bluuebunny/crossref_metadata_2025_split huggingface dataset:
RET fusion mutation detected by re-biopsy 7 years after initial cytotoxic chemotherapy: A case report
Authors: Morikawa Kei , Handa Hiroshi , Ueno Junko , Tsuruoka Hajime , Inoue Takeo , Shimada Naoki , Koike Junki , Nakamura Seiji , Sato Yoshiharu , Mineshita Masamichi 
Published: November 2022

Personalized medicine using molecular-targeted drugs to achieve better therapeutic response and long-term prognosis is common practice for lung cancer treatment. However, in cases before gene batch tests were available, medical treatment continued without the detection of rare mutations. We report a sixty-seven-old year man diagnosed with adenocarcinoma T1cN3M1a, stage IVA. Initial screening performed 7 years earlier using EGFR mutation and ALK immunohistochemical tests were negative. Although first-line cytotoxic combination chemotherapy was remarkably effective, a gradual regression of the primary lesion was noted. After a recent bronchoscopic re-biopsy, RET fusion was detected by gene panel test. In addition, we were able to confirm RET from FFPE specimens obtained from 7-year-old pleural effusion cell blocks. Subsequent administration of the molecular-targeted drug selpercatinib, was highly effective for the primary lesion and all metastatic lesions including brain metastases. We describe a case of RET fusion-positive lung cancer where molecular targeted therapy and cytotoxic drug showed a drastic response and long-term therapy was well maintained. Next generation sequencing was able to correctly diagnose RET fusion mutation using re-biopsy specimen after going undiagnosed for 7 years.
Triglyceride glucose index and Atherogenic index of plasma for predicting colorectal neoplasms in patients without cardiovascular diseases
Authors: Han Muzhou , Wang Hao , Yang Shuyue , Zhu Siying , Zhao Guiping , Shi Haiyun , Li Peng 
Published: November 2022

Background and aimsColorectal neoplasms (CRN) include colorectal cancer (CRC) and colorectal adenoma (CRA). The relationship between CRN and triglyceride-glucose (TyG) index or between CRN and atherogenic index of plasma (AIP) is unclear. This study aims to investigate the roles of TyG index and AIP in predicting CRN in people without cardiovascular disease (CVD).Methods2409 patients without CVD underwent colonoscopy were enrolled. Clinical information and relevant laboratory test results of these patients were collected and recorded. According to endoscopic and pathological results, all participants were divided into a neoplasms group and a non-neoplasms group. The TyG index was calculated as ln (TGs×FPG/2), while AIP was calculated as log (TGs/HDL-C). We used uni- and multivariate logistic regression and restricted cubic spline (RCS) to analyze the association between the TyG inedx, AIP and CRN, develop predictive models and construct the nomograms. Receiver operating characteristic (ROC) curves were utilized to evaluate the predictive value for CRN.ResultsParticipants in the neoplasms group were more likely to be older, have higher TyG index, higher AIP and higher rates of fecal occult blood test positivity, and were more likely to be male, smokers and those with the family history of CRC (P &lt; 0.05). The higher TyG index was related to the higher risk of CRN [OR (95% CI): 1.23 (1.08 - 1.41), P = 0.003]. The higher AIP was related to the higher risk of CRN [OR (95% CI): 1.55 (1.16 - 2.06), P = 0.003]. These two indicators are better for predicting CRN in women than men. The combined use of the TyG index and other independent risk factors (age, sex, smoking status, family history and FOBT) to distinguish CRN was effective, with a sensitivity of 61.0%, a specificity of 65.1% and an AUC of 0.669 (95%CI, 0.639 - 0.698). Likewise, the combined use of the AIP and other independent risk factors to distinguish CRN was also effective, the model had an overall 56.3% sensitivity and 68.7% specificity with an AUC of 0.667 (95%CI, 0.638 - 0.697).ConclusionThis study showed that the TyG index and the AIP might be biomarkers that could be used to predict the risk of CRN in patients without CVD.
Diffusion-weighted MRI to determine response and long-term clinical outcomes in muscle-invasive bladder cancer following neoadjuvant chemotherapy
Authors: Hafeez Shaista , Koh Mu , Jones Kelly , Ghzal Amir El , D’Arcy James , Kumar Pardeep , Khoo Vincent , Lalondrelle Susan , McDonald Fiona , Thompson Alan , Scurr Erica , Sohaib Aslam , Huddart Robert Anthony 
Published: November 2022

