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Aims: To determine the efficacy of XPro1595 to improve pathophysiological and functional outcomes in a mouse model of traumatic brain injury (TBI). Background: Symptoms associated with TBI can be debilitating, and treatment without off-target side effects remains a challenge. This study aimed to investigate the efficacy of selectively inhibiting the soluble form of TNF (solTNF) using the biologic XPro1595 in a mouse model of TBI. Objectives: Use XPro1595 to determine whether injury-induced solTNF promotes hippocampal inflammation and dendritic plasticity and associated functional impairments. Methods: Mild-to-moderate traumatic brain injury (CCI model) was induced in adult male C57Bl/6J WT and Thy1-YFPH mice, with XPro1595 (10 mg/kg, S.C.) or vehicle being administered in a clinically relevant window (60 minutes post-injury). The animals were assessed for differences in neurological function, and hippocampal tissue was analyzed for inflammation and glial reactivity, as well as neuronal degeneration and plasticity. Results: We report that unilateral CCI over the right parietal cortex in mice promoted deficits in learning and memory, depressive-like behavior, and neuropathic pain. Using immunohistochemical and Western blotting techniques, we observed the cortical injury promoted a set of expected pathophysiology’s within the hippocampus consistent with the observed neurological outcomes, including glial reactivity, enhanced neuronal dendritic degeneration (dendritic beading), and reduced synaptic plasticity (spine density and PSD-95 expression) within the DG and CA1 region of the hippocampus, that were prevented in mice treated with XPro1595. Conclusion: Overall, we observed that selectively inhibiting solTNF using XPro1595 improved the pathophysiological and neurological sequelae of brain-injured mice, which provides support for its use in patients with TBI.

Item does not contain fulltext BACKGROUND: Etrolizumab is a gut-targeted anti-β7 integrin monoclonal antibody. In a previous phase 2 induction study, etrolizumab significantly improved clinical remission versus placebo in patients with moderately to severely active ulcerative colitis. We aimed to compare the safety and efficacy of etrolizumab with infliximab in patients with moderately to severely active ulcerative colitis. METHODS: We conducted a randomised, double-blind, double-dummy, parallel-group, phase 3 study (GARDENIA) across 114 treatment centres worldwide. We included adults (age 18-80 years) with moderately to severely active ulcerative colitis (Mayo Clinic total score [MCS] of 6-12 with an endoscopic subscore of ≥2, a rectal bleeding subscore of ≥1, and a stool frequency subscore of ≥1) who were naive to tumour necrosis factor inhibitors. Patients were required to have had an established diagnosis of ulcerative colitis for at least 3 months, corroborated by both clinical and endoscopic evidence, and evidence of disease extending at least 20 cm from the anal verge. Participants were randomly assigned (1:1) to receive subcutaneous etrolizumab 105 mg once every 4 weeks or intravenous infliximab 5 mg/kg at 0, 2, and 6 weeks and every 8 weeks thereafter for 52 weeks. Randomisation was stratified by baseline concomitant treatment with corticosteroids, concomitant treatment with immunosuppressants, and baseline disease activity. All participants and study site personnel were masked to treatment assignment. The primary endpoint was the proportion of patients who had both clinical response at week 10 (MCS ≥3-point decrease and ≥30% reduction from baseline, plus ≥1-point decrease in rectal bleeding subscore or absolute rectal bleeding score of 0 or 1) and clinical remission at week 54 (MCS ≤2, with individual subscores ≤1); efficacy was analysed using a modified intention-to-treat population (all randomised patients who received at least one dose of study drug). GARDENIA was designed to show superiority of etrolizumab over infliximab for the primary endpoint. This trial is registered with ClinicalTrials.gov, NCT02136069, and is now closed to recruitment. FINDINGS: Between Dec 24, 2014, and June 23, 2020, 730 patients were screened for eligibility and 397 were enrolled and randomly assigned to etrolizumab (n=199) or infliximab (n=198). 95 (48%) patients in the etrolizumab group and 103 (52%) in the infliximab group completed the study through week 54. At week 54, 37 (18·6%) of 199 patients in the etrolizumab group and 39 (19·7%) of 198 in the infliximab group met the primary endpoint (adjusted treatment difference -0·9% [95% CI -8·7 to 6·8]; p=0·81). The number of patients reporting one or more adverse events was similar between treatment groups (154 [77%] of 199 in the etrolizumab group and 151 [76%] of 198 in the infliximab group); the most common adverse event in both groups was ulcerative colitis (55 [28%] patients in the etrolizumab group and 43 [22%] in the infliximab group). More patients in the etrolizumab group reported serious adverse events (including serious infections) than did those in the infliximab group (32 [16%] vs 20 [10%]); the most common serious adverse event was ulcerative colitis (12 [6%] and 11 [6%]). There was one death during follow-up, in the infliximab group due to a pulmonary embolism, which was not considered to be related to study treatment. INTERPRETATION: To our knowledge, this trial is the first phase 3 maintenance study in moderately to severely active ulcerative colitis to use infliximab as an active comparator. Although the study did not show statistical superiority for the primary endpoint, etrolizumab performed similarly to infliximab from a clinical viewpoint. FUNDING: F Hoffmann-La Roche.

PURPOSE Cisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting. PATIENTS AND METHODS This noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2 on day 1 and gemcitabine 1,250 mg/m2 on days 1 and 8 (n = 863) or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 on day 1 (n = 862) every 3 weeks for up to six cycles. RESULTS Overall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia ( P ≤ .001); febrile neutropenia ( P = .002); and alopecia ( P < .001) were significantly lower, whereas grade 3 or 4 nausea ( P = .004) was more common. CONCLUSION In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Recognizing sport-related concussion (SRC) is challenging and relies heavily on subjective symptom reports. An objective, biological marker could improve recognition and understanding of SRC. There is emerging evidence that salivary micro-ribonucleic acids (miRNAs) may serve as biomarkers of concussion; however, it remains unclear whether concussion-related miRNAs are impacted by exercise. We sought to determine whether 40 miRNAs previously implicated in concussion pathophysiology were affected by participation in a variety of contact and non-contact sports. Our goal was to refine a miRNA-based tool capable of identifying athletes with SRC without the confounding effects of exercise.This case-control study harmonized data from concussed and non-concussed athletes recruited across 10 sites. Levels of salivary miRNAs within 455 samples from 314 individuals were measured with RNA sequencing. Within-subjects testing was used to identify and exclude miRNAs that changed with either: (a) a single episode of exercise (166 samples from 83 individuals) or (b) season-long participation in contact sports (212 samples from 106 individuals). The miRNAs that were not impacted by exercise were interrogated for SRC diagnostic utility using logistic regression (172 samples from 75 concussed and 97 non-concussed individuals).Two miRNAs (miR-532-5p, miR-182-5p) decreased (adjusted p0.05) after a single episode of exercise, and 1 miRNA (miR-4510) increased only after contact sports participation. Twenty-three miRNAs changed at the end of a contact sports season. Two of these miRNAs (miR-26b-3p, miR-29c-3p) were associated (R0.50; adjusted p0.05) with the number of head impacts sustained in a single football practice. Among the 15 miRNAs not confounded by exercise or season-long contact sports participation, 11 demonstrated a significant difference (adjusted p0.05) between concussed and non-concussed participants, and 6 displayed moderate ability (AUC0.70) to identify concussion. A single ratio (miR-27a-5p/miR-30a-3p) displayed the highest accuracy (AUC = 0.810, sensitivity = 82.4%, specificity = 73.3%) for differentiating concussed and non-concussed participants. Accuracy did not differ between participants with SRC and non-SRC (z = 0.5, p = 0.60).Salivary miRNA levels may accurately identify SRC when not confounded by exercise. Refinement of this approach in a large cohort of athletes could eventually lead to a non-invasive, sideline adjunct for SRC assessment.

