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Professional organizations recently set guidelines for avoiding surgeries of low utility and overutilization for the Choosing Wisely campaign. These include re-excision for invasive cancer close to margins, double mastectomy in patients with unilateral breast cancer, axillary lymph node dissection in patients with limited nodal disease, and sentinel lymph node biopsy (SLNB) in patients ≥70 years with early-stage breast cancer. Variable adherence to these recommendations led us to evaluate implementation rates of low-value surgical guidelines at a safety-net hospital.We retrospectively analyzed breast cancer patients who underwent surgery from 2015 to 2020. Each patient was assessed for eligibility for omission of the listed surgeries. Trends were evaluated by cohorts before and after a fellowship-trained breast surgeon joined the faculty in 2018. Outcomes were compared using Fisher's exact test.Among 195 patients, none underwent re-excision for close margins of invasive cancer. Only 6.7% of patients (3/45) received contralateral mastectomy and 1.8% of eligible patients (3/169) received axillary lymph node dissection. Overall, 60% of patients ≥ 70 years with stage 1 hormone-positive breast cancer (9/15) received SLNB. There was a downward trend from 71% of eligible patients receiving SLNB in 2015-2018 to 50% in 2019-2020.De-implementation of traditional surgical practices, deemed as low-value care, toward newer guidelines is achievable even at community hospitals serving a low socioeconomic community. By avoiding overtreatment, hospitals can achieve effective resource allocation which allow for social distributive justice among patients with breast cancer and ensure strategic use of scarce health economic resources while preserving patient outcomes.

Despite advances in healthcare and improved chemotherapy, disparities in breast cancer outcomes continue to persist. Our aim was to evaluate socioeconomic factors that may impact timing of treatment for patients receiving chemotherapy in underserved communities.A review of patients with breast cancer who received neoadjuvant or adjuvant chemotherapy from 2015-2019 was conducted at a safety-net hospital. The primary outcomes were times from diagnosis to chemotherapy and surgery. Clinicodemographic factors including race, age, clinical stage, primary language, comorbidities, and median income by zip code were collected. Multivariable regression analysis was performed to evaluate for factors associated with the primary outcomes.One hundred patients were identified. For the neoadjuvant group, median time from diagnosis to chemotherapy and surgery was 52 ± 34 days and 256 ± 59 days, respectively. For the adjuvant group, median time from diagnosis to surgery and chemotherapy was 24.5 ± 18 days and 94.5 ± 53 days, respectively. Non-English language and older age were associated with increased time to chemotherapy in the adjuvant group (p 0.05). Language and age were not associated with increased time to surgery in both groups. Race, age, comorbidities, and income were not associated with delay in treatment in either groups.Older age and non-English language were associated with prolonged time from surgery to adjuvant chemotherapy. Targeted interventions directed at patient education and decreasing language barriers especially post-operatively may decrease delays in treatment and subsequently reduce disparities seen in the breast cancer population.

The Choosing Wisely campaign has emerged recently in setting guidelines for surgical procedures of low utility and cost-ineffectiveness. Hospitals caring for underserved medical populations represent a unique opportunity to assess for quality of care and adherence to these guidelines. The Choosing Wisely campaign for breast surgery has highlighted: avoiding surgical re-excision for invasive cancer close to margins of excised breast tissue, avoiding double mastectomy in patients who have a single breast with cancer, avoidance of axillary lymph node dissection in women undergoing lumpectomy with limited nodal disease, and avoiding sentinel lymph node biopsy in patients ≥ 70 years of age with early stage breast cancer. Recent studies have shown variable adherence to these recommendations. In order to evaluate cost-effective surgery at our hospital serving a poorer patient population, we retrospectively analyzed patients who underwent surgery for breast cancer from 2015-2020. A total of 231 patients were identified. There were no patients who underwent re-excision for close margins of invasive cancer. Only 0.9% of patients (2/231) received contralateral mastectomy and only 1.6% of eligible patients (3/191) received axillary lymph node dissection instead of sentinel lymph node biopsy. Although 77.7% of patients ≥ 70 years of age with stage 1 hormone positive breast cancer (14/18) received sentinel lymph node biopsy, there was a downward trend during 2015 to 2020 from 100% to 50% of eligible patients receiving sentinel lymph node biopsy. De-implementation of traditional surgical practices, deemed as low-value care, towards newer cost-effective guidelines are achievable even at community hospitals serving a low socioeconomic community while preserving patient outcome and avoiding overtreatment. By avoiding overtreatment, cost savings can be achieved which allow for social distributive justice amongst breast cancer patients by ensuring careful utilization of scarce health economic resources. Citation Format: Annie Tang, Colin Mooney, Shannon Ugarte, Kevin Knopf, Amal Khoury. High compliance with choosing wisely breast procedures at a safety net hospital [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-56.

Summary: Right-sided heart failure is a common sequela of left heart failure and seldom presents as a primary disorder. The differential diagnosis of right heart failure includes a cardiac tumor. Cardiac malignancies are rare tumors with an overall poor prognosis. We evaluated a 69-year-old man who presented with a 3-week history of progressive lower extremity swelling, ascites, and scrotal swelling. Laboratory studies were significant only for mildly elevated liver function tests. CT scan of the abdomen and pelvis showed ascites, hepatic swelling, and a bland clot in the inferior vena cava extending from the level of the kidneys to the right atrium. A large mass originating from the right atrium was identified, and biopsy confirmed an undifferentiated pleomorphic cardiac sarcoma. Given the extensive tumor and clot burden, he was not an operative candidate. He developed portal hypertension with esophageal varices and expired due to variceal bleeding.

