Treatment strategies for elderly patients with locally advanced esophageal cancer: a systematic review and meta-analysis.

BACKGROUND: Neoadjuvant chemoradiotherapy (nCRT) followed by surgery remains a standard of care for resectable esophageal cancer (EC), and definitive chemoradiotherapy (dCRT) is an alternative for unresectable diseases. However, it is controversial for the use of the two aggressive regimens in elderly patients. METHODS: We systematically searched multiple databases for studies comparing overall survival (OS) and/or progression-free survival (PFS) between dCRT and surgery (nCRT + surgery or surgery alone) or between dCRT and radiotherapy (RT) alone in elderly patients (age ≥ 65 years) until March 28, 2024. Statistical analysis was performed using random-effects model. RESULTS: Fourty-five studies with 33,729 patients were included. dCRT significantly prolonged OS (hazard ratio [HR] = 0.64, 95% confidence interval [CI]: 0.58-0.70) and PFS (HR = 0.67, 95% CI: 0.60-0.76) compared to RT alone for unresectable EC, and resulted in a worse OS compared to surgery for resectable cases (HR = 1.34, 95% CI: 1.23-1.45). Similar results of OS were also observed when the multivariate-adjusted HRs were used as the measure of effect (dCRT vs. RT alone: HR = 0.65, 95% CI: 0.58-0.73; dCRT vs. surgery: HR = 1.49, 95% CI: 1.28-1.74). Subgroup analyses according to age group (≥ 70, ≥ 75, or ≥ 80 years), study design, study region, histological type, radiation field, chemotherapy regimen revealed comparable results. CONCLUSIONS: nCRT + surgery is likely a preferred strategy for elderly patients with good physiological conditions; and dCRT is a better alternative for unresectable cases. Advanced age alone does not appear to be a key predictor for the tolerability of the two aggressive treatments.

First-line treatment with TKI plus brain radiotherapy versus TKI alone in EGFR-mutated non-small cell Lung cancer with brain metastases: a systematic review and meta-analysis.

BACKGROUND: It remains uncertain whether first-line treatment with upfront brain radiotherapy (RT) in combined with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is superior to EGFR-TKIs alone for EGFR-mutated non-small cell lung cancer with newly diagnosed brain metastases (BMs). Therefore, we performed a meta-analysis to address this issue. METHODS: We searched PubMed, Embase, Cochrane Library, and Web of Science databases for eligible studies published until February 28, 2023. The primary outcomes of interest were overall survival (OS) and intracranial progression-free survival (iPFS), reported as hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: Twenty-four retrospective studies with 3184 patients were included. First- or second-generation EGFR-TKIs were used in each study. Upfront brain RT plus EGFR-TKIs significantly prolonged OS (HR = 0.75, 95% CI: 0.64-0.88) and iPFS (HR = 0.61, 95% CI: 0.52-0.72) compared to EGFR-TKIs alone. There were no significant differences in OS and iPFS benefits from the combination therapy between asymptomatic and symptomatic patients, patients with exon 19 and 21 mutations, patients with 1-3 and > 3 BMs, and males and females, respectively (HRs interaction, P > 0.05 for each subgroup comparison). CONCLUSIONS: First-line treatment with upfront brain RT plus EGFR-TKIs is likely to be more effective than EGFR-TKIs alone. The benefits of combination therapy did not appear to be significantly affected by BM-related symptoms, EGFR mutation subtype, number of BMs, or sex.

Analysis of the diagnostic accuracy of Belin/Ambrósio Enhanced Ectasia and Corvis ST parameters for subclinical keratoconus.