Background Children and adolescents with fragile X syndrome (FXS) manifest significant symptoms of anxiety, particularly in response to face-to-face social interaction. In this study we used functional near-infrared spectroscopy (fNIRS) to reveal a specific pattern of brain activation and habituation in response to face stimuli in young girls with FXS, an important but understudied clinical population. Methods Participants were 32 girls with FXS (age: 11.8 ± 2.9 years) and a control group of 28 girls without FXS (age: 10.5 ± 2.3 years) matched for age, general cognitive function and autism symptoms. Functional NIRS was used to assess brain activation during a face habituation task including repeated upright/inverted faces and greeble (nonface) objects. Results Compared to the control group, girls with FXS showed significant hyper-activation in the frontopolar and dorsal lateral prefrontal cortices in response to all face stimuli (upright + inverted). Lack of neural habituation (and significant sensitization) was also observed in the FXS group in the frontopolar cortex in response to upright face stimuli. Finally, aberrant frontopolar sensitization in response to upright faces in girls with FXS was significantly correlated with notable cognitive-behavioral and social-emotional outcomes relevant to this condition including executive function, autism symptoms, depression and anxiety. Conclusions These findings strongly support a hypothesis of neural hyper-activation and accentuated sensitization during face processing in FXS, a phenomenon that could be developed as a biomarker endpoint for improving treatment trial evaluation in girls with this condition.

Introduction: Therapy and immune mediated processes are associated with clonal evolution in multiple myeloma (MM). In this study, we performed whole-exome sequencing (WES) and single cell RNA sequencing (scRNA-seq) on plasma cells (PC) from bone marrow aspirates of the iliac crest (BM) and corresponding osteolytic lesions (OL) to investigate spatial heterogeneity in patients with newly diagnosed (NDMM) and relapsed/refractory MM (RRMM). Next generation flow (NGF) and T-cell receptor sequencing (TCRseq) were performed to investigate the immunogenomic landscape surrounding malignant PC. Methods: In a prospective trial, 18 patients (NDMM: n=10; RRMM: n=8) consented to an imaging-guided biopsy of an OL in addition to the regular BM sampling. At inclusion, 37 different locations were biopsied. Follow-up samples were obtained from 5 patients in remission after therapy. After CD138+ selection, PC were subjected to WES and scRNA-seq (Chromium, 10x genomics). TCRseq was performed using multiplex PCR (ImmunoSEQ, Adaptive biotechnologies) on the CD138- fraction. For scRNA-seq data analyses, Cell Ranger (v3.1.0) and the Seurat R toolkit (v3.1) were used. TCRseq data were analyzed with immunoSEQ ANALYZER (v3.0) and the immunarch R toolkit (v0.6.6.). NGF was performed to study subsets of T-, B-, NK- and dendritic cells (DC). Results: Median PC infiltration was higher in OL compared to random BM (50.0% vs 12.5%, p=0.041). WES revealed more mutations in RRMM compared to NDMM (median; range: 189;120-523 vs 71;23-136, p Conclusion: We report the first prospective clinical trial to investigate spatiotemporal immunogenomic heterogeneity in multiple myeloma as assessed by WES and scRNA-seq of PC and NGF and TCRseq of the non-PC compartment. We demonstrate spatial evolution and reduced TCR diversity especially in patients with RRMM and/or EMD. ScRNA-seq adds another layer of complexity compared to WES and helps identifying how PC create an immune suppressive BM niche. Disclosures Merz: Amgen, BMS, Celgene, Takeda: Honoraria. Block:GlaxoSmithKline LLC: Current Employment. McCarthy:Karyopharm: Consultancy, Honoraria; Magenta: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Juno Therapeutics, a Bristol-Myers Squibb Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board , Research Funding is to Roswell Park, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Starton: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Advisory Board; Genentech: Consultancy, Honoraria. Hillengass:Adaptive, Amgen, BMS, Celgene, GSK, Janssen, Oncotracker, Takeda: Honoraria.

Purpose To describe an unusual case of unilateral, endogenous endophthalmitis in an otherwise healthy, term neonate. Methods A 3-week-old otherwise healthy, term male infant was referred to St. Louis Children's Hospital for a second opinion of presumed panuveitis of the right eye. Patients Single male infant. Results Diffusion weighted magnetic resonance imaging (MRI) demonstrating purulent intraocular contents facilitated the diagnosis of endophthalmitis. Examination of surgical vitreous samples by staining and cytology demonstrated Gram-positive bacterial cocci in short chains, thereby confirming endophthalmitis. Polymerase chain reaction testing of vitreous fluid identified Streptococcus agalactiae, despite an unremarkable systemic workup and a negative pre-partum maternal Group B streptococcal screen. Conclusions Endogenous endophthalmitis is a rare but devastating cause of vision loss in otherwise healthy, term neonates. Prompt diagnosis may be facilitated by MRI imaging and diagnostic vitreous biopsy.

Background Several studies have shown that there are no significant differences in anastomotic leakage associated with Transanal total mesorectal excision (taTME) versus laparoscopic TME (lapTME) for rectal cancer; however, little is known about late anastomotic leakage, such as that primarily found in the chronic presacral sinus. We aimed to compare the occurrence of anastomotic leakage and chronic presacral sinus in rectal cancer for taTME and lapTME. Methods In this retrospective cohort study, data were collected for patients with rectal cancer who underwent surgery between January 2009 and September 2019. Of the 220 patients included in this study, 182 were in the lapTME group and 38 in the taTME group. We compared factors associated with anastomotic leakage and chronic presacral sinus formation between the two groups. A binary-logistic model was used to determine the risk factors for chronic presacral sinus. Results Anastomotic leakage occurred in six patients (15.8%) in the taTME group and 36 patients (19.7%) in the lapTME group. Chronic presacral sinus occurred in three patients (7.9%) in the taTME group and 15 patients (8.2%) in the lapTME group. There was no significant difference in anastomotic leakage or chronic presacral sinus between groups (P = 0.569 and P = 1.000, respectively). Pathologic stage III or higher was significantly associated with chronic presacral sinus formation (P = 0.006). Conclusion There were no significant differences between taTME and lapTME regarding the incidence of anastomotic leakage or chronic presacral sinus. Almost one-third of anastomotic leakages developed into chronic presacral sinus.

Background/Aims: We aimed to estimate the prevalence of comorbidities and medication use in Korean women with rheumatic diseases (RDs) during their childbearing years.Methods: We included women aged 20 to 44 years with seropositive rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and ankylosing spondylitis (AS) (n = 41,547) and age-matched women without seropositive RA, SLE, and AS (n = 208,941) from the National Health Insurance Service-National Health Information Database (2009 to 2016). The prevalence of hypertension (HTN), hyperlipidemia (HLD), diabetes mellitus (DM), and cancer and the use of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CSs), and disease-modifying anti-rheumatic drugs (DMARDs) were estimated.Results: Women of childbearing age with RDs were more likely to have at least one of the measured comorbidities than the controls (odds ratio [OR], 3.0; 95% confidence interval [CI], 2.9 to 3.1). The OR (95% CI) was 2.9 (2.8 to 3.0) for HTN, 2.8 (2.7 to 2.9) for HLD, 1.4 (1.4 to 1.5) for DM, and 1.3 (1.3 to 1.4) for cancer. The SLE group had the highest prevalence and odds of all four measured comorbidities. Almost all (97.9%) women of childbearing age with RDs were taking RD-related medications (NSAIDs, 81.6%; CSs, 77.8%; DMARDs, 87.3%). The RD group was 13.8 times more likely to take NSAIDs and 68.2 times more likely to take CSs than the controls. Use of NSAIDs was more prevalent in RA and AS than SLE, whereas use of CSs and DMARDs was more prevalent in RA and SLE than AS.Conclusions: Korean women with RDs have a greater burden of comorbidities and medication use during their childbearing years than women without RDs of the same age.

