Lost in the plot: missing visual elements in Kaplan-Meier plots of phase III oncology trials.

Missing visual elements (MVE) in Kaplan-Meier (KM) curves can misrepresent data, preclude curve reconstruction, and hamper transparency. This study evaluated KM plots of phase III oncology trials. MVE were defined as an incomplete y-axis range or missing number at risk table in a KM curve. Surrogate endpoint KM curves were additionally evaluated for complete interpretability, defined by (1) reporting the number of censored patients and (2) correspondence of the disease assessment interval with the number at risk interval. Among 641 trials enrolling 518 235 patients, 116 trials (18%) had MVE in KM curves. Industry sponsorship, larger trials, and more recently published trials were correlated with lower odds of MVE. Only 3% of trials (15 of 574) published surrogate endpoint KM plots with complete interpretability. Improvements in the quality of KM curves of phase III oncology trials, particularly for surrogate endpoints, are needed for greater interpretability, reproducibility, and transparency in oncology research.

Editorial Commentary: Augmentation With Allograft Patch Results in Similar Outcomes to Anterior Cable Reconstruction With Autograft Biceps Tendon for Chronic, Retracted, Anterior, L-Shaped Supraspinatus Tears.

Chronic retracted rotator cuff tears are difficult entities to treat. L-shaped tears are a particular subset of such rotator cuff tears that pose challenges for surgeons attempting to reduce the supraspinatus tendon back to the greater tuberosity. Lack of full coverage of the tuberosity, need for medialization of the tendon, undue tension, and incomplete reconstitution of the rotator cable are some of the reasons L-shaped retracted tears of the supraspinatus can be challenging. Anterior cable reconstruction (ACR) is a technique that has gained increasing recent popularity, as is the use of patch augmentation. The long head of the biceps tendon is often readily available for use in ACR, but when it isn't, patch augmentation is an option for partially repairable rotator cuff tears. These produce similar postoperative improvements in range of motion as well as Constant and American Shoulder and Elbow Surgeons scores, but comparison to partial repair is still unknown.

Effectiveness of the nutrition referral system in a multidisciplinary pancreatic cancer clinic.

PURPOSE: Proactive nutrition screening and intervention is associated with improved outcomes for patients with pancreatic adenocarcinoma (PDAC). To better optimize nutrition amongst our PDAC population, we implemented systematic malnutrition screening in the Johns Hopkins pancreas multidisciplinary clinic (PMDC) and assessed the effectiveness of our nutrition referral system. METHODS: This was a single institution prospective study of patients seen in the PMDC, screened for malnutrition using the Malnutrition Screening Tool (MST) (score range=0 to 5, score > 2 indicates risk of malnutrition), and offered referrals to the oncology dietitian. Patients that requested a referral but did not attend a nutrition appointment were contacted by phone to assess barriers to seeing the dietitian. Univariate (UVA) and multivariable (MVA) analyses were carried out to identify predictors of referral status and appointment completion status. RESULTS: A total of 97 patients were included in the study, of which 72 (74.2%) requested a referral and 25 (25.8%) declined. Of the 72 patients who requested a referral, 31 (43.1%) attended an appointment with the oncology dietitian. Data on information session attendance was available for 35 patients, of which 8 (22.9%) attended a pre-clinic information session in which the importance of optimal nutrition was highlighted. On MVA, information session attendance was significantly associated with requesting a referral (OR: 11.1, 95% CI 1.12-1.0E3, p=0.037) and successfully meeting with the oncology dietitian (OR: 5.88, 95% CI 1.00-33.3, p=0.049). CONCLUSION: PMDC teams should institute educational initiatives on the importance of optimal nutrition in order to increase patient engagement with nutrition services.

Editorial Commentary: There Is No Standard for or Standardization of Postoperative Rehabilitation Protocols After Anterior Cruciate Ligament Reconstruction.

