PD-1 blockade in advanced NSCLC: A focus on pembrolizumab.

Non-small cell lung cancer (NSCLC) is one of the most prevalent cancers and is responsible for a large proportion of all cancer-related deaths. Current treatment options are inadequate, reflecting a substantial unmet clinical need. Increasing knowledge regarding the mechanisms and genetic aberrations underlying tumor development and growth has heralded a new era of therapy in oncology, moving away from indiscriminate cytotoxic chemotherapy toward more finely focused, targeted medicine. The development of small-molecule drugs and monoclonal antibodies directed toward specific components of dysfunctional molecular or immune pathways, and mutated genes specific to particular cancer types, is leading the field to more personalized and less toxic treatment options, many of which have demonstrated greater efficacy and survival benefits than their chemotherapeutic counterparts. Particularly successful examples are agents that interfere with the programmed death 1 (PD-1) pathway, which many tumors can hijack to avoid immune surveillance and editing. Pembrolizumab, a monoclonal antibody directed at PD-1 that blocks the engagement between PD-1 and its ligands, has been explored as a treatment for solid tumors, and demonstrated survival benefits in several studies. The use of PD-1 inhibitors such as nivolumab and pembrolizumab in advanced cancers is widespread, and pembrolizumab is available in more than 60 countries for at least one of the following: advanced melanoma, PD-L1-expressing NSCLC, head and neck squamous cell carcinoma, and adult and pediatric patients with refractory classical Hodgkin's lymphoma. This work provides a brief overview of the role of pembrolizumab in the treatment of advanced (recurrent/metastatic) NSCLC

Osteoarthritis prevalence in retired national football league players with a history of ankle injuries and surgery

Context: Ankle injuries are common at all levels of American football, and retired National Football League (NFL) players have a high prevalence of osteoarthritis (OA), but little is known about how ankle injuries influence OA prevalence and daily activities in this population or how surgical interventions for such injuries alter the risk of OA. Objective: To examine (1) the association of ankle-injury history with OA prevalence, (2) the association of surgical intervention after ankle injury with OA prevalence, and (3) the relationships among ankle injuries, reported OA, and daily activities in retired NFL players. Design: Case-control study. Setting: Survey. Patients or Other Participants: Data from the Retired NFL Players General Health Survey. Main Outcome Measure(s): We created a 7-category main exposure variable that differentiated respondents by football-related ankle injury and surgical intervention. Multivariable binomial regression models were used to estimate prevalence ratios and 95% confidence intervals. Among those reporting OA, we examined the distribution of responses regarding whether OA affected daily activities. Results: Among the 2446 respondents, 920 participants experienced OA in any joint during their lifetime. Compared with those reporting no ankle injuries, the prevalence of OA was higher among those with a history of ankle injury. Also, the prevalence of OA was higher among those who had undergone surgery versus those who had not. The number of retired NFL players who reported that OA often affected their daily activities increased with the number of ankle injuries. Conclusions: Among former NFL players, a history of ankle injury increased the prevalence of OA. More ankle injuries increased the probability that OA negatively affected daily activities. Future prospective research is needed to better determine the influence of surgical intervention at the ankle or foot on OA

Association between concussion and mental health in former collegiate athletes

Background: The existing research on the association between concussion and mental health outcomes is largely limited to former professional athletes. This cross-sectional study estimated the association between recurrent concussion and depression, impulsivity, and aggression in former collegiate athletes. Methods: Former collegiate athletes who played between 1987–2012 at a Division I university completed an online questionnaire. The main exposure, total number of self-recalled concussions (sport-related and non-sport-related), were categorized as: zero (referent), one, two, or three or more concussions. The main outcomes were the depression module of The Patient Health Questionnaire (PHQ-9), the Short Form of the Barratt Impulsiveness scale (BIS15); and the 12-item Short Form of the Buss-Perry Aggression Questionnaire (BPAQ-SF). Depression was categorized into a binomial severity classification that differentiated between no or mild depression (PHQ-9 scores <10) and moderate to severe depression (PHQ-9 scores ≥10). Impulsivity and aggression were kept as continuous outcomes. Binomial regression estimated adjusted prevalence ratios (PR). Linear regression estimated adjusted mean differences (MD). Results: Of the 797 respondents with complete data (21.9% completion rate), 38.8% reported at least one concussion. Controlling for alcohol dependence and family history of depression, the prevalence of moderate to severe depression among former collegiate athletes reporting three or more concussions in total was 2.4 times that of those reporting zero concussions [95% Confidence Interval (CI): 1.0, 5.7]. Controlling for alcohol dependence, family history of anxiety, relationship status, obtaining a post-graduate degree, and playing primary college sport professionally, former collegiate athletes reporting two or more concussions in total had higher mean scores for impulsivity, compared to those reporting no concussions (2 concussions MD = 2.7; 95% CI: 1.2, 4.1; 3+ concussions MD = 1.9; 95% CI: 0.6, 3.2). Controlling for alcohol dependence, sex, and relationship status, former collegiate athletes reporting three or more concussions in total had a higher mean score for aggression, compared to those reporting no concussions (MD = 3.0; 95% CI: 1.4, 4.7). Conclusions: Our study found an association between former concussion and greater risk of severe depression and higher levels of impulsivity and aggression among former collegiate athletes. Additional prospective studies better addressing causality and ascertaining valid lifetime concussion histories and medical histories are needed

