Soluble immune checkpoint factors reflect exhaustion of antitumor immunity and response to PD-1 blockade.

BACKGROUNDPrecise stratification of patients with non-small cell lung cancer (NSCLC) is needed for appropriate application of PD-1/PD-L1 blockade therapy.METHODSWe measured soluble forms of the immune-checkpoint molecules PD-L1, PD-1, and CTLA-4 in plasma of patients with advanced NSCLC before PD-1/PD-L1 blockade. A prospective biomarker-finding trial (cohort A) included 50 previously treated patients who received nivolumab. A retrospective observational study was performed for patients treated with any PD-1/PD-L1 blockade therapy (cohorts B and C), cytotoxic chemotherapy (cohort D), or targeted therapy (cohort E). Plasma samples from all patients were assayed for soluble immune-checkpoint molecules with a highly sensitive chemiluminescence-based assay.RESULTSNonresponsiveness to PD-1/PD-L1 blockade therapy was associated with higher concentrations of these soluble immune factors among patients with immune-reactive (hot) tumors. Such an association was not apparent for patients treated with cytotoxic chemotherapy or targeted therapy. Integrative analysis of tumor size, PD-L1 expression in tumor tissue (tPD-L1), and gene expression in tumor tissue and peripheral CD8+ T cells revealed that high concentrations of the 3 soluble immune factors were associated with hyper or terminal exhaustion of antitumor immunity. The combination of soluble PD-L1 (sPD-L1) and sCTLA-4 efficiently discriminated responsiveness to PD-1/PD-L1 blockade among patients with immune-reactive tumors.CONCLUSIONCombinations of soluble immune factors might be able to identify patients unlikely to respond to PD-1/PD-L1 blockade as a result of terminal exhaustion of antitumor immunity. Our data suggest that such a combination better predicts, along with tPD-L1, for the response of patients with NSCLC.TRIAL REGISTRATIONUMIN000019674.FUNDINGThis study was funded by Ono Pharmaceutical Co. Ltd. and Sysmex Corporation.

Establishing clinically meaningful within-individual improvement thresholds for eight patient-reported outcome measures in people with relapsing-remitting multiple sclerosis.

BACKGROUND: As disease-modifying therapies do not reverse the course of multiple sclerosis (MS), assessment of therapeutic success involves documenting patient-reported outcomes (PROs) concerning health-related quality of life, disease and treatment-related symptoms, and the impact of symptoms on function. Interpreting PRO data involves going beyond statistical significance to calculate within-patient meaningful change scores. These thresholds are needed for each PRO in order to fully interpret the PRO data. This analysis of PRO data from the PROMiS AUBAGIO study, which utilized 8 PRO instruments in teriflunomide-treated relapsing-remitting MS (RRMS) patients, was designed to estimate clinically meaningful within-individual improvement thresholds in the same manner, for 8 PRO instruments. RESULTS: The analytical approach followed a triangulation exercise that considered results from anchor- and distribution-based methods and graphical representations of empirical cumulative distribution functions in PRO scores in groups defined by anchor variables. Data from 8 PRO instruments (MSIS-29 v2, FSMC, MSPS, MSNQ, TSQM v1.4, PDDS, HRPQ-MS v2, and HADS) were assessed from 434 RRMS patients. For MSIS-29 v2, FSMC, MSPS, and MSNQ total scores, available anchor variables enabled both anchor- and distribution-based methods to be applied. For instruments with no appropriate anchor available, distribution-based methods were applied. A recommended value for meaningful within-individual improvement was defined by comparing mean change in PRO scores between participants showing improvement of one or two categories in the anchor variable or those showing no change. A "lower bound" estimate was calculated using distribution-based methods. An improvement greater than the lower-bound estimate was considered "clinically meaningful". CONCLUSION: This analysis produced estimates for assessing meaningful within-individual improvements for 8 PRO instruments used in MS studies. These estimates should be useful for interpreting scores and communicating study results and should facilitate decision-making by regulatory and healthcare authorities where these 8 PROs are commonly employed.

