Cachexia, chorea, and pain in chronic nonbacterial osteitis and inflammatory bowel disease: a case report.

BACKGROUND: Inflammatory bowel disease is an inflammatory disorder that primarily impacts the gastrointestinal tract, leading to malnutrition and chronic microscopic intestinal blood loss. Uncontrolled systemic inflammation can impact other parts of the body, known as extraintestinal manifestations. Up to 25% of patients with inflammatory bowel disease are reported to have these complications in their skin, joints, bones, eyes, liver, lung, and pancreas (Rogler et al. in Gastroenterology 161(4):1118-1132, 2021). Neurologic involvement as extraintestinal manifestations are less common, reported at 3-19%, including neuropathies, demyelination, and cerebrovascular events (Morís in World J Gastroenterol. 20(5):1228-1237, 2014). CASE PRESENTATION: A 13-year-old Caucasian boy presented with 1 month of progressive lower-extremity pain, weakness, and weight loss. His physical examination was notable for cachexia, lower-extremity weakness, and chorea. Labs revealed normocytic anemia and systemic inflammation. Imaging revealed symmetric abnormal marrow signal in the pelvis and upper femurs. Pathologic examination of the bone revealed chronic inflammation consistent with chronic nonbacterial osteitis. Endoscopy revealed colonic inflammation consistent with inflammatory bowel disease. CONCLUSIONS: Children and adolescents with musculoskeletal pain lasting more than 2 weeks with systemic signs or symptoms like weight loss should prompt evaluation for systemic inflammatory disorders such as chronic nonbacterial osteitis, which can occur in isolation or associated with inflammatory bowel disease. This patient also had a nonspecific neurologic abnormality, chorea, which resolved with treatment of underlying inflammatory disorder. These extraintestinal manifestations may be concurrent with or precede intestinal inflammation, requiring a high index of suspicion when investigating nonspecific systemic inflammation.

Chemoprophylaxis for venous thromboembolism in pelvic and/or acetabular fractures: A systematic review.

BACKGROUND: It is unclear which pharmacological agents, and at what dosage and timing, are most effective for venous thromboembolism (VTE) prophylaxis in patients with pelvic/acetabular fractures. METHODS: We searched the Cochrane Database of Systematic Reviews, Embase, Web of Science, EBSCO, and PubMed on October 3, 2020, for English-language studies of VTE prophylaxis in patients with pelvic/acetabular fractures. We applied no date limits. We included studies that compared efficacy of pharmacological agents for VTE prophylaxis, timing of administration of such agents, and/or dosage of such agents. We recorded interventions, sample sizes, and VTE incidence, including deep vein thrombosis (DVT) and pulmonary embolism. RESULTS: Two studies (3604 patients) compared pharmacological agents, reporting that patients who received direct oral anticoagulants (DOACs) were less likely to develop DVT than those who received low molecular weight heparin (LMWH) (p < 0.01). Compared with unfractionated heparin (UH), LMWH was associated with lower odds of VTE (odds ratio [OR] = 0.37, 95% confidence interval [CI]: 0.22-0.63) and death (OR = 0.27, 95% CI: 0.10-0.72). Three studies (3107 patients) compared timing of VTE prophylaxis, reporting that late prophylaxis was associated with higher odds of VTE (OR = 1.9, 95% CI: 1.2-3.2) and death (OR = 4.0, 95% CI: 1.5-11) and higher rates of symptomatic DVT (9.2% vs. 2.5%, p = 0.03; and 22% vs. 3.1%, p = 0.01). One study (31 patients) investigated dosage of VTE prophylaxis, reporting that a higher proportion of patients with acetabular fractures were underdosed (23% of patients below range of anti-Factor Xa [aFXa] had acetabular fractures vs. 4.8% of patients within adequate range of aFXa, p<0.01). CONCLUSIONS: Early VTE chemoprophylaxis (within 24 or 48 h after injury) was better than late administration in terms of VTE and death. Many patients with acetabular fractures are underdosed with LMWH, with inadequate aFXa levels. Compared with UH, LMWH was associated with lower odds of VTE and death. DOACs were associated with lower risk of DVT compared with LMWH. LEVEL OF EVIDENCE: III, systematic review of retrospective cohort studies.

Tranexamic acid use in pelvic and/or acetabular fracture surgery: A systematic review and meta-analysis.

