tbuckley/cabot-search huggingface dataset:
Circulating tumor DNA is capable of monitoring the therapeutic response and resistance in advanced colorectal cancer patients undergoing combined target and chemotherapy.
Authors: Hua Cao, Xinyi Liu, Yixin Chen, Pan Yang, Tanxiao Huang, Lele Song, Ruilian Xu
Journal: Journal of Clinical Oncology (2020)

e15524 Background: Colorectal cancer (CRC) is a highly lethal disease worldwide. The majority of patients receiving targeted therapy or chemotherapy develop drug resistance, while its molecular mechanism remains to be elucidated. The plasma circulating tumor DNA (ctDNA) exhibited the potential in identifying gene variations and monitoring drug resistance in CRC treatment. Methods: In this study, we monitored the ctDNA mutational changes in advanced CRC patients underwent first-line therapy with bevacizumab and cetuximab combined with chemotherapy. The mutation spectrum of 43 patients was established by a 605-gene next-generation sequencing (NGS) panel. Results: The baseline measurement shows that genes with the highest mutation frequency were TP53 (74%), APC (58%), KRAS (40%), SYNE1 (33%), LRP1B (23%), TOP1 (23%) and PIK3CA (21%). Mutations in TP53, APC and KRAS were detected in 29 paired plasma and tissue samples with the consistency of 81%, 67% and 42%, respectively. Clinically targetable gene mutations, such as APC, RNF43, SMAD4, BRAD1, KRAS, RAF1, and TP53, were also identified in ctDNA. The overall consistency between ctDNA and tissue samples was 54.6%. Alleviation of mutational burden in BRAF, KRAS, AMER1 and other major driving genes was observed following the first-line therapy. Patients with KRAS and TP53 mutations in tissues appeared to benefit more than the wild-type counterpart. The dynamic change of plasma mutation status was consistent with the tissue tumor burden and was closely correlated with disease progression. Conclusions: ctDNA monitoring is a useful method for molecular genotyping of colorectal cancer patients. Dynamic changes in resistance can be sensitively monitored by gene variation status, which potentially helps to develop treatment strategy.
Myosteatosis to predict postoperative morbidity in pancreatic ductal adenocarcinoma patients receiving neoadjuvant chemotherapy.
Authors: Raphael Louie, Gabriel Aleixo, Allison Mary Deal, Emily Damone, Jaclyn Tremont-Portelli, Kirsten A. Nyrop, Grant Richard Williams, Jen Jen Yeh, Hyeon Yu, Hong Jin Kim, Hyman B. Muss
Journal: Journal of Clinical Oncology (2020)

e16754 Background: Myosteatosis (adipose deposits in muscle) can be detected on cross-sectional imaging through variations in Skeletal Muscle Density (SMD). Patients with myosteatosis tend to have lower overall survival, increased chemotherapy toxicity, and shorter progression-free intervals across cancer types. We investigated whether changes in myosteatosis during neoadjuvant chemotherapy can predict postoperative morbidity risk in patients with pancreatic ductal adenocarcinoma (PDAC). Methods: This is a retrospective cohort study from 2014-2019 of patients with biopsy-proven PDAC who completed neoadjuvant chemotherapy and R0/1 resection (R1: margin &lt; 1mm or microscopically positive). We obtained preoperative patient (age at diagnosis, baseline body mass index (BMI), sex, race, comorbidities) and treatment data (neoadjuvant chemotherapy regimen and duration, time from completion of systemic therapy to surgery, type of operation). Primary outcomes were postoperative complications and 90-day readmission. Average SMD was measured using imaging analysis software at the L3 level on axial abdominal CT scans at the time of diagnosis and at completion of neoadjuvant therapy (SliceOmatic TomoVision QC, Can). We defined SMDΔ as the decrease in SMD during neoadjuvant chemotherapy. Descriptive statistics and Student’s t-test were performed with STATA. Results: We identified 44 patients who received neoadjuvant chemotherapy, achieved a R0/1 resection, and had available CT scans for body composition evaluation. The postoperative complication rate was 43% (n = 19) and 90-day readmission rate was 30% (n = 13). Lower SMD at diagnosis was associated with increased postoperative delirium (p &lt; 0.01) and 90-day readmission (p = 0.02). Greater SMDΔ was associated with increased ICU utilization (p &lt; 0.01) and tube feeding upon discharge (p = 0.03). There was no significant association between preoperative BMI or albumin and our primary outcomes. Conclusions: Preoperative SMD and SMDΔ, rather than albumin or BMI, can predict postoperative morbidity in PDAC patients who received neoadjuvant chemotherapy. This study provides the framework for future studies to develop and validate a tool to predict postoperative morbidity risk in these patients.
Effect evaluation analysis of three years intensive intervention for patients with type 2 diabetes at Xinjiekou Community Center in Beijing
Authors: Yu-ling Li, Qi Yuan, Ai-wu Tang, Shuo Chen, Wei Sun
Journal: BMJ (2013)

