tbuckley/cabot-search huggingface dataset:
Long-term outcome of treatment with infliximab in 614 patients with Crohn's disease: results from a single-centre cohort
Authors: F Schnitzler, H Fidder, M Ferrante, M Noman, I Arijs, G Van Assche, I Hoffman, K Van Steen, S Vermeire, P Rutgeerts
Journal: Gut (2008)

<h3>Background and aims:</h3> This observational study assessed the long-term clinical benefit of infliximab (IFX) in 614 consecutive patients with Crohn's disease (CD) from a single centre during a median follow-up of 55 months (interquartile range (IQR) 27–83). <h3>Methods:</h3> The primary analysis looked at the proportion of patients with initial response to IFX who had sustained clinical benefit at the end of follow-up. The long-term effects of IFX on the course of CD as reflected by the rate of surgery and hospitalisations and need for corticosteroids were also analysed. <h3>Results:</h3> 10.9% of patients were primary non-responders to IFX. Sustained benefit was observed in 347 of the 547 patients (63.4%) receiving long-term treatment. In 68.3% of these, treatment with IFX was ongoing and in 31.7% IFX was stopped, with the patient being in remission. Seventy patients (12.8%) had to stop IFX due to side effects and 118 (21.6%) due to loss of response. Although the yearly drop-out rates of IFX in patients with episodic (10.7%) and scheduled treatment (7.1%) were similar, the need for hospitalisations and surgery decreased less in the episodic than in the scheduled group. Steroid discontinuation also occurred in a higher proportion of patients in the scheduled group than in the episodic group. <h3>Conclusions:</h3> In this large real-life cohort of patients with CD, long-term treatment with IFX was very efficacious to maintain improvement during a median follow-up of almost 5 years and changed disease outcome by decreasing the rate of hospitalisations and surgery.
Transcriptional and Post-Transcriptional Gene Regulation by Long Non-Coding RNA
Authors: Iain M. Dykes, Costanza Emanueli
Journal: Genomics Proteomics & Bioinformatics (2017)

Abstract Advances in genomics technology over recent years have led to the surprising discovery that the genome is far more pervasively transcribed than was previously appreciated. Much of the newly-discovered transcriptome appears to represent long non-coding RNA (lncRNA), a heterogeneous group of largely uncharacterised transcripts. Understanding the biological function of these molecules represents a major challenge and in this review we discuss some of the progress made to date. One major theme of lncRNA biology seems to be the existence of a network of interactions with microRNA (miRNA) pathways. lncRNA has been shown to act as both a source and an inhibitory regulator of miRNA. At the transcriptional level, a model is emerging whereby lncRNA bridges DNA and protein by binding to chromatin and serving as a scaffold for modifying protein complexes. Such a mechanism can bridge promoters to enhancers or enhancer-like non-coding genes by regulating chromatin looping, as well as conferring specificity on histone modifying complexes by directing them to specific loci.
Bedaquiline as a potential agent in the treatment of <i>Mycobacterium abscessus</i> infections
Authors: Silvan Vesenbeckh, Nicolas Schönfeld, Andreas Roth, Gudrun Bettermann, David Krieger, Torsten Thomas Bauer, Holger Rüssmann, Harald Mauch
Journal: European Respiratory Journal (2017)

Mycobacterium abscessus is increasingly being recognised as a significant human pathogen, especially in patients with cystic fibrosis, and the specific M. abscessus subspecies seems to influence the clinical outcome [1]. The pulmonary manifestation of this nontuberculous mycobacteria (NTM) infection is one of the most difficult to treat forms, leading to substantial morbidity and mortality in this population [1, 2]. M. abscessus strains are highly resistant to most antibacterial drugs [2]. The recent development of liposomal amikacin for inhalation for patients with cystic fibrosis suggested a therapeutic breakthrough. However, even though sputum conversion was improved in a phase 2 study, the primary end-point (change from baseline to day 84 on a semi-quantitative mycobacterial growth scale) was not reached [3]. We analysed the minimal inhibitory concentration (MIC) of another promising new anti-tuberculous drug, bedaquiline, using 20 clinical isolates of M. abscessus . No systematic studies on the distribution of MIC for M. abscessus have been performed previously. Bedaquiline may be a potential agent to treat severe or relapsing Mycobacterium abscessus infection <http://ow.ly/3lUp309VZVj>
Sexual Transmission of HIV
Authors: Rachel A. Royce, Arlene Seña, Willard Cates, Myron S. Cohen
Journal: New England Journal of Medicine (1997)

