Telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER): A pilot study for patients treated with surgery for oral cavity carcinoma.

BACKGROUND: To address the rehabilitative barriers to frequency and precision of care, we conducted a pilot study of a biofeedback electropalatography (EPG) device paired with telemedicine for patients who underwent primary surgery +/- adjuvant radiation for oral cavity carcinoma. We hypothesized that lingual optimization followed by telemedicine-enabled biofeedback electropalatography rehabilitation (TEBER) would further improve speech and swallowing outcomes after "standard-of-care" SOC rehabilitation. METHOD: Pilot prospective 8-week (TEBER) program following 8 weeks of (SOC) rehabilitation. RESULTS: Twenty-seven patients were included and 11 completed the protocol. When examining the benefit of TEBER independent of standard of care, "range-of-liquids" improved by +0.36 [95% CI, 0.02-0.70, p = 0.05] and "range-of-solids" improved by +0.73 [95% CI, 0.12-1.34, p = 0.03]. There was a positive trend toward better oral cavity obliteration; residual volume decreased by -1.2 [95% CI, -2.45 to 0.053, p = 0.06], and "nutritional-mode" increased by +0.55 [95% CI, -0.15 to 1.24, p = 0.08]. CONCLUSION: This pilot suggests that TEBER bolsters oral rehabilitation after 8 weeks of SOC lingual range of motion.

Transoral Robotic Surgery and Radiation Volume Deintensification in Unknown Primary Squamous Cell Carcinoma of the Neck: The Phase 2 FIND Nonrandomized Controlled Trial.

Importance: Patients with unknown primary squamous cell carcinoma (CUP) with cervical metastases typically receive comprehensive radiotherapy (RT) of the pharynx and bilateral neck. Typically, these patients receive comprehensive RT of the pharynx and bilateral neck that may produce treatment-related toxic effects. Objective: To determine whether localization of occult oropharyngeal cancers with transoral robotic surgery (TORS) combined with reduced pharyngeal and neck RT volumes provides acceptable disease control. Design, Setting, and Participants: This phase 2, single-group nonrandomized controlled trial at a single institution accrued 32 prospective participants with p16-positive CUP without a primary squamous cell carcinoma on examination and imaging from 2017 to 2019, and 24-month follow-up. The data analysis was conducted from January 2021 to June 2022. Intervention: Diagnostic- (n = 13) or therapeutic-intent (n = 9) TORS, with pharyngeal-sparing radiotherapy (PSRT) prescribed for negative margins or pT0, and unilateral neck RT (UNRT) prescribed for unilateral lymphadenopathy with lateralized primary tumor or pT0. Main Outcomes and Measures: Out-of-radiation treatment volume failure (<15% was hypothesized to be acceptable) and reports of local and regional recurrence, overall survival, toxic effects, swallowing outcomes (per the MD Anderson Dysphagia Inventory), and videofluoroscopic swallow (per Dynamic Imaging Grade of Swallowing Toxic Effects [DIGEST]) ratings. Results: The study sample comprised 22 patients (mean [SD] age, 59.1 [5.7] years; 3 [14%] females and 19 [86%] male) with CUP. Of these, 19 patients (86%) had tumor stage cN1; 2 (9%), cN2; and 1 (5%), cN3. Five patients (23%), 14 patients (64%), and 3 patients (13%) had 0, 1, or 2 primary tumors, respectively. Twenty patients received RT; of these, 9 patients (45%) underwent PSRT and 10 patients (50%), UNRT. In the diagnostic-intent group, 8 patients (62%) and 5 patients (38%) underwent RT and RT-concurrent chemotherapy, respectively. In the therapeutic-intent group, 6 patients (67%) and 1 patient (11%) received adjuvant RT-concurrent chemotherapy, respectively; 2 patients declined RT. Two-year out-of-radiation treatment volume failure, locoregional control, distant metastasis control, and overall survival were 0%, 100%, 95%, and 100%, respectively. Grade 3 or 4 surgical, acute, and late toxic effects occurred in 2 (9%), 5 (23%), and 1 (5%) patients, respectively. PSRT was associated with lower RT dose to superior constrictors (37 vs 53 Gy; mean difference, 16 Gy; 95% CI, 6.4, 24.9), smaller decline in swallowing scores during treatment (19.3 vs 39.7; mean difference, -20.4; 95% CI, -34.1 to -6.1), and fewer patients with worsening DIGEST grade on findings of videofluoroscopic swallow studies at 2 years (0% vs 60%; difference, 60%; 95% CI, 30% to 90%). Conclusions and Relevance: These findings indicate that TORS for p16-positive CUP allows RT volume deintensification with excellent outcomes and support future investigation in randomized clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT03281499.

