tbuckley/cabot-search huggingface dataset:
Human embryonic stem cell–derived hepatoblasts are an optimal lineage stage for hepatitis C virus infection
Authors: Fang Yan, Yi Wang, Wencheng Zhang, Mingyang Chang, Zhiying He, Jinbo Xu, Changzhen Shang, Tao Chen, Jiang Liu, Xin Wang, Xuetao Pei, Yunfang Wang
Journal: Hepatology (2017)

Maturation of hepatic cells can be gradually acquired through multiple stages of hepatic lineage specification, while it is unclear whether hepatitis C virus (HCV) infection is maturationally lineage‐dependent. We investigated the susceptibility to HCV at multiple stages of human embryonic stem cells, definitive endodermal cells, hepatic stem cells, hepatoblasts (hHBs), and mature hepatocytes. Susceptibility to infection occurred initially at the stage of human hepatic stem cells; however, hHBs proved to have the highest permissiveness and infectivity compared with all other stages. The hHBs' susceptibility to HCV correlated with the translocation of occludin, an HCV receptor, from cytoplasm to plasma membrane of HBs. Vascular endothelial cell growth factor enhanced the HCV susceptibility of hHBs through rearrangement of occludin by dephosphorylation; this minimized hHB polarization and prevented hHBs from further maturation. The transcription profiles of different hepatic lineage stages indicated that expression of innate immune response genes was correlated with hepatic maturation; interferon β played an important role in protecting hHBs from HCV infection. HCV‐infected hHBs were able to engraft and integrate into the livers of Fah –/– Rag2 –/– mice and maintained an hHB phenotype for over 12 weeks during the time when HCV antigen was evident. After suppression of interferon β in hHBs, HCV infection was significantly enhanced in the engrafted humanized liver tissue of host mice. Conclusion : Human embryonic stem cell–derived hHBs are the optimal hosts for HCV infectivity; the realization that HCV entry and replication occur primarily at a particular hepatic lineage stage enables us to understand the HCV infection factors, life cycle, and infection dynamics that are facets of the pathogenesis as well as suggesting targets for anti‐HCV treatment. (H epatology 2017;66:717–735).
Caregiver work modifications: A hidden cost of cancer care.
Authors: Emma Blackmon, Janice Bell, Robin L. Whitney, Sarah C. Reed, Katherine Kim, Jill Joseph
Journal: Journal of Clinical Oncology (2016)

190 Background: Recent national reports highlight the dramatically rising costs of cancer care and its impact on financial hardship among survivors. Comparatively little attention, however, has been paid to the contributions of family and friends in unpaid caregiving roles—specifically, the impact of caregiving on caregivers jobs and work life. Methods: Using data collected in the 2012 LIVESTRONG Survey of People Affected by Cancer, we examined the prevalence of cancer survivors reporting that they had a friend or family member providing care to them during or after cancer treatment. Then, among those reporting they had a caregiver employed at that time, we used logistic regression to examine caregiver work modifications (i.e., paid time, unpaid time off, changing hours or duties, or making a change in employment status. All models controlled for survivor age at diagnosis, sex, race/ethnicity, income, education and employment status as potential predictors. Results: Of the respondents (n = 6310), 88% reported a family member or friend provided care as follows (in non-mutually exclusive categories): spouses (64%), friends (47%), parents (40%), siblings (31%), children (28%) or other family member (14%). Among survivors with employed caregivers (n = 4,984), 41% reported that their caregiver made a work modification; of these 57% took paid time off, 41% took unpaid time off, 4% switched from full time to part time and 3% took early retirement. Caregivers were more likely to make work modifications for survivors with low (versus high) income or education and for unemployed (versus employed) survivors. The age of the survivor was also a significant factor, with caregivers making more work modifications for younger survivors (ages 18-64) compared to older survivors (age &gt; 65)—with ORs of caregiver work modfications increasing from 1.70 to 6.92 in a dose response by survivor age. Conclusions: Family and friends provide care to a majority of individuals with cancer and many make substantial modifications to their work—contributions which are not routinely counted in estimates of the cost of cancer care. Interventions may be warranted to support caregivers, particular those of survivors with lower income, less education and those of younger age.
Local excision and selective radical resection after neoadjuvant chemoradiation for rectal cancer.
Authors: E. R. Camp, J. T. Lucas, K. Simpson, N. F. Esnaola
Journal: Journal of Clinical Oncology (2011)

