bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison between Atezolizumab Plus Bevacizumab and Lenvatinib for Hepatocellular Carcinoma in Patients with Child-Pugh Class B in Real-World Clinical Settings
Authors: Ohama Hideko , Hiraoka Atsushi , Tada Toshifumi , Hirooka Masashi , Kariyama Kazuya , Tani Joji , Atsukawa Masanori , Takaguchi Koichi , Itobayashi Ei , Fukunishi Shinya , Tsuji Kunihiko , Ishikawa Toru , Tajiri Kazuto , Ochi Hironori , Yasuda Satoshi , Toyoda Hidenori , Ogawa Chikara , Nishimura Takashi , Hatanaka Takeshi , Kakizaki Satoru , Shimada Noritomo , Kawata Kazuhito , Naganuma Atsushi , Kosaka Hisashi , Matono Tomomitsu , Shibata Hiroshi , Aoki Tomoko , Tada Fujimasa , Nouso Kazuhiro , Morishita Asahiro , Tsutsui Akemi , Nagano Takuya , Itokawa Norio , Okubo Tomomi , Arai Taeang , Imai Michitaka , Koizumi Yohei , Nakamura Shinichiro , Iijima Hiroko , Kaibori Masaki , Hiasa Yoichi , Kudo Masatoshi , Kumada Takashi ,   Real-life Practice Experts for HCC (RELPEC) Study Group,   HCC 48 Group (hepatocellular carcinoma experts from 48 clinics in Japan)
Published: August 2023

Introduction: Systemic treatment is generally recommended for Child-Pugh (CP) A status patients with an unresectable hepatocellular carcinoma (uHCC). This study aimed to elucidate differences regarding therapeutic efficacy between lenvatinib (LEN), a multi-molecular target agent, and atezolizumab plus bevacizumab (Atez/Bev), a newly developed immune-combined therapeutic regimen for CP-B patients affected by uHCC. Methods: From April 2018 to July 2022, 128 patients with uHCC treated with Atez/Bev (n = 29) or LEN (n = 99) as the initial systemic treatment were enrolled (median age 71 years; males 97; CP score 7:8:9 = 94:28:6; median albumin-bilirubin score −1.71). Therapeutic response was evaluated using RECIST, version 1.1. Clinical features and prognosis were retrospectively examined. Results: There were no significant differences between the Atez/Bev and LEN groups in regard to best response (CR:PR:SD:PD = 0:5:12:7 vs. 5:22:25:20, p = 0.415), progression-free survival (PFS) (median 5.0 [95% CI: 2.4–7] vs. 5.5 [95% CI: 3.4–7.9] months, p = 0.332), or overall survival (OS) (5.8 [95% CI: 4.3–11] vs. 8.8 [95% CI: 6.1–12.9] months, p = 0.178). Adverse events (any grade/≥ grade 3) were observed in 72.4%/17.2% (n = 21/5) of patients treated with Atez/Bev and 78.8%/25.3% (n = 78/25) of those treated with LEN (p = 0.46/0.46). Discussion: This retrospective study found no significant differences regarding PFS or OS between CP-B patients given Atez/Bev or LEN as initial systemic treatment for uHCC.
Implementation of a Bleeding Management Algorithm in Liver Transplantation: A Pilot Study
Authors: Sarmiento Ignacio A. , Guzmán María F. , Chapochnick Javier , Meier Jens
Published: August 2023

Objectives: The aims of the study were to compare the consumption of blood products before and after the implementation of a bleeding management algorithm in patients undergoing liver transplantation and to determine the feasibility of a multicentre, randomized study. Background: Liver transplantation remains the only curative therapy for patients with end-stage liver disease, but it carries a high risk of surgical bleeding. Materials and Methods: Retrospective study of patients treated before (group 1) and after (group 2) implementation of a haemostatic algorithm guided by viscoelastic testing, including use of lyophilized coagulation factor concentrates (prothrombin complex and fibrinogen concentrates). Primary outcome was the number of units of blood products transfused in 24 h after surgery. Secondary outcomes included hospital stay, mortality, and cost. Results: Data from 30 consecutive patients was analysed; 14 in group 1 and 16 in group 2. Baseline data were similar between groups. Median total blood product consumption 24 h after surgery was 33 U (IQR: 11–57) in group 1 and 1.5 (0–23.5) in group 2 (p = 0.028). Significantly fewer units of red blood cells, fresh frozen plasma, and cryoprecipitate were transfused in group 2 versus group 1. There was no significant difference in complications, hospital stay, or in-hospital mortality between groups. The cost of haemostatic therapy was non-significantly lower in group 2 versus group 1 (7,400 vs. 15,500 USD; p = 0.454). Conclusion: The haemostatic management algorithm was associated with a significant reduction in blood product use during 24 h after liver transplantation. This study demonstrated the feasibility and provided a sample size calculation for a larger, randomized study.
Combining Poly-(ARD-Ribose) Polymerase and Programmed Cell Death Protein 1 Inhibition in a Patient with Esophagogastric Adenocarcinoma
Authors: Artzenroth Jule Cecilia , Tintelnot Joseph , Haag Georg Martin , Gökkurt Eray , Steffens Johann , Stein Alexander
Published: August 2023

