Preventing metastatic recurrence in low-risk ER/PR + breast cancer patients-a retrospective clinical study exploring the evolving challenge of persistence with adjuvant endocrine therapy.

PURPOSE: In the genomic era, more women with low-risk breast cancer will forego chemotherapy and rely on adjuvant endocrine therapy (AET) to prevent metastatic recurrence. However, some of these patients will unfortunately relapse. We sought to understand this outcome. Preliminary work suggested that early discontinuation of AET, also known as non-persistence, may play an important role. A retrospective analysis exploring factors related to our breast cancer patients' non-persistence with AET was performed. METHODS: Women who underwent Oncotype-DX® testing between 2011 and 2014 with minimum 5 years follow-up were included. 'Low risk' was defined as Oncotype score < 26. Outcomes of recurrence and persistence were determined by chart review. Patient, tumor and treatment factors were collected, and persistent versus non-persistent groups compared using multivariable ANOVA and Fisher Chi square exact test. RESULTS: We identified six cases of distant recurrence among low-risk patients with a median follow-up of 7.7 years. Among them, five of six patients (83%) were non-persistent with AET. The non-persistence rate in our cohort regardless of recurrence was 57/228 (25%). Non-persistent patients reported more severe side effects compared with persistent patients (p = 0.002) and were more likely to be offered a switch in endocrine therapy, rather than symptom-relief (p = 0.006). In contrast, persistent patients were 10.3 times more likely to have been offered symptom-alleviating medications compared with non-persistent patients (p < 0.001). A subset analysis revealed that patients who persisted with therapy had a higher Oncotype-DX® score than patients who discontinued early (p = 0.028). CONCLUSION: Metastatic recurrence in low-risk breast cancer patients may be primarily due to non-persistence with endocrine therapy. Further work is needed to optimize care for patients who struggle with side effects. To our knowledge, these are the first published data suggesting that Oncotype-DX® score may influence persistence with AET.

Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis.

BACKGROUND: Pathogenic variants of the DPYD gene are strongly associated with grade ≥3 toxicity during fluoropyrimidine chemotherapy. We conducted a systematic review and meta-analysis to estimate the risk of treatment-related death associated with DPYD gene variants. MATERIALS AND METHODS: We searched for reports published prior to September 17, 2020, that described patients receiving standard-dose fluoropyrimidine chemotherapy (5-fluorouracil or capecitabine) who had baseline testing for at least one of four pathogenic DPYD variants (c.1129-5923C>G [HapB3], c.1679T>G [*13], c.1905+1G>A [*2A], and c.2846A>T) and were assessed for toxicity. Two reviewers assessed studies for inclusion and extracted study-level data. The primary outcome was the relative risk of treatment-related mortality for DPYD variant carriers versus noncarriers; we performed data synthesis using a Mantel-Haenszel fixed effects model. RESULTS: Of the 2,923 references screened, 35 studies involving 13,929 patients were included. DPYD variants (heterozygous or homozygous) were identified in 566 patients (4.1%). There were 14 treatment-related deaths in 13,363 patients without identified DPYD variants (treatment-related mortality, 0.1%; 95% confidence interval [CI], 0.1-0.2) and 13 treatment-related deaths in 566 patients with any of the four DPYD variants (treatment-related mortality, 2.3%; 95% CI, 1.3%-3.9%). Carriers of pathogenic DPYD gene variants had a 25.6 times increased risk of treatment-related death (95% CI, 12.1-53.9; p < .001). After excluding carriers of the more common but less deleterious c.1129-5923C>G variant, carriers of c.1679T>G, c.1905+1G>A, and/or c.2846A>T had treatment-related mortality of 3.7%. CONCLUSION: Patients with pathogenic DPYD gene variants who receive standard-dose fluoropyrimidine chemotherapy have greatly increased risk for treatment-related death. IMPLICATIONS FOR PRACTICE: The syndrome of dihydropyrimidine dehydrogenase (DPD) deficiency is an uncommon but well-described cause of severe toxicity related to fluoropyrimidine chemotherapy agents (5-fluorouracil and capecitabine). Patients with latent DPD deficiency can be identified preemptively with genotyping of the DPYD gene, or with measurement of the plasma uracil concentration. In this systematic review and meta-analysis, the authors study the rare outcome of treatment-related death after fluoropyrimidine chemotherapy. DPYD gene variants associated with DPD deficiency were linked to a 25.6 times increased risk of fluoropyrimidine-related mortality. These findings support the clinical utility of DPYD genotyping as a screening test for DPD deficiency.

