Type I interferon signaling pathway enhances immune-checkpoint inhibition in KRAS mutant lung tumors.

Lung cancer is the leading cause of cancer mortality worldwide. KRAS oncogenes are responsible for at least a quarter of lung adenocarcinomas, the main subtype of lung cancer. After four decades of intense research, selective inhibitors of KRAS oncoproteins are finally reaching the clinic. Yet, their effect on overall survival is limited due to the rapid appearance of drug resistance, a likely consequence of the high intratumoral heterogeneity characteristic of these tumors. In this study, we have attempted to identify those functional alterations that result from KRAS oncoprotein expression during the earliest stages of tumor development. Such functional changes are likely to be maintained during the entire process of tumor progression regardless of additional co-occurring mutations. Single-cell RNA sequencing analysis of murine alveolar type 2 cells expressing a resident Kras oncogene revealed impairment of the type I interferon pathway, a feature maintained throughout tumor progression. This alteration was also present in advanced murine and human tumors harboring additional mutations in the p53 or LKB1 tumor suppressors. Restoration of type I interferon (IFN) signaling by IFN-ß or constitutive active stimulator of interferon genes (STING) expression had a profound influence on the tumor microenvironment, switching them from immunologically "cold" to immunologically "hot" tumors. Therefore, enhancement of the type I IFN pathway predisposes KRAS mutant lung tumors to immunotherapy treatments, regardless of co-occurring mutations in p53 or LKB1.

Comparisons of assessment pathways after abnormal mammography screening in Denmark, Norway, and Spain.

PURPOSE: To ensure high-quality screening programmes and effective utilization of resources, it is important to monitor how cancer detection is affected by different strategies performed at recall assessment. This study aimed to describe procedures performed at recall assessment and compare and evaluate the performance of the assessment in Denmark, Norway, and Spain in terms of screen-detected cancer (SDC) and interval cancer (IC) rates. METHODS: We included women aged 50-69 years from Denmark, Norway, and Spain, who were recalled for assessment after screening mammography, and recorded all procedures performed during six months after diagnosis, and the timing of the procedures. Women were followed for two years and screen-detected and interval cancer, and sensitivity of recall was calculated and compared. RESULTS: In total, data from 24,645 Danish, 30,050 Norwegian, and 41,809 Spanish women were included in the study. Most of the women had some assessment within 2 months in all three countries. SDC rates were higher in Denmark (0.57) and Norway (0.60) compared to Spain (0.38), as were the IC rates, i.e. 0.25 and 0.18 vs. 0.12, respectively. The sensitivity of the diagnostic follow-up was somewhat higher in Denmark (98.3%) and Norway (98.2%), compared to Spain (95.4%), but when excluding non-invasive assessment pathways, the sensitivities were comparable. CONCLUSION: This comparison study showed variation in the assessment procedures used in the three countries as well as the SDC and IC rates and the sensitivity of recall.

The promoting physical activity in regional and remote cancer survivors (PPARCS) trial: Physical activity maintenance.

INTRODUCTION: The study examined whether increased physical activity (PA) in nonmetropolitan cancer survivors was maintained 12 weeks following the PPARCS intervention. METHODS: PA outcomes were assessed using an accelerometer at baseline, end of the intervention, and at 24 weeks. Linear mixed models were used to examine between-group changes in PA outcomes. RESULTS: The increased moderate-to-vigorous PA (MVPA) following intervention was maintained with significantly higher MVPA in the intervention group at 24 weeks (vs. controls) compared to baseline nett change of 52.5 min/week (95% CI 11.0-94.0.4). CONCLUSIONS: Distance-based interventions using wearables and health coaching may produce MVPA maintenance amongst nonmetropolitan cancer survivors.

Cumulative risk of a false-positive screening result: A retrospective cohort study using empirical data from 10 biennial screening rounds in BreastScreen Norway.

