tbuckley/cabot-search huggingface dataset:
Personalized, ctDNA analysis to detect minimal residual disease and identify patients at high risk of relapse with multiple myeloma.
Authors: Binod Dhakal, Shruti Sharma, Svetlana Shchegrova, Minu Maninder, Meenakshi Malhotra, Himanshu Sethi, Bernhard Zimmermann, Paul R. Billings, Alexey Aleshin, Parameswaran Hari
Journal: Journal of Clinical Oncology (2021)

8029 Background: Despite treatment with high-dose chemotherapy followed by autologous stem cell transplantation (AHCT), MM patients invariably relapse. MRD-negativity post-AHCT has emerged as the most important prognostic marker. Currently, MRD in MM is monitored via bone marrow aspirate sampling. Marrow MRD assays are limited by the spatial heterogeneity of marrow MM localization; extramedullary disease and sampling variability of marrow aspiration. Sensitive, non-invasive blood-based MRD assay is an unmet need. ctDNA as a noninvasive biomarker can be utilized to predict relapse in MM. Here we attempt to evaluate MRD using ctDNA in AHCT recipients with MM. Methods: In this retrospective, single-center study, we analyzed ctDNA MRD in blood samples collected from 28 patients with MM after upfront AHCT. A total of 80 plasma timepoints were available pre and post AHCT with a median follow-up of 92.4 months. Multiparameter flow cytometry (MFC) at 10-4 level was used to assess the MRD from the BM biopsy. Individual bone marrow aspirates or FFPE slides from the time of MM diagnosis and matched normal blood were whole-exome sequenced, and somatic mutations were identified. MRD assessment at 3 months post-AHCT was performed by ctDNA analysis using a personalized, tumor-informed (Signatera TM , bespoke mPCR NGS assay). The prognostic value of ctDNA was evaluated by correlating MRD status with clinical outcomes. Results: Table provides the baseline disease characteristics. Median age was 67 [41-75] years and 16 [57.1%] were males. ctDNA was detectable in 70.8% (17/24) of pre-AHCT, 53.6% (15/28) of ̃3 months post-AHCT, and 39.2% (11/28) of patients during the surveillance phase post-AHCT. Of the 15 ctDNA MRD positive patients, 93.3% (n=14) experienced relapse on follow-up (hazard ratio: 5.64; 95% CI: 1.8-17; p=0.0003). Patients negative for ctDNA at 3 months post-AHCT had significantly superior progression-free survival (PFS) compared to positive (median PFS, 84 months vs. 31 months; p=0.003) The positive predictive value (PPV) for relapse among patients positive for ctDNA at 3 months post-AHCT was 93.3%, and significantly higher than marrow MFC of 68.4%. Conclusions: Our study shows the feasibility that a tumor-informed assay on archival blood samples is predictive of relapse post-AHCT. Future prospective studies with real-time marrow NGS and ctDNA samples are needed to define the role of ctDNA in MM and its prognostic significance.[Table: see text]
Molecular profiling by NGS upon progression disease in advanced stage NSCLC patients.
Authors: Roberto Serna, Alfredo Sanchez, Maria De Julian, Carlos García Girón, Manuel Domine, Ana Blasco, Jose Miguel Sanchez Torres, Juana Oramas, Joaquim Bosch-Barrera, Maria Angeles Sala, Maria Sereno, Ana Laura Ortega, Luis Enrique Chara Velarde, Berta Hernandez, Airam Padilla, Juan Coves, Eloisa Jantus Lewintre, Miguel Angel Molina-Vila, Atocha Romero, Mariano Provencio-Pulla
Journal: Journal of Clinical Oncology (2021)