Erythropoiesis-stimulating agents (ESAs) are available to treat chemotherapy-induced anemia (CIA). In 2007-2008, regulatory notifications advised of venous thromboembolism and mortality risks while the Center for Medicare and Medicaid Services' restricted ESA initiation to patients with hemoglobin

Conscientious use of scarce health economic resources allows for social distributive justice by avoiding over-treatment of patients to allow for appropriate treatment for a broader patient population. Lower socioeconomic status patients with breast cancer have a worse outcome compared to higher socioeconomic status patients in the United States. In part, this is due to poor access to medical care and a failure of logistical care. We implemented a community based breast cancer multidisciplinary program with weekly meetings to discuss patients, coordinate care, and provide cost-effective care to a medically under-served and vulnerable patient population. Breast surgery and medical oncology providers saw patients together in a co-located space and expedited timely initiation of neoadjuvant and adjuvant chemotherapy / hormone therapy for appropriate patients. The conjoint clinic allowed for rapid temporal integration of care in our safety net hospital / community. A single breast cancer navigator provided rapid identification of patients, coordination through clinics, and assistance with social work and other needs. Weekly 30 minute discussion sessions reviewing all new and relevant follow up patient issues were implemented in lieu of a breast cancer tumor board for efficiency. The relevant published clinical literature was reviewed on an ongoing basis. Cost-effective care was obtained by implementing: 1) avoidance of post lumpectomy radiation for selected patients based on PRIME2 trial results, 2) judicious use of post-mastectomy radiation based on a careful re-analysis of the data, 3) avoidance of adjuvant/neoadjuvant Perjeta in HER2+ patients based on a lack of overall survival, 4) adoption of 6 month schedule of adjuvant Herceptin, 5) avoidance of excessive imaging by following NCCN guidelines and clinical judgment, 6) limiting dose dense chemotherapy to appropriate patients (ER- high risk node negative or node positive), and 7) No Nernyx. Using a cost-effectiveness analysis methodology, we are reviewing costs, effectiveness of interventions, and risks with outcomes measured from side effects, complications, recurrence, and mortality. The improvement in temporal parameters and economic endpoints are being currently monitored retrospectively and prospectively and will be presented. Citation Format: Annie Tang, Shannon Ugarte, Rohan John, Amal Khoury, Kevin Knopf. Cost-effective care for newly diagnosed breast cancer patients: Think globally, act locally [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-13-07.

Objective: To assess our adherence to treatment guidelines for diffuse large B-cell lymphoma (DLBCL) established by the American Society of Hematology in 2014 through implementation of a quality improvement initiative (QII) at our institution in 2015. Patients and Methods: Patients with newly diagnosed DLBCL treated from January 1, 2006, through December 31, 2017, were identified. Electronic medical records were reviewed for documentation of American Society of Hematology Practice Improvement Module quality measures (eg, key pathologic features of DLBCL, lymphoma staging, and screening for hepatitis B virus [HBV] infection in patients receiving rituximab-based chemotherapy). We also reviewed assessment of prognosis by revised International Prognostic Index score, testing for hepatitis C virus, HBV, and HIV, chemotherapy education, and the addition of rituximab in the treatment regimen of CD20+ DLBCL. Results: Following QII implementation, we saw improvements in most metrics, including reporting of key molecular features (fluorescence in situ hybridization for c-MYC, BCL2, and BCL6, from 45.5% [75 of 165 patients] before QII to 91.7% [22 of 24 patients] after QII; P

Biosimilar filgrastims are primarily indicated for chemotherapy-induced neutropenia prevention. They are less expensive formulations of branded filgrastim, and biosimilar filgrastim was the first biosimilar oncology drug administered in European Union (EU) countries, Japan, and the U.S. Fourteen biosimilar filgrastims have been marketed in EU countries, Japan, the U.S., and Canada since 2008, 2012, 2015, and 2016, respectively. We reviewed experiences and policies for biosimilar filgrastim markets in EU countries and Japan, where uptake has been rapid, and in the U.S. and Canada, where experience is rapidly emerging. U.S. regulations for designating biosimilar interchangeability are under development, and such regulations have not been developed in most other countries. Pharmaceutical substitution is allowed for new filgrastim starts in some EU countries and in Canada, but not Japan and the U.S. In EU countries, biosimilar adoption is facilitated with favorable hospital tender offers. U.S. adoption is reportedly 24%, while the second filgrastim biosimilar is priced 30% lower than branded filgrastim and 20% lower than the first biosimilar filgrastim approved by the U.S. Food and Drug Administration. Utilization is about 60% in EU countries, where biosimilar filgrastim is marketed at a 30%–40% discount. In Japan, biosimilar filgrastim utilization is 45%, primarily because of 35% discounts negotiated by Central Insurance and hospital-only markets. Overall, biosimilar filgrastim adoption barriers are small in many EU countries and Japan and are diminishing in Canada in the U.S. Policies facilitating improved U.S. adoption of biosimilar filgrastim, based on positive experiences in EU countries and Japan, including favorable insurance coverage; larger price discount relative to reference filgrastim pricing; closing of the “rebate trap” with transparent pricing information; formal educational efforts of patients, physicians, caregivers, and providers; and allowance of pharmaceutical substitution of biosimilar versus reference filgrastim, should be considered. Implications for Practice We reviewed experiences and policies for biosimilar filgrastims in Europe, Japan, Canada, and the U.S. Postmarketing harmonization of regulatory policies for biosimilar filgrastims has not occurred. Acceptance of biosimilar filgrastims for branded filgrastim, increasing in the U.S. and in Canada, is commonplace in Japan and Europe. In the U.S., some factors, accepted in Europe or Japan, could improve uptake, including acceptance of biosimilars as safe and effective; larger cost savings, decreasing “rebate traps” where pharmaceutical benefit managers support branded filgrastim, decreased use of patent litigation/challenges, and allowing pharmacists to routinely substitute biosimilar for branded filgrastim.

