Subtype-selective prenylated isoflavonoids disrupt regulatory drivers of MYCN-amplified cancers.

Transcription factors have proven difficult to target with small molecules because they lack pockets necessary for potent binding. Disruption of protein expression can suppress targets and enable therapeutic intervention. To this end, we developed a drug discovery workflow that incorporates cell-line-selective screening and high-throughput expression profiling followed by regulatory network analysis to identify compounds that suppress regulatory drivers of disease. Applying this approach to neuroblastoma (NBL), we screened bioactive molecules in cell lines representing its MYC-dependent (MYCNA) and mesenchymal (MES) subtypes to identify selective compounds, followed by PLATESeq profiling of treated cells. This revealed compounds that disrupt a sub-network of MYCNA-specific regulatory proteins, resulting in MYCN degradation in vivo. The top hit was isopomiferin, a prenylated isoflavonoid that inhibited casein kinase 2 (CK2) in cells. Isopomiferin and its structural analogs inhibited MYC and MYCN in NBL and lung cancer cells, highlighting the general MYC-inhibiting potential of this unique scaffold.

A PERK-Specific Inhibitor Blocks Metastatic Progression by Limiting Integrated Stress Response-Dependent Survival of Quiescent Cancer Cells.

PURPOSE: The integrated stress response (ISR) kinase PERK serves as a survival factor for both proliferative and dormant cancer cells. We aim to validate PERK inhibition as a new strategy to specifically eliminate solitary disseminated cancer cells (DCC) in secondary sites that eventually reawake and originate metastasis. EXPERIMENTAL DESIGN: A novel clinical-grade PERK inhibitor (HC4) was tested in mouse syngeneic and PDX models that present quiescent/dormant DCCs or growth-arrested cancer cells in micro-metastatic lesions that upregulate ISR. RESULTS: HC4 significantly blocks metastasis, by killing quiescent/slow-cycling ISRhigh, but not proliferative ISRlow DCCs. HC4 blocked expansion of established micro-metastasis that contained ISRhigh slow-cycling cells. Single-cell gene expression profiling and imaging revealed that a significant proportion of solitary DCCs in lungs were indeed dormant and displayed an unresolved ER stress as revealed by high expression of a PERK-regulated signature. In human breast cancer metastasis biopsies, GADD34 expression (PERK-regulated gene) and quiescence were positively correlated. HC4 effectively eradicated dormant bone marrow DCCs, which usually persist after rounds of therapies. Importantly, treatment with CDK4/6 inhibitors (to force a quiescent state) followed by HC4 further reduced metastatic burden. In HNSCC and HER2+ cancers HC4 caused cell death in dormant DCCs. In HER2+ tumors, PERK inhibition caused killing by reducing HER2 activity because of sub-optimal HER2 trafficking and phosphorylation in response to EGF. CONCLUSIONS: Our data identify PERK as a unique vulnerability in quiescent or slow-cycling ISRhigh DCCs. The use of PERK inhibitors may allow targeting of pre-existing or therapy-induced growth arrested "persister" cells that escape anti-proliferative therapies.

PERK Inhibition by HC-5404 Sensitizes Renal Cell Carcinoma Tumor Models to Antiangiogenic Tyrosine Kinase Inhibitors.

PURPOSE: Tumors activate protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK, also called EIF2AK3) in response to hypoxia and nutrient deprivation as a stress-mitigation strategy. Here, we tested the hypothesis that inhibiting PERK with HC-5404 enhances the antitumor efficacy of standard-of-care VEGF receptor tyrosine kinase inhibitors (VEGFR-TKI). EXPERIMENTAL DESIGN: HC-5404 was characterized as a potent and selective PERK inhibitor, with favorable in vivo properties. Multiple renal cell carcinoma (RCC) tumor models were then cotreated with both HC-5404 and VEGFR-TKI in vivo, measuring tumor volume across time and evaluating tumor response by protein analysis and IHC. RESULTS: VEGFR-TKI including axitinib, cabozantinib, lenvatinib, and sunitinib induce PERK activation in 786-O RCC xenografts. Cotreatment with HC-5404 inhibited PERK in tumors and significantly increased antitumor effects of VEGFR-TKI across multiple RCC models, resulting in tumor stasis or regression. Analysis of tumor sections revealed that HC-5404 enhanced the antiangiogenic effects of axitinib and lenvatinib by inhibiting both new vasculature and mature tumor blood vessels. Xenografts that progress on axitinib monotherapy remain sensitive to the combination treatment, resulting in ∼20% tumor regression in the combination group. When tested across a panel of 18 RCC patient-derived xenograft (PDX) models, the combination induced greater antitumor effects relative to monotherapies. In this single animal study, nine out of 18 models responded with ≥50% tumor regression from baseline in the combination group. CONCLUSIONS: By disrupting an adaptive stress response evoked by VEGFR-TKI, HC-5404 presents a clinical opportunity to improve the antitumor effects of well-established standard-of-care therapies in RCC.

