bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcomes in patients with anemia hospitalized for endometrial cancer resection: A nationwide analysis.
Authors: Frasier Kelly , Javaid Saad , Li Vivian , Vinagolu-Baur Julia , Ortega Yaguachi Nataly , Rodriguez Evadne , Del Castillo Olivia , Batista Raquel , Jonas Kenlee , Palma Laura
Published: June 2024

e17585

Background: Endometrial cancer is the most common gynecological malignancy, and It is notably associated with the development of anemia. In light of this, we conducted a retrospective analysis to determine the impact of anemia on patients hospitalized for endometrial cancer resection and other complications during hospitalization. Methods: We conducted a study using the National Inpatient Sample (NIS) data from 2019 and 2020 to identify patients who were admitted with a primary diagnosis of endometrial cancer resection and had a concurrent secondary diagnosis of anemia. Primary outcomes included mortality, and secondary outcomes were the length of stay, total hospitalization charges, and other adverse hospital outcomes. Multivariate logistic regression analysis was used to adjust for confounding variables. Results: A total of 375,109 patients were hospitalized for resection of Endometrial cancer, among whom 55,345 had concurrent anemia. After adjusting for confounding factors, no difference in mortality between the two groups was observed(OR=1.37, 0.91-2.07; p=0.127). However, patients with anemia had a longer length of stay (4.11 days without and 6.05 days with anemia, p<0.001) and a higher total cost of hospitalization ($ 81,112 without and $ 108,436 with anemia, p<0.001). Patients with anemia were at a higher risk of developing sepsis (OR=3.15, 2.60-3.82, p<0.001), acute respiratory failure (OR= 2.64, 2.19-3.19; p<0.001), ICU admission (OR= 2.30, 1.95-2.72; p<0.001), acute coronary syndrome (OR= 2.17, 1.06-4.43; p=0.032), acute kidney injury (OR= 2.78, 2.50-3.09; p<0.001), constipation (OR =1.51, 1.33-1.71; p<0.001), diarrhea (OR= 2.11, 1.61-2.76; p<0.001), pneumonia (OR =2.20, 1.70-2.84; p<0.001), red blood cell transfusion (OR= 9.45, 8.39-10.64; p<0.001), platelet transfusions (OR= 4.43, 3.19-6.16; p<0.001), venous thromboembolism (OR= 2.50, 2.07-3.03; p<0.001), enteral feeding (OR= 6.96, 1.59-30.43; p=0.01), parenteral feeding (OR= 2.91, 2.19-3.85; p<0.001), urinary tract infection (OR =2.08, 1.77-2.43; p<0.001), and the involvement of palliative care (OR= 1.59, 1.18-2.13; p<0.001). There was no difference in having chemotherapy in both groups (OR 0.79, 95% CI 0.29-2.12, p=0.652). Conclusions: Anemia is associated with increased healthcare resource utilization and adverse in-hospital outcomes in patients undergoing resection of Endometrial cancer. Anemia might not be the only predictor of mortality, but identifying and treating it before any interventions can decrease the risk of adverse outcomes and improve quality of life. [Table: see text]
Clinical significance of the risk model based on exosome-derived miRNA and miR-486-5p for endometrial cancer.
Authors: Zheng Jianfeng , Lin Xuefen , Jiang Ruina , Sun Yang
Published: June 2024

e17588

Background: Exosome-derived miRNAs are detectable in various body fluids and play a crucial role in the diagnosis and prognosis of endometrial cancer (EC). The objective of our study is to investigate the clinical significance of an exosome-derived miRNA-based risk model, specifically focusing on miR-486-5p for EC. Methods: The expression profile of plasma-derived exosomal miRNAs was obtained through high-throughput sequencing. The expression profile of mature miRNAs for patients with EC was also obtained from TCGA. The prognostic value of differentially expressed miRNAs was assessed using R packages. The accuracy and stability of exosomal miRNAs in diagnosing EC were assessed using machine learning algorithms. The risk model based on exosome-derived miRNA was established using LASSO Cox regression analysis. The clinical significance of the risk model, including prognosis and anti-tumor therapy, was identified and validated using R packages. The most significant exosomal miRNA, miR-486-5p, was selected for wet experiments, including quantitative real-time PCR, Western Blot, CCK8, colony formation, transwell migration, wound healing, flow cytometry, and dual-luciferase reporter assays. Six databases and comprehensive bioinformatics approaches were integrated to predict targets of miR-486-5p. Data of single cell RNA was used to screen out the recipient cell of exosomal miR-486-5p. Results: A total of 49 exosomal miRNAs exhibited differential expression between plasma samples obtained from women with EC and controls. A total of 33 exosomal miRNAs exhibiting prognostic significance were identified. The area under the receiver operating characteristic curve (AUC) of the diagnostic model calculated by machine learning algorithms exceeded 0.9 in all sets. The risk model based on exosome-derived miRNA could be used to stratify EC patients with different prognosis. The AUC value of the time-dependent ROC curve for the risk model exceeded 0.7. Additionally, our study revealed that patients with EC, stratified based on the risk model, exhibited varying responses to anti-tumor therapy such as Tamoxifen. The single-cell transcriptome sequencing data revealed a significantly elevated expression abundance of FOXO1, the miR-486-5p target gene, in macrophages within the immune microenvironment. The experimental results demonstrated that miR-486-5p exerted a promotive effect on cellular proliferation, migration, invasion, and metabolic dysfunction through the inhibition of FOXO1. Furthermore, we observed that the exclusion of miR-148a-3p via exosomes promoted macrophage M2 polarization by FOXO1-mediated metabolic dysfunction. Conclusions: Our data has provided insights into the clinical significance of the risk model based on exosome-derived miRNA, as well as revealing the mechanism involving miR-486-5p in metabolic dysfunction through FOXO1 for endometrial cancer.
Chemical hair relaxer use and its potential effect on incidence of endometrial cancer in Black women.
Authors: Hedin Tosha , Haider Mahvish
Published: June 2024