BACKGROUND: False-positive screening results are an inevitable and commonly recognized disadvantage of mammographic screening. This study estimated the cumulative probability of experiencing a first false-positive screening result in women attending 10 biennial screening rounds in BreastScreen Norway, which targets women aged 50 to 69 years. METHODS: This retrospective cohort study analyzed screening outcomes from 421,545 women who underwent 1,894,523 screening examinations during 1995-2019. Empirical data were used to calculate the cumulative risk of experiencing a first false-positive screening result and a first false-positive screening result that involved an invasive procedure over 10 screening rounds. Logistic regression was used to evaluate the effect of adjusting for irregular attendance, age at screening, and number of screens attended. RESULTS: The cumulative risk of experiencing a first false-positive screening result was 18.04% (95% confidence interval [CI], 18.00%-18.07%). It was 5.01% (95% CI, 5.01%-5.02%) for experiencing a false-positive screening result that involved an invasive procedure. Adjusting for irregular attendance or age at screening did not appreciably affect these estimates. After adjustments for the number of screens attended, the cumulative risk of a first false-positive screening result was 18.28% (95% CI, 18.24%-18.32%), and the risk of a false-positive screening result including an invasive procedure was 5.11% (95% CI, 5.11%-5.22%). This suggested that there was minimal bias from dependent censoring. CONCLUSIONS: Nearly 1 in 5 women will experience a false-positive screening result if they attend 10 biennial screening rounds in BreastScreen Norway. One in 20 will experience a false-positive screening result with an invasive procedure. LAY SUMMARY: A false-positive screening result occurs when a woman attending mammographic screening is called back for further assessment because of suspicious findings, but the assessment does not detect breast cancer. Further assessment includes additional imaging. Usually, it involves ultrasound, and sometimes, it involves a biopsy. This study has evaluated the chance of experiencing a false-positive screening result among women attending 10 screening examinations over 20 years in BreastScreen Norway. Nearly 1 in 5 women will experience a false-positive screening result over 10 screening rounds. One in 20 women will experience a false-positive screening result involving a biopsy.

Comparison of technical parameters and women's experience between self-compression and standard compression modes in mammography screening: a single-blind randomized clinical trial.

OBJECTIVES: We compared the compression force, breast thickness, and glandular dose, as well as the severity of discomfort and women's experience between the patient-assisted compression (PAC) and standard compression (SC) modes. MATERIALS AND METHODS: We conducted a prospective randomized controlled study at Hospital del Mar in Barcelona, Spain. We included 448 asymptomatic women aged 50 to 69 years old, attending their screening round from December 2017 to December 2019. Mammograms included the two bilateral views. In each woman, one breast was studied with SC and the other with PAC. The mode used in each breast was selected following a randomized list. Compression force, breast thickness, and average glandular dose were obtained for each of the 1792 images. We also recorded the degree of discomfort and women's experience, after mammogram acquisitions, using a predefined survey. RESULTS: Higher compression forces were obtained with PAC than with SC (99.27 N vs 83.25 N, p < 0.001). Breast thickness mode (56.11 mm vs 57.52 mm, p = 0.015) and glandular dose (1.34 mGy vs 1.37 mGy, p = 0.018) were lower in PAC. The discomfort score was slightly higher with PAC (mean 3.94 vs 3.69, p = 0.042), but in the satisfaction survey, more women reported that PAC caused less discomfort. Additionally, 63.2% of women (289/448) preferred PAC. CONCLUSION: PAC achieved higher compression forces without impairing the other technical imaging parameters and enhanced women's experience of screening mammography. We believe there were no clinically significant differences in the severity of discomfort between the two modes. KEY POINTS: • Self-compression allows higher compression forces than the standard compression mode. • Self-compression does not affect technical imaging parameters. • Self-compression improved women's experience of screening mammography when standard compression was used on one breast and self-compression on the other.

Does the patient-assisted compression mode affect the mammography quality? A within-woman randomized controlled trial.