Characterising vincristine-induced peripheral neuropathy in adults: symptom development and long-term persistent outcomes.

BACKGROUND: Decades following the introduction of vincristine as treatment for haematological malignancies, vincristine-induced peripheral neuropathy (VIPN) remains a pervasive, untreatable side-effect. However there remains a gap in understanding the characteristics of VIPN in adults. This study presents a comprehensive phenotyping of VIPN. METHODS: Adult patients (n = 57; age = 59.8 ± 14.6) were assessed cross-sectionally following completion of vincristine (months post treatment = 16.3 ± 15.6, cumulative dose = 7.6 ± 4.4), with a subset of 20 patients assessed prospectively during treatment. Patient reported measures (EORTC-QLQ-CIPN20, R-ODS) were used to profile symptoms and disability. Neurological assessment was undertaken using the Total Neuropathy Score and nerve conduction studies. Sensory threshold and fine motor tasks were also undertaken. Comparisons of data between timepoints were calculated using paired-sample t tests or Wilcoxon matched-pairs signed-rank test. Comparisons between outcome measures were calculated with independent sample t tests or Mann-Whitney U tests for non-parametric data. RESULTS: The majority of patients developed VIPN by mid-treatment (77.8%, 7.0 ± 3.3 weeks post baseline) with the prevalence remaining stable by end-of-treatment (75%, 8.1 ± 1.7 weeks post mid-treatment). By 3 months post-completion, 50% of patients still reported VIPN although there were significant improvements on neurological grading and functional assessment (P < 0.05). VIPN presented with sensorimotor involvement in upper and lower limbs and was associated with decreased sensory and motor nerve amplitudes, reduced fine-motor function and increased disability. CONCLUSION: VIPN in adults presents as a sensorimotor, upper- and lower-limb neuropathy that significantly impacts disability and function. Neuropathy recovery occurs in a proportion of patients; however, VIPN symptoms may persist and continue to affect long-term quality of life.

Length of Stay Prediction Models for Oral Cancer Surgery: Machine Learning, Statistical and ACS-NSQIP.

OBJECTIVE: Accurate prediction of hospital length of stay (LOS) following surgical management of oral cavity cancer (OCC) may be associated with improved patient counseling, hospital resource utilization and cost. The objective of this study was to compare the performance of statistical models, a machine learning (ML) model, and The American College of Surgeons National Surgical Quality Improvement Program's (ACS-NSQIP) calculator in predicting LOS following surgery for OCC. MATERIALS AND METHODS: A retrospective multicenter database study was performed at two major academic head and neck cancer centers. Patients with OCC who underwent major free flap reconstructive surgery between January 2008 and June 2019 surgery were selected. Data were pooled and split into training and validation datasets. Statistical and ML models were developed, and performance was evaluated by comparing predicted and actual LOS using correlation coefficient values and percent accuracy. RESULTS: Totally 837 patients were selected with mean patient age being 62.5 ± 11.7 [SD] years and 67% being male. The ML model demonstrated the best accuracy (validation correlation 0.48, 4-day accuracy 70%), compared with the statistical models: multivariate analysis (0.45, 67%) and least absolute shrinkage and selection operator (0.42, 70%). All were superior to the ACS-NSQIP calculator's performance (0.23, 59%). CONCLUSION: We developed statistical and ML models that predicted LOS following major free flap reconstructive surgery for OCC. Our models demonstrated superior predictive performance to the ACS-NSQIP calculator. The ML model identified several novel predictors of LOS. These models must be validated in other institutions before being used in clinical practice. LEVEL OF EVIDENCE: Level 3 Laryngoscope, 2024.

Impact of goal-directed hemodynamic therapy on perioperative outcomes in head and neck free flap surgery: A before-and-after pilot study.

