Poor Long-term Survival Research Articles

Impact of sarcopenia on long-term survival after cardiac surgery for end-stage renal disease patients.

The long-term mortality of end-stage renal disease (ESRD) patients is still unsatisfactory. Therefore, long-term risk assessments in ESRD patients undergoing cardiac surgery are needed. Recently, sarcopenia is major concern in cardiac surgery because of its association with poor long-term survival. However, the impact of sarcopenia on the long-term survival of ESRD patients undergoing cardiac surgery is not well understood. Eighty-two ESRD patients who underwent elective cardiac surgery were enrolled. Sarcopenia was identified based on noncontrast abdominal computed tomography. The impact of preoperative and intraoperative factors on long-term survival was investigated. Forty-three patients (52%) were diagnosed with sarcopenia. The in-hospital mortality rate was 4.9%. The 5-year overall survival rate was 48%. The multivariate analyses revealed that STS score ≥ 4 (odds ratio, 6.0; confidence interval, 2.5-14.7; p < 0.01) and presence of sarcopenia (odds ratio, 2.4; confidence interval, 1.3-4.5; p = 0.03) were independent risk factors for overall survival. The 5-year survival rates of low-risk (Society of Thoracic Surgeons score of < 4) patients without sarcopenia, low-risk with sarcopenia, more than intermediate-risk (Society of Thoracic Surgeons score of ≥ 4) without sarcopenia, and more than intermediate-risk with sarcopenia groups were 80%, 51%, 50%, and 26%, respectively. Among the ESRD patients, the low risk without sarcopenia group showed an excellent long-term survival, in contrast to more than intermediate-risk patients with sarcopenia, who can expect poor long-term survival. Preoperative assessment of sarcopenia in addition to the surgical risk score can be useful in developing a therapeutic strategy.

Cardiac magnetic resonance imaging for myocardial viability assessment: Optimizing surgical revascularization in ischemic heart disease.

Patients with poor ejection fraction undergoing coronary artery bypass grafting carry higher operative risk and have poor long-term survival. Cardiac magnetic resonance is a useful modality to assess viability which can identify patients likely to benefit most from revascularization. In this study, we aimed to assess the outcome in patients selected for surgical revascularization by cardiac magnetic resonance imaging and identify predictors associated with poor outcomes. The study included patients with severely impaired left ventricular function but with at least six viable segments. Patients requiring emergency surgery, undergoing combined procedures, or where cardiopulmonary bypass was required were excluded. Cardiac magnetic resonance was carried out both preoperatively and at six months postoperatively by the same radiologist in all cases. Late gadolinium enhancement was used for the evaluation of myocardial viability. Amongst a total of 493 segments studied, there were 89 (18.1%) non-viable, 117 (23.7%) hibernating and 287 (58.2%) viable segments. At six months, the number of non-viable segments changed from 89 (18.1%) to 97 (19.7%), with an increase in viable segments from 287 (58.2%) to 374 (75.8%) and a corresponding reduction of hibernating segments from 117 (23.7%) to 22 (4.5%). There was improvement in ejection fraction from 28 ± 5.54 to 37 ± 5.86 (p < 0.0001) in the entire cohort at six months. Overall mortality was 1 (3.2%). Preoperative left ventricular end-systolic volume had the strongest negative correlation with post-operative ejection fraction. Cardiac magnetic resonance aided revascularization is associated with low mortality. Preoperative left ventricular end-systolic volume is an important determinant of postoperative ejection fraction.

Versatile strategies for adult neurogenesis: avenues to repair the injured brain.

Brain injuries due to trauma or stroke are major causes of adult death and disability. Unfortunately, few interventions are effective for post-injury repair of brain tissue. After a long debate on whether endogenous neurogenesis actually happens in the adult human brain, there is now substantial evidence to support its occurrence. Although neurogenesis is usually significantly stimulated by injury, the reparative potential of endogenous differentiation from neural stem/progenitor cells is usually insufficient. Alternatively, exogenous stem cell transplantation has shown promising results in animal models, but limitations such as poor long-term survival and inefficient neuronal differentiation make it still challenging for clinical use. Recently, a high focus was placed on glia-to-neuron conversion under single-factor regulation. Despite some inspiring results, the validity of this strategy is still controversial. In this review, we summarize historical findings and recent advances on neurogenesis strategies for neurorepair after brain injury. We also discuss their advantages and drawbacks, as to provide a comprehensive account of their potentials for further studies.

