Lung cancer diagnosis and mortality beyond 15 years since quit in individuals with a 20+ pack-year history: A systematic review.

Current US lung cancer screening recommendations limit eligibility to adults with a pack-year (PY) history of ≥20 years and the first 15 years since quit (YSQ). The authors conducted a systematic review to better understand lung cancer incidence, risk and mortality among otherwise eligible individuals in this population beyond 15 YSQ. The PubMed and Scopus databases were searched through February 14, 2023, and relevant articles were searched by hand. Included studies examined the relationship between adults with both a ≥20-PY history and ≥15 YSQ and lung cancer diagnosis, mortality, and screening ineligibility. One investigator abstracted data and a second confirmed. Two investigators independently assessed study quality and certainty of evidence (COE) and resolved discordance through consensus. From 2636 titles, 22 studies in 26 articles were included. Three studies provided low COE of elevated lung cancer incidence beyond 15 YSQ, as compared with people who never smoked, and six studies provided moderate COE that the risk of a lung cancer diagnosis after 15 YSQ declines gradually, but with no clinically significant difference just before and after 15 YSQ. Studies examining lung cancer-related disparities suggest that outcomes after 15 YSQ were similar between African American/Black and White participants; increasing YSQ would expand eligibility for African American/Black individuals, but for a significantly larger proportion of White individuals. The authors observed that the risk of lung cancer not only persists beyond 15 YSQ but that, compared with individuals who never smoked, the risk may remain significantly elevated for 2 or 3 decades. Future research of nationally representative samples with consistent reporting across studies is needed, as are better data from which to examine the effects on health disparities across different populations.

Updates to Advanced Prostate Cancer: AUA/SUO Guideline (2023).

PURPOSE: In 2022 the American Urological Association (AUA) requested an Update Literature Review (ULR) to incorporate new evidence generated since the 2020 publication of this guideline. The resulting 2023 Guideline Amendment addresses updated recommendations for patients with advanced prostate cancer. MATERIALS AND METHODS: The ULR addressed 23 of the original 38 guideline statements and included an abstract-level review of eligible studies published since the 2020 systematic review. Sixteen studies were selected for full text review. The current summary presents the updates made to the Guideline as a result of that new literature. RESULTS: The Advanced Prostate Cancer Panel amended evidence- and consensus-based statements based on an updated review to aid clinicians in the management of patients with advanced prostate cancer. These statements are detailed herein. CONCLUSION: This Guideline Amendment provides a framework designed to improve a clinician's ability to treat patients diagnosed with advanced prostate cancer with the most current evidence-based information. Further research and publication of high-quality clinical trials will be essential to continue to improve the quality of care for these patients.

Screening, Referral, Behavioral Counseling, and Preventive Interventions for Oral Health in Children and Adolescents Aged 5 to 17 Years: A Systematic Review for the US Preventive Services Task Force.

Importance: Dental caries is common in children and adolescents aged 5 to 17 years and potentially amenable to primary care screening and prevention. Objective: To systematically review the evidence on primary care screening and prevention of dental caries in children and adolescents aged 5 to 17 years to inform the US Preventive Services Task Force. Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (to October 3, 2022); surveillance through July 21, 2023. Study Selection: Diagnostic accuracy of primary care screening instruments and oral examination; randomized and nonrandomized trials of screening and preventive interventions and systematic reviews of such studies; cohort studies on primary care oral health screening and preventive intervention harms. Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Random-effects meta-analysis was performed for fluoride supplements and xylitol; for other preventive interventions, pooled estimates were used from good-quality systematic reviews. Main Outcomes and Measures: Dental caries, morbidity, functional status, quality of life, harms; diagnostic test accuracy. Results: Three systematic reviews (total 20 684 participants) and 19 randomized clinical trials, 3 nonrandomized trials, and 1 observational study (total 15 026 participants) were included. No study compared screening vs no screening. When administered by dental professionals or in school settings, fluoride supplements compared with placebo or no intervention were associated with decreased change from baseline in the number of decayed, missing, or filled permanent teeth (DMFT index) or decayed or filled permanent teeth (DFT index) (mean difference, -0.73 [95% CI, -1.30 to -0.19]) at 1.5 to 3 years (6 trials; n = 1395). Fluoride gels were associated with a DMFT- or DFT-prevented fraction of 0.18 (95% CI, 0.09-0.27) at outcomes closest to 3 years (4 trials; n = 1525), fluoride varnish was associated with a DMFT- or DFT-prevented fraction of 0.44 (95% CI, 0.11-0.76) at 1 to 4.5 years (5 trials; n = 3902), and resin-based sealants were associated with decreased risk of carious first molars (odds ratio, 0.21 [95% CI, 0.16-0.28]) at 48 to 54 months (4 trials; n = 440). No trial evaluated primary care counseling or dental referral. Evidence on screening accuracy, silver diamine fluoride, xylitol, and harms was very limited, although serious harms were not reported. Conclusions and Relevance: Administration of fluoride supplements, fluoride gels, varnish, and sealants in dental or school settings improved caries outcomes. Research is needed on the effectiveness of oral health preventive interventions in primary care settings and to determine the benefits and harms of screening.

