tbuckley/cabot-search huggingface dataset:
Offer daily aspirin to cut risk of colorectal cancer in people with Lynch syndrome, says NICE
Authors: Pat Lok, Stijntje Dijk
Journal: BMJ (2019)

People with the inherited disease Lynch syndrome should be offered daily aspirin to reduce their risk of colorectal cancer, the National Institute for Health and Care Excellence (NICE) has said in draft guidance.1

People with Lynch syndrome have a 50-80% increased risk of colorectal cancer,2 the second leading cause of cancer deaths in the UK.

This is the first time that NICE has included advice about aspirin for reducing the risk of colorectal cancer among people with Lynch syndrome, although …
Use and findings of K-ras in colorectal cancer (CRC) testing in administrative and electronic medical records (EMR) data from 2005 through 2010.
Authors: Satish Valluri, Sean D Sullivan, Scott David Ramsey, Charles Kreilick, Susan H Foltz Boklage, Sally Haislip, James W. Gilmore, Stephen Szabo, Syam Sarma, Carl V Asche, Brian S. Seal
Journal: Journal of Clinical Oncology (2012)

e14146 Background: The use of K-ras testing in clinical decision-making has grown over the past few years. The objective of this study was to evaluate, in a real world context, the trends and diagnostic findings of K-ras testing using managed care and EMR data. Methods: The Georgia Cancer Specialists Database EMR (2005-2010) and administrative data from the MarketScan and IMPACT database(s) was used to select patients with newly diagnosed colorectal cancer (CRC). We looked for trends in use of K-ras in relation to timing of chemotherapy administration. The EMR data provided information on k-ras mutation type. Results: In MarketScan, of the 23,548 patients with a diagnosis of CRC, 1,730 (7.3%) patients had a test ordered for K-ras between 2005 and 2010. The number of patients receiving K-ras increased with line of therapy: first line 336 patients (8.2%) of 4,098 treated, second line 455 patients (15.2%) of 2,984 treated, and third line 529 patients (33%) of 1,603 treated. We found similar results using the IMPACT database: 2,256 (7.8%) CRC patients had a test ordered for K-ras between 2005 and 2010. K-ras testing increased with line of therapy: first line 244 patients (7.8%), second line 510 (14.6%), and third line 650 patients (33.1%). EMR lab results from stage IV disease (n=349) consisted of 15% mutated type, 60% unknown and 25% wild type. For confirmed test results wild type represented 62.5% and mutated type 37.5%. Conclusions: Over the last six years, use of K-ras testing has increased in use in patients with CRC. The increase has occurred in later lines of therapy. The timing occurring late in therapy may limit the use of agents specific for this test.
Demographics and patterns of care for veterans with colorectal cancer.
Authors: Tanganyika Barnes, Trent P Wang, Fengming Zhong, Victor T Chang, Melanie L. Gonzalez, Emma R Paz-Querubin, Barbara Crump, Monica McPherson, Arpita Gandhi, Basil Kasimis
Journal: Journal of Clinical Oncology (2012)