The anterior cruciate ligament (ACL) is the most studied ligament in the knee and one of the most studied topics in orthopaedics, with little consensus on best options for surgical technique or graft choice. While there is little question that physical rehabilitation is one of the most important variables in the episode of care before and after ACL reconstruction (ACLR), recent research surveying orthopaedic surgeons demonstrates no consensus of how to rehab ACLR patients and how to get them to return to sport safely and quickly. Seventy-two percent of surgeons prescribe "pre-hab" prior to ACLR, and 83% of surgeons use postoperative bracing, with most (55%) bracing for 3 to 6 weeks postoperatively. Patient-reported outcome measures (35%) and assessments of psychological readiness (23%) are not commonly used to progress patients through the stages of rehab. When asked what they believe is the single most important factor in unrestricted return to sport, 52% of surgeons stated functional testing scores were most important, while 38% stated time since surgery, and 5% stated muscle strength. As for average time to return to full activity, 50% of surgeons waited until 9+ months for full return, and 42% allowed return within 6 to 8 months. Reductions in practice variability have been shown in orthopaedic surgery and other fields to reduce costs of care delivery and improve patient outcomes, and with so much variability in ACLR rehabilitation protocols, the orthopaedic community would be wise to strive for more consensus focused on evidence-based recommendations for rehabilitation and to fill in knowledge gaps with focused, high-quality research where needed.

Food and Drug Administration approvals in phase 3 Cancer clinical trials.

BACKGROUND: Phase 3 oncologic randomized clinical trials (RCTs) can lead to Food and Drug Administration (FDA) approvals. In this study, we aim to identify trial-related factors associated with trials leading to subsequent FDA drug approvals. METHODS: We performed a database query through the ClinicalTrials.gov registry to search for oncologic phase 3 RCTs on February 2020. We screened all trials for therapeutic, cancer-specific, phase 3, randomized, multi-arm trials. We then identified whether a trial was used for subsequent FDA drug approval through screening of FDA approval announcements. RESULTS: In total, 790 trials were included in our study, with 225 trials (28.4%) generating data that were subsequently used for FDA approvals. Of the 225 FDA approvals identified, 65 (28.9%) were based on trials assessing overall survival (OS) as a primary endpoint (PEP), two (0.9%) were based on trials with a quality of life (QoL) PEP, and 158 approvals (70.2%) were based on trials with other PEP (P = 0.01). FDA approvals were more common among industry funded-trials (219, 97.3%; P < 0.001), and less common among trials sponsored by national cooperative groups (21, 9.3%; P < 0.001). Finally, increased pre-hoc power and meeting patients' accrual target were associated with FDA approvals (P < 0.001). CONCLUSIONS: The majority of FDA approvals are based on data generated from trials analyzing surrogate primary endpoints and trials receiving industry funding. Additional studies are required to understand the complexity of FDA approvals.

Genetic Network Analysis to Assess the Risk of Human Immunodeficiency Virus Transmission Among Men Who Have Sex With Men Seeking Partners on the Internet.

BACKGROUND: Online partner seeking (OPS) among men who have sex with men (MSM) is associated with increased risk behavior including frequency of unprotected anal intercourse, number of partners, and incidence of sexually transmitted infections (STIs). However, the impact on transmission of human immunodeficiency virus (HIV) is uncertain. METHODS: MSM diagnosed with acute and early HIV infection were recruited from the Primary Infection Resource Consortium. HIV transmission events in the year following infection were inferred using estimated date of infection combined with genetic network analysis with linked sequences defined as ≤0.015 sequences/site difference in the HIV type 1 (HIV-1) pol coding region. Participants completed a detailed baseline questionnaire including reported methods of meeting sexual partners, including OPS, in the prior 3 months, and regression was performed with inferred transmission as the outcome. RESULTS: From 147 MSM who completed the questionnaire, there were an associated 20 inferred HIV transmissions. No association with OPS was found (odds ratio, 0.64 [95% confidence interval, .24-1.69]; P = .37), though individuals who reported OPS were more likely to have reported a greater number of partners (P = .003) and prior STIs (P = .002). Geospatial analysis did not indicate that OPS was associated with increased geographical reach of the user (P = .68). CONCLUSIONS: Individuals reporting OPS did not have increased odds of inferred HIV-1 transmission in the year following infection using genetic linkage analysis despite apparently increased risk behavior. OPS also did not increase the geographic distance between genetically clustered HIV infections, suggesting that individuals mainly use the internet to meet partners in their local region.

Validation of the San Diego Early Test Score for Early Human Immunodeficiency Virus Infection Among Amsterdam Men Who Have Sex With Men.

The San Diego Early Test score is a simple risk-assessment tool for acute, and early human immunodeficiency virus (HIV) infection. Validation in a prospective cohort of Amsterdam men who have sex with men showed fair prediction of HIV seroconversion (AUC, 0.701). This score can help prioritize and target HIV-prevention strategies.

