A computed tomography radiomics-based model for predicting osteoporosis after breast cancer treatment.

Many treatments against breast cancer decrease the level of estrogen in blood, resulting in bone loss, osteoporosis and fragility fractures in breast cancer patients. This retrospective study aimed to evaluate a novel opportunistic screening for cancer treatment-induced bone loss (CTIBL) in breast cancer patients using CT radiomics. Between 2011 and 2021, a total of 412 female breast cancer patients who received treatment and were followed up in our institution, had post-treatment dual-energy X-ray absorptiometry (DXA) examination of the lumbar vertebrae and had post-treatment chest CT scan that encompassed the L1 vertebra, were included in this study. Results indicated that the T-score of L1 vertebra had a strongly positive correlation with the average T-score of L1-L4 vertebrae derived from DXA (r = 0.91, p < 0.05). On multivariable analysis, four clinical variables (age, body weight, menopause status, aromatase inhibitor exposure duration) and three radiomic features extracted from the region of interest of L1 vertebra (original_firstorder_RootMeanSquared, wavelet.HH_glcm_InverseVariance, and wavelet.LL_glcm_MCC) were selected for building predictive models of L1 T-score and bone health. The predictive model combining clinical and radiomic features showed the greatest adjusted R2 value (0.557), sensitivity (83.6%), specificity (74.2%) and total accuracy (79.4%) compared to models that relied solely on clinical data, radiomic features, or Hounsfield units. In conclusion, the clinical-radiomic predictive model may be used as an opportunistic screening tool for early identification of breast cancer survivors at high risk of CTIBL based on non-contrast CT images of the L1 vertebra, thereby facilitating early intervention for osteoporosis.

Investigating Canadian Public Attitudes Toward COVID-19 Vaccine Mandates with a Nested Analysis Framework.

BACKGROUND: Social media is an important medium for studying public attitudes toward COVID-19 vaccine mandates in Canada, and Reddit network communities are a good source for this. METHODS: This study applied a "nested analysis" framework. We collected 20378 Reddit comments via the Pushshift API and developed a BERT-based binary classification model to screen for relevance to COVID-19 vaccine mandates. We then used a Guided Latent Dirichlet Allocation (LDA) model on relevant comments to extract key topics and assign each comment to its most relevant topic. RESULTS: There were 3179 (15.6%) relevant and 17199 (84.4%) irrelevant comments. Our BERT-based model achieved 91% accuracy trained with 300 Reddit comments after 60 epochs. The Guided LDA model had an optimal coherence score of 0.471 with four topics: travel, government, certification, and institutions. Human evaluation of the Guided LDA model showed an 83% accuracy in assigning samples to their topic groups. CONCLUSION: We develop a screening tool for filtering and analyzing Reddit comments on COVID-19 vaccine mandates through topic modelling. Future research could develop more effective seed word-choosing and evaluation methods to reduce the need for human judgment.

Digital Disease Surveillance for Emerging Infectious Diseases: An Early Warning System Using the Internet and Social Media Data for COVID-19 Forecasting in Canada.

BACKGROUND: Emerging Infectious Diseases (EID) are a significant threat to population health globally. We aimed to examine the relationship between internet search engine queries and social media data on COVID-19 and determine if they can predict COVID-19 cases in Canada. METHODS: We analyzed Google Trends (GT) and Twitter data from 1/1/2020 to 3/31/2020 in Canada and used various signal-processing techniques to remove noise from the data. Data on COVID-19 cases was obtained from the COVID-19 Canada Open Data Working Group. We conducted time-lagged cross-correlation analyses and developed the long short-term memory model for forecasting daily COVID-19 cases. RESULTS: Among symptom keywords, "cough," "runny nose," and "anosmia" were strong signals with high cross-correlation coefficients >0.8 ( rCough = 0.825, t - 9; rRunnyNose = 0.816, t - 11; rAnosmia = 0.812, t - 3 ), showing that searching for "cough," "runny nose," and "anosmia" on GT correlated with the incidence of COVID-19 and peaked 9, 11, and 3 days earlier than the incidence peak, respectively. For symptoms- and COVID-related Tweet counts, the cross-correlations of Tweet signals and daily cases were rTweetSymptoms = 0.868, t - 11 and tTweetCOVID = 0.840, t - 10, respectively. The LSTM forecasting model achieved the best performance (MSE = 124.78, R2 = 0.88, adjusted R2 = 0.87) using GT signals with cross-correlation coefficients >0.75. Combining GT and Tweet signals did not improve the model performance. CONCLUSION: Internet search engine queries and social media data can be used as early warning signals for creating a real-time surveillance system for COVID-19 forecasting, but challenges remain in modelling.

