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Objective Choosing chemotherapy for metastatic colorectal cancer (mCRC) requires balancing clinical effectiveness and risk of complications. This study characterized real-world inpatient/emergency department (ED) hospitalizations during first-line chemotherapy among individuals with mCRC. Methods This retrospective cohort study used data from medical and pharmacy claims. All patients had mCRC with ≥1 claim for ≥1 of the 5 most frequently utilized first-line chemotherapy agents (fluorouracil, oxaliplatin, bevacizumab, irinotecan, capecitabine). The main outcome was all-cause hospitalizations (inpatient or ED setting) identified from claims via ICD-9/10-CM coding from index date until 30 days after the end of first-line chemotherapy or last available data. Results A total of 717 individuals (mean age 55 years; 58% male; ECOG 0/1/2+/missing in 44%/39%/6%/11%; median follow-up 116 days) met study criteria. Thirty-four distinct chemotherapy regimens were used. Overall, 40% of patients had ≥1 hospitalization (n=285; total 415 hospitalizations); 12% (n=85) had ≥2 hospitalizations. The median time to first hospitalization was 52 days; median inpatient length of stay was 4 days; infections/neutropenia (21%) and bowel-related complications (17%) were the most common issues associated with inpatient hospitalizations. In univariate analyses, insurance plan type, geographical location, ECOG, and renal disease were associated with hospitalization. In multivariable analyses, ECOG ≥1 was associated with a 67% increase (p

IntroductionProjecting disease spread is challenging because of the heterogeneous nature of human interactions, including both natural societal interactions and how they change in response to pandemics. Simulations can provide important guidance regarding the likely impact of interventions on an assumed base case.MethodsThis paper uses assumptions based on the COVID-19 pandemic to construct a Susceptible-Infectious-Recovered model representative of US society, focusing on the interrelationships of groups with differing contact networks (essential/non-essential workers and urban/non-urban populations). The model is used to explore the impact of interventions (reduced interactions, vaccinations and selective isolation) on overall and group-specific disease spread.ResultsIn the absence of herd immunity, temporary interventions will only reduce the overall number of disease cases moderately and spread them over a greater period of time unless they virtually eliminate disease and no new infections occur from exogenous sources. Vaccinations can provide stronger benefit, but can be limited by efficacy and utilization rates.ConclusionsWhile a highly effective and broadly utilized vaccine might halt disease spread, some combination of increased long-term surveillance and selective isolation of the most vulnerable populations might be necessary to minimize morbidity and mortality if only moderately effective vaccines are available.

Objective. To describe health care resource utilization and costs for patients with advanced soft tissue sarcoma (STS) in the United Kingdom (UK), Spain, Germany, and France. Methods. Physicians abstracted data for adult patients with a diagnosis of advanced STS (other than Kaposi’s sarcoma or gastrointestinal stromal tumor) who received ≥1 lines of systemic therapy. Health care resource utilization related to advanced STS treatment was recorded; associated costs were estimated by applying unit costs. Results. A total of 130 physicians provided data for 807 patients (UK: 199; Spain: 203; Germany: 204; and France: 201). The site of care during active treatment varied based on differences in the health care systems of these four countries. Total mean per-patient health care cost in the UK was £19,457; in Spain, €26,814; in Germany, €20,468; and in France, €24,368. Advanced STS-related systemic treatment costs were driven primarily by drug acquisition and administration costs. Treatment-related costs increased during later lines of therapy for all countries except France, where they decreased after first-line therapy. Pain control and antiemetics were the most common supportive care medications. Conclusions. This study provides real-world data on resource utilization and estimated costs in advanced STS and could inform policymakers about treatment burden.

Background Cachexia and its most visible manifestation, weight loss, represent important poor prognostic factors for patients with non-small cell lung cancer. This work examines how severity of weight loss as an indicator of cachexia affects outcomes. Methods In a retrospective observational study of electronic medical records, patients with non-small cell lung cancer were monitored for weight loss from an initial assessment (within 2 months of index diagnosis) to a landmark at 5 months (at least 3 months after initial assessment). Patients who survived to the landmark were then followed to determine the association of baseline body mass index (BMI) and weight loss during the assessment period with outcomes. Patients were clustered to determine how BMI and weight loss related to survival as approximated by time of last appearance in the database, a strong proxy for time of death. Results Twelve thousand one hundred and one patients were divided into 5 cachexia risk groups based on a combination of weight loss and initial BMI. More severe groups demonstrated progressively worse outcomes, with the most severe group surviving for a median of 263 days (95% CI 254-274) from index and having a 1-year survival rate of 31%. The least severe group survived for a median of 825 days from index (95% CI 768-908) and had a 1-year survival rate of 78%. Cachexia risk group was a stronger predictor of survival than any baseline variable, including disease stage, performance status, or age. Conclusions In this study, we showed that increasing weight loss and, to a lesser extent, decreasing BMI, led to substantially worse outcomes for non-small cell lung cancer patients independent of other variables. We suggest risk score groups that provide an improved approach for identifying poor prognosis patients with the greatest need.