PURPOSE: The purpose of this study is to determine whether tranexamic acid (TXA) use was associated with lower rates of blood transfusion in patients undergoing pelvic and/or acetabular fracture surgery. METHODS: Four studies were included, 3 of which were included in the pooled data analysis for a total of 308 patients. RESULTS: The transfusion rate was significantly lower in the TXA group (44%) compared with the non-TXA group (57%) (P = 0.02). CONCLUSION: TXA use was associated with a significantly lower transfusion rate in patients who underwent pelvic and/or acetabular fracture surgery. LEVEL OF EVIDENCE: Level 3. Systematic review of retrospective cohort studies and prospective randomized controlled trials.

Risk of second cancer among young prostate cancer survivors.

PURPOSE: About 40% of men diagnosed with prostate cancer (Pca) are ≤65 years of age. This study evaluates the risk of second cancer among young Pca patients treated with surgery or radiation. MATERIALS AND METHODS: This is a retrospective review of 150,915 men aged ≤65 years at Pca diagnosis treated with surgery or radiation registered in the Surveillance, Epidemiology, and End Results (SEER) database between 1973 and 2014. Incidence rates of second rectum/rectosigmoid junction (RJ), bladder, and lung cancer in each treatment group were reported with adjustment for potential confounders. Cumulative incidence functions were used to summarize the risk of second cancer after completing initial treatment. RESULTS: Men treated with external beam radiation (BEAM), brachytherapy (SEED), or combined radiation all exhibited a statistically significant increased incidence of second bladder cancer compared to men treated with surgery (adjusted incidence rate ratio [IRR]: 2.09, 1.91, and 2.04, respectively). Incidence of rectum/RJ cancer was also significantly increased in men receiving BEAM and combined radiation (adjusted IRR: 1.58 and 1.98, respectively). There were also significant differences in the cumulative incidence of second bladder cancer after receiving any form of radiation compared to surgery. CONCLUSION: Pca survivors ≤65 years of age at Pca diagnosis had an increased risk of second bladder and rectum/RJ cancer after BEAM and combined radiation treatment after adjusting for confounding factors. Second bladder cancer incidence after either form of radiation treatment was increased even at 5 years after a Pca diagnosis.

Carbon Nanotubes for Radiation-Tolerant Electronics.

Electronics for space applications have stringent requirements on both performance and radiation tolerance. The constant exposure to cosmic radiation damages and eventually destroys electronics, limiting the lifespan of all space-bound missions. Thus, as space missions grow increasingly ambitious in distance away from Earth, and therefore time in space, the electronics driving them must likewise grow increasingly radiation-tolerant. In this work, we show how carbon nanotube (CNT) field-effect transistors (CNFETs), a leading candidate for energy-efficient electronics, can be strategically engineered to simultaneously realize a robust radiation-tolerant technology. We demonstrate radiation-tolerant CNFETs by leveraging both extrinsic CNFET benefits owing to CNFET device geometries enabled by their low-temperature fabrication, as well as intrinsic CNFET benefits owing to CNTs' inherent material properties. By performing a comprehensive study and optimization of CNFET device geometries, we demonstrate record CNFET total ionizing dose (TID) tolerance (above 10 Mrad(Si)) and show transient upset testing on complementary metal-oxide-semiconductor (CMOS) CNFET-based 6T SRAM memories via X-ray prompt dose testing (threshold dose rate = 1.3 × 1010 rad(Si)/s). Taken together, this work demonstrates CNFETs' potential as a technology for next-generation space applications.

Clinicopathologic features and pathogenesis of melanocytic colonization in atypical meningioma.