Comprehensive molecular characterization of adenoid cystic carcinoma reveals tumor suppressors as novel drivers and prognostic biomarkers.

Adenoid cystic carcinoma (ACC) is a MYB-driven head and neck malignancy with high rates of local recurrence and distant metastasis and poor long-term survival. New effective targeted therapies and clinically useful biomarkers for patient stratification are needed to improve ACC patient survival. Here, we present an integrated copy number and transcriptomic analysis of ACC to identify novel driver genes and prognostic biomarkers. A total of 598 ACCs were studied. Clinical follow-up was available from 366 patients, the largest cohort analyzed to date. Copy number losses of 1p36 (70/492; 14%) and of the tumor suppressor gene PARK2 (6q26) (85/343; 25%) were prognostic biomarkers; patients with concurrent losses (n = 20) had significantly shorter overall survival (OS) than those with one or no deletions (p < 0.0001). Deletion of 1p36 independently predicted short OS in multivariate analysis (p = 0.02). Two pro-apoptotic genes, TP73 and KIF1B, were identified as putative 1p36 tumor suppressor genes whose reduced expression was associated with poor survival and increased resistance to apoptosis. PARK2 expression was markedly reduced in tumors with 6q deletions, and PARK2 knockdown increased spherogenesis and decreased apoptosis, indicating that PARK2 is a tumor suppressor in ACC. Moreover, analysis of the global gene expression pattern in 30 ACCs revealed a transcriptomic signature associated with short OS, multiple copy number alterations including 1p36 deletions, and reduced expression of TP73. Taken together, the results indicate that TP73 and PARK2 are novel putative tumor suppressor genes and potential prognostic biomarkers in ACC. Our studies provide new important insights into the pathogenesis of ACC. The results have important implications for biomarker-driven stratification of patients in clinical trials. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Dismal prognosis for cirrhotic patients with hepatitis C after initial failure of direct acting anti-virals, but salvage therapy may be life-saving

Background Effective direct-acting antiviral treatment against hepatitis C virus infection is available in many countries worldwide. Despite good treatment results, a proportion of patients does not respond to treatment. The aim of this study was to investigate the long-term prognosis and the outcome of salvage therapy, after an initial treatment failure, in a nation-wide real-life setting. Method Data from all adult patients registered in the national Swedish hepatitis C treatment register who did not achieve sustained virological response after initial antiviral treatment, was retrieved from 2014 through 2018. Results In total, 288 patients with primary treatment failure were included, of whom 236 underwent a second treatment course as salvage therapy after a median delay of 353 (IQR: 215–650) days. Fifteen patients received a third treatment course as second salvage treatment after a further median delay of 193 (IQR: 160–378) days. One-hundred-eleven out of 124 (90%) non-cirrhotic and 62/79 (78%) cirrhotic patients achieved sustained virological response following the first salvage treatment. Sustained virological response was achieved by 108/112 (96%) patients who received a triple antiviral regimen. In total 69 patients were lost to follow-up or died waiting for salvage treatment. Baseline cirrhosis was associated with poor long-term survival. Conclusion Our study indicates that salvage therapy was effective in most patients with primary treatment failure, in particular when a triple direct acting antiviral regimen was given. To avoid the risk of death or complications, patients with primary treatment failure should be offered salvage therapy with a triple regimen, as soon as possible.

Long-Term Survival of Ischemic Stroke Patients according to Prior Cognitive Status: Dijon Stroke Registry

Introduction: Understanding the influence of preexisting cognitive impairment on the poststroke outcome is a critical challenge in the context of current aging and growing population. This study aimed to assess long-term survival of patients with acute ischemic stroke (IS) according to their premorbid cognitive status and to identify contributing factors of death. Methods: Patients with IS were prospectively identified among residents of Dijon, France, using a population-based registry (2013–2017). The association between case fatality at 5 years and prestroke cognitive status was assessed by multivariable Cox models adjusted for other clinical characteristics and preexisting brain damage on the initial CT scan including leukoaraiosis, old vascular brain lesions, and cortical and central brain atrophy, as well as major arterial occlusion. Results: 1,049 patients were included (mean age ± SD: 76.3 ± 15.2 years old, 54% women). Case fatality rates at 5 years were 38.1% in patients without cognitive impairment, 65.9% in patients with prior mild cognitive impairment (MCI, n = 132, 12.6%), and 86.6% in patients with dementia (n = 164, 15.6%) (p < 0.001). MCI (HR = 1.39; 95% CI: 1.06–1.81, p = 0.016) and dementia (HR = 1.89; 95% CI: 1.45–2.46, p < 0.001) were both independently associated with higher case fatality after adjustment for clinical variables. The association remained significant after further adjustment for preexisting brain damage and major arterial occlusion (HR = 1.47; 95% CI: 1.10–1.98, p = 0.009, for MCI and HR = 1.90; 95% CI: 1.43–2.53, p < 0.001, for dementia) among patients with available data on the CT scan (n = 916). Factors associated with death were roughly similar across groups. Conclusion: This study highlighted a poor long-term survival of IS patients with preexisting cognitive impairment, independently of other contributing factors of death. It is critical to better understand the trajectory of IS patients with preexisting cognitive impairment and to identify prognostic markers to guide clinicians in their management strategies.

