Comorbidities in childhood atopic dermatitis: A population-based study.

BACKGROUND: Atopic dermatitis (AD) is a chronic inflammatory skin disease that is associated with allergic comorbidities. However, studies examining comorbidities in childhood AD are incomplete, which may contribute to suboptimal care. OBJECTIVE: The objective was to compare the risk of developing different allergic and non-allergic comorbidities among children with AD to that of a matched non-AD reference cohort in Sweden. METHODS: This was a nationwide population-based cohort study using longitudinal data from primary and specialist care registers. Patients with AD were identified by confirmed diagnosis in primary or specialist care. The non-AD reference cohort was randomly drawn from the general population and matched 1:1 with the AD patients. The risk of developing the following conditions was evaluated: hypersensitivity and allergic disorders, neurological disorders, psychiatric disorders, infections, immunological and inflammatory disorders, Type 1 diabetes (T1D), endocrine and metabolic disorders, skeletal disorders, ocular disorders and malignancies. RESULTS: This study included 165,145 patients with AD (mild-to-moderate [n = 126,681] and severe [n = 38,464]) and an equally sized reference cohort. Patients with AD displayed a higher risk of developing comorbid conditions for all investigated categories, except for T1D and skeletal disorders, compared with the reference cohort. The highest risk compared with the reference cohort was observed for hypersensitivity and allergic disorders (hazard ratio [HR]: 3.87), followed by malignancies (HR: 2.53) and immunological and inflammatory disorders (HR: 2.36). Patients with AD also had higher risk of developing multiple comorbidities (≥2). The risk of comorbidity onset increased alongside AD severity and patients with active AD were associated with increased risk of comorbidity onset compared with patients in remission. CONCLUSIONS: The clinical burden of AD is substantial for children with AD and patients are at an increased risk of developing several comorbid conditions extending beyond the atopic march. Our results also showed a positive association between worsening severity of AD and an increased risk of comorbidity onset.

Real-World Treatment Patterns and Clinical Outcomes in Advanced Gastrointestinal Neuroendocrine Tumors (GI NET): A Multicenter Retrospective Chart Review Study.

BACKGROUND: We assessed treatment patterns and outcomes of patients with advanced gastrointestinal (GI) neuroendocrine tumors (NET) at four large tertiary referral centers in the U.S. PATIENTS AND METHODS: We performed a retrospective chart review of patients aged ≥18 years at advanced GI NET diagnosis, treated between July 2011 and December 2014. Index date was the histologically confirmed diagnosis date of locally advanced/metastatic GI NET. Data included baseline characteristics, treatment patterns, progression, death, and GI NET-related health care resource utilization from index date through last contact or death. Time-to-event analyses, including treatment discontinuation, progression, and overall survival (OS), were performed using Kaplan-Meier analysis. RESULTS: We identified 273 patients; 156 (57%) had primary ileum NET, and 174 (64%) had functional NET. First-line treatments included somatostatin analog (SSA) alone (89%) or in combination (2%), liver-directed therapy (LDT; 8%), and cytotoxic chemotherapy or interferon (2%). One hundred fifty-five patients continued with second-line therapy, including SSA alone (17%) or in combination (75%, with 3% combined with peptide receptor radionuclide therapy), LDT (4%), and other treatments (3%). Median time (months) to first-line discontinuation was 154.0 for SSAs and 3.8 for cytotoxic chemotherapy. Overall median time to investigator-assessed progression following treatment initiation was 30.3 months. Median OS (months) following first-line initiation was 151.8 for all patients and 178.9 for first-line SSA. CONCLUSION: Our study illustrates the common use of SSAs in both first-line and subsequent treatment of patients with GI NETs, as well as the relatively long survival durations and multiple additional treatments received by patients with this condition. Treatment pattern assessment at later times, following approval of newer treatments, is warranted. IMPLICATIONS FOR PRACTICE: This study, assessing treatment patterns over a period of up to 30 years, showed that SSAs, LDT, cytotoxic chemotherapy, and interferon are common treatments for advanced GI NETs. SSAs alone or in combination with other treatments were the most frequent therapy in first and subsequent lines. Patients in this study remained on SSAs long-term, with median treatment duration of 12.8 years in first line. Treatment patterns should be assessed beyond this study's time period, given recent U.S. Food and Drug Administration approvals for additional treatments for GI NET, which will likely be incorporated in the continuum of care of patients.

Treatment Patterns and Clinical Outcomes in Advanced Lung Neuroendocrine Tumors in Real-World Settings: A Multicenter Retrospective Chart Review Study.

