Wait times and breast cancer survival: a population-based retrospective cohort study using CanIMPACT data.

PURPOSE: The time from breast cancer surgery to chemotherapy has been shown to affect survival outcomes; however, the effect of time from first breast cancer-related healthcare contact to first cancer specialist consultation, or the time from first breast cancer-related healthcare contact to adjuvant chemotherapy on survival has not been well explored. We aimed to determine whether various wait times along the breast cancer treatment pathway (contact-to-consultation, contact-to-chemotherapy, surgery-to-chemotherapy) were associated with overall survival in women within the Canadian province of Ontario. METHODS: We performed a population-based retrospective cohort study of women diagnosed with stage I-III breast cancer in Ontario between 2007 and 2011 who received surgery and adjuvant chemotherapy. This was the Ontario cohort of a larger, nationwide study (the Canadian Team to improve Community-Based Cancer Care along the Continuum - CanIMPACT). We used Cox-proportional hazards regression to determine the association between the contact-to-consultation, contact-to-chemotherapy, and surgery-to-chemotherapy intervals and overall survival while adjusting for cancer stage, age, comorbidity, neighborhood income, immigration status, surgery type, and method of cancer detection. RESULTS: Among 12,782 breast cancer patients, longer surgery-to-chemotherapy intervals (HR 1.13, 95% CI 1.03-1.18 per 30-day increase), but not the contact-to-consultation (HR 0.979, 95% CI 0.95-1.01 per 30-day increase), nor the more comprehensive contact-to-chemotherapy intervals (HR 1.00, 95% CI 0.98-1.02 per 30-day increase) were associated with decreased survival in our adjusted analyses. CONCLUSION: Our findings emphasize the prognostic importance of a shorter surgery-to-chemotherapy interval, whereas the contact-to-consultation and contact-to-chemotherapy intervals have less impact on survival outcomes.

Breast (female), colorectal, and lung cancer survival in people with intellectual or developmental disabilities: A population-based retrospective cohort study.

OBJECTIVES: Cancer is a leading cause of death among people living with intellectual or developmental disabilities (IDD). There is little empirical evidence documenting survival or comparing outcomes to those without IDD. This study investigated the association between IDD and cancer survival among adults with breast (female), colorectal, or lung cancer. METHODS: A population-based retrospective cohort study was conducted in Ontario, Canada, with routinely collected data. Patients with breast, colorectal, or lung cancer were included (2007‒2019). IDD status before cancer was determined using an established administrative data algorithm. The outcomes of interest included death from any cause and death from cancer. Cox proportional hazards models and competing events analyses using multivariable cause-specific hazards regression were completed. Analyses were stratified by cancer type. Interactions with age, sex, and stage at diagnosis, as well as sensitivity analyses, were completed. RESULTS: The final cohorts included 123,695 breast, 98,809 colorectal, and 116,232 lung cancer patients. Individuals with IDD experienced significantly worse survival than those without IDD. The adjusted hazard ratios of all-cause death were 2.74 (95% CI 2.41‒3.12), 2.42 (95% CI 2.18‒2.68), and 1.49 (95% CI 1.34‒1.66) times higher for breast, colorectal, and lung cancer patients with IDD relative to those without. These findings were consistent for cancer-specific deaths. With few exceptions, worse survival for people with IDD persisted regardless of stage at diagnosis. CONCLUSION: People with IDD experienced worse cancer survival than those without IDD. Identifying and intervening on the factors and structures responsible for survival disparities is imperative.