e17591

Background: Research is being conducted to determine chemical hair relaxer’s effects on women’s risk of endometrial cancer (EC). Recent studies have suggested that frequent use (>4 times/year) of chemical relaxers increases incidence of EC by a hazard ratio of 2.55. Black women purchase 60% of chemical straighteners in the United States while being 6.5% of the population. Hair relaxer can be made from sodium hydroxide, lithium hydroxide, or potassium hydroxide. These chemicals can cause a hormone imbalance with estrogen, leading to increased endometrial cancer incidence. This study aims to correlate population data of endometrial cancer and hair relaxer to explain the increased incidence of gynecologic cancer in Black women. Methods: The average rate of incidence per 100,00 per year for endometrial cancer for White and Black women were obtained from the National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program SEER*Stat Database: NPCR and SEER Incidence – U.S. Cancer Statistics 2001–2019 Public Use Research Database. Chemical relaxer was first commercially available in 1971. The average age of endometrial cancer diagnosis was obtained from the National Cancer Institute. Results: Nineteen years of data was collected from the SEER database. EC had 222,464 cases total. In the year 2001, EC incidence was most common in White women at a rate of 25 per 100,000. Black women were second, at a rate of 20 per 100,000. In 2017, Black women surpassed White women for most incidence with a rate of 28, in comparison to White women's rate of 27.5 per 100,000. In the year 2019, Black women increased to the rate of 29 per 100,000, which was greater than White women's rate at 27.6 per 100,000. Conclusions: Studies have shown that ever use of hair relaxer in the past 12 months is associated with higher incidence of EC. The hazard ratio increases to 2.55 when hair relaxer is used 4 or more times per year. The National Cancer Institute states that the average age to be diagnosed with EC is 60 years old for all races of women. Because hair relaxer was made commercially available in 1971, the year 2017 would be when women at the average age of diagnosis would have access to hair relaxer their entire lives. 2017 is also the year when Black women became the racial group with the highest incidence of EC in the United States. Hair relaxer could be an important variable as to why EC incidence in Black women has surpassed White women. In the future, this information could be used to risk stratify women for cancer surveillance or have warning labels placed on hair relaxer boxes.
Assessment of sociodemographic factors in timely endometrial cancer diagnosis following an abnormal transvaginal ultrasound performed for postmenopausal bleeding.
Authors: Atkins Sage , Nolin Angela , Unnithan Shakthi , Myers Evan R. , Moss Haley , Erkanli Alaattin , Havrilesky Laura J.
Published: June 2024

e17595

Background: Postmenopausal bleeding (PMB) is the most common initial presentation of endometrial cancer. The American College of Obstetrics and Gynecology recommends evaluation of PMB with transvaginal ultrasound (TVUS) to determine the endometrial stripe (ES) thickness, followed by tissue sampling if ES >4 mm. We assessed if differences in race, ethnicity, language, or insurance status were associated with delayed endometrial sampling following an abnormal ES on TVUS, and if the timing of endometrial sampling after TVUS was associated with differences in rates of endometrial cancer diagnosis and staging. Methods: We conducted a retrospective study of consecutive patients with an intact uterus and PMB who presented to a single academic institution and underwent TVUS between January 2013-December 2022. TVUS was characterized as normal (ES ≤4 mm), abnormal (ES >4 mm), or inadequate (ES not fully visualized). Prompt sampling was defined as sampling with endometrial pathology within 3 months of abnormal TVUS. Logistic regression analyses were performed to characterize associations between race, ethnicity, preferred language, insurance status and prompt endometrial sampling. We assessed rates of endometrial cancer diagnosis and stage at diagnosis, comparing sampling at ≤3 versus 3-12 months after TVUS. Results: Among 3,369 patients meeting inclusion criteria, 1,671 (50%) had abnormal ES. Out of the total cohort, patients with an abnormal ES comprised 576/1336 (43%) of Black or African American and 946/1889 (50%) of White patients. 307/1671 (18%) of patients with abnormal ES did not receive prompt sampling. Neither race (Black OR 1.03, 95% CI 0.79-1.35 vs White), ethnicity, (Hispanic OR 1.1, 95% CI 0.54-2.27 vs. non-Hispanic), non-English primary/preferred language (OR 0.9, 95% CI 0.47-1.71 vs English), nor Medicare insurance status (OR 0.96, 95% CI 0.65-1.42 vs private insurance, age-adjusted) were associated with prompt endometrial sampling after abnormal ES. Endometrial cancer was diagnosed in 147/1227 (12%) of cases who underwent sampling for abnormal ES (143/1165 (12%) with prompt sampling and 4/62 (6%) with delayed sampling). The stage distribution of endometrial cancers diagnosed after prompt sampling was 107/133 (80%) Stage I and 26/133 (20%) stage II-IV, compared to 2/4 (50%) stage IA and 2/4 (50%) stage II-IV after delayed sampling. Conclusions: One in five patients with PMB and an abnormal appearing endometrium on ultrasound did not receive appropriate sampling within 3 months. Race, ethnicity, language, and insurance status were not associated with timely receipt of endometrial sampling following an abnormal ultrasound. With prompt endometrial sampling for abnormal TVUS, 80% of endometrial cancers are diagnosed at the earliest stage.
Development and validation of a prediction model for lymph node metastasis based on molecular classification in endometrial carcinoma.
Authors: Han Qiuyue , Jiang Quanhong , Xu Jiaqi , Zhang Yuan , Li Li , Kong Beihua , Song Kun , Bu Hualei , Dong Ruifen
Published: June 2024