Background/aim We evaluated timeliness of care at a safety-net hospital after implementation of a multidisciplinary breast program. Patients and methods A prospective database of patients with breast cancer was created after multidisciplinary breast program initiation in 2018. Patients were tracked to obtain time to completion of diagnostic imaging, biopsy, and treatment initiation. Patients with breast cancer diagnosed from 2015-2017 were reviewed for comparison. Results A total of 102 patients were identified. There was no statistical difference in time to completion of imaging, biopsy, and initial treatment between the 2018 and the 2015-2017 cohorts (p>0.05). No statistical difference was observed in time to completion of imaging, biopsy, and initial treatment between different races (p>0.05). Conclusion Within the same socioeconomic status, there was no differential delivery of screening, work-up, and treatment by race. Despite protocol implementations, efficiency of care remained limited in a safety-net hospital with lack of financial resources.

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 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.

Background: Adverse drug/device reactions (ADRs) can result in severe patient harm. We define very serious ADRs as being associated with severe toxicity, as measured on the Common Toxicity Criteria Adverse Events (CTCAE)) scale, following use of drugs or devices with large sales, large financial settlements, and large numbers of injured persons. We report on impacts on patients, clinicians, and manufacturers following very serious ADR reporting. Methods: We reviewed clinician identified very serious ADRs published between 1997 and 2019. Drugs and devices associated with reports of very serious ADRs were identified. Included drugs or devices had market removal discussed at Food and Drug Advisory (FDA) Advisory Committee meetings, were published by clinicians, had sales > $1 billion, were associated with CTCAE Grade 4 or 5 toxicity effects, and had either >$1 billion in settlements or >1,000 injured patients. Data sources included journals, Congressional transcripts, and news reports. We reviewed data on: 1) timing of ADR reports, Boxed warnings, and product withdrawals, and 2) patient, clinician, and manufacturer impacts. Binomial analysis was used to compare sales pre- and post-FDA Advisory Committee meetings. Findings: Twenty very serious ADRs involved fifteen drugs and one device. Legal settlements totaled $38.4 billion for 753,900 injured persons. Eleven of 18 clinicians (61%) reported harms, including verbal threats from manufacturer (five) and loss of a faculty position (one). Annual sales decreased 94% from $29.1 billion pre-FDA meeting to $4.9 billion afterwards (p

Erythropoisis stimulating agent (ESA) use was addressed in Food and Drug Administration (FDA) Oncology Drug Advisory Committee (ODAC) meetings between 2004 and 2008. FDA safety-focused regulatory actions occurred in 2007 and 2008. In 2007, black box warnings advised of early death and venous thromboembolism (VTE) risks with ESAs in oncology. In 2010, a Risk Evaluation Strategies (REMS) was initiated, with cancer patient consent that mortality and VTE risks were noted with ESAs. We report warnings and REMS impacts on ESA utilization among Veterans Administration (VA) cancer patients with chemotherapy-induced anemia (CIA). Data were from Veterans Affairs database (2003-2012). Epoetin and darbepoetin use were primary outcomes. Segmented linear regression was used to estimate changes in ESA use levels and trends, clinical appropriateness, and adverse events (VTEs) among chemotherapy-treated cancer patients. To estimate changes in level of drug prescription rate after policy actions, model-specific indicator variables as covariates based on specific actions were included. ESA use fell by 95% and 90% from 2005, for epoetin and darbepoetin, from 22% and 11%, respectively, to 1% and 1%, respectively, among cancer patients with CIA, respectively (p

Purpose: The US Food and Drug Administration (FDA) has approved epoetin and darbepoetin for chemotherapy-induced anemia (CIA). Approved epoetin and darbepoetin dosing schedules were three times per week and weekly, respectively, although off-label, less frequent scheduling was common. In 2004, 2007, and 2008, a US Food and Drug Administration Advisory Committees warned of risks associated with erythropoiesis-stimulating agents. During this period, lawsuits alleging illegal darbepoetin marketing practices have concluded, resulting in $1.1 billion in fines and settlements and one criminal conviction. No prior study, to our knowledge, has reported on the use of darbepoetin versus epoetin for CIA. Methods: We evaluated the dosing, utilization, and costs of erythropoiesis-stimulating agents among 3,761 South Carolina Medicaid patients with CIA. Results: Epoetin and darbepoetin utilization rates were 22% and 28% in 2003, 10% and 33% in 2007, and 3% and 7% in 2010, respectively. Mean per-patient per-administration epoetin and darbepoetin doses were 40,983 IU and 191 µg, respectively, in 2003 and 47,753 IU and 369 µg, respectively, in 2010. Mean monthly patient costs for epoetin and darbepoetin were $1,030 and $981, respectively, in 2003 and $932 and $1,352, respectively, in 2010. Epoetin use decreased steadily between 2002 and 2010; darbepoetin use increased steadily between 2003 and 2007 and then decreased steadily thereafter. Per-patient dosing of darbepoetin, but not epoetin, increased steadily between 2003 and 2010, and monthly per-patient epoetin costs decreased 3% while the per-patients costs of darbepoetin increased 30% between 2003 and 2010. Conclusion: To our knowledge, our findings are the first data reporting on epoetin versus darbepoetin use for CIA and support recently concluded lawsuits involving allegations of illegal marketing practices of the manufacturer of darbepoetin.