Exclusion of Men from Randomized Phase III Breast Cancer Clinical Trials.

Male breast cancer treatment regimens are often extrapolated from female-based studies because of a paucity of literature analyzing male breast cancer. Using ClinicalTrials.gov, we analyzed breast cancer randomized clinical trials (RCTs) to determine which factors were associated with male-gender inclusion. Of 131 breast cancer RCTs identified, male patients represented 0.087% of the total study population, which is significantly less than the proportion of male patients with breast cancer in the U.S. (0.95%; p < .001). Twenty-seven trials included male patients (20.6%). Lower rates of male inclusion were seen in trials that randomized or mandated hormone therapy as part of the trial protocol compared with trials that did not randomize or mandate endocrine therapy (2.5% vs. 28.6% male inclusion; p < .001). It is imperative for breast cancer clinical trials to include men when allowable in order to improve generalizability and treatment decisions in male patients with breast cancer.

Professional Medical Writer Assistance in Oncology Clinical Trials.

BACKGROUND: The use of professional medical writers (PMWs) has been historically low, but contemporary data regarding PMW usage are scarce. In this study, we sought to quantify PMW use in oncologic phase III randomized controlled trials (RCTs). METHODS: We performed a database query through ClinicalTrials.gov to identify cancer-specific phase III RCTs; we then identified whether a PMW was involved in writing the associated trial manuscript reporting primary endpoint results. RESULTS: Two-hundred sixty trials of 600 (43.3%) used a PMW. Industry-funded trials used PMWs more often than nonindustry trials (54.9% vs. 3.0%, p < .001). Increased PMW usage was further noted among trials meeting their primary endpoint (53.4% vs. 32.9%, p < .001) and trials that led to subsequent Food and Drug Administration approval (63.1% vs. 36.3%, p < .001). By treatment interventions, PMW use was highest among systemic therapy trials (50.2%). Lastly, the use of PMWs increased significantly over time (odds ratio: 1.11/year, p = .001). CONCLUSION: PMW use rates are high among industry-funded trials. We urge continued and increased transparency in reporting the funding and use of PMWs.

Tobacco exposure as a major modifier of oncologic outcomes in human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma.

BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) in the US is rapidly increasing, driven largely by the epidemic of human papillomavirus (HPV)-mediated OPSCC. Although survival for patients with HPV mediated OPSCC (HPV+ OPSCC) is generally better than that of patients with non-virally mediated OPSCC, this effect is not uniform. We hypothesized that tobacco exposure remains a critical modifier of survival for HPV+ OPSCC patients. METHODS: We conducted a retrospective analysis of 611 OPSCC patients with concordant p16 and HPV testing treated at a single institute (2002-2013). Survival analysis was performed using Kaplan-Meier analysis and Cox regression. Recursive partitioning analysis (RPA) was used to define tobacco exposure associated with survival (p < 0.05). RESULTS: Tobacco exposure impacted overall survival (OS) for HPV+ patients on univariate and multivariate analysis (p = 0.002, p = 0.003 respectively). RPA identified 30 pack-years (PY) as a threshold at which survival became significantly worse in HPV+ patients. OS and disease-free survival (DFS) for HPV+ > 30 PY patients didn't differ significantly from HPV- patients (p = 0.72, p = 0.27, respectively). HPV+ > 30 PY patients had substantially lower 5-year OS when compared to their ≤30 PYs counterparts: 78.4% vs 91.6%; p = 0.03, 76% vs 88.3%; p = 0.07, and 52.3% vs 74%; p = 0.05, for stages I, II, and III (AJCC 8th Edition Manual), respectively. CONCLUSIONS: Tobacco exposure can eliminate the survival benefit associated with HPV+ status in OPSCC patients. Until this effect can be clearly quantified using prospective datasets, de-escalation of treatment for HPV + OPSCC smokers should be avoided.

Performance Status Restriction in Phase III Cancer Clinical Trials.