Following the wishes of volunteer patients, 316 cases of type 2 diabetics of our community center in 2008 carried out a three-year intervention from 2008 to 2011 on the basis of rational drug therapy plus the interventions of health education, regular review and lifestyle strengthening. And regular monitoring and recording were performed on the parameters of body mass index (BMI), blood pressure, blood lipids, fasting glucose, 2 h postprandial blood glucose, glycosylated hemoglobin (HbA1c) and liver & kidney function. After intervention, some indicators changed: BMI (25.2±3.5) vs.(25.0±3.3) kg/m2, systolic blood pressure (129.1±11.8) vs. (126.2±7.9) mm Hg (1 mm Hg=0.133 kPa), fasting glucose (7.80±2.81) vs.(7.25± 1.96) mmol/L, 2 h postprandial blood glucose (11.04±4.60) vs. (9.83±3.60) mmol/L, HbA1c (7.39 ± 1.61) vs. (7.17±1.65)%, total cholesterol (5.08±1.21) vs. (4.74±1.35) mmol/L, low density lipoprotein cholesterol (LDL)(3.09±0.87) vs. (2.85±0.83) mmol/L, high density lipoprotein cholesterol (HDL) (1.27±0.33) vs. (1.41±0.32) mmol/L, serum creatinine 65 vs. 72 μmol/L, uric acid 300 vs. 317 μmol/L. And the differences were statistically significant (P<0.05). After intervention, blood pressure compliance rate increased from 72.5% to 88.0%, LDL-C compliance rate improved from 27.2% to 38.6%, HDL-C compliance rate of 54.9% increased to 66.9%. And the differences were statistically significant (P<0.05). The pre-intervention combined compliance rate of 11.4% (n=36) rose to 17.7% (n=56). And there was significant difference (P=0.024).


Key words: 
Diabetes mellitus，type 2; Community health services; Early intervention(education)
Association of microalbuminuria and insulin resistance with acute coronary syndrome
Authors: Shao-nan Li, Guang-lian Li, Zhen Liu, Jian-kai Huang
Journal: BMJ (2011)

Objective To investigate relationship of microalbuminuria (MAU) and insulin resistance (IR) to severity of coronary lesions in patients with acute coronary syndrome (ACS), and its predictive value for short-term prognosis in then.Methods In total, 162 ACS patients admitted to the department of cardiology, Guangzhou First People's Hospital, Guangzhou, Guangdong province during January 2008 to June 2009 were selected and divided into three groups according to their urine albumin excretion rate (UAER): 54 cases in normal group with UAER less than 20 μg/min, 62 cases in microalbuminuria group with UAER of (20-200)μg/min, and 46 cases in mass-albuminuria group with UAER more than 200 μg/min.Difference in IR (by homeostasis model assessment, HOMA ) and severity of coronary lesions among the three groups was assessed.Effects of baseline MAU and IR on main adverse cardiac events within the recent six months were observed in ACS patients after percutaneous coronary intervention (PCI).Results IR increased and coronary lesions aggravated as UAER increasing in all the three groups of ACS patients (P＜0.05 or P＜0.01).MAU associated with IR, with a coefficient of correlation of 0.366 (P＜0.01).Results of multivariate logistic regression analysis showed that both MAU and IR were strong independent predictors for main adverse cardiac events in ACS patients within six months after PCI.Conclusions MAU and IR associate with severity of coronary lesions in ACS patients, suggesting certain predictive value for main adverse cardiac events in short-term after PCI.

