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BackgroundSentinel node biopsy is a surgical technique to explore lymph nodes for surgical staging of endometrial cancer, which has replaced full retroperitoneal lymph node dissection. However, the effectiveness of sentinel node biopsy, its value to patients, and potential harms compared with no-node dissection have never been shown in a randomized trial.Primary ObjectivesStage 1 will test recovery from surgery. Stage 2 will compare disease-free survival at 4.5 years between patients randomized to sentinel node biopsy versus no retroperitoneal node dissection.Study HypothesisThe primary hypothesis for stage 1 is that treatment with sentinel node biopsy will not cause detriment to patient outcomes (lymphedema, morbidity, loss of quality of life) and will not increase treatment-related morbidity or health services costs compared with patients treated without a retroperitoneal node dissection at 12 months after surgery. The primary hypothesis for stage 2 is that disease-free survival at 4.5 years after surgery in patients without retroperitoneal node dissection is not inferior to those receiving sentinel node biopsy.Trial DesignThis phase III, open-label, two-arm, multistage, randomized non-inferiority trial (ENDO-3) will determine the value of sentinel node biopsy for surgical management of endometrial cancer. Patients with endometrial cancer are randomized to receive: (1) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy with sentinel node biopsy or (2) laparoscopic/robotic hysterectomy, bilateral salpingo-oophorectomy without retroperitoneal node dissection. In stage 1, 444 patients will be enrolled to demonstrate feasibility and quality of life. If this is demonstrated, we will enroll another 316 patients in stage 2.Major Inclusion and Exclusion CriteriaInclusion criteria include women aged 18 years or older with histologically confirmed endometrial cancer; clinical stage 1, who meet the criteria for laparoscopic or robotic total hysterectomy and bilateral salpingo-oophorectomy. Patients with uterine mesenchymal tumors are excluded.Primary EndpointsThe endpoint for stage 1 is surgical recovery, with the proportion of patients returning to usual daily activities at 3 months post-surgery as measured with the EQ-5D. Stage 2 is disease-free survival at 4.5 years.Sample Size760 participants (both stages).Estimated Dates for Completing Accrual and Presenting ResultsStage 1 commenced in January 2021 and is planned to be completed in December 2024 when 444 participants have completed 12 months' follow-up. Stage 2 will enroll a further 316 participants for a total of 760 patients.Trial RegistrationNCT04073706.

Background: Diabetic retinopathy (DR), a common complication of diabetes mellitus, is the major cause of visual impairment and blindness. Circ_0000615 was found to be elevated in retina samples of diabetic patients. Hence, the detailed effects and molecular mechanisms of circ_0000615 in DN progression were explored. Methods: The levels of circ_0000615, microRNA (miR)-646 and YAP1 (yes-associated protein 1) were detected using quantitative real-time polymerase chain reaction and Western blot assays. Cell viability, apoptosis, inflammation and reactive oxygen species (ROS) generation were determined using cell counting kit-8 assay, flow cytometry, caspase3 activity analysis, Western blot, enzyme-linked immunosorbent assay (ELISA) and Dichlorofluorescein diacetate (DCFH-DA) assay, respectively. The binding interaction between miR-646 and circ_0000615 or YAP1 was determined using dual-luciferase reporter, RNA immunoprecipitation (RIP), and RNA pull-down assays. Results: Circ_0000615 was elevated in high glucose (HG)-induced human retinal pigment epithelium (HRPE) cells. Knockdown of circ_0000615 attenuated HG-triggered HRPE cell apoptosis, inflammation, and ROS generation. Mechanistically, miR-646 was confirmed to be a target of circ_0000615, inhibition of miR-646 reversed the protective effects of circ_0000615 knockdown on HG-evoked HRPE cell dysfunction. MiR-646 was verified to target YAP1, overexpression of YAP1 abolished the impairment induced by miR-646 on HG-induced HRPE cell damage. Besides that, we confirmed that circ_0000615 could regulate YAP1 expression via miR-646. Conclusion: Circ_0000615 contributed to HG-induced HRPE cell dysfunction via miR-646/YAP1 axis, suggesting a novel insight into the pathogenesis of DR and a potential candidate for DR treatment.

Introduction Natural orifice specimen extraction is the next step in minimally invasive colorectal surgery but can be technically challenging, with additional risks, especially for oncologic surgery. For several key reasons, sigmoid volvulus is well suited for natural orifice specimen extraction surgery. We describe our method and experience with double-stapled anastomosis transrectal natural orifice specimen extraction for sigmoid volvulus. Technique Using 3- or 4-port laparoscopy, the mesentery is separated from the long sigmoid loop. After the distal bowel is tied off and washed out, the rectum is completely transected and the proximal bowel delivered transrectally through a wound protector. Proximal transection is performed externally, and the circular stapler anvil is set before the bowel is returned into the abdominal cavity. The rectum stump is closed with an endoscopic linear stapler, and a circular-stapled anastomosis is performed. Results After successful endoscopic decompression, 6 patients underwent elective laparoscopic sigmoidectomy with natural orifice specimen extraction for volvulus at China Medical University Hospital from 2015 to 2020. The median operative time was 179 minutes (range, 151-236 min). No intraoperative complications were encountered. The median postoperative length of stay was 4 days (range, 2-9 d). One patient experienced postoperative small-bowel ileus resulting in readmission. The median follow-up duration was 12 months (range, 2-49 mo). One recurrence of volvulus was recorded 27 months postsurgery. Conclusion Uncomplicated sigmoid volvulus can be treated effectively with sigmoidectomy and natural orifice specimen extraction. Surgeons who attempt this procedure should be well versed with conventional laparoscopy but do not necessarily need to be experienced with natural orifice specimen extraction for successful surgery.

Objectives Immune checkpoint inhibitors (ICIs) are being increasingly used across cancer types. Emergency room (ER) and inpatient (IP) care, common in patients with cancer, remain poorly defined in this specific population, and risk factors for such care are unknown. Methods We retrospectively reviewed charts for patients with solid tumors who received >1 ICI dose at 1 of 2 sites from January 1, 2011 to April 28, 2017. Demographics, medical history, cancer diagnosis/therapy/toxicity details, and outcomes were recorded. Descriptive data detailing ER/IP care at the 2 associated hospitals during ICI therapy (from first dose to 3 mo after last dose) were collected. The Fisher exact test and multivariate regression analysis was used to study differences between patients with versus without ER/IP care during ICI treatment. Results Among 345 patients studied, 50% had at least 1 ER visit during ICI treatment and 43% had at least 1 IP admission. Six percent of ER/IP visits eventually required intensive care. A total of 12% of ER/IP visits were associated with suspected or confirmed immune-related adverse events. Predictors of ER care were African-American race (odds ratio [OR]: 3.83, P=0.001), Hispanic ethnicity (OR: 3.12, P=0.007), and coronary artery disease (OR: 2.43, P=0.006). Predictors of IP care were African-American race (OR: 2.38, P=0.024), Hispanic ethnicity (OR: 2.29, P=0.045), chronic kidney disease (OR: 3.89, P=0.006), angiotensin converting enzyme inhibitor/angiotensin receptor blocker medication use (OR: 0.44, P=0.009), and liver metastasis (OR: 2.32, P=0.003). Conclusions Understanding demographic and clinical risk factors for ER/IP care among patients on ICIs can help highlight disparities, prospectively identify high-risk patients, and inform preventive programs aimed at reducing such care.