Optimization of a Novel Mandelamide-Derived Pyrrolopyrimidine Series of PERK Inhibitors.

The protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) is one of three endoplasmic reticulum (ER) transmembrane sensors of the unfolded protein response (UPR) responsible for regulating protein synthesis and alleviating ER stress. PERK has been implicated in tumorigenesis, cancer cell survival as well metabolic diseases such as diabetes. The structure-based design and optimization of a novel mandelamide-derived pyrrolopyrimidine series of PERK inhibitors as described herein, resulted in the identification of compound 26, a potent, selective, and orally bioavailable compound suitable for interrogating PERK pathway biology in vitro and in vivo, with pharmacokinetics suitable for once-a-day oral dosing in mice.

Development of optimized drug-like small molecule inhibitors of the SARS-CoV-2 3CL protease for treatment of COVID-19.

The SARS-CoV-2 3CL protease is a critical drug target for small molecule COVID-19 therapy, given its likely druggability and essentiality in the viral maturation and replication cycle. Based on the conservation of 3CL protease substrate binding pockets across coronaviruses and using screening, we identified four structurally distinct lead compounds that inhibit SARS-CoV-2 3CL protease. After evaluation of their binding specificity, cellular antiviral potency, metabolic stability, and water solubility, we prioritized the GC376 scaffold as being optimal for optimization. We identified multiple drug-like compounds with <10 nM potency for inhibiting SARS-CoV-2 3CL and the ability to block SARS-CoV-2 replication in human cells, obtained co-crystal structures of the 3CL protease in complex with these compounds, and determined that they have pan-coronavirus activity. We selected one compound, termed coronastat, as an optimized lead and characterized it in pharmacokinetic and safety studies in vivo. Coronastat represents a new candidate for a small molecule protease inhibitor for the treatment of SARS-CoV-2 infection for eliminating pandemics involving coronaviruses.

Type 2 diabetes mellitus increases the risk of hepatic fibrosis in individuals with obesity and nonalcoholic fatty liver disease.

OBJECTIVE: This study assessed the impact of diabetes mellitus (DM) on nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) with advanced fibrosis prevalence in adults with overweight or obesity in the United States. METHODS: Participants (National Health and Nutrition Examination Survey [NHANES] 2015-2016 database) included 834 middle-aged patients with DM (21.7%) and 3,007 without DM (78.3%). NAFLD was defined by Fatty Liver Index (FLI) ≥ 60 or United States FLI (USFLI) ≥ 30. Moderate-to-high and high risk of advanced fibrosis was defined by fibrosis-4 index (FIB-4) ≥ 1.67 and ≥ 2.67, respectively, and NAFLD fibrosis scores > 0.676 also indicated a high risk. RESULTS: NAFLD prevalence increased with BMI. Steatosis was higher in individuals with overweight with DM versus without DM (USFLI ≥ 30: 48.3% vs. 17.4%; p < 0.01) and in individuals with obesity with DM versus without DM (USFLI ≥ 30: 79.9% vs. 57.6%; p < 0.01). DM significantly increased the proportion of individuals at moderate-to-high risk of fibrosis (FIB-4 ≥ 1.67: 31.8% vs. 20.1%; p < 0.05). In the high risk of advanced fibrosis group (FIB-4 ≥ 2.67), the risk almost doubled (3.8% vs. 7.1%). Among individuals with obesity, DM increased the proportion of adults with moderate and high risk of fibrosis by 1.8- and 2.5-fold, respectively (p < 0.01 and p = 0.39, respectively, vs. without DM). CONCLUSIONS: In this US cohort, DM modestly impacted steatosis, which was primarily obesity-driven. DM added a significant risk of fibrosis to individuals with overweight or obesity, suggesting that screening is imperative in adults with DM.