Impact of Antegrade Pulmonary Blood Flow as Patients Progress Through Single-Ventricle Palliations

BackgroundThe impact of antegrade pulmonary blood flow (APBF) during single-ventricle (SV) palliation continues to be debated. We sought to assess its impact on the hemodynamic profile and the short- and long-term outcomes of patients progressing through stages of SV palliation. MethodsA retrospective single-center study was conducted of SV patients who underwent surgery between January 2010 and December 2020. Patients with APBF were matched to those with no APBF by a propensity score based on body surface area, sex, and type of systemic ventricle. Analysis was performed using appropriate statistics with a significance level of P = .05. ResultsSixty-three patients with APBF were matched with 95 patients with no APBF. At the pre–stage 2 catheterization, APBF patients had a larger left pulmonary artery diameter (z score, 0.1 vs −0.8; P < .042). Patients with APBF had shorter cardiopulmonary bypass time (57.0 vs 79.0 minutes), shorter duration of mechanical ventilation (14.1 vs 17.4 hours), and shorter hospital length of stay (5.0 vs 7.0 days) at stage 2 palliation (P < .05). In the multivariable Cox regression analysis, patients with hypoplastic pulmonary arteries (z scores < −2; adjusted hazard ratio, 9.17) and patients with chromosomal abnormalities/genetic syndrome (adjusted hazard ratio, 4.03) were at increased risk for poor outcomes (P < .05). During the follow-up period, there was no significant difference in risk of the composite poor outcome and long-term survival between groups. ConclusionsSV patients with APBF had shorter cardiopulmonary bypass time, duration of mechanical ventilation, and hospital length of stay after stage 2 palliation. Patients with hypoplastic pulmonary arteries or chromosomal abnormalities/genetic syndromes had increased risk for poor outcomes. Maintaining APBF has better short-term outcomes, but there are no long-term hemodynamic or survival benefits.

Outcome for Children and Young Adults With T-Cell ALL and Induction Failure in Contemporary Trials.

Historically, patients with T-cell acute lymphoblastic leukemia (T-ALL) who fail to achieve remission at the end of induction (EOI) have had poor long-term survival. The goal of this study was to examine the efficacy of contemporary therapy, including allogeneic hematopoietic stem cell transplantation (HSCT) in first remission (CR1). Induction failure (IF) was defined as the persistence of at least 5% bone marrow (BM) lymphoblasts and/or extramedullary disease after 4-6 weeks of induction chemotherapy. Disease features and clinical outcomes were reported in 325 of 6,167 (5%) patients age 21 years and younger treated in 14 cooperative study groups between 2000 and 2018. With a median follow-up period of 6.4 years (range, 0.3-17.9 years), the 10-year overall survival (OS) was 54.7% (SE = 2.9), which is significantly higher than the 27.6% (SE = 2.9) observed in the historical cohort from 1985 to 2000. There was no significant impact of sex, age, white blood cell count, central nervous system disease status, T-cell maturity, or BM disease burden at EOI on OS. Postinduction complete remission (CR) was achieved in 93% of patients with 10-year OS of 59.6% (SE = 3.1%) and disease-free survival (DFS) of 56.3% (SE = 3.1%). Among the patients who achieved CR, 72% underwent HSCT and their 10-year DFS (with a 190-day landmark) was significantly better than nontransplanted patients (63.8% [SE = 3.6] v 45.5% [SE = 7.1]; P = .005), with OS of 66.2% (SE = 3.6) versus 50.8% (SE = 6.8); P = .10, respectively. Outcomes for patients age 21 years and younger with T-ALL and IF have improved in the contemporary treatment era with a DFS benefit among those undergoing HSCT in CR1. However, outcomes still lag considerably behind those who achieve remission at EOI, warranting investigation of new treatment approaches.