e17599

Background: The aim of this study is to develop a robust preoperative model using molecular classification to accurately predict the likelihood of occult lymph node metastasis (LNM) in patients diagnosed with early-stage endometrial cancer (EC). Such a model could help guide surgeons in choosing between systematic lymph node dissection and sentinel lymph node biopsy. Methods: Patients with clinically early-stage EC were included from Qilu Hospital of Shandong University between January 2010 and December 2017. Univariate and multivariate analyses was performed to identify the risk factors associated with occult LNM. Different machine learning (ML) algorithm models were applied to construct several prediction models, based on factors screened by the least absolute shrinkage and selection operator (LASSO). These models were evaluated by the receiver operating characteristic (ROC) derived area under the curve (AUC) values and the optimal model was established to build the nomogram. Bootstrap was used to validate of this model. The AUC, decision-curve analysis, clinical impact curves and interpretability metrics were used to determine the clinical net benefit of the model. Furthermore, risk stratification of EC patients was created based on the nomogram's threshold values. Results: Out of 363 patients with early-stage EC, 35 (9.1%) presented with LNM. Serum carbohydrate antigen 125 (CA125) and depth of myometrial invasion were independent predictive factors of LNM. An optimal ML model based on logistic regression (AUC: 0.744) was established to predict the occult LNM, including five factors screened by LASSO and they are CA125, neutrophil-to-lymphocyte ratio (NLR), histological subtype, depth of myometrial invasion and molecular classification. This model displayed good discrimination ability (AUC: 0.843) and calibration ability. Conclusions: This new preoperative LNM prediction model based on molecular classification can precisely indicate the probability of LNM in patients with early-stage EC, which could provide recommendations for the treatment of systematic lymph node dissection and sentinel lymph node biopsy based on risk stratification.
Vulvo-vaginal cancer trends during the pandemic.
Authors: Stewart Chelsea , Chan Joshua Elbridge , Tran Nathan , Johnson Caitlin Ruth , Darcy Kathleen M. , Tian Chunqiao , Kapp Daniel Stuart , Liao Cheng-I
Published: June 2024

e17609

Background: During the COVID-19 pandemic, many patients in the United States experienced access-to-care issues. We hypothesized this may have disrupted recent trends in incidence for diseases such as vulvar and vaginal carcinoma often identified on physical exam and biopsy. In this study, we aimed to evaluate the impact of the COVID-19 pandemic on vulvar and vaginal carcinoma incidence based on age and race. Methods: Data on cancer incidence were obtained from the United States Cancer Statistics program. We employed SEER*Stat 8.4.1.2 and Joinpoint regression program 5.0.2. We compared actual vulvar and vaginal squamous cell carcinoma incidence rates in the year 2020 to estimated rates based on trends from the years 2001-2019. Results: From 2001-2020, 69,114 cases of vulvar carcinoma and 15,419 cases of vaginal carcinoma were identified. In 2019, the incidence rate was 2.14 and 0.44 per 100,000 people for vulvar and vaginal cancer, respectively. Using data from 2001-2019, there was a 1.19% increase per year in vulvar cases per year (p<0.001), while vaginal cases remained stable (average annual percent change -0.24%, p=0.179). Based on the trend noted in vulvar SCC, we expected incidence of vulvar SCC to be 2.19 per 100,000 patients in 2020, however, the reported 2020 incidence was 1.99 per 100,000. Based on these calculations, there were 9.03% fewer vulvar cases (n=246) in 2020 than expected. Assuming vaginal incidence rates remained stable, there were 9.34% fewer vaginal cases (n=70) in 2020 than expected. Based on race, non-Hispanic Asian and Pacific Islander patients experienced the largest proportional difference in actual vs expected cases of vulvar cancer, with the actual 2020 case numbers being 38% fewer (n=23) than expected based on trends. For vaginal cancer, the largest proportional difference in actual vs expected cases was among Hispanic patients, with the actual 2020 case numbers being 24% fewer than expected (n=32). Conclusions: During the 2020 COVID-19 pandemic, the incidence of vulvo-vaginal cancers was less than expected given the established trends, particularly in NHAPI and Hispanic patients. Further research is warranted to better determine if the above-described gaps were from delayed diagnosis due to access of care or other causes.
PRadR: PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer, a multicentric phase I/II.
Authors: Vinceneux Armelle , Bidaux Anne-Sophie , Cropet Claire , Tatu Delphine , Bernardin Mathilde , Neymarc Séverine , Pérol David , Pouget Jean-Pierre , Constanzo Julie , Foray Nicolas , Djaileb Loic , Kelly Antony , Kryza David , Giraudet Anne-Laure
Published: June 2024