RéSUMé: OBJECTIFS: Le cancer est l'une des principales causes de mortalité chez les personnes vivant avec des déficiences intellectuelles ou des troubles du développement (DI/TD). Il y a peu de preuves empiriques décrivant la survie de ces personnes lorsqu'elles sont atteintes d'un cancer ou comparant leurs résultats à ceux des personnes sans DI/TD. Notre étude porte sur l'association entre les DI/TD et la survie au cancer chez les adultes atteints de cancer du sein (femmes), du colorectum ou du poumon. MéTHODE: Une étude de cohorte rétrospective populationnelle a été menée en Ontario, au Canada, à l'aide de données recueillies systématiquement. Nous avons inclus les patientes et les patients atteints de cancer du sein, du colorectum ou du poumon (2007‒2019). Nous avons identifié la présence des DI/TD avant le cancer à l'aide d'un algorithme de traitement de données administratives reconnu. Les résultats d'intérêt étaient les décès de toutes causes et les décès dus au cancer. Nous avons appliqué des modèles des risques proportionnels de Cox et des analyses des événements concurrents en utilisant la régression multivariée des risques par cause. Nos analyses ont été stratifiées selon le type de cancer. Nous avons tenu compte des interactions avec l'âge, le sexe et le stade au diagnostic et effectué des analyses de sensibilité. RéSULTATS: Les cohortes finales ont inclus 123 695 personnes atteintes de cancer du sein, 98 809 atteintes de cancer colorectal et 116 232 atteintes de cancer du poumon. La survie des sujets ayant des DI/TD a été significativement moins bonne que celle des sujets sans DI/TD. Les rapports de risques instantanés ajustés pour les décès de toutes causes étaient 2,74 fois (IC de 95 % 2,41‒3,12), 2,42 fois (IC de 95 % 2,18‒2,68) et 1,49 fois (IC de 95 % 1,34‒1,66) plus élevés chez les personnes atteintes de cancer du sein, du colorectum et du poumon et ayant des DI/TD que chez les personnes sans DI/TD. Ces constatations ressortent pour tous les décès attribuables à des cancers particuliers. Avec peu d'exceptions, la survie moins bonne pour les personnes ayant des DI/TD persistait quel que soit le stade au moment du diagnostic. CONCLUSION: La survie au cancer était moins bonne chez les personnes ayant des DI/TD que chez celles n'ayant pas de DI/TD. Il est impératif d'identifier les facteurs et les structures responsables de ces disparités dans la survie et d'intervenir en conséquence.

Stage IV breast, colorectal, and lung cancer at diagnosis in adults living with intellectual or developmental disabilities: A population-based cross-sectional study.

BACKGROUND: Cancer is a leading cause of death among people living with intellectual or developmental disabilities (IDD). Although studies have documented lower cancer screening rates, there is limited epidemiological evidence quantifying potential diagnostic delays. This study explores the risk of metastatic cancer stage for people with IDD compared to those without IDD among breast (female), colorectal, and lung cancer patients in Canada. METHODS: Separate population-based cross-sectional studies were conducted in Ontario and Manitoba by linking routinely collected data. Breast (female), colorectal, and lung cancer patients were included (Manitoba: 2004-2017; Ontario: 2007-2019). IDD status was identified using established administrative algorithms. Modified Poisson regression with robust error variance models estimated associations between IDD status and the likelihood of being diagnosed with metastatic cancer. Adjusted relative risks were pooled between provinces using random-effects meta-analyses. Potential effect modification was considered. RESULTS: The final cohorts included 115,456, 89,815, and 101,811 breast (female), colorectal, and lung cancer patients, respectively. Breast (female) and colorectal cancer patients with IDD were 1.60 and 1.44 times more likely to have metastatic cancer (stage IV) at diagnosis compared to those without IDD (relative risk [RR], 1.60; 95% confidence interval [CI], 1.16-2.20; RR, 1.44; 95% CI, 1.24-1.67). This increased risk was not observed in lung cancer. Significant effect modification was not observed. CONCLUSIONS: People with IDD were more likely to have stage IV breast and colorectal cancer identified at diagnosis compared to those without IDD. Identifying factors and processes contributing to stage disparities such as lower screening rates and developing strategies to address diagnostic delays is critical.

Engineered adult stem cells: Current clinical trials status of disease treatment.

Regenerative medicine is an interdisciplinary field involving the process of replacing and regenerating cells/tissues or organs by integrating medicine, science, and engineering principles to enhance the intrinsic regenerative capacity of the host. Recently, engineered adult stem cells have gained attention for their potential use in regenerative medicine by reducing inflammation and modulating the immune system. This chapter introduces adult stem cell engineering and chimeric antigen receptor T cells (CAR T) gene therapy and summarises current engineered stem cell- and extracellular vesicles (EVs)-focused clinical trial studies that provide the basis for the proposal of a personalised medicine approach to diseases diagnosis and treatment.