Monkeypox: a review of epidemiological modelling studies and how modelling has led to mechanistic insight.

Human monkeypox (mpox) virus is a viral zoonosis that belongs to the Orthopoxvirus genus of the Poxviridae family, which presents with similar symptoms as those seen in human smallpox patients. Mpox is an increasing concern globally, with over 80,000 cases in non-endemic countries as of December 2022. In this review, we provide a brief history and ecology of mpox, its basic virology, and the key differences in mpox viral fitness traits before and after 2022. We summarize and critique current knowledge from epidemiological mathematical models, within-host models, and between-host transmission models using the One Health approach, where we distinguish between models that focus on immunity from vaccination, geography, climatic variables, as well as animal models. We report various epidemiological parameters, such as the reproduction number, R0, in a condensed format to facilitate comparison between studies. We focus on how mathematical modelling studies have led to novel mechanistic insight into mpox transmission and pathogenesis. As mpox is predicted to lead to further infection peaks in many historically non-endemic countries, mathematical modelling studies of mpox can provide rapid actionable insights into viral dynamics to guide public health measures and mitigation strategies.

HER2 amplification in colorectal cancer with brain metastasis: A propensity score matching study.

BACKGROUND: The association between human epidermal growth factor receptor-2 (HER2) amplification and brain metastasis (BM) in patients having colorectal cancer (CRC) has been suggested but not yet established. This study investigated the expression patterns of HER2, its association with BM, and its prognostic value in patients having CRC. METHODS: We retrospectively identified 99 patients having metastatic CRC (mCRC) and BM (the BM cohort) and compared them with a cohort of 249 patients having mCRC and without BM (the stage IV cohort) by propensity score matching. Immunohistochemical studies of HER2 on all available paraffin-embedded tumour samples, either from the primary tumour, the metastasis (brain and/or extracranial sites) or both, were performed and analysed. HER2 fluorescent in situ hybridisation was applied when necessary. The expression of HER2 was compared and correlated with survival. RESULTS: HER2 amplifications were detected in 16 (18.4%) of 87 and 9 (3.6%) of 249 patients who had specimens available in the BM and stage IV cohorts, respectively (P < .001). After propensity score matching, HER2 amplification was significantly associated with BM (odds ratio: 5.38, P = .003). HER2 heterogeneity was frequently observed not only at the single tumour level but also in paired tumour samples. A marginally significant longer survival since BM was found in patients having HER2-amplified mCRC than in those without (P = .07). CONCLUSIONS: HER2 amplification was significantly associated with BM in patients having mCRC and might have prognostic value for survival since BM. Given the heterogeneity of HER2 expression, the testing of HER2 status on available tissues from both primary and metastatic tumours should be encouraged.

Impact of Alcohol and Smoking on Outcomes of HPV-Related Oropharyngeal Cancer.