Geriatric Snowmobile Trauma: Longer Courses After Similar Injuries.

BACKGROUND: Snowmobiling is a popular activity that leads to geriatric trauma admissions; however, this unique trauma population is not well characterized. We aimed to compare the injury burden and outcomes for geriatric versus nongeriatric adults injured riding snowmobiles. MATERIALS AND METHODS: A retrospective cohort study was performed using the National Trauma Databank comparing nongeriatric (18-64) and geriatric adults (≥65) presenting after snowmobile-related trauma at level 1 and 2 trauma centers from 2011 to 2015. Demographic, admission, injury, and outcome data were collected and compared. A multivariate logistic regression model assessed for risk factors associated with severe injury (Injury Severity Score >15). Analysis was also performed using chi square, analysis of variance, and Kruskal-Wallis testing. RESULTS: A total of 2471 adult patients with snowmobile trauma were identified; 122 (4.9%) were geriatric. Rates of severe injury (Injury Severity Score >15) were similar between groups, 27.5% in geriatric patients and 22.5% in nongeriatric adults (P = 0.2). Geriatric patients experienced higher rates of lower extremity injury (50.4 versus 40.3%, P = 0.03), neck injury (4.1 versus 1.4%, P = 0.02), and severe spine injury (20.6 versus 7.0%, P = 0.004). Geriatric patients had longer hospitalizations (5 versus 3 d, P < 0.0001), rates of discharge to a facility (36.8% versus 12%, P < 0.0001), and higher mortality (4.1 versus 0.6%, P < 0.0001). Geriatric age did not independently increase the risk for severe injury. CONCLUSIONS: Geriatric age was not a significant predictor of severe injury after snowmobile trauma; however, geriatric patients suffered unique injuries, had longer hospitalizations, had higher rates of discharge to a facility, and had higher mortality. Tailored geriatric care may improve outcomes in this unique sport-related trauma population.

Geriatric Skiers: Active But Still at Risk, a National Trauma Data Bank Study.

BACKGROUND: Downhill skiing accounts for a large portion of geriatric sport-related trauma. We assessed the national burden of geriatric versus nongeriatric ski trauma. MATERIALS AND METHODS: Adults presenting to level 1/2 trauma centers after ski-associated injuries from 2011 to 2015 were identified from the National Trauma Data Bank by ICD-9 code. We compared demographics, injury patterns, and outcomes between geriatric (age ≥65 y) and nongeriatric adult skiers (age 18-64 y). A multiple regression analysis assessed for risk factors associated with severe injury (Injury Severity Score >15). RESULTS: We identified 3255 adult ski trauma patients, and 16.7% (543) were geriatric. Mean ages for nongeriatric versus geriatric skiers were 40.8 and 72.1 y, respectively. Geriatric skiers more often suffered head (36.7 versus 24.3%, P < 0.0001), severe head (abbreviated injury scale score >3, 49.0 versus 31.5%, P < 0.0001) and thorax injuries (22.2 versus 18.1%, P = 0.03) as compared with nongeriatric skiers. Geriatric skiers were also more often admitted to the ICU (26.5 versus 14.9%, P < 0.0001), discharged to a facility (26.7 versus 11.6%, P < 0.0001), and suffered higher mortality rates (1.3 versus 0.4%, P = 0.004). Independent risk factors for severe injury included being male (OR: 1.68, CI: 1.22-2.31), helmeted (OR: 1.41, CI: 1.07-1.85), and having comorbidities (OR: 1.37, CI: 1.05-1.80). Geriatric age was not independently associated with severe injury. CONCLUSIONS: At level 1/2 trauma centers, geriatric age in ski trauma victims was associated with unique injury patterns, higher acuity, increased rates of facility care at discharge, and higher mortality as compared with nongeriatric skiers. Our findings indicate the need for specialized care after high impact geriatric ski trauma.

Short-term Preoperative Diet Decreases Bleeding After Partial Hepatectomy: Results From a Multi-institutional Randomized Controlled Trial.

