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Advanced glycation end-products (AGE) are a pervasive form of protein damage implicated in the pathogenesis of neurodegenerative disease, atherosclerosis and diabetes mellitus. Glycation is typically mediated by reactive dicarbonyl compounds that accumulate in all cells as toxic byproducts of glucose metabolism. Here, we show that AGE crosslinking is harnessed to activate an antibacterial phospholipase effector protein deployed by the type VI secretion system of Enterobacter cloacae. Endogenous methylglyoxal reacts with a specific arginine-lysine pair to tether the N- and C-terminal α-helices of the phospholipase domain. Substitutions at these positions abrogate both crosslinking and toxic phospholipase activity, but in vitro enzyme function can be restored with an engineered disulfide that covalently links the N- and C-termini. Thus, AGE crosslinking serves as a bona fide post-translation modification to stabilize phospholipase structure. Given the ubiquity of methylglyoxal in prokaryotic and eukaryotic cells, these findings suggest that glycation may be exploited more generally to stabilize other proteins. This alternative strategy to fortify tertiary structure could be particularly advantageous in the cytoplasm, where redox potentials preclude disulfide bond formation.

Background: A useful biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in advanced renal cell carcinoma (RCC) has not yet been established. This study aims to investigate whether inflammatory markers are associated with the efficacy of nivolumab plus ipilimumab therapy before and during treatment. Methods: Data from patients with advanced clear cell RCC who received a combination treatment of nivolumab plus ipilimumab were retrospectively analyzed. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels were assessed at baseline and 3, 6, and 9 weeks after treatment initiation. The correlation between these inflammatory markers and the patient's prognosis was investigated. Results: Eighty-four patients were identified. The multivariate analysis identified NLR at week 3, CRP at week 6, and NLR and CRP at week 9 as the consistent predictor associated with poor overall survival (OS) at each time point. The survival analysis and receiver operating characteristic (ROC) curve analysis revealed that an NLR of ≥ 2.4 at week 3, CRP of ≥ 1.4 mg/dL at week 6, and NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 were associated with worse OS (hazard ratios (HR) = 5.70, P = 0.008, HR = 3.23, P = 0.004, HR = 7.38, P < 0.001 and HR = 3.55, P = 0.002). Conclusions: Both NLR and CRP were considered useful biomarkers for understanding the prognosis during nivolumab plus ipilimumab therapy. Furthermore, an NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 are helpful in reconsidering treatment continuation. [ABSTRACT FROM AUTHOR]

Background: People living with advanced, non-malignant chronic conditions often have extensive and complex care needs. Informal or family caregivers often provide the care and support needed by those with advanced chronic conditions at home. These informal caregivers experience many challenges associated with their caring role, which can impact their own wellbeing. Whilst there is growing evidence around the impact on carers, guidance on support for informal caregivers of patients with advanced, non-malignant, chronic conditions is lacking, with little evidence available on effective psychosocial carer interventions. This systematic review explored existing interventions for caregivers of those with advanced, non-malignant, chronic illness, in order to assess the effectiveness of these interventions in improving psychosocial outcomes. Methods: Electronic databases, Medline, CINAHL, EMBASE, and PsycINFO, were searched up to the end of March 2023. Studies meeting the inclusion criteria, focusing on interventions to improve psychosocial outcomes, such as depression, anxiety, quality of life, and caregiver burden, in this cohort of caregivers were included. Data were extracted regarding study setting, design, methods, intervention components, and outcomes. Risk of bias and quality assessment were conducted. Results: A total of 5281 articles were screened, ultimately identifying 12 studies for inclusion, reported in 13 publications. A narrative synthesis revealed mixed results. Psychosocial interventions resulted in more significant improvements in psychosocial outcomes than psychoeducational or support interventions, with interventions for carer-patient dyads also reflecting more positive outcomes for caregivers. Evidence-based interventions, guided by an appropriate theoretical model, were reportedly more effective in improving caregiver outcomes. Differences in outcomes were related to intervention development, design, delivery, and outcome assessment. Conclusions: This review, to our knowledge, is the first to explore the effectiveness of interventions in improving psychosocial outcomes for caregivers of those with advanced, non-malignant, chronic conditions. The review highlights the need for more robust, sufficiently powered, high-quality trials of evidence-based interventions for caregivers of people with advanced chronic illness. Optimal intervention duration and frequency of sessions are unclear and need further exploration. [ABSTRACT FROM AUTHOR]

Abstract Background People living with advanced, non-malignant chronic conditions often have extensive and complex care needs. Informal or family caregivers often provide the care and support needed by those with advanced chronic conditions at home. These informal caregivers experience many challenges associated with their caring role, which can impact their own wellbeing. Whilst there is growing evidence around the impact on carers, guidance on support for informal caregivers of patients with advanced, non-malignant, chronic conditions is lacking, with little evidence available on effective psychosocial carer interventions. This systematic review explored existing interventions for caregivers of those with advanced, non-malignant, chronic illness, in order to assess the effectiveness of these interventions in improving psychosocial outcomes. Methods Electronic databases, Medline, CINAHL, EMBASE, and PsycINFO, were searched up to the end of March 2023. Studies meeting the inclusion criteria, focusing on interventions to improve psychosocial outcomes, such as depression, anxiety, quality of life, and caregiver burden, in this cohort of caregivers were included. Data were extracted regarding study setting, design, methods, intervention components, and outcomes. Risk of bias and quality assessment were conducted. Results A total of 5281 articles were screened, ultimately identifying 12 studies for inclusion, reported in 13 publications. A narrative synthesis revealed mixed results. Psychosocial interventions resulted in more significant improvements in psychosocial outcomes than psychoeducational or support interventions, with interventions for carer-patient dyads also reflecting more positive outcomes for caregivers. Evidence-based interventions, guided by an appropriate theoretical model, were reportedly more effective in improving caregiver outcomes. Differences in outcomes were related to intervention development, design, delivery, and outcome assessment. Conclusions This review, to our knowledge, is the first to explore the effectiveness of interventions in improving psychosocial outcomes for caregivers of those with advanced, non-malignant, chronic conditions. The review highlights the need for more robust, sufficiently powered, high-quality trials of evidence-based interventions for caregivers of people with advanced chronic illness. Optimal intervention duration and frequency of sessions are unclear and need further exploration.

The WHO (World Health Organization) conducted an elimination of cervical cancer program using triple pillar intervention strategy to target 90%-70%-90% of women before the year 2030, including (1) a full vaccination of HPV (human papillomavirus) vaccine to 90% of girls

The Maillard reaction, a chemical reaction between amino acids and sugars, is exploited to produce flavorful food ubiquitously, from the baking industry to our everyday lives. However, the Maillard reaction also occurs in all cells, from prokaryotes to eukaryotes, forming advanced glycation end-products (AGEs). AGEs are a heterogeneous group of compounds resulting from the irreversible reaction between biomolecules and α-dicarbonyls (α-DCs), including methylglyoxal (MGO), an unavoidable byproduct of anaerobic glycolysis and lipid peroxidation. We previously demonstrated that Caenorhabditis elegans mutants lacking the glod-4 glyoxalase enzyme displayed enhanced accumulation of α-DCs, reduced lifespan, increased neuronal damage, and touch hypersensitivity. Here, we demonstrate that glod-4 mutation increased food intake and identify that MGO-derived hydroimidazolone, MG-H1, is a mediator of the observed increase in food intake. RNAseq analysis in glod-4 knockdown worms identified upregulation of several neurotransmitters and feeding genes. Suppressor screening of the overfeeding phenotype identified the tdc-1-tyramine-tyra-2/ser-2 signaling as an essential pathway mediating AGE (MG-H1)-induced feeding in glod-4 mutants. We also identified the elt-3 GATA transcription factor as an essential upstream regulator for increased feeding upon accumulation of AGEs by partially controlling the expression of tdc-1 gene. Furthermore, the lack of either tdc-1 or tyra-2/ser-2 receptors suppresses the reduced lifespan and rescues neuronal damage observed in glod-4 mutants. Thus, in C. elegans, we identified an elt-3 regulated tyramine-dependent pathway mediating the toxic effects of MG-H1 AGE. Understanding this signaling pathway may help understand hedonistic overfeeding behavior observed due to modern AGE-rich diets.

