Predicting short-term treatment toxicity in head and neck cancer through a systematic review and meta-analysis.

INTRODUCTION: Frailty is a recognized condition associated with poorer outcomes in patients with head and neck cancer (HNC). The objective of this study was to ascertain the prognostic significance of various frailty metrics on short-term treatment toxicity in patients with HNC undergoing curative-intent therapy. MATERIALS AND METHODS: A systematic review was performed searching multiple databases. An inverse-variation, random-effects model was used to perform the meta-analysis to evaluate the prognostic significance of various frailty metrics on short-term treatment-related toxicity in this population. RESULTS: A total of 292,560 patients with HNC originating from 36 observational studies were analyzed. The most frequently reported frailty metrics were the modified frailty index (mFI), Geriatric 8 questionnaire (G8), Adjusted Clinical Groups (ACG), Groningen Frailty Indicator (GFI), and comprehensive geriatric assessment (CGA). The overall prevalence of frailty using any metric in all included studies was 7.5 %. The combined odds ratio (OR) for short-term treatment toxicity using the mFI was 2.60 (95 % CI of 1.81-3.72), G8 2.69 (95 % CI 1.37-5.28), ACG 3.43 (95 %CI 2.52-4.67), GFI 2.71 (95 % CI 1.11-6.62), and CGA 3.36 (95 % CI 1.18-9.53). The association of frailty with short-term treatment toxicity using various frailty metrics was more pronounced in patients with upfront surgery (OR 3.00, 95 %CI of 2.35-3.81) compared to definitive (chemo)radiotherapy 2.64 (95 % CI 1.04-6.68). DISCUSSION: Various frailty metrics exists in the HNC literature, with the most common being the mFI, G8, ACG, GFI, and CGA. Patients with HNC and frailty are more than twice as likely to suffer a short-term treatment-related toxicity when undergoing curative-intent HNC treatment than patients without frailty. This effect is more pronounced in patients undergoing upfront surgery.

Loss of Independence in Older Adults With Operable Oral Cavity Cancer: A Retrospective Cohort Study.

OBJECTIVE: To ascertain the effect of curative-intent surgery on loss of independence (LOI) in patients with oral cavity squamous cell carcinoma (OCSCC). STUDY DESIGN: Retrospective observational study of patients diagnosed from 2014 to 2021. SETTING: Single tertiary care academic center. Patients having undergone curative-intent surgical treatment for OCSCC from 2014 to 2021 in the cancer registry. METHODS: LOI as the primary outcome was measured based on a combination of decrease in activities of daily living (ADLs) and/or decline in mobility during treatment. Descriptive statistics were used to compare baseline demographics and multivariable logistic regression was used to assess the association between LOI and perioperative variables of interest. RESULTS: Of the 180 patients included in this study, 139 (79%) were fully independent in ADLs/instrumental ADLs prior to surgery. The average age of the cohort was 74 with 49% males. Thirty-seven (21%) experienced a decline in mobility or increased care needs following surgery, and 18 (10%) experienced an independent decline in functional status. Increasing age, osseous flap reconstruction, high Charlson Comorbidity Index, and major postoperative adverse events were associated with LOI. Fifty-five percent of patients with LOI had recovered to baseline within 7 months from surgery. LOI was associated with poor treatment tolerance (odds ratio: 4.77, 95% confidence interval: 1.87-12.2) while adjusting for multiple confounders. CONCLUSION: LOI is common in older adults undergoing curative-intent surgery for OCSCC and associated with poor treatment tolerance.

Sarcopenia predicts short-term treatment-related toxicity in patients undergoing curative-intent therapy for head and neck cancer: A systematic review and meta-analysis.

Sarcopenia is an increasingly recognized biomarker associated with poorer outcomes. The objective of this study was to ascertain the effect of sarcopenia on treatment tolerance and short-term toxicity in head and neck cancer (HNC). A systematic review was performed using multiple databases. An inverse-variation, random-effects model was used to perform the meta-analysis to evaluate the effect of sarcopenia on severe treatment toxicity and poor treatment tolerance. Sixteen observational studies, including 3187 patients with HNC, were analyzed. The combined odds ratio (OR) for severe treatment toxicity and tolerance was 2.22 (95%CI 1.50-3.29) and 1.40 (95%CI 0.84-2.32), respectively. The effect of sarcopenia on short-term severe treatment toxicity was similar with upfront surgery (OR 2.03, 95%CI 1.22-3.37) and definitive radiotherapy (OR 2.24, 95%CI 1.18-4.27) Patients with sarcopenia are more than twice as likely to suffer a short-term treatment-related toxicity when undergoing curative-intent HNC treatment.

