Prognostic Implications of Unexpected Positive Intraoperative Cultures in Two-Stage Knee Arthroplasty Reimplantations: A Minimum Five-Year Retrospective Analysis.

BACKGROUND: The clinical challenge of unexpected positive intraoperative cultures (UPICs) persists in 2-stage resection arthroplasty for managing periprosthetic joint infections (PJIs) following total knee arthroplasty.(TKA). This study aimed to investigate the incidence of UPICs during the definitive reimplantation phase of 2-stage resection arthroplasty of the knee and to assess both the infection-free and revision-free survivorship of the implanted prosthesis. METHODS: This retrospective study included 450 2-stage resection arthroplasties of primary knee prostheses performed between January 2012 and April 2017. Patients were excluded if they: (1) underwent three or more staged resections, (2) had ambiguous clinical documentation or deviated from the 2-stage protocol, or (3) underwent revision arthroplasty prior to the PJI. Additionally, patients presumed aseptic before the second-stage reimplantation were excluded if they lacked joint aspiration or met the 2011 Musculoskeletal Infection Society criteria for PJI before implantation. RESULTS: After exclusions, 300 patients were analyzed. Among them, 14% had UPIC during the second-stage reimplantation. The follow-up time was 2,316 (range, 1,888 to 3,737) days and 2,531 (range, 1,947 to 3,349) days for UPIC and negative intraoperative culture (NIC) groups, respectively. Rerevision due to subsequent PJI occurred in 26.2% of UPIC patients and 15.1% of NIC patients. The 2-year infection-free survival rates for the NIC, one UPIC, and ≥ two UPIC cohorts were 99.5, 98.2, and 94.3%, respectively, while the 5-year survival rates were 92.1, 91.1, and 54.3%, respectively. The unfavorable survivorship was significantly different in multiple UPIC cases (P < 0.001). Multiple UPICs with pathogens consistent with the first-stage findings were strongly associated with the risk of reinfection (P < 0.001). CONCLUSIONS: An UPIC was identified in 14% of second-stage reimplantations. Patients who had multiple UPICs demonstrated truncated survivorship and suboptimal outcomes relative to the NIC and single UPIC cohorts, especially with pathogen consistency to the first-stage surgery. LEVEL OF EVIDENCE: III.

Multiply robust estimation of natural indirect effects with multiple ordered mediators.

Multiple mediation analysis is a powerful methodology to assess causal effects in the presence of multiple mediators. Several methodologies, such as G-computation and inverse-probability-weighting, have been widely used to draw inferences about natural indirect effects (NIEs). However, a limitation of these methods is their potential for model misspecification. Although powerful semiparametric methods with high robustness and consistency have been developed for inferring average causal effects and for analyzing the effects of a single mediator, a comparably robust method for multiple mediation analysis is still lacking. Therefore, this theoretical study proposes a method of using multiply robust estimators of NIEs in the presence of multiple ordered mediators. We show that the proposed estimators not only enjoy the multiply robustness to model misspecification, they are also consistent and asymptotically normal under regular conditions. We also performed simulations for empirical comparisons of the finite-sample properties between our multiply robust estimators and existing methods. In an illustrative example, a dataset for liver disease patients in Taiwan is used to examine the mediating roles of liver damage and liver cancer in the pathway from hepatitis B/C virus infection to mortality. The model is implemented in the open-source R package "MedMR."

PLK1 and its substrate MISP facilitate intrahepatic cholangiocarcinoma progression by promoting lymphatic invasion and impairing E-cadherin adherens junctions.

Intrahepatic cholangiocarcinoma (iCCA) is a subtype of CCA and has a high mortality rate and a relatively poor prognosis. However, studies focusing on increased cell motility and loss of epithelial integrity during iCCA progression remain relatively scarce. We collected seven fresh tumor samples from four patients to perform RNA sequencing (RNA-seq) and assay for transposase-accessible chromatin using sequencing (ATAC-seq) to determine the transcriptome profile and chromatin accessibility of iCCA. The increased expression of cell cycle regulators, including PLK1 and its substrate MISP, was identified. Ninety-one iCCA patients were used to validate the clinical significance of PLK1 and MISP. The upregulation of PLK1 and MISP was determined in iCCA tissues. Increased expression of PLK1 and MISP was significantly correlated with tumor number, N stage, and lymphatic invasion in an iCCA cohort. Knockdown of PLK1 or MISP reduced trans-lymphatic endothelial migration and wound healing and affected focal adhesions in vitro. In cell‒cell junctions, MISP localized to adherens junctions and suppressed E-cadherin dimerization. PLK1 disrupted adherens junctions in a myosin-dependent manner. Furthermore, PLK1 and MISP promoted cell proliferation in vitro and tumorigenesis in vivo. In iCCA, PLK1 and MISP promote aggressiveness by increasing lymphatic invasion, tumor growth, and motility through the repression of E-cadherin adherens junctions.

Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation.

Cholangiocarcinoma (CCA) exhibits aggressive biological behavior and a poor prognosis. Gemcitabine (GEM)-based chemotherapy is the first-line chemotherapy for advanced CCA but has a response rate of only 20-30%. Therefore, investigating treatments to overcome GEM resistance in advanced CCA is crucial. Among mucin (MUC) family members, MUC4 showed the greatest increase in the resistant versus parental sublines. MUC4 was upregulated in whole-cell lysates and conditioned media from gemcitabine-resistant (GR) CCA sublines. MUC4 mediated GEM resistance by activating AKT signaling in GR CCA cells. The MUC4-AKT axis induced BAX S184 phosphorylation to inhibit apoptosis and downregulated GEM transporter human equilibrative nucleoside transporter 1 (hENT1) expression. The combination of AKT inhibitors and GEM or afatinib overcame GEM resistance in CCA. In vivo, capivasertib (an AKT inhibitor) increased GEM sensitivity in GR cells. MUC4 promoted EGFR and HER2 activation to mediate GEM resistance. Finally, MUC4 expression in patient plasma correlated with MUC4 expression. Paraffin-embedded specimens from non-responders expressed significantly more MUC4 than did those from responders, and this upregulation was associated with poor progression-free survival and overall survival. In GR CCA, high MUC4 expression promotes sustained EGFR/HER2 signaling and AKT activation. The combination of AKT inhibitors with GEM or afatinib might overcome GEM resistance.

A Potential Association of Zinc Deficiency and Tyrosine Kinase Inhibitor-Induced Hand-Foot Skin Reaction.

Hand-foot skin reaction (HFSR) is a common skin-related adverse event induced by multikinase inhibitors targeting both platelet-derived growth factor receptor and vascular endothelial growth factor receptor, possibly due to inadequate repair following frictional trauma. Zinc is a trace element and essential nutrient in humans that plays critical roles in the development and differentiation of skin cells. Zinc transporters (Zrt- and Irt-like proteins and Zn transporters) and metallothioneins are involved in zinc efflux, uptake, and homeostasis and have been reported to be involved in skin differentiation. The underlying mechanism of HFSR remains unclear, and the association between HFSR and zinc has not been previously studied. However, some case reports and case series provide potential evidence to suggest that zinc deficiency may be involved in HFSR development and zinc supplementation may relieve HFSR symptoms. However, no large-scale clinical studies have been conducted to examine this role. Therefore, this review summarizes the evidence supporting a possible link between HFSR development and zinc and proposes potential mechanisms underlying this association based on current evidence.

Does a negative correlation of heme oxygenase-1 with hematoma thickness in chronic subdural hematomas affect neovascularization and microvascular leakage? A retrospective study with preliminary validation.