Surgeon Thyroidectomy Case Volume Impacts Disease-free Survival in the Management of Thyroid Cancer.

OBJECTIVES: To assess the association between surgeons thyroidectomy case volume and disease-free survival (DFS) for patients with well-differentiated thyroid cancer (WDTC). A secondary objective was to assess a surgeon volume cutoff to optimize outcomes in those with WDTC. We hypothesized that surgeon volume will be an important predictor of DFS in patients with WDTC after adjusting for hospital volume and sociodemographic and clinical factors. METHODS: In this retrospective population-based cohort study, we identified WDTC patients in Ontario, Canada, who underwent thyroidectomy confirmed by both hospital-level and surgeon-level administrative data between 1993 and 2017 (N = 37,233). Surgeon and hospital volumes were calculated based on number of cases performed in the year prior by the physician and at an institution performing each case, respectively and divided into quartiles. A multilevel hierarchical Cox regression model was used to estimate the effect of volume on DFS. RESULTS: A crude model without patient or treatment characteristics demonstrated that both higher surgeon volume quartiles (p < 0.001) and higher hospital volume quartiles (p < 0.001) were associated with DFS. After controlling for clustering and patient/treatment covariates and hospital volume, moderately low (18-39/year) and low (0-17/year) volume surgeons (hazard ratios [HR]: 1.23, 95% confidence interval [CI]: 1.09-1.39 and HR: 1.34, 95% CI: 1.17-1.53 respectively) remained an independent statistically significant negative predictor of DFS. CONCLUSION: Both high-volume surgeons and hospitals are predictors of better DFS in patients with WDTC. DFS is higher among surgeons performing more than 40 thyroidectomies a year. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:S1-S15, 2023.

Mode of conception in patients with endometriosis and adverse pregnancy outcomes: a population-based cohort study.

OBJECTIVE: To evaluate the association between endometriosis and adverse pregnancy outcomes. DESIGN: Population-based retrospective cohort study using linked universal health databases through ICES Ontario. PATIENT(S): All singleton pregnancies with an estimated date of confinement between October 2006 and February 2014. INTERVENTION(S): Endometriosis was determined based on a surgical and/or medical diagnosis (defined as an in-hospital admission or surgery with a diagnosis code of International Classification of Diseases [ICD]9-617 or ICD10-N80 and/or 2 medical consults billed as ICD9-617). MAIN OUTCOME MEASURE(S): The association between endometriosis and pregnancy outcomes was quantified by relative risks, derived using modified Poisson regression, and adjusted for maternal age, income quintiles, and history of fibroids (aRR). Mediation analysis was conducted to estimate direct effects of endometriosis diagnosis and indirect effects through mode of conception, namely: infertility without fertility treatment (known infertility but conceived without assistance), ovulation induction or intrauterine insemination, and in vitro fertilization or intracytoplasmic sperm injection, relative to unassisted conception. RESULT(S): A total of 19,099 pregnancies had an antecedent diagnosis of endometriosis, while 768,350 did not. Mean time (standard deviation) from endometriosis diagnosis to the index pregnancy was 5.6 (4.3) years. Endometriosis was associated with an increased risk of hypertensive disorders of pregnancy (aRR, 1.09; 95% confidence interval [CI], 1.02-1.16), preterm birth <37 weeks (aRR, 1.26; 95% CI, 1.20-1.33), early preterm birth <34 weeks (aRR, 1.33; 95% CI, 1.17-1.50), placenta previa (aRR, 2.07; 95% CI, 1.84-2.33), placenta abruption (aRR, 1.55; 95% CI, 1.31-1.83), other placental disorders (aRR, 1.77; 95% CI, 1.36-2.30), cesarean delivery (aRR, 1.18; 95% CI, 1.16-1.21), and stillbirth (aRR, 1.32; 95% CI, 1.09-1.59). Mediation analysis suggests that endometriosis directly affects most adverse pregnancy outcomes studied, except for stillbirth where infertility diagnosis or fertility treatment indirectly accounted for part of the increased risk. CONCLUSION(S): Endometriosis was associated with adverse pregnancy, independent of infertility diagnosis, or fertility treatment. Future studies should investigate the mechanisms of action and potential interventions.