Assessing the Health Economic Outcomes from Commercially Insured Relapsing Multiple Sclerosis Patients Who Switched from Other Disease-Modifying Therapies to Teriflunomide, in the United States.

Objective: Assess patient characteristics, healthcare resource utilization (HCRU), and relapses in patients with multiple sclerosis (MS) who switched to teriflunomide from other disease-modifying therapies (DMTs). Methods: Retrospective study of US Merative™ MarketScan® claims database (Jan 1, 2012-July 31, 2020,) including HIPAA-compliant, deidentified data. Patients ≥18 years with MS diagnosis (based on ICD-9/ICD-10 codes), receiving ≥1 DMT prior to teriflunomide and ≥12 months continuous enrollment pre and post index (date of teriflunomide initiation). Outcomes included inpatient and emergency room claims coinciding with MS diagnosis, MS-related healthcare costs, and annualized relapse rates (ARRs) (indirectly assessed using hospitalization/outpatient claims and steroid use coinciding with MS diagnosis). Results: The analyzed cohort (N=2016) was primarily female (79%); age (mean ± standard deviation) 51.4 ± 9.3 years; MS duration 4.7±2.8 years (at index). The majority (89.2%) were treated with one DMT before switching to teriflunomide. Use of outpatient services (event rate/100 person-years) increased post vs pre index; however, MRI visits significantly reduced over the same period (both P<0.0001). Costs for MS-specific outpatient visits decreased by $371 per patient per year (PPPY) after switching to teriflunomide. Despite an increase in use post index (0.024 to 0.033 rate/100 person-years; P<0.0001), costs for MS-specific laboratory services reduced (pre-index: $271 vs $248 PPPY post-index; P=0.02). Fewer patients had relapses after switching (pre-index: n=417 [20.7%]; post-index: n=333 [16.5%]). ARR was significantly lower after switching (pre-index: 0.269 vs post-index: 0.205; P=0.000). Conclusion: Switching to teriflunomide from existing DMTs in patients with relapsing MS resulted in a reduction in outpatient HCRU in this analysis of US claims data. The real-world effectiveness of teriflunomide was generally consistent with efficacy reported in clinical trials, showing a reduction in relapse following a switch to teriflunomide.

Health economic outcomes of switching to alemtuzumab from other disease-modifying therapies in people with multiple sclerosis in the USA.

Aim: Describe demographics, clinical characteristics, healthcare resource utilization (HCRU) and costs in people with multiple sclerosis (pwMS) switching to alemtuzumab from other disease-modifying therapies (DMTs). Patients & methods: Retrospective, observational study of IBM®MarketScan® claims database. PwMS previously treated with DMTs and initiating alemtuzumab (1 January 2013 to 31 December 2019) were identified. "Index" was date of alemtuzumab initiation (prescription filled). Results: The study cohort (n = 341) was primarily female (72%) with (mean ± standard deviation) age 45.1 ± 9.5 years. At index, duration of MS was 5.3 ± 2.8 years. HCRU (inpatient/outpatient services), outpatient costs (including MS-specific MRI and emergency room visits) and annualized relapse rate significantly reduced over the 2 years following initiation of alemtuzumab. DMT costs reduced over the same period. Conclusion: Health economic and clinical benefits were seen following switching to alemtuzumab from other DMTs for treatment of MS, in this cohort from the USA.

Medication Adherence and Healthcare Utilization in Relapsing-Remitting Multiple Sclerosis Patients Using Teriflunomide.

