tbuckley/cabot-search huggingface dataset:
Characterisation of paediatric pulmonary hypertensive vascular disease from the PPHNet Registry
Authors: Steven H. Abman, Mary P. Mullen, Lynn A. Sleeper, Eric D. Austin, Erika B. Rosenzweig, John P. Kinsella, Dunbar Ivy, Rachel K. Hopper, J. Usha Raj, Jeffrey Fineman, Roberta L. Keller, Angela Bates, Usha S. Krishnan, Catherine M. Avitabile, Alexander Davidson, Marc D. Natter, Kenneth D. Mandl
Journal: European Respiratory Journal (2021)

<b>To characterise the clinical features of diseases associated with paediatric pulmonary hypertension, including natural history, evaluation and therapeutic interventions, longitudinal data from 1500 children from major PH programmes were analysed</b>https://bit.ly/3ff3zjV
Early Dynamics of MELD Scores Predict Corticosteroid Responsiveness to Severe Acute-Onset Autoimmune Hepatitis
Authors: Fumie Noguchi, Po-Sung Chu, Aya Yoshida, Nobuhito Taniki, Rei Morikawa, Yasushi Hasegawa, Karin Yamataka, Hitomi Hoshi, Ryosuke Kasuga, Takaya Tabuchi, Hirotoshi Ebinuma, Masahiro Shinoda, Hideaki Obara, Yuko Kitagawa, Takanori Kanai, Nobuhiro Nakamoto
Journal: Clinical Gastroenterology and Hepatology (2021)
An open-label, pharmacokinetic study to determine the bioavailability, safety and tolerability of single dose oral docetaxel in metastatic prostate cancer (mPC) patients treated with IV docetaxel.
Authors: Christopher G. C. A. Jackson, Yen-chuan Ou, Meng En, Tsu-Yi Chao, Noelyn Anne Hung, David Wang, David Cutler, Douglas Kramer, Jay Zhi, Wing Kai Chan, Min-Fun Rudolf Kwan, Tak Hung
Journal: Journal of Clinical Oncology (2021)

5050 Background: Docetaxel has poor oral bioavailability in part due to extrusion by intestinal p-glycoprotein. To improve IV solubility, it is fomulated with the nonionic surfactant polysorbate 80, requiring steroid premedication to manage hypersensitivity type reactions. Oral administration has the potential to improve tolerability, reduce day-stay utilization and improve patient convenience and allows investigation of alternative dosing schedules. Oradoxel is a new combination of oral docetaxel capsules plus the novel gut-selective P-glycoprotein inhibitor encequidar (HM30181A). Methods: Patients with mPC receiving IV docetaxel were enrolled in 3 cohorts with a dose escalation schedule of Oradoxel 75 mg/m 2 in Cohort 1, 150 mg/m 2 in Cohort 2, 300mg/m 2 in Cohort 3. Oradoxel was given 3 weeks before or after IV docetaxel treatment. Intensive PK samples were taken on days 1-5 for Oradoxel and days 1-4 for IV docetaxel. Dose limiting toxicity (DLT) or serious adverse events (SAE) were assessed per CTCAE v4.03. Results: 3 evaluable patients in each Cohort were studied. No DLT, MTD, or drug-related SAE were observed. PK parameters of Oradoxel vs IV docetaxel are summarized in the table below. Mean absolute bioavailability of Oradoxel was 15.9% (range 8-25%). PK became non linear at 300mg/m 2 . Conclusions: Oradoxel was well tolerated. Based on the results of this and related studies, Oradoxel 300mg/m 2 in divided doses is being further evaluated in phase 2 studies. Clinical trial information: 12616000983404. [Table: see text]
Adjuvant anti-PD-1 ab (Toripalimab) versus high-dose IFN-a2b in resected mucosal melanoma: A phase randomized trial.