e14124 Background: This study is to analyze demographics and patterns of care for veterans with colorectal cancer. Methods: In an IRB approved protocol, we reviewed the records of pts diagnosed with colorectal adenocarcinoma at a VA Medical Center from 1/1/2003 to 12/31/2007. Demographics including age, sex, ECOG PS, stage, grade, site, CEA, hemoglobin (HGB), liver function tests at diagnosis, treatments and cause of death were reviewed. Results: There were 176 pts with colorectal ca with 112 colon (C) and 64 rectal ca (R) pts. One was a woman and the rest were men. The median age at diagnosis was 71 years (range 45-90). Median survival was 1157 days (5-3256). 95 (54%) pts were dead at this analysis. Median ECOG PS is 0. 160 pts had ECOG PS 0-2, 16pts ECOG 3-4. 4 (2.4%). 4 (2.4%) pts has stage 0, 51 (30.7%) stage 1, 42 (25.3%) stage 2, 35 (21.1%) stage 3, and 34 (20.5%) stage 4. 6 (3.7%) has grade 1, 111 (68.1%) grade 2, and 46 (28.2%) grade 3. Median CEA at diagnosis was 2.9 (0-3117), HGB 12.4 g/dl (6.6-16.7), albumin g/dl 3.98(1.7-4.7), AST 23 units/L (4-107), ALT 20 units/L (8-107), ALKP 77 units/L (37-352), Total bilirubin 0.7 mg/dl (0.1-4.5). 29 pts has liver metastasis at diagnosis. 147 pts (85.4%) received surgical resection. Total 43 pts had adjuvant treatment. 17 pts with rectal cancer had neoadjuvant chemoradiation . 7 pts had down staging and 3 pts had no residual disease after neoadjuvant chemoradiatoion. Total 14 pts had recurrence. 23 pts received palliative chemotherapy when metastatic. 54 of 95 pts (57%) died from cancer progression. Conclusions: This study provides a basis for understanding the epidemiology of colorectal cancer patient in a VA medical center.
Effectiveness of First-line Immune Checkpoint Blockade Versus Carboplatin-based Chemotherapy for Metastatic Urothelial Cancer
Authors: Emily Feld, Joanna Harton, Neal J. Meropol, Blythe J.S. Adamson, Aaron Cohen, Ravi B. Parikh, Matthew D. Galsky, Vivek Narayan, John Christodouleas, David J. Vaughn, Rebecca A. Hubbard, Ronac Mamtani
Journal: European Urology (2019)
A multi-centre, open-label study to assess the safety of Stimuvax (BLP25 liposome vaccine or L-BLP25) in non-small cell lung cancer (NSCLC) patients (pts) with unresectable stage III disease
Authors: D. Soulieres, C. Smith, P. M. Ellis, N. Murray, K. Jasas, A. Maksymiuk, G. Goss, M. H. Falk, C. Butts
Journal: Journal of Clinical Oncology (2007)

3075 Background: L-BLP25 is an innovative cancer vaccine that incorporates a synthetic MUC1 lipopeptide in a liposomal delivery system. L-BLP25 is expected to elicit an immune response to cancer cells that express MUC1. Previous clinical studies have demonstrated that L-BLP25 has the potential to extend survival of pts with stage IIIB locoregional NSCLC (Butts C et al., JCO 2005; 23:6674–6681). The present ph I-II study was designed to assess the safety of the current formulation of L-BLP25 using a monophosphoryl lipid A in pts with unresectable stage IIIA and stage IIIB NSCLC. Methods: Pts with stable disease or an objective response to upfront radical therapy with chemoradiation for unresectable stage III NSCLC, plus ECOG 0–1 were eligible. All pts were vaccinated according to a previously described schedule (1). Maintenance immunizations were administered every 6-wks until disease progression. Primary and secondary endpoints were safety and survival respectively. Results: Twenty-two pts were recruited at 7 sites in Canada. 16 pts were evaluated for this interim safety analysis (8 stage IIIA, 8 stage IIIB, median age; 57, ECOG 0 56%, concurrent chemotherapy; 93.8%). Thirteen pts had a partial response and 3 had stable disease following chemoradiation. Thirteen pts experienced an adverse event (AE) during the first 4 vaccinations of which 7 pts had a L-BLP25 related adverse event. Grade 1/2 AEs related to L-BLP25 ≥10% included fatigue, dyspnea, insomnia, anorexia, headache, diarrhea, paresthesia, abdominal pain, influenza-like illness, urinary tract infection and peripheral neuropathy. No pts discontinued L-BLP25 due to an AE and no grade 3/4 AEs related to L-BLP25 were reported. Six pts (37.5%) had an injection site reaction. As of September 2006, 10 pts were still on study treatment. Conclusions: This formulation of L-BLP25 was well tolerated and the side effect profile was similar to that seen in previous studies (1). A controlled global multi-center phase III trial is underway to further evaluate L-BLP25 in this patient population. No significant financial relationships to disclose.
Pivotal Trial of Enfortumab Vedotin in Urothelial Carcinoma After Platinum and Anti-Programmed Death 1/Programmed Death Ligand 1 Therapy
Authors: Jonathan E. Rosenberg, Peter H. O’Donnell, Arjun V. Balar, Bradley A. McGregor, Elisabeth I. Heath, Evan Y. Yu, Matthew D. Galsky, Noah M. Hahn, Elaina M. Gartner, Juan M. Pinelli, Shang-Ying Liang, Amal Melhem-Bertrandt, Daniel P. Petrylak
Journal: Journal of Clinical Oncology (2019)