Introduction: Adverse drug/device reactions (ADRs) can result in severe patient harm. We operationally define titanic ADRs as Common Toxicity Criteria Adverse Events grade 4 or 5 that follow use of drugs or devices that have large sales, large safety financial settlements, and affect large numbers of persons. We report on the impact of titanic ADRs identified between 1997 and 2019. Methods: We reviewed clinician reported titanic ADRs. Data sources included Food and Drug Advisory (FDA) Advisory Committee transcripts, news reports, and medical journals. We reviewed data on timing of titanic ADR reports, Boxed warnings, product withdrawals, and impacts on patients, clinicians, and manufacturers. Results: Overall, twenty titanic ADRs involved 15 drugs and 1 device. Legal settlements totaled $38.4 billion for 874,000 persons reportedly developing titanic ADRs. Five clinicians reported receiving threats from manufacturers’ employees, one clinician lost a university faculty position, and five clinicians were not invited to FDA meetings where their safety findings were discussed. Annual sales for 9 still patented drugs and 1 device decreased 78% from $21.3 billion pre-ADR report to $3.9 billion afterwards. Following FDA approval, the median time to titanic ADRs reporting was 7.5 years. Fourteen drugs received Box warnings a median of 7.5 years following titanic ADR reporting. Six drugs and 1 device were withdrawn from marketing (median of 5 years after titanic ADR reporting). Conclusion: Overall, 874,000 persons were purportedly injured by fifteen drugs and one device that caused titanic ADRs, reputational harms were reported by eleven clinicians , and $38.4 billion in legal settlements were paid . Because titanic ADRs impacts are so large, and investigative processes not always transparent, policy makers should develop an independently funded drug safety board. Funding Statement: This work received support from the National Cancer Institute (1R01 A102713 (CLB), https://www.nih.gov/about-nih/what-we-do/nih-almanac/national-cancer-institute-nci; the American Cancer Society (IRG-13-043-01), https://www.cancer.org/; and an unrestricted grant from Doris Levkoff Meddin. Declaration of Interests: The authors have declared that no competing interests exist.

INTRODUCTION: Ciprofloxacin, levofloxacin, and moxifloxacin belong to the fluoroquinolone class of antibiotics and are amongst the most commonly prescribed antibiotics. In 2018 and 2019, Food and Drug Administration (FDA) and the European Medicine Agency (EMA) requested that manufacturers harmonize FQ safety information related to neuropsychiatric, aortic dissection, and long-term disability. The authors hypothesize that FDA and EMA epidemiologists support a strong association between these drugs and the three toxicities. AREAS COVERED: Studies of FQ-associated neuropsychiatric toxicity, long-term disability, and aortic ruptures/dissections. Clinical sources include FDA Advisory Committee documents, a 2014 Citizen Petition filed with the FDA requesting safety information additions to FQ labels for neuropsychiatric toxicities (partially granted in 2018), an under-review Citizen Petition under review by the FDA requesting a FQ Risk Evaluation and Mitigation Strategy, and safety notifications from the EMA. EXPERT OPINION: FDA and the EMA reports state that neuropsychiatric toxicity, long-term disability, and aortic dissections//aneurysms occur with all FQs. Disability and neuropsychiatric toxicity can occur after one dose or several months after FQs. United States’ and European’ regulators warn physicians not to prescribe FQs for uncomplicated acute urinary tract infection, sinusitis, or bronchitis, unless other possible choices are tried first, as risks outweigh benefits in these settings.

Oncology-associated adverse drug/device reactions can be fatal. Some clinicians who treat single patients with severe oncology-associated toxicities have researched case series and published this information. We investigated motivations and experiences of select individuals leading such efforts. Clinicians treating individual patients who developed oncology-associated serious adverse drug events were asked to participate. Inclusion criteria included having index patient information, reporting case series, and being collaborative with investigators from two National Institutes of Health funded pharmacovigilance networks. Thirty-minute interviews addressed investigational motivation, feedback from pharmaceutical manufacturers, FDA personnel, and academic leadership, and recommendations for improving pharmacovigilance. Responses were analyzed using constant comparative methods of qualitative analysis. Overall, 18 clinicians met inclusion criteria and 14 interviewees are included. Primary motivations were scientific curiosity, expressed by six clinicians. A less common theme was public health related (three clinicians). Six clinicians received feedback characterized as supportive from academic leaders, while four clinicians received feedback characterized as negative. Three clinicians reported that following the case series publication they were invited to speak at academic institutions worldwide. Responses from pharmaceutical manufacturers were characterized as negative by 12 clinicians. One clinician’s wife called the post-reporting time the “Maalox month,” while another clinician reported that the manufacturer collaboratively offered to identify additional cases of the toxicity. Responses from FDA employees were characterized as collaborative for two clinicians, neutral for five clinicians, unresponsive for negative by six clinicians. Three clinicians endorsed developing improved reporting mechanisms for individual physicians, while 11 clinicians endorsed safety activities that should be undertaken by persons other than a motivated clinician who personally treats a patient with a severe adverse drug/ device reaction. Our study provides some of the first reports of clinician motivations and experiences with reporting serious or potentially fatal oncology-associated adverse drug or device reactions. Overall, it appears that negative feedback from pharmaceutical manufacturers and mixed feedback from the academic community and/or the FDA were reported. Big data, registries, Data Safety Monitoring Boards, and pharmacogenetic studies may facilitate improved pharmacovigilance efforts for oncology-associated adverse drug reactions. These initiatives overcome concerns related to complacency, indifference, ignorance, and system-level problems as barriers to documenting and reporting adverse drug events- barriers that have been previously reported for clinician reporting of serious adverse drug reactions.

The risk stratification of prostate cancer and breast cancer tumours from patients relies on histopathology, selective genomic testing, or on other methods employing fixed formalin tissue samples. However, static biomarker measurements from bulk fixed-tissue samples provide limited accuracy and actionability. Here, we report the development of a live-primary-cell phenotypic-biomarker assay with single-cell resolution, and its validation with prostate cancer and breast cancer tissue samples for the prediction of post-surgical adverse pathology. The assay includes a collagen-I/fibronectin extracellular-matrix formulation, dynamic live-cell biomarkers, a microfluidic device, machine-vision analysis and machine-learning algorithms, and generates predictive scores of adverse pathology at the time of surgery. Predictive scores for the risk stratification of 59 prostate cancer patients and 47 breast cancer patients, with values for area under the curve in receiver-operating-characteristic curves surpassing 80%, support the validation of the assay and its potential clinical applicability for the risk stratification of cancer patients.