BACKGROUND: Our previous case series suggested that a 1-week, low-calorie and low-fat diet was associated with decreased intraoperative blood loss in patients undergoing liver surgery. OBJECTIVE: The current study evaluates the effect of this diet in a randomized controlled trial. METHODS: We randomly assigned 60 patients with a body mass index ≥25 kg/m(2) to no special diet or an 800-kcal, 20 g fat, and 70 g protein diet for 1 week before liver resection. Surgeons were blinded to diet assignment. Hepatic glycogen stores were evaluated using periodic acid Schiff (PAS) stains. RESULTS: Ninety four percent of the patients complied with the diet. The diet group consumed fewer daily total calories (807 vs 1968 kcal, P < 0.001) and fat (21 vs 86 g, P < 0.001) than the no diet group. Intraoperative blood loss was less in the diet group: mean blood loss 452 vs 863 mL (P = 0.021). There was a trend towards decreased transfusion in the diet group (138 vs 322 mL, P = 0.06). The surgeon judged the liver to be easier to manipulate in the diet group: 1.86 versus 2.90, P = 0.004. Complication rate (20% vs 17%), length of stay (median 5 vs 4 days) and mortality did not differ between groups. There was no difference in hepatic steatosis between groups. There was less glycogen in hepatocytes in the diet group (PAS stain score 1.61 vs 2.46, P < 0.0001). CONCLUSIONS: A short-course, low-fat, and low-calorie diet significantly decreases bleeding and makes the liver easier to manipulate in hepatic surgery.

A Randomized Prospective Trial of Supine MRI-Guided Versus Wire-Localized Lumpectomy for Breast Cancer.

BACKGROUND: Wire-localized excision of non-palpable breast cancer is imprecise, resulting in positive margins 15-35% of the time. METHODS: Women with a confirmed diagnosis of non-palpable invasive breast cancer (IBC) or ductal carcinoma in situ (DCIS) were randomized to a new technique using preoperative supine magnetic resonance imaging (MRI) with intraoperative optical scanning and tracking (MRI group) or wire-localized (WL group) partial mastectomy. The main outcome measure was the positive margin rate. RESULTS: In this study, 138 patients were randomly assigned. Sixty-six percent had IBC and DCIS, 22% had IBC, and 12% had DCIS. There were no differences in patient or tumor characteristics between the groups. The proportion of patients with positive margins in the MRI-guided surgery group was half that observed in the WL group (12 vs. 23%; p = 0.08). The specimen volumes in the MRI and WL groups did not differ significantly (74 ± 33.9 mL vs. 69.8 ± 25.1 mL; p = 0.45). The pathologic tumor diameters were underestimated by 2 cm or more in 4% of the cases by MRI and in 9% of the cases by mammography. Positive margins were observed in 68% and 58% of the cases underestimated by 2 cm or more using MRI and mammography, respectively, and in 15% and 14% of the cases not underestimated using MRI and mammography, respectively. CONCLUSIONS: A novel system using supine MRI images co-registered with intraoperative optical scanning and tracking enabled tumors to be resected with a trend toward a lower positive margin rate compared with wire-localized partial mastectomy. Margin positivity was more likely when imaging underestimated pathologic tumor size.

Medical Care Costs Were Similar Across the Low-dose Computed Tomography and Chest X-Ray Arms of the National Lung Screening Trial Despite Different Rates of Significant Incidental Findings.

BACKGROUND: The National Lung Screening Trial (NLST) reported lung cancer and all-cause mortality reductions for low-dose computed tomography (LDCT) versus chest x-ray (CXR) screening. Although LDCT lung screening has received a grade B from the United States Preventive Services Task Force and is a covered service under most health plans, concerns remain on the costs engendered by screening, and the impact of the high rate of significant incidental finding (SIF) detection on those costs. METHODS: We linked American College of Radiology Imaging Network NLST and Medicare fee-for-service claims data for participants from 23 sites for 2002-2009. We performed participant-level analyses using generalized linear regression models to estimate the adjusted annual mean of the 3-year total medical costs per person in each study arm and within screen outcome categories (ever positive with abnormalities suspicious for lung cancer, always negative for abnormalities suspicious for lung cancer, but with SIFs, and always negative without SIFs). RESULTS: The adjusted annual mean total per person costs were not significantly different between screening arms [LDCT, $11,029 (95% confidence interval, $10,107-$11,951); CXR, $10,905 (95% confidence interval, $10,059-$11,751)], despite higher proportions of individuals with SIFs in the LDCT versus the CXR arm (18% vs. 4%; P<0.0001). CONCLUSIONS: We found little difference in total annual per person costs between LDCT-screened and CXR-screened Medicare participants, despite the higher number of SIFs in the LDCT arm of the study.