On 25–26 March 2023, the U.S. National Council on Radiation Protection and Measurements (NCRP) held its 2024 annual meeting in Bethesda, Maryland, USA. The NCRP dates from 1929, and this meeting celebrated the 60th anniversary of receiving a U.S. Congressional Charter. For this annual meeting the NCRP felt it was essential to provide a briefing about advanced and small modular nuclear reactors (SMRs). The Journal of Radiological Protection is delighted to publish the following synopsis of material presented at the U.S. NCRP meeting. This synopsis is divided into five sections. The first section provides an overview of the whole meeting together with summaries of two context setting overview papers. The following four sessions of this synopsis are specific to advanced and small modular nuclear power reactors. The meeting also included keynote presentations by three of NCRP annual award recipients. The meeting topical areas were Technology Overview and Critical Issues. The individual papers laid the groundwork to understanding reactor technologies, terminology, and the fundamental concepts and processes for electrical generation. The perspectives of the U.S. Environmental Protection Agency and states, through the Conference of Radiation Control Program Directors were provided. The papers included a discussion of diverse topics including potential emergency preparedness considerations, radiological survey requirements, an evaluation of the future of nuclear power, the economics of reactors (both large and small), and the critical issues identified by the recent National Academies of Sciences' study on advanced reactors. The summary papers were developed to briefly document the major points and concepts presented during the oral papers presented at the 2024 NCRP Annual Meeting. The meeting heralded the dawn of a new era for commercial nuclear power. [ABSTRACT FROM AUTHOR]

Purpose: Hip fracture is common in older people – with prevalence even higher for people with dementia. Research often excludes people with dementia – especially those in the more advanced stages. Therefore, the most appropriate interventions remain unknown. The main aim of this study was to gain consensus about the core considerations needed to deliver a physical intervention for people with advanced dementia who fracture their hip. Materials and Methods: An expert consensus process was undertaken, using Nominal Group Technique, to explore the key considerations when delivering rehabilitation. Data collection was undertaken in January 2023 and involved an online group discussion followed by voting and off-line rating. Qualitative content analysis and quantitative analysis of consensus scoring was undertaken. An international group of seven highly specialised physiotherapists took part. Results: 59 statements were agreed following the process. Content analysis was used to categorise these statements according to the International Classification of Functioning, Disability and Health. Although consensus levels were high, there was disagreement in several areas. Conclusion: The statements provide an overarching understanding of the multidisciplinary expertise that is needed to effectively deliver rehabilitation interventions to this population. People with dementia require highly skilled and trained professionals, providing holistic and person-centred approaches to deliver rehabilitation interventions. IMPLICATIONS FOR REHABILITATION: The expert consensus provides an overarching understanding of the multidisciplinary expertise that is needed to effectively deliver rehabilitation interventions to this population. Physiotherapy - or other interventions - cannot be used in isolation. People with dementia require highly skilled and trained professionals, providing holistic and person-centred approaches to deliver rehabilitation interventions. While our focus was on hip fracture, we suggest these statements can be used for people with advanced dementia with a variety of other conditions. [ABSTRACT FROM AUTHOR]

Introduction: Extranodal NK/T-cell lymphoma (ENKTCL), a non-Hodgkin lymphoma, is known for its destructive local impact on nasal structures and systemic induction of inflammatory cytokines. Concurrent treatment with radiation and nonanthracycline-based chemotherapy has improved survival rates in patients with localized disease stages. However, survival outcomes vary significantly in advanced-stage and relapsed or refractory (R/R) cases. Methods: Therefore, we conducted a meta-analysis using random effects models to assess prognostic factors in advanced or R/R ENKTCL, employing a digital extractor on Kaplan-Meier graphs owing to the scarcity of published prospective trials for these patients. Results: We observed that patients with advanced ENKTCL treated with Lasparaginase had a median progression-free survival (PFS) of 14.3 months and an overall survival (OS) of 19 months. In R/R ENKTCL, PFS and OS were 11.7 and 15.6 months, respectively. Additionally, OS outcomes in advanced-stage ENKTCL were better in the asparaginase group than that in the non-asparaginase group, with PEG-asparaginase showing superior results compared with that using Lasparaginase. Epstein-Barr Virus (EBV)-DNA positivity in the bloodstream prior to treatment was associated with poor outcomes in advanced-stage ENKTCL, and similar trends were observed in patients with R/R ENKTCL and post-treatment EBV viremia. Discussion: Collectively, these findings suggest that chemotherapy with Lasparaginase or PEG-asparaginase can enhance survival in advanced or R/R ENKTCL. However, future strategies must be developed to effectively suppress EBV viremia and achieve a deep response toward tumor eradication. [ABSTRACT FROM AUTHOR]

We aimed to summarize survival data from RCTs in patients with GO adenocarcinoma; estimate and explain worst-, typical-, and best-case-scenarios of survival time; and determine if simple multiples of median overall survival (mOS) could estimate these percentiles. We systematically searched RCTs of systemic therapies for GO adenocarcinoma published 2000–2022. The following key percentiles were extracted from overall survival curves: 90th (worst-case), 75th (lower-typical), 25th (upper-typical), and 10th (best-case). We tested if these percentiles could be estimated by simple multiples of mOS: 0.25 of the median for the 90th percentile, 0.5 for the 75th, 2 for the 25th, and 3 for the 10th. We identified 44 trials (22,447 participants). For first line chemotherapy and immunotherapy combined (CI) trials (n = 3) worst-to-best case survival time ranged from 4 months to not reached, compared to 3–30 months for other trials (n = 27) and 1–23 months for subsequent lines (n = 14). Simple multiples of mOS accurately estimated the following survival percentiles: 90th (n = 3/3 trials), 75th (n = 3/3), and 25th (n = 2/3) in first line CI trials. In other first line trials, the mOS accurately estimated the 90th survival percentile in n = 22/27 trials, 75th percentile in n = 26/27, 25th percentile in 27/27 trials, and 10th percentile in 22/27 trials. Simple multiples of the mOS accurately predicted the 90th, 75th, 25th, and 10th survival percentiles in the majority of trials of second and subsequent lines apart from chemotherapy and immunotherapy only trials. We provide realistic, evidence-based prognostic information as scenarios for survival time which can inform clinical decision-making. Simple multiples of the mOS accurately estimated the percentiles for most groups. [ABSTRACT FROM AUTHOR]

Aim: To assess the efficacy of ctDNA measurement at different time intervals in predicting response and prognosis in patients diagnosed with locally advanced rectal cancer (LARC) who underwent neoadjuvant treatment prior to curative resection. Method: English language randomized controlled trials and observational studies, published from 1946 to January 2024, comparing outcomes between ctDNA‐positive and ctDNA‐negative patients with LARC undergoing neoadjuvant treatment prior to curative surgical resection were included in the search. The search included Ovid MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and the Cochrane Database of Systematic Reviews (CDSR). Results: Data for 1022 patients were analysed. Patients with positive ctDNA in the preoperative period had more than five times the risk of developing distant metastasis (RR [95% CI] 5.03 [3.31–7.65], p < 0.001), while those with positive ctDNA in the postoperative period had more than six times the risk (RR [95% CI] 6.17 [2.38–15.95], p < 0.001). There was no significant relationship between ctDNA status at baseline, pre‐, or postoperative periods and achievement of pCR (RR [95% CI] 1.21 [0.86–1.7], 1.82 [0.94–3.55], 1.48 [0.78–2.82], p = 0.27, 0.08, and 0.23, respectively). However, patients with positive ctDNA in the pre‐ and postoperative periods had more than 13 and 12 times the risk of overall disease relapse after curative‐intent treatment (RR [95% CI] 13.55 [7.12–25.81], 12.14 [3.19–46.14], p < 0.001), respectively. Conclusion: ctDNA could potentially guide treatment and follow‐up in LARC, predicting high‐risk patients for disease relapse, allowing individualized surveillance and treatment strategies. Prospective studies are needed for standardization. [ABSTRACT FROM AUTHOR]

BACKGROUND: Preeclampsia is a multifaceted syndrome that includes maternal vascular dysfunction. We hypothesize that increased placental glycolysis and hypoxia in preeclampsia lead to increased levels of methylglyoxal (MGO), consequently causing vascular dysfunction. METHODS: Plasma samples and placentas were collected from uncomplicated and preeclampsia pregnancies. Uncomplicated placentas and trophoblast cells (BeWo) were exposed to hypoxia. The reactive dicarbonyl MGO and advanced glycation end products (Nε-(carboxymethyl)lysine [CML], Nε-(carboxyethyl)lysine [CEL], and MGO-derived hydroimidazolone [MG-H]) were quantified using liquid chromatography-tandem mass spectrometry. The activity of GLO1 (glyoxalase-1), that is, the enzyme detoxifying MGO, was measured. The impact of MGO on vascular function was evaluated using wire/pressure myography. The therapeutic potential of the MGO-quencher quercetin and mitochondrial-specific antioxidant mitoquinone mesylate (MitoQ) was explored. RESULTS: MGO, CML, CEL, and MG-H2 levels were elevated in preeclampsia-placentas (+36%, +36%, +25%, and +22%, respectively). Reduced GLO1 activity was observed in preeclampsia-placentas (−12%) and hypoxia-exposed placentas (−16%). Hypoxia-induced MGO accumulation in placentas was mitigated by the MGO-quencher quercetin. Trophoblast cells were identified as the primary source of MGO. Reduced GLO1 activity was also observed in hypoxia-exposed BeWo cells (−26%). Maternal plasma concentrations of CML and the MGO-derived MG-H1 increased as early as 12 weeks of gestation (+16% and +17%, respectively). MGO impaired endothelial barrier function, an effect mitigated by MitoQ, and heightened vascular responsiveness to thromboxane A2. CONCLUSIONS: This study reveals the accumulation of placental MGO in preeclampsia and upon exposure to hypoxia, demonstrates how MGO can contribute to vascular impairment, and highlights plasma CML and MG-H1 levels as promising early biomarkers for preeclampsia. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusions Lung cancer, the most common cause of cancer‐related death, is diagnosed mostly in advanced stages, and 5‐year survival is approximately 5.8%. It is critical to identify reliable prognostic factors to optimize treatment responses, guide therapeutic strategies and pave the way to new research. In this study, we aimed to investigate the strongest prognostic factors for advanced non‐small cell lung cancer (NSCLC).We retrospectively analyzed 278 patients with NSCLC. We evaluated the association between potential prognostic factors and overall survival (OS) times using Kaplan–Meier analysis and Cox regression analysis.The median OS in all patients was 15.3 months. In univariate analysis, gender, histologic type, performance status, immunotherapy, radiotherapy, hemoglobin level, serum albumin, sodium–globulin ratio (SGR), neutrophil–lymphocyte ratio (NLR), systemic immune inflammation index (SII), hemoglobin–albumin–lymphocyte–platelet score (HALP), and advanced lung cancer index (ALI) were associated with survival. Models were established for multivariate analyses. In the models, NLR, SGR, HALP, immunotherapy, radiotherapy, and Eastern Cooperative Oncology Group (ECOG) performance status showed independent prognostic features (p < 0.001, p = 0.003, p = 0.002, p < 0.001, p = 0.010, and p = 0.025, respectively). In addition, in the subgroup analysis, prognostic indexes (NLR, SGR, and HALP) were found to have a prognostic effect on survival in multiple subgroups.Pretreatment NLR, SGR, HALP, immunotherapy, radiotherapy, and ECOG performance status are independent prognostic factors for advanced NSCLC patients. These prognostic factors can be used in clinical practice as easily accessible, simple, and useful tools for clinicians. [ABSTRACT FROM AUTHOR]