TPS4608

Background: Prostate Specific Membrane Antigen (PSMA) is highly expressed in neovessels of various solid tumors including Renal Cell Carcinoma, especially clear cell (ccRCC), which is the most frequent sub type. In ccRCC, PSMA expression in tumor vessels is correlated with higher grade and stage as well as in match between primary tumor and metastasis. PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA Ligands Radiolabeled with Lutetium-177 (PRLT), which is already used in daily practice for prostate cancer. 177Lu-PSMA in prostate cancer with renal impairment appeared to be feasible and tolerable in previous studies. The aim of this Phase I/II study NCT06059014 is to assess the safety and clinical activity of this new Radiolabelled Therapy for mccRCC. Methods: PRadR is a multicentric, single-arm, open-label Phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with mccRCC. Patients must have received at least 2 prior regimens, including immunotherapy and antiangiogenic agents as per international guidelines, ECOG 0 to 1, with adequate hematologic, hepatic and renal function with a creatinine clearance according to CKD-EPI ≥ 40 mL/min/1.73m2. Only patients with tumor tracer uptake greater than background will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary endpoints are the incidence of severe toxicity (Safety run in) and the disease control rate at 24 weeks (DCR-24W) as per RECIST V1.1 (Phase II) in patients with a PSMA-positive mccRCC selected through 68Ga-PSMA PET. Secondary endpoints include overall response rate, duration of response, progression free survival, overall survival and safety according to NCI-CTCAE V5.0. During the safety run in, if more than one patient experiences severe toxicity during the first cycle over the first 6 treated patients, then a lower activity of 177Lu-PSMA-1 will be evaluated in an additional cohort of 6 patients (5.9 GBq). Using a Fleming-A’Hern single stage design with a target DCR24w of 30% and an inefficacy bound of 10% (α=5% one sided and 90% power) a total of 33 evaluable patients are required. If at least 7 successes (CR, PR or SD) at 24 weeks of treatment are observed, 177Lu-PSMA-1 will deserve further investigation in this setting. Translational studies will consist in comparing efficacy and toxicity to dosimetry of 177Lu-PSMA-1 in normal tissues and tumor lesions, and biomarkers obtained from blood samples or tumor tissues. First patient was enrolled in November 2023. Clinical trial information: NCT06059014 .
Adjuvant or rescue disitamab vedotin (RC48-ADC) for high-risk non-muscle invasive bladder cancer with HER2 overexpression: A phase II multi-center study.
Authors: Chen Junru , Liu Haoyang , Zhu Qiyu , Xu Chenhao , Wei Qiang , Liu Jiyan , Liu Zhenhua , Shen Pengfei , Bao Yige , Zhang Peng , Liao Banghua , Yao Jin , Chen Ni , Wu Kaijie , Liu Xiaodong , Zeng Hao
Published: June 2024

TPS4625

Background: Non-muscle invasive bladder cancer (NMIBC) comprises approximately three-quarters of newly diagnosed cases of bladder cancer. Based on the risk of disease progression, NMIBC is categorized into low, intermediate, and high risk, with high-risk NMIBC patients facing a 5-year disease progression rate of up to 40%. The current standard treatment for high-risk NMIBC involves transurethral resection of the bladder tumor (TURBT) combined with intravesical Bacillus Calmette-Guérin (BCG) instillation as adjuvant therapy. In cases of BCG instillation treatment failure, the standard approach is radical cystectomy. Multiple studies have reported HER2 positivity in 20-44% of NMIBC cases, and HER2 overexpression (immunohistochemistry ≥2+) is closely linked to the progression and adverse prognosis of bladder cancer. Consequently, HER2 may serve as a novel therapeutic target for bladder cancer. Disitamab Vedotin (DV; RC48-ADC) is an antibody-drug conjugate (ADC) comprising a fully humanized HER2-directed monoclonal antibody conjugated to monomethyl auristatin E (MMAE) via a protease-cleavable mc-vc linker. Results from a Phase II clinical trial (NCT03507166) suggest that Disitamab Vedotin exhibits favorable efficacy and safety in HER2-positive metastatic urothelial carcinoma patients who have previously failed chemotherapy. This clinical trial aims to investigate the efficacy and safety of RC48-ADC as adjuvant or rescue therapy for high-risk NMIBC with HER2 overexpression and to explore molecular biomarkers predicting the efficacy of RC48-ADC. Methods: This multicenter, Phase II clinical trial will enroll two cohorts: Cohort A, consisting of 52 patients undergoing first-line adjuvant therapy, and Cohort B, with 25 patients receiving rescue therapy after BCG instillation failure, both exhibiting HER2 overexpression in high-risk NMIBC. Following the Simon two-stage optimal design, the first stage will involve enrolling 19 patients in Cohort A and 12 patients in Cohort B. After safety and baseline assessments, both cohorts will undergo six cycles of treatment with RC48-ADC (120 mg intravenous infusion every two weeks), totaling 12 weeks of treatment. Primary endpoints include safety, 12-month recurrence-free rate (Cohort A), and 3-month clinical complete response rate (Cohort B). Secondary endpoints encompass the 6-month recurrence-free rate (Cohort A), duration of response (Cohort B), recurrence-free survival, progression-free survival, overall survival, and quality of life (assessed through eEuroQoL EQ-5D and FACT-BI). Additionally, exploratory endpoints will investigate the relationship between biomarkers in tumor tissues, blood, and urine, and treatment efficacy. Clinical trial information: NCT05996952 .
A phase 1/2 study of EG-70 (detalimogene voraplasmid) intravesical monotherapy for patients with BCG-unresponsive non-muscle invasive bladder cancer with carcinoma in situ.
Authors: Bryce Richard , Tosone Christine , Sullivan James C. , Linback Tammy , Steinberg Gary D.
Published: June 2024