Although posterior reversible encephalopathy syndrome (PRES) is induced by various causes, a few cases have occurred after severe anemia correction. In this case report, a 45-year-old female patient visited emergency department with a chief complaint of dizziness due to severe anemia related to hypermenorrhea caused by uterine myoma. Before her operation, she had an abrupt headache and seizure during anemia correction with transfusion and injection of gonadotropin-releasing hormone agonist. Immediately after the operation, she experienced visual disturbances, followed by limb weakness and tonic-clonic movements. Magnetic resonance imaging showed alterations in parietal and occipital lobes suggesting cerebrovascular edema with hypoperfusion. Here, we presented and discussed the clinical and radiologic features of PRES related to anemia correction.

Background: Desmoid tumor, also known as aggressive fibromatosis, is well-characterized by abnormal Wnt/β-catenin signaling. Various therapeutic options, including imatinib, are available to efficiently treat desmoid tumor. However, molecular mechanism of why imatinib works remains poorly understood. Here, we describe the potential roles of NOTCH2 and HES1 in association with clinical response to imatinib as in genome and transcriptome levels. Methods: We identified all somatic mutations in coding and non-coding regions via whole genome sequencing using desmoid tumor samples. To validate the genetic interaction with expression level in desmoid-tumor condition, we utilized large-scale Whole-genome sequencing (WGS) and transcriptome datasets from the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. RNA-sequencing was performed using prospective and retrospective cohort samples to evaluate the expressional relevance with clinical response. Results: Among 20 patients, 4 (20%) had a partial response and 14 (66.7%) had stable disease, 11 of which continued for ≥1 year. With gene-wise functional analyses, we detected significant correlation between recurrent NOTCH2 noncoding mutations and clinical response to imatinib. Based on PCAWG data analyses, NOTCH2 mutations affect its expression levels particularly in the presence of CTNNB1 missense mutations. By analyzing RNA-sequencing with additional desmoid tumor samples, we found that NOTCH2 expression was significantly correlated with HES1 expression. Interestingly, NOTCH2 had no statistical power to discriminate responders and non-responders. Instead, HES1 was differentially expressed with statistical significance between responders and non-responders Conclusions: Imatinib was effective and well tolerated for advanced desmoid tumor treatment. Our results show that HES1, regulated by NOTCH2, as an indicator of sensitivity to imatinib, which provides an important therapeutic consideration for desmoid tumor. Trial Registration: ClinicalTrials.gov, NCT02495519, Registered July 13, 2015- Retrospectively registered, https://www.clinicaltrials.gov/ct2/show/NCT02495519

Purpose The aim of the study was to evaluate the clinical implication of multigene panel testing of beyond BRCA genes in Korean patients with BRCA1/2 mutation-negative breast cancer.Materials and Methods Between 2016 and 2019, a total of 700 BRCA1/2 mutation-negative breast cancer patients received comprehensive multigene panel testing and genetic counseling. Among them, 347 patients completed a questionnaire about cancer worry, genetic knowledge, and preference for the method of genetic tests during pre- and post-genetic test counseling. The frequency of pathogenic and likely pathogenic variants (PV/LPV) were analyzed.Results At least one PV/LPV of 26 genes was found in 76 out of 700 patients (10.9 %). The rate for PV/LPV was 3.4% for high-risk genes (17 PALB2, 6 TP53, and 1 PTEN). PV/LPVs of clinical actionable genes for breast cancer management, high-risk genes and other moderate-risk genes such as ATM, BARD1, BRIP, CHEK2, NF1, and RAD51D, were observed in 7.4%. Patients who completed the questionnaire showed decreased concerns about the risk of additional cancer development (average score, 4.21 to 3.94; p < 0.001), influence on mood (3.27 to 3.13; p < 0.001), influence on daily functioning (3.03 to 2.94; p=0.006); and increased knowledge about hereditary cancer syndrome (66.9 to 68.8; p=0.025) in post-test genetic counseling. High cancer worry scales (CWSs) were associated with age ≤ 40 years and the identification of PV/LPV. Low CWSs were related to the satisfaction of the counselee.Conclusion Comprehensive multigene panel test with genetic counseling is clinically applicable. It should be based on interpretable genetic information, consideration of potential psychological consequences, and proper preventive strategies.

Background Robot-assisted laparoscopic prostatectomy (RALP) is a favored surgical approach for treating prostate cancer. However, RALP does not decrease postoperative pain significantly despite its minimal invasiveness. The pain associated with robot-assisted surgery is most severe during the immediate postoperative period. We aimed to demonstrate that preoperative rectus sheath block (RSB) can reduce acute pain after RALP. Methods A prospective non-randomized study with two parallel groups was performed from June 2020 to August 2020. A total of 100 patients undergoing RALP were divided into two groups: the RSB group (n = 50) and the non-RSB group (n = 50). Ultrasound-guided RSB was performed preoperatively only in the RSB group. The primary outcome of the study was the visual analog scale (VAS) pain score during coughing (VAS-C) 1 h after surgery. In addition, the VAS pain score at rest (VAS-R) and the VAS-C were assessed up to 24 h after surgery. The doses of postoperative opioids consumed were also recorded. Results The RSB group had a significantly lower VAS-C 1 h after RALP (58 [47–73] vs. 74 [63–83] mm, p = 0.001). In addition, the RSB group had significantly lower VAS-R and VAS-C scores, and postoperative opioid requirement, up to 6 h after surgery compared to the non-RSB group. Moreover, the VAS-R was significantly lower in the RSB group than in the non-RSB group 24 h after surgery. Conclusion Preoperative RSB significantly improved analgesia during the early period after RALP. The long-term analgesic efficacy of RSB needs further study.

We examined the safety and efficacy of del Nido cardioplegic solution compared with histidine-tryptophan-ketoglutarate cardioplegic solution in minimally invasive cardiac surgery.Patients who underwent minimally invasive cardiac surgery using del Nido or histidine-tryptophan-ketoglutarate from 2015 to 2019 were enrolled. Various clinical outcomes were compared between the groups. Postoperative laboratory findings including the levels of electrolytes, cardiac enzymes (creatine kinase-MB and troponin I), and serial blood lactate were also measured and compared. Based on 28 baseline covariates, propensity score matching was performed to reduce selection bias.Among 766 patients, del Nido and histidine-tryptophan-ketoglutarate were used in 330 patients (43.1%) and 436 patients (56.9%), respectively. There were no significant intergroup differences in postoperative clinical outcomes and early adverse outcomes among 228 pairs of propensity score-matched patients. Immediate postoperative sodium levels were within the normal range in both groups without a significant difference (P = .50). However, peak creatine kinase-MB (median, 31.9 vs 37.7 ng/mL, P = .026) and troponin I (6.9 vs 9.1 ng/mL, P = .014) levels were significantly lower in the del Nido group. Linear regression analysis revealed a significant association between the peak cardiac enzyme levels and the cardiac ischemic time depending on the cardioplegia type, with lower cardiac isoenzymes for del Nido over histidine-tryptophan-ketoglutarate (P .001) until the crossover point at the cardiac ischemic time over 100 minutes.In comparison with histidine-tryptophan-ketoglutarate solution, del Nido solution seems to have acceptable safety and efficacy with good myocardial protection in minimally invasive cardiac surgery. Further studies focusing on complex surgeries requiring longer cardiac ischemic time are needed.

Mitotane is an adrenolytic drug that exhibits therapeutic effects within a narrow target range (14–20 μg/dL). Various complications develop if the upper limit is exceeded. We present the case of a 5-year-old girl with breast development, acne, and pubic hair who was diagnosed with an adrenal mass that was subsequently excised. The pathological finding was adrenocortical carcinoma with a high risk of malignancy, and adjuvant therapy (combined mitotane and radiation therapy) was recommended. Mitotane was initiated at a low dose to allow monitoring of the therapeutic drug level, and high-dose hydrocortisone was also administered. However, the patient exhibited elevated adrenocorticotropic hormone levels and vague symptoms such as general weakness and difficulty concentrating. It was important to determine if these symptoms were signs of the neurological complications that develop when mitotane level is elevated. Encephalopathy progression and pubertal signs appeared 6 months after diagnosis, induced by high mitotane level. The mitotane decreased to subtherapeutic level several months after its discontinuation, at which time endocrinopathy (central hypothyroidism, hypercholesterolemia, and secondary central precocious puberty) developed. The case shows that low-dose mitotane can trigger neurological and endocrinological complications in a pediatric patient, indicating that the drug dose should be individualized with frequent monitoring of the therapeutic level.