BACKGROUND: Using data from four tertiary referral centers in the U.S., we assessed real-world treatment patterns and clinical outcomes of patients with advanced lung neuroendocrine tumors (NETs). SUBJECTS, MATERIALS, AND METHODS: We performed a retrospective chart review of adult patients with locally advanced/metastatic (typical/atypical) lung NETs treated between July 2011 and December 2014. Index date was histologically confirmed typical/atypical carcinoid tumor diagnosis date. Data included baseline characteristics, treatment patterns, progression, death, and lung NET-related health care resource use from index date through last contact/death. Time to treatment discontinuation and first progression, time from first to second progression, and overall survival (OS) were estimated using Kaplan-Meier analysis. RESULTS: We identified 83 patients; 19 (23%) had functional NET. First-line treatments included somatostatin analogs (SSAs) alone (56%) or in combination with other therapies (6%), cytotoxic chemotherapy (20%), external beam radiation therapy (EBRT) (9%), liver-directed therapy (LDT) (4%), and everolimus/other (5%). Sixty patients had second-line therapy including SSA alone (18%) or in combination (40%), cytotoxic chemotherapy (17%), everolimus (12%), LDT (7%), EBRT (3%), and other treatments (3%). Median time (months) to first-line discontinuation were as follows: SSAs, 43.3; cytotoxic chemotherapy, 3.6. Overall median time (months) to investigator-assessed progression following treatment initiation was 12.4. Median OS (months) following treatment initiation was 66.4 for all patients and 81.5 for patients receiving SSAs. CONCLUSION: SSAs, alone and in combination, are common treatments for advanced lung NETs. Patients have additional treatment options and relatively long survival compared with patients with other advanced cancers. Treatment pattern assessment following approval of newer treatments is needed. IMPLICATIONS FOR PRACTICE: Somatostatin analogs (SSAs), cytotoxic chemotherapy, EBRT, liver-directed therapy, and targeted therapies are common treatments for locally advanced/metastatic (typical/atypical) lung neuroendocrine tumors (NETs). SSAs alone or in combination with other treatment modalities were the most common first- and second-line therapy, followed by cytotoxic chemotherapy. Patients continued treatment with SSAs long-term with median treatment duration of 43 months. Median overall survival was 66 months following initiation of first-line therapy for all patients. Treatment pattern assessment beyond the time period of this study is needed given recent U.S. Food and Drug Administration approvals for additional treatments for lung NETs that will likely be incorporated in the treatment landscape.

Assessment of change in quality of life, carcinoid syndrome symptoms and healthcare resource utilization in patients with carcinoid syndrome.

BACKGROUND: There is limited information on changes over time in carcinoid syndrome (CS) symptoms and quality of life (QoL). This study assessed change in CS symptoms and QoL in patients treated with somatostatin analogs (SSAs) using the Functional Assessment of Cancer Therapy-General (FACT-G) and Patient-Reported Outcomes Measurement Information System (PROMIS)-29 instruments. METHODS: Patients ≥18 years old with CS symptoms and treated with SSA or non-SSA agents in the United States were recruited through a patient advocacy group to complete a two-part, anonymous online survey. Time point (T) 1 survey was fielded from July-October 2016, and T2 survey followed 6 months later. Clinical characteristics and SSA treatment duration were assessed at T1. FACT-G and PROMIS-29 QoL surveys were administered and CS symptoms were assessed at T1 and T2; proportions of patients not experiencing symptoms were compared by McNemar's test. Healthcare resource utilization (HRU) was assessed for the T1-T2 interval, and mean difference in QoL score from T1 to T2 by SSA duration was calculated. RESULTS: Of 117 participants at T1, 89 (76%) completed the T2 survey and served as the study sample; 11 (13%) were treated with SSAs for > 0-2 years, 37 (42%) for > 2-5 years, and 39 (45%) for > 5 years. A higher proportion of patients at T2 vs. T1 reported the following symptoms as not applicable: diarrhea (16% vs. 7%, p < 0.05), flushing (28% vs. 18%, p < 0.05), wheezing (78% vs 66%, p = 0.008). Most patients (89%) had a physical exam and a mean of 7.2 healthcare provider visits between T1 and T2. Patients treated with SSAs for ≤2 years had a mean positive change of 3.7 in their FACT-G total score between surveys, and 6.0 in an additional set of CS-specific questions. Patients receiving SSAs for > 2 years did not appear to associate with a clinically meaningful improvement in QoL score as assessed by FACT-G between T1 and T2; patients also had no clinically meaningful improvement as assessed by PROMIS-29. CONCLUSIONS: There may be clinically important improvement in QoL as measured by FACT-G in patients in earlier years of receiving SSA, which may not appear in later years of SSA treatment.

Health-Related Quality of Life for Long-Acting Octreotide versus Placebo in Patients with Metastatic Midgut Neuroendocrine Tumors in the Phase 3 PROMID Trial.