OBJECTIVE: Chronic subdural hematoma (CSDH) is a common neurological disease among elderly adults. The progression of CSDH is an angiogenic process, involving inflammatory mediators that affect vascular permeability, microvascular leakage, and hematoma thickness. The authors aimed to identify biomarkers associated with angiogenesis and vascular permeability that might influence midline shift and hematoma thickness. METHODS: Medical records and laboratory data of consecutive patients who underwent surgery for CSDH were analyzed. Collected data were basic demographic data, CSDH classification, CSDH thickness, midline shift, heme oxygenase-1 (HO-1) levels in hematomas, and common laboratory markers. Linear regression analysis was used to evaluate the relationship of CSDH thickness with characteristic variables. The chick chorioallantoic membrane (CAM) assay was used to test the angiogenic potency of identified variables in ex ovo culture of chick embryos. RESULTS: In total, 93 patients with CSDH (71.0% male) with a mean age of 71.0 years were included. The mean CSDH thickness and midline shift were 19.7 and 9.8 mm, respectively. The mean levels of HO-1, ferritin, total bilirubin, white blood cells, segmented neutrophils, lymphocytes, platelets, international normalized ratio, and partial thromboplastin time were 36 ng/mL, 14.8 µg/mL, 10.5 mg/dL, 10.3 × 103 cells/µL, 69%, 21.7%, 221.1 × 109 cells/µL, 1.0, and 27.8 seconds, respectively. Pearson correlation analysis revealed that CSDH thickness was positively correlated with midline shift distance (r = 0.218, p < 0.05) but negatively correlated with HO-1 concentration (r = -0.364, p < 0.01) and ferritin level (r = -0.222, p < 0.05). Multivariate linear regression analysis revealed that HO-1 was an independent predictor of CSDH thickness (ß = -0.084, p = 0.006). The angiogenic potency of HO-1 in hematoma fluid was tested with the chick CAM assay; topical addition of CSDH fluid with low HO-1 levels promoted neovascularization and microvascular leakage. Addition of HO-1 in a rescue experiment inhibited CSDH fluid-mediated angiogenesis and microvascular leakage. CONCLUSIONS: HO-1 is an independent risk factor in CSDH hematomas and is negatively correlated with CSDH thickness. HO-1 may play a role in the pathophysiology and development of CSDH, possibly by preventing neovascularization and reducing capillary fragility and hyperpermeability.

Higher reinfection rate after two-stage revision arthroplasty in patients with refractory diabetes mellitus: a retrospective analysis with a minimum ten-year follow up.

BACKGROUND: Treatment protocols for two-stage revision arthroplasty with diabetes mellitus (DM) have not yet been established. The control of glycated hemoglobin (HbA1c) in two-stage revision arthroplasty is still debated. This study aimed to clarify the importance of preoperative HbA1c levels before each stage of revision arthroplasty and to analyze the risk factors for reinfection. METHODS: Five hundred eighty-eight patients suffered from first-time PJI and was treated in our institute from January 1994 to December 2010 were reviewed. The mean follow-up time was 13.8 (range, 10.2-24.8) years. Patients underwent two-stage revision arthroplasty with DM at presentation were included. The endpoint of the study was reinfection of the revision arthroplasty. Demographic, survivorship, and surgical variables were also analyzed. RESULTS: Eighty-eight patients were identified and grouped by HbA1c level before the first stage surgery: Groups 1 and 2 had HbA1c levels < 7% and ≥ 7%, respectively. Reinfection was identified in 4.55% (2/44) and 18.18% (8/44) of the patients in Groups 1 and 2, respectively. Survivorship analysis revealed correction of the HbA1c before the final stage of revision arthroplasty as an independent factor (p < 0.001). The identified risks for reinfection were HbA1c levels ≥ 7% before final-stage surgery, ≥ 3 stages of revision arthroplasty, and extended-spectrum beta-lactamase (ESBL)-Escherichia coli PJI. CONCLUSION: The HbA1c level before the final stage of revision arthroplasty could affect staged revision arthroplasty outcomes. Therefore, the necessity of postponing the elective final-stage revision arthroplasty procedure for HbA1c control should be further investigated in the future.

An Integrative Clinical Model for the Prediction of Pathological Complete Response in Patients with Operable Stage II and Stage III Triple-Negative Breast Cancer Receiving Neoadjuvant Chemotherapy.

Triple-negative breast cancer (TNBC) is treated with neoadjuvant chemotherapy (NAC). The response to NAC, particularly the probability of a complete pathological response (pCR), guides the surgical approach and adjuvant therapy. We developed a prediction model using a nomogram integrating blood tests and pre-treatment ultrasound findings for predicting pCR in patients with stage II or III operable TNBC receiving NAC. Clinical data before and after the first cycle of NAC collected from patients between 2012 and 2019 were analyzed using univariate and multivariate analyses to identify correlations with pCR. The coefficients of the significant parameters were calculated using logistic regression, and a nomogram was developed based on the logistic model to predict the probability of pCR. Eighty-eight patients were included. Five parameters correlated with the probability of pCR, including the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte (PLR) ratio, percentage change in PLR, presence of echogenic halo, and tumor height-to-width ratio. The discrimination performance of the nomogram was indicated by an area under the curve of 87.7%, and internal validation showed that the chi-square value of the Hosmer-Lemeshow test was 7.67 (p = 0.363). Thus, the integrative prediction model using clinical data can predict the probability of pCR in patients with TNBC receiving NAC.

Population attributable fraction based on marginal sufficient component cause model for mediation settings.