e21196 Background: Non-small cells lung cancer (NSCLC) patients treated with Tyrosine Kinase Inhibitors (TKI) at first-line ultimately develop disease progression after 10 to 14 months. Mechanisms underlying TKI-resistance are not complete understood. Tumor re-biopsy is often unfeasible for NSCLC patients and liquid biopsy is a suitable alternative in identify mechanism by which tumors progress. Methods: 113 plasma samples were collected from advanced stage EGFR positive NSCLC patients upon disease progression according to RECIST V1.1. cfDNA NGS profiling was carried out using the Oncomine™ Pan-Cancer Cell-Free Assay and sequenced on an Ion GeneStudio S5 Plus System. Variant calling and annotation were performed with Torrent Suite and Ion Reporter (v5.16) software, respectively. In addition, we developed a bioinformatic pipeline, using RStudio for variant filtering. Results: Overall, 344 somatic variants were detected with an average number of variants per patient of 2.32 and a median Mutant Allele Frequency (MAF) of 0.83%. Most mutated genes were EGFR (63.72%), TP53 (60.18%), APC (16.81%), MAP2K1 (11.50%), PIK3CA (10.62%), FGFR3 (7.08%), KRAS (7.08%) and BRAF (6.19%). As expected, SNPs were the most frequent mutation type (72.67%), following by INDELs (24.41%) and CNVs (2.91%). We found high co-occurrence between MYC-GNA11, MYC-CCND2, HRAS-AR and EGFR-TP53 genes using Jaccard’s score (0.5, 0.5, 0.5 and 0.46, respectively). Within EGFR-mutated patients, 40% had T790M resistance mutation. Finally, we found KRAS mutations and missense PIK3CA mutations were mutually exclusive. Conclusions: Molecular profiling of liquid biopsies collected upon disease progression using NGS help to identify molecular mechanisms underlying treatment failure.
How to teach Breast ERAS protocols: Surgical residents’ perspectives and perioperative practices for mastectomy patients.
Authors: Kristen Jogerst, Taylor Coe, Nikita Gupta, Patricia Cronin, Abbey Fingeret, Barbara A. Pockaj
Journal: Journal of Clinical Oncology (2021)

11033 Background: Breast enhanced recovery after surgery (ERAS) protocols emphasize multimodal analgesia to decrease pain and expedite home recovery, but variability remains for same-day discharge and pain management. The purpose of this qualitative study is to examine how residents learn and apply breast surgery ERAS protocols, how they conceptualize pain management for breast surgery patients, and what influences their decision to discharge a patient home on the day of surgery. Methods: A semi-structured interview guide was adapted from existing instruments in the pain management qualitative literature. Surgical residents who rotated on the breast surgery service within the previous 12 months were interviewed by a single researcher. Interviews were recorded, transcribed, de-identified, and independently inductively coded by two researchers. A codebook was developed and refined using the constant comparative method until interrater reliability (Cohen’s kappa) reached greater than 0.9. Codes were grouped into coding categories and explored for thematic analysis. Results: Twelve interviews were completed with plastic and general surgery residents. Participants spanned post-graduate years 1-4. Preferred discharge narcotic regimens for mastectomy patients ranged from 5-30 tablets of 5mg oxycodone and participants rarely reported the same quantity. Ultimately, 365 primary codes were collapsed into 26 parent codes, with a Cohen’s kappa of 0.93. Six emerging themes were identified. Three themes describe how participants learned through a mixture of templated care, formal education, and informal experiential learning. Two themes delineate how residents would teach breast surgery ERAS protocols: by emphasizing buy-in and by connecting the impetus behind ERAS with the implementation in daily workflow. One theme illustrates the patient-centered culture and how that impacts postoperative management and same-day discharges. Conclusions: Residents learn breast surgery ERAS and postoperative pain management from imitating their seniors, observing patient encounters, completing templated orders, and translating concepts from other ERAS services, more so than from a formal lecture. When implementing new same-day discharge protocols for mastectomy patients, it is important to consider how informal learning and local culture influence postoperative pain management and discharge rates.
Telemedicine visits result in a significantly lower rate of cancellations compared to in-person visits for interventional oncology clinic patients.
Authors: Suken Shah, Stephen Barnett Solomon
Journal: Journal of Clinical Oncology (2021)