Background: Although basic laparoscopic hepatectomy (LH) has become the standard procedure for hepatectomy, the safety of advanced LH remains to be clarified, especially in elderly patients. We investigated the safety of advanced LH in elderly Japanese patients. Methods: Elderly patients (≥ 65 years) who underwent advanced LH between 2016 and 2021 were analyzed using a nationwide claims database in Japan. The perioperative outcomes of patients who underwent open hepatectomy (OH group) or LH (LH group) were compared using propensity score matching (PSM). The primary outcome was in-hospital mortality. The E-value method was performed to assess the strength of the outcome point estimates against possible unmeasured confounding factors. Results: Among 5,021 patients, eligible patients were classified into the OH (n = 4,152) and LH (n = 527) groups. The median patient age was 74 years in both groups. Hepatocellular carcinoma and metastatic liver tumors were the major indications for hepatectomy (OH: 52.5% versus 30.6%; LH: 60.7% versus 26.4%). After PSM, in-hospital mortality rates for OH and LH were 1.7 and 0.76%, respectively. The risk ratio was 0.45 (95% confidence interval, 0.16–1.25; E-value = 3.87). Compared with OH, LH was associated with a longer anesthesia time (411 versus 432 min), lower rate of blood product use (red blood concentrate: 33.5% versus 20.3%; fresh frozen plasma: 29.2% versus 17.1%), and shorter hospital stay (13 versus 12 days). Conclusions: In elderly patients, the safety of advanced LH was similar to that of advanced OH, or might be better in Japan under the current policy of hospital accreditation. [ABSTRACT FROM AUTHOR]

PurposeThere is a pressing need to investigate the impact of type II diabetes mellitus on the posterior cornea in donor tissues given its increasing prevalence and potential impact on endothelial keratoplasty surgical outcomes.MethodsImmortalized human cultured corneal endothelial cells (CECs; HCEC-B4G12) were grown in hyperglycemic media for 2 weeks. Extracellular matrix (ECM) adhesive glycoprotein expression and advanced glycation end products (AGEs) in cultured cells and corneoscleral donor tissues, as well as the elastic modulus for the Descemet membrane (DMs) and CECs of diabetic and nondiabetic donor corneas, were measured.ResultsIn CEC cultures, increasing hyperglycemia resulted in increased transforming growth factor beta-induced (TGFBI) protein expression and colocalization with AGEs in the ECM. In donor corneas, the thicknesses of the DM and the interfacial matrix (IFM) between the DM and stroma both increased from 8.42 ± 1.35 µm and 0.504 ± 0.13 µm in normal corneas, respectively, to 11.13 ± 2.91 µm (DM) and 0.681 ± 0.24 µm (IFM) in non-advanced diabetes (P = 0.013 and P = 0.075, respectively) and 11.31 ± 1.76 µm (DM) and 0.744 ± 0.18 µm (IFM) in advanced diabetes (AD; P = 0.0002 and P = 0.003, respectively). Immunofluorescence in AD tissues versus controls showed increased AGEs (P < 0.001) and markedly increased labeling intensity for adhesive glycoproteins, including TGFBI, that colocalized with AGEs. The elastic modulus significantly increased between AD and control tissues for the DMs (P < 0.0001) and CECs (P < 0.0001).ConclusionsDiabetes and hyperglycemia alter human CEC ECM structure and composition, likely contributing to previously documented complications of endothelial keratoplasty using diabetic donor tissue, including tearing during graft preparation and reduced graft survival. AGE accumulation in the DM and IFM may be a useful biomarker for determining diabetic impact on posterior corneal tissue.

Meiling He,1 Chunfeng Liang,1 Yadan Pang,1 Mengjie Jiang,1 Meiying Long,2 Zhongqiang Yao,3 Xiaoting Wang,1 Ruijun Zhang,1 Qiaoyuan Wu,1 Shixiong Liang,1 Jianxu Li1 1Department of Radiation Oncology, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of China; 2School of Public Health, Guangxi Medical University, Nanning, 530021, People’s Republic of China; 3Department of General Affairs, Guangxi Medical University Cancer Hospital, Nanning, 530021, People’s Republic of ChinaCorrespondence: Shixiong Liang; Jianxu Li, Tel +86 13917716605 ; +86 18878732921, Email shixliang@sina.com; lijianxu1236@163.comPurpose: The combination of radiotherapy and monoclonal antibody against programmed cell death 1 (anti-PD1) showed preliminary efficacy in hepatocellular carcinoma (HCC). This study aimed to identify the prognostic factors and construct a nomogram to predict the overall survival (OS) of patients with advanced HCC after treatment with intensity-modulated radiotherapy (IMRT) plus anti-PD1.Patients and Methods: The OS and progression-free survival (PFS) of 102 patients with BCLC stage C HCC was analyzed using the Kaplan-Meier method. Potential independent prognostic factors were determined using univariate and multivariate Cox regression analyses. A nomogram was established to predict prognosis whose accuracy and reliability was verified by a calibration curve and area under the receiver operating characteristic curve (AUROC).Results: The median PFS and OS rates of the 102 patients with advanced HCC were 9.9 months and 14.3 months, respectively. Ninety-three patients were evaluated for efficacy, including five (5.38%) with complete response and 48 (51.61%) with partial response, with an overall response rate of 56.99%. Grade 3 and 4 adverse reactions (AEs) were observed in 32.35% of patients; no grade 5 AEs occurred. Multivariate Cox analysis revealed albumin and alpha-fetoprotein levels, neutrophil counts 3– 4 weeks after IMRT initiation, and platelet-to-lymphocyte ratio 3– 4 weeks after IMRT initiation to be independent prognostic factors. The nomogram model constructed using these factors had good consistency and accuracy with 1– 3 years AUROC of 78.7, 78.6, and 93.5, respectively.Conclusion: IMRT plus anti-PD1 showed promising efficacy and controllable adverse reactions in treating advanced HCC. The nomogram model demonstrated good reliability and clinical applicability.Plain Language Summary: The combination of radiotherapy and monoclonal antibody against programmed cell death 1 (anti‑PD1) showed preliminary efficacy and manageable safety in HCC. We retrospectively evaluated the efficacy and safety of 102 patients with advanced HCC treated with intensity-modulated radiotherapy (IMRT) plus anti-PD1. The study shows that the combination showed promising efficacy with a median PFS and OS of 9.9 months and 14.3 months, respectively. The adverse reactions were controllable. The novel nomogram model established based on independent prognostic factors including albumin, alpha-fetoprotein, neutrophils count 3– 4 weeks after IMRT initiation and platelet-to-lymphocyte ratio 3– 4 weeks after IMRT initiation demonstrated good reliability.Keywords: hepatocellular carcinoma, advanced, intensity-modulated radiotherapy, antibody against programmed cell death 1, nomogram

Objective·To systematically integrate relevant influencing factors of advanced cancer patients' engagement behavior in advance care planning (ACP).Methods·The systematic search of Chinese and English literature on factors influencing ACP engagement behavior in advanced cancer patients from inception to December 2022 in China National Knowledge Infrastructure (CNKI), Wanfang, China Biomedical Literature Database (Sinomed), PubMed, Cochrane Library, Embase, CINAHL, and PsycINFO was conducted. After the literature quality evaluation, content extraction and summary were conducted by two researchers, and the data of quantitative research and qualitative research were extracted and integrated respectively. The final influencing factors of ACP engagement behavior of advanced cancer patients were obtained. With the help of the theoretical domain, they were mapped to the capability, opportunity, motivation-behavior (COM-B) model step by step.Results·A total of 21 studies were included and 27 factors were summarized, including 9 theoretical domains. Mapping to the COM-B model included 9 capability factors (knowledge of ACP, education level, accurate knowledge of prognosis, knowledge of the time of disease diagnosis, prior experience, subjective life expectancy, age, cancer site, and disease symptom burden), 13 opportunity factors (gender, marital status, race/ethnicity, religious belief, dependent children, family economic condition, place of living, housing type, family support, social support, doctor-patient relationship, acculturation, and whether or not to establish a hospice service center) and 5 motivational factors (ACP attitude, ACP belief, ACP motivation, anxiety and depression, and death attitude). Among them, doctor-patient relationship, religious belief, ACP attitude, educational level, marital status, family support, knowledge of ACP, accurate knowledge of prognosis, age, place of living, attitude toward death, prior experience, and race/ethnicity were more influential factors on ACP engagement behavior.Conclusion·Based on the COM-B model, the influencing factors of ACP engagement behavior in advanced cancer patients can be comprehensively summarized. Future studies can use the above factors as an entry point to design continuous, multifaceted, and comprehensive interventions based on the COM-B model to promote the practice of ACP engagement behavior in advanced cancer patients.