Key words: 
Albuminuria;  Insulin resistance;  Coronary disease
The Medical Genome Initiative: moving whole-genome sequencing for rare disease diagnosis to the clinic
Authors: Christian R. Marshall, David Bick, John W. Belmont, Stacie L. Taylor, Euan Ashley, David Dimmock, Vaidehi Jobanputra, Hutton M. Kearney, Shashikant Kulkarni, Heidi Rehm
Journal: Genome Medicine (2020)

Abstract Clinical whole-genome sequencing (WGS) offers clear diagnostic benefits for patients with rare disease. However, there are barriers to its widespread adoption, including a lack of standards for clinical practice. The Medical Genome Initiative consortium was formed to provide practical guidance and support the development of standards for the use of clinical WGS.
Trends in gender-based disparity in incidence, mortality and survival for major digestive disease cancers in the U.S. (2000-2016).
Authors: Yvonne Sada, Efthalia Zafeiropoulou, Peter Richardson, Jennifer Kramer, Israel Christie, Li Jiao, Yanhong Liu, Elizabeth Chiao, Donna White
Journal: Journal of Clinical Oncology (2020)

e13621 Background: Males have excess risk of most digestive cancers; whether cancer mainly due to virus (stomach), lifestyle including obesity/alcohol (colon/esophagus), or both (liver). We evaluated for secular trends in gender-specific incidence, mortality and survival for these cancers in the U.S. Methods: We used official U.S. Cancer Statistics [USCS] data (2000-2016) to calculate annual age-adjusted incidence and mortality rates (IR/MR). It covers &gt;98% population/all states (vs. SEER-10 statewide registries, covers &lt;1/3rd African-Americans/Whites). We calculated mortality-to-incidence rate ratios (MIR), an established 5-year survival proxy. We used Joinpoint to assess trends in average annual percentage change (AAPC). Results: Table shows age-adjusted IRs and MRs for colon, esophagus and stomach cancer decreased for men and women (all AAPCs negative, all significant but stomach IR women), with both liver IR/MR significantly increasing in both genders. Gender differences in relative burden were seen (e.g., MRs in colon&gt;esophagus&gt;liver&gt;stomach in men vs. colon&gt;stomach&gt;liver&gt;esophagus in women), with greatest male excess in esophagus (e.g., 4.4-fold IR). MIRs suggested less favorable survival (higher=worse) for men for esophagus/colon. Conclusion: Substantial gender disparity persists in digestive cancers, with male excess gap decreasing for colon and increasing for liver. [Table: see text]
Tumor treating fields effects on the blood-brain barrier in vitro and in vivo.
Authors: Ellaine Salvador, Almuth Kessler, Julia Hoermann, Dominik Domroese, Clara Schaeffer, Malgorzata Burek, Catherine Tempel- Brami, Tali Voloshin, Moshe Giladi, Ralf-Ingo Ernestus, Mario Loehr, Carola Foerster, Carsten Hagemann
Journal: Journal of Clinical Oncology (2020)