Background & Aims The functions of the liver and the intestine are closely tied in both physiological and pathologic conditions. The gut microbiota (GM) often cause deleterious effects during hepatic pathogenesis. Autophagy is essential for liver homeostasis, but the impact of hepatic autophagy function on liver-gut interaction remains unknown. Here we investigated the effect of hepatic autophagy deficiency (Atg5Δhep) on GM and in turn the effect of GM on the liver pathology. Methods Fecal microbiota were analyzed by 16S sequencing. Antibiotics were used to modulate GM. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice overexpressing FGF15 gene or in mice given a fibroblast growth factor receptor-4 (FGFR4) inhibitor. Results Atg5Δhep causes liver injury and alterations of intestinal BA composition, with a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs. The composition of GM is significantly changed with an increase in BA-metabolizing bacteria, leading to an increased expression of ileal FGF15 driven by FXR that has a higher affinity to unconjugated BAs. Notably, antibiotics or cholestyramine treatment decreased FGF15 expression and exacerbated liver injury. Consistently, inhibition of FGF15 signaling in the liver enhances liver injury. Conclusions Deficiency of autophagy function in the liver can affect intestinal environment, leading to gut dysbiosis. Surprisingly, such changes provide an adaptive protection against the liver injury through the FGF15-FGFR4 signaling. Antibiotics use in the condition of liver injury may thus have unexpected adverse consequences via the gut-liver axis., Graphical abstract

DNA damage response (DDR) gene alterations in cancer are associated with a higher tumor mutational burden (TMB) and may impact clinical outcomes of urothelial cancer (UC). Here, we explore the prognostic role of DDR alterations in advanced UC treated with anti‐PD‐1/PD‐L1 agents. The study included 53 patients who had FoundationOne genomic sequencing and received anti‐PD‐1/PD‐L1 therapy. Fisher exact test and trend test were used to assess differences in objective response rate (ORR). Overall survival (OS) was measured from the time of initial UC diagnosis and Cox proportional hazard regression analysis was performed to calculate hazard ratio (HR) and 95% confidence interval (CI). The cohort had a median age of 66 with 64% receiving platinum‐based chemotherapy. DDR alterations (including ATM) were associated with a non‐significantly higher ORR to PD‐1/PD‐L1 blockade (41% vs. 21%, p = 0.136). Patients with DDR alterations (excluding ATM) had non‐significantly longer OS, likely due to a small sample size (HR = 0.53, 95% CI 0.20–1.38, p = 0.19). ATM alterations were associated with a non‐significantly higher ORR (40% vs. 29%, p = 0.6), but also with significantly shorter OS (HR = 5.7, 95% CI 1.65–19.74, p = 0.006). Patients with ≥ 3 DDR alterations (including ATM) had substantially higher TMB (p = 0.01) and higher ORR (80%) with PD‐1/PD‐L1 blockade versus 24% ORR in patients with, DDR alterations are associated with higher ORR and nonsignificantly prolonged OS in patients with advanced UC receiving PD‐1/PD‐L1 inhibitors. However, presence of ATM alterations correlated with shorter OS, irrespective of a nonsignificant trend towards higher ORR to anti‐PD‐1/PD‐L1 agents.

At present, natural orifice specimen extraction surgery (NOSES) has attracted more and more attention worldwide, because of its great advantages including minimal cutaneous trauma and post-operative pain, fast post-operative recovery, short hospital stay, and positive psychological impact. However, NOSES for the treatment of gastric cancer (GC) is still in its infancy, and there is great potential to improve its theoretical system and clinical practice. Especially, several key points including oncological outcomes, bacteriological concerns, indication selection, and standardized surgical procedures are raised with this innovative technique. Therefore, it is necessary to achieve an international consensus to regulate the implementation of GC-NOSES, which is of great significance for healthy and orderly development of NOSES worldwide.

Background: Acute acalculous cholecystitis (AAC) is characterized by the development of cholecystitis in the gallbladder without gallstones or with small gallstones unrelated to inflammatory diseases. This disease is not rare in the elderly bedridden patients with co-morbidities and prone to develop life-threatening gangrene or perforation of gallbladder. Early imaging is essential for detecting and effectively treating AAC. This study aimed to evaluate the use of ultrasound diagnostic criteria for the diagnosis and prognosis of elderly long-term bedridden patients with suspected AAC.Methods: We retrospectively studied 374 elderly bedridden patients with clinical manifestations of AC at the acute stage of the disease. Gallbladder anomalies were found in 92 patients by ultrasound examination, which correlated with the duration time of clinical manifestations, complications, as well as therapeutic prognosis. The major and minor ultrasound criteria of AAC were made according to the Tokyo Guidelines 2018. Ultrasound results were thought to be AAC positive when they met two major criteria or one major and two minor criteria.Results: Forty-three (46.7%) of the 92 patients presented with AAC (+) test results based on the ultrasound criteria, with a higher incidence of complications (27.9%) than AAC (–) patients (0%; P < 0.001). The median length of symptoms (8 vs. 4 days, P < 0.001) and duration of antibiotic therapy (13 vs. 5 days, P < 0.001) were longer in the AAC (+) group.Conclusions: The ultrasound-based AAC (+) group often had a worse prognosis than the AAC (–) group. Therefore, patients from the AAC (+) group should receive a follow-up ultrasound examination to detect disease progression early.

Background: The Retzius space-sparing robot-assisted radical prostatectomy (RS-RARP) has shown better results in urinary continence, but its efficacy and safety compared to conventional robot-assisted radical prostatectomy (c-RARP) remain controversial.Material and Methods: A research was conducted in Medline via PubMed, Cochrane Library, EMBASE, and Web of Science up to January 4, 2021, to identify studies comparing RS-RARP to c-RARP. We used RevMan 5.3 and STATA 14.0 for meta-analysis.Results: A total of 14 studies involving 3,129 participants were included. Meta-analysis showed no significant difference in positive surgical margins (PSMs), but the RS-RARP group had significantly higher PSM rates in the anterior site [odds ratio (OR) = 2.25, 95% CI: 1.22–4.16, P = 0.01]. Postoperative continence in RS-RARP group at 1 month (OR = 5.72, 95% CI: 3.56–9.19, P < 0.01), 3 months (OR = 6.44, 95% CI: 4.50–9.22, P < 0.01), 6 months (OR = 8.68, 95% CI: 4.01–18.82, P < 0.01), and 12 months (OR = 2.37, 95% CI: 1.20–4.70, P = 0.01) was significantly better than that in the c-RARP group. In addition, the RS-RARP group had a shorter console time (mean difference = −16.28, 95% CI: −27.04 to −5.53, P = 0.003) and a lower incidence of hernia (OR = 0.35, 95% CI: 0.19–0.67, P = 0.001). However, there were no significant differences in estimated blood loss, pelvic lymph node dissection rate, postoperative complications, 1-year-biochemical recurrence rate, and postoperative sexual function.Conclusions: Compared with c-RARP, RS-RARP showed better recovery of continence, shorter console time, and lower incidence of hernia. Although there was no significant difference in overall PSM, we suggest that the surgeon should be more careful if the lesion is in the anterior prostate.

INTRODUCTION AND OBJECTIVE:The role of CN in the treatment of mRCC has been questioned with the recent approval of novel systemic therapy (ST) agents and the results of the CARMENA trial. Our objec...

To investigate prognostic clustering based on lymphovascular space invasion (LVSI) in relation to histological prognostic factors in endometrial cancer patients through patterns of failure and survival. A secondary objective was to develop iso-prognostic clusters of low-, intermediate- and high-risk patients . Patients with traditional intermediate, intermediate-high and high-risk endometrial cancer treated with primary surgery and staged as 1 to 3C, presented for adjuvant radiotherapy treatment sequentially between 1996 and 2014, were analysed (n = 1187). Histology included was endometrioid/mucinous, clear cell and serous. Distinct prognostic clusters were identified based on recurrence-free and overall survival (OS) using Cox proportional hazard models and Kaplan–Meier technique. Median follow-up period for the entire cohort was 5.4 (3.6–8.6) years. In the absence of LVSI and positive nodes, histology, grade, myometrial invasion and tumour size had no prognostic significance. LVSI was related to histology grade and lymph-node metastasis. The ratio for LVSI to lymph-node metastasis was 3:1 except for serous histology where it was 2:1. Rate of distant relapses in LVSI-negative, LVSI-positive and node-positive patients was 7%, 14% and 26%, respectively. Three distinct prognostic cluster emerged with 5-year OS of 91.0%, 82.9% and 69.9%. LVSI was the most important prognostic factor in endometrial cancer. Using LVSI and lymph-node status, it was possible to stratify endometrial cancer patients in three distinct prognostic clusters of low, intermediate and high risk of relapse. Such stratification could assist in patient selection for evaluating novel adjuvant therapy protocols.