BACKGROUND: In the phase IIIb PROMID study, octreotide long-acting significantly extended time to tumor progression compared with placebo in treatment-naïve patients with well-differentiated metastatic midgut neuroendocrine tumors. We report post hoc analyses for health-related quality of life (HRQoL). METHODS: HRQoL was measured with EORTC QLQ-C30, a 30-item self-report questionnaire (5 functional, 1 global, 9 symptom scales). Assessments were completed at baseline and every 12 weeks until tumor progression. Time to definitive deterioration (TDD; worsening of ≥10 points without further improvement) was analyzed with the Kaplan-Meier method. Linear mixed models were fit to assess change from baseline in QLQ-C30 scores by treatment arm over time. RESULTS: Among 85 patients, 82 (96%) completed the QLQ-C30 at baseline. There were few events of definitive deterioration for many scales. Significantly longer TDD was reported for long-acting octreotide versus placebo for fatigue (median 18.5 months vs. 6.8; p = 0.0006), pain (not reached [NR] vs. 18.2; p = 0.0435) and insomnia (NR vs. 16.4; p = 0.0046). Change from baseline to week 24 fatigue scores were stable for long-acting octreotide (mean 0.78; 95% CI -6.3 to 7.8) but worsened for placebo (mean 9.1; 95% CI 1.9-16.4), and for diarrhea there were improvements for long-acting octreotide (mean -8.0; 95% CI -19.6 to 3.5) and worsening for placebo (mean 11.2; 95% CI -0.7 to 23.1). CONCLUSIONS: HRQoL was maintained with few deteriorations in long-acting octreotide patients, whereas there was earlier and/or more deterioration in placebo patients. In long-acting octreotide patients, HRQoL was maintained or improved for the clinically important neuroendocrine tumor symptoms such as fatigue, insomnia, diarrhea and pain, whereas placebo patients experienced a deterioration of HRQoL scores for these symptoms.

Real-World Treatment Patterns for Lung Neuroendocrine Tumors: A Claims Database Analysis.

OBJECTIVE: The aim of this study was to describe real-world lung neuroendocrine tumor (NET) treatment patterns. METHODS: This study examined cytotoxic chemotherapy (CC), somatostatin analogues (SSA), targeted therapy (TT), interferon, and liver-directed therapies in 2 US claims databases. Patients ≥18 years with ≥1 inpatient or ≥2 outpatient claims for lung NET, initiating pharmacologic treatment between July 1, 2009, and June 30, 2014, were identified and followed until the end of enrollment or study end, whichever occurred first. RESULTS: A total of 785 newly pharmacologically treated lung NET patients were identified: mean (SD) age was 58.6 (9.1) years; 54.0% were female; 78.2% started first-line therapy with CC, 18.1% with SSA, and 1.1% with TT. Mean duration of first-line treatment was 397 days for SSA, 142 days for CC, and 135 days for TT. 74.1% of patients received no pharmacological treatment beyond first-line. The most common second-line treatment was SSA. CONCLUSIONS: Most patients received CC as first-line treatment, with SSA being less common. SSA-treated patients remained on therapy for > 1 year, compared to < 5 months for CC. The high proportion of patients using chemotherapy and the low proportion receiving second-line treatment seems consistent with treatment guidelines for small cell lung cancer rather than for NET. Future studies are warranted to describe reasons for treatment choice, discontinuation, and switching.

Incidence and prevalence of neuroendocrine tumors of the lung: analysis of a US commercial insurance claims database.

BACKGROUND: As reported in Surveillance, Epidemiology, and End Results (SEER) data, US incidence and prevalence of neuroendocrine tumors (NET) has increased over recent years. The study objective was to update incidence and prevalence information for lung NET using administrative claims. METHODS: This descriptive epidemiological study used 2009-2014 data from 2 US claims databases: MarketScan and PharMetrics. Patients (18-64 years old) had ≥1 inpatient or ≥ 2 outpatient claims with NET of bronchus or lung, identified by International Classification of Diseases, 9th Revision, Clinical Modification diagnosis codes. Prevalence was number of lung NET patients divided by number of enrollees/year. Incidence was number of patients with a first observed NET diagnosis who were disease-free for 2 years prior, divided by number of enrollees. Age and gender adjustments performed. RESULTS: The annual number of patients with lung NET identified from 2009 to 2014 ranged from 435 to 796 (MarketScan) and 419-648 (PharMetrics). In MarketScan, there was a 7.4% (95%CI 2.1-13.0; p = 0.027) annual percent change (APC) in the age-adjusted incidence for males and 6.8% (- 0.2-14.3; 0.052) for females. In PharMetrics, APC was - 2.9% (- 13.8-9.4; 0.395) for males; 14.7% (- 12.9-51.2; 0.165) for females. In MarketScan, APC in age-adjusted prevalence for males was 9.9% (4.7-15.3; 0.006); 16.2% (11.4-21.1; <.001) for females. For PharMetrics, APCs were 9.5% (2.3-17.2; 0.021) for males; 16.3% (9.6-23.5; 0.002) for females. CONCLUSIONS: From 2009 to 2014 there was a statistically significant increase in age-adjusted lung NET incidence for males in MarketScan, and a statistically significant increase in age-adjusted prevalence for both genders in PharMetrics. Incidence and prevalence changes, to the extent they exist, may be due to better diagnostic methods, increased awareness of NET among clinicians and pathologists, and/or an actual increase in US disease occurrence. Differences in rates across databases are difficult to explain. These results suggest the need for awareness of the clinically effective and safe treatment options available for lung NET patients among healthcare providers.