Background: Free flap reconstruction for head and neck cancer is associated with a high risk of perioperative complications. One of the modifiable risk factors associated with perioperative morbidity is intraoperative hypotension (IOH). The main aim of this pilot study is to determine if the intraoperative use of goal-directed hemodynamic therapy (GDHT) is associated with a reduction in the number of IOH events in this population. Methods: A before-and-after study design. The patients who had intraoperative GDHT were compared to patients from a previous period before the implementation of GDHT. The primary outcome was the number of IOH episodes defined as five or more successive minutes with a mean arterial pressure <65 mmHg. The secondary outcomes included major postoperative morbidity and 30-day mortality. Results: A total of 414 patients were included. These were divided into two groups. The control group (n = 346; January 1, 2018, to December 31, 2019), and the monitored group (n = 68; January 1, 2020, to May 1, 2021). The median intraoperative administered fluid volume was similar between the control and monitored groups (2250 interquartile range [IQR] [1607-3050] vs. 2210 IQR [1700-2807] mL). The monitored group was found to have an increased use of norepinephrine and dobutamine (respectively, 1.2% vs. 5.9% and 2.4% vs. 30.9%; p < 0.05). When adjusting for confounders (comorbidities, estimated blood loss, and duration of anesthesia) the incidence rate ratio (95% confidence interval) of number of IOH events was 0.94 (0.86-1.03), p = 0.24. The rate of postoperative flap and medical complications did not differ between the two groups. Conclusions: Even though the use of vasopressors/inotropes was higher in the monitored group, the number of IOH episodes and postoperative morbidity and mortality were similar between the two groups. Further change in hemodynamic management will require the use of specific blood pressure targets in the GDHT fluid algorithm.

The Quantification of Radiation Fibrosis Using Clinically Indicated Magnetic Resonance Imaging for Head and Neck Cancer Patients.

Currently, no objective method exists to measure the extent of fibrosis in swallowing musculature in head and neck cancer (HNC) patients. We developed and psychometrically tested a method of quantifying fibrosis volume using magnetic resonance imaging (MRI). The overall aim of this study was to determine if clinical MRI is a reliable tool to measure fibrosis of the pharyngeal musculature in patients with HNC managed with RT and to assess its potential to capture changes in fibrosis over time. Eligible participants were adults with HNC treated with radiation therapy (RT) who received minimally two MRIs and videofluoroscopic swallow (VFS) studies from baseline (pre-RT) up to 1-year post-RT. Two neuroradiologists independently contoured fibrosis volume in batches from MRIs using Vitrea™. Sufficient inter-rater reliability was set at Intraclass Correlation Coefficient (ICC) > 0.75. Two speech-language pathologists independently rated VFSs for swallowing impairment using standardized scales, with discrepancies resolved by consensus. MRI and VFS scores were correlated using Spearman's rank coefficient. Participants included 42 adults (male = 33); mean age 59 (SD = 8.8). ICC (95% Confidence Interval) for fibrosis volume was 0.34 (0, 0.76) for batch one and 0.43 (0, 0.82) for batch two. Consensus meetings were held after each batch. Sufficient reliability was reached by batch three (ICC = 0.95 (0.79, 0.99)). Fibrosis volume increased significantly from 3 to 12 months (mean change = 1.28 mL (SD = 5.21), p = 0.006), as did pharyngeal impairment from baseline to 12 months (mean score change = 3.05 (SD = 3.02), p = 0.003). Fibrosis volume moderately correlated with pharyngeal impairment at 3 and 12 months (0.49, p = 0.004 and 0.59, p = 0.005, respectively). We demonstrated a reliable measure of fibrosis volume in swallowing musculature from existing clinical MRIs and identified that larger fibrosis volume was associated with worse swallowing function. The reliable capture of fibrosis volume offers a pragmatic method for early detection of fibrosis and concomitant dysphagia.

Intra-neuronal alpha-synuclein deposition is related to cardiac noradrenergic deficiency and olfactory dysfunction in neurogenic orthostatic hypotension.