BACKGROUND: Patients with good performance status (PS) tend to be favored in randomized clinical trials (RCTs), possibly limiting the generalizability of trial findings. We aimed to characterize trial-related factors associated with the use of PS eligibility criteria and analyze patient accrual breakdown by PS. METHODS: Adult, therapeutic, multiarm phase III cancer-specific RCTs were identified through ClinicalTrials.gov. PS data were extracted from articles. Trials with a PS restriction ECOG score ≤1 were identified. Factors associated with PS restriction were determined, and the use of PS restrictions was analyzed over time. RESULTS: In total, 600 trials were included and 238,213 patients had PS data. Of those trials, 527 studies (87.8%) specified a PS restriction cutoff, with 237 (39.5%) having a strict inclusion criterion (ECOG PS ≤1). Enrollment criteria restrictions based on PS (ECOG PS ≤1) were more common among industry-supported trials (P<.001) and lung cancer trials (P<.001). Nearly half of trials that led to FDA approval included strict PS restrictions. Most patients enrolled across all trials had an ECOG PS of 0 to 1 (96.3%). Even among trials that allowed patients with ECOG PS ≥2, only 8.1% of those enrolled had a poor PS. Trials of lung, breast, gastrointestinal, and genitourinary cancers all included <5% of patients with poor PS. Finally, only 4.7% of patients enrolled in trials that led to subsequent FDA approval had poor PS. CONCLUSIONS: Use of PS restrictions in oncologic RCTs is pervasive, and exceedingly few patients with poor PS are enrolled. The selective accrual of healthier patients has the potential to severely limit and bias trial results. Future trials should consider a wider cancer population with close toxicity monitoring to ensure the generalizability of results while maintaining patient safety.

Relationship between treatment center case volume and survival for localized Ewing sarcoma: The role of radiotherapy timing.

In the treatment of localized Ewing sarcoma (EWS), delays in local therapy are known to adversely impact overall survival (OS). However, the role of treatment center volume in EWS outcomes, and the interaction between center volume and local therapy timing with definitive radiotherapy, remains unknown. Using the National Cancer Database, we demonstrate that treatment at the lowest EWS volume centers is associated with reduced OS, explained partly by higher rates of delayed local therapy. Treatment at the highest volume centers results in improved OS, but appears independent of radiotherapy timing. Future efforts to improve care for EWS patients across treatment centers are imperative.

Non-English language validation of patient-reported outcome measures in cancer clinical trials.

Patient-reported outcome measures (PROMs) are increasingly incorporated as endpoints in oncology clinical trials but are often only validated in English. ClinicalTrials.gov was queried for cancer-specific randomized control trials (RCTs) addressing a therapeutic intervention and enrolling primarily in the USA. Peer-reviewed validation of Spanish and Chinese versions of each PROM was assessed. Of 103 eligible trials, a PROM was used as a primary endpoint in 25 RCTs (24.3%) and as a secondary endpoint in 78 RCTs (75.7%). A total of 61 of the 103 eligible trials (59.2%) and 17 of the 25 trials with a PROM primary endpoint (68.0%) used a PROM with either no Spanish or Chinese validation. The absence of validated PROM translations may diminish the voices of non-English language speaking trial participants. With an increasingly diverse US population, validation of non-English PROM translations may decrease disparities in trial participation and improve generalizability of study results.

Radiographic retropharyngeal lymph node involvement in HPV-associated oropharyngeal carcinoma: Patterns of involvement and impact on patient outcomes.

BACKGROUND: The objective of the current study was to characterize the incidence, pattern, and impact on oncologic outcomes of retropharyngeal lymph node (RPLN) involvement in HPV-associated oropharyngeal cancer (OPC). METHODS: Data regarding patients with HPV-associated OPC who were treated at The University of Texas MD Anderson Cancer Center with intensity-modulated radiotherapy from 2004 through 2013 were analyzed retrospectively. RPLN status was determined by reviewing pretreatment imaging and/or reports. Outcomes analysis was restricted to patients with lymph node-positive (+) disease. Kaplan-Meier survival estimates were generated and survival curves were compared using the log-rank test. Bayesian information criterion assessed model performance changes with the addition of RPLN status to current American Joint Committee on Cancer staging. Competing risk analysis compared modes of disease recurrence. RESULTS: The incidence of radiographic RPLN involvement was 9% (73 of 796 patients) and was found to vary by primary tumor site. The 5-year rates of freedom from distant metastases (FDM) and overall survival were lower in patients with RPLN(+) status compared with those with RPLN-negative (-) status (84% vs 93% [P = .0327] and 74% vs 87% [P = .0078], respectively). RPLN(+) status was not found to be associated with outcomes on multivariate analysis. Bayesian information criterion analysis demonstrated that current American Joint Committee on Cancer staging was not improved with the inclusion of RPLN. Locoregional and distant disease recurrence probabilities for those patients with RPLN(+) status were 8% and 13%, respectively, compared with 10% and 6%, respectively, for those with RPLN(-) status. RPLN(+) status portended worse 5-year FDM in the low-risk subgroup (smoking history of <10 pack-years) and among patients who received concurrent chemotherapy but not induction chemotherapy. CONCLUSIONS: RPLN(+) status was associated with worse overall survival and FDM on univariate but not multivariate analysis. In subgroup analyses, RPLN(+) status was associated with poorer FDM in both patients with a smoking history of <10 pack-years and those who received concurrent chemotherapy, suggesting that RPLN(+) status could be considered an exclusion criteria in treatment deintensification efforts seeking to omit chemotherapy.

