Protein-membrane interactions: sensing and generating curvature.

Biological membranes are integral cellular structures that can be curved into various geometries. These curved structures are abundant in cells as they are essential for various physiological processes. However, curved membranes are inherently unstable, especially on nanometer length scales. To stabilize curved membranes, cells can utilize proteins that sense and generate membrane curvature. In this review, we summarize recent research that has advanced our understanding of interactions between proteins and curved membrane surfaces, as well as work that has expanded our ability to study curvature sensing and generation. Additionally, we look at specific examples of cellular processes that require membrane curvature, such as neurotransmission, clathrin-mediated endocytosis (CME), and organelle biogenesis.

Effect of Patient Navigation on Completion of Lung Cancer Screening in Vulnerable Populations.

BACKGROUND: Although low-dose, CT-based lung cancer screening (LCS) can decrease lung cancer mortality in high-risk individuals, the process may be complex and pose challenges to patients, particularly those from minority underinsured and uninsured populations. We conducted a randomized controlled trial of telephone-based navigation for LCS within an integrated, urban, safety-net health care system. PATIENTS AND METHODS: Patients eligible for LCS were randomized (1:1) to usual care with or without navigation at Parkland Health in Dallas, Texas. The primary endpoint was completion of the first 3 consecutive steps in a patient's LCS process. We explored differences in completion of LCS steps between navigation and usual care groups, controlling for patient characteristics using the chi-square test. RESULTS: Patients (N=447) were randomized to either navigation (n=225) or usual care (n=222). Mean patient age was 62 years, 46% were female, and 69% were racial/ethnic minorities. There was no difference in completion of the first 3 steps of the LCS algorithm between arms (12% vs 9%, respectively; P=.30). For ordered LCS steps, completion rates were higher among patients who received navigation (86% vs 79%; P=.03). The primary reason for step noncompletion was lack of order placement. CONCLUSIONS: In this study, lack of order placement was a key reason for incomplete LCS steps. When orders were placed, patients who received navigation had higher rates of completion. Clinical team education and enhanced electronic health record processes to simplify order placement, coupled with patient navigation, may improve LCS in safety-net health care systems.

Geographic Accessibility and Completion of Initial Low-Dose CT-Based Lung Cancer Screening in an Urban Safety-Net Population.

BACKGROUND: Recent modifications to low-dose CT (LDCT)-based lung cancer screening guidelines increase the number of eligible individuals, particularly among racial and ethnic minorities. Because these populations disproportionately live in metropolitan areas, we analyzed the association between travel time and initial LDCT completion within an integrated, urban safety-net health care system. METHODS: Using Esri's StreetMap Premium, OpenStreetMap, and the r5r package in R, we determined projected private vehicle and public transportation travel times between patient residence and the screening facility for LDCT ordered in March 2017 through December 2022 at Parkland Memorial Hospital in Dallas, Texas. We characterized associations between travel time and LDCT completion in univariable and multivariable analyses. We tested these associations in a simulation of 10,000 permutations of private vehicle and public transportation distribution. RESULTS: A total of 2,287 patients were included in the analysis, of whom 1,553 (68%) completed the initial ordered LDCT. Mean age was 63 years, and 73% were underrepresented minorities. Median travel time from patient residence to the LDCT screening facility was 17 minutes by private vehicle and 67 minutes by public transportation. There was a small difference in travel time to the LDCT screening facility by public transportation for patients who completed LDCT versus those who did not (67 vs 66 min, respectively; P=.04) but no difference in travel time by private vehicle for these patients (17 min for both; P=.67). In multivariable analysis, LDCT completion was not associated with projected travel time to the LDCT facility by private vehicle (odds ratio, 1.01; 95% CI, 0.82-1.25) or public transportation (odds ratio, 1.14; 95% CI, 0.89-1.44). Similar results were noted across travel-type permutations. Black individuals were 29% less likely to complete LDCT screening compared with White individuals. CONCLUSIONS: In an urban population comprising predominantly underrepresented minorities, projected travel time is not associated with initial LDCT completion in an integrated health care system. Other reasons for differences in LDCT completion warrant investigation.

Tropheryma whipplei Infection (Whipple Disease) in the USA.