Previous studies have shown hypothyroidism was independently associated with nonalcoholic fatty liver disease (NAFLD) in adults, but few studies examined their relationships in pediatric populations. This study aimed to investigate the prevalence of NAFLD in pediatric congenital hypothyroidism (CHT) patients and to identify the association between CHT and NAFLD. This study enrolled pediatric CHT patients receiving levothyroxine treatment at one medical center from 2013 to 2014. Euthyroid subjects (ET) and transient hypothyroidism (THT) patients weaned off medication successfully after age 3 were selected for further comparison. Laboratory data including thyroid functions, liver functions, and metabolic profiles were obtained. The major outcome was the occurrence of NAFLD, diagnosed based on the findings of abdominal ultrasonography. One‐hundred and twenty‐nine subjects (47 in CHT, 47 in THT, and 35 in ET groups) were enrolled. The analysis showed higher fasting serum glucose, insulin, thyroxine (T4), and mean thyroid‐stimulating hormone (TSH) levels in the CHT group. NAFLD prevalence was higher in the CHT (23.4%) group than in the THT (8.5%) and the ET (5.7%) groups, demonstrating an increasing trend across three strata (X2linear‐by‐linear = 5.9, P

Background It remains controversial if radical prostatectomy or definitive radiation therapy produces equivalent outcomes in high‐risk localized prostate cancer. Methods We queried The Surveillance, Epidemiology, and End Results (SEER) database for those who received upfront surgery or who were recommended for surgery but instead received radiation. Inverse probability of treatment weighing was used to adjust for covariate imbalance and the weighted Cox proportional hazards model was used to estimate the effects of treatment groups on survival. A meta‐analysis was performed to pool estimates from published studies. Results Among eligible 62 533 patients, 59 540 had upfront surgery and 2993 patients had upfront radiotherapy. EBRT + BT was associated with a superior cancer‐specific survival (CSS) compared with surgery or EBRT alone (HR, 0.55, 95% CI, 0.3‐1.0; HR, 0.49, 95% CI, 0.24‐0.98, respectively), whereas EBRT was associated with an inferior overall survival (OS) compared with surgery (HR, 1.46, 95% CI, 1.16‐1.8). Radiotherapy (EBRT ± BT) was inferior to surgery by OS (HR, 1.63, 95% CI, 1.13‐2.34) in patients ≤ 65 years, and was superior to surgery by CSS in patients > 65 years (HR, 0.69, 95% CI, 0.49‐0.97). The meta‐analysis showed consistent results. Conclusion EBRT + BT was associated with a significantly better prostate CSS compared with surgery or EBRT. EBRT alone was inferior to surgery by OS., In high‐risk localized prostate cancer, radiotherapy with brachytherapy boost was associated with a longer survival outcome, compared with surgery or radiotherapy without brachytherapy boost.

Background: Recovery of the interstitial cells of Cajal (ICCs) during post-operative ileus (POI) is important for the restoration of gastrointestinal (GI) motility. Acupuncture can protect ICCs, but the underlying mechanisms remain unclear. In this study, we investigated whether miR-222, c-kit and endothelial nitric oxide synthase (eNOS) are involved in the putative effects of acupuncture on ICC recovery. Methods: A POI model was established in Sprague-Dawley rats by colo-colic anastomosis, and then acupuncture was performed at bilateral ST36, SP6 and LR3 once daily for 3 consecutive days. C-kit protein expression in the colonic tissue adjacent to the incision site was determined by immunohistochemistry and Western blotting. mRNA levels of c-kit, eNOS and miR-222 were measured by real-time polymerase chain reaction (RT-PCR). Results: The levels of c-kit mRNA/protein and eNOS mRNA decreased, while miR-222 increased in the colonic tissues of POI model rats. Acupuncture treatment improved GI motility, inhibited the up-regulation of miR-222 and blocked the down-regulation of c-kit mRNA/protein and eNOS mRNA. The levels of miR-222 and c-kit were negatively correlated. Conclusion: Acupuncture at ST36, SP6 and LR3 facilitates ICC recovery and improves post-operative GI motility in part through regulation of miR-222, c-kit and eNOS.

Bladder cancer (BC) is the 2 nd most common genitourinary malignancy with an annual occurrence of 81,190 new cases and 17,240 deaths (1). The majority of patients are diagnosed with superficial BC [non-muscle invasive bladder cancer (NMIBC)] and are managed by a non-systemic therapy approach, which includes transurethral resection (TUR) of tumor with or without intravesical treatment depending on the grade of tumor, depth of invasion and presence of carcinoma in situ. However, BC with muscle invasive disease (MIBC) requires use of cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) or bladder sparing approach with systemic chemotherapy plus definitive radiation therapy. Cisplatin-based NAC in MIBC seems to achieve a pathological complete response in about 40% of patients (2), however a majority of patients tend to have residual disease making them high risk for recurrence of cancer locally or distantly. This highlights a need for identifying biomarkers that predict resistance to cisplatin-based NAC.

BackgroundPatients selection for salvage hysterectomy following chemoradiotherapy of cervical cancer is vital to avoid significant morbidity. The purpose of this study was to describe the role of post-treatment F18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography scanning (FDG-PET/CT) in patient selection for salvage hysterectomy.MethodsThis was a retrospective analysis of 49 patients with cervical cancer treated between January 1996 and December 2012 who were candidates for salvage hysterectomy.ResultsThree groups were defined based on institutional treatment guidelines, as experience in using post-treatment FDG-PET/CT to guide management evolved. Group 1 consisted of 15 patients who underwent planned hysterectomy based on clinical, cytological, or histological suspicion. Of these, only three (20%) patients had residual disease on histology. Group 2 consisted of 13 patients who had post-treatment FDG-PET/CT 3–6 months after the completion of chemoradiotherapy due either to suspicion of recurrence on examination or patients thought to be at high risk of recurrence at the primary site. Of these, eight patients had hysterectomy and four patients showed positive histology for residual tumor. Group 3 had 21 patients who showed isolated FDG uptake at the primary site on first FDG-PET/CT scanning at 6 months. A subsequent FDG-PET/CT scan after 3 months showed disease progression in seven and complete metabolic response in 14, and surgery was avoided in all patients.ConclusionFDG-PET/CT scanning at 6 months after radiotherapy is a good tool for assessing treatment response in patients with cervical cancer. In patients with persistent uptake on 6 months post-treatment FDG-PET/CT, repeat imaging at a 3-month interval helps in selecting patients for salvage hysterectomy.

Background Apolipoprotein E4 (APOE4) and ageing are the most important known risk factors for late-onset Alzheimer’s disease (AD). In the present study, we determined the alterations of IgG, CD19, and Aβ in various brain regions of uninfected male and female APOE3- and APOE4-TR mice at the age of 3 and 10 months to elucidate impacts of AD risk factors on alterations of brain IgG. Results Positive staining for IgG was distributed across the brain, including neocortex, entorhinal cortex, hippocampus, thalamus and cerebellum. IgG positive staining was mainly located on microglia, but not astrocytes. Some IgG positive neurons were also observed, but only in mediodorsal thalamic nucleus. Compared with APOE3-TR mice, 10-month-old female APOE4-TR mice had lower IgG level in AD susceptible brain regions such as neocortex, entorhinal cortex and hippocampus, but no significant changes in thalamus and cerebellum, two regions nearly intact in AD. In addition, the expression of CD19, a specific marker for mature B cells, was significantly reduced in the hippocampus of 10-month-old female APOE4-TR mice. Although there were no obvious differences in plasma IgG levels between APOE4- and age matched female APOE3-TR mice, significant decreased B cell amount in blood of 10-month-old female APOE4-TR mice have also been found. Moreover, more obvious positive staining for Aβ was observed in the cortex of 10-month-old female APOE4-TR mice than other groups. Conclusions Our study demonstrated that AD risk factors were associated with IgG alterations in various brain regions, which might result from the defects of humoral immunity and lead to the impairment of IgG-mediated clearance of Aβ by microglia, therefore facilitated AD progression.

Acute pancreatitis (AP) is one of the leading causes of hospital admission, 20% of which could progress to the severe type with extensive acinar cell necrosis. Clinical studies have reported that diabetes is an independent risk factor of the incidence of AP and is associated with higher severity than nondiabetic subjects. However, how diabetes participates in AP progression is not well defined. To investigate this question, wild-type (wt) and diabetic db/db mice at the age of 16 weeks were used in the study. AP was induced in wt recipients by 10 injections of 50 μg/kg caerulein with a 1 h interval. One hour after the last caerulein injection, bone marrow cells (BMC) isolated from wt and db/db mice were injected intraperitoneally into the recipients ( 1 × 10 7 cells/recipient). The recipients with no BMC injection served as controls. Thirteen hours after BMC injection, serum lipase activity was 1.8- and 1.3-folds higher in mice that received db/db BMC, compared with those with no injection and wt BMC injection, respectively ( p ≤ 0.02 for both). By H&E staining, the overall severity score was 14.7 for no cell injection and 16.6 for wt BMC injection and increased to 22.6 for db/db BMC injection ( p ≤ 0.002 for both). In particular, mice with db/db BMC injection developed more acinar cell necrosis and vacuolization than the other groups ( p ≤ 0.03 for both). When sections were stained with an antibody against myeloperoxidase (MPO), the density of MPO+ cells in pancreatitis was 1.9- and 1.6-folds higher than wt BMC and no BMC injection groups, separately ( p ≤ 0.02 for both). Quantified by ELISA, db/db BMC produced more IL-6, GM-CSF, and IL-10 compared with wt BMC ( p ≤ 0.04 for all). In conclusion, BMC of db/db mice produced more inflammatory cytokines. In response to acinar cell injury, diabetic BMC aggravated the inflammation cascade and acinar cell injury, leading to the progression of acute pancreatitis.