Transmission through sexual contact accounts for 75 to 85 percent of the nearly 28 million infections with the human immunodeficiency virus (HIV) that have occurred so far.1 The probability of infection through sexual contact, although it varies greatly, appears to be lower than that of infection through other routes of exposure (Figure 1). The variability observed among and within routes of HIV exposure depends partly on the viral dose and also on whether the virus is transmitted directly into the blood or onto a mucous membrane. In addition, these differences are influenced by a variety of host factors, including both . . .
Dynamic Changes in PD-L1 Expression and Immune Infiltrates Early During Treatment Predict Response to PD-1 Blockade in Melanoma
Authors: Ricardo E. Vilain, Alexander M. Menzies, James S. Wilmott, Hojabr Kakavand, Jason Madore, Alexander Guminski, Elizabeth Liniker, Benjamin Y. Kong, Adam J. Cooper, Julie R. Howle, Robyn P.M. Saw, Valerie Jakrot, Serigne Lo, John F. Thompson, Matteo S. Carlino, Richard F. Kefford, Georgina V. Long, Richard A. Scolyer
Journal: Clinical Cancer Research (2017)

Abstract Purpose: Disruption of PD-L1/cytotoxic T-cell PD-1 signaling by immune checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD-1 therapies in patients with melanoma, particularly early during treatment, and correlate them with treatment response. Experimental Design: Forty-six tumor biopsies from 23 patients with unresectable AJCC stage III/IV melanoma receiving pembrolizumab/nivolumab were analyzed. Biopsies were collected prior to (PRE, n = 21), within 2 months of commencing treatment (EDT, n = 20) and on disease progression after previous response (PROG, n = 5). Thirteen patients responded (defined as CR, PR, or durable SD by RECIST/irRC criteria), and 10 did not respond. Results: PRE intratumoral and peritumoral PD-1+ T-cell densities were sevenfold (P = 0.006) and fivefold higher (P = 0.011), respectively, in responders compared with nonresponders and correlated with degree of radiologic tumor response (r = −0.729, P = 0.001 and r = −0.725, P = 0.001, respectively). PRE PD-L1 expression on tumor and macrophages was not significantly different between the patient groups, but tumoral PD-L1 and macrophage PD-L1 expression was higher in the EDT of responders versus nonresponders (P = 0.025 and P = 0.033). Responder EDT biopsies (compared with PRE) also showed significant increases in intratumoral CD8+ lymphocytes (P = 0.046) and intratumoral CD68+ macrophages (P = 0.046). Conclusions: Higher PRE PD-1+ T cells in responders suggest active suppression of an engaged immune system that is disinhibited by anti-PD-1 therapies. Furthermore, immunoprofiling of EDT biopsies for increased PD-L1 expression and immune cell infiltration showed greater predictive utility than PRE biopsies and may allow better selection of patients most likely to benefit from anti-PD-1 therapies and warrants further evaluation. Clin Cancer Res; 23(17); 5024–33. ©2017 AACR.
Early Age Hepatocellular Carcinoma Associated With Hepatitis B Infection in South America
Authors: Aaron J. Chan, Domingo Balderramo, Luciana Kikuchi, Esteban Gonzalez Ballerga, Jhon E. Prieto, Monica Tapias, Victor Idrovo, Milagros B. Davalos, Fernando Cairo, Fernando J. Barreyro, Sebastian Paredes, Nelia Hernandez, Karla Avendaño, Javier Diaz Ferrer, Ju Dong Yang, Enrique Carrera, Angelo Z. Mattos, Bruno S. Hirsch, Pablo T. Gonçalves, Flair J. Carrilho, Lewis R. Roberts, Jose D. Debes
Journal: Clinical Gastroenterology and Hepatology (2017)
Tissue-resident T cells in hepatitis B: A new target for cure?
Authors: Fabian J. Bolte, Barbara Rehermann
Journal: The Journal of Experimental Medicine (2017)

