tbuckley/cabot-search huggingface dataset:
Detection of circulating cancer stem cells (cCSCs) as a predictive biomarker for breast cancer relapse or metastasis.
Authors: Monika Pizon, Ulrich A. Pachmann, Katharina Pachmann, Dorothea Schott
Journal: Journal of Clinical Oncology (2019)

e14559 Background: Breast cancer is one of the most common types of cancer in women worldwide. It has been demonstrated that even localized tumors without clinically apparent metastases give rise to circulating epithelial tumor cells (CETCs). Recent studies have provided strong support for the cCSC hypothesis, which suggests that a more aggressive subpopulation of circulating tumor cells is the source of metastatic spread from the primary tumor. Measuring CETCs in blood of patients has emerged as a non-invasive diagnostic procedure for screening patients who may be at high risk for developing metastatic cancers. However, accurate detection of CETCs may provide erroneous results, since CETCs undergoing EMT during metastasis are down-regulated for the expression of epithelial cell markers. Methods: 26 breast cancer patients were included into the study. The determination of CETCs and cCSC was performed using maintrac method and tumorsphere forming assay, respectively. Cell viability, surface marker expression and ALDH 1 activity of the cells in the spheres were evaluated by fluorescence scanning microscope. Results: Sphere formation was observed in 80 % of patients. We found that the number of tumorspheres depended on stage of disease. The number of tumorspheres increased significantly with tumor progression, especially with the presence of metastases. Tumorsphere formation was observed in all metastatic patients (median of 30 tumorspheres/100µl of blood), although only 27% of them had detectable CETCs. Analysis of surface marker expression profile showed that the cells in the spheres had typical phenotype of cancer stem cells. Sphere formation was not observed in healthy subjects (n = 20). Conclusions: There is a high correlation between the numbers of tumorspheres cultured from peripheral blood with clinical stage of disease. Identifying cCSC in blood sample can help clinicians to monitor breast cancer patients and to detect metastasis in early stages.
Clinical Effectiveness of Antifibrotic Medications for Idiopathic Pulmonary Fibrosis
Authors: Timothy M. Dempsey, Lindsey R. Sangaralingham, Xiaoxi Yao, Darshak Sanghavi, Nilay D. Shah, Andrew H. Limper
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

Rationale: Since their approval, there has been no real-world or randomized trial evidence evaluating the effect of the antifibrotic medications pirfenidone and nintedanib on clinically important outcomes such as mortality and hospitalizations.Objectives: To evaluate the clinical effectiveness of the antifibrotic medications pirfenidone and nintedanib in patients with idiopathic pulmonary fibrosis.Methods: Using a large U.S. insurance database, we identified 8,098 patients with idiopathic pulmonary fibrosis between October 1, 2014 and March 1, 2018. A one-to-one propensity score–matched cohort was created to compare patients treated with antifibrotic medications (n = 1,255) with those not on treatment (n = 1,255). The primary outcome was all-cause mortality. The secondary outcome was acute hospitalizations. Subgroup analyses were performed to evaluate mortality differences by drug.Measurements and Main Results: The use of antifibrotic medications was associated with a decreased risk of all-cause mortality (hazard ratio [HR], 0.77; 95% confidence interval [CI], 0.62–0.98; P value = 0.034). However, this association was present only through the first 2 years of treatment. There was also a decrease in acute hospitalizations in the treated cohort (HR, 0.70; 95% CI, 0.61–0.80; P value <0.001). There was no significant difference in all-cause mortality between patients receiving pirfenidone and those on nintedanib (HR, 1.14; 95% CI, 0.79–1.65; P = 0.471).Conclusions: Among patients with idiopathic pulmonary fibrosis, antifibrotic agents may be associated with a lower risk of all-cause mortality and hospitalization compared with no treatment. Future research should test the hypothesis that these treatments reduce early, but not long-term, mortality as demonstrated in our study.
Circulating cell-free tumor DNA chromosomal instability and circulating tumor cells as tools to predict microvascular invasion of hepatocellular carcinoma.
Authors: Jin Wang, Yanzhe Liu, Kuang Chen, Qu Liu, Qian Ziliang, Minggen HU
Journal: Journal of Clinical Oncology (2019)

