Supplemental Breast Cancer Screening in Women with Dense Breasts and Negative Mammography: A Systematic Review and Meta-Analysis.

Background The best supplemental breast cancer screening modality in women at average risk or intermediate risk for breast cancer with dense breast and negative mammogram remains to be determined. Purpose To conduct systematic review and meta-analysis comparing clinical outcomes of the most common available supplemental screening modalities in women at average risk or intermediate risk for breast cancer in patients with dense breasts and mammography with negative findings. Materials and Methods A comprehensive search was conducted until March 12, 2020, in Medline, Epub Ahead of Print and In-Process and Other Non-Indexed Citations; Embase Classic and Embase; Cochrane Central Register of Controlled Trials; and Cochrane Database of Systematic Reviews, for Randomized Controlled Trials and Prospective Observational Studies. Incremental cancer detection rate (CDR); positive predictive value of recall (PPV1); positive predictive value of biopsies performed (PPV3); and interval CDRs of supplemental imaging modalities, digital breast tomosynthesis, handheld US, automated breast US, and MRI in non-high-risk patients with dense breasts and mammography negative for cancer were reviewed. Data metrics and risk of bias were assessed. Random-effects meta-analysis and two-sided metaregression analyses comparing each imaging modality metrics were performed (PROSPERO; CRD42018080402). Results Twenty-two studies reporting 261 233 screened patients were included. Of 132 166 screened patients with dense breast and mammography negative for cancer who met inclusion criteria, a total of 541 cancers missed at mammography were detected with these supplemental modalities. Metaregression models showed that MRI was superior to other supplemental modalities in CDR (incremental CDR, 1.52 per 1000 screenings; 95% CI: 0.74, 2.33; P < .001), including invasive CDR (invasive CDR, 1.31 per 1000 screenings; 95% CI: 0.57, 2.06; P < .001), and in situ disease (rate of ductal carcinoma in situ, 1.91 per 1000 screenings; 95% CI: 0.10, 3.72; P < .04). No differences in PPV1 and PPV3 were identified. The limited number of studies prevented assessment of interval cancer metrics. Excluding MRI, no statistically significant difference in any metrics were identified among the remaining imaging modalities. Conclusion The pooled data showed that MRI was the best supplemental imaging modality in women at average risk or intermediate risk for breast cancer with dense breasts and mammography negative for cancer. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Hooley and Butler in this issue.

Incidence and predictors of demyelinating disease in spondyloarthritis: data from a longitudinal cohort study.

OBJECTIVES: To investigate the incidence of demyelinating disease (DD) among spondyloarthritis (SpA) patients and identify risk factors that predict DD in this patient population. METHODS: Axial SpA (axSpA) and psoriatic arthritis (PsA) patients were identified from a longitudinal cohort database. Each group was analysed according to the presence or absence of DD. Incidence rates (IR) of DD were obtained with competing risk analysis. Cox regression analysis with Fine and Grey's method was used to evaluate predictors of DD development. RESULTS: Among 2260 patients with follow-up data, we identified 18 DD events corresponding to an average IR of 31 per 100 000 persons per year for SpA. The IR of DD at 20 years was higher in axSpA than in PsA (1.30% vs 0.13%, p= 0.01). The risk factors retained in the best predictive model for DD development included ever- (versus never-) smoking (HR 2.918, 95% CI 1.037-8.214, p= 0.0426), axSpA (versus PsA) (HR 8.790, 95% CI 1.242-62.182, p= 0.0294), and presence (versus absence) of IBD (HR 5.698, 95% CI 2.083-15.589, p= 0.0007). History of TNFi therapy was not a predictor of DD. CONCLUSION: The overall incidence of DD in this SpA cohort was low. Incident DD was higher in axSpA than in PsA. A diagnosis of axSpA, the presence of IBD, and ever-smoking predicted the development of DD. History of TNFi use was not found to be a predictor of DD in this cohort.

Assessment of mental workload and its association with work ability in control room operators.