Screening, Referral, Behavioral Counseling, and Preventive Interventions for Oral Health in Adults: A Systematic Review for the US Preventive Services Task Force.

Importance: Dental caries and periodontal disease are common adult oral health conditions and potentially amenable to primary care screening and prevention. Objective: To systematically review the evidence on primary care screening and prevention of dental caries and periodontal disease in adults to inform the US Preventive Services Task Force. Data Sources: MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews (to October 3, 2022); surveillance through July 21, 2023. Study Selection: Diagnostic accuracy studies of primary care screening instruments and oral examination; randomized and nonrandomized trials of screening and preventive interventions; cohort studies on primary care oral health screening and preventive intervention harms. Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently rated study quality. Diagnostic accuracy data were pooled using a bivariate mixed-effects binary regression model. Main Outcomes and Measures: Dental caries, periodontal disease, morbidity, quality of life, harms; and diagnostic test accuracy. Results: Five randomized clinical trials, 5 nonrandomized trials, and 6 observational studies (total 3300 participants) were included. One poor-quality trial (n = 477) found no difference between oral health screening during pregnancy vs no screening in caries, periodontal disease, or birth outcomes. One study (n = 86) found oral health examination by 2 primary care clinicians associated with low sensitivity (0.42 and 0.56) and high specificity (0.84 and 0.87) for periodontal disease and with variable sensitivity (0.33 and 0.83) and high specificity (0.80 and 0.93) for dental caries. Four studies (n = 965) found screening questionnaires associated with a pooled sensitivity of 0.72 (95% CI, 0.57-0.83) and specificity of 0.74 (95% CI, 0.66-0.82) for periodontal disease. For preventive interventions no study evaluated primary care counseling or dental referral, and evidence from 2 poor-quality trials (n = 178) of sealants, and 1 fair-quality and 4 poor-quality trials (n = 971) of topical fluorides, was insufficient. Three fair-quality trials (n = 590) of persons with mean age 72 to 80 years found silver diamine fluoride solution associated with fewer new root caries lesions or fillings vs placebo (mean reduction, -0.33 to -1.3) and decreased likelihood of new root caries lesion (2 trials; adjusted odds ratio, 0.4 [95% CI, 0.3-0.7]). No trial evaluated primary care-administered preventive interventions. Conclusions and Relevance: Screening questionnaires were associated with moderate diagnostic accuracy for periodontal disease. Research is needed to determine benefits and harms of oral health primary care screening and preventive interventions.

How to Mitigate Risk of Premature Cardiovascular Disease Among Children and Adolescents with Mental Health Conditions.

PURPOSE OF REVIEW: The goal of this article is to characterize the myriad of ways that children with mental health conditions can be at risk for premature cardiovascular disease (CVD) and various modalities to ameliorate this risk in childhood in order to improve the life course of these children. REVIEW FINDINGS: Child and adolescent mental health conditions are a common yet underrecognized risk factor for premature CVD. The American Heart Association has recently included psychiatric conditions as a CVD risk factor (CVDRF) and the evidence linking childhood adversity to cardiometabolic disease. There are bidirectional and additive effects from the intrinsic emotional dysregulation and inflammatory changes from the mental health condition, the associations with risky health behaviors, and in some cases, metabolic side effects from pharmacotherapy. These pathways can be potentiated by toxic stress, a physiologic response to stressors from childhood adversity. Toxic stress is also associated with development of mental health conditions with epigenetic effects that can result in transgenerational inheritance of cardiometabolic risk. Exposure to toxic stress and mental health conditions in isolation sometimes compounded by pharmacotherapies used in treatment increase the risk of cardiometabolic diseases in childhood. The multiple pathways, which adversely influence cardiometabolic outcomes, encourage clinicians to consider strategies to mitigate these factors and justify the importance of early screening and treatment for CVDRFs. Mental health, health behaviors, and environmental factors co-occur and intersect in complex pathways that can increase CVD risk over the lifespan. Early detection and response can mitigate the risks associated with premature development of CVD.

Why Are Women Less Represented in Intracerebral Hemorrhage Trials?

