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Objective • To explore the application of four-dimensional pelvic floor ultrasound in the diagnosis of postpartum pelvic floor dysfunction (PFD) and evaluation of curative effect. Methods • A total of 100 patients with postpartum PFD undergoing vaginal delivery in the hospital were enrolled as the research objects between January 2020 and January 2023. A total of 100 postpartum women with good pelvic floor muscle function during the same period were enrolled as a control group. Both groups underwent four-dimensional pelvic floor ultrasound detection. The bladder neck descent (BND), retrovesical angle (RVA), urethral tilt angle (UTA), urethral rotation angle (ROT), levator ani thickness under rest state (LATr), levator ani thickness under Valsalva state (LATs), levator ani hiatus area under rest state (LHAr) and levator ani hiatus area under Valsalva state (LHAs) in both groups were compared. The patients in the study group were given Kegel training for pelvic floor muscle rehabilitation exercise and biofeedback electrical stimulation. According to the clinical curative effect, patients in the study group were divided into a recovery group (n=87) and a non-recovery group (n=13). The value of four-dimensional pelvic floor ultrasound in the diagnosis of PFD and evaluation of curative effect was analyzed. Results • In the observation group, BND, RVA, UTA, ROT, LHAr, and LHAs were higher, while LATr and LATs were lower compared to the control group. (P < .05). The results of ROC curves analysis showed that the AUC of BND combined with RVA, UTA, ROT, LATr, LATs, LHAr, and LHAs in the diagnosis of PFD was 0.818, greater than that of the single index (0.728, 0.705, 0.680, 0.715, 0.677, 0.696, 0.719, 0.654; P < .05). BND, RVA, UTA, ROT, LHAr, and LHAs in the non-recovery group were higher than those in the recovery group, while LATr and LATs were lower than those in the recovery group (P < .05). The results of ROC curves analysis showed that the Area Under the Curve (AUC) of BND combined with RVA, UTA, ROT, LATr, LATs, LHAr, and LHAs for predicting the curative effect were 0.804, greater than that of a single index (0.725, 0.653, 0.651, 0.744, 0.733, 0.720, 0.661, 0.718; P < .05). Conclusion • Four-dimensional pelvic floor ultrasound can be applied to intuitively evaluate the structure and function of postpartum pelvic floor tissues, which can provide a reliable basis for the diagnosis of postpartum PFD and evaluation of curative effect. [ABSTRACT FROM AUTHOR]

Immunopeptidomics is becoming an increasingly important field of study. The capability to identify immunopeptides with pivotal roles in the human immune system is essential to shift the current curative medicine towards personalized medicine. Throughout the years, the field has matured, giving insight into the current pitfalls. Nowadays, it is commonly accepted that generalizing shotgun proteomics workflows is malpractice because immunopeptidomics faces numerous challenges. While many of these difficulties have been addressed, the road towards the ideal workflow remains complicated. Although the presence of Posttranslational modifications (PTMs) in the immunopeptidome has been demonstrated, their identification remains highly challenging despite their significance for immunotherapies. The large number of unpredictable modifications in the immunopeptidome plays a pivotal role in the functionality and these challenges. This review provides a comprehensive overview of the current advancements in immunopeptidomics. We delve into the challenges associated with identifying PTMs within the immunopeptidome, aiming to address the current state of the field. [ABSTRACT FROM AUTHOR]

Background: Cervical cancers are mainly caused by an oncogenic HPV. For locally advanced stages, the standard treatment is radio-chemotherapy (RTCT) followed by brachytherapy. Nevertheless, the prognosis remains highly heterogeneous between patients. Objective: We investigated the prognostic value of HPV circulating tumor DNA (ctDNA) in locally advanced cervical cancers alongside that of Squamous Cell Carcinoma Antigen (SCC-A). Methods: This single-center retrospective study included patients treated in curative intent for an IB3 to IVA squamous cell cervical cancer. Quantification of HPV ctDNA in serum collected at diagnosis was performed using a multiplex digital PCR assay for the simultaneous detection of 8 HPV genotypes. Results: Among the 97 patients included, 76 patients (78.4%) were treated by RTCT, followed by brachytherapy for 57 patients (60%). HPV ctDNA was detected in 59/97 patients at diagnosis (60.8%). This detection was associated with lymph node invasion (p=0.04) but not with tumor stage. A high level of SCC-A at diagnosis was associated with tumor stage (p=0.008) and lymph node invasion (p=0.012). In univariate analysis, better disease-free survival (DFS) was associated with optimal RTCT regimen (p=0.002), exposure to brachytherapy (p=0.0001) and a low SCC-A at diagnosis (continuous analysis, p=0.002). Exploratory analysis revealed that 3/3 patients (100%) whose HPV ctDNA was still detectable at the end of treatment relapsed, while 6/22 patients (27.3%) whose HPV ctDNA was negative at the end of treatment relapsed. Conclusion: HPV ctDNA detection at diagnosis of locally advanced cervical squamous cell carcinomas is frequent and related to node invasion, but not to DFS. The prognostic value of HPV ctDNA detection after treatment warrants specific studies. [ABSTRACT FROM AUTHOR]

The discovery of Suppressor of Cytokine Signaling 1 (SOCS1) in 1997 marked a significant milestone in understanding the regulation of Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways. Subsequent research deciphered its cellular functions, and recent insights into SOCS1 deficiencies in humans underscored its critical role in immune regulation. In humans, SOCS-haploinsufficiency (SOCS1-HI) presents a diverse clinical spectrum, encompassing autoimmune diseases, infection susceptibility, and cancer. Variability in disease manifestation, even within families sharing the same genetic variant, raises questions about clinical penetrance and the need for individualized treatments. Current therapeutic strategies include JAK inhibition, with promising results in controlling inflammation in SOCS1-HI patients. Hematopoietic stem cell transplantation and gene therapy emerge as promising avenues for curative treatments. The evolving landscape of SOCS1 research, emphasizes the need for a nuanced understanding of genetic variants and their functional consequences. [ABSTRACT FROM AUTHOR]

Background: With the increasing efficacy of systemic therapy, liver transplantation plays an important role not only for hepatocellular carcinoma (HCC) but also for nonresectable intrahepatic cholangiocellular carcinoma (iCC), perihilar cholangiocellular carcinoma (phCC) and colorectal liver metastases (CRLM). Aim: To review the current state of knowledge regarding the indications, patient selection and expected outcomes of liver transplantation for HCC, iCC, phCC and CRLM. Results: When combined with neoadjuvant locoregional therapy (LRT) and/or systemic therapy, patients with nonresectable HCC, iCC, pCC and CRLM confined to the liver can be successfully transplanted with 5‑year survival rates exceeding 65%. The key to success is strict patient selection, which includes oncogenetic (e.g., BRAFV600E mutation status) and clinical criteria indicative of individual tumor biology (tumor markers: alpha-fetoprotein, AFP/carbohydrate antigen 19‑9, CA19-9/carcinoembryonic antigen, CEA, stable response to neoadjuvant therapy) in addition to morphometric criteria. Conclusion: Liver transplantation offers the possibility of curative treatment even for nonresectable hepatic malignancies. A major limitation of this treatment is the lack of donor organs. Crucial for success is patient selection based on individual tumor biology. [ABSTRACT FROM AUTHOR]

Objective: Chronic scrotal hyperthermia (SHT) can lead to serious disorders of the male reproductive system, with oxidative stress playing a key role in the onset of these dysfunctions. Thus, we evaluated the impact of caffeine, a potent antioxidant, on cellular and tissue disorders in mice with chronic SHT. Methods: In this experimental study, 56 adult male NMRI mice were allocated into seven equal groups. Apart from the non-treated control group, all were exposed to heat stress. Two groups, termed "preventive" and "curative," were orally administered caffeine. The preventive mice began receiving caffeine immediately prior to heat exposure, while for the curative group, a caffeine regimen was initiated 15 consecutive days following cessation of heat exposure. Each treated group was subdivided based on pairing with a positive control (Pre/curative [Cur]+PC) or a vehicle (Pre/Cur+vehicle). Upon conclusion of the study, we assessed sperm characteristics, testosterone levels, stereological parameters, apoptosis, antioxidant and oxidant levels, and molecular markers. Results: Sperm parameters, testosterone levels, stereological parameters, biochemical factors (excluding malondialdehyde [MDA]), and c-kit gene expression were significantly elevated in the preventive and curative groups, especially the former, relative to the other groups. Conversely, expression levels of the heat shock protein 72 (HSP72) and nuclear factor kappa beta (NF-κβ) genes, MDA levels, and apoptotic cell density were markedly lower in both caffeine-treated groups relative to the other groups, with more pronounced differences observed in the preventive group. Conclusion: Overall, caffeine attenuated cellular and molecular abnormalities induced by heat stress in the testis, particularly in the mice treated under the preventive condition. [ABSTRACT FROM AUTHOR]