The presence vertebral artery (VA) abnormalities in the upper cervical may be a potential cause of catastrophic complication in the posterior approach of the upper cervical spine surgery. The aim of this study was to demonstrate the real incidence of the V3 segment anomaly in patients who need upper cervical surgery, and tried to find out the risk factors of V3 segment anomaly to evaluate the necessary of computed tomographic angiography (CTA) for upper cervical surgery. This systematic review was conducted following the preferred reporting items for systematic reviews and meta-Analyses (PRISMA). Retrospective studies and reports of case series involving human subjects with data on anomalies of vertebral artery in upper cervical spine were included. Data on the prevalence of persistent first intersegmental artery (PIA), fenestration of the VA (FA), posterior inferior cerebellar artery (PICA) were extracted. A total of 16 articles involving 5927 subjects met the inclusion criteria. The total incidence of V3 segment anomaly in the patients with bony abnormalities was 25.9% (74/286): PIA was 17.5%, FA was 6.6% and PICA was 1.8%. The total incidence of V3 segment anomaly in the patients without bony abnormalities was 2.7% (152/5671): PIA was 1.76%, FA was 0.4% and PICA was 0.5%. The total incidence of V3 segment anomaly in Asian population without bony abnormalities was 5.8%, while in European and American population was 0.8 and 0.6%, respectively. Patients with bone abnormalities are high risk factor for VA abnormalities, CTA is of paramount importance to evaluate the variant VA anatomy. However, regarding to the low incidence of V3 variation in normal population, we do not recommend preoperative CT angiography as mandatory part of preoperative.

Aim Our study aimed to evaluate the sleep status of psychiatric nurses in Chinese population and analyse the influencing factors. Design Cross-sectional, correlation design with logistic regression analysis. Methods We investigated 1,044 psychiatric nurses from seven psychiatric hospitals in China. Pittsburgh Sleep Quality Index and Maslach Burnout Inventory General Survey were used as main measures. Results The average Pittsburgh Sleep Quality Index score of 1,044 psychiatric nurses was 7.00 ± 3.59, and 38.63% of nurses had a total Pittsburgh Sleep Quality Index score >7. Our study found that middle-night shift nurses had poor sleep quality and sleep disorders are positively correlated with emotional exhaustion and cynical disregard for job burnout. Middle-night shift nurses showed 1.586 times more likely to suffer from sleep disorders than those non-middle-night shift. The higher the score of emotional exhaustion, the greater the risk of sleep disorders.

The purpose of this study was to evaluate the overall survival (OS), relapse-free survival (RFS) and patterns of failure, in patients with SCC and ADC of cervix treated with definitive radiotherapy and to determine whether ADC should be treated differently. Total of 494 patients treated between January 1996 and December 2012 with definitive radiotherapy were included for analysis. Survival probabilities were estimated using Kaplan–Meier method, and differences between the groups were compared using long-rank test. Cox proportional hazards models were used to determine the role of histology after adjusting for potential confounders impacting on survival. The 5-year RFS of node-negative SCC and ADC was 79% and 75% and of node-positive SCC and ADC was 51% and 37%, respectively. The 5-year OS was 74% for both node-negative SCC and ADC and 54% and 42% for node-positive SCC and ADC, respectively. This difference in RFS and OS among these four subgroups was not significant. The tumour volume (p = 0.005), corpus invasion (p = 0.022) and lymph node involvement (p

Radiotherapy and brachytherapy are the definitive treatments for locally advanced cervix cancer. The use of soft-tissue imaging, particularly magnetic resonance imaging, has enhanced their effectiveness and improved clinical outcomes. However, the use of magnetic resonance imaging is largely restricted to well-resourced centres in both the first and developing world and remains elusive to many less advantaged centres, particularly those in areas with a high burden of cervix cancer. Ultrasound is an accessible, affordable and accurate imaging modality that can be used throughout the brachytherapy procedure. Ultrasound is primarily used to ensure safe insertion of the applicator but can also be used to guide planning. The methods used to utilise ultrasound images for planning are described. Ultrasound is particularly useful as a verification aid to confirm applicator placement after patients are moved and transferred around the radiotherapy department. It can also be used to verify the dimensions of treatment volumes over the course of brachytherapy. There is a crucial unmet need for an accessible economical soft-tissue imaging modality in cervical brachytherapy. Ultrasound has the potential to meet this need.

Background Severe hypercalcemia is often associated with uncontrolled malignancy through several mechanisms. However, calcitriol-mediated hypercalcemia is a rare etiology for advanced solid tumors. Case presentation We report a case of calcitriol-mediated hypercalcemia secondary to immune checkpoint inhibition in a responder with metastatic clear cell renal cell carcinoma (ccRCC). In this case, a 68 year old male with metastatic ccRCC to the liver within 4 months of right radical nephrectomy went on to develop hypercalcemia (12.8 mg/dL) shortly following 2 cycles of nivolumab and ipilimumab. Additional testing showed an elevated calcitriol level (142 pg/mL), low parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP) levels, and a normal 25-hydroxyvitamin D level. FDG-PET imaging showed hypermetabolic mediastinal, hilar, and intra-abdominal lymphadenopathy, however the subsequent lymph node biopsy only showed reactive lymphoid cells without malignancy or granuloma. The hypercalcemia was resistant to initial therapy with calcitonin, hydration, and zoledronic acid but quickly responded to high-dose prednisone (1 mg/kg), followed by normalization of calcitriol levels. The patient was rechallenged with nivolumab and ipilimumab which provided a partial response after 4 cycles. He was maintained on low dose prednisone (10 mg daily) leading to a sustained resolution of his hypercalcemia. Conclusion This case suggests calcitriol-mediated hypercalcemia as a novel immune-related adverse event.

International audience; Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.Funding: Loxo Oncology.

Context Despite the marked efficacy of covalent BTK inhibitors (BTKi) in MCL, WM, and MZL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Low oral bioavailability or short half-life of these agents can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). Pirtobrutinib (LOXO-305) is a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal, low nM potency. Objective To evaluate safety and efficacy of pirtobrutinib in pts with MCL/NHLs. Design BRUIN is an ongoing multi-center phase 1/2 trial (NCT03740529). Enrollment was initiated 21 March 2019. Setting Global: community hospitals, academic medical centers. Patients Previously treated pts with advanced B-cell malignancies. Interventions Oral pirtobrutinib (7 dose escalation levels: 25–300mg once daily) in 28-day cycles. Main Outcomes Measures Determining the maximum tolerated dose/recommended phase 2 dose (RP2D), safety profile, and efficacy based on response assessment using disease-specific criteria per protocol. Results As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were treated on 7 dose levels (25–300mg QD). Pirtobrutinib demonstrated high oral exposures, with doses ≥100 mg QD exceeding the BTK IC90 for the entirety of the dosing interval. No DLTs occurred. The only TEAEs, regardless of attribution or grade in ≥10% of pts (n=323), were fatigue (20%), diarrhea (17%) and contusion (13%). A RP2D of 200mg QD was selected. At the efficacy cutoff date, 35 (57%) MCL pts, 18 (69%) WM pts, and 34 (52%) other NHL pts remained on therapy. Among the 52 efficacy evaluable prior BTKi treated MCL pts, the ORR was 52%. Among the 19 efficacy evaluable pts with WM, the ORR was 68%. For the other 55 efficacy evaluable NHL pts, ORR was 24% (DLBCL), 50% (FL), 22% (MZL), and 75% (Richter's transformation). Conclusion Pirtobrutinib demonstrated promising efficacy in MCL and other NHL pts, was well-tolerated and exhibited a wide therapeutic index.