Locally advanced or metastatic urothelial carcinoma is an incurable disease with limited treatment options, especially for patients who were previously treated with platinum and anti-programmed death 1 or anti-programmed death ligand 1 (PD-1/L1) therapy. Enfortumab vedotin is an antibody-drug conjugate that targets Nectin-4, which is highly expressed in urothelial carcinoma.EV-201 is a global, phase II, single-arm study of enfortumab vedotin 1.25 mg/kg (intravenously on days 1, 8, and 15 of every 28-day cycle) in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum chemotherapy and anti-PD-1/L1 therapy. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 by blinded independent central review. Key secondary end points were duration of response, progression-free survival, overall survival, safety, and tolerability.Enfortumab vedotin was administered to 125 patients with metastatic urothelial carcinoma. Median follow-up was 10.2 months (range, 0.5 to 16.5 months). Confirmed objective response rate was 44% (95% CI, 35.1% to 53.2%), including 12% complete responses. Similar responses were observed in prespecified subgroups, such as those patients with liver metastases and those with no response to prior anti-PD-1/L1 therapy. Median duration of response was 7.6 months (range, 0.95 to 11.30+ months). The most common treatment-related adverse events were fatigue (50%), any peripheral neuropathy (50%), alopecia (49%), any rash (48%), decreased appetite (44%), and dysgeusia (40%). No single treatment-related adverse events grade 3 or greater occurred in 10% or more of patients.Enfortumab vedotin demonstrated a clinically meaningful response rate with a manageable and tolerable safety profile in patients with locally advanced or metastatic urothelial carcinoma who were previously treated with platinum and anti-PD-1/L1 therapies.
Pamiparib in combination with tislelizumab in patients with advanced solid tumours: results from the dose-escalation stage of a multicentre, open-label, phase 1a/b trial
Authors: Michael Friedlander, Tarek Meniawy, Ben Markman, Linda Mileshkin, Paul Harnett, Michael Millward, Joanne Lundy, Alison Freimund, Christie Norris, Song Mu, John Wu, Virginia Paton, Bo Gao
Journal: The Lancet Oncology (2019)
Unexpected role of dendritic cells in pulmonary fibrosis
Authors: Jeoung-Sook Shin
Journal: Thorax (2019)

Pulmonary fibrosis is one of the most devastating diseases in which scars are formed in the lungs in a progressive and non-reversible fashion resulting in breathlessness and respiratory failure. Some treatments may improve symptoms or slow progression of the disease, but the benefits are temporary. Lung transplantation can be an option for treatment but involves serious complications, such as rejection and infection. Therefore, the development of a new treatment is in urgent need.

Past studies have shown that idiopathic pulmonary fibrosis (IPF) is associated with infiltration of lungs by dendritic cells (DCs). DCs are best known for their role in bridging innate and adaptive immunity. They reside in peripheral tissues, capture foreign antigens, produce inflammatory cytokines and present antigens to antigen-specific T lymphocytes inducing antigen-specific immune responses.1 Interestingly, an immunohistochemical analysis has shown that lungs of patients with IPF were associated with lymphoid aggregates and that these aggregates were enriched with DCs.2 Some other studies using flow cytometry have reported a significant increase in the frequency of DCs in the lungs and the bronchial lavage fluid in patients with IPF.3 4 These findings have raised a possibility that DC’s immune-stimulatory activity may play a significant role in the progression of pulmonary fibrosis.