Colorectal cancer is the third most common cause of cancer death in the USA. It is important to identify patients who may experience poor outcomes from available treatments. In this retrospective observational study, treatment patterns and survival outcomes were described among adult patients from the Flatiron Health electronic medical records database who were treated with at least two lines of therapy for metastatic colorectal cancer in the USA between January 2013 and May 2018. Patients with rapid progression were defined as those whose time from start of first- to second-line therapy was ≤ 183 days. A total of 14,315 patients formed the study cohort. The most common first-line treatments were FOLFOX (5-fluorouracil, leucovorin, and oxaliplatin) plus bevacizumab, received by 34.7% (n = 4962) of patients, followed by FOLFOX alone (17.1%, n = 2445). Of all patients, 6991 (48.9%) also received second-line anti-cancer therapy and of those, 3338 (47.7%) had rapid progression and 3653 (52.3%) did not. Median overall survival from the start of first- and second-line therapy was 20.8 months (95% CI 20.2–21.3) and 14.5 months (95% CI 13.9–15.0) for the entire study population, respectively. Median overall survival from the start of second-line therapy was 14.1 (95% CI 13.2–14.8) for patients with rapid progression and 14.6 months (95% CI 13.8–15.4) for patients without rapid progression. Patients diagnosed with metastatic colorectal cancer lived less than 2 years in this real-world database. While the time to initiation of second-line therapy was by definition longer among patients without rapidly progressing disease, survival outcomes were comparable from initiation of second-line therapy.

Objective. To describe real-world treatment patterns and outcomes for patients with advanced soft tissue sarcoma (STS) not amenable to surgery or radiotherapy in the United Kingdom, Spain, Germany, and France. Methods. Physicians completed a web-based medical record abstraction for adult patients with advanced STS (other than Kaposi’s sarcoma or gastrointestinal stromal tumor) who received ≥1 line of systemic therapy. Clinical characteristics, treatments, tumor responses, and mortality data were recorded. Results. A total of 130 physicians provided data for 807 patients. Patients’ mean age at advanced STS diagnosis was 57.1 (±12.3) years; 59% were male. The most commonly identified histologic categories were leiomyosarcoma (28%), liposarcoma (13%), and rhabdomyosarcoma (11%). Overall, 57% of patients received only 1 line of therapy, 32% received 2 lines of therapy, and 11% received ≥3 lines of therapy. The most common first-line regimens were doxorubicin alone (41%), doxorubicin plus ifosfamide (19%), docetaxel plus gemcitabine (9%), paclitaxel alone (4%), and ifosfamide (4%). Median overall survival from start of treatment was estimated to be 17.6 months (95% confidence interval, 15.6–19.0 months). Conclusions. In real-world clinical practice, advanced STS is most commonly treated with older therapies in the United Kingdom, Spain, Germany, and France. New therapies that improve overall survival in advanced STS are needed.

Objective Clinical trials have demonstrated improved outcomes for patients with diffuse large B-cell lymphoma (DLBCL) treated with regimens containing rituximab, but variations in real-world treatment patterns and outcomes have not been studied. The objective of this study was to characterize real-world treatment patterns and outcomes in higher risk DLBCL patients. Methods Patients with an International Prognostic Index score (IPI) ≥3 who received initial rituximab-based therapy from 2005 to 2012 were identified via electronic medical record data from the International Oncology Network. Initial therapy, rates of complete response (CR), post-CR treatments, and outcomes were evaluated. Results Among 257 eligible patients, 75% achieved a CR: 77% (158/206) of patients receiving R-CHOP compared to 71% (36/51) of patients receiving initial therapies other than R-CHOP. Post-CR, 78% of the 158 patients receiving R-CHOP underwent active surveillance; 13% received maintenance rituximab-based treatment; and 6% received radiation therapy. Relapse rates among patients receiving maintenance rituximab, active surveillance, and radiation therapy were 28% (6/21), 19% (24/124), and 0%, (0/10), respectively (P = 0.08). Discussion This study found that active surveillance continues to be the most commonly utilized treatment regimen among DLBCL patients with an IPI score ≥3 achieving a CR on first-line R-CHOP. Other approaches aimed at increasing the time to relapse are being utilized as well, but the clinical benefit of these modalities is unclear. Conclusion Results of this study are consistent with the results from clinical trials and suggest the need for further evaluation of maintenance therapy options for patients at higher risk of relapse.

