financing and intra-group expenses. The practice of applying the CFC rules is just starts forming. In addition, there is a tendency to increase the quality and quantity of information sources used by tax authorities to collect evidence, including the expansion of the practice of information exchange.