Publications by authors named "David Goldstein"

1,175 Publications

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The impact of obesity on neuropathy outcomes for paclitaxel- and oxaliplatin-treated cancer survivors.

J Cancer Surviv 2021 Feb 27. Epub 2021 Feb 27.

Brain and Mind Centre, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW, 2050, Australia.

Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) is a major side effect of neurotoxic cancer treatment, often impacting treatment tolerability and patient functioning. Factors predicting an individual's vulnerability for developing CIPN remain ill-defined. However, patient characteristics may contribute to CIPN risk, with obesity being a prevalent patient comorbidity. This study was aimed at evaluate if being overweight (BMI ≥ 25 kg/m) was associated with worse symptomatic, clinical, and functional CIPN following neurotoxic cancer treatment.

Methods: Three hundred seventy-nine cancer survivors were assessed 5 (IQR 3-5) months post oxaliplatin or paclitaxel treatment via comprehensive patient-reported, clinical, and functional CIPN measures. Patients classified as overweight (BMI ≥ 25 kg/m) were compared to those within the normal BMI range (< 25 kg/m). Multilinear regression was conducted to evaluate the association between patient clinical factors and CIPN severity.

Results: Most patients reported CIPN symptoms (78%), with deficits evident on clinical examination. Overweight patients (n = 242, 63.8%) had significantly worse CIPN across symptomatic, objective clinical, and functional outcomes compared to those with a normal BMI (p < .05). In multivariate linear regression, older age (B = .088, 95%CI = .053-.122, p < .001), larger waist circumference (B = .030, 95%CI = .001-.059, p < .05), and larger BSA (B = 2.41, 95%CI = .34-04.48, p < .05) were associated with CIPN. Diabetes and BMI were significant on univariate analysis but not in the final models.

Conclusions: Overweight patients represent a large proportion of cancer survivors who may be particularly impacted by CIPN, requiring closer monitoring and referral to supportive services. Accessible data such as a patient's general and abdominal obesity status may aid in formulating personalized treatment.

Implications For Cancer Survivors: Identifying routinely measured patient characteristics which may contribute to an individual's CIPN risk profile could assist with informing treatment decisions.
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http://dx.doi.org/10.1007/s11764-021-01012-yDOI Listing
February 2021

Elective neck dissection versus positron emission tomography-computed tomography-guided management of the neck in clinically node-negative early oral cavity cancer: A cost-utility analysis.

Cancer 2021 Feb 26. Epub 2021 Feb 26.

Department of Otolaryngology-Head & Neck Surgery, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Background: In early oral cavity cancer, elective neck dissection (END) for the clinically node-negative (cN0) neck improves survival compared with observation. This paradigm has been challenged recently by the use of positron emission tomography-computed tomography (PET-CT) imaging in the cN0 neck. To inform this debate, we performed an economic evaluation comparing PET-CT-guided therapy with routine END in the cN0 neck.

Methods: Patients with T1-2N0 lateralized oral tongue cancer were analyzed. A Markov model over a 40-year time horizon simulated treatment, disease recurrence, and survival from a US health care payer perspective. Model parameters were derived from a review of the literature.

Results: The END strategy was dominant, with a cost savings of $1576.30 USD, an increase of 0.055 quality-adjusted life years (QALYs), a net monetary benefit of $4303 USD, and a 0.22 life-year advantage. END was sensitive to variation in cost and utilities in deterministic and probabilistic sensitivity analyses. PET-CT became the preferred strategy when decreasing occult nodal disease to 18% and increasing the negative predictive value (NPV) of PET-CT to 89% in 1-way sensitivity analyses. In probabilistic sensitivity analysis, assuming a cost effectiveness threshold of $50,000 USD/QALY, END was dominant in 64% of simulations and cost effective in 69.8%.

Conclusion: END is a cost-effective strategy compared with PET-CT in patients who have node-negative oral cancer. Although lower PET standardized uptake value thresholds would result in fewer false negatives and improved NPV, it is still uncertain that PET-CT would be cost effective, as this would likely result in more false positive tests.
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http://dx.doi.org/10.1002/cncr.33446DOI Listing
February 2021

Effect of age and gender in non-smokers with oral squamous cell carcinoma: Multi-institutional study.

Oral Oncol 2021 Feb 19;116:105210. Epub 2021 Feb 19.

Sydney Head and Neck Cancer Institute, Chris O'Brien Lifehouse, Camperdown, NSW, Australia; Sydney Medical School, Faculty of Medicine and Health Sciences, University of Sydney, Sydney, NSW, Australia; Royal Prince Alfred Institute of Academic Medicine, Sydney Local Health District, NSW, Australia.

Background: In developing countries, oral squamous cell carcinoma (OSCC) is predominantly a cancer affecting older males who smoke tobacco. In countries with effective public health strategies, smoking rates are declining rapidly. It is not clear if patients who develop OSCC without these traditional risk factors represent a clinically distinct cohort with different prognosis. A recent analysis found that elderly non-smoking females with OSCC had significantly worse prognosis, concluding that this was a distinct patient population with poorer survival. The primary aim of this study was to determine the effect of gender and age on prognosis in OSCC, and the interaction between these two variables.

Methods: Multinational multi-institutional data were collected from six sites. The primary outcome of interest was disease specific survival (DSS). Time to local, regional, and distant recurrence were investigated as secondary outcomes.

Results: 3379 patients with OSCC were included. Males had significantly worse DSS compared to females (HR 1.24, 95% CI 1.08-1.43, p = 0.003). Females <70 years of age had significantly better DSS compared to females ≥70 years of age (HR 0.69, 95% CI 0.51-0.94, p < 0.001) but elderly females had similar DSS to males, regardless of age. When age was divided into three groups, the middle-aged group (45-69 years) had a significantly better DSS compared to elderly patients (HR 0.87, 95%CI 0.78-0.96, p < 0.001), however younger patients had similar DSS to elderly patients. When the effect of age (young v middle v elderly) was compared in each gender, young and middle-aged females had the most favourable DSS (log-rank p < 0.001). Middle-aged females who smoked had a 10% survival advantage compared to middle-aged males that smoked at five years.

Conclusions: Age, gender, tumour subsite, and smoking status are important drivers of survival in OSCC. However, gender appears to be the most important predictor with young and middle-aged females having the most favourable prognosis.
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http://dx.doi.org/10.1016/j.oraloncology.2021.105210DOI Listing
February 2021

Evaluation of the Braden scale in predicting surgical outcomes in older patients undergoing major head and neck surgery.

Laryngoscope Investig Otolaryngol 2021 Feb 9;6(1):103-108. Epub 2020 Dec 9.

Department of Otolaryngology Head and Neck Surgery/Surgical Oncology University Health Network, Princess Margaret Cancer Center, University of Toronto Toronto Ontario Canada.

Background: Being able to predict negative postoperative outcomes is important for helping select patients for treatment as well for informed decision-making by patients. Frailty measures are often time and resource intensive to use as screening measures, whereas the Braden scale, a commonly used measure to assess patients at risk of developing pressure ulcers after surgery, may be a potential tool to predict postoperative complication rates and longer length of stay (LOS) in patients undergoing major head and neck cancer surgery.