e14107 Background: 20% of rectal cancer patients with a clinical complete response (CR) after neoadjuvant chemoradiation will have a pathologic CR at radical resection (RR). Local excision (LE) of the primary tumor can identify patients who achieved a pathologic CR/may not require RR. The objective of this study was to explore the predictive/therapeutic value of LE and optimal surgical strategy in this patient population. Methods: We developed a decision analysis/Markov model to compare outcomes following selective versus routine RR in rectal cancer patients with a clinical CR after chemoradiation. All patients in the selective RR strategy underwent LE: patients with a pathologic CR were observed/those with residual disease underwent subsequent RR. Sensitivity/specificity of LE and morbidity/mortality/recurrence/salvage/survival estimates were obtained from the medical literature. Outcomes were quality-adjusted using health state preferences. Results: Quality-adjusted life years (QALYs) after selective RR were 6.22 compared to 6.03 after routine RR (69 additional healthy days gained). Patients with a “true” pathologic CR (at the primary tumor site/mesorectum) gained the greatest benefit (8.46 versus 7.68 QALYs, respectively). Selective RR was the optimal strategy even after model estimates were varied widely over reported ranges. Routine RR became the preferred strategy only if mortality of local excision and probability of pathologic CR were assumed to be >3% and <1%, respectively. Conclusions: Selective RR (based on findings at LE) maximizes quality-adjusted life expectancy compared to routine RR in rectal cancer patients with a clinical CR after neoadjuvant chemoradiation. Routine RR in this increasingly common clinical situation should be strongly reconsidered.
Biological and Therapeutic Potential of Mir-155, 585 and Let-7f in Myeloma in Vitro and In Vivo.
Authors: Sophia Adamia, Mariateresa Fulciniti, Herve Avet-Loiseau, Samir B Amin, Parantu Shah, Daniel Ruben Carrasco, Stephane Minvielle, Philippe Moreau, Kenneth C. Anderson, Nikhil C. Munshi
Journal: Blood (2009)
Impact of obesity on presentation of colorectal cancer
Authors: L. A. Wood, K. M. Inglis, P. J. Veugelers, J. L. Murdoch, P. M. Johnson, G. A. Porter
Journal: Journal of Clinical Oncology (2005)

3645 Background: Obesity has been shown to be associated with reduced survival in patients with colorectal cancer, although mechanisms for this finding are unclear. We hypothesized that, at least in part, this may be due to obesity-associated differences in presentation. Thus, the objective of this study was to examine the impact of obesity on the presentation and pathologic staging of colorectal cancer. Methods: From 02/15/2002 to 02/15/2004, all patients undergoing surgery for primary colorectal cancer at two institutions were enrolled in a prospective cohort study. Body mass index (BMI) was measured at the time of hospital admission for surgery. National Institutes of Health criteria were used to categorize patients: normal/underweight (NW; 18.4 < BMI < 25 kg/m2), overweight (OW; BMI = 25–29.9 kg/m2), obese (OB; BMI = 30–39.9 kg/m2) and severely obese (SOB; BMI> 40 kg/m2). Presentation and pathologic factors were then compared among the groups. Results: The study cohort consisted of 448 patients; 125 (27.9%) were NW, 172 (38.4%) were OW, 127 (28.3%) were OB, and 24 (5.4%) were SOB. No significant differences in age, gender, ethnicity, or tumor grade were found between weight groups. Most patients (90.8%) presented with symptomatic disease; the use of colorectal cancer screening was similar among all weight groups. Among symptomatic patients, bleeding/anemia as the first presenting symptom was significantly associated with increasing BMI (see table). SOB patients were found to have a significantly increased incidence of lymph node metastases, whereas NW patients were more likely to present with metastatic disease (see table). Conclusions: This study identified several obesity-related differences in presentation of colorectal cancer. An obesity-associated increased incidence of node metastases was seen only in the small proportion of obese patients who are SOB. The increased incidence of metastatic disease at presentation among NW patients may reflect disease-related weight loss. No significant financial relationships to disclose.
Reduced Intensity Conditioning with Allogeneic Hematopoietic Cell Transplantation for the Treatment of High-Risk Acute Lymphoblastic Leukemia.
Authors: Ron Ram, Rainer F. Storb, David G. Maloney, Brenda M. Sandmaier, Michael Maris, Judith Shizuru, Thomas Chauncey, Amelia A. Langston, George E. Georges
Journal: Blood (2009)
Prospective phase II trial of pre-resection thoracoscopic (VATS) restaging following neoadjuvant therapy for IIIA(N2) non-small cell lung cancer (NSCLC): Results of CALGB 39803
Authors: M. T. Jaklitsch, L. Gu, D. H. Harpole, T. A. D’Amico, R. J. McKenna, M. J. Krasna, L. J. Kohman, S. J. Swanson, M. M. Decamp, D. J. Sugarbaker
Journal: Journal of Clinical Oncology (2005)