BACKGROUND AND PURPOSE: Fewer women than men tend to be enrolled in clinical trials of intracerebral hemorrhage. It is unclear whether this reflects lower prevalence of intracerebral hemorrhage in women, selection bias, or poor recruitment efforts. We undertook this study to examine differences between men and women in the reasons for exclusion from the iDEF trial (Intracerebral Hemorrhage Deferoxamine). METHODS: The screen failure log included 29 different reasons for exclusion. Chi-square statistics were used to evaluate the differences in reasons for exclusion between men and women. RESULTS: A total of 38.2% of participants in iDEF were women. Three thousand nine hundred eighty-two women (45.7%) and 4736 men (54.3%) were screen failures (P<0.0001). Similar proportions of women (1.28%) and men (1.73%) were excluded due to inability to obtain consent (P=0.1). Patients or families declined participation in 1.26% of women versus 1.31% of men (P=0.9). More women than men failed screening because of age>80 (22.40% versus 12.61%; adjusted P=0.0007) and preexisting do-not-resuscitate/do-not-intubate (3.69% versus 2.83%; adjusted P=0.067). CONCLUSIONS: Lower rates of women enrollment in the iDEF trial may be attributed to older age. Inability to obtain consent or declining participation was similar between women and men, arguing against selection bias. Our findings should be confirmed in other intracerebral hemorrhage trials to determine best strategies to improve women's representation in future trials.

Screening for Chlamydial and Gonococcal Infections: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: The 2014 US Preventive Services Task Force (USPSTF) recommendation statement supported the effectiveness of screening for chlamydia and gonorrhea in asymptomatic, sexually active women 24 years or younger and in older women at increased risk for infection, although evidence for screening in men was insufficient. Objective: To update the 2014 USPSTF review on screening for chlamydial and gonococcal infection in adults and adolescents, including those who are pregnant. Data Sources: Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Ovid MEDLINE (January 1, 2014, through May 28, 2020) with surveillance through May 21, 2021. Study Selection: Randomized clinical trials and observational studies of screening effectiveness, accuracy of risk stratification and alternative screening methods, accuracy of tests, and screening harms. Data Extraction and Synthesis: One investigator abstracted data; a second checked accuracy. Two investigators independently assessed study quality. Main Outcomes and Measures: Complications of infection; infection transmission or acquisition; diagnostic accuracy of anatomical site-specific testing and collection methods; screening harms. Results: Twenty-seven studies were included (N = 179 515). Chlamydia screening compared with no screening was significantly associated with reduced risk of pelvic inflammatory disease (PID) in 2 of 4 trials and with reduced hospital-diagnosed PID (0.24% vs 0.38%); relative risk, 0.6 [95% CI, 0.4-1.0]), but not clinic-diagnosed PID or epididymitis, in the largest trial. In studies of risk prediction instruments in asymptomatic women, age younger than 22 years demonstrated comparable accuracy to extensive criteria. Sensitivity of chlamydial testing was similar at endocervical (89%-100%) and self- and clinician-collected vaginal (90%-100%) sites for women and at meatal (100%), urethral (99%), and rectal (92%) sites for men but lower at pharyngeal sites (69.2%) for men who have sex with men. Sensitivity of gonococcal testing was 89% or greater for all anatomical samples. False-positive and false-negative testing rates were low across anatomical sites and collection methods. Conclusions and Relevance: Screening for chlamydial infection was significantly associated with a lower risk of PID in young women. Risk prediction criteria demonstrated limited accuracy beyond age. Testing for asymptomatic chlamydial and gonococcal infections was highly accurate at most anatomical sites, including urine and self-collected specimens. Effectiveness of screening in men and during pregnancy, optimal screening intervals, and adverse effects of screening require further evaluation.

Efficacy and safety of prothrombin complex concentrate in patients treated with rivaroxaban or apixaban compared to warfarin presenting with major bleeding.

This retrospective study investigated the efficacy and safety of prothrombin complex concentrates (PCCs) for management of major bleeding events (MBE) in 344 patients receiving the anticoagulants rivaroxaban, apixaban or warfarin during the period January 2016 to April 2018. Median (range) PCC dose was 2000 units (1000-4500). Intracranial haemorrhage (ICH) was the most common indication (137/344, 39·8%) for PCC use followed by gastrointestinal bleeding (93/344, 27%). ICH patients more frequently received rivaroxaban (62·5%) or apixaban (52·5%) compared to warfarin (34·5%), P = 0·002; and visceral bleeding patients received warfarin more frequently (24·2%) than rivaroxaban (5%) or apixaban (10%), P = 0·003. Median rivaroxaban and apixaban levels were 230 ng/ml (47-759) and 159 ng/ml (45-255). Median International Normalised Ratio pre- and post-PCC in patients on warfarin were 3·4 (1·9-15·4) and 1·2 (1·0-1·9). Blood products use was the same between groups. Thirty-day mortality and re-bleeding rates in patients with ICH were 35% (P = 0·50) and 18% (P = 0·90) with no differences between the groups. Thrombosis occurred in 4·1% patients within 30 days with no difference between groups. Two of 91 (2·2%) patients with ICH only (both on warfarin) had ischaemic strokes within 30 days post-PCC. In conclusion, there was no difference in the safety (thrombosis) or efficacy (30-day mortality, re-bleeding) in use of PCC for MBE in patients on warfarin, rivaroxaban or apixaban.

