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BACKGROUND: Extrapleural pneumonectomy (EPP) is a complex surgical procedure involving en-bloc resection of the parietal and visceral pleura, lung, pericardium, and ipsilateral diaphragm. Small case series of pleural-based sarcoma of predominantly pediatric patients suggest EPP may be a life-prolonging surgical option. We aimed to describe the characteristics and outcomes of adults who underwent EPP at a specialized sarcoma center. METHODS: Clinicopathologic variables, surgical details, and follow-up information were extracted for patients undergoing EPP for pleural-based sarcoma between August 2017 and December 2020. Primary outcomes were event-free survival (EFS) and overall survival (OS) from the date of EPP. Secondary outcomes were disease-free interval (DFI) prior to EPP, and early and late postoperative complications. RESULTS: Eight patients were identified, seven with soft tissue sarcoma and one with bone sarcoma. Patients had either localized disease with a primary thoracic sarcoma, sarcoma recurrent to the thorax, or de novo metastatic disease. All patients underwent resection of their pleural-based sarcoma by an experienced cardiothoracic surgeon, and some patients had pre or postoperative treatment. The perioperative morbidity was comparable with previously published reports of EPP performed in mesothelioma patients. At median follow-up of 22.5 months, median EFS was 6.0 months and OS was 20.7 months. Six patients (75%) had disease recurrence; five (62.5%) died of progressive disease. Two patients (25%) had not recurred: one died of a radiation-related esophageal rupture, and one was alive with no evidence of disease at 37.0 months. Characteristics of those with the longest EFS included low-grade histology and achieving a metabolic response to preoperative chemotherapy. CONCLUSIONS: In adults with pleural-based sarcoma, EPP is rarely curative but appears to be a feasible salvage procedure when performed at specialized centers. Patient selection is critical with strong consideration given to multimodal therapy to optimize patient outcomes. In the absence of a confirmed response to neoadjuvant treatment, long term survival is poor and EPP should not be recommended.
Subject(s)
Mesothelioma , Pleural Neoplasms , Sarcoma , Adult , Humans , Child , Pneumonectomy/adverse effects , Pneumonectomy/methods , Pleural Neoplasms/diagnosis , Pleural Neoplasms/surgery , Neoplasm Recurrence, Local , Mesothelioma/pathology , Mesothelioma/surgery , Sarcoma/diagnosis , Sarcoma/surgeryABSTRACT
BACKGROUND: Australia has one of the highest rates of asbestos-associated diseases. Mesothelioma remains an area of unmet need with a 5-year overall survival of 10%. First-line immunotherapy with ipilimumab and nivolumab is now a standard of care for unresectable pleural mesothelioma following the CheckMate 743 trial, with supportive data from the later line single-arm MAPS2 trial. RIOMeso evaluates survival and toxicity of this regimen in real-world practice. METHODS: Demographic and clinicopathologic data of Australian patients treated with ipilimumab and nivolumab in first- and subsequent-line settings for pleural mesothelioma were collected retrospectively. Survival was reported using the Kaplan-Meier method and compared between subgroups with the log-rank test. Toxicity was investigator assessed using Common Terminology Criteria for Adverse Events version 5.0. RESULTS: A total of 119 patients were identified from 11 centers. The median age was 72 years, 83% were male, 92% had Eastern Cooperative Oncology Group less than or equal to 1, 50% were past or current smokers, and 78% had known asbestos exposure. In addition, 50% were epithelioid, 19% sarcomatoid, 14% biphasic, and 17% unavailable. Ipilimumab and nivolumab were used first line in 75% of patients. Median overall survival (mOS) was 14.5 months (95% confidence interval [CI]: 13.0-not reached [NR]) for the entire cohort. For patients treated first line, mOS was 14.5 months (95% CI: 12.5-NR) and in second- or later-line patients was 15.4 months (95% CI: 11.2-NR). There was no statistically significant difference in mOS for epithelioid patients compared with nonepithelioid (19.1 mo [95% CI: 15.4-NR] versus 13.0 mo [95% CI: 9.7-NR], respectively, p = 0.064). Furthermore, 24% of the patients had a Common Terminology Criteria for Adverse Events grade greater than or equal to 3 adverse events, including three treatment-related deaths. Colitis was the most frequent adverse event. CONCLUSIONS: Combination immunotherapy in real-world practice has poorer survival outcomes and seems more toxic compared with clinical trial data. This is the first detailed report of real-world survival and toxicity outcomes using ipilimumab and nivolumab treatment of pleural mesothelioma.