Only two prior cases of benign dendritic melanocytes colonizing a meningioma have been reported. We add a third case, describe clinicopathologic features shared by the three, and elucidate the risk factors for this very rare phenomenon. A 29 year-old Hispanic woman presented with headache and hydrocephalus. MRI showed a lobulated enhancing pineal region mass measuring 41 mm in greatest dimension. Subtotal resection of the mass demonstrated an atypical meningioma, WHO grade II, and the patient subsequently underwent radiotherapy. She presented 4 years later with diplopia, and MRI showed an enhancing extra-axial mass measuring 47 mm in greatest dimension and centered on the tentorial incisura. Subtotal resection showed a brain-invasive atypical meningioma with melanocytic colonization. The previous two cases in the literature were atypical meningiomas, one of which was also brain invasive. Atypical meningiomas may be at particular risk for melanocytic colonization as they upregulate molecules known to be chemoattractants for melanocytes. We detected c-Kit expression in a minority of the melanocytes as well as stem cell factor and basic fibroblast growth factor in the meningioma cells, suggesting that mechanisms implicated in normal melanocyte migration may be involved. In some cases, brain invasion with disruption of the leptomeningeal barrier may also facilitate migration from the subarachnoid space into the tumor. Whether there is low-level proliferation of the dendritic melanocytes is unclear. Given that all three patients were non-Caucasian, meningiomas in persons and/or brain regions with increased dendritic melanocytes may predispose to colonization. The age range spanned from 6 years old to 70 years old. All three patients were female. The role of gender and estrogen in the pathogenesis of this entity remains to be clarified. Whether melanocytic colonization may also occur in the more common Grade I meningiomas awaits identification of additional cases.

Report of safety of pulse dosing of lapatinib with temozolomide and radiation therapy for newly-diagnosed glioblastoma in a pilot phase II study.

Epidermal growth factor receptor (EGFR) mutations are commonly observed in Glioblastoma (GBM) and have long posed as a target for new therapies. Trials involving erlotinib have shown mixed results, likely owing to a mechanism of the mutation that may instead favor other EGFR inhibitors, such as lapatinib. We aimed to determine whether or not pulse high-dose lapatinib was a safe and tolerable regimen in addition to standard therapy. We recruited adult patients with newly-diagnosed GBM who had Karnofsky Performance Status ≥60, normal baseline hematological, hepatic, and renal function tests, and no prior history of radiation or treatment with EGFR inhibitor. Lapatinib was administered at 2500 mg twice daily for two consecutive days per week on a weekly basis throughout concomitant and adjuvant standard therapy. The primary endpoints were tolerability and safety. 12 patients were enrolled in this study over 2 years. Of the non-hematological adverse events, there were 2 grade 3 events, fatigue and post-radiation cystic brain necrosis. The most common adverse events in general were fatigue, rashes, and diarrhea. Of the hematological adverse events, there were 13 grade 3 events, all of which were due to lymphopenia and affected 6 of 12 patients. Pulse high-dose lapatinib in addition to standard therapy for newly-diagnosed GBM is a tolerable and safe regimen, but higher rates of lymphopenia should be noted. However, further investigations will be required to evaluate the efficacy of this combination for the treatments of GBM. Trial registration ClinicalTrials.gov Identifier: NCT01591577.

Monitoring and switching patterns of patients with chronic myeloid leukemia treated with imatinib in community settings: a chart review analysis.

OBJECTIVES: Monitoring treatment response is an integral part of chronic myeloid leukemia (CML) treatment. The guidelines recommend regular monitoring using standard methods (e.g., real-time quantitative polymerase chain reaction based on the international scale for molecular response) and treatment adjustment when failure is detected among patients treated with imatinib. The objective of this study was to assess the real-world monitoring and therapy adjustment in this patient population in the US. METHODS: Twenty-nine physicians from community practices across the US participated in an online chart review. Adult patients with chronic phase CML who initiated imatinib as first-line therapy during 2006-2010 were selected. Information was collected up to 36 months after imatinib initiation, including response monitoring, response status, and therapy adjustment upon treatment failure. RESULTS: The study included 297 eligible patients. By 18 months, 47% of patients had received cytogenetic response assessment continuously as recommended by the guidelines. The corresponding proportion was 39% for continuous molecular response assessment. Among patients who experienced treatment failure by 18 months, only 14%-38% of patients switched to a second-generation tyrosine kinase inhibitor as recommended by the National Comprehensive Cancer Network and the European Leukemia Net guidelines. LIMITATIONS: Major limitations included limited generalizability and the inability to accurately assess molecular response due to the variations in testing methods during the study period. CONCLUSIONS: Based on the guidelines, the rates of treatment monitoring and switching upon failure were low, demonstrating the need for improvement in CML care in community settings in the US.

Treatment patterns and economic burden of metastatic and recurrent locally-advanced head and neck cancer patients.