TPS4626

Background: High-risk non-muscle-invasive bladder cancer (NMIBC) is treated with adjuvant intravesical Bacille Calmette-Guérin (BCG). However, approximately 50% of patients experience recurrence and/or progression after BCG treatment and are considered unresponsive. EG-70 (detalimogene voraplasmid) is an investigational drug product that was specifically engineered for intravesical administration to elicit local stimulation of anti-tumor immune responses in the bladder and drive durable efficacy in patients with BCG-unresponsive NMIBC, while mitigating the risk of systemic toxicities from immune stimulation. The phase 1 (dose-escalation) part of the first-in-human LEGEND (NCT04752722) phase 1/2, open-label, multicenter study of EG-70 in patients with high-risk BCG-unresponsive NMIBC with carcinoma in situ (CIS) is complete: intravesical instillation of EG-70 was well tolerated with an overall complete response (CR) rate of 73%; and the recommended phase 2 dose (RP2D) was identified. Here we describe the ongoing phase 2 part of the study, which opened to enrollment in May 2023. Methods: Patient eligibility criteria: age ≥18 years; ECOG PS 0−2; BCG-unresponsive NMIBC with CIS, with or without resected coexisting papillary tumors, ineligible for, or have elected not to undergo, cystectomy; satisfactory bladder function with ability to retain study drug for ≥60 minutes. Prior checkpoint inhibitor treatment is allowed if completed within 30 days before study entry. Patients are treated with EG-70 at the RP2D (800 µg in 50 mL) by intravesical administration on weeks 1, 2, 5, and 6 of a 12-week cycle, for 4 cycles in one of two cohorts: BCG-unresponsive (Cohort 1); BCG-naïve or BCG-incompletely treated (Cohort 2). Patients in either cohort who exhibit stable disease (SD) or CR at week 12 will continue treatment until week 24; patients with progressive disease (PD) will discontinue treatment. Patients who experience or maintain CR at week 24 will receive additional cycles every 12 weeks until week 48; patients with SD or PD at week 24 will discontinue treatment. Patients with PD at any time after week 24 will discontinue treatment. Phase 2 primary objective: evaluate efficacy (CR rate at week 48) and safety of EG-70. Secondary objectives: evaluate progression-free survival, CR rate at 12, 24, 36 and 48 weeks, and duration of response. The study is being conducted in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines and with the principles of the Declaration of Helsinki. All patients provide written informed consent. The ongoing, registration-enabling phase 2 portion of the LEGEND study is anticipated to recruit approximately 100 patients from sites in North America, Europe, and the Asia-Pacific region. Clinical trial information: NCT04752722 .
Nanoliposomal Irinotecan With Fluorouracil and Leucovorin or Gemcitabine Plus Cisplatin in Advanced Cholangiocarcinoma: A Phase II Study of the AIO Hepatobiliary-YMO Cancer Groups (NIFE-AIO-YMO HEP-0315)
Authors: Ettrich Thomas J. , Modest Dominik P. , Sinn Marianne , Striefler Jana K. , Opitz Bernhard , Goetze Thorsten , Gallmeier Eike , Angermeier Stefan , Fischer von Weikersthal Ludwig , Jacobasch Lutz , Waldschmidt Dirk , Niedermeier Michael , Sohm Michael , Berger Andreas W. , Manzini Giulia , Fehrenbach Uli , Auer Timo Alexander , Hosse Clarissa , Vogele Daniel , Sookthai Disorn , Schaaf Marina , Muche Rainer , Hinke Axel , Seufferlein Thomas , Perkhofer Lukas
Published: June 2024

PURPOSE

First-line therapy options in advanced cholangiocarcinoma (CCA) are based on the ABC-02 trial regimen (gemcitabine/cisplatin [G/C]). The NIFE trial examined nanoliposomal irinotecan/fluorouracil/leucovorin (nal-IRI/FU/LV) as alternative first-line therapy in advanced CCA.

METHODS

NIFE is a prospective, open-label, randomized, multicenter phase II study that aimed at detecting efficacy comparable with the standard treatment. Patients with advanced CCA were randomly assigned (1:1) to receive nal-IRI/FU/LV (arm A) or G/C (arm B). Stratification parameters were intrahepatic versus extrahepatic CCA, sex, and Eastern Cooperative Oncology Group (ECOG; 0/1). Arm A was designed as a Simon's optimal two-stage design and arm B served as a randomized control group. The primary goal was to exclude an inferior progression-free survival (PFS) at 4 months of only 40%, while assuming a rate of 60% on G/C population.

RESULTS

Between 2018 and 2020, overall 91 patients were randomly assigned to receive nal-IRI/FU/LV (n = 49) or G/C (n = 42). The NIFE trial formally met its primary end point with a 4-month PFS rate of 51% in patients receiving nal-IRI/FU/LV. The median PFS was 6 months (2.4-9.6) in arm A and 6.9 months (2.5-7.9) in arm B. Median overall survival (OS) was 15.9 months (10.6-20.3) in arm A and 13.6 months (6.5-17.7) in arm B. The exploratory comparison of study arms suggested a numerical but statistically not significant advantage for nal-IRI/FU/LV (hazard ratio for PFS, 0.85 [95% CI, 0.53 to 1.38] and for OS, 0.94 [95% CI, 0.58 to 1.50]). Analysis for stratification parameters revealed no differences for sex and ECOG, but for tumor localization. The objective response rate was 24.5% with nal-IRI/FU/LV and 11.9% with G/C. No unexpected toxicities occurred. AEs related to nal-IRI/FU/LV were mainly GI and to G/C hematologic.

CONCLUSION

Treatment of advanced CCA with nal-IRI/FU/LV demonstrated efficacy in first-line therapy without new safety findings and merits further validation.
Telisotuzumab Vedotin Monotherapy in Patients With Previously Treated c-Met Protein–Overexpressing Advanced Nonsquamous
EGFR
-Wildtype Non–Small Cell Lung Cancer in the Phase II LUMINOSITY Trial
Authors: Camidge D. Ross , Bar Jair , Horinouchi Hidehito , Goldman Jonathan , Moiseenko Fedor , Filippova Elena , Cicin Irfan , Ciuleanu Tudor , Daaboul Nathalie , Liu Chunling , Bradbury Penelope , Moskovitz Mor , Katgi Nuran , Tomasini Pascale , Zer Alona , Girard Nicolas , Cuppens Kristof , Han Ji-Youn , Wu Shang-Yin , Baijal Shobhit , Mansfield Aaron S. , Kuo Chih-Hsi , Nishino Kazumi , Lee Se-Hoon , Planchard David , Baik Christina , Li Martha , Ansell Peter , Xia Summer , Bolotin Ellen , Looman Jim , Ratajczak Christine , Lu Shun
Published: June 2024

PURPOSE

Telisotuzumab vedotin (Teliso-V) is a c-Met–directed antibody-drug conjugate with a monomethyl auristatin E cytotoxic payload. The phase II LUMINOSITY trial (ClinicalTrials.gov identifier:
NCT03539536
) aimed to identify the optimal c-Met protein–overexpressing non–small cell lung cancer (NSCLC) population for treatment with Teliso-V (stage I) and expand the selected group for efficacy evaluation (stage II). Stage II enrolled patients with nonsquamous epidermal growth factor receptor (
EGFR
)-wildtype NSCLC.