Multi-level Influences on Breast Cancer Screening in Primary Care.

BACKGROUND: Use of breast cancer screening is influenced by factors associated with patients, primary care providers, practices, and health systems. OBJECTIVE: We examined the relative effects of these nested levels on four breast cancer screening metrics. DESIGN: A web-based survey was completed at 15 primary care practices within two health systems representing 306 primary care providers (PCPs) serving 46,944 women with a primary care visit between 1/2011-9/2014. Analyses occurred between 1/2017 and 5/2017. MAIN MEASURES: Across four nested levels (patient, PCP, primary care practice, and health system), frequency distributions and adjusted rates of primary care practice characteristics and survey results for four breast screening metrics (percent screened overall, and percent screened age 40-49, 50-74, and 75+) were reported. We used hierarchical multi-level mixed and random effects analysis to assess the relative influences of PCP, primary care practice, and health system on the breast screening metrics. KEY RESULTS: Overall, the proportion of women undergoing breast cancer screening was 73.1% (73.4% for ages 40-49, 76.5% for 50-74, and 51.1% for 75+). Patient ethnicity and number of primary care visits were strongly associated with screening rates. After adjusting for woman-level factors, 24% of the overall variation among PCPs was attributable to the primary care practice level, 35% to the health system level, and 41% to the residual variation among PCPs within practice. No specific provider-level characteristics were found to be statistically significant determinants of screening rates. CONCLUSIONS: After accounting for woman-level characteristics, the remaining variation in breast cancer screening was largely due to provider and health system variation.

A semiparametric joint model for terminal trend of quality of life and survival in palliative care research.

Palliative medicine is an interdisciplinary specialty focusing on improving quality of life (QOL) for patients with serious illness and their families. Palliative care programs are available or under development at over 80% of large US hospitals (300+ beds). Palliative care clinical trials present unique analytic challenges relative to evaluating the palliative care treatment efficacy which is to improve patients' diminishing QOL as disease progresses towards end of life (EOL). A unique feature of palliative care clinical trials is that patients will experience decreasing QOL during the trial despite potentially beneficial treatment. Often longitudinal QOL and survival data are highly correlated which, in the face of censoring, makes it challenging to properly analyze and interpret terminal QOL trend. To address these issues, we propose a novel semiparametric statistical approach to jointly model the terminal trend of QOL and survival data. There are two sub-models in our approach: a semiparametric mixed effects model for longitudinal QOL and a Cox model for survival. We use regression splines method to estimate the nonparametric curves and AIC to select knots. We assess the model performance through simulation to establish a novel modeling approach that could be used in future palliative care research trials. Application of our approach in a recently completed palliative care clinical trial is also presented.

Variation in Screening Abnormality Rates and Follow-Up of Breast, Cervical and Colorectal Cancer Screening within the PROSPR Consortium.