Purpose: Neurogenic orthostatic hypotension (nOH) results from deficient reflexive delivery of norepinephrine to cardiovascular receptors in response to decreased cardiac venous return. Lewy body (LB) forms of nOH entail low 18F-dopamine-derived radioactivity (a measure of cardiac noradrenergic deficiency), olfactory dysfunction by the University of Pennsylvania Smell Identification Test (UPSIT), and increased deposition of alpha-synuclein (ɑ-syn) in dermal sympathetic noradrenergic nerves by the ɑ-syn-tyrosine hydroxylase (TH) colocalization index. This observational, cross-sectional study explored whether combinations of these biomarkers specifically identify LB forms of nOH. Methods: Clinical laboratory data were reviewed from patients referred for evaluation at the National Institutes of Health for chronic autonomic failure between 2011 and 2023. The cutoff value for low myocardial 18F-dopamine-derived radioactivity was 6,000 nCi-kg/cc-mCi, for olfactory dysfunction an UPSIT score ≤ 28, and for an increased ɑ-syn-TH colocalization index ≥ 1.57. Results: A total of 44 patients (31 LB, 13 non-LB nOH) had data for all 3 biomarkers. Compared to the non-LB group, the LB nOH group had low myocardial 18F-dopamine-derived radioactivity, low UPSIT scores, and high ɑ-syn-TH colocalization indexes (p<0.0001 each). Combining the 3 biomarkers completely separated the groups. Cluster analysis identified 2 distinct groups (p<0.0001) independently of the clinical diagnosis, 1 cluster corresponding exactly to LB nOH. Conclusion: LB forms of nOH feature cardiac noradrenergic deficiency, olfactory dysfunction, and increased ɑ-syn-TH colocalization in skin biopsies. Combining the data for these variables efficiently separates LB from non-LB nOH. Independently of the clinical diagnosis, this biomarker triad identifies a pathophysiologically distinct cluster of nOH patients.

Decision Regret Following the Choice of Surgery or Active Surveillance for Small, Low-Risk Papillary Thyroid Cancer: A Prospective Cohort Study.

Background: It is important to understand cancer survivors' perceptions about their treatment decisions and quality of life. Methods: We performed a prospective observational cohort study of Canadian patients with small (<2 cm) low-risk papillary thyroid cancer (PTC) who were offered the choice of active surveillance (AS) or surgery (Clinicaltrials.gov NCT03271892). Participants completed a questionnaire one year after their treatment decision. The primary intention-to-treat analysis compared the mean decision regret scale total score between patients who chose AS or surgery. A secondary analysis examined one-year decision regret score according to treatment status. Secondary outcomes included quality of life, mood, fear of disease progression, and body image perception. We adjusted for age, sex, and follow-up duration in linear regression analyses. Results: The overall questionnaire response rate was 95.5% (191/200). The initial treatment choices of respondents were AS 79.1% (151/191) and surgery 20.9% (40/191). The mean age was 53 years (standard deviation [SD] 15 years) and 77% (147/191) were females. In the AS group, 7.3% (11/151) of patients crossed over to definitive treatment (two for disease progression) before the time of questionnaire completion. The mean level of decision regret did not differ significantly between patients who chose AS (mean 22.4, SD 13.9) or surgery (mean 20.9, SD 12.2) in crude (p = 0.730) or adjusted (p = 0.29) analyses. However, the adjusted level of decision regret was significantly higher in patients who initially chose AS and crossed over to surgery (beta coefficient 10.1 [confidence interval; CI 1.3-18.9], p = 0.02), compared with those remaining under AS. In secondary adjusted analyses, respondents who chose surgery reported that symptoms related to their cancer or its treatment interfered with life to a greater extent than those who chose AS (p = 0.02), but there were no significant group differences in the levels of depression, anxiety, fear of disease progression, or overall body image perception. Conclusions: In this study of patients with small, low-risk PTC, the mean level of decision regret pertaining to the initial disease management choice was relatively low after one year and it did not differ significantly for respondents who chose AS or surgery.

Tilt-evoked, breathing-driven blood pressure oscillations: Independence from baroreflex-sympathoneural function.

PURPOSE: Orthostasis increases the variability of continuously recorded blood pressure (BP). Low-frequency (LF) BP oscillations (Mayer waves) in this setting are related to the vascular-sympathetic baroreflex. Mechanisms of increased high-frequency (HF) BP oscillations at the periodicity of respiration during orthostasis have received less research attention. A previously reported patient with post-neurosurgical orthostatic hypotension (OH) and vascular-sympathetic baroreflex failure had large tilt-evoked, breathing-driven BP oscillations, suggesting that such oscillations can occur independently of vascular-sympathetic baroreflex modulation. In the present study we assessed effects of orthostasis on BP variability in the frequency domain in patient cohorts with or without OH. METHODS: Power spectral analysis of systolic BP variability was conducted on recordings from 73 research participants, 42 with neurogenic OH [13 pure autonomic failure, 14 Parkinson's disease (PD) with OH, 12 parkinsonian multiple system atrophy, and 3 status post-brainstem neurosurgery] and 31 without OH (control group of 16 healthy volunteers and 15 patients with PD lacking OH), before, during, and after 5' of head-up tilt at 90 degrees from horizontal. The data were log transformed for statistical testing. RESULTS: Across all subjects, head-up tilting increased HF power of systolic BP variability (p = 0.001), without a difference between the neurogenic OH and control groups. LF power during orthostasis was higher in the control than in the OH groups (p = 0.009). CONCLUSIONS: The results of this observational cohort study confirm those based on our case report and lead us to propose that even in the setting of vascular-sympathetic baroreflex failure orthostasis increases HF power of BP variability.