A hallmark of chronic hepatitis B virus (HBV) infection is the functional impairment and depletion of antiviral T cells. In this issue of JEM, Pallett et al. (https://doi.org/10.1084/jem.20162115) identify a reservoir of functional HBV-specific T cells among liver-resident T cells.
P0371 : A multi-institution phase II study of gemcitabine/cisplatin/S-1 (GCS) combination chemotherapy for patients with advanced biliary tract cancer (KHBO 1002)
Authors: S. Kobayashi, M. Kanai, E. Hatano, Y. Fujiwara, S. Marubashi, A. Miyamoto, H. Shiomi, S. Kubo, S. Ikuta, H. Yanagimoto, H. Terajima, H. Ikoma, D. Sakai, Y. Kodama, S. Seo, S. Morita, T. Ajiki, H. Nagano, T. Ioka
Journal: Journal of Hepatology (2015)
Meta-Analysis of the Association Between Phosphodiesterase Inhibitors (PDE5Is) and Risk of Melanoma
Authors: Stacy Loeb, Eugenio Ventimiglia, Andrea Salonia, Yasin Folkvaljon, Pär Stattin
Journal: JNCI Journal of the National Cancer Institute (2017)

The US Food and Drug Administration recently announced the need to evaluate the association between PDE5is and melanoma. We performed a meta-analysis on the association between PDE5i and melanoma using random effects models and examined whether it met Hill's criteria for causality. A systematic search of Medline, EMBASE, and the Cochrane Library from 1998 to 2016 identified three case-control studies and two cohort studies, including a total of 866 049 men, of whom 41 874 were diagnosed with melanoma. We found a summary estimate indicating an increased risk of melanoma in PDE5i users (relative risk = 1.11, 95% confidence interval = 1.02 to 1.22). However, the association was only statistically significant among men with low PDE5i exposure (not high exposure) and with low-stage melanoma (not high stage), indicating a lack of dose response and biological gradient. PDE5i use was also associated with basal cell cancer, suggesting a lack of specificity and likely confounding by ultraviolet exposure. Thus, although this meta-analysis found a statistically significant association between PDE5i and melanoma, it did not satisfy Hill's criteria for causality.
Intravitreous injection of AAV2-sFLT01 in patients with advanced neovascular age-related macular degeneration: a phase 1, open-label trial
Authors: Jeffrey S Heier, Saleema Kherani, Shilpa Desai, Pravin Dugel, Shalesh Kaushal, Seng H Cheng, Cheryl Delacono, Annie Purvis, Susan Richards, Annaig Le-Halpere, John Connelly, Samuel C Wadsworth, Rafael Varona, Ronald Buggage, Abraham Scaria, Peter A Campochiaro
Journal: The Lancet (2017)
Expression of histone deacetylases 1 and 2 and histone 4 acetylation in T- and B-cell lymphomas
Authors: Lena Ipsen, Lise Mette Gjerdrum, Christian Poulsen, Peter Jensen, Maxwell Sehested, Elisabeth Ralfki r
Journal: Cancer Research (2007)

AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA

174 

Background: 

Increased expression of histone deacetylases (HDACs), in particular HDAC1 and HDAC2 have been reported in various types of cancers, suggesting these as therapeutic targets. HDAC inhibitors (HDACi) are currently in many hematological clinical trials, where they have shown higher efficacy in cutaneous T-cell lymphoma (CTCL) compared to diffuse large B-cell lymphoma (DLBCL). We wished to investigate whether this difference in disease sensitivity could be correlated with HDAC1 and/or 2 expression as well as with overall H4 acetylation.