Health-related quality of life for everolimus versus placebo in patients with advanced, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (RADIANT-4): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In the phase 3 RADIANT-4 trial, everolimus increased progression-free survival compared with placebo in patients with advanced, progressive, non-functional, well-differentiated gastrointestinal or lung neuroendocrine tumours (NETs). We now report the health-related quality of life (HRQOL) secondary endpoint. METHODS: RADIANT-4 is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 97 centres in 25 countries worldwide. Adults (aged ≥18 years) were eligible for the study if they had pathologically confirmed, advanced (unresectable or metastatic), non-functional, well-differentiated (grade 1 or 2) NETs of lung or gastrointestinal origin. Patients were randomly allocated (2:1) using block randomisation (block size of three) by an interactive voice response system to receive oral everolimus (10 mg per day) or placebo, both with best supportive care, with stratification by tumour origin, WHO performance status, and previous somatostatin analogue treatment. HRQOL was assessed with the Functional Assessment of Cancer Therapy-General (FACT-G) questionnaire at baseline (visit 2, day 1), every 8 weeks (±â€ˆ1 week) during the study for the first 12 months after randomisation, and every 12 weeks thereafter until study drug discontinuation. The primary endpoint, reported previously, was progression-free survival assessed by central review; HRQOL was a prespecified secondary endpoint. The prespecified secondary outcome measure was time to definitive deterioration (≥7 points) in FACT-G total score. Analyses were done on the full analysis set, consisting of all randomised patients, by intention to treat. Only data obtained while receiving the randomly allocated treatment were included in this analysis. Enrolment for RADIANT-4 was completed on Aug 23, 2013, but the trial is ongoing pending final analysis of the key secondary endpoint of overall survival. This trial is registered with ClinicalTrials.gov, number NCT01524783. FINDINGS: Between April 3, 2012, and Aug 23, 2013, 302 patients were enrolled; 205 were randomly allocated everolimus and 97 were assigned placebo. At baseline, 193 (94%) of 205 patients assigned everolimus and 95 (98%) of 97 allocated placebo had completed either fully or partly the FACT-G questionnaire; at week 48, 70 (83%) of 84 patients assigned everolimus and 22 (85%) of 26 allocated placebo completed FACT-G. Median time to definitive deterioration in FACT-G total score was 11·27 months (95% CI 9·27-19·35) with everolimus and 9·23 months (5·52-not estimable) with placebo (adjusted hazard ratio 0·81, 95% CI 0·55-1·21; log-rank p=0·31). INTERPRETATION: HRQOL was maintained for patients with advanced, non-functional, gastrointestinal or lung NETs, with no relevant differences noted between the everolimus and placebo groups. In view of the previous RADIANT-4 findings of longer progression-free survival with everolimus, our findings suggest that everolimus delays disease progression while preserving overall HRQOL, even with the usual toxic effects related to active targeted drug treatment for cancer. FUNDING: Novartis Pharmaceuticals.

Long-term treatment outcomes of acromegaly patients presenting biochemically-uncontrolled at a tertiary pituitary center.

BACKGROUND: Acromegaly is a rare, slowly progressive disorder resulting from excessive growth hormone (GH) production by a pituitary somatotroph tumor. The objective of this study was to examine acromegaly treatment outcomes during long-term care at a specialized pituitary center in patients presenting with lack of biochemical control. METHODS: Data came from an acromegaly registry at the Cedars-Sinai Medical Center Pituitary Center (center). Acromegaly patients included in this study were those who presented biochemically-uncontrolled for care at the center. Biochemical control status, based on serum insulin-like growth factor-1 values, was determined at presentation and at study end. Patient characteristics and acromegaly treatments were reported before and after presentation by presenting treatment status and final biochemical control status. Data on long-term follow-up were recorded from 1985 through June 2013. RESULTS: Seventy-four patients presented uncontrolled: 40 untreated (54.1%) and 34 (45.9%) previously-treated. Mean (SD) age at diagnosis was 43.2 (14.7); 32 (43.2%) were female patients. Of 65 patients with tumor size information, 59 (90.8%) had macroadenomas. Prior treatments among the 34 previously-treated patients were pituitary surgery alone (47.1%), surgery and medication (41.2%), and medication alone (11.8%). Of the 40 patients without prior treatment, 82.5% achieved control by study end. Of the 34 with prior treatment, 50% achieved control by study end. CONCLUSIONS: This observational study shows that treatment outcomes of biochemically-uncontrolled acromegaly patients improve with directed care, particularly for those that initially present untreated. Patients often require multiple modalities of treatment, many of which are offered with the highest quality at specialized pituitary centers. Despite specialized care, some patients were not able to achieve biochemical control with methods of treatment that were available at the time of their treatment, showing the need for additional treatment options.

The association between biochemical control and cardiovascular risk factors in acromegaly.