Mesenchymal subtype neuroblastomas are addicted to TGF-ßR2/HMGCR-driven protein geranylgeranylation.

The identification of targeted agents with high therapeutic index is a major challenge for cancer drug discovery. We found that screening chemical libraries across neuroblastoma (NBL) tumor subtypes for selectively-lethal compounds revealed metabolic dependencies that defined each subtype. Bioactive compounds were screened across cell models of mesenchymal (MESN) and MYCN-amplified (MYCNA) NBL subtypes, which revealed the mevalonate and folate biosynthetic pathways as MESN-selective dependencies. Treatment with lovastatin, a mevalonate biosynthesis inhibitor, selectively inhibited protein prenylation and induced apoptosis in MESN cells, while having little effect in MYCNA lines. Statin sensitivity was driven by HMGCR expression, the rate-limiting enzyme for cholesterol synthesis, which correlated with statin sensitivity across NBL cell lines, thus providing a drug sensitivity biomarker. Comparing expression profiles from sensitive and resistant cell lines revealed a TGFBR2 signaling axis that regulates HMGCR, defining an actionable addiction in that leads to MESN-subtype-dependent apoptotic cell death.

Transferrin Receptor Is a Specific Ferroptosis Marker.

Ferroptosis is a type of regulated cell death driven by the iron-dependent accumulation of oxidized polyunsaturated fatty acid-containing phospholipids. There is no reliable way to selectively stain ferroptotic cells in tissue sections to characterize the extent of ferroptosis in animal models or patient samples. We address this gap by immunizing mice with membranes from lymphoma cells treated with the ferroptosis inducer piperazine erastin and screening ∼4,750 of the resulting monoclonal antibodies generated for their ability to selectively detect cells undergoing ferroptosis. We find that one antibody, 3F3 ferroptotic membrane antibody (3F3-FMA), is effective as a selective ferroptosis-staining reagent. The antigen of 3F3-FMA is identified as the human transferrin receptor 1 protein (TfR1). We validate this finding with several additional anti-TfR1 antibodies and compare them to other potential ferroptosis-detecting reagents. We find that anti-TfR1 and anti-malondialdehyde adduct antibodies are effective at staining ferroptotic tumor cells in multiple cell culture and tissue contexts.

MDM2 and MDMX promote ferroptosis by PPARα-mediated lipid remodeling.

MDM2 and MDMX, negative regulators of the tumor suppressor p53, can work separately and as a heteromeric complex to restrain p53's functions. MDM2 also has pro-oncogenic roles in cells, tissues, and animals that are independent of p53. There is less information available about p53-independent roles of MDMX or the MDM2-MDMX complex. We found that MDM2 and MDMX facilitate ferroptosis in cells with or without p53. Using small molecules, RNA interference reagents, and mutant forms of MDMX, we found that MDM2 and MDMX, likely working in part as a complex, normally facilitate ferroptotic death. We observed that MDM2 and MDMX alter the lipid profile of cells to favor ferroptosis. Inhibition of MDM2 or MDMX leads to increased levels of FSP1 protein and a consequent increase in the levels of coenzyme Q10, an endogenous lipophilic antioxidant. This suggests that MDM2 and MDMX normally prevent cells from mounting an adequate defense against lipid peroxidation and thereby promote ferroptosis. Moreover, we found that PPARα activity is essential for MDM2 and MDMX to promote ferroptosis, suggesting that the MDM2-MDMX complex regulates lipids through altering PPARα activity. These findings reveal the complexity of cellular responses to MDM2 and MDMX and suggest that MDM2-MDMX inhibition might be useful for preventing degenerative diseases involving ferroptosis. Furthermore, they suggest that MDM2/MDMX amplification may predict sensitivity of some cancers to ferroptosis inducers.

Copper-Binding Small Molecule Induces Oxidative Stress and Cell-Cycle Arrest in Glioblastoma-Patient-Derived Cells.

Transition metals are essential, but deregulation of their metabolism causes toxicity. Here, we report that the compound NSC319726 binds copper to induce oxidative stress and arrest glioblastoma-patient-derived cells at picomolar concentrations. Pharmacogenomic analysis suggested that NSC319726 and 65 other structural analogs exhibit lethality through metal binding. Although NSC319726 has been reported to function as a zinc ionophore, we report here that this compound binds to copper to arrest cell growth. We generated and validated pharmacogenomic predictions: copper toxicity was substantially inhibited by hypoxia, through an hypoxia-inducible-factor-1α-dependent pathway; copper-bound NSC319726 induced the generation of reactive oxygen species and depletion of deoxyribosyl purines, resulting in cell-cycle arrest. These results suggest that metal-induced DNA damage may be a consequence of exposure to some xenobiotics, therapeutic agents, as well as other causes of copper dysregulation, and reveal a potent mechanism for targeting glioblastomas.