BACKGROUND: Primary care providers and health systems have prominent roles in guiding effective cancer screening. OBJECTIVE: To characterize variation in screening abnormality rates and timely initial follow-up for common cancer screening tests. DESIGN: Population-based cohort undergoing screening in 2011, 2012, or 2013 at seven research centers comprising the National Cancer Institute-sponsored Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) consortium. PARTICIPANTS: Adults undergoing mammography with or without digital breast tomosynthesis (n = 97,683 ages 40-75 years), fecal occult blood or fecal immunochemical tests (n = 759,553 ages 50-75 years), or Papanicolaou with or without human papillomavirus tests (n = 167,330 ages 21-65 years). INTERVENTION: Breast, colorectal, or cervical cancer screening. MAIN MEASURES: Abnormality rates per 1000 screens; percentage with timely initial follow-up (within 90 days, except 9-month window for BI-RADS 3). Primary care clinic-level variation in percentage with screening abnormality and percentage with timely initial follow-up. KEY RESULTS: There were 10,248/97,683 (104.9 per 1000) abnormal breast cancer screens, 35,847/759,553 (47.2 per 1000) FOBT/FIT-positive colorectal cancer screens, and 13,266/167,330 (79.3 per 1000) abnormal cervical cancer screens. The percentage with timely follow-up was 93.2 to 96.7 % for breast centers, 46.8 to 68.7  % for colorectal centers, and 46.6 % for the cervical cancer screening center (low-grade squamous intraepithelial lesions or higher). The primary care clinic variation (25th to 75th percentile) was smaller for the percentage with an abnormal screen (breast, 8.5-10.3 %; colorectal, 3.0-4.8 %; cervical, 6.3-9.9 %) than for the percentage with follow-up within 90 days (breast, 90.2-95.8 %; colorectal, 43.4-52.0 %; cervical, 29.6-61.4 %). CONCLUSIONS: Variation in both the rate of screening abnormalities and their initial follow-up was evident across organ sites and primary care clinics. This highlights an opportunity for improving the delivery of cancer screening through focused study of patient, provider, clinic, and health system characteristics associated with timely follow-up of screening abnormalities.

Investigating social cognition in epilepsy using a naturalistic task.

OBJECTIVE: The primary objective for this study was to assess social cognition in patients with focal epilepsy using a naturalistic task, which accurately models complex real-world social interaction. METHODS: We conducted an observational study of social cognition in 43 patients with focal epilepsy and in 22 controls. Patients and controls completed The Awareness of Social Inference Test, which measures both basic and advanced social cognition in a realistic video-based format. Patient and controls also completed standard measures of cognitive functioning and measures of depression. RESULTS: Compared to controls, we found that patients with epilepsy (PWEs) had no difficulty identifying positively valenced emotional states (happiness) yet had difficulty identifying most negatively valenced emotional states (anger, fear, and disgust). In addition, PWEs were able to identify sincere exchanges correctly but could not identify sarcastic and insincere exchanges. We found that basic social cognition significantly correlated with standard generalized cognitive measures, whereas advanced social cognition did not. Finally, age at onset had significant impact on social cognition, whereas other epilepsy characteristics did not. SIGNIFICANCE: PWEs have deficits in social cognition when measured using a naturalistic video-based task. Advanced social cognition may be an independent cognitive domain in PWEs that is not adequately measured using standard psychometric instruments. Problems with social cognition may arise as a consequence of epilepsy during the periods of robust social development in childhood and adolescence.

The Association Between Use of Chiropractic Care and Costs of Care Among Older Medicare Patients With Chronic Low Back Pain and Multiple Comorbidities.

OBJECTIVE: The purpose of this study was to determine whether use of chiropractic manipulative treatment (CMT) was associated with lower healthcare costs among multiply-comorbid Medicare beneficiaries with an episode of chronic low back pain (cLBP). METHODS: We conducted an observational, retrospective study of 2006 to 2012 Medicare fee-for-service reimbursements for 72326 multiply-comorbid patients aged 66 and older with cLBP episodes and 1 of 4 treatment exposures: chiropractic manipulative treatment (CMT) alone, CMT followed or preceded by conventional medical care, or conventional medical care alone. We used propensity score weighting to address selection bias. RESULTS: After propensity score weighting, total and per-episode day Part A, Part B, and Part D Medicare reimbursements during the cLBP treatment episode were lowest for patients who used CMT alone; these patients had higher rates of healthcare use for low back pain but lower rates of back surgery in the year following the treatment episode. Expenditures were greatest for patients receiving medical care alone; order was irrelevant when both CMT and medical treatment were provided. Patients who used only CMT had the lowest annual growth rates in almost all Medicare expenditure categories. While patients who used only CMT had the lowest Part A and Part B expenditures per episode day, we found no indication of lower psychiatric or pain medication expenditures associated with CMT. CONCLUSIONS: This study found that older multiply-comorbid patients who used only CMT during their cLBP episodes had lower overall costs of care, shorter episodes, and lower cost of care per episode day than patients in the other treatment groups. Further, costs of care for the episode and per episode day were lower for patients who used a combination of CMT and conventional medical care than for patients who did not use any CMT. These findings support initial CMT use in the treatment of, and possibly broader chiropractic management of, older multiply-comorbid cLBP patients.