BACKGROUND: Whipple disease (WD) is an infection caused by the bacterium Tropheryma whipplei (TW). Few cases have been reported in the USA. AIMS: To report on the demographics, clinical manifestations, diagnostic findings, treatment, and outcomes of TW infection. METHODS: Cases of TW infection diagnosed from 1995 to 2010 were identified in three US referral centers and from 1995 to 2015 in one. Definite classic WD was defined by positive periodic acid-Schiff (PAS) staining and probable WD by specific positive TW polymerase chain reaction (PCR) of intestinal specimens. Localized infections were defined by a positive TW PCR result from samples of other tissues/body fluids. RESULTS: Among the 33 cases of TW infections, 27 (82%) were male. Median age at diagnosis was 53 years (range 11-75). Diagnosis was supported by a positive TW PCR in 29 (88%) and/or a positive PAS in 16 (48%) patients. Classic WD was the most frequent presentation (n = 18, 55%), with 14 definite and 4 probable cases. Localized infections (n = 15, 45%) affected the central nervous system (n = 7), joints (n = 4), heart (n = 2), eye (n = 1), and skeletal muscle (n = 1). Blood PCR was negative in 9 of 17 (53%) cases at diagnosis. Ceftriaxone intravenously followed by trimethoprim and sulfamethoxazole orally was the most common regimen (n = 23, 70%). Antibiotic therapy resulted in clinical response in 24 (73%). CONCLUSIONS: TW infection can present as intestinal or localized disease. Negative small bowel PAS and PCR do not exclude the diagnosis of TW infection, and blood PCR is insensitive for active infection.

Effects of gender in resident evaluations and certifying examination pass rates.

BACKGROUND: Though the proportion of female Internal Medicine (IM) residents and faculty has increased, there is minimal large scale modern data comparing resident performance by gender. This study sought to examine the effects of resident and faculty gender on resident evaluations. METHODS: Retrospective observational study over 5 years in a single IM program. IM certifying examination pass rates were obtained from the American Board of IM. RESULTS: Four hundred eighty-eight residents (195 women, 293 men), evaluated by 430 attending physicians (163 women, 270 men) were included. Twelve thousand six hundred eighty-one evaluations between 2007 and 2012 were analyzed. Female residents scored higher in two domains (Medical Interviewing, and Interpersonal and Communication Skills) (p < 0.01 for each), with no significant difference between genders for the other domains (Medical Knowledge, Overall Patient Care, Physical Examination, Procedural Skills, Professionalism, Practice Based Learning and Improvement, System Based Practices and Overall score). There were no differences in scoring between female and male attending physicians. There were no differences in certifying examination scores between women and men among graduating residents. National pass rates for women were not statistically different to pass rates for men from 1987 to 2015. CONCLUSIONS: Data from one large academic medical center demonstrate higher ratings for female residents on performance domains reflecting bedside care and interpersonal skills, with similar scores for medical knowledge and remaining domains. No significant difference was seen locally in certifying examination scores, nor in recent national pass rates, an objective measure of medical knowledge. Despite imbalanced female representation in areas of medicine, our data suggest that gender-based disparities in Internal Medicine resident medical knowledge and physician competency are no longer present.

Multitarget stool DNA test: clinical performance and impact on yield and quality of colonoscopy for colorectal cancer screening.

BACKGROUND AND AIMS: Multitarget stool DNA (MT-sDNA) testing is now approved by the U.S. Food and Drug Administration for average-risk colorectal cancer screening. Trials leading to its approval used blinded colonoscopy as the reference standard. In the postapproval screen setting, the clinical performance and impact of MT-sDNA testing on unblinded colonoscopy has not been described. We measured the impact that knowledge of a positive MT-sDNA test result has on colonoscopy yield and quality. METHODS: The unblinded group comprised all patients with positive MT-sDNA results on screening from September 1, 2014 to September 30, 2015 at a single tertiary center. Off-label test patients were excluded. The blinded group included all MT-sDNA-positive participants in a preapproval screening study from the same center. Detailed colonoscopy findings and withdrawal times were recorded. RESULTS: There were 172 MT-sDNA-positive patients in the unblinded group and 72 in the blinded group. More total adenomatous/sessile serrated polyps (70% vs 53%, P = .013) and advanced neoplasms (28% vs 21%, P = .27) were detected in unblinded than in blinded groups. Median numbers of polyps detected were 2 (IQR, 1-4) and 1 (IQR, 0-2) in unblinded and blinded groups, respectively (P = .0007). Among polyps detected, flat or slightly raised lesions in the right side of the colon were proportionately more frequent with unblinded (40%) than with blinded examinations (9%) (P = .0017). Median withdrawal time was 19 minutes (IQR, 13-29) in the unblinded group compared with 13 minutes (IQR, 10-20) in the blinded group (P = .0001). CONCLUSIONS: Knowledge of a positive MT-sDNA result appears to have a beneficial impact on the diagnostic yield and quality of subsequent colonoscopy.