Purpose: Multiple sclerosis (MS) is a costly, immune-mediated disease of the central nervous system. Most patients have relapsing-remitting MS (RRMS) for which disease-modifying therapies (DMTs) provide an effective treatment option by reducing relapse rates. However, adherence to DMTs is suboptimal. This study examines the association between adherence to teriflunomide and clinical and healthcare utilization outcomes. Patients and Methods: Patients with RRMS who started treatment with teriflunomide between 1/1/2018 and 12/31/2019 were analyzed using IQVIA PharMetrics® Plus data. RRMS patients were identified via diagnosis codes and treatment types; the first prescription date for teriflunomide was the index date. Highly and poorly adherent patients were identified based on the proportion of days covered (PDC) post-index (PDC ≥0.8 and PDC ≤0.5, respectively). Patient demographics, clinical characteristics, healthcare utilization during the year pre- and post-index, and relapse rate post-index were reported descriptively. Outcomes were compared between highly and poorly adherent patients through logistic regression. Models were adjusted for demographics, comorbidities, and utilization measures during the baseline period. Results: Among the 922 RRMS patients identified, 534 (57.9%) were highly adherent to teriflunomide, while 249 (27.0%) had PDC ≤0.5. The two groups were not statistically different in terms of demographic characteristics and comorbidities; however, poorly adherent patients were more likely to have emergency department (ED) or inpatient visits during baseline (36.9% versus 26.8%, P=0.004; 17.3% versus 10.9%, P=0.013, respectively). Unadjusted results suggested lower likelihood of both relapses and utilization during follow-up among highly adherent patients compared to poorly adherent patients. Adjusted results confirmed that high adherence was associated with decreased likelihood of post-index relapses, ED utilization, and inpatient utilization (OR [95% CI]: 0.55 [0.39-0.76], 0.49 [0.34-0.71], and 0.51 [0.27-0.97], respectively) even after controlling for baseline utilization. Conclusion: High adherence to teriflunomide was found to be associated with fewer relapses and lower healthcare utilization among patients with RRMS.

Persistence, Adherence, and Switching to Higher-Cost Therapy in Patients with Multiple Sclerosis Initiating Oral Disease-Modifying Therapies: A Retrospective Real-World Study.

INTRODUCTION: Therapeutic efficacy of disease-modifying therapies (DMTs) for multiple sclerosis (MS) is often hindered by poor persistence and adherence, impacted by patient-perceived efficacy concerns, adverse effects, inconvenience, and forgetfulness. This study measured persistence, adherence, and time to switching to higher-cost therapy among patients with MS initiating teriflunomide, dimethyl fumarate, fingolimod, or diroximel fumarate treatment. METHODS: This retrospective study used Symphony Health US claims data from patients with MS newly initiated on one of four oral DMTs between January and June 2020. Persistence was defined as the duration a patient continued their medication. Adherence was measured using medication possession ratio (MPR); patients with MPR ≥ 80% were considered adherent. Switching was measured by comparing proportions of patients switching and mean time to switch to one of three higher-cost therapies (ocrelizumab, natalizumab, or cladribine). Kaplan-Meier curves assessed persistence. Chi-square tests determined proportions of patients on therapy after 12 months. RESULTS: A total of 6934 patients newly initiated on oral DMTs met study inclusion criteria (teriflunomide, n = 1968; dimethyl fumarate, n = 3409; diroximel fumarate, n = 616; fingolimod, n = 941). Patients newly initiated on teriflunomide and fingolimod had significantly higher persistence rates after 12 months (60% and 66%, respectively vs 44% dimethyl fumarate and 49% diroximel fumarate; p < 0.0001), and the highest proportion of adherent patients at 6 months (71% and 76%, vs 60% dimethyl fumarate and 58% diroximel fumarate) and 12 months (55% and 59%, vs 40% dimethyl fumarate and 44% diroximel fumarate). Mean time to switching to higher-cost therapies ranged from 247 days (diroximel fumarate to natalizumab) to 342 days (teriflunomide to ocrelizumab), with the highest rate of switching in patients on dimethyl fumarate (7%). CONCLUSION: Patients newly initiated on teriflunomide and fingolimod had better real-world persistence and adherence at 6 and 12 months, and longer time to switch to higher-cost therapies, than patients on dimethyl fumarate or diroximel fumarate.