Multivalent Small-Molecule Pan-RAS Inhibitors.

Design of small molecules that disrupt protein-protein interactions, including the interaction of RAS proteins and their effectors, may provide chemical probes and therapeutic agents. We describe here the synthesis and testing of potential small-molecule pan-RAS ligands, which were designed to interact with adjacent sites on the surface of oncogenic KRAS. One compound, termed 3144, was found to bind to RAS proteins using microscale thermophoresis, nuclear magnetic resonance spectroscopy, and isothermal titration calorimetry and to exhibit lethality in cells partially dependent on expression of RAS proteins. This compound was metabolically stable in liver microsomes and displayed anti-tumor activity in xenograft mouse cancer models. These findings suggest that pan-RAS inhibition may be an effective therapeutic strategy for some cancers and that structure-based design of small molecules targeting multiple adjacent sites to create multivalent inhibitors may be effective for some proteins.

Towards personalized agriculture: what chemical genomics can bring to plant biotechnology.

In contrast to the dominant drug paradigm in which compounds were developed to "fit all," new models focused around personalized medicine are appearing in which treatments are developed and customized for individual patients. The agricultural biotechnology industry (Ag-biotech) should also think about these new personalized models. For example, most common herbicides are generic in action, which led to the development of genetically modified crops to add specificity. The ease and accessibility of modern genomic analysis, when wedded to accessible large chemical space, should facilitate the discovery of chemicals that are more selective in their utility. Is it possible to develop species-selective herbicides and growth regulators? More generally put, is plant research at a stage where chemicals can be developed that streamline plant development and growth to various environments? We believe the advent of chemical genomics now opens up these and other opportunities to "personalize" agriculture. Furthermore, chemical genomics does not necessarily require genetically tractable plant models, which in principle should allow quick translation to practical applications. For this to happen, however, will require collaboration between the Ag-biotech industry and academic labs for early stage research and development, a situation that has proven very fruitful for Big Pharma.

Detection of parasitic plant suicide germination compounds using a high-throughput Arabidopsis HTL/KAI2 strigolactone perception system.

Strigolactones are terpenoid-based plant hormones that act as communication signals within a plant, between plants and fungi, and between parasitic plants and their hosts. Here we show that an active enantiomer form of the strigolactone GR24, the germination stimulant karrikin, and a number of structurally related small molecules called cotylimides all bind the HTL/KAI2 α/ß hydrolase in Arabidopsis. Strigolactones and cotylimides also promoted an interaction between HTL/KAI2 and the F-box protein MAX2 in yeast. Identification of this chemically dependent protein-protein interaction prompted the development of a yeast-based, high-throughput chemical screen for potential strigolactone mimics. Of the 40 lead compounds identified, three were found to have in planta strigolactone activity using Arabidopsis-based assays. More importantly, these three compounds were all found to stimulate suicide germination of the obligate parasitic plant Striga hermonthica. These results suggest that screening strategies involving yeast/Arabidopsis models may be useful in combating parasitic plant infestations.

Interplay between sucrose and folate modulates auxin signaling in Arabidopsis.

As sessile organisms growing in an ever-changing environment, plants must integrate multiple regulatory inputs to promote the appropriate developmental responses. One such nutritional signal is cellular sugar levels, which rise and fall throughout the day and affect a variety of developmental processes. To uncover signaling pathways that modulate sugar perception, compounds from the Library of Active Compounds in Arabidopsis were screened for the ability to perturb developmental responses to sucrose (Suc) in Arabidopsis (Arabidopsis thaliana) seedlings. This screen found that sulfonamides, which inhibit folate biosynthesis in plants, restrict hypocotyl elongation in a sugar-dependent fashion. Transcriptome analysis identified a small set of transcripts that respond to the interaction between sulfonamide and Suc, including a number of transcripts encoding Auxin/Indole-3-Acetic Acids, negative regulators of auxin signal transduction. Chemical inhibition of auxin transport or genetic disruption of auxin signaling relieved this interaction, suggesting that responses to these two nutritional stimuli are mediated by auxin. Reporter systems used to track auxin signaling and distribution showed enhanced activity in the vascular region of the hypocotyl in response to cotreatment of Suc and sulfonamide, yet no change in auxin abundance was observed. Taken together, these findings suggest that the interplay between Suc and folates acts to fine-tune auxin sensitivity and influences auxin distribution during seedling development.