The Impact of Hospital Surgical Volume on Healthcare Utilization Outcomes After Pediatric Thyroidectomy.

BACKGROUND: A positive relationship between an individual surgeon's operative volume and clinical outcomes after pediatric and adult thyroidectomy is well-established. The impact of a hospital's pediatric operative volume on surgical outcomes and healthcare utilization, however, are infrequently reported. We investigated associations between hospital volume and healthcare utilization outcomes following pediatric thyroidectomy in Canada's largest province, Ontario. METHODS: Retrospective analysis of administrative and health-related population-level data from 1993 to 2017. A cohort of 1908 pediatric (<18 years) index thyroidectomies was established. Hospital volume was defined per-case as thyroidectomies performed in the preceding year. Healthcare utilization outcomes: length of stay (LOS), same day surgery (SDS), readmission, and emergency department (ED) visits were measured. Multivariate analysis adjusted for patient-level, disease and hospital-level co-variates. RESULTS: Hospitals with the lowest volume of pediatric thyroidectomies, accounted for 30% of thyroidectomies province-wide and performed 0-1 thyroidectomies/year. The highest-volume hospitals performed 19-60 cases/year. LOS was 0.64 days longer in the highest, versus the lowest quartile. SDS was 83% less likely at the highest, versus the lowest quartile. Hospital volume was not associated with rate of readmission or ED visits. Increased ED visits were, however, associated with male sex, increased material deprivation, and rurality. CONCLUSIONS: Increased hospital pediatric surgical volume was associated with increased LOS and lower likelihood of SDS. This may reflect patient complexity at such centers. In this cohort, low-volume hospitals were not associated with poorer healthcare utilization outcomes. Further study of groups disproportionately accessing the ED post-operatively may help direct resources to these populations.

Surgical Case Volume has an Impact on Outcomes for Patients with Lateral Neck Disease in Thyroid Cancer.

BACKGROUND: This study aimed to assess whether surgical case volume for lateral neck dissection has an impact on the survival of patients who have well-differentiated thyroid cancer (WDTC) with lateral cervical node metastases. The authors used a population-based cohort study design. METHODS: The study cohort consisted of WDTC patients in Ontario Canada who underwent thyroidectomy and lateral neck dissection. These patients were identified using both hospital- and surgeon-level administrative data between 1993 and 2017 (n = 1832). Surgeon and hospital volumes were calculated based on the number of cases managed in the year before the procedure by the physician and at the institution managing each case, respectively, and divided into tertiles. Multilevel Cox regression models were used to estimate the effect of volume on disease-free survival (DFS). RESULTS: A crude model without patient or treatment characteristics demonstrated that DFS was associated with both higher surgeon volume tertiles (p < 0.01) and higher hospital volume tertiles (p < 0.01). After control for clustering, patient/treatment covariates, and hospital volume, the lowest surgeon volume tertile (range, 0-20/year; mean, 6.5/year) remained an independent statistically significant negative predictor of DFS (hazard ratio, 1.71; 95 % confidence interval, 1.22-2.4; p < 0.01). CONCLUSION: Surgeon lateral neck dissection case volume is a predictor of better DFS for thyroid cancer patients, with the lowest surgeon volume tertile (<20 neck dissections per year) demonstrating poorer DFS.

Use of imaging for active surveillance in testicular cancer: Is real-world practice concordant with guidelines?