ObjectiveThis study aims to determine local treatment response and long-term survival outcomes in patients with localised muscle-invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC) using diffusion-weighted MRI (DWI) and apparent diffusion coefficient (ADC) analysis.MethodsPatients with T2-T4aN0-3M0 bladder cancer suitable for NAC were recruited prospectively. DWI was performed prior to NAC and was repeated following NAC completion. Conventional response assessment was performed with cystoscopy and tumour site biopsy. Response was dichotomised into response (&lt;T2) or poor response (≥T2). Patients proceeded to either radical cystectomy or chemo-radiotherapy as standard of care. Tumour ADC values were calculated for all b-values (ADCall) and high b-values (ADCb100). Mean ADC, percentiles, skew, kurtosis, and their change (ΔADC and %ΔADC) were determined. Threshold predictive of response with highest specificity was ascertained using receiver operating characteristic (ROC) analysis. Median overall survival (OS), bladder-cancer-specific survival (bCSS), progression-free survival (PFS), and time to cystectomy were estimated using Kaplan–Meier method. Significant area under the curve (AUC) cut points were used to determine relationship with long-term endpoints and were compared using log-rank test.ResultsForty-eight patients (96 DWI) were evaluated. NAC response was associated with significant increase in mean ΔADC and %ΔADC compared to poor response (ΔADCall 0.32×10−3 versus 0.11×10−3 mm2/s; p=0.009, and %ΔADCall 21.70% versus 8.23%; p=0.013). Highest specificity predicting response was seen at 75th percentile ADC (AUC, 0.8; p=0.01). Sensitivity, specificity, positive predictive power, and negative predictive power of %ΔADCb100 75th percentile was 73.7%, 90.0%, 96.6%, and 52.9%, respectively. %ΔADCb100 75th percentile &gt;15.5% was associated with significant improvement in OS (HR, 0.40; 95% CI, 0.19–0.86; p=0.0179), bCSS (HR, 0.26; 95% CI, 0.08–0.82; p=0.0214), PFS (HR, 0.16; 95% CI, 0.05–0.48; p=0.0012), and time to cystectomy (HR, 0.19; 95% CI, 0.07–0.47; p=0.0004).ConclusionsQuantitative ADC analysis can successfully identify NAC response and improved long-term clinical outcomes. Multi-centre validation to assess reproducibility and repeatability is required before testing within clinical trials to inform MIBC treatment decision making.Advances in knowledgeWe successfully demonstrated that measured change in DWI can successfully identify NAC response and improved long-term survival outcomes.
Back to basic: Trials and tribulations of alkalizing agents in cancer
Authors: Gillies Robert J. , Ibrahim-Hashim Arig , Ordway Bryce , Gatenby Robert A. 
Published: November 2022

“Dysregulated” metabolism is a characteristic of the cancer cell phenotype. This includes persistent use of glycolytic metabolism in normoxic environments (Warburg effect) leading to increased acid production and accumulation of protons in the interstitial space. Although often thought to be disordered, altered cancer metabolism is the outcome of intense Darwinian selection and, thus, must have evolved to maximize cancer cell fitness. In an evolutionary context, cancer-induced acidification of the microenvironment represents a niche construction strategy to promote proliferation. Ecological advantages conferred on the cancer population included remodeling of the extracellular matrix to promote local invasion, suppression of potential competitive proliferation of fibroblasts, and suppression of host immune response. Preclinical data demonstrates that increasing the serum buffering capacity (through, for example, oral sodium bicarbonate and TRIS) can neutralize the acidic tumor microenvironment with inhibition local invasion and proliferation which can be synergistic with the effects of chemotherapy and immunotherapy agents. Here, we describe the proton dynamics in cancer and their influence on tumor progression and metastasis. Additionally, we will discuss targeting the tumor acidosis with alkalizing agents including our bicarbonate clinical trial results.Clinical Trial Registrationclinicaltrials.gov, identifier NCT01350583, NCT01198821 and NCT01846429.
Development and validation of nomograms predicting postoperative survival in patients with chromophobe renal cell carcinoma
Authors: Li Shuaishuai , Zhu Jiawei , He Zhenwei , Ashok Raj , Xue Ning , Liu Zijie , Ding Li , Zhu Haitao 
Published: November 2022