e14524 Background: Extended hepatic surgical margins, especially anatomical resections, were suggested for hepatocellular carcinoma (HCC) patients with pathological microvascular invasion (MVI) to improve patient survival. Here we investigated plasma cell-free tumor DNA (ctDNA) and circulating tumor cells as a tool to evaluate MVI before surgery. Methods: 47 treatment-naïve patients with liver lesions were recruited since June 2018, Peripheral blood samples were collected before surgery for all the individuals. Plasma cfDNA was sent to low-coverage genome-wide sequencing, followed by chromosomal instability analyses by a customized workflow UCAD. Circulating tumor cells (CTC) were analyzed by CELLSEARCH @ System. MVI was reported by pathological examination after surgery. Results: Of the 47 patients recruited, there are 32 hepatocellular carcinoma (HCC), 8 intrahepatic cholangiocarcinoma (ICC), 4 benign lesions, 1 solitary fibrous tumor, 1 neuroendocrine tumor and 1 hepatic epithelioid cell tumor by pathological examinations. MVI was also reported for HCCs. Nineteen of 32 HCC patients (59.4%) was found with elevated chromosomal instability (CIN). The most frequent changed chromosomes include 1q, 6p and 8q. Nine of 19 (47.4%) elevated CIN patients were MVI positive by pathological examinations. Among them, 4 was confirmed as MVI = 2. The other 5 was MVI = 1. 11 of 13 (84.6%) patients with low CIN were MVI negative (MVI = 0) as reported by pathological examinations. The rest 2 were reported as MVI = 1. Two of 32 HCC patients (6.25%) was found with positive CTC (tumor cell count &gt; 0). The patient with CTC = 2 was reported as MVI = 1. The other one with CTC = 1 was MVI = 0. Taking together, 20 patients (62.5%) were found either elevated ctDNA or positive CTC. 9 were confirmed as MVI negative. The overall positive predictive value is 45.0%. 12 patients (38.7%) were both ctDNA CIN low and CTC negative. 10 were confirmed as MVI negative. The negative predictive value (NPV) is 83.3%. Conclusions: Elevated circulating tumor DNA chromosomal instability has good PPV and NPV in the predicting of MVI. In such patients, anatomical hepatic resections might be recommended to improve survival.
Variations in compliance with different endocrine therapies in ER-positive breast cancer in elderly females in a rural population.
Authors: Christian Agbisit, Alexander Johnson, Kathy Robinson, Kristin Delfino, Meghna R. Desai
Journal: Journal of Clinical Oncology (2019)

e12052 Background: Compliance is a serious issue for breast cancer patients on endocrine therapy. There are various factors that may alter compliance across different age groups e.g. side effects, cognitive impairment, socioeconomic status etc. Noncompliance to therapy leads to early discontinuation and poor longterm outcome. The purpose of this study was to examine compliance rates with endocrine therapy i.e. aromatase inhibitors &amp; tamoxifen in different age groups of geriatric breast cancer patients and determine its tolerability and impact on survival. Methods: An institutional database of a total of 269 patients with histologically confirmed invasive or in-situ breast cancer with age 65 years or older at the time of diagnosis was reviewed in an IRB approved fashion. Adjuvant endocrine therapy included tamoxifen, letrozole, anstrozole and fulvestrant. Patients were further subdivided into age groups. Compliance was measured as an early termination of therapy. Fisher’s exact test was used to calculate statistical difference. Results: Out of 266 eligible patients, 221 (83.1%) were offered endocrine therapy. 216 (81.2%) accepted endocrine therapy and 5 (1.9%) declined treatment. Distribution of each therapy was as follows:Anastrozole n = 90, (33.5%), Letrozole n = 88, (32.7%), Fulvestrant n = 6,( 2.3%), Tamoxifen n = 64, (23.8%). Early termination n = 44, (21.4%). Between the ages 65-70, n = 17,(18.had an early termination or noncompliance to therapy, in the age group from 71-80 age group,n = 24,(26.4%) had an early termination, and ages 81 and above,n = 3 (12.5%) had an early termination. There were no statistical differences between Anastrozole, Letrozole, Tamoxifen &amp; Fulvestrant (P = 0.8275, P = 0.4589, P = 0.6136). There was also no statistical difference between age groups (P = 0.2742). Overall survival was worse with early termination,n = 20 vs not n = 6 but did not reach statistical significance ( P = 0.7). Conclusions: In breast cancer patients 65 and older, age can be a factor in noncompliance. However, in our study there were no correlation between age groups and compliance or with which drug used. Tolerability was similar between each endocrine therapy, across different age groups in this geriatric breast cancer population, in a rural setting.
Bioengineering of Metal-organic Frameworks for Nanomedicine
Authors: Yuan Liu, Yanli Zhao, Xiaoyuan Chen
Journal: Theranostics (2019)