e13624 Background: Telemedicine allows increased access to specialists, less time in a waiting room and on-demand options with little to no transportation costs. These changes have been accelerated by the COIVD-19 pandemic. The purpose of the study was to test the hypothesis that a virtual telemedicine clinic would significantly decrease no-show rates and cancellations compared to in-person visits for interventional oncology (IO) clinic patients. Methods: Telemedicine visits were performed by a physician or advanced practice provider (PA or NP) at a single institution, academic medical center including 5 regional sites to patients at home in multiple states. Total patients encounters and data from January 2020 to December 2020 were analyzed. Visit types included new visits and follow up visits. Phone only visits were excluded. Primary outcome measures were an analysis of total cancelled visits (both same day and rescheduled visits), completed visits, and total scheduled visits with calculation of the telemedicine and in-person cancellation rates. Results: There was a total of 9,044 IR clinic visits in 2020 from 6,348 unique patients across the MSK Main Campus and Regional Network. Of these clinic visits, 5586 were telemedicine visits and 3458 were in-person visits. There was a significant decrease in no show and cancellation rates for telemedicine patients (6.3%) compared to in-person visits (8.1%) (p-value &lt;0.00001). Conclusions: Telemedicine visits resulted in a significantly lower rate of visit cancellation compared to in-person visits. This reduction in no-show and cancellation rates may yield significant cost savings by eliminating gaps in the interventional oncology clinic schedule to allow for more efficient use of physician time and resources.
A phase Ib study of proxalutamide (GT0918) in women with androgen receptor-positive metastatic breast cancer.
Authors: Huiping Li, Hanfang Jiang, Yongmei Yin, Zhongsheng Tong, Quchang Ouyang, Kunwei Shen, Zhongyu Yuan, Cuizhi Geng, Ran Ran, Ruyan Zhang, Ya-Xin Liu, Jiayang Zhang, Wei Li, Qing Qu, Qiaoxia Zhou, Xunwei Dong, Luping Meng, Xiaoyan Zhu, Zhen Yi, Youzhi Tong
Journal: Journal of Clinical Oncology (2021)

1019 Background: Androgen receptor (AR) is an emerging prognostic marker and therapeutic target in breast cancer. AR is expressed in 60% to 80% of breast cancers. Recent studies have shown the association between AR signaling and tumor carcinogenesis in breast cancer, suggesting AR pathway as a potential target for breast cancer treatment. However, no AR targeting therapies have been approved for treating breast cancer. GT0918 is a new chemical entity of AR antagonist with possible AR down-regulation. We had finished the phase I study and submitted the paper. Here we present a multicenter, open-label phase Ib trial assessing the safety and efficacy of GT0918 in women with AR positive metastatic breast cancer. The primary objective is to evaluate the efficacy of GT0918. The secondary objectives are to assess its safety and to explore the relevant biomarkers. Methods: This is an expansion study of a phase I dose-escalation trial. In this phase Ib study, only patients with AR positive metastatic breast cancer were enrolled. All eligibled patients would take GT0918 orally once a day, of a 28 -day cycle. After 2 cycles’ safety and tolerability assessment, patients could choose to continue their treatment until they experience disease progression, intolerable toxicities, death, or withdrew consent. The primary efficacy endpoints were 8-week disease control rate (DCR) and 16-week DCR. The secondary efficacy endpoint was progression free survival (PFS). Results: In total, 45 patients were enrolled in the study at 200mg (n = 30) and 300mg (n = 15) doses. The most common (≥10%) treatment-related adverse events (AEs) were asthenia (42.2%), aspartate aminotransferase increased (26.7%), blood cholesterol increased(17.8%), alanine aminotransferase increased (17.8%), decreased appetite (17.8%), blood triglycerides increased (13.3%), blood lactate dehydrogenase increased (13.3%), anaemia (13.3%), blood alkaline phosphatase increased (11.1%), gamma-glutamyltransferase increased (11.1%), urinary tract infection (11.1%). Grade 3/4 AEs were reported in 9 patients (20%). No treatment-related deaths occurred. The 8-week and 16-week DCR were both 22.2% (n = 10) (95% CI 10.08%, 34.37%). The median PFS was 1.8 months (95% CI 1.8, 1.9) in all patients. 12 out of 45 (26.7%) were triple negative breast cancer cases. The median PFS was 1.9 months (95% CI 1.7, 9.1), 4 out of 12 patients (33.3%) &gt; 6 months, 2 out of 12 patients (16.7%) &gt; 9 months. Conclusions: GT0918 has been shown to be well tolerated and may provide potential clinical benefits to AR positive metastatic breast cancer patients. This study demonstrated triple negative in AR positive patients had more benefit. Clinical trial information: NCT04103853 .
Experimental design of preclinical experiments: number of PDX lines vs subsampling within PDX lines
Authors: Jeanette E Eckel-Passow, Gaspar J Kitange, Paul A Decker, Matthew L Kosel, Danielle M Burgenske, Ann L Oberg, Jann N Sarkaria
Journal: Neuro-Oncology (2021)