Lifetime economic burden of prostate cancer.

BACKGROUND: Prostate cancer (PCa) is the most common cancer affecting men in the United States. The initial treatment and subsequent monitoring of PCa patients places a large burden on U.S. health care systems. The objectives of this study were to estimate the total and disease-related per-patient lifetime costs using a phase-based model of cancer care for PCa patients enrolled in Medicare. METHODS: A model was developed to estimate life-time costs for patients diagnosed with PCa. Patients ≥ 65 years old and diagnosed with PCa between calendar years 1991-2002 were selected from the SEER database. Using SEER, we estimated survival times for PCa patients from diagnosis until death. The period of time patients contributed to treatment phases was determined using an algorithm designed to model the natural history of PCa. Costs were obtained from the US SEER-Medicare database and estimated during specific phases of care. Cost estimates were then combined with survival data to yield total and PCa-related life-time costs. RESULTS: Overall, the model estimated life-time costs of $110,520 (95% CI 110,324-110,739) per patient. PCa-related costs made up approximately 31% of total costs ($34,432). CONCLUSIONS: Prostate cancer places a significant burden on U.S. health-care systems with average life-time PCa-related costs in excess of $30,000.

Impact of bleeding-related complications and/or blood product transfusions on hospital costs in inpatient surgical patients.

BACKGROUND: Inadequate surgical hemostasis may lead to transfusion and/or other bleeding-related complications. This study examines the incidence and costs of bleeding-related complications and/or blood product transfusions occurring as a consequence of surgery in various inpatient surgical cohorts. METHODS: A retrospective analysis was conducted using Premier's Perspective™ hospital database. Patients who had an inpatient procedure within a specialty of interest (cardiac, vascular, non-cardiac thoracic, solid organ, general, reproductive organ, knee/hip replacement, or spinal surgery) during 2006-2007 were identified. For each specialty, the rate of bleeding-related complications (including bleeding event, intervention to control for bleeding, and blood product transfusions) was examined, and hospital costs and length of stay (LOS) were compared between surgeries with and without bleeding-related complications. Incremental costs and ratios of average total hospital costs for patients with bleeding-related complications vs. those without complications were estimated using ordinary least squares (OLS) regression, adjusting for demographics, hospital characteristics, and other baseline characteristics. Models using generalized estimating equations (GEE) were also used to measure the impact of bleeding-related complications on costs while accounting for the effects related to the clustering of patients receiving care from the same hospitals. RESULTS: A total of 103,829 cardiac, 216,199 vascular, 142,562 non-cardiac thoracic, 45,687 solid organ, 362,512 general, 384,132 reproductive organ, 246,815 knee/hip replacement, and 107,187 spinal surgeries were identified. Overall, the rate of bleeding-related complications was 29.9% and ranged from 7.5% to 47.4% for reproductive organ and cardiac, respectively. Overall, incremental LOS associated with bleeding-related complications or transfusions (unadjusted for covariates) was 6.0 days and ranged from 1.3 to 9.6 days for knee/hip replacement and non-cardiac thoracic, respectively. The incremental cost per hospitalization associated with bleeding-related complications and adjusted for covariates was highest for spinal surgery ($17,279) followed by vascular ($15,123), solid organ ($13,210), non-cardiac thoracic ($13,473), cardiac ($10,279), general ($4,354), knee/hip replacement ($3,005), and reproductive organ ($2,805). CONCLUSIONS: This study characterizes the increased hospital LOS and cost associated with bleeding-related complications and/or transfusions occurring as a consequence of surgery, and supports implementation of blood-conservation strategies.

Treatment costs of prostate cancer in the first year after diagnosis: a short-term cost of illness study for France, Germany, Italy, Spain and the UK.

