Plasmonics-enhanced spikey nanorattle-based biosensor for direct SERS detection of mRNA cancer biomarkers.

We present a plasmonics-enhanced spikey nanorattle-based biosensor for direct surface-enhanced Raman scattering (SERS) detection of mRNA cancer biomarkers. Early detection of cancers such as head and neck squamous cell carcinoma (HNSCC) is critical for improving patient outcomes in regions with limited access to traditional diagnostic methods. Our method targets Keratin 14 (KRT14), a promising diagnostic mRNA biomarker for HNSCC, using a sandwich hybridization approach with magnetic beads and SERS spikey nanorattles (SpNR). We synthesized SpNR with a core-gap-shell structure to enhance SERS signals, achieving a limit of detection of 90 femtomolar. A pilot study using clinical samples demonstrated the efficacy of our biosensor in distinguishing between tissue with positive or negative diagnosis for HNSCC, highlighting its potential for rapid and sensitive cancer diagnostics in low-resource settings. This plasmonic assay offers a promising avenue for portable and high-specificity detection of nucleic acid biomarkers, with implications for early cancer detection and improved patient care, especially in middle and low-resource settings.

Assessment of the current and emerging criteria for the histopathological classification of lung neuroendocrine tumours in the lungNENomics project.

BACKGROUND: Six thoracic pathologists reviewed 259 lung neuroendocrine tumours (LNETs) from the lungNENomics project, with 171 of them having associated survival data. This cohort presents a unique opportunity to assess the strengths and limitations of current World Health Organization (WHO) classification criteria and to evaluate the utility of emerging markers. PATIENTS AND METHODS: Patients were diagnosed based on the 2021 WHO criteria, with atypical carcinoids (ACs) defined by the presence of focal necrosis and/or 2-10 mitoses per 2 mm2. We investigated two markers of tumour proliferation: the Ki-67 index and phospho-histone H3 (PHH3) protein expression, quantified by pathologists and automatically via deep learning. Additionally, an unsupervised deep learning algorithm was trained to uncover previously unnoticed morphological features with diagnostic value. RESULTS: The accuracy in distinguishing typical from ACs is hampered by interobserver variability in mitotic counting and the limitations of morphological criteria in identifying aggressive cases. Our study reveals that different Ki-67 cut-offs can categorise LNETs similarly to current WHO criteria. Counting mitoses in PHH3+ areas does not improve diagnosis, while providing a similar prognostic value to the current criteria. With the advantage of being time efficient, automated assessment of these markers leads to similar conclusions. Lastly, state-of-the-art deep learning modelling does not uncover undisclosed morphological features with diagnostic value. CONCLUSIONS: This study suggests that the mitotic criteria can be complemented by manual or automated assessment of Ki-67 or PHH3 protein expression, but these markers do not significantly improve the prognostic value of the current classification, as the AC group remains highly unspecific for aggressive cases. Therefore, we may have exhausted the potential of morphological features in classifying and prognosticating LNETs. Our study suggests that it might be time to shift the research focus towards investigating molecular markers that could contribute to a more clinically relevant morpho-molecular classification.

Survival of patients managed in France for duodenal neuroendocrine tumors (D-NET): a 20-year multicenter cohort study from the GTE group: a cohort study.

INTRODUCTION: Duodenal neuroendocrine tumours (D-NETs) have a low incidence; however, their diagnosis has been increasing. Features such as tumour location, size, type, histological grade, and stage were used to adapt the treatment to either endoscopic (ER) or surgical (SR) resections. There is no consensus regarding the definitive treatment. The authors' study aimed to describe the management of non-metastatic, well-differentiated D-NETs in France and its impact on patient survival. METHODS: A registry-based multicenter study using prospectively collected data between 2000 and 2019, including all patients managed for non-metastatic G1 and G2 D-NETs, was conducted in the GTE group. RESULTS: A total of 153 patients were included. Fifty-eight benefited from an ER, and 95 had an SR. No difference in recurrence-free survival (RFS) was observed regardless of treatment type. There was no significant difference between the two groups (ER vs. SR) in terms of location, size, grade, or lymphadenopathy, regardless of the type of incomplete resection performed or regarding the pre-therapeutic assessment of lymph node invasion in imaging. The surgery allowed for significantly more complete resection (patients with R1 resection in the SR group: 9 vs. 14 in the ER group, P <0.001). Among the 51 patients with positive lymph node dissection after SR, tumour size was less than or equal to 1 cm in 25 cases. Surgical complications were more numerous ( P =0.001). In the sub-group analysis of G1-G2 D-NETs between 11 and 19 mm, there was no significant difference in grade ( P =0.977) and location ( P =0.617) between the two groups (ER vs. SR). No significant difference was found in both morphological and functional imaging, focusing on the pre-therapeutic assessment of lymph node invasion ( P =0.387). CONCLUSION: Regardless of the resection type (ER or SR) of G1-G2 non-metastatic D-NETs, as well as the type of management of incomplete resection, which was greater in the ER group, long-term survival results were similar between ER and SR. Organ preservation seems to be the best choice owing to the slow evolution of these tumours.