A Pilot Study of Ultrasound-Guided Cryoablation of Invasive Ductal Carcinomas up to 15 mm With MRI Follow-Up and Subsequent Surgical Resection.

OBJECTIVE: The purpose of this study was to evaluate the effectiveness of ultrasound-guided cryoablation in treating small invasive ductal carcinoma and to assess the role of contrast-enhanced (CE) MRI in determining the outcome of cryoablation. SUBJECTS AND METHODS: Twenty consecutive participants with invasive ductal carcinomas up to 15 mm, with limited or no ductal carcinoma in situ (DCIS), underwent ultrasound-guided cryoablation. Preablation mammography, ultrasound, and CE-MRI were performed to assess eligibility. Clinical status was evaluated at 1 day, 7-10 days, and 2 weeks after ablation. CE-MRI was performed 25-40 days after ablation, followed by surgical resection within 5 days. RESULTS: Ultrasound-guided cryoablation was uniformly technically successful, and postablation clinical status was good to excellent in all participants. Cryoablation was not clinically successful in 15% (three of 20 patients). Three participants had residual cancer at the periphery of the cryoablation site. Two participants had viable nonmalignant tissue within the central zone of cryoablation-induced necrosis. Postablation CE-MRI had a sensitivity of 0% (0/3) and specificity of 88% (15/17). The predictive value of negative findings on CE-MRI was 83% (15/18). Correlations between cancer characteristics, cryoablation procedural variables, postablation CE-MRI findings, and surgical specimen features were not statistically significant. There were also no significant differences in participants with or without residual cancer. CONCLUSION: In our pilot experience, ultrasound-guided cryoablation of invasive ductal carcinomas up to 15 mm has a clinical failure rate of 15% but is technically feasible and well tolerated by patients. The majority of cryoablation failures are manifest as DCIS outside the cryoablation field. Postablation CE-MRI does not reliably predict cryoablation outcome.

Evaluation of an Automated Information Extraction Tool for Imaging Data Elements to Populate a Breast Cancer Screening Registry.

Breast cancer screening is central to early breast cancer detection. Identifying and monitoring process measures for screening is a focus of the National Cancer Institute's Population-based Research Optimizing Screening through Personalized Regimens (PROSPR) initiative, which requires participating centers to report structured data across the cancer screening continuum. We evaluate the accuracy of automated information extraction of imaging findings from radiology reports, which are available as unstructured text. We present prevalence estimates of imaging findings for breast imaging received by women who obtained care in a primary care network participating in PROSPR (n = 139,953 radiology reports) and compared automatically extracted data elements to a "gold standard" based on manual review for a validation sample of 941 randomly selected radiology reports, including mammograms, digital breast tomosynthesis, ultrasound, and magnetic resonance imaging (MRI). The prevalence of imaging findings vary by data element and modality (e.g., suspicious calcification noted in 2.6% of screening mammograms, 12.1% of diagnostic mammograms, and 9.4% of tomosynthesis exams). In the validation sample, the accuracy of identifying imaging findings, including suspicious calcifications, masses, and architectural distortion (on mammogram and tomosynthesis); masses, cysts, non-mass enhancement, and enhancing foci (on MRI); and masses and cysts (on ultrasound), range from 0.8 to1.0 for recall, precision, and F-measure. Information extraction tools can be used for accurate documentation of imaging findings as structured data elements from text reports for a variety of breast imaging modalities. These data can be used to populate screening registries to help elucidate more effective breast cancer screening processes.

Comparing Propensity Score Methods for Creating Comparable Cohorts of Chiropractic Users and Nonusers in Older, Multiply Comorbid Medicare Patients With Chronic Low Back Pain.