7065 Background: N2 nodal downstaging following neoadjuvant therapy for Stage IIIA(N2) NSCLC correlates with improved survival after lung resection. Pathologic assessment of nodes following neoadjuvant therapy may avoid unnecessary thoracotomy. Repeat mediastinoscopy has increased risk and limited efficacy. VATS may provide a safe alternative for restaging. Methods: The primary objective of this prospective multi-institutional study was to determine the feasibility of VATS restaging of ipsilateral nodes in mediastinoscopy proven stage IIIA(N2) NSCLC following 2 cycles neoadjuvant platinum-based chemotherapy (chemo) and/or ≥ 40 Gy radiotherapy (XRT) prior to thoracotomy. The goal of VATS re-staging was to biopsy 3 (-) lymph node stations, 1 (+) N2 node, or pleural carcinomatosis. Results: 70 evaluable patients (pts) were accrued from 10 institutions, 47% male, 97% white, and 71% aged between 50 and 69 years. 60% had performance status (PS) = 0, 40% PS = 1. 47 pts (67%) had XRT, 68 (97%) had chemo. Number of VATS incisions ranged from 1 to 4, median 3. Median time of VATS was 63 minutes, range from 27 to 313. VATS restaging met criteria in 40 pts (57%) and revealed: 4 pleural carcinomatosis, 17 persistent N2 disease, 19 had 3 (-) nodal stations. An additional 13 VATS (18.6%) found no evidence of persistent N2 disease, but had inadequate nodal sampling due to unanticipated obliteration of nodal tissue. Thus, 53 VATS (76%, 95% CI: 64 - 85%) were able to restage the mediastinum. VATS was unsuccessful in 17 (24%): 11 due to adhesions/fibrosis, 4 from tumor bulk preventing nodal access, 1 VATS was aborted due to airway injury, and 1 had inadequate lung deflation. Of the 53 completed VATS, 21 provided cancer tissue, and 31 had histologic tissue obtained during thoracotomy. N2 downstaging occurred in 32 pts (46%). Sensitivity of VATS was 75%, specificity was 100%, and negative predictive value was 75.8%. No deaths, but 1 airway injury was directly attributed to VATS. Conclusions: VATS restaging was feasible and provided pathologic assessment of ipsilateral nodes in treated IIIA(N2) NSCLC. New treatment paradigms can be built on pathologic restaging. No significant financial relationships to disclose.
Neurologic outcome for patients with brain metastasis who undero Gamma Knife RadioSurgery with emphasis on the elderly: Impact of surveillance and salvage therapy
Authors: S. Mazj, S. Rush, S. M. Lichtman
Journal: Journal of Clinical Oncology (2005)