Subject(s)
Asbestos , Lung Neoplasms , Mesothelioma, Malignant , Mesothelioma , Pleural Neoplasms , Humans , Male , Aged , Female , Nivolumab/adverse effects , Ipilimumab/adverse effects , Retrospective Studies , Lung Neoplasms/drug therapy , Lung Neoplasms/etiology , Australia , Mesothelioma/drug therapy , Mesothelioma/etiology , Pleural Neoplasms/drug therapy , Pleural Neoplasms/etiology , Immunotherapy/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
LAY ABSTRACT: Many autistic individuals with intellectual disability experience anxiety, and for those who use few or no words, anxiety may present as behaviour that challenges, such as self-injury and avoiding anxiety-provoking situations. Families report difficulty accessing support from services for autistic individuals experiencing anxiety. Moreover, once receiving support, effective interventions for autistic people with intellectual disability are limited. We completed individual and group discussions with 16 caregivers of autistic people with intellectual disability, to (a) explore their experiences of accessing services for anxiety and/or behaviour that challenges for their child; and (b) understand what matters to caregivers when developing interventions that have been designed for them and the autistic individual with intellectual disability that they support. Caregivers reported that services, in their experience, did not deliver the support that they expected, and that they often needed to 'fight' for support. Caregivers considered services and families working together, the inclusion of peer support, and families being offered interventions that are flexible to individual circumstances to be important. These considerations are valuable for clinicians and researchers developing interventions and aiming to improve outcomes for autistic people with intellectual disability and their families.
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Importance: Post-COVID-19 condition (PCC), also known as long COVID, encompasses the range of symptoms and sequelae that affect many people with prior SARS-CoV-2 infection. Understanding the functional, health, and economic effects of PCC is important in determining how health care systems may optimally deliver care to individuals with PCC. Observations: A rapid review of the literature showed that PCC and the effects of hospitalization for severe and critical illness may limit a person's ability to perform day-to-day activities and employment, increase their risk of incident health conditions and use of primary and short-term health care services, and have a negative association with household financial stability. Care pathways that integrate primary care, rehabilitation services, and specialized assessment clinics are being developed to support the health care needs of people with PCC. However, comparative studies to determine optimal care models based on their effectiveness and costs remain limited. The effects of PCC are likely to have large-scale associations with health systems and economies and will require substantial investment in research, clinical care, and health policy to mitigate these effects. Conclusions and Relevance: An accurate understanding of additional health care and economic needs at the individual and health system levels is critical to informing health care resource and policy planning, including identification of optimal care pathways to support people affected by PCC.
Subject(s)
COVID-19 , Humans , Adult , COVID-19/epidemiology , SARS-CoV-2 , Post-Acute COVID-19 Syndrome , Delivery of Health CareABSTRACT
Human cadavers used for surgical training are embalmed using various methods to facilitate tissue storage and longevity while preserving the natural characteristics required to achieve high fidelity functional task alignment. However, there are no standardized means to evaluate the suitability of embalming solutions for this purpose. The McMaster Embalming Scale (MES) was developed to assess the extent to which embalming solutions allow tissues to achieve physical and functional correspondence to clinical contexts. The MES follows a five-point Likert scale format and evaluates the effect of embalming solutions on tissue utility in seven domains. This study aims to determine the reliability and validity of the MES by presenting it to users after performing surgical skills on tissues embalmed using various solutions. A pilot study of the MES was conducted using porcine material. Surgical residents of all levels and faculty were recruited via the Surgical Foundations program at McMaster University. Porcine tissue was unembalmed (fresh- frozen) or embalmed using one of seven solutions identified in the literature. Participants were blinded to the embalming method as they completed four surgical skills on the tissue. After each performance, participants evaluated their experience using the MES. Internal consistency was evaluated using Cronbach's alpha. Domain to total correlations and a g-study were also conducted. Formalin-fixed tissue achieved the lowest average scores, while fresh frozen tissue achieved the highest. Tissues preserved using Surgical Reality Fluid (Trinity Fluids, LLC, Harsens Island, MI) achieved the highest scores among embalmed tissues. The Cronbach's alpha scores varied between 0.85 and 0.92, indicating a random sample of new raters would offer similar ratings using the MES. All domains except odor were positively correlated. The g-study indicated that the MES is able to differentiate between embalming solutions, but an individual rater's preference for certain tissue qualities also contributes to the variance in scores captured. This study evaluated the psychometric characteristics of the MES. Future steps to this investigation include validating the MES on human cadavers.