BACKGROUND: Modern technology has reduced physical workload and imposed high mental workload on the control room operators in industrial settings. The present study was conducted among control room operators to assess their mental workload, investigate their workability, examine the relationship between mental workload and workability, and determine the factors associated with workability. METHODS: This cross-sectional study was carried out among 213 control room operators in six Iranian process industries. Task Load Index (NASA-TLX) was used to assess the mental workload, and Work Ability Index (WAI) was used to determine workability. The relationships between demographic characteristics and dimensions of mental workload and workability were examined by univariate tests. Logistic regression analysis was also used to determine the factors associated with the operators' workability. RESULTS: The results showed a high mental workload in the study population (82.38±8.8). Yet, the operators showed a good and excellent level of workability (56.4%). Pearson's correlation coefficient revealed a significant inverse linear relationship between the mean score of mental workload and workability (r=-0.581). Besides, regression modeling demonstrated that mental demand (OR=0.90), temporal demand (OR=0.90), effort (OR=0.91), frustration (OR=0.92), from NASA-TLX subscales were significantly associated with workability. Moreover, mental and temporal demands were important factors associated with reduced workability. CONCLUSION: Monitoring tasks imposes high mental workload on the control room operators, which may result in adverse effects on their workability as well as on the safety of the system.

Novel risk genes identified in a genome-wide association study for coronary artery disease in patients with type 1 diabetes.

BACKGROUND: Patients with type 1 diabetes are more at risk of coronary artery disease than the general population. Although evidence points to a genetic risk there have been no study investigating genetic risk factors of coronary artery disease specific to individuals with type 1 diabetes. To identify low frequency and common genetic variations associated with coronary artery disease in populations of individuals with type 1 diabetes. METHODS: A two-stage genome wide association study was conducted. The discovery phase involved the meta-analysis of three genome-wide association cohorts totaling 434 patients with type 1 diabetes and coronary artery disease (cases) and 3123 T1D individuals with no evidence of coronary artery disease (controls). Replication of the top association signals (p < 10-5) was performed in five additional independent cohorts totaling 585 cases and 2612 controls. RESULTS: One locus (rs115829748, located upstream of the MAP1B gene) reached the statistical threshold of 5 × 10-8 for genome-wide significance but did not replicate. Nevertheless, three single nucleotide polymorphisms provided suggestive evidence for association with coronary artery disease in the combined studies: CDK18 rs138760780 (OR = 2.60 95% confidence interval [1.75-3.85], p = 2.02 × 10-6), FAM189A2 rs12344245 (OR = 1.85 [1.41-2.43], p = 8.52 × 10-6) and PKD1 rs116092985 (OR = 1.53 [1.27-1.85], p = 1.01 × 10-5). In addition, our analyses suggested that genetic variations at the ANKS1A, COL4A2 and APOE loci previously found associated with coronary artery disease in the general population could have stronger effects in patients with type 1 diabetes. CONCLUSIONS: This study suggests three novel candidate genes for coronary artery disease in the subgroup of patients affected with type 1 diabetes. The detected associations deserve to be definitively validated in additional epidemiological studies.

Validation of Perceived Wellness Survey (PWS) in a Sample of Iranian Population.

The individual's perception of health, when health is understood to include many dimensions of life, is considered the basis for any improvement in health status. Therefore, the present study aimed to assess the reliability and validity of the Persian version of the Perceived Wellness Scale (PWS) by applying it to employees of the Shiraz University of Medical Sciences. This cross-sectional study was conducted with 180 staff members of the university selected by convenience sampling. The study instrument was a Persian version of the PWS prepared through a translation and back-translation process. The reliability and validity of the instrument were assessed by using confirmatory factor analysis (CFA) and Cronbach's alpha coefficient. A total of 180 employees participated in the study. The mean age of the participants was 32.29 years (SD = 7.39) and 78.1% of the participants were women. The results showed that the Persian version of the PWS is acceptable. Cronbach's alpha coefficient was 0.87 for the whole scale, ranging from 0.68 to 0.85 on different dimensions of the scale. The results of split-half reliability and CFA indicated that the reliability and validity of the PWS are acceptable. The PWS is therefore an effective tool for evaluating the different dimensions of perceived wellness in the Iranian population.

The effect of almonds on anthropometric measurements and lipid profile in overweight and obese females in a weight reduction program: A randomized controlled clinical trial.