Appropriately designed preclinical patient-derived xenograft (PDX) experiments are important to accurately inform human clinical trials. There is little experimental design guidance regarding choosing the number of PDX lines to study, and the number of mice within each PDX line.Retrospective data from IDH-wildtype glioblastoma preclinical experiments evaluating a uniform regimen of fractionated radiation (RT), temozolomide (TMZ) chemotherapy, and concurrent RT/TMZ across 27 PDX lines were used to evaluate experimental designs and empirically estimate statistical power for ANOVA and Cox regression.Increasing the number of PDX lines resulted in more precise and reproducible estimates of effect size. To achieve 80% statistical power using ANOVA, experiments using a single PDX line required subsampling of 6 mice per PDX for each treatment group to detect a difference in survival of 135 days, and 9 mice per PDX to detect a difference of 100 days. Alternatively, a design that used 10 PDX lines had greater than 80% power to detect a difference of 135 days with a single mouse per PDX per treatment group, a difference of 100 days with 2 mice per PDX per treatment, and 35 days with more than 10 mice per PDX per treatment. Power for Cox regression was slightly smaller than ANOVA for very small experiments regardless of effect size and slightly higher than ANOVA for detecting a smaller effect size of 35 days difference in survival for moderate-to-large experiments.Experimental designs using few mice across many PDX lines can provide robust results and account for inter-tumor variability.
Inappropriate Use of the Same Cutoff by Different Sequencing Panels for Tumor Mutation Burden as Immunotherapy Biomarker—Reply
Authors: Cristina Valero, Timothy A. Chan, Luc G. T. Morris
Journal: JAMA Oncology (2021)

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Measurable residual disease response in acute myeloid leukemia treated with venetoclax and azacitidine.
Authors: Keith Pratz, Brian Andrew Jonas, Vinod Pullarkat, Christian Recher, Andre C. Schuh, Michael J. Thirman, Jacqueline Suen Garcia, Courtney Denton Dinardo, Vladimir Vorobyev, Nicola Fracchiolla, Su-Peng Yeh, Jun Ho Jang, Muhit Ozcan, Kazuhito Yamamoto, Arpad Illes, Ying Zhou, Monique Dail, Brenda Chyla, Jalaja Potluri, Hartmut Dohner
Journal: Journal of Clinical Oncology (2021)