The impact of sarcopenia on prognosis of patients with pancreatic cancer: A systematic review and meta-analysis.

To summarize recent findings on the association of low skeletal muscle mass and muscle quality with overall survival and recurrence-free survival in patients with pancreatic cancer. A systematic search was conducted using Medline (via PubMed), Embase and Scopus databases for observational studies reporting on the overall survival and recurrence-free survival. Pooled effect sizes were reported as hazards ratio along with 95% confidence intervals. A total of 34 studies were included. Low skeletal muscle index (indicating muscle mass) was associated with poor overall survival (hazards ratio: 1.50; 95% confidence interval: 1.34, 1.67) and lower recurrence-free survival (hazards ratio: 1.28, 95% confidence interval: 1.15, 1.43). Low skeletal muscle attenuation (indicating muscle quality) was associated with poor overall survival (hazards ratio: 1.32; 95% confidence interval: 1.05, 1.66). Recurrence-free survival was similar in patients with low and normal/high skeletal muscle attenuation (hazards ratio: 1.12, 95% confidence interval: 0.89, 1.40). Both low skeletal muscle mass and poor muscle quality are associated with poor long-term survival. Low skeletal muscle index, but not low skeletal muscle attenuation, are associated with poor recurrence-free survival.

Long-term outcomes of surgical aortic valve replacement in patients receiving chronic dialysis.

Surgical aortic valve replacement (SAVR) has been the standard treatment for symptomatic severe aortic stenosis, which is common among patients receiving long-term dialysis. The aim of this study was to report the long-term outcomes of SAVR in patients receiving chronic dialysis and to identify independent risk factors for early and late mortality. Every consecutive patient with SAVR with or without concomitant cardiac procedures in British Columbia between January 2000 and December 2015 was identified from the provincial cardiac registry. The Kaplan-Meier method was used to estimate survival. Univariate and multivariable models were conducted to determine independent risk factors for short-term mortality and reduced long-term survival. Between 2000 and 2015, 654 patients receiving dialysis underwent SAVR with or without concomitant procedures. The mean follow-up was 2.3 (standard deviation 2.4) years (median 2.5 yr). The overall 30-day mortality was 12.8%. The 5-year and 10-year survival rates were 45.6% and 23.5%, respectively. Twelve patients (1.8%) had redo aortic valve surgery. There was no difference in 30-day mortality or long-term survival between 2 age groups (> 65 yr v. ≤ 65 yr). Anemia and cardiopulmonary bypass (CPB) were independent risk factors for both longer hospital stay and reduced long-term survival. The impact of CPB pump time on mortality occurred mainly within the first 30 days after surgery. When CPB pump time extended beyond 170 minutes, there was a significant increase in 30-day mortality with further prolongation of CPB pump time, and the relationship between 30-day mortality and CPB pump time became approximately linear. Patients receiving dialysis have poor long-term survival with a very low rate of redo aortic valve surgery following SAVR with or without concomitant procedures. Older age (> 65 yr) is not an independent risk factor for either 30-day mortality or reduced long-term survival. Using alternative strategies to limit CPB pump time is an important way to reduce 30-day mortality.

Heart failure with preserved ejection fraction in haemodialysis patients: prevalence, diagnosis, risk factors, prognosis.

Heart failure (HF) is a common complication and the leading cause of mortality in maintenance haemodialysis (MHD) patients. Few studies have investigated heart failure with preserved ejection fraction (HFpEF), which is known to affect a majority of patients. The objective of this study is to explore the prevalence, clinical profiles, diagnosis, risk factors and prognosis of MHD patients with HFpEF. Four hundred thirty-nine patients haemodialyzsed for over 3months were enrolled in the study and evaluated for HF according to the European Society of Cardiology guidelines. Clinical and laboratory parameters were recorded at baseline. The median follow-up of the study was 22.5months. A total of 111 (25.3%) MHD patients were diagnosed with HF, while 94 (84.7%) of the HF patients were classified into HFpEF. The cut-off value of N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 4922.5pg/mL for predicting HFpEF (sensitivity 0.840, specificity 0.723, AUC 0.866) in MHD patients. Age, diabetes mellitus, coronary artery disease and serum phosphorus were independent risk factors for the incidence of HFpEF in MHD patients while normal urine volume, haemoglobin, serum iron and serum sodium were protective factors. MHD patients with HFpEF had a higher risk of all-cause mortality than those without HF (hazard ratio 2.47, 95% confidence interval 1.55-3.91, P<0.0001). The majority of MHD patients with HF were categorized into HFpEF, with a poor long-term survival rate. NT-proBNP beyond 4922.5pg/mL performed well in the prediction of HFpEF in MHD patients.