BACKGROUND: The study aim was to estimate the proportion of acromegaly patients with various comorbidities and to determine if biochemical control was associated with reduced proportion of cardiovascular risk factors. METHODS: Data were from a single-center acromegaly registry. Study patients were followed for ≥12 months after initial treatment. Study period was from first to last insulin-like growth factor-I and growth hormone tests. RESULTS: Of 121 patients, 55% were female. Mean age at diagnosis was 42.4 (SD: 15.0). Mean study period was 8.8 (SD: 7.2) years. Macroadenomas were observed in 93 of 106 patients (87.7%), and microadenomas in 13 (12.3%). Initial treatment was surgery in 104 patients (86%), pharmacotherapy in 16 (13.2%), and radiation therapy in 1 (0.8%). Of 120 patients, 79 (65.8%) achieved control during the study period. New onset comorbidities (reported 6 months after study start) were uncommon (<10%). Comorbidities were typically more prevalent in uncontrolled versus controlled patients-24 (58.5%) vs. 33 (41.8%) had hypertension, 17 (41.5%) vs. 20 (25.3%) had diabetes, 11 (26.8%) vs. 16 (20.3%) had sleep apnea, and 3 (7.3%) vs. 3 (3.8%) had cardiomyopathy-except for colon polyps or cancer (19.5% vs. 20.3%), left ventricular hypertrophy (9.8% vs. 11.4%), and visual defects (14.6% vs. 17.7%). CONCLUSIONS: A greater number of comorbidities were observed in biochemically uncontrolled patients with acromegaly compared to their controlled counterparts in this single-center registry. About a third of the patients remained uncontrolled after a mean of >8 years of treatment, demonstrating the difficulty of achieving control in some patients.

Follow-up intervals in patients with Cushing's disease: recommendations from a panel of experienced pituitary clinicians.

PURPOSE: Follow-up guidelines are needed to assess quality of care and to ensure best long-term outcomes for patients with Cushing's disease (CD). The purpose of this study was to assess agreement by experts on recommended follow-up intervals for CD patients at different phases in their treatment course. METHODS: The RAND/UCLA modified Delphi process was used to assess expert consensus. Eleven clinicians who regularly manage CD patients rated 79 hypothetical patient scenarios before and after ("second round") an in-person panel discussion to clarify definitions. Scenarios described CD patients at various time points after treatment. For each scenario, panelists recommended follow-up intervals in weeks. Panel consensus was assigned as follows: "agreement" if no more than two responses were outside a 2 week window around the median response; "disagreement" if more than two responses were outside a 2 week window around the median response. Recommendations were developed based on second round results. RESULTS: Panel agreement was 65.9% before and 88.6% after the in-person discussion. The panel recommended follow-up within 8 weeks for patients in remission on glucocorticoid replacement and within 1 year of surgery; within 4 weeks for patients with uncontrolled persistent or recurrent disease; within 8-24 weeks in post-radiotherapy patients controlled on medical therapy; and within 24 weeks in asymptomatic patients with stable plasma ACTH concentrations after bilateral adrenalectomy. CONCLUSIONS: With a high level of consensus using the Delphi process, panelists recommended regular follow-up in most patient scenarios for this chronic condition. These recommendations may be useful for assessment of CD care both in research and clinical practice.

EPIDEMIOLOGY OF GASTROINTESTINAL NEUROENDOCRINE TUMORS IN A U.S. COMMERCIALLY INSURED POPULATION.

OBJECTIVE: To estimate incidence and prevalence of gastrointestinal neuroendocrine tumors (GI NETs) in U.S. commercially insured patients. METHODS: This was a retrospective, cross-sectional study using 2009 to 2014 data from MarketScan and PharMetrics commercial claims databases. Patients were 18 to 64 years old, and had 1 inpatient or 2 outpatient claims with GI NET, identified by International Classification of Diseases, 9th Revision, Clinical Modification codes. Incidence was calculated as number of patients with NET who were disease-free for 2 years prior, divided by number of enrollees and reported as per million person-years (PMPY). Prevalence was calculated as the number of GI NET patients divided by the number of enrollees per year. RESULTS: The annual number of patients with GI NET ranged from 2,014 to 3,413 in MarketScan and 1,436 to 2,336 in PharMetrics. Incidence increased from 2011 to 2014: 67.0 to 79.1 PMPY in MarketScan and 47.4 to 58.2 PMPY in PharMetrics. Incidence increased by 24.3% in females and 10.7% in males in MarketScan, and by 17.6% in females and 29.3% in males in PharMetrics. Incidence increased with age and was highest in the 45 to 54 and 55 to 64 age groups. Prevalence increased from 77.9 to 131.2 per million per year (MarketScan) and 50.8 to 108.9 (PharMetrics) from 2009 to 2014. Prevalence was generally higher in females than males and highest in 55 to 64 year olds. These increases may be due to better diagnostics, increased awareness of NET among clinicians and pathologists, and/or actual increase in disease. CONCLUSION: Clinicians may see GI NET with increasing frequency and should become more familiar with its presentation and treatment. ABBREVIATIONS: GI = gastrointestinal; ICD-9-CM = International Classification of Diseases, 9th Revision, Clinical Modification; NET = neuroendocrine tumor; PMPY = per million person-years; SEER = Surveillance, Epidemiology, and End Results.