Subject(s)
Embalming , Formaldehyde , Humans , Animals , Swine , Embalming/methods , Pilot Projects , Reproducibility of Results , CadaverABSTRACT
Importance: The recent development of targeted therapy and immunotherapy has made neoadjuvant therapy an attractive option for patients with hepatocellular carcinoma (HCC). However, surgeons are concerned that adverse effects of neoadjuvant therapy with these agents could lead to delayed or even cancelled surgeries. Objective: To summarize the current evidence regarding toxicity profiles for tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs) among patients with HCC. Data Sources: Medline, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) were searched from January 1990 and December 2021. Study Selection: Single-group, placebo-controlled, and dual-agent clinical trials comparing TKIs and ICIs in patients with HCC were eligible for inclusion. Data Extraction and Synthesis: Following the Preferred Reporting Items in Systematic Reviews and Meta-analysis guideline, 2 reviewers independently extracted data. A random-effects model was used. Main Outcomes and Measures: The primary outcome was the proportion of patients with clinically significant liver-related adverse events. Secondary outcomes included the proportion of patients who experienced clinically relevant (grade 3 or higher) adverse events and significant adverse events (ie, those that were life threatening, required hospitalization, or prolonged disability) as well as the risk ratio (RR) of these complications. Results: Overall, 30 studies with 12â¯921 patients were included. Patients had a mean (range) age of 62 (18-89) years; a mean (SD) 84% (3) were male; a mean (SD) 82% (16) had Barcelona Clinic Liver Cancer stage C HCC; and a mean (SD) 97% (6) had Childs A cirrhosis. Overall, 21% (95% CI, 16%-26%) of patients receiving TKIs had liver toxic effects compared with 28% (95% CI, 21%-35%) of patients receiving ICIs. Severe adverse events occurred in 46% (95% CI, 40%-51%) of patients receiving TKIs compared with 24% (95% CI, 13%-35%) of patients receiving ICIs. Compared with patients receiving sorafenib, other TKIs were associated with similar rates of liver toxic effects (RR, 1.06; 95% CI, 0.92-1.24) but higher rates of severe adverse events (RR, 1.24; 95% CI, 1.07-1.44). Comparing ICIs with sorafenib, there were similar rates of liver toxic effects (RR, 1.10; 95% CI, 0.86-1.40) and severe adverse events (RR, 1.19; 95% CI, 0.95-1.50). Conclusions and Relevance: In this systematic review and meta-analysis, serious adverse events were lower with ICIs than with TKIs, while liver toxic effects were similar. Combination therapy with novel ICIs is an appealing option in trials of neoadjuvant therapy for patients with HCC, requiring evaluation in preoperative trials.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Aged , Aged, 80 and over , Carcinoma, Hepatocellular/drug therapy , Child , Female , Humans , Immunotherapy/adverse effects , Liver Neoplasms/drug therapy , Male , Middle Aged , SorafenibABSTRACT
A useful model for determining the mechanisms by which actin and actin binding proteins control cellular architecture is the Drosophila melanogaster process of spermatogenesis. During the final step of spermatogenesis, 64 syncytial spermatids individualized as stable actin cones move synchronously down the axonemes and remodel the membranes. To identify new genes involved in spermatid individualization, we screened a collection of Drosophila male-sterile mutants and found that, in the line Z3-5009, actin cones formed near to the spermatid nuclei but failed to move, resulting in failed spermatid individualization. However, we show by phalloidin actin staining, electron microscopy and immunocytochemical localization of several actin binding proteins that the early cones had normal structure. We sequenced the genome of the Z3-5009 line and identified mutations in the PFTAIRE kinase L63 interactor 1A (Pif1A) gene. Quantitative real-time PCR showed that Pif1A transcript abundance was decreased in the mutant, and a transgene expressing Pif1A fused to green fluorescent protein (GFP) was able to fully rescue spermatid individualization and male fertility. Pif1A-GFP localized to the front of actin cones before initiation of movement. We propose that Pif1A plays a pivotal role in directing actin cone movement.
