Assessment of Duration of Smoking Cessation Prior to Surgical Treatment of Non-small Cell Lung Cancer.

OBJECTIVE: To define the relationship between the duration of smoking cessation and postoperative complications for patients with lung cancer undergoing surgical treatment. BACKGROUND: Smoking increases the risk of postoperative morbidity and mortality in patients with lung cancer undergoing surgical treatment. Although smoking cessation before surgery can mitigate these risks, the ideal duration of preoperative smoking cessation remains unclear. METHODS: Using a uniquely compiled Veterans Health Administration dataset, we performed a retrospective cohort study of patients with clinical stage I non-small cell lung cancer undergoing surgical treatment between 2006 and 2016. We characterized the relationship between duration of preoperative smoking cessation and risk of postoperative complications or mortality within 30-days using multivariable restricted cubic spline functions. RESULTS: The study included a total of 9509 patients, of whom 6168 (64.9%) were smoking at the time of lung cancer diagnosis. Among them, only 662 (10.7%) patients stopped smoking prior to surgery. Longer duration between smoking cessation and surgery was associated with lower odds of major complication or mortality (adjusted odds ratio [aOR] for every additional week, 0.919; 95% confidence interval [CI], 0.850-0.993; P = 0.03). Compared to nonsmokers, patients who quit at least 3 weeks before surgery had similar odds of death or major complication (aOR, 1.005; 95% CI, 0.702-1.437; P = 0.98) whereas those who quit within 3 weeks of surgery had significantly higher odds of death or major complication (aOR, 1.698; 95% CI, 1.203-2.396; P = 0.003). CONCLUSION: Smoking cessation at least 3 weeks prior to the surgical treatment of lung cancer is associated with reduced morbidity and mortality. Providers should aggressively encourage smoking cessation in the preoperative period, since it can disproportionately impact outcomes in early-stage lung cancer.

Assessment of Updated Commission on Cancer Guidelines for Intraoperative Lymph Node Sampling in Early Stage NSCLC.

INTRODUCTION: The American College of Surgeons Commission on Cancer recently updated its sampling recommendations for early stage NSCLC from at least 10 lymph nodes to at least one N1 (hilar) and three N2 (mediastinal) lymph node stations. Nevertheless, intraoperative lymph node sampling minimums remain subject to debate. We sought to evaluate these guidelines in patients with early stage NSCLC. METHODS: We performed a cohort study using a uniquely compiled data set from the Veterans Health Administration. We manually abstracted data from operative notes and pathology reports of patients with clinical stage I NSCLC receiving surgery (2006-2016). Adequacy of lymph node sampling was defined using count-based (≥10 lymph nodes) and station-based (≥three N2 and one N1 nodal stations) minimums. Our primary outcome was recurrence-free survival. Secondary outcomes were overall survival and pathologic upstaging. RESULTS: The study included 9749 patients. Count-based and station-based sampling guidelines were achieved in 3302 (33.9%) and 2559 patients (26.3%), respectively, with adherence to either sampling guideline increasing over time from 35.6% (2006) to 49.1% (2016). Adherence to station-based sampling was associated with improved recurrence-free survival (multivariable-adjusted hazard ratio = 0.815, 95% confidence interval: 0.667-0.994, p = 0.04), whereas adherence to count-based sampling was not (adjusted hazard ratio = 0.904, 95% confidence interval: 0.757-1.078, p = 0.26). Adherence to either station-based or count-based guidelines was associated with improved overall survival and higher likelihood of pathologic upstaging. CONCLUSIONS: Our study supports station-based sampling minimums (≥three N2 and one N1 nodal stations) for early stage NSCLC; however, the marginal benefit compared with count-based guidelines is minimal. Further efforts to promote widespread adherence to intraoperative lymph node sampling minimums are critical for improving patient outcomes after curative-intent lung cancer resection.

Medicare Spending on Drugs With Accelerated Approval.

