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ImportanceLip, oral, and pharyngeal cancers are important contributors to cancer burden worldwide, and a comprehensive evaluation of their burden globally, regionally, and nationally is crucial for effective policy planning.ObjectiveTo analyze the total and risk-attributable burden of lip and oral cavity cancer (LOC) and other pharyngeal cancer (OPC) for 204 countries and territories and by Socio-demographic Index (SDI) using 2019 Global Burden of Diseases, Injuries, and Risk Factors (GBD) Study estimates.Evidence ReviewThe incidence, mortality, and disability-adjusted life years (DALYs) due to LOC and OPC from 1990 to 2019 were estimated using GBD 2019 methods. The GBD 2019 comparative risk assessment framework was used to estimate the proportion of deaths and DALYs for LOC and OPC attributable to smoking, tobacco, and alcohol consumption in 2019.FindingsIn 2019, 370 000 (95% uncertainty interval [UI], 338 000-401 000) cases and 199 000 (95% UI, 181 000-217 000) deaths for LOC and 167 000 (95% UI, 153 000-180 000) cases and 114 000 (95% UI, 103 000-126 000) deaths for OPC were estimated to occur globally, contributing 5.5 million (95% UI, 5.0-6.0 million) and 3.2 million (95% UI, 2.9-3.6 million) DALYs, respectively. From 1990 to 2019, low-middle and low SDI regions consistently showed the highest age-standardized mortality rates due to LOC and OPC, while the high SDI strata exhibited age-standardized incidence rates decreasing for LOC and increasing for OPC. Globally in 2019, smoking had the greatest contribution to risk-attributable OPC deaths for both sexes (55.8% [95% UI, 49.2%-62.0%] of all OPC deaths in male individuals and 17.4% [95% UI, 13.8%-21.2%] of all OPC deaths in female individuals). Smoking and alcohol both contributed to substantial LOC deaths globally among male individuals (42.3% [95% UI, 35.2%-48.6%] and 40.2% [95% UI, 33.3%-46.8%] of all risk-attributable cancer deaths, respectively), while chewing tobacco contributed to the greatest attributable LOC deaths among female individuals (27.6% [95% UI, 21.5%-33.8%]), driven by high risk-attributable burden in South and Southeast Asia.Conclusions and RelevanceIn this systematic analysis, disparities in LOC and OPC burden existed across the SDI spectrum, and a considerable percentage of burden was attributable to tobacco and alcohol use. These estimates can contribute to an understanding of the distribution and disparities in LOC and OPC burden globally and support cancer control planning efforts.

Background: Both valvular heart disease (VHD) and atrial fibrillation (AF) frequently coexist. AF is an important cause of arrhythmias with a definitive cardiovascular morbidity. The use of either vitamin K antagonists (VKAs/warfarin) or direct oral anticoagulants (DOACs) (also known as new oral anticoagulants (NOACs)) has been the mainstay for preventing stroke and systemic embolism in patients with VHD and/or AF, and this has been broadly discussed. However, there are limited studies on anticoagulation therapy for patients with valvular atrial fibrillation (VAF). The main aim of this meta-analysis was to evaluate the outcomes (stroke–vascular events and intracranial bleeding) following DOAC and VKA treatment amongst patients with VAF. Methods: We identified clinical trials and observational studies published in the last 10 years. A systematic review and a meta-analysis were performed to evaluate the outcomes of patients with valvular atrial fibrillation following DOAC vs. VKA treatment. Data evaluation was performed using Review Manager 5.4; the endpoints were stroke–vascular events and intracranial bleeding following DOAC and VKA treatment amongst VAF patients. Risk ratios (RR) were evaluated with 95% confidence intervals. Using random effects models, forest plots were obtained. Heterogeneity was assessed by using the I2 statistic. Results: Eight studies were included in this metanalysis, and a total of fifteen thousand two hundred and fifteen patients (DOAC (8732) and VKA (6483)) were pooled. We found a significant risk reduction in stroke–vascular events when using DOACs in comparison with using VKAs (pooled RR: 0.76; 95% CI: 0.64–0.90, p = 0.002). A total of 14862 patients (DOAC (8561) and VKA (6301)) were pooled from a total of six studies for intracranial bleeding. We found a significant risk reduction in terms of intracranial bleeding when using DOACs in comparison with using VKAs (pooled RR: 0.43; 95% CI: 0.24–0.77, p ≤ 0.05). Conclusions: When compared to VKAs, DOAC agents were found to have less risk of stroke–vascular events and intracranial bleeding. Further prospective studies are essential to establish the efficacy and safety of DOAC agents in patients with various subtypes of VAF.