Additive Manufacturing, also popularly known as "3D printing" and Novel Materials which can also be named "Advanced Materials" are part of Emerging and Disruptive Technologies because of their actual use nowadays, in the case of Additive Manufacturing and the big potential it could have on the world, in case of Novel Materials. More interestingly, both Additive Manufacturing and Novel Materials can be used together and would change many things about how we think in society, even starting from how we construct bridges and houses (AM can make both of them) to combining them and having impressive directions. In terms of Global Security, both Additive Manufacturing and Novel Materials can help on the military part. [ABSTRACT FROM AUTHOR]

Objective·To systematically integrate relevant influencing factors of advanced cancer patients' engagement behavior in advance care planning (ACP). Methods·The systematic search of Chinese and English literature on factors influencing ACP engagement behavior in advanced cancer patients from inception to December 2022 in China National Knowledge Infrastructure (CNKI), Wanfang, China Biomedical Literature Database (Sinomed), PubMed, Cochrane Library, Embase, CINAHL, and PsycINFO was conducted. After the literature quality evaluation, content extraction and summary were conducted by two researchers, and the data of quantitative research and qualitative research were extracted and integrated respectively. The final influencing factors of ACP engagement behavior of advanced cancer patients were obtained. With the help of the theoretical domain, they were mapped to the capability, opportunity, motivation-behavior (COM-B) model step by step. Results·A total of 21 studies were included and 27 factors were summarized, including 9 theoretical domains. Mapping to the COM-B model included 9 capability factors (knowledge of ACP, education level, accurate knowledge of prognosis, knowledge of the time of disease diagnosis, prior experience, subjective life expectancy, age, cancer site, and disease symptom burden), 13 opportunity factors (gender, marital status, race/ethnicity, religious belief, dependent children, family economic condition, place of living, housing type, family support, social support, doctor-patient relationship, acculturation, and whether or not to establish a hospice service center) and 5 motivational factors (ACP attitude, ACP belief, ACP motivation, anxiety and depression, and death attitude). Among them, doctor-patient relationship, religious belief, ACP attitude, educational level, marital status, family support, knowledge of ACP, accurate knowledge of prognosis, age, place of living, attitude toward death, prior experience, and race/ethnicity were more influential factors on ACP engagement behavior. Conclusion·Based on the COM-B model, the influencing factors of ACP engagement behavior in advanced cancer patients can be comprehensively summarized. Future studies can use the above factors as an entry point to design continuous, multifaceted, and comprehensive interventions based on the COM-B model to promote the practice of ACP engagement behavior in advanced cancer patients. [ABSTRACT FROM AUTHOR]

Purpose of Review: To provide a comprehensive overview of the current understanding and developments in the treatment options for adrenocortical carcinoma (ACC), focusing on the strategies utilized for advanced disease. Recent Findings: Research has delved into the genomic landscape of ACC, revealing potential targets for therapy. Despite the failure of inhibitors aimed at the insulin like growth factor 1(IGF-1) receptor, other approaches, including vascular endothelial growth factor receptor (VEFGR) tyrosine kinase inhibitors and immune checkpoint inhibitors, are being investigated. There are also ongoing trials of combination treatments such as lenvatinib with pembrolizumab and cabozantinib with atezolizumab. Summary: ACC remains a challenging malignancy with limited effective treatment options. Although EDP-M stands as the frontline treatment, the search for effective second-line therapies is ongoing. Targeted therapies and immunotherapies, especially in combination regimens, are demonstrating potential and are the subject of continued research. The evolving genomic landscape emphasizes the significance of targeted therapies and the need for further in-depth studies to solidify effective treatment regimens for ACC. [ABSTRACT FROM AUTHOR]

We present 7 years of clinical experience with single-agent pembrolizumab immune checkpoint inhibitor immunotherapy in non-small cell lung cancers (NSCLC) from four UK cancer centres. This multi-institutional retrospective cohort study included 226 metastatic NSCLC patients. Outcomes were number and severity of immune-related adverse events (irAEs), median progression-free survival (mPFS) and median overall survival (mOS). Within our cohort, 119/226 (53%) patients developed irAEs. Of these, 54/119 (45%) experienced irAEs affecting two or more organ systems. The most common irAEs were diarrhoea and rash. The development of an irAE was associated with better mOS (20.7 versus 8.0 months; P < 0.001) and mPFS (12.0 versus 3.9 months; P < 0.001). The development of grade 3/4 toxicities was associated with worse outcomes compared with the development of grade 1/2 toxicities (mOS 6.1 months versus 25.2 months, P < 0.01; mPFS 5.6 months versus 19.3 months, P = 0.01, respectively). Females had a higher proportion of reported grade 3/4 toxicities (13/44 [29.5%] versus 10/74 [13.5%], P = 0.03). Using a multiple Cox regression model, the presence of irAEs was associated with a better overall survival (hazard ratio = 0.42, 95% confidence interval 0.29–0.61; P < 0.01) and better PFS (hazard ratio 0.38, 95% confidence interval 0.27–0.53; P < 0.001). In this multicentre retrospective cohort study, the development of at least one irAE was associated with significantly longer mPFS and mOS; however, more severe grade 3 and 4 irAEs were associated with worse outcomes. Delayed-onset irAEs, after the 3-month timepoint, were associated with better clinical outcomes. • Multi-institution experience (n = 226) of pembrolizumab monotherapy in advanced lung cancer. • Development of immune-related adverse events (irAEs) associated with improved outcomes. • Onset of irAEs at >3 months from treatment start associated with better outcomes. • Patients with CTCAE grade 1–2 toxicity did better than those with grade 3–4 toxicity. [ABSTRACT FROM AUTHOR]

The third-generation EGFR-TKIs, such as osimertinib, aumolertinib, and furmonertinib, have been recommended as the preferred treatment for EGFRmutant advanced non-small cell lung cancer (NSCLC). Among them, furmonertinib shows several advantages in terms of clinical efficacy. Firstly, compared to osimertinib and aumolertinib, furmonertinib was the first EGFRTKI with median progression-free survival (mPFS) of over 20.0m (20.8 m) for advanced NSCLC with classical EGFR-mutations. Furthermore, furmonertinib achieved a mPFS of 18.1m in advanced NSCLC with unfavorable prognostic factors, such as the 21 L858R mutation and central nervous system (CNS) metastasis, which is unrivalled by osimertinib. Secondly, furmonertinib is the only FDA-approved EGFR-TKI for breakthrough therapy in newly-diagnosed advanced NSCLC with EGFR ex20ins mutation. Thirdly, the relatively longer mPFS of 20.8m was observed in furmonertinib compared to osimertinib and aumolertinib (15.2m and 15.3 m) in EGFR-mutant advanced NSCLC with CNS metastases. More importantly, the efficacy of furmonertinib increases within the dose range of 80-240 mg per day. Finally, furmonertinib can be an optional treatment for advanced NSCLC patients who develop resistance to osimertinib or aumolertinib. In conclusion, furmonertinib may be a glittering star in the field of EGFR-TKI, which requires further exploration and expansion. [ABSTRACT FROM AUTHOR]

Testicular germ cell tumor (GCT) is the most common solid tumor in adolescent and young adult men. Progress in the management of GCT has been made in the last 50 years, with a substantial improvement in cure rates for advanced disease, from 25% in the 1970s to nearly 80%. However, relapsed or platinum-refractory disease occurs in a proportion, 20% of whom will die from disease progression. This article reviews the current evidence-based treatments for extracranial GCT, the acute and chronic toxic effects that may result, and highlights contemporary advances and progress in the field. [ABSTRACT FROM AUTHOR]

Abstract The accumulation of advanced glycation end-products (AGEs) elicits morphofunctional kidney impairment. AGEs levels can be noninvasively estimated by skin autofluorescence (SAF). We explored whether high SAF predicts kidney outcomes in type 2 diabetes (T2D) individuals. The study was conducted as a predefined analysis of the Brazilian Diabetes Study, a prospective single-center cohort of T2D adults. Data from 155 individuals followed for up to 1716 days were considered. The incidence of major adverse kidney events (MAKE) was 9.6%. Individuals with above-median SAF had a higher incidence of MAKEs (4.6% vs. 21%; p = 0.002), with an HR of 3.39 [95% CI: 1.06–10.85; p = 0.040] after adjustment by age and gender. The mean adjusted eGFR change was 1.08 units (SE: 1.15; 95%CI: –1.20, 3.37) in the low SAF and –5.19 units [SE: 1.93; 95%CI: –9.10, –1.29] in the high SAF groups (between-subject difference: F: 5.62, p = 0.019). The high-SAF group had a greater prevalence of rapid decliners than the low-SAF group (36.7% vs. 15.8%; p = 0.028). In conclusion, high SAF was related to increased incidence of MAKEs and faster decline in eGFR among T2D subjects. This should be considered by healthcare providers when identifying individuals more prone to diabetes-related kidney complications.