BACKGROUND: Due to the wholesome benefits of nuts increased consumption of them has been recommended. However, because of nut's high energy density, the role of them in the treatment of overweight and obesity is vague. This current clinical trial study aims to investigate the effects of a balanced hypocaloric almond-enriched diet (AED) (almond group) in comparison to a balanced hypocaloric nut-free diet (NFD) (nut-free group) on body weight and cardiovascular disease risk factors in women with body mass index (BMI) >25 for 3-month. MATERIALS AND METHODS: A total of 108 overweight and obese women were assigned in our 3-month randomized controlled trial. The subjects were randomly divided into two groups regarding a balanced hypocaloric diet with or without almond. The planned reduced calorie diets for both groups were identical except for the almond group who consumed 50 g of almonds daily. Anthropometric and laboratory measurements of the participants who completed the study were made prior to and at the end of the study. RESULTS: A total of 100 subjects completed the study. Weight, BMI, waist circumference, waist to hip circumference ratio, total cholesterol, and triglyceride, total: High density lipoprotein-cholesterol (HDL-C), fasting blood sugar and diastolic blood pressure decreased significantly in the almond group compared to the nut-free group (P > 0.001). Greater reduction in low density lipoprotein-cholesterol (P > 0.002) and systolic blood pressure (P > 0.001) and greater increase in HDL-C (P = 0.001) were found in the nut-free group. CONCLUSION: The balanced hypocaloric AED in comparison to the balanced hypocaloric NFD led to a greater weight-loss and overall better improvements in studied cardiovascular disease risk factors.

Quality of life of childbearing age women and its associated factors: an application of seemingly unrelated regression (SUR) models.

PURPOSE: This article is a report of using seemingly unrelated regression (SUR) models to examine the determinants of different dimensions of quality of life (QoL) among childbearing age women. There are a limited number of studies on QoL and its associated factors among women in developing countries such as Iran. Therefore, more attention should be focused on identifying these issues. METHODS: We administered the Persian's abbreviated version of the World Health Organization Quality of Life (WHOQOL-BREF) questionnaire to 1,067 married women aged between 15 and 49 years. The women were chosen via a multistage research design from the rural region of Shiraz, the center of Fars Province in Iran in 2008. Clinical and socio-demographic characteristics as well as their reproductive health-related characteristics were investigated. To identify associated factors of QoL dimensions, ordinary least squares (OLS) regression and SUR were used and their findings were compared. RESULTS: The WHOQOL-BREF showed acceptable consistency (Cronbach's alpha range: 0.62-0.75 across domains). Lower age, absence of long-term illness, economic status satisfaction, higher level of education, lower number of pregnancies, and higher body mass index were important associated factors of different dimensions of the QoL among these women. The estimated parameters for these factors were in close agreement in both OLS and SUR estimation methods. However, the SUR estimator provided the higher precision of the estimates than the OLS estimator, as the parameters obtained by SUR are characterized by lower standard errors. Women's age, income satisfaction, and level of education were common for all domains. CONCLUSIONS: This study presents a novel approach to simultaneously predict QoL domains using the SUR estimators and the results are relevant for implementing objective QoL. SUR estimators performed consistently better than the OLS estimators, since SUR takes the correlation between error terms into account. Thus, the SUR method could be a useful methodology for predicting QoL domains.

Combination of FDG PET/CT Radiomics and Clinical Parameters for Outcome Prediction in Patients with Hodgkin's Lymphoma.

PURPOSE: The aim of the study is to evaluate the prognostic value of a joint evaluation of PET and CT radiomics combined with standard clinical parameters in patients with HL. METHODS: Overall, 88 patients (42 female and 46 male) with a median age of 43.3 (range 21-85 years) were included. Textural analysis of the PET/CT images was performed using freely available software (LIFE X). 65 radiomic features (RF) were evaluated. Univariate and multivariate models were used to determine the value of clinical characteristics and FDG PET/CT radiomics in outcome prediction. In addition, a binary logistic regression model was used to determine potential predictors for radiotherapy treatment and odds ratios (OR), with 95% confidence intervals (CI) reported. Features relevant to survival outcomes were assessed using Cox proportional hazards to calculate hazard ratios with 95% CI. RESULTS: albumin (p = 0.034) + ALP (p = 0.028) + CT radiomic feature GLRLM GLNU mean (p = 0.012) (Area under the curve (AUC): 95% CI (86.9; 100.0)-Brier score: 3.9, 95% CI (0.1; 7.8) remained significant independent predictors for PFS outcome. PET-SHAPE Sphericity (p = 0.033); CT grey-level zone length matrix with high gray-level zone emphasis (GLZLM SZHGE mean (p = 0.028)); PARAMS XSpatial Resampling (p = 0.0091) as well as hemoglobin results (p = 0.016) remained as independent factors in the final model for a binary outcome as predictors of the need for radiotherapy (AUC = 0.79). CONCLUSION: We evaluated the value of baseline clinical parameters as well as combined PET and CT radiomics in HL patients for survival and the prediction of the need for radiotherapy treatment. We found that different combinations of all three factors/features were independently predictive of the here evaluated endpoints.

