Radiologists and Clinical Trials: Part 2: Practical Statistical Methods for Understanding and Monitoring Independent Reader Performance.

Though many clinical trials rely on medical image evaluations for primary or key secondary endpoints, the methods to monitor reader performance are all too often mired in the legacy use of adjudication rates. If misused, this simple metric can be misleading and sometimes entirely contradictory. Furthermore, attempts to overcome the limitations of adjudication rates using de novo or ad hoc methods often ignore well-established research conducted over the last half-century and can lead to inaccurate conclusions or variable interpretations. Underperforming readers can be missed, expert readers retrained, or worse, replaced. This paper aims to standardize reader performance evaluations using proven statistical methods. Additionally, these methods will describe how to discriminate between scenarios of concern and normal medical interpretation variability. Statistical methods are provided for inter-reader and intra-reader variability and bias, including the adjudicator's bias. Finally, we have compiled guidelines for calculating correct sample sizes, considerations for intra-reader memory recall, and applying alternative designs for independent readers.

From natural disaster to pandemic: A health-system pharmacy rises to the challenge.

PURPOSE: This report describes a health-system pharmacy's response to a natural disaster while staff members simultaneously prepared for the coronavirus disease 2019 (COVID-19) pandemic. By detailing our experience, we hope to help other institutions that are current facing or could encounter similar crises. SUMMARY: In early March 2020, a tornado destroyed the health system's warehouse for storage of most clinical supplies, including personal protective equipment and fluids. The pharmacy purchasing team collaborated with suppliers and manufacturers to recover losses and establish alternative storage areas. Days later, the pharmacy department was forced to address the impending COVID-19 pandemic. Key elements of the COVID-19 response included reducing the potential for virus exposure for patients and staff; overcoming challenges in sourcing of staff, personal protective equipment, and medications; and changing care delivery practices to maintain high-quality patient care while maximizing social distancing. The pharmacy department also created distance learning opportunities for 70 pharmacy students on rotations. After an initial plan, ongoing needs include adjustment in patient care activities if significant staff losses occur, when and how to resume clinical activities, and how to best utilize the resources accumulated. Elements of practice changes implemented to reduce COVID-19 threats to patients and pharmacy personnel have proven beneficial and will be further evaluated for potential continuation. CONCLUSION: The pharmacy department's efforts to respond to a natural disaster and unprecedented pandemic have proven successful to this point and have illuminated several lessons, including the necessity of cohesive department communication, staff flexibility, prioritization of teamwork, and external collaboration.

Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone.

BACKGROUND: Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies. METHODS: The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only). RESULTS: Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment. CONCLUSION: Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab. TRIAL REGISTRATION: ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

Predictors of pneumonia on routine chest radiographs in patients with COPD: a post hoc analysis of two 1-year randomized controlled trials.

Background: Patients with COPD are at risk for life-threatening pneumonia. Although anatomical abnormalities in the thorax may predispose to pneumonia, those abnormalities identified on routine chest X-rays (CXRs) in patients with COPD have not been studied to better understand pneumonia risk. Methods: We conducted a post hoc exploratory analysis of data from two replicate year-long clinical trials assessing the impact of fluticasone furoate-vilanterol versus vilanterol alone on COPD exacerbations (GSK studies: HZC102871/NCT01009463 and HZC102970/NCT01017952). Abnormalities on baseline CXRs from 179 patients who developed pneumonia and 50 randomly selected patients who did not were identified by blinded consensus readings conducted by two radiologists. Positive and negative likelihood ratios and diagnostic odds ratios (ORs) were calculated to evaluate the markers for subsequent pneumonia development during the 1-year study period. Results: Baseline characteristics distinguishing the pneumonia and non-pneumonia groups included a lower body mass index (24.9 vs 27.5 kg/m2, P=0.008), more severe airflow obstruction (mean post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio: 42.3% vs 47.6%, P=0.003), and prior pneumonia (36% vs 20%, P=0.030). Baseline CXR findings with the highest diagnostic ORs were: elevated hemi-diaphragm (OR: 6.87; 95% CI: 0.90, 52.26), thick tracheal-esophageal stripe (OR: 4.39 [0.25, 78.22]), narrow cardiac silhouette (OR: 2.91 [0.85, 9.99]), calcified pleural plaque/mid-chest pleural thickening (OR: 2.82 [0.15, 53.76]), and large/prominent pulmonary artery shadow (OR: 1.94 [0.95, 3.97]). The presence of a narrow cardiac silhouette at baseline was associated with a statistically significant lower mean pre-bronchodilator FEV1 (P=0.040). There was also a trend for a lower mean pre-bronchodilator FEV1 in patients with a large/prominent pulmonary artery shadow at baseline (P=0.095). Conclusion: Findings on routine CXR that relate to pathophysiological mechanisms of pneumonia could help determine pneumonia risk in patients with COPD.

Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions.

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm.Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy.Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin.Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73-83. ©2017 AACR.

Lugano 2014 criteria for assessing FDG-PET/CT in lymphoma: an operational approach for clinical trials.

An operationalized workflow paradigm is presented and validated with pilot subject data. This approach is reproducible with a high concordance rate between individual readers (kappa 0.73 [confidence interval 0.59-0.87; P=<0.0001]) using a 5-point scale to assess [18F] labeled fluorodeoxyglucose metabolic activity in lymphomatous lesions. These results suggest an operationally practical 5-point scale workflow paradigm for potential use in larger clinical trials evaluating lymphoma therapeutics.

Investigator and independent review committee exploratory assessment and verification of tumor response in a non-Hodgkin lymphoma study.