We compare coupled nonlinear climate models and their simplified forced counterparts with respect to predictability and phase space topology. Various types of uncertainty plague climate change simulation, which is, in turn, a crucial element of Earth System modelling. Since the currently preferred strategy for simulating the climate system, or the Earth System at large, is the coupling of sub-system modules (representing, e.g. atmosphere, oceans, global vegetation), this paper explicitly addresses the errors and indeterminacies generated by the coupling procedure. The focus is on a comparison of forced dynamics as opposed to fully, i.e. intrinsically, coupled dynamics. The former represents a particular type of simulation, where the time behaviour of one complex systems component is prescribed by data or some other external information source. Such a simplifying technique is often employed in Earth System models in order to save computing resources, in particular when massive model inter-comparisons need to be carried out. Our contribution to the debate is based on the investigation of two representative model examples, namely (i) a low-dimensional coupled atmosphere-ocean simulator, and (ii) a replica-like simulator embracing corresponding components.Whereas in general the forced version (ii) is able to mimic its fully coupled counterpart (i), we show in this paper that for a considerable fraction of parameter- and state-space, the two approaches qualitatively differ. Here we take up a phenomenon concerning the predictability of coupled versus forced models that was reported earlier in this journal: the observation that the time series of the forced version display artificial predictive skill. We present an explanation in terms of nonlinear dynamical theory. In particular we observe an intermittent version of artificial predictive skill, which we call on-off synchronization, and trace it back to the appearance of unstable periodic orbits. We also find it to be governed by a scaling law that allows us to estimate the probability of artificial predictive skill. In addition to artificial predictability we observe artificial bistability for the forced version, which has not been reported so far. The results suggest that bistability and intermittent predictability, when found in a forced model set-up, should always be cross-validated with alternative coupling designs before being taken for granted.

The promise of precision and personalized medicine is rooted in accurate, highly sensitive, and specific disease biomarkers. This is particularly true for cancer-a disease characterized by marked tumor heterogeneity and diverse molecular signatures. Although thousands of biomarkers have been described, only a very small number have been successfully translated into clinical use. Undoubtedly, there is need for rapid, quantitative, and more cost effective biomarkers for tumor diagnosis and prognosis, to allow for better risk stratification and aid clinicians in making personalized treatment decisions. This is particularly true for cancers where specific biomarkers are either not available (e.g., renal cell carcinoma) or where current biomarkers tend to classify individuals into broad risk categories unable to accurately assess individual tumor aggressiveness and adverse pathology potential (e.g., prostate cancer), thereby leading to problems of over-diagnosis and over-treatment of indolent cancer and under-treatment of aggressive cancer. This perspective highlights an emerging class of cancer biomarkers-live-single-cell phenotypic biomarkers, as compared to genomic biomarkers, and their potential application for cancer diagnosis, risk-stratification, and prognosis.

Aim: Describe hairy cell leukemia (HCL) treatment patterns using a large, nationally representative US database. Patients & methods: Adults newly diagnosed with HCL (1 January 2006 to 30 June 2014) with continuous health plan enrollment ≥180 days pre- and 90 days post-diagnosis were identified from the QuintilesIMS PharMetrics Plus Health Plan Claims Database. Treatment patterns by line of therapy were assessed over the variable follow-up. Results: Among 749 HCL patients (77.4% male; mean age 55.6; mean 32.3 months follow-up), only 37.7% initiated first-line therapy during the available follow-up in a mean of 4.4 months following diagnosis; the majority (75.5%) received cladribine (mean duration 7.3 days). Thirty-eight patients (5.1%) received second-line treatment. Conclusion: Over 2.7 years follow-up, more than a third of patients initiated first-line therapy which appeared to provide a long-lasting response.

Background Mortality in patients with myelodysplastic syndromes (MDS) is high, and patients are likely to require hospitalizations, emergency department (ED) visits, and transfusions. The relationships between these events and the MDS complications of anemia, neutropenia, and thrombocytopenia are not well understood. Patients and methods A total of 1864 patients registered in the United States’ Surveillance Epidemiology and End Results (SEER) program and aged ≥66 years old when diagnosed with MDS in 2001 or 2002 were included. Medicare claims were used to identify MDS complications and utilization (hospitalizations, ED visits, and transfusions) until death or the end of 2005. Mortality was based on SEER data. Kaplan–Meier incidence rates were estimated and multivariable Cox models were used to study the association between complications and outcomes. Results The 3-year incidence of anemia, neutropenia, and thrombocytopenia was 81%, 25%, and 41%, and the incidence of hospitalization, ED visit, and transfusion was 62%, 42%, and 45%, respectively. Median survival time was 22 months. Cytopenia complications were significantly associated with each of these outcomes. Conclusions All types of cytopenia are common among patients with MDS and are risk factors for high rates of health care utilization and mortality. Management of the complications of MDS may improve patient outcomes.

The study goal was to characterize older chronic lymphocytic leukemia (CLL) patients and to evaluate outcomes in those patients who initiated infused therapy. Patients 66 years of age and older in the Surveillance, Epidemiology, and End Results (SEER) program with a CLL diagnosis were matched to their Medicare Part A and Part B claims for long-term follow-up. Treatment patterns, survival after initiation of infused therapy, and both hematologic and hospitalization outcomes were assessed. There were 6433 CLL patients identified, and 2040 received infused therapy. Treated patients were categorized as receiving rituximab monotherapy (16%), rituximab plus chemotherapy (14%), and chemotherapy alone (70%) based on the initial 60 days after infusion. Rituximab plus chemotherapy compared with chemotherapy alone was associated with a 25% lower risk of overall mortality (95% confidence interval, 9%-38%). Restricting to patients age 70 years and older did not change the risk reduction for rituximab plus chemotherapy. Hematologic interventions were more common with rituximab plus chemotherapy compared with chemotherapy alone, but there was no difference in all-cause hospitalizations. These analyses, based on observational data, suggest that the benefits of initial therapy with rituximab in a heterogeneous group of older CLL patients are comparable with those demonstrated in younger patients.