Effects of a Surgical Receipt Program on the Supply Costs of Five General Surgery Procedures.

BACKGROUND: Surgical supplies occupy a large portion of health care expenditures but is often under the surgeon's control. We sought to assess whether an automated, surgeon-directed, cost feedback system can decrease supply expenditures for five common general surgery procedures. MATERIALS AND METHODS: An automated "surgical receipt" detailing intraoperative supply costs was generated and emailed to surgeons after each case. We compared the median cost per case for 18 mo before and after implementation of the surgical receipt. We controlled for price fluctuations by applying common per-unit prices in both periods. We also compared the incision time, case length booking accuracy, length of stay, and postoperative occurrences. RESULTS: Median costs decreased significantly for open inguinal hernia ($433.45 to $385.49, P < 0.001), laparoscopic cholecystectomy ($886.77 to $816.13, P = 0.002), and thyroidectomy ($861.21 to $825.90, P = 0.034). Median costs were unchanged for laparoscopic appendectomy and increased significantly for lumpectomy ($325.67 to $420.53, P < 0.001). There was an increase in incision-to-closure minutes for open inguinal hernia (71 to 75 min, P < 0.001) and laparoscopic cholecystectomy (75 to 96 min, P < 0.001), but a decrease in thyroidectomy (79 to 73 min, P < 0.001). There was an increase in booking accuracy for laparoscopic appendectomy (38.6% to 55.0%, P = 0.001) and thyroidectomy (32.5% to 48.1%, P = 0.001). There were no differences in postoperative occurrence rates and length of stay duration. CONCLUSIONS: An automated surgeon-directed surgical receipt may be a useful tool to decrease supply costs for certain procedures. However, curtailing surgical supply costs with surgeon-directed cost feedback alone is challenging and a multimodal approach may be necessary.

A mathematical model to describe survival among liver recipients from deceased donors with risk of transmitting infectious encephalitis pathogens.

BACKGROUND: Between 2002 and 2013, the organs of 13 deceased donors with infectious encephalitis were transplanted, causing infections in 23 recipients. As a consequence, organs from donors showing symptoms of encephalitis (increased probability of infectious encephalitis (IPIE) organs) might be declined. We had previously characterized the risk of IPIE organs using data available to most transplant teams and not requiring special diagnostic tests. If the probability of infection is low, the benefits of a transplant from a donor with suspected infectious encephalitis might outweigh the risk and could be lifesaving for some transplant candidates. METHODS: Using organ transplant data and Cox Proportional Hazards models, we determined liver donor and recipient characteristics predictive of post-transplant or waitlist survival and generated 5-year survival probability curves. We also calculated expected waiting times for an organ offer based on transplant candidate characteristics. Using a limited set of actual cases of infectious encephalitis transmission via transplant, we estimated post-transplant survival curves given an organ from an IPIE donor. RESULTS: 54% (1256) of patients registered from 2002-2006 who died or were removed from the waiting list because of deteriorated condition within 1 year could have had an at least marginal estimated benefit by accepting an IPIE liver with some probability of infection, with the odds increasing to 86% of patients if the probability of infection was low (5% or less). Additionally, 54% (1252) were removed from the waiting list prior to their estimated waiting time for a non-IPIE liver and could have benefited from an IPIE liver. CONCLUSION: Improved allocation and utilization of IPIE livers could be achieved by evaluating the patient-specific trade-offs between (a) accepting an IPIE liver and (b) remaining on the waitlist and accepting a non-IPIE liver after the estimated waiting time.