Screening for Elevated Blood Lead Levels in Childhood and Pregnancy: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force.

Importance: Elevated blood lead level is associated with serious, often irreversible, health consequences. Objective: To synthesize evidence on the effects of screening, testing, and treatment for elevated blood lead level in pregnant women and children aged 5 years and younger in the primary care setting to inform the US Preventive Services Task Force. Data Sources: Cochrane CENTRAL and Cochrane Database of Systematic Reviews (through June 2018) and Ovid MEDLINE (1946 to June 2018); surveillance through December 5, 2018. Study Selection: English-language trials and observational studies of screening for and treating elevated lead levels in asymptomatic children and pregnant women. Data Extraction and Synthesis: Independent critical appraisal and data abstraction by 2 reviewers using predefined criteria. Main Outcomes and Measures: Elevated blood lead level, morbidity, mortality, clinical prediction tools, test accuracy, adverse events. Results: A total of 24 studies (N = 11 433) were included in this review. No studies evaluated the benefits or harms of screening vs no screening in children. More than 1 positive answer on the 5-item 1991 Centers for Disease Control and Prevention (CDC) screening questionnaire was associated with a pooled sensitivity of 48% (95% CI, 31.4% to 65.6%) and specificity of 58% (95% CI, 39.9% to 74.0%) for identifying children with a venous blood lead level greater than 10 µg/dL (5 studies [n = 2265]). Adapted versions of the CDC questionnaire did not demonstrate improved accuracy. Capillary blood lead testing demonstrated sensitivity of 87% to 91% and specificity greater than 90%, compared with venous measurement (4 studies [n = 1431]). Counseling and nutritional interventions or residential lead hazard control techniques did not reduce blood lead concentrations in asymptomatic children, but studies were few and had methodological limitations (7 studies [n = 1419]). One trial (n = 780) of dimercaptosuccinic acid (DMSA) chelation therapy found reduced blood lead levels in children at 1 week to 1 year but not at 4.5 to 6 years, while another trial (n = 39) found no effect at 1 and 6 months. Seven-year follow-up assessments showed no effect on neuropsychological development, a small deficit in linear growth (height difference, 1.17 cm [95% CI, 0.41 to 1.93]), and poorer cognitive outcomes reported as the Attention and Executive Functions subscore of the Developmental Neuropsychological Assessment (unadjusted difference, -1.8 [95% CI, -4.5 to 1.0]; adjusted P = .045) in children treated with DMSA chelation. Evidence was too limited to determine the accuracy of screening questionnaires or benefits and harms of treatment in pregnant women. Conclusions and Relevance: Screening questionnaires were not accurate for identifying children with elevated blood lead levels. Chelating agents in children were not significantly associated with sustained effects on blood level levels but were associated with harms.

Systemic Pharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline.

BACKGROUND: A 2007 American College of Physicians guideline addressed pharmacologic options for low back pain. New evidence and medications have now become available. PURPOSE: To review the current evidence on systemic pharmacologic therapies for acute or chronic nonradicular or radicular low back pain. DATA SOURCES: Ovid MEDLINE (January 2008 through November 2016), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists. STUDY SELECTION: Randomized trials that reported pain, function, or harms of systemic medications versus placebo or another intervention. DATA EXTRACTION: One investigator abstracted data, and a second verified accuracy; 2 investigators independently assessed study quality. DATA SYNTHESIS: The number of trials ranged from 9 (benzodiazepines) to 70 (nonsteroidal anti-inflammatory drugs). New evidence found that acetaminophen was ineffective for acute low back pain, nonsteroidal anti-inflammatory drugs had smaller benefits for chronic low back pain than previously observed, duloxetine was effective for chronic low back pain, and benzodiazepines were ineffective for radiculopathy. For opioids, evidence remains limited to short-term trials showing modest effects for chronic low back pain; trials were not designed to assess serious harms. Skeletal muscle relaxants are effective for short-term pain relief in acute low back pain but caused sedation. Systemic corticosteroids do not seem to be effective. For effective interventions, pain relief was small to moderate and generally short-term; improvements in function were generally smaller. Evidence is insufficient to determine the effects of antiseizure medications. LIMITATIONS: Qualitatively synthesized new trials with prior meta-analyses. Only English-language studies were included, many of which had methodological shortcomings. Medications injected for local effects were not addressed. CONCLUSION: Several systemic medications for low back pain are associated with small to moderate, primarily short-term effects on pain. New evidence suggests that acetaminophen is ineffective for acute low back pain, and duloxetine is associated with modest effects for chronic low back pain. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42014014735).

Nonpharmacologic Therapies for Low Back Pain: A Systematic Review for an American College of Physicians Clinical Practice Guideline.