Authors: Chuanliang Cui, Bin Lian, Lu Si, Zhihong Chi, Xinan Sheng, Yan Kong, Xuan Wang, Hui Tian, Lili Mao, Xue Bai, Bixia Tang, Xieqiao Yan, Siming Li, Li Zhou, Jun Guo
Journal: Journal of Clinical Oncology (2021)

9573 Background: Immunotherapies including anti PD-1 ab and high-dose IFN-a2b (HDI) have been approved for adjuvant therapies in resected cutaneous melanoma, but their roles in mucosal melanoma are still unknown. To determine the efficacies of toripalimab versus HDI as adjuvant therapy in patients (pts) with resected mucosal melanoma, this open-label, phase randomized trial was conducted. Methods: Mucosal melanoma pts who have undergone complete resections of localized with or without regional lymphatic disease were randomly (1:1) assigned to receive HDI (15x10 6 IU/m 2 /d1-5/w/ 4weeks IH, followed by 9x10 6 IU tiw IH) or toripalimab (3mg/kg intravenously q2w) for 52 weeks unless disease recurrence, unacceptable toxicity or consent withdrawal. Head and neck primary would receive adjuvant radiotherapy within 6-8weeks after enrollment. The primary end point was RFS in the intention-to-treat population. Data cutoff was December 10, 2020. Clinical trial information: NCT03178123. Results: From Jul 2017 to May 2019, 187 pts were screened, and 145 were randomized into HDI group (n = 72) and toripalimab group (n = 73). The median age was 58years; M:F 37.2%: 62.8%; localized disease 80.7%, regional lymphatic disease 19.3%; local excision ± CLND 37.2%, wide excision ± CLND 62.8%; head and neck primary 39.3%( 87.5% received adjuvant radiotherapy); PDL-1positive 51.0%(CPS≥1%, 22C3), PDL-1 negative 49.0%. There was no difference in baseline characteristics between two groups. At a median follow-up of 31.5 months, there were 93 RFS events (43 in HDI group vs. 50 in toripalimab group), 76 DMFS events (35 vs. 41respectively) and 65 OS events (30 vs. 35 respectively). The median RFS, DMFS and OS were shown in the table. In the HDI group, 32.6% of pts received anti PD-1 ab in the following treatment. Grade 3/4 AEs were reported in 83.3% of pts in HDI group (most decrease of leukocytes or neutrophils) and 15.1% of pts in toripalimab group (mainly increase of amylase or liver enzymes). Discontinuations of treatment due to any AE occurred in 20.8% of HDI group and 15.1% of toripalimab group. Conclusions: Both adjuvant toripalimab and HDI therapy improve RFS of mucosal melanoma. Toripalimab shows longer RFS in PDL1 (+) subgroup and better tolerance than HDI. Clinical trial information: NCT03178123. [Table: see text]
Effect of healthcare fragmentation on breast, stomach, and colorectal cancer mortality in Colombia: A measurement estimated through administrative databases.