Subject(s)
Drosophila Proteins , Drosophila melanogaster , Actins/genetics , Actins/metabolism , Animals , Drosophila/metabolism , Drosophila Proteins/genetics , Drosophila Proteins/metabolism , Drosophila melanogaster/genetics , Drosophila melanogaster/metabolism , Male , Spermatids/metabolism , Spermatogenesis/genetics , Testis/metabolismABSTRACT
BACKGROUND: Some studies suggest that the observed higher mortality in women compared with men after coronary artery bypass grafting (CABG) is due to confounding. Our meta-analysis aimed to (1) summarize the effect of sex on mortality after CABG and (2) identify whether unmeasured confounding likely explains the apparent higher mortality in women. METHODS: We searched MEDLINE, Embase, and CENTRAL databases for studies examining sex and 30-day mortality after CABG. We used random-effects meta-analysis to estimate the summary odds ratio (OR) of mortality in women versus men using (1) unadjusted study results and (2) adjusted study results. Available confounders data from included studies were identified. Using the OR of measured confounders and the risk of death to inform unmeasured confounding effects, we performed bias analysis simulation to correct potential unmeasured confounding in the summary OR. RESULTS: From 7,138 retrieved studies, 112 were included (N = 5,008,262 patients); 25 studies reported adjusted OR (N = 770,450 patients). Overall 30-day mortality was 4.9% in women versus 3.3% in men. The unadjusted summary OR (1.81; 95% confidence interval, 1.72-1.91) and adjusted summary OR (1.40, 95% confidence interval, 1.35-1.45) demonstrated women had an increased risk for 30-day mortality compared with men. Simulations correcting for unmeasured confounding mostly ranged from 1.05 to 1.80, which supports a higher risk for death in women after CABG. CONCLUSIONS: The findings of this review suggest that confounding is unlikely to account for the increased risk for mortality in women after CABG and that biological factors have a causal effect.
Subject(s)
Coronary Artery Bypass/methods , Coronary Artery Disease/surgery , Postoperative Complications/mortality , Risk Assessment/methods , Coronary Artery Bypass/mortality , Coronary Artery Disease/mortality , Female , Global Health , Humans , Risk Factors , Survival Rate/trendsABSTRACT
Background & Aims. Postoperative weight loss is common following hepato-pancreato-biliary (HPB) surgical resections; however, the extent of weight loss and the association with poor outcomes have not been well described. We assessed the average percentage of weight loss and risk factors associated with sustained postoperative weight loss. Materials and Methods. We enrolled patients undergoing major HPB surgical resections from 2011-2016 at a single institution. We evaluated percent change in weight postoperatively, incidence of complications, and nutritional clinical markers at 1, 3, and 6 months postoperatively compared to preoperative baseline. We used multiple logistic regression to evaluate factors associated with significant weight loss (>10% from baseline) at 3 months from surgery. Results. Among 262 patients undergoing HPB surgery, liver surgery patients lost 2.5% of baseline weight at 3 months postoperatively but regained baseline weight by 6 months. Pancreatic surgery patients lost 7.7% at 3 months and were unable to recover their baseline weights at 6 months. Forty-three (16%) patients had major postoperative complications including abdominal abscess (5.3%) and anastomotic leak (3.8%). Patients who experienced major postoperative complications had a greater percentage weight loss at 3 months compared to those without major complications: median 11% (interquartile range (IQR): 7%-15%) vs 4% (IQR: 0%-8%), P < .001. In the multivariable analysis, major postoperative complications were associated with significant weight loss at 3 months (OR 3.39, 95% CI 1.38-8.33). Conclusions. Due to the association of weight loss and major postoperative complications, patients who experience significant weight loss (>10% from baseline) may benefit from nutritional assessment for dietary intervention.