Trends in the Incidence and Outcomes of Hospitalized Cancer Patients With Clostridium difficile Infection: A Nationwide Analysis.

Background: Patients with cancer have several risk factors for Clostridium difficile infection (CDI), but the impact of CDI on outcomes in this population needs elucidation. We analyzed the incidence of CDI and its impact on outcomes in patients with cancer using the National Hospital Discharge Survey (NHDS) database from 2001 to 2010. Methods: Diagnosis codes were used to identify patients with cancer and CDI events. Demographics, diagnoses, length of stay (LOS), and discharge information were abstracted. Multivariate linear and logistic regression models with weighted analysis were conducted to study CDI incidence and CDI-associated outcomes. Analyses were performed using SAS version 9.4. Results: During the 10-year study period, 20.1 million discharges had a cancer diagnosis. CDI developed in 1.09% of patients with cancer versus 0.77% of patients without cancer (adjusted odds ratio [aOR], 1.28; 95% CI, 1.28-1.29; P<.001). The incidence of CDI in patients with cancer increased during the 10-year study period (64.7 per 10,000 discharges in 2001-2002 to 109.1 in 2009-2010; P<.001). In multivariable analysis, compared with patients with cancer without CDI, patients with cancer and CDI had a longer mean LOS (5.67 days; 95% CI, 5.39-5.94) and higher rates of in-hospital mortality (aOR, 1.18; 95% CI, 1.16-1.20) and discharge to a care facility (aOR, 1.74; 95% CI, 1.72-1.75; all P<.001). Conclusions: In this national database, CDI incidence increased significantly in patients with cancer over the study period and was associated with prolonged hospitalization, increased mortality, and discharge to a care facility. Despite increased attention, CDI remained a serious infection and merits appropriate prevention and management.

Embolization of portosystemic shunts for treatment of medically refractory hepatic encephalopathy.

Treatment options for refractory hepatic encephalopathy (HE) are limited. Patients who fail medical management may harbor large portosystemic shunts (PSSs) which are possible therapeutic targets. This study aims to describe patient selection, effectiveness, and safety of percutaneous PSS embolization in those with medically refractory HE. A retrospective evaluation of consecutive adult patients with medically refractory HE referred for PSS embolization at a tertiary center was performed (2003-2015). Patient data collected included the type of HE, medications, Model for End-Stage Liver Disease (MELD) score, shunt type, embolization approach, and materials used. Outcomes of interest were immediate (7 days), intermediate (1-4 months), and longer-term (6-12 months) effectiveness and periprocedural safety. Effectiveness was determined based on changes in hospitalization frequency, HE medications, and symptoms. Twenty-five patients with large PSS were evaluated for shunt embolization. Five were excluded due to high MELD scores (n = 1), comorbid conditions (n = 1), or technical considerations (n = 3). Of 20 patients who underwent embolization, 13 had persistent and 7 had recurrent HE; 100% (20/20) achieved immediate improvement. Durable benefit was achieved in 100% (18/18) and 92% (11/12) at 1-4 and 6-12 months, respectively. The majority (67%; 8/12) were free from HE-related hospitalizations over 1 year; 10% developed procedural complications, and all resolved. Six developed new or worsening ascites. In conclusion, PSS embolization is a safe and effective treatment strategy that should be considered for select patients with medically refractory HE. Liver Transplantation 22 723-731 2016 AASLD.

Broad 4-hydroxyphenylpyruvate dioxygenase inhibitor herbicide tolerance in soybean with an optimized enzyme and expression cassette.