Authors: Nicolás Rozo Agudelo, Laura Estefania Saldaña Espinel, Andres Felipe Patiño Benavidez, Oscar Andres Gamboa Garay, Giancarlo Buitrago
Journal: Journal of Clinical Oncology (2021)

e18808 Background: Fragmentation in healthcare leads to adverse outcomes in cancer patients. Currently there is no fragmentation measurement that has been acknowledged to reliably assess healthcare fragmentation across different health systems. We aimed to measure cancer healthcare fragmentation through administrative databases in Colombia and to calculate its effect on breast, stomach and colorectal cancer mortality. Methods: We conducted a cohort study based on health administrative databases from 2013 to 2017. We combined data from two Colombian national health databases (Capitation Payment Unit database and Vital Statistics from DANE). We developed an algorithm based on ICD-10 codes and oncological procedures to select incident cases of breast, stomach and colorectal cancer. To measure healthcare fragmentation, we identified the number of providers between the dates of the first and last registered services. For patients who died during observation we adjusted the number of providers for survival time in days, otherwise survival time was set to 31 december, 2017. We categorized fragmentation in quartiles and evaluated its effect on mortality rate by Kaplan Meier estimates. Results: We identified three cohorts of patients based on primary tumor site. Age distribution was similar in stomach and colorectal cancer. Fragmentation measured as a continuous variable has a non-parametric distribution in all cohorts. The median of follow-up time ranged between 2.4 to 4.4 years. All-cause mortality rates were highest in stomach cancer, lowest in breast cancer. When measured as quartiles, fragmentation has a consistent dose-response effect increasing all-cause mortality rates. Conclusions: Healthcare fragmentation can be measured through algorithms applied to administrative databases in Colombia. Fragmentation is a predictor for all-cause mortality across different oncologic populations. This measurement based on real-world national administrative data could be used as an indicator of high-quality oncological healthcare for the Colombian healthcare system.[Table: see text]
Characterization of Kinase Activity By Phosphoproteomics in Myeloid Cell Lines for Identification of Driving Oncogenic Pathways
Authors: Mahmoud Hallal, Manfred Heller, Rémy Bruggmann, Ramanjaneyulu Allam, Raphael Jeancourt, Elisabeth Oppliger Leibundgut, Cédric Simillion, Nicolas Bonadies
Journal: Blood (2017)
Clonal hematopoiesis in prostate cancer inferred from somatic tumor profiling.
Authors: Catherine Handy Marshall, Albert E Holler, Hua-Ling Tsai, Lukasz Gondek, Jun Luo, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2021)

e17001 Background: Clonal hematopoiesis (CH) is a process associated with normal aging and may complicate the interpretation of liquid-biopsy genomic testing in oncology. Little is known about the prevalence of CH in prostate cancer as detected on somatic tumor profiling, or its association with clinical parameters and outcomes in prostate cancer. We sought to estimate the prevalence and clinical characteristics of patients with CH identified from tissue-based prostate cancer specimens. Methods: This was a retrospective study of men with prostate adenocarcinoma who underwent clinical somatic tissue-based next-generation sequencing using commercial platforms (n = 364). Patients with known hematologic malignancies (n = 7), and those with only liquid biopsies were excluded (n = 34), leaving 323 cases. Classical CH mutations were defined as those in DNMT3A, TET2 or ASXL1. Additional CH mutations included were defined as those in BCORL1, GNAS, SF3B1, JAK2 or PPM1D. Chi-squared tests were used to compare prevalence by categorical variables, Kruskal-Wallis tests to compare means across groups, and Cox proportional hazards were used for time-to-event analyses. Results: The prevalence of CH mutations in prostate cancer was 9% (30/323), and the prevalence of classical CH mutations was 7% (22/323)(Table). The most common mutations were in DNMT3A (n = 9), TET2 (n = 8) and ASXL1 (n = 5); other less common CH alterations were in GNAS and SF3B1 (n = 3 each), followed by CBL and JAK2 (n = 1 each). The most common site of tumor biopsy was the prostate (N = 266) followed by visceral (n = 19) and lymph node (N = 19) metastases. Men with any CH mutation were not significantly older at age of prostate cancer diagnosis (64 vs 62 years; p = 0.19) than those without; however, men with classical CH mutations were statistically older at diagnosis than those without (66 vs 62 years; p = 0.04). There was no difference in prevalence of CH mutations by Gleason sum (P = 0.67). Among men with localized disease at diagnosis, the median metastasis-free survival was 3.9 years in those with overall CH mutations and 6.6 years in those without CH mutations (HR [adjusted for age and Gleason] 1.3; 95% CI 0.7-2.3; p = 0.4). OS from the time of diagnosis to death was also numerically shorter in those with any CH mutation (median 9.7 years in those with and 14.2 years in those without CH mutations; HR 1.2, 95% CI 0.6-2.5; p = 0.6). Conclusions: CH can be detected in about 7-9% of prostate cancer patients from tissue-based tumor samples, is associated with older age, and may be linked to adverse oncological outcomes. The prognostic impact of CH in the context of specific systemic therapies (hormonal, chemotherapeutic) remains to be elucidated.[Table: see text]
Multi-omics analysis to reveal the role of gut microbiome–associated serum metabolites in the detection of colorectal cancer and adenoma.