The association of DCs with pulmonary fibrosis has been also observed in animal models. Intratracheal challenge of mice with bleomycin induced severe fibrosis in the lungs and the fibrosis was …
Design and synthesis of glycomimetics: Recent advances
Authors: Alice Tamburrini, Cinzia Colombo, Anna Bernardi
Journal: Medicinal Research Reviews (2019)

Abstract In the past few decades, our understanding of glycan information‐encoding power has notably increased, thus leading to a significant growth also in the design and synthesis of glycomimetic probes. Combining data from multiple analytical sources, such as crystallography, nuclear magnetic resonance spectroscopy, and other biophysical methods (eg, surface plasmon resonance and carbohydrate microarrays) has allowed to shed light on the key interaction events between carbohydrates and their protein‐targets. However, the low metabolic stability of carbohydrates and their high hydrophilicity, which translates in low bioavailability, undermine their development as drugs. In this framework, the design of chemically modified analogues (called carbohydrate mimics or glycomimetics) appears as a valid alternative for the development of therapeutic agents. Glycomimetics, as structural and functional mimics of carbohydrates, can replace the native ligands in the interaction with target proteins, but are designed to show enhanced enzymatic stability and bioavailability and, possibly, an improved affinity and selectivity toward the target. In the present account, we specifically focus on the most recent advances in the design and synthesis of glycomimetics. In particular, we highlight the efforts of the scientific community in the development of straightforward synthetic procedures for the preparation of sugar mimics and in their preliminary biological evaluation.
Volanesorsen and Triglyceride Levels in Familial Chylomicronemia Syndrome
Authors: Joseph L. Witztum, Daniel Gaudet, Steven D. Freedman, Veronica J. Alexander, Andres Digenio, Karren R. Williams, Qingqing Yang, Steven G. Hughes, Richard S. Geary, Marcello Arca, Erik S.G. Stroes, Jean Bergeron, Handrean Soran, Fernando Civeira, Linda Hemphill, Sotirios Tsimikas, Dirk J. Blom, Louis O’Dea, Eric Bruckert
Journal: New England Journal of Medicine (2019)

Familial chylomicronemia syndrome is a rare genetic disorder that is caused by loss of lipoprotein lipase activity and characterized by chylomicronemia and recurrent episodes of pancreatitis. There are no effective therapies. In an open-label study of three patients with this syndrome, antisense-mediated inhibition of hepatic APOC3 mRNA with volanesorsen led to decreased plasma apolipoprotein C-III and triglyceride levels.
PD-1 silencing impairs the anti-tumor function of chimeric antigen receptor modified T cells by inhibiting proliferation activity
Authors: Jianshu Wei, Can Luo, Yao Wang, Yelei Guo, Hanren Dai, Chuan Tong, Dongdong Ti, Zhiqiang Wu, Weidong Han
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Blocking programmed death-1 (PD-1) is considered to be a promising strategy to improve T cell function, and this is being explored in many ongoing clinical trials. In fact, our knowledge about PD-1 is primarily based on the results of short-term experiments or observations, but how long-lasting PD-1 blockade can affect T cell function remains unclear. <h3>Methods</h3> We planned to use shRNA-based gene knockdown technology to mimic long-lasting PD-1 blockade. We constructed PD-1 steadily blocked chimeric antigen receptor modified T (CAR-T) cells, and with these cells we can clearly study the effects of PD-1 knockdown on T cell function. The anti-tumor function, proliferation ability and differentiation status of PD-1 silenced CAR-T cells were studied by in vitro and animal experiments. <h3>Results</h3> According to short-term in vitro results, it was reconfirmed that the resistance to programmed death-ligand 1 (PD-L1)-mediated immunosuppression could be enhanced by PD-1 blockade. However, better anti-tumor function was not presented by PD-1 blocked CAR-T cells in vitro or in vivo experiments. It was found that PD-1 knockdownmight impair the anti-tumor potential of CAR-T cells because it inhibited T cells' proliferation activity. In addition, we observed that PD-1 blockade would accelerate T cells' early differentiation and prevent effector T cells from differentiating into effect memory T cells, and this might be the reason for the limited proliferation of PD-1 silenced CAR-T cells. <h3>Conclusion</h3> These results suggest that PD-1 might play an important role in maintaining the proper proliferation and differentiation of T cells, and PD-1 silencing would impair T cells' anti-tumor function by inhibiting their proliferation activity.
Patient-reported symptom burden and quality of life in advanced lung cancer.
Authors: Shrividya Iyer, Alex Rider, Gavin Taylor-Stokes, Adam Roughley
Journal: Journal of Clinical Oncology (2012)