Materials and methods: 

Paraffin-embedded tissue samples from 38 patients with primary nodal DLBCL and 75 patients with CTCL with known clinical outcome were obtained for immunohistochemical analysis of HDAC1, HDAC2 and H4ace. Stained samples were grouped in three staining categories (neg/low, moderate, high) based on the proportion of positive cells and staining intensity. Comparisons were done using Chi-square tests with exact probabilities. Survival curves were plotted according to Kaplan and Meier method using Log-rank tests.

Results: 

There was no difference in the expression profile of HDAC1 between DLBCL and CTCL (P=0.10). The expression profile of HDAC1 was also similar in different subtypes of DLBCL and CTCL, and no correlation was observed between expression and aggressiveness of subtypes. However, the expression profile of HDAC2 was significantly different between DLBCL and CTCL with a high expression in only 31.2% of CTCL compared to 60.6% of DLBCL (P<0.0001). Of the 24/75 CTCL cases with high HDAC2 expression, 15/29 had aggressive phenotypes. There was no difference in HDAC2 expression between DLBCL subtypes. Comparison of HDAC1 and HDAC2 protein expression with survival, revealed no significant correlations for either type of lymphoma. High level of histone H4 acetylation was more common in DLBCL (35.3%) compared to CTCL (14.3%) (P=0.02). In addition, a low H4 acetylation level was correlated with significantly longer survival in CTCL patients (P=0.0451). This correlation was not observed in DLBCL.

Conclusion: 

Expression of HDAC1 and HDAC2 was common in both CTCL and DLBCL, with HDAC2 being significantly more so in DLBCL. In contrast, Histone 4 acetylation was significantly lower in CTCL, which could conceivably be of therapeutic importance.
Combined analysis of randomized controlled trial (RCT) and patient-preference trial (PPT) evaluating second-line chemotherapy (SLC) in advanced gastric cancer (AGC).
Authors: Soonil Lee, Jung Hun Kang, Do Hyoung Lim, Keon-Woo Park, Sung Yong Oh, In Gyu Hwang, Jeeyun Lee, Joon Oh Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Se Hoon Park
Journal: Journal of Clinical Oncology (2012)

4064 Background: While prolonged overall survival (OS) from SLC compared to best supportive care (BSC) has recently been demonstrated for AGC (Park et al, ASCO 2011), the prognosis of pretreated AGC remains poor. We assessed whether patient preference, willing to participate onto RCT, or other parameters contributed to this OS improvement. Methods: In the phase III trial, pretreated AGC patients (n=372) were first offered RCT. If a patient agreed to participate, randomly assigned 2:1 to SLC or BSC (n=202). If refused RCT, but agreed to receive treatment of their preference, they were offered SLC or BSC (PPT; n=170). OS of RCT participants was compared to that of whole patient population according to prognostic subgroups. In addition, analyses of OS unadjusted for multiple comparisons were conducted across predefined subgroups. Results: Median OS was 6.3 months among 254 patients treated with SLC and 3.3 months among 118 patients treated with BSC (HR, 0.507; 95% CI, 0.405 to 0.637; one-sided p&lt;0.001). Compared to the RCT patients, younger age group, those with an ECOG performance status (PS) of 0, and with one prior chemotherapy were under-represented in the PPT patients. OS was comparable between RCT (5.0 months) and PPT (4.4 months) patients even after controlling for major prognostic factors (log-rank p=0.322). The OS benefit for SLC was preserved when analyzed according to baseline parameters. Parameters that were associated significantly with a prolonged OS included a PS of 0, the chemotherapy-free interval ≥3 months, and one prior chemotherapy. When the analysis was adjusted for these three parameters, patients who received SLC still had improved OS (HR, 0.554; 95% CI, 0.441 to 0.696; p&lt;0.001). Conclusions: The 54% participation rate obtained in the current study represents the best achievable rate for this kind of phase III RCT involving BSC only arm. Even if we consider differences in the baseline characteristics between RCT and PPT patients, it is concluded that the RCT results can be generalized for the patient population and provided additional evidence supporting the use of SLC in patients with pretreated AGC.
Ramucirumab (RAM) as second-line treatment in patients (pts) with advanced hepatocellular carcinoma (HCC): Analysis of REACH pts by Child-Pugh (CP) score.
Authors: Andrew X. Zhu, Ari David Baron, Peter Malfertheiner, Masatoshi Kudo, Seiji Kawazoe, Denis Pezet, Florian Weissinger, Giovanni Brandi, Carlo Barone, Takuji Okusaka, Yoshiyuki Wada, Joon Oh Park, Baek-Yeol Ryoo, Jae Yong Cho, Hyun Cheol Chung, Chung-Pin Li, Chia-Jui Yen, Kuan-Der Lee, Ling Yang, Ian Chau
Journal: Journal of Clinical Oncology (2015)