Objectives:This study aims to estimate the annual U.S. societal costs associated with treatment of metastatic breast cancer (MBC) patients using an incidence-based cost-of-illness (COI) framework.Methods:An incidence-based COI model was constructed in which MBC patients were simulated from diagnosis through active treatment, palliative care, and death over 5 years. Key model parameters included: annual incidence of breast cancer in the metastatic stage, utilization of cancer therapies and other medical care resources, treatment-related adverse events, unit costs, work days missed by patient and caregiver, and wage rates. Overall survival was based on SEER data and costs were assigned to living patients monthly, according to their disease management phase. The outcomes measures were total discounted societal costs, cost/year, and cost/patient-year.Results:The annual incidence of MBC in the United States in 2007 was estimated to be 49,674 patients (de novoand progressed from earlier stages). The total discounted cost to society attributable to MBC was $12.2 billion for the incident cohort, or $98,571 per patient-year. The 5-year direct medical cost of this incident cohort was $9.3 billion, or $75,415 per patient-year. Treatment-related costs (active treatment, toxicity management, and medical follow-up) contributed 44 percent of MBC expenditure, followed by palliative/best supportive care costs (31 percent). Lost productivity accounted for approximately 21 percent of the total cost ($2.6 billion over 5 years or $21,153 per patient-year).Conclusions:The societal burden of MBC in the United States is substantial. Earlier detection and effective treatment could lead to a significant decrease in costs while improving overall disease prognosis.

The use of granulocyte colony-stimulating (G-CSF) factors to avoid chemotherapy induced neutropenia is a major cost driver in clinical oncology. Short acting formulations, while less convenient, are 39% the cost of the longer formulation (Pegfilgrastim). We analyzed the use of G-CSF vs. Neulasta in the Veterans Administration (VA) health care system as currently practiced by clinical judgement and analyzed this economically. A survey of 23 sites within the VA on the relative frequency of use of filgrastim, Tbo-filgrastim, Filgrastim-sndz and Pegfilgrastim was conducted. Cost was estimated using 340B pricing. A maximally cost-effecient strategy of 100% Tbo-filgrastim would result in a cost of $62,336 per 100 patient episodes. Tbo-filgrastim was the preferred treatment in 18 of 23 sites surveyed. Cost results ranged from a minimum of $62,336 (4 of 23 sites) to a maximum of $201,356 (2 of 23 sites) with a mean cost of $99,080. The VA was overall 73% efficient, and therefore highly cost-effective, in minimizing use of Pegfilgrasim. As in Europe cost-efficiency favors the use of Tbo-filgrastim over Pegfilgrastim; further cost-saving opportunities exist with the following strategies : (1) avoid G-CSF use where there is no convincing evidence of efficacy (i.e. low risk patients, treatment of neutropenia rather than prophylaxis) (2) use daily filgrastim in lieu of pegfilgrastim whenever possible (3) use Tbo-filgrastrim rather than filgrastrimn (4) continue to examine strategies using 2 or 4 day courses of G-CSf as opposed to 8 days which would cut cost an additional 50 to 75%. Survey data showed that uptake of biosimilar G-CSF in the VA system has been extremely rapid. All sites are using biosimilar GCSF for all new patients; 6 of 23 sites were comfortable shifting current patients on branded G-CSF to the biosimilar. Survey data shows an overwhelming use of filgrastrim compared to pegfilgrastim in the VA system, in contradistinction to the rest of the United States - resulting in an efficiency of 73% (i.e. only 27% of patients are being given pegfilgrastrim). This represents a great savings to the VA system which can be emulated in other sites in the United States. Switching to a Tbo-filgrastim, although heralded by some as cost savings, only engendered a cost savings of 2.2% - small compared to other clinical changes. Disclosures No relevant conflicts of interest to declare.

ABSTRACT Background: In 2014, the American Society of Hematology (ASH) established a practice improvement module (PIM) incorporating quality metrics for management of diffuse large B cell lymphoma (DLBCL). Such PIMs have allowed physicians to monitor the quality of care in their practice. We implemented a DLBCL quality improvement initiative (QII) at our institution in January, 2015. In an appraisal of this initiative, we reviewed the ASH PIM metrics and included several others to assess adherence to guidelines for treatment of DLBCL and to examine the need for institutional improvement. Methods: Patients who were newly diagnosed with DLBCL and received treatment at our institution from January 2006 through December 2017 were identified. Electronic medical records were reviewed for documentation of ASH PIM quality measures (e.g., key pathologic features of DLBCL, lymphoma staging, screening for hepatitis B virus (HBV) infection in patients receiving rituximab-based chemotherapy, etc). We also reviewed the proportion of patients who had assessment of prognosis by revised International Prognostic Index (r-IPI) score, testing for hepatitis C (HCV), HIV viral infections, chemotherapy education, and the addition of rituximab in the treatment regimen of CD20+ DLBCL. Results: Following implementation of the QII, our institution saw improvement in most quality metrics. Particularly significant were improvements in reporting of key molecular features (45.45% to 91.6%, P < 0.0001), screening for HBV (41.82% to 91.67%, P < 0.001) and HIV infections (33.94% to 87.5%, P < 0.0001). All patients post-QII had a PET-CT scan for staging of DLBCL and there was a significantly lower use of bone marrow biopsy (61.2% to 33.33%, P = 0.011). Conclusion: Implementation of a quality initiative and employing standardized metrics can aid in improving institutional quality of care for patients with newly diagnosed DLBCL, and allows opportunity to build and ensure better adherence to evolving national and professional patient care guidelines. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Frontline treatment options for patients with follicular lymphoma (FL) include chemotherapy plus rituximab [1]. Randomized clinical trials have demonstrated that rituximab added to frontline CHOP (cyclophosphamide [C], doxorubicin, vincristine [V], and prednisone [P]) or CVP results in improved overall survival in patients with advanced disease [2,3]. However, the impact of rituximab has not been evaluated in routine clinical practice where differences in the treated population and treatment practices could produce differences between trial efficacy and "real-world" effectiveness. In this study, we used data from the Surveillance, Epidemiology, and End Results (SEER)—Medicare database to identify a cohort of 1,117 elderly patients (>66) who received frontline CHOP or CVP, with or without rituximab. The median age was 73, compared to between 52 and 57 in the clinical trials [2,3] depending on the treatment group and trial, and 38% had Stage I/II disease, an exclusion criterion in the trials. In multivariate analysis, we found chemotherapy regimens that included rituximab were associated with lower overall mortality and non-Hodgkin's lymphoma (NHL)—specific mortality, but not mortality due to other causes. Our findings indicate that the survival benefits of rituximab observed in clinical trials translate into benefits for elderly patients in routine clinical practice.

