Changes in sex-specific incidence of lymphoid neoplasms across the lifespan.

Not available.

Protocol and validity testing of femoroacetabular posterior translation with dynamic hip ultrasonography.

OBJECTIVE: To describe femoroacetabular posterior translation (FAPT) using dynamic hip ultrasonography (DHUS), and to determine the inter- and intra-rater reliability of hip ultrasound measurements of FAPT. MATERIALS AND METHODS: The study design was a feasibility study of 13 healthy young adults (26 hips) using test-retest analysis. The data was collected prospectively over a 2-week time period. Three DHUS measurements (posterior neutral (PN), flexion, adduction, and internal rotation (PFADIR), and stand and load (PStand) were measured by four independent raters (2 senior who divided the cohort, 1 intermediate, 1 junior) at two time points for bilateral hips of each participant. Reliability was assessed by calculating the intraclass correlation coefficient (ICC) along with 95% confidence intervals (CIs) for each rater and across all raters. RESULTS: A total of 468 US scans were completed. The mean age of the cohort was 25.7 years (SD 5.1 years) and 54% were female. The inter-rater reliability was excellent for PFADIR (ICC 0.85 95% CI 0.76-0.91), good for PN (ICC 0.69 95% CI 0.5-0.81), and good for PStand (ICC 0.72 95% CI 0.55-0.83). The intra-rater reliability for all raters was good for PFADIR (ICC 0.60 95% CI 0.44-0.73), fair for PN (ICC 0.42 95% CI 0.21-0.59), and fair for PStand (ICC 0.42 95% CI 0.22-0.59). CONCLUSION: This is the first study to present a protocol using dynamic ultrasonography to measure FAPT. DHUS measure for FAPT was shown to be reliable across raters with varying levels of ultrasound experience.

No Association of IFNL4 Genotype With Opportunistic Infections and Cancers Among Men With Human Immunodeficiency Virus 1 Infection.

BACKGROUND: IFNL4 genetic variants that are strongly associated with clearance of hepatitis C virus have been linked to risk of certain opportunistic infections (OIs) and cancers, including Kaposi sarcoma, cytomegalovirus infection, and herpes simplex virus infection. As the interferon (IFN) λ family plays a role in response to viral, bacterial, and fungal infections, IFNL4 genotype might affect risk for a wide range of OIs/cancers. METHODS: We examined associations between genotype for the functional IFNL4 rs368234815 polymorphism and incidence of 16 OIs/cancers among 2310 men with human immunodeficiency virus (2038 white; 272 black) enrolled in the Multicenter AIDS Cohort Study during 1984-1990. Our primary analyses used Cox proportional hazards models adjusted for self-reported racial ancestry to estimate hazard ratios with 95% confidence intervals, comparing participants with the genotypes that generate IFN-λ4 and those with the genotype that abrogates IFN-λ4. We censored follow-up at the introduction of highly effective antiretroviral therapies. RESULTS: We found no statistically significant association between IFNL4 genotype and the incidence of Kaposi sarcoma (hazard ratio, 0.92 [95% confidence interval, .76-1.11]), cytomegalovirus infection (0.94 [.71-1.24]), herpes simplex virus infection (1.37 [.68-2.93]), or any other OI/cancer. We observed consistent results using additive genetic models and after controlling for CD4 cell count through time-dependent adjustment or restriction to participants with a low CD4 cell count. CONCLUSIONS: The absence of associations between IFNL4 genotype and these OIs/cancers provides evidence that this gene does not affect the risk of disease from opportunistic pathogens.

Menopausal hormone therapy and risk of biliary tract cancers.