National Trends and Factors Associated With Inpatient Mortality in Adult Patients With Opioid Overdose.

BACKGROUND: The prevalence of opioid misuse and opioid-related mortality has increased dramatically over the past decade. There is limited evidence on factors associated with mortality from opioid overdose in the inpatient setting. The primary objective was to report national trends in opioid overdose and mortality. The secondary objectives were to explore factors associated with inpatient mortality and report differences in prescription opioid overdose (POD) versus illicit opioid overdose (IOD) cohorts. METHODS: Using the 2010-2014 Nationwide Inpatient Sample, we performed a cross-sectional analysis and identified a weighted estimate of 570,987 adult patients with an International Classification of Disease, Ninth Revision, or External Cause of Injury code of POD or IOD. We performed multivariable logistic regression to identify predictors of inpatient mortality. The odds ratio (OR) and their associated 95% confidence interval (CI) are reported. RESULTS: Of the 570,987 patients with opioid overdose, 13.8% had an admissions diagnosis of IOD, and the remaining had POD. Among all opioid overdose admissions, the adjusted odds of IOD admissions increased by 31% per year (OR, 1.31; 95% CI, 1.29-1.31; P < .001); however, the adjusted odds POD admissions decreased by 24% per year (OR, 0.76; 95% CI, 0.75-0.77; P < .001). The mortality was 4.7% and 2.3% among IOD and POD admissions, respectively. The odds of inpatient mortality increased by 8% per year among IOD admissions (OR, 1.08; 95% CI, 1.02-1.14; P < .007). The odds of inpatient mortality increased by 6% per year among all POD admissions (OR, 1.06; 95% CI, 1.03-1.09; P < .001). Those with IOD compared to POD had higher odds of mortality (OR, 2.03; 95% CI, 1.79-2.29; P < .001). Patients with age ≥80 years of age and those with a diagnosis of a solid tumor malignancy had higher odds of mortality. Odds of inpatient mortality were decreased in African American versus Caucasian patients and in patients undergoing alcohol rehabilitation therapy. CONCLUSIONS: The increase in mortality provides a strong basis for further risk reduction strategies and intervention program implementation. Medical management of not only the opioid overdose but also the comorbidities calls for a multidisciplinary approach that involves policy makers and health care teams.

A Simple Symptom Score for Acute Human Immunodeficiency Virus Infection in a San Diego Community-Based Screening Program.

Background: Treatment of acute human immunodeficiency virus (HIV) infection (AHI) decreases transmission and preserves immune function, but AHI diagnosis remains resource intensive. Risk-based scores predictive for AHI have been described for high-risk groups; however, symptom-based scores could be more generalizable across populations. Methods: Adults who tested either positive for AHI (antibody-negative, HIV nucleic acid test [NAT] positive) or HIV NAT negative with the community-based San Diego Early Test HIV screening program were retrospectively randomized 2:1 into a derivation and validation set. In the former, symptoms significant for AHI in a multivariate logistic regression model were assigned a score value (the odds ratio [OR] rounded to the nearest integer). The score was assessed in the validation set using receiver operating characteristics and areas under the curve (AUC). An optimal cutoff score was found using the Youden index. Results: Of 998 participants (including 261 non-men who have sex with men [MSM]), 113 had AHI (including 4 non-MSM). Compared to HIV-negative cases, AHI cases reported more symptoms (median, 4 vs 0; P < .01). Fever, myalgia, and weight loss were significantly associated with AHI in the multivariate model and corresponded to 11, 8, and 4 score points, respectively. The summed score yielded an AUC of 0.85 (95% confidence interval [CI], .77-.93). A score of ≥11 was 72% sensitive and 96% specific (diagnostic OR, 70.27). Conclusions: A 3-symptom score accurately predicted AHI in a community-based screening program and may inform allocation of resources in settings that do not routinely screen for AHI.

Antifungal Prophylaxis with Posaconazole Delayed-Release Tablet and Oral Suspension in a Real-Life Setting: Plasma Levels, Efficacy, and Tolerability.