With an optimized expression cassette consisting of the soybean (Glycine max) native promoter modified for enhanced expression driving a chimeric gene coding for the soybean native amino-terminal 86 amino acids fused to an insensitive shuffled variant of maize (Zea mays) 4-hydroxyphenylpyruvate dioxygenase (HPPD), we achieved field tolerance in transgenic soybean plants to the HPPD-inhibiting herbicides mesotrione, isoxaflutole, and tembotrione. Directed evolution of maize HPPD was accomplished by progressively incorporating amino acids from naturally occurring diversity and novel substitutions identified by saturation mutagenesis, combined at random through shuffling. Localization of heterologously expressed HPPD mimicked that of the native enzyme, which was shown to be dually targeted to chloroplasts and the cytosol. Analysis of the native soybean HPPD gene revealed two transcription start sites, leading to transcripts encoding two HPPD polypeptides. The N-terminal region of the longer encoded peptide directs proteins to the chloroplast, while the short form remains in the cytosol. In contrast, maize HPPD was found almost exclusively in chloroplasts. Evolved HPPD enzymes showed insensitivity to five inhibitor herbicides. In 2013 field trials, transgenic soybean events made with optimized promoter and HPPD variant expression cassettes were tested with three herbicides and showed tolerance to four times the labeled rates of mesotrione and isoxaflutole and two times the labeled rates of tembotrione.

Adjuvant chemotherapy for resected early-stage non-small cell lung cancer.

BACKGROUND: To evaluate the effects of administering chemotherapy following surgery, or following surgery plus radiotherapy (known as adjuvant chemotherapy) in patients with early stage non-small cell lung cancer (NSCLC),we performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data. Results were first published in The Lancet in 2010. OBJECTIVES: To compare, in terms of overall survival, time to locoregional recurrence, time to distant recurrence and recurrence-free survival:A. Surgery versus surgery plus adjuvant chemotherapyB. Surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapyin patients with histologically diagnosed early stage NSCLC.(2)To investigate whether or not predefined patient subgroups benefit more or less from cisplatin-based chemotherapy in terms of survival. SEARCH METHODS: We supplemented MEDLINE and CANCERLIT searches (1995 to December 2013) with information from trial registers, handsearching relevant meeting proceedings and by discussion with trialists and organisations. SELECTION CRITERIA: We included trials of a) surgery versus surgery plus adjuvant chemotherapy; and b) surgery plus radiotherapy versus surgery plus radiotherapy plus adjuvant chemotherapy, provided that they randomised NSCLC patients using a method which precluded prior knowledge of treatment assignment. DATA COLLECTION AND ANALYSIS: We carried out a quantitative meta-analysis using updated information from individual participants from all randomised trials. Data from all patients were sought from those responsible for the trial. We obtained updated individual participant data (IPD) on survival, and date of last follow-up, as well as details of treatment allocated, date of randomisation, age, sex, histological cell type, stage, and performance status. To avoid potential bias, we requested information for all randomised patients, including those excluded from the investigators' original analyses. We conducted all analyses on intention-to-treat on the endpoint of survival. For trials using cisplatin-based regimens, we carried out subgroup analyses by age, sex, histological cell type, tumour stage, and performance status. MAIN RESULTS: We identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone. IPD were available for 26 of these trials and our analyses are based on 8447 participants (3323 deaths) in 34 trial comparisons. There was clear evidence of a benefit of adding chemotherapy after surgery (hazard ratio (HR)= 0.86, 95% confidence interval (CI)= 0.81 to 0.92, p< 0.0001), with an absolute increase in survival of 4% at five years.We identified 15 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone. IPD were available for 12 of these trials and our analyses are based on 2660 participants (1909 deaths) in 13 trial comparisons. There was also evidence of a benefit of adding chemotherapy to surgery plus radiotherapy (HR= 0.88, 95% CI= 0.81 to 0.97, p= 0.009). This represents an absolute improvement in survival of 4% at five years.For both meta-analyses, we found similar benefits for recurrence outcomes and there was little variation in effect according to the type of chemotherapy, other trial characteristics or patient subgroup.We did not undertake analysis of the effects of adjuvant chemotherapy on quality of life and adverse events. Quality of life information was not routinely collected during the trials, but where toxicity was assessed and mentioned in the publications, it was thought to be manageable. We considered the risk of bias in the included trials to be low. AUTHORS' CONCLUSIONS: Results from 47 trial comparisons and 11,107 patients demonstrate the clear benefit of adjuvant chemotherapy for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy. This is the most up-to-date and complete systematic review and individual participant data (IPD) meta-analysis that has been carried out.