This study aimed at using single‐sample gene set enrichment analysis scores to cluster naso/pharyngeal swab specimen samples from coronavirus disease 2019 (COVID‐19) patients into two clusters. One cluster with higher fractions of immune cells and more active inflammatory‐related pathways was called the Immunity‐High (Immunity‐H) group, and the other one was called the Immunity‐Low group. We explored impacts of the method on COVID‐19 treatment. First, given that the Immunity‐H group was mainly enriched in inflammatory‐related pathways and had higher fractions of inflammatory cells, the Immunity‐H group may obtain more curative effects from anti‐inflammatory treatment. Second, we searched some hot genes from the PubMed platform that had been studied by researchers and found these genes upregulated in the Immunity‐H group, so we speculated the Immunity‐H group and Immunity‐Low group may have different curative effects from drugs targeting these genes. Finally, we screened out hub genes for the Immunity‐H group and predicted potential drugs for these hub genes by a public data set (http://dgidb.genome.wustl.edu). These hub genes are significantly upregulated in the Immunity‐H group and neutrophils so that the Immunity‐H group may obtain different treatment results from potential drugs compared with the Immunity‐Low group. Therefore, the cluster method may provide help in drug development and administration for COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Background/Aim: The albumin-globulin ratio (AGR) is a useful biomarker for predicting postoperative complications and a poor prognosis in patients with various types of cancer and can be evaluated without invasive testing or surgery. In this study, we aimed to evaluate the usefulness of the AGR in predicting the short- and long-term prognoses of patients with gastric cancer who underwent radical resection at our institution. Patients and Methods: This study is a retrospective cohort analysis in which eligible patients were selected from the medical records of patients who underwent radical resection for gastric cancer at Yokohama City University from 2000 to 2020 and their medical records were reviewed. A total of 240 patients with gastric cancer were classified into high-AGR (>1.57) and low-AGR (=1.57) groups and their overall survival (OS), recurrence-free survival (RFS), and postoperative complication rates were compared. Results: Of the total 240 patients, 87 were classified into the high AGR group and 153 were classified into the low AGR group; the incidence of postoperative complications in the two groups did not differ to a statistically significant extent (34.4% vs. 39.2%, p=0.491). The long-term findings showed that the 5-year OS and RFS rates were significantly better in the high AGR group [84.0% vs. 64.8% (p=0.005), 80.0% vs. 61.9% (p=0.015), respectively]. Conclusion: Preoperative low AGR is a risk factor for OS and DFS in patients with gastric cancer who undergo surgery. The AGR may be a useful biomarker that can be applied as a prognostic indicator for patients with gastric cancer. [ABSTRACT FROM AUTHOR]

Background/Aim: This study aimed to evaluate the clinical impact of the Naples Prognostic Score (NPS) in patients with gastric cancer and to clarify the potential of the NPS as a nutritional and inflammation evaluation system. Patients and Methods: This study included 158 patients who underwent curative treatment for gastric cancer between 2005 and 2020. The prognosis and clinical pathological parameters of the high-NPS (NPS >2) and low-NPS (NPS=0, 1) groups were analyzed. Results: The overall survival (OS) rates at 3 and 5 years were 86.7% and 77.7%, respectively, in the low-NPS group and 55.4% and 47.4%, respectively, in the high-NPS group. There were significant differences in OS between the two groups. Uni- and multivariate analyses demonstrated that the NPS was an independent prognostic factor for OS (HR=2.495, 95%CI=1.240-5.451). In addition, the 3- and 5-year recurrence-free survival (RFS) rates were 82.1% and 76.0%, respectively, in the NPS-low group, and 43.8% and 36.6% in the NPS-high group. Univariate and multivariate analyses demonstrated that the NPS was an independent prognostic factor for RFS (HR=2.739, 95%CI=1.509-4.972). When the first site of recurrence was compared between the low-NPS group and high-NPS group, there were significant differences in peritoneal recurrence (8.7% vs. 34.3%, p=0.001) and hematologic recurrence (5.6% vs. 21.9%, p=0.004). Conclusion: The NPS was a significant prognostic factor in patients with gastric cancer who received curative treatment. The NPS may be a promising biomarker for the treatment and management of gastric cancer. [ABSTRACT FROM AUTHOR]

Vanishing white matter (VWM) is a devastating autosomal recessive leukodystrophy, resulting in neurological deterioration and premature death, and without curative treatment. Pathogenic hypomorphic variants in subunits of the eukaryotic initiation factor 2B (eIF2B) cause VWM. eIF2B is required for regulating the integrated stress response (ISR), a physiological response to cellular stress. In patients' central nervous system, reduced eIF2B activity causes deregulation of the ISR. In VWM mouse models, the extent of ISR deregulation correlates with disease severity. One approach to restoring eIF2B activity is by inhibition of GSK3ß, a kinase that phosphorylates eIF2B and reduces its activity. Lithium, an inhibitor of GSK3ß, is thus expected to stimulate eIF2B activity and ameliorate VWM symptoms. The effects of lithium were tested in zebrafish and mouse VWM models. Lithium improved motor behavior in homozygous eif2b5 mutant zebrafish. In lithium-treated 2b4he2b5ho mutant mice, a paradoxical increase in some ISR transcripts was found. Furthermore, at the dosage tested, lithium induced significant polydipsia in both healthy controls and 2b4he2b5ho mutant mice and did not increase the expression of other markers of lithium efficacy. In conclusion, lithium is not a drug of choice for further development in VWM based on the limited or lack of efficacy and significant side-effect profile. [ABSTRACT FROM AUTHOR]

Despite recent advances in frontline therapy for diffuse large B-cell lymphoma (DLBCL), at least a third of those diagnosed still will require second or further lines for relapsed or refractory (rel/ref) disease. A small minority of these can be cured with standard chemoimmunotherapy/stem-cell transplant salvage approaches. CD19-directed chimeric antigen receptor T-cell (CAR-19) therapies are increasingly altering the prognostic landscape for rel/ref patients with DLBCL and related aggressive B-cell non-Hodgkin lymphomas. Long-term follow up data show ongoing disease-free outcomes consistent with cure in 30–40% after CAR-19, including high-risk patients primary refractory to or relapsing within 1 year of frontline treatment. This has made CAR-19 a preferred option for these difficult-to-treat populations. Widespread adoption, however, remains challenged by logistical and patient-related hurdles, including a requirement for certified tertiary care centers concentrated in urban centers, production times of at least 3–4 weeks, and high per-patients costs similar to allogeneic bone-marrow transplantation. Bispecific antibodies (BsAbs) are molecular biotherapies designed to bind and activate effector T-cells and drive them to B-cell antigens, leading to a similar cellular-dependent cytotoxicity as CAR-19. May and June of 2023 saw initial approvals of next-generation BsAbs glofitamab and epcoritamab in DLBCL as third or higher-line therapy, or for patients ineligible for CAR-19. BsAbs have similar spectrum but generally reduced severity of immune related side effects as CAR-19 and can be administered in community settings without need to manufacture patient-specific cellular products. To date and in contrast to CAR-19, however, there is no convincing evidence of cure after BsAbs monotherapy, though follow up is limited. The role of BsAbs in DLBCL treatment is rapidly evolving with trials investigating use in both relapsed and frontline curative-intent combinations. The future of DLBCL treatment is bound increasingly to include effector cell mediated immunotherapies, but further optimization of both cellular and BsAb approaches is needed. [ABSTRACT FROM AUTHOR]

In the present study we have discussed around sixteen different animal models used worldwide for the scientific research and new drug discovery. The main aim of the using experimental animal models in drug discovery is to establish and provide evidence for non-clinical 'proof-of-concept' for the safety, efficacy, and target of interest for specific drug molecules. Experimental preparations developed in one species for the purpose of studying phenomena occurring in another species. The use of experimental animal models serves to better understand the origins, pathology, and the overall nature of comparable diseases of humans being. Similarly, animal models perform duties for in the development of safe and effective treatments and cures of such diseases and/or associated symptoms. Experimental animal models for drug discovery and development have played a major role in the characterization of the pathophysiology of diseases and associated mechanisms of injury, drug target identification, and evaluation of novel therapeutic agents for toxicity, pharmacokinetics and pharmacodynamics activity. Through animal model researchers can perform experiments that would be impractical or ethically prohibited with humans. There are various animal models used for screening of uncountable therapeutic activities, in this review our main focus is animal models used for peptic ulcer. Peptic ulcer is one of the worldwide diseases where 10% of adults are affected by peptic ulcer once in their lifetime. The antiulcer models for drug development against gastric and duodenal ulcer studies are limited in number that has hindered the progress of targeted therapy in this field. Therefore, it is necessary to review the literature on experimental animal models that are used to screen agents with potential antigastric ulcer activity and describe their biochemical basis in order to facilitate their use in the development of new preventive and curative antiulcer drugs. There are many models used to induce ulcer such as pylorus ligation or it can be chemically induced by ethanol, NSAIDs (e.g. indomethacin) or many more. In this review paper, current in-vivo animal models of ulcers and the pathophysiological mechanisms underlying their induction, their drawbacks, as well as the challenges associated with their use have been discussed. [ABSTRACT FROM AUTHOR]