Largely due to tumor heterogeneity, risk stratification of patients diagnosed with ductal carcinoma in situ (DCIS) of the breast remains a significant challenge. Management of DCIS is also problematic as we wish to personalize treatment of a patient’s tumor in order to avoid overtreatment of lower-risk lesions or undertreatment of DCIS that may recur or progress into invasive cancer. Matching treatment to the underlying severity of the illness is key to practicing cost-effective cancer care in an era where this is a very large concern to society. The aim of this study was to analytically validate a precision risk-stratification tool based on phenotype, which is capable of predicting which patients will develop invasive cancer with greater than 80% sensitivity and specificity. Leveraging the novel capability to rapidly culture primary breast biopsy cells, we present a “biopsy-on-a-chip” microfluidic platform that quantifies dynamic and static phenotypic biomarkers via machine vision to generate predictive clinical scores via machine learning algorithms to determine if a DCIS patient will experience invasive cancer. 47 consecutive lumpectomy or mastectomy samples were collected and objectively analyzed in a blinded study, measuring 1000 phenotypic biomarkers with single-cell resolution using machine vision software. Biomarker measurements were input into machine learning algorithms to develop predictive statistical algorithms. Statistical algorithms were able to independently predict surgical adverse pathology features such as extranodal extension, grade, lymphovascular invasion, lymph invasion, lobular carcinoma in situ (LCIS), and DCIS with sensitivities and specificities greater than 90%. Additional machine learning based algorithms were able to predict if DCIS patients were more likely to develop subsequent metastasis as measured by lymphovascular invasion and/or lymphatic invasion with area under the curve (AUC) > 0.85. This study is the first study to demonstrate the prediction of breast cancer adverse pathology features from live primary biopsy cells and provides the basis to develop a powerful precision risk-stratification tool to risk-stratify DCIS. Furthermore, the methodology described and its ability to rapidly analyze primary breast biopsy tissue with single-cell resolution in a high-throughput manner engenders a powerful research tool to further understand tumor heterogeneity in breast cancer towards the development of personalized therapeutics. Applications of cost effectiveness analysis to our methodology will achieve the triple goal of providing cost-effective, patient-centered, and appropriate breast cancer and DCIS care. Note: This abstract was not presented at the conference. Citation Format: Ashok Chander, Michael Manak, Jonathan Varsanik, Brad Hogan, Grannum Sant, Kevin Knopf. Risk stratification of ductal carcinoma in situ: Analytical validation of a prognostic test analyzing live-primary cells via phenotypic biomarkers and machine learning at single-cell resolution [abstract]. In: Proceedings of the AACR Special Conference: Advances in Breast Cancer Research; 2017 Oct 7-10; Hollywood, CA. Philadelphia (PA): AACR; Mol Cancer Res 2018;16(8_Suppl):Abstract nr A31.

BACKGROUND. Breast cancer recurrence is associated with significant morbidity, mortality, and cost. Patients with early stage HER2+ tumors are at increased risk of recurrence. The use of trastuzumab for these patients has been shown to reduce recurrences and improve overall survival. METHODS. A Monte Carlo simulation was conducted based on Surveillance, Epidemiology, and End Results incidence rates for 2005, United States Census data for 2005, and the results of key trials of the adjuvant use of trastuzumab. Patients included in this analysis had incident, HER2+, stage I to III breast cancer. The number of recurrences that could be prevented with trastuzumab, the cardiac adverse events that might occur, and the associated cost savings were estimated. RESULTS. Approximately 31,200 women had HER2+ breast cancer in 2005, of whom 7298 would have had a recurrence over the subsequent 5 years despite standard of care adjuvant treatment. If trastuzumab were added to their regimen, 2791 women might have avoided recurrence, and 948 may have had an asymptomatic or symptomatic cardiac adverse event, for a ratio of expected recurrences to cardiac adverse events of 3.2 (95% confidence interval, 1.5-5.9). In economic terms, avoidance of future breast cancer recurrences was associated with lifetime reduction in future direct and indirect costs on the order of $240 million to $1.7 billion. CONCLUSIONS. On the basis of the simulation results, targeting HER2+ tumors with trastuzumab in the adjuvant setting should prevent a significant number of women from recurrence events, with important outcomes for patients, physicians, payers, and society. Cancer 2010. © 2010 American Cancer Society.