Compressed sensing of spatial electron paramagnetic resonance imaging.

PURPOSE: To improve image quality and reduce data requirements for spatial electron paramagnetic resonance imaging (EPRI) by developing a novel reconstruction approach using compressed sensing (CS). METHODS: EPRI is posed as an optimization problem, which is solved using regularized least-squares with sparsity promoting penalty terms, consisting of the l1 norms of the image itself and the total variation of the image. Pseudo-random sampling was employed to facilitate recovery of the sparse signal. The reconstruction was compared with the traditional filtered back-projection reconstruction for simulations, phantoms, isolated rat hearts, and mouse gastrointestinal (GI) tracts labeled with paramagnetic probes. RESULTS: A combination of pseudo-random sampling and CS was able to generate high-fidelity EPR images at high acceleration rates. For three-dimensional (3D) phantom imaging, CS-based EPRI showed little visual degradation at nine-fold acceleration. In rat heart datasets, CS-based EPRI produced high quality images with eight-fold acceleration. A high resolution mouse GI tract reconstruction demonstrated a visual improvement in spatial resolution and a doubling in signal-to-noise ratio (SNR). CONCLUSION: A novel 3D EPRI reconstruction using compressed sensing was developed and offers superior SNR and reduced artifacts from highly undersampled data.

Uniform spinning sampling gradient electron paramagnetic resonance imaging.

PURPOSE: To improve the quality and speed of electron paramagnetic resonance imaging (EPRI) acquisition by combining a uniform sampling distribution with spinning gradient acquisition. THEORY AND METHODS: A uniform sampling distribution was derived for spinning gradient EPRI acquisition (uniform spinning sampling, USS) and compared to the existing (equilinear spinning sampling, ESS) acquisition strategy. Novel corrections were introduced to reduce artifacts in experimental data. RESULTS: Simulations demonstrated that USS puts an equal number of projections near each axis whereas ESS puts excessive projections at one axis, wasting acquisition time. Artifact corrections added to the magnetic gradient waveforms reduced noise and correlation between projections. USS images had higher SNR (85.9 ± 0.8 vs. 56.2 ± 0.8) and lower mean-squared error than ESS images. The quality of the USS images did not vary with the magnetic gradient orientation, in contrast to ESS images. The quality of rat heart images was improved using USS compared to that with ESS or traditional fast-scan acquisitions. CONCLUSION: A novel EPRI acquisition which combines spinning gradient acquisition with a uniform sampling distribution was developed. This USS spinning gradient acquisition offers superior SNR and reduced artifacts compared to prior methods enabling potential improvements in speed and quality of EPR imaging in biological applications.

Trajectories of Health Care Contact Days for Patients With Stage IV Non-Small Cell Lung Cancer.

Importance: Patients with stage IV non-small cell lung cancer (NSCLC) experience substantial morbidity and mortality. Contact days (ie, the number of days with health care contact outside the home) measure how much of a person's life is consumed by health care, yet little is known about patterns of contact days for patients with NSCLC. Objective: To describe the trajectories of contact days in patients with stage IV NSCLC and how trajectories vary by receipt of cancer-directed treatment in routine practice. Design, Setting, and Participants: A retrospective, population-based decedent cohort study was conducted in Ontario, Canada. Participants included adults aged 20 years or older who were diagnosed with stage IV NSCLC (January 1, 2014, to December 31, 2017) and died (January 1, 2014, to December 31, 2019); there was a maximum 2-year follow-up. Data analysis was conducted from February 22 to August 16, 2023. Exposure: Systemic cancer-directed therapy (yes or no) and type of therapy (chemotherapy vs immunotherapy vs targeted therapy). Main Outcomes and Measures: Contact days (days with health care contact, outpatient or institution-based, outside the home) were identified through administrative data. The weekly percentage of contact days and fitted models with cubic splines were quantified to describe trajectories from diagnosis until death. Results: A total of 5785 decedents with stage IV NSCLC were included (median age, 70 [IQR 62-77] years; 3108 [53.7%] were male, and 1985 [34.3%] received systemic therapy). The median overall survival was 108 (IQR, 49-426) days, median contact days were 36 (IQR, 21-62), and the median percentage that were contact days was 33.3%. A median of 5 (IQR, 2-10) days were spent with specialty palliative care. Patients who did not receive systemic therapy had a median overall survival of 66 (IQR, 34-130) days and median contact days of 28 (IQR, 17-44), of which a median of 5 (IQR, 2-9) days were spent with specialty palliative care. Overall and for subgroups, normalized trajectories followed a U-shaped distribution: contact days were most frequent immediately after diagnosis and before death. Patients who received targeted therapy had the lowest contact day rate during the trough (10.6%; vs immunotherapy, 15.4%; vs chemotherapy, 17.7%). Conclusions and Relevance: In this cohort study, decedents with stage IV NSCLC had a median survival in the order of 3.5 months and spent 1 in every 3 days alive interacting with the health care system outside the home. These results highlight the need to better support patients and care partners, benchmark appropriateness, and improve care delivery.