METHODS

Eligible patients had locally advanced/metastatic c-Met protein–overexpressing NSCLC and ≤2 previous lines of therapy (including ≤1 line of systemic chemotherapy). c-Met protein overexpression in nonsquamous
EGFR
-wildtype NSCLC was defined as ≥25% tumor cells with 3+ staining (high [≥50% 3+]; intermediate [≥25%–<50%]). Teliso-V was administered at 1.9 mg/kg once every 2 weeks. The primary end point was overall response rate (ORR) by independent central review.

RESULTS

In total, 172 patients with nonsquamous
EGFR
-wildtype NSCLC received Teliso-V in stages I and II. ORR was 28.6% (95% CI, 21.7 to 36.2; c-Met high, 34.6% [95% CI, 24.2 to 46.2]; c-Met intermediate, 22.9% [95% CI, 14.4 to 33.4]). The median duration of response was 8.3 months (95% CI, 5.6 to 11.3; c-Met high, 9.0 [95% CI, 4.2 to 13.0]; c-Met intermediate: 7.2 [95% CI, 5.3 to 11.5]). The median overall survival was 14.5 months (95% CI, 9.9 to 16.6; c-Met high, 14.6 [95% CI, 9.2 to 25.6]; c-Met intermediate, 14.2 [95% CI, 9.6 to 16.6]). The median progression-free survival was 5.7 months (95% CI, 4.6 to 6.9; c-Met high, 5.5 [95% CI, 4.1 to 8.3]; c-Met intermediate: 6.0 [95% CI, 4.5 to 8.1]). Most common any-grade treatment-related adverse events (AEs) were peripheral sensory neuropathy (30%), peripheral edema (16%), and fatigue (14%); the most common grade ≥3 AE was peripheral sensory neuropathy (7%).

CONCLUSION

Teliso-V was associated with durable responses in c-Met protein–overexpressing nonsquamous
EGFR
-wildtype NSCLC, especially in those with high c-Met. AEs were generally manageable.
Ultrasound Rounds: Intraoperative Point-of-Care Ultrasound Identifies Intracardiac Thrombus and Pulmonary Embolism Allowing for Alteration in Surgical Management
Authors: Adler Adam C.
Published: June 2024

Most of the cases demonstrating describing acute findings using point-of-care ultrasound (POCUS) have been described in emergency medicine and critical care medicine. While the use of POCUS has become more prevalent in anesthesia practice, documentation of acute findings resulting in alteration in management based on real-time ultrasound findings during pediatric anesthesia remains limited. This case highlights the use of POCUS during cardiopulmonary collapse occurring during correction of neuromuscular scoliosis. POCUS excluded the presumed diagnosis of venous air embolism and identified an intracardiac thrombus leading to the diagnosis and treatment of pulmonary embolism.
Classicist Drama in Digital Times
Authors: Yeh Michelle
Published: June 2024

This article begins with an overview of the rise of internet drama, or web drama, in China in the past fifteen years. The new platform boasts several advantages, which accounts for its rapid development. Web drama has become so popular that it is replacing television drama series as the mainstream. The article then examines a major genre of web drama: stories set in traditional China. While costume drama or period drama, whether based on history or fiction, has always been popular, classicist web drama series in recent years stand out for their authenticity and creativity. Based on two case studies, the article explores two distinct themes. The first is Royal Nirvana (2019), a pseudo-historical drama that integrates Song-dynasty culture into the plot. In doing so, it beautifully demonstrates the appeal of “Chinese style” or “Asian aesthetics” in popular imagination. The second case study is The Untamed (2019), a fantasy martial arts tale that features two male protagonists who start out as diametrically opposed but end up as soul mates and loyal allies. The drama series skillfully transforms danmei or BL (boys’ love) in the original story into a subtly titillating relationship between two men. The article concludes with a discussion of the new business model that web drama has successfully introduced into the entertainment industry in contemporary China.
The Body That Counts
Authors: Hsieh Chieh-Ting
Published: June 2024

This article is intended to analyze the “digital techniques of dance” implied in the different dance notations from the perspective of Medienwissenschaft. Medienwissenschaft, which is often translated as German “media theories,” regards media as techniques through which concepts are developed. The digital technique is therefore redefined here as the technique of counting in general through which the concept of number is developed. The digital technique of dance in this article is also defined as the “technique of counting number with the body in dance.” This article's analysis of the digital techniques of dance begins with the notation developed by Rudolf Laban for the Western modern dance and that developed by Zhu Zai-yu for the ancient Chinese dance. These notations were once researched by one of the most important dance researchers and choreographers, Liu Feng-hsueh, for her Chinese modern dance. The analysis of these notations indicates that the digital technique of Laban's notation is based on partition of time and space and the digital technique of Zhu Zai-yu's notation is based on interpretation of force. The article argues that it is only through the analysis of the digital technique of dance that “Chineseness” in modern dance can be based not only on the “spirit of the arts,” which haunts dance like a ghost, but also on digital technique as the technique of the body. For research on Chinese modern dance, it is the body that counts.
Çin’in Nükleer Stratejisinde Sapma: ABD Kaynaklı Tehdit Algıları ve Garantili Misilleme Arayışı
Authors: Sarı İsmail
Published: June 2024