Agreement between athlete-recalled and clinically documented concussion histories in former collegiate athletes

Background: Athlete-recalled and clinically documented concussion histories have been used in research on former athletes, but both have limitations. Comparisons of these 2 types of concussion histories are needed to improve the accuracy of estimates of concussion history for future research and clinical care. Purpose: To estimate the agreement between athlete-recalled and clinically documented concussion histories during college and to explore reasons for differences. Study: Cohort study (diagnosis); Level of evidence, 3. Methods: Athlete-recalled concussion histories were provided by a convenience sample of 130 former collegiate athletes using an online questionnaire, and they were individually linked to previously collected clinical data that tracked medically diagnosed concussions at the host institution from 1996 to 2012. The intraclass correlation coefficient (ICC2,1) was used to assess agreement between athlete-recalled and clinically documented concussion histories. Descriptive analyses were performed to assess reasons for disagreement. Results: Agreement between athlete-recalled and clinically documented concussion histories was low (ICC2,1 = 0.21; 95% confidence interval, 0.05-0.37), but it was higher for women (ICC2,1 = 0.65; 95% confidence interval, 0.44-0.79) and for athletes playing more recently (2005-2012; ICC2,1 = 0.39; 95% confidence interval, 0.01-0.67). Of the 53 athletes who self-reported college sportsrelated concussions, 40% believed that they sustained impacts that should have been diagnosed as concussions but were undetected, and 21% admitted nondisclosure of suspected concussions. Common reasons for nondisclosure included the following: did not think injury was serious enough (91%), did not know it was a concussion (73%), and did not want to leave the game/practice (73%). Conclusion: Given the low agreement between athlete-recalled and clinically documented concussion histories, methodologic research is needed to improve the quality of tools used to assess concussion histories in former athletes. © 2014 The Author(s)

Concussion Nondisclosure During Professional Career Among a Cohort of Former National Football League Athletes

Background: Despite a focus on the incidence and effects of concussion, nondisclosure of sports-related concussions among retired players from the National Football League (NFL) has yet to be examined. Purpose: Examine the prevalence of and factors associated with nondisclosure of sports-related concussions in former NFL athletes. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A sample of 829 former NFL players completed a general health survey. This historical cohort included players who had played before World War II to 2001. Respondents retrospectively recalled sports-related concussions that they sustained during their professional careers and whether at least one of these sports-related concussions was not reported to medical staff. We computed the prevalence of nondisclosure among those recalling sport-related concussions during their professional careers. Multivariable binomial regression estimated adjusted prevalence ratios (PR) with 95% confidence intervals (CIs) controlling for race/ethnicity, number of years played, primary position played, professional career concussion history, and playing era. Playing era was categorized by whether the majority of a player’s career was before or after a 1976 rule change to limit contact (“spearing”). Results: Overall, 417 (50.3%) respondents reported they had sustained a concussion and did not inform medical staff at least once during their professional playing career. Nonwhite respondents had a higher prevalence of nondisclosure than white/non-Hispanic respondents (adjusted PR = 1.19; 95% CI, 1.02-1.38). An interaction between professional career concussion history and playing era was also found (P =.08). Compared with those in the pre–spearing rule change group with 1 or 2 concussions, all other groups had larger prevalences of nondisclosure (increases ranging from 41% to 153% in multivariable models). Across concussion strata, nondisclosure prevalence was generally higher in the post–spearing rule change group than the pre–spearing rule change group, with the largest differences found among those with 1 or 2 concussions or those with 3 or 4 concussions. Conclusion: A large proportion of former NFL players in this historical cohort reported at least one instance of not disclosing sports-related concussions to medical staff. Future research on concussion nondisclosure needs to identify mechanisms to improve football players’ intentions to disclose concussion-related symptoms to health care providers and to equip health care providers with more effective strategies for timely identification of concussion