Despite evidence of genetic signatures in normal tissue correlating with disease risk, prospectively identifying genetic drivers and cell types that underlie subsequent pathologies has historically been challenging. The human prostate is an ideal model to investigate this phenomenon because it is anatomically segregated into three glandular zones (central, peripheral, and transition) that develop differential pathologies: prostate cancer in the peripheral zone (PZ) and benign prostatic hyperplasia (BPH) in the transition zone (TZ), with the central zone (CZ) rarely developing disease. More specifically, prostatic basal cells have been implicated in differentiation and proliferation during prostate development and regeneration; however, the contribution of zonal variation and the critical role of basal cells in prostatic disease etiology are not well understood. Using single‐cell RNA sequencing of primary prostate epithelial cultures, we elucidated organ‐specific, zone‐specific, and cluster‐specific gene expression differences in basal cells isolated from human prostate and seminal vesicle (SV). Aggregated analysis identified ten distinct basal clusters by Uniform Manifold Approximation and Projection. Organ specificity compared gene expression in SV with the prostate. As expected, SV cells were distinct from prostate cells by clustering, gene expression, and pathway analysis. For prostate zone specificity, we identified two CZ‐specific clusters, while the TZ and PZ populations clustered together. Despite these similarities, differential gene expression was identified between PZ and TZ samples that correlated with gene expression profiles in prostate cancer and BPH, respectively. Zone‐specific profiles and cell type‐specific markers were validated using immunostaining and bioinformatic analyses of publicly available RNA‐seq datasets. Understanding the baseline differences at the organ, zonal, and cellular level provides important insight into the potential drivers of prostatic disease and guides the investigation of novel preventive or curative treatments. Importantly, this study identifies multiple prostate basal cell populations and cell type‐specific gene signatures within prostate basal epithelial cells that have potential critical roles in driving prostatic diseases. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Unpredictable chronic mild stress (UCMS) leads to variable metabolic effects. Oxidative stress (OS) of adipose tissue (AT) and mitochondrial energy homeostasis is little investigated. This work studied the effects of UCMS on OS and the antioxidant/redox status in AT and mitochondrial energy homeostasis in rats. Twenty‐four male Wistar rats (180–220 g) were divided into two equal groups; the normal control (NC) group and the UCMS group which were exposed to various stresses for 28 days. An indirect calorimetry machine was used to measure volumes of respiratory gases (VO2& VCO2), total energy expenditure (TEE), and food intake (FI). The AT depots were collected, weighed, and used for measuring activities and gene expression of key antioxidant enzymes (GPx1, SOD, CAT, GR, GCL, and GS), OS marker levels including superoxide anion (SA), peroxynitrite radical (PON), nitric oxide (NO), hydrogen peroxide (H2O2), lipid peroxides (LPO), t‐protein carbonyl content (PCC), and reduced/oxidized glutathione levels (GSH, GSSG). Additionally, AT mitochondrial fractions were used to determine the activities of the tricarboxylic acid cycle (TCA) cycle enzymes (CS, α‐KGDH, ICDH, SDH, MDH), respiratory chain complexes I–III, II–III, IV, the nicotinamide coenzymes NAD+, NADH, and ATP/ADP levels. Compared with the NC group, the UCMS group showed very significantly increased OS marker levels, lowered antioxidant enzyme activities and gene expression, as well as lowered TCA cycle and respiratory chain activity and NAD+, NADH, and ATP levels (p <.001 for all comparisons). Besides, the UCMS group had lowered TEE and insignificant FI and weight gain. In conclusion, AT of the UCMS‐subjected rats showed a state of disturbed redox balance linked to disrupted energy homeostasis producing augmentation of AT. Significance statement: Adipose tissue (AT) during periods of unpredictable chronic mild stress (UCMS) may encounter some oxidative metabolic change. This work studied oxidative stress of AT and mitochondrial energy homeostasis in rats exposed to UCMS. This study detected profound oxidative stress (OS) in AT of UCMS‐subjected rats, leading to redox imbalance. Besides, the presence of a reduction of the tricarboxylic acid cycle (TCA) cycle and respiratory chain activities consequently marked reduction in adenosine triphosphate (ATP) levels, thus indicating mitochondrial metabolic exhaustion and disruption of energy homeostasis. These findings can impact the TEE and be associated parallelly with both TEE and food intake (FI), resulting in insignificant weight changes. Future research investigating the role of antioxidants as a prophylactic or curative treatment during UCMS is suggested. [ABSTRACT FROM AUTHOR]

In this article, I rethink the perceived/received wisdom of the mandatory vaccine policy which has been punted so ardently, largely uncritically, in South Africa. I investigate whether this line of argument could be justified from a comparative South African constitutional perspective. It became evident in the early stages of my research that the legal perspective is too narrow and constricting to allow for a proper understanding of the puzzle. Following Friedman's suggestion of the schism between Western-based curative medicine and preventive strategies, I employ a critical public health theoretical framework complemented by insights from the social sciences. Given that the vaccine is a product of an outdated paradigm, South Africa's erroneous approach to the pandemic led to disastrous consequences and fared less favourably than the rest of Africa. It is concluded that a mandatory vaccine policy is both unconstitutional and unjustifiable, in the wider view.

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Cellular therapies provide a curative‐intent option for patients with relapsedand refractory lymphomas. Current options including high dose chemotherapyfollowed by autologous or allogeneic hematopoietic stem cell transplantation or CD19 chimericantigen receptor T‐cell (CART) therapy. The indication varies according to lymphoma sub‐type and line oftherapy. The sequencing of these therapies and their use in second‐line orlater settings to manage these diseases is undergoing significant changes, withCD19 CAR T becoming a preferred option for relapsed aggressive B‐cell lymphoma.The mechanism of both therapies causes significant yet distinctlymphodepletion, infectious, and inflammatory toxicities. The resulting patternand timing of immune reconstitution helps guide risk‐mitigating strategies,revaccination, and infectious prophylaxis. In this review, we discuss theindication, efficacy, toxicity and immune reconstitution of autologoushematopoietic stem cell transplantation and CAR T therapy for use in thetreatment of lymphoma. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) and other forms of dementia are together a leading cause of disability and death in the aging global population, imposing a high personal, societal, and economic burden. They are also among the most prominent examples of failed drug developments. Indeed, after more than 40 AD trials of anti-amyloid interventions, reduction of amyloid-β (Aβ) has never translated into clinically relevant benefits, and in several cases yielded harm. The fundamental problem is the century-old, brain-centric phenotype-based definitions of diseases that ignore causal mechanisms and comorbidities. In this hypothesis article, we discuss how such current outdated nosology of dementia is a key roadblock to precision medicine and articulate how Network Medicine enables the substitution of clinicopathologic phenotypes with molecular endotypes and propose a new framework to achieve precision and curative medicine for patients with neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Background: Lymph node (LN) status is vital to evaluate the curative potential of relatively early gastric cancer (GC; T1–T2) treatment (endoscopic or surgery). Currently, there is a lack of robust and convenient methods to identify LN metastasis before therapeutic decision-making. Methods: Genome-wide expression profiles of long noncoding RNA (lncRNA) in primary T1 gastric cancer data from The Cancer Genome Atlas (TCGA) was used to identify lncRNA expression signature capable of detecting LN metastasis of GC and establish a 10-lncRNA risk-prediction model based on deep learning. The performance of the lncRNA panel in diagnosing LN metastasis was evaluated both in silico and clinical validation methods. In silico validation was conducted using TCGA and Asian Cancer Research Group (ACRG) datasets. Clinical validation was performed on T1 and T2 patients, and the panel's efficacy was compared with that of traditional tumor markers and computed tomography (CT) scans. Results: Profiling of genome-wide RNA expression identified a panel of lncRNA to predict LN metastasis in T1 stage gastric cancer (AUC = 0.961). A 10-lncRNA risk-prediction model was then constructed, which was validated successfully in T1 and T2 datasets (TCGA, AUC = 0.852; ACRG, AUC = 0.834). Thereafter, the clinical performance of the lncRNA panel was validated in clinical cohorts (T1, AUC = 0.812; T2, AUC = 0.805; T1 + T2, AUC = 0.764). Notably, the panel demonstrated significantly better performance compared with CT and traditional tumor markers. Conclusions: The novel 10-lncRNA could diagnose LN metastasis robustly in relatively early gastric cancer (T1–T2), with promising clinical potential. [ABSTRACT FROM AUTHOR]

Objective • The purpose of this study is to analyze the clinical prognosis of idiopathic sudden sensorineural hearing loss in patients with total deafness, and to check the differences in different age groups and hearing loss degrees. Methods • From February 2021 to January 2022, 75 patients with complete deafness and idiopathic sudden sensorineural hearing loss were analyzed retrospectively. According to different age stages, they were divided into five groups: children’s group, youth group, middle-aged group, pre-senile group and elderly group, with 15 cases in each group. According to the degree of initial hearing loss, the patients were divided into three groups: 81-89dbhl (81dB Hearing Loss Group), 90-99 dbhl (90 dB group) and ≥100 dbhl (100 dB group), with 25 cases in each group. All patients were given routine comprehensive treatment. Analyze the general situation of each group, the relationship between each age group and the degree of hearing loss, the relationship between each age group and the curative effect, the relationship between each hearing loss group and the curative effect, and the relationship between each age group and the vertigo. To analyze the relationship between hearing loss group and curative effect. Results • (1) Patients with idiopathic sudden sensorineural hearing loss had more unilateral hearing loss than bilateral hearing loss, P < .05. (2) The clinical therapeutic effect of (3) 81 dB group was the highest, followed by 90 dB group. Compared with the total effective rate data of 100 dB group, P < .05. (4) The clinical efficacy of patients with complete deafness and idiopathic sudden sensorineural hearing loss without vertigo in all ages was higher than that of patients with vertigo (P < .05). The clinical effect of hearing loss in patients without vertigo was higher than that in patients with vertigo (P < .05). Conclusion • The patients with total deafness and Idiopathic sudden sensorineural hearing loss are mainly young and middle-aged people aged 14-59, with 100 dB as the boundary, and important information for predicting clinical prognosis and curative effect can be obtained.It is also suggested that for young and middle-aged patients aged 14-59, the focus of treatment may be more on restoring hearing function so that they can continue their work, study and social activities. For patients with mild hearing loss, the goal of treatment may be to maintain the existing hearing level or slow down the process of hearing loss. For patients with severe hearing loss, the focus of treatment may be to restore hearing function to improve their quality of life. [ABSTRACT FROM AUTHOR]