Background Cachexia and its most visible manifestation, weight loss, represent important poor prognostic factors for patients with non‐small cell lung cancer. This work examines how severity of weight loss as an indicator of cachexia affects outcomes. Methods In a retrospective observational study of electronic medical records, patients with non‐small cell lung cancer were monitored for weight loss from an initial assessment (within 2 months of index diagnosis) to a landmark at 5 months (at least 3 months after initial assessment). Patients who survived to the landmark were then followed to determine the association of baseline body mass index (BMI) and weight loss during the assessment period with outcomes. Patients were clustered to determine how BMI and weight loss related to survival as approximated by time of last appearance in the database, a strong proxy for time of death. Results Twelve thousand one hundred and one patients were divided into 5 cachexia risk groups based on a combination of weight loss and initial BMI. More severe groups demonstrated progressively worse outcomes, with the most severe group surviving for a median of 263 days (95% CI 254–274) from index and having a 1‐year survival rate of 31%. The least severe group survived for a median of 825 days from index (95% CI 768–908) and had a 1‐year survival rate of 78%. Cachexia risk group was a stronger predictor of survival than any baseline variable, including disease stage, performance status, or age. Conclusions In this study, we showed that increasing weight loss and, to a lesser extent, decreasing BMI, led to substantially worse outcomes for non‐small cell lung cancer patients independent of other variables. We suggest risk score groups that provide an improved approach for identifying poor prognosis patients with the greatest need.

Purpose To evaluate the advantages and disadvantages of pre-approval requirements for safety data to detect cardiovascular (CV) risk contained in the December 2008 U.S. Food and Drug Administration (FDA) guidance for developing type 2 diabetes drugs compared with the February 2008 FDA draft guidance from the perspective of diabetes population health. Methods We applied the incremental net health benefit (INHB) framework to quantify the benefits and risks of investigational diabetes drugs using a common survival metric (life-years [LYs]). We constructed a decision analytic model for clinical program development consistent with the requirements of each guidance and simulated diabetes drugs, some of which had elevated CV risk. Assuming constant research budgets, we estimate the impact of increased trial size on drugs investigated. We aggregate treatment benefit and CV risks for each approved drug over a 35-year horizon under each guidance. Results The quantitative analysis suggests that the December 2008 guidance adversely impacts diabetes population health. INHB was −1.80 million LYs, attributable to delayed access to diabetes therapies (−0.18 million LYs) and fewer drugs (−1.64 million LYs), but partially offset by reduced CV risk exposure (0.02 million LYs). Results were robust in sensitivity analyses. Conclusion The health outcomes impact of all potential benefits and risks should be evaluated in a common survival measure, including health gain from avoided adverse events, lost health benefits from delayed or forgone efficacious products, and impact of alternative policy approaches. Quantitative analysis of the December 2008 FDA guidance for diabetes therapies indicates that negative impact on patient health will result. © 2014 The Authors. Pharmacoepidemiology and Drug Safety published by John Wiley & Sons, Ltd.

Pancreatic adenocarcinoma has few effective treatment options and poor survival. The objective of this study was to characterize treatment patterns and estimate the costs and resource use associated with its treatment in a commercially-insured US population.In this retrospective claims-based analysis, individuals ≥18 years old with evidence of pancreatic adenocarcinoma between January 1, 2001 and December 31, 2010 were selected from a managed care database. Treatment phase (either initial non-metastatic or metastatic) was determined using a claims-based algorithm. Patients in the pancreatic cancer population were matched 1:3 to a control population. Resource use (events/person-years), treatment patterns, and healthcare costs (per-patient per-month, PPPM) were determined during a variable length follow-up period (from first pancreatic cancer diagnosis to earliest of death, disenrollment, or study end).In this study, 5262 pancreatic cancer patients were matched to 15,786 controls. Rates of office visits, inpatient visits, ER visits, and inpatient stays, and mean total all-cause healthcare costs PPPM ($15,480 vs $1001) were significantly higher among cancer patients than controls (all p 0.001). Mean inpatient costs were the single largest cost driver ($9917 PPPM). Also, mean total all-cause healthcare costs were significantly higher during the metastatic treatment phase vs the initial treatment phase of non-metastatic disease ($21,637 vs $10,358, p 0.001).These results indicate that pancreatic cancer imposes a substantial burden on the US healthcare system, and that treatment of more advanced disease is significantly more costly than initial treatment of non-metastatic disease.Additional research is needed to validate the accuracy of the claims-based algorithms used to identify the treatment phase.