Phase II multicenter trial combining nivolumab and radiosurgery for NSCLC and RCC brain metastases.

Background: Anti-PD-1 has activity in brain metastases (BM). This phase II open labeled non-randomized single arm trial examined the safety and efficacy of combining nivolumab with radiosurgery (SRS) in the treatment of patients with BM from non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC). Methods: This was a multicenter trial (NCT02978404) in which patients diagnosed with NSCLC or RCC, having ≤ 10 cc of un-irradiated BM and no prior immunotherapy were eligible. Nivolumab (240 mg or 480 mg IV) was administered for up to 2 years until progression. SRS (15-21 Gy) to all un-irradiated BM was delivered within 14 days after the first dose of nivolumab. The primary endpoint was intracranial progression free survival (iPFS). Results: Twenty-six patients (22 NSCLC and 4 RCC) were enrolled between August 2017 and January 2020. A median of 3 (1-9) BM were treated with SRS. Median follow-up was 16.0 months (0.43-25.9 months). Two patients developed nivolumab and SRS related grade 3 fatigue. One-year iPFS and OS were 45.2% (95% CI 29.3-69.6%) and 61.3% (95% CI 45.1-83.3%), respectively. Overall response (partial or complete) of SRS treated BM was attained in 14 out of the 20 patients with ≥1 evaluable follow-up MRI. Mean FACT-Br total scores were 90.2 at baseline and improved to 146.2 within 2-4 months (P = .0007). Conclusions: The adverse event profile and FACT-Br assessments suggested that SRS during nivolumab was well tolerated. Upfront SRS with the initiation of anti-PD-1 prolonged the 1-year iPFS and achieved high intracranial control. This combined approach merits validation randomized studies.

The influence of telehealth-based cancer rehabilitation interventions on disability: a systematic review.

PURPOSE: To characterize delivery features and explore effectiveness of telehealth-based cancer rehabilitation interventions that address disability in adult cancer survivors. METHODS: A systematic review of electronic databases (CINAHL Plus, Cochrane Library: Database of Systematic Reviews, Embase, National Health Service's Health Technology Assessment, PubMed, Scopus, Web of Science) was conducted in December 2019 and updated in April 2021. RESULTS: Searches identified 3,499 unique studies. Sixty-eight studies met inclusion criteria. There were 81 unique interventions across included studies. Interventions were primarily delivered post-treatment and lasted an average of 16.5 weeks (SD = 13.1). They were most frequently delivered using telephone calls (59%), administered delivered by nursing professionals (35%), and delivered in a one-on-one format (88%). Risk of bias of included studies was primarily moderate to high. Included studies captured 55 measures of disability. Only 54% of reported outcomes had data that allowed calculation of effect sizes ranging -3.58 to 15.66. CONCLUSIONS: The analyses suggest small effects of telehealth-based cancer interventions on disability, though the heterogeneity seen in the measurement of disability makes it hard to draw firm conclusions. Further research using more diverse samples, common measures of disability, and pragmatic study designs is needed to advance telehealth in cancer rehabilitation. IMPLICATIONS FOR CANCER SURVIVORS: Telehealth-based cancer rehabilitation interventions have the potential to increase access to care designed to reduce disability across the cancer care continuum.

Integrated, Longitudinal Analysis of Cell-free DNA in Uveal Melanoma.