Endoscopic submucosal dissection (ESD) was developed for the removal of benign and early malignant lesions in the gastrointestinal tract. We aimed to evaluate the performance and safety of a novel high-pressure waterjet-assisted ESD knife in colorectal applications. Six female German Landrace pigs with an average weight of 62 kg (range 60–65 kg) were used in this prospective, randomized, and controlled study. Twenty-four ESDs were performed by three endoscopists: Twelve each with the new Erbe HYBRIDknife® flex T-Type (HK-T) and the Olympus DualKnife® J (DK-J), including six rectal and six colonic ESDs per instrument. The order of performance was randomized regarding anatomic position and instrument. As the primary endpoint, ESD knife performance characteristics were combined and rated on a 5-point Likert scale, with 5 Likert points (LP) representing the best response (5 = very good). The HK-T was rated significantly better than the DK-J (4.7 LP versus 4.4 LP, p = 0.0295), mainly because of HK-T injection ability (5 LP versus 3 LP, p < 0.0001) and hemostasis (5 LP versus 4 LP, p = 0.0452). There was no difference in procedure time (HK-T: 35 min versus DK-J: 34 min, p = 0.8005), resection diameter (3.1 cm versus 2.8 cm, p = 0.3492), injection volume (41 mL versus 46 mL, p = 0.5633), and complication rates. HK-T is as effective as DK-J in colorectal ESD in terms of dissection quality but has better injection and hemostatic properties. The impact of these technical advantages on the ESD treatment of patients with large superficial colorectal lesions remains to be clinically verified. [ABSTRACT FROM AUTHOR]

Background: Colorectal cancer (CRC) is one of the most common malignancies, and early detection plays a crucial role in enhancing curative outcomes. While colonoscopy is considered the gold standard for CRC diagnosis, noninvasive screening methods of DNA methylation biomarkers can improve the early detection of CRC and precancerous lesions. Methods: Bioinformatics and machine learning methods were used to evaluate CRC‐related genes within the TCGA database. By identifying the overlapped genes, potential biomarkers were selected for further validation. Methylation‐specific PCR (MSP) was utilized to identify the associated genes as biomarkers. Subsequently, a real‐time PCR assay for detecting the presence of neoplasia or cancer of the colon or rectum was established. This screening approach involved the recruitment of 978 participants from five cohorts. Results: The genes with the highest specificity and sensitivity were Septin9, AXL4, and SDC2. A total of 940 participants were involved in the establishment of the final PCR system and the subsequent performance evaluation test. A multiplex TaqMan real‐time PCR system has been illustrated to greatly enhance the ability to detect precancerous lesions and achieved an accuracy of 87.8% (95% CI 82.9–91.5), a sensitivity of 82.7% (95% CI 71.8–90.1), and a specificity of 90.1% (95% CI 84.3–93.9). Moreover, the detection rate of precancerous lesions of this assay reached 55.0% (95% CI 38.7–70.4). Conclusion: The combined detection of the methylation status of SEPT9, SDC2, and ALX4 in plasma holds the potential to further enhance the sensitivity of CRC detection. [ABSTRACT FROM AUTHOR]

Introduction: As of 2011, India has a population of 1.21 billion people. It is the second most populous country in the world, next only to China. In absolute numbers the population of persons above 60 years was around 76.62 million in 2001, will rise to nearly 179 million by 2031 and 324 million by 2050. In addition, as people age there are increased chances of becoming disabled, and once disabled, there are increased chances of deterioration with decreased likelihood of recovering from disability. AIM: To assess the Geriatric Morbidity pattern, Activities of daily Living (ADL) and Mini Mental Scale Evaluation (MMSE). Methodology: A Cross sectional study with multistage random sampling technique was used to select the requisite number of elderly for a sample size of 600. Results: Mean age of the study population is 66.9 with SD ± 5.73 years ranging from 60 to 88 year. Multi-morbidity was seen early in nearly 70% the study population, this seems to increase with increasing age which ranged from 57.4% to 85.3% and this association was statistically significant (p value = 0.002). The total morbidity in the study population was found to be 96.3%. Conclusion: Curative medicine has a very limited role to deal with the problems of elderly in terms of impairments and diseases. Palliative care is needed to tackle impairments and complications of NCDs. [ABSTRACT FROM AUTHOR]

Background: We used a genome‐wide discovery approach to identify methylation markers associated with metastasis in men with localized prostate cancer (PCa), as better identification of those at high risk of metastasis can inform treatment decision‐making. Methods: We identified men with localized PCa at Kaiser Permanente California (January 1, 1997–December 31, 2006) who did not receive curative treatment and followed them for 10 years to determine metastasis status. Cases were chart review‐confirmed metastasis, and controls were matched using density sampling. We extracted DNA from the cancerous areas in the archived diagnostic tissue blocks. We used Illumina's Infinium MethylationEPIC BeadChip for methylation interrogation. We used conditional logistic regression and Bonferroni's correction to identify methylation markers associated with metastasis. In a separate validation cohort (2007), we evaluated the added predictive utility of the methylation score beyond clinical risk score. Results: Among 215 cases and 404 controls, 31 CpG sites were significantly associated with metastasis status. Adding the methylation score to the clinical risk score did not meaningfully improve the c‐statistic (0.80–0.81) in the validation cohort, though the score itself was statistically significant (p < 0.01). In the validation cohort, both clinical risk score alone and methylation marker score alone are well calibrated for predicted 10‐year metastasis risks. Adding the methylation score to the clinical risk score only marginally improved predictive risk calibration. Conclusion: Our findings do not support the use of these markers to improve clinical risk prediction. The methylation markers identified may inform novel hypothesis in the roles of these genetic regions in metastasis development. [ABSTRACT FROM AUTHOR]

Background: Oncologic impact of genetic alteration across synchronous colorectal cancer (CRC) still remains unclear. This study aimed to compare the oncologic relevance according to genetic alteration between synchronous and solitary CRC with performing systematic review. Methods: Multicenter retrospective analysis was performed for CRC patients with curative resection. Genetic profiling was consisted of microsatellite instability (MSI) testing, RAS (K-ras, and N-ras), and BRAF (v-Raf murine sarcoma viral oncogene homolog B1) V600E mutation. Multivariate analyses were conducted using logistic regression for synchronicity, and Cox proportional hazard model with stage-adjusting for overall survival (OS) and disease-free survival (DFS). Results: It was identified synchronous (n = 36) and solitary (n = 579) CRC with similar base line characteristics. RAS mutation was associated to synchronous CRC with no relations of MSI and BRAF. During median follow up of 77.8 month, Kaplan–meier curves showed significant differences according to MSI-high for OS, and in RAS, and BRAF mutation for DFS, respectively. In multivariable analyses, RAS and BRAF mutation were independent factors (RAS, HR = 1.808, 95% CI = 1.18–2.77, p = 0.007; BRAF, HR = 2.417, 95% CI = 1.32–4.41, p = 0.004). Old age was independent factor for OS (HR = 3.626, 95% CI = 1.09–12.00, p = 0.035). Conclusion: This study showed that oncologic outcomes might differ according to mutation burden characterized by RAS, BRAF, and MSI between synchronous CRC and solitary CRC. In addition, our systematic review highlighted a lack of data and much heterogeneity in genetic characteristics and survival outcomes of synchronous CRC relative to that of solitary CRC. [ABSTRACT FROM AUTHOR]

In this installment of the "Paradigm Shifts in Perspective" series, the authors, all scientists who have been involved in colorectal cancer (CRC) research for most or all of their careers, have watched the field develop from early pathological descriptions of tumor formation to the current understanding of tumor pathogenesis that informs personalized therapies. We outline how our understanding of the pathogenetic basis of CRC began with seemingly isolated discoveries—initially with the mutations in RAS and the APC gene, the latter of which was initially found in the context of intestinal polyposis, to the more complex process of multistep carcinogenesis, to the chase for tumor suppressor genes, which led to the unexpected discovery of microsatellite instability (MSI). These discoveries enabled the authors to better understand how the DNA mismatch repair (MMR) system not only recognizes DNA damage but also responds to damage by DNA repair or by triggering apoptosis in the injured cell. This work served, in part, to link the earlier findings on the pathogenesis of CRC to the development of immune checkpoint inhibitors, which has been transformative—and curative—for certain types of CRCs and other cancers as well. These discoveries also highlight the circuitous routes that scientific progress takes, which can include thoughtful hypothesis testing and at other times recognizing the importance of seemingly serendipitous observations that substantially change the flow and direction of the discovery process. What has happened over the past 37 years was not predictable when this journey began, but it does speak to the power of careful scientific experimentation, following the facts, perseverance in the face of opposition, and the willingness to think outside of established paradigms. [ABSTRACT FROM AUTHOR]

• Many monogenic connective tissue disorders are deemed incurable due to challenges to repair and regenerate mature connective tissues. • Innovative treatment modalities have been developed to correct mutations or consequences thereof in animal models. Some have been or are currently evaluated in clinical trials or have recently been approved by regulatory authorities. • Awareness of these modalities may inspire the development of curative approaches for connective tissue disorders in a personalized medicine approach. Connective tissue disorders can be caused by pathogenic variants (mutations) in genes encoding extracellular matrix (ECM) proteins. Such disorders typically manifest during development or postnatal growth and result in significant morbidity and mortality. The development of curative treatments for connective tissue disorders is hampered in part by the inability of many mature connective tissues to efficiently regenerate. To be most effective, therapeutic strategies designed to preserve or restore tissue function will likely need to be initiated during phases of significant endogenous connective tissue remodeling and organ sculpting postnatally and directly target the underlying ECM protein mutations. With recent advances in whole exome sequencing, in-vitro and in-vivo disease modeling, and the development of mutation-specific molecular therapeutic modalities, it is now feasible to directly correct disease-causing mutations underlying connective tissue disorders and ameliorate their pathogenic consequences. These technological advances may lead to potentially curative personalized medicine approaches for connective tissue disorders that have previously been considered incurable. In this review, we highlight innovative therapeutic modalities including gene replacement, exon skipping, DNA/mRNA editing, and pharmacological approaches that were used to preserve or restore tissue function in the context of connective tissue disorders. Inherent to a successful application of these approaches is the need to deepen the understanding of mechanisms that regulate ECM formation and homeostasis, and to decipher how individual mutations in ECM proteins compromise ECM and connective tissue development and function. [ABSTRACT FROM AUTHOR]