ObjectiveThe purpose of our study is to construct and validate nomograms that effectively predict postoperative overall survival and cancer-specific survival for patients with chromophobe renal cell carcinoma (chRCC).MethodClinical, social, and pathological data from 6016 patients with chRCC collected from the SEER database were screened from 2004 to 2015. They were randomly assigned to a training cohort (n = 4212) and a validation cohort (n = 1804) at a 7:3 ratio. Cox regression and least absolute shrinkage and selection operator (LASSO) analyses were used to identify the prognostic factors affecting overall survival (OS) and cancer-specific survival (CSS) and establish nomograms. Their performance was validated internally and externally by calculating Harrell’s C-indexes, area under the curve (AUC), calibration, and decision curves. For external validation, samples from postoperative patients with chRCC at 3 independent centers in Xuzhou, China, were collected. Risk stratification models were built according to the total scores of each patient. Kaplan-Meier curves were generated for the low-risk, intermediate-risk, and high-risk groups to evaluate survival.ResultsThe C-indexes, AUC curves, and decision curves revealed the high ability of the nomograms in predicting OS and CSS, overall better than that of AJCC and TNM staging. Moreover, in internal and external validation, the calibration curves of 5-, 8-, and 10-year OS agreed with the actual survival. Kaplan-Meier curves indicated significant differences in survival rates among the 3 risk groups in OS or CSS.ConclusionThe nomograms showed favourable predictive power for OS and CSS. Thus, they should contribute to evaluating the prognosis of patients with chRCC. Furthermore, the risk stratification models established on the nomograms can guide the prognosis of patients and further treatment.
Acquired von Willebrand syndrome (AVWS) type 2, characterized by decreased high molecular weight multimers, is common in children with severe pulmonary hypertension (PH)
Authors: Wieland Ivonne , Diekmann Franziska , Carlens Julia , Hinze Laura , Lambeck Katharina , Jack Thomas , Hansmann Georg 
Published: November 2022

Background and objectivesEmerging evidence suggests that increased degradation of von Willebrand factor and decrease in high molecular weight multimers occurs in patients with pulmonary hypertension (PH). However, the link between acquired von Willebrand Syndrome (AVWS) type 2 and PH remains poorly understood.Material and methodsWe retrospectively evaluated the charts of 20 children with PH who underwent bilateral lung transplantation (LuTx) between 2013 and 2022. Von Willebrand variables were determined in 14 of these patients; 11 patients had complete diagnostics including multimer analysis.ResultsWe confirmed AVWS in 82% of the children studied (9 of 11 patients by multimer analysis). The two remaining patients had suspected AVWS type 2 because of a VWF:Ac/VWF:Ag ratio of &lt;0.7. Platelet dysfunction or suspicion of VWD type 1 were found in two separate patients. All but one of the 14 children with severe PH had a coagulation disorder. Most patients (9 proven, 2 suspected) had AVWS type 2. Notably, 3 of 5 patients (60%) with normal VWF:Ac/VWF:Ag ratio &gt;0.7 had abnormal VWF multimers, indicating AVWS type 2. Hemostatic complications were observed in 4 of 12 (33%) patients with VWS and 3 of 6 (50%) patients without diagnostics and therapy.ConclusionFor children with moderate to severe PH, we recommend systematic analysis of von Willebrand variables, including multimer analysis, PFA-100 and platelet function testing. Awareness of the diagnosis “AVWS” and adequate therapy may help to prevent these patients from bleeding complications in case of surgical interventions or trauma.
SARS-CoV-2 viral clearance and viral load kinetics in young children (1–6 years) compared to adults: Results of a longitudinal study in Germany
Authors: Sandoni Anna , Schaffrath Rosario Angelika , Michel Janine , Kuttig Tim , Wurm Juliane , Damerow Stefan , Iwanowski Helena , Finkel Bianca , Schrick Livia , Buchholz Udo , Haas Walter , Varnaccia Gianni , Kubisch Ulrike , Jordan Susanne , Schienkiewitz Anja , Nitsche Andreas , Loss Julika 
Published: November 2022