Artificial Intelligence in Medicine: A Caution About Good Intentions and Where It May Lead.

Implementing Artificial Intelligence in medicine is revolutionizing how medicine is practiced. It has much promise in bringing about improved clinical outcomes and efficiency while decreasing costs. There are also concerns and unintended consequences that are being realized and significant efforts to consider ethical principles in the implementation of Artificial Intelligence in medicine. One potential consequence may be the loss of what has been described as the soul of medicine: the physician-patient relationship. This relationship is especially precious in the context of what the US Surgeon General Vivek H. Murthy MD has called an "Epidemic of Loneliness and Isolation." This commentary describes considerations and potential steps to protect this vital relationship while implementing Artificial Intelligence approaches to improving patient care. If not vigilant, Artificial Intelligence may unintentionally erode the physician-patient relationship resulting in physician/patient isolation.

Lateral neck dissection surgeon volume and complications in head and neck endocrine malignancy.

Background: Increased surgeon volume is associated with decreased complications for many surgeries, including thyroidectomy. We sought to use two national databases to assess for associations between surgeon volume and complications in patients undergoing lateral neck dissection for thyroid or parathyroid malignancy. Methods: Lateral neck dissections for thyroid and parathyroid cancer from the Nationwide Inpatient Sample and State Inpatient Database were analyzed. The primary outcome was any inpatient complication common to thyroidectomy, parathyroidectomy, or lateral neck dissection. The principle independent variable was surgeon volume. Multivariable analysis was then performed on this retrospective cohort study. Results: The 1,094 Nationwide Inpatient Sample discharges had a 28% (305/1,094) complication rate. After adjustment, surgeons with volumes between 3-34 neck dissections/year demonstrated a surgeon volume-complication rate association [adjusted odds ratio: 1.03; 95% confidence interval (CI): 1.01-1.05]. The 1,235 State inpatient Database discharges had a 21% (258/1,235) overall complication rate, and no association between surgeon volume and complication rates (P=0.25). Conclusions: This retrospective review of 2,329 discharges for patients undergoing lateral neck dissection for thyroid or parathyroidectomy demonstrated somewhat conflicting results. The Nationwide Inpatient Sample demonstrated increasing complication rates for increasing surgeon volume among intermediate volume surgeons, while the State Inpatient Database demonstrated no surgeon volume-complication association. Given these disparate results, and further limitations with these databases, conclusions regarding surgical volume and clinical decision making based on these data should be assessed cautiously.

Deep-Learning-Based Screening and Ancillary Testing for Thyroid Cytopathology.

Thyroid cancer is the most common malignant endocrine tumor. The key test to assess preoperative risk of malignancy is cytologic evaluation of fine-needle aspiration biopsies (FNABs). The evaluation findings can often be indeterminate, leading to unnecessary surgery for benign post-surgical diagnoses. We have developed a deep-learning algorithm to analyze thyroid FNAB whole-slide images (WSIs). We show, on the largest reported data set of thyroid FNAB WSIs, clinical-grade performance in the screening of determinate cases and indications for its use as an ancillary test to disambiguate indeterminate cases. The algorithm screened and definitively classified 45.1% (130/288) of the WSIs as either benign or malignant with risk of malignancy rates of 2.7% and 94.7%, respectively. It reduced the number of indeterminate cases (N = 108) by reclassifying 21.3% (N = 23) as benign with a resultant risk of malignancy rate of 1.8%. Similar results were reproduced using a data set of consecutive FNABs collected during an entire calendar year, achieving clinically acceptable margins of error for thyroid FNAB classification.

Study Design, Rationale, and Methodology for Promote Weight Loss in Patients With Peripheral Artery Disease Who Also Have Obesity: The PROVE Trial.