Interpretation of endpoints (e.g. overall response rate) in clinical trials depends on the accurate and reliable measurement and identification of tumors. Regulatory agencies recommend blinded reviews of imaging data by independent review committees (IRCs). Differences in response outcomes that arise between IRCs and site investigators raise regulatory/sponsor concerns. Here, we evaluate discrepant tumor response assessments by the IRC and unblinded investigators (complete versus partial response, respectively) occurring in 52 (13% of 393 IRC-assessed responders) of 447 enrolled patients with treatment-naïve non-Hodgkin lymphoma from a randomized study. The IRC and investigators were 'likely correct' in 73% and 25% of cases, respectively (p < .001). Investigators were more likely to make errors by misinterpreting lymph node data and not utilizing PET results. This post hoc finding suggests a possible role for post-training site evaluation/audit, with retraining as needed, and a specialized consensus committee for concurrent blinded review of site/central data.

Companion diagnostics and molecular imaging-enhanced approaches for oncology clinical trials.

In the era of personalized medicine, diagnostic approaches are helping pharmaceutical and biotechnology sponsors streamline the clinical trial process. Molecular assays and diagnostic imaging are routinely being used to stratify patients for treatment, monitor disease, and provide reliable early clinical phase assessments. The importance of diagnostic approaches in drug development is highlighted by the rapidly expanding global cancer diagnostics market and the emergent attention of regulatory agencies worldwide, who are beginning to offer more structured platforms and guidance for this area. In this paper, we highlight the key benefits of using companion diagnostics and diagnostic imaging with a focus on oncology clinical trials. Nuclear imaging using widely available radiopharmaceuticals in conjunction with molecular imaging of oncology targets has opened the door to more accurate disease assessment and the modernization of standard criteria for the evaluation, staging, and treatment responses of cancer patients. Furthermore, the introduction and validation of quantitative molecular imaging continues to drive and optimize the field of oncology diagnostics. Given their pivotal role in disease assessment and treatment, the validation and commercialization of diagnostic tools will continue to advance oncology clinical trials, support new oncology drugs, and promote better patient outcomes.

Operation CeaseFire-New Orleans: an infectious disease model for addressing community recidivism from penetrating trauma.

BACKGROUND: CeaseFire, using an infectious disease approach, addresses violence by partnering hospital resources with the community by providing violence interruption and community-based services for an area roughly composed of a single city zip code (70113). Community-based violence interrupters start in the trauma center from the moment penetrating trauma occurs, through hospital stay, and in the community after release. This study interprets statistics from this pilot program, begun May 2012. We hypothesize a decrease in penetrating trauma rates in the target area compared with others after program implementation. METHODS: This was a 3-year prospective data collection of trauma registry from May 2010 to May 2013. All intentional, target area, penetrating trauma treated at our Level I trauma center received immediate activation of CeaseFire personnel. Incidences of violent trauma and rates of change, by zip code, were compared with the same period for 2 years before implementation. RESULTS: During this period, the yearly incidence of penetrating trauma in Orleans Parish increased. Four of the highest rates were found in adjacent zip codes: 70112, 70113, 70119, and 70125. Average rates per 100,000 were 722.7, 523.6, 286.4, and 248, respectively. These areas represent four of the six zip codes citywide that saw year-to-year increases in violent trauma during this period. Zip 70113 saw a lower rate of rise in trauma compared with 70112 and a higher but comparable rise compared with that of 70119 and 70125. CONCLUSION: Hospital-based intervention programs that partner with culturally appropriate personnel and resources outside the institution walls have potential to have meaningful impact over the long term. While few conclusions of the effect of such a program can be drawn in a 12-month period, we anticipate long-term changes in the numbers of penetrating injuries in the target area and in the rest of the city as this program expands. LEVEL OF EVIDENCE: Therapeutic study, level IV.

Pharmacist and physician collaboration in the patient's home.

OBJECTIVE: To review the historical perspective and current incidence of home visits by physicians and pharmacists, discuss the concept of pharmacists providing care "incident-to" the physician, and introduce a new endeavor of collaborative, incident-to home visits by a pharmacist and physician. DATA SOURCES: A literature search was performed using MEDLINE (1966-May 2003). The search terms used were home visit, house call, incident-to, collaborative care, physician, and pharmacist. STUDY SELECTION AND DATA EXTRACTION: All pertinent articles were evaluated. DATA SYNTHESIS: Home visits were once considered a hallmark of patient care, but have decreased to an average of 0.4 home visits per week for primary care physicians. Home visits are essential for patients unable to commute to the office due to a disability or illness. However, home visits also allow the physician to determine how conditions affect a patient's everyday life, in addition to assessing the living environment. Minimal documented evidence exists of pharmacists making home visits and no documented evidence exists of pharmacists and physicians collaboratively making home visits. The pharmacist complements the value of the visit by assessing medication appropriateness as well as medication administration, storage, accessibility, and adherence. CONCLUSIONS: Current practice styles often compromise services that were once paramount to patient care, as evidenced by a decline in home visits. Recent trends in health care attempt to compensate for high-volume practices and managed care restrictions. A collaborative relationship between a pharmacist and physician with visits into the patient's home is a movement toward improved continuity of care.

The pediatric spine: anatomical and dynamic considerations preceding manipulation.

Spinal manipulation is effective for the treatment of many conditions, albeit not without possible complications. The incidence of subtle growth plate fractures following high-velocity techniques in children is surely under-appreciated because of the occult nature of these injuries.

Plasmacytoma of the cricoid cartilage with airway mass effect.

Although multiple myeloma is a common plasma cell dyscrasia, the deposition and organization of these malignant cells in the cricoid cartilage is rare. We report a case of plasmacytoma of the cricoid cartilage and secondary airway obstruction. This important report emphasizes the potential difficulty in diagnosing this condition, consequences of advanced disease, and the importance of combining laryngofissure biopsy and detailed imaging modalities to confirm the diagnosis and guide treatment.