OBJECTIVE: To calculate the total cost per patient of prostate cancer treatment and the economic cost burden by stage, in the first year after diagnosis, for five European countries. METHODS: Data from the Information Management Systems, Inc. database, survival data, expert opinion, published data and unit costs from various published official sources were used to calculate total costs per patient by stage for each country, from a payer's perspective. Diagnostic costs, first surgery, radio-, chemo- and hormonal therapy costs were included. Costs were aggregated for incident cases. RESULTS: The mean direct costs per patient for initial treatment were euro3698 in Germany, euro3256 in Spain, euro3682 in the UK, euro5226 in Italy and euro5851 in France. The total costs for all diagnosed patients in the first year from diagnosis were (million euro) 116.7 (UK), 244 (Germany), 385 (France), 202 (Italy) and 114.6 (Spain). CONCLUSIONS: The direct initial healthcare cost burden of the most common non-skin-related male cancer, prostate cancer, in France, Germany, Italy, Spain and the UK is considerable. Given the high and increasing prevalence of prostate cancer due to ageing populations in Europe, and the significant cost burden of the disease, national health policy makers should be aware of prostate cancer as a priority disease area.

Neutropenia-related costs in patients treated with first-line chemotherapy for advanced non-small cell lung cancer.

BACKGROUND: Neutropenia is a major adverse event often associated with chemotherapy administration. Neutropenia-related complications often lead to increased use of costly health care including inpatient and outpatient services. Monitoring and treatment of neutropenia thus place an economic burden on the health care system. OBJECTIVES: To evaluate (a) costs and medical resource use for chemotherapy- related afebrile and febrile neutropenia in an elderly population with Stage IIIB or Stage IV non-small cell lung cancer (NSCLC), and (b) costs unrelated to neutropenia and total all-cause health care costs during first-line chemotherapy. METHODS: Study patients in this retrospective database analysis were aged 65 years or older with a diagnosis of Stage IIIB or Stage IV NSCLC in the Surveillance, Epidemiology and End Results (SEER) cancer registry from 1998 through 2002. Neutropenia was identified by the presence of a primary or secondary diagnosis code for diseases of white blood cells (ICD-9-CM = 288.xx) during a period of first-line chemotherapy treatment. Febrile neutropenia was defined by (a) an inpatient hospitalization with a primary or secondary diagnosis for neutropenia occurring at any time during first-line chemotherapy or (b) intravenous or intramuscular antibiotic administration occurring after the initial neutropenia diagnosis and during first-line chemotherapy. Patients with neutropenia without these events were considered to have afebrile neutropenia. Patients were followed in the SEER-Medicare database to evaluate costs (defined as all Medicare payments, primary insurer payments, and patient copayments and deductibles) and resource use associated with afebrile or febrile neutropenia while on first-line chemotherapy. If a patient switched to second-line chemotherapy, the day prior to the switch was defined as the end of first-line treatment. If a switch to second-line therapy did not occur, then first-line therapy was assumed to end 30 days following administration of the last first-line agent. Costs were summed for 2 main types of cost measures: neutropenia-related costs, defined as costs for claims with either a primary or secondary diagnosis of neutropenia, and costs unrelated to neutropenia. Costs were classified using ICD-9-CM diagnosis and procedure codes appearing on the claims, with confidence intervals [CIs] for cost measures estimated by using nonparametric bootstrapping methods. Group comparisons of patient characteristics, medical utilization, and cost study measures were made using 2-sided Pearson chi-square and t-test statistics for categorical and continuous measures, respectively. The no neutropenia group was used as the reference category for comparisons involving patient characteristic, medical utilization, and total all-cause health care cost study measures. For total neutropenia-related costs, afebrile and febrile neutropenia study groups were compared. RESULTS: Among elderly patients treated first-line for advanced NSCLC, 5,138 met inclusion criteria, of whom 1,228 (23.9%) developed afebrile (n = 740, 14.4%) or febrile neutropenia (n = 488, 9.5%) while on first-line chemotherapy. Mean per patient costs for treating neutropenia during first-line chemotherapy were $12,148 (standard deviation [SD] = $15,432, 95% confidence interval [CI] = $10,915-$13,607) for patients with febrile neutropenia and $3,099 (SD = $4,541, 95% CI = $2,796-$3,431) for patients with afebrile neutropenia (P<0.001), with mean (SD) length of follow-up (duration of first-line chemotherapy) of 4.5 (4.8) and 5.5 (7.0) months, respectively. Expressed as a percentage of total all-cause health care costs during first-line chemotherapy, neutropenia-related costs accounted for 32.2% of total costs for patients with febrile neutropenia (mean [SD] = $37,694 [$26,078]) and 9.1% of total costs for patients with afebrile neutropenia (mean [SD] = $34,204 [$26,317]). Mean neutropenia-related costs per patient per month (PPPM) during first-line chemotherapy were $2,700 for patients with febrile neutropenia and $563 for patients with afebrile neutropenia. PPPM costs unrelated to neutropenia for patients with afebrile neutropenia, febrile neutropenia, and no neutropenia, respectively, were $5,655, $5,677, and $6,146. In sensitivity analyses, results were highly sensitive to the definition of neutropenia (i.e., claims with primary diagnosis only vs. primary or secondary diagnosis) but insensitive to the type of chemotherapy regimen. CONCLUSION: Neutropenia is a major adverse event that places patients at an increased risk of infection and subsequent morbidity and mortality. For elderly patients undergoing first-line chemotherapy for NSCLC, neutropenia, particularly febrile neutropenia, is associated with substantially higher total all-cause health care costs.