BACKGROUND AND AIMS: Gallbladder cancer (GBC) has a female predominance, whereas the other biliary tract cancers (BTCs) have a male predominance, suggesting that sex hormones may be involved in carcinogenesis. We sought to evaluate the association between menopausal hormone therapy (MHT) and the risk of BTC in women. APPROACH AND RESULTS: This nested case-control study was conducted in the UK Clinical Practice Research Datalink. Cases diagnosed between 1990 and 2017 with incident primary cancers of the gallbladder (GBC), cholangiocarcinoma (CCA), ampulla of Vater (AVC), and mixed type were matched to 5 controls on birth year, diagnosis year, and years in the general practice using incidence density sampling. Conditional logistic regression was used to calculate ORs and 95% CIs for associations between MHT use and BTC type. The sample consisted of 1,682 BTC cases (483 GBC, 870 CCA, 105 AVC, and 224 mixed) and 8,419 matched controls with a mean age of 73 (SD, 11) years. Combined formulations (estrogen-progesterone) were associated with an increased GBC risk (OR, 1.97; 95% CI, 1.08, 3.59). Orally administered MHT was associated with an increased GBC risk (OR, 2.28; 95% CI, 1.24, 4.17). Estrogen-only formulations (OR, 0.59; 95% CI, 0.34, 0.93) and cream or suppository administrations (OR, 0.57; 95% CI, 0.34, 0.95) were associated with decreased CCA risk. The number of prescriptions, dose, duration of use, and time since last use were not associated with GBC or CCA risk. MHT use was not associated with risk of AVC or mixed cancer. CONCLUSIONS: Combination MHT formulations and oral administrations were associated with increased GBC risk, whereas estrogen-only formulations were associated with a lower CCA risk. MHT formulation and administration should be carefully considered when prescribing.

Sex disparities in the incidence of 21 cancer types: Quantification of the contribution of risk factors.

BACKGROUND: Cancer incidence is higher in men than in women at most shared anatomic sites for currently unknown reasons. The authors quantified the extent to which behaviors (smoking and alcohol use), anthropometrics (body mass index and height), lifestyles (physical activity, diet, medications), and medical history collectively explain the male predominance of risk at 21 shared cancer sites. METHODS: Prospective cohort analyses (n = 171,274 male and n = 122,826 female participants; age range, 50-71 years) in the National Institutes of Health-AARP Diet and Health Study (1995-2011). Cancer-specific Cox regression models were used to estimate male-to-female hazard ratios (HRs). The degree to which risk factors explained the observed male-female risk disparity was quantified using the Peters-Belson method. RESULTS: There were 26,693 incident cancers (17,951 in men and 8742 in women). Incidence was significantly lower in men than in women only for thyroid and gallbladder cancers. At most other anatomic sites, the risks were higher in men than in women (adjusted HR range, 1.3-10.8), with the strongest increases for bladder cancer (HR, 3.33; 95% confidence interval [CI], 2.93-3.79), gastric cardia cancer (HR, 3.49; 95% CI, 2.26-5.37), larynx cancer (HR, 3.53; 95% CI, 2.46-5.06), and esophageal adenocarcinoma (HR, 10.80; 95% CI, 7.33-15.90). Risk factors explained a statistically significant (nonzero) proportion of the observed male excess for esophageal adenocarcinoma and cancers of liver, other biliary tract, bladder, skin, colon, rectum, and lung. However, only a modest proportion of the male excess was explained by risk factors (ranging from 50% for lung cancer to 11% for esophageal adenocarcinoma). CONCLUSIONS: Men have a higher risk of cancer than women at most shared anatomic sites. Such male predominance is largely unexplained by risk factors, underscoring a role for sex-related biologic factors.

Postdiagnosis Aspirin Use Associated With Decreased Biliary Tract Cancer-Specific Mortality in a Large Nationwide Cohort.

BACKGROUND AND AIMS: Biliary tract cancer (BTC) is rare and has limited treatment options. We aimed to examine aspirin use on cancer-specific survival in various BTC subtypes, including gallbladder cancer, ampulla of Vater cancer, and cholangiocarcinoma. APPROACH AND RESULTS: Nationwide prospective cohort of newly diagnosed BTC between 2007 and 2015 were included and followed until December 31, 2017. Three nationwide databases, namely the Cancer Registration, National Health Insurance, and Death Certification System, were used for computerized data linkage. Aspirin use was defined as one or more prescriptions, and the maximum defined daily dose was used to evaluate the dose-response relationship. Cox's proportional hazards models were applied for estimating HRs and 95% CIs. Analyses accounted for competing risk of cardiovascular deaths, and landmark analyses to avoid immortal time bias were performed. In total, 2,519 of patients with BTC were exposed to aspirin after their diagnosis (15.7%). After a mean follow-up of 1.59 years, the 5-year survival rate was 27.4%. The multivariate-adjusted HR for postdiagnosis aspirin users, as compared with nonusers, was 0.55 (95% CI: 0.51 to 0.58) for BTC-specific death. Adjusted HRs for BTC-specific death were 0.53 (95% CI: 0.48 to 0.59) and 0.42 (95% CI: 0.31 to 0.58) for ≤ 1 and > 1 maximum defined daily dose, respectively, and showed a dose-response trend (P < 0.001; nonusers as a reference). Cancer-specific mortality was lower with postdiagnosis aspirin use in patients with all major BTC subtypes. CONCLUSIONS: The nationwide study revealed that postdiagnosis aspirin use was associated with improved BTC-specific mortality of various subtypes. The findings suggest that additional randomized trials are required to investigate aspirin's efficacy in BTC.