Background Overweight and obesity are associated with adverse functional outcomes in people with peripheral artery disease (PAD). The effects of weight loss in people with overweight/obesity and PAD are unknown. Methods The PROVE (Promote Weight Loss in Obese PAD Patients to Prevent Mobility Loss) Trial is a multicentered randomized clinical trial with the primary aim of testing whether a behavioral intervention designed to help participants with PAD lose weight and walk for exercise improves 6-minute walk distance at 12-month follow-up, compared with walking exercise alone. A total of 212 participants with PAD and body mass index ≥25 kg/m2 will be randomized. Interventions are delivered using a Group Mediated Cognitive Behavioral intervention model, a smartphone application, and individual telephone coaching. The primary outcome is 12-month change in 6-minute walk distance. Secondary outcomes include total minutes of walking exercise/wk at 12-month follow-up and 12-month change in accelerometer-measured physical activity, the Walking Impairment Questionnaire distance score, and the Patient-Reported Outcomes Measurement Information System mobility questionnaire. Tertiary outcomes include 12-month changes in perceived exertional effort at the end of the 6-minute walk, diet quality, and the Short Physical Performance Battery. Exploratory outcomes include changes in gastrocnemius muscle biopsy measures of mitochondrial cytochrome C oxidase activity, mitochondrial biogenesis, capillary density, and inflammatory markers. Conclusions The PROVE randomized clinical trial will evaluate the effects of exercise with an intervention of coaching and a smartphone application designed to achieve weight loss, compared with exercise alone, on walking performance in people with PAD and overweight/obesity. Results will inform optimal treatment for the growing number of patients with PAD who have overweight/obesity. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04228978.

Novel use and utilization of robotic Hoyer-Hook system for suspension of panniculus morbidus.

Panniculus morbidus is a complication of morbid obesity characterized by massive abdominal folds that hang below the beltline. Ulceration, dermatitis, and sinus tract formation of the pannus can cause significant morbidity to the patient and impair activities of daily living. If patients fail medical management, the next step is surgical excision. Challenging aspects of the procedure include adequate suspension of the pannus, cost, and prevention of intra-abdominal injuries. We present a case of a 70-year-old female with panniculus morbidus with endometrial carcinoma. We successfully performed a panniculectomy using a novel combination of towel hooks and the Hoyer lift to suspend the abdomen. In the same anesthesia event, she underwent robotic-assisted hysterectomy. No intra-operative or post-operative complications were encountered, and the patient was satisfied with her results. In this case, we demonstrated an effective and cost-efficient approach to panniculectomy in the severely obese patient.

International Collaboration Trends in Facial Plastic and Reconstructive Surgery: A Systematic Bibliometric Scoping Review.

Importance: Research in facial plastic and reconstructive surgery (FPRS) in the global health setting, especially in low- and middle-income countries (LMICs), is increasing year by year. As this work progresses, it will be crucial to include voices and perspectives of individuals living in the LMICs being studied. Objective: To characterize and understand international collaborations in published literature on FPRS care in a global health setting and report patterns in whether these articles included authors from the LMICs in which the studies took place. Evidence Review: A systematic bibliometric scoping review of articles in Scopus from 1971 to 2022 was performed using a set list of search terms; studies were included using predetermined inclusion and exclusion criteria. Studies met criteria for inclusion if the abstract or text contained information regarding surgeons from a different country performing surgery or conducting research in an LMIC within the domain of FPRS. Exclusion criteria were studies that did not mention a facial plastic or reconstructive surgery and studies where both an HIC and LMIC were not mentioned. Findings: A total of 286 studies met criteria for inclusion. The highest percentage of studies (n = 72, 25.2%) were conducted across multiple countries. A total of 120 studies (41.9%) discussed cleft lip/palate. Overall, 141 studies (49.5%) included at least 1 author from the host LMIC; 89 (31.1%) had first authors from LMICs, and 72 (25.2%) had senior authors from LMICs. A total of 79 studies (27.6%) described humanitarian clinical service trips without mentioning research or education in the text. The remaining studies described research, education projects, or a combination. The published literature on humanitarian service trips had the lowest rate of inclusion of a first or senior author from the host LMICs. Conclusions and Relevance: In this systematic bibliometric scoping review, findings showed a general trend of increased international work in the field of FPRS. However, there continues to be a paucity of inclusive authorship trends, with the majority of studies not including first or senior authors from LMICs. The findings presented here encourage new collaborations worldwide, as well as the improvement of existing efforts.

Thyroid Cytopathology Cancer Diagnosis from Smartphone Images Using Machine Learning.