This manuscript describes the Advanced Breast Cancer (ABC) international consensus guidelines updated at the last two ABC international consensus conferences (ABC 6 in 2021, virtual, and ABC 7 in 2023, in Lisbon, Portugal), organized by the ABC Global Alliance. It provides the main recommendations on how to best manage patients with advanced breast cancer (inoperable locally advanced or metastatic), of all breast cancer subtypes, as well as palliative and supportive care. These guidelines are based on available evidence or on expert opinion when a higher level of evidence is lacking. Each guideline is accompanied by the level of evidence (LoE), grade of recommendation (GoR) and percentage of consensus reached at the consensus conferences. Updated diagnostic and treatment algorithms are also provided. The guidelines represent the best management options for patients living with ABC globally, assuming accessibility to all available therapies. Their adaptation (i.e. resource-stratified guidelines) is often needed in settings where access to care is limited.

IntroductionThe accumulation of tissue-advanced glycation end products in skin results from complex and consecutive reactions and can be measured by skin autofluorescence (SAF) reader devices. This overview discusses studies evaluating the utilization of SAF in screening renal and cardiac disease.Materials and methodsLiterature search was performed using Google Scholar, PubMed, Springer, Ovid, and ScienceDirect.ResultsSAF was an independent predictor of progression of chronic kidney disease (CKD) and was elevated in subjects on hemodialysis and peritoneal dialysis. Furthermore, SAF was significantly associated with cardiovascular events, cardiovascular mortality, and all-cause mortality in CKD patients. Other studies revealed a correlation between SAF and arterial stiffness, vascular damage, and subclinical atherosclerosis. A vegetarian diet was associated with lower SAF levels, whereas malnutrition was correlated with higher levels and increased mortality.ConclusionsSAF measurement may be useful in managing renal and cardiac disease. Future studies are needed to clarify the specific role of SAF in the management of CKD and its noninvasive office utilization to identify comorbidities in inflammatory diseases, such as psoriasis.

Objective To investigate the predictive effect of circulating tumor cell (CTC) combined with neutrophil to lymphocyte ratio (NLR) on efficacy of advanced gastric cancer. Methods The clinicopathological data of 36 patients with advanced gastric cancer who received firstline treatment in Jiangning Hospital Affiliated to Nanjing Medical University and Jiangsu Cancer Hospital from June 2022 to January 2023 were collected. The optimal cutoff values of CTC and NLR were calculated using X-tile software, and the patients were divided into high CTC group (CTC>15, n=21) and low CTC group (CTC≤15, n=15), high NLR group (NLR>2.32, n=20) and low NLR group (NLR≤2.32, n=16). COX regression analysis and survival curve were used to analyze the relationship between CTC, NLR and progression free survival (PFS). Receiver operating characteristic (ROC) curves compared the predictive power of CTC, NLR, and the combination in predicting the outcome of advanced gastric cancer. Results Multivariate COX regression analysis showed that CTC (HR=7.441, P=0.045) and NLR (HR=4.690, P=0.011) were associated with PFS in patients with advanced gastric cancer. Patients in CTC group and low NLR group had longer PFS than those in high CTC group and high NLR group, respectively (P

Objective: To explore the efficacy of tislelizumab combined with pemetrexed and carboplatin chemotherapy in elderly patients with advanced lung adenocarcinoma and its effects on serum insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) levels. Methods: Ninety-four driver gene-negative elderly patients with advanced lung adenocarcinoma admitted to the Fourth Affiliated Hospital of Nanjing Medical University from July 2021 to December 2022 were selected as the study subjects. They were divided into chemotherapy group (pemetrexed combined with carboplatin, n=48) and tislelizumab group (pemetrexed+carboplatin+tislelizumab, n=46) by the random number table method, and both groups were treated for 4 cycles, with 21 days as a cycle. The clinical efficacy, immune function ［T lymphocyte subsets (CD4+, CD8+, CD4+/CD8+］ and serum indicators (IGF-1, IGFBP-3) before and after treatment were recorded in both groups, and the adverse reactions were assessed. Results: The clinical efficacy and objective response rate (58.70% vs 29.17%, χ2=8.329, P＜0.01) in tislelizumab group were significantly higher than those in chemotherapy group. After 4 cycles of treatment, the CD4+, CD4+/CD8+ and IGFBP-3 levels in both groups were significantly increased compared with those before treatment (P＜0.05), and the indicators in tislelizumab group were higher than those in chemotherapy group (P＜0.05); CD8+ and IGF-1 levels were significantly decreased in both groups compared with those before treatment (P＜0.05), and the indicators in tislelizumab group were lower than those in chemotherapy group (P＜0.05). Adverse reactions were mainly grade 1-2 in both groups, and there was no significant difference in the incidence of adverse reactions between two groups (P＞0.05). Conclusion: The first-line therapy of tislelizumab combined with platinum-containing dual-drug for elderly advanced lung adenocarcinoma can improve the clinical efficacy, improve the balance of CD4+/CD8+, regulate the expression of serum IGF-1 and IGFBP-3 levels. The adverse reactions are controllable, and the treatment regimen is safe and reliable.

Purpose: To compare clinical outcomes between gonioscopy-assisted transluminal trabeculotomy (GATT) and trabeculectomy (TRAB) in patients with advanced-stage pseudoexfoliation glaucoma (PEXG). Methods: This comparative study comprised 62 patients who underwent GATT (N = 31) or TRAB (N = 31) for advanced-stage PEXG. Primary outcome was cumulative probability of surgical success at the end of 12-month follow-up. Success was determined as intraocular pressure (IOP) reduction ≥ 30% from baseline, IOP between 6 and 18 mmHg and IOP upper limits for IOP < 15 mmHg and < 12 mmHg, separately. Secondary outcomes were IOP reduction, antiglaucoma medication (AGM) use, and complications in the study. Results: Age, sex, cup/disc ratio, mean deviation, pattern standard deviation, and retinal nerve fiber layer thickness did not significantly differ between the groups (p > 0.05 for all). The probability of cumulative surgical success at the end of 12 months was similar between the two groups for IOP < 15 mmHg and < 18 mmHg but significantly higher after TRAB (92.0%) than GATT (82.5%) for IOP < 12 mmHg (log-rank test p = 0.035). Percentage of IOP reduction from baseline was similar between the groups (53.1 ± 18.6% in GATT group and 53.0 ± 16.6% in TRAB group, p = 0.98) at the end of 12 months. No significant difference in the mean number of AGM was present at the 12-month visit (1.3 ± 1.4 in GATT and 1.1 ± 1.4 in TRAB, p = 0.65). Conclusion: At the end of 12 months, IOP reduction rate was similar between GATT and TRAB. Cumulative surgical success was higher after TRAB than GATT for IOP < 12 mmHg. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effects of telizumab injection combined with albumin paclitaxel and carboplatin on intestinal flora and prognostic nutritional index (PNI) and systemic immune inflammatory index (SII) in patients with advanced non small cell lung cancer (NSCLC). Methods: 115 patients with advanced NSCLC who were treated in Nanjing Jiangning Hospital and Zhongda Hospital Affiliated to Southeast University from May 2020 to February 2023 were selected. Patients were divided into control group and study group according to the random number table method, 57 cases and 58 cases respectively. Control group was treated with albumin paclitaxel and carboplatin, and study group was treated with tirelizumab injection on the basis of control group. The objective response rate (ORR), disease control rate (DCR), serum tumor markers [cytokeratin 19 fragment (CYFRA21-1), carcinoembryonic antigen (CEA), carbohydrate antigen 125 (CA125)], intestinal flora (bifidobacterium, lactobacillus, Enterococcus), SII and PNI were compared between two groups, and the incidence of adverse reactions during treatment was observed. Results: The ORR (44.83%) and DCR (77.59%) in study group were higher than those in control group (24.56%, 50.88%) (P<0.05). Compared with control group after treatment, CYFRA21-1, CEA, CA125, Enterococcus and SII in study group were lower, and bifidobacterium, lactobacillus and PNI were higher (P<0.05). There was no difference in the incidence of adverse reactions between two groups (P>0.05). Conclusion: Tirelizumab injection combined with albumin paclitaxel and carboplatin in the treatment of patients with advanced NSCLC, which can improve clinical efficacy and improve SII, PNI and intestinal flora. [ABSTRACT FROM AUTHOR]