The Limited Utility of Ranking Hospitals Based on Their Colon Surgery Infection Rates.

BACKGROUND: The Centers for Medicare and Medicaid Services (CMS) use colon surgical site infection (SSI) rates to rank hospitals and apply financial penalties. The CMS' risk-adjustment model omits potentially impactful variables that might disadvantage hospitals with complex surgical populations. METHODS: We analyzed adult patients who underwent colon surgery within facilities associated with HCA Healthcare from 2014 to 2016. SSIs were identified from National Health Safety Network (NHSN) reporting. We trained and validated 3 SSI prediction models, using (1) current CMS model variables, including hospital-specific random effects (HCA-adapted CMS model); (2) demographics and claims-based comorbidities (expanded-claims model); and (3) demographics, claims-based comorbidities, and NHSN variables (claims-plus-electronic health record [EHR] model). Discrimination, calibration, and resulting rankings were compared among all models and the current CMS model with published coefficient values. RESULTS: We identified 39 468 colon surgeries in 149 hospitals, resulting in 1216 (3.1%) SSIs. Compared to the HCA-adapted CMS model, the expanded-claims model had similar performance (c-statistic, 0.65 vs 0.67, respectively), while the claims-plus-EHR model was more accurate (c-statistic, 0.70; 95% confidence interval, .67-.73; P = .004). The sampling variation, due to the low surgical volume and small number of infections, contributed 74% of the total variation in observed SSI rates between hospitals. When CMS model rankings were compared to those from the expanded-claims and claims-plus-EHR models, 18 (15%) and 26 (22%) hospitals changed quartiles, respectively, and 10 (8.3%) and 12 (10%) hospitals changed into or out of the lowest-performing quartile, respectively. CONCLUSIONS: An expanded set of variables improved colon SSI risk predictions and quartile assignments, but low procedure volumes and SSI events remain a barrier to effectively comparing hospitals.

The Chile Biliary Longitudinal Study: A Gallstone Cohort.

Gallbladder cancer (GBC) is a highly fatal cancer that can be cured through cholecystectomy if identified early. The presence of gallstones is the primary risk factor for GBC, but few people with gallstones develop GBC. A key question is what drives the development of GBC among persons with gallstones. We initiated the Chile Biliary Longitudinal Study (Chile BiLS) to address this question. From 2016 to 2019, Chile BiLS enrolled 4,726 women aged 50-74 years with ultrasound-detected gallstones from southern-central Chile, accounting for an estimated 36% of eligible women with gallstones in the study area. The median age was 59 years; 25% of the women were Amerindian (Mapuche), 60% were obese, 25% had diabetes, and 6% had cardiovascular disease. Participants will be followed for gallbladder dysplasia or cancer for 6 years. As of April 30, 2020, over 91% of those eligible completed the year 2 follow-up visit. Data being collected include epidemiologic and sociodemographic information, anthropometric measurements, blood pressure, and tooth counts. Biosamples being taken include baseline plasma, buffy coat, red blood cells, serum, blood clot from serum, and PAXgene whole blood (PreAnalytiX GmbH, Hombrechtikon, Switzerland). Complete gallbladder sampling is conducted for most participants undergoing cholecystectomy. The Chile BiLS cohort study will increase our understanding of GBC etiology and could identify potential risk stratification and early detection strategies in high-risk areas.

Point-of-Care Ultrasound, the New Musculoskeletal Physical Examination.

ABSTRACT: The availability of handheld ultrasound offers physicians an opportunity to better define anatomy and pathophysiology, thus enhancing the diagnostic capabilities of a standard physical examination. The medical community increasingly embraces the potential for point-of-care ultrasound across medical specialties. The primary aim of this review was to identify and compile information on the current clinical utility of point-of-care ultrasound for musculoskeletal examination. This information will enable health care providers to understand the current utility and potential of musculoskeletal point-of-care ultrasound, thus facilitating its appropriate adoption into clinical practice.