Associations between BMI Change and Cardiometabolic Risk in Retired Football Players

Purpose Elevated rates of cardiometabolic diseases have been observed in former American football players. The current study sought to determine whether change in body mass index (ΔBMI) after retirement influences the prevalence of CHD, diabetes, or high blood pressure (HBP) in former professional football players. Methods Retired professional football players (n = 3729) were sent a survey with questions regarding health status, playing history, and demographic information. Self-reported BMI at the time of retirement was subtracted from current self-reported BMI to calculate ΔBMI. Prevalence of CHD, diabetes, and HBP were determined by asking participants if they had ever been diagnosed by a health care professional. Binomial regression with a Poisson residual and robust variance estimation was used to compute crude prevalence ratios (PR) and 95% confidence intervals (CI) for each outcome. Adjusted PR values were calculated by adjusting for BMI at the time of retirement, age, years of football experience, race, exercise habits, alcohol use, steroid history, smoking history, and playing position. Results Complete data were available for 2062 respondents. Prevalence of CHD increased 25%-31% for each five-point increase in ΔBMI after retirement (crude PR = 1.25, 95% CI = 1.03-1.52, P = 0.026; adjusted PR = 1.31, 95% CI = 1.11-1.55, P = 0.001). Diabetes prevalence increased 69%-88% for each five-point ΔBMI increase (crude = 1.88, 95% CI = 1.45-2.44, P < 0.001; adjusted = 1.69, 95% CI = 1.32-2.15, P < 0.001). A five-point increase in ΔBMI was associated with a 35%-40% increase in HBP prevalence (crude = 1.40, 95% CI = 1.27-1.53, P < 0.001; adjusted = 1.35, 95% CI = 1.24-1.47, P < 0.001). Conclusions After controlling for relevant covariates, postretirement ΔBMI was positively and independently associated with prevalence of CHD, diabetes, and HBP. Postretirement interventions using diet and/or exercise to influence body composition may improve long-term health in retired football players

Malignant pleural mesothelioma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.

Biological, physical and clinical aspects of cancer treatment with ionising radiatio

Musculoskeletal injury history is associated with lower physical and mental health in a historical cohort of former national football league players

Context: Little research has examined health-related quality of life in former National Football League (NFL) players. Objective: Examine the association of musculoskeletal injury history and current self-reported physical and mental health in former NFL players. Setting: Cross-sectional questionnaire. Patients or Other Participants: Historical cohort of 2,103 former NFL players that played at least one season between 1940 and 2001. Intervention: Players were grouped by self-reported professional career musculoskeletal injury history and whether injuries affected current health: (1) no musculoskeletal injury history; (2) musculoskeletal injury history, currently affected by injuries; and (3) musculoskeletal injury history, not currently affected by injuries. Main Outcome Measure: The Short Form 36 Measurement Model for Functional Assessment of Health and Well-Being (SF-36) yielded physical and mental health composite scores (PCS and MCS, respectively); higher scores indicated better health. Multivariable linear regression computed mean differences (MD) among injury groups. Covariates included demographics, playing history characteristics, surgical intervention for musculoskeletal injuries, and whether injury resulted in premature end to career. MD with 95% CI excluding 0.00 were deemed significant. Results: Overall, 90.3% reported at least one musculoskeletal injury during their professional football careers, of which 74.8% reported being affected by their injuries at time of survey completion. Adjusting for covariates, mean PCS in the “injury and affected” group was lower than the “no injury” (MD = −3.2; 95% CI: −4.8, −1.7) and “injury and not affected” groups (MD = −4.3; 95% CI: −5.4, −3.3); mean MCS did not differ. Conclusion: Many players reported musculoskeletal injuries, highlighting the need for developing and evaluating injury management interventions

Prevalence of and Risk Factors for Total Hip and Knee Replacement in Retired National Football League Athletes