Physical exercise is an indispensable element in the multidisciplinary treatment of fibromyalgia syndrome (FMS). The present study examined if men diagnosed with FMS engaged in any type of physical activity or exercise, the perceived effects from exercise, and who specifically recommended exercise. A qualitative cross-cultural study was performed in fibromyalgia clinical units in Spain and the United States. A total of 17 participants, 10 men from Spain and 7 men from the US, were included. In Spain, a focus group was completed in two parts, one month apart in 2018. In the US, five individual interviews and one joint interview with two men were completed in 2018. Three central themes appeared in the qualitative data: (1) Understanding what constitutes physical activity or exercise, (2) Facilitating or discouraging the performance of physical exercise, and (3) Effects of physical activity or exercise on psychological and social symptoms. The actual practice of exercise by patients with FMS is often perceived as leading to pain and fatigue, rather than a treatment facilitator. Physical activity and exercise can provide benefits, including relaxation, socialization, and increased muscle tone. However, minor opioids limit physical activity as they cause addiction, drowsiness, and decrease physical activity in Spanish men. Recommendations in a clinical setting should incorporate exercise as well as physical activity via daily life activities.

Study Design. Retrospective cohort study. Objective. Hounsfield units (HUs) are known to correlate with clinical outcomes, but no study has evaluated how they correlate with biomechanical computed tomography (BCT) and dual-energy x-ray absorptiometry (DXA) measurements. Summary of Background. Low bone mineral density (BMD) represents a major risk factor for fracture and poor outcomes following spine surgery. DXA can provide regional BMD measurements but has limitations. Opportunistic HUs provide targeted BMD estimates; however, they are not formally accepted for diagnosing osteoporosis in current guidelines. More recently, BCT analysis has emerged as a new modality endorsed by the International Society for Clinical Densitometry for assessing bone strength. Methods. Consecutive cases from 2017 to 2022 at a single institution were reviewed for patients who underwent BCT in the thoracolumbar spine. BCT-measured vertebral strength, trabecular BMD, and the corresponding American College of Radiology Classification were recorded. DXA studies within three months of the BCT were reviewed. Pearson Correlation Coefficients were calculated, and receiver-operating characteristic curves were constructed to assess the predictive capacity of HUs. Threshold analysis was performed to identify optimal HU values for identifying osteoporosis and low BMD. Results. Correlation analysis of 114 cases revealed a strong relationship between HUs and BCT vertebral strength (r=0.69; P<0.0001; R 2=0.47) and trabecular BMD (r=0.76; P<0.0001; R 2=0.58). However, DXA poorly correlated with opportunistic HUs and BCT measurements. HUs accurately predicted osteoporosis and low BMD (Osteoporosis: C=0.95, 95% CI 0.89–1.00; Low BMD: C=0.87, 95% CI 0.79–0.96). Threshold analysis revealed that 106 and 122 HUs represent optimal thresholds for detecting osteoporosis and low BMD. Conclusion. Opportunistic HUs strongly correlated with BCT-based measures, while neither correlated strongly with DXA-based BMD measures in the thoracolumbar spine. HUs are easy to perform at no additional cost and provide accurate BMD estimates at noninstrumented vertebral levels across all American College of Radiology-designated BMD categories.

Neurointestinal diseases result from dysregulated interactions between the nervous system and the gastrointestinal (GI) tract, leading to conditions such as Hirschsprung’s disease and irritable bowel syndrome. These disorders affect many people, significantly diminishing their quality of life and overall health. Central to GI motility are the interstitial cells of Cajal (ICC), which play a key role in muscle contractions and neuromuscular transmission. This review highlights the role of ICC in neurointestinal diseases, revealing their association with various GI ailments. Understanding the functions of the ICC could lead to innovative perspectives on the modulation of GI motility and introduce new therapeutic paradigms. These insights have the potential to enhance efforts to combat neurointestinal diseases and may lead to interventions that could alleviate or even reverse these conditions.