Analysis of early hypertension and clinical outcome with bevacizumab: results from seven phase III studies.

BACKGROUND: Hypertension is associated with antivascular endothelial growth factor treatment, but the clinical implications of hypertension are uncertain. To assess the prognostic and predictive value of bevacizumab-related hypertension, a comprehensive analysis of whether hypertension and efficacy outcomes are associated was conducted on seven company-sponsored placebo-controlled phase III studies of bevacizumab. METHODS: Patient-specific data were available from 6,486 patients with metastatic colorectal, breast, non-small cell lung, pancreatic, and renal cell cancers. Primary hypertension endpoint was a blood pressure (BP) increase of >20 mmHg systolic or >10 mmHg diastolic within the first 60 days of treatment. Additional endpoints included other predefined thresholds of change in BP and severity of hypertension graded using the National Cancer Institute's Common Terminology Criteria for Adverse Events. To analyze the general prognostic importance of an early BP increase, multivariate Cox regression models were used to assess the correlation between BP changes and progression-free (PFS) and overall survival (OS) outcomes in the control groups. To analyze whether early BP increases could predict for benefit from bevacizumab, similar analyses were conducted in the bevacizumab-treated and control groups. RESULTS: In six of seven studies, early BP increase was neither predictive of clinical benefit from bevacizumab nor prognostic for the course of the disease. For study AVF2107g, early increased BP was associated with longer PFS and OS times in the bevacizumab group but shorter OS time in the control group. CONCLUSIONS: Early treatment-related BP increases do not predict clinical benefit from bevacizumab based on PFS or OS outcomes. BP increases do not appear to have general prognostic importance for patients with advanced cancer.

Fast gated EPR imaging of the beating heart: spatiotemporally resolved 3D imaging of free-radical distribution during the cardiac cycle.

In vivo or ex vivo electron paramagnetic resonance imaging (EPRI) is a powerful technique for determining the spatial distribution of free radicals and other paramagnetic species in living organs and tissues. However, applications of EPRI have been limited by long projection acquisition times and the consequent fact that rapid gated EPRI was not possible. Hence in vivo EPRI typically provided only time-averaged information. In order to achieve direct gated EPRI, a fast EPR acquisition scheme was developed to decrease EPR projection acquisition time down to 10-20 ms, along with corresponding software and instrumentation to achieve fast gated EPRI of the isolated beating heart with submillimeter spatial resolution in as little as 2-3 min. Reconstructed images display temporal and spatial variations of the free-radical distribution, anatomical structure, and contractile function within the rat heart during the cardiac cycle.

Improving the evaluation of new cancer treatments: challenges and opportunities.

There are, at present, ten times more anticancer drugs being tested in clinical trials than there were 15 years ago. Many of the new classes of agents, however, are predicted to work in only small subpopulations of patients, target unconventional aspects of tumour development and interact with other agents in an unpredictable manner. How can clinical trials be re-designed to accommodate the new features of targeted anticancer drugs?

Randomized Phase II Trial Comparing Bevacizumab Plus Carboplatin and Paclitaxel With Carboplatin and Paclitaxel Alone in Previously Untreated Locally Advanced or Metastatic Non-Small-Cell Lung Cancer.

