External validation of the Melanoma Institute Australia Sentinel Node Metastasis Risk Prediction Tool using the National Cancer Database.

BACKGROUND: To improve patient selection for sentinel node (SN) biopsy, the Melanoma Institute of Australia (MIA) created a predictive model based on readily available clinicopathologic factors. OBJECTIVES: Validation of the MIA nomogram using the National Cancer Database (NCDB), a nationwide oncology outcomes database for >1500 Commission-accredited cancer programs in the United States. METHODS: A total of 60,165 patients were included in the validation. The probability of SN positivity was calculated for each patient. Using calculated probabilities, a receiver operating characteristic curve was generated to assess the model's discrimination ability. RESULTS: At baseline, the NCDB cohort had different clinicopathologic characteristics compared with the original MIA data set. Despite these differences, the MIA nomogram retained high-predictive accuracy within the NCDB dataset (C-statistic, 0.733 [95% CI, 0.726-0.739]), although calibration weakened for the highest risk decile. LIMITATIONS: The NCDB collects data from hospital registries accredited by the Commission on Cancer. CONCLUSIONS: In conclusion, this study validated the use of the MIA nomogram in a nationwide oncology outcomes database collected from >1500 Commission-accredited cancer programs in the United States, demonstrating the potential for this nomogram to predict SN positivity and reduce the number of negative SN biopsies.

Identify factors for insufficient (> 2 yr) mammogram screening among Oregonian women.

PURPOSE: Women with breast cancer diagnosed from mammogram screenings have a lower mortality risk than women diagnosed from symptoms. Currently, the U.S Preventive Services Task Force recommends biannual screening for women aged 50-74 years old. In this study, we aimed to identify factors associated with inadequate screening defined as "no mammogram screening within past 2 years" to guide cancer prevention and early detection efforts. METHODS: This study utilized area-based probabilistic sampling survey data, collected across Oregon in 2019. Dataset weights were calculated using a raking approach. Demographic and behavior information were collected with existing validated questionnaire items from national surveys. Weighted multivariable logistic regression analyses with missing-value imputations were conducted to identify factors associated with inadequate mammogram screening. RESULTS: The study included 254 women 50-74 years old without previous breast or ovarian cancer history. 19.29% of the sample reported no mammogram within two years, including 1.57% with no previous mammograms. Following unadjusted analyses, the significant factors included education, occupation status, health insurance and smoking and were therefore included into the adjusted model. In the multivariate adjusted model education remained significant while occupation status, health insurance and smoking were no longer significant. Compared to women with a college graduate degree, women with less than college graduate degree were at higher risk of inadequate screening [OR (95% CI) = 3.23 (1.54, 6.74)]. CONCLUSIONS: Lack of education was significantly associated with inadequate mammogram screening even after adjusting for occupation status, health insurance and smoking, which should prompt further outreach and education.

Feasibility of Treating Adults with Ewing or Ewing-Like Sarcoma with Interval-Compressed Vincristine, Doxorubicin, and Cyclophosphamide Alternating with Ifosfamide and Etoposide.