Background: Recently, several clinical studies have reported that combination treatments of radiation therapy (RT) and immunotherapy in patients with multiple lesions can improve tumor regression a...

RationalePulmonary fibrosis is a devastating lung disease with few therapeutic options. Chitinase 1 (CHIT1), an 18 glycosyl hydrolase family member, contributes to the pathogenesis of pulmonary fibrosis through regulation of Transforming Growth Factor (TGF)-β signaling and effector function. Therefore, CHIT1 is a potential therapeutic target of pulmonary fibrosis.ObjectivesThis study aimed to identify and characterize a druggable CHIT1 inhibitor with strong antifibrotic activity and minimal toxicity for therapeutic application to pulmonary fibrosis.MethodsExtensive screening of small molecule libraries identified the aminoglycoside antibiotic Kasugamycin as a potent CHIT1 inhibitor.Measurements and Main ResultsElevated levels of CHIT1 were detected in the lungs of patients with pulmonary fibrosis. In vivo bleomycin- and TGF-β-stimulated murine models of pulmonary fibrosis, Kasugamycin showed impressive anti-fibrotic effects in both preventive and therapeutic conditions. In vitro studies also demonstrated that Kasugamycin inhibits fibrotic macrophage activation, fibroblast proliferation and myofibroblast transformation. Null mutation of transforming growth factor beta associated protein 1 (TGFBRAP1), a recently identified CHIT1 interacting signaling molecule, phenocopied antifibrotic effects of Kasugamycin in in vivo lungs and in vitro fibroblasts responses. Kasugamycin inhibits physical association between CHIT1 and TGFBRAP1, suggesting that antifibrotic effect of Kasugamycin is mediated through regulation of TGFBRAP1, at least in part.ConclusionsThese studies demonstrate that Kasugamycin is a novel CHIT1 inhibitor with strong antifibrotic effect that can be further developed as an effective and safe therapeutic drug for pulmonary fibrosis.

OBJECTIVE: To determine if surgery and anesthesia in the elderly may promote Alzheimer’s Disease and Related Dementias (ADRD). BACKGROUND: There is a substantial conflicting literature concerning the hypothesis that surgery and anesthesia promotes ADRD. Much of the literature is confounded by indications for surgery or has small sample size. This study examines elderly patients with appendicitis, a common condition that strikes mostly at random after controlling for some known associations. METHODS: A matched natural experiment of patients undergoing appendectomy for appendicitis versus control patients without appendicitis using Medicare data from 2002 to 2017, examining 54,996 patients without previous diagnoses of ADRD, cognitive impairment, or neurological degeneration, who developed appendicitis between ages 68 through 77 years and underwent an appendectomy (the “Appendectomy” treated group), matching them 5:1 to 274,980 controls, examining the subsequent hazard for developing ADRD. RESULTS: The hazard ratio (HR) for developing ADRD or death was lower in the Appendectomy group than controls: HR = 0.96 (95% CI 0.94, 0.98), P < 0.0001, (28.2% in Appendectomy versus 29.1% in controls, at 7.5 years). The HR for death was 0.97 (0.95, 0.99), P = 0.002, (22.7% versus 23.1% at 7.5 years). The HR for developing ADRD alone was 0.89 (0.86, 0.92), P < 0.0001, (7.6% in Appendectomy versus 8.6% in controls, at 7.5 years). No subgroup analyses found significantly elevated rates of ADRD in the Appendectomy group. CONCLUSIONS: In this natural experiment involving 329,976 elderly patients, exposure to appendectomy surgery and anesthesia did not increase the subsequent rate of ADRD.

Colorectal carcinoma metastases to the head and neck are exceedingly rare. Patients may present with vague symptoms that may lead to a delay in diagnosis. We report the case of a 51-year-old man with a known history of stage IIIB colorectal adenocarcinoma who presented with right-sided molar tooth bleeding and right-sided palate swelling that led to difficulty speaking, eating and weight-loss of 15 pounds. Imaging studies revealed a 3.1×4.8×3 cm mass that was centred around the posterior aspect of the maxilla. Pathology revealed moderately differentiated intestinal type adenocarcinoma of colonic subtype, immune histochemistry was positive for CDX2, CK20 and MUC2, thus confirming metastatic disease to the maxilla. The patient is undergoing chemoradiation therapy for palliation of his symptoms. Clinicians should be aware of this potentional site of metastatic disease and suspect the diagnosis in a timely manner to avoid delays in making a diagnosis.

Over 40% of children with autism spectrum disorder (ASD) experience difficulty in using speech to meet their daily communication needs. Although augmentative and alternative communication (AAC) can be of benefit, the AAC intervention must support beginning communicators in the early social interactions that provide the foundation for more sophisticated communication skills. An AAC video visual scene display approach uses an AAC app (provided on a tablet computer), including videos based on the interests of the child and infused with AAC supports, to provide opportunities for social interaction and communication between the child and the communication partner. The purpose of this study was to investigate the impact of video visual scene display technology on the communicative turns taken by three preschoolers with ASD and complex communication needs during a high-interest, shared activity (i.e., watching videos). All three participants demonstrated a large increase in the number of communicative turns taken with their partner (Tau-U of 1.00) following the introduction of the video VSD app. The results provide evidence that a video VSD approach may be a promising intervention to increase participation in communication opportunities for young children with ASD.

Background: The goal of this article was to investigate the feasibility of 64Cu labeling in prostate-specific membrane antigen imaging and therapy (PSMA I&T) for PSMA positron emission tomography (...

Aims Familial hypercholesterolemia (FH) is currently a worldwide health issue. Understanding the characteristics of patients is important for proper diagnosis and treatment. This study aimed to analyze the phenotypic and genetic features, including threshold cholesterol levels, of Korean patients with FH. Methods A total of 296 patients enrolled in the Korean FH registry were included, according to the following criteria: low-density lipoprotein-cholesterol (LDL-C) ＞190 mg/dL with tendon xanthoma or family history compatible with FH, or LDL-C ＞225 mg/dL. DNA sequences of three FH-associated genes were obtained using whole-exome or target exome sequencing. Threshold cholesterol levels for differentiating patients with FH/pathogenic variant (PV) carriers and predictors of PVs were identified. Results Of the 296 patients, 104 had PVs and showed more obvious clinical findings, including higher cholesterol levels. PV rates ranged from 30% to 64% when patients were categorized by possible or definite type according to the Simon Broome criteria. Frequent PV types included missense variants and copy number variations (CNVs), while the most frequent location of PVs was p.P685L in LDLR. The threshold LDL-C levels for patient differentiation and PV prediction were 177 and 225 mg/dL, respectively. Younger age, tendon xanthoma, and higher LDL-C levels were identified as independent predictors of PVs, while traditional cardiovascular risk factors were predictors of coronary artery disease. Conclusions Korean patients with FH had variable PV rates depending on diagnostic criteria and distinctive PV locations. The reported threshold LDL-C levels pave the way for efficient patient care in this population.