Introduction: Esophagogastric adenocarcinoma (EGA) is one of the leading causes of cancer-related mortality worldwide. Therapeutic options are limited for patients with recurrent or metastatic disease. Targeted therapy may be a suitable treatment for selected patients, but its efficacy remains elusive. Case Presentation: Here, a 52-year-old male patient with advanced EGA Siewert Type II shows a significant response to combination therapy with olaparib and pembrolizumab. After progression following first- and second-line therapy, including a programmed cell death ligand 1 (PD-L1) inhibitor, next-generation sequencing of a tumor sample was performed to identify possible molecular targets. A mutation in RAD51C, a member of the homology-directed repair (HDR) system, was identified in addition to high PD-L1 expression. As a result, therapy with the poly-(ARD-Ribose) polymerase (PARP) inhibitor olaparib and the programmed cell death protein 1 (PD1)-inhibitor pembrolizumab was initiated. A durable partial response lasting for more than 17 months was observed. A second molecular profiling from a newly occurring subcutaneous metastasis showed a loss of FGF10 but no fluctuations in the gene alteration of RAD51C and SMARCA4. Interestingly, the new lesion showed HER2-positivity (immunohistochemistry 3+ and fluorescence in situ hybridization [FISH]-positivity) in 30% of tumor cells. Conclusion: In this case, a long-lasting response to the combination of olaparib and pembrolizumab was observed despite previous treatment with a PD-L1 inhibitor. This case illustrates the need for further clinical trials to analyze the efficacy of PARP inhibitor combinations in EGA.
Real-World Experience with Vismodegib on Advanced and Multiple BCCs: Data from the RELIVIS Study
Authors: Ruiz-Salas Verónica , Podlipnik Sebastian , Sandoval-Clavijo Alejandra , Sanmartin-Jiménez Onofre , Bernia-Petit Eduardo , Bonfill-Ortí Montserrat , Bassas-Freixas Patricia , Yebenes-Marsal Mireia , Flórez-Menéndez Ángeles , Solá-Ortigosa Joaquim , Just-Sarobé Miquel , Aguayo-Ortiz Rafael , Masferrer i Niubó Emili , Quintana-Codina Mónica , Deza Gustavo , Jaka Ane , Fuentes Maria José , Cañueto Javier , Toll Agustí
Published: August 2023

Background: Vismodegib is approved for advanced cases of basal cell carcinomas not amenable to surgery or radiotherapy. Large studies on the use of vismodegib in clinical practice are scarce. Objectives: The main objective of the study was to analyse the evolution and therapeutic management of relapses and lack of response in patients who had received vismodegib for locally advanced and/or multiple basal cell carcinomas in a real-life multicentre setting. Methods: This nationwide retrospective study collected data on patients treated with vismodegib in 15 specialized centres. We included patients who first received vismodegib until intolerable toxicity, maximum response, or progressive disease. Exploratory research variables referred to patient and tumour characteristics, vismodegib effectiveness and safety, relapse rate and management, and mortality. A multivariable logistic regression model was used to identify predictors of complete clinical response. Results: 133 patients with advanced BCC were included in the registry. The objective response rate (ORR) was 77.5% and nearly half of the patients (45.9%) achieved complete remission. Long-term information and detailed information of subsequent treatments after a regime of vismodegib was available for 115 patients. Only 34% of the patients in this group were subsequently treated with other therapies or vismodegib rechallenge. Sixty-nine percent of the patients who had shown a complete remission with vismodegib remained free of recurrence while 30.7% relapsed. Almost half of the patients who received additional therapies after the first course of vismodegib achieved complete tumour remission. Three and 2 out of 9 patients who were rechallenged with vismodegib achieved complete and partial responses, respectively, with an ORR of 55.5%. Conclusion: Our study confirms efficacy of vismodegib in routine clinical practice. The risk of recurrence after achieving complete response with vismodegib was lower than previous reports. Rechallenge with vismodegib is feasible and most patients responded to re-treatment.
Characterization of Gene Regulatory Elements in Human Fetal Cortical Development: Enhancing Our Understanding of Neurodevelopmental Disorders and Evolution
Authors: Guo Qiuyu , Wu Sarah , Geschwind Daniel H.
Published: August 2023

The neocortex is the region that most distinguishes human brain from other mammals and primates [Annu Rev Genet. 2021 Nov;55(1):555–81]. Studying the development of human cortex is important in understanding the evolutionary changes occurring in humans relative to other primates, as well as in elucidating mechanisms underlying neurodevelopmental disorders. Cortical development is a highly regulated process, spatially and temporally coordinated by expression of essential transcriptional factors in response to signaling pathways [Neuron. 2019 Sep;103(6):980–1004]. Enhancers are the most well-understood cis-acting, non-protein-coding regulatory elements that regulate gene expression [Nat Rev Genet. 2014 Apr;15(4):272–86]. Importantly, given the conservation of both DNA sequence and molecular function of the majority of proteins across mammals [Genome Res. 2003 Dec;13(12):2507–18], enhancers [Science. 2015 Mar;347(6226):1155–9], which are far more divergent at the sequence level, likely account for the phenotypes that distinguish the human brain by changing the regulation of gene expression. In this review, we will revisit the conceptual framework of gene regulation during human brain development, as well as the evolution of technologies to study transcriptional regulation, with recent advances in genome biology that open a window allowing us to systematically characterize cis-regulatory elements in developing human brain [Hum Mol Genet. 2022 Oct;31(R1):R84–96]. We provide an update on work to characterize the suite of all enhancers in the developing human brain and the implications for understanding neuropsychiatric disorders. Finally, we discuss emerging therapeutic ideas that utilize our emerging knowledge of enhancer function.
Publication Rates and Characteristics of Clinical Trials in Deep Brain and Responsive Neurostimulation
Authors: Chua Melissa M.J. , Warren Aaron E.L. , Cosgrove G. Rees , Rolston John D.
Published: August 2023