BACKGROUND: Vincristine, doxorubicin, and cyclophosphamide (VDC) alternating with ifosfamide and etoposide (IE) administered every 2 weeks demonstrated a superior event-free survival compared with 3-week dosing in a landmark pediatric trial and is now standard of care for younger patients. Only 12% of patients enrolled in that trial were over 18 years of age; thus, the feasibility of interval-compressed VDC/IE in adults remains poorly described. We conducted a retrospective analysis of our institutional experience using this regimen. MATERIALS AND METHODS: Pharmacy administration records at Oregon Health and Science University were reviewed to identify patients with Ewing and Ewing-like sarcoma aged 18 years and older who received VDC/IE every 2 weeks. RESULTS: We identified 24 patients. Median age was 28 years (range 18-60 years). At diagnosis, 67% had localized disease. The most common primary sites were extremity (38%) and pelvis (17%); another 25% had extraosseous disease. The median interval between cycles was 15.0 days, with no difference between patients aged <30 years versus ≥30 years. The median number of admissions for toxicity per patient was two, primarily for febrile neutropenia. Early treatment discontinuation occurred in 17%. Dose reductions were minimal, with mean cumulative doses achieved comparable to original planned dose and no difference between patients aged <30 years versus ≥30 years. CONCLUSION: For adults with Ewing and Ewing-like sarcoma, administration of interval-compressed chemotherapy is feasible, without significant dose reductions required. Our results are comparable to prior studies involving a primarily pediatric population. IMPLICATIONS FOR PRACTICE: For Ewing sarcoma, interval-compressed vincristine, doxorubicin, and cyclophosphamide alternating with ifosfamide and etoposide administered every 2 weeks rather than every 3 weeks has been shown to improve event-free survival in pediatric patients. However, in adults, oncologists may be hesitant to pursue interval-compressed therapy because of concerns for feasibility. In the adult population in this study, a median interval between cycles of 15.0 days (mean 17.0 days) was achieved, comparable to the interval achieved in AEWS0031 (median 15.0, mean 17.3 days). Given that this was achieved without unexpected toxicity or substantial dose reductions and that clinical outcomes were favorable compared with adult historical controls, these results support the use of this regimen in adults.

Artificial Intelligence Applied to Non-Invasive Imaging Modalities in Identification of Nonmelanoma Skin Cancer: A Systematic Review.

BACKGROUND: The objective of this study is to systematically analyze the current state of the literature regarding novel artificial intelligence (AI) machine learning models utilized in non-invasive imaging for the early detection of nonmelanoma skin cancers. Furthermore, we aimed to assess their potential clinical relevance by evaluating the accuracy, sensitivity, and specificity of each algorithm and assessing for the risk of bias. METHODS: Two reviewers screened the MEDLINE, Cochrane, PubMed, and Embase databases for peer-reviewed studies that focused on AI-based skin cancer classification involving nonmelanoma skin cancers and were published between 2018 and 2023. The search terms included skin neoplasms, nonmelanoma, basal-cell carcinoma, squamous-cell carcinoma, diagnostic techniques and procedures, artificial intelligence, algorithms, computer systems, dermoscopy, reflectance confocal microscopy, and optical coherence tomography. Based on the search results, only studies that directly answered the review objectives were included and the efficacy measures for each were recorded. A QUADAS-2 risk assessment for bias in included studies was then conducted. RESULTS: A total of 44 studies were included in our review; 40 utilizing dermoscopy, 3 using reflectance confocal microscopy (RCM), and 1 for hyperspectral epidermal imaging (HEI). The average accuracy of AI algorithms applied to all imaging modalities combined was 86.80%, with the same average for dermoscopy. Only one of the three studies applying AI to RCM measured accuracy, with a result of 87%. Accuracy was not measured in regard to AI based HEI interpretation. CONCLUSION: AI algorithms exhibited an overall favorable performance in the diagnosis of nonmelanoma skin cancer via noninvasive imaging techniques. Ultimately, further research is needed to isolate pooled diagnostic accuracy for nonmelanoma skin cancers as many testing datasets also include melanoma and other pigmented lesions.

Weight trajectories and obesity remission among school-aged children.