Background/Aims: This study assessed the efficacy and safety of adalimumab (ADA) and explored predictors of response in Korean patients with ulcerative colitis (UC).Methods: A prospective, observational, multicenter study was conducted over 56 weeks in adult patients with moderately to severely active UC who received ADA. Clinical response, remission, and mucosal healing were assessed using the Mayo score.Results: A total of 146 patients were enrolled from 17 academic hospitals. Clinical response rates were 52.1% and 37.7% and clinical remission rates were 24.0% and 22.0% at weeks 8 and 56, respectively. Mucosal healing rates were 39.0% and 30.1% at weeks 8 and 56, respectively. Prior use of anti-tumor necrosis factor-α (anti-TNF-α) did not affect clinical and endoscopic responses. The ADA drug level was significantly higher in patients with better outcomes at week 8 (P

Background/Aims: Nutritional status influences quality of life among patients with inflammatory bowel disease (IBD), although there is no clear method to evaluate nutritional status in this setting. Therefore, this study examined whether bioelectrical impedance analysis (BIA) could be used to evaluate the nutritional status of patients with IBD. Methods: We retrospectively analyzed data from 139 Korean patients with IBD who were treated between November 2018 and November 2019. Patients were categorized as having active or inactive IBD based on the Harvey-Bradshaw index (a score of ≥5 indicates active Crohn’s disease) and the partial Mayo scoring index (a score of ≥2 indicates active ulcerative colitis). BIA results and serum nutritional markers were analyzed according to disease activity. Results: The mean patient age was 45.11±17.71 years. The study included 47 patients with ulcerative colitis and 92 patients with Crohn’s disease. Relative to the group with active disease (n=72), the group with inactive disease (n=67) had significantly higher values for hemoglobin (PPPP=0.047), muscle mass (P=0.046), skeletal muscle mass (P=0.042), body mass index (P=0.027), and mineral content (P=0.034). Moreover, the serum nutritional markers were positively correlated with the BIA results. Conclusions: Nutritional markers evaluated using BIA were correlated with serum nutritional markers and inversely correlated with disease activity. Therefore, we suggest that BIA may be a useful tool that can help existing nutritional tests monitor the nutritional status of IBD patients.

Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma subtype, accounting for 30-40% of lymphoma diagnoses. Though aggressive, cure is achievable in approximately 60% of cases with primary chemo-immunotherapy, and in a further substantial minority by salvage therapy and autologous stem cell transplantation. Despite promising activity in early phase clinical trials, no intensified or novel treatment regimen has improved outcomes over R-CHOP21 in randomised studies. However, there remain several areas of controversy including the most appropriate prognostic markers, CNS prophylaxis and the optimal treatment for patients with high-risk disease. This position statement presents an evidence-based synthesis of the literature for application in Australasian practice. This article is protected by copyright. All rights reserved.

Purpose The role of epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs) in the management of persistent subsolid nodules (SSNs) is unclear. This study aimed to investigate the impact of EGFR-TKIs on concurrent SSNs in patients with stage IV non–small cell lung cancer (NSCLC).Materials and Methods Patients who received an EGFR-TKI for at least 1 month for stage IV NSCLC and had concurrent SSN(s) that had existed for at least 3 months on chest computed tomography were included in this retrospective study. Size change of each nodule before and after EGFR-TKI therapies were evaluated using a cutoff value of 2 mm; increase (≥ 2 mm), decrease (≤ –2 mm), and no change (–2 mm < size change < +2 mm).Results A total of 77 SSNs, 51 pure ground-glass (66.2%) and 26 part-solid nodules (33.8%), were identified in 59 patients who received gefitinib (n=45) and erlotinib (n=14). Among 58 EGFR mutation analysis performed for primary lung cancer, 45 (77.6%) were EGFR mutant. The proportions of decrease group were 19.5% (15/77) on per-nodule basis and 25.4% (15/59) on per-patient basis. Four SSNs (5.2%) disappeared completely. On per-patient based multivariable analysis, EGFR exon 19 deletion positivity for primary lung cancer was associated with a decrease after initial EGFR-TKI therapy (adjusted odds ratio, 4.29; 95% confidence interval, 1.21 to 15.29; p=0.025).Conclusion Approximately 20% of the concurrent SSNs decreased after the initial EGFR-TKI therapy. EGFR exon 19 deletion positivity for primary lung cancer was significantly associated with the size change of concurrent SSNs.

Purpose Salivary gland cancers (SGCs) are relatively rare but comprise various histologic subtypes, which complicates design of prospective trials. Systemic chemotherapy plays a limited role in treatment of SGCs, but cisplatin and docetaxel showed efficacy in a previous preclinical study. Here, we conduct a prospective, phase II study to evaluate the efficacy and toxicities of cisplatin plus weekly docetaxel in patients with metastatic or recurrent SGC.Materials and Methods We included patients with histologically confirmed SGCs of the following subtypes: mucoepidermoid carcinoma, adenocarcinoma, ductal carcinoma, or adenoid cystic carcinoma. Patients had no prior systemic chemotherapy for metastatic or recurrent tumors and at least one measurable lesion. Patients were treated with docetaxel 35 mg/m2 (D1, 8) and cisplatin 70 mg/m2 (D1) every 21 days.Results Forty-one patients were enrolled between April 2014 and October 2020. The median age was 58 years (range, 32 to 73 years). The most common histologic subtype was adenoid cystic carcinoma (63.4%), followed by ductal carcinoma (24.4%). The most common metastatic site was the lung (75.6%). The median treatment cycle was 5.5 (range, 3 to 8), and the objective response rate was 46.3%, with three complete responses. The median duration of response was 6.8 months (interquartile range, 4.0 to 10.2). The progression-free survival and overall survival were 9.4 months (95% confidence interval [CI], 8.4 to 10.5) and 28.2 months (95% CI, 22.7 to 33.6), respectively. There were no treatment-related deaths. The most common grade 3/4 adverse events were neutropenia (4.9%) and fatigue (4.9%).Conclusion Cisplatin plus weekly docetaxel is effective and tolerable with manageable toxicity as first-line therapy in patients with metastatic or recurrent SGC.

Purpose The usefulness of rehabilitation in patients with reduced lung function before lung surgery remains unclear, and there is no adequate method for evaluating the effect of rehabilitation. We aimed to evaluate the usefulness of rehabilitation in patients with non-small cell lung cancer (NSCLC) undergoing lung cancer surgery.Materials and Methods We retrospectively analyzed the medical records of NSCLC patients at Korea University Guro Hospital between 2018 and 2020. Patients were divided into two groups depending on whether they underwent rehabilitation. Pulmonary function test (PFT) data and muscle determined using chest computed tomography (CT) images were analyzed. Because the baseline characteristics were different between the two groups, propensity score matching was performed.Results Of 325 patients, 75 (23.1%) and 250 (76.9%) were included in the rehabilitation and non-rehabilitation (control) groups, respectively. The rehabilitation group had a worse general condition at baseline. After propensity score matching, 45 patients remained in each group. Pulmonary function (forced expiratory volume in 1 second, %) (p=0.001) and the Hounsfield unit of erector spinae muscle (p=0.001) were better preserved in the rehabilitation group. Muscle loss of 3.4% and 0.6% was observed in the control and rehabilitation groups, respectively (p=0.003). In addition, the incidence of embolic events was lower in the rehabilitation group (p=0.044).Conclusion Pulmonary rehabilitation is useful in patients with NSCLC undergoing lung surgery. Pulmonary rehabilitation preserves lung function, muscle and reduces embolic events after surgery. Pulmonary rehabilitation is recommended for patients with NSCLC undergoing surgery.

Purpose Histologic change is a resistant mechanism in lung cancer. The most common histological change is the switch from adenocarcinoma (AdenoCa) to small cell carcinoma (SCC) against to tyrosine kinase inhibitor (TKI) inhibitors. However, it is not clear whether other treatment modalities are involved in the histologic changes. Materials and methods We investigated histological changes in eight cases, after various treatments, and compared the molecular profiles between primary tumors and changed tumors using exome sequencing where tissue was available. Results Three cases of AdenoCa that were changed into SCC retained the initial mutations after TKI and/or surgical treatment. After treatment with TKI and immunotherapy, an EGFR-mutant AdenoCa changed to squamous cell carcinoma (SqCa). SqCa in a patient treated with surgery was changed into combined adenoCa and SqCa. These two cases showed the same genetic variations between the two distinct non-small cell carcinomas. Only surgical treatment might induce histologic change. Three patients experienced two histologic changes, which the changed tumors returned to its original state or changed to a combined tumor after treatments. Four cases showed combined histology in first or second change. Two SqCas were changed to SCC. Conclusion The histology of non-small cell carcinoma can be changed to a single pattern or combined subtypes after various treatment modalities, and the phenotypic changes seem not fixed. Therefore, additional morphologic changes may occurred regardless of their genetic status and types of treatments. To refine the new treatment strategy, consecutive repeated biopsies in progressive disease or recurrent tumor are necessary.