Methods: A retrospective analysis of Braden scale scores was performed on a prospectively collected cohort of patients undergoing major head and neck surgery recruited between December 2011 and April 2014. The association of Braden scale score with the primary outcomes of complications and LOS was analyzed using logistic regression and linear regression models on univariate analysis (UVA), respectively. Multivariate analysis (MVA) was performed based on a backward stepwise selection algorithm.

Results: There were 232 patients with a mean (SD) Braden scale score of 14.9 (2.8) with a range from 9 to 23. The Braden scale (β = -.07 per point; 95% CI -0.09, -0.04,  < .001) was an independent predictor of increased LOS on UVA, but not on MVA when adjusted for other variables. For overall complications, as well as type of complication, the Braden scale score was not a significant predictor of complications on either UVA or MVA.

Conclusion: In the sample population, the Braden scale did not demonstrate an ability to predict negative outcomes in head and neck surgery patients.

Level Of Evidence: Level 2b individual cohort study.
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http://dx.doi.org/10.1002/lio2.491DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883615PMC
February 2021

Head and neck imaging surveillance strategy for HPV-positive oropharyngeal carcinoma following definitive (chemo)radiotherapy.

Radiother Oncol 2021 Feb 16;157:255-262. Epub 2021 Feb 16.

Department of Medical Imaging, University of Toronto, Canada; Department of Medical Imaging, Princess Margaret Cancer Centre, University of Toronto, Canada.

Purpose: To describe the utilization pattern of head and neck (HN) surveillance imaging and explore the optimal strategy for radiologic "residual" lymph node (LN) surveillance following definitive (chemo)radiotherapy (RT/CRT) in human papillomavirus (HPV)+ oropharyngeal carcinoma (OPC).

Methods: All HPV+ OPC patients who completed RT/CRT from 2012 to 2015 were included. Schedule and rationale for post-treatment HN-CT/MRI were recorded. Imaging findings and oncologic outcomes were evaluated.

Results: A total of 1036 scans in 412 patients were reviewed: 414 scans for first post-treatment response assessment and 622 scans for the following reasons: follow-up of radiologic "residual" LN(s) (293 scans/175 patients); local symptoms (227/146); other (17/16); unknown (85/66). Rate of scans with "unstated" reason varied significantly among clinicians (3-28%, p < 0.001) and none of them yielded any positive imaging findings. First post-treatment scans identified 192 (47%) patients with radiologic "residual" LNs. Neck dissection (ND) was performed in 28 patients: 16 immediately (6/16 positive), 10 after one follow-up scan (2/10 positive), and 2 after 2nd follow-up scan (1/2 positive). Thirty patients had >2 consecutive follow-up scans at 2-3-month intervals, and none showed subsequent imaging progression or regional failure.

Conclusions: Pattern of HN imaging utilization for surveillance varied significantly among clinicians. Imaging surveillance reduces the need for ND. However, routine HN-CT/MR surveillance without clinical symptoms/signs does not demonstrate proven value in identifying locoregional failure or toxicity. Radiologic "residual" LNs without adverse features are common. If two subsequent follow-up scans demonstrate stable/regressing radiologic "residual" LNs, clinical surveillance without further imaging appears to be safe in this population.
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http://dx.doi.org/10.1016/j.radonc.2021.02.005DOI Listing
February 2021

Genome sequencing analysis identifies new loci associated with Lewy body dementia and provides insights into its genetic architecture.

Authors:
Ruth Chia Marya S Sabir Sara Bandres-Ciga Sara Saez-Atienzar Regina H Reynolds Emil Gustavsson Ronald L Walton Sarah Ahmed Coralie Viollet Jinhui Ding Mary B Makarious Monica Diez-Fairen Makayla K Portley Zalak Shah Yevgeniya Abramzon Dena G Hernandez Cornelis Blauwendraat David J Stone John Eicher Laura Parkkinen Olaf Ansorge Lorraine Clark Lawrence S Honig Karen Marder Afina Lemstra Peter St George-Hyslop Elisabet Londos Kevin Morgan Tammaryn Lashley Thomas T Warner Zane Jaunmuktane Douglas Galasko Isabel Santana Pentti J Tienari Liisa Myllykangas Minna Oinas Nigel J Cairns John C Morris Glenda M Halliday Vivianna M Van Deerlin John Q Trojanowski Maurizio Grassano Andrea Calvo Gabriele Mora Antonio Canosa Gianluca Floris Ryan C Bohannan Francesca Brett Ziv Gan-Or Joshua T Geiger Anni Moore Patrick May Rejko Krüger David S Goldstein Grisel Lopez Nahid Tayebi Ellen Sidransky Lucy Norcliffe-Kaufmann Jose-Alberto Palma Horacio Kaufmann Vikram G Shakkottai Matthew Perkins Kathy L Newell Thomas Gasser Claudia Schulte Francesco Landi Erika Salvi Daniele Cusi Eliezer Masliah Ronald C Kim Chad A Caraway Edwin S Monuki Maura Brunetti Ted M Dawson Liana S Rosenthal Marilyn S Albert Olga Pletnikova Juan C Troncoso Margaret E Flanagan Qinwen Mao Eileen H Bigio Eloy Rodríguez-Rodríguez Jon Infante Carmen Lage Isabel González-Aramburu Pascual Sanchez-Juan Bernardino Ghetti Julia Keith Sandra E Black Mario Masellis Ekaterina Rogaeva Charles Duyckaerts Alexis Brice Suzanne Lesage Georgia Xiromerisiou Matthew J Barrett Bension S Tilley Steve Gentleman Giancarlo Logroscino Geidy E Serrano Thomas G Beach Ian G McKeith Alan J Thomas Johannes Attems Christopher M Morris Laura Palmer Seth Love Claire Troakes Safa Al-Sarraj Angela K Hodges Dag Aarsland Gregory Klein Scott M Kaiser Randy Woltjer Pau Pastor Lynn M Bekris James B Leverenz Lilah M Besser Amanda Kuzma Alan E Renton Alison Goate David A Bennett Clemens R Scherzer Huw R Morris Raffaele Ferrari Diego Albani Stuart Pickering-Brown Kelley Faber Walter A Kukull Estrella Morenas-Rodriguez Alberto Lleó Juan Fortea Daniel Alcolea Jordi Clarimon Mike A Nalls Luigi Ferrucci Susan M Resnick Toshiko Tanaka Tatiana M Foroud Neill R Graff-Radford Zbigniew K Wszolek Tanis Ferman Bradley F Boeve John A Hardy Eric J Topol Ali Torkamani Andrew B Singleton Mina Ryten Dennis W Dickson Adriano Chiò Owen A Ross J Raphael Gibbs Clifton L Dalgard Bryan J Traynor Sonja W Scholz

Nat Genet 2021 Feb 15. Epub 2021 Feb 15.

Neurodegenerative Diseases Research Unit, Laboratory of Neurogenetics, National Institute of Neurological Disorders and Stroke, Bethesda, MD, USA.