PURPOSE: Population attributable fraction (PAF), defined as the proportion of the occurrence of a disease which will be reduced by eliminating risk factors in a population, is one of the most common measurements for evaluating the benefit of a health-related policy in epidemiologic study. In this article, we propose an alternative PAF defined based on sufficient cause framework, which decompose the occurrence of a disease into several pathways including mediation and mechanistic interaction. METHODS: We propose a formal statistical definition and regression-based estimator for PAF based on sufficient cause framework within mediation settings. Under monotonicity assumption, the proposed method can decompose the occurrence of a disease into nine PAFs corresponding to all types of mechanisms attributing to exposure and the mediator, including the portion attributing to exposure directly, to mediator, to indirect effect through mediator, to the mechanistic interaction, to both of mediation and interaction, and to none of exposure or mediator. RESULTS: We apply the proposed method to explore the mechanism of a hepatitis C virus (HCV)-induced hepatocellular carcinoma (HCC) mediated by and/or interacted with alanine aminotransferase (ALT) and hepatitis B virus (HBV). When treating ALT as mediator, 56.77% of diseased subjects can be attributable to either HCV or abnormal ALT. When treating HBV as mediator, HCC is mainly induced by an exogenous high HBV viral load directly. CONCLUSIONS: The proposed method can identify the impact of exposure and pathway effects, and benefit to allocate the resources on intervention strategies.

Identification and robust estimation of swapped direct and indirect effects: Mediation analysis with unmeasured mediator-outcome confounding and intermediate confounding.

Counterfactual-model-based mediation analysis can yield substantial insight into the causal mechanism through the assessment of natural direct effects (NDEs) and natural indirect effects (NIEs). However, the assumptions regarding unmeasured mediator-outcome confounding and intermediate mediator-outcome confounding that are required for the determination of NDEs and NIEs present practical challenges. To address this problem, we introduce an instrumental blocker, a novel quasi-instrumental variable, to relax both of these assumptions, and we define a swapped direct effect (SDE) and a swapped indirect effect (SIE) to assess the mediation. We show that the SDE and SIE are identical to the NDE and NIE, respectively, based on a causal interpretation. Moreover, the empirical expressions of the SDE and SIE are derived with and without an intermediate mediator-outcome confounder. Then, a multiply robust estimation method is derived to mitigate the model misspecification problem. We prove that the proposed estimator is consistent, asymptotically normal, and achieves the semiparametric efficiency bound. As an illustration, we apply the proposed method to genomic datasets of lung cancer to investigate the potential role of the epidermal growth factor receptor in the treatment of lung cancer.

Genome-wide causal mediation analysis identifies genetic loci associated with uterine fibroids mediated by age at menarche.