People living with multiple sclerosis (MS for short) can find it difficult to maintain treatment plans. This can impact how well disease-modifying therapies (DMTs) work. This means treatments may not be as effective at controlling symptoms or stopping new symptoms (relapse). In this study, we looked at health records of 6934 previously diagnosed people living with MS in the USA. These people started DMTs for the first time between January and June 2020. Researchers studied how long people continued their treatment (known as persistence) and how often people took their treatment as recommended (adherence). We also studied how many people switched to a more expensive treatment (ocrelizumab, natalizumab, or cladribine). We measured persistence based on how many days people continued their treatment. We measured adherence through the number of people who took their treatment at least 80% of the time. After 1 year, more people who took teriflunomide and fingolimod continued treatment than people on dimethyl fumarate or diroximel fumarate. These people were also more likely to follow their treatment plan. People taking dimethyl fumarate were most likely to switch to a more expensive treatment. On average, people who changed to a more expensive treatment did so after around 8 months. In this study, we found that people with MS who started teriflunomide or fingolimod for the first time were more likely to continue treatment and take treatment as recommended than those on dimethyl fumarate or diroximel fumarate. They also took longer to switch to a more expensive treatment.

Radiotherapy Patterns of Care for Locally-advanced Non-small Cell Lung Cancer in the Pre- and Post-durvalumab Era: A Region-wide Survey in a Japanese Prefecture.

The promising results of the PACIFIC study led to the approval of consolidation durvalumab for coverage by the National Health Insurance (NHI) in 2018 for patients with locally-advanced unresectable non-small cell lung carcinoma (NSCLC) treated with definitive concurrent chemoradiotherapy (CCRT). However, the effect of NHI coverage on the patterns of care for this population remains unclear. Here, we conducted a questionnaire-based survey to determine the patterns of care for patients with stage II-III NSCLC treated with definitive radiotherapy in 2017 (pre-durvalumab era) or in 2019 (post-durvalumab era). Data were obtained from 11 radiotherapy facilities in Gunma prefecture, which has a population of 1.94 million. We identified 80 and 83 patients with stage II-III NSCLC who received definitive radiotherapy in Gunma in 2017 and 2019, respectively. At a given facility, CCRT was the treatment of choice in a significantly greater proportion of patients in 2019 than in 2017 (66% ± 20% vs 51% ± 29%, P = 0.041). Intensity-modulated radiotherapy (IMRT) was more frequent in 2019 than in 2017 (24% vs 1.2%). Carboplatin plus paclitaxel was used for CCRT at higher rate in 2019 than in 2017 (73% vs 44%). Consolidation durvalumab was performed in 73% (40/55) of CCRT-treated patients in 2019, and the treatment was performed for the planned 12 months in 45% (18/40) of patients. These data indicate that NHI coverage of durvalumab might be a possible reason for choosing CCRT in patients with stage II-III NSCLC in the real-world setting.

The effects of PSA kinetics on the outcome of hypofractionated salvage radiotherapy for biochemical recurrence of prostate cancer after prostatectomy.