The genetic basis of Lewy body dementia (LBD) is not well understood. Here, we performed whole-genome sequencing in large cohorts of LBD cases and neurologically healthy controls to study the genetic architecture of this understudied form of dementia, and to generate a resource for the scientific community. Genome-wide association analysis identified five independent risk loci, whereas genome-wide gene-aggregation tests implicated mutations in the gene GBA. Genetic risk scores demonstrate that LBD shares risk profiles and pathways with Alzheimer's disease and Parkinson's disease, providing a deeper molecular understanding of the complex genetic architecture of this age-related neurodegenerative condition.
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http://dx.doi.org/10.1038/s41588-021-00785-3DOI Listing
February 2021

Hemoglobin, Body Mass Index, and Age as Risk Factors for Paclitaxel- and Oxaliplatin-Induced Peripheral Neuropathy.

JAMA Netw Open 2021 Feb 1;4(2):e2036695. Epub 2021 Feb 1.

Prince of Wales Clinical School, UNSW Medicine, University of New South Wales Sydney, Sydney, Australia.

Importance: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating adverse effect of neurotoxic cancer treatments including taxanes and platinum agents. Limited knowledge exists of potential prechemotherapy factors associated with CIPN development.

Objective: To identify the association of pretreatment blood-based and clinical factors with CIPN persistence in patients who received paclitaxel or oxaliplatin.

Design, Setting, And Participants: This cohort study assessed pretreatment blood-based clinical factors and demographic characteristics of 333 patients treated with paclitaxel and oxaliplatin chemotherapy at urban multicenter cancer clinics and academic institutions in Australia between September 2015 and February 2020. Comprehensive neuropathy assessments were undertaken 3 to 12 months posttreatment. Posttreatment CIPN severity was compared with blood-based factors within 30 days prior to commencing chemotherapy. Data were analyzed between March and December 2020.

Exposures: Paclitaxel or oxaliplatin chemotherapy.

Main Outcomes And Measures: CIPN was measured using composite neurological grading scales, nerve conduction studies, and assessments of fine motor skills (grooved pegboard test), sensory function (grating orientation test and 2-point discrimination), and patient-reported outcomes. Independent samples t tests and Mann-Whitney U tests with post hoc Bonferroni correction were used to compare CIPN between patients according to blood-based factor normative ranges. Linear regression was used to identify blood-based and clinical associations with CIPN development.

Results: The study included 333 participants (266 [79.9%] women; median [interquartile range] age, 58 [18] years) who were consecutively recruited and referred (228 treated with paclitaxel, 105 treated with oxaliplatin; 138 [41.4%] with breast cancer, 83 [24.9%] with colorectal cancer). Most participants had grade 1 CIPN or higher (238 [71.5%] participants). Participants with low hemoglobin pretreatment had worse CIPN posttreatment (median [IQR] composite neurological grading scale score, 5 [2-8] vs 4 [1-6]; P = .002; grooved pegboard mean [SD] time, 84.2 [28.7] vs 72.9 [21.1] seconds; P = .002; grating orientation task, 4.8 [2.8] vs 3.9 [1.8] mm; P = .03; 2-point discrimination, 45% vs 28%; P = .01), with no other impairments outside normative ranges associated with CIPN. In the multivariable model, several factors were associated with worse CIPN (F4,315 = 18.6; P < .001; r2 = .19) including for lower hemoglobin (β = -0.47; 95% CI, -0.73 to -0.21; P < .001), higher body mass index (β = 0.08; 95% CI, 0.02 to 0.12; P = .007), older age (β = 0.08; 95% CI, 0.06 to 0.11; P < .001), and female sex (β = -1.08; 95% CI, -1.76 to -0.16; P = .01).

Conclusions And Relevance: The results of this cohort study suggest that participants with low pretreatment hemoglobin, higher body mass index, older age, and female sex were more likely to develop paclitaxel- or oxaliplatin-induced CIPN posttreatment. Future research should investigate prospectively whether these risk factors are associated with a higher incidence of CIPN development.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.36695DOI Listing
February 2021

Association of the Implementation of a Standardized Thyroid Ultrasonography Reporting Program With Documentation of Nodule Characteristics.

JAMA Otolaryngol Head Neck Surg 2021 Feb 11. Epub 2021 Feb 11.

Department of Otolaryngology-Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada.

Importance: Although most thyroid nodules are benign, the potential for malignant neoplasms is associated with unnecessary workup in the form of imaging, fine-needle aspiration, and diagnostic surgery. The American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) is commonly used to assess the malignant neoplasm risk potential of thyroid nodules imaged by ultrasonography. However, standardized reporting of ACR TI-RADS descriptors is inconsistent.

Objective: To increase the documentation rate of ACR TI-RADS thyroid nodule characteristics to 80% in 18 months.

Design, Setting, And Participants: This prospective interrupted time series quality improvement study was conducted from December 1, 2018, to March 31, 2020, at a tertiary outpatient head and neck clinic among 229 patients who had at least 1 documented thyroid nodule identified on bedside clinic ultrasonography. Data analysis was performed throughout the entire study period because this was a quality improvement study with iterative small cycle changes; final analysis of the data was performed in April 2020.

Main Outcomes And Measures: The primary outcome was the documentation rates of 6 ACR TI-RADS ultrasonographic descriptors. Secondary outcomes included nodule fine-needle aspiration biopsy rate and physician-reported clinic flow efficiency.

Results: A total of 229 patients had at least 1 documented thyroid nodule and were included in the analysis. Size was the most frequently documented nodule characteristic (72 of 74 [97.3%]) at baseline, followed by echogenic foci (31 of 74 [41.9%]), composition (23 of 74 [31.1%]), echogenicity (17 of 74 [23.0%]), margin (6 of 74 [8.1%]), and shape (1 of 74 [1.4%]). After 3 Plan, Do, Study, Act (PDSA) cycles, the final intervention consisted of a standardized ultrasonography reporting form and educational initiatives for surgical trainees. After the third PDSA cycle (n = 36), reporting of nodule size, echogenic foci, and composition increased to 100%. Similarly, reporting of echogenicity (34 of 36 [94.4%]), shape (28 of 36 [77.8%]), and margin (25 of 36 [69.4%]) all increased. This represented a cumulative 90.3% documentation rate (195 of 216), a 56.5% increase from baseline (95% CI, 50.0%-61.9%). The standardized reporting form was used in 83.3% of eligible thyroid ultrasonography cases (30 of 36) after PDSA cycle 3, demonstrating good fidelity of implementation. There were no unintended consequences associated with clinic workflow, as a balancing measure, reported by staff surgeons.

Conclusions And Relevance: This study suggests that implementation of an ACR TI-RADS-based reporting form in conjunction with educational initiatives improved documentation of ultrasonographic thyroid nodule characteristics, potentially allowing for improved bedside risk stratification and communication among clinicians.
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http://dx.doi.org/10.1001/jamaoto.2020.5233DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7879387PMC
February 2021

Investigation of Relation of Radiation Therapy Quality With Toxicity and Survival in LAP07 Phase 3 Trial for Locally Advanced Pancreatic Carcinoma.

Int J Radiat Oncol Biol Phys 2021 Feb 6. Epub 2021 Feb 6.