Background Enzalutamide, a major antiandrogen indicated for metastatic castration-resistant prostate cancer, has worrisome toxicities in aging patients. Dose reduction might limit toxicity, but potential loss of efficacy is a concern. We compare up-front low-dose versus standard-dose enzalutamide. Patients and Methods Records of prostate cancer patients receiving enzalutamide were retrospectively retrieved. Selection criteria were: age ≥ 75, metastatic disease, surgical or medical castration, and rising prostate-specific antigen (PSA). Data were excluded of those missing follow-up PSA values. Low-dose enzalutamide (≤ 80 mg per day) was compared to standard dose (160 mg per day). Progression-free survival analyzed the time from start of enzalutamide to event, defined as ≥ 25% and ≥ 2 ng/mL PSA increase above nadir, or death from any cause. Results Fifty-nine patients were identified, of whom 16 received low-dose and 43 standard-dose therapy. Patients in the low-dose group were significantly old, with a median (range) age of 84.6 (74.9-93.8) years; median (range) PSA at start of enzalutamide was 59.2 (11.0-1058.3) ng/mL; 11 had bone metastases only, 2 metastatic lymph nodes only, and 3 bone and lymph node localizations. Pain score was > 3/10 in 4 patients (27%), Eastern Cooperative Oncology Group performance status was ≥ 2 in 9 (56%); 3 patients had received prior abiraterone and 3 bicalutamide. None received chemotherapy. PSA decrease of ≥ 50% at 12 weeks was observed in 67% patients (10/15), versus 45.0% with standard dose. Median (range) PSA at last follow-up was 1.6 (0-599.3) ng/mL. Median progression-free survival was 11.2 months, versus 11.9 months for patients receiving the standard dose (P = .612). Conclusion Low-dose enzalutamide in very old, symptomatic, poor-performance patients with metastatic disease was associated with high response rate and survival comparable to standard dose.

Situs inversus totalis (SIT) is a rare congenital anatomical variation. However, patients with SIT combined with cancer are rare and these patients with two types of lung cancer have not been reported. We report here a case of combined lung adenocarcinoma and solitary fibrous tumor of the pleura with SIT and discuss its clinicopathological features and outcomes. A 68-year-old asymptomatic woman was referred to the Affiliated Hospital of Qingdao University because of an abnormal shadow on chest radiography. Computed tomography showed SIT and an irregularly shaped nodule (measuring 38 × 27 mm in diameter) in the pleural area of the left lower lobe and a 5-mm nodule in the dorsal segment of the lower lobe of the left lung. Surgery was then performed. For such patients, we should eliminate anxiety in patients, perform regular reexaminations, focus on the individual features of these patients, and avoid misdiagnosis because of habitual thinking. At the same time, the lymph nodes should be completely removed and different parts of the tumor with different properties should be treated differently according to the situation.

Purpose Neoadjuvant chemotherapy (NAC) is the standard of care for eligible patients with cT2-4a N0 M0 bladder cancer undergoing surgical resection. The extent to which (and if) NAC increases patient survival is not clear as clinical trials and meta-analyses have generated both negative and “borderline” positive results. The novel method of calculating restricted mean survival times (RMST) may provide a more meaningful way to quantify treatment efficacy due to inherent statistical limitations of conventional hazard ratios. In this study we analyzed the survival benefit attributable to NAC in bladder cancer by calculating RMST of previously published clinical trials. Materials and methods All published randomized controlled clinical trials of bladder cancer with available survival data comparing NAC plus radical cystectomy with cystectomy alone were included. RMSTs were calculated for each cohort at the 5-year and total follow-up time periods, comparing the NAC and radical cystectomy groups. Fixed effect meta-analysis of the 5-year RMSTs was then performed to calculate the net impact of NAC on overall survival. Results For 2 among 7 included trails, RMST analysis changed the statistical significance. The SWOG 8,710 trial that had previously suggested a survival benefit associated with NAC (P = 0.06) was found to have a clearer beneficial association by 5-year RMST (6.5 month benefit; P = 0.01) and total follow-up RMST (13.6 month benefit over 168 months; P = 0.04). The International Collaboration of Trialists trial that had previously suggested a survival benefit with NAC (P = 0.04) was found to have a beneficial association by total follow-up RMST (6.7 months benefit over 120 months; P = 0.04) but not 5-year RMST (P = 0.10). The interpretation of other trials did not change. Fixed effect meta-analysis suggested a clinically significant overall survival benefit associated with NAC (3.2 months benefit over 60 months; P Conclusions Evaluation of published randomized controlled trials using RMSTs strengthens the association of neoadjuvant chemotherapy with survival benefit in bladder cancer. As RMST may enable improved detection of clinical benefit when compared to conventional statistical methods, consideration should be given to RMST-based endpoints in future clinical trial design.

Background: Novel coronavirus pneumonia (NCP) is an emerging, highly contagious community acquired pneumonia (CAP) caused by severe acute SARS-CoV-2. Nucleic acid test currently played a crucial role in diagnosis of suspected COVID-19 patients. However, a high false-negative rate of this “gold standard” test has been reported and posed a major setback in blocking the spread of the virus. We here aim to describe an optimized laboratory detection strategy to reduce the false negative rate. Methods: Suspected NCP patients were asked to collect both coughed up specimen and pharyngeal swab. Samples from the same patient were mixed and tested at a single pool. SARS-CoV-2 was then detected by real-time RT-PCR using two different detection kits. Only if both results were negative was the test reported as negative. The patients will be excluded after two consecutive negative tests at 24 hour intervals. We also used multiplex PCR to detect 13 common respiratory tract pathogens (RTP). Results: Using this strategy, we confirmed 85 SARS-CoV-2 infections from 181 suspected patients, and 94.12% of patients were positive in the first test. The 96 excluded patients were followed up, and no additional NCP was found. We also found that 31.25% patients in 96 non-NCP patients were infected with at least one RTP that may cause CAP. Conclusion: Our studies suggest that dual reagents screening with pooled coughed up specimen and pharyngeal swab samples reduced the false negative rate of nucleic acid testing. During the epidemic of NCP in Anhui province, there was a certain proportion of infection and co-infection of other common pathogens of CAP. In comparison with SARS-CoV-2 detection alone, combining multiple pathogen detection reduces the rate of miss diagnosis.

Background Some cancer patients who are diagnosed with thromboembolism may require dual treatment with vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and factor Xa inhibitors (low-molecular-weight heparin [LMWH] or direct oral anticoagulants [DOACs]). However, to the authors' knowledge, the safety of such combinations has not been well characterized. Methods Patients with advanced cancer who were treated with concurrent VEGFR TKIs and factor Xa inhibitors between 2010 and 2018 at The Ohio State University Comprehensive Cancer Center were included. Charts were reviewed retrospectively for clinically significant bleeding events occurring during concurrent treatment compared with those occurring during factor Xa inhibitor therapy alone, using each patient as their own control. The Fisher exact test was used to compare distribution of bleeding severities. The Cox proportional hazards model was used to compare bleeding risk between groups. Results Among 86 patients, there were 29 clinically significant bleeding events (including 8 major bleeding events) reported during concurrent treatment and 17 events (including 4 major bleeding events) reported during factor Xa inhibitor therapy alone over a median follow-up of 63 days. Concurrent treatment was associated with significantly higher risks of overall bleeding (hazard ratio, 2.45; 95% confidence interval, 1.28-4.69 [P = .007]) and first-onset bleeding (hazard ratio, 2.23; 95% confidence interval, 1.13-4.42 [P = .02]). Analysis of 6-month bleeding risk and the subgroups of patients treated with concurrent TKIs and LMWH versus LMWH alone demonstrated a similar trend. The sample size was inadequate for comparisons between treatment with concurrent TKIs and DOACs versus DOACs alone. Conclusions Concurrent treatment with VEGFR TKIs and LMWH was found to be associated with a significantly increased risk of bleeding events when compared with LMWH therapy alone.