Introduction: Prompt dissemination of clinical trial results is essential for ensuring the safety and efficacy of intracranial neurostimulation treatments, including deep brain stimulation (DBS) and responsive neurostimulation (RNS). However, the frequency and completeness of results publication, and reasons for reporting delays, are unknown. Moreover, the patient populations, targeted anatomical locations, and stimulation parameters should be clearly reported for both reproducibility and to identify lacunae in trial design. Here, we examine DBS and RNS trials from 1997 to 2022, chart their characteristics, and examine rates and predictors of results reporting. Methods: Trials were identified using ClinicalTrials.gov. Associated publications were identified using ClinicalTrials.gov and PubMed.gov. Pearson’s χ2 tests were used to assess differences in trial characteristics between published and unpublished trials. Results: Across 449 trials, representing a cumulative cohort of 42,769 patient interventions, there were 37 therapeutic indications and 44 stimulation targets. The most common indication and target were Parkinson’s disease (40.55%) and the subthalamic nucleus (35.88%), respectively. Only 0.89% of trials were in pediatric patients (11.58% were mixed pediatric and adult). Explored targets represented 75% of potential basal ganglia targets but only 29% of potential thalamic targets. Allowing a 1-year grace period after trial completion, 34/169 (20.12%) had results reported on ClinicalTrials.gov, and 107/169 (63.31%) were published. ∼80% of published trials included details about stimulation parameters used. Published and unpublished trials did not significantly differ by trial characteristics. Conclusion: We highlight key knowledge and performance gaps in DBS and RNS trial research. Over one-third of trials remain unpublished >1 year after completion; pediatric trials are scarce; most of the thalamus remains unexplored; about one-in-five trials fail to report stimulation parameters; and movement disorders comprise the most studied indications.
Racial and Ethnic Diversity in Janus Kinase Inhibitor Alopecia Areata Clinical Trials: A Systematic Review
Authors: Ezemma Ogechi , Devjani Shivali , Jothishankar Balaji , Kelley Kristen J. , Senna Maryanne
Published: August 2023

Background: Alopecia areata (AA) is a chronic autoimmune disease that causes non-scarring alopecia. A few studies have shown increased odds of AA in Black individuals compared to White individuals and increased odds of AA in Latinos compared to non-Latinos. Another study showed that Asians have lower odds of AA compared to Whites. Baricitinib, a Janus kinase inhibitor (JAKi), became the first Federal Drug Administration (FDA)-approved medication for adult patients with severe AA in June 2022. Objectives: The aim of this review was to analyze published JAKi AA randomized controlled trials to characterize and assess the racial and ethnic representation of participants. Animal studies, studies unrelated to AA, and studies not investigating JAKis were excluded. Methods: PubMed and clinicaltrials.gov were searched for systematic reviews of clinical trials between 1990 and 2022. Results: Six clinical trials were included with a total of 1,690 subjects. Four trials were industry-sponsored, while two were university-sponsored. The three largest races represented included White (59.9%), Asian (28.0%), and African American/Black (8.1%). Three out of the 10 patients identified as Hispanic. None of the trials included sub-analyses of clinical efficacy based on race and/or ethnicity. Conclusions: Our results show that populations with lower odds of AA (Whites and Asians) are overrepresented in JAKi AA clinical trials compared to Black and Hispanic/Latino patients.
Assessing Tumor Volume for Sporadic Vestibular Schwannomas: A Comparison of Methods of Volumetry
Authors: Balossier Anne , Delsanti Christine , Troude Lucas , Thomassin Jean-Marc , Roche Pierre-Hugues , Régis Jean
Published: August 2023

Introduction: The size of vestibular schwannomas (VS) is a major factor guiding the initial decision of treatment and the definition of tumor control or failure. Accurate measurement and standardized definition are mandatory; yet no standard exist. Various approximation methods using linear measures or segmental volumetry have been reported. We reviewed different methods of volumetry and evaluated their correlation and agreement using our own historical cohort. Methods: We selected patients treated for sporadic VS by Gammaknife radiosurgery (GKRS) in our department. Using the stereotactic 3D T1 enhancing MRI on the day of GKRS, 4 methods of volumetry using linear measurements (5-axis, 3-axis, 3-axis-averaged, and 1-axis) and segmental volumetry were compared to each other. The degree of correlation was evaluated using an intraclass correlation test (ICC 3,1). The agreement between the different methods was evaluated using Bland-Altman diagrams. Results: A total of 2,188 patients were included. We observed an excellent ICC between 5-axis volumetry (0.98), 3-axis volumetry (0.96), and 3-axis-averaged volumetry (0.96) and segmental volumetry, respectively, irrespective of the Koos grade or Ohata classification. The ICC for 1-axis volumetry was lower (0.72) and varied depending on the Koos and Ohata subgroups. None of these methods were substitutable. Conclusion: Although segmental volumetry is deemed the most accurate method, it takes more effort and requires sophisticated computation systems compared to methods of volumetry using linear measurements. 5-axis volumetry affords the best adequacy with segmental volumetry among all methods under assessment, irrespective of the shape of the tumor. 1-axis volumetry should not be used.
Proton Beam Therapy for Intrahepatic Cholangiocarcinoma: A Multicenter Prospective Registry Study in Japan
Authors: Mizumoto Masashi , Terashima Kazuki , Makishima Hirokazu , Suzuki Motohisa , Ogino Takashi , Waki Takahiro , Iwata Hiromitsu , Tamamura Hiroyasu , Uchinami Yusuke , Akimoto Tetsuo , Okimoto Tomoaki , Iizumi Takashi , Murakami Masao , Katoh Norio , Maruo Kazushi , Shibuya Kei , Sakurai Hideyuki
Published: August 2023