OBJECTIVE: Patients who use complementary and integrative health services like chiropractic manipulative treatment (CMT) often have different characteristics than do patients who do not, and these differences can confound attempts to compare outcomes across treatment groups, particularly in observational studies when selection bias may occur. The purposes of this study were to provide an overview on how propensity scoring methods can be used to address selection bias by balancing treatment groups on key variables and to use Medicare data to compare different methods for doing so. METHODS: We described 2 propensity score methods (matching and weighting). Then we used Medicare data from 2006 to 2012 on older, multiply comorbid patients who had a chronic low back pain episode to demonstrate the impact of applying methods on the balance of demographics of patients between 2 treatment groups (those who received only CMT and those who received no CMT during their episodes). RESULTS: Before application of propensity score methods, patients who used only CMT had different characteristics from those who did not. Propensity score matching diminished observed differences across the treatment groups at the expense of reduced sample size. However, propensity score weighting achieved balance in patient characteristics between the groups and allowed us to keep the entire sample. CONCLUSIONS: Although propensity score matching and weighting have similar effects in terms of balancing covariates, weighting has the advantage of maintaining sample size, preserving external validity, and generalizing more naturally to comparisons of 3 or more treatment groups. Researchers should carefully consider which propensity score method to use, as using different methods can generate different results.

The SPORT value compass: do the extra costs of undergoing spine surgery produce better health benefits?

BACKGROUND: The Spine Patient Outcomes Research Trial aimed to determine the comparative effectiveness of surgical care versus nonoperative care by measuring longitudinal values: outcomes, satisfaction, and costs. METHODS: This paper aims to summarize available evidence from the Spine Patient Outcomes Research Trial by addressing 2 important questions about outcomes and costs for 3 types of spine problem: (1) how do outcomes and costs of spine patients differ depending on whether they are treated surgically compared with nonoperative care? (2) What is the incremental cost per quality adjusted life year for surgical care over nonoperative care? RESULTS: After 4 years of follow-up, patients with 3 spine conditions that may be treated surgically or nonoperatively have systematic differences in value endpoints. The average surgical patient enjoys better health outcomes and higher treatment satisfaction but incurs higher costs. CONCLUSIONS: Spine care is preference sensitive and because outcomes, satisfaction, and costs vary over time and between patients, data on value can help patients make better-informed decisions and help payers know what their dollars are buying.

Peer review of clinical and translational research manuscripts: Perspectives from statistical collaborators.

Research articles in the clinical and translational science literature commonly use quantitative data to inform evaluation of interventions, learn about the etiology of disease, or develop methods for diagnostic testing or risk prediction of future events. The peer review process must evaluate the methodology used therein, including use of quantitative statistical methods. In this manuscript, we provide guidance for peer reviewers tasked with assessing quantitative methodology, intended to complement guidelines and recommendations that exist for manuscript authors. We describe components of clinical and translational science research manuscripts that require assessment including study design and hypothesis evaluation, sampling and data acquisition, interventions (for studies that include an intervention), measurement of data, statistical analysis methods, presentation of the study results, and interpretation of the study results. For each component, we describe what reviewers should look for and assess; how reviewers should provide helpful comments for fixable errors or omissions; and how reviewers should communicate uncorrectable and irreparable errors. We then discuss the critical concepts of transparency and acceptance/revision guidelines when communicating with responsible journal editors.

Microwave imaging for neoadjuvant chemotherapy monitoring: initial clinical experience.

INTRODUCTION: Microwave tomography recovers images of tissue dielectric properties, which appear to be specific for breast cancer, with low-cost technology that does not present an exposure risk, suggesting the modality may be a good candidate for monitoring neoadjuvant chemotherapy. METHODS: Eight patients undergoing neoadjuvant chemotherapy for locally advanced breast cancer were imaged longitudinally five to eight times during the course of treatment. At the start of therapy, regions of interest (ROIs) were identified from contrast-enhanced magnetic resonance imaging studies. During subsequent microwave examinations, subjects were positioned with their breasts pendant in a coupling fluid and surrounded by an immersed antenna array. Microwave property values were extracted from the ROIs through an automated procedure and statistical analyses were performed to assess short term (30 days) and longer term (four to six months) dielectric property changes. RESULTS: Two patient cases (one complete and one partial response) are presented in detail and demonstrate changes in microwave properties commensurate with the degree of treatment response observed pathologically. Normalized mean conductivity in ROIs from patients with complete pathological responses was significantly different from that of partial responders (P value = 0.004). In addition, the normalized conductivity measure also correlated well with complete pathological response at 30 days (P value = 0.002). CONCLUSIONS: These preliminary findings suggest that both early and late conductivity property changes correlate well with overall treatment response to neoadjuvant therapy in locally advanced breast cancer. This result is consistent with earlier clinical outcomes that lesion conductivity is specific to differentiating breast cancer from benign lesions and normal tissue.