2551 Background: The greatest hurdle, which even potent and effective drugs targeting central nervous system (CNS) tumors and other disorders face, is the blood brain barrier (BBB). The inability to cross the tight regulatory mechanism renders these drugs futile. Of late, administration of tumor treating fields (TTFields) as part of a combined treatment modality for glioblastoma demonstrated increased overall patient survival. Still, the effects of TTFields on the BBB have not yet been investigated. Here, we report the potential of TTFields application to open up the BBB. Methods: Murine brain endothelial cells were treated with 100-300 kHz TTFields for 24-96 h. Cells were also allowed to recover from 24-96 h after treatment. Subsequently, changes in cell morphology, integrity, and permeability were observed via staining of intercellular junction proteins (IJP) as well as transendothelial electrical resistance (TEER)and permeability assays. In vivo, rats were treated with 100 kHz TTFields or heat for 72 h after which they were IV injected with Evan´s Blue (EB)/ TRITC-dextran (TD) which was later quantified from the brain. Rat brain cryosections were also stained for IJPs as well as immunoglobulin G (IgG) to assess vessel structure. Finally, serial dynamic contrast-enhanced (DCE) MRI with gadolinium (Gd) contrast agent was performed pre- and post- TTFields. Results: Upon TTFields application, IJPs such as claudin-5 were delocalized from the cell membrane to the cytoplasm with maximal effects at 100 kHz. In addition, BBB integrity was significantly reduced and permeability for 4 kDa molecules was significantly increased. Cell morphology recovery was first observed at 48 h post-treatment and completely restored to normal after 96 h, indicating a reversibility of the TTFields effect on the BBB. In addition, EB and TD permeated the rat brain post-TTFields treatment. Brain cryosections displayed IJPs delocalization as well as IgG accumulation in the brain parenchyma. Confirming these observations, increased Gd in the brain was shown by DCE-MRI post-TTFields application. A reversion to normal conditions was detected 96 h after end of treatment, which was demonstrated by no difference in contrast enhancement between control and treated rats. Conclusions: TTFields application both in vitro and in vivo points towards its ability to transiently open the BBB. This presents TTFields as a novel aid for drug delivery geared towards treatment of CNS tumors and other related diseases. Hence, it is indicative of the possibility of an enhanced and more effective combinatorial therapeutic strategy.
Concomitant limb cryocompression and scalp cooling to reduce paclitaxel-induced neuropathy and alopecia.
Authors: Raghav Sundar, Gayathiri Magarajah, Samuel Guan Wei Ow, Gloria Chan, Joan Choo, Lim Siew Eng, Andrea Wong, Joy Vijayan, Zarinah Hairom, Emily Ang, Richard Paxman, Einar Wilder-Smith, Nitish Thakor, Soo-Chin Lee, Aishwarya Bandla
Journal: Journal of Clinical Oncology (2020)

e24157 Background: Scalp cooling is an FDA approved method to mitigate chemotherapy-induced alopecia (CIA) caused by paclitaxel. Chemotherapy-induced peripheral neuropathy (CIPN) is a dose limiting toxicity of paclitaxel. Several recent randomized studies have suggested limb hypothermia as a mechanism to ameliorate paclitaxel-induced neuropathy. The safety, tolerability and feasibility of concomitant limb hypothermia and scalp cooling to prevent these two common adverse effects of paclitaxel has not been previously studied. Methods: A proof-of-concept study was conducted in breast cancer patients receiving weekly paclitaxel chemotherapy. Each subject underwent concomitant scalp and four-limb cryocompression with each chemotherapy infusion (3 hours) for a maximum of 12 cycles. Limb cryocompression was administered at cyclic pressure (5-15 mmHg) and temperatures starting at 11°C (established as lowest tolerable temperature in a separate healthy volunteer study) and adjusted according to patient tolerability. Skin surface temperature and tolerance scores were recorded. CIPN was assessed via EORTC Quality of Life Questionnaire-CIPN before (QOL pre ), after completion (QOL post ) and 3-months post chemotherapy (QOL 3m ). Results: Fifteen patients enrolled in the study, of which 14 completed all 12 cycles of concomitant scalp cooling and limb cryocompression during chemotherapy without any side effects barring transient erythema over the limbs. None had intolerance to scalp cooling. Eight patients safely tolerated 12 cycles of cryocompression at 11°C. Of the remaining, 6 completed all 12 cycles at device temperatures ranging from 14-25°C. One patient withdrew at the 6 th cycle, finding 25°C intolerable. Median QOL pre was 19 (range 17-19), QOL post 20 (18-29) (p = 0.04, Wilcoxon signed-rank) and QOL 3m was 19 (18-21) (vs QOL pre ; p = 1). QOL showed no significant differences from pre-chemotherapy to 3 months post-chemotherapy suggesting preservation of nerve function. Conclusions: Delivery of concomitant scalp cooling and limb cryocompression is feasible, safe and generally well-tolerated. Future limb hypothermia trials should not preclude patients from undergoing scalp-cooling concomitantly to reduce CIA. Clinical trial information: NCT03248193 .
KITE-439: A phase I study of HPV16 E7 T cell receptor-engineered T cells in patients with relapsed/refractory HPV16-positive cancers.
Authors: Kedar Kirtane, Erminia Massarelli, Glenn J. Hanna, Christopher Austin Klebanoff, George Blumenschein, Michael Russell Bishop, Sylvia Lee, Jiaxin Niu, Sabina Adhikary, Stephanie H. Astrow, Katherine Rodriguez, Rong Chu, A. Scott Jung
Journal: Journal of Clinical Oncology (2020)