Introduction: Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control. Methods: Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6–76 Gy (RBE) in 20–22 fr, 13 received 74.0–76.0 Gy (RBE) in 37–38 fr, and 6 received 60–70.2 Gy (RBE) in 20–30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results: The 59 patients (35 men, 24 women; median age: 71 years; range: 41–91 years) had PS of 0 (n = 47), 1 (n = 10), and 2 (n = 2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A (n = 46), B (n = 7), and unknown (n = 6); the median maximum tumor diameter was 5.0 cm (range 2.0–15.2 cm); and the clinical stage was I (n = 12), II (n = 19), III (n = 10), and IV (n = 18). At the last follow-up, 17 patients were alive (median follow-up: 36.7 months; range: 24.1–49.9 months) and 42 had died. The median OS was 21.7 months (95% CI: 14.8–34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI: 6.1–11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of grade 3 or higher. Conclusion: PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors.
Aromatic Amino Acids and Their Interactions with Gut Microbiota-Related Metabolites for Risk of Gestational Diabetes: A Prospective Nested Case-Control Study in a Chinese Cohort
Authors: Li Ninghua , Li Jing , Wang Hui , Liu Jinnan , Li Weiqin , Yang Kai , Huo Xiaoxu , Leng Junhong , Yu Zhijie , Hu Gang , Fang Zhongze , Yang Xilin
Published: August 2023

Introduction: The aim of this study was to explore associations of aromatic amino acids (AAA) in early pregnancy with gestational diabetes mellitus (GDM), and whether high AAA and gut microbiota-related metabolites had interactive effects on GDM risk. Methods: We conducted a 1:1 case-control study (n = 486) nested in a prospective cohort of pregnant women from 2010 to 2012. According to the International Association of Diabetes and Pregnancy Study Group’s criteria, 243 women were diagnosed with GDM. Binary conditional logistic regression was performed to examine associations of AAA with GDM risk. Interactions between AAA and gut microbiota-related metabolites for GDM were examined using additive interaction measures. Results: High phenylalanine and tryptophan were associated with increased GDM risk (OR: 1.72, 95% CI: 1.07–2.78 and 1.66, 1.02–2.71). The presence of high trimethylamine (TMA) markedly increased the OR of high phenylalanine alone up to 7.95 (2.79–22.71), while the presence of low glycoursodeoxycholic acid (GUDCA) markedly increased the OR of high tryptophan alone up to 22.88 (5.28–99.26), both with significant additive interactions. Furthermore, high lysophosphatidylcholines (LPC18:0) mediated both interactive effects. Conclusions: High phenylalanine may have an additive interaction with high TMA, while high tryptophan may have an additive interaction with low GUDCA toward increased risk of GDM, both being mediated via LPC18:0.
Behandlungserfahrungen mit Rituximab bei Patienten mit rheumatoider Arthritis-assoziierter interstitieller Lungenerkrankung in Ankara, Türkei
Authors: Xanthouli Panagiota
Published: August 2023

Objective: To demonstrate the effects of rituximab (RTX) in patients with rheumatoid arthritis-related interstitial lung disease (RA-ILD). Methods: A total of 165 patients who used RTX for the management of rheumatoid arthritis were retrospectively scrutinised. Among these, 26 patients diagnosed with RA-ILD were analysed (61.5% male, mean age at RTX infusion 61.4 ± 6.5 years). To evaluate the efficacy of RTX on lung response, patients with pulmonary function test results and/or thorax computed tomography (chest-CT) of pre- and post-RTX were compared. Disease progression was defined as either a decline of ≥10% in forced vital capacity (FVC) and/or a decline of ≥15% in diffusion capacity of carbon monoxide (DLCO), or an increase of parenchymal involvement on chest-CT images according to the radiologists’ assessment. Results: Among 26 patients, the most common radiologic pattern was usual interstitial pneumonia (42.3%), followed by non-specific interstitial pneumonia (38.5%). Data for lung response was available in 20 patients. Median pre- and post-RTX DLCO values were 71.0% (60.0–77.0) and 63.0% (47.0–74.0), respectively (p = 0.06). Median pre- and post-RTX FVC values were 74.0% (61.0–99.0) and 84.0% (63.0–100.0), respectively (p = 0.28). Overall, stabilization or regression of RA-ILD was provided in 13 (65.0%) patients, whereas 7 patients had progressive RA-ILD. Post-RTX, 5 patients were diagnosed with RA-ILD.
Explainable Alzheimer’s Disease Detection Using Linguistic Features from Automatic Speech Recognition
Authors: Tang Lijuan , Zhang Zhenglin , Feng Feifan , Yang Li-Zhuang , Li Hai
Published: August 2023

Introduction: Alzheimer’s disease (AD) is the most prevalent type of dementia and can cause abnormal cognitive function and progressive loss of essential life skills. Early screening is thus necessary for the prevention and intervention of AD. Speech dysfunction is an early onset symptom of AD patients. Recent studies have demonstrated the promise of automated acoustic assessment using acoustic or linguistic features extracted from speech. However, most previous studies have relied on manual transcription of text to extract linguistic features, which weakens the efficiency of automated assessment. The present study thus investigates the effectiveness of automatic speech recognition (ASR) in building an end-to-end automated speech analysis model for AD detection. Methods: We implemented three publicly available ASR engines and compared the classification performance using the ADReSS-IS2020 dataset. Besides, the SHapley Additive exPlanations algorithm was then used to identify critical features that contributed most to model performance. Results: Three automatic transcription tools obtained mean word error rate texts of 32%, 43%, and 40%, respectively. These automated texts achieved similar or even better results than manual texts in model performance for detecting dementia, achieving classification accuracies of 89.58%, 83.33%, and 81.25%, respectively. Conclusion: Our best model, using ensemble learning, is comparable to the state-of-the-art manual transcription-based methods, suggesting the possibility of an end-to-end medical assistance system for AD detection with ASR engines. Moreover, the critical linguistic features might provide insight into further studies on the mechanism of AD.
Multicenter Phase II Trial of Lenvatinib plus Hepatic Intra-Arterial Infusion Chemotherapy with Cisplatin for Advanced Hepatocellular Carcinoma: LEOPARD
Authors: Ikeda Masafumi , Yamashita Tatsuya , Ogasawara Sadahisa , Kudo Masatoshi , Inaba Yoshitaka , Morimoto Manabu , Tsuchiya Kaoru , Shimizu Satoshi , Kojima Yasushi , Hiraoka Atsushi , Nouso Kazuhiro , Aikata Hiroshi , Numata Kazushi , Sato Tosiya , Okusaka Takuji , Furuse Junji
Published: August 2023