OBJECTIVE: To characterize treatment patterns and measure the economic burden associated with metastatic (mHNC) and recurrent, locally-advanced head and neck cancer (rHNC). METHODS: Administrative claims from Medicare- and privately-insured individuals during 2004-2008 were used in this retrospective database study of patients with advanced HNC. Patients diagnosed with HNC were matched 1:1 to cancer-free controls to measure the incremental economic burden of HNC. Outcomes of interest were measured during the 6 months following the date of a secondary tumor diagnosis for metastatic patients or the date of a diagnosis indicating rHNC. To assess treatment patterns, HNC patients were evaluated for the use frequency of treatments (radiotherapy, chemotherapy and surgery). Costs were reported in 2008 US$ from a third-party payer perspective and were analyzed using generalized linear models and two-part regression models adjusting for differences in age and baseline Charlson Comorbidity Index (excluding cancer diagnoses) between the HNC and control cohorts. Components of cost included inpatient, outpatient and other medical services as well as pharmacy costs. RESULTS: The mHNC cohort consisted of 1042 patients and the rHNC cohort included 324 patients. The most common treatments for mHNC patients were supportive care (90.2%), radiation therapy (48.5%), surgery (41.9%) and chemotherapy (38.3%). Patients with rHNC frequently received HNC-related supportive care (71.0%), radiation therapy (67.9%) and chemotherapy (27.2%); HNC-related surgery was infrequent (12.7%) during the study period. The 6-month incremental adjusted total costs were $60,414 per patient for mHNC and $21,141 per patient for rHNC (p<0.0001). Approximately 46-58% of the incremental cost was attributable to outpatient visits, 27-37% to inpatient costs and 11-13% to pharmacy, depending on the HNC cohort. LIMITATIONS: The identification of mHNC/rHNC was based on diagnosis codes and treatment patterns with the limitation of the claims database. CONCLUSIONS: Metastatic and recurrent, locally-advanced HNC patients frequently receive cancer-related treatments and incur substantial economic burden.

Effect of adalimumab on clinical laboratory parameters in patients with Crohn's disease: results from the CHARM trial.

BACKGROUND: Nutritional deficiencies and anemia are common in Crohn's disease (CD). METHODS: We evaluated the effect of adalimumab on changes in laboratory values using data from CHARM, in which patients were randomized to adalimumab 40 mg every other week (eow), adalimumab 40 mg weekly, or placebo for 56 weeks. Mean changes in laboratory values from baseline to Weeks 26 and 56 were compared between adalimumab and placebo using analysis of covariance models. Percentages of patients with suboptimal laboratory values at Weeks 26 and 56 were compared between treatment groups using Cochran-Mantel-Haenszel (CMH) tests. Pearson correlation coefficients for associations between changes in Crohn's Disease Activity Index (CDAI) score and changes in laboratory values were estimated at Weeks 4, 26, and 56. RESULTS: The intention-to-treat analysis included 778 patients randomized to adalimumab eow (N = 260), adalimumab weekly (N = 257), or placebo (N = 261). Baseline abnormalities in laboratory values were common across treatment groups. CMH tests revealed significantly lesser rates of suboptimal laboratory values with adalimumab vs. placebo at Week 26, including hypoalbuminemia, calcium deficiency, low hemoglobin, low hematocrit, low red blood cell count, elevated platelet count, and elevated C-reactive protein concentration (all P < 0.05). These improvements persisted at Week 56. Improvements in CDAI from baseline to Weeks 4, 26, and 56 were significantly correlated with changes from baseline for albumin, hemoglobin, and C-reactive protein (all P < 0.001). CONCLUSIONS: Adalimumab therapy for moderately to severely active CD was associated with significant improvements in nutritional, hematologic, and inflammatory markers.

Quantitative characterization of bone marrow edema pattern in rheumatoid arthritis using 3 Tesla MRI.