ObjectiveTo investigate SARS-COV-2 viral clearance and viral load kinetics in the course of infection in children aged 1–6 years in comparison with adults.MethodsProspective cohort study of infected daycare children and staff and their close contacts in households from 11/2020 to 06/2021. Adult participants took upper respiratory tract specimen from themselves and/or their children, for PCR tests on SARS-CoV-2. Data on symptoms and exposure were used to determine the date of probable infection for each participant. We determined (a) viral clearance, and (b) viral load dynamics over time. Samples were taken from day 4–6 to day 16–18 after diagnosis of the index case in the respective daycare group (5 samples per participant).ResultsWe included 40 children (1–6 years) and 67 adults (18–77 years) with SARS-CoV-2 infection. Samples were available at a mean of 4.3 points of time per participant. Among the participants, the 12-day study period fell in different periods within the individual course of infection, ranging from day 5–17 to day 15–26 after assumed infection.Children reached viral clearance at a median of 20 days after assumed infection (95% CI 17–21 days, Kaplan-Meier Analysis), adults at 23 days (95% CI 20–25 days, difference not significant). In both children and adults, viral load decreased over time with trajectories of the mean viral load not being statistically different between groups. Kaplan-Meier calculations show that from day 15 (95% CI 13–15), 50% of all participants had a viral load &lt;1 million copies/ml, i.e. were no longer infectious or negative.ConclusionChildren aged 1–6 and adults infected with SARS-CoV-2 (wild type and Alpha variant) did not differ significantly in terms of viral load kinetics and time needed to clear the virus. Therefore, containment measures are important also in the daycare settings as long as the pandemic continues.
Efficacy and safety of oncolytic virus combined with chemotherapy or immune checkpoint inhibitors in solid tumor patients: A meta-analysis
Authors: Liu Xiangxing , Zhang Jiaojiao , Feng Keqing , Wang Simin , Chen Liming , Niu Suping , Lu Qian , Fang Yi 
Published: November 2022

Background: In recent years, several clinical trials have focused on oncolytic virus (OVs) combined with chemotherapy or immune checkpoint inhibitors (ICIs) in solid tumor patients, which showed encouraging effects. However, few studies have concentrated on the summary on the safety and efficacy of the combined treatments. Therefore, we conducted this meta-analysis to explore the safety and curative effect of the combined therapy.Methods: We searched the PubMed, Cochrane Library, Embase, and Clinicaltrials.gov databases to comprehensively select articles on OVs combined with chemotherapy or ICIs for the solid tumor treatment. Overall survival (OS), progression-free survival (PFS), 1-year survival rate, 2-year survival rate, objective response rate (ORR), and adverse events (AEs) were the outcomes.Results: Fifteen studies with 903 patients were included in this meta-analysis. The pooled ORR was 32% [95% confidence interval (CI): 27–36%, I2 = 24.9%, p = 0.239]. Median OS and median PFS were 6.79 months (CI: 4.29–9.30, I2 = 62.9%, p = 0.044) and 3.40 months (CI: 2.59–4.22, I2 = 0.0%, p = 0.715), respectively. The 1-year survival rate was 38% (CI: 0.29–0.47, I2 = 62.9%, p = 0.044), and the 2-year survival rate was 24% (CI: 12–37%, I2 = 0.0%, p = 0.805). The most common AEs were fever (63%, CI: 57–69%, I2 = 2.3%, p = 0.402), fatigue (58%, CI: 51–65%, I2 = 49.2%, p = 0.096), chill (52%, CI: 43–60%, I2 = 0.0%, p = 0.958), and neutropenia (53%, CI: 47–60%, I2 = 0.0%, p = 0.944).Conclusion: OVs combined with ICIs showed a better efficacy than OVs combined with chemotherapy, which lends support to further clinical trials of OVs combined with ICIs. In addition, OVs combined with pembrolizumab can exert increased safety and efficacy. The toxicity of grades ≥3 should be carefully monitored and observed. However, high-quality, large-scale clinical trials should be completed to further confirm the efficacy and safety of OVs combined with ICIs.Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/login.php], identifier [RD42022348568].
Gut microbiota mediated hypoglycemic effect of Astragalus membranaceus polysaccharides in db/db mice
Authors: Song Qianbo , Cheng Sau Wan , Li Dan , Cheng Huiyuan , Lai Yuen Sze , Han Quanbin , Wu Hoi Yan , Shaw Pang Chui , Zuo Zhong 
Published: November 2022

Gut microbiota has been reported to be closely associated with Type-II diabetes. Restoration of disordered gut microbiota ecosystem has been developed into a therapeutic strategy and gradually applied on Type-II diabetes treatment with both western drugs and herbal polysaccharides. Although Astragalus membranaceus polysaccharides (AMP) have also been used to treat Type-II diabetes, no study investigated correlations between gut microbiota regulation and its hypoglycemic effect. In the present study, the role of gut microbiota on the hypoglycemic effect of AMP in db/db mice was investigated for the first time. Sixteen days treatment of AMP at the dosage of 600 mg/kg in db/db mice not only alleviated its diabetic symptoms significantly but also restored its gut microbiota community with increased production of fecal short chain fatty acids (SCFA). Our further Pearson correlation analyses revealed that the relative abundance of two intestinal bacteria, Akkermansia and Faecalibaculum, were significantly positively correlated with the hypoglycemic effect of AMP as well as fecal SCFA production. It was also noted that treatment of AMP resulted in increased secretion of glucagon-like peptide-1 (GLP-1) in serum and enhanced intestinal integrity. Further mechanistic study revealed that the increased SCFA after AMP treatment could stimulate GLP-1 secretion and improve intestinal integrity via enhancing the expression of G protein-coupled receptors 41/43 and tight junction proteins (Occudin and ZO-1), respectively, leading to the alleviation of diabetic symptoms in db/db mice.
Enhanced nitrogen use efficiency, growth and yield of wheat through soil urea hydrolysis inhibition by Vachellia nilotica extract
Authors: Rana Muhammad Ajmal , Mahmood Rashid , Nadeem Faisal , Wang Yun , Jin Chongwei , Liu Xingxing 
Published: November 2022