Introduction: Hepatic arterial infusion chemotherapy (HAIC) with cisplatin and lenvatinib exhibits strong antitumor effects against advanced hepatocellular carcinoma (HCC). Higher antitumor activity is expected for the combination treatment. The aim of this trial was to evaluate the efficacy and safety of lenvatinib in combination with HAIC using cisplatin in patients with advanced HCC. Methods: In this multicenter, open-labeled, single-arm, phase II trial, patients with advanced HCC categorized as Child-Pugh class A with no prior history of systemic therapy were enrolled. Patients received lenvatinib plus HAIC with cisplatin (lenvatinib: 12 mg once daily for patients ≥60 kg, 8 mg once daily for patients <60 kg; HAIC with cisplatin: 65 mg/m2, day 1, every 4–6 weeks, maximum of six cycles). The primary endpoint was the objective response rate (ORR) assessed using modified RECIST by the Independent Review Committee. The secondary endpoints were the ORR assessed using RECIST v1.1, progression-free survival, overall survival, and frequency of adverse events associated with the treatment. Results: A total of 36 patients were enrolled between September 2018 and March 2020. In the 34 evaluable patients, the ORR assessed by the Independent Review Committee using modified RECIST and RECIST v1.1 were 64.7% (95% confidence interval [CI]: 46.5–80.3%) and 45.7% (95% CI: 28.8–63.4%), respectively. The median progression-free survival and overall survival were 6.3 months (95% CI: 5.1–7.9 months) and 17.2 months (95% CI: 10.9 – not available, months), respectively. The main grade 3–4 adverse events were increased aspartate aminotransferase (34%), leukopenia (22%), increased alanine aminotransferase (19%), and hypertension (11%). Conclusion: Lenvatinib plus HAIC with cisplatin yielded a favorable ORR and overall survival and was well tolerated in patients with advanced HCC. Further evaluation of this regimen in a phase III trial is warranted.
Intention to Undergo Clinical Breast Examination and Its Associated Factors among Women Attending Rural Primary Healthcare Facilities in South Central Ethiopia
Authors: Ketema Bezawit , Kaba Mirgissa , Negash Sarah , Addissie Adamu , Kantelhardt Eva Johanna
Published: August 2023

Background: Breast cancer is a global public health problem with higher mortality in developing countries. The Ethiopian National Cancer Control Plan recommends clinical breast examination (CBE) for all women aged >18 years. However, there is low breast examination practice in Ethiopia. Therefore, this study aimed to describe level of intention to undergo CBE and associated factors among women visited selected rural healthcare facilities in south central Ethiopia using Theory of Planned Behavior (TPB). Methods: This study used facility-based cross-sectional study design. A total of 420 women participated in this study. Interviewer-administered structured questionnaire was adopted from previously published research works and Ajzen’s TPB manual. Statistical Package for Social Sciences (SPSS), version 27, was used for analysis. Binary logistic regression model was used to determine factors associated with intention to undergo CBE. Results: In this study, nine out of ten women had never had CBE. Mean score for intention to undergo CBE was 12.55 (SD ± 3.22; min 5, max 20). Intention to undergo CBE was negatively associated with being in the second and middle wealth quantiles compared to the highest wealth quantile, and with the spouse not being able to read or write compared to having attended formal education. Positive attitude and higher subjective norm had relevant association with intention to undergo CBE. Conclusion: The high score for intention to undergo CBE should encourage primary healthcare facilities to offer CBE. Behavioral change communication interventions could address women’s attitude, subjective norm, and spouse’s education associated with intention to undergo CBE.
Social Health and Change in Cognitive Capability among Older Adults: Findings from Four European Longitudinal Studies
Authors: Maddock Jane , Gallo Federico , Wolters Frank J. , Stafford Jean , Marseglia Anna , Dekhtyar Serhiy , Lenart-Bugla Marta , Verspoor Eline , Perry Marieke , Samtani Suraj , Vernooij-Dassen Myrra , Wolf-Ostermann Karin , Melis Rene , Brodaty Henry , Ikram Mohammad Arfan , Welmer Anna-Karin , Davis Daniel , Ploubidis George B. , Richards Marcus , Patalay Praveetha ,   on behalf of the SHARED Consortium
Published: August 2023