Subject(s)
Biliary Tract Surgical Procedures , Digestive System Surgical Procedures , Biliary Tract Surgical Procedures/adverse effects , Digestive System Surgical Procedures/adverse effects , Humans , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Retrospective Studies , Weight LossABSTRACT
BACKGROUND: Primary anatomic total shoulder arthroplasty can be challenging in patients with complex glenoid wear patterns and bone loss. Severe retroversion (>15°) or significant bone loss may require bone grafting. This review summarizes the rate of revision and long-term outcomes of anatomic total shoulder arthroplasty with bone graft. METHODS: A systematic search of MEDLINE, Embase, PubMed, and CENTRAL databases was conducted from the date of inception to 23 October 2018. Two reviewers independently screened articles for eligibility and extracted data for analysis. The primary outcome was rate of revision. The secondary outcomes were rate of component loosening, functional outcome, and range of motion. RESULTS: Of the 1056 articles identified in the search, 26 underwent full-text screening and 7 articles were included in the analysis. All procedures were one-stage anatomic total shoulder arthroplasties. The rate of revision was 5.4% with component loosening and infection listed as indications over a weighted mean follow-up period of 6.3 years. Complications occurred in 12.6% of patients. CONCLUSION: Glenoid bone grafting in anatomic total shoulder arthroplasty results in comparable revision rates and improvement in pain compared to augmented glenoid components and reverse shoulder arthroplasty. Due to the low quality of evidence, further prospective studies should be conducted. LEVEL OF EVIDENCE: IV.
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INTRODUCTION: The reported use of cannabis within surgical population is increasing. Cannabis use is potentially associated with increased harms and varied effects on pain control. These have important implications to perioperative care. METHODS: We conducted a retrospective cohort study comparing surgical patients reporting cannabis use preoperatively to control patients with no cannabis exposure, in a 1:2 ratio. To control for confounding, we used a propensity score-matched analysis to assess the adjusted association between cannabis use and study outcomes. Our primary outcome was a composite of (1) respiratory arrest or cardiac arrest, (2) intensive care admission, (3) stroke, (4) myocardial infarction and (5) mortality during this hospital stay. Secondarily, we assessed the effects on pain control, opioid usage, induction agent dose and nausea-vomiting. RESULTS: Between January 2018 and March 2019, we captured 1818 patients consisting of cannabis users (606) and controls (1212). For propensity score-matched analyses, 524 cannabis patients were compared with 1152 control patients. No difference in the incidence of composite outcome was observed (OR 1.06, 95% CI 0.23 to 3.98). Although a higher incidence of arrhythmias (2.7% vs 1.6%) and decreased incidence of nausea-vomiting needing treatment (9.6% vs 12.6%) was observed with cannabis users vs controls, results were not statistically significant. No significant differences were observed with other secondary outcomes. CONCLUSION: Our results do not demonstrate a convincing association between self-reported cannabis use and major surgical outcomes or pain management. Perioperative decisions should be made based on considerations of dose, duration, and indication.