Poor treatment tolerance in head and neck cancer patients with low muscle mass.

BACKGROUND: We ascertain the role of a low cervical paraspinal skeletal muscle index (CPSMI) as a biomarker for poor treatment tolerance in patients with operable mucosal head and neck squamous cell carcinoma (HNSCC). METHODS: A prospective cohort of patients with operable HNSCC requiring microvascular reconstruction was evaluated. Low CPSMI was calculated using preoperative CT neck imaging. Poor treatment tolerance, a composite measure of incomplete therapy or severe morbidity/mortality during treatment, was the primary outcome. RESULTS: One hundred and twenty-seven patients underwent extirpative surgery with a mean age was 60.5. Poor treatment tolerance occurred in 71 (56%) patients with 21 not completing recommended adjuvant therapy and 66 having severe treatment-related morbidity. A low CPSMI was independently associated with poor treatment tolerance (OR 2.49, 95%CI 1.10-5.93) and delay to adjuvant therapy (OR 4.48, 95%CI 1.07-27.6) after adjusting for multiple confounders. CONCLUSION: Low CPSMI was independently associated with poor treatment tolerance in patients with operable HNSCC.

Visual Impairment, Eye Disease, and 3-Year Cognitive Decline: The Canadian Longitudinal Study on Aging.

PURPOSE: To examine the longitudinal association between vision-related variables and the 3-year change in cognitive test scores in a community-dwelling sample of adults and to explore whether sex, education, or hearing loss act as effect modifiers. METHODS: Data came from two waves of a 3-year population-based prospective cohort study (Canadian Longitudinal Study on Aging), which consisted of 30,097 randomly selected people aged 45-85 years from 7 Canadian provinces. Visual impairment (VI) was defined as binocular presenting visual acuity worse than 20/40. Participants were asked if they had ever had a diagnosis of age-related macular degeneration (AMD), glaucoma, or cataract. Cognitive change over 3 years was examined by calculating the difference between baseline and follow-up scores for the Rey Auditory Verbal Learning Test (RAVLT) and the RAVLT delayed test (memory tests), the Controlled Oral Word Association Test (COWAT) and the Animal Naming Test (ANT) (verbal fluency tests), and the Mental Alternation Test (MAT) (processing speed test). Multiple linear regression was used. RESULTS: VI, AMD, and cataract were not associated with 3-year changes on any of the 5 cognitive tests after adjusting for age, sex, ethnicity, education, income, smoking, diabetes, stroke, heart disease, and province. A report of glaucoma was associated with greater declines in MAT scores (ß = -0.60, 95% CI -1.03, -0.18). No effect modification was detected. CONCLUSIONS: Glaucoma was associated with worsening processing speed. Further research to confirm this finding and to understand the possible reason is necessary.

Cervical paraspinal skeletal muscle index outperforms frailty indices to predict postoperative adverse events in operable head and neck cancer with microvascular reconstruction.

OBJECTIVE: Sarcopenia is increasingly being recognized as a negative prognostic factor in patients with head and neck cancer (HNC). We associate a sarcopenia biomarker measured radiographically from computed tomography (CT) of the neck to postoperative adverse events in patients with operable HNC. PATIENTS AND METHODS: A prospective cohort of treatment-naïve HNC patients undergoing surgery with microvascular reconstruction was performed. Cervical paraspinal skeletal muscle index (CPSMI) was calculated using preoperative CT neck imaging and adjusted for height and sex. Postoperative adverse events, including Clavien-Dindo Grade 3+ complications and fistula, were recorded within 30-days of the index surgery. Multivariate logistic regression was used to evaluate the association between CPSMI and postoperative complications. The modified frailty index (mFI) and Risk Assessment Index (RAI) were compared with CPSMI outcomes. RESULTS: A total of 127 patients with mucosal HNC were included in the study. The mean age was 60.5 years, and 87 (68.5%) patients were male. Sixty Clavien-Dindo grade 3+ events occurred; 17 patients developed an oro/pharyngocutaneous fistula. Low CPSMI was independently associated with Clavien-Dindo Grade 3+ events (OR 2.80, 95% CI of 1.18-6.99) and fistula (OR of 6.10, 95% CI of 1.53-24.3) when adjusted for multiple factors. CPSMI outperformed the mFI and RAI frailty indices to predict postoperative adverse events (p < .05). CONCLUSION: Low CPSMI is independently associated with postoperative adverse events and outperforms current frailty indices inoperable HNC with microvascular reconstruction.