PURPOSE: To develop imaging techniques that provide quantitative characterization of bone marrow edema pattern (BME) in wrist joints of patients with rheumatoid arthritis (RA), including volume, signal intensity changes, and perfusion properties. MATERIALS AND METHODS: Fourteen RA patients and three controls were scanned using 3 Tesla MR. BME was semi-automatically segmented in water images obtained from iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) sequences. BME perfusion parameters (enhancement and slope) were evaluated using three-dimensional (3D) dynamic enhanced MRI (DCE-MRI). Experimental reproducibility, inter- and intra-observer reproducibility of BME quantification were evaluated using root mean square coefficients of variation (RMS-CV) and intraclass correlation (ICC). RESULTS: The RMS-CV for BME volume quantification with repeated scans were 6.9%. The inter-observer ICC was 0.993 and RMS CV was 5.2%. The intra-observer ICC was 0.998 and RMS CV was 2.3%. Both maximum enhancement and slope during DCE-MRI were significantly higher in BME than in normal bone marrow (P < 0.001). No significant correlation was found between BME quantification and clinical evaluations. CONCLUSION: A highly reproducible semi-automatic method for quantifying BME lesion burden in RA was developed, which may enhance our capability of predicting disease progression and monitoring treatment response.

Comorbidity burden, healthcare resource utilization, and costs in chronic gout patients refractory to conventional urate-lowering therapy.

Patients with chronic gout refractory to conventional urate-lowering therapy have high rates of flares and incidence of tophi, which impose a significant disease and potentially economic burden. This study examined healthcare resource use and costs stratified by disease burden. Adult patients diagnosed with gout (ICD-9-CM:274.xx) and having had ≥3 flares defined by clinical surrogates within a 12-month period were selected for the case cohort from the Thomson MarketScan databases (2003/Q3-2008/Q3). Only patients who had received allopurinol treatment and a diagnosis of tophi (ICD-9-CM:274.8x) at any time before the first flare (index date) or within 12 months postindex were included and were matched in a 1:1 ratio with control gout-free subjects. The comorbidity burden, healthcare resource use, and annual healthcare costs (2008 US$) in the 12-month postindex period were compared between both cohorts using regression models adjusted for demographic characteristic and stratified for patients with ≥6 flares. A total of 679 gout patients met the inclusion criteria for the study and had a higher prevalence of comorbidities than their matched controls. Gout cohort had a significantly higher incidence of emergency room, hospitalizations, outpatient visits, and other medical services than did their matched controls (all comparisons, uncorrected P < 0.01). After adjusting for baseline characteristics, the refractory gout cohort incurred an incremental total annual healthcare cost of $10,222 where 40% of the annual medical cost was for gout-related care compared with control cohort (P < 0.01). Patients with refractory gout have a significant economic burden compared with a gout-free population.

Economic evaluation of denosumab compared with zoledronic acid in hormone-refractory prostate cancer patients with bone metastases.