Subject(s)
Cannabis , Humans , Length of Stay , Perioperative Care , Postoperative Complications , Propensity Score , Retrospective StudiesABSTRACT
BACKGROUND: The COVID-19 pandemic has challenged cancer care globally, introducing resource limitations and competing risks into clinical practice. AIMS: To describe the COVID-19 impact on medical oncology care provision in an Australian setting. METHODS: Calvary Mater Newcastle and Newcastle Private Hospital medical oncology data from 1 February to 31 April 2019 versus 2020 were retrospectively analysed. RESULTS: Three hundred and sixty-four inpatient admissions occurred in 2020, 21% less than in 2019. Total inpatient days decreased by 22% (2842 vs 2203). April was most impacted (36% and 44% fewer admissions and inpatient days respectively). Mean length of stay remained unchanged (6.4 vs 6.2 days, P = 0.7). In all, 5072 outpatient consultations were conducted, including 417 new-patient consultations (4% and 6% increase on 2019 respectively). Telephone consultations (0 vs 1380) replaced one-quarter of face-to-face consultations (4859 vs 3623, -25%), with minimal telehealth use (6 vs 69). Day Treatment Centre encounters remained stable (3751 vs 3444, -8%). The proportion of new patients planned for palliative treatment decreased (35% vs 28%, P = 0.04), observation increased (16% vs 23%, P = 0.04) and curative intent treatment was unchanged (both 41%). Recruiting clinical trials decreased by one-third (45 vs 30), two trials were activated (vs 5 in 2019) and 45% fewer patients consented to trial participation (62 vs 34). CONCLUSION: Our medical oncology teams adapted rapidly to COVID-19 with significant changes to care provision, including fewer hospital admissions, a notable transition to telephone-based outpatient clinics and reduced clinical trial activity. The continuum of care was largely defended despite pandemic considerations and growing service volumes.
Subject(s)
COVID-19 , Telemedicine , Australia/epidemiology , Humans , Medical Oncology , Pandemics , Retrospective Studies , SARS-CoV-2ABSTRACT
BACKGROUND: Intraabdominal surgery is a known risk factor for splanchnic vein thrombosis (SVT). SVT incidence, management, and prognosis after hepatopancreatobiliary surgery are unknown. OBJECTIVES: To determine the incidence and prognosis of SVT following hepatopancreatobiliary surgery and describe current practices in anticoagulation for postoperative SVT. PATIENTS/METHODS: Multicenter retrospective cohort study of adults undergoing hepatopancreatobiliary surgery. Multivariable analyses for predictors of SVT, major bleeding, and 90-day mortality were performed. RESULTS: Of 1815 patients included, 89 (4.9%) had cirrhosis and 1532 (84.4%) had active cancer. The most frequent surgeries were pancreaticoduodenectomy (40.6%), open (30.7%), and laparoscopic (11.0%) liver resection. Sixty (3.3%) patients experienced SVT within 90 days of surgery. Among patients with SVT, 23.3% were symptomatic and 75.0% were treated with therapeutic anticoagulation. Planned duration of anticoagulation averaged 3 to 6 months. By multivariable analysis, SVT predictors were: operative time (adjusted odds ratio [aOR] per hour increase 1.32, 95% confidence interval [CI] 1.20-1.46), cirrhosis (aOR 3.22, 95% CI 1.28-8.10), and postoperative intraabdominal infection (aOR 2.99, 95% CI 1.72-5.19). Postoperative major bleeding occurred in 22.1% of patients and 4.0% died within 90 days. Predictors of postoperative mortality were age (aOR per 10-year increase 1.79, 95% CI 1.38-2.30), operative time (aOR 1.31 (1.17-1.45), cirrhosis (aOR 4.42, 95% CI 1.96-9.96), postoperative intraabdominal infection (aOR 2.66, 95% CI 1.55-4.57), postoperative major bleeding (aOR 4.12, 95% CI 2.36-7.30), and postoperative SVT (aOR 3.15, 95% CI 1.42-6.97). CONCLUSION: SVT occurred in 1 in 30 patients after hepatopancreatobiliary surgery and was associated with a 3-fold independent increase in 90-day mortality.
Subject(s)
Splanchnic Circulation , Venous Thrombosis , Adult , Hemorrhage , Humans , Incidence , Retrospective Studies , Risk Factors , Venous Thrombosis/diagnosis , Venous Thrombosis/epidemiologyABSTRACT
An amendment to this paper has been published and can be accessed via the original article.