4108 Background: REACH was a global, randomized, double-blind, phase III study evaluating the efficacy and safety of RAM as a single-agent treatment of pts with advanced HCC after prior sorafenib therapy. The primary outcome for the ITT population was presented at ESMO 2014. The overall survival (OS) HR for the ITT population (RAM 283; placebo [PBO] 282) was 0.866 (95% CI 0.717, 1.046; p = 0.1391). In pts with baseline alpha-fetoprotein (AFP) ≥ 400 ng/mL (RAM 119; PBO 131), OS HR was 0.67 (95% CI 0.51–0.90; p = 0.0059). Methods: Efficacy and safety of RAM based on CP score are presented for all pts enrolled in REACH inclusive of ITT (n = 565) and CP B (n = 78) population. Results: In REACH, pts with CP5 (N = 177 RAM, N = 180 PBO), CP6 (N = 108 RAM, N = 100 PBO), and CP7+8 (CPB) (N = 39 RAM, N = 39 PBO) were enrolled. Baseline pt characteristics were generally balanced between treatment arms by CP score. The table below shows OS, PFS, ORR and DCR according to CP score. The safety profile of RAM in pts with CP5 and CP6 was similar, and consistent with that observed in the ITT analysis of CP A pts. In pts with CP7+8 (CP B), an increase in liver events grade ≥ 3 was observed on the RAM vs PBO arm (56% vs 41%), including an increase in hepatic encephalopathy grade ≥ 3 (10% vs 0%). This observation led to exclusion of CP B pts from enrollment after 441 total pts were randomized during the study. Conclusions: A greater RAM treatment benefit was observed in pts with lower CP scores. In the CP B pt population, an increase in liver adverse events was observed for RAM, specifically hepatic encephalopathy. A consistent and clinically meaningful improvement in OS, regardless of CP score, was observed in pts with elevated baseline AFP levels ( ≥ 400 ng/mL). Clinical trial information: NCT01140347. CP A CP A CP B CP5 CP6 CP7+8 REACH efficacy population OS HR 95% CI p 0.796 0.625, 1.015 0.0647 0.955 0.712, 1.280 0.7609 0.998 0.623, 1.599 0.9946 PFS HR 95% CI p 0.587 0.469, 0.735 < 0.0001 0.778 0.581, 1.041 0.0912 0.738 0.457, 1.194 0.2219 ORR RAM 8.5% 5.6% 0% PBO 0.6% 1.0% 2.6% DCR RAM 62.1% 47.2% 48.7% PBO 46.1% 45.0% 28.2% REACH pts with baseline AFP ≥ 400 ng/mL* OS HR 95% CI p 0.611 0.429, 0.870 0.0058 0.639 0.418, 0.978 0.0384 0.674 0.332, 1.368 0.2756
Successful Renal Transplant Tolerance Following a Haplo-Identical Allogenic Hematopoietic Stem Cell Transplant - a Case Report and Review of Literature
Authors: Neil Shah, Adam S. Vesole, Michele L. Donato, David S. Siegel, Joshua R. Richter, Noa Biran, Alan P Skarbnik, Robert Korngold, Scott D. Rowley, David H. Vesole
Journal: Blood (2016)
Influence of sex and anthropometric factors on tumor biologic characteristics of colorectal cancer: A cohort study.
Authors: Jenny Brandstedt, Sakarias Wangefjord, Signe Borgquist, Bjorn Nodin, Jakob Eberhard, Karin Jirstrom
Journal: Journal of Clinical Oncology (2013)