OBJECTIVES: Evaluate the image quality of a mammography screening device using the patient-assisted compression (PAC) compared with the standard compression (SC) mode. METHODS: This prospective within-woman, randomized controlled trial was conducted between September 2017 and December 2019. Participants were asymptomatic women aged 50 to 69 years attending their second or subsequent screening mammography round. By random assignment, one breast underwent the SC and the other breast, the PAC. Image quality was evaluated as perfect, good, moderate, or inadequate (PGMI) on 10 criteria for the craniocaudal (CC) view and 8 criteria for the mediolateral oblique (MLO) view. Pearson's chi-square test, with Yates' correction if pertinent, was performed to compare image quality between compression modes. RESULTS: A total of 444 participants were included (mean [± standard deviation] age, 60 [± 4.9] years). There were no differences in the percentages of PGMI between the PAC and SC modes for the CC view (perfect, 37% [162/444] vs 37% [163/444]; good, 1% [5/444] vs 2% [9/444]; moderate, 62% [277/444] vs 61% [271/444]; inadequate, 0% vs 0.2% [1/444]; p = .88) or for the MLO view (perfect, 53% [237/444] vs 56% [247/444]; good, 22% [99/444] vs 22% [97/444]; moderate, 23% [102/444] vs 22% [98/444]; inadequate, 1% [6/444] vs 0.5% [2/444]; p = .72). No differences were found when we stratified by laterality or when analyzed by PGMI criteria. CONCLUSION: PAC does not seem to impair mammographic image quality. Future research should focus in a daily practice setting. KEY POINTS: No differences were found in the distribution of the PGMI classification, a tool for quality assessment, between patient-assisted compression and standard compression. Similar results were found on stratification of image quality by mammographic view and breast laterality for both types of compression. None of the PGMI criteria had significantly more errors in patient-assisted compression than in standard compression.

Mammographic features of benign breast lesions and risk of subsequent breast cancer in women attending breast cancer screening.

OBJECTIVES: To evaluate the mammographic features in women with benign breast disease (BBD) and the risk of subsequent breast cancer according to their mammographic findings. METHODS: We analyzed data from a Spanish cohort of women screened from 1995 to 2015 and followed up until December 2017 (median follow-up, 5.9 years). We included 10,650 women who had both histologically confirmed BBD and mammographic findings. We evaluated proliferative and nonproliferative BBD subtypes, and their mammographic features: architectural distortion, asymmetries, calcifications, masses, and multiple findings. The adjusted hazard ratios (aHR) and 95% confidence intervals (95% CI) for breast cancer were estimated using a Cox proportional hazards model. We plotted the adjusted cumulative incidence curves. RESULTS: Calcifications were more frequent in proliferative disease with atypia (43.9%) than without atypia (36.8%) or nonproliferative disease (22.2%; p value < 0.05). Masses were more frequent in nonproliferative lesions (59.1%) than in proliferative lesions without atypia (35.1%) or with atypia (30.0%; p value < 0.05). Multiple findings and architectural distortion were more likely in proliferative disease (16.1% and 4.7%) than in nonproliferative disease (12.8% and 1.9%). Subsequent breast cancer occurred in 268 (2.5%) women. Compared with women who had masses, the highest risk of subsequent breast cancer was found in those with architectural distortions (aHR, 2.21; 95% CI, 1.16-4.22), followed by those with multiple findings (aHR, 1.89; 95% CI, 1.34-2.66), asymmetries (aHR, 1.66; 95% CI, 0.84-3.28), and calcifications (aHR, 1.60; 95% CI, 1.21-2.12). CONCLUSION: BBD subtypes showed distinct mammographic findings. The risk of subsequent breast cancer was high in those who have shown architectural distortion, multiple findings, asymmetries, and calcifications than in women with masses. KEY POINTS: • The presence of mammographic findings in women attending breast cancer screening helps clinicians to assess women with benign breast disease (BBD). • Calcifications were frequent in BBDs with atypia, which are the ones with a high breast cancer risk, while masses were common in low-risk BBDs. • The excess risk of subsequent breast cancer in women with BBD was higher in those who showed architectural distortion compared to those with masses.