Background While there are validated patient-reported outcomes (PRO) instruments for use in specific cancer populations, no validated general instruments exist for use in conditions common to multiple cancers, such as muscle wasting and consequent physical disability. The Medicare Current Beneficiary Survey (MCBS), a survey in a nationally representative sample of Medicare beneficiaries, includes items from three well known scales with general applicability to cancer patients: Katz activities of daily living (ADL), Rosow–Breslau instrumental ADL (IADL), and a subset of physical performance items from the Nagi scale. Objective This study evaluated properties of the Katz ADL, Rosow–Breslau IADL, and a subset of the Nagi scale in patients with pancreatic cancer, lung cancer, and myeloproliferative neoplasms (MPN) using data from MCBS linked with Medicare claims in order to understand the potential utility of the three scales in these populations; understanding patient-perceived significance was not in scope. Methods The study cohorts included Medicare beneficiaries aged ≥65 years as of 1 January of the year of their first cancer diagnosis with one or more health assessments in a community setting in the MCBS Access to Care data from 1991 to 2009. Beneficiaries had at least two diagnoses in de-identified Medicare claims data linked to the MCBS for one of the following cancers: pancreatic, lung, or MPN. The Katz ADL, Rosow–Breslau IADL, and Nagi scales were calculated to assess physical functioning over time from cancer diagnosis. Psychometric properties for each scale in each cohort were evaluated by testing for internal consistency, test–retest reliability, and responsiveness by comparing differences in mean scale scores over time as cancer progresses, and differences in mean scale scores before and after hospitalization (for lung cancer cohort). Results The study cohorts included 90 patients with pancreatic cancer, 863 with lung cancer, and 135 with MPN. Among each cancer cohort, the Katz ADL, Rosow–Breslau IADL, and Nagi scales had acceptable internal consistency (Cronbach’s alpha generally between 0.70 and 0.90) and test–retest reliability for consecutive surveys before diagnosis and consecutive surveys after diagnosis (when patients’ functioning was more stable). Compared with mean scale scores at the survey 1–2 years before cancer diagnosis (baseline), mean scale scores at the first survey after cancer diagnosis were significantly higher (P

The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the number and quality of innovative, cost-effective new medicines, without incurring unsustainable R&D costs. However, it is widely acknowledged that trends in industry R&D productivity have been moving in the opposite direction for a number of years. Here, we present a detailed analysis based on comprehensive, recent, industry-wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall R&D productivity. We then propose specific strategies that could have the most substantial impact in improving R&D productivity.

713 Background: Exploratory analyses from RAISE (NCT01183780), FOLFIRI with ramucirumab or placebo in previously treated mCRC pts, suggested pts with treatment-emergent neutropenia may have improved overall survival (OS) compared to pts who did not experience neutropenia on study (Ciuleanu T, et al. abst. 2475, ESMO 2016). Subsequent analyses suggested an even stronger association between baseline ANC and OS, with high baseline ANC associated with shorter OS. A retrospective observational study was conducted to test this association as a pre-specified hypothesis. Methods: The IMS Oncology Database (electronic medical record data from US community practices) was used to identify pts ≥ 18 yrs with mCRC (ICD-9 code 153.x, 154.0 or 154.1) who initiated second-line fluoropyrimidine and irinotecan (+/- bevacizumab; bev) in 2007-2013, following progression during or after first-line fluoropyrimidine and oxaliplatin (+/- biologic). Eligible pts had ≥ 1 ANC in the 60 days prior to second-line therapy. Pts were stratified by second-line bev use and high/low baseline ANC ( ≥ or < 5.5x109/L) and matched by propensity scores. OS based on a validated proxy was analyzed using the Kaplan-Meier method and a Cox proportional hazards model, adjusted for age, gender, ECOG PS, stage, length of first-line treatment, and BMI. Results: 747 eligible pts were identified, of whom 617 were matched. Pts with baseline characteristic data had a median age of 59 yr, 57% were male, 67% were Caucasian, 74% had stage IV disease at diagnosis, and 63% had ECOG PS of 0/1 at start of second-line. Bev-treated pts with high baseline ANC (n = 122) had a median OS (mOS) of 7.7 mo vs 14.7 mo in pts with low baseline ANC (n = 323); adjusted HR 1.69 (95% CI, 1.35, 2.12; p < 0.0001). Pts with high baseline ANC not treated with bev (n = 59) had a mOS 5.4 mo vs 14.4 mo in pts with low baseline ANC (n = 113); adjusted HR 2.73 (95% CI, 1.89, 3.93; p < 0.0001). There was a modest interaction effect between bev treatment and baseline ANC (p = 0.012), indicating greater bev benefit in the high ANC group. Conclusions: Baseline ANC appears to be a strong prognostic factor and potentially a weak predictive factor for antiangiogenic therapy for OS in pts with previously treated mCRC.