The feasibility and efficacy of hypofractionated salvage radiotherapy (HS-RT) for prostate cancer (PC) with biochemical recurrence (BR) after prostatectomy, and the usefulness of prostate-specific antigen (PSA) kinetics as a predictor of BR, were evaluated in 38 patients who received HS-RT without androgen deprivation therapy between May 2009 and January 2017. Their median age, PSA level and PSA doubling time (PSA-DT) at the start of HS-RT were 68 (53-74) years, 0.28 (0.20-0.79) ng/ml and 7.7 (2.3-38.5) months, respectively. A total dose of 60 Gy in 20 fractions (three times a week) was three-dimensionally delivered to the prostate bed. After a median follow-up of 62 (30-100) months, 19 (50%) patients developed a second BR after HS-RT, but only 1 patient died before the last follow-up. The 5-year overall survival and BR-free survival rates were 97.1 and 47.4%, respectively. Late grade 2 gastrointestinal and genitourinary morbidities were observed in 0 and 5 (13%) patients, respectively. The PSA level as well as pathological T-stage and surgical margin status were regarded as significant predictive factors for a second BR by multivariate analysis. BR developed within 6 months after HS-RT in 11 (85%) of 13 patients with a PSA-DT < 10 months compared with 1 (17%) of 6 with a PSA-DT ≥ 10 months (median time to BR: 3 vs 14 months, P < 0.05). Despite the small number of patients, our HS-RT protocol seems feasible, and PSA kinetics may be useful for predicting the risk of BR and determining the appropriate follow-up schedule.

Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial.

BACKGROUND: Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain. OBJECTIVES: This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy. METHODS: A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl. RESULTS: Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses. CONCLUSIONS: In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402).

Asymmetric Synthesis of the Aromatic Fragment of Sespendole.

Sespendole is an indole sesquiterpene alkaloid bearing two isoprenyl groups, one of which is highly oxidized. Herein, we disclose an eight-step synthesis of the aromatic fragment of sespendole in an optically pure form, starting from 4-bromo-2-fluoronitrobenzene. The key steps were a Claisen rearrangement at room temperature for introduction of the prenyl group and a coupling between the dianion generated from prenylated bromo-N-tosylanilide and a chiral epoxy aldehyde.

Analytical performance of a new automated chemiluminescent magnetic immunoassays for soluble PD-1, PD-L1, and CTLA-4 in human plasma.

Current clinically approved biomarkers for the PD-1 blockade cancer immunotherapy are based entirely on the properties of tumour cells. With increasing awareness of clinical responses, more precise biomarkers for the efficacy are required based on immune properties. In particular, expression levels of immune checkpoint-associated molecules such as PD-1, PD-L1, and CTLA-4 would be critical to evaluate the immune state of individuals. Although quantification of their soluble form leased from the membrane will provide quick evaluation of patients' immune status, available methods such as enzyme-linked immunosorbent assays to measure these soluble factors have limitations in sensitivity and reproducibility for clinical use. To overcome these problems, we developed a rapid and sensitive immunoassay system based on chemiluminescent magnetic technology. The system is fully automated, providing high reproducibility. Application of this system to plasma of patients with several types of tumours demonstrated that soluble PD-1, PD-L1, and CTLA-4 levels were increased compared to those of healthy controls and varied among tumour types. The sensitivity and detection range were sufficient for evaluating plasma concentrations before and after the surgical ablation of cancers. Therefore, our newly developed system shows potential for accurate detection of soluble PD-1, PD-L1, and CTLA-4 levels in the clinical practice.

Association Between Laryngopharyngeal Reflux and Radiation-induced Mucositis in Head and Neck Cancer.

BACKGROUND/AIM: We investigated whether laryngopharyngeal reflux (LPR) is a risk factor for radiation-induced mucositis. PATIENTS AND METHODS: This was a retrospective cohort study using our departmental database. The study included patients with stage I or II laryngeal and hypopharyngeal cancers treated with radiation therapy alone between April 2009 and March 2014. Based on endoscopic findings, baseline laryngeal signs were evaluated using the reflux finding score (RFS), and the severity of mucositis was assessed during and after radiation therapy. RESULTS: Fifty-eight patients were enrolled. Thirty-one patients were categorized as high RFS (LPR-likely), while 27 patients were categorized as low RFS (LPR-unlikely). Grade 3 mucositis occurred more frequently in the high RFS group (p<0.042). Furthermore, grade 3 mucositis developed earlier in the high RFS group (p<0.001). CONCLUSION: High RFS (i.e., increased likelihood of LPR) appears to be a potential risk factor for developing severe radiation-induced mucositis.