8272 Purpose: Patients who underwent gamma knife radiosurgery (GKRS) for brain metastasis (BM) patients were followed to determine the neurologic outcome. Material and Methods: 72 consecutive, prospective patients (12 patients age >70 years: 16.6%) underwent GKRS for BM during the period 11/91 to 9/02. Nineteen (two elderly) patients received whole brain radiation therapy (WBRT) prior to GKRS and 9 (one elderly) patients received WBRT with GKRS combined. The diagnoses were: NSCLC-31, small cell lung-13, breast-22, other-6. Patients were followed after GKRS with clinical evaluation and MRI at 6 weeks, 12 weeks and every 12 weeks thereafter. Salvage therapy was instituted when clinically appropriate in the form of further GKRS, surgical resection, external beam radiotherapy or temozolomide. Patients were considered to have a neurologic death (ND) if there were neurologic symptoms at death and/or patients were steroid dependent and still alive at follow up. Results: 72 patients (50 females;22 males) with median age of 60 years (range 35–82 years) underwent GKRS for BM. Salvage therapy was instituted for 26 patients during follow up. Fifteen (including 2 elderly) patients underwent further GKRS and 8 patients underwent surgical resection (2 for new tumors and 6 for treated lesions that progressed). Eight patients who had not previously received WBRT received GKRS and 8 patients who had previously received WBRT received a second course of external beam therapy to the whole brain or a partial brain field. Upon final follow up, 40 patients were deceased. Of the 40 (6 elderly) deceased patients, 6 (15%) had neurologic symptoms at death. Of the 32 (6 elderly) remaining patients, 4 (12.5%) have irreversible neurologic symptoms and/or steroid dependency from their BM. Conclusion: A strategy of close follow-up and salvage therapy results in a relatively low rate (10/72; 13.9%); (3/12; 33% elderly group) of neurologic symptoms among patients who received GKRS and as part of their treatment for BM. Therefore 88% of patients less than 70 years and 75% of those older did not have significant neurologic sequelae. This therapy should be considered for patients of all ages. No significant financial relationships to disclose.
Autocrine lysophosphatidic acid signaling activates β-catenin and promotes lung allograft fibrosis
Authors: Pengxiu Cao, Yoshiro Aoki, Linda Badri, Natalie M. Walker, Casey M. Manning, Amir Lagstein, Eric R. Fearon, Vibha N. Lama
Journal: Journal of Clinical Investigation (2017)

Tissue fibrosis is the primary cause of long-term graft failure after organ transplantation. In lung allografts, progressive terminal airway fibrosis leads to an irreversible decline in lung function termed bronchiolitis obliterans syndrome (BOS). Here, we have identified an autocrine pathway linking nuclear factor of activated T cells 2 (NFAT1), autotaxin (ATX), lysophosphatidic acid (LPA), and β-catenin that contributes to progression of fibrosis in lung allografts. Mesenchymal cells (MCs) derived from fibrotic lung allografts (BOS MCs) demonstrated constitutive nuclear β-catenin expression that was dependent on autocrine ATX secretion and LPA signaling. We found that NFAT1 upstream of ATX regulated expression of ATX as well as β-catenin. Silencing NFAT1 in BOS MCs suppressed ATX expression, and sustained overexpression of NFAT1 increased ATX expression and activity in non-fibrotic MCs. LPA signaling induced NFAT1 nuclear translocation, suggesting that autocrine LPA synthesis promotes NFAT1 transcriptional activation and ATX secretion in a positive feedback loop. In an in vivo mouse orthotopic lung transplant model of BOS, antagonism of the LPA receptor (LPA1) or ATX inhibition decreased allograft fibrosis and was associated with lower active β-catenin and dephosphorylated NFAT1 expression. Lung allografts from β-catenin reporter mice demonstrated reduced β-catenin transcriptional activation in the presence of LPA1 antagonist, confirming an in vivo role for LPA signaling in β-catenin activation.
Serious wound healing complications (sWHC) following surgery in patients (pts) with metastatic colorectal cancer (mCRC) receiving bevacizumab (BV): Results from the BRiTE observational cohort study (OCS)
Authors: M. M. Sugrue, D. M. Purdie, S. Feng, P. J. Flynn, A. Grothey, D. J. Sargent, J. D. Berlin, F. F. Kabbinavar, W. Dong, M. F. Kozloff
Journal: Journal of Clinical Oncology (2008)