Department of Radiation Oncology, Tenon Hospital, Institut Universitaire du Cancer, AP-HP.Sorbonne Université, Paris, France. Electronic address:

Purpose: The XXXXX multicenter randomized study assessed whether chemoradiotherapy (CRT) increases overall survival (OS) versus continuation chemotherapy in patients whose locally advanced pancreatic cancer (LAPC) was controlled after 4 months of induction chemotherapy. This analysis investigated whether failure to adhere to radiation therapy (RT) guidelines influenced survival and toxicity.

Methods And Materials: This is a planned analysis of secondary objectives in the framework of a randomized international phase III trial. The protocol included detailed written RT guidelines. All participating institutions undertook an initial benchmark case to check adherence to protocol guidelines. Centers with major deviation were not allowed to include patients until they achieved a significant improvement and rigorously followed the guidelines. On-trial RT quality assurance (RTQA) consisted of a central review of treatment plan with dose-volume histograms for each patient. Adherence to guidelines was graded as per protocol (PP), minor deviation (MiD), or major deviation (MaD).

Results: Fifty-seven benchmark cases were evaluated, 26% were classified as PP, 60% MiD, and 14% MaD. Among the 442 included patients, 133 patients were randomized in the CRT arm and 117 were assessable for RT quality analysis. RT quality was graded as PP in 38.5% of patients, MiD in 43.6% of patients, and MaD in 17.9% of patients. Most frequent protocol violations were dose distribution heterogeneities. Median overall survival was 17 months with PP and MiD versus 13.4 months with MaD (HR 1.63; [95% CI, 0.99-2.71]; P=.055). There was no difference in terms of progression free survival (HR: 1.09 [95% CI ; 0.66-1.8] p=0.72). Patients with MaD had more nausea than patients treated PP or with MiD (P=0.0045).

Conclusions: MaD was associated with a trend for worst survival. There was no difference in terms of progression free survival. Due to the low rate of major deviations, their impact on the XXX trial results may be negligeable.
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http://dx.doi.org/10.1016/j.ijrobp.2021.01.055DOI Listing
February 2021

Young age is not a predictor of disease specific survival in oral cancer: A multi-institutional study.

Oral Oncol 2021 Feb 3;115:105162. Epub 2021 Feb 3.

Sydney Head and Neck Cancer Institute, Department of Head and Neck Surgery, Chris O'Brien Lifehouse, Camperdown, NSW, Australia; Sydney Medical School, Faculty of Medicine and Health Sciences, The University of Sydney, NSW, Australia; Royal Prince Alfred Institute of Academic Surgery, Sydney Local Health District, NSW, Australia. Electronic address:

Background: Over the last few decades evidence has accumulated for increasing incidence of oral cavity squamous cell carcinoma (OSCC) in a younger cohort. Prior studies examining the effect of age at diagnosis on prognosis have produced conflicting data.

Methods: A multi-institutional cohort study was performed across 6 different sites in Australia, Canada, India and Singapore. Disease-free (DFS), overall (OS) and disease-specific (DSS) survival were analysed. The association of the number of adverse features with survival outcomes was investigated.

Results: From 3179 patients, age was a significant predictor of OS with patients older than 45 years having a 66% increased risk of death (HR 1.66, 95%CI 1.33 - 2.07, p < 0.001). The number of adverse features was a significant predictor of OS with 3 or more adverse features having a 199% increased risk (HR 2.99, 95%CI 2.61-3.43. p < 0.001). The estimate effect was greater in patients ≤ 45 years (HR 3.49 vs HR 2.81). Age was not a significant predictor of DSS with similar rates of death from OSCC in multivariable models. The number of adverse features was a significant predictor of DFS with ≥ 3 adverse features having a 140% increased risk of death. The number of adverse features was a significant predictor of DSS with ≥ 3 adverse features having a 230% increased risk of disease specific death.

Conclusions: Age is not an independent predictor of disease specific mortality in OSCC. Differences in outcomes are due to the confounding effect of adverse clinicopathological features and the ability to tolerate surgery and adjuvant therapy.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105162DOI Listing
February 2021

Predictive value of neutrophils count for local tumor control after chemoradiotherapy in patients with locally advanced pancreatic carcinoma.

Int J Radiat Oncol Biol Phys 2021 Feb 3. Epub 2021 Feb 3.

Service d'Oncologie Radiothérapie, Hôpital Tenon, Paris, France; GERCOR (Groupe Coopérateur Multidisciplinaire en Oncologie), Paris, France.

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http://dx.doi.org/10.1016/j.ijrobp.2021.01.052DOI Listing
February 2021

Comparing unilateral vs. bilateral neck management in lateralized oropharyngeal cancer between surgical and radiation oncologists: An international practice pattern survey.

Oral Oncol 2021 Mar 30;114:105165. Epub 2021 Jan 30.

Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Canada.

Background: Management of the neck in oropharyngeal carcinoma varies due to a lack of clarity of patterns of lymphatic drainage and concern of failure in the contralateral neck. With recent advances in transoral surgical techniques, surgical management has become increasingly prevalent as the primary treatment modality. We compare international practice patterns between surgical and radiation oncologists.

Methods: A survey of neck management practice patterns was developed and pilot tested by 6 experts. The survey comprised items eliciting the nature of clinical practice, as well as patterns of neck management depending on extent of nodal disease and location and extent of primary site disease. Proportions of surgical and radiation oncologists treating the neck bilaterally were compared using the chi-squared statistic.

Results: Two-hundred and twenty-two responses were received from 172 surgical oncologists, 44 radiation oncologists, 3 medical oncologists, and 3 non-oncologists from 32 different countries. For tongue base cancers within 1 cm of midline (67% vs. 100%, p < 0.001), and for tonsil cancers with extension to the medial 1/3 of the soft palate (65% vs. 100%, p < 0.001) or tongue base (77% vs. 100%, p < 0.001), surgical oncologists were less likely to treat the neck bilaterally. For isolated tonsil fossa cancers with no nodal disease, both surgical and radiation oncologists were similarly likely to treat unilaterally (99% vs. 97%, p = NS). However, with increasing nodal burden, radiation oncologists were more likely to treat bilaterally for scenarios with a single node < 3 cm (15% vs. 2%, p < 0.001), a single node with extranodal extension (41% vs. 18%, p < 0.001), multiple positive nodes (55% vs. 23% p < 0.001), and node(s) > 6 cm (86% vs. 33%, p < 0.001). For tumors with midline extension, even with a negative PET in the contralateral neck, the majority of surgical and radiation oncologists would still treat the neck bilaterally (53% and 84% respectively).

Conclusions: The present study demonstrates significant practice pattern variability for management of the neck in patients with lateralized oropharyngeal carcinoma. Surgical oncologists are less likely to treat the neck bilaterally, regardless of tumor location or nodal burden. Even in the absence of disease in the contralateral neck on imaging, them majority of practitioners are likely to treat bilaterally when the disease approaches midline.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105165DOI Listing
March 2021

Weekly Paclitaxel-Induced Neurotoxicity in Breast Cancer: Outcomes and Dose Response.

Oncologist 2021 Feb 1. Epub 2021 Feb 1.

Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.

Background: Paclitaxel treatment produces significant peripheral neuropathy, but the time course of neuropathy development and outcomes are unclear. Dose reduction is the only strategy to prevent neurotoxicity, however, the impact of dose-reduction on neuropathy outcomes remains unknown. This study aimed to prospectively evaluated neuropathy development from weekly paclitaxel treatment and evaluate the impact of dose-reduction on post-treatment neuropathy outcomes.

Patients And Methods: Breast cancer patients receiving paclitaxel (80mg/m ) weekly for 12-weeks were prospectively assessed using patient reported (Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity; FACTGOG-Ntx), clinical (Total Neuropathy Score clinical version; TNSc) and neurophysiological measures up to 12-months post completion. The impact of dose-reduction on post-treatment (3.6 ± 0.1 months) clinical and patient reported outcomes was evaluated in 105 weekly paclitaxel-treated patients.

Results: Significant neuropathy was present by 6-weeks across patient-reported, clinical, and objective neurophysiological assessments, increasing in prevalence and severity over the treatment course. Limited recovery occurred, with significant neuropathy being maintained up to 12 months (p < .05). Patients who received dose reduction had worse patient reported (FACT-GOG-Ntx: 40.2 ± .1.4) and clinical neuropathy outcomes (TNSc: 4.3 ± 0.4) compared to those who received the full dose (FACT-GOG-Ntx: 45.9 ± 0.9; TNSc: 3.3 ± 0.3, p < .05). Patients who ceased treatment early demonstrated the worse deficits (TNSc: 5.0 ± 0.6; FACT-GOG-Ntx: 37.3 ± 2.7) compared to those who received the complete dose (TNSc: 3.5 ± 0.3; FACT-GOG-Ntx: 45.3 ± 0.9, p < .05).

Conclusions: Weekly paclitaxel produces symptomatic and objective neuropathy early in the treatment course which can persist. Dose reduction does not necessarily lead to more favorable neuropathy outcomes, with individual risk factors likely important in addition to cumulative dose.

Implications For Practice: Weekly paclitaxel schedules are extensively used in breast cancer. Patients may develop symptomatic and objective neuropathy early in the treatment course, with these individuals requiring closer monitoring. Furthermore, neuropathy is a long-term sequela that may impact quality of life and require appropriate supportive services. Results suggest that dose reduction does not necessarily lead to better neuropathy outcomes. Understanding schedule-specific toxicity and risk factors for neuropathy will be critical to determining individualized treatment strategies and improving quality of life in breast cancer survivors.
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http://dx.doi.org/10.1002/onco.13697DOI Listing
February 2021

A Cross-Sectional Study of Sub-Basal Corneal Nerve Reduction Following Neurotoxic Chemotherapy.

Transl Vis Sci Technol 2021 Jan 12;10(1):24. Epub 2021 Jan 12.

School of Optometry & Vision Science, University of New South Wales, Sydney, Australia.

Purpose: Sub-basal corneal nerves have been shown to change during neurotoxic chemotherapy treatment. This cross-sectional study investigated corneal nerve morphology in patients who have completed neurotoxic chemotherapy well after treatment cessation and its association with peripheral nerve function.

Methods: Central corneal nerve fiber length (CNFL) and inferior whorl length (IWL), average nerve fiber length (ANFL), corneal nerve fiber density (CNFD) and corneal nerve branch density (CNBD), and nerve fiber area (CNFA) were examined using in vivo corneal confocal microscopy in patients with cancer who had completed treatment with either paclitaxel or oxaliplatin between 3 and 24 months prior to assessment in comparison with 2 separate groups of healthy controls. Neurological assessments were conducted including clinician- and patient-reported outcomes, and neurological grading scales.

Results: Both paclitaxel- ( = 40) and oxaliplatin-treated ( = 30) groups had reduced IWL and ANFL compared to the respective healthy control groups ( = 15 in each group) (paclitaxel: IWL = = 0.02, ANFL = = 0.009; and oxaliplatin: IWL = = 0.008, ANFL = 0.02). CNFL and CNFD reduction were observed only in the paclitaxel-treated group compared with healthy controls ( = 0.008 and = 0.02, respectively), whereas CNFA was reduced in the oxaliplatin-treated group ( = 0.04). IWL reduction correlated with worse fine hand dexterity in chemotherapy-treated patients ( = -0.33, = 0.007).

Conclusions: There is evidence of corneal nerve loss in patients with cancer who have been treated with paclitaxel and oxaliplatin well after treatment cessation associated with worse upper limb function.

Translational Relevance: Sub-basal corneal nerve reduction is evident even after cessation of neurotoxic treatment. In vivo corneal confocal microscopy may be useful in the monitoring of nerve function in patients receiving chemotherapy.
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http://dx.doi.org/10.1167/tvst.10.1.24DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7804570PMC
January 2021

De novo TRIM8 variants impair its protein localization to nuclear bodies and cause developmental delay, epilepsy, and focal segmental glomerulosclerosis.

Am J Hum Genet 2021 02 27;108(2):357-367. Epub 2021 Jan 27.

Division of Nephrology, Columbia University, New York, NY 10032, USA. Electronic address:

Focal segmental glomerulosclerosis (FSGS) is the main pathology underlying steroid-resistant nephrotic syndrome (SRNS) and a leading cause of chronic kidney disease. Monogenic forms of pediatric SRNS are predominantly caused by recessive mutations, while the contribution of de novo variants (DNVs) to this trait is poorly understood. Using exome sequencing (ES) in a proband with FSGS/SRNS, developmental delay, and epilepsy, we discovered a nonsense DNV in TRIM8, which encodes the E3 ubiquitin ligase tripartite motif containing 8. To establish whether TRIM8 variants represent a cause of FSGS, we aggregated exome/genome-sequencing data for 2,501 pediatric FSGS/SRNS-affected individuals and 48,556 control subjects, detecting eight heterozygous TRIM8 truncating variants in affected subjects but none in control subjects (p = 3.28 × 10). In all six cases with available parental DNA, we demonstrated de novo inheritance (p = 2.21 × 10). Reverse phenotyping revealed neurodevelopmental disease in all eight families. We next analyzed ES from 9,067 individuals with epilepsy, yielding three additional families with truncating TRIM8 variants. Clinical review revealed FSGS in all. All TRIM8 variants cause protein truncation clustering within the last exon between residues 390 and 487 of the 551 amino acid protein, indicating a correlation between this syndrome and loss of the TRIM8 C-terminal region. Wild-type TRIM8 overexpressed in immortalized human podocytes and neuronal cells localized to nuclear bodies, while constructs harboring patient-specific variants mislocalized diffusely to the nucleoplasm. Co-localization studies demonstrated that Gemini and Cajal bodies frequently abut a TRIM8 nuclear body. Truncating TRIM8 DNVs cause a neuro-renal syndrome via aberrant TRIM8 localization, implicating nuclear bodies in FSGS and developmental brain disease.
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http://dx.doi.org/10.1016/j.ajhg.2021.01.008DOI Listing
February 2021

Overdose Receiving Centers - An Idea Whose Time Has Come?