Background: Osteoarthritis is a substantial cause of disability. Joint replacement prevalence relates to the burden of severe osteoarthritis, and identifying risk factors for end-stage disease may indicate intervention opportunities. American football has high youth and elite participation, and determining risk factors for severe osteoarthritis may support future morbidity prevention. Purpose: To (1) determine the prevalence of hip and knee replacement in retired National Football League (NFL) athletes, (2) examine risk factors for replacement, and (3) identify the association between knee injuries and knee replacement. Study Design: Case-control study; Level of evidence, 3. Methods: Retired NFL athletes who participated in a general health survey were included. This historical cohort included those playing between 1929 and 2001. The association between self-reported playing or injury history, and replacement after retirement, was assessed with prevalence ratios (PRs). Models were adjusted for potential confounders of age and weight. Results: Data for 2432 retired male NFL players (69.3% response rate) who had participated in football for a mean 15.2 years were included, in which 277 players reported replacement after retirement (11.4%). More participants reported knee replacement (7.7%) than hip replacement (4.6%). The majority of participants reported previous severe knee injury (53%), and the most prevalent was meniscal tear (32.2%). In multivariable models, age (10-year increase, PR, 2.23; 95% CI, 1.99-2.51), current weight (PR, 1.10; 95% CI, 1.06-1.14), and reporting 1 (PR, 1.78; 95% CI, 1.14-2.77), 2 (PR, 1.91; 95% CI, 1.16-3.15), or ≥3 knee injuries (PR, 3.44; 95% CI, 2.33-5.09) were associated with knee replacement. Age (10-year increase, PR, 1.86; 95% CI, 1.59-2.18), linemen (PR, 1.62; 95% CI, 1.03-2.55), and reporting 1 (PR, 1.72; 95% CI, 1.05-2.80), 2 (PR, 2.77 95% CI, 1.58-4.84), or ≥3 (PR, 2.44; 95% CI, 1.52-3.91) hip injuries were associated with hip replacement. Each reported knee injury type was cross-sectionally associated with replacement after retirement (P <.05). Conclusion: Knee replacement was more prevalent than hip replacement. Risk factors differed between the hip and the knee, with age and severe joint injury associated with hip and knee replacement, weight with knee replacement, and playing position associated with hip replacement. Joint injury and weight management may be prevention opportunities to reduce morbidity and end-stage osteoarthritis in this population

Associations of lifetime concussion history and repetitive head impact exposure with resting-state functional connectivity in former collegiate American football players: An NCAA 15-year follow-up study

The objective of this study was to examine associations of lifetime concussion history (CHx) and an advanced metric of lifetime repetitive head impact exposure with resting-state functional connectivity (rsFC) across the whole-brain and among large-scale functional networks (Default Mode; Dorsal Attention; and Frontoparietal Control) in former collegiate football players. Individuals who completed at least one year of varsity collegiate football were eligible to participate in this observational cohort study (n = 48; aged 36-41 years; 79.2% white/ Caucasian; 12.5±4.4 years of football played; all men). Individuals were excluded if they reported history/suspicion of psychotic disorder with active symptoms, contraindications to participation in study procedures (e.g., MRI safety concern), or inability to travel. Each participant provided concussion and football playing histories. Self-reported concussion history was analyzed in two different ways based on prior research: dichotomous "High"(≥3 concussions; n = 28) versus "Low"(<3 concussions; n = 20); and four ordinal categories (0-1 concussion [n = 19]; 2-4 concussions [n = 8]; 5-7 concussions [n = 9]; and ≥8 concussions [n = 12]). The Head Impact Exposure Estimate (HIEE) was calculated from football playing history captured via structured interview. Resting-state fMRI and T1-weighted MRI were acquired and preprocessed using established pipelines. Next, rsFC was calculated using the Seitzman et al., (2020) 300-ROI functional atlas. Whole-brain, within-network, and between-network rsFC were calculated using all ROIs and network-specific ROIs, respectively. Effects of CHx and HIEE on rsFC values were examined using separate multivariable linear regression models, with a-priori α set to 0.05. We observed no statistically significant associations between rsFC outcomes and either CHx or HIEE (ps ≥ .12). Neither CHx nor HIEE were associated with neural signatures that have been observed in studies of typical and pathological aging. While CHx and repetitive head impacts have been associated with changes in brain health in older former athletes, our preliminary results suggest that associations with rsFC may not be present in early midlife former football players