BACKGROUND: The aim of this study was to evaluate the impact of adverse lifestyle factors on outcomes in patients with human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC). METHODS: From 2010 to 2019, 150 consecutive non-metastatic OPSCC patients receiving curative treatment in our institution were retrospectively enrolled. HPV positivity was defined as p16 expression ≥75%. The effects of adverse lifestyle factors on overall survival (OS) and disease-free survival (DFS) on OPSCC patients were determined. RESULTS: The median follow-up duration was 3.6 years. Of the 150 OPSCCs, 51 (34%) patients were HPV-positive and 99 (66%) were HPV-negative. The adverse lifestyle exposure rates were 74.7% (n = 112) alcohol use, 57.3% (n = 86) betel grid chewing, and 78% (n = 117) cigarette smoking. Alcohol use strongly interacted with HPV positivity (HR, 6.00; 95% CI, 1.03-35.01), leading to an average 26.1% increased risk of disease relapse in patients with HPV-positive OPSCC. Heavy smoking age ≥30 pack-years was associated with increased risk of death (HR, 2.05; 95% CI, 1.05-4.00) and disease relapse (HR, 1.99; 95% CI, 1.06-3.75) in OPSCC patients. In stratified analyses, the 3-year absolute risk of disease relapse in HPV-positive OPSCC patients reached up to 50% when alcohol use and heavy smoking for ≥30 pack-years were combined. CONCLUSIONS: Alcohol acted as a significant treatment-effect modifier for DFS in HPV-positive OPSCC patients, diluting the favorable prognostic effect of HPV positivity. Heavy smoking age ≥30 pack-years was an independent adverse prognostic factor of OS and DFS in OPSCC patients. De-intensification treatment for HPV-related OPSCC may be avoided when these adverse lifestyle factors are present.

Service process factors affecting patients' and clinicians' experiences on rapid teleconsultation implementation in out-patient neurology services during COVID-19 pandemic: a scoping review.

BACKGROUND: The adoption of teleconsultation for outpatient neurology services was limited until the onset of the COVID-19 pandemic which forced many outpatient neurology services to rapidly switch to virtual models. However, it remains unclear how this change has impacted patients' and clinicians' perceptions of service quality. The purpose of this scoping review is to identify process factors that influence patients' and clinicians' experiences of outpatient teleconsultation services during COVID-19. METHODS: Arksey and O'Malley scoping review framework was used to search PubMed, Scopus, CINAHL, and PsycInfo for original peer-reviewed research studies that examined the experiences of synchronous teleconsultation between a clinician and patient in a home-setting since the World Health Organization announced the COVID-19 global pandemic. The service quality model SERVQUAL was used to conduct a deductive thematic analysis to identify the key factors that impacted the patients' and clinicians' perception of teleconsultation services. RESULTS: A total of nineteen studies published between January 1, 2020, and April 17, 2021, were identified. The most common service process factors affecting the patients' and clinicians' experiences of teleconsultation were technical issues, addressing logistical needs, communication, ability to perform clinical activities, appropriate triage, and administrative support. CONCLUSIONS: Our findings identified six key service process factors affecting the patients' and clinicians' teleconsultation experiences in outpatient neurology services. The need for improvement of triage process and standardizing administrative virtual care pathway are identified as important steps to improve patients and clinicians' teleconsultation experiences compared to pre-COVID era. More research is needed to assess outpatient neurology teleconsultation service quality from patients' and clinicians' perspectives.

Exploring the dynamic transitions of polysubstance use patterns among Canadian youth using Latent Markov Models on COMPASS data.