Introduction: In this study, we examine whether social health markers measured at baseline are associated with differences in cognitive capability and the rate of cognitive decline over an 11-to-18-year period among older adults and compare results across studies. Methods: We applied an integrated data analysis approach to 16,858 participants (mean age 65 years; 56% female) from the National Survey for Health and Development (NSHD), the English Longitudinal Study of Aging (ELSA), the Swedish National Study on Aging and Care in Kungsholmen (SNAC-K), and the Rotterdam Study. We used multilevel models to examine social health in relation to cognitive capability and the rate of cognitive decline. Results: Pooled estimates show distinct relationships between markers of social health and cognitive domains, e.g., a large network size (≥6 people vs. none) was associated with higher executive function (0.17 standard deviation [SD] [95% CI: 0.00, 0.34], I2 = 27%) but not with memory (0.08 SD [95% CI: −0.02, 0.18], I2 = 19%). We also observed pooled associations between being married or cohabiting, having a large network size, and participating in social activities with slower decline in cognitive capability. However, estimates were close to zero, e.g., 0.01 SD/year (95% CI: 0.01, 0.02) I2 = 19% for marital status and executive function. There were clear study-specific differences: results for average processing speed were the most homogenous, and results for average memory were the most heterogeneous. Conclusion: Overall, markers of good social health have a positive association with cognitive capability. However, we found differential associations between specific markers of social health and cognitive domains and differences between studies. These findings highlight the importance of examining between-study differences and considering the context specificity of findings in developing and deploying interventions.
Vocabulary Diversity in Personal Narratives Produced in Response to the Global TALES Protocol in Dutch-Speaking Students with and without Dyslexia
Authors: Van Vreckem Christel , Desoete Annemie , Simoens Delfine , Van de Vyver Aveline , Pauwels Jana , Van Laethem Charlotte , Van Lierde Kristiane
Published: August 2023

Introduction: This study examines whether there are differences in expressive vocabulary between participants with and without dyslexia in personal narratives in response to the Global TALES protocol. Methods: 22 monolingual Dutch-speaking participants aged 11–16 with dyslexia and 22 age and gender-matched peers without dyslexia were assessed on measures of decoding, reading comprehension, and spelling of words, pseudowords, verbs, and sentences. The participants also produced personal narratives in response to the six prompts contained in the Global TALES protocol. We analyzed the personal narratives for expressive vocabulary and counted the total number of different words (TNDW). Results: The study revealed a significant relationship between TNDW and reading comprehension (r = 0.45, p = 0.002, BF10 = 17.70), spelling words (r = 0.42, p = 0.005, BF10 = 8.93), and spelling and writing conventions in sentences (r = 0.37, p = 0.016, BF10 = 3.11). The Global TALES protocol was successful in eliciting personal narratives in the Dutch-speaking participants with and without dyslexia. Participants with dyslexia used fewer different words (M = 192.27, SD = 64.37; 95% CI: [151.84–232.71]) compared to peers without dyslexia (M = 265.50, SD = 116.28; 95% CI: [225.06–305.93]; F(1, 42) = 6.68; p = 0.013; η2 = 0.14). When we compared the probability of models, Bayesian factors revealed moderate evidence for group differences in TNDW (BF = 3.94). Conclusion: Our findings indicate that older school-age participants with dyslexia may lag behind their peers in expressive vocabulary in a personal narrative discourse task that is relevant to everyday functioning. The results of this study highlight the relationship between expressive vocabulary and reading comprehension and the importance of the assessment of spoken language skills in children with dyslexia. Reading problems might lead to less advanced spoken language, which in turn may negatively affect the expressive vocabulary growth in individuals with dyslexia.
PD-L1 (22C3) Expression Correlates with Clinical and Molecular Features of Lung Adenocarcinomas in Cytological Samples
Authors: Anderson Sarah A. , Harbi Djamel , Oramas Mogrovejo Diana , Floyd Antoinette D. , Eltoum Isam-Eldin , Fatima Huma , Rosenblum Frida , Lora Gonzalez Manuel , Lin Diana , Mackinnon Alexander C. , Siegal Gene P. , Winokur Thomas , Yalniz Ceren , Huo Lei , Harada Shuko , Huang Xiao
Published: August 2023

Introduction: PD-L1 expression is the most widely used predictive marker for immune checkpoint inhibitor (ICI) therapy in patients with lung adenocarcinoma. However, the current understanding of the association between PD-L1 expression and treatment response is suboptimal. A significant percentage of patients have only a cytological specimen available for clinical management. Therefore, it is relevant to examine the impact of molecular features on PD-L1 expression in cytological samples and how it might correlate with a therapeutic response. Methods: We evaluated patients diagnosed with adenocarcinoma of the lung who had both in-house targeted next-generation sequencing analysis and paired PD-L1 (22C3) immunohistochemical staining performed on the same cell blocks. We explored the association between molecular features and PD-L1 expression. In patients who underwent ICIs therapy, we assessed how a specific gene mutation impacted a therapeutic response. Results: 145 patients with lung adenocarcinoma were included in this study. PD-L1-high expression was found to be more common in pleural fluid than in other sample sites. Regional lymph node samples showed a higher proportion of PD-L1-high expression (29%) compared with lung samples (6%). The predictive value of PD-L1 expression was retained in cytological samples. Mutations in KRAS were also associated with a PD-L1-high expression. However, tumors with TP53 or KRAS mutations showed a lower therapy response rate regardless of the PD-L1 expression. Conclusion: Cytological samples maintain a predictive value for PD-L1 expression in patients with lung adenocarcinoma as regards the benefit of ICI treatment. Specific molecular alterations additionally impact PD-L1 expression and its predictive value.
Differential Gene Expression of SARS-CoV-2 Positive Bronchoalveolar Lavages: A Case Series
Authors: Haslbauer Jasmin D. , Savic Prince Spasenija , Stalder Anna K. , Matter Matthias S. , Zinner Carl P. , Jahn Kathleen , Obermann Ellen , Hanke Jasmin , Leuzinger Karoline , Hirsch Hans H. , Tzankov Alexandar
Published: August 2023