Objective: To investigate the effect of Camrelizumab combine with chemotherapy on immune function, neutrophil to lymphocyte ratio (NLR), C-reactive protein to albumin ratio (CAR) in patients with advanced non-squamous non-small cell lung cancer (NSCLC). Methods: Used retrospective analysis, 100 patients with advanced non-squamous NSCLC who were admitted to the first affiliated hospital of Anhui medical university north district from January 2020 to December 2022 were selected, and patients were divided into control group (n=48) and observation group (n=52) according to the treatment methods. Control group received chemotherapy with pemetrexed disodium combined with cisplatin injection or nedaplatin for injection, and observation group received Camrelizumab treatment on the basis of control group. The efficacy, immune function, tumor markers, NLR, and CAR were compared between two groups, and the incidence of adverse reactions during treatment were observed simultaneously in two groups. Results: Compared with control group, the clinical total effective rate in observation group was higher (P<0.05). 4 cycles after treatment, compared with control group, the carcinoembryonic antigen (CEA), cytokeratin 19 fragment antigen 21-1 (CYFRA21-1), carbohydrate antigen 125 (CA125), NLR, CAR and CD8+ in observation group were lower, while CD3+, CD4+ and CD4+/CD8+ were higher (P<0.05). There was no difference in the incidence of adverse reactions between two groups (P>0.05). Conclusion: Patients with advanced non-squamous NSCLC combine with Camrelizumab treatment on the basis of chemotherapy, which is helpful to control disease progression, improve clinical efficacy, reduce tumor markers levels, improve immune function, and reduce NLR and CAR. [ABSTRACT FROM AUTHOR]

Purpose: The numerous first-line treatment regimens for human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC) necessitate a comprehensive evaluation to inform clinical decision-making. We conducted a Bayesian network meta-analysis (NMA) to compare the efficacy and safety of different interventions. Methods: We systematically searched for relevant randomized controlled trials (RCTs) in Pubmed, Embase, Cochrane Library and online abstracts from inception to June 1, 2023. NMA was performed to calculate and analyze progression-free survival (PFS), overall survival (OS), objective response rate (ORR), and adverse events of grade 3 or higher (≥ 3 AEs). Results: Out of the 10,313 manuscripts retrieved, we included 28 RCTs involving 11,680 patients. Regarding PFS and ORR, the combination of trastuzumab with tyrosine kinase inhibitors (TKIs) was more favorable than dual-targeted therapy. If only using trastuzumab, combination chemotherapy is superior to monochemotherapy in terms of PFS. It is important to note that the addition of anthracycline did not result in improved PFS. For patients with hormone receptor-positive HER2-positive diseases, dual-targeted combined with endocrine therapy showed better benefit in terms of PFS compared to dual-targeted alone, but it did not reach statistical significance. The comprehensive analysis of PFS and ≥ 3 AEs indicates that monochemotherapy combined with dual-targeted therapy still has the optimal balance between efficacy and safety. Conclusion: Monochemotherapy (Docetaxel) plus dual-target (Trastuzumab and Pertuzumab) therapy remains the optimal choice among all first-line treatment options for ABC. The combination of trastuzumab with TKIs (Pyrotinib) demonstrated a significant improvement in PFS and ORR, but further data are warranted to confirm the survival benefit. [ABSTRACT FROM AUTHOR]

Background: The clinical efficacy and safety of camrelizumab as a third- or laterline regimen in patients with advanced non-small cell lung cancer (NSCLC) have not been determined in large clinical trials. Objective: This study aimed to evaluate the clinical efficacy and safety of camrelizumab in combination with albumin-bound paclitaxel as a third- or later-line treatment for patients with advanced NSCLC. Methods: A total of 257 patients with advanced NSCLC who were histopathologically confirmed and failed in clinical second-line therapy regimens at Jiangxi Province Cancer hospital from January 2018 to December 2021 were retrospectively selected. Patients with advanced NSCLC were divided into the single treatment group (STG) of camrelizumab, and the combined treatment group (CTG) of camrelizumab in combination with albumin-bound paclitaxel according to the treatment regimen. The primary outcomes of interest were clinical efficacy[objective response rate (ORR) and disease control rate (DCR)], progression-free survival (PFS), and overall survival (OS). Survival data were analyzed using the Kaplan-Meier method, and the log-rank test was performed. Additionally, Cox proportional hazard regression was used to analyze the correlation of prognosis and baseline characteristics between subgroups, to identify the potential independent risk factors for PFS and OS. Furthermore, the occurrence of side effects was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03). Results: Of the 257 patients with advanced NSCLC included in the research, 135 patients received camrelizumab, and 122 patients received camrelizumab plus albumin-bound paclitaxel. The ORR of CTG and STG was 59.84% and 50.38%, and the DCR was 77.05% and 65.93%, respectively. The median PFS in CTG was higher than that in the STG (5.27 vs. 3.57 months, P = 0.0074), and the median OS was longer (7.09 vs. 6.47 months, P < 0.01). The lines of treatment, metastases, and PD-L1 expression levels were independent risk factors for the mPFS and mOS of patients with advanced NSCLC. The occurrence of adverse events was similar between camrelizumab and camrelizumab plus albumin-bound paclitaxel groups. Conclusion: Camrelizumab combined with albumin-bound paclitaxel as the third- or later-line regimen greatly prolonged PFS and OS of advanced NSCLC patients. A prospective clinical trial is warranted. [ABSTRACT FROM AUTHOR]

Objective To explore the preoperative predictors of lymphovascular invasion (LVI) in patients with advanced gastric cancer, and establish the corresponding nomogram prediction model and conduct internal validation. Methods A total of 246 cases of advanced gastric cancer who underwent surgical resection in the Department of Gastrointestinal Surgery of Hengshui People's Hospital from January 2018 to December 2021 were selected. Patients were divided into the LVI positive group and the LVI negative group according to postoperative pathological diagnosis. The age, gender, tumor differentiation, tumor size, tumor site, Borrmann classification, Lauren's classification, cT stage, cN stage and systemic immune-inflammation index (SII) of patients were collected and compared between the two groups. The predictors that were statistically different between the two groups were subjected to multivariate Logistic regression and further developed into a visual prediction model. Bootstrap method was applied for internal validation of the prediction efficiency of the model. Results The differences of tumor size, Borrmann classification, tumor differentiation, Lauren classification, cT staging, cN staging and SII were statistically significant between the two groups ( P＜0.05). Multivariate Logistic regression analysis showed that tumor size (OR=2.184, 95%CI: 1.224-3.898), Borrmann classification (OR=2.517, 95%CI: 1.294- 4.896), cT staging (OR=1.860, 95%CI: 1.045-3.308), cN staging (OR=1.816, 95%CI: 1.004-3.285) and SII (OR=1.001, 95%CI: 1.000-1.002) were independent predictors of LVI in advanced gastric cancer. A preoperative nomogram prediction model for advanced gastric cancer LVI was developed based on results of multivariate analysis. By internal validation, the area under curve (AUC) value of the subject operating characteristic (ROC) curve of the nomogram was 0.735, which was higher than that of tumor size (0.599), Borrmann staging (0.564), cT staging (0.604), cN staging (0.582) and SII (0.615), respectively. The calibration curve showed that the probability of predicted LVI by the nomogram was in a good agreement with the probability of actual LVI occurrence. The Hosmer-Lemeshow test showed good model fit (χ² =4.387, P=0.821). Conclusion The established nomogram prediction model can help to predict the probability of LVI in advanced gastric cancer preoperatively, which can provide a guideline for clinical individualized treatment. [ABSTRACT FROM AUTHOR]

Background To evaluate the claim that oncologists overestimate expected survival time (EST) in advanced cancer. Methods We pooled 7 prospective studies in which observed survival time (OST) was compared with EST (median survival in a group of similar patients estimated at baseline by the treating oncologist). We hypothesized that EST would be well calibrated (approximately 50% of EST longer than OST) and imprecise (<30% of EST within 0.67 to 1.33 of OST), and that multiples of EST would provide well-calibrated scenarios for survival time: worst-case (approximately 10% of OST <1/4 of EST), typical (approximately 50% of OST within half to double EST), and best-case (approximately 10% of OST >3 times EST). Associations between baseline characteristics and calibration of EST were assessed. Results Characteristics of 1,211 patients: median age 66 years, male 61%, primary site lung (40%) and upper gastrointestinal (16%). The median OST was 8 months, and EST was 9 months. Oncologists' estimates of EST were well calibrated (50% longer than OST) and imprecise (28% within 0.67 to 1.33 of OST). Scenarios for survival time based on simple multiples of EST were well calibrated: 8% of patients had an OST less than 1/4 their EST (worst-case), 56% had an OST within half to double their EST (typical), and 11% had an OST greater than 3 times their EST (best-case). Calibration was independent of age, sex, and cancer type. Conclusions Oncologists were no more likely to overestimate survival time than to underestimate it. Simple multiples of EST provide well-calibrated estimates of worst-case, typical, and best-case scenarios for survival. [ABSTRACT FROM AUTHOR]

ObjectivesSoluble receptor for advanced glycation end products is a known plasma marker of alveolar epithelial injury. However, RAGE is also expressed on cell types beyond the lung, and its activation leads to up-regulation of pro-inflammatory mediators. We sought to examine the relationship between plasma soluble receptor for advanced glycation end products and primary pulmonary dysfunction, extrapulmonary organ dysfunction, and mortality in pediatric acute respiratory distress syndrome patients at two early time points following acute respiratory distress syndrome diagnosis and compare these results to plasma surfactant protein-D, a marker of pure alveolar epithelial injury.DesignProspective observational study.SettingFive academic PICUs.PatientsTwo hundred fifty-eight pediatric patients 30 days to 18 years old meeting Berlin Criteria for acute respiratory distress syndrome.InterventionsNone.Measurements and main resultsPlasma was collected for soluble receptor for advanced glycation end products and surfactant protein-D measurements within 24 hours (day 1) and 48 to 72 hours (day 3) after acute respiratory distress syndrome diagnosis. Similar to surfactant protein-D, plasma soluble receptor for advanced glycation end products was associated with a higher oxygenation index (p < 0.01) and worse lung injury score (p < 0.001) at the time of acute respiratory distress syndrome diagnosis. However, unlike surfactant protein-D, plasma soluble receptor for advanced glycation end products was associated with worse extrapulmonary Pediatric Logistic Organ Dysfunction score during ICU stay (day 3; p < 0.01) and positively correlated with plasma levels of interleukin-6 (p < 0.01), tumor necrosis factor-α (p < 0.01), and angiopoietin-2 (p < 0.01). Among children with indirect lung injury, plasma soluble receptor for advanced glycation end products was associated with mortality independent of age, sex, race, cancer/bone marrow transplant, and Pediatric Risk of Mortality score (day 3; odds ratio, 3.14; 95% CI, 1.46-6.75; p < 0.01).ConclusionsUnlike surfactant protein-D, which is primarily localized to the alveolar epithelium plasma soluble receptor for advanced glycation end products is systemically expressed and correlates with markers of inflammation, extrapulmonary multiple organ dysfunction, and death in pediatric acute respiratory distress syndrome with indirect lung injury. This suggests that unlike surfactant protein-D, soluble receptor for advanced glycation end products is a multifaceted marker of alveolar injury and increased inflammation and that receptor for advanced glycation end products activation may contribute to the pathogenesis of multiple organ failure among children with indirect acute respiratory distress syndrome.