Controlled structure, tunable porosity, and readily chemical functionalizability make metal-organic frameworks (MOFs) a powerful biomedical tool.Nanoscale MOF particles have been increasingly studied as drug carriers, bioimaging agents, and therapeutic agents due to their excellent physiochemical properties.In this review, we start with MOF as a nanocarrier for drug delivery, covering therapeutic MOF agents followed by a comprehensive discussion of surface bioengineering of MOF for improved biostability, biocompatibility, and targeted delivery.Finally, we detail the challenges and prospects of the future of MOF research for biomedical applications.
National trends in the use of immunotherapy in the up front management of glioblastoma.
Authors: Richard White, Stephen Abel, Shaakir Hasan, Vivek Verma, Tulika Ranjan, Stephen Karlovits, Rodney E Wegner
Journal: Journal of Clinical Oncology (2019)

e13500 Background: Glioblastoma (GBM) carries an abysmal prognosis. Current standard of care involves an aggressive multimodality approach including surgical resection followed by adjuvant chemoradiation. Despite this approach, overall survival remains poor and treatment approaches continue to evolve. Given the successes of immunotherapy in other disease sites, implementation in GBM management may improve outcomes. Methods: We conducted this NCDB-driven retrospective study to analyze treatment trends and outcomes from 2004-2015 with respect to GBM and immunotherapy. We queried the NCDB diagnosed between 2004-2015 with GBM and excluded patients treated without surgery, extracranial radiation, or chemotherapy as well as those lost to follow up. Results: Of the 39,317 eligible patients in this study, 511 were treated with immunotherapy and 38,806 lack thereof. Median overall survival for all patients was 15 months with a 2 and 5 year survival rate of 29% and 8%, respectively. Factors positively influencing delivery of immunotherapy included younger age, higher income, facility location in a metropolitan location, greater distance to the treatment facility, treatment at an academic facility, treatment outside of the years 2007 to 2009, and Caucasian race. On propensity matched analysis, survival was 18 months and 17 months with and without immunotherapy, respectively (p = 0.15). Higher comorbidity, lower income, and male gender predicted for worse survival. Conclusions: The results of the NCDB analysis showed an initial decrease and then increase in the use of immunotherapy in the management of GBM. Propensity-matched and –adjusted analyses did not show an overall survival benefit, consistent with data from randomized trials.
A breakthrough in treatment of cancer patients with grade 4/profound febrile neutropenia.
Authors: Calin Ioan Cainap, Simona Sorana Cainap, Sanziana Cetean- Gheorghe, Daniel Corneliu Leucuta, Ovidiu Vasile Bochis, Alexandra Gherman
Journal: Journal of Clinical Oncology (2019)

e14513 Background: febrile neutropenia (FN) remains one of the most serious side effects of chemotherapy treatment, which is life-threatening. Late consequence of FN is dose reduction and delaying of therapies. Actual guidelines allows granulocyte-colony-stimulating factors (G-CSF) in management of profound FN in addition to antibiotics and supportive care Methods: it is an original prospective study, approved by local ethics comitee, which included 73 patients with confirmed malignancy, treated in our Institute with chemotherapy, who developed febrile neutropenia (FN) and were hospitalised. Patients with myeloablative chemotherapy and bone marrow transplantation support, severe renal impairment, abnormal liver function or with a history of allergic reactions to the antibiotics were excluded from the study. There were recorded 96 episodes of grade 4 FN (1-3 episodes / patients). Each of one was hospitalised according to institutional guideline but with a dose of G-CSF of 16 µg/Kg/day i.v. continous infusion Results: median age of included patients was 59 years, with approximately 48 % male and 52% female, whithout significance in terms of recovery from FN (p = 1.00). 30% of the patients had prophilactic G-CSF administrated, but not significant for recovery from aplasia for included patients (p = 0.34). Median chemotherapy line responsible for FN was 2, and median cycle which produced FN was 3. Median level of neutrophiles (PMN) 450/mm 3 and leucocytes (WBC) 1875/ mm 3 at time of FN, 10 patients being in profound FN (PMN &lt; 100/mm 3 ). Median time to recovery was 25.5 hours for 72 included patients, with 1 patient dead whithout recovery. Predictive factors for shortened recovery were lower levels of reactive protein C (p &lt; 0.001) and procalcitonine (p = 0.002) and higher WBC (p = 0.006) and PMN (p &lt; 0.001) at time of administration of responsible chemotherapy regimen for FN. The earlier cycle responsible, between a line of chemotherapy, for FN, the better chance for patient to have shortened duration of FN (p &lt; 0.0001). Conclusions: continous i.v. administration of G-CSF could represents a very effective alternative for patients with profound febrile neutropenia, with the shortest ever reported interval for neutrophiles recovery
Comparison of HPV detection in HIV-infected and HIV-uninfected Kenyan women with or without cervical dysplasia.
Authors: Elkanah Omenge, Yan Tong, Philip Tonui, John M. Ong’echa, Kapten Muthoka, Stephen Kiptoo, Titus Maina, Peter Itsura, Ann Moormann, YeungChing Wong, Aaron Ermel, Tao Liu, Joseph Hogan, Patrick J. Loehrer, Darron Brown, Susan Cu-Uvin
Journal: Journal of Clinical Oncology (2019)