We continuously determined posaconazole plasma concentrations (PPCs) in 61 patients with hematological malignancies receiving posaconazole (PCZ) delayed-release tablets (DRT; 48 patients; median duration of intake, 92 days) and PCZ oral solution (OS; 13 patients; median duration of intake, 124 days). PCZ DRT and OS antifungal prophylaxis was efficient and well tolerated. Thirty-four of 48 patients (71%) receiving DRT always had PPCs of >0.7 mg/liter, while 14 of 48 patients (29%) had at least one PPC of ≤0.7 mg/liter. In patients receiving OS, 4 of 13 patients (31%) always had PPCs of >0.7 mg/liter, 6 of 13 patients (46%) had at least one PPC of ≤0.7 mg/liter, and 3 (23%) patients never reached a PPC of 0.7 mg/liter. In patients with at least one determined PPC, the mean proportion of all PPCs of >0.7 mg/liter was 91% for PCZ DRT, whereas it was 52% for PCZ OS (P = 0.001). In the per sample analysis, PPCs were significantly more likely to be >0.7 mg/liter in patients receiving DRT than in patients receiving OS (PPCs were >0.7 mg/liter in 91.4% [297/325] of patients receiving DRT versus 70.3% [85/121] of patients receiving OS; P < 0.001). Patients receiving PCZ DRT had higher proportions of PPCs of >0.7 mg/liter than patients receiving OS both in the per patient and in the per sample analyses. Two patients (3%) had side effects during PCZ prophylaxis, and one (2%) had fungal breakthrough infection. Therapeutic drug monitoring enables detection of extended periods of PPCs of ≤0.7 mg/liter (e.g., due to nonadherence or graft-versus-host disease), which may also be associated with the loss of protective intracellular PCZ concentrations, regardless of the PCZ formulation.

Superior mesenteric artery calcification is associated with cardiovascular risk factors, systemic calcified atherosclerosis, and increased mortality.

BACKGROUND: Atherosclerosis is a major risk factor for morbidity and mortality. However, epidemiologic data are sparse regarding risk factors for superior mesenteric artery calcification (SMAC), the association between SMAC and disease in other arterial beds, or the independent contribution of SMAC to risk of mortality. The objective of this study was to test the hypothesis that presence and extent of SMAC are associated with cardiovascular disease (CVD) risk factors, calcification in other arterial beds, and both cardiovascular and all-cause mortality, independent of classic risk factors and calcification in other arterial beds. METHODS: Arterial calcification in the superior mesenteric artery, celiac trunk, coronaries, thoracic aorta, abdominal aorta, and iliac arteries was evaluated by computed tomography in adults with no known CVD. Multiple logistic regression models examined risk factor associations for SMAC and SMAC as a risk factor for calcification in other arterial beds. Cox models were used to examine the association between SMAC and mortality. RESULTS: The average age of subjects was 56 years; 43.7% (1877/4300) were women, and 6.7% (290) had SMAC. Age (odds ratio [OR], 1.09; 95% confidence interval, 1.06-1.11), male sex (OR, 1.79; 95% CI, 1.08-3.03), dyslipidemia (OR, 1.38; 95% CI, 1.01-1.88), and any smoking (OR, 1.60; 95% CI, 1.20-2.14) were associated with SMAC presence. Notably, body mass index, body fat percentage, hypertension, diabetes, and family history of coronary heart disease were not significant risk factors for the presence of SMAC. SMAC presence was associated with calcification in all five other arterial beds (OR, 6.02; 95% CI, 3.76-9.66). During a median follow-up time of 9.4 years, there were 234 deaths, 76 of which were CVD related. SMAC extent (represented as per-unit increase in log [SMAC score + 1]; OR, 1.31; 95% CI, 1.01-1.71) was significantly associated with CVD mortality after full adjustment for risk factors and calcification in other arterial beds. SMAC presence (OR, 1.52; 95% CI, 1.10-2.12) and extent (OR, 1.25; 95% CI, 1.06-1.48) were also both significantly associated with all-cause mortality after full adjustment. CONCLUSIONS: SMAC is associated with specific CVD risk factors as well as with calcification in all other arterial beds. SMAC extent was significantly associated with incident cardiovascular mortality, whereas both SMAC presence and extent were significantly associated with all-cause mortality, even after adjustment for risk factors and calcification in other arterial beds. Further studies are needed to determine whether SMAC is simply a marker for advanced and systemic disease or whether it confers increased mortality risk through an independent mechanism.