BackgroundAdvanced glycation end-products (AGE) are formed through nonenzymatic glycation of free amino groups in proteins or lipid. They are associated with inflammation and oxidative stress, and their accumulation in the body is implicated in chronic disease morbidity and mortality. We examined the association between postdiagnosis dietary Nε-carboxymethyl-lysine (CML)-AGE intake and mortality among women diagnosed with breast cancer.MethodsPostmenopausal women aged 50 to 79 years were enrolled in the Women's Health Initiative (WHI) between 1993 and 1998 and followed up until death or censoring through March 2018. We included 2,023 women diagnosed with first primary invasive breast cancer during follow-up who completed a food frequency questionnaire (FFQ) after diagnosis. Cox proportional hazards (PH) regression models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) of association between tertiles of postdiagnosis CML-AGE intake and mortality risk from all causes, breast cancer, and cardiovascular disease.ResultsAfter a median 15.1 years of follow-up, 630 deaths from all causes were reported (193 were breast cancer-related, and 129 were cardiovascular disease-related). Postdiagnosis CML-AGE intake was associated with all-cause (HRT3vsT1, 1.37; 95% CI, 1.09-1.74), breast cancer (HRT3vsT1, 1.49; 95% CI, 0.98-2.24), and cardiovascular disease (HRT3vsT1, 1.91; 95% CI, 1.09-3.32) mortality.ConclusionsHigher intake of AGEs was associated with higher risk of major causes of mortality among postmenopausal women diagnosed with breast cancer.ImpactOur findings suggest that dietary AGEs may contribute to the risk of mortality after breast cancer diagnosis. Further prospective studies examining dietary AGEs in breast cancer outcomes and intervention studies targeting dietary AGE reduction are needed to confirm our findings.

Desmoplastic small round cell tumor (DSRCT) is an uncommon and aggressive malignancy with male predominance. It commonly occurs in the abdominal cavity and is usually diagnosed with help of histopathology. It shows a characteristic EWSR1-WT1 gene fusion in most cases. We hereby report a series of 3 cases of DSRCT that we encountered at our institute. All of them presented in an advanced stage as quoted in the previously available literature. The ideal treatment should include a multidisciplinary team. The chemotherapy regimen used is usually Ewing’s sarcoma protocol of multiagent chemotherapy. Surgical approaches which include cytoreduction and intra-peritoneal hyperthermic chemotherapy are the procedure of choice but rarely feasible. Newer clinical trials of targeted therapy are in progress for improving the treatment and thereby the prognosis of DSRCT.

Abstract Introduction Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non‐squamous, non‐small cell lung cancer (NSCLC). Data regarding the addition of bevacizumab, especially in maintenance treatment, are insufficient. Methods Eligibility criteria included: no prior chemotherapy; advanced, non‐squamous, NSCLC; performance status ≤1; and epidermal growth factor receptor mutation‐negative. Patients (N = 108) received induction chemotherapy with cisplatin, pemetrexed, and bevacizumab every 3 weeks for four cycles, and tumor response was needed to confirm four‐week response duration. Patients with at least stable disease were randomized to pemetrexed/bevacizumab or pemetrexed alone. The primary endpoint was progression‐free survival (PFS) after induction chemotherapy. Myeloid‐derived suppressor cell (MDSC) counts of peripheral blood samples were also analyzed. Results Thirty‐five patients each were randomized to the pemetrexed/bevacizumab group and the pemetrexed alone group. PFS was significantly better in the pemetrexed/bevacizumab group than in the pemetrexed alone group (7.0 vs. 5.4 months, hazard ratio: 0.56 [0.34–0.93], log‐rank p = 0.023). In patients with partial response to induction therapy, median overall survival was 23.3 months in the pemetrexed alone group and 29.6 months in the pemetrexed/bevacizumab group (log‐rank p = 0.077). Pretreatment monocytic (M)‐MDSC counts tended to be greater in the pemetrexed/bevacizumab group with poor PFS than in those with good PFS (p = 0.0724). Conclusions Addition of bevacizumab to pemetrexed as maintenance therapy prolonged PFS in patients with untreated, advanced, non‐squamous NSCLC. Furthermore, an early response to induction therapy and pretreatment M‐MDSC counts may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin and pemetrexed.

Abstract Triplet DCF (docetaxel, cisplatin and 5-flurouracil) and doublet CP/CF (carboplatin and paclitaxel/cisplatin and 5-fluorouracil) regimens were prospectively evaluated in advanced squamous anal cell carcinoma (SCCA), and validated as standard treatments. Even though the high efficacy and good tolerance of DCF regimen were confirmed in 3 independent prospective trials, doublet CP regimen is still recommended in several guidelines based in its better safety profile with similar efficacy compared to CF regimen. We performed a propensity score-adjusted method with inverse probability of treatment weighted (IPTW) and matched case control (MCC) comparison among patients with metastatic or non-resectable locally advanced recurrent SCCA, treated with chemotherapy as first line regimen. The primary endpoint was the overall survival (OS), and the secondary endpoint was the progression-free survival (PFS). 247 patients were included for analysis. 154 patients received DCF and 93 patients received a doublet regimen. The median OS was 32.3 months with DCF and 18.3 months with doublet regimens (HR 0.53, 95%CI 0.38–0.74; p = 0.0001), and the median PFS was 11.2 months with DCF versus 7.6 months with doublet regimens (HR 0.53, 95%CI 0.39–0.73; p

Purpose: To investigate the association between skin advanced glycation end-products (AGEs) levels, blood antioxidative vitamin and carotenoid concentrations, and severe erectile dysfunction (ED) in community-dwelling men. Materials and Methods: This cross-sectional study used the 5-Item International Index of Erectile Function to identify 335 community- dwelling men with ED. The accumulation of skin AGEs was assessed noninvasively by measuring skin autofluorescence. Background-adjusted multivariable logistic regression analyses using the inverse probability of treatment weighting method were performed to evaluate the effects of AGEs, vitamins, and carotenoids on severe ED. Moreover, multiple linear regression analyses were performed to assess the association between skin AGEs levels and serum carotenoid concentrations. Results: The median age of study participants was 57 years. Of the 335 men, 289 (86.3%) and 46 (13.7%) were classified into the mild/moderate and severe ED groups, respectively. Multivariable analyses revealed that skin AGEs levels, blood vitamins C and E, lutein, zeaxanthin, β-cryptoxanthin, α-carotene, β-carotene, total lycopene, and cis-lycopenes concentrations were significantly associated with severe ED, whereas all-trans lycopene concentrations were not. In the multiple linear regression analyses, serum zeaxanthin concentrations were negatively and significantly correlated with skin AGEs levels. Conclusions: Higher skin AGEs levels and lower blood antioxidative vitamin and carotenoid concentrations were significantly associated with severe ED. Serum zeaxanthin levels were negatively and significantly correlated with skin AGEs levels, suggesting the possible effects of zeaxanthin on ED by decreasing tissue AGEs levels.

With the continuous development of immunotherapy, the treatment of patients with advanced non-small cell lung cancer (NSCLC) is gradually becoming more and more precise. The clinical benefit of immune checkpoint inhibitors in patients with NSCLC with positive programmed cell death-ligand 1 (PD-L1) expression is obvious, but the effect in patients with negative expression remains inexact. This article reviews the treatment options available for advanced NSCLC patients with negative PD-L1 expression, aiming at providing references and options for their treatment.