3579 Background: How body size influences risk of molecular subtypes of colorectal cancer (CRC) remains unclear. In this study, we investigated the relationship between height, weight, BMI, WHR and risk of CRC according to expression of beta-catenin, cyclin D1, p53 and microsatellite instability (MSI) status. Methods: Immunohistochemical expression of beta-catenin, cyclin D1, p53 and MSI-screening status was assessed in tissue microarrays with tumours from 584 cases of incident colorectal cancer in the Malmö Diet and Cancer Study. Four anthropometric factors: height, weight, body mass index (BMI), waist- hip ratio (WHR) were categorized by quartiles of baseline anthropometric measurements, and relative risks of CRC according to expression of betacatenin, cyclin D1, p53 and MSI screening status were calculated using multivariate Cox regression models. Results: Expression of cytoplasmatic and nuclear betacatenin, cyclin D1, p53 and MSS all revealed a positive association with increased weight and BMI in the overall analysis. Negative expression of the above mentioned factors was more frequently associated with increased height. MSI was not associated with any of the anthropometric factors in overall analysis and according to gender.Gender specific analysis revealed no association between any anthropometric factors and positive and negative cytoplasmatic beta-catenin expression, beta-catenin nuclear negativity, cyclin D1 negativity and p53 positivity. Nuclear beta-catenin positivity, cyclin D1 positivity, p53 negativity and MSS were all associated with increased weight in women. In men, positive expression of cytoplasmatic and nuclear beta-catenin, cyclin D1 positivity and p53 positivity were all associated with increased WHR. Negative expression of betacatenin was associated with increased weight, while there were no associations between any anthropometric factors and cyclin D1 negativity, MSS or MSI status in men. Conclusions: Findings from this large prospective cohort study demonstrate an association between obesity, measured as weight and BMI, and risk of CRC according to the expression of beta-catenin, cyclin D1, p53 and MSI status.
Determinants of and outcomes associated with chemoimmunotherapy dose density in elderly subjects with diffuse large B-cell lymphoma (DLBCL).
Authors: Usha S. Perepu, Kelcy C Weibel, Anna M Button, Laura S. Jacobus, Brian Smith, James R. Cerhan, Brian K. Link
Journal: Journal of Clinical Oncology (2012)

8061 Background: RCHOP is the standard first line therapy for DLBCL but elderly patients often receive suboptimal doses. Relative dose intensity (RDI) less than 70-90% has previously been associated with inferior survival in CHOP treated patients. We now investigate the clinical determinants of immunochemotherapy dose delivery and comparative effectiveness of dose intensity on lymphoma-specific outcomes in persons over the age of 60. Methods: SPORE MER (Molecular Epidemiology Resource) is a prospectively accrued observational study in which University of Iowa and Mayo Clinic patients with a diagnosis of Non Hodgkins lymphoma have been enrolled since 2003. We reviewed data from the Iowa patients along with medical records from DLBCL patients over the age of 60 treated with anthracycline based chemo immunotherapy consecutively enrolled up through to December 2009. Statistical tests of associations between RDI and clinicopathologic factors, as well as survival outcomes, were performed. Results: We identified 92 patients over the age of 60. The median age was 70. 47 subjects experienced at least 1 dose reduction, 26 subjects had dose delays, and 20 subjects were unable to complete therapy. RDI ranged from 0.30-1.70 (median 0.92) for doxorubicin and from 0.29-1.70 (median 0.97) for cyclophosphamide. 24 and 19% of subjects received &lt; 80% of RDI for dox and cy respectively. Age (p&lt; 0.001 for both dox and cy) and performance status (p=0.04 for dox) but not number of medications, ACE27 co-morbidity score, body surface area, nor need for acute care visits were associated with decreased RDI. Adjusted for IPI, RDI did NOT have a significant effect on event-free or lymphoma-specific survival. Conclusions: Among clinical variables, age is the dominant variable associated with delivery dose intensity for chemotherapy in elderly patients treated for DLBCL; and among elderly patients receiving chemo immunotherapy, we did not find an association between dose intensity and lymphoma-specific outcomes. [Table: see text]