Chemotherapy-induced anemia (CIA) commonly occurs in cancer patients receiving conventional myelosuppressive chemotherapy. Two national guidelines regarding the use of erythropoiesis-stimulating agents (ESAs) in CIA were released in 2002. Because of poorer disease outcomes and increased risk of adverse events associated with ESAs in recent studies, the use of ESAs has been increasingly restricted in practice guidelines in the years 2007 and 2008.The aim of this study was to provide a baseline for adherence to national guidelines in the use of ESAs for CIA between 2002 and 2006.This retrospective study used the Varian Medical Oncology database (Varian Medical Systems, Inc., Palo Alto, California) of electronic medical records, representing 17 outpatient oncology organizations at 71 clinic locations in the United States. Adults diagnosed with any malignant neoplasm who started conventional cytotoxic chemotherapy between January 1, 2002, and September 30, 2006, were included. The proportion of patients receiving an ESA was calculated by hemoglobin (Hb) level during each chemotherapy cycle, stratified by line of chemotherapy and year. Logistic regression modeling identified predictors of ESA use in anemic patients during the first chemotherapy cycle.The records of 17,731 cancer patients were evaluated. Median (SD) age was 61 (13) years, and 58.9% were female. Most patients (84.1%) had a solid tumor. Many patients (41.3%) received platinum containing chemotherapy and 74.4% received combination chemotherapy. During the first 5 cycles of first-line chemotherapy among patients with CIA (Hb11 g/dL), ESAs were used by 55.8% of patients at cycle 1 and 68.9% at cycle 5. ESA use in CIA patients increased across lines of chemotherapy and time. Few patients (2.8%) received an ESA at Hb13 g/dL. The statistically significant predictors of ESA use included age65 years, eastern US residence, private health insurance, community-based care, and solid tumors, especially lung cancer.The patterns we observed were generally consistent with prevailing ESA labels and national guidelines during 2002 through 2006. Although ESA use in patients with CIA increased over chemotherapy cycles, lines of chemotherapy, and time,70% of CIA episodes were treated with ESAs during the initial 5 chemotherapy cycles.

In this paper the authors perform an extensive sensitivity analysis of the Indian summer monsoon rainfall to changes in parameters and boundary conditions which are influenced by human activities. For this study, the authors use a box model of the Indian monsoon which reproduces key features of the observed monsoon dynamics such as the annual course of precipitation and the transitions between winter and summer regimes. Because of its transparency and computational efficiency, this model is highly suitable for exploring the effects of anthropogenic perturbations such as emissions of greenhouse gases and sulfur dioxide, and land cover changes, on the Indian monsoon. Results of a systematic sensitivity analysis indicate that changes in those parameters which are related to emissions of greenhouse gases lead to an increase in Indian summer rainfall. In contrast, all parameters related to higher atmospheric aerosol concentrations lead to a decrease in Indian rainfall. Similarly, changes in parameters which can be related to forest conversion or desertification, act to decrease the summer precipitation. The results indicate that the sign of precipitation changes over India will be dependent on the direction and relative magnitude of different human perturbations.

To evaluate the efficacy and safety of vindesine in patients with metastatic melanoma after complete metastasectomy. One hundred and forty-two patients with metastatic spread to regional sites, lymph nodes, and distant sites after complete metastasectomy were randomized to receive either treatment with vindesine for 2 years or observation alone. Vindesine 3 mg/m intravenously was administered biweekly for the first 26 weeks following 3-week intervals for an additional 26 weeks and thereafter every 4 weeks for 52 weeks. One hundred and thirty-nine patients were eligible for intent-to-treat analysis. Median follow-up time was 46 months. Median recurrence free survival was 7.9 months in the vindesine group and 7.6 months in the observational group (P=0.40). Three-year overall survival rate was 54.9% (37 patients) for patients receiving vindesine in comparison to 43.6% (31 patients) in the observation arm (P=0.07). No grade IV toxicity was observed. The two major side effects in the vindesine group were alopecia and peripheral neuropathy. Ten patients went off treatment because of grade III toxicity. Adjuvant treatment with vindesine did not significantly prolong disease free or overall survival in high-risk melanoma patients. Thus, this randomized trial did not confirm earlier reports of beneficial effects of adjuvant vindesine and can therefore not be recommended.

Animals are often exposed to or can ingest heavy metals along with their food. Therefore, we tested whether the hindgut microbiota of Mastotermes darwiniensis possesses the capability to form methyl mercury. The termite M. darwiniensis (Isoptera) was fed with saw dust containing different concentrations of inorganic mercury. Methyl mercury was determined by purge-and-trap capillary gas chromatography-atom fluorescence spectrometry (CGC-AFS) using ethyl mercury chloride as the internal standard. Total mercury concentrations were determined in the termite tissue by inductive coupled plasma-isotope dilution mass spectrometry (ICP-IDMS) after microwave-assisted digestion. The obtained results showed in vivo methyl mercury production in terrestrial insects for the first time. Desulfovibrio intestinalis isolated from M. darwiniensis was identified as a biomethylating species of the intestinal microbiota.

Background The economic burden of tyrosine kinase inhibitor (TKI) treatment failure in chronic myeloid leukemia (CML) is not well understood. The objective of this study was to quantify the economic burden associated with treatment failure versus successfully remaining on TKI therapy. Methods Treatment episodes for adult CML patients initiating a TKI of interest (imatinib, dasatinib, or nilotinib; index TKI) during July 1, 2008, to December 31, 2011, with continuous enrollment for ≥ 120 days before and 1 year after the initiation were identified from the IMS PharMetrics Plus Health Plan Claims Database. Eligible episodes of TKI treatment failure were matched to those without failure using propensity scores based on patients' baseline demographic and clinical characteristics. Treatment failure was defined as a switch to a nonindex TKI or discontinuation (gap in pharmacy claims ≥ 60 days) of index TKI over the 1-year follow-up. Mean all-cause health care resource utilization and costs per episode (in 2012 US dollars) over follow-up were compared between failures and nonfailures. Results Among 1774 eligible episodes, 547 failures were matched to 547 nonfailures. Failures had fewer TKI prescription fills but higher utilization of all other services versus nonfailures. Consequently, failures incurred lower pharmacy costs ($51,238 vs. $72,450; Δ−$21,212) but higher medical costs ($52,619 vs. $18,180; Δ$34,439) than nonfailures, resulting in higher total costs ($103,857 vs. $90,630; Δ$13,227) (all P Conclusion Total health care costs are higher for episodes of TKI treatment failure than those of ongoing treatment, largely as a result of costly medical (nonpharmacologic) services. Avoiding treatment failure by optimal CML management may reduce health care costs.