ABSTRACT
BACKGROUND: Radial head excision has historically been a common surgical procedure for the operative management of radial head fractures and post-traumatic conditions. With recent advances in other surgical techniques, controversy exists regarding its indications. This review evaluates the indications and outcomes of radial head excision in traumatic and non-traumatic elbow pathology. METHODS: Multiple databases were searched for studies involving radial head excision. Screening and data abstraction were conducted in duplicate. Only studies reporting outcomes for radial head excision were included. RESULTS: Twenty-seven studies with 774 radial head excision patients were included. The most common indications involved acute excision of comminuted radial head fractures (n = 347) and rheumatoid arthritis (n = 201). Post-operative functional scores after acute excision were reported to be good to excellent. In the chronic setting of rheumatoid disease, radial head excision resulted in improved range of motion, although pain was not effectively relieved. DISCUSSION: Outcomes of radial head excision for acute fracture are good to excellent; however, it should not be performed when concurrent or ligamentous injuries are present. Although some studies compared excision to open reduction and internal fixation or replacement, more data are needed to make proper conclusions. The strength of these conclusions is limited by the quality of included literature.
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Sorafenib is a multikinase inhibitor capable of facilitating apoptosis, mitigating angiogenesis and suppressing tumor cell proliferation. In late-stage hepatocellular carcinoma (HCC), sorafenib is currently an effective first-line therapy. Unfortunately, the development of drug resistance to sorafenib is becoming increasingly common. This study aims to identify factors contributing to resistance and ways to mitigate resistance. Recent studies have shown that epigenetics, transport processes, regulated cell death, and the tumor microenvironment are involved in the development of sorafenib resistance in HCC and subsequent HCC progression. This study summarizes discoveries achieved recently in terms of the principles of sorafenib resistance and outlines approaches suitable for improving therapeutic outcomes for HCC patients.
Subject(s)
Carcinoma, Hepatocellular/drug therapy , Drug Resistance, Neoplasm/genetics , Liver Neoplasms/drug therapy , Sorafenib/therapeutic use , Apoptosis/drug effects , Carcinoma, Hepatocellular/genetics , Carcinoma, Hepatocellular/pathology , Cell Proliferation/drug effects , Drug Resistance, Neoplasm/drug effects , Humans , Liver Neoplasms/genetics , Liver Neoplasms/pathology , Sorafenib/adverse effects , Tumor Microenvironment/drug effectsABSTRACT
Cancer immunotherapy has achieved positive clinical responses in the treatment of various cancers, including gastric cancer (GC). In this study, we characterized the heterogeneity of T cells isolated from GC patients at the single-cell level using single-cell RNA sequencing. We identified different immune cell subtypes and their heterogeneous transcription factors and depicted their developmental trajectories. In particular, we focused on exhausted CD8+ cells and Tregs and discovered that, as compared to control, the IRF8 transcription factor was downregulated in CD8+ tumour-infiltrating lymphocytes (TILs) from GC tissues, and that GC patients with lower IRF8 levels in blood CD8+ T cells tended to be a at a more advanced disease stage. These findings provide a theoretical basis for targeted immune therapy in GC.
Subject(s)
CD8-Positive T-Lymphocytes/metabolism , Sequence Analysis, RNA/methods , Single-Cell Analysis , Stomach Neoplasms/immunology , T-Lymphocytes, Regulatory/metabolism , Aged , Aged, 80 and over , Case-Control Studies , Down-Regulation , Female , Humans , Interferon Regulatory Factors/genetics , MaleABSTRACT
We sought to compare the effectiveness of two World Health Organization (WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant (RR/MDR) tuberculosis (TB): a standardised regimen of 9-12â months (the "shorter regimen") and individualised regimens of ≥20â months ("longer regimens").We collected individual patient data from observational studies identified through systematic reviews and a public call for data. We included patients meeting WHO eligibility criteria for the shorter regimen: not previously treated with second-line drugs, and with fluoroquinolone- and second-line injectable agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects meta-regression to calculate adjusted odds ratios and adjusted risk differences (aRDs) for failure or relapse, death within 12â months of treatment initiation and loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine studies of shorter regimens and 2717 out of 13â104 (20.7%) individuals from 53 studies of longer regimens. Treatment success was higher with the shorter regimen than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less loss to follow-up with the former (aRD -0.15, 95% CI -0.17-â-0.12). The risk difference for failure or relapse was slightly higher with the shorter regimen overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16), prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09, 95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised shorter regimen was associated with substantially less loss to follow-up during treatment compared with individualised longer regimens and with more failure or relapse in the presence of resistance to component medications. Our findings support the need to improve access to reliable drug susceptibility testing.