AN APPROACH TO USING DATA MINING TO SUPPORT EARLY IDENTIFICATION OF ACROMEGALY.

OBJECTIVE: Data mining using insurance claims presents an opportunity to incorporate new analytic techniques in identifying rare conditions. This study aims to identify dyads of clinical conditions associated with acromegaly that may, with further validation and testing, be used to initially identify and diagnose this rare disease more accurately and efficiently. METHODS: This case-control study used two claims databases to identify acromegaly patients (cases) (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM]: 253.0) from 2008-2013. Each case was assigned two nonacromegaly controls (same age, gender, and region). Matched patients were randomly split into development and validation datasets. With expert clinician input, we isolated common associated conditions using ICD-9-CM codes. We identified all 2-way combinations of these conditions (dyads) and calculated the rate and risk relative (RR) to controls. Dyads meeting certain criteria (case rate ≥5% [or ≥1% if RR ≥5] or observed RR > expected) were replicated in the validation dataset to confirm results. RESULTS: We identified 3,731 cases and 7,462 controls: mean age 41.8 (SD, 16.1) years, 51.8% female. A total of 32 and 38 dyads, reduced from 630, met study criteria. Among replicated dyads, case rates varied -15.9% (hypertension and metabolic disorder) to 0.6% (arthritis and menstrual abnormalities). The highest RRs (e.g., valvular insufficiency and colon polyps [RR, 13.5; rate, 0.7%]) also exceeded expected values. Replication showed similar RR direction and size. CONCLUSION: This novel analytic approach revealed several dyads that were significantly associated with an acromegaly diagnosis. Presence of high-risk condition pairs, if verified by a detailed data source (e.g., medical charts), may be incorporated into screening tools or serve as potential markers for physicians to consider an acromegaly diagnosis. ABBREVIATIONS: ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification ID = identification RR = relative risk.

BIOCHEMICAL CONTROL DURING LONG-TERM FOLLOW-UP OF 230 ADULT PATIENTS WITH CUSHING DISEASE: A MULTICENTER RETROSPECTIVE STUDY.

OBJECTIVE: Cushing disease (CD) results from excessive exposure to glucocorticoids caused by an adrenocorticotropic hormone-secreting pituitary tumor. Inadequately treated CD is associated with significant morbidity and elevated mortality. Multicenter data on CD patients treated in routine clinical practice are needed to assess treatment outcomes in this rare disorder. The study purpose was to describe the burden of illness and treatment outcomes for CD patients. METHODS: Eight pituitary centers in four U.S. regions participated in this multicenter retrospective chart review study. Subjects were CD patients diagnosed at ≥18 years of age within the past 20 years. Descriptive statistical analyses were conducted to examine presenting signs, symptoms, comorbidities, and treatment outcomes. RESULTS: Of 230 patients, 79% were female (median age at diagnosis, 39 years; range, 18 to 78 years). Length of follow-up was 0 to 27.5 years (median, 1.9 years). Pituitary adenomas were 0 to 51 mm. The most common presenting comorbidities included hypertension (67.3%), polycystic ovary syndrome (43.5%), and hyperlipidemia (41.5%). Biochemical control was achieved with initial pituitary surgery in 41.4% patients (91 of 220), not achieved in 50.0% of patients (110 of 220), and undetermined in 8.6% of patients (19 of 220). At the end of follow-up, control had been achieved with a variety of treatment methods in 49.1% of patients (110 of 224), not achieved in 29.9% of patients (67 of 224), and undetermined in 21.0% of patients (47 of 224). CONCLUSION: Despite multiple treatments, at the end of follow-up, biochemical control was still not achieved in up to 30% of patients. These multicenter data demonstrate that in routine clinical practice, initial and long-term control is not achieved in a substantial number of patients with CD. ABBREVIATIONS: BLA = bilateral adrenalectomy CD = Cushing disease CS = Cushing syndrome eCRF = electronic case report form MRI = magnetic resonance imaging PCOS = polycystic ovary syndrome.

Health-related quality of life in patients with neuroendocrine tumors: an investigation of treatment type, disease status, and symptom burden.