Successful treatment of radiation-induced mucositis with proton pump inhibitor administration: A report of two laryngeal cancer cases.

Presently, the relationship between laryngopharyngeal reflux (LPR) and radiation-induced mucositis has not been fully explored. In the present study, we report 2 cases of laryngeal cancer in which radiation-induced mucositis ameliorated after proton pump inhibitor (PPI) administration. Case 1 was diagnosed with T1aN0M0 right glottis carcinoma and was treated with radiation therapy. Grade 3 mucositis occurred after administration of 46Gy irradiation. PPI was administered and mucositis ameliorated quickly without cessation of radiation therapy. Case 2 was diagnosed with T2N0M0 supraglottic cancer and was treated with concurrent chemoradiation therapy. Grade 3 mucositis occurred after administration of 44Gy irradiation. PPI was administered and mucositis ameliorated quickly without cessation of chemoradiation therapy. In both cases, a remarkable therapeutic effect of PPI was observed in the perilaryngeal areas including the epiglottic vallecula, arytenoid, and postcricoid area. In both cases, LPR involvement was suspected before the onset of radiation therapy. The two cases presented here, indicated a causal relationship between LPR and radiation-induced mucositis. In cases of severe mucositis in the perilaryngeal area in patients with LPR prior to radiation therapy, PPI administration may be an effective therapeutic option.

Inhaled aztreonam lysine versus inhaled tobramycin in cystic fibrosis. An economic evaluation.

RATIONALE: Pseudomonas aeruginosa infection is a significant cause of morbidity and mortality in patients with cystic fibrosis and is associated with a high economic burden. A recently published comparator trial demonstrated that outcomes in patients with cystic fibrosis with chronic P. aeruginosa infections switched from tobramycin solution for inhalation to aztreonam lysine for inhalation were better than those of patients who continued on tobramycin. OBJECTIVES: To compare overall costs of treatment of chronic inhaled tobramycin and aztreonam lysine in patient with cystic fibrosis who have chronic Pseudomonas infection, taking differences in outcomes into account. METHODS: A cost-effectiveness analysis with a 3-year time horizon was performed to simulate the economic consequences of either treatment from the perspective of a third party payer in the United States. We extrapolated results from the comparator trial and used data regarding clinical outcomes, quality of life, and costs from published literature and proprietary databases. A Markov structure was used to consider transitions between health states, defined principally by levels of percent predicted of FEV1. Extensive scenario and probabilistic sensitivity analyses were performed. MEASUREMENTS AND MAIN RESULTS: Use of aztreonam lysine for inhalation was associated with an average cost saving of $41,947 per patient over 3 years, as well as greater quality-adjusted life-years and total life-years. Scenario analyses demonstrated that these findings were robust to changes in key assumptions. CONCLUSIONS: It appears, with high likelihood, that the use of aztreonam solution for inhalation is associated with cost savings, an increase in quality-adjusted life-years, and improved clinical outcomes among patients with extensive prior use of tobramycin solution for inhalation who are naive to inhaled aztreonam lysine.

Economic Burden of COPD in the Presence of Comorbidities.