Above and Beyond Age: Prediction of Major Postoperative Adverse Events in Head and Neck Surgery.

OBJECTIVE: Major postoperative adverse events (MPAEs) following head and neck surgery are not infrequent and lead to significant morbidity. The objective of this study was to ascertain which factors are most predictive of MPAEs in patients undergoing head and neck surgery. METHODS: A cohort study was carried out based on data from patients registered in the National Surgical Quality Improvement Program (NSQIP) from 2006 to 2018. All patients undergoing non-ambulatory head and neck surgery based on Current Procedural Terminology codes were included. Perioperative factors were evaluated to predict MPAEs within 30-days of surgery. Age was classified as both a continuous and categorical variable. Retained factors were classified by attributable fraction and C-statistic. Multivariate regression and supervised machine learning models were used to quantify the contribution of age as a predictor of MPAEs. RESULTS: A total of 43 701 operations were analyzed with 5106 (11.7%) MPAEs. The results of supervised machine learning indicated that prolonged surgeries, anemia, free tissue transfer, weight loss, wound classification, hypoalbuminemia, wound infection, tracheotomy (concurrent with index head and neck surgery), American Society of Anesthesia (ASA) class, and sex as most predictive of MPAEs. On multivariate regression, ASA class (21.3%), hypertension on medication (15.8%), prolonged operative time (15.3%), sex (13.1%), preoperative anemia (12.8%), and free tissue transfer (9%) had the largest attributable fractions associated with MPAEs. Age was independently associated with MPAEs with an attributable fraction ranging from 0.6% to 4.3% with poor predictive ability (C-statistic 0.60). CONCLUSION: Surgical, comorbid, and frailty-related factors were most predictive of short-term MPAEs following head and neck surgery. Age alone contributed a small attributable fraction and poor prediction of MPAEs. LEVEL OF EVIDENCE: 3.

Visual Impairment, Eye Disease, and the 3-year Incidence of Depressive Symptoms: The Canadian Longitudinal Study on Aging.

PURPOSE: Our goal was to explore the longitudinal association between vision-related variables and incident depressive symptoms in a community-dwelling sample of older adults and to examine whether sex, education, or hearing loss act as effect modifiers. METHODS: A 3-year prospective cohort study was performed using data from the Canadian Longitudinal Study on Aging consisting of 30,097 individuals aged 45-85 years. Visual acuity was evaluated with habitual distance correction using an illuminated Early Treatment of Diabetic Retinopathy Study chart. Visual impairment was defined as binocular presenting visual acuity worse than 20/40. Incident depressive symptoms was defined using a cut-off score of 10 or greater on the Center for Epidemiologic Studies Depression scale. Participants were asked if they had ever had a physician diagnosis of age-related macular degeneration (AMD), glaucoma, or cataract. Multivariable Poisson regression was used. RESULTS: Of 22,558 participants without depressive symptoms at baseline, 7.7% developed depressive symptoms within 3 years. Cataract was associated with incident depressive symptoms (relative risk = 1.20, 95% confidence interval 1.05, 1.37) after adjusting for age, sex, income, education, partner status, smoking, level of comorbidity, hearing loss, and province. Visual impairment, AMD, and glaucoma were not associated with incident depressive symptoms. No effect modification was detected. CONCLUSIONS: Our longitudinal data confirm that the risk of depressive symptoms is higher in those who report ever having a cataract. Further research should confirm this and interventions should be considered.

Stem Cell-Derived Neurons as Cellular Models of Sporadic Alzheimer's Disease.

Alzheimer's disease (AD) occurs as either an autosomal dominant inherited disease or sporadically. While familial mutant genes can be expressed in cells or in animal models to assess dysregulated functions, sporadic AD cannot be replicated in models given our lack of understanding of causality. Furthermore, the study of sporadic forms of AD is difficult given the inaccessibility of brain tissues in living individuals and the manifestation of symptoms years after the onset of disease. Here, the objective was to assess if induced pluripotent stem cell-derived neurons from well-ascertained sporadic AD individuals could represent potential cellular models to determine the underlying molecular mechanisms of disease. We used cryopreserved peripheral blood mononuclear cells from three well-ascertained sporadic AD and three non-cognitively impaired (NCI) individuals of the CIMA-Q cohort to obtain iPSC-derived neurons. Microtubule associated protein 2 was decreased in AD neurons, whereas expression of AD-associated amyloid precursor protein, tau, and amyloid-ß peptide was similar in AD and NCI individuals. RNA sequencing identified several upregulated and downregulated mRNAs in AD relative to NCI neurons. Of these, complement Factor H (CFH), signal regulatory protein beta1 (SIRPB1), and insulin like growth factor binding protein 5 (IGFBP5) were previously associated with AD. In addition, several transcription factors not previously associated with AD, but involved in neuronal proliferation and differentiation were differentially expressed. The results identify novel avenues for the study of the underlying causes of sporadic AD and support the establishment of additional lines to identify mechanisms of disease in sporadic AD individuals.