OBJECTIVE: To investigate the diagnostic accuracy of the parameters in the Belin/Ambrósio Enhanced Ectasia Display built in Pentacam, which is designed for the screening of subclinical keratoconus (SKC) built in Pentacam, and the parameters in Corneal visualization Scheimpflug technology (Corvis ST). METHODS: A retrospective study: The fellow eyes of unilateral keratoconus cases were diagnosed with SKC. Patients presented to Shanxi Eye Hospital with SKC from October 2020 to November 2021 were included as the SKC group, and myopic patients undergoing corneal refractive surgery at the Refractive Surgery Department in our hospital within the same period were included as the control group. The Belin/Ambrósio and Corvis ST parameters were extracted from the system and analyzed using independent samples t test. Receiver operating curves (ROCs) were also created to test the diagnostic accuracy of each parameter. RESULTS: There were 70 patients (70 eyes) in the SKC group and 137 patients (137 eyes) in the control group. For Corvis ST parameters, Radius (P = 0.021), PachySlope (P = 0.040), SP-A1 (P = 0.002), A2 Deformation Amp. (P = 0.028), A2 Deflection Length (P < 0.001), Max ICR (P = 0.005), DA Ratio Max (1 mm) (P = 0.023), IR (P = 0.016), CBI (P = 0.003) and TBI (P < 0.001) were statistically different between the two groups. For Belin/Ambrósio parameters, PPI min. Axis, ART min, ART max, ART avg, Pachy min, Front K2, Astig, BAD-Df, BAD-Db, BAD-Dp, BAD-Dt, BAD-Da, BAD-D, PPI min, PPI max, PPI max. Axis, PPI avg and Dist.Apex-Thin.Loc. were significantly different between the two groups (all p < 0.001). TBI and BAD-D showed the best diagnostic accuracy, with AUCs of 0.944 and 0.965, respectively. CONCLUSIONS: Some Belin/Ambrósio and Corvis ST parameters differed between SKC eyes and eyes with normal cornea. TBI and BAD-D showed the ideal diagnostic performance for SKC. In clinical practice, conventional corneal topography could not be replaced by Corvis ST.

Local Immunosuppression in Wuzhishan Pig to Rhesus Monkey Descemet's Stripping Automated Endothelial Keratoplasty: An Innovative Method to Promote the Survival of Xenografts.

INTRODUCTION: Corneal xenotransplantation is an effective solution for human corneal shortage. We investigated the feasibility and efficacy of different postoperative protocols on xeno-Descemet's stripping automated endothelial keratoplasty (DSAEK) grafts. METHODS: Thirty rhesus monkeys were randomly divided into three groups: control group (C) and only Descemet's membrane (DM) stripping, DSAEK 1 (D1) and DSAEK 2 (D2) groups, DM stripping followed by endothelial keratoplasty. Betamethasone 3.5 mg was subconjunctivally injected in groups control and D1 postoperatively, whereas rhesus monkeys in group D2 received topical 0.1% tacrolimus and topical steroids. All groups were evaluated by slit lamp, anterior segment optical coherence tomography, and laser scanning confocal microscopy for at least 9 months. RESULTS: Twenty-four monkeys met the inclusion criteria. Nine months after the DSAEK surgery, most corneas were transparent. Graft rejection was observed in 25% and 28.57% of the cases in group D1 and group D2 (p > 0.05), respectively. Corneal endothelium densities in DSAEK groups were 2,715.83 ± 516.20/mm2 (D1) and 2,220.00 ± 565.13/mm2 (D2) (p > 0.05). CONCLUSIONS: Xenogeneic corneal endothelial grafts can survive and function in rhesus monkey eyes for a prolonged period of time with subconjunctival steroid or topical tacrolimus and steroid treatment. Furthermore, topical drugs are more suitable for clinical use.

[Effects of SMILE with different residual stromal thicknesses on corneal biomechanical properties of rabbits in vivo].

Femtosecond laser small incision lenticule extraction (SMILE) with different residual stromal thicknesses (RST) is set to investigate its effect on corneal biomechanical properties of rabbits in vivo. In this study, 24 healthy adult Japanese rabbits were randomly divided into group A and B. The RST of group A was set 30% of the corneal central thickness (CCT), and the RST of group B was 50% of the CCT. The thickness of the corneal cap in both groups was set one third of CCT. Corneal visualization Scheimpflug technology (Corvis ST) and Pentacam three-dimensional anterior segment analyzer were used to determine corneal biomechanical and morphological parameters before surgery, and 1 week, 1 month and 3 months after surgery. Pearson correlation analysis was used to analyze factors affecting corneal biomechanical parameters after SMILE. The results showed that the corneal stiffness of group A was significantly higher than that of group B at 1 week and 1 month after surgery, and most biomechanical parameters returned to preoperative levels at 3 months postoperatively. The results of correlation analysis showed that postoperative CCT and RST were the main factors affecting corneal biomechanical parameters after SMILE. There was no significant difference in corneal posterior surface height (PE) between 3 months after surgery and before surgery in both two groups. It indicates that although the ability to resist deformation of cornea decreases in SMILE with thicker corneal cap and less RST, there is no tendency to keratoconus, which may be related to the preservation of more anterior stromal layer.