Adoptive cellular therapy using cells enriched for NKG2D+CD3+CD8+T cells after autologous transplantation for myeloma.

The number of circulating lymphocytes on day 15 after transplantation correlates with improved survival in patients with myeloma, but the lymphocyte subset responsible is unknown. NKG2D is a natural killer (NK) cell activating receptor that mediates non-MHC restricted and TCR-independent cell lysis. Our preliminary results indicate that CD3(+)CD8(+) T cells expressing NKG2D may be a critical lymphocyte population. A phase II trial examined the feasibility of infusing ex vivo-expanded cells enriched for NKG2D(+)CD3(+)CD8(+) T cells at weeks 1, 2, 4, and 8 after an autologous transplantation. In addition, low-dose IL-2 (6 × 10(5) IU/m(2)/day) was administered for 4 weeks, beginning on the day of transplantation. Twenty-three patients were accrued and 19 patients are evaluable. There were no treatment-related deaths. All patients completed their course of IL-2 and demonstrated normal engraftment. When compared with patients with myeloma who underwent transplantation not receiving posttransplantation immune therapy, the treated patients demonstrated an increase in the number of circulating NKG2D(+)CD3(+)CD8(+) T cells/µL (P < .004), CD3(+)CD8(+) T cells/µL (P < .04), CD3(+)CD8(+)CD56(+) T cells/µL (P < .004), and NKG2D(+)CD3(-)CD56(+) T cells/µL (P < .003). Myeloma cell-directed cytotoxicity by the circulating mononuclear cells increased after transplantation (P < .002). When compared to posttransplantation IL-2 therapy alone in this patient population, the addition of cells enriched for NKG2D(+)CD3(+)CD8(+) T cells increased tumor-specific immunity, as demonstrated by enhanced lysis of autologous myeloma cells (P = .02). We postulate that this regimen that increased the number and function of the NKG2D(+)CD3(+)CD8(+) T cells after transplantation may improve clinical outcomes by eliminating residual malignant cells in vivo.

A proof of principle clinical trial to determine whether conjugated linoleic acid modulates the lipogenic pathway in human breast cancer tissue.

Conjugated linoleic acid (CLA) is widely used as a "nutraceutical" for weight loss. CLA has anticancer effects in preclinical models, and we demonstrated in vitro that this can be attributed to the suppression of fatty acid (FA) synthesis. We tested the hypothesis that administration of CLA to breast cancer patients would inhibit expression of markers related to FA synthesis in tumor tissue, and that this would suppress tumor proliferation. Women with Stage I-III breast cancer were enrolled into an open label study and treated with CLA (1:1 mix of 9c,11t- and 10t,12c-CLA isomers, 7.5 g/d) for ≥ 10 days before surgery. Fasting plasma CLA concentrations measured pre- and post-CLA administration, and pre/post CLA tumor samples were examined by immunohistochemistry for Spot 14 (S14), a regulator of FA synthesis, FA synthase (FASN), an enzyme of FA synthesis, and lipoprotein lipase (LPL), the enzyme that allows FA uptake. Tumors were also analyzed for expression of Ki-67 and cleaved caspase 3. 24 women completed study treatment, and 23 tumors were evaluable for the primary endpoint. The median duration of CLA therapy was 12 days, and no significant toxicity was observed. S14 expression scores decreased (p = 0.003) after CLA administration. No significant change in FASN or LPL expression was observed. Ki-67 scores declined (p = 0.029), while cleaved caspase 3 staining was unaffected. Decrements in S14 or Ki-67 did not correlate with fasting plasma CLA concentrations at surgery. Breast tumor tissue expression of S14, but not FASN or LPL, was decreased after a short course of treatment with 7.5 g/day CLA. This was accompanied by reductions in the proliferation index. CLA consumption was well-tolerated and safe at this dose for up to 20 days. Overall, CLA may be a prototype compound to target fatty acid synthesis in breast cancers with a "lipogenic phenotype".