BACKGROUND: Many studies examining weight trajectories have used adiposity measures shown to be problematic for trajectory analysis in children with obesity, and remission of obesity remains poorly understood. OBJECTIVES: To describe weight trajectories for school-aged children, the rate of obesity remission and factors associated. METHODS: Children between 6 and 11 years of age with ≥3 valid height and weight measurements from an Oregon hospital-system over a minimum six-month period were included. Percent distance from the median body mass index (BMI) was used for modeling. Latent class analysis and linear mixed models were used to classify children based on their weight trajectory. RESULTS: We included 11,247 subjects with a median of 2.1 years of follow-up, with 1,614 (14.4%) classified as overweight and 1,794 (16.0%) classified as obese. Of subjects with obesity, 1% experienced remission during follow-up, whereas 23% of those with overweight moved to within a healthy weight range. Latent class analysis identified three classes within each weight-based stratum over time. The majority of children with overweight or obesity had a flat trajectory over time. Lower socioeconomic status was associated with a worsening trajectory. Latent class models using alternate measures (BMI, BMI z-scores, tri-ponderal mass index (TMI)) differed substantially from each other. CONCLUSIONS: Obesity remission was uncommon using the adiposity metric of distance from the median though transition from overweight to healthy weight was more common. Children with low socioeconomic status have worse trajectories overall. The choice of adiposity metric may have a substantial effect on the outcomes.

Statistical considerations for repeatability and reproducibility of quantitative imaging biomarkers.

Quantitative imaging biomarkers (QIBs) are increasingly used in clinical studies. Because many QIBs are derived through multiple steps in image data acquisition and data analysis, QIB measurements can produce large variabilities, posing a significant challenge in translating QIBs into clinical trials, and ultimately, clinical practice. Both repeatability and reproducibility constitute the reliability of a QIB measurement. In this article, we review the statistical aspects of repeatability and reproducibility of QIB measurements by introducing methods and metrics for assessments of QIB repeatability and reproducibility and illustrating the impact of QIB measurement error on sample size and statistical power calculations, as well as predictive performance with a QIB as a predictive biomarker.

Predictors of Virologic Failure Among a Cohort of HIV-infected Children in Southern Ethiopia.

BACKGROUND: Optimal care for children with HIV infection includes timely assessment of treatment failure. Using HIV viral load to define treatment failure remains a challenge in resource-limited settings. METHODS: Children with HIV infection who were already on or starting first-line antiretroviral therapy were enrolled and followed over time. We examined clinical and immunologic predictors of virologic failure (VF), defined as consecutive viral load measurements > 1000 copies/mL (VF). Children were followed every 6 months with clinical assessments, immunologic assays and viral load testing until treatment failure or up to 18 months. RESULTS: Of the 484 children with complete data, we observed a prevalence of 15% who had VF at enrollment, and 18 who developed VF over 10.5 person-years of follow-up for an incidence of 4.97 [95% CI: 3.04-7.70) per 100 person-years. Lower adherence, lower CD4 T-cell count, lower white blood cells count, lower platelets and a lower glomerular filtration rate were all associated with increased VF. However, in a multivariable analysis, renal function (estimated glomerular filtration rate < 90 mL/min), odds ratio: 11.5 (95% CI: 1.5-63.7), and lower adherence, odds ratio: 3.9 (95% CI: 1.1-13.4), were the only factors associated with development of VF. CONCLUSIONS: We identified a significant risk of VF in children with HIV infection in a prospective cohort study in southern Ethiopia and limited predictive value of clinical variables for VF. This provides further evidence that rapid and reliable viral load testing is needed to adequately address the HIV epidemic, along with implementation of adherence interventions in sub-Saharan Africa.

Multiomics analysis of serial PARP inhibitor treated metastatic TNBC inform on rational combination therapies.

In a pilot study, we evaluated the feasibility of real-time deep analysis of serial tumor samples from triple negative breast cancer patients to identify mechanisms of resistance and treatment opportunities as they emerge under therapeutic stress engendered by poly-ADP-ribose polymerase (PARP) inhibitors (PARPi). In a BRCA-mutant basal breast cancer exceptional long-term survivor, a striking tumor destruction was accompanied by a marked infiltration of immune cells containing CD8 effector cells, consistent with pre-clinical evidence for association between STING mediated immune activation and benefit from PARPi and immunotherapy. Tumor cells in the exceptional responder underwent extensive protein network rewiring in response to PARP inhibition. In contrast, there were minimal changes in the ecosystem of a luminal androgen receptor rapid progressor, likely due to indifference to the effects of PARP inhibition. Together, identification of PARPi-induced emergent changes could be used to select patient specific combination therapies, based on tumor and immune state changes.