Background: Understanding what factors lead to youth polysubstance use (PSU) patterns and how the transitions between use patterns can inform the design and implementation of PSU prevention programs. We explore the dynamics of PSU patterns from a large cohort of Canadian secondary school students using machine learning techniques. Methods: We employed a multivariate latent Markov model (LMM) on COMPASS data, with a linked sample (N = 8824) of three-annual waves, Wave I (WI, 2016-17, as baseline), Wave II (WII, 2017-18), and Wave III (WIII, 2018-19). Substance use indicators, i.e., cigarette, e-cigarette, alcohol and marijuana, were self-reported and were categorized into never/occasional/current use. Outcomes: Four distinct use patterns were identified: no-use (S1), single-use of alcohol (S2), dual-use of e-cigarettes and alcohol (S3), and multi-use (S4). S1 had the highest prevalence (60.5%) at WI, however, S3 became the prominent use pattern (32.5%) by WIII. Most students remained in the same subgroup over time, particularly S4 had the highest transition probability (0.87) across the three-wave. With time, those who transitioned typically moved towards a higher use pattern, with the most and least likely transition occurring S2→S3 (0.45) and S3→S2 (<0.01), respectively. Among all covariates being examined, truancy, being measured by the # of classes skipped, significantly affected transition probabilities from any low→high (e.g., ORS2→S4 = 2.41, 95% CI [2.11, 2.72], p < 0.00001) and high→low (e.g., ORS3→S1 = 0.38, 95% CI [0.33, 0.44], p < 0.00001) use directions over time. Older students, blacks (vs. whites), and breakfast eaters were less likely to transition from low→high use direction. Students with more weekly allowance, with more friends that smoked, longer sedentary time, and attended attended school unsupportive to resist or quit drug/alcohol were more likely to transition from low→high use direction. Except for truancy, all other covariates had inconsistent effects on the transition probabilities from the high→low use direction. Interpretation: This is the first study to ascertain the dynamics of use patterns and factors in youth PSU utilizing LMM with population-based longitudinal health surveys, providing evidence in developing programs to prevent youth PSU. Funding: The Applied Health Sciences scholarship; the Microsoft AI for Good grant; the Canadian Institutes of Health Research, Health Canada, the Canadian Centre on Substance Abuse, the SickKids Foundation, the Ministère de la Santé et des Services sociaux of the province of Québec.

Accelerated coronary calcium burden in breast cancer patients after radiotherapy: a comparison with age and race matched healthy women.

BACKGROUND: Radiotherapy (RT) might lead to atherosclerotic plaque buildup and coronary artery stenosis of breast cancer (BC) survivors, and coronary artery calcium (CAC) might be a sign of preclinical atherosclerosis. This study explores possible determinants affecting the acceleration of CAC burden in BC patients after adjuvant RT. METHODS: Female BC patients receiving adjuvant RT from 2002 to 2010 were included. All patients received noncontrast computed tomography (NCCT) of thorax before and after adjuvant RT. Their CAC burden was compared with healthy controls from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort. The progression of the CAC burden was manifested by the increment of CAC percentiles (%CACinc). RESULTS: Ninety-four patients, including both left- and right-side BC, were enrolled in this study. From undergoing the first to second NCCT, the %CACinc in BC patients significantly increased rather than non-BC women. In addition, the %CACinc was significantly higher in left-side than right-side BC patients (p < 0.05), and significant differences in most heart outcomes were found between the two groups. Besides, the lower the mean right coronary artery (RCA) dose, the lower the risks of CAC percentiles increase ≥ 50% after adjusting the disease's laterality. CONCLUSIONS: A significantly higher accelerated CAC burden in BC patients than non-BC women represents that BC could affect accelerated CAC. A higher risk of accelerated CAC burden was found in left-side than right-side BC patients after adjuvant RT. A decrease of the mean RCA dose could reduce more than 50% of the risk of accelerated CAC burden in BC patients.

Targeting the Copper Transport System to Improve Treatment Efficacies of Platinum-Containing Drugs in Cancer Chemotherapy.

The platinum (Pt)-containing antitumor drugs including cisplatin (cis-diamminedichloroplatinum II, cDDP), carboplatin, and oxaliplatin, have been the mainstay of cancer chemotherapy. These drugs are effective in treating many human malignancies. The major cell-killing target of Pt drugs is DNA. Recent findings underscored the important roles of Pt drug transport system in cancer therapy. While many mechanisms have been proposed for Pt-drug transport, the high-affinity copper transporter (hCtr1), Cu chaperone (Atox1), and Cu exporters (ATP7A and ATP7B) are also involved in cDDP transport, highlighting Cu homeostasis regulation in Pt-based cancer therapy. It was demonstrated that by reducing cellular Cu bioavailable levels by Cu chelators, hCtr1 is transcriptionally upregulated by transcription factor Sp1, which binds the promoters of Sp1 and hCtr1. In contrast, elevated Cu poisons Sp1, resulting in suppression of hCtr1 and Sp1, constituting the Cu-Sp1-hCtr1 mutually regulatory loop. Clinical investigations using copper chelator (trientine) in carboplatin treatment have been conducted for overcoming Pt drug resistance due in part to defective transport. While results are encouraging, future development may include targeting multiple steps in Cu transport system for improving the efficacies of Pt-based cancer chemotherapy. The focus of this review is to delineate the mechanistic interrelationships between Cu homeostasis regulation and antitumor efficacy of Pt drugs.