INTRODUCTION: Imaging is an integral component of active surveillance (AS) following orchiectomy for stage 1 non-seminoma (NSGCT) and seminoma germ cell tumors. In this population-based study, we describe use of imaging among patients with early-stage testicular cancer and evaluate whether they are concordant with guideline recommendations. METHODS: This is a population-based, retrospective cohort study to describe use of imaging among all patients with early-stage testicular cancer treated with AS in the Canadian province of Ontario. The Ontario Cancer Registry was linked to electronic records of treatment to identify use of chest and abdomen/pelvis imaging. Data from 2000-2010 were included, with followup for up to five years for patients with non-seminoma and 10 years for patients with seminoma. The key outcome of interest was the frequency of imaging at temporal milestones following orchiectomy. Compared to the most contemporaneous guidelines in Ontario, any discordant frequency of imaging was defined as underuse or overuse. Substantial under- or overuse was defined as >1 imaging test less/ more than what was recommended during a 12-month period. RESULTS: The study population included 569 patients with NSGCT (median age 28) and 1107 with seminoma (median age 37). Among patients with NSGCT, adherence with body imaging was low in years 1-3 of surveillance (range 26-37%, predominantly underuse) and higher in years 4-5 (63-67%, predominantly overuse). Adherence with chest imaging was even lower (range 11-34% during years 1-5). Among patients with seminoma, adherence with abdominal and chest imaging was relatively stable and comparable throughout the 10-year followup period (range 23-47% abdomen and 28-47% chest). Multivariable analysis confirmed that underuse of imaging was more common in recent years. NSGCT histology was associated with underuse in years 1-2 but overse in years 3-5. CONCLUSIONS: In routine clinical practice, patients with testicular cancer commonly receive imaging discordant to the protocol for AS, with a substantial proportion receiving both under- and overuse at various times during surveillance followup.

A Population-Based Analysis of Outpatient Thyroidectomy: Safe and Under-Utilized.

OBJECTIVES/HYPOTHESIS: Performance of thyroidectomy on an outpatient basis has gained popularity although many jurisdictions have not shifted their practice despite a strong safety profile. We sought to assess the uptake and safety of outpatient thyroidectomy in Ontario. STUDY DESIGN: Retrospective cohort study. METHODS: This was a population-based retrospecive cohort of adult patients undergoing hemithyroidectomy or total thyroidectomy between 1993 and 2017 in Ontario, Canada. Outpatient surgery was defined as discharge home on the same day of surgery. Outcomes of interest include 30-day all cause death, hematoma, emergency department use, and readmission. To adjust for confounding, propensity scores were calculated. Logistic regression models with inverse probability of treatment weighting (IPTW) were then used to estimate the exposure-outcome relationship. RESULTS: The final cohort consisted of 81,199 patients: 8,442 underwent same day surgery and 72,757 were admitted. The proportion of patients undergoing outpatient thyroidectomy increased overtime (2.3% in 1993-1994 to 17.8% in 2016-2017). Factors associated with higher odds of outpatient thyroidectomy included: younger age, less material deprivation, less comorbidities, and higher surgeon volume. The absolute number of deaths (≤5) and hematomas (64, 0.8%) in the outpatient cohort was low. After IPTW adjustment, patients with outpatient management had lower odds of neck hematoma (OR 0.73[95CI% 0.58-0.93)], but higher odds of emergency department use (OR 1.67[95%CI 1.56-1.79]). CONCLUSIONS: Outpatient thyroidectomy is not associated with an increased mortality risk. Less than one in five patients undergo outpatient thyroidectomy in Ontario, despite a well-established safety profile. LEVEL OF EVIDENCE: 3 Laryngoscope, 131:2625-2633, 2021.

Mental Health Resource Use Among Patients Undergoing Curative Intent Treatment for Bladder Cancer.

