Comparison of lung cancer occurring in fibrotic versus non-fibrotic lung on chest CT.

PURPOSE: Evaluate the behavior of lung nodules occurring in areas of pulmonary fibrosis and compare them to pulmonary nodules occurring in the non-fibrotic lung parenchyma. METHODS: This retrospective review of chest CT scans and electronic medical records received expedited IRB approval and a waiver of informed consent. 4500 consecutive patients with a chest CT scan report containing the word fibrosis or a specific type of fibrosis were identified using the system M*Model Catalyst (Maplewood, Minnesota, U.S.). The largest nodule was measured in the longest dimension and re-evaluated, in the same way, on the follow-up exam if multiple time points were available. The nodule doubling time was calculated. If the patient developed cancer, the histologic diagnosis was documented. RESULTS: Six hundred and nine patients were found to have at least one pulmonary nodule on either the first or the second CT scan. 274 of the largest pulmonary nodules were in the fibrotic tissue and 335 were in the non-fibrotic lung parenchyma. Pathology proven cancer was more common in nodules occurring in areas of pulmonary fibrosis compared to nodules occurring in areas of non-fibrotic lung (34% vs 15%, p < 0.01). Adenocarcinoma was the most common cell type in both groups but more frequent in cancers occurring in non-fibrotic tissue. In the non-fibrotic lung, 1 of 126 (0.8%) of nodules measuring 1 to 6 mm were cancer. In contrast, 5 of 49 (10.2%) of nodules in fibrosis measuring 1 to 6 mm represented biopsy-proven cancer (p < 0.01). The doubling time for squamous cell cancer was shorter in the fibrotic lung compared to non-fibrotic lung, however, the difference was not statistically significant (p = 0.24). 15 incident lung nodules on second CT obtained ≤ 18 months after first CT scan was found in fibrotic lung and eight (53%) were diagnosed as cancer. CONCLUSIONS: Nodules occurring in fibrotic lung tissue are more likely to be cancer than nodules in the nonfibrotic lung. Incident pulmonary nodules in pulmonary fibrosis have a high likelihood of being cancer.

Performance of Xpert HPV on Self-collected Vaginal Samples for Cervical Cancer Screening Among Women in South Africa.

OBJECTIVES: Self-sampling may increase access to cervical cancer screening in low-resource settings. Using Xpert HPV, we compared test performance of self- and clinician-collected samples in HIV-positive and HIV-negative women in South Africa. MATERIALS AND METHODS: Three hundred thirty HIV-positive and 375 HIV-negative women in the screening group and 202 HIV-negative and 200 HIV-positive women in the referral group, aged 30-65 years, participated in the study. All women self-collected a vaginal sample, and then, a cervical sample was collected by a clinician (both tested using Xpert HPV), followed by colposcopic examination and collection of histologic specimens. RESULTS: There was good agreement between self- and clinician-collected samples for detection of any high-risk human papillomavirus (HPV, κ = 0.72 [95% CI = 0.669-0.771]). Prevalence of HPV and sensitivity of the test to detect cervical intraepithelial neoplasia 2+ was similar in self- and clinician-collected samples. Specificity was lower in self-collected than in clinician-collected samples in both HIV-negative (self: 77.5% [95% CI = 72.8-81.8] vs clinician: 86.9% [95% CI = 82.9-90.2]) and HIV-positive (self: 44.0% [95% CI = 38.0-50.1] vs clinician: 59.7% [95% CI = 53.6-65.6]) women. Restricting the definition of screen-positive to 3 of 5 channels on HPV Xpert improved specificity in both HIV-negative (self: 83.2% [95% CI = 78.8-87.0] vs clinician: 89.7% [95% CI = 86.1-92.7]) and HIV-positive (self: 54.2% [95% CI = 48.1-60.2] vs clinician: 67.4% [95% CI = 61.5-72.9]) women. CONCLUSIONS: The self-collected sample had good agreement with the clinician-collected sample for the detection of HPV, and restricting the HPV types may improve the specificity in HIV-positive women.

A Trial of Sertraline or Cognitive Behavior Therapy for Depression in Epilepsy.