BACKGROUND: The morbidity and mortality associated with COPD exacts a considerable economic burden. Comorbidities in COPD are associated with poor health outcomes and increased costs. Our objective was to assess the impact of comorbidities on COPD-associated costs in a large administrative claims dataset. METHODS: This was a retrospective observational study of data from the Truven Health MarketScan Commercial Claims and Encounters and the MarketScan Medicare Supplemental Databases from January 1, 2009, to September 30, 2012. Resource consumption was measured from the index date (date of first occurrence of non-rule-out COPD diagnosis) to 360 days after the index date. Resource use (all-cause and disease-specific [ie, COPD- or asthma-related] ED visits, hospitalizations, office visits, other outpatient visits, and total length of hospital stay) and health-care costs (all-cause and disease-specific costs for ED visits, hospitalizations, office visits, and other outpatient visits and medical, prescription, and total health-care costs) were assessed. Generalized linear models were used to evaluate the impact of comorbidities on total health-care costs, adjusting for age, sex, geographic location, baseline health-care use, employment status, and index COPD medication. RESULTS: Among 183,681 patients with COPD, the most common comorbidities were cardiovascular disease (34.8%), diabetes (22.8%), asthma (14.7%), and anemia (14.2%). Most patients (52.8%) had one or two comorbidities of interest. The average all-cause total health-care costs from the index date to 360 days after the index date were highest for patients with chronic kidney disease ($41,288) and anemia ($38,870). The impact on total health-care costs was greatest for anemia ($10,762 more, on average, than a patient with COPD without anemia). CONCLUSIONS: Our analysis demonstrated that high resource use and costs were associated with COPD and multiple comorbidities.

Effects of GOLD-Adherent Prescribing on COPD Symptom Burden, Exacerbations, and Health Care Utilization in a Real-World Setting.

Global initiative for chronic Obstructive Lung Disease (GOLD) guidelines recommend specific drug therapy protocols for chronic obstructive pulmonary disease (COPD) patients based on symptoms and exacerbation risk. This study used electronic health records (EHRs) to assess the effect of adherence and nonadherence to GOLD prescribing guidelines on COPD symptom burden, exacerbations, and health care resource utilization (HCRU) during the 180 days following index treatment start. Included patients had COPD (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] codes 490.xx, 491.xx, 492.xx, 496.xx), a valid GOLD stage within the study period (January 1, 2007 to December 31, 2012), and were 40 to 90 years of age at first GOLD staging (GOLD date). Adherence or nonadherence to GOLD-defined prescribing was based on COPD medication prescribed within 180 days on either side of the GOLD date. Of 4234 patients included in the analysis, approximately 36% were prescribed GOLD-adherent pharmacotherapy. Prevalence of all COPD-related symptoms during the 180 days following index treatment start were significantly reduced in the GOLD-adherent (n=1531) versus the GOLD-nonadherent group (n=2703). GOLD-adherent prescribing was associated with significant reductions in proportions of patients with all-cause hospitalizations and emergency department (ED) visits (unadjusted odds ratios [ORs], 0.69 and 0.63, respectively), as well as respiratory-specific ED visits (unadjusted OR, 0.65), compared with GOLD-nonadherent prescribing. In analyses that divided patients receiving GOLD-nonadherent treatment into undertreated and overtreated patients, undertreatment was associated with significant increases in many COPD symptoms, and both undertreatment and overtreatment were associated with increases in some HCRU endpoints. GOLD-adherent prescribing delivers moderate benefits with respect to COPD symptoms and HCRU.

Clinical and economic outcomes in a real-world population of patients with elevated triglyceride levels.

OBJECTIVE: This study investigated real-world treatment patterns, healthcare utilization, and costs of hypertriglyceridemia in a large commercially insured United States population. METHODS: This observational claims study was conducted among adult patients with TG > 500 mg/dL between 01/01/2007 and 04/30/2013. Patients were stratified into mutually exclusive cohorts based on their first available TG measurement (index date): TG ≥ 1500 (Cohort A); 750 ≤ TG < 1500 (Cohort B), and 500 < TG < 750 (Cohort C). Study inclusion required ≥ 12 months of eligibility pre- (baseline) and post-index date (follow-up). Patient characteristics and outcomes were assessed descriptively. Costs associated with acute pancreatitis episodes were estimated using a Generalized Linear Model regression. RESULTS: We identified a total of 1964 patients in Cohort A, 7432 in Cohort B, and 17,500 in Cohort C. Patients were young (mean age 46-48) and mostly male (75%-80%). Treatment switching and augmentation occurred rarely, and almost 50% of patients discontinued their initial treatment. At baseline, healthcare utilization and costs were highest in Cohort A (mean all-cause medical and pharmacy costs, $8850). At follow-up, the number of patients with dyslipidemia-related office and pharmacy claims and related costs almost doubled across the cohorts. Mean all-cause costs/patient in Cohort A at follow-up were $12,642, of which $3730 were dyslipidemia-related. Acute pancreatitis episodes were associated with >300% increase in total all-cause costs in Cohort A. CONCLUSIONS: These results suggest that severe hypertriglyceridemia is undertreated and healthcare utilization and costs scale with magnitude of TG elevation. Patients with more severe hypertriglyceridemia received greater medical and pharmacy services. Managing severe hypertriglyceridemia more aggressively and preventing acute pancreatitis may generate cost savings.