INTRODUCTION: Neuroendocrine tumors (NETs) are malignant solid tumors arising in hormone-secreting tissue. They have historically been very difficult to treat, and advanced NETs are considered incurable. Surgery is the only potentially curative treatment option, though research is ongoing, investigating the efficacy of targeted therapies combined with more traditional chemotherapies. Frequent bowel movements and episodes of flushing are the most common symptoms. METHODS: The present study reports data from an anonymous patient survey of 663 eligible NET patients, identified with the assistance of patient advocacy groups. This study investigated the impact of treatment (surgery alone; surgery plus somatostatin analogue; other treatments) on quality of life (QOL). Finally, we investigate whether recurrent disease results in poorer QOL compared to disease treated curatively with surgery and remaining in remission. RESULTS AND DISCUSSION: Results suggest that increased frequency of bowel movements and presence of any flushing symptoms are correlated with decreased quality of life. Treatment groups differed on most Patient Reported Outcomes Measurement Information System (PROMIS) global health and PROMIS-29 scores, including physical function, fatigue, pain, social function, and general physical and mental health, with the surgery group reporting significantly better scores than the other groups (effect size of differences ranged from 0.28 to 0.54). This may be possibly due to effective symptom control reached for these patients through surgery alone. After adjustment for carcinoid syndrome, the association with the treatment group disappeared for all domains except physical functioning. In terms of disease status, patients with recurrent disease reported poorer physical, social, and mental functions. Depression scores were similar between groups; however, patients with recurrent disease reported significantly higher anxiety compared to those with no current NET. Physical functioning was even more markedly different between groups, with recurrent NET patients reporting significantly impaired overall physical function, impaired sleep, and significant fatigue compared to those with no current NET. To our knowledge, this is the first study to comprehensively examine the effect of treatment group, disease status, and symptom burden on the quality of life in NET patients in a large sample. Limitations and future research directions are discussed.

IDENTIFICATION OF POTENTIAL MARKERS FOR CUSHING DISEASE.

OBJECTIVE: Cushing disease (CD) causes a wide variety of nonspecific symptoms, which may result in delayed diagnosis. It may be possible to uncover unusual combinations of otherwise common symptoms using International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. Our aim was to identify and evaluate dyads of clinical symptoms or conditions associated with CD. METHODS: We conducted a matched case-control study using a commercial healthcare insurance claims database designed to compare the relative risk (RR) of individual conditions and dyad combinations of conditions among patients with CD versus matched non-CD controls. RESULTS: With expert endocrinologist input, we isolated 10 key conditions (localized adiposity, hirsutism, facial plethora, polycystic ovary syndrome, abnormal weight gain, hypokalemia, deep venous thrombosis, muscle weakness, female balding, osteoporosis) with RRs varying from 5.3 for osteoporosis to 61.0 for hirsutism (and infinite RR for localized adiposity). The RRs of dyads of these conditions ranged from 4.1 for psychiatric disorders/serious infections to 128.0 for hirsutism/fatigue in patients with versus without CD. Construction of uncommon dyads resulted in further increases in RRs beyond single condition analyses; for example, osteoporosis alone had an RR of 5.3, which increased to 8.3 with serious infections and to 52.0 with obesity. CONCLUSION: This study demonstrated that RR of any one of 10 key conditions selected by expert opinion was ≥5 times greater in CD compared to non-CD, and nearly all dyads had RR≥5. An uncommon dyad of osteoporosis and obesity had an RR of 52.0. If clinicians consider the diagnosis of CD when the highest-risk conditions are seen, identification of this rare disease may improve.

INCIDENCE AND PREVALENCE OF ACROMEGALY IN THE UNITED STATES: A CLAIMS-BASED ANALYSIS.

OBJECTIVE: Acromegaly, a rare endocrine disorder, results from excessive growth hormone secretion, leading to multisystem-associated morbidities. Using 2 large nationwide databases, we estimated the annual incidence and prevalence of acromegaly in the U.S. METHODS: We used 2008 to 2013 data from the Truven Health MarketScan® Commercial Claims and Encounters Database and IMS Health PharMetrics healthcare insurance claims databases, with health plan enrollees <65 years of age. Study patients had ≥2 claims with acromegaly (International Classification of Diseases, 9th Revision, Clinical Modification Code [ICD-9CM] 253.0), or 1 claim with acromegaly and 1 claim for pituitary tumor, pituitary surgery, or cranial stereotactic radiosurgery. Annual incidence was calculated for each year from 2009 to 2013, and prevalence in 2013. Estimates were stratified by age and sex. RESULTS: Incidence was up to 11.7 cases per million person-years (PMPY) in MarketScan and 9.6 cases PMPY in PharMetrics. Rates were similar by sex but typically lowest in ≤17 year olds and higher in >24 year olds. The prevalence estimates were 87.8 and 71.0 per million per year in MarketScan and PharMetrics, respectively. Prevalence consistently increased with age but was similar by sex in each database. CONCLUSION: The current U.S. incidence of acromegaly may be up to 4 times higher and prevalence may be up to 50% higher than previously reported in European studies. Our findings correspond with the estimates reported by a recent U.S. study that used a single managed care database, supporting the robustness of these estimates in this population. Our study indicates there are approximately 3,000 new cases of acromegaly per year, with a prevalence of about 25,000 acromegaly patients in the U.S. ABBREVIATIONS: CT = computed tomography GH = growth hormone IGF-1 = insulin-like growth factor 1 ICD-9-CM Code = International Classification of Diseases, 9th Revision, Clinical Modification Codes MRI = magnetic resonance imaging PMPY = per million person-years.