STUDY QUESTION: Could the direct contribution of genetic variants to the pathophysiology of uterine fibroids and the contribution mediated by age at menarche be different? SUMMARY ANSWER: Age at menarche plays a mediation role in the genetic influence on uterine fibroids, and four causal genetic mechanisms underlying the age at menarche-mediated effects of common genetic loci on uterine fibroid development were identified. WHAT IS KNOWN ALREADY: Uterine fibroids are common benign tumors developing from uterine smooth muscle. Genome-wide association studies (GWASs) have identified over 30 genetic loci associated with uterine fibroids in different ethnic populations. Several genetic variations in or nearby these identified loci were also associated with early age at menarche, one of the major risk factors of uterine fibroids. Although the results of GWASs reveal how genetic variations affect uterine fibroids, the genetic mechanism of uterine fibroids mediated by age at menarche remains elusive. STUDY DESIGN, SIZE, DURATION: In this study, we conducted a genome-wide causal mediation analysis in two cohorts covering a total of 69 552 females of Han Chinese descent from the Taiwan Biobank (TWB). TWB is an ongoing community- and hospital-based cohort aiming to enroll 200 000 individuals from the general Taiwanese population between 30 and 70 years old. It has been enrolling Taiwanese study participants since 2012 and has extensive phenotypic data collected from 148 291 individuals as of May 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS: We recruited individuals in two cohorts, with 13 899 females in TWB1 and 55 653 females in TWB2. The two sets of individuals are almost distinct, with only 730 individuals enrolled in both cohorts. Over 99% of the participants are Han Chinese. Approximately 21% of participants developed uterine fibroids. DNA samples from both cohorts were genotyped using two different customized chips (TWB1 and TWB2 arrays). After quality control and genotype imputation, 646 973 TWB1 single-nucleotide polymorphisms (SNPs) and 686 439 TWB2 SNPs were assessed in our analysis. There were 99 939 SNPs which overlapped between the TWB1 and TWB2 arrays, 547 034 TWB1 array-specific SNPs and 586 500 TWB2 array-specific SNPs. We performed GWASs for screening potential risk SNPs for age at menarche and for uterine fibroids. We subsequently identified causal mediation effects of risk SNPs on uterine fibroids mediated by age at menarche. MAIN RESULTS AND THE ROLE OF CHANCE: In addition to known loci at LIN28B associated with age at menarche and loci at WNT4 associated with uterine fibroids, we identified 162 SNPs in 77 transcripts that were associated with menarche-mediated causal effects on uterine fibroids via four different causal genetic mechanisms: a both-harmful group with 52 SNPs, a both-protective group with 34 SNPs, a mediator-harmful group with 22 SNPs and a mediator-protective group with 54 SNPs. Among these SNPs, rs809302 in SLK significantly increased the risk of developing uterine fibroids by 3.92% through a mechanism other than age at menarche (P < 10-10), and rs371721345 in HLA-DOB was associated with a 2.70% decreased risk (P < 10-10) in the occurrence of uterine fibroids, mediated by age at menarche. These findings provide insights into the mechanism underlying the effect of genetic loci on uterine fibroids mediated by age at menarche. LIMITATIONS, REASONS FOR CAUTION: A potential issue is that the present study relied upon self-reported age at menarche and uterine fibroid information. Due to the experimental design, the consistency between self-reports and medical records for uterine fibroids in Taiwan cannot be checked. Fortunately, the literature support that self-reporting even years later remains a practical means for collecting data on menarche and uterine fibroids. We found that the impact of under-reporting of uterine fibroids is less in our study. In addition, the rate of reporting a diagnosis of uterine fibroids was within the rates of medical diagnosis based on national health insurance data. Future work investigating the consistency between self-reports and medical records in Taiwan can remedy this issue. WIDER IMPLICATIONS OF THE FINDINGS: This study is the first to investigate whether and to what extent age at menarche mediates the causal effects of genetic variants on uterine fibroids by using genome-wide causal mediation analysis. By treating age at menarche as a mediator, this report provides an insight into the genetic risk factors for developing uterine fibroids. Thus, this article represents a step forward in deciphering the role of intermediated risk factors in the genetic mechanism of disease. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the China Medical University, Taiwan (CMU110-ASIA-13 and CMU107-Z-04), the Ministry of Science and Technology, Taiwan (MOST 110-2314-B-039-058) and the International Joint Usage/Research Center, the Institute of Medical Science, the University of Tokyo, Japan (K2104). The authors have no competing interests. TRIAL REGISTRATION NUMBER: N/A.

Path-specific effects in the presence of a survival outcome and causally ordered multiple mediators with application to genomic data.

Causal multimediation analysis (i.e. the causal mediation analysis with multiple mediators) is critical for understanding the effectiveness of interventions, especially in medical research. Deriving the path-specific effects of exposure on the outcome through a set of mediators can provide detail about the causal mechanism of interest However, existing models are usually restricted to partial decomposition, which can only be used to evaluate the cumulative effect of several paths. In genetics studies, partial decomposition fails to reflect the real causal effects mediated by genes, especially in complex gene regulatory networks. Moreover, because of the lack of a generalized identification procedure, the current multimediation analysis cannot be applied to the estimation of path-specific effects for any number of mediators. In this study, we derive the interventional analogs of path-specific effect for complete decomposition to address the difficulty of nonidentifiability. On the basis of two survival models of the outcome, we derive the generalized analytic forms for interventional analogs of path-specific effects by assuming the normal distributions of mediators. We apply the new methodology to investigate the causal mechanism of signature genes in lung cancer based on the cell cycle pathway, and the results clarify the gene pathway in cancer.

A Pilot Study Exploring the Association of Entacapone, Gut Microbiota, and the Subsequent Side Effects in Patients With Parkinson's Disease.