We examined the performance of deep learning models on the classification of thyroid fine-needle aspiration biopsies using microscope images captured in 2 ways: with a high-resolution scanner and with a mobile phone camera. Our training set consisted of images from 964 whole-slide images captured with a high-resolution scanner. Our test set consisted of 100 slides; 20 manually selected regions of interest (ROIs) from each slide were captured in 2 ways as mentioned above. Applying a baseline machine learning algorithm trained on scanner ROIs resulted in performance deterioration when applied to the smartphone ROIs (97.8% area under the receiver operating characteristic curve [AUC], CI = [95.4%, 100.0%] for scanner images vs 89.5% AUC, CI = [82.3%, 96.6%] for mobile images, P = .019). Preliminary analysis via histogram matching showed that the baseline model was overly sensitive to slight color variations in the images (specifically, to color differences between mobile and scanner images). Adding color augmentation during training reduces this sensitivity and narrows the performance gap between mobile and scanner images (97.6% AUC, CI = [95.0%, 100.0%] for scanner images vs 96.0% AUC, CI = [91.8%, 100.0%] for mobile images, P = .309), with both modalities on par with human pathologist performance (95.6% AUC, CI = [91.6%, 99.5%]) for malignancy prediction (P = .398 for pathologist vs scanner and P = .875 for pathologist vs mobile). For indeterminate cases (pathologist-assigned Bethesda category of 3, 4, or 5), color augmentations confer some improvement (88.3% AUC, CI = [73.7%, 100.0%] for the baseline model vs 96.2% AUC, CI = [90.9%, 100.0%] with color augmentations, P = .158). In addition, we found that our model's performance levels off after 15 ROIs, a promising indication that ROI data collection would not be time-consuming for our diagnostic system. Finally, we showed that the model has sensible Bethesda category (TBS) predictions (increasing risk malignancy rate with predicted TBS category, with 0% malignancy for predicted TBS 2 and 100% malignancy for TBS 6).

A Clinical Study to Assess Diffuse Reflectance Spectroscopy with an Auto-Calibrated, Pressure-Sensing Optical Probe in Head and Neck Cancer.

Diffuse reflectance spectroscopy (DRS) is a powerful tool for quantifying optical and physiological tissue properties such as hemoglobin oxygen saturation and vascularity. DRS is increasingly used clinically for distinguishing cancerous lesions from normal tissue. However, its widespread clinical acceptance is still limited due to uncontrolled probe-tissue interface pressure that influences reproducibility and introduces operator-dependent results. In this clinical study, we assessed and validated a pressure-sensing and automatic self-calibration DRS in patients with suspected head and neck squamous cell carcinoma (HNSCC). The clinical study enrolled nineteen patients undergoing HNSCC surgical biopsy procedures. Patients consented to evaluation of this improved DRS system during surgery. For each patient, we obtained 10 repeated measurements on one tumor site and one distant normal location. Using a Monte Carlo-based model, we extracted the hemoglobin saturation data along with total hemoglobin content and scattering properties. A total of twelve cancer tissue samples from HNSCC patients and fourteen normal tissues were analyzed. A linear mixed effects model tested for significance between repeated measurements and compared tumor versus normal tissue. These results demonstrate that cancerous tissues have a significantly lower hemoglobin saturation compared to normal controls (p < 0.001), which may be reflective of tumor hypoxia. In addition, there were minimal changes over time upon probe placement and repeated measurement, indicating that the pressure-induced changes were minimal and repeated measurements did not differ significantly from the initial value. This study demonstrates the feasibility of conducting optical spectroscopy measurements on intact lesions prior to removal during HNSCC procedures, and established that this probe provides diagnostically-relevant physiologic information that may impact further treatment.

Octreotide may improve pharyngocutaneous fistula healing through downregulation of cystatins: A pilot study.