Clinicopathologic Features and Treatment Characteristics of Congenital Corneal Opacity Infants and Children Aged 3 Years or Less: A Retrospective Single Institution Analysis.

OBJECTIVE: In this retrospective single institution study, we investigated the clinicopathologic features and treatment characteristics of 90 patients with congenital corneal opacities (CCO) (117 eyes) who were 3 years and younger and treated at our hospital. SUBJECT AND METHODS: We reviewed the clinical data of patients with CCO who presented for the first time for treatment at our hospital between January 1, 2017, and December 31, 2017. CCO were classified using the "STUMPED" (Sclerocornea, Tears in Descement's membrane, Metabolic, Peters, Endothelial dystrophy and Dermoid) method and confirmed by pathological examination. -Results: Seventy percent of the patients had unilateral CCO. Iridocorneal adhesions (61 eyes, 52.1%) and cataracts (22 eyes, 18.8%) were the 2 most common ocular abnormalities. Systemic abnormalities were present in 5 patients (5.6%), including growth retardation (4 patients) and congenital brain defects (1 patient). Eighty-five eyes (72.6%) underwent penetrating keratoplasty (PK), and lamellar keratoplasty (LK) was performed in 30 (25.6%) eyes. Forty-seven (95.9%) eyes with Peters anomaly and all 16 eyes with sclerocornea received PK, and all 24 eyes with dermoids were treated with LK. CONCLUSION: Our study demonstrates that CCO has varied manifestations in infants and young children in China. A thorough medical history, careful clinical examination, and the use of accessory examinations such as ultrasound biomicroscopy are critical for the accurate diagnosis and classification of CCO and to provide guidance on therapeutic choices.

Targeting selective autophagy and beyond: From underlying mechanisms to potential therapies.

BACKGROUND: Autophagy is an evolutionarily conserved turnover process for intracellular substances in eukaryotes, relying on lysosomal (in animals) or vacuolar (in yeast and plants) mechanisms. In the past two decades, emerging evidence suggests that, under specific conditions, autophagy can target particular macromolecules or organelles for degradation, a process termed selective autophagy. Recently, accumulating studies have demonstrated that the abnormality of selective autophagy is closely associated with the occurrence and progression of many human diseases, including neurodegenerative diseases, cancers, metabolic diseases, and cardiovascular diseases. AIM OF REVIEW: This review aims at systematically and comprehensively introducing selective autophagy and its role in various diseases, while unravelling the molecular mechanisms of selective autophagy. By providing a theoretical basis for the development of related small-molecule drugs as well as treating related human diseases, this review seeks to contribute to the understanding of selective autophagy and its therapeutic potential. KEY SCIENTIFIC CONCEPTS OF REVIEW: In this review, we systematically introduce and dissect the major categories of selective autophagy that have been discovered. We also focus on recent advances in understanding the molecular mechanisms underlying both classical and non-classical selective autophagy. Moreover, the current situation of small-molecule drugs targeting different types of selective autophagy is further summarized, providing valuable insights into the discovery of more candidate small-molecule drugs targeting selective autophagy in the future. On the other hand, we also reveal clinically relevant implementations that are potentially related to selective autophagy, such as predictive approaches and treatments tailored to individual patients.

Mitochondrial Sirtuins in Cancer: A Revisited Review from Molecular Mechanisms to Therapeutic Strategies.

The sirtuin (SIRT) family is well-known as a group of deacetylase enzymes that rely on nicotinamide adenine dinucleotide (NAD+). Among them, mitochondrial SIRTs (SIRT3, SIRT4, and SIRT5) are deacetylases located in mitochondria that regulate the acetylation levels of several key proteins to maintain mitochondrial function and redox homeostasis. Mitochondrial SIRTs are reported to have the Janus role in tumorigenesis, either tumor suppressive or oncogenic functions. Although the multi-faceted roles of mitochondrial SIRTs with tumor-type specificity in tumorigenesis, their critical functions have aroused a rising interest in discovering some small-molecule compounds, including inhibitors and activators for cancer therapy. Herein, we describe the molecular structures of mitochondrial SIRTs, focusing on elucidating their regulatory mechanisms in carcinogenesis, and further discuss the recent advances in developing their targeted small-molecule compounds for cancer therapy. Together, these findings provide a comprehensive understanding of the crucial roles of mitochondrial SIRTs in cancer and potential new therapeutic strategies.