e16570 Background: The main objective of our study was to assess patient reported symptom burden and impact on quality of life in advanced non small cell lung cancer (NSCLC) patients in the United States. Methods: Patients with advanced (stage IIIB/IV) NSCLC (N=450) were recruited with informed consent in a nationwide (US) lung cancer study from Oct-Dec 2011. Patient reported symptoms were assessed using the Lung Cancer Symptom Scale (LCSS) on a 0-100 visual analogue scale and included six symptoms: fatigue, appetite loss, shortness of breath, cough, pain and blood in sputum. An average symptom burden index was calculated. Quality of life was assessed using the Functional Assessment of Cancer Therapy- Lung (FACT-L).Higher scores indicate higher symptom severity on the LCSS and better quality of life on the FACT-L. Correlation between the total FACT-L score and LCSS symptom burden index was assessed. A multivariate regression analysis was performed with FACT-L total score as the dependent variable and LCSS symptom scores as predictors controlling for age, gender, stage and performance status. Results: Majority of the patients were male (59%), Caucasian (74%), smokers/ex-smokers (78%) with an average age of 64 years. Proportion of patients reporting each lung cancer symptom was: Fatigue (100%), loss of appetite (97%), shortness of breath (95%), cough (93%), pain (92%) and blood in sputum (63%). The average (SD) symptom burden index was 42.3 (21.5).The mean± SD severity scores on symptoms were: fatigue (53.2±24.7), loss of appetite (48.1±25.8), cough (48.4±29.9), shortness of breath (44.7± 27), pain (39.7± 28.1) and blood in sputum (18.4±23.6). The average (SD) FACT-L score was 71.7 (25.3). A significant negative correlation was found between the LCSS symptom burden index and FACT-L scores (ρ= -0.82; p&lt;0.001). Loss of appetite (β=-0.204; p&lt;0.001), cough (β= -0.145; p&lt;0.01), pain (β=-0.265; p&lt;0.001), shortness of breath (β = -0.145; p&lt;0.01), age (β= 0.217; p&lt;0.05) and performance status (β = 0.283; p&lt;0.001) were found to be significant predictors of quality of life. Conclusions: Cough, pain, shortness of breath and loss of appetite contribute to symptom burden and have a significant negative impact on quality of life in advanced NSCLC patients.
Variations of T cells following metronomic and standard chemotherapy in patients with solid tumors.
Authors: Anna Koumarianou, Marianna Christodoulou, Iordanis Papadopoulos, Spyros Stergiopoulos, George Peros, George Dimitriadis, Nikolaos Tountas, Theofanis Economopoulos, Dimitrios G. Pectasides, Vassiliki Pappa, Nikolaos Xiros
Journal: Journal of Clinical Oncology (2012)