Association of Primary Treatment Modality for Advanced-Stage Oropharyngeal Squamous Cell Carcinoma With Survival Outcomes.

Importance: Definitive chemoradiotherapy and upfront surgical treatment are both accepted as the standard of care for advanced-stage oropharyngeal squamous cell carcinoma. However, the optimal primary treatment modality remains unclear. Objective: To evaluate the comparative effectiveness of definitive chemoradiotherapy and upfront surgical treatment for advanced-stage oropharyngeal cancer. Design, Setting, and Participants: This retrospective comparative effectiveness analysis used data from the population-based Taiwan Cancer Registry. Included patients were diagnosed with clinical stage III or IV oropharyngeal squamous cell carcinoma from 2007 to 2015 and were identified from the registry. Patients with T4b or N3 disease were excluded. Data were analyzed from June 2019 through December 2020. Interventions: Definitive chemoradiotherapy or upfront surgical treatment. Main Outcomes and Measures: The primary outcome was overall survival, for which data were available through December 31, 2018. Secondary outcomes were progression-free survival, locoregional recurrence-free survival, and distant metastasis-free survival. Results: Among 1180 patients, 694 patients (58.8%) were in the definitive chemoradiotherapy group and 486 patients (41.2%) were in the upfront surgical treatment group. The median (interquartile range) follow-up was 3.62 (1.63-5.47) years, and most patients were men (1052 [89.1%] men) with a primary tumor in the tonsils (712 patients [60.3%]), moderately differentiated histology (604 patients [51.2%]), clinical N2 disease (858 patients [72.7%]), and clinical stage IVA disease (938 patients [79.5%]). The mean (SD) age was 54.59 (10.35) years. Primary treatment with an upfront surgical procedure was associated with a decreased risk of death during the study period (hazard ratio [HR], 0.81; 95% CI, 0.69-0.97; P = .02). However, when adjusted for age, subsite, histological grade, and T and N classification, upfront surgical treatment was no longer associated with an increased risk of death during the study period (HR, 0.96; 95% CI, 0.80-1.16; P = .70). Progression-free survival was worse in the group receiving upfront surgical treatment than in the group receiving chemoradiotherapy (HR, 1.64; 95% CI, 1.09-2.46; P = .02), and this difference persisted after adjusting for other factors associated with prognosis (ie, age, tumor subsite, histological grade, and T and N classification) (HR, 1.72; 95% CI, 1.12-2.66; P = .01). Conclusions and Relevance: This study found that definitive chemoradiotherapy was associated with effectiveness that was comparable with that of upfront surgical treatment when adjusted for baseline factors associated with prognosis. These findings suggest that definitive chemoradiotherapy should be considered to avoid accumulating toxic effects associated with surgical treatment and chemoradiotherapy.

Cost-Effectiveness Analysis of Afatinib, Erlotinib, and Gefitinib as First-Line Treatments for EGFR Mutation-Positive Non-Small-Cell Lung Cancer in Ontario, Canada.