Comparative study of functional optical zone: small incision lenticule extraction versus femtosecond laser assisted excimer laser keratomileusis.

AIM: To investigate the size of functional optical zone (FOZ) after small incision lenticule extraction (SMILE) versus femtosecond laser assisted excimer laser keratomileusis (FS-LASIK) for myopia correction and potential associated factors for FOZ. METHODS: A total of 133 patients who received corneal refractive surgery in our hospital between November 2018 and July 2021 were retrospectively enrolled. There were 63 patients (123 eyes) in SMILE group and 70 patients (139 eyes) in FS-LASIK group. The size of FOZ was measured using Pentacam 3-dementional anterior segment analyzer before and 3mo after surgery, so as to analyze postoperative achieved functional optical zone (AFOZ) and its contributing parameters. RESULTS: When planned functional optical zone (PFOZ) was 6.5 mm for both groups, AFOZ was 1.45±0.27 and 1.67±0.25 mm smaller than preoperative FOZ in SMILE group and FS-LASIK group 3mo after surgery. AFOZ in SMILE group was significantly larger than that in FS-LASIK group (P<0.001). Variation of FOZ was negatively correlated with preoperative spherical equivalent (SE) and positively correlated with variation of mean keratometry value (ΔKm), variation of spherical aberration (ΔSA), and variation of Q-value (ΔQ, all P<0.001) in both groups. Multiple variable linear regression equations were ΔFOZ=1.354-0.1×pre-SE+0.336×ΔQ+1.462×ΔSA in SMILE group and ΔFOZ=1.512+0.137×ΔQ+0.468×ΔSA in FS-LASIK group. CONCLUSION: AFOZ is significantly smaller than preoperative FOZ in both SMILE and FS-LASIK groups. With the same PFOZ, larger AFOZ is achieved in SMILE group than in FS-LASIK group.

The Corneal Ectasia Model of Rabbit: A Validity and Stability Study.

Keratoconus is a bilateral progressive degenerative corneal disease characterized by localized corneal thinning and dilatation. The pathogenesis of keratoconus is not fully elucidated. To gain a better understanding of the pathophysiology of this disease and to explore potential treatments, animal models are essential for basic research. Several attempts have been made to establish animal models of corneal ectasia by using collagenase. However, continuous changes of the cornea have not been well-tracked for the model. In this study, corneal morphology and biomechanical behavior in vivo were determined before and after collagenase Ⅱ treatment at 2, 4, and 8 weeks. The elastic modulus and histology of cornea tissues ex vivo were measured at 8 weeks postoperatively. The results showed that the posterior corneal curvature (Km B) increased and central corneal thickness (CCT) decreased after collagenase treatment. The mechanical properties of ectatic corneas weakened significantly and the collagen fiber interval in the stromal layer was increased and disorganized. This study provides insights into the changes of corneal morphology and biomechanical properties in a rabbit model of corneal ectasia. Changes observed at 8 weeks indicated that the cornea was still undergoing remodeling.

Comparison of Two Cyberknife Planning Approaches for Multiple Brain Metastases.