Prognosis was not deteriorated by multiple primary cancers in esophageal cancer patients treated by radiotherapy.

Esophageal cancer patients are often associated with multiple primary cancers (MPC). The aim of this study is to evaluate the effect of MPC on prognosis in esophageal cancer patients treated by radiotherapy. Between 2001 and 2008, esophageal cancer patients treated by definitive radiotherapy at Gunma Cancer Center were retrospectively reviewed. Exclusion criteria were preoperative or postoperative radiotherapy, palliative radiotherapy, follow-up of <6 months, radiation dose of <50 Gy and no information on MPC. We analyzed 167 esophageal cancer patients and 56 (33.5%) were associated with MPC. Gastric cancer was the most frequent tumor (38.2%), followed by head and neck cancer (26.5%). Median follow-up time was 31.5 months (range 6.1-87.3 months). Patients with MPC included more stage I/II esophageal cancer than those without MPC (66.1% vs. 36.9%, P < 0.01). The 5-year overall survival rate for esophageal cancer with MPC was relatively better than those without MPC (46.1% vs. 26.7%), although the difference did not reach statistical significance in univariate analysis (P = 0.09). Stage I/II esophageal cancer patients had a significantly better overall survival than stage III/IV patients (P < 0.01). Among esophageal cancer patients with MPC, there was no difference in overall survival between antecedent and synchronous cancer (P = 0.59). Our study indicated that the prognosis of esophageal cancer patients treated by radiotherapy was primarily determined by the clinical stage itself, but not the presence of MPC.

Stereocontrolled synthesis of an indole moiety of sespendole and stereochemical assignment of the side chain.

Two possible diastereomers of the indole moiety of sespendole were synthesized from 3-hydroxy-4-nitrobenzaldehyde in a highly stereoselective manner. Comparison of (1)H and (13)C NMR spectra of the two synthetic materials with those sespendole leads us to propose that the relative stereochemistry of the epoxyalcohol is syn.

Health care utilization & costs for cystic fibrosis patients with pulmonary infections.

PURPOSE: To examine patterns of health care utilization and costs among cystic fibrosis (CF) patients with pulmonary infections. DESIGN: Retrospective administrative claims database analysis. METHODOLOGY: We used administrative claims data (including both medical and pharmacy claims) to examine health care utilization and costs among CF patients with pulmonary infections over one year. We conducted a subgroup analysis in which we examined selected outcome measures among patients with tobramycin for inhalation (TIS) prescriptions by the number of TIS prescriptions filled. PRINCIPAL FINDINGS: Among 1,064 CF patients identified with pulmonary infections, 80% had at least one CF-related office visit, 34% had a CF-related hospital stay, and 95% filled at least one prescription over one year. Total annual CF-related health care costs averaged $29,000 plus $20,000 for prescription drugs. In the subgroup analysis, there was a trend towards longer lengths of stay and higher inpatient costs with fewer numbers of TIS prescriptions filled. CONCLUSION: CF patients with pulmonary infections have substantial levels of health care utilization and costs.