BACKGROUND: Bone metastases are common in patients with hormone-refractory prostate cancer. In a study of autopsies of patients with prostate cancer, 65%-75% had bone metastases. Bone metastases place a substantial economic burden on payers with estimated total annual costs of $1.9 billion in the United States. Skeletal-related events (SREs), including pathologic fractures, spinal cord compression, surgery to bone, and radiation to bone, affect approximately 50% of patients with bone metastases. They are associated with a decreased quality of life and increased health care costs. Zoledronic acid is an effective treatment in preventing SREs in solid tumors and multiple myeloma. Recently, denosumab was FDA-approved for prevention of SREs in patients with bone metastases from solid tumors. A Phase 3 clinical trial (NCT00321620) demonstrated that denosumab had superior efficacy in delaying first and subsequent SREs compared with zoledronic acid. However, the economic value of denosumab has not been assessed in patients with hormone-refractory prostate cancer. OBJECTIVE: To compare the cost-effectiveness of denosumab with zoledronic acid in the treatment of bone metastases in men with hormone-refractory prostate cancer. METHODS: An Excel-based Markov model was developed to assess costs and effectiveness associated with the 2 treatments over a 1- and 3-year time horizon. Because the evaluation was conducted from the perspective of a U.S. third-party payer, only direct costs were included. Consistent with the primary outcome in the Phase 3 trial, effectiveness was assessed based on the number of SREs. The model consisted of 9 health states defined by SRE occurrence, SRE history, disease progression, and death. A hypothetical cohort of patients with hormone-refractory prostate cancer received either denosumab 120 mg or zoledronic acid 4 mg at the model entry and transitioned among the 9 health states at the beginning of each 13-week cycle. Transition probabilities associated with experiencing the first SRE, subsequent SREs, disease progression, and death were primarily derived from the results of the Phase 3 clinical trial and were supplemented with published literature. The model assumed that a maximum of 1 SRE could occur in each cycle. Drug costs included wholesale acquisition cost, health care professional costs associated with drug administration, and drug monitoring costs, if applicable. Nondrug costs included incremental costs associated with disease progression, costs associated with SREs, and terminal care costs, which were derived from the literature. Adverse event (AE) costs were estimated based on the incidence rates reported in the Phase 3 trial. Resource utilization associated with AEs was estimated based on consultation with a senior medical director employed by the study sponsor. All costs were presented in 2010 dollars. The base case estimated the incremental total cost per SRE avoided over a 1-year time horizon. Results for a 3-year time horizon were also estimated. One-way sensitivity analyses and probabilistic sensitivity analyses (PSA) were performed to test the robustness of the model. RESULTS: In the base case, the total per patient costs incurred over 1 year were estimated at $35,341 ($19,230 drug costs and $16,111 nondrug costs) for denosumab and $27,528 ($10,960 drug costs and $16,569 nondrug costs) for zoledronic acid, with an incremental total direct cost of $7,813 for denosumab. The estimated numbers of SREs per patient during the 1-year period were 0.49 for denosumab and 0.60 for zoledronic acid, resulting in an incremental number of SREs of -0.11 in the denosumab arm. The estimated incremental total direct costs per SRE avoided with the use of denosumab instead of zoledronic acid were $71,027 for 1 year and $51,319 for 3 years. The 1-way sensitivity analysis indicated that the results were sensitive to the drug costs, median time to first SRE, and increased risk of SRE associated with disease progression. Results of the PSA showed that based on willingness-to-pay thresholds of $70,000, $50,000, and $30,000 per SRE avoided, respectively, denosumab was cost-effective compared with zoledronic acid in 49.5%, 17.5%, and 0.3% of the cases at 1 year, respectively, and 79.0%, 49.8%, and 4.1% of the cases at 3 years, respectively. CONCLUSIONS: Although denosumab has demonstrated benefits over zoledronic acid in preventing or delaying SREs in a Phase 3 trial, it may be a costly alternative to zoledronic acid from a U.S. payer perspective.

Healthcare costs associated with bevacizumab and cetuximab in second-line treatment of metastatic colorectal cancer.

OBJECTIVE: To compare the health care costs of patients with metastatic colorectal cancer (mCRC) who received second-line treatment with Avastin (bevacizumab) versus Erbitux (cetuximab), from the third-party payer's perspective. METHODS: Patients with mCRC were selected from the PharMetrics claims database if they received second-line therapy containing either bevacizumab (second-line bevacizumab cohort) or cetuximab (second-line cetuximab cohort). Six-month costs following second-line therapy start date and average monthly healthcare costs while on second-line therapy (in 2009 US$) were calculated and compared between the two groups. RESULTS: A total of 2188 patients with mCRC who met the eligibility criteria were included in the analysis, including 1808 patients receiving bevacizumab and 380 patients receiving cetuximab in second-line treatment. Demographic and baseline characteristics were similar between the two groups. Patients' mean age was 61 years and 56% were males. In second-line treatment, bevacizumab was commonly used with oxaliplatin (43.5%) and irinotecan-based regimens (40.4%), whereas cetuximab was commonly used with irinotecan-based regimens (68.2%). Bevacizumab patients had significantly lower total all-cause healthcare costs than cetuximab patients (adjusted difference: -$10,231, p = 0.020), and lower medical costs (-$10,796, p = 0.012) during the 6 months following second-line therapy initiation. Approximately half of the difference in total all-cause healthcare costs was attributable to the lower chemotherapy and targeted therapy costs (-$5635, p = 0.032) of bevacizumab patients than those of cetuximab patients. While on second-line therapy, bevacizumab patients also had lower average monthly all-cause healthcare costs than cetuximab patients. LIMITATIONS: Second-line treatment in the current study was defined based on changes in mCRC medications, not based on disease progression due to the limited clinical information available in claims. CONCLUSION: The use of bevacizumab in second-line therapy was associated with significantly lower healthcare costs in mCRC patients, compared to the use of cetuximab.

Comparison of skeletal complications and treatment patterns associated with early vs. delayed zoledronic acid therapy in multiple myeloma.