Factors that Influence Treatment Delay for Patients with Breast Cancer.

INTRODUCTION: The diagnosis or treatment of breast cancer is sometimes delayed. A lengthy delay may have a negative psychological impact on patients. The aim of our study was to evaluate the sociodemographic, clinical and pathological factors associated with delay in the provision of surgical treatment for localised breast cancer, in a prospective cohort of patients. METHODS: This observational, prospective, multicentre study was conducted in ten hospitals belonging to the Spanish national public health system, located in four Autonomous Communities (regions). The study included 1236 patients, diagnosed through a screening programme or found to be symptomatic, between April 2013 and May 2015. The study variables analysed included each patient's personal history, care situation, tumour history and data on the surgical intervention, pathological anatomy, hospital admission and follow-up. Treatment delay was defined as more than 30 days elapsed between biopsy and surgery. RESULTS: Over half of the study population experienced surgical treatment delay. This delay was greater for patients with no formal education and among widows, persons not requiring assistance for usual activities, those experiencing anxiety or depression, those who had a high BMI or an above-average number of comorbidities, those who were symptomatic, who did not receive NMR spectroscopy, who presented a histology other than infiltrating ductal carcinoma or who had poorly differentiated carcinomas. CONCLUSIONS: Certain sociodemographic and clinical variables are associated with surgical treatment delay. This study identifies factors that influence surgical delays, highlighting the importance of preventing these factors and of raising awareness among the population at risk and among health personnel.

Breast density, benign breast disease, and risk of breast cancer over time.

OBJECTIVES: Assessing the combined effect of mammographic density and benign breast disease is of utmost importance to design personalized screening strategies. METHODS: We analyzed individual-level data from 294,943 women aged 50-69 years with at least one mammographic screening participation in any of four areas of the Spanish Breast Cancer Screening Program from 1995 to 2015, and followed up until 2017. We used partly conditional Cox models to assess the association between benign breast disease, breast density, and the risk of breast cancer. RESULTS: During a median follow-up of 8.0 years, 3697 (1.25%) women had a breast cancer diagnosis and 5941 (2.01%) had a benign breast disease. More than half of screened women had scattered fibroglandular density (55.0%). The risk of breast cancer independently increased with the presence of benign breast disease and with the increase in breast density (p for interaction = 0.84). Women with benign breast disease and extremely dense breasts had a threefold elevated risk of breast cancer compared with those with scattered fibroglandular density and without benign breast disease (hazard ratio [HR] = 3.07; 95%CI = 2.01-4.68). Heterogeneous density and benign breast disease was associated with nearly a 2.5 elevated risk (HR = 2.48; 95%CI = 1.66-3.70). Those with extremely dense breast without a benign breast disease had a 2.27 increased risk (95%CI = 2.07-2.49). CONCLUSIONS: Women with benign breast disease had an elevated risk for over 15 years independently of their breast density category. Women with benign breast disease and dense breasts are at high risk for future breast cancer. KEY POINTS: • Benign breast disease and breast density were independently associated with breast cancer. • Women with benign breast disease had an elevated risk for up to 15 years independently of their mammographic density category.

Effect of an information leaflet on breast cancer screening participation: A cluster randomized controlled trial.