ObjectiveThe gut microbiota (GM) can have complicated and often undetermined interactions with the function of many organs in the body. GM is altered in a variety of liver diseases, but the significance of such changes on the liver disease is still unclear. Hepatic autophagy deficiency causes liver injury accompanied with cholestasis. Here, we investigated the impact of such hepatic changes on GM and in turn the effect of gut dysbiosis on liver injury.DesignFecal microbiota from mice with liver-specific loss of autophagy-related gene 5 (Atg5), Atg5Δhep mice, were analyzed by 16S sequencing. Antibiotics (ABX) was used to modulate GM in mice. Cholestyramine was used to reduce the enterohepatic bile acid (BA) level. The functional role of fibroblast growth factor 15 (FGF15) and ileal farnesoid X receptor (FXR) was examined in mice over-expressing FGF15 gene, or given a fibroblast growth factor receptor 4 (FGFR4) inhibitor.ResultsThe composition of GM was significantly changed with a notable increase of BA-metabolizing bacteria in Atg5Δhep mice, leading to a lower proportion of tauro-conjugated BAs and a higher proportion of unconjugated BAs in the intestine, which markedly activated ileal FXR with an increased expression of FGF15. ABX or cholestyramine treatment exacerbated liver injury and ductular reaction, and decreased FGF15 expression, whereas modulating FGF15 signaling altered liver phenotypes in the autophagy-deficient mice.ConclusionGut dysbiosis can remedy liver injury in Atg5Δhep mice through the FXR-FGF15 signaling. Antibiotics use in the condition of liver injury may have unexpected adverse consequences via the gut-liver axis.SHORT SUMMARYWhat is already known about this subject?Gut microbiota (GM) can be altered during hepatic pathogenesis.GM are involved in bile acid (BA) metabolism.Autophagy deficiency in the liver disrupts BA homeostasis and causes cholestatic injury.What are the new findings?Deficiency of autophagy in the liver causes alteration of GM, which leads to a higher proportion of BA-metabolizing bacteria.GM contribute to the activation of ileal farnesoid X receptor (FXR) and a higher expression of fibroblast growth factor 15 (FGF15) in autophagy deficient condition in the liver, which is associated with decreased levels of conjugated BAs and increased levels of unconjugated BAs in the intestine.Manipulations that lead to GM alteration, intestinal BA signaling, or FGF15 signaling can all modulate the liver phenotype.BA and GM together can act as a sensor to liver injury to trigger FGF15-mediated protective mechanism.How might it impact on clinical practice in the foreseeable future?These findings indicate that gut dysbiosis in the scenario of liver disease can be beneficial, suggesting cautions should be exercised in the use of antibiotics during specific liver diseases.If antibiotics need to be used in patients with liver diseases it may be beneficial to enhance the FXR-FGF15 feedback signaling to retain the protective effect of GM.

Background DNA damage response (DDR) genomic alterations may play an important role in clinical outcomes of patients with urothelial cancer (UC). However, data on the prognostic role of DDR gene alterations in patients with advanced UC remain unclear. Materials and Methods We retrospectively collected data of three independent patient cohorts with relapsed or advanced UC including 81 and 91 patients from four institutions who underwent FoundationOne genomic sequencing as well as 129 patients selected from The Cancer Genome Atlas bladder cohort. Fisher's exact test was used to determine differences of mutation frequency among the three cohorts. Logistic regression analysis was performed to calculate odds ratio (OR) and 95% confidence interval (CI). Overall survival (OS) was measured from time of initial diagnosis and Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% CI. Results DDR genomic alterations were present in 76.5% (62/81), 40.7% (37/91), and 51.2% (66/129) of the three cohorts. ATM alterations consistently correlated with significantly shorter OS, whereas other DDR alterations (excluding ATM) were associated with better prognosis. In 152 patients treated with platinum pooled from the three cohorts, the prognostic value of alterations in ATM as compared with other predefined DDR genes was substantially different (ATM: adjusted HR [HR], 2.03; 95% CI, 1.03–4; p = .04; other DDR: adjusted HR, 0.49; 95% CI, 0.31–0.8; p = .003). Conclusions Genomic alterations in ATM and other DDR genes may have opposite prognostic value in relapsed and/or advanced UC. ATM may have a complex role in UC progression. Implications for Practice Somatic mutations of DNA damage response (DDR) genes are frequently found in urothelial cancer and appear to play an important role in tumorigenesis, progression, treatment response, and outcomes. In a set of DDR genes, ATM alterations were associated with worse survival, while other alterations were associated with better survival in advanced urothelial cancer. The results of this study suggest a complex role of ATM in tumor progression and call for further studies to determine the underlying mechanisms and biomarker clinical utility.

Depression may be associated with reduced monoamine neurotransmission, particularly serotonin and norepinephrine (NE). Reuptake of NE by the norepinephrine transporter (NET) is the primary mechanism by which many of the antidepressants are high-affinity substrates for NET. This study aimed to examine the effect of lentivirus-mediated shRNA targeting NET in locus coeruleus (LC) on depression-like behaviors of rats. We randomly assigned 60 male Wistar rats to 6 experimental groups: (1) Control group: without chronic unpredictable mild stress (CUMS) and without NET-shRNA treatment; (2) shRNA group: without CUMS + NET-shRNA; (3) CUMS group: 3-week CUMS without NET-shRNA; (4) CUMS + nonsense shRNA group; (5) CUMS + amygdala (Amy)-shRNA group; (6) CUMS+ locus coeruleus (LC)-shRNA group. First, recombinant lentiviral vector expressing shRNA (ShRNA-629, ShRNA-330, ShRNA-1222, ShRNA-1146 or ShRNA- negative control) against NET were produced, and their efficiency in knocking down of NET in PC12 cells were assessed by Q-PCR and western blot analysis. Second, shRNA was injected into the rat LC bilaterally to investigate whether it could prevent the depressive-like behavior induced by 3-week CUMS. Third, we tested the depressive-like behavior of the rats in the forced swimming test, the open field test, the sucrose preference test, as well as the body weight gain at the end of the seventh week. Finally, the protein expressions of NET was measured by western blot and the NE levels were measured by high performance liquid chromatography. Q-PCR and western blot showed that the ShRNA-1146 had the best interference efficiency targeting on NET in PC12 cells (p p p p p

The COVID-19 pandemic is a significant global event in the history of infectious diseases. The SARS-CoV-2 appears to have originated from bats but is now easily transmissible among humans, primarily through droplet or direct contact. Clinical features of COVID-19 include high fever, cough, and fatigue which may progress to ARDS. Respiratory failure can occur rapidly after this. The primary laboratory findings include lymphopenia and eosinopenia. Elevated D-dimer, procalcitonin, and CRP levels may correlate with disease severity. Imaging findings include ground-glass opacities and patchy consolidation on CT scan. Mortality is higher in patients with hypertension, cardiac disease, diabetes mellitus, cancer, and COPD. Elderly patients are more susceptible to severe disease and death, while children seem to have lower rates of infection and lower mortality. Diagnostic criteria and the identification of persons under investigation have evolved as more data has emerged. However, the approach to diagnosis is still very variable from region to region, country to country, and even among different hospitals in the same city. The importance of a clinical pathway to implement the most effective and relevant diagnostic strategy is of critical importance to establish the control of this virus that is responsible for more and more deaths each day.

The outbreak of the novel coronavirus disease 2019 (COVID-19) infection began in December 2019 in Wuhan, and rapidly spread to many provinces in China. The number of cases has increased markedly in Anhui, but information on the clinical characteristics of patients is limited. We reported 75 patients with COVID-19 in the First Affiliated Hospital of USTC from Jan 21 to Feb 16, 2020, Hefei, Anhui Province, China. COVID-19 infection was confirmed by real-time RT-PCR of respiratory nasopharyngeal swab samples. Epidemiological, clinical and laboratory data were collected and analyzed. Of the 75 patients with COVID-19, 61 (81.33%) had a direct or indirect exposure history to Wuhan. Common symptoms at onset included fever (66 [88.0%] of 75 patients) and dry cough (62 [82.67%]). Of the patients without fever, cough could be the only or primary symptom. The most prominent laboratory abnormalities were lymphopenia, decreased percentage of lymphocytes (LYM%), decreased CD4+ and CD8+ T cell counts, elevated C-reactive protein (CRP) and lactate dehydrogenase (LDH). Patients with elevated interleukin 6 (IL-6) showed significant decreases in the LYM%, CD4+ and CD8+ T cell counts. Besides, the percentage of neutrophils, CRP, LDH and Procalcitonin levels increased significantly. We concluded that COVID-19 could cause different degrees of hematological abnormalities and damage of internal organs. Hematological profiles including LYM, LDH, CRP and IL-6 could be indicators of diseases severity and evaluation of treatment effectiveness. Antiviral treatment requires a comprehensive and supportive approach. Further targeted therapy should be determined based on individual clinical manifestations and laboratory indicators.

Supplemental Digital Content is available in the text, Elderly women with early-stage, nonmetastatic breast cancer do not always receive recommendations for definitive surgical treatment. The reasons vary and include patient and provider-related reasons. We queried the surveillance, epidemiology, and end results database from 2010 to 2013 for women age 60 and older with stage I/II/III invasive breast cancer for whom local treatment was known. We divided the patients into 3 groups: patients for whom surgery was performed; patients for whom surgery was recommended but not performed; patients for whom surgery was not recommended and not performed. We used Kaplan–Meier method to generate OS curves and the Cox proportional hazard test to compare survival outcomes. A total of 119,404 patients were eligible for study with a median age between 70 and 74 years old. Compared with patients who received breast surgery, patients who did not receive surgery had a worse overall survival (OS) (hazard ratio [HR], 7.39; 95% confidence interval [CI], 6.98–7.83, P

One of the major criticisms of laparoscopic colectomy is the requirement of an additional mini laparotomy to remove the resected specimen. This may be associated with postoperative pain and wound complications. Therefore, the use of a natural orifice as a delivery route for the specimen extraction without a laparotomy incision can subsequently reduce the risk of wound complications. In this video, we demonstrate the natural orifice specimen extraction procedure with a side-to-end single-stapling colorectal anastomosis.