BACKGROUND: This study retrospectively compared the risks of skeletal-related events (SREs) and zoledronic acid (ZOL) treatment discontinuation associated with early vs. delayed ZOL therapy for patients with symptomatic multiple myeloma (MM). PATIENTS AND METHODS: Data were collected from a physician-administered medical chart review among US patients with a confirmed diagnosis of symptomatic MM treated after 01/01/2002. Early and delayed ZOL therapy were defined, respectively, as initiating ZOL ≤ 60 days (N = 126) vs. > 60 days (N = 186) after the first symptomatic MM diagnosis. Kaplan-Meier analysis with a log-rank test was performed to compare the risk of SREs between the cohorts. Cox proportional hazard modeling compared the risk of SREs associated with early vs. delayed ZOL treatment, controlling for demographic factors, stage of MM, bone health status, and presence of major comorbidities at diagnosis. Time to ZOL discontinuation was evaluated using the Kaplan-Meier method, following patients from the date of ZOL initiation. RESULTS: Time to the first SRE was significantly longer for patients who received early treatment with ZOL (P = .005). At 2 years after diagnosis, the SRE-free rate was 74.6% vs. 56.5% in the early vs. delayed treatment group, respectively. Early ZOL therapy was associated with a significantly lower risk of any SRE (hazard rate [HR] = .625 vs. delayed ZOL therapy; P = .029). At 2 years from ZOL therapy initiation, rates of ZOL discontinuation were 9.6% vs. 16.4% among patients with early vs. delayed therapy, respectively (P < .05). CONCLUSION: Early treatment with ZOL was associated with significantly reduced risks of SREs and with better treatment persistence compared with delayed treatment.

Increased risks of developing anxiety and depression in young patients with Crohn's disease.

OBJECTIVES: Crohn's disease (CD) is associated with substantial psychosocial burden and increased risks for mental health disorders. This retrospective cohort study compared the risks of developing anxiety disorders and depression and incidences of psychotropic medication use between young CD patients and matched CD-free controls. METHODS: Medical claims, prescription drug claims, enrollment, and demographic data for patients <18 years diagnosed with CD were obtained from the MarketScan database (1 January 2000-30 June 2006). Each CD patient was matched with five CD-free controls based on exact age, sex, and months of health plan enrollment. Incidence rates and risks of developing anxiety disorders and depression and psychotropic medication use in the 6 months after the index date were compared, as were risks of developing persistent anxiety or depression (receiving medical services related to a diagnosis of anxiety or depression or psychotropic therapy for >1 year). RESULTS: After adjustment for patient characteristics, the risks of developing anxiety disorders (hazard ratio (HR) [95% confidence interval (CI);[equals;2.28 [1.65-3.17]) and depression (HR [95% CI;[equals;1.74 [1.35-2.25]) after CD diagnosis were significantly greater for the CD cohort (N=2,144) than for CD-free controls (N=10,720). Patients with CD also had greater risks of developing persistent anxiety and persistent depression (HR [95% CI;[equals;4.35 [2.22-8.50] and 2.75 [1.73-4.38], respectively). CONCLUSIONS: Compared with matched CD-free controls, young patients with CD had significantly greater risks of developing anxiety disorders and depression, were more likely to receive psychotropic treatments, and had significantly greater risks of developing persistent anxiety and depression.

Demographic and laboratory data may predict positive temporal artery biopsy.

BACKGROUND: Temporal artery biopsy is performed in patients suspected of having giant cell arteritis. This study was conducted to evaluate clinical and laboratory criteria correlating with positive biopsy results in an effort to limit the number of negative biopsies performed. METHODS: A retrospective review was performed of patients who underwent temporal artery biopsy at two urban medical centers from 2002 to 2009. A multivariate analysis of patient demographics, clinically relevant signs and symptoms, laboratory data, and pathologic outcomes was performed. RESULTS: Temporal artery biopsy histologically confirmed giant cell arteritis in 24% of cases. The mean age of those with disease was 77.8 y and those without were 73.1 y; age was found to be statically significant (P = 0.0227); 76% were female and 24% were male; gender was not significant (P = 0.9594); 42% were Caucasian (39% had a positive temporal artery biopsy), 27% were Hispanic (17% positive), and 31% of the patients were African-American (3% positive); ethnicity was significant (P = 0.0005). The PPV of elevated ESR was 27%; sensitivity was 100%; specificity was 16%. A history of headache or visual disturbance was not predictive of a positive biopsy CONCLUSION: Fewer negative biopsy results may be achieved by screening patients with normal ESR or lower risk patients with other modalities.