Investigating the Relationship Between Rare Genetic Variants and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease.

Background and Aims: Nonalcoholic Fatty Liver Disease (NAFLD) is a complex human disease. Common genetic variation in the patatin-like phospholipase domain containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2) genes have been associated with an increased risk of developing NAFLD, nonalcoholic steatohepatitis (NASH), and fibrosis in adults. The role of rare genetic variants in the development and progression of NAFLD in children is not well known. We aimed to explore the role of rare genetic variants in pediatric patients with advanced fibrosis. Methods: Whole exome sequencing data was generated for 229 pediatric patients diagnosed with NAFLD recruited from the NASH Clinical Research Network (NASH CRN). Case-control single variant and gene-based collapsing analyses were used to test for rare variants that were enriched or depleted within the pediatric NAFLD cohort specifically for advanced fibrosis (cases) versus those without fibrosis (controls) or six other histologic characteristics. Exome data from non-NAFLD population controls were also used for additional analyses. All results were adjusted for multiple testing using a Bonferroni correction. Results: No genome-wide significant associations were found between rare variation and presence of advanced fibrosis or NASH, nor the severity of steatosis, inflammation, or hepatocellular ballooning. Significantly, no enrichment of rare variants in PNPLA3 or TM6SF2 was observed across phenotypes. Conclusion: In a cohort of children with histologically proven NAFLD, no genome-wide significant associations were found between rare genetic variation and advanced fibrosis or six other histologic features. Of particular interest was the lack of association with genes of interest in adults: PNPLA3 and TM6SF2, though limitations in sample size may reduce the ability to detect associations, particularly with rare variation.

Multimodal detection of molecular residual disease in high-risk locally advanced squamous cell carcinoma of the head and neck.

Up to 30% of patients with locally advanced head and neck squamous cell carcinoma (LA-HNSCC) relapse. Molecular residual disease (MRD) detection using multiple assays after definitive therapy has not been reported. In this study, we included patients with LA-HNSCC (stage III Human Papilloma virus (HPV)-positive, III-IVB HPV-negative) treated with curative intent. Plasma was collected pre-treatment, at 4-6 weeks (FU1) and 8-12 weeks (FU2) post-treatment. Circulating tumor DNA (ctDNA) was analyzed using a tumor-informed (RaDaR®) and a tumor-naïve (CAPP-seq) assay. HPV DNA was measured using HPV-sequencing (HPV-seq) and digital PCR (dPCR). A total of 86 plasma samples from 32 patients were analyzed; all patients with at least 1 follow-up sample. Most patients were stage III HPV-positive (50%) and received chemoradiation (78%). No patients had radiological residual disease at FU2. With a median follow-up of 25 months, there were 7 clinical relapses. ctDNA at baseline was detected in 15/17 (88%) by RaDaR and was not associated with recurrence free survival (RFS). Two patients relapsed within a year after definitive therapy and showed MRD at FU2 using RaDaR; detection of ctDNA during follow-up was associated with shorter RFS (p < 0.001). ctDNA detection by CAPP-seq pre-treatment and during follow-up was not associated with RFS (p = 0.09). HPV DNA using HPV-seq or dPCR during follow-up was associated with shorter RFS (p < 0.001). Sensitivity and specificity for MRD at FU2 using RaDaR was 40% and 100% versus 20 and 90.5% using CAPP-seq. Sensitivity and specificity for MRD during follow-up using HPV-seq was 100% and 91.7% versus 50% and 100% using dPCR. In conclusion, HPV DNA and ctDNA can be detected in LA-HNSCC before definitive therapy. The RaDaR assay but not CAPP-seq may detect MRD in patients who relapse within 1 year. HPV-seq may be more sensitive than dPCR for MRD detection.

Impact of Pain on Symptom Burden in Chemotherapy-Induced Peripheral Neurotoxicity.