Uveal melanomas are rare tumors arising from melanocytes that reside in the eye. Despite surgical or radiation treatment, approximately 50% of patients with uveal melanoma will progress to metastatic disease, most often to the liver. Cell-free DNA (cfDNA) sequencing is a promising technology due to the minimally invasive sample collection and ability to infer multiple aspects of tumor response. We analyzed 46 serial cfDNA samples from 11 patients with uveal melanoma over a 1-year period following enucleation or brachytherapy (n = ∼4/patient) using targeted panel, shallow whole genome, and cell-free methylated DNA immunoprecipitation sequencing. We found detection of relapse was highly variable using independent analyses (P = 0.06-0.46), whereas a logistic regression model integrating all cfDNA profiles significantly improved relapse detection (P = 0.02), with greatest power derived from fragmentomic profiles. This work provides support for the use of integrated analyses to improve the sensitivity of circulating tumor DNA detection using multi-modal cfDNA sequencing. Significance: Here, we demonstrate integrated, longitudinal cfDNA sequencing using multi-omic approaches is more effective than unimodal analysis. This approach supports the use of frequent blood testing using comprehensive genomic, fragmentomic, and epigenomic techniques.

Autoimmune PaneLs as PrEdictors of Toxicity in Patients TReated with Immune Checkpoint InhibiTors (ALERT).

BACKGROUND: Immune-checkpoint inhibitors (ICI) can lead to immune-related adverse events (irAEs) in a significant proportion of patients. The mechanisms underlying irAEs development are mostly unknown and might involve multiple immune effectors, such as T cells, B cells and autoantibodies (AutoAb). METHODS: We used custom autoantigen (AutoAg) microarrays to profile AutoAb related to irAEs in patients receiving ICI. Plasma was collected before and after ICI from cancer patients participating in two clinical trials (NCT03686202, NCT02644369). A one-time collection was obtained from healthy controls for comparison. Custom arrays with 162 autoAg were used to detect IgG and IgM reactivities. Differences of median fluorescent intensity (MFI) were analyzed with Wilcoxon sign rank test and Kruskal-Wallis test. MFI 500 was used as threshold to define autoAb reactivity. RESULTS: A total of 114 patients and 14 healthy controls were included in this study. irAEs of grade (G) ≥ 2 occurred in 37/114 patients (32%). We observed a greater number of IgG and IgM reactivities in pre-ICI collections from patients versus healthy controls (62 vs 32 p < 0.001). Patients experiencing irAEs G ≥ 2 demonstrated pre-ICI IgG reactivity to a greater number of AutoAg than patients who did not develop irAEs (39 vs 33 p = 0.040). We observed post-treatment increase of IgM reactivities in subjects experiencing irAEs G ≥ 2 (29 vs 35, p = 0.021) and a decrease of IgG levels after steroids (38 vs 28, p = 0.009). CONCLUSIONS: Overall, these results support the potential role of autoAb in irAEs etiology and evolution. A prospective study is ongoing to validate our findings (NCT04107311).

Distinctive clinical and genetic features of lean vs overweight fatty liver disease using the UK Biobank.

BACKGROUND: Lean NAFLD may differ from NAFLD found in overweight or obese patients. We used the UK biobank to conduct a cross-sectional study that examined features that distinguish lean NAFLD from overweight or obese NAFLD. METHODS: MRI-PDFF data were used to identify patients with NAFLD, with NAFLD defined as PDFF ≥ 5%. BMI patient cohorts were identified, with lean defined as a BMI < 25, and overweight or obese defined as a BMI ≥ 25. Variables of interest to fatty liver disease, including single nucleotide polymorphisms, were chosen from the UK biobank data portal. Logistic regression was used to generate models predictive of NAFLD in each cohort. RESULTS: 1007 patients had NAFLD, and of these, 871 had BMI ≥ 25, and 136 BMI < 25. Factors associated with NAFLD in patients with BMI < 25 included male sex, white blood cell count, red blood cell count, triglycerides, ALT, creatinine, visceral adipose tissue, rs58542926 T, and rs738409 G. In contrast, factors associated with NAFLD in patients with BMI ≥ 25 included male sex, waist circumference, HDL cholesterol, triglycerides, serum glucose, ALT, creatinine, urate, visceral adipose tissue, rs1260326 T, rs1044498 C, rs58542926 T, and rs738409 G. For lean patients, our generated prediction score had an AUC of 0.92, sensitivity of 0.90 and specificity of 0.81. For overweight or obese patients, the prediction score had an AUC of 0.86, sensitivity of 0.87 and specificity of 0.70. CONCLUSIONS: Our analysis suggests that lean and overweight or obese NAFLD are distinct entities. We have developed a risk score incorporating both clinical and genetic factors that accurately classify lean patients with NAFLD, with the potential to serve as a tool for screening purposes.