PURPOSE: To compare the delivery efficiency, plan quality, and planned treatment volume (PTV) and normal brain dosimetry between different Cyberknife planning approaches for multiple brain metastases (MBM), and to evaluate the effects of the number of collimators on the related parameters. METHODS: The study included 18 cases of MBM. The Cyberknife treatment plans were classified as Separate or Combined. For the Separate plan, each lesion was targeted by the collimator auto-selection method (Conformality 2/3 collimators). For the Combined plan, a PTV including all PTVs was targeted by the collimators. Monitor units (MUs), number of nodes and beams, estimated fraction treatment time (EFTT), new conformity index (nCI), dose gradient index (GI), homogeneity index (HI), PTV minimum/maximum dose (Dmax/Dmin), volume doses (D2% and D98%), maximum doses to lenses, optic nerves, and brainstem as well as normal brain 3, 6, 10, and 12 Gy (V 3Gy -V 12Gy) were compared. RESULTS: Compared to the Combined plan, the Separate plan had fewer nodes and beams, shorter EFTT, smaller PTV Dmin, normal brain dose, and GI, and larger HI. The Separate plan with 2 collimators also had worse PTV coverage. In the Combined plan, more collimators increased beams, EFTT, GI, and normal brain dose but improved the PTV Dmin. Among treatments based on the Separate approach, there were obvious differences between plans for most of the items except the nCI. Fewer collimators resulted in significantly reduced beams, EFTT, PTV D98%, and normal brain dose with improved GI, although PTV Dmin and MUs were decreased while HI was increased. CONCLUSION: Both approaches met the requirements for SRS/HFSRT. We found that Separate plans improved treatment efficiency and normal tissue dosimetry.

Hotspots and trends in liver kinase B1 research: A bibliometric analysis.

INTRODUCTION: In the past 22 years, a large number of publications have reported that liver kinase B1 (LKB1) can regulate a variety of cellular processes and play an important role in many diseases. However, there is no systematic bibliometric analysis on the publications of LKB1 to reveal the research hotspots and future direction. METHODS: Publications were retrieved from the Web of Science Core Collection (WoSCC), Scopus, and PubMed databases. CiteSpace and VOSviewer were used to analysis the top countries, institutions, authors, source journals, discipline categories, references, and keywords. RESULTS: In the past 22 years, the number of LKB1 publications has increased gradually by year. The country, institution, author, journals that have published the most articles and cited the most frequently were the United States, Harvard University, Prof. Benoit Viollet, Journal of Biochemistry and Plos One. The focused research hotspot was the molecular functions of LKB1. The emerging hotspots and future trends are the clinical studies about LKB1 and co-mutated genes as biomarkers in tumors, especially in lung adenocarcinoma. CONCLUSIONS: Our research could provide knowledge base, frontiers, emerging hotspots and future trends associated with LKB1 for researchers in this field, and contribute to finding potential cooperation possibilities.

Therapeutic potential of Rho-associated kinase inhibitor Y27632 in corneal endothelial dysfunction: an in vitro and in vivo study.

AIM: To investigate the effects of a selective inhibitor of Rho-associated kinase (ROCK), Y-27632, on inbred Wuzhishan porcine corneal endothelial cells (PCECs) in vitro and in vivo studies. METHODS: Primary PCECs were trypsinized from Wuzhishan miniature porcine corneal tissues. The optimal concentration of Y-27632 on PCECs was determined through MTT and 5-ethynyl-2'-deoxyuridine (EdU)-labeling assays. Seven New Zealand rabbits were used as a corneal endothelial dysfunction model, and a PCECs suspension supplemented with Y-27632 was injected into the anterior chamber of the rabbits. The progression of rabbit corneal opacity and edema were observed by slit lamp examination. The rabbits were sacrificed, and rabbit globes were enucleated for trypan blue-alizarin red staining, hematoxylin-eosin staining, and immunofluorescence analysis. RESULTS: Administration of 100 µmol/L Y-27632 facilitated PCECs' proliferation obviously. The rabbit corneas injected with PCECs suspension and 100 µmol/L Y-27632 were restored to transparency significantly after 14d. CONCLUSION: The 100 µmol/L Y-27632 treatment improves PCECs' proliferation significantly. And our results suggest that Y-27632 and PCECs can be used to treat corneal endothelial dysfunction.

Systematic Review and Meta-Analysis of Clinical Outcomes of Penetrating Keratoplasty Versus Deep Anterior Lamellar Keratoplasty for Keratoconus.