Authors: Feng Chen, Xudong Dai, Wei Cui
Journal: Journal of Clinical Oncology (2021)

3539 Background: Gut microbiome and their metabolites have been revealed to be associated with the initiation and progression of colorectal cancer (CRC), and gut microbiome produced or associated metabolites could enter the circulation system. Methods: Integrated analysis of untargeted serum metabolomics by liquid chromatography–mass spectrometry (LS-MS) and metagenome sequencing of fecal samples derived from matched individuals were used to profile serum metabolites that are both significantly affected by CRC and co-related with the gut microbiome. Targeted LC-MS was further used to test the ability of these metabolites for discriminating CRC and adenoma from healthy individuals. Results: More than 300 gut microbiome–associated serum metabolites with significantly altered abundance in both colorectal carcinoma (CRC) and adenoma patients have been identified. A panel of eight gut microbiome–associated serum metabolites (GMSM panel) was established and accurately discriminated CRC and adenoma from normal population. The GMSM panel–based CRC and colorectal adenoma prediction model yielded an area under the curve (AUC) of 0.94 (95% confidence interval: 0.90–0.99) and AUC of 0.91 (sensitivity 82%, specificity 91%) in the training and validation set respectively. This GMSM model shows significantly superior performance to the clinical marker carcinoembryonic antigen (CEA) (AUC 0.72), and more importantly, it suggests promising diagnostic potential in detecting adenoma (AUC = 0.81) and early-stage CRC (AUC = 0.91). Conclusions: Our results indicate that gut microbiome reprogramming in CRC patients is associated with the alterations of the serum metabolome, and these gut microbiome–associated serum metabolites has potential application for the detection of earlier CRC and adenoma.
Association of the anorectal microbiome and patient-reported gastrointestinal outcomes in patients with anal cancer.
Authors: Ramez Kouzy, Daniel Lin, Molly Blue El Alam, Joseph Abi Jaoude, Grace L. Smith, Eugene Jon Koay, Bruce D. Minsky, Prajnan Das, Emma B. Holliday, Ann Klopp, Cullen M. Taniguchi, Lauren Elizabeth Colbert
Journal: Journal of Clinical Oncology (2021)

e15504 Background: Among patients with anal cancer undergoing chemoradiotherapy, the association between the microbiome and toxicity is not well documented. We sought to quantify the gastrointestinal-related patient-reported outcomes (PROs) and local microbiome profiles of patients with anal cancer receiving chemoradiotherapy in order to check for potential profiles that can help in predicting toxicity during treatment. Methods: We prospectively followed patients with non-metastatic squamous cell carcinoma of the anal canal who received definitive chemoradiotherapy. Anorectal swab samples were collected before treatment initiation and at 4 subsequent timepoints. Consequently, PROs were collected using the bowel subdomain of the Expanded Prostate Cancer Index Composite (EPIC). Samples were sequenced using 16S rRNA of the V4 region. Sequence reads were grouped by amplicon sequence variants (ASV’s) representative of unique bacterial species. We then used Linear discriminant analysis Effect Size (LEfSe) with an effect size of 4 to identify taxa at baseline that were differentially enriched in patients with high vs. low toxicity by end of treatment. We compared the EPIC scores with the relative abundance of species identified in the LEfSe using a paired Wilcoxon test. Results: The study included 22 patients (18 women and 4 men), whose median age was 59 years. Most patients were Stage III (59%) with negative HIV status (94%). The majority of patients (91%) received standard of care chemoradiotherapy. Overall toxicity was the highest at week 5 of treatment. At all individual time points, alpha diversity of the microbiome did not correlate with patient-reported GI function, additionally overall baseline diversity was not predictive of eventual GI outcomes. The LEfSe identified that patients with low patient reported toxicity at week 5 had higher of abundance of Selenomonas at baseline, while patients with higher toxicity had high abundance of baseline Actinobacteria, Peptoniphilus, Clostridiales , and Clostridia. When comparing the relative abundance of bacterial species among patients with high and low toxicities, patients with higher relative abundance of Clostridia and Actinobacteria had significantly higher toxicity (p = 0.03). Conclusions: Certain microbiome profiles at baseline are associated with anal cancer patients’ gastrointestinal-related PROs during chemoradiation. Our data provide novel avenues to study the potential uses of the local microbiome as a biomarker in predicting treatment toxicities in anal cancer.