OBJECTIVE: Limited evidence is available to guide treatment of depression for persons with epilepsy. We evaluated the comparative effectiveness of sertraline and cognitive behavior therapy (CBT) for depression, quality of life, seizures, and adverse treatment effects. METHODS: We randomly assigned 140 adult outpatients with epilepsy and current major depressive disorder to sertraline or weekly CBT for 16 weeks. The primary outcome was remission from depression based on the Mini International Neuropsychiatric Interview (MINI). Secondary outcomes included the Quality of Life in Epilepsy Inventory-89 (QOLIE-89) seizure rates, the Adverse Events Profile (AEP), the Beck Depression Inventory, and MINI Suicide Risk Module. RESULTS: In the intention-to-treat analysis, 38 (52.8%; 95% confidence interval [CI] = ±12) of the 72 subjects assigned to sertraline and 41 (60.3%; 95% CI = ±11.6) of the 68 subjects in the CBT group achieved remission; the lower bound of efficacy for both groups was greater than our historical placebo control group upper bound of 33.7%. Difference in time to remission between groups was 2.8 days (95% CI = ±0.43; p = 0.79). The percent improvement of mean QOLIE-89 scores was significant for both the CBT (25.7%; p < 0.001) and sertraline (28.3%; p < 0.001) groups. The difference in occurrence of generalized tonic-clonic seizures between groups was 0.3% (95% CI = ±8.6; p = 0.95). Suicide risk at final assessment was associated with persistent depression (p < 0.0001) but not seizures or sertraline. INTERPRETATION: Depression remitted in just over one-half of subjects following sertraline or CBT. Despite the complex psychosocial disability associated with epilepsy, improving depression benefits quality of life. Serotonin reuptake inhibition does not appear to increase seizures or suicidality in persons with epilepsy. ANN NEUROL 2019;86:552-560.

Use of Bisphosphonates in Elderly Patients With Newly Diagnosed Multiple Myeloma.

Background: Bisphosphonates reduce skeletal-related events (SREs) in patients with multiple myeloma (MM) and, in some studies, improved survival. Since 2011, bisphosphonate use has been recommended by NCCN for all patients with newly diagnosed MM receiving antineoplastic therapy independent of the presence of bone disease. This study investigated their use after these guidelines were established. Methods: We identified patients aged ≥65 years in the SEER-Medicare database with newly diagnosed MM between January 1, 2012, and December 31, 2013, who received antineoplastic therapy, had ≥6 months of follow-up, and did not receive prior bisphosphonates. Presence of SREs at diagnosis was identified, including pathologic fracture, spinal cord compression, radiation to bone, or surgery to bone. Use of bisphosphonates was defined as having ≥1 claim for an intravenous or oral bisphosphonate within 6 months after the start of antineoplastic therapy. We used multivariable modeling to compare users with nonusers, controlling for demographic and clinical covariates. We compared overall survival between users and nonusers using proportional hazards analysis. Results: Of 1,309 patients identified, 720 (55%) used a bisphosphonate. Factors associated with use included SRE at diagnosis (adjusted odds ratio [AOR], 2.60; 95% CI, 1.98-3.40), hypercalcemia (AOR, 1.74; 95% CI, 1.26-2.41), and use of proteasome inhibitor + immunomodulatory imide therapy (AOR, 1.70; 95% CI, 1.21-2.39). Chronic kidney disease (AOR, 0.48; 95% CI, 0.35-0.66) was associated with decreased use. Bisphosphonate use was associated with reduced mortality (hazard ratio, 0.70; 95% CI, 0.56-0.88). Conclusions: Although bisphosphonate use is recommended for all patients with newly diagnosed MM receiving antineoplastic therapy, 45% of patients in the United States did not receive this guideline-recommended care.

Study protocol: a cluster randomized controlled trial of web-based decision support tools for increasing BRCA1/2 genetic counseling referral in primary care.