OBJECTIVE: To evaluate the impact of an information leaflet about the risk-benefit balance of breast cancer screening on women's participation. METHODS: This cluster randomized controlled trial was conducted within a population-based breast cancer screening program and included women from the catchment areas of two hospitals in Barcelona, Spain. We evaluated women aged 50-69 years invited to screening between September 2019 and January 2020. The intervention group received an information leaflet on the benefits and harms of mammography screening. The control group received the usual invitation letter. The clusters consisted of the processing days of the invitation letter, assigned to the intervention with a simple random allocation scheme. We compared the participation rate at the individual level between groups, stratified by hospital and by per-protocol and intention-to-treat analyses. RESULTS: We included 11,119 women (137 clusters): 5416 in the intervention group (66 clusters) and 5703 in the control group (71 clusters). A total of 36% (1964/5393) of the women in the intervention group and 37% (2135/5694) of those in the control group attended screening, respectively. Overall, we found no differences in participation among groups (difference in participation - 1.1%; 95%CI; - 2.9 to 0.7%). In a hospital attending a population with a low socioeconomic status, attendance was lower in the intervention group (- 1.4, 95%CI: - 5.7% to - 0.03%). CONCLUSIONS: Overall participation in our program was unaffected by a new information leaflet on the risk-benefit balance of breast cancer screening. However, participation was lower in certain populations with lower socioeconomic status TRIAL REGISTRATION: Trial registration number ISRCTN13848929 .

Severe Cardiac Dysfunction and Death Caused by Arrhythmogenic Right Ventricular Cardiomyopathy Type 5 Are Improved by Inhibition of Glycogen Synthase Kinase-3ß.

BACKGROUND: Arrhythmogenic cardiomyopathy/arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiac disease characterized by fibrofatty replacement of the myocardium, resulting in heart failure and sudden cardiac death. The most aggressive arrhythmogenic cardiomyopathy/ARVC subtype is ARVC type 5 (ARVC5), caused by a p.S358L mutation in TMEM43 (transmembrane protein 43). The function and localization of TMEM43 are unknown, as is the mechanism by which the p.S358L mutation causes the disease. Here, we report the characterization of the first transgenic mouse model of ARVC5. METHODS: We generated transgenic mice overexpressing TMEM43 in either its wild-type or p.S358L mutant (TMEM43-S358L) form in postnatal cardiomyocytes under the control of the α-myosin heavy chain promoter. RESULTS: We found that mice expressing TMEM43-S358L recapitulate the human disease and die at a young age. Mutant TMEM43 causes cardiomyocyte death and severe fibrofatty replacement. We also demonstrate that TMEM43 localizes at the nuclear membrane and interacts with emerin and ß-actin. TMEM43-S358L shows partial delocalization to the cytoplasm, reduced interaction with emerin and ß-actin, and activation of glycogen synthase kinase-3ß (GSK3ß). Furthermore, we show that targeting cardiac fibrosis has no beneficial effect, whereas overexpression of the calcineurin splice variant calcineurin Aß1 results in GSK3ß inhibition and improved cardiac function and survival. Similarly, treatment of TMEM43 mutant mice with a GSK3ß inhibitor improves cardiac function. Finally, human induced pluripotent stem cells bearing the p.S358L mutation also showed contractile dysfunction that was partially restored after GSK3ß inhibition. CONCLUSIONS: Our data provide evidence that TMEM43-S358L leads to sustained cardiomyocyte death and fibrofatty replacement. Overexpression of calcineurin Aß1 in TMEM43 mutant mice or chemical GSK3ß inhibition improves cardiac function and increases mice life span. Our results pave the way toward new therapeutic approaches for ARVC5.

Enhanced Mobility and Large Linear Nonsaturating Magnetoresistance in the Magnetically Ordered States of TmNiC_{2}.

We have studied the magnetic, magnetotransport, and galvanomagnetic properties of TmNiC_{2}. We find that the antiferromagnetic and field induced metamagnetic and ferromagnetic orderings do not suppress the charge density wave. The persistence of Fermi surface pockets, open as a result of imperfect nesting accompanying the Peierls transition, results in an electronic carriers mobility of the order of 4×10^{3} cm^{2} V^{-1} s^{-1} in ferromagnetic state, without any signatures for a significant deterioration of nesting properties. This is independently evidenced by high, nonsaturating linear magnetoresistance reaching 440% at T=2 K and an analysis of the Hall conductivity. We thus demonstrate that, the coexistence of charge density wave and magnetism provides an alternative route to maintain high electronic mobility in the magnetically ordered state.

Safety and efficacy of endoscopic ultrasound-guided gallbladder drainage combined with endoscopic retrograde cholangiopancreatography in the same session.