Prehosp Emerg Care 2021 Feb 2:1-4. Epub 2021 Feb 2.

Drug overdose deaths have been the leading cause of accidental death in the United States with two thirds involving opioids. Strong evidence supports the efficacy of medications for addiction treatment such as buprenorphine and harm reduction strategies such as naloxone distribution. While emergency medical service (EMS) systems have defined specialty centers for the treatment of many significant life threatening disease (trauma, stroke, myocardial infarction) implementation of opioid use disorder systems of care that integrate EMS are uncommon. As fentanyl drives the third wave of the opioid epidemic, EMS systems are uniquely positioned to direct patients to hospitals that can provide the best care for patients with Opiate Use Disorder (OUD.) Emergency Departments which have established systems for early intervention and treatment for patients with opioid use disorders have shown higher engagement in treatment programs. This, in turn, leads to lower mortality. EMS systems which designate specialty centers for overdose patients may show a public health mortality benefit.
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http://dx.doi.org/10.1080/10903127.2020.1864073DOI Listing
February 2021

Decision-making in Surgery or Active Surveillance for Low Risk Papillary Thyroid Cancer During the COVID-19 Pandemic.

Cancers (Basel) 2021 Jan 20;13(3). Epub 2021 Jan 20.

Princess Margaret Cancer Centre, Department of Otolaryngology-Head and Neck Surgery/Surgical Oncology, University Health Network and University of Toronto, Toronto, ON M5G 2C4, Canada.

We describe our experience conducting a prospective observational cohort study on the management of small, low risk papillary thyroid cancer during the COVID-19 pandemic. Our study participants are given the choice of active surveillance (AS) or surgery, and those in the AS arm are followed at the study center, whereas surgical patients undergo usual care. During the pandemic we have transitioned from in-person research patient visits to largely virtual care of patients under AS. As of 30 October 2020, we had enrolled 181 patients enrolled in our study (including 25 during the pandemic), of which 92.3% (167/181) consented to telephone communication and 79.0% (143/181) consented to secure videoconferencing communication. Prior to the pandemic, 74.5% (117/157) of our patients chose AS over surgery, whereas during the pandemic, 96.0% (24/25) chose AS. Of the 133 study patients who were under AS within the timeframe from 12 March 2020, to 30 October 2020, the percentage of patients who missed appointments was 8.3% (11/133, for neck ultrasound and physician visits, respectively) and delayed appointments was 23.3% (31/133). This preliminary data suggests that prospective observational research on AS of thyroid cancer can safely continue during the pandemic.
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http://dx.doi.org/10.3390/cancers13030371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7864172PMC
January 2021

Ex vivo culture of intact human patient derived pancreatic tumour tissue.

Sci Rep 2021 Jan 21;11(1):1944. Epub 2021 Jan 21.

Pancreatic Cancer Translational Research Group, School of Medical Sciences, Lowy Cancer Research Centre, UNSW Sydney, Sydney, NSW, Australia.

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is attributed to the highly fibrotic stroma and complex multi-cellular microenvironment that is difficult to fully recapitulate in pre-clinical models. To fast-track translation of therapies and to inform personalised medicine, we aimed to develop a whole-tissue ex vivo explant model that maintains viability, 3D multicellular architecture, and microenvironmental cues of human pancreatic tumours. Patient-derived surgically-resected PDAC tissue was cut into 1-2 mm explants and cultured on gelatin sponges for 12 days. Immunohistochemistry revealed that human PDAC explants were viable for 12 days and maintained their original tumour, stromal and extracellular matrix architecture. As proof-of-principle, human PDAC explants were treated with Abraxane and we observed different levels of response between patients. PDAC explants were also transfected with polymeric nanoparticles + Cy5-siRNA and we observed abundant cytoplasmic distribution of Cy5-siRNA throughout the PDAC explants. Overall, our novel model retains the 3D architecture of human PDAC and has advantages over standard organoids: presence of functional multi-cellular stroma and fibrosis, and no tissue manipulation, digestion, or artificial propagation of organoids. This provides unprecedented opportunity to study PDAC biology including tumour-stromal interactions and rapidly assess therapeutic response to drive personalised treatment.
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http://dx.doi.org/10.1038/s41598-021-81299-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820421PMC
January 2021

A cross-sectional study of ocular surface discomfort and corneal nerve dysfunction after paclitaxel treatment for cancer.

Sci Rep 2021 Jan 19;11(1):1786. Epub 2021 Jan 19.

School of Optometry and Vision Science, University of New South Wales Sydney, Sydney, Australia.

Ocular surface dysfunction is common in patients receiving anti-cancer drug treatment. The effects of paclitaxel, a neurotoxic chemotherapeutic drug, on ocular surface discomfort associated with dry eye disease was investigated. Patients with cancer who had completed paclitaxel treatment between 3 and 24 months prior to assessment (n = 29) and age- and sex-matched healthy control subjects (n = 29) were recruited and assessed with the Ocular Surface Disease Index (OSDI) to measure ocular surface discomfort. In-vivo corneal confocal microscopy was used to evaluate corneal nerve parameters in the right eye. Peripheral neurotoxicity was assessed using patient-reported outcomes and clinical grading scales. The paclitaxel group had significantly worse OSDI total scores compared with controls (Median, Md = 19.3 and Md = 0, p = 0.007, respectively). Corneal nerve fiber and inferior whorl lengths were reduced in the paclitaxel group compared with controls (14.2 ± 4.0 and 14.4 ± 4.0 mm/mm vs. 16.4 ± 4.0 and 16.9 ± 4.9 mm/mm, respectively, p = 0.04). When analyzed by presence of peripheral neuropathy, paclitaxel-treated patients with neuropathy showed worse OSDI total scores compared to those without peripheral neuropathy post-treatment (p = 0.001) and healthy controls (p < 0.001). More severe ocular discomfort and worse visual function was associated with greater peripheral neurotoxicity symptoms (r = 0.60, p = 0.001) and neuropathy severity (r = 0.49, p = 0.008), respectively. Patients who have been treated with paclitaxel have a higher risk of ocular surface discomfort associated with dry eye disease, particularly those with peripheral neuropathy. Future longitudinal studies should investigate the clinical impact of corneal nerve reduction in dry eye disease.
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http://dx.doi.org/10.1038/s41598-021-81398-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815840PMC
January 2021

Cases in Precision Medicine: Genetic Testing to Predict Future Risk for Disease in a Healthy Patient.

Ann Intern Med 2021 Jan 19. Epub 2021 Jan 19.

Columbia University Irving Medical Center, New York, New York (H.M.R., A.G.G.).

Genetic testing is performed more routinely in clinical practice, and direct-to-consumer tests are widely available. It has obvious appeal as a preventive health measure. Clinicians and their healthy patients increasingly inquire about genetic testing as a tool for predicting diseases, such as cancer, heart disease, or dementia. Despite demonstrated utility for diagnosis in the setting of many diseases, genetic testing still has many limitations as a predictive tool for healthy persons. This article uses a hypothetical case to review key considerations for predictive genetic testing.
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http://dx.doi.org/10.7326/M20-5713DOI Listing
January 2021

Metabolic and lifestyle risk factors for chemotherapy-induced peripheral neuropathy in taxane and platinum-treated patients: a systematic review.