TPS3149 Background: Human papillomavirus 16 (HPV16) is the most prominent subtype across invasive head and neck cancers, as well as cervical cancer and other anogenital cancers (Saraiya M, et al. J Natl Cancer Inst. 2015). The HPV16 E7 (E7) viral antigen is important for the survival of HPV-positive tumor cells but is absent from normal human tissue, making it an attractive target for anti-cancer therapy. Preclinical efficacy has been observed with MHC class I-restricted T cell receptor (TCR)-engineered T cells targeting E7 on HPV16-positive tumor cells (Jin BY, et al. JCI Insight. 2018). This Phase 1, first-in-human, open-label, multicenter study (NCT03912831) will evaluate the safety and efficacy of KITE-439, an autologous TCR-engineered T cell therapy targeting E7, in HLA-A*02:01–positive patients with relapsed/refractory HPV16-positive cancers. Methods: A single-patient dose-escalation schema will be used in Phase 1A of the study, enrolling up to 30 patients. Phase 1A will evaluate safety and inform the recommended dose of KITE-439 for Phase 1B. Approximately 45 patients with squamous cell cancer of the head and neck, cervical cancer, and other HPV16-positive tumors will be included in Phase 1B. Patients in Phase 1A and Phase 1B may receive optional bridging therapy followed by cyclophosphamide and fludarabine conditioning chemotherapy. Patients will then receive an infusion of KITE-439 at 1 × 10 6 up to 1 × 10 8 TCR-transduced T cells/kg along with daily subcutaneous IL-2 therapy for a maximum of 14 doses post-infusion. The primary endpoint for Phase 1A is the incidence of adverse events defined as dose-limiting toxicities. The primary endpoint for Phase 1B is investigator-assessed objective response rate per modified RECIST v1.1 criteria (Eisenhauer EA, et al. Eur J Cancer. 2009). Secondary endpoints for Phase 1B include duration of response, progression-free survival, overall survival, and safety. Patients ≥ 18 years must be HLA-A*02:01–positive and have relapsed/refractory HPV16-positive cancer, an ECOG PS of ≤ 1, and adequate bone marrow and organ function. Key exclusion criteria include a history of stroke, myocardial infarction, or symptomatic deep vein thrombosis/pulmonary embolism, known infection with human immunodeficiency virus, detectable hepatitis C, or detectable hepatitis B. This study is currently open and accruing patients. Clinical trial information: NCT03912831 .
Role of cytoglobin, a novel radical scavenger, in stellate cell activation and hepatic fibrosis
Authors: Le Thi Thanh Thuy, Hoang Hai, Norifumi Kawada
Journal: Clinical and Molecular Hepatology (2020)