Background: Characterization of the different genomic alterations (GAs) in urothelial carcinoma (UC), by site of origin, may identify contrasting therapeutic opportunities and inform distinct putative pathogenetic mechanisms. Objective: To describe the genomic landscape of UC based on the anatomic site of the primary tumor. Design, setting, and participants: In total, 479 upper tract UC (UTUC) and 1984 bladder UC (BUC) patients underwent comprehensive genomic profiling (CGP) to evaluate all classes of GAs, tumor mutational burden (TMB), and microsatellite instability (MSI) status. Targetable GAs and signatures were assessed according to the European Society for Medical Oncology Scale for Clinical Actionability of molecular Targets (ESCAT). Intervention: Hybrid-capture–based CGP. Outcome measurements and statistical analysis: Descriptive analyses and differences between anatomic subgroups were reported. Results and limitations: In total, 39% of patients with UC harbored one or more tier 1–2 GAs, suggesting potential benefit from approved or investigational therapies. UTUC cases were enriched in FGFR3 short variant (SV) GA (20% vs 13%) and HRAS SV GA (7.3% vs 3%), the latter attributed specifically to enrichment in renal pelvis UC (9.5%) versus ureteral UC (1.8%, p = 0.002). RB1 GAs were more frequent in BUC than in UTUC (21% vs 7.8% p < 0.001). Non-FGFR3 kinase fusions were observed in 1% of patients, including BRAF/RAF1 fusions in 0.5%. BRAF mutations/fusions were observed in 2% of cases and were mutually exclusive with FGFR3 GA (p = 0.002). There were no differences of TMB high/MSI high for primary tumor and metastatic sites, but UTUC was enriched for MSI high (3.4%) relative to BUC (0.8%, p < 0.001). Conclusions: Differences in the genomic landscapes of UTUC and BUC were modest; however, patients with UTUC were enriched for FGFR3 and HRAS SV relative to BUC. Further investigation on UC, stratified by the site of origin, is warranted. In addition, these results suggest an opportunity for the routine incorporation of CGP prior to systemic therapy initiation in metastatic UC. Patient summary: Genomic profiling of advanced urothelial carcinoma can inform several therapeutic opportunities for patients, particularly those with upper tract urothelial carcinoma, an infrequent and generally aggressive tumor entity with nonoverlapping clinical features compared with its bladder counterpart, which is often treated based on the data extrapolated from bladder cancer.

Background Oxidative stress is related to brain injury after spontaneous intracerebral hemorrhage (ICH). Myeloperoxidase (MPO) is a potent oxidizing enzyme. We tested the hypothesis that serum MPO concentrations are increased after ICH and they correlate with stroke severity and outcome. Methods Serum MPO concentrations were measured in 128 ICH patients and 128 controls. Odds ratios of dependent variables, including early neurological deterioration, hematoma growth, 1-week mortality, 6-month mortality, 6-month unfavorable outcome (modified Rankin Scale score > 2) and 6-month overall survival, were calculated and adjusted for age, sex, hematoma volume, National Institutes of Health Stroke Scale (NIHSS) score and vascular risk factors. Results As compared to the controls, the patients had significantly increased serum MPO concentrations. MPO concentrations of the ICH patients were strongly correlated with hematoma volume and NIHSS scores. Serum MPO were independently associated with the above-mentioned study points. Its area under receiver operating characteristic curve was equivalent to those of hematoma volume and NIHSS score. Moreover, serum MPO significantly improved the discriminatory ability of hematoma and NIHSS in predicting 6-month mortality and unfavorable outcome. Conclusions Serum MPO concentrations rise in ICH patients and there is a correlation between MPO concentrations and severity or prognosis.

Objectives The role of adjuvant radiotherapy for lymph node-negative stage IB patients with tumor-related negative prognostic factors is not uniformly accepted. It is advocated based on the GOG 92 trial, which was initiated in 1989. The aim of the current study is to report the oncological outcome of “intermediate risk” patients treated by tailored surgery without adjuvant radiotherapy. Data from two institutions that refer these patients for adjuvant radiotherapy served as a control group. Methods Included were patients with stage IB cervical cancer treated with radical hysterectomy and pelvic lymphadenectomy, who had negative pelvic lymph nodes but a combination of negative prognostic factors adopted from the GOG 92 trial. Data were obtained from prospectively collected databases of three institutions. Radical surgery was a single-treatment modality in one of them and in the remaining two institutes it was followed by adjuvant chemoradiation. Results In 127 patients who received only radical surgery, with a median follow-up of 6.1 years, the local recurrence rate was 1.6% (2 cases), and total recurrence was 6.3% (8 cases). Disease-specific survival at 5 years was 95.7% (91.9%; 99.4%) and 91% (83.7%; 98.3%) at 10 years. The only significant factor for disease-specific survival was tumor size ≥4 cm (P = 0.032). The recurrence rate, local control or overall survival did not differ from the control group. Adjuvant radiotherapy was not a significant prognostic factor within the whole cohort. Conclusions An excellent oncological outcome, especially local control, can be achieved by both radical surgery or combined treatment in stage IB lymph node-negative cervical cancer patients with negative prognostic factors. The substantially better outcome than in the GOG 92 trial can be attributed to more accurate pre-operative and pathological staging and an improvement in surgical techniques.

Objective To systematically study demographic, clinical, electrophysiological and nerve ultrasound characteristics of ulnar neuropathy with abnormal non-localizing electrophysiology (NL-UN) and further define the utility of ultrasound over and above the conventional electro-diagnostic approach. Method NL-UNs were prospectively identified from 113 consecutive referrals with suspected ulnar neuropathy. All received electro-diagnostic tests and ulnar nerve ultrasound. NL-UN severity was graded using clinical and electrophysiological scales. Results In 64 of 113 referrals, an ulnar mono- neuropathy was confirmed by electrophysiology. Sixteen of these 64 (25%) had NL-UN, predominantly males (14 out of 16 patients) with severe or moderate clinical and electrophysiological ratings. Ultrasound showed focal ulnar neuropathy at the elbow in 13 out of 16, and diffuse ulnar nerve abnormality in three, and identified a likely or possible causative mechanism in 11. Conclusion A significant proportion (a quarter) of ulnar neuropathies with abnormal electrophysiology were NL-UN, of heterogeneous etiology; the majority were males with significant disability and axonal loss. Ultrasound had a significant role in localization and classification that facilitated management. Significance To our knowledge, this is the first systematic prospective study that analyzes the demographic, clinical, electrophysiological and ultrasound characteristics of NL-UN in a routine clinical neurophysiology setting.

Endometrial cancer is the most common gynecologic cancer in women today. It is surgically staged, and while surgery is the primary treatment modality, the identification of disease extent—in particular extrauterine spread—prior to surgery is important to optimize treatment decision making. Ultrasound and MRI are useful for evaluating the extent of local disease, while CT and PET are used for detecting lymph node or distant metastases. Diffusion-weighted MRI has also been used for detecting small metastatic deposits in lymph nodes and omentum. Extrauterine soft tissue involvement can be detected by ultrasound, CT, MRI, and PET. Recently, intraoperative visualization techniques, such as sentinel lymph node mapping, are increasingly used to avoid extensive surgical staging without compromising treatment. Imaging is also used for planning adjuvant treatment and detection of postoperative residual disease in high-risk patients, monitoring and detecting recurrent disease, and in post-treatment surveillance of asymptomatic patients with high risk of relapse.