Background: Non-alcoholic fatty liver disease (NAFLD) is a common form of chronic liver disease, a more severe form of NAFLD is non-alcoholic steatohepatitis (NASH). Hepatic injury in NASH is caused by oxidative stress and inflammation brought on by lipotoxicity. Aleglitazar is a dual peroxisome proliferator-activated receptor (PPAR) agonist which has anti-inflammatory, antioxidant, and anti-apoptotic effects Aim: To investigate the possible curative effect of Aleglitazar against NASH as well as the possible involvement of PPAR in this effect Methods: NASH was induced using highfat diet. Mice received Aleglitazar (10 mg/kg/day), Aleglitazar (10 mg/kg/day, i.p.) + PPAR-γ blocker (GW-9962) (1mg/kg/day, i.p.) and Aleglitazar (10 mg/kg/day, i.p.) + PPAR-α blocker (MK-886) (10 mg/kg/day, i.p.) for 6 weeks. Blood samples were taken for analysis of alanine and aspartate transaminases (ALT&AST), tumor necrosis factor (TNF-α), matrix metalloproteinase-1 (MMP-1), adiponectin, cholesterol, highdensity lipoprotein (HDL), and triglyceride levels. At the same time, the livers of the mice were removed for light microscopic examination and the detection of reduced glutathione (GSH) content Results: Increases in triglyceride, cholesterol, MMP-1, TNF-α, AST, ALT, and triglyceride levels were observed in NASH animals, whereas reductions in HDL, adiponectin, and GSH content were observed along with vesicular steatosis, lobular inflammation, and hepatocyte ballooning and degeneration. Aleglitazar treatment improved histopathological alterations and lowered MMP-1, TNF-α, AST, ALT, triglyceride, and cholesterol levels while increasing HDL, adiponectin, and GSH levels. The use of GW-9662 and MK-886 significantly abrogated the hepatic protective effect of Aleglitazar as well as reduced the antiinflammatory and antioxidant effects Conclusion: Aleglitazar cured NASH in mice through activation of PPAR, and its anti-inflammatory and antioxidant properties may have had a positive impact. [ABSTRACT FROM AUTHOR]

L'hyper-médicalisation de nos sociétés et notre confiance sans borne envers la médecine curative nous ont fait peu à peu perdre le sens profond des mots des maux. Nombreux sont aujourd'hui ceux qui interpellent les pouvoirs publics afin que soit promue une « politique du Care ». Le recours aux anglicismes est assurément « tendance » mais opposer le « cure » et le « care » ne fait pas sens. Nous invitons le lecteur à tenter de recouvrer la signification et la valeur du verbe soigner et du mot soin(s), pluriel et pourtant si singulier. Pour mener cette quête nous porterons notre attention sur quelques œuvres d'art qui peut-être nous permettrons, en trois temps, de (re)découvrir le sens profond de la relation de soins. The hyper-medicalization of our societies and our absolute confidence in curative medicine have made us gradually lose the deep meaning of the words of ailments. Many are now calling on the public authorities to promote a "policy of Care". The use of anglicisms is certainly "trendy" but opposing "cure" and "care" does not make sense. We invite our readers to try to recover the meaning and the value of the verb to treat and the word care(s), plural and yet so singular. To carry out this quest, we will focus our attention on a few works of art which will perhaps allow us, in three stages, to (re)discover the deep meaning of the care relationship. [ABSTRACT FROM AUTHOR]

Background: The low level of circulating tumor DNA (ctDNA) in the blood is a well-known challenge for the application of liquid biopsies in early-stage non-small cell lung cancer (NSCLC) management. Studies of metastatic NSCLC indicate that ctDNA levels are associated with tumor metabolic activity as measured by 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET/CT). This study investigated this association in NSCLC patients considered for potentially curative treatment and explored whether the two methods provide independent prognostic information. Method: Patients with stage I-III NSCLC who had routinely undergone an 18F-FDG PET/CT scan and exploratory ctDNA analyses were included. Tumor glucose uptake was measured by maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) from the 18F-FDG PET/CT scans. ctDNA detectability and quantity, using variant allele frequency, were estimated by tumor-informed ctDNA analyses. Results: In total, 63 patients (median age 70 years, 60% women, and 90% adenocarcinoma) were included. The tumor glucose uptake (SUVmax, MTV, and TLG) was significantly higher in patients with detectable ctDNA (n = 19, p < 0.001). The ctDNA quantity correlated with MTV (Spearman's ρ = 0.53, p = 0.021) and TLG (Spearman's ρ = 0.56, p = 0.013) but not with SUVmax (Spearman's ρ = 0.034, p = 0.15). ctDNA detection was associated with shorter OS independent of MTV (HR: 2.70, 95% CI: 1.07–6.82, p = 0.035) and TLG (HR: 2.63, 95% CI: 1.06–6.51, p = 0.036). Patients with high tumor glucose uptake and detectable ctDNA had shorter overall survival and progression-free survival than those without detectable ctDNA, though these associations were not statistically significant (p > 0.05). Conclusion: There was a positive correlation between plasma ctDNA quantity and MTV and TLG in early-stage NSCLC patients. Despite the correlation, the results indicated that ctDNA detection was a negative prognostic factor independent of MTV and TLG. [ABSTRACT FROM AUTHOR]

Globally, clear-cell renal cell carcinoma (ccRCC) represents the most prevalent type of kidney cancer. Surgery plays a key role in the treatment of this cancer, although one third of patients are diagnosed with metastatic ccRCC and about 25% of patients will develop a recurrence after nephrectomy with curative intent. Molecular-target-based agents, such as tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs), are recommended for advanced cancers. In addition to cancer cells, the tumor microenvironment (TME) includes non-malignant cell types embedded in an altered extracellular matrix (ECM). The evidence confirms that interactions among cancer cells and TME elements exist and are thought to play crucial roles in the development of cancer, making them promising therapeutic targets. In the TME, an unfavorable pH, waste product accumulation, and competition for nutrients between cancer and immune cells may be regarded as further possible mechanisms of immune escape. To enhance immunotherapies and reduce resistance, it is crucial first to understand how the immune cells work and interact with cancer and other cancer-associated cells in such a complex tumor microenvironment. [ABSTRACT FROM AUTHOR]

Atrial fibrillation (AF) often requires invasive treatment by ablation to decrease symptom burden. The pulmonary veins (PV) are thought to trigger paroxysms of AF, and ablative PV isolation (PVI) is a cornerstone in AF treatment. However, incomplete PVI, where electrical conduction between the PV and left atrium (LA) is maintained, is curative of AF in a subset of patients. This implies that an antiarrhythmic effect other than electrical isolation between the PV and LA plays a role in AF prevention in these patients. We reason that the PV myocardium constitutes an arrhythmogenic substrate conducive to reentry in the patients with curative incomplete PVI. This PV substrate is amenable to ablation, even when conduction between the LA and PV persists. We propose that PV ablation strategies are differentiated to fit the arrhythmogenic mechanisms in the individual patient. PV substrate modification in patients with PV reentry may constitute a new therapeutic approach that is potentially simpler and more effective, in this subgroup of patients. [ABSTRACT FROM AUTHOR]

Knowledge on the myeloproliferative neoplasms (MPNs) - polycythemia vera (PV), essential thrombocythemia (ET), primary myelofibrosis (PMF) - has accumulated since the discovery of the JAK/STAT-activating mutations associated with MPNs: JAK2V617F, observed in PV, ET and PMF; and the MPL and CALR mutations, found in ET and PMF. The intriguing lack of disease specificity of these mutations, and of the chronic inflammation associated with MPNs, triggered a quest for finding what precisely determines that MPN patients develop a PV, ET or PMF phenoptype. The mechanisms of action of MPN-driving mutations, and concomitant mutations (ASXL1, DNMT3A, TET2, others), have been extensively studied, as well as the role played by these mutations in inflammation, and several pathogenic models have been proposed. In parallel, different types of drugs have been tested in MPNs (JAK inhibitors, interferons, hydroxyurea, anagrelide, azacytidine, combinations of those), some acting on both JAK2 and inflammation. Yet MPNs remain incurable diseases. This review aims to present current, detailed knowledge on the pathogenic mechanisms specifically associated with PV, ET or PMF that may pave the way for the development of novel, curative therapies. [ABSTRACT FROM AUTHOR]

Over the last decade, the incidence of infective endocarditis (IE) has increased, with a change in the frequency of causative bacteria. Early evidence has substantially demonstrated the crucial role of bacterial interaction with human platelets, with no clear mechanistic characterization in the pathogenesis of IE. The pathogenesis of endocarditis is so complex and atypical that it is still unclear how and why certain bacterial species will induce the formation of vegetation. In this review, we will analyze the key role of platelets in the physiopathology of endocarditis and in the formation of vegetation, depending on the bacterial species. We provide a comprehensive outline of the involvement of platelets in the host immune response, investigate the latest developments in platelet therapy, and discuss prospective research avenues for solving the mechanistic enigma of bacteria–platelet interaction for preventive and curative medicine. [ABSTRACT FROM AUTHOR]