Associations between reproductive factors and biliary tract cancers in women from the Biliary Tract Cancers Pooling Project.

BACKGROUND & AIMS: Gallbladder cancer (GBC) is known to have a female predominance while other biliary tract cancers (BTCs) have a male predominance. However, the role of female reproductive factors in BTC etiology remains unclear. METHODS: We pooled data from 19 studies of >1.5 million women participating in the Biliary Tract Cancers Pooling Project to examine the associations of parity, age at menarche, reproductive years, and age at menopause with BTC. Associations for age at menarche and reproductive years with BTC were analyzed separately for Asian and non-Asian women. Hazard ratios (HRs) and 95% CIs were estimated using Cox proportional hazards models, stratified by study. RESULTS: During 21,681,798 person-years of follow-up, 875 cases of GBC, 379 of intrahepatic bile duct cancer (IHBDC), 450 of extrahepatic bile duct cancer (EHBDC), and 261 of ampulla of Vater cancer (AVC) occurred. High parity was associated with risk of GBC (HR ≥5 vs. 0 births 1.72; 95% CI 1.25-2.38). Age at menarche (HR per year increase 1.15; 95% CI 1.06-1.24) was associated with GBC risk in Asian women while reproductive years were associated with GBC risk (HR per 5 years 1.13; 95% CI 1.04-1.22) in non-Asian women. Later age at menarche was associated with IHBDC (HR 1.19; 95% CI 1.09-1.31) and EHBDC (HR 1.11; 95% CI 1.01-1.22) in Asian women only. CONCLUSION: We observed an increased risk of GBC with increasing parity. Among Asian women, older age at menarche was associated with increased risk for GBC, IHBDC, and EHBDC, while increasing reproductive years was associated with GBC in non-Asian women. These results suggest that sex hormones have distinct effects on cancers across the biliary tract that vary by geography. LAY SUMMARY: Our findings show that the risk of gallbladder cancer is increased among women who have given birth (especially women with 5 or more children). In women from Asian countries, later age at menarche increases the risk of gallbladder cancer, intrahepatic bile duct cancer and extrahepatic bile duct cancer. We did not see this same association in women from Western countries. Age at menopause was not associated with the risk of any biliary tract cancers.

Development and Validation of a Clinical Prediction Rule to Predict Transmission of Methicillin-Resistant Staphylococcus aureus in Nursing Homes.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) colonization among nursing home residents is high. Health-care workers (HCWs) often serve as a vector in MRSA transmission. The ability to identify residents who are likely to transmit MRSA to HCWs' hands and clothing during clinical care is important so that infection control measures, such as Contact Precautions, can be employed. Using data on demographic and clinical characteristics collected from residents of community nursing homes in Maryland and Michigan between 2012 and 2014, we developed a clinical prediction rule predicting the probability of MRSA transmission to HCWs' gowns. We externally validated this model in a cohort of Department of Veterans Affairs nursing home residents from 7 states between 2012 and 2016. The prediction model, which included sex, race, resident dependency on HCWs for care, the presence of any medical device, diabetes mellitus, and chronic skin breakdown, showed good performance (C statistic = 0.70; sensitivity = 76%, specificity = 49%) in the development set. The decision curve analysis indicated that this model has greater clinical utility than use of a nares surveillance culture for MRSA colonization, which is current clinical practice for placing hospital inpatients on Contact Precautions. The prediction rule demonstrated less utility in the validation cohort, suggesting that a separate rule should be developed for residents of Veterans Affairs nursing homes.

Can Dynamic Ultrasonography of the Hip Reliably Assess Anterior Femoral Head Translation?