Ten-year survival and cost following breast cancer recurrence: estimates from SEER-medicare data.

OBJECTIVE: A variety of pharmacologic therapies are available or in development for the prevention of breast cancer recurrence. Assessing the value of these treatments is compromised by a paucity of data on the impact of recurrence on economic costs and survival. The purpose of this study was to shed light on these issues. METHODS: We conducted a retrospective analysis of linked SEER-Medicare data. All patients in the National Cancer Institute's Surveillance Epidemiology and End Results (SEER) registry who were diagnosed with nonmetastatic breast cancer during 1991-1993 were identified, and their subsequent Medicare claims were scanned for evidence of further breast cancer events (local or distant recurrence, contralateral breast cancer). Medicare claims were then scanned from the time of the event through 2002 to assess patterns of survival and costs. RESULTS: We identified 10,798 patients in SEER who were diagnosed with nonmetastatic breast cancer during 1991-1993, including 1833 who subsequently had another breast cancer event (local recurrence, 958; distant recurrence, 622; contralateral breast cancer, 253). Median survival was 37 months and 8 months among patients with local and distant recurrence, respectively; 53% of patients with contralateral breast cancer remained alive after all the data were censored at 97 months. Expected 10-year costs (2004 US$, discounted 3%) attributable to distant recurrence, local recurrence, and contralateral breast cancer were $11,450 (SE 2056), $19,596 (SE 1754), and $19,183 (SE 4131), respectively. CONCLUSION: Breast cancer recurrence and contralateral breast cancer lead to substantial increases in costs, amounting to approximately $11,000-19,000 over 10 years depending on type. The impact of these events on survival also varies considerably by type.

Outcomes of thromboprophylaxis with enoxaparin vs. unfractionated heparin in medical inpatients.

BACKGROUND: Clinical trials have shown low-molecular weight heparin (LMWH) to be at least as safe and efficacious as unfractionated heparin (UFH) for preventing venous thromboembolism (VTE) in acutely-ill medical inpatients. OBJECTIVE: To compare clinical and economic outcomes among acutely-ill medical inpatients receiving the LMWH enoxaparin versus UFH prophylaxis in clinical practice. METHODS: Using a large, multi-hospital, US database, we identified persons aged > or =40 years hospitalized for > or =6 days for an acute medical condition (including circulatory disorders, respiratory disorders, infectious diseases, or neoplasms) from Q4 1999 to Q1 2002. From these patients, those who received thromboprophylaxis with either enoxaparin or UFH were identified. Surgical patients and those requiring or ineligible for anticoagulation were excluded. We compared the incidence of deep-vein thrombosis (DVT), pulmonary embolism (PE), and all VTE (i.e., DVT and/or PE). Secondary outcomes were occurrence of side-effects, length of hospital stay and total costs. RESULTS: 479 patients received enoxaparin prophylaxis and 2,837 received UFH. The incidence of VTE was 1.7% with enoxaparin prophylaxis versus 6.3% with UFH (RR = 0.26; p < 0.001). Occurrence of side effects, length of stay (10.00 days with enoxaparin vs. 10.26 days with UFH; p = 0.348) and total costs ($18,777 vs. $17,602; p = 0.463) were similar in the 2 groups. CONCLUSION: We observed a 74% lower risk of VTE among patients receiving enoxaparin prophylaxis versus UFH prophylaxis. There was no significant difference in side effects or economic outcomes. These results provide evidence that the LMWH enoxaparin is more effective than UFH in reducing the risk of VTE in current clinical practice.