Background: Transcriptomic data on bronchoalveolar lavage (BAL) from COVID-19 patients are currently scarce. Objectives: This case series seeks to characterize the intra-alveolar immunopathology of COVID-19. Method: BALs were performed on 14 patients (5 COVID-19, of which 3 mild and 2 largely asymptomatic, 9 controls). Controls included asthma (n = 1), unremarkable BALs (n = 3), infections with respiratory syncytial virus (n = 1), influenza B (n = 1), and infections with other coronaviruses (n = 3). SARS-CoV-2 RNA load was measured by quantitative nucleic acid testing, while the detection of other pathogens was performed by immunofluorescence or multiplex NAT. Results: Gene expression profiling showed 71 significantly downregulated and 5 upregulated transcripts in SARS-CoV-2-positive lavages versus controls. Downregulated transcripts included genes involved in macrophage development, polarization, and crosstalk (LGALS3, MARCO, ERG2, BTK, RAC1, CD83), and genes involved in chemokine signaling and immunometabolism (NUPR1, CEBPB, CEBPA, PECAM1, CCL18, PPARG, ALOX5, ALOX5AP). Upregulated transcripts featured genes involved in NK-T cell signaling (GZMA, GZMH, GNLY, PRF1, CD3G). Patients with mild COVID-19 showed a significant upregulation of genes involved in blood mononuclear cell/leukocyte function (G0S2, ANXA6, FCGR2B, ADORA3), coagulation (von Willebrand factor [VWF]), interferon response (IFRD1, IL12RB2), and a zinc metalloprotease elevated in asthma (CPA3) compared to asymptomatic cases. In-silico comparison of the 5 COVID-19 BAL cases to a published cohort of lethal COVID-19 showed a significant upregulation of “antigen processing and presentation” and “lysosome” pathways in lethal cases. Conclusions: These data underscore the heterogeneity of immune response in COVID-19. Further studies with a larger dataset are required to gain a better understanding of the hallmarks of SARS-CoV-2 immunological response.
High Systemic Immune-Inflammation Index, Predicting Early Allograft Dysfunction, Indicates High 90-Day Mortality for Acute-On-Chronic Liver Failure after Liver Transplantation
Authors: Fu Zongli , Cheng Pengrui , Jian Qian , Wang Hanyu , Ma Yi
Published: August 2023

Introduction: The aim of the study was to investigate the relationship between systemic immune-inflammation index (SII) and early allograft dysfunction (EAD) and 90-day mortality after liver transplantation (LT) in acute-on-chronic liver failure (ACLF). Methods: Retrospective record analysis was done on 114 patients who had LT for ACLF. To identify the ideal SII, the receiver operating characteristic curve was used. The incidence of EAD and 90-day mortality following LT were calculated. The prognostic value of SII was assessed using the Kaplan-Meier technique and the Cox proportional hazards model. Results: The cut-off for SII was 201.5 (AUC = 0.728, p < 0.001). EAD occurred in 40 (35.1%) patients of the high SII group and 5 (4.4%) patients of the normal SII group, p < 0.001. 18 (15.8%) deaths occurred in the high SII group and 2 (1.8%) deaths occurred in the normal SII group, p = 0.008. The multivariate analysis demonstrated that SII ≥201.5, MELD ≥27 were independent prognostic factors for 90-day mortality after LT. Conclusion: SII predicts the occurrence of EAD and is an independent risk factor for 90-day mortality after LT.
Assessment of Developmental Language Disorder in Multilingual Children: Results from an International Survey
Authors: Scharff Rethfeldt Wiebke , McNeilly Lemmietta , Laasonen Marja , Meir Natalia , Abutbul-Oz Hadar , Smolander Sini , Niegia Garcia Goulart Bàrbara , Frances Hunt Emily
Published: August 2023

Introduction: The Multilingual-Multicultural Affairs Committee of the International Association of Communication Disorders (IALP) conducted a survey of diagnostic criteria for developmental language disorder (DLD) in multilingual children to discover how clinicians apply terminology and diagnostic criteria to multilingual children in different parts of the world. Methods: An international web survey was used to survey 354 participants from 44 countries about their assessment practices, and clinical opinions about assessing multilingual children for DLD. Results: The findings show that most clinicians felt confident in assessing multilingual children, and they applied the DLD terminology and inclusionary criteria to multilingual children with difficulty learning language. Clinicians used different procedures to assess heritage and societal languages. Barriers to access to services included a lack of knowledge by parents and referral sources about services available and typical multilingual development, with additional reasons differing by geographical region. Discussion: Speech pathologists across the globe have many similarities in the way that they assess multilingual children. Differences may be attributed to clinical experience, professional education, the clinician’s role, the system they work in, and the clinician’s own language skills. This paper advances knowledge of current clinical practices, which can be used to evaluate frameworks in international and national contexts, with implications for policy and practice to improve access to clinical services.
Lipid Metabolism Pathway Genes and Lung Cancer: ACADSB rs12220683G>C Is Associated with Better Survival Outcome in Patients with Non-Small Cell Lung Cancer
Authors: Yoo Seung Soo , Do Sook Kyung , Choi Jin Eun , Kang Hyo-Gyoung , Hong Mi Jeong , Lee Jang Hyuck , Lee Won Kee , Do Young Woo , Lee Eung Bae , Park Ji Eun , Choi Sun Ha , Seo Hyewon , Lee Yong Hoon , Lee Jaehee , Lee Shin Yup , Cha Seung Ick , Kim Chang Ho , Park Jae Yong
Published: August 2023