BACKGROUND: A 2007 American College of Physicians guideline addressed nonpharmacologic treatment options for low back pain. New evidence is now available. PURPOSE: To systematically review the current evidence on nonpharmacologic therapies for acute or chronic nonradicular or radicular low back pain. DATA SOURCES: Ovid MEDLINE (January 2008 through February 2016), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists. STUDY SELECTION: Randomized trials of 9 nonpharmacologic options versus sham treatment, wait list, or usual care, or of 1 nonpharmacologic option versus another. DATA EXTRACTION: One investigator abstracted data, and a second checked abstractions for accuracy; 2 investigators independently assessed study quality. DATA SYNTHESIS: The number of trials evaluating nonpharmacologic therapies ranged from 2 (tai chi) to 121 (exercise). New evidence indicates that tai chi (strength of evidence [SOE], low) and mindfulness-based stress reduction (SOE, moderate) are effective for chronic low back pain and strengthens previous findings regarding the effectiveness of yoga (SOE, moderate). Evidence continues to support the effectiveness of exercise, psychological therapies, multidisciplinary rehabilitation, spinal manipulation, massage, and acupuncture for chronic low back pain (SOE, low to moderate). Limited evidence shows that acupuncture is modestly effective for acute low back pain (SOE, low). The magnitude of pain benefits was small to moderate and generally short term; effects on function generally were smaller than effects on pain. LIMITATION: Qualitatively synthesized new trials with prior meta-analyses, restricted to English-language studies; heterogeneity in treatment techniques; and inability to exclude placebo effects. CONCLUSION: Several nonpharmacologic therapies for primarily chronic low back pain are associated with small to moderate, usually short-term effects on pain; findings include new evidence on mind-body interventions. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42014014735).

Management of Suspected Opioid Overdose With Naloxone in Out-of-Hospital Settings: A Systematic Review.

BACKGROUND: Naloxone is effective for reversing opioid overdose, but optimal strategies for out-of-hospital use are uncertain. PURPOSE: To synthesize evidence on 1) the effects of naloxone route of administration and dosing for suspected opioid overdose in out-of-hospital settings on mortality, reversal of overdose, and harms, and 2) the need for transport to a health care facility after reversal of overdose with naloxone. DATA SOURCES: Ovid MEDLINE (1946 through September 2017), PsycINFO, Cochrane Central Register of Controlled Trials, CINAHL, U.S. Food and Drug Administration (FDA) materials, and reference lists. STUDY SELECTION: English-language cohort studies and randomized trials that compared different doses of naloxone, administration routes, or transport versus nontransport after reversal of overdose with naloxone. Main outcomes were mortality, reversal of overdose, recurrence of overdose, and harms. DATA EXTRACTION: Dual extraction and quality assessment of individual studies; consensus assessment of overall strength of evidence (SOE). DATA SYNTHESIS: Of 13 eligible studies, 3 randomized controlled trials and 4 cohort studies compared different administration routes. At the same dose (2 mg), 1 trial found similar efficacy between higher-concentration intranasal naloxone (2 mg/mL) and intramuscular naloxone, and 1 trial found that lower-concentration intranasal naloxone (2 mg/5 mL) was less effective than intramuscular naloxone but was associated with decreased risk for agitation (low SOE). Evidence was insufficient to evaluate other comparisons of route of administration. Six uncontrolled studies reported low rates of death and serious adverse events (0% to 1.25%) in nontransported patients after successful naloxone treatment. LIMITATION: There were few studies, all had methodological limitations, and none evaluated FDA-approved autoinjectors or highly concentrated intranasal formulations. CONCLUSION: Higher-concentration intranasal naloxone (2 mg/mL) seems to have efficacy similar to that of intramuscular naloxone for reversal of opioid overdose, with no difference in adverse events. Nontransport after reversal of overdose with naloxone seems to be associated with a low rate of serious harms, but no study evaluated risks of transport versus nontransport. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42016053891).

Comparative Effectiveness of Fluorescent Versus White Light Cystoscopy for Initial Diagnosis or Surveillance of Bladder Cancer on Clinical Outcomes: Systematic Review and Meta-Analysis.