Günümüz uluslararası ilişkilerinde konvansiyonel ve nükleer güçler arasındaki etkileşim, devletlerin tehdit algılarını ve davranışlarını önemli ölçüde etkileyen karmaşık bir dinamik yaratmaktadır. Çin’in 2021 yılının ortalarında üç yeni füze silosu inşa ettiğinin ortaya çıkması, Çin’in geleneksel “asgari nükleer caydırıcılık” stratejisinde bir değişiklik olup olmadığına dair soruları gündeme getirmiştir. Bu çalışma, Çin’in uzun süredir devam eden nükleer stratejisinden saptığını ileri sürmektedir. ABD ve Çin arasındaki konvansiyonel dengede meydana gelen olumsuz değişiklikler Çin’i nükleer kabiliyetlerini arttırmaya ve konvansiyonel kabiliyetlerini geliştirerek nükleer gücünün caydırıcılık kabiliyetini arttırmaya teşvik etmiştir. Bir devlet nükleer caydırıcılığının hasmının konvansiyonel yetenekleri tarafından zayıflatılabileceğini algıladığında, nükleer caydırıcılığını güçlendirerek karşılık verme eğilimindedir. Benzer şekilde, nükleer kuvvetlerinin beka kabiliyetini arttırmak için konvansiyonel kabiliyetlerini de geliştirebilir. Çinli uzmanlar ABD’nin konvansiyonel hassas vuruş kabiliyetlerini Çin’in garantili misilleme kabiliyeti için önemli bir tehdit olarak görmektedir. Ayrıca, Çin’in nükleer cephaneliğinin geçmişe kıyasla daha çeşitli konvansiyonel tehditlerle karşı karşıya olduğuna inanmaktadırlar. Bu çalışma, Çin’in nükleer füze silolarını genişletmesinin ardındaki nedenleri analiz etmeyi amaçlamakta ve nükleer silahların Çin’in askeri doktrinindeki rolünü ve Çin ordusundaki son modernizasyon çabalarını incelemektedir. Çin’in tehdit algılarına bağlı olarak gelişen nükleer kabiliyetlerini ve bunların küresel güvenlik dinamikleri üzerindeki etkisini anlamak bu araştırmanın odak noktasıdır.
A Theoretical Analysis of The European Union’s Immigration Policies in The Case of The Ukraine and Syria Humanitarian Crisis: Is It an Identity Exclusion? A Xenophobic Double Standard?
Authors: Uygur Mehmet Recai , Eser Hamza Bahadır
Published: June 2024

In this study, the different attitudes of the European Union towards Ukrainian and Syrian refugees in its migration policies were examined. The intellectual infrastructure of these attitudes is analyzed within the framework of international relations theories such as The English School, which emphasizes the phenomenon of international society, Social Constructivism theory which emphasizes the construction of common identity and Securitization theory, which examines the process of making a political phenomenon a security issue. In addition to these approaches, the reasons for the double standard of the European Union in their migration policies are also examined in terms of the framework of geographical proximity. It emphasized to what extent the historical memories of European countries have an impact on their migration policies in the text. The theoretical analysis of the different attitudes of the European Union in the face of basically two similar events examined how these policies evolved into xenophobia and how they are fed by the current xenophobic phenomenon in Western Europe. In conclusion, it can be stated that xenophobia is a socio-psychological phenomenon in Western Europe, and this phenomenon is effective both in the determination of daily populist politics and in the attitudes preferred in the face of refugee policies.
Nation Building in Saudi Arabia: From Rentierism to Territorial Nationalism
Authors: Özev Muharrem Hilmi
Published: June 2024

Makale, Suudi Arabistan’da devam eden dinamik sosyopolitik dönüşümü ülkesel (territorial) milliyetçilik kavramı çerçevesinde ele almakta ve geleneksel, dini ve milliyetçi faktörler arasındaki karmaşık etkileşimi incelemektedir. Hızlı genç nüfus artışı, rentier ekonomiyi dönüştürme zorunluluğu, hanedanlık içi yapısal dönüşüm, din kurumunun değişen rolü, kadın hakları konusu ve askerileşme sürecini içeren çeşitli unsurları Veliaht Prens Muhammed bin Selman›ın ülkesel milliyetçiliği geliştirme çabaları içinde geniş bir bağlamda değerlendiren makale, Suudi Arabistan’daki cari modernizasyon stratejilerinin, petrol gelirleri, petro-dolar birikimi, eğlence sektöründeki ilerlemeler ve ulus inşa çabalarının canlanması gibi önemli unsurlara bağlılıklarını ve sonuçlarını değerlendirmektedir. Suudi Arabistan içerisindeki gelişmeler kadar Suudi dış politikasını da şekillendiren uluslararası dinamikleri, jeopolitik gelişmeleri de analiz çerçevesine dahil eden makale, Suudi Arabistan’ın devam eden dönüşümünün çok yönlü doğasına dair içgörüler sunmaktadır.
Delta-Aminolevulinic acid dehydratase enzyme activity and susceptibility to lead toxicity in Uganda’s urban children
Authors: mukisa Ambrose , Kasozi Denis , Aguttu Claire , Kyambadde Joseph
Published: June 2024