BACKGROUND: Chemotherapy-induced peripheral neurotoxicity (CIPN) affects the quality of life of cancer survivors. However, the impact of pain on symptom burden remains undefined. This study aimed to define differences in the clinical symptom profile of patients with painful and nonpainful CIPN. PATIENTS AND METHODS: A total of 579 participants (median age, 59 years [IQR, 19 years]; F=66%) were assessed cross-sectionally 6 months posttreatment. CIPN severity was graded using multiple methods, including patient-reported outcome measures, a clinically graded scale (NCI-CTCAE), and a neurologic examination score. Participants were classified into subgroups based on patient symptom report, with painful CIPN characterized by the presence of shooting/burning pain, and nonpainful CIPN characterized by the presence of numbness or tingling without shooting/burning pain. Behavioral changes were assessed via structured patient interview regarding symptom impact on sleep, exercise, and treatment-seeking. RESULTS: Among 579 participants, 24% (n=140) reported painful CIPN, 48% (n=280) reported nonpainful CIPN, and 28% (n=159) had no CIPN. Participants with painful CIPN demonstrated higher CIPN severity than those with nonpainful CIPN across multiple measures, including NCI-CTCAE, neurologic grading, and patient report (all P<.05). Participants with painful CIPN were more likely to report that their symptoms affected their ability to exercise (P=.007), produced sleep impairment, and increased treatment-seeking behavior due to their symptoms (both P<.001) compared with participants with nonpainful CIPN. CONCLUSIONS: Overall, participants with painful CIPN reported higher scores across all CIPN severity measures, including behavioral changes. This study underlines the need for accurate identification of different CIPN subgroups in hopes of informing better treatment and rehabilitation options for cancer survivors with painful CIPN.

Phenoconversion in pure autonomic failure: a multicentre prospective longitudinal cohort study.

We aimed to describe the clinical features of patients with pure autonomic failure (PAF) preceding phenoconversion that could be useful as predictive markers for advancing α-synuclein-associated neurodegeneration of the brain. Patients diagnosed with PAF were evaluated at 8 Centers (7-US based and 1 European) and enrolled in a longitudinal observational cohort study (NCT01799915). Subjects underwent detailed assessments of motor, sleep, olfactory, cognitive, and autonomic function and were followed prospectively to determine whether they developed parkinsonism or dementia for up to 10 years. We identified incident cases of Parkinson disease (PD), dementia with Lewy bodies (DLB), or multiple system atrophy (MSA) and computed hazard ratios for phenoconversion as functions of clinical features. A total of 209 participants with PAF with a median disease duration of 6 years (IQR: 3-10) were enrolled. Of those, 149 provided follow-up information at an office or telemedicine visit. After a mean follow-up duration of 3 years, 48 (33%) participants phenoconverted (42% to PD, 35% to DLB, and 23% to MSA). Faster phenoconversion from study enrollment to any diagnosis was associated with urinary and sexual dysfunction [HR 5.9, 95%CI: 1.6-22, and HR: 3.6, 95%CI: 1.1-12] followed by subtle motor signs [HR: 2.7, 95%CI: 1.2-6], trouble swallowing [HR 2.5, 95%CI: 1.4-4.5], and changes in speech [HR:2.4, 95%CI:1.1-4.8] at enrollment. Subjects reporting deterioration of handwriting were more likely to phenoconvert to PD (HR: 2.6, 95%CI: 1.1-5.9, ) and those reporting difficulty handling utensils were more likely to phenoconvert to DLB (HR: 6.8, 95%CI: 1.2-38). Patients with a younger age of PAF onset [HR: 11, 95%CI: 2.6-46], preserved olfaction [HR: 8.7, 95%CI: 1.7-45], anhidrosis [HR: 1.8, 95%CI: 1-3.1, p=0.042], and severe urinary problems [HR 1.6, 95%CI: 1-2.5, p=0.033] were more likely to phenoconvert to MSA. The best autonomic predictor of PD was a blunted heart rate increase during the tilt-table test (HR: 6.1, 95%CI: 1.4-26). Patients with PAF have an estimated 12% (95% CI: 9%-15%) per year annual risk following study entry of phenoconverting to a manifest CNS synucleinopathy.

Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome.

Post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (PI-ME/CFS) is a disabling disorder, yet the clinical phenotype is poorly defined, the pathophysiology is unknown, and no disease-modifying treatments are available. We used rigorous criteria to recruit PI-ME/CFS participants with matched controls to conduct deep phenotyping. Among the many physical and cognitive complaints, one defining feature of PI-ME/CFS was an alteration of effort preference, rather than physical or central fatigue, due to dysfunction of integrative brain regions potentially associated with central catechol pathway dysregulation, with consequences on autonomic functioning and physical conditioning. Immune profiling suggested chronic antigenic stimulation with increase in naïve and decrease in switched memory B-cells. Alterations in gene expression profiles of peripheral blood mononuclear cells and metabolic pathways were consistent with cellular phenotypic studies and demonstrated differences according to sex. Together these clinical abnormalities and biomarker differences provide unique insight into the underlying pathophysiology of PI-ME/CFS, which may guide future intervention.