BACKGROUND AND AIM: Endoscopic ultrasound-guided gallbladder drainage (EUS-GBD) is an emerging option for acute cholecystitis in non-surgical candidates. Combining endoscopic retrograde cholangiopancreatography (ERCP) for common bile duct stones with EUS-GBD in a single session might become a non-surgical management strategy to comprehensively treat gallstone disease in selected patients. METHODS: Single-center retrospective cohort study comparing outcomes between EUS-GBD alone (group A) and single-session ERCP combined with EUS-GBD (group B). Consecutive patients who underwent EUS-GBD with a lumen-apposing metal stent (LAMS) between June 2011 and August 2018 were analyzed. Exclusion criteria were subjects included in randomized clinical trials, patients who had had ERCP within 5 days of EUS-GBD, patients in whom ERCP or EUS-GBD was carried out for salvage of one or the other procedure, and patients who underwent concurrent EUS-guided biliary drainage. RESULTS: One hundred and nine consecutive patients underwent EUS-GBD with LAMS during the study period. Seventy-one patients satisfied the inclusion criteria and 34 patients were in group A and 37 in group B. Baseline characteristics were similar in both groups. There were no significant differences in technical (97.1% vs 97.3%; P = 0.19) and clinical success rates (88.2% vs 94.6%; P = 0.42) of EUS-GBD in group A versus group B. Rate of adverse events was similar in both groups, five (14.7%) in group A versus five (13.5%) in group B. CONCLUSIONS: Single-session EUS-GBD combined with ERCP has comparable rates of technical and clinical success to EUS-GBD alone. A combined EUS-GBD and ERCP procedure does not appear to increase adverse events and makes possible comprehensive treatment of gallstone disease by purely endoscopic means.

Long-term risk of screen-detected and interval breast cancer after false-positive results at mammography screening: joint analysis of three national cohorts.

BACKGROUND: We assessed the long-term risk of screen-detected and interval breast cancer in women with a first or second false-positive screening result. METHODS: Joint analysis had been performed using individual-level data from three population-based screening programs in Europe (Copenhagen in Denmark, Norway, and Spain). Overall, 75,513 screened women aged 50-69 years from Denmark (1991-2010), 556,640 from Norway (1996-2008), and 517,314 from Spain (1994-2010) were included. We used partly conditional Cox hazards models to assess the association between false-positive results and the risk of subsequent screen-detected and interval cancer. RESULTS: During follow-up, 1,149,467 women underwent 3,510,450 screening exams, and 10,623 screen-detected and 5700 interval cancers were diagnosed. Compared to women with negative tests, those with false-positive results had a two-fold risk of screen-detected (HR = 2.04, 95% CI: 1.93-2.16) and interval cancer (HR = 2.18, 95% CI: 2.02-2.34). Women with a second false-positive result had over a four-fold risk of screen-detected and interval cancer (HR = 4.71, 95% CI: 3.81-5.83 and HR = 4.22, 95% CI: 3.27-5.46, respectively). Women remained at an elevated risk for 12 years after the false-positive result. CONCLUSIONS: Women with prior false-positive results had an increased risk of screen-detected and interval cancer for over a decade. This information should be considered to design personalised screening strategies based on individual risk.

A systematic review and quality assessment of individualised breast cancer risk prediction models.

BACKGROUND: Individualised breast cancer risk prediction models may be key for planning risk-based screening approaches. Our aim was to conduct a systematic review and quality assessment of these models addressed to women in the general population. METHODS: We followed the Cochrane Collaboration methods searching in Medline, EMBASE and The Cochrane Library databases up to February 2018. We included studies reporting a model to estimate the individualised risk of breast cancer in women in the general population. Study quality was assessed by two independent reviewers. Results are narratively summarised. RESULTS: We included 24 studies out of the 2976 citations initially retrieved. Twenty studies were based on four models, the Breast Cancer Risk Assessment Tool (BCRAT), the Breast Cancer Surveillance Consortium (BCSC), the Rosner & Colditz model, and the International Breast Cancer Intervention Study (IBIS), whereas four studies addressed other original models. Four of the studies included genetic information. The quality of the studies was moderate with some limitations in the discriminative power and data inputs. A maximum AUROC value of 0.71 was reported in the study conducted in a screening context. CONCLUSION: Individualised risk prediction models are promising tools for implementing risk-based screening policies. However, it is a challenge to recommend any of them since they need further improvement in their quality and discriminatory capacity.