This is the first evaluation of the Yemen Field Epidemiology Training Program (Y-FETP) to assess if it met its objectives. We collected data using mixed methods including desk review, a focus group discussion with the Y-FETP staff, in-depth interviews with 21 program stakeholders, and an online survey for the program’s graduates. We transcribed/analyzed qualitative data using explanatory quotations and survey data using descriptive methods. The desk review indicated that Y-FETP covers 18 (82%) out of 22 governorates and conducted >171 outbreak investigations, 138 surveillance system analyses/evaluations, 53 planned studies, published >50 articles and had >155 accepted conference abstracts. Qualitative findings showed Y-FETP helped save lives and reduced morbidity/mortality using building capacities in outbreak response; provided evidence-based data for decision-making; and increased awareness about public health issues. An online survey showed that Y-FETP helped 60 to 80% of graduates conduct outbreak investigations, surveillance analysis/evaluation, manage surveillance systems/projects, engage in public health communication (reports/presentation), and use basic statistical methods. However, the evaluation revealed that Y-FETP is primarily funded by donors; thus, it is not sustainable. Other challenges include low graduate retention and limited training in policy development and management. Y-FETP achieved its main objectives of increasing the number of epidemiologists in the workforce, making a positive impact on public health outcomes.

Objective To explore the clinical efficacy and immunomodulatory effects of anlotinib capsule combined with GP regimen in the treatment of advanced non-small cell lung cancer(NSCLC). Methods Forty patients with advanced NSCLC admitted to Nanjing Jiangbei Hospital from October 2020 to October 2022 were divided into two groups using a random number table method. The chemotherapy group ( n=20) was treated with GP regimen, and the combined group ( n=20) was treated with anlotinib capsule on the basis of the chemotherapy group. The short-term efficacy, immune function indexes (CD3+, CD4+, CD4+/CD8+, NK cells) and FACT-L scale scores of the two groups were detected before treatment and 4 months after treatment, and the incidence of adverse reactions was recorded. Results After treatment, the disease control rate (95.00% vs 70.00%, χ2=4.329, P=0.037) and the total effective rate (70.00% vs 30.00%, χ2=6.400, P=0.011) of the combined group were better than those of the chemotherapy group. After treatment, CD3+, CD4+, CD4+/CD8+ , NK cells and FACT-L and KPS scores in the two groups were increased, and those in the combined group were higher than those in the chemotherapy group (P0.05). Conclusion Anlotinib capsule+GP regimen can improve the overall therapeutic effect of patients with advanced NSCLC, not only improve the function of the patient ‘s immune system, but also has high safety, and has certain clinical application value.

BackgroundThe clinical efficacy and safety of camrelizumab as a third- or later-line regimen in patients with advanced non-small cell lung cancer (NSCLC) have not been determined in large clinical trials.ObjectiveThis study aimed to evaluate the clinical efficacy and safety of camrelizumab in combination with albumin-bound paclitaxel as a third- or later-line treatment for patients with advanced NSCLC.MethodsA total of 257 patients with advanced NSCLC who were histopathologically confirmed and failed in clinical second-line therapy regimens at Jiangxi Province Cancer hospital from January 2018 to December 2021 were retrospectively selected. Patients with advanced NSCLC were divided into the single treatment group (STG) of camrelizumab, and the combined treatment group (CTG) of camrelizumab in combination with albumin-bound paclitaxel according to the treatment regimen. The primary outcomes of interest were clinical efficacy[objective response rate (ORR) and disease control rate (DCR)], progression-free survival (PFS), and overall survival (OS). Survival data were analyzed using the Kaplan-Meier method, and the log-rank test was performed. Additionally, Cox proportional hazard regression was used to analyze the correlation of prognosis and baseline characteristics between subgroups, to identify the potential independent risk factors for PFS and OS. Furthermore, the occurrence of side effects was assessed according to the Common Terminology Criteria for Adverse Events (CTCAE 4.03).ResultsOf the 257 patients with advanced NSCLC included in the research, 135 patients received camrelizumab, and 122 patients received camrelizumab plus albumin-bound paclitaxel. The ORR of CTG and STG was 59.84% and 50.38%, and the DCR was 77.05% and 65.93%, respectively. The median PFS in CTG was higher than that in the STG (5.27 vs. 3.57 months, P = 0.0074), and the median OS was longer (7.09 vs. 6.47 months, P < 0.01). The lines of treatment, metastases, and PD-L1 expression levels were independent risk factors for the mPFS and mOS of patients with advanced NSCLC. The occurrence of adverse events was similar between camrelizumab and camrelizumab plus albumin-bound paclitaxel groups.ConclusionCamrelizumab combined with albumin-bound paclitaxel as the third- or later-line regimen greatly prolonged PFS and OS of advanced NSCLC patients. A prospective clinical trial is warranted.

This phase 2 study investigated sapanisertib (selective dual inhibitor of mTORC1/2) alone, or in combination with paclitaxel or TAK-117 (a selective small molecule inhibitor of PI3K), versus paclitaxel alone in advanced, recurrent, or persistent endometrial cancer. Patients with histologic diagnosis of endometrial cancer (1–2 prior regimens) were randomized to 28-day cycles on four treatment arms: 1) weekly paclitaxel 80 mg/m2 (days 1, 8, and 15); 2) weekly paclitaxel 80 mg/m2 + oral sapanisertib 4 mg on days 2–4, 9–11, 16–18, and 23–25; 3) weekly sapanisertib 30 mg, or 4) sapanisertib 4 mg + TAK-117 200 mg on days 1–3, 8–10, 15–17, and 22–24. Of 241 patients randomized, 234 received treatment (paclitaxel, n = 87 [3 ongoing]; paclitaxel+sapanisertib, n = 86 [3 ongoing]; sapanisertib, n = 41; sapanisertib+TAK-117, n = 20). The sapanisertib and sapanisertib+TAK-117 arms were closed to enrollment after futility analyses. After a median follow-up of 14.4 (paclitaxel) versus 17.2 (paclitaxel+sapanisertib) months, median progression-free survival (PFS; primary endpoint) was 3.7 versus 5.6 months (hazard ratio [HR] 0.82; 95% confidence interval [CI] 0.58–1.15; p = 0. 139); in patients with endometrioid histology (n = 116), median PFS was 3.3 versus 5.7 months (HR 0.66; 95% CI 0.43–1.03). Grade ≥ 3 treatment-emergent adverse event rates were 54.0% with paclitaxel versus 89.5% paclitaxel+sapanisertib. Our findings support inclusion of chemotherapy combinations with investigational agents for advanced or metastatic disease. The primary endpoint was not met and toxicity was manageable. Trial registration: ClinicalTrials.gov number, NCT02725268 • Patients with endometrioid tumors showed improvement (PFS, CBR, and CBR-16) with paclitaxel + sapanisertib vs paclitaxel. • There were no significant differences in PFS between the paclitaxel and paclitaxel + sapanisertib arms. • Treatment with paclitaxel + sapanisertib had limited toxicity with no new safety signals. [ABSTRACT FROM AUTHOR]

Treatment of advanced melanoma has been transformed by novel systemic therapies. The purpose of this study is to describe the current utilization patterns of immunotherapies with respect to survival outcomes in advanced melanoma. We performed a retrospective cohort study of patients with Stage 3 and 4 melanoma at our institution (2009-2019). Primary outcomes included overall survival (OS) and progression free survival (PFS). Kaplan–Meier survival analysis and Cox proportional hazards regression analysis evaluated associations between covariates and survival outcomes. Of 244 patients, 5-y OS was 62.4%. Lymphovascular invasion (hazard ratio [HR] = 2.462, P = 0.030) was associated with shorter PFS whereas female gender (HR = 0.324, P = 0.010) was associated with longer PFS. Residual tumor (HR = 146, P = 0.006) and Stage 4 disease (HR = 3.349, P = 0.011) were associated with shorter OS. Use of immunotherapy increased from 2% to 23% over the study period, and use of neoadjuvant immunotherapy also increased up to 2016. Timing of immunotherapy administration was not significantly associated with survival. Of the 193 patients who received 2 or more treatment types, the most common treatment sequence was surgery followed by immunotherapy (n = 117, 60.6%). Immunotherapy is increasingly used for treatment of advanced melanoma. In this heterogeneous cohort, there was no significant association between timing of immunotherapy and survival outcomes. [ABSTRACT FROM AUTHOR]

To summarise the prognostic value of patient‐reported outcomes (PROs) in advanced gastro‐oesophageal (GO) cancer. We systematically searched multiple databases using search terms related to advanced GO cancer, PRO and prognosis. Studies examining the relationship between baseline PROs and prognosis were included. Two reviewers independently screened articles and extracted data on study design, survival and associations between PROs and survival, in both univariable and multivariable analyses. QUIPS was used for quality assessment. From 3004 studies screened, seven studies were eligible, comprising PRO data from 2761 of 3408 (81%) participants. Median survival times ranged from 4.5 to 9.5 months. Among participants with oesophageal squamous cell carcinoma (SCC), physical functioning, social functioning and fatigue (QLQ‐C30) were associated with overall survival (OS) in one univariable analysis. Among three studies of participants with adenocarcinoma, univariable analyses revealed associations between OS and global quality of life (QOL), physical functioning, role functioning and social functioning; two studies showed association with pain. There was an association between emotional functioning, fatigue, lack of mobility, lack of self‐care, appetite loss/anorexia and OS in one study. One multivariable analysis among participants with oesophageal SCC showed physical and social functioning was associated with OS. Among participants with adenocarcinoma, multivariable analyses showed associations between OS and physical functioning/lack of mobility, appetite loss/anorexia (three studies), global QOL, role functioning/lack of self‐care, pain (two studies) and social functioning (one study). Physical functioning, role functioning, social functioning, pain, anorexia and global QOL were associated with OS in advanced GO cancer. [ABSTRACT FROM AUTHOR]