Cytoglobin (Cygb), a stellate cell-specific globin, has recently drawn attention due to its association with liver fibrosis. In the livers of both humans and rodents, Cygb is expressed only in stellate cells and can be utilized as a marker to distinguish stellate cells from hepatic fibroblast-derived myofibroblasts. Loss of Cygb accelerates liver fibrosis and cancer development in mouse models of chronic liver injury including diethylnitrosamine-induced hepatocellular carcinoma, bile duct ligation-induced cholestasis, thioacetamide-induced hepatic fibrosis, and choline-deficient L-amino acid-defined diet-induced non-alcoholic steatohepatitis. This review focuses on the history of research into the role of reactive oxygen species and nitrogen species in liver fibrosis and discusses the current perception of Cygb as a novel radical scavenger with an emphasis on its role in hepatic stellate cell activation and fibrosis.
The impact of obesity on treatment and outcomes in ovarian cancer by race/ethnicity.
Authors: Alexandra Martin, Adrianne Rose Mallen, Sweta Sinha, Ali Wells, Kathryn Cline, Clarissa Lam, Lauren Peres, Jing-Yi Chern
Journal: Journal of Clinical Oncology (2020)

e18067 Background: Concern for toxicities in obese ovarian cancer patients may limit weight-based chemotherapy dosing, which has been associated with poor survival. We sought to evaluate the impact of obesity on treatment and outcomes by race/ethnicity at a National Cancer Institute (NCI)-designated Comprehensive Cancer Center (CCC). Methods: 66 minority (non-Hispanic black, Hispanic) epithelial ovarian cancer patients diagnosed 2006 and treated with frontline chemotherapy were frequency matched to two non-Hispanic white (NHW) patients by 5-year age group and stage (n = 198). For frontline carboplatin, relative dose intensity (RDI) was calculated by dividing the dose received by the expected dose, with an RDI &lt; 0.85 indicating carboplatin dose reduction. Patient characteristics and RDI were compared by obesity and race/ethnicity. Cox proportional hazards regression was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between obesity, race/ethnicity and RDI with mortality, adjusting for confounders. Results: Minorities were more likely to be obese, underinsured, and to experience delays in chemotherapy compared to NHW. Compared to normal/overweight patients, obese patients were more likely to experience carboplatin under dosing in the neoadjuvant (p = 0.004) and adjuvant (p &lt; 0.0001) setting, but there were no differences in RDI by race/ethnicity or toxicities. No association with survival was observed for dose reduction and BMI. Compared to NHW, minorities had similar survival in the first 4 years after diagnosis (HR = 0.99, 95% CI = 0.60-1.63), but an increased risk of mortality &gt; 4 years after diagnosis (HR = 4.07, 95% CI = 1.92, 8.60). Conclusions: Even though minorities were more likely to be obese, there were no differences in dosing by race/ethnicity at an NCI CCC. Minorities had similar survival to NHW in the first 4 years after diagnosis, likely due to similar access to quality care at an NCI CCC. However, &gt; 4 years after diagnosis, the racial/ethnic survival disparity persisted after adjustment for clinical and pathologic characteristics. Expansion of this work to other patient populations may help determine if findings are similar outside of a tertiary care center.
Effects of benazepril on yon Willebrand factor and albuminuria in patients with type 2 diabetes mellitus associated with hypertension
Authors: Shu-ying Li, Gang Wei, Yue-hua Li, Qiu-di Ji
Journal: BMJ (2008)

Fifty-six hypertensive diabetic patients (glyeosylated hemoglobin A1c 130/80 mm Hg.All the patients were treated for 12 weeks.In both groups,plasma yon Willebrand factor and urine albumin decreased significantly from baseline.Except for urine albumin,no significant inter-group difference in plasma van Willebrand factor and target blood pressure was observed.Benazepril and amledipine seem to show similar efficacy in lowering blood pressure and improving endothelial function,but benazepril may be more effective in kidney protection.

Key words: 
Diabetes mellitus,type 2 ; Angiotensin-converting enzyme inhibitors