Tailored treatment of patients with hepatocellular carcinoma with portal vein invasion: experience from a multidisciplinary hepatobiliary tumor program within a NCI comprehensive cancer center.

BACKGROUND: Hepatocellular carcinoma (HCC) with portal vein invasion (PVI) has a poor prognosis with limited treatment options. Intra-arterial brachytherapy (IAB) and transarterial chemoembolization (TACE) yield local control but risk accelerating liver dysfunction. The outcomes, survival, and safety of selective liver-directed treatment are reported. METHODS: Thirty-seven consecutive patients with HCC and PVI treated between 2009 and 2015 were reviewed from a prospectively collected database. Univariate analysis, Kaplan-Meier plots using the log-rank method, and multivariate analyses were performed. Statistical significance was defined as P<0.05. Overall survival was reported in months (median; 95% CI). RESULTS: Most patients (59%) had PVI identified at initial HCC diagnosis. The liver-directed therapy group (n=22) demonstrated a survival advantage versus the systemic/supportive care group (n=14) [23.6 (5.8, 30.9) vs. 6.0 (3.5, 8.8) months]. Patients indicated for liver directed therapy had unilateral liver involvement (100% vs. 43%, P<0.0001), lower median alkaline phosphatase (105.5 vs. 208.0, P=0.002), and lower mean Child-Turcotte-Pugh (CTP) score (5.9 vs. 7.2, P=0.04) and tolerated treatment without serious complications. CONCLUSIONS: In HCC patients presenting with PVI, liver-directed therapy was safely performed in patients with limited venous involvement and preserved liver function. Liver-directed therapy extended survival for these patients indicated for palliative chemotherapy by traditional guidelines.

Cause-specific quantile residual life regression.

We propose a cause-specific quantile residual life regression where the cause-specific quantile residual life, defined as the inverse of the cumulative incidence function of the residual life distribution of a specific type of events of interest conditional on a fixed time point, is log-linear in observable covariates. The proposed test statistic for the effects of prognostic factors does not involve estimation of the improper probability density function of the cause-specific residual life distribution under competing risks. The asymptotic distribution of the test statistic is derived. Simulation studies are performed to assess the finite sample properties of the proposed estimating equation and the test statistic. The proposed method is illustrated with a real dataset from a clinical trial on breast cancer.

Neutrophil Gelatinase-Associated Lipocalin Biomarker and Urinary Tract Infections: A Diagnostic Case-Control Study (NUTI Study).

OBJECTIVES: Acute uncomplicated urinary tract infection (UTI) in women is often treated based on symptoms alone. Urinary tract infection symptoms are highly sensitive but lack specificity and result in overuse of antibiotics. We sought to determine if urine neutrophil gelatinase-associated lipocalin (uNGAL) levels in urine can accurately discriminate between UTI and healthy women. METHODS: We recruited adult women aged 18 to 85 years presenting in the ambulatory setting from November 2014 to January 2016. Cases were defined as women with Centers for Disease Control and Prevention-defined UTI symptoms and a positive urine culture of more than 10 organisms/mL on a midstream clean-catch specimen. Women without UTI symptoms were matched by age and menopausal status as control subjects. Exclusion criteria were no UTIs within 8 weeks, urinary tract anomalies, renal disease, pregnancy, or diabetes. Clean-catch urine samples were obtained for measuring uNGAL, prior to antibiotic treatment of cases. We used Mann-Whitney U test to compare the 2 groups. Receiver operating characteristic curves were plotted to compare the performance of uNGAL to established urinary markers. RESULTS: We enrolled 50 UTI cases and 50 control subjects. Urine NGAL levels were higher in the UTI group than in the control subjects (P < 0.0001). Using a cutoff of 23.9 ng/mL, NGAL achieved 98% sensitivity and 100% specificity. The receiver operating characteristic curve had an area under the curve of 0.97 (95% confidence interval, 0.93-1.00), which was significantly high and showed that uNGAL can identify UTI. CONCLUSIONS: Urine NGAL has the potential as a biomarker for diagnosing UTIs in adult women.