Visual impairment in older institutionalised Canadian seniors with dementia.

PURPOSE: To estimate the prevalence of visual impairment (VI) in a sub-population of Canadian long-term care facilities, i.e. residents affected by dementia. METHODS: This study was conducted in the long-term care facility units at the Institut universitaire de gériatrie de Montréal. All residents ≥65 years old (y.o.), having a clinical diagnosis of dementia, and able to understand French or English, were eligible for participation in the study. All residents participating in the study received a complete eye exam by an experienced optometrist. For the purpose of the study, VI was defined as a distance visual acuity (VA) <6/12 (0.30 logMAR, 20/40) in the better seeing eye. RESULTS: One hundred and fifty residents, 68-102 y.o. took part into the study. All participants had a diagnosis of dementia recorded in their clinical chart. VI was present in 37.3% (95% CI: 29.1-46.1%) (n = 50) of residents in whom monocular VA could be measured. Ocular refraction for their better seeing eye improved the VA to ≥6/12 (0.30 logMAR, 20/40) in 40% (n = 20) of those 50 residents. When VI remained after refraction, it was due in order of frequency to cataract, age-related macular degeneration, and primary open angle glaucoma. CONCLUSIONS: Our data showed that an appreciable proportion (37.3%) of older residents with dementia also have VI, and that VI can be corrected in many by updating their refraction. Others could potentially be helped through cataract surgery. It is therefore important to offer regular eye care services to those residents, knowing that many are not able to express their visual needs.

Patterns of Cognitive Decline Prior to Dementia in Persons with Mild Cognitive Impairment.

Only a limited number of studies have investigated the decline of discrete cognitive domains as individuals progress from mild cognitive impairment (MCI) to dementia. Thus, the goal of this longitudinal study was to evaluate the cognitive changes underway during the years preceding a diagnosis of probable Alzheimer's disease (AD), and to compare these changes to those found in MCI participants who do not progress to dementia. Participants were compared as a function of whether they later converted to AD (n = 47) or not (n = 74). Cognitive change was assessed prior to the conversion year, using that year as a starting point. A combination of polynomial regression analyses and mixed ANOVAs assessed 1) the trajectory of cognitive decline for each domain and 2) the differences between non-progressors and those who had converted to AD. The different cognitive domains demonstrated very different patterns of decline in the group of MCI progressors. A quadratic function, i.e., many years of stable performance followed by a rapid decline just prior to diagnosis, was observed for delayed recall, working memory, and spatial memory. In contrast, a gradual linear decline was observed for immediate recall, executive function, and visuo-spatial abilities. Finally, language in progressors was impaired on all time periods relative to non-progressors, but there was no further change between the first assessments and conversion to AD. Individuals with MCI who progress to AD show abnormal cognition at least two years prior to their dementia diagnosis. The pattern of symptom change observed appears to depend upon the cognitive domain and thus, clinical studies should not assume similar rate of decline across domains. In contrast and, apart from verbal memory, the non-progressors present a performance similar to that of healthy older adults.

Sodium intake and physical activity impact cognitive maintenance in older adults: the NuAge Study.

This study examines the association between sodium intake and its interaction with physical activity on cognitive function over 3 years in older adults residing in Québec, Canada. We analyzed a subgroup from the NuAge cohort (aged 67-84 years) with nutrient intake data, including sodium, from a food frequency questionnaire administered at baseline. Baseline physical activity was assessed using the Physical Activity Scale for the Elderly (PASE; high-low). Modified Mini Mental State Examination (3MS) was administered at baseline and annually for 3 additional years. Controlling for age, sex, education, waist circumference, diabetes, and dietary intakes, analyses showed an association between sodium intake and cognitive change over time in the low PASE group only. Specifically, in the low PASE group, elders in the low sodium intake tertile displayed better cognitive performance over time (mean decline in 3MS over years: mean [M] = -0.57, standard error [SE] = 0.002) compared with the highest (M = -1.72, SE = 0.01) and mid sodium intake (M = -2.07, SE = 0.01) groups. This finding may have significant public health implications, emphasizing the importance of addressing multiple lifestyle factors rather than a single domain effect on brain health.