Inclusion body myositis (IBM) belongs to the group of idiopathic inflammatory myopathies and is characterized by a slowly progressive disease course with asymmetric muscle weakness of predominantly the finger flexors and knee extensors. The disease leads to severe disability and most patients lose ambulation due to lack of curative or disease-modifying treatment options. Despite some genes reported to be associated with hereditary IBM (a distinct group of conditions), data on the genetic susceptibility of sporadic IBM are very limited. This review gives an overview of the disease and focuses on the current genetic knowledge and potential therapeutic implications. [ABSTRACT FROM AUTHOR]

Bladder cancer (BCa) is one of the most diagnosed urological malignancies. A timely and accurate diagnosis is crucial at the first assessment as well as at the follow up after curative treatments. Moreover, in the era of precision medicine, proper molecular characterization and pathological evaluation are key drivers of a patient-tailored management. However, currently available diagnostic tools still suffer from significant operator-dependent variability. To fill this gap, physicians have shown a constantly increasing interest towards new resources able to enhance diagnostic performances. In this regard, several reports have highlighted how artificial intelligence (AI) can produce promising results in the BCa field. In this narrative review, we aimed to analyze the most recent literature exploring current experiences and future perspectives on the role of AI in the BCa scenario. We summarized the most recently investigated applications of AI in BCa management, focusing on how this technology could impact physicians' accuracy in three widespread diagnostic areas: cystoscopy, clinical tumor (cT) staging, and pathological diagnosis. Our results showed the wide potential of AI in BCa, although larger prospective and well-designed trials are pending to draw definitive conclusions allowing AI to be routinely applied to everyday clinical practice. [ABSTRACT FROM AUTHOR]

β-Thalassemia is an inherited hematological disorder that results from genetic changes in the β-globin gene, leading to the reduced or absent synthesis of β-globin. For several decades, the only curative treatment option for β-thalassemia has been allogeneic hematopoietic cell transplantation (allo-HCT). Nonetheless, rapid progress in genome modification technologies holds great potential for treating this disease and will soon change the current standard of care for β-thalassemia. For instance, the emergence of the CRISPR/Cas9 genome editing platform has opened the door for precision gene editing and can serve as an effective molecular treatment for a multitude of genetic diseases. Investigational studies were carried out to treat β-thalassemia patients utilizing CRISPR-based CTX001 therapy targeting the fetal hemoglobin silencer BCL11A to restore γ-globin expression in place of deficient β-globin. The results of recently carried out clinical trials provide hope of CTX001 being a promising one-time therapeutic option to treat β-hemoglobinopathies. This review provides an insight into the key scientific steps that led to the development and application of novel CRISPR/Cas9–based gene therapies as a promising therapeutic platform for transfusion-dependent β-thalassemia (TDT). Despite the resulting ethical, moral, and social challenges, CRISPR provides an excellent treatment option against hemoglobin-associated genetic diseases. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterised by gradual memory loss and declining cognitive and executive functions. AD is the most common cause of dementia, affecting more than 50 million people worldwide, and is a major health concern in society. Despite decades of research, the cause of AD is not well understood and there is no effective curative treatment so far. Therefore, there is an urgent need to increase understanding of AD pathophysiology in the hope of developing a much-needed cure. Dissecting the cellular and molecular mechanisms of AD pathogenesis has been challenging as the most commonly used model systems such as transgenic animals and two-dimensional neuronal culture do not fully recapitulate the pathological hallmarks of AD. The recent advent of three-dimensional human brain organoids confers unique opportunities to study AD in a humanised model system by encapsulating many aspects of AD pathology. In the present review, we summarise the studies of AD using human brain organoids that recapitulate the major pathological components of AD including amyloid- β and tau aggregation, neuroinflammation, mitochondrial dysfunction, oxidative stress and synaptic and circuitry dysregulation. Additionally, the current challenges and future directions of the brain organoids modelling system are discussed. [ABSTRACT FROM AUTHOR]

Our study aimed to evaluate the baseline neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII) in relation to invasion, metastasis, and resectability for patients with gastric cancer, respectively, as predictors of death during hospitalization or surgical complications. A retrospective cohort study was conducted on 657 gastric cancer subjects. Inflammatory biomarkers were computed. The associations with tumor stage, metastasis, optimal procedure, in-hospital mortality, and surgical complications were evaluated. Subjects who underwent curative-intent surgery presented lower median NLRs (2.9 vs. 3.79), PLRs (166.15 vs. 196.76), and SIIs (783.61 vs. 1122.25), and higher LMRs (3.34 vs. 2.9) than those who underwent palliative surgery. Significantly higher NLRs (3.3 vs. 2.64), PLRs (179.68 vs. 141.83), and SIIs (920.01 vs. 612.93) were observed for those with T3- and T4-stage cancer, in comparison with those with T1- and T2-stage cancer. Values were significantly higher in the case of metastasis for the NLR (3.96 vs. 2.93), PLR (205.22 vs. 167.17), and SII (1179 vs. 788.37) and significantly lower for the LMR (2.74 vs. 3.35). After the intervention, the NLR, PLR, and SII values were higher (p < 0.01) for patients with surgical complications, and the NLR and SII values were higher for those who died during hospitalization. Higher NLRs, PLRs, SIIs, and lower LMRs were associated with a more aggressive tumor; during early follow-up, these were related to post-operative complications and death during hospitalization. [ABSTRACT FROM AUTHOR]

Encore Abstract - previously submitted to AACR 2023 The research was funded by: MorphoSys AG Keyword: Aggressive B-cell non-Hodgkin lymphoma B Conflicts of interests pertinent to the abstract. b B J. Duell b Research funding: MorphoSys AG, Regeneron B P. Abrisqueta b Consultant or advisory role: Janssen, Celgene, AbbVie, AstraZeneca Honoraria: Janssen, Celgene, AbbVie, AstraZeneca, Gilead Other remuneration: Speakers' bureau: Janssen, Celgene, AbbVie, AstraZeneca, Gilead B M. Andre b Research funding: Roche, Johnson & Johnson, Takeda Educational grants: Roche, Bristol-Myers-Squib, Celgene, Gilead, AbbVie, AstraZeneca Other remuneration: Advisory board: Takeda, Bristol-Myers-Squibb, Karyopharm, Gilead, Incyte. B Introduction: b Tafasitamab, an anti-CD19 immunotherapy that enhances antibody-dependent cellular cytotoxicity and phagocytosis, received accelerated approval in the USA and conditional authorization in Europe in combination with lenalidomide (LEN) for patients (pts) with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) ineligible for autologous stem cell transplant (ASCT) based on the results of the open-label, multicenter, single-arm, Phase II L-MIND study (NCT02399085; Salles G., et al. [Extracted from the article]

Cardiovascular diseases represent a major cause of morbidity and mortality, necessitating research to improve diagnostics, and to discover and test novel preventive and curative therapies, all of which warrant experimental models that recapitulate human disease. The translation of basic science results to clinical practice is a challenging task, in particular for complex conditions such as cardiovascular diseases, which often result from multiple risk factors and comorbidities. This difficulty might lead some individuals to question the value of animal research, citing the translational 'valley of death', which largely reflects the fact that studies in rodents are difficult to translate to humans. This is also influenced by the fact that new, human-derived in vitro models can recapitulate aspects of disease processes. However, it would be a mistake to think that animal models do not represent a vital step in the translational pathway as they do provide important pathophysiological insights into disease mechanisms particularly on an organ and systemic level. While stem cell-derived human models have the potential to become key in testing toxicity and effectiveness of new drugs, we need to be realistic, and carefully validate all new human-like disease models. In this position paper, we highlight recent advances in trying to reduce the number of animals for cardiovascular research ranging from stem cell-derived models to in situ modelling of heart properties, bioinformatic models based on large datasets, and state-of-the-art animal models, which show clinically relevant characteristics observed in patients with a cardiovascular disease. We aim to provide a guide to help researchers in their experimental design to translate bench findings to clinical routine taking the replacement, reduction, and refinement (3R) as a guiding concept. [ABSTRACT FROM AUTHOR]

Background: In end-stage chronic liver disease, transplantation represents the only curative option. However, the shortage of donors results in the death of many patients. To overcome this gap, it is mandatory to develop new therapeutic options. In the present study, we decellularised pig livers and reseeded them with allogeneic porcine mesenchymal stromal cells (pMSCs) to understand whether extracellular matrix (ECM) can influence and/or promote differentiation into hepatocyte-like cells (HLCs). Methods: After decellularisation with SDS, the integrity of ECM-scaffolds was examined by histological staining, immunofluorescence and scanning electron microscope. DNA quantification was used to assess decellularisation. pMSCs were plated on scaffolds by static seeding and maintained in in vitro culture for 21 days. At 3, 7, 14 and 21 days, seeded ECM scaffolds were evaluated for cellular adhesion and growth. Moreover, the expression of specific hepatic genes was performed by RT-PCR. Results: The applied decellularisation/recellularisation protocol was effective. The number of seeded pMSCs increased over the culture time points. Gene expression analysis of seeded pMSCs displayed a weak induction due to ECM towards HLCs. Conclusions: These results suggest that ECM may address pMSCs to differentiate in hepatocyte-like cells. However, only contact with liver-ECM is not enough to induce complete differentiation. [ABSTRACT FROM AUTHOR]