A retrospective chart review of drug treatment patterns and clinical outcomes among patients with metastatic or recurrent soft tissue sarcoma refractory to one or more prior chemotherapy treatments.

BACKGROUND: Limited clinical data on real-world practice patterns are available for patients with metastatic/relapsed soft tissue sarcomas (STS). The primary objective of this study was to evaluate treatment patterns in patients with metastatic/relapsed STS following failure of prior chemotherapy by examining data collected from 2000 to 2011 from a major tertiary academic cancer center in the United States. METHODS: Medical records, including community-based referral records, from a tertiary cancer center for adult patients with metastatic/relapsed STS with confirmed disease progression who commenced second-line treatment between January 1, 2000 and February 4, 2011, and with at least 3 months of follow-up data following second-line treatment initiation, were retrospectively reviewed. Overall survival, time to progression, and clinician-reported tumor response were collected. RESULTS: A total of 99 patients (leiomyosarcoma, n = 48; synovial cell sarcoma, n = 7; liposarcoma, n = 5; or other histological subtypes, n = 39) received an average of four lines of treatment (maximum of 10). No consistent or dominant regimens were used in each treatment line beyond the second line. Median second-line treatment duration was 4.1 months (95% confidence interval, 3.0-5.0). Overall, 72 of 99 patients (73%) discontinued second-line treatment due to progressive disease. Median progression-free survival from initiation of second-line treatment varied across regimens from 2.0 to 6.6 months (overall median, 5.4 months). CONCLUSIONS: Wide variations in treatment were evident, with no single standard of care for patients with metastatic/relapsed STS. Most patients discontinued second-line treatment due to progressive disease, often receiving additional systemic therapy with other drugs. These data suggest a high unmet need for more efficacious treatment options and improved data collection to guide practice among patients with relapsed/refractory STS.

Incremental healthcare resource utilization and costs in US patients with Cushing's disease compared with diabetes mellitus and population controls.

PURPOSE: Resource utilization and costs in Cushing's disease (CD) patients have not been studied extensively. We compared CD patients with diabetes mellitus (DM) patients and population-based controls to characterize differences in utilization and costs. METHODS: Using 2008-2012 MarketScan® database, we identified three patient groups: (1) CD patients; (2) DM patients; and (3) population-based control patients without CD. DM and control patients were matched to CD patients by age, gender, region, and review year in a 2:1 ratio. Outcomes included annual healthcare resource utilization and costs. RESULTS: There were 1852 CD patients, 3704 DM patients and 3704 controls. Mean age was 42.9 years; 78.2 % were female. CD patients were hospitalized more frequently (19.3 %) than DM patients (11.0 %, p < .001) or controls (5.6 %, p < .001). CD patients visited the ED more frequently (25.4 %) than DM patients (21.1 %, p < .001) or controls (14.3 %, p < .001). CD patients had more office visits than DM patients (19.1 vs. 10.7, p < .001) or controls (7.1, p < .001). CD patients on average filled more prescriptions than DM patients (51.7 vs. 42.7, p < .001) or controls (20.5, p < .001). Mean total healthcare costs for CD patients were $26,269 versus $12,282 for DM patients (p < .001) and $5869 for controls (p < .001). CONCLUSIONS: CD patients had significantly higher annual rates of healthcare resource utilization compared to matched DM patients and population controls without CD. CD patient costs were double DM costs and quadruple control costs. This study puts into context the additional burdens of CD over DM, a common, chronic endocrine condition affecting multiple organ systems, and population controls.

Incidence of Cushing's syndrome and Cushing's disease in commercially-insured patients <65 years old in the United States.

PURPOSE: To estimate the incidence of Cushing's syndrome (CS) and Cushing's disease (CD) in the US. METHODS: MarketScan Commercial database 2007-2010 (age <65 years) was used. CS patients were defined with ≥2 claims of CS diagnosis, while CD patients were defined with CS plus a benign pituitary adenoma diagnosis or hypophysectomy in the same calendar year. Annual incidence was calculated by dividing the number of CS or CD cases by the total number of members with the same enrollment requirement during the calendar years. RESULTS: CS incidence rates per million person-years were 48.6 in 2009 and 39.5 in 2010. The lowest rates of CS were in ≤17-year-olds and highest rates were in 35 to 44-year-olds. CD incidence rates were 7.6 in 2009 and 6.2 in 2010. The lowest rates of CD were in ≤17-year-olds and highest rates were in 18 to 24-year-olds. The rates varied by sex (2.3-2.7 in males, 9.8-12.1 in females). In females, lowest rates ranged 2.5-4.0 in ≤17-year-olds and highest 16.7-27.2 in 18-24 year olds. In males, there were too few cases to report estimates by age. CONCLUSIONS: In the first large US-based study, the annual incidence of CS in individuals <65 years old was nearly 49 cases per million, substantially higher than previous estimates, which were based primarily on European data. Using similar methods, we estimated the incidence of CD at nearly 8 cases per million US population. These estimates, if confirmed in other epidemiologic databases, represent a new data reference in these rare conditions.