Health-related quality of life after isolated limb perfusion compared to extended resection, or amputation for locally advanced extremity sarcoma: Is a limb salvage strategy worth the effort?
Authors: Sophie J.M. Reijers, Olga Husson, Vicky L.M.N. Soomers, Lukas B. Been, Han J. Bonenkamp, Michiel A.J. van de Sande, Cornelis Verhoef, Winette T.A. Van Der Graaf, Winan J. van Houdt
Journal: Journal of Clinical Oncology (2021)

e23539 Background: Induction isolated limb perfusion (ILP) followed by limb-sparing resection or extended resection are frequently used limb salvation strategies (LSS) in locally advanced extremity soft tissue sarcoma (eSTS) to prevent amputation. However little is known about the long term health-related quality of life (HRQoL) in these patients. The aim of this study was to compare long-term patient reported outcomes (PROs) such as HRQoL after ILP compared to extended resection or amputation. Methods: Patients treated with an ILP, extended resection, or amputation were selected from the respondents of a multi-institutional cross-sectional cohort survivorship study (SURVSARC) conducted 2-10 years after diagnosis among sarcoma survivors registered in the Netherlands Cancer Registry (NCR). Extended resection was defined as resection for stage III eSTS, details regarding amputation levels other than upper or lower extremity are unknown. Used PROs were the EORTC QLQ-C30, Cancer worry scale (CWS), the Hospital Anxiety and Depression Scale (HADS), and the Toronto Extremity Salvage Score (TESS). Results: We identified 96 eSTS survivors and assigned them into four groups: ILP (N = 20), extended resection (N = 48), primary amputation (N = 20), and amputation after ILP (N = 8). While there were no differences in PROs between ILP and extended resections, results showed better functioning and functionality after these two LSS groups versus the amputation groups. The amputation groups scored significantly lower on the EORTC QLQ-C30 physical functioning scale (p &lt; 0.001, 62.7 and 65.7 versus 78.0 and 84.1) and role functioning scale (p = 0.038, 67.5 and 52.8 versus 79.2 and 80.9), which both account for a difference with ‘medium’ clinical relevance. Also for the TESS, the scores were significantly lower for the amputation groups compared to the LSS groups (upper extremity p = 0.007 with 68.9 and 71.6 versus 93.3 and 91.1; lower extremity p &lt; 0.001 with 72.2 and 50.9 versus 84.5 and 85.5). There were no significant differences on cancer worry, anxiety and depression were found between all groups. Conclusions: Based on this survivorship study, HRQoL in eSTS survivors treated with ILP followed by limb-sparing resection is not inferior to extended resections, however it is superior in maintenance of physical functioning and functionality compared to an amputation.[Table: see text]
Oncology trial enrollment trends following the first wave of the COVID-19 pandemic.