Intrahepatic Cholangiocarcinoma (iCCA) is an aggressive cancer with diverse mutational profiles. An important molecular subtype is fibroblast growth factor receptor 2 (FGFR2) fusion. The effect of FGFR2 fusions on prognosis is unknown. Our aim was to assess the outcomes in resected CCA patients in relation to FGFR2 status. Surgically treated CCA patients from a single institution were retrospectively reviewed between 2008 and 2014. FGFR rearrangements were detected by fluorescence in situ hybridization (FISH). Data included patient demographics, tumor pathology, disease-free survival (DFS) and overall survival (OS). Ninety-five patients underwent surgical resection for iCCA. Twelve (13%) of these were found to have FGFR2 fusion, none of which were treated with FGFR targeted therapy. Patients with FGFR2 fusions were found to have a longer 5-year (83 vs. 32%, p = 0.01) and 10-year (46 vs. 22%, p = 0.04) OS. Five and 10-year DFS was also increased (68 vs. 33% p = 0.04) and (68 vs. 25 %, p = 0.02,). FGFR2 fusion status was the strongest independent factor associated with improved OS (HR 0.23, 0.09–0.62, p=0.003) and DFS (HR 0.18, 0.05–0.67, p=0.01). Patients with CCA FGFR2 fusion have improved OS and DFS following surgical resection. [ABSTRACT FROM AUTHOR]

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for patients with hematologic malignances. Haploidentical HSCT (Haplo-HSCT) is an alternative option for patients who do not have an HLAmatched donor. The use of post-transplantation high dose cyclophosphamide (PT-Cy) is commonly employed for graft-versus-host disease (GVHD) prophylaxis in haplo-HSCT. Cyclophosphamide (Cy) is an alkylating agent with antineoplastic and immunosuppressive activity, whose bioactivation requires the activity of polymorphic enzymes in the liver to produce phosphoramide mustard, which is a DNA alkylating agent. To identify polymorphisms in the genes of Cy metabolism and correlate them with post-HSCT complications [GVHD, sinusoidal obstruction syndrome (SOS), hemorrhagic cystitis (HC) and transplant-related mortality (TRM)], we designed a custom next-generation sequencing panel with Cy metabolism enzymes. We analyzed 182 patients treated with haplo-HSCT with PT-Cy from 2007 to 2019, detecting 40 variants in 11 Cy metabolism genes. Polymorphisms in CYP2B6, a major enzyme involved in Cy activation, were associated with decreased activity of this enzyme and a higher risk of Graf-versus-host disease (GVHD). Variants in other activation enzymes (CYP2A6, CYP2C8, CYP2C9, CYP2C19) lead to decreased enzyme activity and were associated with GVHD. Polymorphisms in detoxification genes such as glutathione S-transferases decreased the ability to detoxify cyclophosphamide metabolites due to lower enzyme activity, which leads to increased amounts of toxic metabolites and the development of III-IV acute GVHD. GSMT1*0 a single nucleotide polymorphism previously recognized as a risk factor for SOS was associated with a higher risk of SOS. We conclude that polymorphisms of genes involved in the metabolism of cyclophosphamide in our series are associated with severe grades of GVHD and toxicities (SOS and TRM) after haplo-HSCT and could be used to improve the clinical management of transplanted patients. [ABSTRACT FROM AUTHOR]

Gene therapy is an exciting therapeutic concept that offers the promise of a cure for an array of inherited and acquired disorders. The liver has always been a key target for gene therapy as it controls essential biological processes including digestion, metabolism, detoxification, immunity, and blood coagulation. Metabolic disorders of hepatic origin number several hundreds, and for many, liver transplantation remains the only cure. Liver-targeted gene therapy is an attractive treatment modality for many of these conditions. After years of failure, substantial progress in this field in the past decade has resulted in promising clinical efficacy and safety in patients with monogenetic disorders with Valoctocogene roxaparvovec (Roctavian), the first gene therapy for treatment for hemophilia A, to be approved in Europe. Another, Etranacogene dezaparvovec (AMT-061) for hemophilia B is also in the final stages of approval. A number of other liver targeted gene therapy products are at an advanced stage of development, thus heralding a new era of potentially curative molecular medicine. This review explores the recent clinical advances in liver targeted gene therapy as well as the challenges that need to be overcome for the widespread adoption of this new treatment paradigm. [ABSTRACT FROM AUTHOR]

Plasma Epstein Barr virus (EBV)-DNA is employed as a biomarker for EBER (EBV-encoded RNA) positive nasopharyngeal cancer (NPC) patients. In Europe, the use of plasma EBV-DNA is limited by the lack of harmonization among different European Conformity (CE)-marked EBV-DNA detection methods and BamHI-W, the latter being the gold standard assay in endemic areas. Our Institution demonstrated that three CE-marked (i.e., ELITech, Abbott, Artus) and BamHI-W assays significantly agreed in plasma EBV-DNA quantification in non-endemic NPC (1). In this setting, the role of plasma EBV-DNA was better defined only before curative treatment, (2) with undetectable baseline plasma EBV-DNA levels holding a positive prognostic significance in terms of disease-free survival (DFS) and overall survival (OS) (2). However, the value of CE-marked assays in Longitudinal assessment of plasma EBV-DNA (LEA) -alongside the curative management and follow-up of non-endemic NPC - is still lacking (1; 2). Herein, we present the results of the LEA study (Ethics Comittee n. 150/23) concerning the dynamics of plasma EBD-DNA viral load in a single-Institution cohort of non-endemic NPC patients. From 2012 to 2023 we retrospectively collected data of all EBER-positive NPC patients treated with curative intent at our Institution. All subjects underwent plasma EBV-DNA quantification at the following time-points: 1) pre-treatment (within 1 month since treatment start); 2) post-treatment (2A, early post-treatment, within 6 weeks after treatment completion and/or 2B, late post-treatment, within 16 weeks after treatment end); 3) follow-up phase. EBV-DNA results were classified as negative (if EBV-DNA was not detected) or positive (if EBV-DNA was detected and quantifiable or detected but not quantifiable) and were expressed as log IU/ml. Descriptive statistics were performed on all available data. The role of pre-treatment EBV-DNA as predictive factor for disease recurrence was assessed by estimating the Receiver Operating Characteristic (ROC) curve at different cut-offs. The predictive value of post-treatment (2A, 2B) EBV-DNA load was assessed considering its ability to forecast recurrence. For patients with both 2A and 2B available samples, the 2B value was considered for post-treatment analyses. At the data cut-off (Aug, 07th, 2023), 169 EBV-related NPC patients were identified. Median age at diagnosis was 50 years (range: 22-75). Most of them were male (72%) and staged as III/IV (84%) according to AJCC classification (VIII Ed.). Only two patients presented oligo-metastatic disease at distant sites, and they were not included in the final analyses on the predictive value of EBV-DNA. At a median follow-up of 66 months (range: 9-134), 41 patients (24.2%) recurred and 139 (82.2%) were still alive. Out of 167 evaluable patients, median viral load of pre-treatment plasma EBV-DNA was of 2.59 log IU/ml (range: 1.59-5.11), while it was undetectable only in six (3.5%) patients who did not recur. All 41 recurrences occurred in patients with pre-treatment detectable EBV-DNA. In addition, subjects with undetectable baseline EBV-DNA had almost significantly (p=0.07) higher DFS with respect to those who showed detectable baseline values (DFS: 66 vs. 47 months, respectively). For pre-treatment plasma EBV-DNA, the best cut-off in terms of disease recurrence prediction was not identified within total population (area under curve, AUC: 0.56) and in early (at 1-y) recurrent patients (n=20) (AUC: 0.58). Regarding the predictive value of post-treatment EBV-DNA measurement (2A, 2B; within 16 weeks), its accuracy, sensitivity, specificity were 78%, 61%, and 80%, respectively, with regards to recurrence detection at any time-point during the follow-up. Moreover, its negative predictive value (NPV) was 94%, which resulted stable across the first three years of follow-up (93% at 1st-y, 95% at 2nd-y, 95% at 3rd-y). On the other hand, its overall positive predictive value (PPV) was 27%, which progressively decreased during follow-up (40% at 1st-y, 34% at 2nd-y, 30% at 3rd-y). To our knowledge, this is the largest longitudinal evaluation of plasma EBV-DNA quantification in non-endemic EBV-related NPC patients. Undetectable pre-treatment plasma EBV-DNA confirmed its positive prognostic role. NPV of post-treatment (within 16 weeks since curative therapy end) plasma EBV-DNA was 94%, remaining stable during follow-up time (first 3 years) whereas its sensitivity and PPV were lower - 61% and 27%, respectively. The LEA study provides additional data on the significance of plasma EBV-DNA in non-endemic curable NPC, which can also guide clinicians towards a standardization of the timing of plasma EBV-DNA assessment in this setting. [ABSTRACT FROM AUTHOR]

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease without effective curative therapy. Recent evidence shows increased circulating myeloid-derived suppressor cells (MDSCs) in cancer, inflammation, and fibrosis, with some of these cells expressing B7H3. We sought to investigate the role of MDSCs in IPF and its potential mediation via B7H3. Here we prospectively collected peripheral blood samples from IPF patients to analyze for circulating MDSCs and B7H3 expression to assess their clinical significance and potential impact on co-cultured lung fibroblasts and T-cell activation. In parallel, we assess MDSC recruitment and potential B7H3 dependence in a mouse model of pulmonary fibrosis. Expansion of MDSCs in IPF patients correlated with disease severity. Co-culture of soluble B7H3 (sB7H3)-treated mouse monocytic MDSCs (M-MDSCs), but not granulocytic MDSCs (G-MDSCs), activated lung fibroblasts and myofibroblast differentiation. Additionally, sB7H3 significantly enhanced MDSC suppression of T-cell proliferation. Activated M-MDSCs displayed elevated TGFb and Arg1 expression relative to that in G-MDSCs. Treatment with anti-B7H3 antibodies inhibited bone marrow-derived MDSC recruitment into the bleomycin-injured lung, accompanied by reduced expression of inflammation and fibrosis markers. Selective telomerase reverse transcriptase (TERT) deficiency in myeloid cells also diminished MDSC recruitment associated with the reduced plasma level of sB7H3, lung recruitment of c-Kit+ hematopoietic progenitors, myofibroblast differentiation, and fibrosis. Lung single-cell RNA sequencing (scRNA-seq) revealed fibroblasts as a predominant potential source of sB7H3, and indeed the conditioned medium from activated mouse lung fibroblasts had a chemotactic effect on bone marrow (BM)-MDSC, which was abolished by B7H3 blocking antibody. Thus, in addition to their immunosuppressive activity, TERT and B7H3-dependent MDSC expansion/recruitment from BM could play a paracrine role to activate myofibroblast differentiation during pulmonary fibrosis with potential significance for disease progression mediated by sB7H3. [ABSTRACT FROM AUTHOR]