Introduction: Altered lipid metabolism has been reported to be associated with prognosis in multiple cancers. This study aimed to investigate the association of polymorphisms in lipid metabolism pathway genes with survival outcomes in patients with surgically resected non-small cell lung cancer (NSCLC). Methods: In total, 744 patients with surgically resected NSCLC (380 in the discovery cohort and 364 in the validation cohort) were included in this study. The association between 176 polymorphisms of lipid metabolism pathway genes and the clinical outcomes of NSCLC patients was analyzed. Results: Among the polymorphisms investigated, ACADSB rs10902859G>A was associated with significantly better overall survival (OS) in the discovery, validation, and combined cohorts. ACADSB rs10902859G>A was located in the repressed region and had strong linkage disequilibrium (D′ = 1.00 and r2 = 0.94), with rs12220683G>C located in the H3K4me3 peak region, which indicates the presence of active promoters. ACADSB rs12220683G>C was also associated with better OS in the discovery, validation, and combined cohorts (in a dominant model; adjusted hazard ratio [aHR] = 0.53, 95% confidence interval [CI] = 0.30–0.94, p = 0.03; aHR = 0.37, 95% CI = 0.15–0.89, p = 0.03; and aHR = 0.47, 95% CI = 0.29–0.75, p = 0.002, respectively). In vitro luciferase assay demonstrated that the promoter activity of ACADSB was significantly increased in the rs12220683 variant C allele compared with that in the wild G allele (p = 3 × 10−5). Conclusion: These results suggest that ACADSB rs12220683G>C increases promoter activity and that increased ACADSB expression may result in better OS in patients with surgically resected NSCLC.
Atezolizumab in Combination with Bevacizumab for the Management of Patients with Hepatocellular Carcinoma in the First-Line Setting: Systematic Literature Review and Meta-Analysis
Authors: Vogel Arndt , Finn Richard S. , Blanchet Zumofen Marie-Hélène , Heuser Carolina , Sanchez Alvarez Javier , Leibfried Michael , Mitchell Catherine R. , Batson Sarah , Redhead Gabrielle , Gaillard Vincent E. , Kudo Masatoshi
Published: August 2023

Background: In 2020, atezolizumab-bevacizumab became the new standard of care (SOC) for first-line unresectable hepatocellular carcinoma (HCC) patients, following a decade where sorafenib was the preferred first-line treatment. In the last few years, a number of novel systemic treatments with non-inferiority and superiority to sorafenib have been approved as first-line treatments. Objectives: The objective of this systematic literature review (SLR) and network meta-analysis (NMA) was to compare randomised controlled trial evidence for atezolizumab-bevacizumab with globally relevant pharmacological comparators for first-line treatment of patients with unresectable HCC. Methods: Randomised controlled trials investigating first-line treatment of HCC in adults with no prior systemic treatment were eligible for inclusion into the SLR and were retrieved from Embase, MEDLINE, and Evidence-Based Medicine (EBM) Reviews. Interventions of interest for the NMA included atezolizumab-bevacizumab, sorafenib, lenvatinib, durvalumab (including in combination with tremelimumab), cabozantinib (including in combination with atezolizumab), camrelizumab (including in combination with rivoceranib), pembrolizumab (including in combination with lenvatinib), and tislelizumab. Random effects NMA was conducted for survival endpoints within a Bayesian framework with an informative prior distribution for between-study heterogeneity. The hazard ratios for relative treatment effect were estimated with 95% credible intervals (CrIs). Results: The SLR identified 49 studies, of which eight formed a connected evidence network permitting the indirect treatment comparison of atezolizumab-bevacizumab with comparators of interest. The indirect comparisons suggested an improved overall survival (OS) with atezolizumab-bevacizumab versus most comparators. All indirect treatment comparison results for atezolizumab-bevacizumab included the null value within the 95% CrI (n = 1) for OS and progression-free survival (PFS). Conclusions: The results of the NMA indicate atezolizumab-bevacizumab is associated with superior or comparable OS and PFS together with a manageable safety profile compared with globally relevant comparators in the unresected HCC indication. The findings support that atezolizumab-bevacizumab remains SOC for the management of first-line unresectable HCC patients.
Evaluation of the CLL-IPI and IPS-E Prognostic Indices in a Young Middle Eastern Population with Chronic Lymphocytic Leukemia: A Retrospective Analysis at the Kuwait Cancer Control Center
Authors: Alshemmari Salem H. , Alsarraf Ahmad , Kunhikrishnan Anita , Pandita Ramesh
Published: August 2023

Introduction: The Chronic Lymphocytic Leukemia International Prognostic Index (CLL-IPI) is a powerful prognostic tool validated in multiple Western populations. However, its utility in the young Middle Eastern population is unknown. Methodology: We conducted a retrospective analysis of 152 unselected patients with chronic lymphocytic leukemia (CLL) diagnosed between 2008 and 2022 at the Kuwait Cancer Control Center, which serves as the sole cancer center in Kuwait. The evaluation of the CLL-IPI was based on the assessment of event-free survival (EFS) across the entire cohort. Subsequently, we compared the CLL-IPI with the International Prognostic Score for Early-stage patients (IPS-E) in order to predict the time to first treatment specifically within the subgroup of patients diagnosed with early-stage disease. Results: The median age of the study cohort was 59.9 years (IQR, 53.1–68.8). The 5-year EFS rates for the low, intermediate, and high/very high-risk categories were approximately 82%, 34%, and 23%, respectively, p < 0.001 (C-statistic = 0.67). On multivariate analysis, advanced stage and unmated IGHV status were independent prognostic factors of EFS. In those with early-stage disease, cumulative 5-year treatment incidence rates for the low, intermediate, and high/very high-risk categories based on the CLL-IPI score were approximately 8%, 55%, and 55%, respectively, p = 0.001 (C-statistic = 0.70). However, based on the IPS-E score, the cumulative 5-year treatment incidence rates for the low, intermediate, and high-risk categories were approximately 0%, 10%, and 60%, respectively, p < 0.001 (C-statistic = 0.73). Conclusions: The CLL-IPI and the IPS-E are valid stratification tool in our young Middle Eastern population.