Objective To build on the recently completed GRADE (Glycemia Reduction Approaches in Diabetes: A Comparative Effectiveness Study) randomised trial examining the comparative effectiveness of second line glucose lowering drugs in achieving and maintaining glycaemic control in adults with type 2 diabetes. Design Emulation of a target trial. Setting Medical and pharmacy claims data from the OptumLabs Data Warehouse, a de-identified US national dataset of beneficiaries of commercially insured and Medicare Advantage plans, 29 March 2013 to 30 June 2021. Participants Adults (≥18 years) with type 2 diabetes who first started taking glimepiride, sitagliptin, liraglutide, insulin glargine, or canagliflozin between 29 March 2013 and 30 June 2021. Participants were treatment naive or were receiving metformin monotherapy at the time of starting the study drug. Main outcome measures The main outcomes were time to primary and secondary metabolic failure of the assigned treatment, calculated as days to haemoglobin A1c levels of ≥7.0% and >7.5%, respectively. Secondary metabolic, cardiovascular, and microvascular outcomes were analysed as specified in the GRADE statistical analysis plan. Propensity scores were estimated with the gradient boosting method, and inverse propensity score weighting was used to emulate randomisation to the treatment groups, which were then compared with Cox proportional hazards regression. (Results The study cohort included participants starting treatment with glimepiride (n=20 511), liraglutide (n=5569), sitagliptin (n=13 039), insulin glargine (n=7262), and canagliflozin (n=5290). The insulin glargine arm was excluded because of insufficient control of confounding. Median times to primary metabolic failure were 439 (95% confidence interval 400 to 489) days in the canagliflozin arm, 439 (426 to 453) days in the glimepiride arm, 624 (567 to 731) days in the liraglutide arm, and 461 (442 to 482) days in the sitagliptin arm. Median time to secondary metabolic failure was also longest in the liraglutide arm. Adults receiving liraglutide had the lowest one year cumulative incidence rate of primary metabolic failure (0.37, 95% confidence interval 0.35 to 0.40) followed by sitagliptin (0.44, 0.43 to 0.45), glimepiride (0.45, 0.44 to 0.45), and canagliflozin (0.46, 0.44 to 0.48). Similarly, the one year cumulative incidence rate of secondary metabolic failure was 0.27 (0.25 to 0.29) in the canagliflozin arm, 0.28 (0.27 to 0.29) in the glimepiride arm, 0.23 (0.21 to 0.26) in the liraglutide arm, and 0.28 (0.27 to 0.29) in the sitagliptin arm. No differences were observed between the study arms in the rates of microvascular and macrovascular complications. Conclusions In this target trial emulation of an expanded GRADE study framework, liraglutide was more effective in achieving and maintaining glycaemic control as a second line glucose lowering drug than canagliflozin, sitagliptin, or glimepiride.

Malignant peritoneal mesothelioma (MPeM) is a rare malignancy and represents 5% to 30% of malignant mesothelioma cases. The primary curative therapy for MPeM is radical cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), with the strongest predictor of long-term survival being complete cytoreduction. There is a paucity of high-quality evidence available to guide management in MPeM; however, NCCN Guidelines for the management of MPeM were updated this year. In well-selected patients, 5-year overall survival exceeds 65%, but achieving optimal results requires careful preoperative evaluation and expert surgical management. Preoperative patient selection includes histology review and staging with cross-sectional imaging. Ideal candidates for curative intent surgery are those with epithelioid MPeM, a low peritoneal cancer index, and a good performance status. Contraindications to curative intent surgery include the sarcomatoid MPeM, distant metastases, extensive nodal metastases, and extensive small bowel serosal or mesentery involvement not amenable to complete cytoreduction. Those with biphasic histology, bicavitary disease, and metastatic lymphadenopathy may be considered for surgery following response to neoadjuvant therapy. CRS involves resection of all peritoneal disease, the extent of which varies case by case. Key aspects involve careful evaluation of all peritoneal surfaces, complete parietal peritonectomy and omentectomy, and evaluating suspicious abdominal lymph node basins. Once maximum cytoreduction is achieved, HIPEC is performed using a platinum-based perfusate. Postoperative protocols are recommended to optimize recovery and mitigate HIPEC-specific complications, namely chemotherapy-mediated nephrotoxicity and bone marrow suppression.

Mesothelioma is a rare cancer originating in mesothelial surfaces of the peritoneum, pleura, and other sites. These NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) focus on peritoneal mesothelioma (PeM). The NCCN Guidelines for PeM provide recommendations for workup, diagnosis, and treatment of primary as well as previously treated PeM. The diagnosis of PeM may be delayed because PeM mimics other diseases and conditions and because the disease is so rare. The pathology section was recently updated to include new information about markers used to identify mesothelioma, which is difficult to diagnose. The term “malignant” is no longer used to classify mesotheliomas, because all mesotheliomas are now defined as malignant.

Immune checkpoint inhibitors (ICIs) induce profound benefits in cancer patients with mismatch repair gene mutations or high levels of microsatellite instability. Herein, we present a case of a patient with history of Muir-Torre/Lynch syndrome and metastatic gastric adenocarcinoma in the presence of an MSH2 gene mutation. The patient was initially treated with a PD-1 inhibitor, pembrolizumab, but developed grade 4 myocarditis requiring treatment with infliximab and a prolonged steroid taper. Following discontinuation of pembrolizumab, surveillance testing showed no radiographic or endoscopic evidence of progression for 7 months, until biopsy results from a repeat upper endoscopy indicated local disease recurrence. The patient was subsequently rechallenged with another PD-1 inhibitor, nivolumab, at a 50% dose reduction without recurrent adverse events and eventually achieved a complete response after 13 cycles. This case highlights the relative importance of considering careful rechallenge with ICI therapy in patients with microsatellite instability–high malignancies and a high risk of severe adverse events.