RNA methyltransferase SPOUT1/CENP-32 links mitotic spindle organization with the neurodevelopmental disorder SpADMiSS.

SPOUT1/CENP-32 encodes a putative SPOUT RNA methyltransferase previously identified as a mitotic chromosome associated protein. SPOUT1/CENP-32 depletion leads to centrosome detachment from the spindle poles and chromosome misalignment. Aided by gene matching platforms, we identified 24 individuals with neurodevelopmental delays from 18 families with bi-allelic variants in SPOUT1/CENP-32 detected by exome/genome sequencing. Zebrafish spout1/cenp-32 mutants showed reduction in larval head size with concomitant apoptosis likely associated with altered cell cycle progression. In vivo complementation assays in zebrafish indicated that SPOUT1/CENP-32 missense variants identified in humans are pathogenic. Crystal structure analysis of SPOUT1/CENP-32 revealed that most disease-associated missense variants mapped to the catalytic domain. Additionally, SPOUT1/CENP-32 recurrent missense variants had reduced methyltransferase activity in vitro and compromised centrosome tethering to the spindle poles in human cells. Thus, SPOUT1/CENP-32 pathogenic variants cause an autosomal recessive neurodevelopmental disorder: SpADMiSS ( SPOUT1 Associated Development delay Microcephaly Seizures Short stature) underpinned by mitotic spindle organization defects and consequent chromosome segregation errors.

Ripretinib versus sunitinib in gastrointestinal stromal tumor: ctDNA biomarker analysis of the phase 3 INTRIGUE trial.

INTRIGUE was an open-label, phase 3 study in adult patients with advanced gastrointestinal stromal tumor who had disease progression on or intolerance to imatinib and who were randomized to once-daily ripretinib 150 mg or sunitinib 50 mg. In the primary analysis, progression-free survival (PFS) with ripretinib was not superior to sunitinib. In clinical and nonclinical studies, ripretinib and sunitinib have demonstrated differential activity based on the exon location of KIT mutations. Therefore, we hypothesized that mutational analysis using circulating tumor DNA (ctDNA) might provide further insight. In this exploratory analysis (N = 362), baseline peripheral whole blood was analyzed by a 74-gene ctDNA next-generation sequencing-based assay. ctDNA was detected in 280/362 (77%) samples with KIT mutations in 213/362 patients (59%). Imatinib-resistant mutations were found in the KIT ATP-binding pocket (exons 13/14) and activation loop (exons 17/18). Mutational subgroup assessment showed 2 mutually exclusive populations with differential treatment effects. Patients with only KIT exon 11 + 13/14 mutations (ripretinib, n = 21; sunitinib, n = 20) had better PFS with sunitinib versus ripretinib (median, 15.0 versus 4.0 months). Patients with only KIT exon 11 + 17/18 mutations (ripretinib, n = 27; sunitinib, n = 25) had better PFS with ripretinib versus sunitinib (median, 14.2 versus 1.5 months). The results of this exploratory analysis suggest ctDNA sequencing may improve the prediction of the efficacy of single-drug therapies and support further evaluation of ripretinib in patients with KIT exon 11 + 17/18 mutations. ClinicalTrials.gov identifier: NCT03673501.

Upper-limb dysfunction in cancer survivors with chemotherapy-induced peripheral neurotoxicity.

INTRODUCTION: Upper-limb symptoms are often reported in the context of chemotherapy-induced peripheral neurotoxicity (CIPN), but objective quantification of functional deficits is often lacking. We examined and compared a range of neurophysiological and functional assessments of the upper-limb in the assessment of CIPN severity. METHODS: Cross-sectional assessment of neurotoxic chemotherapy-treated patients was undertaken using patient-reported and clinically-graded CIPN measures. Upper-limb functional assessments comprised of assessing fine motor skills, sensory perception, and neurophysiological measures of the median nerve. Group comparisons between participants who reported absence or presence of upper-limb functional deficits were investigated. RESULTS: 60 participants who were 11.5 (IQR = 4.0-26.0) months post-neurotoxic chemotherapy treatment reported CIPN. 65% (n = 39) reported upper-limb CIPN symptoms. Reduction in fine motor skills, sensory perception and median nerve SNAP amplitudes were associated with higher CIPN severity. Participants who self-reported presence of upper-limb functional deficits had worse CIPN severity across all measures, compared to participants who reported no upper-limb functional deficits. CONCLUSIONS: Participants who reported upper-limb symptoms and functional deficits had worse CIPN severity and quality-of-life. There is a high burden of upper-limb dysfunction long after neurotoxic chemotherapy treatment cessation. Focus on research into supportive care and rehabilitation options to improve upper-limb function is warranted to improve patient quality-of-life.