4105 Background: BV prolongs overall survival and progression-free survival when added to chemotherapy (CT) for 1st and 2nd-line treatment (tx) of pts with mCRC. Inhibiting VEGF can impair and delay wound healing, which may manifest clinically as postoperative WHC. Because of BV's long estimated half-life (∼20 days), the risk of WHC may persist after its discontinuation. A pooled analysis of 2 randomized 1st-line mCRC studies reported WHC events (including perforation, fistula, and abscess) in 13% (10/75) of pts who had major surgery while on BV (Scappaticci, J Surg Oncol 2005;91:173–180). BRiTE, a large community-based OCS of BV tx for mCRC, collected data on postoperative sWHC in pts undergoing surgery. The incidence of and potential risk factors associated with sWHC in BRiTE are now reported. Methods: Pts and methods for BRiTE have been described (Kozloff, ASCO 2006; A3537). sWHC were summarized for pts who had surgical procedures on study and by timing of surgery from last BV dose. Results: 622 mCRC pts had surgery after starting tx with 1st-line BV + CT. sWHC incidence was 3.7% (23/ 622 pts). There were more sWHC events associated with major abdominal surgeries and when the interval between the last BV dose and surgery was <60 days (Table). Among 23 pts with sWHC, other factors possibly associated with wound healing impairment included infection (12 pts), tumor involvement at the operative site (4 pts), history of diabetes on medication (2 pts), and obesity (4 pts). Conclusions: The BRiTE OCS offers a unique opportunity to evaluate the risk of WHC associated with BV use in a general population of pts with more than 600 mCRC pts undergoing surgery after starting 1st line BV-containing tx. The overall rate of sWHC was low among mCRC pts in BRiTE who had surgery during BV tx + CT, especially in pts who underwent surgery ≥60 days from last BV dose. Descriptions of the sWHC events and associated factors will be presented. WHCs by Time Post-BV and by Surgery Category Type of surgery Time from last BV to first surgery (days) 0–13 14–27 28–59 ≥60 Incidence of WHCs All surgeries 6/93(6.5%) 3/89(3.4%) 9/167(5.4%) 5/273(1.8%) Major abdominal 2/24 3/36 6/107 3/175 Minor (e.g. line placement) 1/24 0/14 1/13 0/17 Other (e.g. orthopedic) 3/45 0/39 2/47 2/81 Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech, Inc. Genentech, Inc., Roche, sanofi-aventis Genentech, Inc. Genentech, Inc., Roche, sanofi-aventis
Phase I trial of the HDAC inhibitor LBH589 in combination with sorafenib in patients with renal cell carcinoma, non-small cell lung cancer and soft tissue sarcomas.
Authors: Charles Mackie Butler, Lydia T. Laboccetta, Alan Brisendine, Thomas E. Keane, Carol Arthur Sherman, Harry A. Drabkin
Journal: Journal of Clinical Oncology (2012)

440 Background: LBH589 is a novel histone deacetylase inhibitor (HDACi) that induces apoptosis of tumor cells. In renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) cell lines, the combination of sorafenib and HDACi was found to have synergistic inhibition, which correlated with the induction of an ER stress response. In this phase I study, we evaluated the combination of LBH589 and sorafenib in previously treated patients with RCC (9pts), soft tissue sarcomas (1pt), and NSCLC (6pts). The trial was designed to determine the safety profile and maximum tolerated dose of LBH589 and sorafenib when administered concurrently. Methods: Patients were dosed with either i.v. or oral LBH 589 (three times per week, continuously) every twenty eight days in combination with standard daily dose sorafenib (400 mg bid). The dose escalation was based on a “3+3” algorithmic design. LBH was initially administered at an i.v. dose of 5 mg/m2 with escalation to 10 mg/m2. Due to the manufacturer’s phase-out of the i.v. formulation, this was then changed to an oral formulation administered three times a week (doses 15 mg, 20 mg, and 25 mg). Results: Sixteen patients, median age 57 years, have been treated. Dose limiting toxicities were observed with grade 4 thrombocytopenia in two patients at the oral dose of 25 mg. There were no other grade 4 events. Grade 3 events included fatigue (2 pts), hypophosphatemia (2 pts), hypertension (1 pts), anemia (1 pt), rash (1 pt) and hand-foot erythroderma (1 pt). Common toxicities for the combination were fatigue (81%), weight loss (62%), loss of appetite (56%), diarrhea (56%), rash (50%), thrombocytopenia (31%), and hand-foot erythroderma (25%). No patients had significant QT prolongation. There was 1 partial response in a patient with lung cancer (31 weeks). Stable disease was noted in seven patients with RCC (78+, 48, 47, 31, 21, 17, and 10+ weeks). Seven patients had progressive disease Conclusions: The administration of oral LBH589 at a dose of 20 mg was found to be well tolerated and will be used in the expansion phase of the trial. Prolonged stable disease was observed in patients previously treated with sorafenib alone, sunitinib and axitinib.