BACKGROUND: Hip microinstability has gained attention recently as a potential cause of hip pain. Currently there is a lack of evidence-based objective diagnostic criteria surrounding this diagnosis. Previous studies have shown translation of the femoral head during extreme hip positions. However, reliable assessment of femoral head translation is lacking. QUESTIONS/PURPOSES: (1) How precise is musculoskeletal ultrasound for measuring anterior femoral head translation during the hip anterior apprehension test? (2) What is the intra- and interrater reliability of dynamic ultrasonography in assessing anterior femoral head translation? METHODS: We recruited 10 study participants (20 hips) between the ages of 22 and 50 years with no history of hip pain or functional limitations. Test-retest methodology was used. Seven females and three males were enrolled. The mean age of study participants was 27 years (SD 8.7 years); mean body mass index was 22.6 kg/m (SD 2.2 kg/m). All study participants underwent dynamic hip ultrasonography by three different physicians 1 week apart. Each hip was visualized in two neutral positions (neutral and neutral with the contralateral hip flexed [NF]) and two dynamic positions, which sought to replicate the apprehension test, although notably study participants had no known hip pathology and therefore no apprehension. The first maintained the hip in extension and external rotation off to the side of the examination table (EER1), and the second held the hip off of the bottom of the examination table (EER2). One hundred twenty ultrasound scans (480 images) were performed. Mean and SD were calculated using absolute values of the difference in ultrasound measurements (mm) between positions NF and EER1 and NF and EER2 calculated for each physician as well as an average of all three physicians. Intraclass correlation coefficient (ICC) analysis was used to examine intra- and interrater reliability. RESULTS: The mean absolute difference for NF and EER1 was 0.84 mm (SD 0.93 mm) and for NF and EER2 0.62 mm (SD 0.40 mm) on Study Day 1. Similarly, on Study Day 2, the mean absolute difference for NF and EER1 position was 0.90 mm (SD 0.74 mm) and for NF and EER2 1.03 mm (SD 1.18 mm). Cumulative values of ICC analysis indicated excellent intrarater reliability in all four positions: neutral 0.794 (95% confidence interval [CI], 0.494-0.918), NF 0.927 (95% CI, 0.814-0.971), EER1 0.929 (95% CI, 0.825-0.972), and EER2 0.945 (95% CI, 0.864-0.978). Similarly, interrater ICC analysis cumulative values were excellent for NF, EER1, and EER2 and fair to good for the neutral position: neutral 0.725 (95% CI, 0.526-0.846), NF 0.846 (95% CI, 0.741-0.913), EER1 0.812 (95% CI, 0.674-0.895), and EER2 0.794 (95% CI, 0.652-0.884). CONCLUSIONS: This study offers the first ultrasound protocol of which we are aware for measuring anterior femoral head translation. Hip dynamic ultrasound may assist in providing precise objective clinical-based diagnostic evidence when evaluating complex hip pain and suspected microinstability. Musculoskeletal ultrasound is a reliable office-based method of measuring anterior femoral head translation that can be utilized by physicians with varying experience levels. Future studies are needed to investigate ultrasound anterior femoral head translation taking into account sex, prior hip surgery, hip osseous morphology, and ligamentous laxity. LEVEL OF EVIDENCE: Level III, diagnostic study.

Electronically Available Comorbidities Should Be Used in Surgical Site Infection Risk Adjustment.

BACKGROUND: Healthcare-associated infections such as surgical site infections (SSIs) are used by the Centers for Medicare and Medicaid Services (CMS) as pay-for-performance metrics. Risk adjustment allows a fairer comparison of SSI rates across hospitals. Until 2016, Centers for Disease Control and Prevention (CDC) risk adjustment models for pay-for-performance SSI did not adjust for patient comorbidities. New 2016 CDC models only adjust for body mass index and diabetes. METHODS: We performed a multicenter retrospective cohort study of patients undergoing surgical procedures at 28 US hospitals. Demographic data and International Classification of Diseases, Ninth Revision codes were obtained on patients undergoing colectomy, hysterectomy, and knee and hip replacement procedures. Complex SSIs were identified by infection preventionists at each hospital using CDC criteria. Model performance was evaluated using measures of discrimination and calibration. Hospitals were ranked by SSI proportion and risk-adjusted standardized infection ratios (SIR) to assess the impact of comorbidity adjustment on public reporting. RESULTS: Of 45394 patients at 28 hospitals, 573 (1.3%) developed a complex SSI. A model containing procedure type, age, race, smoking, diabetes, liver disease, obesity, renal failure, and malnutrition showed good discrimination (C-statistic, 0.73) and calibration. When comparing hospital rankings by crude proportion to risk-adjusted ranks, 24 of 28 (86%) hospitals changed ranks, 16 (57%) changed by ≥2 ranks, and 4 (14%) changed by >10 ranks. CONCLUSIONS: We developed a well-performing risk adjustment model for SSI using electronically available comorbidities. Comorbidity-based risk adjustment should be strongly considered by the CDC and CMS to adequately compare SSI rates across hospitals.