PURPOSE: To investigate the efficacy and safety of bevacizumab plus carboplatin and paclitaxel in patients with advanced or recurrent non-small-cell lung cancer. PATIENTS AND METHODS: In a phase II trial, 99 patients were randomly assigned to bevacizumab 7.5 (n = 32) or 15 mg/kg (n = 35) plus carboplatin (area under the curve = 6) and paclitaxel (200 mg/m2) every 3 weeks or carboplatin and paclitaxel alone (n = 32). Primary efficacy end points were time to disease progression and best confirmed response rate. On disease progression, patients in the control arm had the option to receive single-agent bevacizumab 15 mg/kg every 3 weeks. RESULTS: Compared with the control arm, treatment with carboplatin and paclitaxel plus bevacizumab (15 mg/kg) resulted in a higher response rate (31.5% v 18.8%), longer median time to progression (7.4 v 4.2 months) and a modest increase in survival (17.7 v 14.9 months). Of the 19 control patients that crossed over to single-agent bevacizumab, five experienced stable disease, and 1-year survival was 47%. Bleeding was the most prominent adverse event and was manifested in two distinct clinical patterns; minor mucocutaneous hemorrhage and major hemoptysis. Major hemoptysis was associated with squamous cell histology, tumor necrosis and cavitation, and disease location close to major blood vessels. CONCLUSION: Bevacizumab in combination with carboplatin and paclitaxel improved overall response and time to progression in patients with advanced or recurrent non-small-cell lung cancer. Patients with nonsquamous cell histology appear to be a subpopulation with improved outcome and acceptable safety risks.

Assessing Barriers and Facilitators to Lung Cancer Screening: Initial Findings from a Patient Navigation Intervention.

Low-dose computed tomography-based lung cancer screening represents a complex clinical undertaking that could require multiple referrals, appointments, and time-intensive procedures. These steps may pose difficulties and raise concerns among patients, particularly minority, under-, and uninsured populations. The authors implemented patient navigation to identify and address these challenges. They conducted a pragmatic randomized controlled trial of telephone-based navigation for lung cancer screening in an integrated, urban safety-net health care system. Following standardized protocols, bilingual (Spanish and English) navigators educated, motivated, and empowered patients to traverse the health system. Navigators made systematic contact with patients, recording standardized call characteristics in a study-specific database. Call type, duration, and content were recorded. Univariable and multivariable multinomial logistic regression was performed to investigate associations between call characteristics and reported barriers. Among 225 patients (mean age 63 years, 46% female, 70% racial/ethnic minority) assigned navigation, a total of 559 barriers to screening were identified during 806 telephone calls. The most common barrier categories were personal (46%), provider (30%), and practical (17%). System (6%) and psychosocial (1%) barriers were described by English-speaking patients, but not by Spanish-speaking patients. Over the course of the lung cancer screening process, provider-related barriers decreased 80% (P = 0.008). The authors conclude that patients undergoing lung cancer screening frequently report personal and health care provider-related barriers to successful participation. Barrier types may differ among patient populations and over the course of the screening process. Further understanding of these concerns may increase screening uptake and adherence. Clinical Trial Registration number: (NCT02758054).

Body composition analysis of obesity and hepatic steatosis in mice by relaxation compensated fat fraction (RCFF) MRI.

PURPOSE: To develop and validate a quantitative magnetic resonance imaging (MRI) methodology for phenotyping animal models of obesity and fatty liver disease on 7T small animal MRI scanners. MATERIALS AND METHODS: A new MRI acquisition and image analysis technique, relaxation-compensated fat fraction (RCFF), was developed and validated by both magnetic resonance spectroscopy and histology. This new RCFF technique was then used to assess lipid biodistribution in two groups of mice on either a high-fat (HFD) or low-fat (LFD) diet. RESULTS: RCFF demonstrated excellent correlation in phantom studies (R(2) = 0.99) and in vivo compared to histological evaluation of hepatic triglycerides (R(2) = 0.90). RCFF images provided robust fat fraction maps with consistent adipose tissue values (82% ± 3%). HFD mice exhibited significant increases in peritoneal and subcutaneous adipose tissue volumes in comparison to LFD controls (peritoneal: 6.4 ± 0.4 cm(3) vs. 0.7 ± 0.2, P < 0.001; subcutaneous: 14.7 ± 2.0 cm(3) vs. 1.2 ± 0.3 cm(3) , P < 0.001). Hepatic fat fractions were also significantly different between HFD and LFD mice (3.1% ± 1.7% LFD vs. 27.2% ± 5.4% HFD, P = 0.002). CONCLUSION: RCFF can be used to quantitatively assess adipose tissue volumes and hepatic fat fractions in rodent models at 7T.