e17015 Background: Cervical cancer, a malignancy caused by human papillomavirus (HPV) infection, is the most common malignancy in women living in sub-Saharan African countries including Kenya. HIV co-infection accelerates the natural course of cervical cancer. To determine the specific HPV type distribution in HIV-infected women compared to HIV-uninfected women, with and without evidence of cervical dysplasia. Methods: Demographic information, behavioral data, and a cervical swab were collected from women 18 and 45 years of age, HIV-infected or HIV-uninfected, who presented for cervical cancer screening at Moi Referral and Teaching Hospital in Eldoret, Kenya. Women were triaged based on the presence or absence of cervical dysplasia. HPV testing was performed using the Roche Linear Array Assay. Results were compared between women with or without HIV co-infection and between those with or without cervical dysplasia, using Chi-square tests or Fisher’s exact tests. Results: 223 women had normal VIAs. All had HPV testing, 221 had valid results: 115 HIV-infected women (mean age 37 years) and 106 HIV-uninfected (mean age 33 years). 175 women had abnormal VIAs. 143 women had HPV testing performed, 140 had valid results: 70 HIV-infected women (mean age 38.5 years) and 70 HIV-uninfected (mean age 31.3 years). Greater than 90% of all HIV-infected women in both projects were receiving anti-retroviral therapy at enrollment. HPV of any type was detected in 48% of all women with normal VIA vs. 61% of women with abnormal VIA (P = 0.018). High risk (HR)-HPV was detected in 38% of all women with normal VIA vs. 51% of all women with abnormal VIA (P = 0.012). HIV-uninfected women with normal VIA had significantly lower detection of all HPV (P = 0.026), high risk-HPV (P = 0.018), IARC high risk-HPV (P = 0.047), A9 types (P = 0.050), and individual types HPV 16 (P = 0.0274), HPV 18 (P = 0.007), and HPV 51 (P = 0.009) than HIV-uninfected women with abnormal VIA. Among HIV-infected women, there was no difference in detection of any group of HPV types or individual types with respect to VIA results. Conclusions: HIV-uninfected women without cervical dysplasia had lower detection of oncogenic HPV than HIV-uninfected women with dysplasia. In contrast, HPV detection did not differ among HIV-infected women between those with or without cervical dysplasia. In addition, VIA appears to lack specificity for HPV-associated cervical dysplasia, as 39% of women with abnormal VIA examinations did not have any HPV detected, and 49% of women with abnormal VIA examinations did not have any HR-HPV detected.
The Circulating Cell-free Genome Atlas (CCGA) Study: Follow-up (F/U) on non-cancer participants with cancer-like cell-free DNA signals.
Authors: Allen Lee Cohn, Michael Seiden, Kathryn N. Kurtzman, Earl Hubbell, Samuel Gross, Oliver Venn, Eric T. Fung, Minetta C. Liu, Eric A. Klein, Geoffrey R. Oxnard, Anne-Renee Hartman, David Michael Waterhouse
Journal: Journal of Clinical Oncology (2019)