PURPOSE: We systematically reviewed the comparative effectiveness of fluorescent vs white light cystoscopy on bladder cancer clinical outcomes. MATERIALS AND METHODS: Systematic literature searches of Ovid MEDLINE® (January 1990 through September 2015), Cochrane databases and reference lists were performed. A total of 14 randomized trials of fluorescent cystoscopy using 5-aminolevulinic acid or hexaminolevulinic acid vs white light cystoscopy for the diagnosis of initial or recurrent bladder cancer that reported bladder cancer recurrence, progression, mortality and harms were selected for review. RESULTS: Fluorescent cystoscopy was associated with a decreased risk of bladder cancer recurrence vs white light cystoscopy at short-term (less than 3 months, 10 trials, RR 0.59, 95% CI 0.40 to 0.88, I2=69%), intermediate-term (3 months to less than 1 year, 6 trials, RR 0.70, 95% CI 0.56 to 0.88, I2=19%) and long-term followup (1 year or more, 12 trials, RR 0.81, 95% CI 0.70 to 0.93, I2=49%). However, the findings were inconsistent, and potentially susceptible to performance and publication bias (strength of evidence low). There were no differences between cystoscopic methods in risk of mortality (3 trials, RR 1.28, 95% CI 0.55 to 2.95, I2=41%) (strength of evidence low) or progression (9 trials, RR 0.74, 95% CI 0.52 to 1.03, I2=0%) (strength of evidence moderate). Estimates for short-term recurrence (6 trials, RR 0.62, 95% CI 0.38 to 1.00), long-term recurrence (7 trials, RR 0.75, 95% CI 0.62 to 0.92) and progression (4 trials, RR 0.51, 95% CI 0.28 to 0.96) were statistically significant in the subgroup of trials that used hexaminolevulinic acid, but there were no statistically significant interactions based on the photosensitizer used. Fluorescent cystoscopy was not associated with a decreased risk of long-term recurrence in 3 trials that used methods to reduce performance bias with initial cystoscopy (RR 0.96, 95% CI 0.79 to 1.18, I2=36%). Data on harms were sparse. CONCLUSIONS: Fluorescent cystoscopy was associated with a reduced risk of bladder cancer recurrence vs white light cystoscopy. However, additional trials that adequately guard against performance bias are needed to confirm these findings. Fluorescent cystoscopy with hexaminolevulinic acid may be associated with a decreased risk of progression, but more studies with long-term followup are needed to better understand the effects of the photosensitizer used on progression.

Intravesical Therapy for the Treatment of Nonmuscle Invasive Bladder Cancer: A Systematic Review and Meta-Analysis.

PURPOSE: We systematically review the benefits and harms of intravesical therapies for nonmuscle invasive bladder cancer. MATERIALS AND METHODS: Systematic literature searches were performed of Ovid MEDLINE (January 1990 through February 2016), the Cochrane databases and reference lists. Randomized and quasi-randomized trials of intravesical bacillus Calmette-Guérin, mitomycin C, gemcitabine, thiotepa, valrubicin, doxorubicin, epirubicin and interferon vs transurethral bladder tumor resection alone, and head-to-head trials of intravesical therapies were selected. Data were pooled using a random effects model. RESULTS: Overall 39 trials evaluated adjuvant intravesical therapy vs transurethral bladder tumor resection alone. Bacillus Calmette-Guérin was associated with a decreased risk of bladder cancer recurrence (3 trials, RR 0.56, 95% CI 0.43-0.71) and progression (4 trials, RR 0.39, 95% CI 0.24-0.64) (strength of evidence low). Mitomycin C, doxorubicin, epirubicin and thiotepa were also associated with a decreased risk of recurrence, with no difference in risk of progression (strength of evidence low). There were 55 trials that compared one intravesical therapy agent against another. There were no differences between bacillus Calmette-Guérin vs mitomycin C in recurrence risk (RR 0.95, 95% CI 0.81-1.11), but bacillus Calmette-Guérin was associated with a decreased risk of recurrence in the subgroup of trials of maintenance regimens (RR 0.79, 95% CI 0.71-0.87, strength of evidence low). Bacillus Calmette-Guérin was associated with a lower recurrence risk vs doxorubicin, epirubicin, interferon alpha-2a, bacillus Calmette-Guérin plus interferon alpha-2b, and thiotepa (strength of evidence low to moderate). Bacillus Calmette-Guérin was associated with higher rates of local and systemic adverse events than other intravesical agents (strength of evidence low). Head-to-head trials showed no clear differences between standard and lower doses of bacillus Calmette-Guérin in recurrence, progression or mortality risk (strength of evidence low). Limited evidence suggested that bacillus Calmette-Guérin maintenance regimens are associated with reduced recurrence risk vs no further intravesical therapy in responders to induction therapy (strength of evidence low). CONCLUSIONS: For nonmuscle invasive bladder cancer several intravesical therapies are associated with a decreased risk of recurrence vs transurethral bladder tumor resection alone. Bacillus Calmette-Guérin is the only agent associated with a decreased progression risk vs transurethral bladder tumor resection alone, but may be associated with a higher risk of adverse events than other intravesical therapies, indicating trade-offs between potential benefits and harms.

Harms of Breast Cancer Screening: Systematic Review to Update the 2009 U.S. Preventive Services Task Force Recommendation.