Predictors of patient survival following liver transplant in non-alcoholic steatohepatitis: A systematic review and meta-analysis.

Background: Non-alcoholic steatohepatitis (NASH) is the second-leading indication for liver transplantation (LT) worldwide and is projected to become the leading indication. Our study aimed to determine clinical variables that predict post-LT survival in NASH. Methods: A systematic review and meta-analysis was performed. On June 18, 2020 and April 28, 2022, Ovid MEDLINE ALL, Ovid Embase, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials were searched. No date limits were applied. Inclusion criteria specified the type of study and our study's population/comparison and outcome/timepoints. Pediatric, animal, retransplantation-only, and studies classifying cryptogenic cirrhosis patients with body mass index (BMI) <30 as NASH were excluded. Studies with duplicate cohorts and missing information were excluded from the meta-analysis. Studies were appraised using the Newcastle-Ottawa Scale. This study was preregistered in PROSPERO (CRD42020196915). Findings: Out of 8583 studies identified, 25 studies were included in the systematic review, while 5 studies were included in the meta-analysis. Our quantitative review suggested that the following variables were predictive of post-LT NASH patient survival: recipient age, functional status, pre-LT hepatoma, model for end-stage liver disease (MELD) score, diabetes mellitus (DM), pre-LT dialysis, hepatic encephalopathy, portal vein thrombosis, hospitalization/ICU at LT, and year of LT. Predictors of graft survival included recipient age, BMI, pre-LT dialysis, and DM. Our pooled meta-analyses included five predictors of patient survival. Increased patient mortality was associated with older recipient age (HR=2·07, 95%CI: 1·71-2·50, I2=0, τ2=0, p=0·40) and pretransplant DM (HR=1·18, 95%CI: 1·08-1·28, I2=0, τ2=0, p=0·76). Interpretation: Our systematic review and meta-analysis aimed to synthesise predictive variables of mortality in LT NASH patients. Clinically, this might help to identify modifiable risk factors that can be optimized in the post-transplant setting to improve patient outcomes and optimises decision making in the resource-limited LT setting. Funding: Toronto General and Western Hospital Foundation.

Construct Validity of the EuroQoL-5 Dimension and the Health Utilities Index in Head and Neck Cancer.

OBJECTIVE: The objective of this study was to evaluate the construct validity of 2 health utility instruments-the EuroQoL-5 Dimension (EQ-5D) and the Health Utilities Index-Mark 3 (HUI-3)-and to compare them with disease-specific measures in patients with head and neck cancer. STUDY DESIGN: Prospective cross-sectional analysis. SETTING: Princess Margaret Cancer Centre. METHODS: Patients were administered the EQ-5D, HUI-3, the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and its head and neck cancer module (EORTC QLQ-H&N35), and the University of Washington Quality of Life Questionnaire (UWQoL). Several a priori expected relations were examined. The correlative and discriminative properties of the various instruments were examined. RESULTS: A total of 209 patients completed the 4 questionnaires. A significant ceiling effect was observed among EQ-5D responses (23% reported a maximum score of 1). The EQ-5D (rho = 0.79) and HUI-3 (rho = 0.60) had a strong correlation with the social-emotional domain of the UWQoL. The EQ-5D had a moderate correlation with the physical domain of the UWQoL (rho = 0.42), whereas the HUI-3 had a weak correlation (rho = 0.29). The EQ-5D and HUI-3 were able to distinguish among levels of health severity measured on the EORTC QLQ-C30 though not the QLQ-H&N35. Comparatively, the UWQoL was able to distinguish levels of disease severity on the EORTC QLQ-C30 and QLQ-H&N35. CONCLUSION: The results of this study demonstrate that disease-specific domains from head and neck quality-of-life instruments are not strongly correlated with the EQ-5D and HUI-3. Consideration should be put toward development of a disease-specific preference-based measure for health economic evaluation. LEVEL OF EVIDENCE: 4.

Development and Validation of an Oral Cavity Cancer Outcomes Prediction Score Incorporating Patient-Derived Xenograft Engraftment.