OBJECTIVES: In recent years, there have been rapid advances in the field of keratoconus. Penetrating keratoplasty and deep anterior lamellar keratoplasty are the standard surgical procedures. Nevertheless, controversy remains regarding the outcomes of both procedures in the treatment of keratoconus. Therefore, we conducted a meta-analysis comparing postoperative outcome measures of penetrating keratoplasty versus deep anterior lamellar keratoplasty for keratoconus. MATERIALS AND METHODS: We searched PubMed, Embase, Web of Science, and the Cochrane Database of Systematic Reviews for eligible studies comparing best-corrected visual acuity, spherical equivalent, refractive cylinder, topography cylinder, and graft rejection episodes and complications of penetrating keratoplasty and deep anterior lamellar keratoplasty. Seven risk domains from software Review Manager 5.3 (The Cochrane Collaboration, Oxford, UK) were applied as quality assessments for the eligible studies. A random-effects model was used for data synthesis. RESULTS: Thirteen eligible studies were included in our meta-analysis, which encompassed 530 eyes that underwent penetrating keratoplasty and 568 eyes that underwent deep anterior lamellar keratoplasty. With regard to best-corrected visual acuity, refractive cylinder, and topography cylinder, we found no significant differences in results between the 2 procedures (P = .49 and .47, respectively). However, spherical equivalent results were significantly greater in the deep anterior lamellar keratoplasty group than in the penetrating keratoplasty group (P < .001). The risk of graft rejection episodes was more prominent in the penetrating keratoplasty than in the deep anterior lamellar keratoplasty group (odds ratio = 2.69; P = .001). The odds ratio for complications was 1.79 (P = .03). Three studies showed moderate risk of bias, and the other 10 showed high risk of bias. CONCLUSIONS: Deep anterior lamellar keratoplasty is preferred over penetrating keratoplasty for the treatment of keratoconus because of its low risk of rejection and complications.

Reducing porcine corneal graft rejection, with an emphasis on porcine endogenous retrovirus transmission safety: a review.

Donor cornea shortage is a primary hurdle in the development of corneal transplantation. Of all species, porcine corneas are the ideal transplantation material for humans. However, the xenoimmune rejection induced by porcine corneal xenotransplantation compromises surgical efficacy. Although the binding of IgM/IgG in human serum to a genetically modified porcine cornea is significantly weaker than that of the wild type (WT), genetically modified porcine corneas do not display a prolonged graft survival time in vivo. Conversely, costimulatory blockade drugs, such as anti-CD40 antibodies, can reduce the xenoimmune response and prolong graft survival time in animal experiments. Moreover, porcine endothelial grafts can survive for more than 6mo with only the subconjunctival injection of a steroid-based immunosuppressants regime; therefore, they show great value for treating corneal endothelial disease. In addition, zoonotic transmission is a primary concern of xenotransplantation. Porcine endogenous retrovirus (PERV) is the most significant virus assessed by ophthalmologists. PERV integrates into the porcine genome and infects human cells in vitro. Fortunately, no evidence from in vivo studies has yet shown that PERV can be transmitted to hosts.

Long-term safety of laser in situ keratomileusis in eyes with thin corneas: 5-year follow-up.

AIM: To investigate the long term (≥5y) efficacy, predictability, and safety of laser in situ keratomileusis (LASIK) in eyes with thin corneas [central corneal thickness (CCT) <500 µm]. METHODS: A total of 339 patients met the criteria of this study. Finally, 175 eyes of 89 patients who had thin corneas and underwent LASIK≥5y ago returned to our clinic and included in this study. Preoperative parameters recorded included uncorrected visual acuity (UCVA), corrected distance visual acuity (CDVA), manifest refraction, CCT and corneal topography. At returning visits, in addition to visual acuity and manifest refraction, ultrasound CCT and corneal topography were performed. Optical coherence tomography was used to measure the CCT, LASIK flap thickness, and residual stromal bed thickness (RSBT). Safety index, efficacy index, percentage of eyes within ±0.5 D and ±1.0 D of refraction, percent tissue altered (PTA), and percentage stromal bed thickness (PSBT) were calculated. RESULTS: The safety index was 1.09 and efficacy index was 0.99. The percentages of eyes within ±0.5 D and ±1.0 D were 71.2% and 87.7%, respectively. The mean PTA was 40%±6% (range 20% to 55%); 76 eyes (43.4%) had PTA <40% and 99 eyes (56.6%) had PTA≥40%. The mean RSBT was 303±27 µm (range 240 to 390 µm), and 2 eyes had RSBT<250 µm. The mean PSBT was 61%±9% (range 51% to 85%). No eyes developed ectasia. CONCLUSION: In this cohort with the PSBT of 50% or more, LASIK is safe with follow-up for at least 5y.