BACKGROUND: Patients with bladder cancer may experience mental health distress. Mental health-care service (MHS) use can quantify the magnitude of the problem. METHODS: The Ontario Cancer Registry was used to identify all patients with bladder cancer treated with curative-intent cystectomy or radiotherapy in Ontario, Canada (2004-2013). Population-level databases were used to identify MHS use (visits to general practitioner, psychiatrist, emergency department, or hospitalization). Generalized estimating equations were used to compare rates of MHS use. Baseline, peritreatment, and posttreatment MHS use were defined as visits from 2 years to 3 months before, 3 months before to 3 months after, and from 3 months after to 2 years after start of treatment, respectively. RESULTS: From 2004 to 2013, 4296 patients underwent cystectomy (n = 3332) or curative-intent radiotherapy (n = 964). Compared with baseline, the rate of MHS use was higher in the peritreatment (adjusted rate ratio [aRR] = 1.64, 95% confidence interval [CI] = 1.48 to 1.82) and posttreatment periods (aRR = 1.45, 95% CI =1.30 to 1.63). By 2 years posttreatment, 24.6% (95% CI = 23.4% to 25.9%) of all patients had MHS use. Patients with baseline MHS use had substantially higher MHS use in the peritreatment (aRR = 5.77, 95% CI = 4.86 to 6.86) and posttreatment periods (aRR = 4.58, 95% CI = 3.78 to 5.55). Female patients had higher use MHS use overall, but males had a higher incremental increase in the posttreatment period compared with baseline (2-sided Pinteraction = .02). Male patients had a statistically significant increase in MHS use following surgery or radiotherapy, whereas female patients only had an increase following surgery. CONCLUSIONS: MHS use is common among patients undergoing treatment for bladder cancer, particularly in the peritreatment period. Screening for mental health concerns in this population is warranted.

Disruption of the tumour-associated EMP3 enhances erythroid proliferation and causes the MAM-negative phenotype.

The clinically important MAM blood group antigen is present on haematopoietic cells of all humans except rare MAM-negative individuals. Its molecular basis is unknown. By whole-exome sequencing we identify EMP3, encoding epithelial membrane protein 3 (EMP3), as a candidate gene, then demonstrate inactivating mutations in ten known MAM-negative individuals. We show that EMP3, a purported tumour suppressor in various solid tumours, is expressed in erythroid cells. Disruption of EMP3 by CRISPR/Cas9 gene editing in an immortalised human erythroid cell line (BEL-A2) abolishes MAM expression. We find EMP3 to associate with, and stabilise, CD44 in the plasma membrane. Furthermore, cultured erythroid progenitor cells from MAM-negative individuals show markedly increased proliferation and higher reticulocyte yields, suggesting an important regulatory role for EMP3 in erythropoiesis and control of cell production. Our data establish MAM as a new blood group system and demonstrate an interaction of EMP3 with the cell surface signalling molecule CD44.

Use and overuse of diagnostic neck ultrasound in Ontario: Retrospective population-based cohort study.

OBJECTIVE: To provide an overview of the use and possible overuse of diagnostic neck ultrasound (DNUS) by describing and comparing both the ordering rates and the downstream results of DNUS by regions across Ontario. DESIGN: Retrospective population-based cohort study based on electronic health care data. SETTING: Ontario. PARTICIPANTS: Ontario residents (adults aged > 18 years) who had a diagnosis of thyroid cancer between October 1, 1999, and June 30, 2014, and residents who had a DNUS in 2012. MAIN OUTCOME MEASURES: Proportion of Ontario residents in each sub-Local Health Integration Network (LHIN) group who had their first DNUS in 2012 and went on to other relevant tests, diagnoses, and surgery. The sub-LHIN groups were based on increasing age- and sex-adjusted rates of first DNUS. RESULTS: There were 77 238 DNUS tests in 2012 and there was a 7.4-fold variation in the rate of test ordering across the sub-LHIN populations leading to variable rates of actual disease, suggesting screening or uncertain indications for tests. CONCLUSION: Across Ontario, the indications for ordering DNUS are variable, and screening or testing without indication might be a common practice. Establishing effective guidelines for the ordering of DNUS would potentially reduce costs and ultimately reduce the rates of thyroid cancer.

Inflammatory responses to a pathogenic West Nile virus strain.