Risk of hospital readmission and associated factors after a positive sample for a multidrug-resistant microorganism.

BACKGROUND: To determine the risk of hospital readmission and associated factors in patients with a positive sample for multidrug-resistant microorganisms (MRM) and to analyze whether there is a higher risk of hospital readmission with some of the more common MRM. METHODS: Retrospective cohort study (2012-16) performed in a tertiary-care teaching hospital in Barcelona. Patients were divided into two groups, depending on the presence or absence of an MRM-positive sample during hospital admission. Logistic regression models were used to estimate the risk of hospital readmission in the first 30 and 90 days, and the first year for patients with an MRM-positive sample compared with those without. The models were stratified by the presence or absence of an MRM-positive sample and by grouped Charlson comorbidity index. RESULTS: We included 983 patients with an MRM-positive sample and 39 323 patients without. The risk of hospital readmission in the first 30 days was 41% higher in admitted patients with an MRM-positive sample (95%CI=1.17 to 1.69) than in those without. Stratified models showed similar results to the overall results for all Charlson comorbidity index groups. When the models were stratified by the presence of an MRM-positive sample, methicillin-resistant Staphylococcus aureus showed the highest risk of readmissions within the more common MRM [103% (95%CI=1.10 to 3.75)]. CONCLUSION: MRMs seem to be an important risk factor for hospital readmissions both among patients with and without comorbidities. Specific types of MRM may represent a higher risk for hospital readmissions than other MRMs, depending on the particular environment or hospital.

KRAS oncogene in non-small cell lung cancer: clinical perspectives on the treatment of an old target.

Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed. Moreover, the role of KRAS oncogene in NSCLC remains unclear and its predictive and prognostic impact remains controversial. The study of the underlying biology of KRAS in NSCLC patients could help to determine potential candidates to evaluate novel targeted agents and combinations that may allow a tailored treatment for these patients. The aim of this review is to update the current knowledge about KRAS-mutated lung adenocarcinoma, including a historical overview, the biology of the molecular pathways involved, the clinical relevance of KRAS mutations as a prognostic and predictive marker and the potential therapeutic approaches for a personalized treatment of KRAS-mutated NSCLC patients.

Interval Breast Cancer Rates and Histopathologic Tumor Characteristics after False-Positive Findings at Mammography in a Population-based Screening Program.

Purpose To compare rates and tumor characteristics of interval breast cancers (IBCs) detected after a negative versus false-positive screening among women participating in the Norwegian Breast Cancer Screening Program. Materials and Methods The Cancer Registry Regulation approved this retrospective study. Information about 423 445 women aged 49-71 years who underwent 789 481 full-field digital mammographic screening examinations during 2004-2012 was extracted from the Cancer Registry of Norway. Rates and odds ratios of IBC among women with a negative (the reference group) versus a false-positive screening were estimated by using logistic regression models adjusted for age at diagnosis and county of residence. Results A total of 1302 IBCs were diagnosed after 789 481 screening examinations, of which 7.0% (91 of 1302) were detected among women with a false-positive screening as the most recent breast imaging examination before detection. By using negative screening as the reference, adjusted odds ratios of IBCs were 3.3 (95% confidence interval [CI]: 2.6, 4.2) and 2.8 (95% CI: 1.8, 4.4) for women with a false-positive screening without and with needle biopsy, respectively. Women with a previous negative screening had a significantly lower proportion of tumors that were 10 mm or less (14.3% [150 of 1049] vs 50.0% [seven of 14], respectively; P < .01) and grade I tumors (13.2% [147 of 1114] vs 42.9% [six of 14]; P < .01), but a higher proportion of cases with lymph nodes positive for cancer (40.9% [442 of 1080] vs 13.3% [two of 15], respectively; P = .03) compared with women with a previous false-positive screening with benign biopsy. A retrospective review of the screening mammographic examinations identified 42.9% (39 of 91) of the false-positive cases to be the same lesion as the IBC. Conclusion By using a negative screening as the reference, a false-positive screening examination increased the risk of an IBC three-fold. The tumor characteristics of IBC after a negative screening were less favorable compared with those detected after a previous false-positive screening. © RSNA, 2017 Online supplemental material is available for this article.