#3650 LINACLOTIDE IS PROTECTIVE AGAINST RENAL ISCHEMIA-REPERFUSION INJURY

Abstract Background and Aims Renal ischemia-reperfusion injury is associated with delayed graft function and poor long-term graft survival following transplantation. Linaclotide is a guanylate cyclase C (GC-C) receptor agonist that increases intracellular cGMP concentrations and promotes intestinal transport capacity by activating the GC-C receptor. Since CKD is a deficiency of cGMP in the kidney, increasing cGMP in the kidney by linaclotide would suppress fibrosis, protecting the kidney. Method An AKI rat model of unilateral nephrectomy plus contralateral ischaemia (30 min) and impaired reperfusion (up to 14 days) was used. Linaclotide was administered before and after surgery for 2 weeks, and blood and renal tissue samples were collected to determine its effect on renal function and whether it was protective against the progression of CKD. Results In the I/R injury+ group, creatinine levels were lower in the linaclotide-treated group than in the non-treated group. Sirius red staining showed significant improvement in fibrosis. The hydroxyproline content of kidneys was determined by the basic hydroxyproline method. RNA seq showed that genes down-regulated in I/R injury+ were the oxidative stress markers SOD3 and Gpx1. The expression of genes down-regulated in I/R injury+ was up-regulated to a degree similar to that in I/R injury- by treatment with linaclotide. These data suggest that linaclotide may ameliorate renal fibrosis by suppressing renal dysfunction through its antioxidant effects. Conclusion The antioxidant effect of linaclotide was found to suppress the decrease in renal function caused by I/R. We would like to apply this finding to human renal transplantation in the future to prevent renal function deterioration due to I/R.

Long-Term Outcomes of Tracheostomy-Dependent Children.

To estimate the 1-, 5-, and 10-year survival and decannulation rates of children with a tracheostomy. Ambidirectional cohort. Tertiary children's hospital. All patients (<18 years) that had a tracheostomy placed between 2009 and 2020 were included and followed until 21 years of age, decannulation, or death. The Kaplan-Meier method estimated cumulative probabilities of death and decannulation. A total of 551 children underwent tracheostomy at a median age of 7.2 months (interquartile range [IQR]: 3.8-49.2). Children were followed for a median of 2.1 years (IQR: 0.7-4.2, range 0-11.5). The cumulative probability of mortality at 1year was 11.9% (95% confidence interval [CI]: 9.4-15.1), at 5years was 26.1% (95% CI: 21.6-31.3), and at 10years was 41.6% (95% CI: 32.7-51.8). Ventilator dependence at index discharge (hazard ratio [HR]: 2.04, 95% CI: 1.10-3.81, p = .03), severe neurologic disability (HR: 2.79, 95% CI: 1.61-4.84, p < .001), and cardiac disease (HR: 1.69, 95% CI: 1.08-2.65, p = .02) were associated with time to death. The cumulative probability of decannulation was 10.4% (95% CI: 8.0-13.5), 44.9% (95% CI: 39.4-50.9), and 54.1% (95% CI: 47.4-61.1) at 1 year, 5 years, and 10 years, respectively. Ventilator dependence (HR: 0.43, 95% CI: 0.31-0.60, p < .001), severe neurologic disability (HR: 0.20, 95% CI: 0.14-0.30, p < .001), and tracheostomy indicated for respiratory failure (HR: 0.68, 95% CI: 0.48-0.96, p = .03) correlated with longer decannulation times. After tracheostomy, estimated mortality approaches 42% by 10 years and decannulation approaches 54%. Children with ventilator support at discharge and severe neurological disability had poorer long-term survival and longer times to decannulation.

Ultra-sensitive, tumor-informed ctDNA profiling in patients with gastroesophageal cancer and treated with pembrolizumab and longitudinal ctDNA kinetics.