Retrospective real-world comparison of medical visits, costs, and adherence between nilotinib and dasatinib in chronic myeloid leukemia.

OBJECTIVE: To compare healthcare resource utilization, costs, and treatment adherence associated with dasatinib versus nilotinib treatment as second-line therapies in chronic myeloid leukemia (CML) patients. METHODS: Two large retrospective claims databases (01/1999-06/2009) were combined to identify CML patients (ICD-9 code 205.1x) who received one or more prescriptions of dasatinib or nilotinib. Studied patients had continuous enrollment ≥ 1 month prior to and after the index date, defined as the first prescription for dasatinib or nilotinib. Patients were followed for up to 6 months from the index date to the earliest of the termination of healthcare plan enrollment or end of data availability. Patients with bone marrow or stem cell transplant during the study period were excluded. Poisson regression models were used to compare healthcare resource utilization between the two groups. Results were reported as incidence rate ratios (IRR). Healthcare cost differences were estimated for each cost component using generalized linear models or two-part models. Treatment adherence was measured by the proportion of days covered (PDC) and compared using generalized linear models. Multivariate regressions were used to control for potential confounding factors. RESULTS: A total of 521 CML patients receiving second-line tyrosine kinase inhibitors (TKI) (452 dasatinib and 69 nilotinib) were studied. During the study period, dasatinib patients were estimated to have more than twice as many inpatient days (IRR = 2.44; p < 0.001) and nearly double the number of inpatient admissions (IRR = 1.99; p = 0.047) compared to nilotinib patients. Over the follow-up period, dasatinib patients incurred $8828 more in total medical service costs (p < 0.001); cost differences were mainly driven by an adjusted inpatient cost difference of $8520 (p = 0.003). Dasatinib patients were less adherent, with a PDC value approximately 13% lower compared to nilotinib patients (p = 0.009). CONCLUSIONS: Among CML patients treated with second-line TKIs, nilotinib patients were more adherent and experienced lower healthcare resource utilization, resulting in medical service cost savings compared to dasatinib patients.

Comparative effectiveness without head-to-head trials: a method for matching-adjusted indirect comparisons applied to psoriasis treatment with adalimumab or etanercept.

The absence of head-to-head trials is a common challenge in comparative effectiveness research and health technology assessment. Indirect cross-trial treatment comparisons are possible, but can be biased by cross-trial differences in patient characteristics. Using only published aggregate data, adjustment for such biases may be impossible. Although individual patient data (IPD) would permit adjustment, they are rarely available for all trials. However, many researchers have the opportunity to access IPD for trials of one treatment, a new drug for example, but only aggregate data for trials of comparator treatments. We propose a method that leverages all available data in this setting by adjusting average patient characteristics in trials with IPD to match those reported for trials without IPD. Treatment outcomes, including continuous, categorical and censored time-to-event outcomes, can then be compared across balanced trial populations. The proposed method is illustrated by a comparison of adalimumab and etanercept for the treatment of psoriasis. IPD from trials of adalimumab versus placebo (n = 1025) were re-weighted to match the average baseline characteristics reported for a trial of etanercept versus placebo (n = 330). Re-weighting was based on the estimated propensity of enrolment in the adalimumab versus etanercept trials. Before matching, patients in the adalimumab trials had lower mean age, greater prevalence of psoriatic arthritis, less prior use of systemic treatment or phototherapy, and a smaller mean percentage of body surface area affected than patients in the etanercept trial. After matching, these and all other available baseline characteristics were well balanced across trials. Symptom improvements of ≥75% and ≥90% (as measured by the Psoriasis Area and Severity Index [PASI] score at week 12) were experienced by an additional 17.2% and 14.8% of adalimumab-treated patients compared with the matched etanercept-treated patients (respectively, both p < 0.001). Mean percentage PASI score improvements from baseline were also greater for adalimumab than for etanercept at weeks 4, 8 and 12 (all p < 0.05). Matching adjustment ensured that this indirect comparison was not biased by differences in mean baseline characteristics across trials, supporting the conclusion that adalimumab was associated with significantly greater symptom reduction than etanercept for the treatment of moderate to severe psoriasis.