Extragastric recurrence of early gastric cancer (EGC) after curative resection is rare, but prognosis has been poor in previous reports. Recently, single patient classifier (SPC) genes, such as secreted frizzled-related protein 4 (SFRP4) and caudal-type homeobox 1 (CDX1), were associated with prognosis and chemotherapy response in stage II–III gastric cancer. The aim of our study is, therefore, to elucidate predictive factors for extragastric recurrence of EGC after curative resection, including with the expression of SPC genes. We retrospectively reviewed electronic medical records of 1974 patients who underwent endoscopic or surgical curative resection for EGC. We analyzed clinicopathological characteristics to determine predictive factors for extragastric recurrence. Total RNA was extracted from formalin-fixed, paraffin-embedded (FFPE) tumor tissue and amplified by real-time reverse transcription polymerase chain reaction to evaluate expression of SPC genes. Overall incidences of extragastric recurrence were 0.9%. In multivariate analysis, submucosal invasion (odds ratio [OR] = 6.351, p = 0.032) and N3 staging (OR = 171.512, p = 0.012) were independent predictive factors for extragastric recurrence. Mean expression of SFRP4 in extragastric recurrence (−2.8 ± 1.3) was significantly higher than in the control group (−4.3 ± 1.6) (p = 0.047). Moreover, mean expression of CDX1 in extragastric recurrence (−4.6 ± 2.0) was significantly lower than in the control group (−2.4 ± 1.8) (p = 0.025). Submucosal invasion and metastasis of more than seven lymph nodes were independent predictive factors for extragastric recurrence. In addition, SFRP4 and CDX1 may be novel predictive markers for extragastric recurrence of EGC after curative resection. [ABSTRACT FROM AUTHOR]

Purpose: Unresectable recurrence is a critical predictor of outcomes for colorectal cancer patients. We attempted to identify the prognostic factors, especially for unresectable recurrence-free survival (URFS) as a new endpoint, in patients with resectable colorectal liver-only metastasis (CRLOM).We investigated patients with resectable CRLOM, who underwent an R0 resection for both CRC and CRLOM between January, 2014 and March, 2019 at a single institution. The exclusion criteria were patients who received neoadjuvant treatment, the absence of data for genetic analyses, and the presence of multiple cancers, synchronous CRC, or familial adenomatous polyposis. The prognostic factors were examined retrospectively using data on pre-hepatectomy factors, including primary tumor molecular profiling results.We analyzed the data of 101 patients who underwent curative-intent surgery for CRLOM. Multivariate analysis revealed that KRAS G12D mutation-positivity (hazard ratio [HR]: 7.69; p < 0.01), RYR2 mutation-positivity (HR: 4.03; p < 0.01), and KRAS G12S mutation-positivity (HR: 3.96; p = 0.03), CA19-9 > 37 U/ml before hepatectomy (HR: 3.62; p < 0.01), and primary tumor pN2 stage (HR: 3.22; p = 0.03) were significant predictors of the URFS.This is the first study to show that specific KRAS and RYR2 mutations were associated with the URFS.Methods: Unresectable recurrence is a critical predictor of outcomes for colorectal cancer patients. We attempted to identify the prognostic factors, especially for unresectable recurrence-free survival (URFS) as a new endpoint, in patients with resectable colorectal liver-only metastasis (CRLOM).We investigated patients with resectable CRLOM, who underwent an R0 resection for both CRC and CRLOM between January, 2014 and March, 2019 at a single institution. The exclusion criteria were patients who received neoadjuvant treatment, the absence of data for genetic analyses, and the presence of multiple cancers, synchronous CRC, or familial adenomatous polyposis. The prognostic factors were examined retrospectively using data on pre-hepatectomy factors, including primary tumor molecular profiling results.We analyzed the data of 101 patients who underwent curative-intent surgery for CRLOM. Multivariate analysis revealed that KRAS G12D mutation-positivity (hazard ratio [HR]: 7.69; p < 0.01), RYR2 mutation-positivity (HR: 4.03; p < 0.01), and KRAS G12S mutation-positivity (HR: 3.96; p = 0.03), CA19-9 > 37 U/ml before hepatectomy (HR: 3.62; p < 0.01), and primary tumor pN2 stage (HR: 3.22; p = 0.03) were significant predictors of the URFS.This is the first study to show that specific KRAS and RYR2 mutations were associated with the URFS.Results: Unresectable recurrence is a critical predictor of outcomes for colorectal cancer patients. We attempted to identify the prognostic factors, especially for unresectable recurrence-free survival (URFS) as a new endpoint, in patients with resectable colorectal liver-only metastasis (CRLOM).We investigated patients with resectable CRLOM, who underwent an R0 resection for both CRC and CRLOM between January, 2014 and March, 2019 at a single institution. The exclusion criteria were patients who received neoadjuvant treatment, the absence of data for genetic analyses, and the presence of multiple cancers, synchronous CRC, or familial adenomatous polyposis. The prognostic factors were examined retrospectively using data on pre-hepatectomy factors, including primary tumor molecular profiling results.We analyzed the data of 101 patients who underwent curative-intent surgery for CRLOM. Multivariate analysis revealed that KRAS G12D mutation-positivity (hazard ratio [HR]: 7.69; p < 0.01), RYR2 mutation-positivity (HR: 4.03; p < 0.01), and KRAS G12S mutation-positivity (HR: 3.96; p = 0.03), CA19-9 > 37 U/ml before hepatectomy (HR: 3.62; p < 0.01), and primary tumor pN2 stage (HR: 3.22; p = 0.03) were significant predictors of the URFS.This is the first study to show that specific KRAS and RYR2 mutations were associated with the URFS.Conclusions: Unresectable recurrence is a critical predictor of outcomes for colorectal cancer patients. We attempted to identify the prognostic factors, especially for unresectable recurrence-free survival (URFS) as a new endpoint, in patients with resectable colorectal liver-only metastasis (CRLOM).We investigated patients with resectable CRLOM, who underwent an R0 resection for both CRC and CRLOM between January, 2014 and March, 2019 at a single institution. The exclusion criteria were patients who received neoadjuvant treatment, the absence of data for genetic analyses, and the presence of multiple cancers, synchronous CRC, or familial adenomatous polyposis. The prognostic factors were examined retrospectively using data on pre-hepatectomy factors, including primary tumor molecular profiling results.We analyzed the data of 101 patients who underwent curative-intent surgery for CRLOM. Multivariate analysis revealed that KRAS G12D mutation-positivity (hazard ratio [HR]: 7.69; p < 0.01), RYR2 mutation-positivity (HR: 4.03; p < 0.01), and KRAS G12S mutation-positivity (HR: 3.96; p = 0.03), CA19-9 > 37 U/ml before hepatectomy (HR: 3.62; p < 0.01), and primary tumor pN2 stage (HR: 3.22; p = 0.03) were significant predictors of the URFS.This is the first study to show that specific KRAS and RYR2 mutations were associated with the URFS. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to compare the diagnostic accuracy of perioperative ΔcfDNA to ΔCEA (over the first 2 years post-operatively) for identifying disease recurrence in colon cancer. Methods: Patients presenting for elective resection for colon cancer with curative intent were screened for inclusion. Perioperative cfDNA levels were measured at seven different times points(pre-operative and post-operative at 3 h, 6 h, 24 h, 48 h, POD3 and POD5). CEA levels were measured on the same patients up to 2 years post-operatively. Change in trend (Δ) was defined as the β coefficient using a logistic regression model. Statistical analysis was performed using SPSS, version 23. Results: Longitudinal data on twenty-two patients were analysed (n = 16 male, n = 6 female) for a median of 29 months (IQR 23 months) during which time three patients developed (distant) recurrence. Perioperative ΔcfDNA at 48Hrs, POD3 and POD5 were significantly associated with early recurrence. ΔCEA was significantly associated with early recurrence at 6 months, 1 year and 2 years post-operatively, only when disease recurrence was macroscopically established. ΔcfDNA was associated with an area under the curve (AUC) of 0.947 (95% CI 0.88–1.0, p < 0.001) and ΔCEA was associated with an AUC of 0.9382 (95%CI 0.88–0.99, p < 0.0001). This translated into a specificity of 97% (95%CI 86.51–99.87%) for ΔcfDNA and 77.5% sensitivity (95%CI 62.5–87.7%) in the immediate perioperative period and an 88.9% specificity (95%CI 56.5–99.4%) and 76.5% sensitivity (95%CI 63.24–86%) for ΔCEA over the first 2 years post-operatively. Conclusions: In this pilot study, following curative resection for colon cancer changing trends in perioperative cfDNA (ΔcfDNA) identify those at risk of recurrent disease before recurrence develops which is at least 6 months earlier than CEA changes (ΔCEA) which are only observed when recurrence is established. [ABSTRACT FROM AUTHOR]