Background and Aims: Entacapone, one of the most common drugs distributed among patients with Parkinson's disease, is a peripherally acting catechol-O-methyltransferase (COMT) inhibitor that is used in addition to levodopa to control symptoms. However, there have been negative effects reported against entacapone, namely, gastrointestinal (GI) problems and drowsiness. In this pilot study, we aim to examine the hypothesis that the discomfort induced by entacapone might be originated from the shift of microbial composition by adjusting the effect of levodopa. Methods: The population in this pilot study consisted of 13 PD patients treated with levodopa only and 11 with both levodopa and entacapone. The 16S rRNA gene sequence data were processed, aligned, and categorized using the DADA2. Alpha diversity indices for Observed, Chao1, Shannon, and Simpson metrics were calculated with Phyloseq 1.32.0. Dissimilarities were calculated using unweighted unique fraction metrics (Unifrac), weighted Unifrac, and Canberra distance. Functional differences were calculated by PICRUSt2 based on the KEGG database. Results: Results of 16S rRNA sequencing analysis showed that while entacapone did not influence the species richness, the composition of the microbial community shifted considerably. Relative abundances of bacteria related to constipation and other GI disorders also altered significantly. Functional enrichment analysis revealed changes in the metabolic activity of alanine, aspartate, and glutamate. These amino acids are related to common side effects of entacapone such as auditory hallucinations, fatigue, and nightmare. Conclusion: Our findings provide testable hypothesis on the cause of unpleasant side effects of entacapone, which in the long run could possibly be reduced through gut microbiota manipulation.

Robust inference on effects attributable to mediators: A controlled-direct-effect-based approach for causal effect decomposition with multiple mediators.

Effect decomposition is a critical technique for mechanism investigation in settings with multiple causally ordered mediators. Causal mediation analysis is a standard method for effect decomposition, but the assumptions required for the identification process are extremely strong. Moreover, mediation analysis focuses on addressing mediating mechanisms rather than interacting mechanisms. Mediation and interaction for mediators both contribute to the occurrence of disease, and therefore unifying mediation and interaction in effect decomposition is important to causal mechanism investigation. By extending the framework of controlled direct effects, this study proposes the effect attributable to mediators (EAM) as a novel measure for effect decomposition. For policymaking, EAM represents how much an effect can be eliminated by setting mediators to certain values. From the perspective of mechanism investigation, EAM contains information about how much a particular mediator or set of mediators is involved in the causal mechanism through mediation, interaction, or both. EAM is more appropriate than the conventional path-specific effect for application in clinical or medical studies. The assumptions of EAM for identification are considerably weaker than those of causal mediation analysis. We develop a semiparametric estimator of EAM with robustness to model misspecification. The asymptotic property is fully realized. We applied EAM to assess the magnitude of the effect of hepatitis C virus infection on mortality, which was eliminated by controlling alanine aminotransferase and treating hepatocellular carcinoma.

Correlation between drug sensitivity profiles of circulating tumour cell-derived organoids and clinical treatment response in patients with pancreatic ductal adenocarcinoma.

INTRODUCTION: Pancreatic ductal adenocarcinoma (PDAC) is highly aggressive and has poor prognosis. There are few biomarkers to inform treatment decisions, and collecting tumour samples for testing is challenging. METHODS: Circulating tumour cells (CTCs) from patients with PDAC liquid biopsies were expanded ex vivo to form CTC-derived organoid cultures, using a laboratory-developed biomimetic cell culture system. CTC-derived organoids were tested for sensitivity to a PDAC panel of nine drugs, with tests conducted in triplicate, and a weighted cytotoxicity score (CTS) was calculated from the results. Clinical response to treatment in patients was evaluated using Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 criteria at the time of blood sampling and 3 months later. The correlation between CTS and clinical response was then assessed. RESULTS: A total of 41 liquid biopsies (87.8% from patients with Stage 4 disease) were collected from 31 patients. The CTC-derived organoid expansion was achieved in 3 weeks, with 87.8% culture efficiency. CTC-derived organoid cultures were positive for EpCAM staining and negative for CD45 staining in the surface marker analysis. All patients had received a median of two lines of treatment prior to enrolment and prospective utility analysis indicated significant correlation of CTS with clinical treatment response. Two representative case studies are also presented to illustrate the relevant clinical contexts. CONCLUSIONS: CTCs were expanded from patients with PDAC liquid biopsies with a high success rate. Drug sensitivity profiles from CTC-derived organoid cultures correlated meaningfully with treatment response. Further studies are warranted to validate the predictive potential for this approach.

Risk factors of first and recurrent genitourinary tract infection in patients with type 2 diabetes treated with SGLT2 inhibitors: A retrospective cohort study.