OBJECTIVE: The objective of this study was to compare the cost effectiveness of first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) for the treatment of non-small-cell lung cancer. METHODS: This study used Ontario Cancer Registry-linked administrative data to identify patients with a primary diagnosis of lung cancer who received EGFR-TKIs as first-line treatment between 1 January, 2014 and 31 August, 2019. A net benefit regression approach accounting for baseline covariates and propensity scores was used to estimate incremental net benefits and incremental cost-effectiveness ratios. Outcome measures were calculated over a 68-month period and were discounted with an annual rate of 1.5%. Sensitivity analyses were conducted to assess and characterize the uncertainties. RESULTS: A total of 547 patients were included in the study, of whom 20.1%, 23.6%, and 56.3% received afatinib, erlotinib, and gefitinib, respectively. Erlotinib was dominated by afatinib and gefitinib. Compared to gefitinib, afatinib was associated with higher effectiveness (adjusted incremental quality-adjusted life-year: 0.21), higher total costs (adjusted incremental costs: $9745), and an incremental cost-effectiveness ratio of $46,506 per quality-adjusted life-year gained. Results from the sensitivity analyses indicated the findings of the base-case analysis were robust. CONCLUSIONS: Contrary to previously published studies, our study established head-to-head comparisons of effectiveness and treatment-related costs of first-line EGFR-TKIs. Our findings suggest afatinib was the most cost-effective option among the three EGFR-TKIs.

Factors affecting treatment selection and overall survival for first-line EGFR-tyrosine kinase inhibitor therapy in non-small-cell lung cancer.

Aim: To investigate the factors associated with treatment selection and overall survival for first-line EGFR-tyrosine kinase inhibitors (EGFR-TKIs) therapy among patients with non-small-cell lung cancer. Materials & methods: We conducted a retrospective cohort study of linked administrative health databases in Ontario, Canada. Results: A total of 1011 patients received an EGFR-TKI as first-line therapy. Treatment selection and overall survival associated with these treatments were affected by age, sex, geographical residency, comorbidities and different sites of metastasis. Conclusion: Though recent approval of osimertinib offers a potential new standard of care in the first-line setting, earlier generation TKIs remain pillars in treatment of non-small-cell lung cancer therapeutic armamentarium. Our findings may contribute to optimizing treatment sequencing of EGFR-TKIs to maximize clinical benefits.

Targeting the Proline-Glutamine-Asparagine-Arginine Metabolic Axis in Amino Acid Starvation Cancer Therapy.

Proline, glutamine, asparagine, and arginine are conditionally non-essential amino acids that can be produced in our body. However, they are essential for the growth of highly proliferative cells such as cancers. Many cancers express reduced levels of these amino acids and thus require import from the environment. Meanwhile, the biosynthesis of these amino acids is inter-connected but can be intervened individually through the inhibition of key enzymes of the biosynthesis of these amino acids, resulting in amino acid starvation and cell death. Amino acid starvation strategies have been in various stages of clinical applications. Targeting asparagine using asparaginase has been approved for treating acute lymphoblastic leukemia. Targeting glutamine and arginine starvations are in various stages of clinical trials, and targeting proline starvation is in preclinical development. The most important obstacle of these therapies is drug resistance, which is mostly due to reactivation of the key enzymes involved in biosynthesis of the targeted amino acids and reprogramming of compensatory survival pathways via transcriptional, epigenetic, and post-translational mechanisms. Here, we review the interactive regulatory mechanisms that control cellular levels of these amino acids for amino acid starvation therapy and how drug resistance is evolved underlying treatment failure.

Real-world effectiveness of nivolumab in patients with non-small-cell lung cancer: a systematic review and meta-analysis.

Background: The effectiveness of immunotherapies for non-small-cell lung cancer under real-world clinical settings remains uncertain. Materials & methods: Systematic searches of PubMed, EMBASE and Web of Science were conducted. Random-effects models were used to estimate pooled median overall survival and progression-free survival estimates. Results: 36 studies of nivolumab were included for narrative synthesis and 11 of these studies were included for meta-analysis. Age, sex, histology and prior lines of treatment did not affect survival outcomes, while Eastern Cooperative Oncology Group Performance Status and brain metastasis were inversely associated with survival. In the meta-analysis, nivolumab was associated with 9.6 months (95% CI: 8.4-10.9) of overall survival and 2.6 months (95% CI: 1.6-3.6) of progression-free survival. Conclusion: Very-low-certainty evidence suggested the real-world effectiveness of nivolumab was consistent with those observed in the clinical trials.

A new concordant partial AUC and partial c statistic for imbalanced data in the evaluation of machine learning algorithms.