7018 Background: In the phase 3 VIALE-A trial, rates of composite complete remission (CRc; complete remission [CR] + CR with incomplete hematologic recovery [CRi]) and measurable residual disease response (MRD&lt;10 -3 ) were higher in patients (pts) treated with venetoclax (Ven) + azacitidine (Aza) compared to Aza alone (23.4%/7.6%, p&lt;0.001). There is limited evidence of the clinical significance of MRD monitoring in pts receiving low-intensity chemotherapy. Herein, we explored the outcomes of pts treated with Ven+Aza who achieved both CRc and MRD&lt;10 -3 in the VIALE-A trial (NCT02993523). Methods: Enrolled pts were ≥18 years and unfit for intensive chemotherapy. Pts received Ven 400 mg orally; days 1–28 and Aza 75 mg/m 2 ; days 1-7/28-day cycle. Bone marrow aspirate samples for multiparametric flow cytometry assessments by integrated leukemia-associated immunophenotypes and different than normal procedures were collected for central analysis (Covance Central Laboratory Services) at baseline, end of cycle 1, and every 3 cycles thereafter. Assessments were performed independent of disease responses. MRD response was defined as &lt;1 residual blast /1000 leukocytes (&lt;10 -3 ). CRc, DoR, OS, and EFS were assessed. Disease assessments were per modified International Working Group response criteria for AML. Results: 211/286 (74%) pts treated with Ven+Aza with at least one valid post-baseline MRD assessment were considered MRD evaluable; 78/211 (37%) achieved MRD&lt;10 -3 and 133/211 (63%) had MRD≥10 -3 . Median age (MRD&lt;10 -3 / MRD≥10 -3 ) was 76 (range: 49-89)/77 (58-91) yrs. Pts (MRD&lt;10 -3 / MRD≥10 -3 ) received median of 14.5 (range: 1-28) /7.0 (1-30) cycles of Ven+Aza. At median follow-up of 22.0 (range: 20.1-23.0)/20.8 (19.8-22.3) months (mos), CRc + MRD&lt;10 -3 / MRD≥10 -3 was achieved by 67 (86%)/ 97 (73%); 20/67 (30%) achieved CRc + MRD&lt;10 -3 by end of cycle 1. Median DoR, OS, and EFS were not reached in pts with CRc + MRD&lt;10 -3 response (Table). The 12-mo estimates for DoR, OS, and EFS for pts with CRc + MRD&lt;10 -3 response were 81.2%, 94.0%, and 83.2%, respectively. Adverse events ≥grade 3 (MRD&lt;10 -3 / MRD≥10 -3 ) were febrile neutropenia (50%/43%), neutropenia (50%/35%), and thrombocytopenia (44%/44%), similar to the overall population. Conclusions: Pts with best response of CRc who achieved MRD&lt;10 -3 response with Ven+Aza treatment had longer DoR, OS, and EFS than pts who were CRc and MRD positive. Clinical trial information: NCT02993523. [Table: see text]
Clinical utility of stool-based <i>SDC2</i> methylation test for the detection and screening of colorectal cancer in a Chinese population.
Authors: Yanmei Liu, Weiguo Yin, Lei Peng, Xianshu Wang, Hongzhi Zou, Haibo Zhou
Journal: Journal of Clinical Oncology (2021)