PurposePoor oral health is associated with head and neck cancer (HNC). We evaluated whether a national oral health screening program (OHSP) could reduce the risk of HNC.Materials and MethodsData from 408,247 healthy individuals aged ≥ 40 years from the National Health Insurance System-National Health Screening program during 2003 and 2004 in Korea were analyzed. The risk of HNC was compared between subjects who underwent OHSP (HEALS-Dental+, n=165,292) and routine health check-ups only (HEALS-Dental‒, n=242,955). The impact of individual oral health-related factors on HNC risk was evaluated in HEALS-Dental+.ResultsA total of 1,650 HNC cases were diagnosed. The 10-year HNC-free rate was 99.684% with a median follow-up of 11 years. The risk of all HNC (hazard ratio [HR], 1.16; 95% confidence interval [CI], 1.03 to 1.29; p=0.011) and oropharyngeal cancer (HR, 1.48; 95% CI, 1.13 to 1.94; p=0.005) was significantly higher in HEALS-Dental‒ than in HEALS-Dental+. In HEALS-Dental+, oral cavity cancer was marginally reduced (p=0.085), and missing teeth was a significant factor for HNC (HR, 1.24; 95% CI, 1.02 to 1.50; p=0.032). Toothbrushing was a significant factor in univariate analysis (p=0.028), but not in multivariate analysis (p=0.877).ConclusionThe National OHSP significantly reduced the long-term HNC risk, particularly the incidence of oropharyngeal cancer. Routine OHSP should be considered at the population level.

PurposeThe clinical significance of body mass index (BMI) on long-term outcomes has not been extensively investigated in Asian patients with colorectal cancer (CRC). This study aims to describe the association between BMI and survival, plus providing BMI cut-off value for predicting prognosis in CRC patients.Materials and MethodsA total of 1,182 patients who had undergone surgery for stage I-III CRC from June 2004 to February 2014 were included. BMI was categorized into four groups based on the recommendation for Asian ethnicity. The optimal BMI cut-off value was determined to maximize overall survival (OS) difference. ResultsIn multivariable analysis, underweight BMI was significantly associated with poor OS (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.55 to 3.71; p < 0.001) and obese BMI was associated with better OS (HR, 0.72; 95% CI, 0.53 to 0.97; p=0.036) compared with the normal BMI. Overweight and obese BMI were associated with better recurrence-free survival (HR, 0.64; 95% CI, 0.42 to 0.99; p=0.046 and HR, 0.58; 95% CI, 0.38 to 0.89; p=0.014, respectively) compared with the normal BMI group. BMI cutoff value was 20.44 kg/m2. Adding the BMI cutoff value to cancer staging could increase discriminatory performance in terms of integrated area under the curve and Harrell’s concordance index. ConclusionCompared to normal BMI, underweight BMI was associated with poor survival whereas obese BMI was associated with better survival. BMI cut-off value of 20.44 kg/m2 is a useful discriminator in Asian patients with CRC.

Background Di-(2-ethylhexyl) phthalate (DEHP) is the most common endocrine disrupting chemical used as a plasticizer. DEHP is associated with the development of endometrium-related diseases through the induction of inflammation. The major therapeutic approaches against endometrial cancer and endometriosis involve the suppression of inflammatory response. Korean red ginseng (KRG) is a natural product with anti-inflammatory and anti-carcinogenic properties. Thus, the purpose of this study is to investigate the effects of KRG on DEHP-induced inflammatory response in endometrial cancer Ishikawa cells and a mouse model of endometriosis. Methods RNA-sequencing was performed and analyzed on DEHP-treated Ishikawa cells in the presence and absence of KRG. The effects of KRG on DEHP-induced cyclooxygenase-2 (COX-2) mRNA levels in Ishikawa cells were determined by RT-qPCR. Furthermore, the effects of KRG on the extracellular signal-regulated kinases (ERKs) pathway, COX-2, and nuclear factor-kappa B (NF-κB) p65 after DEHP treatment of Ishikawa cells were evaluated by western blotting. In the mouse model, the severity of endometriosis induced by DEHP and changes in immunohistochemistry were used to assess the protective effect of KRG. Results According to the RNA-sequencing data, DEHP-induced inflammatory response-related gene expression was downregulated by KRG. Moreover, KRG significantly inhibited DEHP-induced ERK1/2/NF-κB/COX-2 levels in Ishikawa cells. In the mouse model, KRG administration significantly inhibited ectopic endometriosis growth after DEHP-induced endometriosis. Conclusions Overall, these results suggest that KRG may be a promising lead for the treatment of endometrial cancer and endometriosis via suppression of the inflammatory response.

Aerosol generating procedures are avoided for COVID-19 patients to lower the risk of transmission to healthcare providers. However, when bronchoscopy is indicated, it remains unclear if the procedure performed under general anesthesia leads to contamination of the surroundings and if standard endoscopy reprocessing methods are effective in eradicating SARS-CoV-2. We share our experience of bronchoscopic retrieval of airway foreign body under general anesthesia in a patient tested positive for novel 2019 coronavirus disease (COVID 19). We focus on anesthesia techniques to minimise aerosolization.

Aims Mismatches between the risk status of a patient and coronary imaging data can lead to conflicting strategies to prevent a cardiovascular event. We evaluated whether statin use was associated with cardiovascular benefit in high-risk individuals whose coronary computed tomography angiography (CCTA) results showed normal coronary arteries. Methods Among asymptomatic individuals whose CCTA showed normal or near normal coronary arteries, 3,389 persons with high- or very-high-risk status were included in this retrospective study. After 1:2 propensity score matching, 906 individuals (302 new statin users and 604 controls; mean age 61 years; male 58%) were analysed. The primary outcome variable was major adverse cardiovascular and cerebrovascular events (MACCEs) that consisted of cardiovascular death, nonfatal myocardial infarction, coronary revascularisation, and nonfatal ischemic stroke. Results At a median follow-up of 5.8 years, 20 statin users and 17 controls (7.4 and 5.6 events/1,000 person-year, respectively; hazard ratio [HR) 1.04; p=0.92) experienced MACCE. Kaplan-Meier curves showed similar MACCE rates in both groups (p=0.91). In separate analyses for persons with normal (p=0.29) or near normal coronary arteries (p=0.67), MACCE rates did not differ between the groups. Age (HR 1.04; p=0.044), male sex (HR 3.06, p=0.018), and smoking (HR 2.87, p=0.019) were independently associated with MACCEs. In subgroup analyses, no significant factors affected the relationship between statin use and MACCEs. Conclusions Statin use was not associated with cardiovascular risk reduction in high-risk persons with normal or near normal coronary arteries. More individualised lipid-lowering therapy may benefit this population.