BACKGROUND: BRCA1 and BRCA2 mutations confer a substantial breast risk of developing breast cancer to those who carry them. For this reason, the United States Preventative Services Task Force (USPSTF) has recommended that all women be screened in the primary care setting for a family history indicative of a mutation, and women with strong family histories of breast or ovarian cancer be referred to genetic counseling. However, few high-risk women are being routinely screened and fewer are referred to genetic counseling. To address this need we have developed two decision support tools that are integrated into clinical care. METHOD: This study is a cluster randomized controlled trial of high-risk patients and their health care providers. Patient-provider dyads will be randomized to receive either standard education that is supplemented with the patient-facing decision aid, RealRisks, and the provider-facing Breast Cancer Risk Navigation Toolbox (BNAV) or standard education alone. We will assess these tools' effectiveness in promoting genetic counseling uptake and informed and shared decision making about genetic testing. DISCUSSION: If found to be effective, these tools can help integrate genomic risk assessment into primary care and, ultimately, help expand access to risk-appropriate breast cancer prevention options to a broader population of high-risk women. TRIAL REGISTRATION: This trial is retrospectively registered with ClinicalTrials.gov Identifier: NCT03470402 : 20 March 2018.

Psychosocial factors related to non-persistence with adjuvant endocrine therapy among women with breast cancer: the Breast Cancer Quality of Care Study (BQUAL).

Non-adherence to adjuvant endocrine therapy (ET) for breast cancer (BC) is common. Our goal was to determine the associations between psychosocial factors and ET non-persistence. We recruited women with BC receiving care in an integrated healthcare system between 2006 and 2010. Using a subset of patients treated with ET, we investigated factors related to ET non-persistence (discontinuation) based on pharmacy records (≥90 days gap). Serial interviews were conducted at baseline and every 6 months. The Functional Assessment of Cancer Therapy (FACT), Medical Outcomes Survey, Treatment Satisfaction Questionnaire (TSQM), Impact of Events Scale (IES), Interpersonal Processes of Care measure, and Decision-making beliefs and concerns were measured. Multivariate models assessed factors associated with non-persistence. Of the 523 women in our final cohort who initiated ET and had a subsequent evaluation, 94 (18 %) were non-persistent over a 2-year follow-up. The cohort was primarily white (74.4 %), stage 1 (60.6 %), and on an aromatase inhibitor (68.1 %). Women in the highest income category had a lower odds of being non-persistent (OR 0.43, 95 % CI 0.23-0.81). Quality of life and attitudes toward ET at baseline were associated with non-persistence. At follow-up, the FACT, TSQM, and IES were associated with non-persistence (p < 0.001). Most women continued ET. Women who reported a better attitude toward ET, better quality of life, and more treatment satisfaction, were less likely to be non-persistent and those who reported intrusive/avoidant thoughts were more likely to be non-persistent. Interventions to enhance the psychosocial well-being of patients should be evaluated to increase adherence.

A prospective cohort study of early discontinuation of adjuvant chemotherapy in women with breast cancer: the breast cancer quality of care study (BQUAL).

For many women with non-metastatic breast cancer, adjuvant chemotherapy prevents recurrence and extends survival. Women who discontinue chemotherapy early may reduce those benefits, but little is known about what predicts early discontinuation. We sought to determine prospectively the rate and reasons for early discontinuation of adjuvant chemotherapy in women with breast cancer. We conducted a prospective cohort study among three U.S. health care organizations. Of 1158 women with newly diagnosed non-metastatic breast cancer, 2006-2010, we analyzed 445 (38.4 %) patients who initiated standard adjuvant chemotherapy as defined by accepted guidelines. We interviewed patients at baseline and twice during treatment regarding sociodemographic/psychosocial factors and treatment decision-making and collected clinical data. They were categorized according to the number of cycles required by the chemotherapy regimen they had initiated. The outcome was early discontinuation (<80 % of planned cycles). Of patients analyzed, 392 (88.1 %) completed the prescribed therapy. The strongest predictor was receipt of a regimen entailing >4 cycles of therapy (18.1 % for longer regimens, 7.4 % for 4 cycles) (odds ratio [OR] 2.59, 95 % CI 1.32-5.08), controlling for race, age, stage, hormone receptor status, social support, optimism, spirituality, stress, and physical symptoms. Higher levels of psychological symptoms on the Memorial symptom assessment scale also increased the odds of early discontinuation (OR 1.92, 95 % CI 0.998-3.68). The large majority of patients who initiated adjuvant chemotherapy for breast cancer completed their prescribed regimens, but early discontinuation was associated with lengthier regimens and, with borderline statistical significance, for those with psychological side effects.