BACKGROUND: In 2009, the U.S. Preventive Services Task Force recommended biennial mammography screening for women aged 50 to 74 years and selective screening for those aged 40 to 49 years. PURPOSE: To review studies of screening in average-risk women with mammography, magnetic resonance imaging, or ultrasonography that reported on false-positive results, overdiagnosis, anxiety, pain, and radiation exposure. DATA SOURCES: MEDLINE and Cochrane databases through December 2014. STUDY SELECTION: English-language systematic reviews, randomized trials, and observational studies of screening. DATA EXTRACTION: Investigators extracted and confirmed data from studies and dual-rated study quality. Discrepancies were resolved through consensus. DATA SYNTHESIS: Based on 2 studies of U.S. data, 10-year cumulative rates of false-positive mammography results and biopsies were higher with annual than biennial screening (61% vs. 42% and 7% vs. 5%, respectively) and for women aged 40 to 49 years, those with dense breasts, and those using combination hormone therapy. Twenty-nine studies using different methods reported overdiagnosis rates of 0% to 54%; rates from randomized trials were 11% to 22%. Women with false-positive results reported more anxiety, distress, and breast cancer-specific worry, although results varied across 80 observational studies. Thirty-nine observational studies indicated that some women reported pain during mammography (1% to 77%); of these, 11% to 46% declined future screening. Models estimated 2 to 11 screening-related deaths from radiation-induced cancer per 100,000 women using digital mammography, depending on age and screening interval. Five observational studies of tomosynthesis and mammography indicated increased biopsies but reduced recalls compared with mammography alone. LIMITATIONS: Studies of overdiagnosis were highly heterogeneous, and estimates varied depending on the analytic approach. Studies of anxiety and pain used different outcome measures. Radiation exposure was based on models. CONCLUSION: False-positive results are common and are higher for annual screening, younger women, and women with dense breasts. Although overdiagnosis, anxiety, pain, and radiation exposure may cause harm, their effects on individual women are difficult to estimate and vary widely. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Treatment of muscle-invasive bladder cancer: A systematic review.

There is uncertainty regarding the use of bladder-sparing alternatives to standard radical cystectomy, optimal lymph node dissection techniques, and optimal chemotherapeutic regimens. This study was conducted to systematically review the benefits and harms of bladder-sparing therapies, lymph node dissection, and systemic chemotherapy for patients with clinically localized muscle-invasive bladder cancer. Systematic literature searches of MEDLINE (from 1990 through October 2014), the Cochrane databases, reference lists, and the ClinicalTrials.gov Web site were performed. A total of 41 articles were selected for review. Bladder-sparing therapies were found to be associated with worse survival compared with radical cystectomy, although the studies had serious methodological shortcomings, findings were inconsistent, and only a few studies evaluated currently recommended techniques. More extensive lymph node dissection might be more effective than less extensive dissection at improving survival and decreasing local disease recurrence, but there were methodological shortcomings and some inconsistency. Six randomized trials found cisplatin-based combination neoadjuvant chemotherapy to be associated with a decreased mortality risk versus cystectomy alone. Four randomized trials found adjuvant chemotherapy to be associated with decreased mortality versus cystectomy alone, but none of these trials reported a statistically significant effect. There was insufficient evidence to determine optimal chemotherapeutic regimens.

Urinary Biomarkers for Diagnosis of Bladder Cancer: A Systematic Review and Meta-analysis.

BACKGROUND: Urinary biomarkers may be a useful alternative or adjunct to cystoscopy for diagnosis of bladder cancer. PURPOSE: To systematically review the evidence on the accuracy of urinary biomarkers for diagnosis of bladder cancer in adults who have signs or symptoms of the disease or are undergoing surveillance for recurrent disease. DATA SOURCES: Ovid MEDLINE (January 1990 through June 2015), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists. STUDY SELECTION: 57 studies that evaluated the diagnostic accuracy of quantitative or qualitative nuclear matrix protein 22 (NMP22), qualitative or quantitative bladder tumor antigen (BTA), fluorescence in situ hybridization (FISH), fluorescent immunohistochemistry (ImmunoCyt [Scimedx]), and Cxbladder (Pacific Edge Diagnostics USA) using cystoscopy and histopathology as the reference standard met inclusion criteria. Case-control studies were excluded. DATA EXTRACTION: Dual extraction and quality assessment of individual studies. Overall strength of evidence (SOE) was also assessed. DATA SYNTHESIS: Across biomarkers, sensitivities ranged from 0.57 to 0.82 and specificities ranged from 0.74 to 0.88. Positive likelihood ratios ranged from 2.52 to 5.53, and negative likelihood ratios ranged from 0.21 to 0.48 (moderate SOE for quantitative NMP22, qualitative BTA, FISH, and ImmunoCyt; low SOE for others). For some biomarkers, sensitivity was higher for initial diagnosis of bladder cancer than for diagnosis of recurrence. Sensitivity increased with higher tumor stage or grade. Studies that directly compared the accuracy of quantitative NMP22 and qualitative BTA found no differences in diagnostic accuracy (moderate SOE); head-to-head studies of other biomarkers were limited. Urinary biomarkers plus cytologic evaluation were more sensitive than biomarkers alone but missed about 10% of bladder cancer cases. LIMITATION: Restricted to English-language studies; no search for studies published only as abstracts; statistical heterogeneity present in most analyses; few studies for qualitative NMP22, quantitative BTA, and Cxbladder; and methodological shortcomings in almost all studies. CONCLUSION: Urinary biomarkers miss a substantial proportion of patients with bladder cancer and are subject to false-positive results in others. Accuracy is poor for low-stage and low-grade tumors. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO registration number: CRD42014013284).