Background: Pharyngocutaneous fistula (PCF) and salivary leaks are well known complications of head and neck surgery. The medical management of PCF has included the use of octreotide without a well-defined understanding of its therapeutic mechanism. We hypothesized that octreotide induces alterations in the saliva proteome and that these alterations may provide insight into the mechanism of action underlying improved PCF healing. We undertook an exploratory pilot study in healthy controls that involved collecting saliva before and after a subcutaneous injection of octreotide and performing proteomic analysis to determine the effects of octreotide. Methods: Four healthy adult participants provided saliva samples before and after subcutaneous injection of octreotide. A mass-spectrometry based workflow optimized for the quantitative proteomic analysis of biofluids was then employed to analyze changes in salivary protein abundance after octreotide administration. Results: There were 3076 human, 332 Streptococcus mitis, 102 G. haemolyans, and 42 Granulicatella adiacens protein groups quantified in saliva samples. A paired statistical analysis was performed using the generalized linear model (glm) function in edgeR. There were and ~300 proteins that had a p < .05 between the pre- and post-octreotide groups ~50 proteins with an FDR-corrected p < .05 between pre- and post-groups. These results were visualized using a volcano plot after filtering on proteins quantified by 2 more or unique precursors. Both human and bacterial proteins were among the proteins altered by octreotide treatment. Notably, four isoforms of the human cystatins, belonging to a family of cysteine proteases, that had significantly lower abundance after treatment. Conclusion: This pilot study demonstrated octreotide-induced downregulation of cystatins. By downregulation of cystatins in the saliva, there is decreased inhibition of cysteine proteases such as Cathepsin S. This results in increased cysteine protease activity that has been linked to enhanced angiogenic response, cell proliferation and migration that have resulted in improved wound healing. These insights provide first steps at furthering our understanding of octreotide's effects on saliva and reports of improved PCF healing.

Non-surgical Management of Locally Advanced Basal Cell Carcinoma of the Upper Extremity With Vismodegib.

Basal cell carcinoma (BCC) is a common skin malignancy that can present reconstructive challenges in patients with locally advanced diseases of the extremities. This article highlights three cases of locally advanced BCC of the extremities managed with vismodegib (Erivedge, Genentech). Vismodegib is a sonic hedgehog pathway (Shh) inhibitor approved by the FDA for use in metastatic or recurrent BCC. All three patients in our case series demonstrated significant clinical responses with reductions in tumor size which obviated the need for complex reconstructive surgery or amputation.

A comprehensive survey of collaborative biostatistics units in academic health centers.

The organizational structures of collaborative biostatistics units in academic health centers (AHCs) in the United States and their important contributions to research are an evolving and active area of discussion and inquiry. Collaborative biostatistics units may serve as a centralized resource to investigators across various disciplines or as shared infrastructure for investigators within a discipline (e.g., cancer), or a combination of both. The characteristics of such units vary greatly, and there has been no comprehensive review of their organizational structures described in the literature to date. This manuscript summarizes the current infrastructure of such units using responses from 129 leaders. Most leaders were over 45 years old, held doctoral degrees, and were on a 12-month appointment. Over half were tenured or on a tenure track and held primary appointments in a school of medicine. Career advancement metrics most important included being funded as co-investigator on NIH grants and being either first or second author on peer-reviewed publications. Team composition was diverse in terms of expertise and training, and funding sources were typically hybrid. These results provide a benchmark for collaboration models and evaluation and may be used by institutional administrators as they build, evaluate, or restructure current collaborative quantitative support infrastructure.

Kidney tubule health, mineral metabolism and adverse events in persons with CKD in SPRINT.

BACKGROUND: Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown. METHODS: Among 2377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia). RESULTS: At baseline, the mean age was 73 ± 9 years and mean estimated glomerular filtration rate (eGFR) was 46 ± 11 mL/min/1.73 m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL) and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD) and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL [hazard ratio (HR) = 1.08 per 2-fold higher biomarker level, 95% confidence interval (CI) 1.03-1.13], higher MCP-1 (HR = 1.11, 95% CI 1.03-1.19) and lower UMOD (HR = 0.91, 95% CI 0.85-0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P > 0.10 for all interactions). CONCLUSIONS: Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.

European Respiratory Society guideline on non-CPAP therapies for obstructive sleep apnoea.

Treatment of obstructive sleep apnoea (OSA) in adults is evolving, as new therapies have been explored and introduced in clinical practice, while other approaches have been refined or reconsidered. In this European Respiratory Society (ERS) guideline on non-continuous positive airway pressure (CPAP) therapies for OSA, we present recommendations determined by a systematic review of the literature. It is an update of the 2011 ERS statement on non-CPAP therapies, advanced into a clinical guideline. A multidisciplinary group of experts, including pulmonary, surgical, dentistry and ear-nose-throat specialists, methodologists and patient representatives considered the most relevant clinical questions (for both clinicians and patients) relating to the management of OSA. Eight key clinical questions were generated and a systematic review was conducted to identify published randomised clinical trials that answered these questions. We used the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach to assess the quality of the evidence and the strength of recommendations. The resulting guideline addresses gastric bypass surgery, custom-made dual-block mandibular advancement devices, hypoglossal nerve stimulation, myofunctional therapy, maxillo-mandibular osteotomy, carbonic anhydrase inhibitors and positional therapy. These recommendations can be used to benchmark quality of care for people with OSA across Europe and to improve outcomes.