BACKGROUND: The U.S. Food and Drug Administration provides accelerated approval to drugs on the basis of surrogate end points deemed to be "reasonably likely" to predict clinical benefit. To receive full approval, drugs must complete a confirmatory trial. Although most accelerated approved drugs ultimately receive full approval, others remain on the market without full approval for many years, and some are withdrawn before full approval is granted. Until confirmatory trials are completed and full approval is granted, there is uncertainty surrounding each drug's clinical benefits. OBJECTIVE: To estimate fee-for-service Medicare payments on accelerated approved drugs without full approvals. DESIGN: Cross-sectional analysis. SETTING: Fee-for-service Medicare Part B and Part D drug claims in 2019. PARTICIPANTS: Beneficiaries enrolled in Medicare Part B and Part D plans. MEASUREMENTS: Medicare spending for drugs treating accelerated approved indications without full approval, beneficiary spending, and drug characteristics. RESULTS: In 2019, 45 drugs associated with 69 accelerated approved indications lacked full approval. Of those, the fee-for-service Medicare program spent $1.2 billion on 36 drugs across 55 indications. Medicare beneficiaries had $209 million in out-of-pocket spending on these drugs. Oncology drugs represented 82% of these indications and 72% of the Medicare spending. Extrapolating to Medicare Advantage, total Medicare spending on these drugs in 2019 was $1.8 billion. LIMITATIONS: The study drugs may have clinical benefit and may come to receive full approval after this analysis. The algorithm used to identify accelerated approved indications is novel. Generalizability to other years is unclear. CONCLUSION: In 2019, fee-for-service Medicare spent $1.2 billion on accelerated approved drugs without full approval. Medicare should adjust incentives to encourage sponsors to complete confirmatory trials as soon as possible. PRIMARY FUNDING SOURCE: Laura and John Arnold Foundation.

The First 2 Years of Biosimilar Epoetin for Cancer and Chemotherapy-Induced Anemia in the U.S.: A Review from the Southern Network on Adverse Reactions.

Biosimilars are biologic drug products that are highly similar to reference products in analytic features, pharmacokinetics and pharmacodynamics, immunogenicity, safety, and efficacy. Biosimilar epoetin received Food and Drug Administration (FDA) approval in 2018. The manufacturer received an FDA nonapproval letter in 2017, despite receiving a favorable review by FDA's Oncologic Drugs Advisory Committee (ODAC) and an FDA nonapproval letter in 2015 for an earlier formulation. We discuss the 2018 FDA approval, the 2017 FDA ODAC Committee review, and the FDA complete response letters in 2015 and 2017; review concepts of litigation, naming, labeling, substitution, interchangeability, and pharmacovigilance; review European and U.S. oncology experiences with biosimilar epoetin; and review the safety of erythropoiesis-stimulating agents. In 2020, policy statements from AETNA, United Health Care, and Humana indicated that new epoetin oncology starts must be for biosimilar epoetin unless medical need for other epoetins is documented. Empirical studies report that as of 2012, reference epoetin use decreased from 40%-60% of all patients with cancer with chemotherapy-induced anemia to <5% of such patients because of safety concerns. Between 2018 and 2020, biosimilar epoetin use varied, increasing to 81% among one private insurer's patients covered by Medicare whose cancer care is administered with Oncology Analytics and to 41% with the same private insurer's patients with cancer covered by commercial health insurance and administered by the private insurer, to 0% in several Veterans Administration Hospitals, increasing to 100% in one large county hospital in California, and with yet-to-be-reported data from most oncology settings. We conclude that biosimilar epoetin appears to have overcome some barriers since 2015, although current uptake in the U.S. is variable. Pricing and safety considerations for all erythropoiesis-stimulating agents are primary determinants of biosimilar epoetin oncology uptake. IMPLICATIONS FOR PRACTICE: Few oncologists understand substitution and interchangeability of biosimilars with reference drugs. Epoetin biosimilar is new to the market, and physician and patient understanding is limited. The development of epoetin biosimilar is not familiar to oncologists.

Improving oncology biosimilar launches in the EU, the USA, and Japan: an updated Policy Review from the Southern Network on Adverse Reactions.

The EU, the USA, and Japan account for the majority of biological pharmacotherapy use worldwide. Biosimilar regulatory approval pathways were authorised in the EU (2006), in Japan (2009), and in the USA (2015), to facilitate approval of biological drugs that are highly similar to reference products and to encourage market competition. Between 2007 and 2020, 33 biosimilars for oncology were approved by the European Medicines Agency (EMA), 16 by the US Food and Drug Administration (FDA), and ten by the Japan Pharmaceuticals and Medical Devices Agency (PMDA). Some of these approved applications were initially rejected because of manufacturing concerns (four of 36 [11%] with the EMA, seven of 16 [44%] with the FDA, none of ten for the PMDA). Median times from initial regulatory submission before approval of oncology biosimilars were 1·5 years (EMA), 1·3 years (FDA), and 0·9 years (PMDA). Pharmacists can substitute biosimilars for reference biologics in some EU countries, but not in the USA or Japan. US regulation prohibits substitution, unless the biosimilar has been approved as interchangeable, a designation not yet achieved for any biosimilar in the USA. Japan does not permit biosimilar substitution, as prescribers must include the product name on each prescription and that specific product must be given to the patient. Policy Reviews published in 2014 and 2016 in The Lancet Oncology focused on premarket and postmarket policies for oncology biosimilars before most of these drugs received regulatory approval. In this Policy Review from the Southern Network on Adverse Reactions, we identify factors preventing the effective launch of oncology biosimilars. Introduction to the market has been more challenging with therapeutic than for supportive care oncology biosimilars. Addressing region-specific competition barriers and educational needs would improve the regulatory approval process and market launches for these biologics, therefore expanding patient access to these products in the EU, the USA, and Japan.