J Cancer Surviv 2021 Jan 12. Epub 2021 Jan 12.

Brain and Mind Centre, Faculty of Medicine and Health, University of Sydney, Sydney, Australia.

Purpose: Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common dose-limiting toxicity of cancer treatment causing functional impairment and impacting quality of life. Effective prevention and treatment of CIPN are lacking, and CIPN risk factors remain ill-defined. Metabolic syndrome and associated conditions have emerged as potential risk factors, due to their high prevalence and independent association with nerve dysfunction. This systematic review aimed to investigate the association between these common metabolic-lifestyle factors and CIPN.

Methods: Searches were undertaken using Medline, Embase, CINAHL, Scopus, and Web of Science databases, with additional studies identified from bibliographic references cited by original and review articles. Articles that analyzed metabolic-lifestyle risk factors associated with CIPN for patients treated with platinum- or taxane-based chemotherapy were included.

Results: Searches identified 6897 titles; 44 articles had full text review, with 26 studies included. Overall incidence of neuropathy ranged from 16.9 to 89.4%. Obesity had the most consistent patient-oriented evidence as a risk factor for CIPN, with moderate evidence suggesting diabetes did not increase CIPN incidence or severity. A limited number of studies supported an association with low physical activity and greater CIPN risk.

Conclusions: Comorbidities and lifestyle factors, particularly obesity and low physical activity, may contribute to the development of CIPN. The implementation of sensitive outcome measures in large-scale clinical trials is required to further elucidate CIPN risk factors and evaluate if changes in lifestyle would improve long-term CIPN outcomes for cancer survivors.

Implications For Cancer Survivors: Better understanding of CIPN risk profiles may inform personalized medicine strategies and help elucidate pathophysiological mechanisms which could be targeted for neuroprotection.
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http://dx.doi.org/10.1007/s11764-021-00988-xDOI Listing
January 2021

Longitudinal Assessment of Frailty and Quality of Life in Patients Undergoing Head and Neck Surgery.

Laryngoscope 2021 Jan 11. Epub 2021 Jan 11.

Department of Otolaryngology - Head and Neck Surgery, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, Ontario, Canada.

Objective: To understand changes in frailty and quality of life (QOL) in frail versus non-frail patients undergoing surgery for head and neck cancer (HNC).

Methods: Prospective cohort study of patients (median age 67 (50, 88)) with HNC undergoing surgery from December 2011 to April 2014. Fried's Frailty Index, Vulnerable Elders Survey (VES-13), and comprehensive QOL assessments (EORTC QLQ-C30 and HN35) were completed at baseline and 3, 6, and 12-month post-operative visits. Change in frailty and QOL over time was compared between frailty groups (non-frail (score 0), pre-frail (score 1-2), and frail (score 3-5)) using a mixed effects model. Predictors of long-term elevated frailty (12 months > baseline) were analyzed using logistic regression.

Results: The study had 108 patients classified as non-frail (47%), 104 pre-frail (mean (SD) 1.3 (0.4), 45%), and 17 frail (3.4 (0.6); 7%). Frailty score decreased significantly for frail patients 3 months post-operatively (2.1 (1.0); P = .002) and remained significantly lower than baseline at 6 and 12 months (2.1 (1.4); P = .0008 and 2.2 (1.5); P = .005, respectively) while frailty score increased for non-frail patients at 3 months (1.1 (1.0); P < .001) and then decreased. Forty-eight patients (21%) had long-term elevated frailty, with baseline frailty and marital status identified as predictors on univariate analysis. The frail population had significantly worse QOL scores at baseline, which persisted 12 months post-operatively.

Conclusions: Frail patients demonstrate a decrease in frailty score following surgical treatment of HNC. Frail patients have significantly worse QOL scores on longitudinal assessment and would benefit from supportive services throughout their care.

Level Of Evidence: 3 Laryngoscope, 2021.
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http://dx.doi.org/10.1002/lary.29375DOI Listing
January 2021

Failure to replicate the association of rare loss-of-function variants in type I IFN immunity genes with severe COVID-19.

medRxiv 2020 Dec 21. Epub 2020 Dec 21.

A recent report found that rare predicted loss-of-function (pLOF) variants across 13 candidate genes in TLR3- and IRF7-dependent type I IFN pathways explain up to 3.5% of severe COVID-19 cases. We performed whole-exome or whole-genome sequencing of 1,934 COVID-19 cases (713 with severe and 1,221 with mild disease) and 15,251 ancestry-matched population controls across four independent COVID-19 biobanks. We then tested if rare pLOF variants in these 13 genes were associated with severe COVID-19. We identified only one rare pLOF mutation across these genes amongst 713 cases with severe COVID-19 and observed no enrichment of pLOFs in severe cases compared to population controls or mild COVID-19 cases. We find no evidence of association of rare loss-of-function variants in the proposed 13 candidate genes with severe COVID-19 outcomes.
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http://dx.doi.org/10.1101/2020.12.18.20248226DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781338PMC
December 2020

Causal Genetic Variants in Stillbirth. Reply.

N Engl J Med 2020 12;383(27):2687-2688

Columbia University Vagelos College of Physicians and Surgeons, New York, NY

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http://dx.doi.org/10.1056/NEJMc2032136DOI Listing
December 2020

Geographical heterogeneity in the American Joint committee on Cancer oral cancer staging and prognostic implications.

Oral Oncol 2021 Feb 21;113:105122. Epub 2020 Dec 21.

Fellow, Head and Neck Oncology, Chris O'Brien Lifehouse Hospital, Sydney, Australia.

Objectives: The AJCC 8th edition (AJCC 8) has introduced depth of invasion (DOI) and extranodal extension (ENE) into staging for oral squamous cell carcinoma (OSCC). Although validations have been performed on institutional datasets have shown a good performance, particularly in early OSCC, there have been no studies on diverse patient populations that determine the impact on prognostic heterogeneity.

Materials And Methods: Retrospective analysis of 4710 patients with oral squamous cell carcinoma (OSCC) treated with surgery +/- adjuvant therapy in 8 institutions in Australia, North America and Asia. With overall survival (OS) as endpoint, the prognostic performance of AJCC 7th and 8th editions were compared using Akaike Information Criterion (AIC), Bayesian Information Criteria (BIC), Harrell's concordance index (C-index).

Results: When comparing AJCC 8 to AJCC 7, the heterogeneity in prediction of OS increased for T-category and N-category while remaining unchanged for TNM staging, suggesting AJCC 8 increased complexity with no improvement in predictive value. There were significant differences in median DOI and incidence of ENE between geographical regions, resulting in dissimilar rates of stage-migration when adopting AJCC 8.

Conclusion: In an attempt to improve prognostic performance, AJCC 8 introduced more variables; however heterogeneity in these results in significant geographical differences in model discrimination and performance. Caution should be applied as this may result in inaccurate and unreliable prognostic predictions that may impact treatment recommendations.
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http://dx.doi.org/10.1016/j.oraloncology.2020.105122DOI Listing
February 2021

Barriers and enablers to the implementation of protocol-based imaging in pancreatic cancer: A qualitative study using the theoretical domains framework.