Breast compression parameters and mammographic density in the Norwegian Breast Cancer Screening Programme.

OBJECTIVES: To investigate possible associations between breast compression parameters, including compression force, pressure and compressed breast thickness, and mammographic density assessed by an automated software. METHODS: We obtained data on breast compression parameters, breast volume, absolute and percentage dense volume, and body mass index for 14,698 women screened with two-view (craniocaudal, CC, and mediolateral oblique, MLO) digital mammography, in the Norwegian Breast Cancer Screening Programme, 2014-2015. The Spearman correlation coefficient (ρ) was used to measure correlation between breast compression parameters, breast volume and absolute and percentage dense volume. Linear regression was used to examine associations between breast compression parameters and absolute and percentage dense volume, adjusting for breast volume, age and BMI. RESULTS: A fair negative correlation was observed between compression pressure and absolute dense volume (ρ = - 0.37 for CC and ρ = - 0.34 for MLO). A moderate negative correlation was identified for compressed breast thickness and percentage dense volume (ρ = - 0.56 for CC and ρ = - 0.62 for MLO). These correlations were corroborated by the corresponding associations obtained in the adjusted regression analyses. CONCLUSIONS: Results from this study indicate that breast compression parameters may influence absolute and percentage dense volume measured by the automated software. KEY POINTS: • A fair correlation was identified between compression pressure and absolute dense volume • A moderate correlation was identified between compressed breast thickness and percentage dense volume • Breast compression may influence automated density estimates.

Clinical and histologic characteristics of breast cancers in women with previous pathologic diagnosis of benign breast disease in Spain.

Women with a benign breast disease (BBD) have an increased risk of subsequent breast carcinoma. Information is scarce regarding the characteristics of breast carcinomas diagnosed after a BBD. Our aim was to point out the differences in clinical and histologic characteristics of breast carcinomas diagnosed in women with and without a previous pathologic diagnosis of BBD in the context of population-based mammography screening. Retrospective cohort study of all women aged 50-69 years who were screened at least once in a population-based screening program in Spain, between 1994 and 2011 and followed up until December 2012. The mean follow-up was 6.1 years. We analyzed 6645 breast carcinomas, of whom 238 had a previous pathologic diagnosis of BBD. Information on clinical and histologic characteristics was collected from pathology reports. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence intervals (95%CI) of occurrence of selected histologic characteristics of breast carcinomas in women with and without a previous BBD. Women with a previous BBD had a higher proportion of ductal carcinoma in situ (DCIS) compared with women without a BBD (22.1% and 13.6%, respectively). Among those diagnosed with an invasive breast carcinoma, women with previous BBD were more likely to be diagnosed with carcinomas sized >2 cm (OR = 1.46; 95%CI = 1.03-2.08), metastatic positive (OR = 2.66; 95%CI = 1.21-5.86), and with a high Ki-67 proliferation rate (OR = 1.93; 95%CI = 1.24-2.99). No differences were found across histologic subtypes of BBD. Screening participants with a previous pathologic diagnosis of BBD had a higher proportion of DCIS. However, invasive carcinomas detected in women with a BBD were associated with clinical and histologic characteristics conferring a worst prognosis.