Factors Leading to Transmission Risk of Acinetobacter baumannii.

OBJECTIVES: To identify patient and healthcare worker factors associated with transmission risk of Acinetobacter baumannii during patient care. DESIGN: Prospective cohort study. SETTING: ICUs at a tertiary care medical center. PATIENTS: Adult ICU patients known to be infected or colonized with A. baumannii. MEASUREMENTS AND MAIN RESULTS: Cultures of skin, respiratory tract, and the perianal area were obtained from participants and evaluated for the presence of A. baumannii. Healthcare worker-patient interactions were observed (up to five interactions/patient) and activities were recorded. Healthcare worker hands/gloves were sampled at room exit (prior to hand hygiene or glove removal) and then evaluated for the presence of A. baumannii. Two hundred fifty-four healthcare worker-patient interactions were observed among 52 patients; A. baumannii was identified from healthcare worker hands or gloves in 77 (30%) interactions. In multivariate analysis, multidrug-resistant A. baumannii (odds ratio, 4.78; 95% CI, 2.14-18.45) and specific healthcare worker activities (touching the bed rail [odds ratio, 2.19; 95% CI, 1.00-4.82], performing a wound dressing [odds ratio, 8.35; 95% CI, 2.07-33.63] and interacting with the endotracheal tube or tracheotomy site [odds ratio, 5.15; 95% CI, 2.10-12.60]), were associated with hand/glove contamination. CONCLUSIONS: Healthcare worker hands/gloves are frequently contaminated with A. baumannii after patient care. Patient-level factors were not associated with an increased transmission risk; however, having multidrug-resistant-A. baumannii and specific healthcare worker activities led to an increased contamination risk. Our findings reveal a potential selective advantage possessed by multidrug-resistant-A. baumannii in this environment and suggest possible areas for future research.

Case report: upper extremity deep venous thrombosis in a 19-year-old baseball player.

This report describes a case of a collegiate baseball player who presented with 3 weeks of worsening right shoulder pain and mild swelling and faint discoloration of the right arm and hand. He was found to have a nonocclusive clot on his brachial vein and was treated with anticoagulants. This was his second lifetime thrombosis. A hematologic workup revealed no evidence of a hereditary origin, and thrombosis was believed to be related to recent exertion (baseball throwing). Upper extremity deep vein thromboses are extremely uncommon. However, because they can have potentially life-threatening consequences, deep vein thromboses must be on the differential for any athlete who presents with increased pain, swelling, or discoloration of an extremity.

Sex Differences in Cancer Incidence Rates by Race and Ethnicity: Results from the Surveillance, Epidemiology, and End Results (SEER) Registry (2000-2019).

Men have 2-3 times the rate of most non-sex-specific cancers compared to women, but whether this is due to differences in biological or environmental factors remains poorly understood. This study investigated sex differences in cancer incidence by race and ethnicity. Cancer incidence data from the Surveillance, Epidemiology, and End Result (SEER) program (2000-2019) were used to calculate male-to-female incidence rate ratios (MF IRRs) for each cancer site, stratified by race and ethnicity, and age-standardized to the 2000 U.S. population for individuals ages ≥ 20 years. Among 49 cancer sites, 44 showed male predominance (MF IRR > 1), with seven inconsistencies across race and ethnicity, including cancers of the lip, tongue, hypopharynx, retroperitoneum, larynx, pleura cancers, and Kaposi sarcoma. Four cancers exhibited a female predominance (MF IRR < 1), with only gallbladder and anus cancers varying by race and ethnicity. The MF IRRs for cancer of the cranial nerves and other nervous system malignancies showed no sex differences and were consistent (MF IRR = 1) across race and ethnicity. The MF IRRs for most cancers were consistent across race and ethnicity, implying that biological etiologies are driving the observed sex difference. The lack of MF IRR variability by race and ethnicity suggests a minimal impact of environmental exposure on sex differences in cancer incidence. Further research is needed to identify biological drivers of sex differences in cancer etiology.