IMPORTANCE: Patient-derived xenografts (PDXs) offer the opportunity to identify patients with oral cavity squamous cell carcinoma (OSCC) who are at risk for recurrence and optimize clinical decision-making. OBJECTIVE: To develop and validate a prediction score for locoregional failure (LRF) and distant metastases (DM) in OSCC that incorporates PDX engraftment in addition to known clinicopathological risk factors. DESIGN, SETTING, AND PARTICIPANTS: In this retrospective cohort study, PDX models were generated from patients with OSCC treated with curative intent at Princess Margaret Cancer Centre (Toronto, Canada) between 2006 and 2018. The cohort included 288 patients (aged ≥18 years) with a new diagnosis of nonmetastatic (M0) OSCC whose tumor samples were available for engraftment under the skin of xenograft mice. Patients were scored as a nonengrafter if PDX formation did not occur within 6 months. Data analysis was performed between August 2006 and May 2018. INTERVENTIONS: All patients received up-front curative-intent surgery followed by either observation or postoperative radiation with or without concurrent chemotherapy based on institutional guidelines. MAIN OUTCOMES AND MEASURES: Main outcomes were LRF, DM, and overall survival (OS). Multivariable analysis (MVA) was used to identify predictors of LRF and DM. Factors retained in the final MVA were used to construct a prediction score and classify patients into risk groups. RESULTS: Overall, 288 patients (mean [SD] age at diagnosis, 63.3 [12.3] years; 112 [39%] women and 176 [61%] men) with OSCC were analyzed. The MVA identified pT3-4, pathologic extranodal extension, and engraftment as predictors of LRF and DM. Patients whose tumors engrafted (n = 198) were more likely to develop LRF (hazard ratio [HR], 1.98; 95% CI, 1.24-3.18) and DM (HR, 2.64; 95% CI, 1.21-5.75) compared with nonengrafters. A prediction score based on the aforementioned variables identified patients at high risk and low risk for LRF (43.5% vs 26.5%), DM (38.2% vs 8.4%), and inferior OS (34% vs 66%) at 5 years. Additionally, rapid engraftment was shown to be similarly prognostic, with rapid engrafters demonstrating higher rates of relapse and poor OS. CONCLUSIONS: In this cohort study, a prediction score using OSCC PDX engraftment, in conjunction with pT3-4 and pathologic extranodal extension, was associated with improved prognostic utility of existing clinical models and predicted patients at risk for LRF, DM, and poor survival.

A Comparison of Patient-Reported Outcomes Following Consent for Genetic Testing Using an Oncologist- or Genetic Counselor-Mediated Model of Care.

This study compares knowledge, experience and understanding of genetic testing, and psychological outcomes among breast and ovarian cancer patients undergoing multi-gene panel testing via genetic counselor-mediated (GMT) or oncologist-mediated (OMT) testing models. A pragmatic, prospective survey of breast and ovarian cancer patients pursuing genetic testing between January 2017 and August 2019 was conducted at the Princess Margaret Cancer Centre in Toronto, Canada. A total of 120 (80 GMT; 40 OMT) individuals completed a survey administered one week following consent to genetic testing. Compared to OMT, the GMT cohort had higher median knowledge (8 vs. 9; p = 0.025) and experience/understanding scores (8.5 vs. 10; p < 0.001) at the time of genetic testing. Significant differences were noted in the potential psychological concerns experienced, with individuals in the GMT cohort more likely to screen positive in the hereditary predisposition domain of the Psychosocial Aspects of Hereditary Cancer tool (55% vs. 27.5%; p = 0.005), and individuals in the OMT cohort more likely to screen positive in the general emotions domain (65.0% vs. 38.8%; p = 0.007). The results of this study suggest that OMT can be implemented to streamline genetic testing; however, post-test genetic counseling should remain available to all individuals undergoing genetic testing, to ensure any psychologic concerns are addressed and that individuals have a clear understanding of relevant implications and limitations of their test results.

Real World Outcomes and Hepatotoxicity of Infliximab in the Treatment of Steroid-Refractory Immune-Related Adverse Events.