AIMS: This retrospective study investigated the risk factors of sodium-glucose cotransporter 2 inhibitors (SGLT2i) -related genitourinary tract infection (GUTI). METHODS: We used longitudinal claims data from May 2016 to December 2017 from the Chang Gung Research Database. Diabetic patients who used SGLT2i were included. The baseline characteristics risk factors between patients who had GUTI and no GUTI were analyzed. RESULTS: There were 428(3.43%) patients with the first occurrence of urinary tract infection (UTI) and 5(0.04%) patients with genital tract infection (GTI). Female patients aged ≥ 65 years with HbA1c ≥ 9%, eGFR < 60 ml/min/1.73 m2, urine albumin/creatinine ratio (UACR) level ≥30 mg/g, dyslipidemia, diabetic microvascular complications and mood disorder had a higher risk of having the first occurrence of UTI. There was no significant risk factor of GTI. 117 UTI and 3 GTI patients received SGLT2i rechallenging. The recurrent UTI rate was 28.2% and no recurrent GTI was diagnosed. The risk factors included CHD, eGRF < 45 ml/min/1.73 m2, and mood disorder (OR, 95% CI: 4.39, 1.15-16.74; 4.11, 1.51-11.19; 5.93, 1.39-25.34, respectively). CONCLUSIONS: In diabetic patients who had underlying disease of eGRF < 45 ml/min/1.73 m2, CHD, and mood disorder had higher risk of recurrent UTI after rechallenging SGLT2i.

Secondary primary malignancy in patients with head and neck squamous cell carcinoma: 27-year experience from the perspective of diagnostic tools.

BACKGROUND: The survival rate of head and neck squamous cell carcinoma (HNSCC) patients with secondary primary malignancy (SPM) showed no significant improvement for decades, however, the impact of advances in diagnostic tools is rarely mentioned. This study investigated the clinical characteristic of HNSCC with SPM over a 27-year period especially from the perspective of diagnostic tools. METHODS: This study evaluated 157 HNSCC patients with SPM. The patients were divided into two groups according to the time of SPM diagnosis (Group A:1992-2003; Group B: 2004-2014). Age, gender, stage of first primary malignancy (FPM), SPM interval, overall survival, and disease-free survival were compared between groups. RESULTS: Group B had significantly more SPM developed rate (p = 0.002), more SPM patients with advanced stage of FPM (p = 0.001), synchronous SPM (p = 0.006), and shorter SPM interval (p<0.001) compared to Group A. The survival rate in Group B was not significantly better than Group A. CONCLUSION: Among patients diagnosed with HNSCC recently, more SPMs are diagnosed in a shorter time interval and in a more advanced stage. The overall advances in diagnostic tools cannot significantly improve SPM survival, however, it enables more patients to receive corresponding treatment.

Correlation Between Objective and Subjective High-Pitched Voice Impairment in Patients After Thyroid Surgery.

Objectives: High-pitched voice impairment (HPVI) is not uncommon in patients without recurrent laryngeal nerve (RLN) or external branch of superior laryngeal nerve (EBSLN) injury after thyroidectomy. This study evaluated the correlation between subjective and objective HPVI in patients after thyroid surgery. Methods: This study analyzed 775 patients without preoperative subjective HPVI and underwent neuromonitored thyroidectomy with normal RLN/EBSLN function. Multi-dimensional voice program, voice range profile and Index of voice and swallowing handicap of thyroidectomy (IVST) were performed during the preoperative(I) period and the immediate(II), short-term(III) and long-term(IV) postoperative periods. The severity of objective HPVI was categorized into four groups according to the decrease in maximum frequency (Fmax): <20%, 20-40%, 40-60%, and >60%. Subjective HPVI was evaluated according to the patient's answers on the IVST. Results: As the severity of objective HPVI increased, patients were significantly more to receive bilateral surgery (p=0.002) and have subjective HPVI (p<0.001), and there was no correlation with IVST scores. Among 211(27.2%) patients with subjective HPVI, patients were significantly more to receive bilateral surgery (p=0.003) and central neck dissection(p<0.001). These patients had very similar trends for Fmax, pitch range, and mean fundamental frequency as patients with 20-40% Fmax decrease (p>0.05) and had higher Jitter, Shimmer, and IVST scores than patients in any of the objective HPVI groups; subjective HPVI lasted until period-IV. Conclusion: The factors that affect a patient's subjective HPVI are complex, and voice stability (Jitter and Shimmer) is no less important than the Fmax level. When patients have subjective HPVI without a significant Fmax decrease after thyroid surgery, abnormal voice stability should be considered and managed. Fmax and IVST scores should be interpreted comprehensively, and surgeons and speech-language pathologists should work together to identify patients with HPVI early and arrange speech therapy for them. Regarding the process of fibrosis formation, anti-adhesive material application and postoperative intervention for HPVI require more future research.