BACKGROUND AND PURPOSE Carotid blowout syndrome (CBS) is a devastating complication of head and neck cancer (HNC). In this study, we describe radiological features that can predict imminent (

Purpose: This study aimed to investigate the clinicopathologic features and survival in patients with both breast cancer (BrC) and colorectal cancer (CRC).Methods: Between 1996 and 2019, patients who were diagnosed with both BrC and CRC were evaluated retrospectively. Patients with distant metastasis, palliative resection, and previous cancer histories except for BrCs or CRCs were excluded. Altogether, 105 patients were divided into the B=C group (n=21), B-first group (n=40), and C-first group (n=44) according to the definition of synchronous and metachronous cancers. The clinicopathologic features and overall survival were evaluated.Results: TNM stages and histologic types were comparable among the 3 groups (P=0.434). The interval of diagnosis was 67.1±40.4 and 59.3±47.2 months in the B- and C-first groups, respectively. The incidence of adjuvant chemotherapy in the B-first group was 57.5%, which was higher than the B=C and C-first groups (P

The clinicoprognostic implications of head and neck involvement of mycosis fungoides (MF) are poorly understood.To evaluate the association of head and neck involvement on the clinicoprognostic features of MF.The clinical features and survival outcomes of patients with MF in a Korean academic medical center database were retrospectively evaluated according to the presence of head and neck involvement at diagnosis.Cases of MF with (group A, n = 39) and without (group B, n = 85) head and neck involvement at diagnosis were identified. Advanced-stage disease (stages IIB-IVB) was more common in group A (43.6%) than in group B (5.9%) (P .001). MF progression, extracutaneous dissemination, and large-cell transformation more commonly occurred in group A than in group B. The 10-year overall survival rate was worse in group A (53.4%) compared with group B (81.6%) (P .001). Head and neck involvement at diagnosis was associated with poor prognosis in early-stage MF (stages IA-IIA) and was independently associated with worse progression-free survival (hazard ratio, 24.4; 95% confidence interval, 2.2-267.6; P = .009).A single center, retrospective design.Head and neck involvement of MF was associated with a poor prognosis.

Objective Right ventricular heart failure (RVHF) is a critical complication in patients with respiratory failure, particularly among those who transitioned to lung transplantation using venovenous (VV) extracorporeal membrane oxygenation (ECMO). In these patients, both cardiac and respiratory functions are supported using venoarterial or venoarterial-venous ECMO. However, these modalities increase the risk of device-related complications, such as thromboembolism, bleeding, and limb ischemia, and they may disturb early rehabilitation. Due to these limitations, a right ventricular assist device with an oxygenator (Oxy-RVAD) using ECMO may be considered for patients with RVHF with VV ECMO. Design A retrospective case series and literature review. Setting A single tertiary care university hospital. Participants The study comprised lung transplantation candidates on ECMO bridging who developed right-sided heart failure. Interventions An RVAD with ECMO. Measurements and Main Results Of eight patients who underwent the study protocol, seven were bridged successfully to lung transplantation (BTT), and all patients with BTT were discharged, with a 30-day survival rate of 100% (7/7 patients). The 180-day survival rate was 85% (6/7 patients). Conclusions The study suggested that Oxy-RVAD using ECMO may be a viable option for bridging patients with RVHF to lung transplantation. Trial Registration Retrospectively registered.

Objective This study was aimed to compare the oncologic outcomes of patients with non-endometrioid endometrial cancer who underwent minimally invasive surgery with the outcomes of patients who underwent open surgery. Method This is a retrospective, multi-institutional study of patients with non-endometrioid endometrial cancer who were surgically staged by either minimally invasive surgery or open surgery. Oncologic outcomes of the patients were compared according to surgical approach. Results 113 patients met the inclusion and exclusion criteria. 57 underwent minimally invasive surgery and 56 underwent open surgery. Patients who underwent minimally invasive surgery had smaller tumors (median size, 3.3 vs. 5.2%, p = 0.0001) and a lower lymphovascular space invasion rate (29.8% vs. 48.2%, p = 0.045). In the overall population, the numbers and rate of recurrence were significantly higher in the open surgery group (p = 0.016). In multivariate analysis, disease stage and tumor size were associated with DFS in contrast to surgical procedure. Conclusion Minimally invasive surgery showed similar survival outcomes when compared to open surgery in non-endometrioid endometrial cancer patients, irrespective of disease stage. When minimally invasive surgery is managed by expert surgeons, non-endometrioid histological subtypes should not be considered a contraindication for minimally invasive surgery.

Lynch syndrome (LS) is an inherited syndrome associated with an increased risk of cancer caused by abnormalities in DNA mismatch repair (MMR) genes. Immune checkpoint inhibitors (ICIs) have been reported to lead to a good response in cancers accompanied by LS. However, ICI therapy can cause immune-related adverse events (irAEs). In addition, post ICI treatment, some patients can show a falsely aggravated response, called pseudoprogression, causing difficulties in initial drug response evaluation. A 61-year-old man presented with back and pelvic bone pain. He had a history of surgery for stomach and colon cancer, and his daughter was treated for endometrial cancer. The patient was diagnosed with primary urothelial carcinoma (UC) in the left ureter with adrenal gland and multiple bone metastases. Through nextgeneration sequencing (NGS), mutations in MLH1 and MSH2 were identified, and diagnosis of LS was confirmed. On the 11th day from the start of atezolizumab, left pleural effusion occurred with exacerbation of the rib metastasis; the amount of effusion increased, and percutaneous catheter drainage (PCD) was performed. On the 27th day, right pleural effusion developed, and drainage was initiated. After the third cycle of atezolizumab, the bilateral pleural fluid decreased, and the drainage tube was removed. Positron emission tomography/computed tomography (PET-CT) revealed improvement in the cancer lesions, including metastatic bone lesions. This is a rare case of bilateral pleural effusion due to pseudoprogression of rib lesions after atezolizumab treatment in a patient with ureter cancer accompanied by LS. UC associated with LS is expected to show a good response to ICI therapy. For proper identification of pseudoprogression, appropriate response evaluation and close monitoring of the side effects are necessary.

BACKGROUND Atherosclerosis and vascular inflammatory response have been considered as risk factors for non-typhoidal Salmonella (NTS) vascular infection. The study aims to assess the risk of vascular infection by measuring atherosclerosis severity, NTS vascular infection (NTSVI) score, and serum levels of inflammatory markers in people with NTS bacteremia. METHODS A prospective observational study was conducted in two medical centers and two regional hospitals. Adults aged ≥50 years with NTS bacteremia who underwent computed tomography (CT) scan for revealing vascular infections were enrolled. The degree of atherosclerosis was scaled by a calcium score determined by a CT scan. Serum concentrations of inflammatory biomarkers were determined in the patients enrolled in a medical center. RESULTS Fourteen (20.3%) of 69 patients with NTS bacteremia had vascular infections. Calcium scores over the thoracic (12,540 vs. 3,261, P = 0.0005) and abdominal (9755 vs. 3,461, P = 0.0006) aorta of those with vascular infections were higher than those without vascular infection. All vascular infections were present in the high-risk group (NTSVI score ≥1), yielding a sensitivity of 100% and specificity of 30.9%. Among 17 low-risk patients (NTSVI score

Background Impact of immeasurable time bias (IMTB) is yet to be examined in self-controlled designs. Methods We conducted case-crossover, case-time-control, and case-case-time-control analyses using Korea's healthcare database. Two empirical examples among elderly patients were used: 1) benzodiazepines-hip fracture; 2) benzodiazepines-mortality. For cases, the date of hip fracture diagnosis or death was defined as the index date, and the inherited date of their matched cases for controls or future cases. Exposure was assessed in the 1-30 day (hazard) and 61-90 day (control) windows preceding the index date. A non-missing exposure setting included in- and outpatient prescriptions and the pseudo-outpatient setting included only the outpatients. Conditional logistic regression was done to estimate odds ratio (OR) with 95% confidence intervals (CI), where the relative difference in OR among the two settings was calculated to quantify the IMTB. Results The IMTB had negligible impacts in the hip fracture example in the case-crossover (non-missing exposure setting OR 1.27, 95% CI 1.12-1.44; pseudo-outpatient setting 1.21, 1.06-1.39; magnitude 0.05), case-time-control (1.18, 0.98-1.44; 1.13, 0.92-1.38; 0.04), and case-case-time-control analyses (0.99, 0.80-1.23; 0.94, 0.75-1.18; 0.05). In the mortality example, IMTB had significant impacts in the case-crossover (1.44, 1.36-1.52; 0.72, 0.67-0.78; 1.00), case-time-control (1.38, 1.26-1.51; 0.68, 0.61-0.76; 1.03), and case-case-time-control analyses (1.27, 1.15-1.40; 0.62, 0.55-0.69; 1.05). Conclusions Although IMTB had negligible impacts on the drug's effect on acute events as these are unlikely to be accompanied with hospitalizations, it negatively biased the drug's effect on mortality, an outcome with prodromal phases, in the three self-controlled designs.