4040 Background: Metastatic esophagogastric cancer (mEGC) is a lethal disease with poor long-term survival. Recent studies have established anti-PD-1 therapy in combination with chemotherapy as the standard of care for first-line therapy for mEGC. KeyLargo (NCT03342937) was a single arm phase II study of pembrolizumab in combination with oxaliplatin and capecitabine in the first line treatment of patients (pts) with HER2 negative mEGC. While high response rates were noted, not all pts received benefit, emphasizing the need for better biomarkers. Paired tumor biopsies and plasma were collected for optimal biomarker testing. In this retrospective study, we employed a novel, tumor-informed ctDNA approach as a tool for longitudinal disease monitoring and dynamic tumor evolution. Methods: Thirty-six pts were enrolled between January 2018 and January 2020. Of 34 evaluable pts, 25 pts achieved a response (ORR = 74%), including 6 pts with a complete response (CR) and 19 pts with a partial response (PR). Our initial analysis includes baseline tumor samples collected from 16 pts with over 59 corresponding on-treatment (OT; up to cycle 35) plasma samples. NeXT Personal, a tumor-informed ctDNA assay, generated personalized liquid biopsy panels derived from somatic variants (SV) from tumor whole genome sequencing. Each personalized assay includes up to 1,800 SVs for sensitive minimal residual disease (MRD) detection and a constant set of 2,100 clinically actionable variants (CAV). Results: Of the 36 pts who enrolled on KeyLargo, 32 pts had baseline tumor and longitudinal plasma samples collected and stored for testing. In this initial cohort of 16 pts, MRD events dynamically varied from 5.3 to 302,000 parts per million (PPM). 16/16 (100%) pts were MRD-positive at baseline, with a limit of detection between 1.5 and 4.6 PPM. OT samples were collected every 3 cycles (9 weeks). The ratio of PPM (rPPM) between baseline and the first available OT sample (typically Cycle 4 to 7) correlated with progression free survival (PFS; p = 0.0004, logrank). rPPM was significantly reduced in pts having a best overall response of PR/CR (98% mean rPPM) versus progressive disease (25% mean rPPM, p &lt; 0.037, U-test). Two pts demonstrated CR, each with 11/11 (100%) MRD-negative plasma samples over approximately two years. CAVs were identified in longitudinal samples with TP53 repeatedly detected in 5 patients and a PIK3CA mutation emerging in the final 3 (of 9) timepoints from one patient. Conclusions: ctDNA was present in all pts at baseline; OT PPM reductions correlated with PFS and best overall response. CAV profiling suggested a de novo PIK3CA variant arising during therapy in one patient. These findings suggest that tumor-informed plasma-based ctDNA profiling in mEGC may detect known CAVs arising during therapy, and with subsequent investigations, may inform therapeutic decisions.

Evaluation of the prognostic value of computed tomography-derived body composition in patients undergoing endovascular aneurysm repair.

Endovascular aneurysm repair (EVAR) is the most common mode of repair of abdominal aortic aneurysms (AAA) in the UK. EVAR ranges from standard infrarenal repair to complex fenestrated and branched EVAR (F/B-EVAR). Sarcopenia is defined by lower muscle mass and function, which is associated with inferior perioperative outcomes. Computed tomography-derived body composition analysis offers prognostic value in patients with cancer. Several authors have evaluated the role of body composition analysis in predicting outcomes in patients undergoing EVAR; however, the evidence base is limited by heterogeneous methodology. Six hundred seventy-four consecutive patients (58 (8.6%) female, mean (SD) age 74.4 (6.8) years) undergoing EVAR and F/B-EVAR at three large tertiary centres were retrospectively recruited. Subcutaneous and visceral fat indices (SFI and VFI), psoas and skeletal muscle indices, and skeletal muscle density were measured at the L3 vertebral level from pre-operative computed tomographies. The maximally selected rank statistic technique was used to define optimal thresholds to predict mortality. There were 191 deaths during the median follow-up period of 60.0months. Mean (95% CI) survival in the low SMI versus high SMI subgroups was 62.6 (58.5-66.7) versus 82.0 (78.7-85.3) months (P<0.001). Mean (95% CI) survival in the low SFI versus high SFI subgroups was 56.4 (48.2-64.7) versus 77.1 (74.2-80.1) months (P<0.001). One-year mortality in the low SMI versus high SMI subgroups was 10% versus 3% (P<0.001). Low SMI was associated with increased odds of one-year mortality (OR 3.19, 95% CI 1.60-6.34, P<0.001). Five-year mortality in the low SMI versus high SMI subgroups was 55% versus 28% (P<0.001). Low SMI was associated with increased odds of five-year mortality (OR 1.54, 95% CI 1.11-2.14, P<0.01). On multivariate analysis of all patients, low SFI (HR 1.90, 95% CI 1.30-2.76, P<0.001) and low SMI (HR 1.88, 95% CI 1.34-2.63, P<0.001) were associated with poorer survival. On multivariate analysis of asymptomatic AAA patients, low SFI (HR 1.54, 95% CI 1.01-2.35, P<0.05) and low SMI (HR 1.71, 95% CI 1.20-2.42, P<0.01) were associated with poorer survival. Low SMI and SFI are associated with poorer long-term survival following EVAR and F/B-EVAR. The relationship between body composition and prognosis requires further evaluation, and external validation of the thresholds proposed in patients with AAA is required.