Prognostic Indicators of Non-Transection Nerve Injury and Vocal Fold Motion Impairment After Thyroid Surgery - Correlation Between Intraoperative Neuromonitoring Findings and Perioperative Voice Parameters.

Objectives: In patients with recurrent laryngeal nerve (RLN) injury after thyroid surgery, unrecovered vocal fold motion (VFM) and subjective voice impairment cause extreme distress. For surgeons, treating these poor outcomes is extremely challenging. To enable early treatment of VFM impairment, this study evaluated prognostic indicators of non-transection RLN injury and VFM impairment after thyroid surgery and evaluated correlations between intraoperative neuromonitoring (IONM) findings and perioperative voice parameters. Methods: 82 adult patients had postoperative VFM impairment after thyroidectomy were enrolled. Demographic characteristics, RLN electromyography (EMG), and RLN injury mechanism were compared. Multi-dimensional voice program, voice range profile and Index of voice and swallowing handicap of thyroidectomy (IVST) were administered during I-preoperative; II-immediate, III-short-term and IV-long-term postoperative periods. The patients were divided into R/U Group according to the VFM was recovered/unrecovered 3 months after surgery. The patients in U Group were divided into U1/U2 Group according to total IVST score change was <4 and ≥4 during period-IV. Results: Compared to R Group (42 patients), U Group (38 patients) had significantly more patients with EMG >90% decrease in the injured RLN (p<0.001) and thermal injury as the RLN injury mechanism (p=0.002). Voice parameter impairments were more severe in U Group compared to R Group. Compared to U1 group (19 patients), U2 Group (19 patients) had a significantly larger proportion of patients with EMG decrease >90% in the injured RLN (p=0.022) and thermal injury as the RLN injury mechanism (p=0.017). A large pitch range decrease in period-II was a prognostic indicator of a moderate/severe long-term postoperative subjective voice impairment. Conclusion: This study is the first to evaluate correlations between IONM findings and voice outcomes in patients with VFM impairment after thyroid surgery. Thyroid surgeons should make every effort to avoid severe type RLN injury (e.g., thermal injury or injury causing EMG decrease >90%), which raises the risk of unrecovered VFM and moderate/severe long-term postoperative subjective voice impairment. Using objective voice parameters (e.g., pitch range) as prognostic indicators not only enables surgeons to earlier identify patients with low voice satisfaction after surgery, and also enable implementation of interventions sufficiently early to maintain quality of life.

How the Severity and Mechanism of Recurrent Laryngeal Nerve Dysfunction during Monitored Thyroidectomy Impact on Postoperative Voice.

Intraoperative neuromonitoring can qualify and quantify RLN function during thyroid surgery. This study investigated how the severity and mechanism of RLN dysfunction during monitored thyroid surgery affected postoperative voice. This retrospective study analyzed 1021 patients that received standardized monitored thyroidectomy. Patients had post-dissection RLN(R2) signal <50%, 50-90% and >90% decrease from pre-dissection RLN(R1) signal were classified into Group A-no/mild, B-moderate, and C-severe RLN dysfunction, respectively. Demographic characteristics, RLN injury mechanisms(mechanical/thermal) and voice analysis parameters were recorded. More patients in the group with higher severity of RLN dysfunction had malignant pathology results (A/B/C = 35%/48%/55%, p = 0.017), received neck dissection (A/B/C = 17%/31%/55%, p < 0.001), had thermal injury (p = 0.006), and had asymmetric vocal fold motion in long-term postoperative periods (A/B/C = 0%/8%/62%, p < 0.001). In postoperative periods, Group C patients had significantly worse voice outcomes in several voice parameters in comparison to Group A/B. Thermal injury was associated with larger voice impairments compared to mechanical injury. This report is the first to discuss the severity and mechanism of RLN dysfunction and postoperative voice in patients who received monitored thyroidectomy. To optimize voice and swallowing outcomes after thyroidectomy, avoiding thermal injury is mandatory, and mechanical injury must be identified early to avoid a more severe dysfunction.