PLoS One 2020 17;15(12):e0243312. Epub 2020 Dec 17.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Background: Accurate pre-operative imaging plays a vital role in patient selection for surgery and in allocating stage-appropriate therapies to patients diagnosed with pancreatic cancer (PC). This study aims to: (1) understand the current diagnosis and staging practices for PC; and (2) explore the factors (barriers and enablers) that influence the use of a pancreatic protocol computed tomography (PPCT) or magnetic resonance imaging (MRI) to confirm diagnosis and/or accurately stage PC.

Methods: Semi-structured interviews were conducted with radiologists, surgeons, gastroenterologists, medical and radiation oncologists from the states of New South Wales (NSW) and Victoria, Australia. Interviews were conducted either in person or via video conferencing. All interviews were recorded, transcribed verbatim, de-identified and data were thematically coded according to the 12 domains explored within the Theoretical Domains Framework (TDF). Common belief statements were generated to compare the variation between participant responses.

Findings: In total, 21 clinicians (5 radiologists, 10 surgeons, 2 gastroenterologists, 4 medical and radiation oncologists) were interviewed over a four-month-period. Belief statements relevant to the TDF domains were generated. Across the 11 relevant domains, 20 themes and 30 specific beliefs were identified. All TDF domains, with the exception of social influences were identified by participants as relevant to protocol-based imaging using either a PPCT or MRI, with the domains of knowledge, skills and environmental context and resources being offered by most participants as being relevant in influencing their decisions.

Conclusions: To maximise outcomes and personalise therapy it is imperative that diagnosis and staging investigations using the most appropriate imaging modalities are conducted in a timely, efficient and effective manner. The results provide an understanding of specialists' opinion and behaviour in relation to a PPCT or MRI and should be used to inform the design of future interventions to improve compliance with this practice.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243312PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746147PMC
January 2021

Assessing the Role of Rare Genetic Variation in Patients With Heart Failure.

JAMA Cardiol 2020 Dec 16. Epub 2020 Dec 16.

Institute for Genomic Medicine, Columbia University Medical Center, New York, New York.

Importance: Sequencing studies have identified causal genetic variants for distinct subtypes of heart failure (HF) such as hypertrophic or dilated cardiomyopathy. However, the role of rare, high-impact variants in HF, for which ischemic heart disease is the leading cause, has not been systematically investigated.

Objective: To assess the contribution of rare variants to all-cause HF with and without reduced left ventricular ejection fraction.

Design, Setting, And Participants: This was a retrospective analysis of clinical trials and a prospective epidemiological resource (UK Biobank). Whole-exome sequencing of patients with HF was conducted from the Candesartan in Heart Failure-Assessment of Reduction in Mortality and Morbidity (CHARM) and Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) clinical trials. Data were collected from March 1999 to May 2003 for the CHARM studies and September 2003 to July 2007 for the CORONA study. Using a gene-based collapsing approach, the proportion of patients with HF and controls carrying rare and presumed deleterious variants was compared. The burden of pathogenic variants in known cardiomyopathy genes was also investigated to assess the diagnostic yield. Exome sequencing data were generated between January 2018 and October 2018, and analysis began October 2018 and ended April 2020.

Main Outcomes And Measures: Odds ratios and P values for genes enriched for rare and presumed deleterious variants in either patients with HF or controls and diagnostic yield of pathogenic variants in known cardiomyopathy genes.

Results: This study included 5942 patients with HF and 13 156 controls. The mean (SD) age was 68.9 (9.9) years and 4213 (70.9%) were male. A significant enrichment of protein-truncating variants in the TTN gene (P = 3.35 × 10-13; odds ratio, 2.54; 95% CI, 1.96-3.31) that was further increased after restriction to variants in exons constitutively expressed in the heart (odds ratio, 4.52; 95% CI, 3.10-6.68). Validation using UK Biobank data showed a similar enrichment (odds ratio, 4.97; 95% CI, 3.94-6.19 after restriction). In the clinical trials, 201 of 5916 patients with HF (3.4%) had a pathogenic or likely pathogenic cardiomyopathy variant implicating 21 different genes. Notably, 121 of 201 individuals (60.2%) had ischemic heart disease as the clinically identified etiology for the HF. Individuals with HF and preserved ejection fraction had only a slightly lower yield than individuals with midrange or reduced ejection fraction (20 of 767 [2.6%] vs 15 of 392 [3.8%] vs 166 of 4757 [3.5%]).

Conclusions And Relevance: An increased burden of diagnostic mendelian cardiomyopathy variants in a broad group of patients with HF of mostly ischemic etiology compared with controls was observed. This work provides further evidence that mendelian genetic conditions may represent an important subset of complex late-onset diseases such as HF, irrespective of the clinical presentation.
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http://dx.doi.org/10.1001/jamacardio.2020.6500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745141PMC
December 2020

Temporal Artery Posterior Auricular Skin Free Flap for Secondary Oral Cavity Reconstruction.

Laryngoscope 2020 Dec 15. Epub 2020 Dec 15.

Department of Otolaryngology - Head and Neck Surgery / Surgical Oncology, University of Toronto, Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1002/lary.29250DOI Listing
December 2020

The possible association between COVID-19 and postural tachycardia syndrome.

Heart Rhythm 2020 Dec 11. Epub 2020 Dec 11.

Autonomic Medicine Section, Clinical Neurosciences Program, Division of Intramural Research, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2020.12.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7729277PMC
December 2020

Circulating tumour cells in pancreatic cancer: A systematic review and meta-analysis of clinicopathological implications.

Pancreatology 2021 Jan 3;21(1):103-114. Epub 2020 Dec 3.

Pancreatic Research Group, Ingham Institute for Applied Medical Research, South Western Sydney Clinical School, University of New South Wales, Australia. Electronic address:

Background: The detection and quantification of circulating tumour cells (CTCs) in pancreatic cancer (PC) has the potential to provide prognostic information. The aim of this review was to provide an overview of the literature surrounding CTCs in PC.

Methods: A systematic literature review on CTCs in PC between 2005-2020 was performed. Data based on peripheral vein samples were used to determine the positivity rate of CTCs, their prognostic significance and their relative numbers compared to portal vein (PV) samples.

Results: The overall CTC detection rate in forty-four articles was 65% (95%CI: 55-75%). Detection rate for CellSearch was 26% (95%CI: 14-38%), which was lower than for both filtration and microfluidic techniques. In nine studies with >50 patients, overall survival was worse with CTC positivity (HR 1.82; 95%CI: 1.61-2.05). Five of seven studies which described PV CTC collection provided patient-level data. PV CTC yield was 7.7-fold (95%CI 1.35-43.9) that of peripheral blood.

Conclusions: CTCs were detected in the peripheral circulation of most patients with PC and may be related to prognosis and disease stage. PV blood contains more CTCs than peripheral blood sampling. This review points to the maturation of techniques of CTC enrichment, and its evidence base for eventual clinical deployment.
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http://dx.doi.org/10.1016/j.pan.2020.11.022DOI Listing
January 2021