Incidence and Risk of Suicide Among Patients With Head and Neck Cancer in Rural, Urban, and Metropolitan Areas.

Importance: Patients with head and neck cancer (HNC) are known to be at increased risk of suicide compared with the general population, but there has been insufficient research on whether this risk differs based on patients' rural, urban, or metropolitan residence status. Objective: To evaluate whether the risk of suicide among patients with HNC differs by rural vs urban or metropolitan residence status. Design, Setting, and Participants: This cross-sectional study uses data from the Surveillance, Epidemiology, and End Results database on patients aged 18 to 74 years who received a diagnosis of HNC from January 1, 2000, to December 31, 2016. Statistical analysis was conducted from November 27, 2020, to June 3, 2021. Exposures: Residence status, assessed using 2013 Rural Urban Continuum Codes. Main Outcomes and Measures: Death due to suicide was assessed by International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes (U03, X60-X84, and Y87.0) and the cause of death recode (50220). Standardized mortality ratios (SMRs) of suicide, assessing the suicide risk among patients with HNC compared with the general population, were calculated. Suicide risk by residence status was compared using Fine-Gray proportional hazards regression models. Results: Data from 134 510 patients with HNC (101 142 men [75.2%]; mean [SE] age, 57.7 [10.3] years) were analyzed, and 405 suicides were identified. Metropolitan residents composed 86.6% of the sample, urban residents composed 11.7%, and rural residents composed 1.7%. The mortality rate of suicide was 59.2 per 100 000 person-years in metropolitan counties, 64.0 per 100 000 person-years in urban counties, and 126.7 per 100 000 person-years in rural counties. Compared with the general population, the risk of suicide was markedly higher among patients with HNC in metropolitan (SMR, 2.78; 95% CI, 2.49-3.09), urban (SMR, 2.84; 95% CI, 2.13-3.71), and rural (SMR, 5.47; 95% CI, 3.06-9.02) areas. In Fine-Gray competing-risk analyses that adjusted for other covariates, there was no meaningful difference in suicide risk among urban vs metropolitan residents. However, compared with rural residents, residents of urban (subdistribution hazard ratio, 0.52; 95% CI, 0.29-0.94) and metropolitan counties (subdistribution hazard ratio, 0.55; 95% CI, 0.32-0.94) had greatly lower risk of suicide. Conclusions and Relevance: The findings of this cross-sectional study suggest that suicide risk is elevated in general among patients with HNC but is significantly higher for patients residing in rural areas. Effective suicide prevention strategies in the population of patients with HNC need to account for rural health owing to the high risk of suicide among residents with HNC in rural areas.

Issues and limitations of available biomarkers for fluoropyrimidine-based chemotherapy toxicity, a narrative review of the literature.

Fluoropyrimidine-based chemotherapies are widely used to treat gastrointestinal tract, head and neck, and breast carcinomas. Severe toxicities mostly impact rapidly dividing cell lines and can occur due to the partial or complete deficiency in dihydropyrimidine dehydrogenase (DPD) catabolism. Since April 2020, the European Medicines Agency (EMA) recommends DPD testing before any fluoropyrimidine-based treatment. Currently, different assays are used to predict DPD deficiency; the two main approaches consist of either phenotyping the enzyme activity (directly or indirectly) or genotyping the four main deficiency-related polymorphisms associated with 5-fluorouracil (5-FU) toxicity. In this review, we focused on the advantages and limitations of these diagnostic methods: direct phenotyping by evaluation of peripheral mononuclear cell DPD activity (PBMC-DPD activity), indirect phenotyping assessed by uracil levels or UH2/U ratio, and genotyping DPD of four variants directly associated with 5-FU toxicity. The risk of 5-FU toxicity increases with uracil concentration. Having a pyrimidine-related structure, 5-FU is catabolised by the same physiological pathway. By assessing uracil concentration in plasma, indirect phenotyping of DPD is then measured. With this approach, in France, a decreased 5-FU dose is systematically recommended at a uracil concentration of 16 ng/ml, which may lead to chemotherapy under-exposure as uracil concentration is a continuous variable and the association between uracil levels and DPD activity is not clear. We aim herein to describe the different available strategies developed to improve fluoropyrimidine-based chemotherapy safety, how they are implemented in routine clinical practice, and the possible relationship with inefficacy mechanisms.