Predicting venous thromboembolism in multiple myeloma: development and validation of the IMPEDE VTE score.

Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). The International Myeloma Working Group (IMWG) developed guidelines recommending primary thromboprophylaxis, in those identified at high-risk of VTE by the presence of risk factors. The National Comprehensive Cancer Network (NCCN) has adopted these guidelines; however, they lack validation. We sought to develop and validate a risk prediction score for VTE in MM and to evaluate the performance of the current IMWG/NCCN guidelines. Using 4446 patients within the Veterans Administration Central Cancer Registry, we used time-to-event analyses to develop a risk score for VTE in patients with newly diagnosed MM starting chemotherapy. We externally validated the score using the Surveillance, Epidemiology, End Results (SEER)-Medicare database (N = 4256). After identifying independent predictors of VTE, we combined the variables to develop the IMPEDE VTE score (Immunomodulatory agent; Body Mass Index ≥25 kg/m2 ; Pelvic, hip or femur fracture; Erythropoietin stimulating agent; Dexamethasone/Doxorubicin; Asian Ethnicity/Race; VTE history; Tunneled line/central venous catheter; Existing thromboprophylaxis). The score showed satisfactory discrimination in the derivation cohort, c-statistic = 0.66. Risk of VTE significantly increased as score increased (hazard ratio 1.20, P = <.0001). Within the external validation cohort, IMPEDE VTE had a c-statistic of 0.64. For comparison, when evaluating the performance of the IMWG/NCCN guidelines, the c-statistic was 0.55. In summary, the IMPEDE VTE score outperformed the current IMWG/NCCN guidelines and could be considered as the new standard risk stratification for VTE in MM.

Social network analysis of public health programs to measure partnership.

In order to prevent chronic diseases, community-based programs are encouraged to take an ecological approach to public health promotion and involve many diverse partners. Little is known about measuring partnership in implementing public health strategies. We collected data from 23 Missouri communities in early 2012 that received funding from three separate programs to prevent obesity and/or reduce tobacco use. While all of these funding programs encourage partnership, only the Social Innovation for Missouri (SIM) program included a focus on building community capacity and enhancing collaboration. Social network analysis techniques were used to understand contact and collaboration networks in community organizations. Measurements of average degree, density, degree centralization, and betweenness centralization were calculated for each network. Because of the various sizes of the networks, we conducted comparative analyses with and without adjustment for network size. SIM programs had increased measurements of average degree for partner collaboration and larger networks. When controlling for network size, SIM groups had higher measures of network density and lower measures of degree centralization and betweenness centralization. SIM collaboration networks were more dense and less centralized, indicating increased partnership. The methods described in this paper can be used to compare partnership in community networks of various sizes. Further research is necessary to define causal mechanisms of partnership development and their relationship to public health outcomes.

Density-functional theory and Monte Carlo simulations of the phase behavior of a simple model liquid crystal.

We consider the phase behavior of a simple model of a liquid crystal by means of modified mean-field density-functional theory (MMF DFT) and Monte Carlo simulations in the grand canonical ensemble (GCEMC). The pairwise additive interactions between liquid-crystal molecules are modeled via a Lennard-Jones potential in which the attractive contribution depends on the orientation of the molecules. We derive the form of this orientation dependence through an expansion in terms of rotational invariants. Our MMF DFT predicts two topologically different phase diagrams. At weak to intermediate coupling of the orientation dependent attraction, there is a discontinuous isotropic-nematic liquid-liquid phase transition in addition to the gas-isotropic liquid one. In the limit of strong coupling, the gas-isotropic liquid critical point is suppressed in favor of a fluid- (gas- or isotropic-) nematic phase transition which is always discontinuous. By considering three representative isotherms in parallel GCEMC simulations, we confirm the general topology of the phase diagram predicted by MMF DFT at intermediate coupling strength. From the combined MMF DFT-GCEMC approach, we conclude that the isotropic-nematic phase transition is very weakly first order, thus confirming earlier computer simulation results for the same model [see M. Greschek and M. Schoen, Phys. Rev. E 83, 011704 (2011)].

Nanoconfinement-induced structures in chiral liquid crystals.