BACKGROUND: West Nile virus (WNV) circulates across Australia and was referred to historically as Kunjin virus (WNVKUN). WNVKUN has been considered more benign than other WNV strains circulating globally. In 2011, a more virulent form of the virus emerged during an outbreak of equine arboviral disease in Australia. METHODS: To better understand the emergence of this virulent phenotype and the mechanism by which pathogenicity is manifested in its host, cells were infected with either the virulent strain (NSW2012), or less pathogenic historical isolates, and their innate immune responses compared by digital immune gene expression profiling. Two different cell systems were used: a neuroblastoma cell line (SK-N-SH cells) and neuronal cells derived from induced pluripotent stem cells (iPSCs). RESULTS: Significant innate immune gene induction was observed in both systems. The NSW2012 isolate induced higher gene expression of two genes (IL-8 and CCL2) when compared with cells infected with less pathogenic isolates. Pathway analysis of induced inflammation-associated genes also indicated generally higher activation in infected NSW2012 cells. However, this differential response was not paralleled in the neuronal cultures. CONCLUSION: NSW2012 may have unique genetic characteristics which contributed to the outbreak. The data herein is consistent with the possibility that the virulence of NSW2012 is underpinned by increased induction of inflammatory genes.

Explaining the Variation in Surgical Practice for Differentiated Thyroid Cancer in Ontario, Canada.

IMPORTANCE: In the management of differentiated thyroid cancer (DTC), the extent of surgical treatment required for most patients remains controversial and varies widely. This variation may be associated with the Enthusiasm Hypothesis, the notion that geographic differences in use of health care services are driven by the prevalence of physicians with a preference for particular services. OBJECTIVE: To evaluate the Enthusiasm Hypothesis and its applicability to the variation in the surgical treatment of thyroid cancer in Ontario, Canada. DESIGN, SETTING, AND PARTICIPANTS: This population-based study obtained electronic data on all health care-associated events for the complete population of insured residents of Ontario, Canada. Patients (n = 28 754) who were 18 years of age or older and underwent an initial therapeutic thyroid surgical procedure for a papillary or follicular carcinoma diagnosis between January 1, 2000, and December 31, 2015, were included. The final data analysis was performed January 31, 2019. EXPOSURES: Therapeutic thyroid cancer surgical procedure. MAIN OUTCOMES AND MEASURES: Numbers of surgeons, extent of surgical treatment, and case volumes in 14 geographic regions in Ontario. RESULTS: In total, 28 754 patients with DTC were included, of whom 22 600 (78.6%) were female, with a mean (SD) age of 49 (14) years. The use of total thyroidectomy for DTC varied widely across geographic regions of Ontario, from 45.8% to 77.1% of all cancer cases. More than 90% of the overall variation in practice (total thyroidectomy vs less-than-total thyroidectomy) could be explained by the practices of the high-volume surgeons (enthusiasts) in regions with the highest rates of thyroid cancer diagnosis. CONCLUSIONS AND RELEVANCE: The Enthusiasm Hypothesis appears to be consistent with the findings of this study. The practices of the high-volume surgeons who were enthusiastic for total thyroidectomy in the geographic regions with the highest rates of thyroid cancer diagnosis may account for the variation in practice across Ontario between 2000 and 2015.

Determinants of Zika virus host tropism uncovered by deep mutational scanning.

Arboviruses cycle between, and replicate in, both invertebrate and vertebrate hosts, which for Zika virus (ZIKV) involves Aedes mosquitoes and primates1. The viral determinants required for replication in such obligate hosts are under strong purifying selection during natural virus evolution, making it challenging to resolve which determinants are optimal for viral fitness in each host. Herein we describe a deep mutational scanning (DMS) strategy2-5 whereby a viral cDNA library was constructed containing all codon substitutions in the C-terminal 204 amino acids of ZIKV envelope protein (E). The cDNA library was transfected into C6/36 (Aedes) and Vero (primate) cells, with subsequent deep sequencing and computational analyses of recovered viruses showing that substitutions K316Q and S461G, or Q350L and T397S, conferred substantial replicative advantages in mosquito and primate cells, respectively. A 316Q/461G virus was constructed and shown to be replication-defective in mammalian cells due to severely compromised virus particle formation and secretion. The 316Q/461G virus was also highly attenuated in human brain organoids, and illustrated utility as a vaccine in mice. This approach can thus imitate evolutionary selection in a matter of days and identify amino acids key to the regulation of virus replication in specific host environments.