BACKGROUND: In classification and diagnostic testing, the receiver-operator characteristic (ROC) plot and the area under the ROC curve (AUC) describe how an adjustable threshold causes changes in two types of error: false positives and false negatives. Only part of the ROC curve and AUC are informative however when they are used with imbalanced data. Hence, alternatives to the AUC have been proposed, such as the partial AUC and the area under the precision-recall curve. However, these alternatives cannot be as fully interpreted as the AUC, in part because they ignore some information about actual negatives. METHODS: We derive and propose a new concordant partial AUC and a new partial c statistic for ROC data-as foundational measures and methods to help understand and explain parts of the ROC plot and AUC. Our partial measures are continuous and discrete versions of the same measure, are derived from the AUC and c statistic respectively, are validated as equal to each other, and validated as equal in summation to whole measures where expected. Our partial measures are tested for validity on a classic ROC example from Fawcett, a variation thereof, and two real-life benchmark data sets in breast cancer: the Wisconsin and Ljubljana data sets. Interpretation of an example is then provided. RESULTS: Results show the expected equalities between our new partial measures and the existing whole measures. The example interpretation illustrates the need for our newly derived partial measures. CONCLUSIONS: The concordant partial area under the ROC curve was proposed and unlike previous partial measure alternatives, it maintains the characteristics of the AUC. The first partial c statistic for ROC plots was also proposed as an unbiased interpretation for part of an ROC curve. The expected equalities among and between our newly derived partial measures and their existing full measure counterparts are confirmed. These measures may be used with any data set but this paper focuses on imbalanced data with low prevalence. FUTURE WORK: Future work with our proposed measures may: demonstrate their value for imbalanced data with high prevalence, compare them to other measures not based on areas; and combine them with other ROC measures and techniques.

Collaboration Between RSK-EphA2 and Gas6-Axl RTK Signaling in Arginine Starvation Response That Confers Resistance to EGFR Inhibitors.

Many human malignancies require extracellular arginine (Arg) for survival because the key enzyme for de novo Arg biosynthesis, argininosuccinate synthetase 1 (ASS1), is silenced. Recombinant arginine deiminase (ADI-PEG20), which digests extracellular Arg, has been in clinical trials for treating ASS1-negative tumors. Reactivation of ASS1 is responsible for the treatment failure. We previously demonstrated that ASS1 reactivation is transcriptionally regulated by c-Myc via the upstream Gas6-Axl tyrosine kinase (RTK) signal. Here, we report that another RTK EphA2 is coactivated via PI3K-ERK/RSK1 pathway in a ligand-independent mechanism. EphA2 is also regulated by c-Myc. Moreover, we found that knockdown Axl upregulates EphA2 expression, demonstrating cross-talk between these RTKs. ADIR cell lines exhibits enhanced sensitivities to nutrient deprivation such as charcoal-stripped FBS and multiple RTK inhibitor foretinib but resistance to EGFR inhibitors. Knockdown EphA2, and to lesser extent, Axl, overcomes EGFRi resistance. c-Myc inhibitor JQ1 can also sensitize ADIR cells to ADI-PEG20. This study elucidates molecular interactions of multiple RTKs in Arg-stress response and offers approaches for developing strategies of overcoming ADI-PEG20 resistance.

Prognostic value of volumetric metabolic parameter changes determined by during and after radiotherapy-based 18 F-FDG PET/CT in stage III non-small cell lung cancer.