3525 Background: In 2020, colorectal cancer (CRC) ranks second in incidence and third in mortality among all types of cancers in China based on data from GLOBOCAN. Moreover, the rates of incidence and mortality have been continuously rising over the past several decades. In addition to conventional methods for detection and screening of CRC such as gFOBT, FIT, and colonoscopy, a stool-based methylation test of human SDC2 gene was recently approved by National Medical Product Association (NMPA) of China. We hereby report the performance of this newly approved test in a hospital-based cohort of more than 10,000 patients in the real world of daily clinical practice. Methods: The methylation target, human SDC2 gene, was extracted from stool and purified via sequence-specific capture technology. The isolated DNA was further treated with bisulfite before it was subsequently amplified by quantitative methylation-specific polymerase chain reaction (qMSP) to analyze the fecal level of SDC2 methylation. Subjects were further examined by colonoscopy or CT imaging. Pathological examination would also be performed in cases deemed necessary. Results: A total of 11,284 individuals were tested using the novel SDC2 methylation test. Among them, 858 and 10,426 were tested positive and negative, respectively. Follow-up visits, treatment, and medical information were complete for 429 positive and 780 negative patients who were included in this final analysis. Positive predictive value (PPV) of CRC and adenomas was 36.4% (156/429) and 24.5% (105/429), respectively. Stratified analysis implies that SDC2 methylation level in CRC was significantly higher than those in adenoma and normal groups. In CRC, no significant correlation was observed between SDC2 methylation and clinicopathological features including gender and grade of dysplasia. In &lt; 65 and ≥ 65 age groups, the CRC detection rate in males was higher than that in females―almost two times higher in ≥ 65 age group. Conclusions: The stool-based SDC2 methylation test demonstrated high accuracy in the detection of CRC and advanced adenomas. It is a sensitive and valid modality expected to play a significant role to aid diagnosis and screening of CRC and precancerous lesions in order to reduce the morbidity and mortality of this malignant disease.
Impact of Public Health Policies on Alcohol‐Associated Liver Disease in Latin America: An Ecological Multinational Study
Authors: Luis Antonio Díaz, Francisco Idalsoaga, Eduardo Fuentes‐López, Andrea Márquez‐Lomas, Carolina A. Ramírez, Juan Pablo Roblero, Roberta C. Araujo, Fátima Higuera‐de‐la‐Tijera, Luis Guillermo Toro, Galo Pazmiño, Pedro Montes, Nelia Hernandez, Manuel Mendizabal, Oscar Corsi, Catterina Ferreccio, Mariana Lazo, Mayur Brahmania, Ashwani K. Singal, Ramon Bataller, Marco Arrese, Juan Pablo Arab
Journal: Hepatology (2021)

Background and Aims Alcohol‐associated liver disease (ALD) is the leading cause of liver‐related mortality in Latin America, yet the impact of public health policies (PHP) on liver disease is unknown. We aimed to assess the association between alcohol PHP and deaths due to ALD in Latin American countries. Approach and Results We performed an ecological multinational study including 20 countries in Latin America (628,466,088 inhabitants). We obtained country‐level sociodemographic information from the World Bank Open Data source. Alcohol‐related PHP data for countries were obtained from the World Health Organization Global Information System of Alcohol and Health. We constructed generalized linear models to assess the association between the number of PHP (in 2010) and health outcomes (in 2016). In Latin America, the prevalence of obesity was 27% and 26.1% among male and female populations, respectively. The estimated alcohol per capita consumption among the population at 15 years old or older was 6.8 L of pure alcohol (5.6 recorded and 1.2 unrecorded). The overall prevalence of alcohol use disorders (AUD) was 4.9%. ALD was the main cause of cirrhosis in 64.7% of male and 40.0% of female populations. A total of 19 (95%) countries have at least one alcohol‐related PHP on alcohol. The most frequent PHP were limiting drinking age (95%), tax regulations (90%), drunk‐driving policies and countermeasures (90%), and government monitoring systems and community support (90%). A higher number of PHP was associated with a lower ALD mortality (PR, 0.76; 95% CI, 0.61‐0.93; P = 0.009), lower AUD prevalence (PR, 0.80; 95% CI, 0.65‐0.99; P = 0.045), and lower alcohol‐attributable road traffic deaths (PR, 0.81; 95% CI, 0.65‐1.00; P = 0.051). Conclusions Our study indicates that in Latin America, countries with higher number of PHP have lower mortality due to ALD, lower prevalence of AUD, and lower alcohol‐attributable road traffic mortality.
Covid-19: Regeneron’s antibody combination cuts deaths in seronegative patients, trial finds
Authors: Elisabeth Mahase
Journal: BMJ (2021)

Covid-19: Regeneron's antibody combination cuts deaths in seronegative patients, trial finds Elisabeth MahaseRegeneron's antibody combination treatment cut deaths in seronegative patients-meaning those who had not mounted their own antibody response to covid-19-by one fifth, the Recovery trial has found. 1 The researchers found that for every 100 seronegative patients treated with the combination of casirivimab and imdevimab, there were six fewer deaths.They said patients admitted to hospital should now be routinely tested for antibodies to determine whether the treatment could benefit them. 1