5574 Background: A noninvasive cell-free DNA (cfDNA)-based cancer detection assay offers the hope of a blood test that might reduce morbidity and mortality of cancers, particularly those without recommended screening tests (eg, some gynecologic cancers). CCGA (NCT02889978) is a prospective, multi-center, longitudinal, case-control study evaluating models for discriminating cancer versus non-cancer. Here, we report F/U of control participants (pts) who demonstrated a cancer-signal in CCGA. Methods: Clinically evaluable samples (N = 2508) from pts enrolled without a cancer diagnosis (dx; NC) and treatment-naive pts with newly diagnosed cancer (C) were divided into training (n = 1564; 580 NC, 984 C) and test (n = 944; 368 NC, 576 C) sets. Classification performance (cancer/non-cancer) was assessed via 3 prototype assays: whole-genome bisulfite (WGBS), whole-genome (WGS), and targeted (507 gene) sequencing. Notable outlier NC pts were identified with cancer-like scores in either ≥2 assay classification results or by the presence of known cancer drivers with ≥1 assay classification result suggesting cancer. All pts are currently in F/U in accordance with study protocol (to date: 80% with &gt; 10 mo and 15% with &gt; 22 mo F/U). Results: Among training and test sets, 8 ( &lt; 1%) NC pts were identified with a cancer-like signal. To-date, 2 have been diagnosed with a gynecologic malignancy: 1 stage IIIc clear cell endometrial carcinoma and 1 stage IIIc ovarian cancer, 3 and 2 months (mo) post-enrollment [PE], respectively. Among C pts in the study, sensitivity (at 98% specificity; WGBS) in these cancer types was: uterine/endometrial: 11% (n = 27 train) and 22% (n = 9 test); ovarian: 82% (n = 17) and 71% (n = 7). In addition, a third NC pt was diagnosed with a stage IV lung cancer 15 mo PE. Conclusions: This cfDNA-based assay detected a cancer-like signal that anticipated a clinical presentation of cancer in undiagnosed pts as early as 15 months prior to the actual dx. High specificity ( &gt; 99%) requires accounting for undiagnosed cancers in study design and analysis. Together, these data suggest that this prototype assay may have high performance detecting a variety of gynecological and other cancers. Clinical trial information: NCT02889978.
Modeling longer-term efficacy of neratinib in the extended adjuvant setting for early-stage breast cancer.
Authors: Mark D. Danese, Marc Halperin, Deepa Lalla, Bin Yao, John Crown, Quan V. Doan
Journal: Journal of Clinical Oncology (2019)

e12011 Background: Long-term efficacy in the extended adjuvant setting requires a long follow-up. In the ExteNET trial, neratinib was given for a year and invasive disease-free survival (iDFS) assessed at 2 and 5 years. In women with HER2+ hormone receptor positive (HR+) cancer who initiated neratinib, the observed difference in iDFS between neratinib and placebo at 5 years (4.5%) was greater than at 2 years (3.7%). The objective of these analyses was to extrapolate the effect of neratinib on iDFS beyond 5 years in patients with HER2+/HR+ early stage breast cancer who initiated treatment after receiving adjuvant trastuzumab. Methods: We analyzed the 5-year follow-up of the ExteNET trial using flexible spline-based parametric survival models to project iDFS risk at 10 years. Analyses included only HR+ patients. Several model specifications were explored including various combinations of the following variables: treatment as a time varying covariate, nodal status (0, 1-3, ≥4 nodes), and months from last trastuzumab treatment to randomization. The regression models included different combinations of interaction terms, either a proportional hazards or a proportional odds (PO) link function, and either 2 or 6 knots. The model fit was compared using Akaike Information Criterion (AIC). Results: In general, the fit statistics among the 16 models were comparable; however, the model with the lowest AIC included no interaction terms, 2 knots, and the PO link function. The mean iDFS event rate at 10 years was estimated to be 12.2% for neratinib and 18.9% for placebo for a difference of 6.8% (range across 16 models: 6.8%-7.8%). The recurrence rate and the difference between treatment groups were largest in women with ≥4 positive nodes. Conclusions: Based on these analyses, the projected 10-year difference in iDFS between placebo and neratinib patients seems likely to persist. However, because the data was limited to 5 years, we could not include the effect of hormonal therapy cessation. Also, low event rates in the node negative group may require longer follow-up to evaluate. In absence of longer-term data for neratinib, flexible parametric survival modeling of the iDFS suggests that the effect of neratinib therapy may remain stable.