e21027 Background: Evidence suggests that the interaction of chemotherapy with effector (Teffs) and suppressor (Tregs) T-cells may influence the survival of patients. We investigated the impact of metronomic (p.o.) and standard intravenous (i.v.) chemotherapy on Tregs and Teffs. Methods: Blood samples were collected from 37 cancer patients, before (pre) and after (post) the first cycle of i.v. (n=18) or p.o. (n=19) chemotherapy. CD4+CD25- Teffs and CD4+CD25+ Tregs were freshly isolated with magnetic-bead sorting (Miltenyi Biotec). Teffs:Tregs co-cultures were developed in the presence of CD2, CD3 and CD28 antibodies for the study of the Tregs over Teffs suppressive capacity. The cell proliferation was evaluated utilizing a colorimetric ELISA (O.D. at 450 nm) (Roche Applied Science). Statistical analyses using Mann-Whitney and Tukey’s (one-way ANOVA) tests were performed in order to determine if changes in the numerical and/or functional T-cell characteristics occurred in association with a particular chemotherapy approach. Results: Decreased numbers of total T-cells were observed in all patients regardless chemotherapy type. The post-chemotherapy group displayed higher ratio of Tregs to Teffs cells as well as higher Tregs over Teffs suppression (expressed as the % difference in Teff proliferation rate between single Teffs cultures and Teffs:Tregs co-cultures) compared to the pre-chemotherapy group (0.17±0.02 vs 0.09±0.07, p=0.002 and 30.65%±12.12 vs 10.65%±16.80, respectively). Subgroup analyses revealed that these parameters were significantly higher in patients treated with p.o. chemotherapy compared to those treated with i.v. chemotherapy (0.21±0.04 vs 0.12±0.03, p=0.01 and 44.43%±7.34 vs 16.87%±22.99, respectively). Patients receiving drugs targeting the mitotic spindle, such as docetaxel or vinorelbine, exhibited a stronger Tregs suppression (44.32%±6.78) as compared to those treated with DNA sequence-interfering drugs, such as epirubicin or cisplatin (10.30%±38.85). Conclusions: Chemotherapy influences the immune response in favor of Tregs and against Teffs in a drug-specific manner. Compared to i.v., p.o. chemotherapy correlates with greater repression of Teffs function.
Impact of Cumulative Chemotherapy Dose on Survival With Adjuvant FEC-D Chemotherapy for Breast Cancer
Authors: Zachary Veitch, Omar F. Khan, Derek Tilley, Patricia A. Tang, Domen Ribnikar, Douglas A. Stewart, Xanthoula Kostaras, Karen King, Sasha Lupichuk
Journal: Journal of the National Comprehensive Cancer Network (2019)

Reductions in adjuvant chemotherapy dose <85% for historical regimens (ie, cyclophosphamide/methotrexate/fluorouracil) are known to affect breast cancer survival. This threshold, in addition to early versus late dose reductions, are poorly defined for third-generation anthracycline/taxane-based chemotherapy. In patients with breast cancer receiving adjuvant 5-fluorouracil/epirubicin/cyclophosphamide followed by docetaxel (FEC-D), we evaluated the impact of chemotherapy total cumulative dose (TCD), and early (FEC) versus late (D only) dose reductions, on survival outcomes.Women with stage I-III, hormone receptor-positive/negative, HER2-negative breast cancer treated with adjuvant FEC-D chemotherapy from 2007 through 2014 in Alberta, Canada, were included. TCD for cycles 1 to 6 of <85% or ≥85% was calculated. Average cumulative dose was also calculated for early (cycles 1-3) and late (cycles 4-6) chemotherapy. Survival outcomes (disease-free survival [DFS] and overall survival [OS]) were estimated using Kaplan-Meier and multivariate analysis. Cohorts were evaluated for uniformity.Characteristics were reasonably balanced for all cohorts. Overall, 1,302 patients were evaluated for dose reductions, with 16% being reduced <85% (n=202) relative to ≥85% (n=1,100; 84%). Patients who received TCD ≥85% relative to <85% had superior 5-year DFS (P=.025) and OS (P<.001) according to Kaplan-Meier analysis, which remained significant on univariate and multivariate analyses. In stratified late and early dose reduction cohorts, DFS and OS showed a significant inferior survival trend for dose reduction early in treatment administration in 5-year Kaplan-Meier (P=.002 and P<.001, respectively) and multivariate analyses (hazard ratio [HR], 1.46; P=.073, and HR, 1.77; P=.011, respectively). Dose delays of <14 or ≥14 days and granulocyte colony-stimulating factor use did not affect outcomes.Chemotherapy TCD <85% for adjuvant FEC-D affects breast cancer survival. Late reductions (D only) were not shown to adversely affect DFS or OS. Conversely, early reductions (FEC±D) negatively affected patient outcomes.