A non-muscle myosin heavy chain 9 genetic variant is associated with graft failure following kidney transplantation.

Despite current matching efforts to identify optimal donor-recipient pairs for kidney transplantation, alloimmunity remains a major source of late transplant failure. Additional genetic parameters in donor-recipient matching could help improve longterm outcomes. Here, we studied the impact of a non-muscle myosin heavy chain 9 gene (MYH9) polymorphism on allograft failure. We conducted an observational cohort study, analyzing the DNA of 1,271 kidney donor-recipient transplant pairs from a single academic hospital for the MYH9 rs11089788 C&gt;A polymorphism. The associations of the MYH9 genotype with risk of graft failure, biopsy-proven acute rejection (BPAR), and delayed graft function (DGF) were estimated. A trend was seen in the association between the MYH9 polymorphism in the recipient and graft failure (recessive model, p = 0.056), but not for the MYH9 polymorphism in the donor. The AA-genotype MYH9 polymorphism in recipients was associated with higher risk of DGF (p = 0.03) and BPAR (p = 0.021), although significance was lost after adjusting for covariates (p = 0.15 and p = 0.10, respectively). The combined presence of the MYH9 polymorphism in donor-recipient pairs was associated with poor long-term kidney allograft survival (p = 0.04), in which recipients with an AA genotype receiving a graft with an AA genotype had the worst outcomes. After adjustment, this combined genotype remained significantly associated with 15-year death-censored kidney graft survival (hazard ratio, 1.68; 95% confidence interval, 1.05-2.70; p = 0.03). Our results reveal that recipients with an AA-genotype MYH9 polymorphism receiving a donor kidney with an AA genotype have significantly elevated risk of graft failure after kidney transplantation.

Proof of concept: Detection of cell free RNA from EDTA plasma in patients with lung cancer and non-cancer patients

IntroductionNucleic acid sequencing technologies have advanced significantly in recent years, thereby allowing for the development of liquid biopsies as new means to detect cancer biomarkers and cancer heterogenicity. Most of the assays available, clinically, focus on cell free DNA (cfDNA), however, cell free RNA (cfRNA) is also present. cfRNA has the potential to complement and improve cancer detection especially in cancers like lung cancer, which are usually only diagnosed at late stages and therefore have poor long-term survival outcomes. MethodsRemnant EDTA plasma was collected from lung cancer patients and non-cancer individuals at the University of Maryland Medical Center. RNA was extracted and processed for next generation sequencing with a tagmentation-based library preparation approach. ResultscfRNA was successfully extracted and sequenced from 52 EDTA-treated plasma samples with volumes as low as 1.5 mL. This quantity was sufficient to prepare libraries with the length of libraries averaging from 264 bp to 381 bp and resulted in over 2.2 to 3.6 million total sequence reads respectively. Sequential dilution of cfRNA samples from healthy individuals indicated that the starting cfRNA concentration influenced the detection of differentially expressed genes. ConclusionsThis proof-of-concept study provides a framework for screening cfRNA for identifying biomarkers for early detection of lung cancer (and other cancers), using minimal amounts of samples (1.5 mL) from standard EDTA 3-mL collection tubes routinely used for patient care. Further studies in large populations are required to establish limit of detection and other parameters including precision, accuracy, sensitivity, and specificity, to standardize this method.

China special issue on gastrointestinal tumors-Cetuximab retreatment plus camrelizumab and liposomal irinotecan in patients with RAS wild-type metastatic colorectal cancer: Cohort B of the phase II CRACK study.