Identification of Hip BMD Loss and Fracture Risk Markers Through Population-Based Serum Proteomics.

Serum proteomics analysis may lead to the discovery of novel osteoporosis biomarkers. The Osteoporotic Fractures in Men (MrOS) study comprises men ≥65 years old in the US who have had repeated BMD measures and have been followed for incident fracture. High-throughput quantitative proteomic analysis was performed on baseline fasting serum samples from non-Hispanic white men using a multidimensional approach coupling liquid chromatography, ion-mobility separation, and mass spectrometry (LC-IMS-MS). We followed the participants for a mean of 4.6 years for changes in femoral neck bone mineral density (BMD) and for incident hip fracture. Change in BMD was determined from mixed effects regression models taking age and weight into account. Participants were categorized into three groups: BMD maintenance (no decline; estimated change ≥0 g/cm2 , n = 453); expected loss (estimated change 0 to 1 SD below the estimated mean change, -0.034 g/cm2 for femoral neck, n = 1184); and accelerated loss (estimated change ≥1 SD below mean change, n = 237). Differential abundance values of 3946 peptides were summarized by meta-analysis to determine differential abundance of each of 339 corresponding proteins for accelerated BMD loss versus maintenance. Using this meta-analytic standardized fold change at cutoffs of ≥1.1 or ≤0.9 (p < 0.10), 20 proteins were associated with accelerated BMD loss. Associations of those 20 proteins with incident hip fracture were tested using Cox proportional hazards models with age and BMI adjustment in 2473 men. Five proteins were associated with incident hip fracture (HR between 1.29 and 1.41 per SD increase in estimated protein abundance). Some proteins have been previously associated with fracture risk (eg, CD14 and SHBG), whereas others have roles in cellular senescence and aging (B2MG and TIMP1) and complement activation and innate immunity (CO7, CO9, CFAD). These findings may inform development of biomarkers for future research in bone biology and fracture prediction. © 2017 American Society for Bone and Mineral Research.

Low physical function as a risk factor for incident diabetes mellitus and insulin resistance.

Data from 1790 HIV-infected and uninfected men in the Multicenter AIDS Cohort Study (MACS) were analyzed to evaluate relationships between physical function, incident diabetes mellitus (DM) and insulin resistance among HIV-infected and -uninfected men. DM was defined in two ways, using less stringent and more stringent criteria. The 10-item Physical Functioning Scale from the Short Form-36 Health Survey measured baseline physical function. Cumulative DM incidence was highest among HIV-uninfected and HIV-infected men with low physical function. Physical function was a risk factor for DM in HIV-uninfected men and remained so after controlling for BMI, DM family history and race. Among HIV-infected men, physical function was an independent risk factor for DM using the less stringent diabetes definition. This study supports our previous findings that low physical function is an important risk factor for DM in the MACS cohort.

Self-reported low physical function is associated with diabetes mellitus and insulin resistance in HIV-positive and HIV-negative men.

AIM: To investigate the association between self-reported physical function (as a surrogate for physical activity) and diabetes mellitus (DM) and insulin resistance (IR) among HIV-positive and -negative men. METHOD: A total of 384 HIV-negative and 274 HIV-positive men from the Pitt Men's Study contributed data. DM was defined by fasting serum glucose levels. IR was calculated using the homeostasis model assessment. The Physical Functioning 10 Scale from the Short Form-36 Health Survey measured physical function. Multivariate logistic regression assessed the independent association between physical function and DM and IR. RESULTS: Physical function, older age and Black race were associated with DM in multivariate analyses. Physical function/HIV interaction, older age, higher body mass index, HIV infection and Black race were associated with IR in multivariate analyses. CONCLUSION: Self-reported low physical function is associated with DM and IR in HIV-negative and -positive men.