We employ Monte Carlo simulations in a specialized isothermal-isobaric and in the grand canonical ensemble to study structure formation in chiral liquid crystals as a function of molecular chirality. Our model potential consists of a simple Lennard-Jones potential, where the attractive contribution has been modified to represent the orientation dependence of the interaction between a pair of chiral liquid-crystal molecules. The liquid crystal is confined between a pair of planar and atomically smooth substrates onto which molecules are anchored in a hybrid fashion. Hybrid anchoring allows for the formation of helical structures in the direction perpendicular to the substrate plane without exposing the helix to spurious strains. At low chirality, we observe a cholesteric phase, which is transformed into a blue phase at higher chirality. More specifically, by studying the unit cell and the spatial arrangement of disclination lines, this blue phase can be established as blue phase II. If the distance between the confining substrates and molecular chirality are chosen properly, we see a third structure, which may be thought of as a hybrid, exhibiting mixed features of a cholesteric and a blue phase.

Defect topologies in a nematic liquid crystal near a patchy colloid.

Using isothermal-isobaric Monte Carlo simulations we investigate defect topologies due to a spherical colloidal particle immersed in a nematic liquid crystal. Defects arise because of the competition between the preferential orientation at the colloid's surface and the far-field director ̂n(0). Considering a chemically homogeneous colloid as a special case we observe the well-known surface and saturn ring defect topologies for weak and strong perpendicular anchoring, respectively; for homogeneous, strong parallel anchoring we find a boojum defect topology that has been seen experimentally [see P. Poulin and D. A. Weitz, Phys. Rev. E 57, 626 (1998)] but not in computer simulations. We also consider a heterogeneous, patchy colloid where the liquid-crystal molecules anchor either preferentially planar or perpendicular at the surface of the colloid. For a patchy colloid we observe a boojum ring defect topology in agreement with recent experimental studies [see M. Conradi, M. Ravnik, M. Bele, M. Zorko, S. Zumer, and I. Musevic, Soft Matter 5, 3905 (2009)]. We also observe two other novel defect topologies that have not been reported thus far neither experimentally nor theoretically.

Finite-size scaling analysis of isotropic-polar phase transitions in an amphiphilic fluid.

We present Monte Carlo simulations of the isotropic-polar (IP) phase transition in an amphiphilic fluid carried out in the isothermal-isobaric ensemble. Our model consists of Lennard-Jones spheres where the attractive part of the potential is modified by an orientation-dependent function. This function gives rise to an angle dependence of the intermolecular attractions corresponding to that characteristic of point dipoles. Our data show a substantial system-size dependence of the dipolar order parameter. We analyze the system-size dependence in terms of the order-parameter distribution and a cumulant involving its first and second moments. The order parameter, its distribution, and susceptibility observe the scaling behavior characteristic of the 3D Ising universality class. Because of this scaling behavior and because all cumulants have a common intersection irrespective of system size we conclude that the IP phase transition is continuous. Considering pressures 1.3 ≤ P ≤ 3.0 we demonstrate that a line of continuous phase transitions exists which is analogous to the Curie line in systems exhibiting a ferroelectric transition. Our results are qualitatively consistent with Landau's theory of continuous phase transitions.

Fluid bridges confined between chemically nanopatterned solid substrates.

We discuss equilibrium properties of classical fluids confined to nanoscopic volumes by solid substrates. The substrates themselves are endowed with wettable chemical patterns of variable symmetry. We develop a thermodynamic description suitable for these highly anisotropic systems. Based upon a combination of Monte Carlo simulations in the grand canonical ensemble and lattice density functional theory at mean-field level we analyze the structure and phase behaviour of the confined fluid. Under suitable thermodynamic conditions the fluid may condense partially in regions controlled by the wettable nanopatterns. The resulting fluid bridges are established as thermodynamic phases and exhibit unique rheological features.

Effect of fluid-substrate attraction and pore geometry on fluid adsorption.

We employ grand canonical ensemble Monte Carlo simulations to investigate the impact of substrate curvature on the phase behavior of an adjacent fluid. The substrates consist of a periodic sequence of grooves in the x direction; the grooves are infinitely long in the y direction. The shape of the grooves is controlled by a parameter eta. For eta = 0 the substrates are planar. If eta = 1, the grooves are wedge shaped. If eta > 1 the grooves become concave and in the limit eta = infinity rectangular. The fluid-substrate potential representing a groove consists of two contributions, namely, that of the homogeneous substrate base corresponding to a semi-infinite solid and that of a finite piece of solid with nonplanar surfaces. Whereas the former contribution can be calculated analytically, the latter needs to be evaluated numerically. For very large values of eta, that is in (almost) rectangular grooves, we observe capillary condensation of that portion of fluid located inside the grooves. As eta decreases capillary condensation gives way to continuous filling. In all cases, a nearly planar film-gas interface eventually forms in the direction normal to the surface of the substrate base and outside the grooves if one increases the chemical potential sufficiently.