Authors: Elizabeth W. Lamont, Kevin Blum, Ron G. Katriel, Lisa G Ensign
Journal: Journal of Clinical Oncology (2021)

1565 Background: The first wave of the COVID-19 pandemic was associated with a negative effect on global oncology clinical research and development including documented decreases in new trial launches and patients enrolling on existing trials. We sought to evaluate secular trends in patient enrollment on global oncology trials of drugs and/or biological agents coincident with trends in the pandemic through 10/31/2020. Methods: This time-series study of global oncology clinical trial patient enrollment relied on data from the Medidata Enterprise Data Store, which comprises studies using the RAVE electronic data capture platform, and eCDC. We quantified the number of patients enrolling on oncology trials according to contiguous pandemic waves between 01/05/2020 and fixed right censoring at 10/31/2020. For this study, we defined pandemic waves empirically through review of peaks and nadirs of global case counts/week from eCDC data: wave 1 (01/05/2020-05/02/2020), wave 2 (05/03/2020-08/22/2020), wave 3 (08/23/2020-10/31/2020). We used negative binomial regressions to evaluate associations between time periods (i.e., waves) and counts of new trial enrollees and time periods and counts of new COVID-19 patients. Results: A total of 54,752 patients enrolled in 1,176 oncology trials world-wide during the observation period: 14,888 patients during wave 1, 19,631 patients during wave 2, and 20,233 patients during wave 3 of the pandemic. Compared to wave 1, the incidence of new trial enrollees increased by 10% in wave 2 (incidence rate ratio [IRR] 1.10, 95% confidence interval [CI] 0.95-1.26) and by 29% in wave 3 (IRR 1.29, 95% CI: 1.10-1.52). Over the same period, 47,336,995 people were diagnosed with COVID-19 infection: 3,481,165 patients during wave 1, 20,205,244 patients during wave 2, and 23,650,586 patients during wave 3. Compared to wave 1, the incidence of new COVID-19 patients increased by 617% in wave 2 (IRR 6.17, 95% CI: 2.76-13.77) and by 1,155% (IRR 11.55, 95% CI: 4.61-28.95) in wave 3. Conclusions: Despite substantial increases in the incidence of COVID-19 following the first wave of the pandemic, the number of patients enrolled in oncology clinical trials increased notably during the same period. Future research seeks to understand the mechanism through which the oncology research and development enterprise adapted to the shock of the COVID-19 pandemic. eCDC Source: European Centre for Disease Prevention and Control. Data provided subject to license available at: https://www.ecdc.europa.eu/en/copyright
Species-Wide Transposable Element Repertoires Retrace the Evolutionary History of the <i>Saccharomyces cerevisiae</i> Host
Authors: Claudine Bleykasten-Grosshans, Romeo Fabrizio, Anne Friedrich, Joseph Schacherer
Journal: Molecular Biology and Evolution (2021)

Transposable elements (TE) are an important source of genetic variation with a dynamic and content that greatly differ in a wide range of species. The origin of the intraspecific content variation is not always clear and little is known about the precise nature of it. Here, we surveyed the species-wide content of the Ty LTR-retrotransposons in a broad collection of 1,011 Saccharomyces cerevisiae natural isolates to understand what can stand behind the variation of the repertoire that is the type and number of Ty elements. We have compiled an exhaustive catalog of all the TE sequence variants present in the S. cerevisiae species by identifying a large set of new sequence variants. The characterization of the TE content in each isolate clearly highlighted that each subpopulation exhibits a unique and specific repertoire, retracing the evolutionary history of the species. Most interestingly, we have shown that ancient interspecific hybridization events had a major impact in the birth of new sequence variants and therefore in the shaping of the TE repertoires. We also investigated the transpositional activity of these elements in a large set of natural isolates, and we found a broad variability related to the level of ploidy as well as the genetic background. Overall, our results pointed out that the evolution of the Ty content is deeply impacted by clade-specific events such as introgressions and therefore follows the population structure. In addition, our study lays the foundation for future investigations to better understand the transpositional regulation and more broadly the TE-host interactions.