Osteopetrosis (marble bone disease) is a family of rare genetic disorders characterized by impaired osteoclast function leading to hyperdense, hypovascular, brittle bone. Typical imaging shows increased bone mass and thickened cortical and trabecular bone. Bones are more prone to fracture and osteomyelitis may develop. When considering dental implant placement in a patient with osteopetrosis, the potential for bony fracture and/or osteomyelitis should be considered along with the decreased likelihood of successful osseointegration because of hypovascularity. This clinical report describes an unusual imaging presentation and successful osseointegration of multiple dental implants supporting an implant-supported fixed mandibular prosthesis with long-term survival.

Objective A surgical site infection after oculoplastic surgery is a serious complication that can lead to endophthalmitis and vision loss. Although performing these procedures in a minor-surgery setting is common, there is a lack of evidence in the literature regarding the incidence of postoperative infections. The objective of this study was to determine the infection rate associated with elective outpatient oculoplastic procedures performed in a minor-surgery setting. Methods A retrospective review was completed for all patients who underwent elective oculoplastic surgery in the minor-procedure room at the Misericordia Health Centre in Winnipeg between April and December 2018. Operations were performed by 2 senior oculoplastic surgeons. Data collected included the type of procedure, number of surgical incisions, type and number of sutures, use of prophylactic antibiotics, time to follow-up, complications, and presence of surgical site infection. Results Review of 539 patients showed an infection rate of 0.37% (2 of 539). Infection cases were an exposed orbital implant using a temporalis fascia graft and ptosis repair using a frontalis sling. Thirteen complications were identified, corresponding to a complication rate of 2.41% (13 of 539). Conclusion Study results show an infection rate of 0.37% for elective oculoplastic surgery in a minor-procedure setting.

Background Lentigo maligna/lentigo maligna melanoma (LM/LMM) can present with subclinical extension that may be difficult to define preoperatively and lead to incomplete excision and potential recurrence. Preliminarily studies have used reflectance confocal microscopy (RCM) to assess LM/LMM margins. Objective To evaluate the correlation of LM/LMM subclinical extension defined by RCM compared to the gold standard histopathology. Methods Prospective study of LM/LMM patients referred for dermatologic surgery. RCM was performed at the clinically-defined initial surgical margin followed by margin-controlled staged excision with paraffin-embedded tissue and histopathology was correlated with RCM results. Results Seventy-two patients were included. Mean age was 66.8 years (SD 11.1; 38 – 89 years); 69.4% were males. 70/72 (97.2%) lesions were located on the head neck with mean largest clinical diameter of 1.3cm (0.3 – 5 cm). Diagnostic accuracy for detection of residual melanoma in the tumor debulk (after biopsy) had a sensitivity of 96.7% and a specificity of 66.7% when compared to the histopathology. RCM margin assessment revealed an overall agreement with final histopathology of 85.9% (kappa 0.71; p Limitations No RCM imaging beyond initial planned margins was performed. Conclusion RCM showed moderate to excellent overall agreement between RCM imaging of LM/LMM and histopathology of staged excision margins.

A 75-year-old Caucasian woman presented with sudden-onset multifocal scotomas in her right eye's central vision for 1 day. There were subtle white intraretinal foveal lesions that correlated with patchy inner retinal hyperreflectivity on optical coherence tomography, suggestive of paracentral acute middle maculopathy. Initial cerebrovascular work-up was negative. Review of systems was positive for lethargy and jaw claudication. The sedimentation rate and c-reactive protein were elevated, but platelet count was normal. The patient was started on 60 mg oral prednisone daily and underwent bilateral temporal artery that confirmed the diagnosis of giant cell arteritis.

Sarcopenia is an objective marker of poor outcome following cardiac surgery through median sternotomy. However, the clinical impact of sarcopenia after minimally invasive cardiac surgery (MICS) has not been well established. This study aimed to analyze the influence of sarcopenia on the early and late outcomes following MICS. We retrospectively examined 1248 patients who underwent MICS via right mini-thoracotomy or upper sternotomy between February 2009 and April 2020. Patients older than 65 years who underwent preoperative computed tomography were enrolled. Sarcopenia was defined as the lowest sex-specific quartile of the body surface area adjusted psoas muscle area. The early operative and late survival outcomes were compared, and the predictor of late composite outcome was analyzed using Cox proportional regression model. Early and late composite outcomes in both groups were also compared. A total of 367 patients were classified into the sarcopenia (n = 92) or non-sarcopenia (n = 275) group. Patients in the sarcopenia group were older, and had lower preoperative hemoglobin and albumin levels. They had higher estimated surgical mortality, but similar early mortality and major morbidity. The survival and late composite outcome were comparable between the two groups. Sarcopenia was neither an independent predictor of late death nor a composite outcome in the multivariable model. After MICS, patients with sarcopenia displayed comparable perioperative outcomes and survival. The clinical impact of sarcopenia on postoperative outcomes might be alleviated by MICS and early recovery protocol after MICS. MICS could be a reasonable approach for elderly patients with sarcopenia.

Background: Many patients in the Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) had a significant improvement (> 10%) in the left ventricular ejection fraction (LVEF) during the course of the study, but the factors and outcomes associated with such improvement are uncertain. Methods: We examined factors and rates of mortality, cause-specific mortality, and implantable cardioverter defibrillator (ICD) shocks associated with improvement in LVEF by analyzing patients in the SCD-HeFT who were randomized to placebo or an ICD and who had an LVEF checked during follow-up. Results: During a median follow-up of 3.99 years, of 837 patients who had at least two follow-up LVEF measurements, 276 (33%) patients had > 10% improvement in LVEF and 561 (67%) patients had no significant change in LVEF. Factors significantly associated with LVEF improvement included female sex, white race, history of hypertension, a QRS duration < 120 ms, and beta-blocker use. Improvement in LVEF was associated with a significant improvement in survival. There was no significant association between improvement in LVEF and cause-specific death, but there was a significant association between improvement in LVEF and reduced risk of receiving appropriate ICD shocks. Conclusions: About a third of patients in this analysis, who were randomized to placebo or an ICD in SCD-HeFT, had a significant improvement in LVEF during follow-up; improvement in LVEF was associated with improved survival but not with cause-specific death, and with decreased likelihood of receiving appropriate ICD shocks.

Objective: : To develop an international Core Outcome Set (COS), a minimal collection of outcomes that should be measured and reported in all future clinical trials evaluating treatments of acute simple appendicitis in children.Summary Background Data: A previous systematic review identified 115 outcomes in 60 trials and systematic reviews evaluating treatments for children with appendicitis, suggesting the need for a COS.Methods: The development process consisted of four phases: (1) an updated systematic review identifying all previously reported outcomes, (2) a two-stage international Delphi study in which parents with their children and surgeons rated these outcomes for inclusion in the COS, (3) focus groups with young people to identify missing outcomes, and (4) international expert meetings to ratify the final COS.Results: The systematic review identified 129 outcomes which were mapped to 43 unique outcome terms for the Delphi survey. The first-round included 137 parents (eight countries) and 245 surgeons (10 countries), the second-round response rates were 61% and 85% respectively, with ten outcomes emerging with consensus. After two young peoples’ focus groups, two additional outcomes were added to the final COS (12): mortality, bowel obstruction, intra-abdominal abscess, recurrent appendicitis, complicated appendicitis, return to baseline health, readmission, reoperation, unplanned appendectomy, adverse events related to treatment, major and minor complications.Conclusion: An evidence-informed COS based on international consensus, including patients and parents has been developed. This COS is recommended for all future studies evaluating treatment of simple appendicitis in children, to reduce heterogeneity between studies and facilitate data synthesis and evidence-based decision-making.