Confidence intervals for the ratio of two median residual lifetimes with left-truncated and right-censored data.

The confidence intervals for the ratio of two median residual lifetimes are developed for left-truncated and right-censored data. The approach of Su and Wei (1993) is first extended by replacing the Kaplan-Meier survival estimator with the estimator of the conditional survival function (Lynden-Bell, 1971). This procedure does not involve a nonparametric estimation of the probability density function of the failure time. However, the Su and Wei type confidence intervals are very conservative even for larger sample size. Therefore, this article proposes an alternative confidence interval for the ratio of two median residual lifetimes, which is not only without nonparametric estimation of the density function of failure times but is also computationally simpler than the Su and Wei type confidence interval. A simulation study is conducted to examine the accuracy of these confidence intervals and the implementation of these confidence intervals to two real data sets is illustrated.

Dietary modifications, weight loss, and changes in metabolic markers affect global DNA methylation in Hispanic, African American, and Afro-Caribbean breast cancer survivors.

BACKGROUND: Lower levels of global DNA methylation in tissue and blood have been associated with increased cancer risk. Conversely, cross-sectional analyses of healthier lifestyle patterns have been associated with higher levels of global DNA methylation. OBJECTIVE: In this trial, we explored the associations between changes in lifestyle modifications (diet, weight loss), metabolic markers, and global epigenetic biomarkers in white blood cells. METHODS: Study participants were Hispanic, African American, and Afro-Caribbean overweight and sedentary female breast cancer survivors (n = 24) who participated in a larger randomized, crossover, pilot study of a 6-mo weight loss intervention and who had available blood specimens. Anthropometric measures, a food-frequency questionnaire, and peripheral blood were collected at baseline, 6 mo, and 12 mo. Plasma samples were analyzed for metabolic markers (insulin, glucose). We measured DNA methylation of long interspersed nucleotide element 1 (LINE-1) and satellite 2 by pyrosequencing and MethyLight, respectively, and global DNA methylation by the luminometric methylation assay (LUMA). RESULTS: DNA methylation of LINE-1 was statistically significantly elevated at 6 mo [75.5% vs. 78.5% (P < 0.0001)] and 12 mo [75.5% vs. 77.7% (P < 0.0001)], compared to baseline. Over a 12-mo period, changes in percentage body fat and plasma glucose concentrations were positively associated with LINE-1 DNA methylation (ß = 0.19, P = 0.001) and LUMA DNA methylation levels (ß = 0.24, P = 0.02), respectively. Similarly, 12-mo changes in dietary measures such as vegetable (ß = 0.009, P = 0.048), protein (ß = 0.04, P = 0.001), and total caloric (ß = 0.05, P = 0.01) intake were positively associated with changes in LUMA DNA methylation, as was intake of fruit positively associated with changes in LINE-1 DNA methylation (ß = 0.004, P = 0.02). CONCLUSIONS: Our hypothesis-generating results suggest that lifestyle modifications may be associated with changes in global DNA methylation detectable at 6 and 12 mo. These biomarkers may be useful intermediate biomarkers to use in future intervention trials. This trial was registered at clinicaltrials.gov as NCT00811824.

An alternative approach to confidence interval estimation for the win ratio statistic.

Pocock et al. (2012, European Heart Journal 33, 176-182) proposed a win ratio approach to analyzing composite endpoints comprised of outcomes with different clinical priorities. In this article, we establish a statistical framework for this approach. We derive the null hypothesis and propose a closed-form variance estimator for the win ratio statistic in all pairwise matching situation. Our simulation study shows that the proposed variance estimator performs well regardless of the magnitude of treatment effect size and the type of the joint distribution of the outcomes.