// Ming Yin 1, 6 , Petros Grivas 2, 7 , Hamid Emamekhoo 3 , Prateek Mendiratta 2 , Siraj Ali 4 , JoAnn Hsu 5 , Monali Vasekar 1 , Joseph J. Drabick 1 , Sumanta Pal 5 and Monika Joshi 1 1 Department of Medicine, Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, USA 2 Department of Hematology and Medical Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland Clinic, Cleveland, OH, USA 3 Department of Medicine, Division of Hematology-Oncology, University of Wisconsin Carbone Cancer Center, WI, USA 4 Foundation Medicine, Cambridge, MA, USA 5 Department of Medical Oncology, City of Hope Comprehensive Cancer Center, Duarte, CA, USA 6 Department of Medicine, Division of Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA 7 Department of Medicine, Division of Oncology, University of Washington, Seattle, WA, USA Correspondence to: Monika Joshi, email: mjoshi@pennstatehealth.psu.edu Keywords: biomarkers; prognosis; bladder cancer; genomic alterations; next generation sequencing Received: November 30, 2017 Accepted: March 02, 2018 Published: March 30, 2018 ABSTRACT Background: Mutations of DNA repair genes, e.g. ATM/RB1 , are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of ATM/RB1 mutations in UC can inform clinical decision making and trial designs. Results: In the discovery dataset, ATM/RB1 mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45–4.92, p = 0.002). There was a higher mutation load in patients carrying ATM/RB1 mutations (median mutation load: 6.7 versus 5.5 per Mb, p = 0.072). In the validation dataset, ATM/RB1 mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97–3.59, p = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, p = 0.126). Materials and Methods: Exome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of ATM/RB1 mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS). Conclusions: ATM/RB1 mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of ATM/RB1 mutation status to immunotherapy and platinum-based chemotherapy.

Objectives: This study aimed to assess the accuracy of ocular ultrasound performed by emergency physicians for diagnosis of retinal detachment. Methods: This was a prospective single-center observational study conducted between September 2013 and February 2015. All adult patients presenting to the emergency department with acute onset of visual changes were eligible to participate. Patients who met one of the following criteria were excluded: a diagnosis of retinal detachment had already been made by an ophthalmologist prior to attendance; pre-existing retinal detachment currently under treatment; hemodynamically unstable; suspected rupture eyeball; and unable to give consent. Six emergency physicians performed emergency ocular ultrasound using a linear 10-MHz ultrasound probe. An abnormal lifting of the retina or the presence of a retinal flap was considered diagnostic of retinal detachment. The final diagnosis of the ophthalmologist who was blinded to the study was used as the gold standard. Results: Among the 139 patients evaluated, 16 (12%) had retinal detachments and 14 of them were correctly identified (true positives). Of the 123 patients (88%) without retinal detachment, 107 patients were correctly identified (true negatives). The sensitivity and specificity of emergency ocular ultrasound for retinal detachment were 88% (95% confidence interval = 60 to 98) and 87% (95% confidence interval = 79 to 92), respectively. Conclusion: Emergency ocular ultrasound is a useful adjunct for the diagnosis of retinal detachment.

Background CXC chemokine ligand-12 (CXCL12), a member of the CXC chemokine subfamily, is involved in both focal angiogenesis and inflammatory reactions. We examined serum CXCL12 concentration in intracerebral hemorrhage (ICH) patients and its correlation to stroke severity and outcome. Methods The study was carried out on 105 ICH patients on 105 healthy controls. Serum samples were at admission obtained to measure CXCL12 concentrations. The National Institutes of Health Stroke Scale (NIHSS) and hematoma volume were recorded to assess stroke severity. Results As compared to the controls, CXCL12 concentrations were significantly increased in the patients. Also, non-survivors within 6 months and patients with an unfavorable outcome (modified Rankin Scale score > 2) at 6 months had higher CXCL12 concentrations than other remaining ones. CXCL12 concentrations had positive correlation with NIHSS scores and hematoma volume. Serum CXCL12 significantly discriminated patients at risk of 6-month mortality and 6-month unfavorable outcome under receiver operating characteristic curve. Moreover, serum CXCL12 was independently associated with the mortality, overall survival and unfavorable outcome. Conclusions Serum CXCL12 concentrations are enhanced after ICH and CXCL12 in serum has the potential to reflect severity and prognosis following hemorrhagic stroke.

Background: The aim of this study was to retrospectively investigate the 18-year experience of prenatal diagnosis of fetal karyotype analysis by amniocentesis. Methods: In this study, the authors reviewed the cytogenetic results of 40,208 fetuses with indications for amniocentesis enrolled from December 1998 to December 2015. Cytogenetic analysis of amniotic fluid was performed in all these pregnancies. Eight indications for amniocentesis were included. The detection rate and distribution of abnormal karyotypes were observed in each indication. Results: Among all these samples, abnormal maternal serum screening test was the most common indication for amniocentesis (17,536, 43.67%), followed by advanced maternal age (11,734, 29.18%), abnormal ultrasound findings (5,328, 13.25%), and required by pregnant women (2,557, 6.36%). Chromosomal abnormality was detected in 1,349 (3.36%) samples, 63.01% of the abnormalities were numerical, and 36.99% were structural. The detection rates of abnormal karyotype were 55.60% in one of the couple with chromosomal abnormality, 4.43% in the pregnant women with pathological ultrasound finding, 2.83% in the pregnant women with advanced age, and 2.73% in women with abnormal maternal serum screening tests. Of the fetuses with chromosome aberrations, 680 (50.41%) had trisomy 13, trisomy 18, or trisomy 21, and 138 (10.23%) had sex chromosome disorder. The other 531 abnormal samples included translocation, mosaicism, inversion, deletion, addition, and marker chromosome. Conclusions: Cytogenetic analysis, therefore, remained an effective approach to decrease the birth defects of fetuses with indications for amniocentesis. These results could provide meaningful suggestions for clinical genetic consulting and prenatal diagnosis.

Background Breast angiosarcoma is a rare malignancy with limited publications confined to small retrospective case reviews and case reports. Knowledge of this disease is limited because information from previous studies is insufficient and inconsistent. Methods We obtained data from the Surveillance, Epidemiology, and End Results Program for non-metastatic primary and secondary breast angiosarcoma, and performed analysis to determine clinicopathological characteristics and estimate their associations with overall survival (OS). Results Median age was 50–54 years in primary breast angiosarcoma and 70–74 years in secondary breast angiosarcoma, while median OS was 93 and 32 months, respectively. Age, tumor grade and tumor spread were associated with poor survival outcomes. Compared with primary breast angiosarcoma, patients with secondary breast angiosarcoma had a “nominal” increased death risk (HR = 1.89, 95% CI, 1.43–2.50, p

Objectives: The aim of this study was to quantify the shift in patients from the FIGO 2009 to the FIGO 2018 staging using a prospectively collected dataset where pre-treatment MRI and PET-CT were used. A secondary aim was to explore the distribution of known prognostic factors in both staging schema. Methods: Prospectively collected dataset of 1047 cervix cancer patients staged with MRI and PET-CT, between 1996 and 2014, were redistributed using FIGO 2018 staging criteria. Standard deviation inter-quartile and contingency tables were used to present the distribution of patients according to FIGO 2009 and FIGO 2018 criteria. Logistic regression was used to evaluate the association of node positivity and nodal size. Results and Discussion: In total, 853 patients were available for analyses. Based on MRI and PET findings, according to FIGO 2009, the incidence of lymph node metastasis was similar in (1) stages 1b1 and 2a1, (2) 1b, 2a2, 2b and 3a (3) 3b and 4a. Nodal metastases were found in 43% patients who were upstaged from FIGO 2009 to newly created FIGO 2018 stages 3c1 and 3c2. Contribution to stage 3c1 came from 31, 41, 29, 30, 32, 33 and 34% of stages 1b1, 1b2, 2a1, 2a2, 3a and 3b, respectively. FIGO 2009 stages 1b1 and 1b2 contributed 5 and 6%, stages 2a1, 2a2, 2b and 3a contributed 16, 15 and 15% to para-aortic nodes, while stage 3b contributed 24%. These findings will likely influence cervix cancer treatment policies.

Tumor biomarkers are important in the early screening, diagnosis, therapeutic evaluation, recurrence and prognosis prediction of tumors. Primary liver cancer is one of the most common malignant tumors; it has high incidence and mortality rates and seriously endangers human health. The main pathological types of primary liver cancer include hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (ICC) and combined HCC‑cholangiocarcinoma (cHCC‑CC). In the present review, a systematic outline of the current biomarkers of primary liver cancer is presented, from conventional blood biomarkers, histochemical biomarkers and potential biomarkers to resistance‑associated biomarkers. The important relationships are deeply elucidated between biomarkers and diagnosis, prognosis, clinicopathological features and resistance, as well as their clinical significance, in patients with the three main types of primary liver cancer. Moreover, a summary of several important biomarker signaling pathways is provided, which is helpful for studying the biological mechanism of liver cancer. The purpose of this review is to provide help for clinical or medical researchers in the early diagnosis, differential diagnosis, prognosis and treatment of HCC.