Soil urease inhibition slows down the urea hydrolysis and prolongs nitrogen (N) stay in soil, resulting in an increased N uptake by plants. Apart from several chemical urease inhibitors, the urease inhibition potential of plant extracts is rarely reported. In our previous study, the soil urease inhibition by Vachellia nilotica leaf extract was reported; however, its role in relation to growth and yield of wheat (Triticum aestivum) under pot and field conditions remains unknown. The acetonic extracts of 10, 20, and 50 g Vachellia nilotica leaves were given code names viz. Vn.Fl-10, Vn.Fl-20 and Vn.Fl-50, respectively, and coated on 100 g of urea individually. The enhancements of growth (total number of tillers, number of productive tillers, number of spikelets per spike, number of grains per spike, and 1000-grains weight) and yield (biological yield, straw yield, and grain yield) parameters of wheat by Vn.Fl-20 and Vn.Fl-50 coated urea treatments were compared with uncoated urea in a pot experiment. The experiment indicated that the Vachellia nilotica extract coatings were effective at improving N persistence in soil, as reflected by increased grain and straw N concentrations as well as uptakes. The reproduction of the aforementioned results, at the half and full recommended dose of urea under field conditions, reconfirmed the effectiveness of Vachellia nillotica coatings. Moreover, the Vn.Fl-20 and Vn.Fl-50 coated urea, at the half as well as full recommended dose under field conditions, proved equally effective in terms of higher biological, straw, and grain yield, and grain N uptake. The increments in the total number of tillers, number of productive tillers, 1000-grain weight, biological yield, straw yield, grain yield, grain N concentration, grain N-, and straw N uptake along with nitrogen use efficiency (NUE) components, i.e. nitrogen partial factor productivity (NPFP), nitrogen agronomic efficiency (NAE), partial nitrogen balance (PNB), and nitrogen recovery efficiency (NRE) of wheat highlighted the superiority of Vn.Fl-20 coating over the hydroquinone (Hq) coating on urea at the full recommended dose under field conditions. Given the findings of this study, Vachellia nilotica leaf extract coating (Vn.Fl-20) can be used as a natural urease inhibitor to reduce urea hydrolysis and enhance wheat productivity.
A systematic review of the pharmacological modulation of autobiographical memory specificity
Authors: Cawley Emma , Piazza Giulia , Das Ravi K. , Kamboj Sunjeev K. 
Published: November 2022

BackgroundOver-general autobiographical memory (AM) retrieval is proposed to have a causal role in the maintenance of psychological disorders like depression and PTSD. As such, the identification of drugs that modulate AM specificity may open up new avenues of research on pharmacological modeling and treatment of psychological disorders.AimThe current review summarizes randomized, placebo-controlled studies of acute pharmacological modulation of AM specificity.MethodA systematic search was conducted of studies that examined the acute effects of pharmacological interventions on AM specificity in human volunteers (healthy and clinical participants) measured using the Autobiographical Memory Test.ResultsSeventeen studies were identified (986 total participants), of which 16 were judged to have low risk of bias. The presence and direction of effects varied across drugs and diagnostic status of participants (clinical vs. healthy volunteers). The most commonly studied drug—hydrocortisone—produced an overall impairment in AM specificity in healthy volunteers [g = −0.28, CI (−0.53, −0.03), p = 0.03], although improvements were reported in two studies of clinical participants. In general, studies of monoamine modulators reported no effect on specificity.ConclusionPharmacological enhancement of AM specificity is inconsistent, although monaminergic modulators show little promise in this regard. Drugs that reduce AM specificity in healthy volunteers may be useful experimental-pharmacological tools that mimic an important transdiagnostic impairment in psychological disorders.Systematic review registrationPROSPERO, identifier CRD42020199076, https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020199076.