We have cloned the Escherichia coli fliAZY operon, which contains the fliA gene (the alternative sigma factor sigma F) and two novel genes, fliZ and fliY. Transcriptional mapping of this operon shows two start sites, one of which is preceded by a canonical E sigma F-dependent consensus and is dependent on sigma F for expression in vivo and in vitro. We have overexpressed and purified sigma F and demonstrated that it can direct core polymerase to E sigma F-dependent promoters. FliZ and FliY are not required for motility but may regulate sigma F activity, perhaps in response to a putative cell density signal that may be detected by FliY, a member of the bacterial extracellular solute-binding protein family 3.

The pharmaceutical industry is under growing pressure from a range of environmental issues, including major losses of revenue owing to patent expirations, increasingly cost-constrained healthcare systems and more demanding regulatory requirements. In our view, the key to tackling the challenges such issues pose to both the future viability of the pharmaceutical industry and advances in healthcare is to substantially increase the number and quality of innovative, cost-effective new medicines, without incurring unsustainable RD costs. However, it is widely acknowledged that trends in industry RD productivity have been moving in the opposite direction for a number of years. Here, we present a detailed analysis based on comprehensive, recent, industry-wide data to identify the relative contributions of each of the steps in the drug discovery and development process to overall RD productivity. We then propose specific strategies that could have the most substantial impact in improving RD productivity.

We have studied a novel class of DNA sequences that cause DNA polymerases to pause. These sequences have the central consensus Py-G-C and are not necessarily adjacent to hairpins in the DNA template. Since most consensus sequences do not cause pauses under standard conditions, additional template features must exist that make it difficult to incorporate nucleotides at these positions. We believe that these pauses result from constraints that make the conformation change involved in nucleotide selection more difficult. These pauses can obscure parts of DNA sequencing ladders and prevent DNA amplification by the polymerase chain reaction. The addition of betaine, and some related compounds, relieves these pauses.

Background The aim of this study was to conduct a retrospective database analysis to describe the chemotherapy treatment patterns and outcomes of patients with gastric cancer. Methods Individuals diagnosed with gastric cancer were identified from the IMS Oncology Database, which contains electronic medical record (EMR) data collected from a variety of community practices, and the Truven Health MarketScan® Research database, an administrative claims database. Eligible patients were 18 years of age or older and had an ICD-9 code 151.0–151.9. Patients were excluded if they had evidence of cancer within 6 months of the index diagnosis. Results There were 5257 eligible patients identified in EMR data: 1982 (37.7 %) of these patients also had data regarding chemotherapy treatments. Of the 1982 patients who received first-line therapy, 42.3 %, 18.1 %, and 7.9 % went on to receive a second, third, and fourth line of chemotherapy, respectively. There were 11891 eligible patients identified in the administrative database; 5299 (44.6 %) had data regarding chemotherapy. Of those initiating chemotherapy, 2888 (54.5 %) received a second line and 1598 (30.2 %) received a third line of treatment. The average total cost of care during first-line therapy was $40,811 [standard deviation (SD) = $49,916], which was incurred over an average of 53.5 (SD = 63.4) days. A similar pattern was evident in second-line treatment (mean/SD, $26,588/$33,301) over 41.2 (SD = 55.7) days. Conclusions Costs and duration of care received vary among gastric cancer patients in the U.S. There is a need to understand which regimens may be associated with better health outcomes and to standardize treatment as appropriate.