Background With rapid industrialization, urbanization, and population explosion in sub-Saharan Africa including Uganda, the population has experienced increased exposure to environmental lead subsequently causing elevated blood lead levels. Mean blood levels of 332µg/dL,120µg/dʟ, 25µg/dL,11µg/dL, and 10µg/dL in children under 18 years of age in Nigeria, DR Congo, South Africa, Sudan, and Uganda respectively. Susceptibility to lead toxicity correlates with one’s nutrition status, age, and genetics. This study expounded susceptibility to lead toxicity by relating blood lead levels, delta-aminolevulinic acid dehydratase (ALAD) enzyme activity, and genetic variations of proteins that code for ALAD in urban children of Uganda aged between 6 and 60 months. Methods A total of 198 blood samples were analyzed for blood lead levels (BLL), on an atomic absorption spectrophotometer whereas hemoglobin (Hb) levels, and ALAD enzyme activity, were analyzed on a spectrophotometer before DNA extraction, polymerase chain reaction, and restriction fragment length digestion for ALAD polymorphism. Results Geometric means of BLL (10.55µg/dL, SD = 7.4), Hb (7.85g/dL, SD = 1.3) and ALAD enzyme activity (37.15 units/L BLL, S.D = 9.7), corresponded to samples that coded for ALAD1 allele (99.05%) compared to the 0.05% that coded for ALAD2 with BLL (14.5µg/ dL, SD = 4.7), Hb (6.1 g/ dL), ALAD enzyme activity (33.8 units/L, SD=1.45). There was a significant relationship with a negative linear correlation between BLL, Hb (status, and ALAD enzyme activity in the three isozymes (ALAD1-1, ALAD1-2, and ALAD2-2) in the strength of ALAD1-1 (r = 0.42, p-value = 0.02) ˂ ALAD1-2 (r = 0.62, effective size = 0.43, p-value = ˂ 0.001) ˂ ALAD2-2 (r = 0.67, effective size = 0.86, p-value = ˂ 0.001). Conclusions Most of the study participants coded for the ALAD1 allele hence hoarded blood lead, which could result in delayed exposure and adverse effects later in their lives.
A potential role of arcadia in conditioned media - umbilical cord derived mesenchymal stem cell on cartilage repair
Authors: Soetjahjo Bintang , Adriansyah Denny , Riawan Wibi
Published: June 2024

Background Certain conditions can stimulate stem cells to produce secretory factors that differ from each condition, such as hypoxia. Umbilical Cord-derived Mesenchymal Stem Cells have been known to have higher proliferation rates, plasticity, and better self-improvement ability than MSCs from other sources. The objective was to analyze the secreting proteins in the Conditioned Medium - Umbilical cord-derived Mesenchymal Stem Cells (CM-UCMSCs) which potentially has a role in the chondrogenesis of cartilage defect. Methods We used SDS PAGE combined with electrospray ionization mass spectrometry using mass spectrometer to perform a proteomic analysis of CM-UCMSCs which conditioned in a state of fasting (without serum albumin). Then, we continue to analyze to identify proteins of interest using Mascot sequence matching software. Then Analyzed using in silico / molecular docking to know the interaction of each protein with the cartilage repair factor. Results SDS PAGE performed on all secreted products in CM-UCMSCs. We found one dominant band, then we used Mass Spectrometry continued Mascot sequencing protein that band, conclude that the protein was a D4A9T1/ RNF-111/ Arkadia Protein. And then using in silico/ molecular docking method analyzed that Arkadia Protein worked synergistically with TGF-β1 Protein through activation of TGF-β1 receptors to induce the chondrogenesis. Conclusions Our results show that the fasting state on CM-UCMSCs promoted secreted Arkadia protein. From in silico model prediction, this protein suspects to have an important role in the process of repairing cartilage defects. However, further research is needed before feasible and safe for the clinical application of CM-UCMSCs in cartilage repair.
Evaluation of role of Tigecycline among clinically significant multidrug resistant pathogens from a tertiary care hospital
Authors: Remash Annapoorna , Rao Pooja , Shenoy Suchitra , Baliga Shrikala , Kassim Shafir
Published: June 2024

Background Tigecycline, a glycylcycline antibiotic is a promising option for the treatment of single or multidrug resistant pathogens. The aim of the study was to evaluate the in-vitro Tigecycline susceptibility of various pathogens from clinical samples received at the tertiary care hospitals in South India. Methods The analysis of specimens from patients admitted were carried out in this prospective cross sectional study. The identification and antimicrobial susceptibility testing was performed by semi-automated Vitek 2 systems and Kirby Bauer method. Pattern of data analysis was done by descriptive statistics. Results Among 2574 isolates, 812 isolates were Gram positive pathogens and 1762 isolates were Gram negative pathogens. Resistance to Tigecycline was more common among Gram negative pathogens (18.62%) in comparison to the Gram positive pathogens (0.49%). Among 740 Extended Spectrum Beta Lactamases (ESBL) producers such as Klebsiella species & E coli, 629 isolates were susceptible, and 93 isolates were resistant to the tigecycline. All the methicillin resistant Staphylococcus aureus (MRSA) isolates were susceptible to tigecycline. Conclusion Multidrug resistant (MDR) pathogens like Acinetobacter species, and Klebsiella species were found to be highly effective in vitro to tigecycline for elimination of infections caused by both Gram positive and Gram negative pathogens. The use of combination therapy becomes crucial to prevent the development of Pan Drug resistance.
Attribution clause as a tool for addressing contractual imbalances and applicability in civil contracts
Authors: Al-Samadi Mamooa , Balas Hashim
Published: June 2024

Abstract* Attribution rules act as a tool to modify the terms of a contract by accepting pre-specified terms and conditions. This methodology ensures that the contractual relationship is protected while addressing potentially complex scenarios that may arise during contract execution due to evolving circumstances. To maintain the binding force of the contract, Parties expedite dispute resolution and protect the integrity of their contracts by choosing recourse and prior agreeing to remedies, which encourages continuity in enforcement. These clauses are intended to automatically amend the terms of the contract without requiring the parties to participate in the amendment process. These items adjust the amount of funds subject to the obligation according to changes observed by external indicators associated with the obligation. This is done by comparing the price of a particular currency with the price of a different commodity. In the case of payment in gold or foreign currency, it represents an assault on the binding legal force of the national currency by competing with it as a means of payment and considering it as one of them. Terms of payment in gold and foreign currency are excluded from the attribution requirement, which replaces legal means of payment with new means of payment. It does not constitute a basis for determining the extent of fulfillment of the obligation, and we conclude that the attribution clause is a distinct legal system that deals with amending contractual terms and the contractual imbalance they cause. Amendment is permitted in the event of circumstances occurring that would upset the balance throughout the contract implementation period, and we recommend adopting the attribution clause as an automatic adjustment tool.