The addition of chemotherapy to radiotherapy did not reduce the rate of distant metastases in low-risk HPV-related oropharyngeal cancer in a real-world setting.

BACKGROUND: Distant metastases (DM) are a leading cause of death for patients with oropharyngeal cancer (OPSCC). The objective of this study was to compare the rates of DM after chemoradiotherapy (CRT) and radiotherapy alone (RT) in patients with human papillomavirus (HPV)-positive and HPV-negative OPSCC. METHOD: In a retrospective population-based study of 525 patients across Ontario, Canada, in 1998/99/03/04, we compared treatment effectiveness using cumulative incidence function curves and cause-specific Cox regression models. RESULTS: Sixty of 525 patients developed DM. There was no difference in rates (overall 10%-15%) between HPV-positive and HPV-negative patients or between CRT- and RT-treated patients. CRT reduced the risk of DM for the 15% of all HPV-positive patients with higher risk (T4 and/or N3) and not for HPV-negative patients (hazard ratio, 1.82 [0.65-5.07]). CONCLUSION: The addition of platin-based chemotherapy to conventional RT did not decrease the rates of DM in the majority of patients with HPV-positive or in HPV-negative OPSSC.

A Population-Based Study on NIFTP Incidence and Survival: Is NIFTP Really a "Benign" Disease?

BACKGROUND: This study aimed to determine the incidence of noninvasive follicular thyroid neoplasm with papillary-like features (NIFTP) in Ontario, Canada and the predictors of disease-free survival (DFS) by comparing patients with follicular variant papillary thyroid cancer (FVPTC) and patients with NIFTP. METHODS: This population-based retrospective cohort study included all patients who had definitive surgery for well-differentiated thyroid cancer (WDTC) in Ontario, Canada between 1990 and 2001 and were followed until 2014. A conservative decision rule was applied to subtype-select FVPTCs into NIFTPs after pathology report review. The primary outcome was DFS, for which Cox proportional hazard regression analysis was performed to assess the impact of FVPTC versus NIFTP. RESULTS: At pathology re-review of the 725 FVPTC cases, 318 were reclassified as potential NIFTP. The median follow-up time was 15.3 years for the entire cohort and 15.9 years for those alive at the last follow-up visit. Disease failure occurred for 109 patients, 79 (19.4%) in the FVPTC group and 30 (9.4%) in the NIFTP group (p < 0.01). This effect was sustained in the multivariable analysis, with FVPTC showing significantly worse DFS than NIFTP (hazard ratio, 1.84; 95% confidence interval, 1.17-2.89). After recategorization of certain FVPTCs into NIFTPs, the findings showed that NIFTP accounted for 16.8% (1.461/8.699 per 100,000) of all WDTCs. CONCLUSION: The disease failure rate for NIFTP was 9.4%. The NIFTP diagnosis is challenging for the pathologist and may make tumor behavior difficult to predict for this entity. Caution should be used in the management of patients with an NIFTP.

Does metformin usage improve survival in head and neck squamous cell carcinoma? A population-based study.

BACKGROUND: We sought to expand upon preliminary data suggesting that metformin confers a survival benefit to patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A large-scale retrospective cohort study of all patients in Ontario diagnosed with squamous cancer of the larynx, hypopharynx, and nasopharynx between Dec 1st 2007 to Dec 1st 2012 was undertaken. The Institute for Clinical and Evaluative Sciences was accessed to obtain patient demographic, treatment and outcome information. We included patients on metformin at the time of diagnosis. Kaplan Meier methods and Cox Regression models were used. RESULTS: Patients taking metformin at the time of diagnosis had a higher comorbid status but were otherwise similar to patients without metformin usage. Using multivariate analysis, neither overall survival nor disease specific survival was improved in patients on metformin (OS: HR 1.123, p = .338; DSS: HR 1.048, p = .792). CONCLUSIONS: No survival advantage was observed in patients with HNSCC taking metformin at the time of diagnosis.