The aim of this prospective study was to evaluate the prognostic value of volumetric metabolic parameters assessed by during and after radiation-based therapy 18 F-FDG PET/CT in patients with stage III non-small cell lung cancer (NSCLC). We enrolled stage III NSCLC patients who had planned to receive definitive chemo-radiation or radiotherapy (RT) and underwent 18 F-FDG PET/CT before treatment (PET1), during RT (at the fifth week, PET2) and after treatment (3 months later, PET3). By comparing with PET1, percentage changes of metabolic tumor volume (ΔMTV) and tumor total lesion glycolysis (ΔTLG) of PET2 and PET3 were calculated. We used medians of ΔTLG and ΔMTV as cut-off values to stratify patients. Their prognostic values were evaluated by progression-free survival (PFS) and overall survival (OS). Thirty patients were enrolled initially. Five were excluded due to multiple metastases or double cancer. The remaining 25 patients had PET2 at a median of 46 Gy. Data on PET3 were available in 19 patients. During-RT ΔTLG (cut-off: 65%) was a significant prognostic factor for PFS (P = 0.02) and OS (P < 0.01). During-RT ΔMTV (cut-off: 42%) had marginal significance for PFS (P = 0.07) and was significant for OS (P = 0.02). Of the PET3 parameters, neither ΔTLG nor ΔMTV was a significant prognostic factor for PFS and OS. We conclude that ΔTLG of during-RT 18 F-FDG PET/CT may predict treatment response and thus provide opportunities to modify treatment for poor responders.

Adjuvant radiotherapy after curative surgery for oral cavity squamous cell carcinoma and treatment effect of timing and duration on outcome-A Taiwan Cancer Registry national database analysis.

Conduct an accurate risk assessment of resected oral cavity squamous cell carcinoma (OSCC) patients by accessing a nationwide systemic investigation is pivotal to improve treatment outcomes. In this article, we tried to determine the impact of different prognostic factors for OSCC patients who received adjuvant radiotherapy (RT) after curative surgery, using Taiwan's national cancer registry database (TCR). A nationwide, large population-based study was conducted using TCR with patients identified from 2007 to 2015. The study variables included age, gender, cancer subsites, stage, histology grade, margin and extra-nodal extension (ENE) status, treatment type, surgery to RT interval (ORI), total RT treatment time (RTT), and RT dose. Univariate and multivariate analysis were performed to identify predictors of the variables associated with overall survival (OS), cause-specific survival (CSS), local-regional relapse-free survival (LRFS), and distant metastasis-free survival (DMFS). 8986 OSCC patients treated with surgery and adjuvant RT were analyzed. In multivariate analysis, worse outcomes were associated with males, older age, subsite in the oral tongue, advanced stage, higher histologic grade, involved margin, and positive ENE. ORI only showed an adverse trend in LRFS, when exceeding 7 weeks (P = .06). RTT >8 weeks was a significant poor predictor in OS, CSS and LRFS (P < .001). Extreme RT dose (>70 Gy or ≤50 Gy) also demonstrated an adverse impact on the outcomes. Prolonged RT treatment time and extreme RT doses were identified as significantly poor prognostic predictors in OSCC patients who received adjuvant RT after curative surgery.

Modulating Chemosensitivity of Tumors to Platinum-Based Antitumor Drugs by Transcriptional Regulation of Copper Homeostasis.

Platinum (Pt)-based antitumor agents have been effective in treating many human malignancies. Drug importing, intracellular shuffling, and exporting-carried out by the high-affinity copper (Cu) transporter (hCtr1), Cu chaperone (Ato x1), and Cu exporters (ATP7A and ATP7B), respectively-cumulatively contribute to the chemosensitivity of Pt drugs including cisplatin and carboplatin, but not oxaliplatin. This entire system can also handle Pt drugs via interactions between Pt and the thiol-containing amino acid residues in these proteins; the interactions are strongly influenced by cellular redox regulators such as glutathione. hCtr1 expression is induced by acute Cu deprivation, and the induction is regulated by the transcription factor specific protein 1 (Sp1) which by itself is also regulated by Cu concentration variations. Copper displaces zinc (Zn) coordination at the zinc finger (ZF) domains of Sp1 and inactivates its DNA binding, whereas Cu deprivation enhances Sp1-DNA interactions and increases Sp1 expression, which in turn upregulates hCtr1. Because of the shared transport system, chemosensitivity of Pt drugs can be modulated by targeting Cu transporters. A Cu-lowering agent (trientine) in combination with a Pt drug (carboplatin) has been used in clinical studies for overcoming Pt-resistance. Future research should aim at further developing effective Pt drug retention strategies for improving the treatment efficacy.