Patients with metastatic colorectal cancer (mCRC) have poor long-term survival. Rechallenge with anti-epidermal growth factor receptor (anti-EGFR) based therapy has shown certain activity as late-line therapy. To further improve clinical outcomes, we evaluated the antitumor efficacy and safety of cetuximab in combination with camrelizumab and liposomal irinotecan in patients with RASwt mCRC pretreated with anti-EGFR-based therapy. Patients with RASwt mCRC who had received at least two prior systemic therapies, including anti-EGFR-based treatment in the metastatic or unresectable disease setting, were enrolled in cohort B. Patients were treated with cetuximab (500 mg/m2 ) and camrelizumab (200 mg) plus liposomal irinotecan (HR070803, 60 mg/m2 ) intravenously once every 2 weeks. The primary endpoint was the objective response rate (ORR) by RECIST v1.1. The secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and safety. At the data cutoff (23 November 2022), 19 patients were enrolled in the two stages, and 16 were evaluable for efficacy analyses. The ORR was 25% (95% confidence interval [CI]: 10.2%-49.5%), and DCR was 75% (95% CI: 50.5%-89.8%). The median PFS and OS were 6.9 (95% CI: 2.6-11.2) and 15.1 (95% CI: 6.1-24.0) months, respectively. Grade 3 treatment-related adverse events (TRAEs) occurred in 15.8% (3/19) of patients. No grade ≥4 TRAEs were found in the safety population. Our study suggests that anti-EGFR retreatment therapy with cetuximab plus camrelizumab and liposomal irinotecan (HR070803) is a promising late-line treatment option with good antitumor activity and well-tolerated toxicity in RASwt mCRC patients.

Impact of sarcopenia and low muscle attenuation on outcomes of ovarian cancer: a systematic review and meta-analysis.

The aim of this study was to examine the association of sarcopenia and low muscle attenuation with survival and other clinical outcomes in patients with ovarian cancer. Systematic search was done in PubMed, EMBASE and Scopus databases for observational studies that documented the link between sarcopenia and outcomes of interest in patients with ovarian cancer, with long-term survival as a primary outcome. Other outcomes included risk of recurrence, progression-free survival and complications. Pooled effect sizes were reported as hazards ratio (HR), relative risk ratio (RR) or weighted mean difference (WMD). Random effects model was used for the analysis. Twenty-two studies were selected, of which all, except one, were retrospective in design. Low skeletal muscle index (SMI, indicating muscle mass) (HR 1.30, 95% CI: 1.07, 1.58) and low muscle quality (HR 1.24, 95% CI: 1.03, 1.49) were associated with poor long-term survival, but not with the risk of recurrence and progression-free survival. Both low skeletal muscle index (SMI) (RR 1.49, 95% CI: 1.13, 1.98) and low muscle quality (RR 1.99, 95% CI: 1.04, 3.79) were associated with increased risk of complications. Both low skeletal muscle mass and low muscle quality showed significant association with poor long-term survival and an increased risk of complications. However, they do not have a significant association with the risk of recurrence and progression-free survival. There is a need for more prospective studies to confirm these associations.

Intratumoral microbiome impacts immune infiltrates in tumor microenvironment and predicts prognosis in esophageal squamous cell carcinoma patients.

Different intratumoral microbiotaexist in different tumors and play a crucial function in carcinogenesis. However, whether they impact clinical outcomes in esophageal squamous cell carcinoma (ESCC) and their mechanism remain unclear. 16S rDNA amplicon sequencing was performed on surgically resected samples from 98 ESCC patients to analyze intratumoral microbiome abundance and composition. Multiplex fluorescent immunohistochemistry staining was used to profile the phenotypes of immune infiltrates in the tumor microenvironment (TME). Patients with higher intratumoral Shannon index had significantly worse surgical outcomes. When patients were divided into short-term survivors and long-term survivors based on the median survival time, both intratumoral alpha-diversity and beta-diversity were found to be significantly inconsistent, and the relative abundance of Lactobacillus and Leptotrichia emerged as the two microorganisms that probably influenced the survival of ESCC patients. Only Lactobacillus in ESCC was validated to significantly worsen patients' prognoses and to be positively correlated with the Shannon index. Multivariate analysis revealed that the intratumoral Shannon index, the relative abundance of Lactobacillus, and the pathologic tumor-node-metastasis (pTNM) stage were independently associated with patients' overall survival. Furthermore, the relative abundance of both Lactobacillus and Shannon index was positively correlated with the proportions of PD-L1+ epithelial cells (ECs) and tumor-associated macrophages (TAMs). The Shannon index was negatively correlated with the proportions of natural killer (NK) cells in the TME. A high abundance of intratumoral Lactobacillus and bacterial alpha-diversity was associated with the formation of the immunosuppressive TME and predicted poor long-term survival in ESCC patients.