Improving accuracy in nodal staging of oral cancer: Proposal of a new system.

BACKGROUND: Despite introduction of extranodal extension (ENE) into the AJCC 8th edition of oral cancer staging, previous criticisms persist, such as limited discrimination between sub-stages and doubtful prognostic value of contralateral nodal disease. The purpose of this study was to compare our novel nodal staging system, based on the number of positive nodes and ENE, to the AJCC staging system in surgically treated patients. 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) and disease specific survival (DSS) as endpoint, the prognostic performance of AJCC 8th and 7th editions were compared using hazard consistency, hazard discrimination, likelihood difference and balance. RESULTS: Our new nodal staging system (PN) a progressive and linear increase in hazard ratio (HR) from pN0 to pN3, with good separation of Kaplan Meier curves. Using the predetermined criteria for evaluation of a staging system, our proposed staging model outperformed AJCC 8th and 7th editions in prediction of OS and DSS. CONCLUSION: PN was the lymph node staging system that provided the most accurate prediction of OS and DSS for patients in our cohort of OSCC. Additionally, it can be easily adopted, addresses the shortcomings of the existing systems and should be considered for future editions of the TNM staging system.

Post-COVID dysautonomias: what we know and (mainly) what we don't know.

Following on from the COVID-19 pandemic is another worldwide public health challenge that is referred to variously as long COVID, post-COVID syndrome or post-acute sequelae of SARS-CoV-2 infection (PASC). PASC comes in many forms and affects all body organs. This heterogeneous presentation suggests involvement of the autonomic nervous system (ANS), which has numerous roles in the maintenance of homeostasis and coordination of responses to various stressors. Thus far, studies of ANS dysregulation in people with PASC have been largely observational and descriptive, based on symptom inventories or objective but indirect measures of cardiovascular function, and have paid little attention to the adrenomedullary, hormonal and enteric nervous components of the ANS. Such investigations do not consider the syndromic nature of autonomic dysfunction. This Review provides an update on the literature relating to ANS abnormalities in people with post-COVID syndrome and presents a theoretical perspective on how the ANS might participate in common features of PASC.

Linking the Extended Autonomic System with the Homeostat Theory: New Perspectives about Dysautonomias.

Dysautonomias are conditions in which altered functions of one or more components of the autonomic nervous system (ANS) adversely affect health. This essay is about how elucidating mechanisms of dysautonomias may rationalize personalized treatments. Emphasized here are two relatively new ideas-the "extended" autonomic system (EAS) and the "homeostat" theory as applied to the pathophysiology and potential treatments of dysautonomias. The recently promulgated concept of the EAS updates Langley's ANS to include neuroendocrine, immune/inflammatory, and central components. The homeostat theory builds on Cannon's theory of homeostasis by proposing the existence of comparators (e.g., a thermostat, glucostat, carbistat, barostat) that receive information about regulated variables (e.g., core temperature, blood glucose, blood gases, delivery of blood to the brain). Homeostats sense discrepancies between the information and response algorithms. The presentation links the EAS with the homeostat theory to understand pathophysiological mechanisms of dysautonomias. Feed-forward anticipatory processes shift input-output curves and maintain plateau levels of regulated variables within different bounds of values-"allostasis". Sustained allostatic processes increase long-term wear-and-tear on effectors and organs-allostatic load. They decreaseing thresholds for destabilizing and potentially fatal positive feedback loops. The homeostat theory enables mathematical models that define stress, allostasis, and allostatic load. The present discussion applies the EAS and homeostat concepts to specific examples of pediatric, adolescent/adult, and geriatric dysautonomias-familial dysautonomia, chronic orthostatic intolerance, and Lewy body diseases. Computer modeling has the potential to take into account the complexity and dynamics of allostatic processes and may yield testable predictions about individualized treatments and outcomes.