Use of medications to reduce risk for primary breast cancer: a systematic review for the U.S. Preventive Services Task Force.

BACKGROUND: Medications to reduce risk for primary breast cancer are recommended for women at increased risk; however, use is low. PURPOSE: To update evidence about the effectiveness and adverse effects of medications to reduce breast cancer risk, patient use of such medications, and methods for identifying women at increased risk for breast cancer. DATA SOURCES: MEDLINE and Cochrane databases (through 5 December 2012), Scopus, Web of Science, clinical trial registries, and reference lists. STUDY SELECTION: English-language randomized trials of medication effectiveness and adverse effects, observational studies of adverse effects and patient use, and diagnostic accuracy studies of risk assessment. DATA EXTRACTION: Investigators independently extracted data on participants, study design, analysis, follow-up, and results, and a second investigator confirmed key data. Investigators independently dual-rated study quality and applicability using established criteria. DATA SYNTHESIS: Seven good- and fair-quality trials indicated that tamoxifen and raloxifene reduced incidence of invasive breast cancer by 7 to 9 cases in 1000 women over 5 years compared with placebo. New results from STAR (Study of Tamoxifen and Raloxifene) showed that tamoxifen reduced breast cancer incidence more than raloxifene by 5 cases in 1000 women. Neither reduced breast cancer-specific or all-cause mortality rates. Both reduced the incidence of fractures, but tamoxifen increased the incidence of thromboembolic events more than raloxifene by 4 cases in 1000 women. Tamoxifen increased the incidence of endometrial cancer and cataracts compared with placebo and raloxifene. Trials provided limited and heterogeneous data on medication adherence and persistence. Many women do not take tamoxifen because of associated harms. Thirteen risk-stratification models were modest predictors of breast cancer. LIMITATION: Data on mortality and adherence measures and for women who are nonwhite, are premenopausal, or have comorbid conditions were lacking. CONCLUSION: Medications reduced the incidence of invasive breast cancer and fractures and increased the incidence of thromboembolic events. Tamoxifen was more effective than raloxifene but also increased the incidence of endometrial cancer and cataracts. Use is limited by adverse effects and inaccurate methods to identify candidates. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis.

BACKGROUND: Identifying risk factors for breast cancer specific to women in their 40s could inform screening decisions. PURPOSE: To determine what factors increase risk for breast cancer in women aged 40 to 49 years and the magnitude of risk for each factor. DATA SOURCES: MEDLINE (January 1996 to the second week of November 2011), Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews (fourth quarter of 2011), Scopus, reference lists of published studies, and the Breast Cancer Surveillance Consortium. STUDY SELECTION: English-language studies and systematic reviews of risk factors for breast cancer in women aged 40 to 49 years. Additional inclusion criteria were applied for each risk factor. DATA EXTRACTION: Data on participants, study design, analysis, follow-up, and outcomes were abstracted. Study quality was rated by using established criteria, and only studies rated as good or fair were included. Results were summarized by using meta-analysis when sufficient studies were available or from the best evidence based on study quality, size, and applicability when meta-analysis was not possible. Data from the Breast Cancer Surveillance Consortium were analyzed with proportional hazards models by using partly conditional Cox regression. Reference groups for comparisons were set at U.S. population means. DATA SYNTHESIS: Sixty-six studies provided data for estimates. Extremely dense breasts on mammography or first-degree relatives with breast cancer were associated with at least a 2-fold increase in risk for breast cancer. Prior breast biopsy, second-degree relatives with breast cancer, or heterogeneously dense breasts were associated with a 1.5- to 2.0-fold increased risk; current use of oral contraceptives, nulliparity, and age 30 years or older at first birth were associated with a 1.0- to 1.5-fold increased risk. LIMITATIONS: Studies varied by measures, reference groups, and adjustment for confounders, which could bias combined estimates. Effects of multiple risk factors were not considered. CONCLUSION: Extremely dense breasts and first-degree relatives with breast cancer were each associated with at least a 2-fold increase in risk for breast cancer in women aged 40 to 49 years. Identification of these risk factors may be useful for personalized mammography screening. PRIMARY FUNDING SOURCE: National Cancer Institute.