BACKGROUND AND AIMS: Current guidelines state that infliximab is contraindicated for the treatment of immune checkpoint inhibitor-related hepatitis (ir-hepatitis) due to the risk of inducing further liver damage. As this recommendation is largely based on the use of infliximab for rheumatologic diseases, we evaluated the efficacy and hepatotoxicity of infliximab in patients with steroid-refractory immune-related adverse events (irAEs). METHODS: We retrospectively reviewed consecutive patients treated with infliximab for irAEs at Princess Margaret Cancer Centre. To assess hepatotoxicity, we compared the mean value of ALT, AST, and total bilirubin (BT) before and after infliximab treatment. We used logistic regression to assess factors associated with infliximab efficacy. RESULTS: Between January 2010 and February 2019, 56 patients were identified. The median age of the patients was 63 (27-84) years. Colitis was the most frequent toxicity (66%), followed by pneumonitis (11%). Infliximab was used to treat ir-hepatitis in one patient. The median number of infliximab doses was 1 (1-3) and led to toxicity resolution in 43 (76%) patients. The mean ALT, AST, and BT levels before and after infliximab treatment were not statistically different. The patient treated for ir-hepatitis had a complete recovery, with no incremental liver toxicity. CONCLUSIONS: In this dose-limited setting, infliximab was effective in resolving irAEs and did not induce hepatotoxicity.

Genetic Risk Factors for CVD in Type 1 Diabetes: The DCCT/EDIC Study.

OBJECTIVE: The role of genetic factors in the risk of cardiovascular disease (CVD) for patients with type 1 diabetes (T1D) remains unknown. We therefore examined whether previously identified genetic factors for coronary artery disease (CAD) are associated with the risk of CVD above and beyond established demographic and clinical factors in the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) study. RESEARCH DESIGN AND METHODS: Polygenic risk scores (PRS) and individual genetic variants identified in previous studies were obtained from genome-wide genotyping performed in 1,371 DCCT/EDIC participants. Two composite CVD outcomes were considered: major adverse cardiovascular events (MACE) (CVD death or nonfatal myocardial infarction [MI] or stroke) and any CVD (MACE plus confirmed angina, silent MI, revascularization, or congestive heart failure). Cox proportional hazards models assessed the association between the genetic factors and the risk of CVD with adjustment for other factors (including age, lipids, blood pressure, and glycemia). RESULTS: CAD PRS was strongly associated with the subsequent risk of any CVD (42% and 38% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001) and with the risk of MACE (50% and 40% higher risk per 1-SD increase in unadjusted and fully adjusted models, respectively; P < 0.0001). Several individual single nucleotide polymorphisms were also nominally associated with the risk of any CVD and MACE. CONCLUSIONS: Genetic factors are associated with the risk of subsequent CVD in individuals with T1D above and beyond the effect of established risk factors such as age, lipids, blood pressure, and glycemia.

Risk Factors for Longitudinal Resting Heart Rate and Its Associations With Cardiovascular Outcomes in the DCCT/EDIC Study.

OBJECTIVE: Individuals with diabetes have higher resting heart rate compared with those without, which may be predictive of long-term cardiovascular disease (CVD) risk. Using data from the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) study, we evaluated whether the beneficial effect of intensive versus conventional diabetes therapy on heart rate persisted, the factors mediating the differences in heart rate between treatment groups, and the effects of heart rate on future CVD risk. RESEARCH DESIGN AND METHODS: Longitudinal changes in heart rate, from annual electrocardiograms over 22 years of EDIC follow-up, were evaluated in 1,402 participants with type 1 diabetes. Linear mixed models were used to assess the effect of DCCT treatment group on mean heart rate over time, and Cox proportional hazards models were used to estimate the effect of heart rate on CVD risk during DCCT/EDIC. RESULTS: At DCCT closeout, 52% of participants were male and mean ± SD age was 33 ± 7 years, diabetes duration 12 ± 5 years, and HbA1c 7.4 ± 1.2% (intensive) and 9.1 ± 1.6% (conventional). Through EDIC, participants in the intensive group had significantly lower heart rate in comparison with the conventional group. While significant group differences in heart rate were fully attenuated by DCCT/EDIC mean HbA1c, higher heart rate predicted CVD and major adverse cardiovascular events independent of other risk factors. CONCLUSIONS: After 22 years of follow-up, former intensive versus conventional therapy remained significantly associated with lower heart rate, consistent with the long-term beneficial effects of intensive therapy on CVD. DCCT treatment group effects on heart rate were explained by differences in DCCT/EDIC mean HbA1c.